CZ295245B6 - Novel inhibitors of HIV protease - Google Patents

Abstract

In the present invention, there are disclosed HIV protease novel inhibitors comprising substituted borane, carborane or metallacarborane clusters having 6 to 12 boron atoms in each individual cluster, wherein charge of each individual borane, carborane or metallacarborane cluster is 0. -1 or -2. The borane, carborane or metallacarborane clusters are substituted on periphery with groups increasing interaction energy between HIV protease and the inhibitor, wherein number of the borane, carborane or metallacarborane clusters in the inhibitor molecule ranges from 1 to 9, wherein the carborane clusters in the metallacarborane inhibitors are coordinated to a transient metal atom being selected from the group consisting of Co, Fe, Ni and Ru. Disclosed is also the use of these inhibitors in vitro as well as in vivo. Introduction of the derivative of the boron cluster compounds as a novel structural element provides inhibition properties for HIV protease and mutants thereof that are resistant to other inhibitors. Low toxicity, stability and biocompatibility along with high efficiency make these boron compounds suitable for AIDS therapy.

Description

Technical field

The invention relates to novel HIV protease inhibitors and their use, both in vitro and in vivo.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) has been identified as the etiological agent of AIDS independently in Paris and Washington (Barre Sinoussi, F., Chermann, J., Rey, J., Nugerye, R., Charmaret, M., Gruest, S., Danget J., Axler-Blin, C., Rouzioux, F., Rosenbauum, C., Montagnier, L. (1983) Science 220, 868-871; Popovic, M., Samgadharan, MG, Read, E., Gallo. RC (1984) Science 224: 497-500). The efforts of the past 18 years to develop effective virostatics against AIDS have led to the discovery of a number of drugs that have greatly aided in the treatment of this disease. Yet the disease is still failing to control and stop the disease from spreading. AIDS remains a serious global problem. Especially in developing countries and especially in Central Africa, the epidemic reaches catastrophic proportions that threaten the very essence of nations and society.

Human immunodeficiency virus (HIV) belongs to the genus Lentivirus of the family Retroviridae. This family includes viruses that contain the diploid RNA genome and replicate by reverse transcriptase. Retroviruses are further subdivided into three genera: oncoviruses, lentiviruses and spumaviruses (Gelderblom, HR, Marxk, PA, Ozel, M., Gheysen, D., Munn, RJ, Joy, KI, Pauli, G. (1991) AIDS 5, 159-180). Genus Lentivirus includes viruses that cause slow chronic diseases. The most prominent representatives are HIV-1, HIV-2 (hereinafter HTV) and monkey lentivirus SIV.

Mature HIV virion is a spherical particle with a diameter of approximately 100 to 110 nm. The capsid protein-encapsulated viral core consists of two copies of genomic single-stranded RNA, nucleocapsid proteins (NC) and viral reverse transcriptase (RT), integrase (IN) and protease (PR) enzymes. The surface coat is composed of a phospholipid membrane originating from the host cell. Prominent from the envelope are button-like shapes composed of three molecules of the SU glycosylated surface protein, which are loosely anchored in the TM transmembrane protein (Gelderblom, HR, Marx, PA, Ozel, M., Gheysen, D., Munn, RJ, Joy, KI, Pauli , G. (1991) AIDS 5,159-180).

The HIV genome consists of two identical RNA molecules of approximately 9.2 kb which encode 9 different genes. The basic genome structure, which is typical for all retroviruses, consists of three structural genes gag, pol and env. In addition to the structural genes, 6 genes encoding proteins with regulatory function that are involved in virus replication have been identified in the HIV genome.

The replication cycle of HIV within the host cell can be divided into several stages (Krausslich, HG. (1993) Regulation of Gene Expression in Animal Viruses, edited by L. Carrasco, et al., Plenum Press, New York): SU surface coat glycoprotein it recognizes and binds with high affinity to the CD4 + protein receptor, which is expressed on the surface of T-lymphocytes. In addition, a host cell-specific co-receptor is also required for efficient binding. The virus enters the cell by endocytosis or fusion of the viral envelope to the cell surface, and the capsid content reaches the cytoplasm of the cell. Reverse transcriptase (RT) transcribes viral RNA into double stranded DNA, which is integrated into the host cell chromosome by integrase (IN). Thus, it persists in a quiescent state (latent infection) until it is activated and the viral genes are transcribed by the host RNA polymerase II. According to proviral mRNA, viral polyprotein precursors Gag and Gag-Pol are synthesized on host cell ribosomes. Post-translationally modified polyproteins and genomic RNA are concentrated at the cell surface and released from the cell in a virion by a process called budding. Gag and Gag-Pol polyprotein precursors are cleaved in the immature particle by the virus encoded

Protease (PR) to produce functional proteins, thereby forming a mature, infectious particle. If HIV PR is damaged or inhibited, virion remains immature.

The most studied is HIV-1 PR. It is a dimeric aspartic protease that consists of two identical non-covalently bound subunits. The primary structure of the monomer unit is 99 amino acids. Crystallographic structural analyzes (Wlodawer, A., Miller, M. Jaskólski, M., Sathyanarayana, BK, Baldwin, E., Weber, IT, Selk, LM, Clawson, L. Schneider , J., Ketn, SBH (1989) Science 245, 616-621), which revealed exact double rotational C ₂ symmetry and high β-structure content. Four of the chains in the nucleus of the molecule form a písmena-shaped leaf characteristic of all aspartic proteases. The triplet of the active site (Asp25-Thr26-Gly27) is located at the fold of the protein chain and its structure is stabilized by a hydrogen bonding network.

HIV PR must first be autocatalytically cleaved from the precursor and subsequently cleaved in nine precisely defined sites. HTV PR specifically cleaves a viral polyprotein even though the cleavage sites differ quite a bit in the amino acid sequence. In contrast to other endopeptidases (pepsin, trypsin, renin) hydrolyzing peptide bonds in the vicinity of certain amino acids, similar HIV sequence dependence cannot be easily established in HIV PR. Rather, the specificity resulting from the cumulative effect of mutually independent predominantly weak interactions between the individual side chains in the substrate and the corresponding site under the enzyme is assumed. Hydrophobic interactions, surface area, polarity, secondary structure potential and other influences have a significant influence (Poorman, R. A. Tomasselli, A.G. Heinrikson, R. L. Kézdy, FJ (1991) J. Biol. Chem. 266, 14554-14561).

HIV protease inhibitors

Several steps in the HIV life cycle have been selected as a point of possible therapeutic intervention. These are mainly reverse transcriptase (dideoxynucleosides, their analogues and non-nucleoside inhibitors), virion binding and entry into the host cell (soluble CD4 receptors and their derivatives, polyanionic compounds, fusion inhibitors), integration of provirus by integrase integration into the host chromosome, regulation of transcription by protein products of genes tat and rev et al (for a summary of De Clerq, E. (1998) Collect. Czech. Chem. Commun. 63, 449-479). The maturation of retrovirus, and in particular its most important HIV protease enzyme, which is the subject of this patent application, has also been the subject of extensive research and rational drug design. Seven inhibitors have been or will be approved for clinical use in the Czech Republic: saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir and atazanavir. All of these inhibitors competitively inhibit the binding of natural substrates to HTV PR and reduce viral infectivity by blocking virion maturation.

Development of resistance to HIV PR inhibitors

The introduction of protease inhibitors at the turn of 1995 and 1996 and the introduction of highly active antiretroviral therapy (HAART) led to a slower onset of opportunistic infections and a decrease in mortality, increasing patients and doctors' chances of finding satisfactory AIDS therapy. Unfortunately, soon after the introduction of new drugs, their limits appeared.

Application of a PR inhibitor suppresses virus replication. If replication is incompletely suppressed, a small population of virus resistant to the respective inhibitor may survive under selection pressure. This phenomenon leads to virus resistance (Larder, B. Richman, D., Vella, S. (1998) HIV resistance and implications for therapy, MediCom Inc., Atlanta, USA). To date, mutations have been observed at at least 49 positions in the 99 amino acid monomer (Gulnik, S. Erickson, J.W., Xie, D. (2000) Vitamins and Hormones 58, 213-256).

The main factors responsible for the rapid development of resistant variants are the natural variability of the HIV genome (polymorphism) and dynamic viral replication during the latent phase and during steady state (Erickson, J. W. Burt, SK (1996) Annu Rev. Pharmacol. Toxicol 36,

-2GB 295245 B6

545-571). The genetic variability of HIV is probably due to the combination of high errors in reverse transcriptase, genomic recombination, and selectivity of the human immune system.

There are several possible strategies by which a virus can develop resistance to protease inhibitors. Major ones include mutations in the enzyme binding site that directly affect binding; mutations outside the enzyme binding site that affect the binding of the inhibitor indirectly; mutation of HIV PR cleavage sites in polyprotein substrates. Mutations that reduce the stability of the HIV PR dimer and hence affinity for the inhibitor may contribute to resistance, and ultimately mutations outside the protease region itself, which may result, for example, in a more efficient reading frame shift (Erickson, JW, Burt, SK (1996) Annu, Rev. Pharmacol., Toxicol., 36, 545-571, Boden, D., Markowitz, M. (199%), Antimicrob. Agents Chemother. 42, 2775-2783).

Known HIV protease inhibitors can be divided into three basic groups: (i) compounds designed as isosteres of the transit state of the substrate (statin, hydroxyethylamine, hydroxymethylene, hydroxyethylene, α, β-difluoro ketones, etc.) (ii) substances designed by rational design based on geometric similarity with a substrate (eg DMP series inhibitors) (iii) compounds with random structural similarity to the substrate, obtained by screening natural substances isolated eg from biological material (Lebon F., Ledecq M. (2000) Curr. Med. Chem. 7, 455 -477).

Design of viral protease inhibitors is a non-trivial problem. Unlike many other enzymes whose substrate is a simple organic molecule (eg nitric oxide synthase has L-arginine as a natural substrate, and so simple modifications such as N '' - OH-Arg or N '-Me-Arg are very successful inhibitors ), the situation is considerably more complicated when designing an inhibitor for this enzyme. Indeed, the natural substrate is a polypeptide that is recognized and cleaved at a specific site to produce functional enzymes and virion structural proteins. In theory, both by molecular modeling methods at the semi-empirical level and ab initio calculations, the practical design of a specific HIV VP inhibitor is a complex problem where a low molecular weight substrate must have a higher affinity for the enzyme than a natural polypeptide.

All HIV protease inhibitors used in medical practice (saquinavir, ritonavir, indinavir, nelfmavir, amprenavir, lopinavir and atazanavir) can be assigned to group (i). They are peptidomimetic in nature and are competitive inhibitors of the active enzyme center. However, such agents usually have unfavorable pharmacodynamic properties (orally significant doses of drugs need to be administered orally to achieve an effective concentration in the infected cells), and resistance to them develops over time. Thus, in order to overcome resistance, it is generally sought to identify non-peptide inhibitors that can be developed by rational drug design based on structural information obtained by X-ray analysis of HIV PR complexes and known inhibitors, or by testing combinatorial or other libraries of chemical compounds.

SUMMARY OF THE INVENTION

These drawbacks overcome the HIV protease inhibitors of the invention, which comprise clusters selected from the group consisting of borates and / or carboranes and / or metallacarboranes, with a number of boron atoms in each individual cluster of 6-12, wherein the charge of each individual borane, carborane, or metallacarborane cluster is The 0, -1 or -2, borane, carborane, or metallacarborane clusters are peripherally substituted by groups that increase the interaction energy between the HIV protease and the inhibitor, wherein the number of borane, carborane, or metallocarborane clusters in the inhibitor molecule is 1 to 9, the inhibitors are coordinated to a transition metal atom selected from the group consisting of Co, Fe, Ni and Ru.

Other heteroatoms may be present in the clusters and are selected from the group consisting of N, P, Si, Ge, Sn, S.

-3 CZ 295245 B6

The HIV protease inhibitors of the invention are characterized by the general formula I, (R *) _n A (-XY-Z) _m (I), wherein A is a cluster anion Β _Β0 Η ₁₀ ⁽² Λ B12H12 ^(2_) , CB6H ₇ ^H , CB7H8 ^W CB7H ₈ ^(_) ΟΒ, ΗιοθΟΒ ^ Η ^ θ CBnHn ⁰ SiBltHl2 ⁽⁾ SiBnH, / ² ', SnBuHu ^, GeBnH, / ² ^, 7,8-C2B ₉ H ₁₂ ^(-> 7 9-C2B9Hl2 ^H Sí2B, H _{12 0} ^(_) [(l, 2-O2B9Hn) 2-3-Co (III)] ^(-> [(l, 7-C2B H ₉ ') 2-3 -CO (III)] ^(-) [(€ 2Β9Ηη) Οο (ΠΙ) (C2B8Hio) JCO (III) (C2B9Hl 1)] ^{(Λ 2} [(l, 2-C2B H _{9 N)} - 3 ^ ( 111)] ^ [(1,7-C ₂ B ₉ H ₂ O) 2-3 ^ (111)] ^ [(1,2-C ₂ B ₉ H ₂ O) 2-3 - ^ (111)] ^ [l- (C ₅ H ₅₎ Fe (III), (CB ₁₀ H ,,)] ^w, [(C5H5) Co (III) (1,2-CB10H,,)] ^ [(C5H5) Ni (III ) (1,2-CB10H11)] ^h , [(C2B, 0H, 2) 2M (III)] ^(} or Neutral Cluster 1,2-C ₂ B ₈ Hio, 1,6-C ₂ B ₈ H, o , 1,1 OC ₂ B ₈ H, o, 1,2-C ₂ BioH, 2, 1,7-C ₂ BioH, 2,1,1,12-C2B, oH, ₂ , P ₂ B, oH, o, SBuHn, NB "Hh, PB" H ", [[(C ₅ H ₅ ) (1,2-C ₂ B ₉ H") - Co (III)], [(C ₅ H ₅ ) (1,7-C _2- B ₉ H '- 3-Co (III)], [(C ₅ H ₅ ) (1,2-C ₂ B ₉ H, -) - Fe (III)], [(C ₅ H ₅ ) ( 1,7-C ₂ B ₉ H ₂ -Fe (III)], [(C ₅ H ₅ ) (1,2-C ₂ B ₉ H,, Νί (ΠΙ)], [(C ₅ H ₅ ) Fe (II) (C ₃ B ₈ H ") ], [(C ₅ H ₅ ) Ru (II) (C ₃ B ₈ H ")], [(C ₃ B ₈ H") ₂ -Fe (II)], [(C ₅ H ₅ ) Fe (II ) (C ₃ B ₇ H, _O )], [1- (C ₅ H ₅ ) Fe (II) (PC ₂ B ₈ H, _O )], [(C ₂ B ₉ H ₂ ) - CO (III) (C ₃ B ₈ H ")], [(C ₂ B, _O H, ₂ ) -M (III) (C ₅ H ₅ )] wherein the substituents of the formula —X — Y — Z and R ¹ are attached to boron atoms, carbon or heteroatoms of cluster A wherein j is 1 to 3,

M is Fe, Co, Ni, Ru and wherein R ¹ is the same or different and is selected from the group consisting of hydrogen, halogen, methyl, hydroxy, phenyl, phenylene, thiol, methoxy and trifluoromethoxy, m is 0, 1 and 2, n is 0 to 12,

X is identical or different and represent -O-, -C (= O) -, -CH ₂ -, -N (R ³⁾ -, -P (R ³⁾ -, -S-, C-C, of alkanediyl, -O (CH ₂ CH ₂ O) _q -, phenylene substituted independently with 0-3 substituents of R ^14, if Metallacarboranes type [(1,2-C2B ₉ Hii) 2-3 M (III)] ^(_) X is further a bridged group>S,>N,>P,> O ₂ P,> O ₂ P (= O), phenylene substituted independently with 0 to 3 substituents R ¹⁴ , ethanediyl substituted independently with 0 to 3 substituents R ¹⁴ , on wherein Y is as defined above, wherein q is 0 to 12, wherein R ³ is the same or different and denotes hydrogen, C 1 to C 8 alkyl substituted with 0 to 3 R ¹⁰ , C 2 to C ₈ alkenyl substituted with 0 to 3 R ¹⁰ , C 2 to C 8 alkynyl substituted with 0 to 3 R ¹⁰ , and a C 3 to C ₁₄ carbocyclic system substituted with 0 to 5 R ¹⁰ or 0 to 5 R ¹¹ , or a 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen , Sulfur and nitrogen or the same heterocycle substituted with 0-2 R ^11, wherein R ¹⁰ is identical or different and represent a keto, halogen, cyano, -CH 2 N (R ⁷⁾ (R ^8), -N (R ⁷⁾ (R ⁸ ) - C (= O) O (R ⁷⁾ - C (= O) (R ^5), -OC (= O) ^(R7), -O (R ⁷⁾ C 2 -C ₆ alkoxyalkyl, - S (= O) _k (R ^7), -NHC (= NH) NH (R ⁷⁾ -C (= NH) NH (R ⁷⁾ -C (= O) N (R ⁷⁾ (R ⁸⁾ , -N (R ⁸⁾ C (= O) (R ⁷⁾ = N-O (R ^8), -N ^(R8) C (= O) (R ⁸⁾ -OC (= O) N ( R ⁷ ) (R ⁸ ), -N (R ⁷ ) C (= O) N (R ⁷ ) (R ⁸ ), -N (R ⁸ ) S (= O) 2N (R ⁷ ) (R ⁸ ), -N ^(R8) S (= O) 2 (R ^7), -S (= O) 2 N (R ⁷⁾ (R ⁸⁾ C, -C4 alkyl, C ₂ to C ₄ alkenyl, C ₃ to C , cycloalkyl, C ₃ to C ₆ cycloalkylmethyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C ₇ to C, o aryl, -C (= O) -NH (OH), - C (= O) -NH ( NH ₂ ), —B (OH) ₂ ,

-4C 295245 B6 sulfonamide, formyl, C ₃ -C ₆ cycloalkoxy, C 1 -C ₄ alkyl substituted with -N (R ⁷ ) (R ⁸ ), C 1 -C 4 hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy , Cl-C4 alkoxycarbonyl, C] to C4 alkylcarbonyloxy, Cl-C4 alkylcarbonyl, Ci to C4 alkylcarbonylamino, -OCH 2 C (= O) (R ^7), 2- (l-morpholino) ethoxy, azido, -C (R ⁸ ) = N-O (R ^8), C 5 to C ₁₄ carbocyclic residue substituted with 0-5 ^R11, or a 5- to membered heterocyclic ring containing 1-4 heteroatoms selected independently from oxygen, sulfur and nitrogen or the same heterocycle substituted with 0 až2R ⁿ wherein k is 0, 1 and 2 wherein R ⁷ is the same or different and denotes hydrogen, phenyl substituted with 0-3 R ¹⁴ , phenylmethyl substituted with 0-3 R ¹⁴ , C 1 -C 6 alkyl substituted with 0-3 R ¹⁴ , C 2-6 C ₄ alkenyl substituted with 0-3 R ¹⁴ , C 1 -C 6 alkylcarbonyl substituted with 0-3 R ¹⁴ , C 1 -C 6 alkoxycarbonyl substituted with 0-3 R ¹⁴ , C 1 -C 6 alkyl laminocarbonyl substituted with 0-3 R ¹⁴ , C 3 -C ₆ alkoxyalkyl substituted with 0-3 R ¹⁴ , any amino protecting group when R ^{7 is} attached to a nitrogen atom, or any hydroxy protecting group when R ^{7 is} attached to an oxygen atom wherein R ¹⁴ is different or the same and denotes

H, keto, halogen, cyano, -CH ₂ NH _2, -NH _2, -C (= O) OH, -OC (= O) (Ci to C ₃ alkyl), -OH, C ₂ to C ₆ alkoxyalkyl, -C (= O) NH _2, -OC (= O) NH _2, -NHC (= O) NH _2, -S (= O) ₂ NH _2, C, to C ₄ alkyl, C ₂ to C ₄ alkenyl, , C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C ₇ -C 10 arylalkyl, -C (= O) -NH (OH), -C (= O) - NH (NH ₂ ), -B (OH) ₂ , C ₃ -C ₆ cycloalkoxy, C 1 -C ₄ alkyl substituted with -NH ₂ , C 1 -C ₄ hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C ₄ haloalkyl, C 1 -C ₄ C ₄ haloalkoxy, C 1 -C ₄ alkoxycarbonyl, C 1 -C ₄ alkylcarbonyloxy, C 1 -C ₄ alkylcarbonyl, C 1 -C ₄ alkylcarbonylamino, -OCH ₂ C (= O) OH, 2- (1-morpholino) ethoxy, azido, aryl (C 1 -C ₃ alkyl), C ₅ -C ₁₄ carbocyclic radical, 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0 to 3 R ⁶ , wherein R ⁶ , when it is a substituent on carbon , is different or the same and denotes phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C 1 -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, C ₇ -C ₁₀ arylalkyl, C 1 -C ₄ alkoxy, -C (= O) OH, -C (= O) -NH (OH), -C (= O) -NH (NH ₂ ), -B (OH) ₂ , sulfonamide, formyl, C ₃ -C ₆ cycloalkoxy, -O (R ⁷ ), C 1 -C 4 alkyl substituted with -N (R ⁷ ) (R ⁸ ), -N (R ⁷ ) (R ⁸ ), C ₂ -C ₆ alkoxyalkyl, Ci to C ₄ hydroxyalkyl, methylenedioxy, ethylenedioxy, Cl to _C4 haloalkyl, Cl to _C4 haloalkoxy, Ci to C ₄ alkoxycarbonyl, Ci to C ₄ alkylcarbonyloxy, Ci to C ₄ alkylcarbonyl, Ci to C ₄ alkylcarbonylamino, -S (= O) _C (R ^7), -S (= O) 2N ^{(R7) (R8),} -NHS (= O) 2 (R ^8), -OCH 2 C (= O) OH, 2- (l-morpholino ) ethoxy, -C (R ⁸⁾ = N-O (R ⁸⁾ a 5- to membered heterocyclic ring containing 1-4 heteroatoms selected independently from oxygen, sulfur and nitrogen or the same heterocycle substituted with 0-3 R ^9, C 3 to C ₄ carbon chain whose second co nec is attached to the adjacent carbon atom on the ring to form a 5- or 6-membered ring, the 5- or 6-membered ring may be substituted on any of the aliphatic carbons by halogen, C 1 -C ₄ alkyl, C 1 -C ₄ alkoxy, hydroxy, -N (R ⁷ ) (R ⁸ ) or, when R ^{6 is} attached to a saturated carbon atom, R ⁶ may be = O or = S, where k and R ⁷ are as defined above,

Wherein R ⁸ is the same or different and denotes hydrogen, hydroxy, trifluoromethyl, C 1 -C ₆ alkoxy, C ₂ -C ₆ alkenyl, phenylmethyl, amino, C 1 -C ₆ alkyl substituted with 0 to 3 groups selected independently from hydroxy , C 1 to C ₄ alkoxy, halogen, amino, any amino protecting group when R ^{8 is} bonded to a nitrogen atom, or any hydroxy protecting group when R ^{8 is} bonded to an oxygen atom, where R ⁹ is different or the same and denote hydrogen or methyl, R ^6, when a substituent on nitrogen, is different or the same and represent phenyl, phenylmethyl, phenethyl, hydroxy, Cl-C4 hydroxyalkyl, C, -C4 alkoxy, C, to C4 alkyl, C3 to C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, -CH 2 N (R ⁷ ) (R ⁸ ), -N (R ⁷ ) (R ⁸ ), C ₂ -C ₆ alkoxyalkyl, C 1 -C ₄ haloalkyl, C 1 -C ₄ alkoxycarbonyl, -C (= O) OH, Ci to C ₄ alkylcarbonyloxy, C] to C ₄ alkylcarbonyl, C ^(R8) = N-O (R ⁸⁾ wherein R ⁷ and R ⁸ have the aforementioned meaning,

R ⁷ and R ⁸ may alternatively be attached to form - (CH 2) 4 -, - (CH 2) 5 -, -CH ₂ CH ₂ N (R ⁹ ) CH ₂ CH ₂ - or -CH ₂ CH ₂ OCH ₂ CH ₂ -, wherein R ⁵ is identical or different and denote hydrogen, halogen, phenylmethyl, phenethyl, -C (= O) -NH (OH), -C (= O) -NH (NH _2), -B (OH _2), a sulfonamide group, azido , formyl, phenoxy, phenylmethoxy, nitro, cyano, -CH ₂ N (R ⁷⁾ (R ^8), -N (R ⁷⁾ (R ^8), -OCH 2 C (= O) OH, - C (= O) O ( R ⁷ ), -OC (= O) R ⁷ ), -O (R ⁷ ), C ₂ -C ₆ alkoxyalkyl, -S (= O) _k (R ⁷ ), -NHC (= NH) NH (R ⁷ ) , -C (= NH) NH (R ⁷⁾ -C (= O) N (R ⁷⁾ (R ^8), -N ^(R8) C (= O) (R ⁷⁾ = N-O ( R ⁸ ), -N (R ⁸ ) C (= O) O (R ⁸ ), OC (= O) N (R ⁷ ) (R ⁸ ), -N (R ⁷ ) C (—O) N (R ⁸ ) ⁷⁾ (R ⁸⁾ -C (R ⁸⁾ = N-O (R ^8), -N ^(R8) S (= O) 2N ^{(R7) (R8),} -N (R ⁸⁾ (= O) 2 (R ⁷ ), -S (= O) 2 N (R ⁷ ) (R ⁸ ), C 1 -C 4 alkyl, C ₂ -C ₄ alkenyl, C ₃ -C 10 cycloalkyl, C ₃ -C ₆ cycloalkylmethyl , C ₇ -C 10 arylalkyl, C ₃ -C ₆ cycloalkyloxy, C 1 -C ₄ alkyl substituted with -N (R ⁷ ) (R ⁸ ), C 1 -C 4 hydroxyalkyl, C 1 -C 4 h aloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkoxycarbonylamino, 2- (1-morpholino) ethoxy, - (C 4 -C 3 alkyl) aryl substituted with 0-2 R ⁶ , C 5 -C ₁₄ carbocyclic radical substituted with 0-3 R ⁶ , A 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0 to 3 R ⁶ , wherein k, R ⁶ , R ⁷ and R ⁸ are as defined above, wherein R ¹¹ when is a substituent on carbon, is different or the same and denotes phenethyl, phenoxy, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, C ₇ -C ₁₀ arylalkyl, -C (= O) -NH (OH), -C (= O) -NH (NH _2), -B (OH) _2, C ₂ to C ₆ alkoxyalkyl, methylenedioxy, ethylenedioxy, C] to C ₄ alkylcarbonyloxy, -NHS (= O) ₂ (R ^8), phenylmethoxy, halogen, 2- (1-morpholino) ethoxy, -C (= O) O (R ⁷ ), -C (= O) N (R ⁷ ) N (R ⁷ ) (R ⁸ ), cyano, sulfonamide, formyl, C3-C6 cycloalkoxy, Cl-C4 haloalkyl, Cj-C4 haloalkoxy, C2 -C4 haloalkenyl, C2 to C4 haloalkynyl, -N (R ⁷⁾ (R ⁸⁾ - C (R ⁸ ) = N - O (R ⁸ ), - NO 2, - O (R ⁷ ), -N (R ¹² ) (R ¹³ ), - S (= O) k (R ⁷ ), - S ( = O) kN (R ⁷⁾ (R ⁸⁾ -C (= O) N (R ⁷⁾ (R ⁸⁾ -OC (= O) N (R ⁷⁾ (R ⁸⁾ -C (= O ) (R ^5), -OC (= O) (R ^5), -OC (= O) (R ⁷⁾ phenyl, -C (= O) N (R ⁷ HC-C4 alkyl), N (R ⁷⁾ (R ⁸⁾ -C (= O) N ^{(R12) (R13),} -C (= O) - (Ci to C4 alkyl) -, -N ^(R7) C (O) O (R ⁷ ),

C 1 -C ₄ alkoxy substituted with 0 to 4 groups independently selected from: -R ⁵ , C ₃ to C ₆ cycloalkyl, -C (= O) O (R ⁷ ), -C (= O) N (R ⁷ ) ( R ⁸ ), -N (R ⁷ ) (R ⁸ ) or hydroxyl,

C 1 -C ₄ alkyl substituted with 0 to 4 groups independently selected from: -R ⁵ , = N (R ⁸ ), = NN (R ⁷ ) C (= O) N (R ⁷ ) (R ⁸ ), or -N ( R ⁷ ) (R ⁸ )

C ₂ to C ₄ alkenyl substituted with 0-4 ^R5, C2-C4 alkynyl substituted with 0-4 R ^5, a 5- to membered heterocyclic ring containing 1-4 heteroatoms selected independently from oxygen, sulfur and nitrogen, C 3 to C ₄

295245 B6 -6CZ carbon chain whose second end is attached to the adjacent carbon atom on the ring to form a 5- or membered ring, said 5- or 6-Elenna ring can be substituted at one of the aliphatic carbons with halogen, Ci to _C4 alkyl, C 1 to C ₄ alkoxy, hydroxy, -N (R ⁷ ) (R ⁸ ), or when R ^{11 is} attached to a saturated carbon atom, R ¹¹ may be = O or = S where k, R ⁵ , R ⁷ and R 11 ⁸ have the aforementioned meanings, where R ¹² is identical or different and denote hydrogen or a C] to C ₃ alkyl, wherein R ¹³ is identical or different and represent -C (= O) N (R ⁷⁾ (R ⁸⁾ - C (= O) N (R ⁷⁾ NH (R ⁸⁾ -C (= O) C (R ⁵⁾ 2 N (R ⁷⁾ (R ⁸⁾ -C (= O) C ^(R) 2 N ( R ⁷⁾ NH (R ⁸⁾ -C (= O) C (R ⁵⁾ 2 N (R ⁷⁾ C (= O) (R ⁷⁾ -C (= O) H, -C (= O) (R ⁵ ), -O (= O) - (O) to C 4 alkyl) -N (R ⁷ ) (R ⁸ ), -O (= O) - (O) to C ₄ alkyl) -, N (R) ⁷ ) C (= O) O (R ⁷ ) or 1 to 3 amino acids linked by amide bonds to the nitrogen atom via carboxyl groups, wherein R ⁵ , R ⁷ and R ⁸ have the aforementioned wherein R ¹¹ , when it is a substituent on nitrogen, is different or the same and denotes phenyl, phenylmethyl, phenethyl, hydroxyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 C6 cycloalkylmethyl, -CH 2 N (R ⁷⁾ (R ^8), -N (R ⁷⁾ (R ⁸⁾ C 2 -C ₆ alkoxyalkyl, Ci to _C4 haloalkyl, Ci to C ₄ alkoxycarbonyl, -C (= O) OH, Ci to C ₄ alkylcarbonyloxy, C] to C ₄ alkylcarbonyl or -C ^(R8) = N-O (R ⁸⁾ wherein R ⁷ and R ⁸ have the aforementioned meanings, wherein Y is the same or different and represent C to C ₁₀ alkanediyl substituted with 0 to 4 R ² groups; oligoethylene glycol or oligoethylene glycol substituted substituted with R ^2; or C 1 -C 10 cycloalkanediyl substituted with 0-4 R ² groups; —C (= O) -; —S (= O) k—; -P (= O) (OR ³⁾ -X-; -P (= O) (N (R ³⁾ (R ⁴⁾⁾ - CO--; -P (= O) (N (R ³⁾ (R ⁴⁾⁾ - CO--; —0 (= O) -X—; - (CF 2) _q -; phenylene substituted independently with 0 to 3 substituents R ¹⁴ , wherein k, q and R ³ are as previously defined, wherein R ² is different or the same and denotes hydrogen, -A, -X-A, -O (R ⁷ ), -S (R ⁷⁾ -N (R ⁷⁾ -C (= 0) 0 (R ^7), keto, C] -C8 alkyl substituted with O to 3 R ^5, C 2 -C ₈ alkenyl substituted with up to 3 R ⁵ , phenyl, phenyl substituted independently with 0 to 5 substituents R ¹⁴ , phenylene substituted independently with 0 to 3 substituents R ¹⁴ , alkynyl substituted with 0 to 3 R ⁵ , C 1 to C ₈ perfluoroalkyl, C ₃ to C ₁₄ carbocycle substituted with 0 to 3 R ⁵ or 0 to 3 R ⁶ , or 5 to 1 membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0 to 2, oligoethylene glycol, R ⁶ wherein A, X, R ⁵ , R ⁶ , and R ⁷ are as defined above, wherein R ⁴ is different or the same and denotes hydrogen, C 1 to C 8 alkyl substituted with 0 to 3 R ¹⁰ , C 2 to C ₈ alkenyl substituted with 0 to 3 R ¹⁰ C 2 to C 8 alkynyl substituted with 0 to 3 R ¹⁰ , and a C 3 to C ₁₄ carbocyclic residue substituted with 0 to 5 R ¹⁰ or 0 to 5 R ¹¹ , or a 5 to 1 membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen or the same heterocycle substituted with O to 2 R ¹¹ wherein R ¹⁰ and R ¹¹ have the above in this claim hereinbefore defined, wherein Z is identical or different and denote hydrogen, a, -X-a, -C (= O ) -X-A, -CH (OH) -X-A, -CH (NH ₂₎ -X-A, -NH-A, -NH-CH (OH) CH-NH-and-S (= 0) _to - X — A, —O — P (= O) (OR ³ ) - X — A, —O — P (= O) (N (R ³ ) (R ⁴ )) - X — A, R ^3, and C ³ to C C] ₀ alkyl substituted with up to four groups R ^2, wherein K, a, X, R ^2, R ³ and R ⁴ have the above in this claim above, and their pharmaceutically utilizable salts.

-7 GB 295245 B6

HIV protease inhibitors and their pharmaceutically acceptable salts may also have the general formula II (R ') _n A (-X-Z) _m (II), wherein A, X, Z and R ¹ and m, n are as previously defined.

In particular, HIV protease inhibitors are the compounds [(S-HO-TCH 2 -CH 2 O-1-BsHiojir-BsHnj-S-4'-Na] [8- (OH-1,2-C ₂ B ₉ H ₁₀ ) (1 ', 2 '-C ₂ B ₉ H' - 3,3'-Co] Na.iiH ₂ O [8,8'-p-O- (C ₂ H ₉ H 10) ₂ -3-Co] Na [(8- (HO) _2] -P (O) Ol, 2-C ₂ B ₉ H _10o ) - (1 ', 2'-C ₂ B ₉ H ₁₀ ) -3-Co] Na.nH ₂ O [(C ₂ B ₉ H ₁₀ ) _2] -3-Fe] Na. 4H ₂ O [(1,2-C ₂ B ₉ H ₁₀ ) -3,3'-Co (1 ', 2'-C ₂ B ₉ Hii) -8- (OCH ₂ CH _{2) 2} OCH (C ₆ H ₅₎ CH 2 (C 6 H ₅₎ (OH)] to [(l, 2-C ₂ B ₉ H ₁₀₎ -3,3'-Co (l ', 2'-C ₂ B ₉ H ₁₁ ) -8- (OCH ₂ CH ₂ ) ₂ OCH (C ₆ H ₅ ) CH (C ₆ H ₅ ) (OCH ₂ CH ₂ ) ₂ -8O- (1 '', 2-C ₂ B ₉ H ₁₀ ) -3,3'-Co (r, 2'-C ₂ B ₉ Hi ₁ )] Na ₂ [(1,2-C ₂ B ₉ H ₁₀ ) -3,3'-Co (r, 2'-C ₂ B ₉ H ₁₀ ) -8,8'-p-NH-CH ₂ -CH (OH) -CH ₂ -8,8'-p-NH- (r ', 2C ₂ B ₉ H ₁₀ ) -3,3''-Co(1',2'-C ₂ B ₉ H ₁₀ )] and [3,3 '-Co- (1', 2'-C ₂ B ₉ H ₁₀ ), (8-1, 2- C ₂ B ₉ Hi ₀ - (O-CH ₂ -CH ₂ ) 4 O-8-1, 2-C ₂ B ₉ H ₁₀ ) (1 ', 2'-C ₂ B ₉ H],) 3,3' -CO] The _second

Process for the preparation of the novel compounds [(1,2-C ₂ B ₉ Hi ₀ ) -3,3'-Co (r, 2'-C ₂ B ₉ Hii) -8- (OCH ₂ CH ₂ ) ₂ OCH (C ₆ H ₅ ) CH ₂ (C ₆ H ₅ ) (OH)] Na a [(1,2-C ₂ B ₉ H ₁₀ ) -3,3 '-Co (r, 2 ^° -C ₂ B ₉ H _n ) -8- (OCH ₂ CH _{2) 2} OCH (C ₆ H ₅₎ CH (C ₆ H 5) (OCH ₂ CH _{2) 2} -8-O- (1, 2-C ₂ B ₉ Hio) -3,3 '-Co (1', 2'-C ₂ B ₉ H, I)] Na ₂ according to the invention is characterized in that iso-hydrobenzoin deprotonated with one or two equivalents of NaH is treated at room temperature with a solution containing one or two equivalents. -dioxane-cobalt bis (dicarbollide) in toluene.

Process for the preparation of the new compound [(1,2-C ₂ B ₉ H, _O ) -3,3'-Co (1 ', 2'-C ₂ B ₉ H ₁₀ ) -8,8'-p-NH-CH ₂ -CH (OH) -CH ₂ -8,8'-p-NH- (1,2-C ₂ B ₉ H ₁₀ ) -3,3-Co (1 ', 2'-C ₂ B ₉ H ₁₀ ) ] consists in that the compound [(l, 2-C ₂ B ₉ Hio) -3,3'-Co (r, 2'-C ₂ B9Hio) -8,8'-p-NH] deprotonated with NaH and dissolved in diethylene glycol dimethyl ether (DME) is treated with epichlorohydride at room temperature and the product is obtained by purifying the reaction mixture on a silica gel column.

A process for preparing the novel compounds [3,3'-CO- (R ', 2'-C ₂ B ₉ Hii) (8-l, 2-C ₂ B ₉ Hio- _{(0-CH2 -CH2)} 40-8-

1.2- (C ₂ B ₉ H ₁₀ ) (r, 2'-C ₂ B ₉ H ₁₁ ) -3,3'-Co] Na ₂ consists in the formation of [(8-HO- (CH ₂ -CH ₂₎ O) ₂ -

1.2- C ₂ B ₉ H] o) (r, 2'-C ₂ B ₉ H N) -3,3'-Co] Me3NH deprotonated with NaH, and dissolved in diethyleneglycol dimethylether (DME) is treated at room temperature for 8-dioxan-cobalt bis (dicarbollide) and the product is obtained by purifying the reaction mixture on a silica gel column.

The invention also relates to a medicament for the treatment of AIDS, characterized in that it comprises at least one HIV protease inhibitor of the formula I and / or of the formula II, preferably of the aforementioned novel compound.

-8EN 295245 B6

The introduction of boron cluster compound derivatives as a novel structural element provides very remarkable inhibitory properties for HIV protease and its mutants that are resistant to other inhibitors. Low toxicity, stability and biocompatibility, together with high efficacy, is a priority over known and previously used HIV protease inhibitors, which have a number of side effects.

Overview of pictures

Figure 1 shows the structure of the compounds described in the Examples. Each of the compounds is abbreviated. Figure 2 shows a model of the interaction of GB-16 with HTV-1 protease. Figure 3 shows a model of compound GB-24 inserted into the active site of the HIV-1 protease. Figure 4 shows a graph of the initial rate of enzyme reaction on substrate concentration. Figure 5 shows the inhibitory effect of GB-8, GB-12 and GB-16 inhibitors in tissue cultures transfected with the proviral clone NL4-3.

Examples

The present invention is further illustrated by the following examples, which are not intended to limit it in any way.

1. Molecular modeling

2. Synthesis of known compounds

3. Synthesis of new compounds

4. Testing the efficacy of known and new substances in vitro

5. Testing of inhibition of HTV infectivity in tissue cultures.

The structures and abbreviations of all the compounds described in the examples are shown in Figure 1. Boron atoms bearing hydrogen or substituents are indicated by gray beads, carbon atoms bearing hydrogen or substituents by black beads, cobalt and iron are designated by the appropriate element designation. Clusters are numbered in a standard way.

1. Molecular modeling

The basic philosophical concept of our design is represented by HIV protease inhibitors containing borane, carborane or metallacarborane clusters. These clusters, hitherto exclusively designed and used in medicine for neutron capture boron therapy by NCBT (Larson B. et al. (1997) Advances in Boron Neutron Capture Therapy. Vol. 1, Elsevier Science BV; Soloway AH (1998) Chem. Rev. 98, 1515-1562, Hawthorne MF, Madema A. (1999) Chem Rev. 99, 3421-3434, Hawthorne MF (1993) Angew Chem Intl., 32, 950-984, Valliant JF (2002) Coord. Chem., Rev. 232, 173-230, Sivaav IB (2002) Russ, Chem Bull, Intl., 51, 13621374, Hawthorne MF, Lee MW (2003) J. Neuro-Oncology, 62, 33-45 )) represent a new, potentially important structural unit for selective interactions with proteins and thus the generation of highly potent and stable, non-toxic inhibitors with great therapeutic potential.

-9EN 295245 B6

Two compounds were selected to analyze the putative way of binding carbohydrate cage inhibitors to HIV protease by molecular modeling: GB-16 and GB-

24. The related compound [8,8'-p-propargylthio (1,2-C ₂ B ₉ Hio) 2-3-Co] ~ (code in the Cambridge Structural Database: TENQAE) was used as the starting crystal structure (Vohlidal et al. (1996) Collect., Czech. Chem. Commun., 61, 877). By means of molecular modeling, hydrogen atoms were added and the sulfur atom replaced by a phosphate group, respectively. connecting chain. The added atoms or groups were optimized by the semi-empirical MNDO method. Compound models were inserted into the active site of the wild-type HIV-1 protease according to the QF34 inhibitor template (code at Protein Data Bank 1IZI). (Weber J., Mesters JR, LepsikM., PrejdovaJ., Svec M., Sponarova J., Mlcochova P., Skalicka K., Strisovsky K., Uhlikova T., Soucek M., Machala L., Stankova M., Vondrasek J., Klimkait T., Kraeusslich HG, Hilgenfeld R., Konvalinka J. (2002) J. Mol. Biol., 324 (4), 739-754).

Molecular modeling results show that compounds based on metallacarborane clusters meet the space and size requirements for binding the inhibitor to the active site of the HTV protease. Furthermore, complex structures between HIV protease and inhibitors show two essential advantages of patented substances. First, it is apparent from the measured distances between the oxygen atoms of the inhibitor and the protease that the functional groups of the metallacarborane inhibitors may occupy a position which allows the formation of hydrogen bridges with catalytic aspartates (Fig. 2). Second, the significant complementarity of the surfaces between the active site of the HIV protease and the metallacarborane inhibitor allows for strong hydrophobic interactions with the enzyme cavity (Fig. 3), which ensure strong binding.

Figure 2 shows a model of the interaction of GB-16 (1) with Asp25 and Asp25 '(2) catalytic aspartates, which are part of the active site of the HTV-1 protease. GB-16 inhibitor atoms are represented by beads, bars represent bonds between them. The color code for the GB-16 inhibitor is as follows: black beads represent carbon atoms, gray beads represent boron atoms, white beads represent oxygen atoms, and phosphorus (P) and cobalt (Co) atoms are described. Smaller white spheres and white lines between them indicate the atoms and chemical bonds that make up the Asp25 and Asp25 'catalytic aspartates. The bars with numbers indicate the distances (in Angstroms, Angstroms = 0.1nm) between the oxygen atoms of the catalytic aspartates and the GB-16 inhibitor. The fact that the distances do not exceed 2.5 Å confirms that the functional position of the GB-16 inhibitor functional group and the catalytic aspartates is optimal for the formation of hydrogen bridges. The active site of the HTV protease (except for the catalytic aspartates) is represented by a bar model and colored gray.

Figure 3 shows a model of GB-24 inserted into the HTV-1 protease active site. It can be seen that the surface of the inhibitor is highly complementary to the protease cavity. This close approximation of predominantly hydrophobic surfaces causes a strong binding between the GB-24 inhibitor and the HIV-1 protease. The Van der Waals surface of the inhibitor (1) is represented by the calotte model (black), while the cavity of the HIV protease is presented as the Connoly surface (gray dots). The catalytic aspartates of the HIV-1 protease Asp25 and Asp25 '(2) are colored black, while the remainder of the active site is gray.

2. Synthesis of known compounds

GB-1 [(8-HO- (CH ₂ -CH ₂ O) ₂ -1,2-C ₂ B ₉ H ₁₀ ) (1 ', 2'-C ₂ B ₉ H ₁ ) -3,3'- Co] Na

The substance was prepared by reaction of a known neutral compound, a derivative of 8-dioxane-cobalt bis (dicarbollide) (Plešek J, Chamomile S, Franken A, Císařová I, Nachtigal C. (1997) Collection Czechoslovak. Chem. Commun. 62, 47-56) sNaOH in aqueous dioxane according to the following procedure: 1.0 g of 8-dioxane-cobalt bis (dicarbollide) was dissolved in 50 ml of dioxan-water 4: 6 and 10 ml of 10% NaOH solution was added. The reaction mixture was heated at 80 ° C for two

-10GB 295245 B6 hours. After cooling, 100 mL of water was added, dioxane was evaporated in the cold, and then 50 mL of 3M HCl was added. The aqueous phase was extracted with diethyl ether (3 x 30 mL). The combined organic extracts were shaken with water (2 x 20 mL), separated and an additional 50 mL of H ₂ O was added and the ether was evaporated. Ethanol was added to dissolve the product and the product was precipitated with excess (CH ₃ ) ₃ N.HCl in water, filtered and dried under vacuum. Yield of (8-HO- (CH ₂ -CH ₂ O) ₂ -1,2CzB ^wjCPCP^ QBB ^nH ^^CojCO ^^NH: 0.99g, 86%.

1 H NMR: acetone-d ₆ , 4.27 (2H, CH _carborane ), 4.1 µm (2H, CH ₂ -O), 3.97s (2H, CH ₂ ), 3.81 (2H, CH) _2- O), 3.64-3.59 m (4H, 2CH ₂ -O), 3.10s (2H, 2CH _carborane ), [2.95] (H10 '), [2.79] (H4' , 7 '), [2.72] (H10), 2.90 (9H, (CH3) ₃ NH, [2.48] (H8'), [2.06] (H9 ', 12')> [2 , 06, 1.81] (H4, 7, 9, 12), [1.73] (H6 '), [1.68] (H5', 11 '), [1.59] (H5, 11), [ 1.49] (H6).

BNMR: acetone-d ₆ : 23.8s (B8), 5.2 (B8 '), (131), 0.5 (BIO') (135), -2.5 (BIO) (139), -4 , 6 (B4 ', 7') (142), -7, From, -7.5d (B9, 12, 9 ', 12') (overlap = overlap), -8.7 (B4, 7) (176 ), -17.2 (B5 ', 11') (150), -20.3 (B5, 11) (150), -22.1d (B6 ') (overlap), -28.5 (B6) ( 135). MS m / z = 415.3.

Analysis:% B calculated: 41.22, found: 40.84,% Co calculated: 12.49, found: 12.33.

The trimethylammonium salt was converted to the sodium salt by the following procedure: 1 g of salt was shaken between 3M HCl (50 mL) and diethyl ether (30 mL), the organic layer was separated and shaken twice with 3M HCl (50 mL). The organic extract was shaken successively three times with 50 ml of 10% aqueous Na ₂ CO ₃ solution, 50 ml of water, the ether phase was separated and evaporated to dryness and dried in vacuo.

There is a description in the literature of the preparation of this compound by another, more complex method (Sivaav IB, Staříkova ZA, Sjoberg S, Bregadze VI. (2002) J. Orgcmomet. Chem. 649, 1-8).

GB-8 [8- (OH-1,2-C ₂ B ₉ H ₁₀ ) (1 ', 2'-C ₂ B ₉ H ₁₁ ) -3,3'-Co] Na.nH ₂ 0

The compound was prepared by direct hydroxylation of cobalt bis (dicarbollide anion) by diluting H ₂ SO 4 at higher temperatures, as described in the literature (Plešek J., Grüner B, Báča J, Fušek J, Císařová I. (2002) J. Organometal. Chem. 649,181-190).

GB-12 [8,8'-p-O- (C ₂ B ₉ H ₁₀ ) ₂ -3-Co] Na

The bridged cobalt bis (dicarbollide) derivative was prepared based on the described procedures by reacting the unsubstituted ion with paraformaldehyde (Plešek J, Chamomile S, Baska K, Todd LJ, F. WW. (1976) Collection Czechoslovak. Chem. Comrnun. 41, 3509-3515 ).

GB-16 [(8- (HO) ₂ -P (O) Ol, 2-C ₂ B ₉ H ₁₀ ) - (1 ', 2'-C ₂ B ₉ H ₁₀ ) -3-Co] Na ₂ . nH ₂ O

The compound was prepared by reacting GB-8 with phosphoryl chloride and hydrolyzing the resulting intermediate as described (Plešek J, Gruner B, Císařová I, Báča J, Selucký P, Rais J. (2002) J. Organometal. Chem., 657, 59-70).

-11 GB 295245 B6

GB-23 [(C ₂ B ₉ H ₁₀ ) ₂ -3-Fe] Na ₄ H ₂ O

The compound was prepared by a procedure described in the literature (Hawthome MF, Young DC, Wegner PA (1965) 7 Am. Chem. Soc. 87, 1818).

3. Synthesis of new compounds

Numbers of chemical shifts in NMR spectra are given in ppm.

GB-21 [(1,2-C ₂ B ₉ Hi ₀ ) -3,3'-Co (1 ', 2'-C ₂ B ₉ Hii) -8- (OCH ₂ CH ₂ ) ₂ OCH ₍ C ₆ H ₅ ) CH2 ( _C6 H5) (OH)] Na

GB-22 [(1,2-C ₂ B ₉ H ₁₀ ) -3,3'-Co (r, 2'-C ₂ B ₉ H ₁₁ ) -8- (OCH ₂ CH ₂ ) ₂ OCH (C ₆ H5) CH (C ₆ H ₅ ) (OCH ₂ CH ₂ ) ₂ -8O- (1,2 '' - C ₂ B ₉ H ₁₀ ) -3,3'-Co (1 ', 2'-C ₂ B) ₉ Hii)] Na ₂

To a meso-hydrobenzoin deprotonated with one or two equivalents of NaH was added dropwise a solution containing one or two equivalents of 8-dioxane-cobalt bis (dicarbollide) in toluene. The reaction time for the disubstituted product was 5 hours. The reaction mixture was quenched with water 30 ml, a few drops of 10% acetic acid and the reaction products were taken up in diethyl ether (2 x 30 ml), the organic phase was evaporated and purified by silica gel chromatography.

GB-21 1 HNMR: 400 MHz, acetone-d ₆ , 8.01 (s, 1H, HO-), 7.24-7.17 (m, 10H, overlaped 2 Ph-groups), 4.24 (broad) s, 2H, H ₂ O), CH _carborane : 4.23 (s, H) and 3.10 (s, 2H), O-CH ₂ CH ₂ OB grouping: 4.11 (t, 2H) and 3 81 (t, 2H), O-CH ₂ CH ₂ O- group: both CH ₂ groups resonate in the range of 3.64-3.59 (m, 4H).

¹ H NMR: (128 MHz) acetone-d ₆ : 23.92s (2B, B8), 5.57d (2B, B8 '), 0.5d (2B, BIO') -2.47d (2B, BIO) , -4.6d (4B, B4 ', 7'), -6.92d, -7.347d (8B, B9, 12, 9 ', 12'), -8.63d (4B, B4, 7 ), -17.17 d (4B, B5 ', 11'), -20.21d (4B, B5, 11), -21.97d (2B, B6 '), -28.44d (2B, B6).

GB-22

Ή NMR: 400 MHz, acetone-d ₆ , 7.33-7.24 (asym. M., 10 H, 2 Ph-groups), 3.78 (s, 2H, 2 CH groups), 265 (s, 8H, 2x2 H ₂ O), CH _carborane : 4.2 (s, H) and 3.1 (s, 2H), O-CH ₂ CH ₂ OB grouping: 4.1 (t, 2H) and 3.8 (t, 2H) O-CH ₂ CH ₂ O- group: both CH ₂ groups 3.6 (m, 4H).

^{1] 1} H NMR: (128 MHz) acetone-d ₆ : 23.92s (2B, B8), 5.57d (2B, B8 '), 0.5d (2B, BIO'), -2.47d (2B, BIO), -4.6d (4B, B4 ', 7'), -6.92d, -7.347d (8B, B9, 12, 9 ', 12'), -8.63d (4B, B4) , 7), -17.17d (4B, B5 ', 11'), -20.21d (4B, B5, 11), -21.97d (2B, B6 '), -28.44d ( 2B, B6).

Detailed characterization of compounds with other substituents terminal (o-PhCH ₂ -C ₆ H ₄ -, pt-octyl-C ₆ H ₄ -, and -O-CH ₃ O-C ₆ H 4 are described in Plešek et al .: Polyhedron 2002 Generally, two CH _carborane groups are characteristic of * HNMR: 4.23 (s, H) and 3.10 (s, 2H), O-CH ₂ CH ₂ OB grouping: 4.11 (t , 2H) and 3.81 (t, 2H), O-CH ₂ CH ₂ O- group: both CH ₂ groups resonate between 3.64-3.59 (m, 4H) Hydrating water: characteristically broad signal at about 4.30.

-12EN 295245 B6 ⁿ B NMR: Overlap of two sextets with a 1: 1: 2: 2: 2: 1 intensity ratio, ie 12 signals theoretically. Distinguishable is 11, two coincide (at -22.1). Only the signal at 23.4 is a singlet (Corresponds to B ₍₈ -) - 0-), the others are doublets. The extremely large spectrum range of about 52 (Na from + 22.93 to -28.42) is given by the spectrum range of the substituted ligand - the hidden unsubstituted ligand signals range only 22.5.

GB-24 [(1,2-C ₂ B ₉ H ₁₀ ) -3,3'-Co (1 ', 2'-C ₂ B ₉ H ₁₀ ) -8,8'-p-NH-CH ₂ - CH (OH) -CH ₂ -8,8'-p-NH- (1,2C ₂ B ₉ H ₁₀ ) -3,3'-Co (1 ', 2'-C ₂ B ₉ H ₁₀ )]

Twice 150 mg (0.44 mmol) of the amino derivative [(l, 2-C ₂ B ₉ H, o) -3,3'-Co (r, 2'-C ₂ B ₉ Hio) -8,8 ' -pNH] prepared according to the described procedure H ₂ SO ₄ (Plesek J, Chamomile S, Basa K, Todd LJ, F. WW. (1976) Collection Czechoslovak. Chem. Commun. 41, 3509-3515; Plesek J, RajabiFH, Vangani V, Fusek J. (1994) Collection Czechoslovak. Chem. Commun. 59, 1326-1336) was dissolved in diethylene glycol dimethyl ether (DME) (15 ml) in two flasks and the solution was added under stirring under a dry nitrogen atmosphere. mg of NaH with a large specific surface area (2 m ² g ^-1 ). The reaction mixture in flask A was stirred for 1 hour at room temperature, then 35 μΐ of epichlorohydrin was added over the septum and the reaction mixture was stirred for 2 hours at room temperature. From flask B, the resulting solution was transferred via cannula through flask A to flask A. The reaction mixture was stirred for 2h at room temperature and then at reflux for 26h. After cooling, silica gel for chromatography (Meter, 2g) was added to the flask and the solvent was evaporated in vacuo. The silica gel coated with the evaporated reaction products was loaded onto a silica gel column (2 x 25 cm) and the reaction products were eluted first with 2: 1 benzenhexane until the unreacted starting material was eluted, then with benzene. The material corresponding to the red spot on TLC (Silufol, benzene) with R _F = 0.37 was collected. The solution was evaporated and the product was purified again by silica gel chromatography. Yield 105 mg (32%).

Ή NMR: 400 MHz, acetone-d ₆ , 7.41 (2H, NH), 4.791 (2H, CH 2), 4.241 (2H, CH) 3, 296 (8H, CH 3 carbborane) · ⁿ B NMR: (128 MHz ) acetone-d ₆ : 5.044 s (4B), -1.021 d (4B), -8.66 d, -9.891 d, -11.15 d (16B), -15.77 d (8B), - 25, 59d (4B).

GB-25 [3,3 '-Co- (1', 2'-C ₂ B ₉ H 3), (8-1,2-C ₂ B ₉ H ₁₀ - (O-CH ₂ -CH ₂ ) ₄ ) O-8-1,2-C ₂ B ₉ H ₁₀ ) (1 ', 2'-C ₂ B ₉ H, 3,3'-Co) Na ₂ [(8-HO- (CH ₂ -CH) ₂ 0) ₂ -l, 2-C ₂ B ₉ Hio) (r, 2'-C ₂ B ₉ H ₁₁₎ -3,3'-Co] Me3NH (lOOmg, 0.2 mmol), prepared as described below was Dissolve in anhydrous ethylene glycol dimethyl ether (DME) (30 mL) and add solid NaH (98%) with a large specific surface area (12 mg, 0.49 mmol) with stirring. The reaction mixture was stirred at room temperature for 2h. Then, the reaction flask was evacuated and 10 mL of solvent was distilled off along with the Me3N residues. To the flask was added dropwise a solution of 8-dioxane-cobalt-bis (dicarbollide) (84 mg, 0.2 mmol) (Plešek J, Chamomile S, Franken A, Císařová I, Nachtigal C. (1997) Collection Czechoslovak. Chem. Commun. 62, 4756) in 20 ml of anhydrous toluene. The reaction mixture was heated at 80 ° C for 2h with stirring. After cooling, 5 g of silica gel GC for LC was added and the solvents were evaporated in vacuo. The silica gel was poured onto a dry column of the same silica gel 2.5 x 25 cm and the product eluted with CH 3 CN-CHCl 3 1: 3, collecting a fraction containing the main yellow-orange band. The solvents were evaporated in vacuo. Yield 141 mg (82%). The product was characterized by ¹ H and ¹ B NMR spectroscopy:

-13 GB 295245 B6

Ή {B + -} NMR, 400 MHz, acetone-d ₆ ; 4.15 (2H, _carborane CH.), 4.104 (4H, _carborane CH.) 3.790 to 3.712 m (12H, _CH2 O), 3,632 m (4H, _CH2 -O), [2.95] (H10 '), [2.89] (H4', 7 '), [2.69] (H10), [2.61] (H8'), [2.058] (H9 ', 12'), [1.846] ( H4, 7, 9, 12), [1.73] (H6 ')> [1.622] (H5', 11 '), [1.541] (H5, 11), [1.46] (H6).

1 H NMR: (128 MHz) acetone-d ₆ : 23.92s (2B, B8), 5.57d (2B, B8 '), 0.5d (2B, BIO'), -2.47d (2B, BIO) ), -4.6d (4B, B4 ', 7'), -6.92d, -7.347d (8B, B9, 12, 9 ', 12'), -8.63d (4B, B4, 7), -17.17d (4B, B5 ', 11'), -20.21d (4B, B5, 11), -21.97d (2B, B6 '), -28.44d (2B) , B6).

4. Testing the efficacy of known and new substances in vitro

Both known and novel substances were first tested for their ability to inhibit specific HIV protease activity in vitro using pure recombinant HIV protease and a chromogenic peptide substrate derived from the amino acid sequence of one of the cleavage sites of the viral poly15 protein. Testing was performed according to a method published by one of the co-authors of this PV (Konvalinka, J., Litera, J., Weber, J., Vondráček, J., Hradilek, M., Souček, M., Pichová, I., Majer, P , Ceiling, P., Sedlacek, I, Heuser, A.-M., Kottler, H., and Kraeusslich, H.-G. (1997) Eur J.

Biochem. 250, 559-566). In a typical experiment, to 15μΜ of a chromogenic substrate with the sequence KARVNIeF (NO ₂ ) EANIe-NH ₂ (where Nle denotes norleucine and F (NO ₂ ) is para-nitrophenyl20 alanine) in 1 ml acetate buffer pH 4.7 containing 0.3 M NaCl various amounts of test inhibitor dissolved in DMSO (such that the final DMSO concentration does not exceed 2.5%) are added and the reaction is started by adding pure recombinant HIV protease to a final concentration of 8 nM. The progress of the reaction is monitored on a spectrophotometer as a decrease in absorbance at 305 nm. IC ₅₀ and K i values of the test compounds were calculated from experimental data as 25 described in the work (Majer, P., Urban, J., Gregorova, E., Konvalinka, J., Novek, P.,

Stehlikova, J., Andreansky, M., Sedlacek, J. and Strop, P. (1993) Arch. Biochem. Biophys. 304, 1-8). The mechanism of action of the test compounds (type of inhibition) was determined from the initial rate of response to substrate concentration at various inhibitor concentrations (Lineweaver-Burk yield) and is demonstrated in Figure 4. In addition, inhibition was tested for 30 wt HIV-2, HIV-1 mutant PR 3/1 and cathepsin D. The results are shown in Table 2.

Table 1: Values of IC ₅ for each set of inhibitors for the wt HIV-1 PR.

Inhibitor ic ₅₀ GB-1 6,1 μΜ GB-8 13,5 μΜ GB-12 5,2 μΜ GB-16 6.2 μΜ GB-18 1,1 μΜ GB-21 130 ηΜ GB-22 50 ηΜ GB-23 550 ηΜ GB-24 160 ηΜ GB-25 60 ηΜ

- 14GB 295245 B6

Table 2: K values; and IC ₅₀ for GB-16 inhibitor and various proteases.

Type of recombinant protease IC ₅ o Κ wt HIV-1 PR 6.2 μΜ 16,3 μΜ wt HIV-2 PR 15,4 μΜ 7.4 μΜ HIV-1 PR 3/1 13,4 μΜ 3,6 μΜ cathepsin D 32,9 μΜ 17,2 μΜ

An example of determining the mechanism of action of the GB 16 inhibitor by Lineweaver and Burk yield is shown in Figure 4. The dependence of the initial rate of enzyme reaction on substrate concentration at different inhibitor concentrations (here, 0 and 15 μΜ) is measured. The measurement was performed at pH 4.7; 37 ° C in 0.1 M acetate buffer containing 0.3 M NaCl. Y-axis: reciprocal value of the initial rate of enzyme reaction, X-axis: reciprocal value of substrate concentration (in mol / dm ³ ). It is a competitive inhibitor.

5. Testing of inhibition of HTV infectivity in tissue cultures

Blocking of HIV infectivity in tissue cultures was tested by a published published method variant (Benyoucef S, Hober D, Shen L, Ajana F, Gerard Y, Bocket-Mouton L, Mouton Y, Wattre P. (1996) Microbiol Immunol. 40 (5) , 381-8). Briefly, HeLa cells were transfected with DNA encoding HIV HIV pNL-43 containing the beta-galactosidase gene at the site of the nef virus gene in the presence of various concentrations of test compounds. The transfected cell supernatant was used for another round of reporter cell infection. The infectivity was quantified by the enzymatic activity of beta-galactosidase in the infected cells and the infected cells were visualized using the chromogenic substrate beta-galactosidase (X-gal). The viral proteins of newly generated virions were resolved by SDS PAGE and immunochemically visualized with antibodies against the capsid protein (Western blot).

The inhibitory properties of GB-8, GB-12 and GB-16 were determined by tissue culture experiments. HIV was produced in 293 T cells transfected with the proviral clone NL 4-3 using the Chen-Okayama method. All transfections were performed in duplicate. The medium was changed the day after transfection and protease inhibitors dissolved in DMSO were added to fresh medium. Control cells were incubated at the same DMSO concentration as the test cells. Viral infectivity was quantified by titrating the cell supernatant with TZM cells (reporter cells carrying an HIV LTR promoter linked to the beta-galactosidase gene activated by the Tat protein produced by the virus in its genome). Two days after infection, reporter cells were lysed and fixed with methanol / acetone. Beta-galactosidase activity of infected cells was visualized by blue staining after addition of the chromogenic substrate X-gal. The result of a typical experiment is shown in Figure 5. The experiment demonstrates that a 10 μΜ inhibitor solution of GB-16 reduces HIV infectivity to about 27% of the initial value; A 100 μΜ inhibitor solution of GB-8 was required for comparable activity.

GB-8, GB-12 and GB-16 inhibitors block the infectivity of the virus. 293T cells were transfected with the NL4-3 proviral clone. Test substances were added to the medium in DMSO to the final concentration indicated in Figure 5. Cell supernatants (containing virus) were harvested 2 days after transfection and titrated with TZM cells that were stained and infected cells were counted. Control without inhibitor was set equal to 100%.

Industrial applicability

The invention is useful in the pharmaceutical industry and medicine for the treatment of AIDS.

Claims (10)

HIV protease inhibitors comprising clusters selected from the group consisting of borates and / or carboranes and / or metallacarboranes, having a number of boron atoms in each individual cluster of 6 to 12, wherein the charge of each individual borane, carborane, or metallacarborane cluster is 0, -1 or The -2, borane, carborane, or metallacarborane clusters are peripherally substituted by groups increasing the interaction energy between the HIV protease and the inhibitor, wherein the number of borane, carborane, or metallacarborane clusters in the inhibitor molecule is 1 to 9, the carborane clusters in the metallactarborane inhibitors a transition metal selected from the group consisting of Co, Fe, Ni and Ru. HIV protease inhibitors according to claim 1 comprising clusters in which other heteroatoms are selected and selected from the group consisting of N, P, Si, Ge, Sn, S. Third HIV protease inhibitors as claimed in claim 1 or 2 of the formula I (R @ ¹⁾ @ - X-Y-Z) _m (I) wherein A is an anion cluster Biohem _O ^(2_) Bi2Hi2 ^(2_) CB6H ₇ ⁽⁾ , CB7H8 ^(_) , CB7H ₈ ^W , CBpH10 ^ CB10H10 ^, CBhHi / SiBnHi / SiBnHn ^{( -2)} , SnBnH, / ²⁴ , GeBuHu ^, 7,8- ^ ¾ ^ 7,9-C2B ₉ H ₁₂ ^w , Si2B10H12 ^, [(1,2 - ^^) 2-3- ^ 0 (111)] ^ [(1,7-W, 9, -3 ^ 0 (111)] ^ [(C2B9Hn) Co ( ffl) (C2BgH10) JCO (III) (C2B9Hl1)] ⁽²⁾ [(l, 2-C2B H _{9 N)} - 3 ^ (111)] ^ [(1,7-C ₂ B ₉ H! Ο ^ -Ε ^ ΠΙ)] * - *, [(1,2-C ₂ B ₉ Hn) ₂ -3-Ni (III)] ⁽ ->, [HC 5 H 5) Fe (III) (CB 10 H 11)] ⁽ - ⁾ , [(C ₅ H ₅ ) Co (m) (1,2-CB _{1 (1} H 1 _I ))] - ^{( )} , [(C ₅ H ₅ N ₁ H ₂ O ₂ -C ₁ H ₃ )]] - [(C ₂ B ₁₀ H ₁₂ ) ₂ M (III) ] ^H or neutral cluster 1,2-C ₂ B ₈ H ₁₀ , 1,6-C ₂ B ₈ Hio, 1,1O-C ₂ B ₈ Hio, 1,2-C ₂ BioH] ₂ , 1,7- C ₂ BioH] ₂ , 1,12-C ₂ BioH] ₂ , P ₂ BioHio, SBnHn, NBhHh, PBhHh, [[(C ₅ H ₅ ) (1,2-C ₂ B ₉ H ₁₁ ) -Co (III )], [(C ₅ H ₅ ) (1,7-C ₂ B ₉ H ₁₁ ) -3-Co (III)], [(C ₅ H ₅ ) (1,2-C ₂ B ₉ H, i ) -Fe (ni)], [(C ₅ H ₅₎ (l, 7-C ₂ B ₉ H _u) -Fe (III)], [(C ₅ H ₅ X, 2-C ₂ B ₉ H _u Ni (m)], [(C ₅ H ₅ ) Fe (II) (C ₃ B ₈ H ₁₁ )], [(C ₅ B ₅ Ru) (n) (C ₃ B ₈ H _n )], [(C ₃ B ₈ H _n ) ₂ - Fe (II)], [(C ₅ H ₅ ) Fe (II) (C ₃ B ₇ H ₁₀ )], [HC ₅ H ₅ ) Fe (II) (PC ₂ B ₈ H ₁₀ )], [(C ₂ B ₉ H _n ) -CO ( _{n 1} ) (C ₃ B ₈ H _n )], [(C ₂ B ₁₀ H ₁₂ ) -M (III) (C ₅ H ₅ )] wherein the substituents of the general formula —X — Y— Z and R ¹ are attached to the boron, carbon or heteroatoms of cluster A when it is 3, M is Fe, Co, Ni, Ru and wherein R ¹ is the same or different and is selected from the group consisting of hydrogen, halogen, methyl, hydroxy, phenyl, phenylene, thiol, methoxy and trifluoromethoxy, m is 0, 1 and 2, n is 0 to 12, X is different or the same and denotes -O-, -C (= O) -, -CH ₂ -, -N (R ³ ) -, -P (R ³ ) -, -S-, C 1 -C 10 alkanediyl, —O (CH ₂ CH ₂ O) _q -, phenylene substituted independently with 0 to 3 R ¹⁴ substituents, in the case of [(1,2-C ₂ B ₉ Hn) _2] -3-1-4 4 (111)] metallacarboranes X is further a bridged group>S,>N,>P,> O ₂ P,> O ₂ P (= O), phenylene substituted independently with 0 to 3 R ¹⁴ substituents, ethanediyl substituted independently with 0 to 3 R ¹⁴ substituents, to which a substituent Y is attached, wherein M is as previously defined, Wherein q is 0 to 12, wherein R ³ is the same or different and denotes hydrogen, C 1 -C 8 alkyl substituted with 0-3 R ¹⁰ , C 2 -C 8 alkenyl substituted with 0-3 R ¹⁰ , C 2 -C 8 alkynyl substituted 0-3 R ^10, and C ₃ to C _M carbocyclic ring system substituted with 0-5 ^R10 or 0-5 ^R11, or a 5- to membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0-2 R ^11, wherein R ¹⁰ is identical or different and represent a keto, halogen, cyano, -CH 2 N (R ⁷⁾ (R ^8), -N (R ⁷⁾ (R ⁸⁾ -C (= O) O (R ⁷ ), -C (= O) (R ⁵ ), -OC (= O) (R ⁷ ), -O (R ⁷ ), C ₂ -C ₆ alkoxyalkyl, -S (= O) _k ^(R7), -NHC (= NH) NH (R ⁷⁾ -C (= NH) NH (R ⁷⁾ -C (= O) N (R ⁷⁾ (R ^8), -N (R ⁸ ) C (= O) (R ⁷ ), = N - O (R ⁸ ), - N (R ⁸ ) C (= O) (R ⁸ ), - OC (= O) N (R ⁷ ) (R ⁸⁾ ), -N (R ⁷⁾ C (= O) N (R ⁷⁾ (R ^8), -N ^(R8) S (= O) 2N ^{(R7) (R8),} -N (R ⁸⁾ S (= O) 2 (R ⁷ ), —S (= O) 2N (R ⁷ ) (R ⁸ ), C 1 -C 4 al alkyl, C ₂ -C ₄ alkenyl, C ₃ -C 10 cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, nitro, C ₇ -C 10 arylalkyl, -C (= O) -NH (OH), -C (= O) -NH (NH _2), -B (OH) _2, sulfonamide, formyl, C ₃ to C ₆ cycloalkoxy, C to C ₄ alkyl substituted with -N (R ⁷⁾ (R ^8), C until C4 hydroxyalkyl, methylenedioxy, ethylenedioxy, Cl-C4 haloalkyl, Cj-C4 haloalkoxy, Cl-C4 alkoxycarbonyl, Cl-C4 alkylcarbonyloxy, Cl-C4 alkylcarbonyl, Cl-C4 alkylcarbonylamino, -OCH 2 C (= O) (R ⁷⁾ 2 - (l-morpholino) ethoxy, azido, -C ^(R8) = N-O (R ^8), C 5 to C _i4 carbocyclic residue substituted with 0-5 ^R11, or a 5- to membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen or the same heterocycle substituted with 0 až2R ^n, where k assumes the values 0, 1 and 2, where R ⁷ is identical or different and denote hydrogen, phenyl substituted with 0-3 ^R14, phenylmethyl substituted with 0-3 R ¹⁴ , C 1 -C 6 alkyl substituo 0 to 3 R ¹⁴ , C 2 to C ₄ alkenyl substituted with 0 to 3 R ¹⁴ , C 1 to C 6 alkylcarbonyl substituted with 0 to 3 R ¹⁴ , C 1 to C 6 alkoxycarbonyl substituted with 0 to 3 R ¹⁴ , C 1 to C 6 alkylaminocarbonyl substituted with 0 to 3 R ¹⁴ , C 3 -C ₆ alkoxyalkyl substituted with 0 to 3 R ¹⁴ , any amino protecting group when R ^{7 is} attached to a nitrogen atom, or any hydroxy protecting group when R ^{7 is} attached to an oxygen atom, where R ¹⁴ is different or same and denotes H, keto, halogen, cyano, -CH ₂ NH _2, -NH _2, -C (= O) OH, - OC (= O) (Ci to _C3 alkyl), -OH, C ₂ to C ₆ alkoxyalkyl, -C (= O) NH _2, -OC (= O) NH _2, -NHC (= O) NH _2, -S (= O) _{2 NH2,} Ci to C ₄ alkyl, C ₂ to C ₄ alkenyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, nitro, C ₇ -C ₁₀ arylalkyl, -C (= O) -NH (OH), -C (= O) --NH (NH _2), -B (OH) _2, C ₃ to C ₆ cycloalkoxy, Ci to C ₄ alkyl substituted with -NH _2, C-C ₄ hydroxyalkyl, methylenedioxy, ethylenedioxy, C] to C ₄ haloalkyl, C C ₁ -C ₄ haloalkoxy, C 1 -C ₄ alkoxycarbonyl, C 1 -C ₄ alkylcarbonyloxy, C 1 -C ₄ alkylcarbonyl, C 1 -C ₄ alkylcarbonylamino, -OCH ₂ C (= O) OH, 2- (1-morpholino) ethoxy, azido , aryl (C ₁ -C ₃ alkyl), C ₅ -C ₁₄ carbocyclic radical, 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0 to 3 R ⁶ , wherein R is ⁶ when it is a substituent on carbon denotes phenyl, phenylmethyl, phenethyl, phenoxy, phenylmethoxy, halogen, hydroxy, nitro, cyano, C 1 -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, C ₇ -C 1 _O arylalkyl, C ₄ -C ₄ alkoxy, -C (= O) OH, -C (= O) -NH (OH), -C (= O) -NH (NH ₂ ), -B (OH) ₂ , sulfonamide, formyl, C ₃ -C ₆ cycloalkoxy, -O (R ⁷ ), C 1 -C 4 alkyl substituted with -N (R ⁷ ) (R ⁸ ), -N (R ⁷ ) (R ⁸ ), C ₂ -C ₆ alkoxyalkyl , C 1 -C ₄ hydroxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C ₄ haloalkyl, C 1 -C ₄ halo -17CZ 295245 B6 alkoxy, Ci to C ₄ alkoxycarbonyl, Ci to C ₄ alkylcarbonyloxy, Ci to C ₄ alkylcarbonyl, Ci to C ₄ alkylcarbonylamino, -S (= O) _k (R ^7), -S (= O) 2N ( R ⁷ ) (R ⁸ ), -NHS (= O) 2 (R ⁸ ), -OCH 2 C (= O) OH, 2- (1-morpholino) ethoxy, -C (R ⁸ ) = N-O (R ⁸⁾ ), A 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0 to 3 R ⁹ , a C 3 to C ₄ carbon chain having the other end attached to the adjacent ring carbon atom to form A 5- or 6-membered ring, the 5- or 6-membered ring may be substituted on any of the aliphatic carbons by halogen, C 1 -C ₄ alkyl, C 1 -C ₄ alkoxy, hydroxy, -N (R ⁷ ) (R ⁸ ), or when R ^{6 is} attached to a saturated carbon atom, R ⁶ may be = O or = S, where R ⁷ is as previously defined, wherein R ⁸ is the same or different and denotes hydrogen, hydroxy, trifluoromethyl, C 1 -C ₆ alkoxy, C ₂ to C _6, and 1-phenyl, phenylmethyl, amino, C 1 -C ₆ alkyl substituted with 0 to 3 groups selected independently from hydroxy, C ₁ -C ₄ alkoxy, halogen, amino, any amino-protecting group when R ^{8 is} attached to a nitrogen atom, or any protecting group at the hydroxy group when R ^{8 is} bonded to an oxygen atom, wherein R ⁹ is different or the same and denotes hydrogen or methyl, wherein R ⁶ , when a substituent on the nitrogen, is different or the same denotes phenyl, phenylmethyl, phenethyl, hydroxy, C ₁ -C ₄ hydroxyalkyl, C 1 -C ₄ alkoxy, C 1 -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, -CH ₂ N (R ⁷ ) (R ⁸ ), -N (R ⁷ ) ⁷ ) (R ⁸ ), C ₂ -C ₆ alkoxyalkyl, C 1 -C ₄ haloalkyl, C 1 -C ₄ alkoxycarbonyl, -C (= O) OH, C 1 -C ₄ alkylcarbonyloxy, C 1 -C ₄ alkylcarbonyl C (R ⁸⁾ ) = N-O (R ⁸⁾ wherein R ⁷ and R ⁸ have the aforementioned meaning, R ⁷ and R ⁸ may alternatively be attached to form - (CH 2) 4 -, - (CH 2) 5 -, -CH ₂ CH ₂ N (R ⁹ ) CH ₂ CH ₂ - or -CH ₂ CH ₂ OCH ₂ CH ₂ -, wherein R ⁵ is identical or different and denote hydrogen, halogen, phenylmethyl, phenethyl, -C (= O) -NH (OH), -C (= O) -NH (NH _2), -B (OH _2), a sulfonamide group, azido , formyl, phenoxy, phenylmethoxy, nitro, cyano, -CH ₂ N (R ⁷⁾ (R ^8), -N (R ⁷⁾ (R ^8), -OCH 2 C (= O) OH, -C (= O) O ( R ⁷ ), -OC (= O) R ⁷ ), -O (R ⁷ ), C ₂ -C ₆ alkoxyalkyl, -S (= O) _k (R ⁷ ), -NHC (= NH) NH (R ⁷ ) , -C (= NH) NH (R ⁷⁾ -C (= O) N (R ⁷⁾ (R ^8), -N ^(R8) C (= O) (R ⁷⁾ = N-O ( R ^8), -N ^(R8) C (= O) O (R ⁸⁾ OC (= O) N (R ⁷⁾ (R ^8), -N ^(R7) C (O) N (R ⁷ ) (R ⁸ ), —C (R ⁸ ) = N — O (R ⁸ ), —N (R ⁸ ) S (= O) 2N (R ⁷ ) (R ⁸ ), —N (R ⁸ ) S (= O) 2 (R ^7), -S (= O) 2 N (R ⁷⁾ (R ^8), C, to C4 alkyl, _C2 to _C4 alkenyl, _{C3-C) 0} cycloalkyl, C ₃ to C ₆ cycloalkylmethyl, C ₇ to Cio arylalkyl, C ₃ to C ₆ cycloalkyloxy, C to C ₄ alkyl substituted with -N (R ⁷⁾ (R ^8), C] -C4 hydroxyalkyl, and C C4 haloalkyl, Cj-C4 haloalkoxy, Ci to C4 alkoxycarbonylamino, 2- (l-morpholino) ethoxy, - (Ci-C3 alkyl) aryl substituted with one 0-2 R ^6, C 5 to C ₄ carbocyclic residue substituted with 0-3 R ⁶ 5 to 10-membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0 to 3 R ⁶ , wherein k, R ⁶ , R ⁷ and R ⁸ are as defined above, wherein R ¹¹ when substituent on carbon, is different or the same and denotes phenethyl, phenoxy, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, C ₇ -C ₁₀ arylalkyl, -C (= O) -NH (OH), -C (= O) -NH (NH _2), -B (OH) _{2, C2} to Ce alkoxyalkyl, methylenedioxy, ethylenedioxy, C] to C ₄ alkylcarbonyloxy, -NHS (= O) ₂ (R ⁸⁾ phenylmethoxy , halogen, 2- (l-morpholino) ethoxy, -C (= O) O (R ⁷⁾ -C (= O) N (R ⁷⁾ N (R ⁷⁾ (R ^8), cyano, sulfonamide, formyl, C ₃ -C ₆ cycloalkoxy, C] to C ₄ haloalkyl, C] to C ₄ haloalkoxy, C ₂ to C ₄ haloalkenyl, C ₂ to C ₄ haloalkynyl, —N (R ⁷ ) (R ⁸ ), -18GB 295245 B6 -C (R> NO (R ⁸ ), -NO 2, -O (R ⁷ ), -N (R ¹² ) (R ¹³ ), —S (= O) k (R ⁷ ), —S (= O) ) kN (R ⁷⁾ (R ⁸⁾ -C (= O) N (R ⁷⁾ (R ⁸⁾ -OC (= O) N (R ⁷⁾ (R ⁸⁾ - C (= O) ( R ⁵ ), -OC (= O) (R ⁵ ), -OC (= O) O (R ⁷ ), phenyl, -C (= O) N (R ⁷ HC 1 to C 4 alkyl), N (R ⁷ ) (R ⁸ ), -C (= O) N (R ¹² ) (R ¹³ ), -C (= O) - (C 1 -C ₄ alkyl) - N (R ⁷ ) C (= O) O (R ⁷⁾ ) C 1 -C ₄ alkoxy substituted with 0 to 4 groups independently selected from: -R ⁵ , C ₃ -C ₆ cycloalkyl, -C (= O) O (R ⁷ ), -C (= O) N (R ⁷ ) (R ⁸ ), -N (R ⁷ ) (R ⁸ ) or hydroxyl, C 1 -C ₄ alkyl substituted with 0 to 4 groups independently selected from: -R ^5, -N (R ⁸⁾ = NN (R ⁷⁾ C (= O) N (R ⁷⁾ (R ⁸⁾ or -N (R ⁷⁾ (R ⁸⁾ C ₂ to C ₄ alkenyl substituted with 0 to 4 R ⁵ , C ₂ to C ₄ alkynyl substituted with 0 to 4 R ⁵ , 5- to 6-membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen, C 3 to C ₄ carbon chain the other end is attached to the adjacent carbon atom on the ring and creates 5nebo membered ring which 5nebo 6-membered ring can be substituted at one of the aliphatic carbons with halogen, Ci to _C4 alkyl, Ci to C ₄ alkoxy, hydroxy, - N (R ⁷ ) (R ⁸ ), or when R ^{11 is} attached to a saturated carbon atom, R ¹¹ may be = O or = S, where k, R ⁵ , R ⁷ and R ⁸ are as defined above, wherein R ¹² is the same or different and represent hydrogen or Cl to _C3 alkyl, wherein R ¹³ is identical or different and represent -C (= O) N (R ⁷⁾ (R ⁸⁾ -C (= O) N (R ⁷⁾ NH (R ⁸⁾ -C (= O) C (R ⁵⁾ 2 N (R ⁷⁾ (R ⁸⁾ -C (= O) C (R ⁵⁾ 2 N (R ⁷⁾ NH (R ⁸⁾ - C (= O) C (R ⁵⁾ 2 N (R ⁷⁾ C (= O) (R ⁷⁾ -C (= O) H, -C (= O) (R ⁵⁾ -C (= O ) - (C 1 -C 4 alkyl) -N (R ⁷ ) (R ⁸ ), -C (= O) - (C ₁ -C ₄ alkyl) -, N (R ⁷ ) C (= O) O (R ⁷ ) or 1 to 3 amino acids linked by amide bonds to the nitrogen atom via carboxyl groups wherein R ⁵ , R ⁷ and R ⁸ are as defined above, wherein R ¹¹ , when it is a substituent on nitrogen, is different or the same and denotes phenyl, phenylmethyl, phenethyl, hydroxyl, C 1 -C ₄ hydroxyalkyl, C 1 -C _{4 4} alkoxy, Ci to C ₄ alkyl, C ₃ to C ₆ cycloalkyl, C ₃ to C ₆ cycloalkylmethyl, -CH ₂ N (R ⁷⁾ (R ^8), -N (R ⁷⁾ (R ⁸⁾ C ₂ to C ₆ alkoxyalkyl, C 1 -C ₄ haloalkyl, C 1 -C ₄ alkoxycarbonyl, -C (= O) OH, C 1 -C ₄ alkylcarbonyloxy, C 1 -C ₄ alkylcarbonyl or -C (R ⁸ ) = N-O (R ⁸ ) wherein R ⁷ and R ⁸ are as defined above, wherein Y is different or the same and denotes C 1 -C 10 alkanediyl substituted with 0 to 4 R ² groups; oligoethylene glycol or oligoethylene glycol substituted substituted with R ^2; or C 1 to C 10 cycloalkanediyl substituted with 0 to 4 R ² groups; —C (= O) -; —S (= O) k—; -P (= O) (OR ³⁾ -X-; -P (= O) (N (R ³⁾ (R ⁴⁾⁾ - CO--; -P (= O) (N (R ³⁾ (R ⁴⁾⁾ - CO--; —C (= O) —X—; - (CF 2) q -; phenylene substituted independently with 0 to 3 substituents R ¹⁴ , wherein k, q and R ³ are as previously defined, wherein R ² is different or the same and denotes hydrogen, -A, -X-A, -O (R ⁷ ), -S (R ⁷⁾ -N (R ⁷⁾ -C (= O) (R ^7), keto, Ci-C8 alkyl substituted with 0-3 ^R5, C2-Cg alkenyl substituted with 0-3 R ^5, phenyl, phenyl substituted independently with 0 to 5 substituents R ¹⁴ , phenylene substituted independently with 0 to 3 substituents R ¹⁴ , alkynyl substituted with 0 to 3 R ⁵ , C 1 to C 8 perfluoroalkyl, C ₃ to C ₁₄ carbocycle substituted with 0 to 3 R ⁵ or 0 or a 5 to 1 membered heterocycle containing from 1 to 3 R ⁶ ; -19GB 295245 B6 1-4 heteroatoms selected independently from oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0-2, oligoethylene glycol, R ⁶ wherein A, X, R ⁵ , R ⁶ , and R ⁷ are as defined above, wherein R ^{4 *} is different or the same and represent H, Ci-Cg alkyl substituted with 0-3 ^R10, C2-Cg alkenyl substituted with 0-3 ^R10, C2-Cg alkynyl substituted with 0-3 R ^10, and C ₃ to C] ₄ carbocyclic residue substituted with 0 to 5 R ¹⁰ or 0 to 5 R ¹¹ , or a 5- to 10-membered heterocycle containing 1 to 4 heteroatoms selected independently from oxygen, sulfur and nitrogen, or the same heterocycle substituted with 0 to 2 R ¹¹ , wherein R ¹⁰ and R ¹¹ are at the front in this claim hereinbefore defined, wherein Z is identical or different and denote hydrogen, a, -X-a, -C (= O) -X-a, -CH (OH) -X-a, -CH (NH ₂₎ -X-A, -NH-A, -NH-CH (OH) CH-NH-A, - S (= O) _-X-A, -O-P (= O) (OR ³⁾ - X-A —O — P (-O) (N (R ³ ) (R ⁴ )) - X — A, R ³ and C 1 -C 10 alkyl substituted with 0 to 4 groups us R ^2, wherein K, A, X, R ^2, R ³ and R ⁴ have the above in this claim above, and their pharmaceutically utilizable salts. HIV protease inhibitors according to claims 1 and 2 of the general formula II (RbnA1-X-Z) _m (II), wherein A, X, Z and R ¹ and m and n are as defined in the preceding claim, and their pharmaceutically usable salts. Compounds [(8-HO- (CH ₂ -CH ₂ O) 2-1,2-C ₂ B ₉ H ₁₀ ) (1 ', 2'-C ₂ B ₉ H ₁₁ ) -3,3'-Co] Na [ 8- (OH-1,2-C ₂ B ₉ H ₁₀ ) (1 ', 2'-C ₂ B ₉ H ₁₁ ) -3,3'-Co] Na.nH 2 O [8,8'-p -O- (C ₂ B ₉ H ₁₀ ) ₂ -3-Co] Na [(8- (HO) ₂ -P (O) Ol, 2-C ₂ B ₉ H ₁₀ ) - (1 ', 2' -C ₂ B ₉ Hi ₀ ) -3-Co] Na.nH ₂ O [(C ₂ B ₉ H _{) 0} ) ₂ -3-Fe] Na ₄ H ₂ O [(1,2-C ₂ B ₉ H) ₁₀ ) -3,3 '-Co (1', 2'-C ₂ B ₉ H ₁₁ ) -8- (OCH ₂ CH ₂ ) ₂ OCH (C ₆ H ₅ ) CH ₂ (C ₆ H ₅ ) ( OH)] Na [(1,2-C ₂ B ₉ H ₁₀ ) -3,3'-Co (1 ', 2'-C ₂ B ₉ Hi]) - 8- (OCH ₂ CH ₂ ) ₂ OCH (C ₆ H5) CH (C ₆ H ₅ ) (OCH ₂ CH ₂ ) ₂ -80- <r ', 2-C ₂ B ₉ H ₁₀ -3'',3'-Co (r, 2'-C ₂ B ₉ H ₁₁ )] Na ₂ [(1,2-C ₂ B ₉ H ₁₀ ) -3,3 ^, -Co (r, 2'-C ₂ B ₉ H ₁₀ ) -8,8'-p -NH-CH ₂ -CH (OH) -CH ₂ -8,8'-g-NH- (1,2C ₂ B ₉ H ₁₀ ) -3,3-Co (1 ', 2'-C ₂ B ₉ H, o)] a [3,3'-Co- (1 ', 2'-C ₂ B ₉ Hi ₁ ) (8-1,2-C ₂ B ₉ Hi ₀ - (O-CH ₂ -CH 2) 40 -) 8-1,2-C ₂ B ₉ H ₁₀ ) (1 ', 2'-C ₂ B ₉ H ₁₁ ) 3,3'-Co] Na ₂ . A process for preparing compounds [(1,2-C ₂ B ₉ H ₁₀ ) -3,3'-Co (1 ', 2 ^, -C ₂ B ₉ H ₁₁ ) -8- (OCH 2 CH 2) 2 OCH (C 6 H 5) CH 2 (C 6 H 5) (OH) )] Na a [(1,2-C2B9H10>-3,3'-Co (1 ', 2'-C2B9H11) -8- (OCH2CH2) 2OCH (C6H5) CH (C6H5) (OCH2CH2) 2-8-0 - (l, 2-C2B9H1o) ^-3,3, -CO (r, 2'-C2B ₉ H ₁ i)] Na ₂ according to claim 5, characterized in that the deprotonated hydrobenzoin weso-one Or two equivalents of NaH is treated at room temperature with a solution containing one or two equivalents of 8-dioxane-cobalt bis (dicarbollide) in toluene. 7. A process for preparing the compound [(l, 2-C ₂ B ₉ H ₁₀₎ -3,3'-Co (r, 2'-C2B9H ₁ o) -8,8'-p-NH-CH 2 -CH (OH) - CH ₂ -8,8 ^, -p-NH- (1,2-C ₂ B ₉ H ₁₀ ) -3,3'-Co (1 ', 2'-C ₂ B ₉ H ₁₀ )] according to claim 5, characterized by in that the substance [(l, 2-C ₂ B ₉ Hio) -3,3'-Co (r, 2'-C ₂ B9Hio) -8,8-pNH] deprotonated with NaH, and dissolved in diethyleneglycol dimethylether ( DME) is treated with epichlorohydrin at room temperature and the product is obtained by purifying the reaction mixture on a silica gel column. 8. A process for preparing a compound [3,3'-CO- (l \ 2 ' H C2B _9] |) (8-l, 2-C2B Hio- _{9 (0-CH2 -CH2)} 40-8L2 -C ₂ B ₉ Hi ₀ ) (1 ', 2'-C ₂ B ₉ Hii) -3,3'-Co] Na ₂ according to claim 5, characterized in that the substance [(8-HO- <CH _2)] -CH ₂ 0) ₂ -l, 2-C ₂ B ₉ Hio) ^(l, 2'-C ₂ B ₉ H _N) -3,3'-Co] Me3NH deprotonated with NaH, and dissolved in diethyleneglycol dimethylether treated at room 8-dioxan-cobalt bis (dicarbollide) and the product is obtained by purifying the reaction mixture on a silica gel column. Medicament for the treatment of AIDS, characterized in that it comprises at least one HIV protease inhibitor of the formula I according to claim 3 and / or of the formula II according to claim 4. A medicament for the treatment of AIDS, characterized in that it comprises at least one of the HIV protease inhibitors according to claim 5. 4 drawings