MXPA99007077A - Quinoxaline in triple combination with protease inhibitors and reverse transcriptase inhibitors as medicines for treating aids - Google Patents
Quinoxaline in triple combination with protease inhibitors and reverse transcriptase inhibitors as medicines for treating aidsInfo
- Publication number
- MXPA99007077A MXPA99007077A MXPA/A/1999/007077A MX9907077A MXPA99007077A MX PA99007077 A MXPA99007077 A MX PA99007077A MX 9907077 A MX9907077 A MX 9907077A MX PA99007077 A MXPA99007077 A MX PA99007077A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- amino
- hydroxy
- alkoxy
- chlorine
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title claims abstract description 17
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 title claims abstract description 15
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 title claims abstract description 12
- 229940079593 drugs Drugs 0.000 title abstract description 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N Quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title description 3
- 208000005721 HIV Infections Diseases 0.000 claims abstract description 10
- -1 trifluoromethoxy, hydroxy Chemical group 0.000 claims description 341
- 239000000460 chlorine Substances 0.000 claims description 112
- 229910052801 chlorine Inorganic materials 0.000 claims description 112
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 112
- 229910052731 fluorine Inorganic materials 0.000 claims description 112
- 239000011737 fluorine Substances 0.000 claims description 112
- 125000000217 alkyl group Chemical group 0.000 claims description 107
- 125000001153 fluoro group Chemical group F* 0.000 claims description 102
- 125000003545 alkoxy group Chemical group 0.000 claims description 86
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 73
- 125000004043 oxo group Chemical group O=* 0.000 claims description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 34
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 31
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 31
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 30
- 125000002252 acyl group Chemical group 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 24
- 229910052740 iodine Inorganic materials 0.000 claims description 22
- HBOMLICNUCNMMY-XLPZGREQSA-N Zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 20
- 239000011630 iodine Substances 0.000 claims description 20
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 150000003254 radicals Chemical class 0.000 claims description 18
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 15
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229960002555 Zidovudine Drugs 0.000 claims description 13
- 125000004414 alkyl thio group Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- JTEGQNOMFQHVDC-NKWVEPMBSA-N 4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2-dihydropyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 125000005110 aryl thio group Chemical group 0.000 claims description 8
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- 229940064914 Retrovir Drugs 0.000 claims description 7
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000001769 aryl amino group Chemical group 0.000 claims description 7
- BXZVVICBKDXVGW-NKWVEPMBSA-N ddIno Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 7
- 229960002656 didanosine Drugs 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 6
- 125000005125 aryl alkyl amino carbonyl group Chemical group 0.000 claims description 6
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 6
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 6
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- WREGKURFCTUGRC-POYBYMJQSA-N ddC Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 229960000523 zalcitabine Drugs 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 229940072253 Epivir Drugs 0.000 claims description 5
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 102000033147 ERVK-25 Human genes 0.000 claims description 4
- NCDNCNXCDXHOMX-XGKFQTDJSA-N Ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbamate Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 229960000311 ritonavir Drugs 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 229960001627 Lamivudine Drugs 0.000 claims description 3
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- NJBBLOIWMSYVCQ-OKHMJZBSSA-N (4R)-N-tert-butyl-3-[2-hydroxy-3-[[(2R)-2-[(2-isoquinolin-5-yloxyacetyl)amino]-3-methylsulfanylpropanoyl]amino]-4-phenylbutanoyl]-1,3-thiazolidine-4-carboxamide Chemical compound O=C([C@@H](NC(=O)COC=1C2=CC=NC=C2C=CC=1)CSC)NC(C(O)C(=O)N1[C@@H](CSC1)C(=O)NC(C)(C)C)CC1=CC=CC=C1 NJBBLOIWMSYVCQ-OKHMJZBSSA-N 0.000 claims description 2
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 2
- HVKXNVXQUMOOJU-UHFFFAOYSA-N 1,3-thiazolidine-3-carboxamide Chemical compound NC(=O)N1CCSC1 HVKXNVXQUMOOJU-UHFFFAOYSA-N 0.000 claims description 2
- WKVDSZYIGHLONN-RRKCRQDMSA-N 5-chloro-1-[(2R,4S,5R)-4-fluoro-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound C1[C@H](F)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Cl)=C1 WKVDSZYIGHLONN-RRKCRQDMSA-N 0.000 claims description 2
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 2
- 108010092799 EC 2.7.7.49 Proteins 0.000 claims description 2
- 229960001203 Stavudine Drugs 0.000 claims description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims description 2
- 229960004748 abacavir Drugs 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000005225 alkynyloxycarbonyl group Chemical group 0.000 claims description 2
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000004429 atoms Chemical group 0.000 claims description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
- 125000005222 heteroarylaminocarbonyl group Chemical group 0.000 claims description 2
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 claims description 2
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- KKSZSACCVDIWIE-UHFFFAOYSA-N isoquinoline-3-carboxamide Chemical compound C1=CC=C2C=NC(C(=O)N)=CC2=C1 KKSZSACCVDIWIE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 238000005065 mining Methods 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002829 nitrogen Chemical class 0.000 claims description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 2
- 229910052711 selenium Inorganic materials 0.000 claims description 2
- 239000011669 selenium Substances 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 claims description 2
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical class N1=C(C=NC2=CC=CC=C12)* 0.000 claims 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- BFBANPSMOLPPCN-UHFFFAOYSA-N 1-amino-1,6-diphenylhexan-3-ol Chemical compound C=1C=CC=CC=1C(N)CC(O)CCCC1=CC=CC=C1 BFBANPSMOLPPCN-UHFFFAOYSA-N 0.000 claims 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 claims 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical group C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims 1
- CZQZNHUZXWMRIJ-NSHDSACASA-N N1[C@@H](CCCC1)C(=O)NSC1=CC=CC=C1 Chemical compound N1[C@@H](CCCC1)C(=O)NSC1=CC=CC=C1 CZQZNHUZXWMRIJ-NSHDSACASA-N 0.000 claims 1
- 231100000765 Toxin Toxicity 0.000 claims 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 1
- 125000004948 alkyl aryl alkyl group Chemical group 0.000 claims 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical group ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
- 239000003053 toxin Substances 0.000 claims 1
- 206010000565 Acquired immunodeficiency syndrome Diseases 0.000 abstract description 16
- 150000003252 quinoxalines Chemical class 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 description 30
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- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 description 3
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- CBVCZFGXHXORBI-PXQQMZJSSA-N Indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 3
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- 125000005842 heteroatoms Chemical group 0.000 description 3
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- 230000001988 toxicity Effects 0.000 description 3
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- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 2
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- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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Abstract
The invention relates to the use of quinoxalines in triple combination with protease inhibitors and reverse transcriptase inhibitors as medicines for treating AIDS and/or HIV infections.
Description
USE OF QUINOXALINES IN TERNARIAL COMBINATIONS WITH
PROTEASE INHIBITORS AND INHIBITORS OF
REVERSE TRANSCRIPT AS A MEDICATION FOR THE
TREATMENT OF IMMUNODEFICIENCY SYNDROME
ACQUIRED (AIDS) AND / OR INFECTIONS FOR HUMAN IMMUNODEFICIENCY VIRUSES (HIV).
Field of Invention
The present invention relates to the use of quinoxalines in ternary combinations with protease inhibitors and reverse transcriptase inhibitors as a medicament for the treatment of AIDS and / or HIV infections.
Background of the Invention
The human immunodeficiency virus (HIV) causes a persistent and progressive chronic disease. HIV destroys the immune system (acquired immunodeficiency syndrome, AIDS) and the central and peripheral nervous system. In addition, the HIV virus also causes multiple other clinical manifestations in the morbid picture of ARC / AIDS - in particular,
Ref: 030972 opportunistic infections (I.O.), caused by other viruses, such as, for example, herpes virus (HSV I and II), cytomegalovirus (CMV) or I. O. caused by bacteria, fungi or parasites.
HIV belongs to the family of retroviruses; One of the fundamental enzymatic activities essential in the reproduction cycle of these viruses is the protease (Huff, J.R., J. Med. Chem. (1991), 34, 2305-2314). Analogous substances of small peptide or non-peptidic molecules of the natural substrates of the protease inhibit HIV replication (Roberts, NA et al., Science (1990) 248, 358-361; Lam, PYS et al., Science (1994), 263, 380-384) in vitro and in vivo.
Analogous substances from the natural substrates of reverse transcriptase, such as azidothymidine (AZT), dideoxy cytidine (DDC), dideoxyinosine (DDI) and 3 '-thia zi tidine (lamivudine), inhibit HIV replication in vitro and in vitro. alive. AZT serves, for example, for the treatment of patients with ARC / AIDS. The long-term therapy of HIV-infected patients with AZT leads, however, to a marrow toxicity; In addition, isolates of AZT-resistant virus are generated. It has been described in some patients who have been treated with DDC or DDI, for example, intolerances, such as, for example, a peripheral neuropathy. Therefore, new inhibitors are needed for tolerable and effective therapy.
Description of the invention
The ternary combination, now found, of quinoxalines with protease inhibitors and reverse transcriptase inhibitors is new and its synergistic effect on the reproduction of HIV when used to fight AIDS or AIDS infections.
HIV is much better than the state of the art.
It has now been found that the quinoxalines of the general formula (I)
as well as the tautomeric forms thereof of general formula (la)
where 1) n means zero one, two, three, or four, the various substituents signify R 1 independently of one another, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethyl, trifluoromethoxy, hydroxy, C?-C8 alkyl, C5-C8 cycloalkyl, C6-C6 alkoxy (C6-C6 alkoxy) - (C? -C-alkoxy), C? -C6-thio alkyl, Ci- C-sulfinyl-alkyl, C -C6-sul alkyl fonyl, nitro, amino, azido, alky1-Ci-C-amino, di (alkyl-Ci-Cd) -amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, acyl C ? - Cs, a cil -Ci-Ce-oxy, acyl- Ci-Cd-ano, cyano, carbamoyl, carboxy, (alkyl-Ci-Cß) -oxi carbonyl, hydrosulphonic, sulfamoyl
a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenylsulfinyl, phenylsul fonyl, phenoxysulfonyl, phenylsul phonoyloxy, anilinosulphonyl, phenylsulphonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radicals substituted by up to five R6 radicals independent of each other, R6 denotes fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, t-riflumethyl toxy, nitro, amino, azido, C? -Cg alkyl, C3-C8 cycloalkyl, C? -C6 alkoxy, alkyl-Ci-C? -thi or, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl alkyl, C 1 -C 6 alkylamino, di (C 1 -Ci) alkylamino, (C 1 -C 5 alkyl) -oxycarbonyl, phenyl, phenoxy, 2-pyridyl, 3-pyridyl or 4-pyridyl, R 'hydrogen, C 1 -C 6 alkoxy, hydroxy, picolyl, cyclopropyl or i-sopropenyloxycarbonyl and R- hydrogen, hydroxy, Ci-Cß alkoxy, aryloxy, acyl-Ci-Cd -oxi, cyano, amino, alkyl-Ci-Ce-amino, di (al-Ci-Ci) -amino, arylamino, acyl-Ci-Cg-amino, C 1 -C 7 alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Ci-Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy C: -C6, alkyl-Ci-Ce-amino, di (alkyl-Ci-Cg) -amino, alkyl-C? -C6-thio alkyl-Ci-Cg-sulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; alkenyl C2-Ca / optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl -C? -Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy C? ~ Cg, al qui 1 -C? -Cg-amino, di (alky1-C? -Cg) -amino, to the quil-Ci-Cg-thio, alkyl-Ci-Cß-sulfonyl, pheni 1 s ul foni 1 o, oxo, thioxo, carboxy, carbamoyl; C3-C8 alenyl, optionally substituted by frucor, chloro or hydroxy, C? -C alkoxy, oxo, phenyl; C3-C8 alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Cx-Cg-oxy, benzoylcyan, benzylsi, phenoxy, C alco-Cß alkoxy, alkyl-Ci- Cg-amino, (alkyl-Ci-Cg) -amino, alkyl-Ci-Cg-thio, to which 1-C? -CG-sulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl;
Cs-Cs cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Ci-Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy C? -Cd, alky1-C -Cg-amino, di (alkyl-Ci-Cg) -amino, the quyl -C: -Cg-thio, alkyl-Ci-Cg-sulfonyl, phenyl-1-phonyl, oxo, thioxo, carboxy, carbamoyl; C3 ~ C8 cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-C? -Cg-oxy, benzoyloxy, benzyloxy, phenoxy, C1-C alkoxy, C1-Ci- Cg-amino, di (alkyl-Ci-Cg) -amino, alkyl-C? -Cg-thio, alkyl-Ci-C-sulfonyl, phenyl-sulphonic, oxo, thioxo, carboxy, carbamoyl; (C 3 -C 8 cycloalkyl) - (C 1 -C 4 alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Ci-Cg-oxy, benzoyloxy, benzyloxy, phenoxy , alkoxy Ci-Cg, alkyl-Ci-Cg-amino, di (alkyl-Ci-C6) -amino, alkyl-C? -Cg-thio, alkyl-Ci-Cg-sulfonyl, phenylsul fonyl, oxo, thioxo, carboxy , carbamoyl; (C3-C8 cycloalkenyl) - (C1-C4 alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-C? -Cg-oxy, benzoyloxy, benzyloxy, phenoxy , alkoxy Ci-Cg, alkyl-Ci-Cg-amino, di (alkyl-C: -Cd) -amino, alkyl-Ci-Cg-thio, alkyl-C-C-sulphonyl, phenylsul fonyl, oxo, thioxo, carboxy , carbamoyl; alkyl-Ci-Cg-carbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Ci-Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy Ci-Cg, alkyl- Ci-Cg-amino, di (C 1 -C 6 alkyl) -amino, alkyl-Ci-Cg-thio, alkyl-Ci-Cg-sulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; alkenyl-C2-C8-carbonyl, optionally substituted by fluorine, chlorine or hydroxy, C4-C4 alkoxy, oxo, phenyl; (C3-C8-cycloalkyl) -carbonyl, optionally substituted by fluorine, chlorine or hydroxy, Ci-C4 alkoxy, oxo, phenyl; (C5-C8 cycloalkenyl) -carbonyl, optionally substituted by fluorine, chlorine or hydroxy, C, C, oxo alkoxy, phenyl; (C3-C8 cycloalkyl) - (C 1 -C 3 alkyl) -carbonyl, optionally substituted by fluorine, chlorine or hydroxy, C 1 -C alkoxy, oxo, phenyl;
(C5-C6 cycloalkenyl) - (C 1 -C 3 alkyl) -carbonyl, optionally substituted by fluorine, chlorine or hydroxy, C 1 -C 6 alkoxy, oxo, phenyl; alkyl-C? -C6-oxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, C? -C4 alkoxy, C? -C4-amino alkyl, di (alkyl-Ci-C) -amino, alkyl-? C? -C4-thio; alkenyl-C2-C8-oxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C13 alkoxy, oxo, phenyl; C2-C8 alkynyl-oxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy, oxo, phenyl; C 1 -C 8 alkylthiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C 1 -C 4 alkoxy, oxo, phenyl; alkeni 1 -C 2 -C 8 -thiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C 1 -C alkoxy, oxo, phenyl; C 1 -C 8 -aminocarbonyl alkyl and di (C 1 -C 8 alkylamino) -aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C 1 -C 4 alkoxy, oxo, phenyl; pyrrolidin-1-yl, morpholinecarbonyl, piperidincarbonyl, peperazinylcarbonyl or 4-methyl-piperazin-1-ylcarbonyl or, optionally substituted by C1-C4 alkyl, alkenyl Cc-Cg, C1-C4 acyl, oxo, thioxo, carboxy or phenyl; alkenyl-C2-C8-aminocarbonyl and di (alkenyl-Ci-C3) -aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy, oxo, phenyl; alkyl-Ci-Cg-sulfonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy, oxo, phenyl; alkenyl-Ci-Cg-sulphonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy, oxo, phenyl; or aryl, arylcarbonyl, aryl (thiocarbonyl), (arylthio) carbonyl, (arylthio) thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl,
(arylamino) thiocarbonyl, arylalkylaminocarbonyl, aryl sulfonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl or, aryl (alkylthio) carbonyl substituted by up to five independent R6 radicals in each casewherein the alkyl moiety may contain 1 to 5 carbon atoms, respectively, and R ° being defined as above, or teroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl (heteroarylthio) carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl, heteroaryl ( alkylthio) carbonyl, heteroarylalkylaminocarbonyl, wherein the alkyl radical may contain 1 to 3 carbon atoms, respectively, R3 and R4 being the same or different, independently of one another, hydrogen, C? ~C alquilo alkyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto, acyl-C1-C4-0XI, benzoyloxy, benzyloxy, phenoxy, C1-C4 alkoxy, alkyl-C? -C4-amino, di (alkyl-Ci- C4) -amino, alkyl-C1-C4 -thio, alkyl -C1-C4-sulfonyl, alkyl-C? -C4-sulfinyl, carboxy, carbamoyl; C2-C8 alkenyl, optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyl-C1-C4-OXI, benzoyl, benzyloxy, phenoxy, C1-C4 alkoxy, alkyl-C? -C4-amino, di ( C 1 -C 4 alkyl) amino, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkyl sulfinyl, carboxy, carbamoyl; C3-C8 cycloalkyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto, acyl -C1-C4-oxy, benzoyl, benzyloxy, phenoxy, C1-C4 alkoxy, alkyl-C? -C4-amino, di ( alkyl-C 4 -C 4) -amino, C 1 -C 4 alkyl-thio, C 1 -C 4 alkyl sulfonyl, C 1 -C 4 alkyl sulphinyl, carboxy, carbamoyl; C3 ~ C8 cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto, acyl-C? -C4-oxy, benzoyloxy, benzyloxy, phenoxy, C1-C4 alkoxy, alkyl-C? -C4-amino, di (C 1 -C 4 alkyl) -amino, C 1 -C 4 -C 1 alkyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy, carbamoyl; aryl, arylalkyl, heteroaryl or heteroarylalkyl substituted by up to five R6 radicals independent of each other, the alkyl moiety may contain 1 to 3 C atoms, respectively, and R6 being defined as above, R4 may also be part of a saturated cyclocarbocyl or heterocyclic or unsaturated with 3 to 8 C atoms, which may be substituted, if appropriate, by fluorine, chlorine, hydroxy, amino, Ci-Cg alkyl, C2-Cg alkenyl, Ci-Cg alkynyl, acyl-Ci-Cg-oxy, benzoyloxy, C alco-Cg alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl, X means oxygen, sulfur, selenium or substituted nitrogen NR ", R-having the meanings mentioned above, in combination with protease inhibitors and inhibitors of t ranscript reverse handle are very suitable to be used as a medicine to fight AIDS and HIV infections.
The alkyl groups indicated in the definitions set forth above may be straight or branched chain. If not defined otherwise, they preferably contain 1-8, particularly preferably 1-6, in particular 1-4 carbon atoms. Examples are the methyl, ethyl, propyl, 1-methyl, butyl, 1-methylpropi group. 1 or, 2-methylpropyl, 1,1-dimethyl and the like.
The alkenyl groups indicated in the definitions set forth above may be straight or branched chain and contain 1 to 3 double bonds, if not defined otherwise, these groups preferably contain 2-8, in particular 2-6 C atoms. are the 2-propenyl, 1-methyl t-tyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-bu tyl, 2, 3-dimethyl group -2-butenyl, 3, 3-dichloro-2 -propene, pentadienyl and the like.
The alkynyl groups indicated in the definitions set forth above may be straight or branched chain and contain 1 to 3 triple bonds. If not defined otherwise, they preferably contain 2-8, particularly preferably 3-6 carbon atoms. Examples are the 2-propynyl and 3-butynyl group and the like.
The cycloalkyl and cycloalkene groups indicated in the definitions set forth above contain, if not otherwise defined, preferably 3-8, particularly preferably 4-6 carbon atoms. Examples are the cyclopropyl, cyclobutyl, cyclopenyl, cycloalkyl group. clopenteni 1, cyclohexyl or cyclohexenyl.
The acyl groups indicated in the definitions set forth above may be aliphatic, cycloaliphatic or aromatic. If not defined otherwise, they preferably contain 1-8, particularly preferably 2-7 C atoms. Examples for acyl groups are the formyl, acetyl, chloroacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, isobutyryl, pivaloyl group , cyclohexanoyl or benzoyl.
The aryl groups indicated in the definitions set forth above are preferably aromatic groups with 6-14 C atoms, in particular with 6-10 C atoms, such as, for example, phenyl, naphthyl.
In the above-mentioned heterocyclic groups or heteroaryl groups they are considered as heteroatoms in particular, for example, O, S, N, existing in the case of a cycle containing saturated N in this NZ place, meaning Z, H or R5 with the definitions corresponding above.
If not defined otherwise, the heterocyclic rings preferably have 1-13 C atoms and 1-6 heteroatoms, in particular 3-9 C atoms and 1-4 heteroatoms.
For the heteroaryl groups indicated in the definitions set forth above, for example, heteroaromatic radicals, such as 2-thienyl or 3-thienyl, 2-furyl or 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrimidyl, indolyl, quinolyl or isoquinolyl.
The aralkyl groups listed in the definitions set forth above are, for example, benzyl, phenylethyl, naphthylmethyl or is tiryl.
The abovementioned substituents R1 to R5 are preferably substituted three times, more preferably twice, in particular once by the corresponding substituents indicated.
For definitions of compound substituents (such as, for example, arylalkoxy carbonyl), the margins described above are also preferable as preferred for the different substituents.
Depending on the different substituents, the compounds of the formulas I and can contain several asymmetric carbon atoms.
Therefore, both the pure stereoisomers and mixtures thereof, such as, for example, the corresponding racemate, are subject of the invention.
The pure stereoisomers of the compounds of the formulas I and can be manufactured directly or subsequently separated by known methods or analogously to known methods.
The compounds of the formulas I and I can be manufactured according to known methods or modifications thereof (see, for example, Rodd's Chemistry of Carbon Compounds, S. Coffey, M. F. Ansell (ed.): Elservier, Amsterdam, 1989;
volume IV, part IJ, page 301-311. Heterocyclic Compounds, R. C. Elderfield (editor); Wiley, New York, 1957; volume 6, page 491 - 495).
In the context of the invention, protease inhibitors correspond to substances analogous to known peptides of different structures, which are suitable for the treatment of diseases induced by retroviruses.
In particular, they can be indicated
1. ) Acid 2, 4, 7, 12 - 1 et raaza t ridecan- 13 -oico, 10-hydroxy-2-methyl-5- (1-methyl-ethyl) -1- [2- (1-methylethyl) -4 -thiazolyl] -3,6-dioxo-8,11 -bis- (phenyl-methyl) -, 5-1-aiazolylmethyl ester co [5S- (5R *, 8R *, 10R *, 11R *)]; PCT WO 95/07696; PCT WO 95/20384 Al; PCT WO 95/009614 Al [ABBOTT (Ritonavir) ABT-538]
3-isoquinolinecarboxamide, N- (1, 1-dimethyl tile) decahydro-2- [2-hydroxy-3- [(3-hydroxy-2-methylbenzoyl) amino] -4 - (phenylthio) butyl] -3S-] 2- (2S *, 3S *), 3. alpha., 4a. beta., 8a. beta.]] -, monoethanesulfonate (salt); PCT WO 95/09843; US 5484926; [AGOURON (Viracep®) AG-1343]
Carbamic acid, [3 - [[(4-aminophenyl) sulfonyl]]
(2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S- [3R * (ÍS *, 2R *)]] -; PCT WO
94/05639; [VÉRTEX PHARM. (Kisseii, Glaxo
Wellcome), VX-478]
(S) -N- [(alphaS) -alpha- [(lR) -2- [((3S, 4aS, 8aS) -3- (butyl tere. -carbamoyl) octahydro-2 (ÍH) • isoquinolinyl) -1 -hydroxyethyl) phenethyl-2-quinaldamido] -succinamide (EP 432 695 A2)
2 (R) -benzyl-5- (2 (S) - (N-butyl tere. -carbamoyl) -4- (3-pyridylmethyl) piperazin-1-yl) -4 (S) -hydroxy-N- (2 (R) -hydroxyindan-1 (S) -yl) pentanamide (L-735524, EP 569 083 Al, EP 541 168 Al)
N- (quinolin-2-ylcarbonyl) -aspargin-1 (S) -benzyl-3- (3-butyl tere. -1-iso-butylureido) -2 (R) -hydroxypropylamide (SC 52 151, PCT WO 92 / 08688 Al, WO 92/08699 Al, WO 92/08698 Al, WO 92/08701 Al, WO 92/08700 Al)
NI- (2R-hydroxy-3- ((3-methylbutyl) methylsulfonyl) amino) -IS- (phenyl-methyl) propyl) -2S- ((2-quinolinylcarboni 1) -amino) butanediamide (AM 11 686, PCT WO 94/04492)
2S, 3S, 5S) -5 (N- (N- ((N-methyl-N- ((2-isopropyl-4-oxazolyl) methyl) amino-carbonyl) val ini 1) amino) -2- (N- ((5-thiazolyl) methoxy carbonyl) amino-1,6-diphenyl-3-hydroxyhexane (A 84 538, PCT WO 94/14436)
(R) -N-butyl tere. -3- ((2S, 3S) -2-hydroxy-3-N- ((R) -2-N- (isoquinolin-5-yl-oxyacetyl) amino-3-methyl thiopropanoyl) -amino-phenylbutanoyl) -5, 5-dimethyl-l, 3-thiazolidin -carboxamide (KNI 272 / Nippon Mining)
Tetrahydrofuran-3-yl ester of the acid. { 3 [(4-amino-benzenesulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxy-propyl} -carbamic
(3S, 6R) -3 - (- ethylbenzyl) -6 - (- ethylphenethyl) -4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 9411361)
12. ) N- [5-L- [N- (2 -quinol inc to rbonyl) -L- asparaginyl] amino- (4R, 3S) -epoxy-6-phenyl-hexanoyl] -isoleucine (EP 601 486 A)
13. ) N-butyl tere. -1- [2- (R) -hydroxy-4-phenyl) -3 (S) - [[N- (2-quinolinyl carbonyl) asparaginyl] amino] butyl-4 (R) (phenyl) piperidin-2 ( S) -carboxamide (EP 560 268 A)
[3, '' S- (3 '' 'R *, 4' ', S *)] - N- [l'-oxo-l * - (3'- [l' "- oxo-2 '" - aza-3"'-phenyl -met i 1 -4' '' -hoxyroxy-5 '' '- (2' '' - N -butyl tere, carbamido) phenyl] pentyl-4" -methyl) -1, 2, 3, 4 -tetrahydroisoquinoline (EP 609 625 A)
2- [2-hydroxy-3- (-hydroxy-2-methyl-benzoylamino) -4-phenylsulfamyl-butyl] -decahydro-isoquinoline-3-carboxylic acid ester. butylamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA)
16. ) 2H-1,4-diazepil-2-one, hexahydro-6-hydroxy-1,3,4,7-tetrakis (phenyl-methyl) -, [3S '- (3. alpha., 6. beta., 7. beta.)] (PCT WO 94/08977)
OH
In the context of the invention, the reverse transcriptase inhibitors correspond to different nucleosides. Preferred are zidovudine (Retrovir) AZT), didanosine (DDI), dideoxyitidine (DDC), Lamivudine (Epivir, 3-TC®), Stavudine (D4T), BW 935U83, BW 1592U89; in particular zidovudine and Epivir. The indicated nucleosides can be prepared according to generally known procedures (see Merck Index, 11th edition Rahway, NJ 1989, Drugs 45 (4), 488 et seq., 45 (5), 637 et seq., 1993, Drugs 44 (4), 656 and following, 1992, Clin. Pharmacol.Ther.55, No. 2, 198, 1994, Anti viral -Chem.Chemmother.2, No. 3, 125-32, 1991, Anti Viral -Res T. 23, Suppl. 1, 67, 1994, Abstracts of the 34th ICAAC, Orlando 4.-7.10.94). It is especially preferable to use Retrovir (AZT).
Preferably quinoxalines of the formulas (I) and (Ia) are used, where n means zero, one or two, the different substituents means independently R 1 fluoro, chloro, bromo, trifluoromethyl, hydroxy, C 1 -C 4 alkyl , C 1 -C 4 alkoxy, (C 1 -C alkoxy) - (C 1 -C 4 alkoxy), C 1 -C 1 alkyl, nitro, amino, di (C 1 -C 4 alkyl) -amino, piperidino, morpholino, 1- pyrrolidinyl, 4-methylpiperazinyl, C 1 -C 4 acyl, C 1 -C 4 acyloxy, acyl C 4 -C 4 amino, cyano, carbamoyl, carboxy, (C 1 -C 6 alkyl) oxycarbonyl, hydroxy sul fonilo, sulfamoilo
a phenyl, phenoxy, phenylthio, phenylsul fonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two R6 radicals independent of each other, R6 being able to mean fluorine, chlorine, bromine, cyano, ilo, nitro, amino, alkyl
C1-C4, (C 1 -C 4 alkyl) -oxycarbonyl, phenyl, phenoxy, R 'hydrogen and R * C 1 -Cg alkyl, optionally substituted by fluorine, chlorine, hydroxy, acyl -C?-C4-oxy , benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, alkyl-Ci-Cinylamino, di (C 1 -C 4 alkyl) -amino, C 1 -C 4 -alkyl, oxo, thioxo, carboxy, carbamoyl; C2-Cg alkenyl, optionally substituted by fluorine, chlorine, hydroxy, acyl -C1-C4-OXI, benzoyloxy, benzyloxy, phenoxy, C-C4 alkoxy, C 1 -C 4 -alkylamino, di (at 1 qu -C1-C4 -amino, di (alkyl-C1-C) -amino, C 1 -C 4 -alkyl or, oxo, thioxo, carboxy, carbamoyl, C3-C8-alenyl, C3-Cs alkynyl, optionally substituted by fluorine, chlorine, hydroxy, acyl-Ci-C4-0XI, benzoyloxy, benzyloxy, phenoxy, C1-C4 alkoxy, alkyl-C? -C4-amino, di (C1-C) alkylamine, alkyl-C C4-thio, oxo, thioxo, carboxy, carbamoyl, C-C-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkyl, acyl-C? -C4-oxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) -amino, alkyl, -C 1 -C 4 -thio, oxo, thioxo, carboxy, carbamoyl; C 3 -C 8 cycloalkenyl, given the case substituted by fluorine, chlorine, hydroxy, C1-C4 alkyl, acyl-C? -C4-oxy, benzoyloxy, benzyloxy, phenoxy, C1-C4, alkyl-C? -C4-amino, di (alkyl-C? -C4) ) -amino, to whom 1 -C1-C4-1 io, oxo, thio x, carboxy, carbamoyl; (C3-C6-cycloalkyl) - (C1-C2alkyl), optionally substituted by fluorine, chlorine, hydroxy, C1-C4alkyl, acyl -C1-C4 -oxi, benzoyloxy, benzyloxy, phenoxy, C4-C4 alkoxy, to the quyl -Ct.-C4-amino, di (alkyl-C? -C4) -amino, to the quyl -C1-C-thio, oxo, carboxy, carbamoyl; (C3-C6cycloalkenyl) - (C? -C2 alkyl), optionally substituted by fluorine, chlorine, hydroxy, C? -C4 alkyl, acyl-C? -C4-oxy, benzoyloxy, benzyloxy, phenoxy, C-alkoxy 1- C, alkyl-C1-C-amino, di (alkyl-Ci-C) -amino, alkyl-C? ~ C4-1io-oxo, thioxo, carboxy, carbamoyl; alkyl-Cx-Cg-carbonyl, optionally substituted by fluorine, chlorine, hydroxy, C 1 -C alkyl, aci 1 -Ci -C 4 -oxi, benzoyloxy, benzyloxy, flenoxy, C 1 -C 4 alkoxy, C 1 alkyl- C4-amino, alkenyl -C? -C4-amino, di (C? -C4 alkyl) -amino, 1-pyrrolidinyl, piperidini, morpholino, 4-methylpiperazin-1-yl, alkyl-C? -C4-thi or , oxo, thioxo, carboxy, carbamoi lo; alkenyl -C2-Cg-carbonyl, optionally substituted by fluorine, chlorine or hydroxy; (Cycloalkyl-Cs-Ce) -carbonyl, (cycloalkenyl -Cs-Cg) -carbonyl, (C3-Cg cycloalkyl) - (al qui 1-C? -C2) -carbonyl, (C5-C6 cycloalkenyl) - ( alkyl-C? -C2) -carbonyl alkyl-Ci-Cg-oxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, C1-C4 alkoxy, alkyl-C? -4-amino, di (al-Cyl) : ~ C4) -amino, alkyl -C? ~ C4 -thio; alkenyl-C2-Cg-oxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, Ci-C4 alkoxy; C2-Cg-oxycarbonyl alkynyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy; alkyl-Ci-Cg-thiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C 1 -C 4 alkoxy; alkenyl-C2-C6-thiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C? -C4 alkoxy; alkyl-Cx-Cg-a -carbonyl and di (alkyl-Ca-Cg) -aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C 1 -C 4 -alkoxy; pyrrolidin-1-yl, morpholinecarbonyl, piperidincarbonyl, piperazinylcarbonyl or 4-methyl-pipera cin-1-ylcarbonyl; alkenyl-C2-C-aminocarbonyl and di (alkenyl-C? -Cg) -aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy; alkyl-Ci-C4-sulphonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy; alkenyl-C? -C4-sulfonyl; or aryl, aricalbonyl, (aryl thio) carbonyl, aryloxycarbonyl, arylaminocarbonyl,
(aryl ino) thiocarbonyl, aryl sulfonyl, arylalkylaminocarbonyl, arylalkyl, arylalkenyl, arylalkylcarbonyl, arylalkoxycarbonyl, aryl (alkyl) carbonyl substituted by up to five R6 radicals independent of each other, the alkyl moiety may contain 1 to 3 C atoms, respectively, and defined Rc as above, or 1- or 2-naphthylmethyl, 2-, 3- or 4-p-colyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3 - or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-t-ienylacetyl, 2-, 3- or 4-pi coli loxycarbonyl, 2- or 3-furyl and thioxycarbonyl or, 2- or 3-thienylmethyloxycarbonyl, and R3 and R4 being the same or different, independently of one another hydrogen, C?-C4 alkyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto, acyl -C? -C4-oxy, benzoyloxy, phenoxy, C1-C4 alkoxy, alkyl-C? -C-amino / di (alkyl-C? -C4) -amino, alkyl-C1-C4-1, alkyl -C1-C4- sulf onyl, alkyl -C1-C-sulfinyl, carboxy, carbamoyl; C2-C3 alkenyl, optionally substituted by fluorine or chlorine; C3 ~ C cycloalkyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto, acyl-C? -C4-oxy, benzoyloxy, benzyloxy, phenoxy, C1-C4 alkoxy, alkyl-C? -C4-amino, di (C 1 -C 4 alkyl) -amino, C 1 -C 4 alkyl, 1C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, carboxy, carbamoyl; C3-C8 cycloalkenyl, optionally substituted by fluorine or chlorine; aryl, benzyl, heteroaryl or heteroarylmethyl substituted by up to two radicals R < independent of each other, R3 and R4 can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 C atoms, which may be substituted, if appropriate, by fluorine, chlorine, hydroxy, amino, acyl -C1 -C 4 -oxi, benzoyloxy, C 1 -C 4 alkoxy, oxo thioxo, carboxy, carbamoyl, and X means oxygen or sulfur, optionally in an isomeric form, in combination with protease inhibitors of the series: acid 2, 4, 7 , 12 -tetratriazidemide- 13 -oic acid, 10-hydroxy-2-methyl-5- (1-methyl-ethyl) < <9-1 - [2- (1-methylethyl) -4-thiazolyl ] -3,6-dioxo-8, 11-bis- (phenyl-methyl) -, 5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)]; -isoquinolinecarboxamide, N- (1,1-dimethylethyl) decahydro-2- [2-hydroxy-3- [(3-hydroxy-2-methylbenzoyl) amino] -4 - (phenylthio) butyl] - [3S- [2- (2S *, 3S *), 3. alpha, 4a beta., 8a bet a.]] -, monoet anosul phona to (salt), carbamic acid, [3- [[(4-aminophenyl) sulfonyl] (2-methylpr opyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3 S - [3 R *, (1 S *, 2R *)]] -; (S) -N [(alphas) -alpha- [(IR) -2- [((3S, 4aS, 8aS) -3- (butyl tere. -carbamoyl) -octahydro-2 (ÍH) -isoquinolinyl) -1 -hydroxyethyl) phenethyl-2-quinaldamido] -succimamide 2 (R) -benzyl-5- (2 (S) - (-butyl tere. -carbamoyl) -4- (3-pyridylmethyl) piperazin-1-yl) - 4 (S) -hydroxy-N- (2 (R) -hydroxyindan-l (S) -yl) pentanamide 6.) N- (quinolin-2-ylcarbonyl) -asparagine-1 (S) -benzyl-3- ( 3-butyl tert-1-iso-butylureido)
2 (R) -hydropropylamide 7.) NI- (2R-hydroxy-3- ((3-methylbutyl) methylsulphyl) amino) -lS- (phenylmethyl) propyl) -2S ((2-quinolinylcarbonyl) -amino) ) butanedi amide 8.) (2S, 3S, 5S) -5 (N- (N-methyl-N- ((2-isopropy 1,4-oxazolyl) methyl) amino) -carbonyl) valinyl) amino) - 2- (N - ((5-thiazolyl) methoxycarbonyl) amino-1, β-diphenyl-3-hydroxyhexane 9.) (R) -N-butyl tere. -3- ((2S, 3S) -2-Hydroxy -3-N- ((R) -2-N- (isoquinolin-5-ylxyacetyl) amino-3-methyl thiopropanoyl) -amino-4-phenylbutanoyl) -5 , 5-dimethyl-l, 3-ti to zolidin-4-carboxyamide 10.) tetrahydrofuran-3-yl ester of the acid. { 3- [(4-amino-benzenesulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxy-propyl} -carbamic 11.) (3S, 6R) -3- (-ethyl-benzyl) -6- (-ethyl-phenethyl) -4-hydroxy-2H-pyran-2-one 12.) N- [5-L- [N- (2- quinolinecarbonyl) -L- asparaginyl] amino- (4R, 3S) -epoxy-6-phenyl-hexanoyl] -isoleucine 13.) N-butyl tere. -1- [2 - (R) -hydroxy-4-phenyl) -3 (S) - [[N- (2-quinolinylcanebonyl) asparaginyl] amino] butyl -4 (R) - (phenylthio) piperidin-2 (S) -carboxamide 14.) [3"'S- (3'" R *, 4"'S *)] - N- [r-oxo-l'-oxo-l'- (3" - [!' '' - oxo-2 '' '-aza-3' '' -phenyl -methyl-4 '' '-hydroxy-5' '' - (2 '' '-N-butyl tere.-carbamido) phenyl] pentyl-4"-methyl) -1, 2, 3, 4-tetrahydroisoquinoline 15.) 2- [2-hydroxy-3- (3-hydroxy-2-methyl-benzoylamino) - -phenylsul-familyl-butyl] -decahydro-isoquinoline-3-carboxylic acid butylamide 16.) 2H -1, 4 -diazepine-2 -one, hexahydro-6-hydroxy-1, 3, 4, 7-tetrakis (phenyl-methyl) -, [3 S '- (3. alpha, 6. beta. , 7. beta)] and inhibitors of trans cript asa inverse to be used as a medicine to fight AIDS and HIV infections.
Quinoxalines of the general formulas (I) and (a), in which n means zero, one or two, are especially preferable, the different substituents independently of one another denote fluorine, chlorine, bromine, trifluoromethyl, hydroxy, alkyl C 1 - C 4, C 1 -C 4 alkoxy, (C 1 -C 4 alkoxy) - (α 1 coxy C 2 -C 2), C 1 -C 4 alkyl or, nitro, amino, C 1 -C 4 alkylamino, di ( alkyl-C? ~ C4) -amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, acyl C? -C4, acyl-C? -C4-oxy, acyl-C? -C4-amino, cyano, carbamoyl, carboxy, (C 1 -C 4 alkyl) -oxycarbonyl, hydroxy sulfonyl, sulfamoyl
a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysul fonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two R6 radicals independent of each other, which may be R fluorine, chlorine, bromine, cyano, trifluoride Nitro, amino, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, (C 1 -C 4 alkoxy) oxycarbonyl, phenyl, phenoxy, R 'hydrogen and C: -Cg alkyl, optionally substituted by C 1 -C 6 alkoxy; C4 or alkyl-C? -C4 -thio; C2-C6 alkenyl, optionally substituted by oxo; C3-C-alenyl; C3-C8 alkynyl, in particular 2-butinyl; C3-Cg cycloalkyl; C5-C6 cycloalkenyl; (C3-C6 cycloalkyl) - (C? -C2 alkyl), in particular cyclopropylmethyl, optionally substituted by C? -C4 alkyl; (C3-Cg cycloalkenyl) - (C? -C2 alkyl), in particular cyclohexenylmethyl; alkyl-Ci-Ce-carbonyl, optionally substituted by fluorine, chlorine, hydroxy, benzoyloxy, phenoxy, C1-C4 alkoxy, alkyl-Ci-C4-amino, alkenyl-C? -C4-amino, di (alkyl-C) ~ C4) -amini, 1-pyrrolidinyl, piperidino, morpholino, 4-methyl-1-yl, alkyl-Ci-C4-1i or; alkenyl-C2-Cg-carbonyl; alkyl -Ci-Cg-oxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, C1-C4 alkoxy, alkyl-Ci-C4-amino, di (C1-C-alkyl) -amino, alkyl-C? C4- t í o;
alkenyl-C ^ -G-oxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pennynyloxycarbonyl; al-C2-C6-oxycarbonyl, in particular propynyloxycarbonyl, butynyloxycarbonyl; alkyl-Ci-Cg-t-iocarbonyl; alkenyl-C2-Cg-thiocarbonyl, in particular allyl-carbonyl; alkyl-Ci-Cg-aminocarbonyl and di (alkyl-Ci-Cg) -aminocarbonyl; pyrrolidin-1-yl, morpholinecarbonyl, piperidincarbonyl, piperazinylcarbonyl or 4-methyl-piperazin-1-ylcarbonyl; alkenyl -C2-Cg-aminocarbonyl and di (alkenyl-Ci-Cg) -aminocarbonyl; alkyl-C? -C-sulphonyl; Quenil-C? ~ C4 -sulfonyl, or aryl, in particular phenyl, aryl carbonyl, in particular benzoyl, (aryl thio) carbonyl, aryloxycarbonyl, arylaminocarbonyl,
(arylamino) t-carbonyl, arylalkylaminocarbonyl, arylsul fonyl, arylalkyl, in particular, benzyl, phenylethyl, arylalkenyl, arylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl substituted by up to two R6 radicals independent of each other, and may contain C.sub.1 alkyl having 3 to 3 carbon atoms, respectively, and R6 being defined as above, 0- or 2- naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3- furylmethyl, 2- or 3-thienylmethyl. , 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl,
2- or 3- furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3- t -ienylacetyl, .2-,
3- or -picolyloxycarbonyl, 2- or 3-furylmethyl oxycarbonyl 1, 2- or 3-thienylmethyloxycarbonyl, and. R3 and R4 being the same or different, independently meaning hydrogen, C?-C4 alkyl, optionally substituted by hydroxy, mercapto, C?-C 4 alkoxy, C alqu-C 4 alkyl-uncle, C alqu-C 4 alkyl -sulfonyl, alkyl-C? -C4-sulfinyl, carboxy, carbamoyl; C2-C6 alkenyl, aryl, benzyl, thienyl or thienylmethyl substituted by up to two radicals Rd independent of each other, with R6 being defined as above, R3 and R4 can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 atoms of C, which may be substituted, if appropriate by oxo or thioxo, and X signifying oxygen or sulfur, in combination with protease inhibitors of the acid series 2, 4, 7, 12-tetraaza tridecan-13 -oi co, 10- hydroxy-2-methyl-5- (1-methyl-ethyl) -1- [2- (1-methylethyl) -4-thiazolyl] -3,6-dioxo-8,11-bis- (phenyl-methyl) ) - thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)]; 3-is oquinolinecarboxamide, N- (1, 1- dimethylethyl) decahydro-2- [2-hydroxy-3- [(3-hydroxy-2-methylbenzoyl) amino] -4 - (phenylthio) butyl] - [3S- [ 2- (2S *, 3S *), 3. alpha., 4a. beta., 8 beta.]] -, monoe tanosul phona to (salt); carbamic acid, [3- [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-l- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S- [3R * (ÍS *, 2R *)]] -;
4. ) (S) -N- [(alphaS) -alpha- [(IR) -2- [((3S, 4aS, 8aS) -3- (butyl tere. -carbamoyl) -octahydro-2 (ÍH) -isoquinolinyl) -1-hydroxyethyl) phenethyl-2-quinaldamido] -succinamide 5.) 2 (R) -benzyl-5- (2 (S) - (N-butyl tert-carbamoyl) -4 - (3-pyridylmethyl) piperazine-1 -yl) - 4 (S) -hydroxy-N- (2 (R) -hydroxydan-1 (S) -yl) pentanamide 6.) N- (quinolin-2-ylcarbonyl) -aspargin-1 (S) -benzyl -3- (3-butyl tere. -1-iso-butylidene) -2 (R) -hydroxypropylamide 7.) 2 (1H) -pyrimidinone, 4-amino-1 - [2-hydroxymethyl) -1, 3- oxatiolan-5-yl] -, [(2R- cis) - (9CI)] (Epivir) and reverse transcriptase inhibitors to be used as a medicine to fight AIDS and HIV infections.
Especially preferable is the combination of S-isopropoxycarbonyl-6-me-toxy-3- (methyl t -methyl) -3,4-dihydro-quinoxazoline-2 (1H) -thione of the formula (A)
or 1 (2H) -quinoxalinecarboxylic acid, 2-ethyl-7-fluoro-3, 4-dihydro-3-oxo, ester 1-methyl tylyl [(S) - (9C1)] of the formula (B )
with (S) -N- [(alphas) -alpha-. (IR) -2- [((3S, 4aS, 8aS) -3- (butyl tere. -carbamoyl) -octa-hydro-2- (ÍH) -isoquinylinyl) -1-hydroxyethyl) phenethyl-2-quinaldamined] - succionamide (Saquinivir) of the formula (C)
or 2 (R) -benzyl-5- (2 (S) - (N-butyl tere. -carbamoyl) -4 - (3-pyridimethyl) piperazin-1-yl) -4 (S) -hydroxy-N- ( 2 (R) -hydroxyindan-1 (S) -yl) pentamide of the formula (D)
or acid 2, 4, 7, 12 - 1 etraza tridecan-13-oi co, 10-hydroxy-2-methyl-5- (1-methylethyl) -1- [2- (1-methyl-ethyl) -4-thiazolyl] -3,6-dioxo-8, ll-bis- (phenyl-methyl) -, 5-thiazolylmethyl ester [5S- (5R *, 8R *, 10R *, 11R *)]
(E) and Retrovir (AZT) or Epivir to be used to fight AIDS or HIV infections.
The quinoxalines of the general formulas (I) and (Ia) are known [see EP 509 398 Al; EP 708 093; EP 657 166]. The above-mentioned protease inhibitors are also known [see documents EP 432 695, EP 569 083 Al, EP 541 168 Al, PCT WO 92/08688 al, WO 92/08699 Al, WO 92/08698 A1, WO 92/08701 To WO 92/08700 Al, PCT WO 94/04 0492, PCT WO 94/14436, PCT WO 94/11361, EP 601 486 A, EP 560 268 A, EP 609 625 A, PCT WO 94/08977].
The use of the combination of these compounds offers advantages in the treatment of retrovirus-induced diseases - in particular induced by HIV - in comparison with monotherapy or combinations of two of the individual compounds. The advantageous and better use of the combination of these compounds for the treatment of AIDS or HIV infections results above all from the antiviral synergistic efficacy, but also from the invariable tolerance of the combined substances in the range of toxicity with which they survive. 50% of cells - in comparison with Tox-50 of individual components. For other combinations - for example AZT in combination with Ganciclovir, it is known that when using a combination synergistic toxicity occurs [see M: N: Prichard et. to the.; Antimicrob. Agents Chemotherapy (1991), 35, 1060-1065].
The lower active dose that results for the treatment thanks to the use of the ternary combination of the substances reduces, besides the probability of forming isolations of resistant virus.
The invention relates to the ternary combination classes of HIV reverse transcriptase inhibitors and HIV protease compounds for the prevention and treatment of infections caused by HIV, as well as for the treatment of HIV-induced diseases, as AIDS Related Complex (ARC) or AIDS.
HIV infection in cell culture
The HIV test was performed with modifications according to the method of Pauwels et al. [see Journal of Virological Methods 2 0_, (1988), 309-321].
Normal human blood lymphocytes
(PBL) were enriched by Ficoll -Hypaque and stimulated in RPMI 1640, 20% fetal calf serum with phytohemagglutinin (90 μg / ml) and interleukin-2 (40 U / ml). For infectious HIV infection, PBL were centrifuged, the cell pellets were then suspended in 1 ml of HIV viral solution for adsorption and incubated for 1 hour at 37 ° C.
The viral adsorption solution was centrifuged and the infected cell pellets were incorporated into a growth medium, so that it was adjusted to 1 × 10 5 cells per ml. The cells infected in this way were pipetted, introducing x 10 'cells / well in the microtitre plate wells of 96.
As an alternative, H9 cells were used instead of PBLs for antiviral tests.
The checking of the combinatorial effect of the substances to be tested was carried out by chequerboard evaluation (chequerboardi ti tra tion).
The first vertical row of the microtiter plate contained only growth medium and cells that were not infected, but were otherwise treated in the same way as the one described above (cell control). The second vertical row of the microtiter plate obtained only cells infected with HIV (virus control) in growth medium. The other wells contained the compounds according to the invention - separately or in corresponding combinations - in different concentrations, starting from the wells of the 3rd vertical row of the microtiter plate, from which the substances to be tested were diluted in double dilution steps 2 (50 μl volume per glass). For the combination, dilutions of the second substance were prepared in a separate 96 microtiter plate, and then added by pipette to the first prepared plate. The third compound was prepared in a respectively fixed concentration, so that, for example, 4 degrees of dilution (corresponding to 4 test preparations) of the 3rd inhibitor were tested. 100 μL, respectively, of the prepared cells infected with HIV (see above) were added. With them, the test concentrations of the three inhibitors were covered in the range of approximately 10 to 50 times above and below the IC50 concentrations of the individual compounds.
The test preparations were incubated at 37 ° C until it could be checked under a microscope in the virus control without treating the formation of syncytia in the host cell typical for HIV (between day 3 and 8 after infection). In the control of untreated virus, these test conditions resulted in approximately 20-50 syncytes, whereas the control of untreated cells did not present any syncytium.
The supernatants of the 96-well plate were then collected and examined in a test
ELISA specifies for HIV regarding the presence of a specific antigen for HIV
(Vironostika Antigen HIV, Organon Téknika).
Inhibitory values were converted by calculation according to the cut-off values of corresponding cell or virus controls or according to internal controls of the test at inhibitory values in percent (%), and IC50 values were determined as cell concentrations. treated and infected, to which 50% of the virus-specific antigen was suppressed by treatment with the compounds. For the analysis of the synergistic efficacy of the compounds, the differential values between the calculated and measured inhibitory values of the combinations were determined (Prichard, MN et al, Antimicrob, Agents Chemoth, (1993), 37, 540-545). .
The ternary combination surprisingly shows a synergistic efficacy in margins of concentrations in which an antiviral effect is not observed by treatment with a compound or a combination of two.
For example they present both 0.5 nM of Retrovir and 0.1 nM of Retrovir in combination with 0.1 to about 10 nM of quinoxaline and about 70 to 6 nM of Indinavir or 0.2 to 6 nM of quinoxaline with about 10 to 50 nM Indinavir, respectively, a strong synergetic action.
It has surprisingly been found that thanks to the use of the ternary combination of the compounds a synergistic effect is achieved in HIV. This was shown by way of example by studies of ternary combinations of the quinoxaline derivative with Indinavir and Retrovir.
The ternary combinations according to the invention serve for the treatment and prophylaxis of retrovirus-induced diseases in human and animal medicine.
As indication fields in human medicine can be indicated, for example:
1. ) The treatment and prophylaxis of human infections by retroviruses. 2.) The treatment or prophylaxis of diseases caused by HIV I (human immunodeficiency virus, formerly called HTLV III / LAV) (AIDS) and the stages associated with them, such as ARC (AIDS related complex) and LAS (syndrome) lymphadenopa ti co), as well as immunodeficiency and encephalopathy caused by this virus. 3.) For the treatment or prophylaxis of an HTLV-1 or HTLV-II infection. 4.) For the treatment or prophylaxis of the AIDS-carrier status.
As indications in animal medicine can be indicated, for example: Infections with a) maedivisna (in sheep and goats) b) progressive pneumonia virus (PPV) (in sheep and goats) c) arthritis virus encephalitis goat (in sheep and goats) ) d) zwoegersiekt e virus (in sheep) e) infectious anemia virus (of the horse) f) infections caused by the cat leukemia virus (FIV) g) infections caused by the cat immunodeficiency virus (FIV) ) h) infections caused by the monkey immunodeficiency virus (SIV)
From the field of indication in human medicine, points 2, 3 and 4 above are preferable.
The present invention includes pharmaceutical preparations which in addition to the appropriate pharmaceutically inert, non-toxic excipients, contain one or more compounds of the formulas (1 / (la)) in combination with a protease inhibitor and a reverse transcriptase inhibitor or consisting of one or more active compounds of the formulas (1 / (la)), the protease inhibitor and the reverse transcriptase inhibitor, and processes for the production of these preparations, in particular the combination of the test compounds.
The active compounds of the formulas (I) and (la), the protease inhibitors and the reverse transcriptase inhibitors can be present in the aforementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5% by weight, preferably of about 0.5. up to 95% by weight, of the total mixture.
The abovementioned pharmaceutical preparations may contain, in addition to the compounds of the formulas (I) / (la) in combination with one of the above-mentioned protease inhibitors, also other pharmaceutical active substances.
The preparation of the abovementioned pharmaceutical preparations is carried out in a conventional manner according to known methods, for example by mixing the active substance (s) with the carrier substance (s).
It has generally proved advantageous both in human medicine and also in animal medicine to administer the active substance (s) according to the invention every 24 hours in total amounts of about 0.5 to about 500, preferably 1 to 100 mg / kg of body weight. , if necessary in the form of several individual doses, to obtain the desired results. An individual dose contains the active substance (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg of body weight. However, it may be necessary to defer from the dosages indicated, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and application of the medication, as well as the period or interval during which the administration is performed.
The combinations of two in the treatment of patients infected with HIV show an efficacy superior to monotherapy. However, with a therapy scheme of this type, resistant viruses can also occur.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention is that which is clear from the present description.
Having described the invention as above, the content of the following is claimed as property.
Claims (6)
1. A medicament, characterized in that it contains, in a ternary combination, quinoxalines of the general formula (I) as well as the tautomeric forms thereof of the general formula (la) where 1) n means zero, one, two, three, or four, the different substituents independently means fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethyl, trifluoromethoxy, hydroxy, C? -C8 alkyl, C5 cycloalkyl -C8, Ci-Cg alkoxy, (Ci-C6 alkoxy) - (C 1 -C 4 alkoxy), C 1 -C 6 alkyl or C 1 -Cg-sulfinyl alkyl, C 1 -C 6 alkyl sulphonyl , nitro, amino, azido, alkyl -C? -C. { -amino, di (alkyl-C? ~ Cg) -amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, thiomorpholino, imidazolyl, triazolyl, tetrazolyl, acyl C? ~ Cg, acyl-Ci-Cg-oxy, acyl -Ci-Cg-amino, cyano, carbamoyl, carboxy, (alkyl-Ci-Cg) -oxocarbonyl, hydrosulfonyl, sulphamoyl or a phenyl, phenoxy, phenoxycarbonyl, phenylthio, phenyl sulfinyl, phenylsulfonyl, phenoxy sulphonyl, phenylsulfonyloxy, anilinosulfonyl moiety , phenyl sulfonylamino, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl substituted by up to five R6 radicals independent of each other, R6 being able to mean fluorine, chlorine, bromine, iodine, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, azido, Ci-Cg alkyl, C 3 -C 6 cycloalkyl, Ci-Cβ alkoxy, alkyl-Ci-Cg-1 io,. alkyl -Ci-Cg-sulfinyl, alkyl-Ci-Cg-sulfonyl, alkyl-Ci- C6-amino, di (alkyl-C-Cg) -amino, (alkyl-Ci- C) -oxycarbonyl, phenyl, phenoxy, 2-pyridyl, 3-pyridyl or 4-pyridyl, R 'hydrogen, C?-C6 alkoxy, hydroxy, picolyl, cyclopropyl or isopropenyloxycarbonyl and R * hydrogen, hydroxy, C?-C6 alkoxy, aryloxy, acyl-Ci-Cg- oxy, cyano, amino, alkyl 1 -Ci-Cg-amino, di (alkylC?-C6) -amino, arylamino, acyl-Ci-Cg-amino, C?-C8 alkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Cx-Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy C? ~ C6, alkyl-Ci-Cg-amino, di (alkyl-C-C6) -amino, alkyl-Ci-Cg-thio alkyl-Ci-Cg-sul fonyl, fer? Ilsulfonyl, oxo, thioxo, carboxy, carbamoyl; C2-C8 alkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl -Ci-Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy Ci-Cg, alkyl-Ci-Cg amino, di (C 1 -C 6 alkyl) -amino, alkyl-Ci-Cg-thio, alkyl-Ci-Cg-sulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C 3 -C 8 -aryl, optionally substituted by fluorine, chlorine or hydroxy, C 1 -C 4 alkoxy, oxo, phenyl; C3-C8 alkynyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Ci-Cg-oxy, benzoylcyo, benzyloxy, phenoxy, Ci-C6 alkoxy / alkyl-Ci-Cg -amino, (alkyl -C? -C6) -amino, alkyl-Ci-Cg-thio, alkyl-Ci-Cg-sulphonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C3 -C8 cycloalkyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-C? -Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy C? -Cg, alkyl-Ci -Cß-amino, di (alkyl-C? -Cg) -amino, the quil-Ci-Cg-thio, alkyl-Ci-Cg-sulfonyl, phenylsulfonyl, oxo, thioxo, carboxy, carbamoyl; C3-C8 cycloalkenyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl -Ci-Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy C? -Cg, alkyl-Ci- Cg-amino, di (al qui 1 -C? ~ Cg) -amino, alkyl-Ci-Cg-thio, alkyl-Ci-Cg-sulfonyl, phenylsul fonyl, oxo, thioxo, carboxy, carbamoyl; (C3-C3-cycloalkyl) - (C1-C4 alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Ci-Cg-oxy, benzoyloxy, benzyloxy, phenoxy, alkoxy C? -Cg, alkyl-Ci-Cg-amino, di (alkyl-Ci-Cg) -amino, alkyl-Ci-Cg-tio, alkyl-C? -C6-sulfonyl, phenylsulfonyl, oxo, thioxo, carboxy , carbamoyl; (C3-C8 cycloalkenyl) - (C1-C4 alkyl), optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-C? -Cg-oxy, benzoyloxy, benzyloxy, phenoxy alkoxy Ci-Cg, alkyl-Ci-Cg-amino, di (alkyl-Ci-C6) -amino, alkyl-Ci-Cg- tí or, alkyl-C? -C6-sulfonyl, phenylsulfonyl, oxo, thioxo, carboxy , carbamoílo; alkyl-Ci-Cg-carbonyl, optionally substituted by fluorine, chlorine, bromine, iodine, cyano, amino, mercapto, hydroxy, acyl-Ci-Cß-oxy, benzoyloxy, benzyloxy, phenoxy, Ci-C6 alkoxy, alkyl- Ci-Cg-amino, di (C 1 -C 6 alkyl) -amino, C 1 -C 6 alkyl-thio, alkyl-Ci-Cg-sulfonyl, phenyl sulfonyl, oxo, thioxo, carboxy, carbamoyl; alkenyl-C2-C? -carbonyl, optionally substituted by fluorine, chlorine or hydroxy, alkoxy Ci-C4, oxo, phenyl; (C3-C8-cycloalkyl) -carbonyl, optionally substituted by fluorine, chlorine or hydroxy, Ci-C4 alkoxy, oxo, phenyl; (C5-C8 cycloalkenyl) -carbonyl, optionally substituted by fluorine, chlorine or hydroxy, Ci-C4 alkoxy, oxo, phenyl; (C3-C8-cycloalkyl) - (C-C3-alkyl) -carbonyl, optionally substituted by fluorine, chlorine or hydroxy, C-alkoxy? -C4, oxo, phenyl; (cycloalkenyl-Cs-Cg) - (C 1 -C 3) alkylcarbonyl, optionally substituted by fluorine, chlorine or hydroxy, C 1 -C 4 alkoxy, oxo, phenyl; C 1 -C 8 alkyloxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, di (C 1 -C 4 alkyl) amino, alkyl C? -C4-thio; alkenyl-C2-C8-oxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy, oxo, phenyl; C2-C8 alkynyloxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, alkoxy Ci-C4, oxo, phenyl; alkyl-Ci-Ce-thiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, alkoxy Ci-C4, oxo, phenyl; alkenyl-C2-C8-thiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, alkoxy Ci-C4, oxo, phenyl; alkyl-C? -C8-aminocarbonyl and di (alkyl-Ci-Cg) -aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy, oxo, phenyl; pyrrolidin-1-yl, morpholinecarbonyl, piperidincarbonyl, peperacinicarbonyl or 4-methyl-piperazin-1-yl-carbonyl, optionally substituted by C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 acyl, oxo, thioxo , carboxy or phenyl; alkenyl-C2-C8-aminocarbonyl and di (alkenyl-Ci-Cg) -aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, alkoxy Ci-C4, oxo, phenyl; alkyl-C6-sulphonyl, optionally substituted by fluorine, chlorine, hydroxy, alkoxy Ci-C4, oxo, phenyl; alkenyl-Ci-Cg-sulfonyl, optionally substituted by fluorine, chlorine, hydroxy, Ci-alkoxy, oxo, phenyl; or aryl, arylcarbonyl, aryl 1 (ti ocarboni 1 o), (arylthio) carbonyl, (arylthio) thiocarbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylalkylaminocarbonyl, arylsul fonyl, arylalkyl, arylalkenyl, arylalkynyl, arylalkylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, aryl (alkylthio) carbonyl substituted by up to five R6 radicals independent of each other, the alkyl moiety may contain 1 to 5 atoms of C, respectively, and R6 being defined as above, or heteroarylalkylcarbonyl or heteroarylalkenylcarbonyl, heteroaryloxycarbonyl (heteroarylthio) -carbonyl, heteroarylaminocarbonyl, heteroarylalkyloxycarbonyl or, heteroaryl (alkylthio) carbonyl, heteroarylalkylaminocarbonyl, may contain the alkyl moiety to 3 C atoms, respectively, where R and R4 are the same or different, independently of one another, hydrogen, C? -C8 alkyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto, acyl- Ct. ~ C4 -oxi, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 -alkylamino, di (C 1 -C 4 alkyl) -amino, C 1 -C 4 alkyl-t or, alkyl-C? -C4-sulfonyl, alkyl-C? -C4-sulfinyl, carboxy, carbamoyl; alkenyl C? - Cβ, optionally substituted by fluorine or chlorine, hydroxy, amino, mercapto, acyl-C? -C4-oxy, benzoyl, benzyloxy, phenoxy, C? -C4 alkoxy, C? -C4-amino alkyl, di ( alkylCyclamino, alkylC? -C4-1, to which 1 -C? -C4-sulfonyl, alkyl-C? -C4-sulfinyl, carboxy, carbamoyl; C3-C8-cycloalkyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto, acyl-C? -C4 -oxi, benzoyl, benzyloxy, phenoxy, C1-C4 alkoxy, alkyl-C? -C4-amino, di (alkyl-C? -4) -amino, alkyl -C? -C4-thi or, alkyl-C? ~ C4-sulfonyl, alkyl-C1-C4-sulfinyl, carboxy, carbamoyl; C3-C8 cycloalkenyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto , acyl-C? -C4-oxy, benzoyloxy, benzyloxy, phenoxy, C? -C4 alkoxy, C? -C4-amino alkyl, di (C-C4 alkyl) -amino, C? -C4 alkyl or, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkyl sulphinyl, carboxy, carbamoyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl substituted by up to five R 6 radicals independent of each otherwherein the alkyl moiety may contain 1 to 3 C atoms, respectively, and R 6 being defined as above, R 3 and R 4 may also be part of a saturated or unsaturated cyclocarboxylic or heterocyclic group with 3 to 8 C atoms, which may be substituted, as the case may be, by fluorine, chlorine, hydroxy, amino, Ci-Cg alkyl, C2-C6 alkenyl, Ci-Cg alkynyl, acyl-Ci-Cβ-oxy, benzoyloxy, C alco-Cg alkoxy, oxo, thioxo, carboxy, carbamoyl or phenyl, X means oxygen, sulfur, selenium or substituted nitrogen N-R2, wherein R2 can have the meanings mentioned above, in combination with protease inhibitors and reverse transcriptase inhibitors.
2. The medicament according to claim 1, characterized in that it contains quinoxalines of the general formulas (I) and (la), in which n means zero, one or two, the different substituents means independently R 1 fluoro, chloro, bromo, trifluoromethyl, hydroxy, alkyl C? - Ci r alkoxy C? -C4, (C 1 -C 4 alkoxy) - (C 1 -C 4 alkoxy), C 1 -C 4 alkyl-, nitro, amino, di (C 1 -C 4 alkyl) -amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methyl-piperazinyl, C?-C4-acyl, acyl-C?-C-oxy, acyl -C?-C-amino, cyano, carbamoyl, carboxy, (C 1 -C 4 alkyl) - oxycarbonyl, hydroxysulfonyl, sulfamoyl or a phenyl, phenoxy, phenylthio, phenylsulfonyl, phenoxysul fonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl radical substituted by up to two R6 radicals independent of one another, R6 being able to mean fluorine, chlorine, bromine , cyano, tri fluoromethyl, nitro, amino, C 1 -C 4 alkyl, (C 1 -C 4 alkyl) -oxycarbonyl, phenyl, phenoxy, R 2 hydrogen and R 5 C 1 -C 6 alkyl, optionally substituted by fluorine, chlorine, hydroxy , acil - C? -C4 -oxi, benzoyloxy, benzyloxy, phenoxy, alkoxy C? - Ci r alkyl-C? -C4-amino, di (alkyl-C? -C4) -amino, alkyl-C? ~ C -thio, oxo, thioxo, carboxy, carbamoyl; C2-Cg alkenyl, optionally substituted by fluorine, chlorine, hydroxy, acyl -C?-C4-o.xy, benzoyloxy, benzyloxy, phenoxy, C alco-C4 alkoxy, C 1 -C 4 -alkylamino, di ( C 1 -C 4 -amino, di (C 1 -C 4 alkyl) -amino, C 1 -C 4 alkyl, oxo, thioxo, carboxy, carbamoyl, C 3 -C 8 -aryl, C 3 -C 8 alkynyl, case substituted by fluorine, chlorine, hydroxy, acyl-Ci- C4-0XI, benzoyloxy, benzyloxy, phenoxy, C1-C4 alkoxy, C 1 -C 4 -alkylamino, di (C 1 -C 4 alkyl) amino, alkyl I-C1-C4 -thio, oxo, thioxo, carboxy, carbamoyl, C3-C8 cycloalkyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkyl, acyl-C? -C4-oxy, benzoyloxy, benzyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 -alkylamino, di (C 1 -C 4 alkyl) -amino, alkyl, -C 1 -C 4 -thi, oxo, thioxo, carboxy, carbamoyl; C3-Cs cycloalkenyl , optionally substituted by fluorine, chlorine, hydroxy, C? -C4alkyl, acyl-C? -C4-oxy, benzoyloxy, benzyloxy, phenoxy, C1-C4, alkyl-C? -C4-amino, di (alkyl), -C? -C4) -amino, alkyl-C? -C4-thi or, oxo, t ioxo, carboxy, carbamoyl; (C3-Cg cycloalkyl) - (C 1 -C 2 alkyl), optionally substituted by fluorine, chlorine, hydroxy, C 1 -C 4 alkyl, a C y C 4 -Co 4 -oxy, benzoyloxy, benzyloxy, phenoxy C alkoxy -C 4, C 1 -C 4 alkyl-amino, di (C 1 -C 4 alkyl) -amino, C 1 -C 4 alkyl-thio, oxo, carboxy, carbamoyl; (cycloalkenyl-C3-C-) -i-C-C2-alkyl), optionally substituted by fluorine, chlorine, hydroxy, C? -C4alkyl, acyl -C1-C-oxy, benzoyloxy, benzyloxy, phenoxy, C1-alkoxy -C 4, C 1 -C 4 alkyl-amino, di (C 1 -C 4 alkyl) -amino, C 1 -C 4 alkyl or oxo, thioxo, carboxy, carbamoyl; alkyl-Ci-Cg-carbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkyl, acyl-C? -C4-oxy, benzoyloxy, benzyloxy, flenoxy, C1-C4 alkoxy, at quil -C! C4 -amino, alkenyl-C? ~ C4 -amino, di (C 1 -C 4 alkyl) -amino, 1-pyrrolidinyl, piperidini, morpholino, 4-methylpiperazin-1-yl, C 1 -C 4 alkyl-thio, oxo, thioxo, carboxy, carbamoyl; alkenyl -C2-Cg-carbonyl, optionally substituted by fluorine, chlorine or hydroxy; (C3-Cg cycloalkyl) -carbonyl, (cycloalkenyl-Cs-Cg) -carbonyl, (cycloalkyl-C3-Cg) - (alkyl-C-C2) -carbonyl, (cycloalkenyl-C5-Cg) - (alkyl- C? -C2) -carbonyl alkylCi-Cg-oxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, C? -C4 alkoxy, alkyl-C? -C4-amino, di (alkylC? C4) -amino, alkyl-C1-C4-uncle; alkenyl-C2-C6-oxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, Ci-C alkoxy; alkynyl-C2-Cg-oxycarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy; alkyl-Ci-Cg-thiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C 1 -C 4 alkoxy; alkenyl-C2-Cg-thiocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C alkoxy; alkyl-Ci-Cg-aminocarbonyl and di (here 1-C? -Cg) -aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, C1-C4 alkoxy; pyrrolidin-1-yl, morpholinecarbonyl, piperidincarbonyl, piperazinylcarbonyl or 4-methyl-pipe racin-1-ylcarbonyl or; alkenyl-C2-Cg-aminocarbonyl and di (alkenyl-Ci-Ce) -aminocarbonyl, optionally substituted by fluorine, chlorine, hydroxy, Ci-C4 alkoxy; alkyl-Cj-C4-sulphonyl, optionally substituted by fluorine, chlorine, hydroxy, Ci-C4 alkoxy; alkenyl-C? -C4-sulfonyl; or aryl, aricalbonyl, (aryl thio) carbonyl, aryl oxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, arylsulfonyl, arylalkylaminocarbonyl, arylalkyl, arylalkenyl, aryl, alkyl aryl, arylalkoxycarbonyl, aryl (alkyl to) carbonyl substituted by up to five R6 radicals independent of each other, the alkyl moiety may contain 1 to 3 carbon atoms, respectively, and R6 being defined as arrib, or 1- or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3-thienylmethyl, 2- or 3-pyrrolylmethyl. , 2-, 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3-tienylacetyl, 2-, 3-or 4-picolyloxycarbonyl, 2- or 3-furylmethyloxycarbonyl, 2- 3- tieni Imetíloxi carboni lo, y. R3 and R4 being the same or different, independently meaning hydrogen, Ct.-C4 alkyl, optionally substituted by fluorine, chlorine, hydroxy, amino, mercapto, acyl-C? ~ C4-oxy, benzoyloxy, phenoxy, alkoxy C ? C4, alkyl-C? -C4-amino, di (C? -C4 alkyl) -amino, C? -C4 alkyl-thio, C 1 -C 4 alkyl sulphonyl, C 1 -C 4 alkyl sulphin , carboxy, carbamoyl; C2-Cg alkenyl, optionally substituted by fluorine or chlorine; C3-Cg cycloalkyl, optionally substituted by fluorine, chlorine, hydroxy, amine, mercapto, acyl -C1-C4-OXI, benzoyloxy, benzyloxy, phenoxy, C1-C4 alkoxy, alkyl-Ci-Ci-amino, di (alkyl) -Ci-C4) -amino, alkyl-C? -C4-l, or, to the 1-C1-C4-sulfonyl, alkyl-C? -C4-sulfinyl, carboxy, carbamoyl; C3-Cs cycloalkenyl, optionally substituted by fluorine or chlorine; aryl, benzyl, heteroaryl or heteroarylmethyl substituted by up to two R6 radicals independent of each other, R and R "can also be part of a saturated or unsaturated carbocyclic or heterocyclic ring with 3 to 6 C atoms, which may be substituted, given the by fluorine, chlorine, hydroxy, amino, acyl -Ci-C4-oxy, benzoyloxy, C, -C-alkoxy, oxo-thioxo, carboxy, carbamoyl, and X means oxygen or sulfur, optionally in an isomeric form.
3. The medicament according to claim 1, characterized in that it contains quinoxalines of the general formulas (I) and (la), in which n means zero, one or two, the different substituents means independently R 1 fluoro, chloro, bromo, trifluoromyl, , hydroxy, alkyl C? ~ C4, C1-C4 alkoxy, (C1-C4 alkoxy) - (C6-alkoxy) C2), C 1 -C 4 alkylthio, nitro, amino, C 1 -C 4 -amino, di (C 1 -C 4 alkyl) -amino, piperidino, morpholino, 1-pyrrolidinyl, 4-methylpiperazinyl, acyl C1-C4, acyl-C? -C4-oxy, acyl-C? -C4-amino, cyano, carbamoyl, carboxy, (C 1 -C 4 alkyl) -oxycarbonyl, hydroxy sulphonyl, sulfamoyl or a phenyl radical, phenoxy, phenylthio, phenylsulfonyl, phenoxysulfonyl, benzoyl, 2-pyridyl, 3-pyridyl or 4-pyridyl substituted by up to two R6 radicals independent of each other, R6 being able to mean fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, alkyl C ? ~ C4, C1-C4 alkoxy, (C 1 -C 4 alkyl) -oxycarbonyl, phenyl, phenoxy, R 'hydrogen and R-C 1 -Cg alkyl, optionally substituted by C 1 -C 4 alkoxy or C 1 alkyl- C4-uncle; C2-Cg alkenyl, optionally substituted by oxo; C3-C6-alenyl; C3 ~ C8 alkynyl, in particular 2-butynyl; C3-Cg cycloalkyl; C5-Cg cycloalkenyl; (C3-Cg cycloalkyl) - (C 1 -C 2 alkyl), in particular cyclopropylmethyl, optionally substituted by C 1 -C 4 alkyl; (cycloalkenyl-C-Cg) - (C 1 -C 2 alkyl), in particular cyclohexenylmethyl; alkyl-Ci-Cg-carbonyl, optionally substituted by fluorine, chlorine, hydroxy, benzoyloxy, phenoxy, C 1 -C 4 alkoxy, C 1 -C 4 -alkylamino, C 1 -C 4 alkylamino, di (alkyl) Ci-C4) -amini, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl, alkyl-Ci-C4-1 i; alkenyl-C2-Cg-carbonyl; alkyl-Ci-Cg-oxycarbonyl, optionally substituted by fluorine, chlorine, bromine, hydroxy, C1-C4 alkoxy, alkyl-C? -C4-amino, di (C1-C4 alkyl) -amino, alkyl-C1- C4- 1 í o; alkenyl-C2-Cg-oxycarbonyl, in particular vinyloxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl; alkyl-C2-Cg-oxycarbonyl, 'in particular propynyloxycarbonyl, butynyloxycarbonyl; to the Ci-Cg-thiocarbonyl quil; alkenyl-C2-Cg-thiocarbonyl, in particular allyl thiocarbonyl; alky1-C? -Cg-aminocarbonyl and di (al-C? -Cg) -aminocarbonyl; pyrrolidinyl, morpholinecarbonyl, piperidincarbonyl, piperazinylcarbonyl or 4-methyl-piperazin-1-ylcarbonyl; alkenyl -C2-Cg-aminocarbonyl and di (alkenyl-Ci-Cg) -aminocarbonyl; alkyl-C? -C-sulphonyl; alkenyl-C? -C4-sulfonyl; or aryl, in particular phenyl, arylcarbonyl, in particular benzoyl, (arylthio) carbonyl, aryloxycarbonyl, arylaminocarbonyl, (arylamino) thiocarbonyl, aryl alkyl aminocarbonyl, arylsul fonyl, aryalkyl, in particular, benzyl, phenylethyl, arylalkenyl, arylcarbonyl, aryl alkoxycarbonyl, aryl (alkylthio) carbonyl substituted by up to two R6 radicals independent of each other, the alkyl moiety contains 1 to 3 C atoms, respectively, and R6 being defined as above, 0-1 or 2-naphthylmethyl, 2-, 3- or 4-picolyl, 2- or 3-furylmethyl, 2- or 3- 1ienylmethyl, 2- or 3-pyrrolylmethyl, 2-, 3- or 4-pyridylcarbonyl, 2- or 3-furylcarbonyl, 2- or 3-thienylcarbonyl, 2- or 3- t -ienylacetyl, 2-, 3- or 4-picolyloxycarbonyl, 2-3-furylmethyloxycarbonyl, 2- or 3-thienylmethyloxycarbonyl, R3 and R4 being the same or different, independently meaning hydrogen, C? -C4 alkyl, optionally substituted by hydroxy, mercapto, C1-C4 alkoxy, C1-C4 alkyl-thio, C-C4 alkyl-sulfonyl , alkyl-C? -C4-sulfinyl, carboxy, carbamoyl; C2-C6 alkenyl, aryl, benzyl, thienyl or thienylmethyl substituted by up to two R6 radicals independent of each other, where R6 is defined as above, R3 and R4 can also be part of a saturated or unsaturated carbocyclic or saturated cycle with 3 to 6 C atoms, which may be substituted, optionally by oxo- or thioxo and X means oxygen or sulfur.
4. The medicament according to claims 1 to 3, characterized in that it contains one or more protease inhibitors chosen from the group that includes: 1.) Acid 2, 4, 7, 12-1 and raazat ridecan-13 -oi co, 10-hydroxy- 2-methyl-5- (1-methyl-ethyl) -1- [2- (1-methylethyl) -4-thiazolyl] -3,6-dioxo-8,11-bis- (phenyl-methyl) - ester 5-thiazolyl-1-yl [5S- (5R *, 8R *, 10R *, 11R *)]; PCT WO 95/07696; PCT WO 95/20384 Al; PCT WO 95/009614 Al [ABBOTT (Ritonavir) ABT-538] 3-isoquinolinecarboxamide, N- (1, 1-dimethylethyl) decahydro-2- [2-hydroxy-3 - [(3-hydroxy-2-methyl-1-benzoyl) amino] -4 - (phenylthio) butyl] -3S-] 2- (2S *, 3S *), 3. alpha., 4a. beta., 8a. beta.]] -, monoe t anosulphone to (salt); PCT WO 95/09843; US 5484926; [AGOURON (Viracep®) AG-1343] Carbamic acid, [3- [[(4-aminophenyl) sulfonyl]] (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -, tetrahydro-3-furanyl ester, [3S- [3R * (ÍS *, 2R *)]] -; PCT. WO 94/05639; [VÉRTEX PHARM. (Kisseii, Glaxo Wellcome), VX-478] (S) -N- [(alphaS) -alpha- [(IR) -2- [((3S, 4aS, 8aS) -3- (butyl tere. -carba oil) octahydro-2 (lH) 'isoquinolinyl) - 1-hydroxyethyl) phenethyl-2-quinaldamido] -succinamide (EP 432 695 A2) 2 (R) -encyl-5- (2 (S) - (-butyl tere. -carbamoyl) -4- (3-pyridylmethyl) piperazin-1-yl) -4 (S) -hydroxy-N- (2 ( R) -hydroxyindan-1 (S) -yl) pentanamide (L-735524, EP 569 083 Al, EP 541 168 Al) CH N- (quinolin-2-ylcarbonyl) -aspargin-1 (S) -benzyl-3- (3-butyl tert-1-iso-butylureido) -2 (R) -hydroxypropylamide (SC 52 151, PCT WO 92 / 08688 Al, WO 92/08699 Al, WO 92/08698 Al, WO 92/08701 Al, WO 92/08700 Al) Nl- (2R-hydroxy-3- ((3-methylbutyl) methylsulfonyl) amino) -1S- (phenyl-methyl) propyl) -2S- ((2-quinolinylcarbonyl) -amino) but anodiamide (AM 11 686, PCT WO 94/04492) 2S, 3S, 5S) -5 (N- (N- ((N-methyl-N- ((2-isopropyl-4-oxazolyl) ethyl) amino-carbonyl 1) valinyl) amino) -2 (N- (( 5-thiazolyl) toxin rbonyl) amino-1,6-diphenyl-3-hydroxyhexane (A 84 538, PCT WO 94/14436) (R) -N-butyl tere. -3- ((2S, 3S) -2-hydroxy-3-N- ((R) -2-N- (isoquinolin-5-yloxyacetyl) amino-3-methylthiopropanoyl) -amino-4-phenylbutyoloyl) -5 , 5-dimethyl-l, 3-thiazolidin -carboxamide (KNI 272 / Nippon Mining) t-rahydro-furan-3-yl ester of the acid. { 3 '[(4-amino-benzenesulfonyl) -isobutyl-amino] -1-benzyl-2-hydroxy-propyl} -carbamic (3S, 6R) -3 - (- ethylbenzyl) -6 - (- ethylphenethyl) -4-hydroxy-2H-pyran-2-one (VB 11 478, PCT WO 9411361) N- [5-L- [N- (2-quinolinecarbonyl) -L-asparaginyl] amino- (4R, 3S) -epoxy-6-phenyl-1-hexanoyl] -isoleucine (EP 601 486 A) N-butyl tere. -1- [2- (R) -hydroxy-4-phenyl) -3 (S) - [[N- (2-quinolinylcarbonyl) asparaginyl] amino] util- (R) (phenylthio) piperidin-2 (S) - carboxamide (EP 560 268 A) [3 '' 'S- (3' '' R *, 4 '' 'S *)] - N- [1-oxo-l' - (3"'[l"' - oxo-2 '"- aza-3"'-phenyl-methyl-4' '' -hydroxy-5 '' - (2 '' '-N-butyl t-ee-carbamido) phenyl] pentyl-4" -methyl) -1 , 2, 3, 4 tetrahydroisoquinoline (EP 609 625 A) 2- [2-Hydroxy-3- (-hydroxy-2-methyl-1-yl-benzoyl-amino) -4-phenylsulfamyl-butyl] -decahydro-1-soquinolin-3-carboxylic acid tere. bu tilamide (AG 1343 Agouron Pharmaceuticals Inc., San Diego USA) 2H-1, 4-diazepil-2-one, hexahydro-6-hydroxy -1, 3,, 7-1e trache (phenyl-methyl) -, [3 S '- (3. alpha., 6. beta., 7. beta.)] (PCT WO 94/08977) OH
5. The medicament according to claims 1 to 4, characterized in that it contains one or more inhibitors of the reverse transcriptase of the group including zidovudine (Retrovir) AZT), didanosine (DDI), dideoxycytidine (DDC), Lamivudine (3-TC®), Stavudine ( D4T), BW 935U83, BW 1592U89 and Epivir.
6. The use of quinoxalines, protease inhibitors and reverse transcriptase inhibitors of claims 1 to 5 for the preparation of medicaments for the therapy of HIV infections.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19703131.5 | 1997-01-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99007077A true MXPA99007077A (en) | 2000-05-01 |
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