WO2015121413A1

WO2015121413A1 - New active pharmaceutical ingredient combinations with compounds based on tri(hetero)aryl pyrazoles

Info

Publication number: WO2015121413A1
Application number: PCT/EP2015/053091
Authority: WO
Inventors: Andreas Urban; Steffen Wildum
Original assignee: Aicuris Gmbh & Co. Kg
Priority date: 2014-02-14
Filing date: 2015-02-13
Publication date: 2015-08-20
Also published as: AR099428A1

Abstract

The present invention concerns new pharmaceutical active ingredient combinations from new compounds of non-nucleoside reverse transcriptase inhibitors with one or more additional and different antivirally active pharmaceutical ingredient(s). Furthermore, the present invention concerns the combined use of said pharmaceutical active ingredient combinations for the prevention and/or treatment of viral infections and of diseases caused by them. The combination partners in accordance with the invention preferably belong to different antiretroviral drug action classes and can be administered simultaneously in a single pharmaceutical composition or are provided separately in different pharmaceutical dosage forms that can be administered either simultaneously or sequentially. In particular, selected combination partners can be provided in proportions with synergistic antiviral effect. In particular, the present inventions concerns the combined use of said pharmaceutical active ingredient combinations for prevention and/or treatment of retroviral infections as well as of diseases caused by retroviruses, such as HIV infections, and of diseases such as AIDS, caused by them in humans and/or animals.

Description

New active pharmaceutical ingredient combinations with compounds based on tri(hetero)aryl pyrazoles

[0001] The technical field of this invention concerns new active pharmaceutical ingredient combinations used for prevention and/or treatment of viral infections and of diseases caused by them.

[0002] It has been known for some time that monotherapy with the currently available antiretrovirally-effective HIV medications leads within a short time to treatment failure through selection of resistant HI viruses. For this reason, combination therapy is normally used with several, preferably three substances with different retroviral action from different drug action classes. This is usually summarised under the generic term HAART {highly active antiretroviral therapy). Through the introduction of HAART in the 1990s it was possible to bring about long-term slowing of the progression of HIV-induced diseases, particularly AIDS, and thus to significantly extend the life expectancy of HIV-infected patients (The Lancet, Volume 372, Issue 9635, Pages 293 - 299, 26 July 2008; Palella et al., N. Engl. J. Med. 1998, 238, 853-860).

[0003] The antiviral substances currently on the market that are effective against the HI virus inhibit either the replication of the virus through inhibition of its essential viral enzyme, namely reverse transcriptase (so-called reverse transcriptase inhibitors, or RTI), of protease (so-called protease inhibitors, or PI) or of integrase (so-called integrase inhibitors, or II); or they inhibit the entry of HI viruses into the target cells (so-called entry inhibitors, or El); see on this the overview in Flexner, Nature Reviews Drug Discovery 2007, 6, 959- 966.

[0004] Accordingly there are different drug action classes of antiretroviral substances that are effective against the HI virus:

[0005] RT inhibitors: nucleoside RT inhibitors and nucleotide RT inhibitors work through competitive inhibition or chain termination in DNA polymerisation. On the other hand, non-nucleoside RT inhibitors bind allosterically to a hydrophobic pocket in the proximity of the active center of the RT and induce a change in the conformation of the enzyme.

[0006] The currently available protease inhibitors block the active center of the viral protease and thus prevent newly created particles from maturing into infectious virions. [0007] The currently approved integrase inhibitors Raltegravir, Elvitegravir and Dolutegravir bind to the active center of the HIV integrase and prevent the integration of the proviral DNA into the host cell genome.

[0008] Entry inhibitors (fusions inhibitors and co-receptor antagonists) prevent the HIV infection of cells through interaction with the HIV envelope protein or through blocking the cellular co-receptors CCR5 or CXCR4.

[0009] Despite the progress in antiretroviral chemotherapy, recent trials (R. Johnston, HIV Cure: Controversy, Consensus, and a Consortium; AIDS Research and Human retroviruses. September 2010, 26(9): 943-946) show that with the medications available eradication of HIV and associated curing of the HIV infection cannot be achieved. The latent virus remains, among other places, in resting lymphocytes, thus constituting a reservoir for its constant reactivation, and thus the starting situation for a new propagation of the virus (Finzi et al., Nature Med. 1999, 5, 512-517; Lewin et al., J Int AIDS Soc. 201 1 Jan 24; 14:4). As a result, HIV-infected patients must depend on a lifelong efficient retroviral therapy.

[0010] Since furthermore, for each drug action class, anti-HIV therapeutic active pharmaceutical ingredients accumulate characteristic resistance mutations, after some time there may be an equally combined selection of viruses and thus multi-resistant viruses may be created, despite combination therapy consisting of various antiretroviral active pharmaceutical ingredients from different drug action classes. This then leads to failure of the indicated combination therapy; often concomitantly with the loss of effectiveness of an entire substance class. This

cross-resistance problem is most characteristic of the NNRTIs action class, since here often even a single point mutation in the RT may be sufficient to cause a loss of effectiveness of all known NNRTIs (see overview in Kavlick & Mitsuya, Antiretroviral Chemotherapy (Publisher: De Clercq E.), 2001 , ASM Press, 279-312). Furthermore the creation of resistances is usually favoured by poor "compliance" on the part of patients, caused by an unfavourable side-effects profile and/or a complicated dosage regimen for antiretroviral HIV active pharmaceutical ingredients.

[0011] Overcoming this is an essential goal of current research in the area of HIV infections and the disease caused by it, AIDS. Consequently, there is in principle an ongoing need for additional active ingredients and their combinations for effective treatment of viral infections and of diseases caused by them. Of particular relevance are such active ingredients and their combinations against which, if possible, there is not yet any resistance or multi-resistance of the viruses targeted, particularly the HI viruses to be targeted. [0012] This invention was therefore based on the general problem of providing active pharmaceutical ingredients and particularly active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections, particularly of retroviral infections such as in the case of HIV and diseases caused by them, wherein effectiveness must be maintained particularly in the presence of resistant or multi-resistant viruses.

[0013] The particular problem to be solved by this invention is to make available active pharmaceutical ingredient combinations with improved antiretroviral effectiveness for the treatment of retroviral infectious diseases, preferably of HIV-1 induced infections in humans and/or animals, which do not exhibit the above-described disadvantages, which therefore in particular address the underlying problem of resistance and cross-resistance (multi-resistance) of HI viruses.

[0014] The inventors have now found that new active pharmaceutical ingredient combinations of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) based on tri(hetero)aryl pyrazoles with at least one additional known and different antivirally active pharmaceutical ingredient for use in prophylaxis and/or treatment of viral infections and diseases caused by them may be effective in an additive, additive/synergistic or synergistic manner and thereby particularly against resistant or multi-resistant viruses. The effectiveness against resistant virus forms is based on the fact that a new group of NNRTI compounds, against which up to now no resistance has accumulated, is always a combination partner of the combination of active ingredients pursuant to the invention.

[0015] In particular the inventors have discovered new active pharmaceutical ingredient combinations of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) based on tri(hetero)aryl pyrazoles with at least one additional known and different antivirally active pharmaceutical ingredient, for use in the prevention and/or treatment of viral infections and of diseases caused by these, wherein the combination partners are not antagonistic. [0016] The inventors have further, and surprisingly, found that new NNRT!s based on tri(hetero)aryl pyrazoles in combination with compounds of known antiretrovirally-effective pharmaceutical ingredients may exhibit improved antiviral, particularly anti-retroviral, activity, since the combination preparations pursuant to the invention are effective against viruses, particularly against HI viruses that already exhibit resistance, particularly cross-resistance, to known anti-HIV active pharmaceutical ingredients. [0017] Consequently this invention concerns new active pharmaceutical ingredient combinations made from new compounds of non-nucleoside inhibitors of reverse transcriptase with at least one different antivirally active pharmaceutical ingredient. The combination partners pursuant to the invention belong to different a nti retroviral drug action classes and may at the same time be administered in a joint pharmaceutical composition or may exist separately in various pharmaceutical forms such as combination preparations, wherein the pharmaceutical forms may be administered either simultaneously or at intervals (sequentially). In particular, specific combination partners pursuant to the invention exist in a synergistic, antivirally-effective relationship.

[0018] This invention also concerns the use of the new active ingredient combinations in the prevention and/or treatment of viral infections as well as virally-induced diseases. In particular this invention concerns the use of the new active ingredient combinations in the prevention and/or treatment of retroviral infections as well as retrovirally-induced diseases, such as HIV and HIV-induced diseases such as AIDS in humans and/or animals.

[0019] In particular the invention provides new active pharmaceutical ingredient combinations against which up to now no resistance or multi-resistance by viruses, particularly by HI viruses, were developed. Consequently the new active pharmaceutical ingredient

combinations are suitable for use in the prevention and/or treatment of resistant or multi-resistant forms of HIV in a patient infected with it. Furthermore the present invention provides

pharmaceutical compositions and combination preparations of the new active ingredient combinations. [0020] The new NNRTIs pursuant to the present invention are based on tri(hetero)aryl pyrazoles. The chemical substance class of pyrazoles has already been described many times for various indications: US 5,624,941 and EP 576357 describe pyrazoles as cannabinoid receptor antagonists; EP 418845, EP 554829 and WO 04/050632 among other things for the treatment of inflammatory and thrombotic diseases; WO 03/037274 as sodium ion channel inhibitors for the treatment of pain; WO 06/015860 as adenosine receptor ligands for the treatment of inflammatory and obstructive respiratory diseases; EP 1762568 as inhibitors of platelet aggregation; WO 07/002559 as modulators of the activity of nuclear receptors; WO 07/020388 and WO 05/080343 as cannabinoid receptor modulators, among other things for the treatment of obesity and psychiatric and neurological disorders; WO 07/009701 and EP 1743637 for the treatment of cardiovascular risk factors; and DE 10 2004 054 666 to fight weeds or to regulate plant growth. [0021] WO 201 1/058149 describes tricyclic pyrazole derivatives as PI3k inhibitors for the treatment of autoimmune diseases. WO 2008/074982 describes pyrazole derivatives as CB1 receptor modulators in the treatment of overweight. Pyrazole derivatives as agents against blood platelet aggregation for the treatment of ischemic diseases are described in WQ 2004/069824 and WO 2006/004027. Pyrazole derivatives as COX-1 Inhibitors are described in WO

2004/050632 and US 2004/01 16475. WO 2008/017932 describes various aryl sulfonamides, among them a pyrazole-containing example, as carbonic anhydrase inhibitors.

[0022] DE 10 2008 015 033 and DE 10 2008 015 032 describe phenyl-substituted pyrazoles and their use for the treatment and prevention of infections with retroviruses.

[0023] The subject of the invention is new active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, said combinations comprising a) at least one antivirally active pharmaceutical ingredient of the compound according to Formula (I)

wherein

X stands for N or CH and

R1 stands for a halo substituent and

R2 stands for H or CH3,

or one of their physiologically acceptable salts, solvates or one of the solvates of their salts, and b) at least one antivirally active pharmaceutical ingredient different from a) selected from a group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors and combinations thereof, as well as physiologically acceptable salts, solvates or the solvates of the salts.

[0024] The term "viral infections" or similar terms in the context of the invention means the active or passive penetration of viruses into an organism such as plants, animals or humans and their proliferation. This may result in the development of an infectious disease. Within the context of the invention "viral infection" preferably means retroviral infection, such as an infection with the human immunodeficiency virus (HIV or HI virus). [0025] The HI virus is an enveloped RNA virus belonging to the group of lentiviruses from the family of retroviruses. Its genome consists of two single-stranded RNAs of 9.2 kilobase pairs and it encodes nine genes. To date two types of HIV are known, H!V-1 and HIV-2. The HI virus causes a chronic persistent, progressive infection. The disease proceeds through various stages from the asymptomatic infection, through the so-called AIDS-related-complex (hereinafter ARC), to the full clinical picture of AIDS. AIDS is the final stage of the disease. A characteristic of the HIV infection is the long clinical latency period with persistent viremia, which leads in the end stage to failure of the immune defenses and thus to AIDS.

[0026] The term "diseases caused by them", or similar expressions, refers to the diseases caused either directly or indirectly by a viral infection - for example by a retrovirus such as HIV - e.g. AIDS as a direct infectious disease resulting from a retroviral infection with HIV.

Consequently, AIDS would be a retrovirally-induced disease in the context of the present invention. [0027] The term "retrovirally-induced diseases" or similar expressions refer in the context of the invention to diseases that are caused by retroviruses, i.e. enveloped viruses with single (+)-strand-RNA-genomes, the genetic information of which (ss(+)-RNA) is accordingly present in the form of ribonucleic acids. In particular the HI virus is a retrovirus that in the end stage of the infection may lead to the clinical picture of AIDS (Acquired Immune Deficiency Syndrome). In this context "an H!V-induced disease" would be AIDS.

[0028] Within the scope of the present invention the terms "HIV-induced diseases and HIV- -induced diseases" describe acute infections that as a rule lead to an acute HIV-caused disease after an incubation period of about three to six weeks. This is characterised by fever, night sweats, fatigue, rashes, oral ulcers or arthralgia (joint pain). After a subsequent multi-year latent phase, which is usually symptom-free, these infections generally lead to a transitional ARC and in the end stage to AIDS. [0029] Within the scope of the present invention the term "AIDS and its preliminary stages" includes both the full-blown clinical picture of AIDS in the end stage as well as all the prior phases of an HIV- infection, characterised by its average latent phase of nine to eleven years and ARC.

[0030] As salts, within the scope of the present invention, physiologically acceptable salts of the compounds pursuant to the invention are preferred.

[0031] Physiologically acceptable salts of the compounds contained in the combination preparations pursuant to the invention preferably include acid addition salts of mineral acids, carboxylic acids, and sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, benzene sulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid or similar acid addition salts.

[0032] Physiologically acceptable salts of the compounds contained in the combination preparations pursuant to the invention also include salts of common bases, such as preferably alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium- and magnesium salts) and ammonium salts, derived from ammonia or organic amines with 1 to 16 C atoms, such as preferably ethyl amine, diethyl amine, triethy! amine, ethyl diisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and

N-methy!piperidine or similar salts of customary bases.

[0033] Solvates within the scope of the invention are those forms of compounds that in a solid or liquid state through coordination with solvent molecules form a complex. Hydrates are a special form of the solvate in which the coordination takes place with water. [0034] Accordingly, within the scope of the present invention the term solvates also always includes their hydrates with the above-cited definition.

[0035] Within the scope of the present invention the cited substituents, unless otherwise specified, have the following meaning: halogen or halo stands for fluorine, chlorine, bromine or iodine, with fluorine and chlorine always being preferred, unless otherwise specified. [0036] The antivirally active pharmaceutical ingredients in the active pharmaceutical ingredient combinations pursuant to the invention that are cited under b) and that differ from a), which are selected from a group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof are known to the person skilled in the art. These include all antiretroviral pharmaceutical ingredients, particularly anti-HIV compounds that are medically approved, that are currently in approval proceedings or that are still in development and that are based on one of the active principles of the drug action classes discussed above. Within the scope of the invention the following compounds are cited as preferable:

[0037] HIV protease inhibitors selected from the group comprising Saquinavir (SQV), Indinavir (IDV), Ritonavir (RTV), Nelfinavir (NFV), Amprenavir (APV), Lopinavir (LPV), Atazanavir (ATV), Fosamprenavir (FPV), Tipranavir (TPV), Darunavir (DRV).

[0038] Nucleoside and nucleotide HIV reverse transcriptase inhibitors selected from the group including Zidovudine (AZT), Lamivudine (3TC), Didanosine (ddl), Zalcitabine (ddC), Stavudine (d4T), Abacavir (ABC), Tenofovir (TDF or TAF), Emtricitabine (FTC), Amdoxovir (DAPD), Apricitabine (dOTC), Racivir (RCV), Elvucitabine (ACH- 26,443), Festinavir (4'Ed4T).

[0039] According to the invention, non-nucleoside inhibitors of HIV reverse transcriptase are not non-nucleoside HIV reverse transcriptase inhibitors based on tri(hetero)aryl pyrazoles, but are selected from a group comprising Efavirenz (EFV), Etravirine (ETV), Nevirapine (NVP), Rilpivirine (RPV), Delavirdine (DLV), Doravirine (DOR), VM-1500 and Lersivirine (LER) or a physiologically acceptable salt, a solvate or a solvate of the salt thereof.

[0040] Entry inhibitors (Els) selected from the group comprising Maraviroc { VC) and Enfuvirtide (T-20), Cenicriviroc (TAK-652, TBR-652), Ibalizumab (TMB-355), PRO-140,

AMD-070, I CB9471.

[0041] HIV integrase inhibitors (lis) selected from the group comprising Raltegravir (RAL), Elvitegravir (EVG), Dolutegravir (DTG), GSK-1265744.

[0042] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein a) comprises at least one antivirally active pharmaceutical ingredient of the compound according to Formula (I) in which X stands for N or CH and

R1 stands for fluorine, chlorine, bromine or iodine, R2 stands for H or CH3.

[0043] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein a) comprises at least one antiviraliy active pharmaceutical ingredient of the compound according to Formula (I) in which

X stands for N or CH and

R1 stands for fluorine or chlorine,

R2 stands for H or CH3. [0044] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein a) comprises at least one antiviraliy active pharmaceutical ingredient of the compound according to Formula (I), the compound of Formula (I) being a compound of Formula (II)

or one of its physiologically acceptable salts, solvates or a solvate of the salts thereof. [0045] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein a) comprises at least one antiviraliy active pharmaceutical ingredient of the compound according to Formula (I), the compound of Formula (I) being a compound of Formula (III)

(I I I) or one of its physiologically acceptable salts, solvates or a solvate of the salt thereof.

[0046] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein a) comprises at least one antivirally active pharmaceutical ingredient of the compound according to Formula (I), the compound of Formula (I) being a compound of Formula (IV)

or one of its physiologically acceptable salts, solvates or a solvate of the salt thereof.

[0047] Within the context of the invention it may suffice that in the active pharmaceutical ingredient combinations pursuant to a) and b) only two different antivirally active pharmaceutical ingredients for use in the prevention and/or treatment of viral infections and of diseases caused by them are combined. The statement under b), being it that "at least one antivirally active pharmaceutical ingredient different from a), selected from a group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors and combinations thereof as well as physiologically acceptable salts, solvates or the solvates of the salts thereof is to be understood to the effect that of the active pharmaceutical ingredient combinations also at least two, three or four of the active pharmaceutical ingredients that fall under the generic terms of b) may pursuant to the invention be combined with one another. These combinations of different active pharmaceutical ingredients from different drug action classes under b) are to be selected for the purpose of a highly active a nti retroviral therapy, the combination forms of which are well known to the person skilled in the art and that may, for example, be taken from Table C below.

[0048] Consequently further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is a nucleoside or nucleotide reverse transcriptase inhibitor, selected from a group comprising Zidovudine (AZT), Lamivudine (3TC), Didanosine (ddl), Zaicitabine (ddC), Stavudine (d4T), Abacavir (ABC), Tenofovir (TDF or TAF), Emtricitabine (FTC), Amdoxovir (DAPD), Apricitabine (dOTC), Racivir (RCV), Elvucitabine (ACH-126,443) and Festinavir (4'Ed4T) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salt thereof.

[0049] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is a non-nucleoside reverse transcriptase inhibitor, selected from a group comprising Efavirenz (EFV), Etravirine (ETV), Nevirapine (NVP), Rilpivirine (RPV), Delavirdine (DLV), Doravirine (DOR), VM- 500 and Lersivirine (LER) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof.

[0050] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is a protease inhibitor, selected from a group comprising Saquinavir (SQV), Indinavir (IDV), Ritonavir (RTV), Nelfinavir (NFV), Amprenavir (APV), Lopinavir (LPV), Atazanavir (ATV), Fosamprenavir (FPV), Tipranavir (TPV) and Darunavir (DRV) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof. [0051] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is an entry inhibitor, selected from a group comprising Maraviroc (MVC), Enfuvirtide (T-20), Cenicriviroc (TAK-652, TBR-652), Ibalizumab (TMB-355), PRO-140, AMD-070 and INCB9471 as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof. [0052] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is an Integrase inhibitor, selected from a group comprising Raltegravir (RAL), Elvitegravir (EVG), Dolutegravir (DTG) and GSK- 265744 as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof.

[0053] Further subject matter of the invention are the above-cited active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein under b) at least two or at least three or at least four of the antivirally active pharmaceutical ingredients specifically cited above, selected from the drug action classes of nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors may be combined with one another as highly active antiretroviral therapies. Here preferably at least two or at least three or at least four of the active pharmaceutical ingredients specifically cited above may be combined with one another for the purpose of a HAART from various drug action classes.

[0054] In particular, the inventors have surprisingly found that the compounds from a) as NNRTIs based on tri(hetero)aryl pyrazoles in combination with the compounds of antiretroviral pharmaceutical ingredients from b), which do not belong to the drug action class of NNRTIs and are therefore based on different active principles from the tri-(hetero)aryl pyrazoles, exhibit a synergistic antiviral, particularly a synergistic antiretroviral activity. [0055] The terms "synergistic antiviral activity or synergistic antiretroviral activity or synergistic antiviral effectiveness or synergistic antiretroviral effectiveness" within the context of the invention refer to the interaction of the compounds that fall under a) and b) of the active pharmaceutical ingredient combinations described herein, wherein the compounds under b) do not belong to the drug action class of NNRTIs, which is further characterised by the fact that the compounds of a) and b) boost each other to such an extent in their antiviral or antiretroviral activity/effectiveness that the various compounds combined have a stronger effect than the respective individual compounds pursuant to a) and b) added together.

[0056] Thus, the present invention also concerns the unexpected extent of synergy between NNRTIs based on tri(hetero)ary! pyrazoles in combination with compounds of known antiretrovirally effective pharmaceutical ingredients, particularly in combination with compounds of known antiretrovirally effective pharmaceutical ingredients of a drug action class other than NNRTI against HI viruses, in particular against resistant and multi-resistant HI viruses. [0057] Within the context of the present invention the expression "a drug action class different from NNRTIs" or similar expressions, refer to a compound of an antiviral, preferably an antiretroviral pharmaceutical ingredient from the drug action classes: nucleoside RT inhibitors (NRTIs) and nucleotide RT inhibitors (NtRTIs); protease inhibitors (Pis); integrase inhibitors (lis) and entry inhibitors (Els).

[0058] Through the administration of new NNRTI compounds from a) in combination with the antivirally active pharmaceutical ingredients from b) that do not belong to the drug action class of the NNRTIs the active pharmaceutical ingredients in combination target, for example, the respective different mechanisms in the replication of a virus, by means of which their therapeutic use in prevention and/or treatment of viral infections and of diseases caused by them may be reinforced in the form of synergistic active ingredient combinations. Consequently, these active ingredient combinations pursuant to the invention can show a synergistic effect in the inhibition of HIV replication, since the individual active ingredients of the aforementioned synergistic antiviral combinations may be effective in a different way against HIV replication.

[0059] In this connection, for example, the compounds of Formula (I) pursuant to a), which work as NNRTI, target other receptor sites of an HI virus than the combinable compounds of b) pursuant to the invention that do not belong to the drug action class of NNRTIs.

[0060] Through the use of such active pharmaceutical ingredient combinations from compounds according to a) and the antivirally active pharmaceutical ingredients from b) that do not belong to the drug action class of NNRTIs it is possible to reduce the dosage of the compounds that fall under b) that would have been required for a desired therapeutic or preventive effect, in comparison to the dosage that is required if the drug is used in monotherapy.

[0061] Furthermore, the inventors have found targeted combinations of the NNRTIs pursuant to the invention with already-known NRTIs and NtRTIs, Pis, lis and Els that exhibit a high degree of antiretroviral synergy that is significantly greater than the normal magnitude of the synergy of the combinations solely of the known NRTIs and NtRTIs, Pis, lis and Els. For this, reference is made to Tables A, A1 , A2, B, B1 , B2 further below.

[0062] Consequently, the new active pharmaceutical ingredient combinations of the present invention that exhibit a level of synergy may reduce or eliminate the side effects of standard antiretroviral individual therapies without adversely affecting the antiviral action of the drugs. For the specific active ingredient combinations that exhibit a level of synergy reference is made to Tables A and B further below. These combinations reduce the risk of resistance to therapeutic forms with only one known antivirally active pharmaceutical ingredient or to HAART therapeutic forms with multiple known active pharmaceutical ingredients, and at the same time limit the associated toxicity to a minimum. These combinations may aiso heighten the effectiveness of the known antivirally active ingredient without increasing its toxicity.

[0063] Consequently, further subject matter of the present invention are combinations of active pharmaceutical ingredients for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein the compound from a) and the at least one compound from b) are present in a synergistic antiviral combination, wherein the antivirally active pharmaceutical ingredients cited under b) are selected from a group comprising nucleoside and nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors or a physiologically acceptable salt, solvate or a solvate of the salt thereof.

[0064] Further subject matter of the present invention are combinations of active pharmaceutical ingredients for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein the compound from a) and the at least one compound from b) are present in a synergistic antiviral combination, said synergistic antiviral combination being characterised in that a synergistic increase of the antiviral effectiveness of the combinations of the compounds from a) and b) exists as compared with the antiviral effectiveness of the individual single compounds from a) and b) and it extends beyond the sum of the effectiveness of the two active pharmaceutical ingredients used individually.

[0065] In the above context, further subjects of the invention are synergistica!ly antivirally active ingredient combinations from a) and b) with the following specific antivirally active pharmaceutical ingredients under b): [0066] Subject matter of the invention are combinations of active pharmaceutical ingredients from a) and b) for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein the said at least one compound from b) is a nucleoside and nucleotide reverse transcriptase inhibitor, selected from the group comprising Stavudine, Zidovudine, Tenofovir, Lamivudine, Abacavir and Didanosine or a physiologically acceptable salt, solvate or a solvate of the salt thereof.

[0067] The subject matter of the invention are combinations of active pharmaceutical ingredients from a) and b) for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein the said at least one compound from b) is a protease inhibitor, selected from the group comprising Nelfinavir, Atazanavir, and Darunavir or a physiologically acceptable salt, solvate or a solvate of the salt thereof. [0068] Subject matter of the invention are combinations of active pharmaceutical ingredients from a) and b) for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein said at least one compound from b) is an entry inhibitor, selected from the group comprising Maraviroc and Enfuvirtide or a physiologically acceptable salt, solvate or a solvate of the salt thereof.

[0069] Subject matter of the invention are combinations of active pharmaceutical ingredients from a) and b) for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein the said at least one compound from b) is an integrase inhibitor which is Raltegravir.

[0070] In this context, further subject matter of the invention are the aforementioned synergistic antivirally active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein under b) at least two or at least three or at least four of the antivirally active pharmaceutical ingredients specifically cited above, selected from the drug action classes of nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors, may be combined with one another. Here preferably at least two or at least three or at least four of the antivirally active pharmaceutical ingredients specifically cited above are combined for the purpose of a HAART from different drug action classes.

[0071] Further subject matter of the invention are the active pharmaceutical ingredient combinations described in greater detail above for use in the prevention and or treatment of viral infections and of diseases caused by them, said viral infections being infections with retroviruses.

[0072] Further subject matter of the invention are the active pharmaceutical ingredient combinations described in greater detail above for use in the prevention and/or treatment of viral infections and of diseases caused by them, wherein said retroviral infections are HIV-1 retroviral infections.

[0073] Further subject matter of the invention are the active pharmaceutical ingredient combinations described in greater detail above for use in the prevention and/or treatment of viral infections and of diseases caused by them, the disease induced thereby being AIDS. [0074] In conjunction with the results from Tables A and B the inventors have been able to provide a new therapeutic approach that goes beyond the synergistic action of new antivirally active ingredient combinations and their combined use against viral infections and diseases. [0075] The new therapeutic approach, which is directed at the use of the active ingredient combinations pursuant to the invention in the prevention and/or treatment of viral infections and of diseases caused by them, in particular retroviral infections by the HI virus and AIDS, addresses the problem of resistant or multi-resistant viruses, particularly of resistant or multi-resistant HI viruses in a patient as compared with known anti-HIV pharmaceutical ingredients selected from the drug action classes of nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors as well as known combinations thereof within the framework of a HAART. [0076] Consequently, further subject matter of the present invention are active

pharmaceutical ingredient combinations provided for use in the prevention and/or treatment of viral infections and of diseases caused by them, where the use is characterised in that the prevention and/or treatment is carried out on a patient who suffers from an infection with resistant HIV-1 and thus does not respond to therapy with at least one antiviral!y active pharmaceutical ingredient selected from the drug action classes of the nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors, where the proof of resistant HIV 1 infection is provided by a genotypic resistance test of the viral genome. [0077] Consequently further subject matter of the present invention are active

pharmaceutical ingredient combinations provided for use in the prevention and/or treatment of viral infections and of diseases caused by them, where the use is characterised in that prevention and/or treatment is carried out on a patient who suffers from an infection with multi-resistant HIV-1 and thus does not respond to therapy with at least two different antivirally active pharmaceutical ingredients selected from the drug action classes of the nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors, as well as to combinations thereof, where the proof of multi-resistant HIV-1 infection is provided by a genotypic resistance test of the viral genome. [0078] In the context of the present invention the expression "resistant HI viruses" or similar expressions refer to types of these viruses that do not respond to individual known HIV-specific virostatics.

[0079] The expression "resistant HI viruses" means, for example, that HI viruses with resistance to nucleoside or nucleotide RT Inhibitors or non-nucleoside RT Inhibitors or integrase inhibitors or entry inhibitors or protease inhibitors are present in a patient, or HI viruses with resistance to other active principles are present in a patient. [0080] In the context of the present invention the expression "multi-resistant HI viruses" or similar expressions refer to types of these viruses that do not respond to almost all known HIV-specific virostatics. [0081] The expression "multi-resistant HI viruses" means, for example, that HI viruses with resistance to nucleoside or nucleotide RT Inhibitors and/or non-nucleoside RT Inhibitors and/or integrase inhibitors and/or entry inhibitors and/or protease inhibitors are present in a patient, or HI viruses with resistance to other active principles are present in a patient. [0082] In order to clinically clarify the presence of simple resistance and cross-resistance, normally the standard procedure is that before the start of treatment a genotypic resistance test (sequencing of the viral genome) is performed, which provides information on which therapeutic options still exist or, based on existing resistance, no longer exist. From this a medical professional obtains information on when, for example, the therapy with the active pharmaceutical ingredient combinations pursuant to the invention might be indicated, in order to start an effective antiviral therapy despite the presence of simple or cross resistance.

[0083] A further subject matter of the invention are active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, pursuant to one of the preceding claims, wherein the compound from a) is administered in a daily dose of 0. 1 -30 mg/kg body weight, preferably in a daily dose of 0.1 - 25 mg/kg body weight, further preferred in a daily dose of 0.1 - 20 mg/kg body weight, further preferred in a daily dose of 0.1 - 15 mg/kg body weight, further preferred in a daily dose of 0.1 - 10 mg/kg body weight, further preferred in a daily dose of 0. 1 - 5 mg/kg body weight, and as a function of which the at least one compound from b) and any other compound from b) is administered in a daily dose of 0.1 - 30 mg/kg body weight, preferably in a daily dose of 0.1 - 25 mg/kg body weight, further preferred in a daily dose of 0. 1 -20 mg/kg body weight, further preferred in a daily dose of 0. 1 -1 5 mg/kg body weight, further preferred in a daily dose of 0.1 - 10 mg/kg body weight, further preferred in a daily dose of 0.1 - 5 mg/kg body weight.

[0084] A further subject matter of the invention are active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, pursuant to one of the preceding claims, wherein the compound from a) is administered in a single dose of 0.1 - 15 mg/kg body weight, preferably in a single dose of 0.1 - 12.5 mg/kg body weight, further preferred in a single dose of 0.1 - 10 mg/kg body weight, further preferred in a single dose of 0.1 - 7.5 mg/kg body weight, further preferred in a single dose of 0. 1 -5 mg/kg body weight, further preferred in a single dose of 0.1 - 2.5 mg/kg body weight and as a function of which the at least one compound from b) and any other compound from b) is administered in a single dose of 0.1 - 1 5 mg/kg body weight, preferably in a single dose of 0.1 -12.5 mg/kg body weight, further preferred in a single dose of 0.1 - 10 mg/kg body weight, further preferred in a single dose of 0.1 - 7.5 mg/kg body weight, further preferred in a single dose of 0.1 - 5 mg/kg body weight, further preferred in a single dose of 0.1 - 2.5 mg/kg body weight. [0085] A further subject matter of the invention are active pharmaceutical ingredient combinations for use in the prevention and/or treatment of viral infections and of diseases caused by them, pursuant to one of the preceding claims, wherein the compound from a) is present in a single dose of 0.1 - 1000 mg, preferably of 1 - 800 mg, further preferred of 1 - 600 mg, further preferred of 1 - 400 mg, further preferred of 1 - 200 mg per dose unit and as a function of which the at least one compound from b) and any other compound from b) is administered in a single dose of 0.1 - 1000 mg, preferably of 1 - 800 mg, further preferred of 1 - 600 mg, further preferred of 1 - 400 mg, further preferred of 1 - 200 mg per dose unit.

[0086] The active ingredient combinations pursuant to the invention may be present together in the form of pharmaceutical compounds and be administered together or may be present as separately administered combination preparations for each active ingredient in a suitable administration form for each active ingredient and be either administered simultaneously or at intervals (sequentially). [0087] Within the context of this invention the term "combination preparation" always means the combination of two of the antiviral, in particular antiretroviral, pharmaceutical ingredients pursuant to the invention in separate and respectively suitable administration forms, wherein the antivirally active pharmaceutical ingredient under a) is always a compound pursuant to Formula (I). Here the individual active ingredients are present in pharmaceutical compositions adapted to each of them and are taken separately. Thus, for example, the combinations of active ingredients pursuant to the invention may be present in two separate tablets to be taken orally.

[0088] On the other hand, pursuant to the invention the presence of the active ingredient combinations in a pharmaceutical composition means that at least two different compounds of the invention from a) and b) are present in a pharmaceutical mixture with at least one inert, non-toxic pharmaceutical excipient, wherein the antivirally active pharmaceutical ingredient under a) is always a compound pursuant to Formula (I).

[0089] Within the context of the invention "separately administered combination preparations" means that the active ingredients pursuant to the invention according to a) and b) are each separately present in an administration form suitable to them and are administered either simultaneously or at intervals (sequentially). Here the combination partner pursuant to a) is always a non-nucleoside reverse transcriptase inhibitor based on tri-(hetero )aryl pyrazoles pursuant to the compounds according to Formula (I).

[0090] A further subject matter of the invention are, consequently, pharmaceutical compounds comprising a compound a) pursuant to the subjects described above and at least one antivirally active pharmaceutical ingredient b) pursuant to the subjects described above and at least one inert, non-toxic and pharmaceutically suitable excipient.

[0091] A further subject matter of the invention is a combination preparation comprising a compound a) pursuant to the subject matter described above and at least one antivirally active pharmaceutical ingredient b) pursuant to the subjects described above and in each case at least one inert, non-toxic and pharmaceutically suitable excipient.

[0092] A further subject matter of the invention is a combination preparation pursuant to the subjects described above, wherein the compound a) and the antivirally active pharmaceutical ingredient b) are present separately in a suitable administration form.

[0093] A further subject matter of the invention is a combination preparation pursuant to the subjects described above, wherein the suitable administration form may in each case be selected from a group comprising capsules, tablets, patches or liquids.

[0094] A further subject matter of the invention is a combination preparation pursuant to the subjects described above, wherein the compound a) and the antivirally active pharmaceutical ingredient b) may be administered separately in a suitable administration form pursuant to the subject matter described above, either simultaneously or sequentially.

[0095] A further subject matter of the invention is a combination preparation pursuant to the subjects described above, wherein the sequential administration is carried out with a delay of no more than 24 hours, preferably of no more than 12 hours, preferably of no more than 10 hours, further preferred of no more than 8 hours, still further preferred of no more than 6 hours, still further preferred of no more than 4 hours, most preferred of no more than 1 hour.

[0096] Surprisingly and unexpectedly it has been shown to be advantageous that by means of the active pharmaceutical ingredient combinations pursuant to the invention, the problems described above with regard to the development of resistance or multi-resistance may be markedly reduced.

[0097] The unexpectedly high degree of antiviral synergy of the corresponding combination preparations pursuant to the invention provides the following advantages: complete viral suppression, particularly the suppression of HIV, and viral, particularly retroviral, suppression over long periods of time; an improved toxicity profile and the limitation of the occurrence of resistance to active ingredients by already-present mutations, and thus the limitation of the development of multi-resistant HI viruses. The use of the combination preparations pursuant to the invention may, under certain circumstances, reduce the number of pills to be taken by the patient and thus also positively affect the consent/compliance of a patient as compared with HAART therapy.

[0098] The active pharmaceutical ingredient combinations of the present invention are further advantageous in that through targeted combinations of the NNRTIs pursuant to the invention, with already-known NRTIs and NtRTIs, Pis, lis and Els, a high degree of a nti retroviral synergy may be produced in the mode of action, that is significantly greater than the normal level of synergy of the combinations consisting solely of the known NRTIs and NtRTIs, Pis, lis and Els. For this, reference is made to Tables A, A1 , A2, B, B1 , B2 further below.

[0099] The pharmaceutical compositions or combination preparations of the present invention are characterised particularly by an advantageous, synergistically antiretroviral activity spectrum. [00100] The already-known antiretroviral active ingredients of the present invention, selected from the drug action classes of the NRTIs and NtRTIs, NNRTIs, Pis, lis and Els, are commercially available and described extensively in the patent literature and scientific literature (for overviews, see for example in Flexner, Nahire Reviews Drug Discovery 2007;6:959-966; De Clercq. Advances in Pharmacology. 2013;67:3 7-358; De Clercq. International Journal of Antimicrobial Agents. 2009;333:307-20).

[00101] Pursuant to the invention, the drug action classes of NRTIs and NtRTIs preferably comprise the active ingredients Zidovudine (AZT), Lamivudine (3TC), Didanosine (ddl), Zaicitabine (ddC), Stavudine (d4T), Abacavir (ABC), Tenofovir (TDF or TAF), Emtricitabine (FTC), Amdoxovir (DAPD)_, Apricitabine (dOTC), Racivir (RCV), Elvucitabine (ACH-126,443) and Festinavir (4'Ed4T) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof.

[00102] Pursuant to the invention, the drug action class of NNRTIs preferably comprises the active ingredients Efavirenz (EFV), Etravirine (ETV), Nevirapine (NVP), Rilpivirine (RPV), Delavirdine (DLV), Doravirine (DOR), VM-1500 and Lersivirine (LER) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof. [00103] Pursuant to the invention, the drug action ciass of Pis preferably comprises the following active ingredients: Saquinavir (SQV), Indinavir (!DV), Ritonavir (RTV), Nelfinavir (NFV), Amprenavir (APV), Lopinavir (LPV), Atazanavir (ATV), Fosamprenavir (FPV), Tipranavir (TPV) and Darunavir (DRV) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof.

[00104] Pursuant to the invention, the drug action class of lis preferably comprises the active ingredients Raltegravir (RAL), Elvitegravir (EVG), Dolutegravir (DTG) and GSK-1265744 as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof.

[00 05] Pursuant to the invention, the drug action class of Els preferably comprises the active ingredients Maraviroc (MVC), Enfuvirtide (T-20), Cenicriviroc (TAK-652, TBR-652), Ibalizumab (T B-355), PRO-140, AMD-070 and INCB9471 as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof.

[00106] As already noted above, the problem of cross-resistance is most pronounced in the drug action class of NNRTIs, since here often only a single point mutation in the RT may suffice to bring about a loss of activity of all known NNRTIs.

[00107] Therefore, pursuant to the invention, however, the NNRTIs of the invention may be combined with already known NNRTI compounds in order to produce at least one additive a nti retroviral effect which still addresses the problem of cross-resistance of HI viruses. The drug action class of the already-known NNRTIs preferably comprises within the scope of the invention Efavirenz (EFV), Etravirine (ETV), Nevirapine (NVP), Rilpivirine (RPV), Delavirdine (DLV), Doravirine (DOR), VM-1500 and Lersivirine (LER) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof. [00108] The possibility of overcoming cross-resistance in HIV by providing the new active ingredient combinations of the present invention constitutes a significant advantage of the subject matter of the invention.

[00109] Further preferred embodiments of the invention are shown in the following paragraphs:

[00110] In a more preferred embodiment of the invention the compound according to Formula (I) is the compound of Formula (II) or a physiologically acceptable salt, solvate or a solvate of the salt thereof:

Formula (II).

[00111] In another more preferable embodiment the compound according to Formula

(I) is the compound according to Formula (III) or a physiologically acceptable salt, solvate or a solvate of the salt thereof:

Formula (III).

[00112] In another more preferable embodiment the compound according to

Formula (I) is the compound of Formula (IV) or a physiologically acceptable salt, solvate or a solvate of the salt thereof:

Formula (IV).

[00113] Pursuant to the invention, it is equally preferable to combine the compounds according to Formulas (II; III; IV) with the following compounds either individually or in additional combinations:

[00114] HIV protease inhibitors selected from the group comprising Saquinavir (SQV), Indinavir (IDV), Ritonavir (RTV), Nelfinavir (NFV), Amprenavir (APV), Lopinavir (LPV), Atazanavir (ATV), Fosamprenavir (FPV), Tipranavir (TPV) and Darunavir (DRV) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof.

[00115] Nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase selected from the group comprising Zidovudine (AZT), Lamivudine (3TC), Didanosine (ddl), Zalcitabine (ddC), Stavudine (d4T), Abacavir (ABC), Tenofovir (TDF or TAF), Emtricitabine (FTC), Amdoxovir (DAPD), Apricitabine (dOTC), Racivir (RCV), Elvucitabine (ACH-126,443) and Festinavir (4'Ed4T) as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof. [00 16] Entry inhibitors (Els) selected from the group comprising Maraviroc (MVC),

Enfuvirtide (T-20), Cenicriviroc (TAK-652, TBR-652), Ibalizumab (TMB- 355), PRO-MO, A D-070 and INCB9471 as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof. [001 17] Inhibitors of HIV integrase (Ms) selected from the group comprising Raltegravir (RAL), Elvitegravir (EVG), Dolutegravir (DTG) and GSK-1265744 as well as combinations thereof and physiologically acceptable salts, solvates or the solvates of the salts thereof.

[00118] In a further more preferred embodiment the antivirally active pharmaceutical ingredient under b) is a nucleoside or nucleotide reverse transcriptase inhibitor that is preferably selected from the group consisting of Stavudine, Zidovudine, Tenofovir, Lamivudine and Abacavir.

[001 9] In a further more preferred embodiment the antivirally active pharmaceutical ingredient under b) is a protease inhibitor, preferably selected from the group consisting of Saquinavir, Indinavir, Ritonavir, Nelfinavir, Lopinavir, Atazanavir, Tipranavir and Darunavir.

[00120] In a further more preferred embodiment the antivirally active pharmaceutical ingredient under b) is an entry inhibitor, preferably selected from the group consisting of Maraviroc and Enfuvirtide.

[00121] In a further more preferred embodiment the antivirally active pharmaceutical ingredient under b) is an integrase inhibitor that is preferably Raltegravir. [00122] A still more preferred embodiment of the invention are active pharmaceutical ingredient combinations, consisting of a synergistic antiviral combination of a compound a) pursuant to Formula (II) or a physiologically acceptable salt, solvate or a solvate of the salt thereof and an antivirally active pharmaceutical ingredient b) from the group Zidovudine or Tenofovir or Stavudine or Lamivudine.

[00123] A still more preferred embodiment of the invention are active pharmaceutical ingredient combinations, consisting of a synergistic antiviral combination of a com ound a) pursuant to Formula (II) or a physiologically acceptable salt, solvate or a solvate of the salt thereof and an antivirally active pharmaceutical ingredient b) from the group Atazanavir or Darunavir or Nelfinavir.

[00124] A still more preferred embodiment of the invention are active pharmaceutical ingredient combinations, consisting of a synergistic antiviral combination of a compound a) pursuant to Formula (II) or a physiologically acceptable salt, solvate or a solvate of the salt thereof and an antivirally active pharmaceutical ingredient b) that is altegravir.

[00 25] A still more preferred embodiment of the invention are active pharmaceutical ingredient combinations, consisting of a synergistic antiviral combination of a compound a) pursuant to Formula (III) or a physiologically acceptable salt, solvate or a solvate of the salt thereof and an antivirally active pharmaceutical ingredient b) that is Didanosine.

[00126] The invention further provides a drug for use in the prevention and/or treatment for patients who suffer from a viral, in particular a retroviral infection, such as HIV-1 , which comprises at least one of the active pharmaceutical ingredient combinations pursuant to the invention either as a pharmaceutical composition or in the form of a combination preparation.

[00127] The combination preparations pursuant to the invention may be administered simultaneously or sequentially. The combination preparations may exist in various suitable administration forms, for example as separate capsules and/or as separate tablets and/or as separate patches and/or in the form of separate liquids that contain the suitable concentrations of the active ingredients pursuant to the invention. [00128] In this context, it is within the scope of the invention if the individual active ingredients of the combination preparations are present in a suitable pharmaceutical formulation and possibly in different administration forms with different administration regimens. [00129] Thus it is within the scope of the invention to administer one of the active ingredients as a combination partner, for example orally in the form of tablets or capsules, for example once or twice daily; whereas the at least one other combination partner is administered, for example, with a longer interval of at least one day. Said at least one other combination partner may, for example, also be administered with an interval of at least one week or at least one month. This may even be in an administration form other than oral, such as for example by means of intramuscular, intravenous or subcutaneous application.

[00130] In sequential administration the delay until administration of the second active ingredient substance should not be selected such that the additive or additive/synergistic or purely synergistic advantage of the invention is lost.

[00131] Any delay in specific sequential administration pursuant to the invention of the combination preparations - irrespective of whether in the same administration form or in different administration forms - will not be more than 24 hours, preferably no more than 12 hours, preferably no more than 10 hours, further preferred of more than 8 hours, still further preferred no more than 6 hours, still further preferred no more than 4 hours. Most preferred is a delay of less than 1 hour; for example before and after eating. [00132] Preferably, but not exclusively, to simplify the administration, the active ingredient combinations of the present invention are presented in the same form of uniform dosing and in the same pharmaceutical composition, for example as capsules or as tablets or in the form of a liquid that contains the suitable concentrations of active ingredients from different drug action classes pursuant to the invention.

[00133] The quantity of the active ingredient combinations pursuant to a) and b) necessary for the suppression of HIV will naturally differ from patient to patient. The precise administration of the quantities of active ingredients will in the end be determined by the medical professional, who will take into account the relevant factors such as body weight, administration route, concomitant medications, age, sex and general condition and the nature and severity of the specific disease.

[00134] In this connection preferred mg-doses of the antivirally active pharmaceutical ingredients pursuant to a) for a single dose are in the range of 0.1 - 1000 mg, preferably in a range of 1 - 800 mg, further preferred in a range of 1 - 600 mg, further preferred in a range of 1 - 400 mg, further preferred in a range of 1 - 200 mg and depending on these mg-doses, the mg-doses of the antivirally active pharmaceutical ingredients pursuant to b) for a single dose are in the range of 0.1 - 1000 mg, preferably in a range of 1 - 800 mg, further preferred in a range of 1 - 600 mg, further preferred in a range of 1 - 400 mg, further preferred in a range of 1 - 200 mg.

[00135] In general, pursuant to the invention the preferred maximum effective daily quantity is regarded as a quantity from 0.0 mg/kg to 50 mg/kg body weight of antivirally active pharmaceutical ingredients pursuant to a) and b), specially preferred is a quantity of 0.1 mg/kg to 10 mg/kg body weight of antivirally active pharmaceutical ingredients pursuant to a) and b), for prevention and/or treatment of a viral infection, particularly an HIV infection. Pursuant to the invention, it may be expedient to administer the dose required as two, three, four or more partial doses at certain intervals over the day. The partial doses may be formulated as single dose forms that include, for example, from 1 to 1000 mg and particularly from 5 to 200 mg of active ingredient per single dose form.

[00136] The quantity of active ingredient that may be combined with the appropriate pharmaceutical carrier materials in order to produce a single dose form will vary depending on the host/patient to be treated and the specific type of administration. A typical preparation will contain approx. 5% to approx. 95% active compound (wt./wt.) pursuant to a) and b). Preferably such preparations contain approx. 20% to approx.80% active compound pursuant to a) and b).

[00137] Further preferred mg-doses of possible antivirally active pharmaceutical ingredients pursuant to b) may be found in the active ingredient matrix in Table C. For the compounds according to Formula (I) the doses listed above in mg are for a single dose.

[00138] The active pharmaceutical ingredient combinations pursuant to the invention are expediently administered as often as clinically necessary, either in the form of pharmaceutical compositions or combination preparations. This may mean, for example that preferably once to twice daily, a combination pursuant to the invention of a) and b) is administered, with the above-cited doses of the active ingredient combinations; either in a pharmaceutical composition or as a combination preparation. [00139] The compounds of Formula (I) pursuant to a) contained in the active pharmaceutical ingredient combinations pursuant to the invention may be manufactured by converting a compound of Formula (V)

Formula (V), in which

Hal stands for chlorine, bromine or iodine and

R stands for a halo substituent, selected from the group consisting of fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred, with a compound of Formula (VI)

Formula (VI), in which Hal stands for chlorine, bromine or iodine and

X stands for N or CH, the asterisk stands for an optimal substitution point for -CH3.

[00140] The conversion generally takes place in two stages in inert solvents, first forming an organo-metallic component, followed by the conversion in the presence of a catalyst complex and a base, preferably in a temperature range from 50°C to 150°C under high pressure and the exclusion of oxygen and.

[00141] The production of compounds according to Formula (I) pursuant to a) may be illustrated, for example, by the following synthesis diagram. Synthesis diagram:

[00142] Among the areas of indication for the pharmaceutical preparations pursuant to the invention or combination preparations in human medicine, the following may be cited as examples:

1. ) The treatment and prevention of human retrovirus infections.

2. ) The treatment and prevention of infections, and diseases (acute diseases up to and including AIDS) caused by HIV, particularly by HIV-1 , and the associated stages such as ARC (AIDS-related-complex) and LAS (Lymphadenopathy Syndrome) as well as the low immunity and encephalopathy caused by the HI virus.

3. ) The treatment of HIV infections induced by single, multiple or multi-resistant HI viruses. In order to clarify this, normally the standard procedure is that before the start of treatment a genotypic resistance test (sequencing of the viral genome) is performed, which provides information on which therapeutic options exist.

4.) The treatment or prevention of the HIV-carrier state (HIV-transmitter state). [00143] In veterinary medicine, the following indications may, for example, be listed:

I fections with

a) Maedi-visna (e.g. in sheep and goats) b) progressive pneumonia virus (PPV) (e.g. in sheet and goats) c) caprine arthritis encephalitis-virus (e.g. in sheep and goats) d) Zwoegerziekte (Maedi-visna) virus (e.g. in sheep) e) infectious anemia virus (e.g. in horses) f) infections caused by the feline leukemia virus g) infections caused by the feline immunodeficiency virus (FIV) h) infections caused by the simian immunodeficiency virus (SIV)

[00144] Within the scope of the invention Points 2.), 3.) and 4.) of the above-cited indication areas are preferred in human medicine for the use of the active pharmaceutical ingredient combinations pursuant to the invention.

[00145] The active pharmaceutical ingredient combinations pursuant to the invention may also be used, among other things, against HI viruses that demonstrate resistance against known NNRTIs, such as Efavirenz or Nevirapine. [00146] The active pharmaceutical ingredient combinations pursuant to the invention usually work systemically. For this purpose they may be administered in a suitable manner, such as by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctiva!, otic routes or as an implant or stent. [00147] For these application routes the active pharmaceutical ingredient combinations pursuant to the invention may be administered in suitable application forms.

[00148] The following are suitable for oral application: Fast-acting and/or modified application forms functioning according to the prior art that release the active ingredient combinations pursuant to the invention and that contain the pharmaceutical compositions or combination preparations pursuant to the invention in crystalline and/or amorphised and/or dissolved form such as tablets (coated or uncoated tablets, for example enteric-coated or delayed-dissoiving or soluble or insoluble coatings that control the release of the compounds pursuant to the invention), tablets or film tablets or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), lozenges, granules, pellets, powder, emulsions, suspensions, aerosols or solutions that disintegrate quickly in the oral cavity.

[00149] Parenteral application may take place while circumventing a resorption step (e.g. intravenous, intra-arterSal, intracardial, intraspinal or intralumbal routes) or incorporating resorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal routes). Application forms suitable for parenteral application are, among others, injection and infusion preparations in the form of solutions, suspensions, emulsions lyophilisates or sterile powders.

[00150] For the other application routes inhalation drug forms (among others powder inhalators, nebulisers), nose drops or solutions, sprays; tablets, films/wafers or capsules to be administered lingualiy, sublingually or buccally, via suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophile suspensions, ointments, creams, transdermal treatment systems (such as patches), milk, pastes, foams, powders, implants or stents are suitable.

[00151 ] The pharmaceutical compositions or combination preparations pursuant to the invention may be transferred to the application forms listed. This may be done in a known manner through mixing with inert, non-toxic pharmaceutically suitable excipients. [00152] These inert, non-toxic pharmaceutically suitable excipients include, among other things, carrier substances (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or surfactants (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilisers (e.g. antioxidants such as ascorbic acid), colorants (e.g. inorganic pigments such as iron oxides and ) and taste and/or odor correctors.

[00153] In a particularly preferred embodiment the active pharmaceutical ingredient combinations pursuant to the invention are present either in pharmaceutical compositions or in the form of combination preparations, each with a pharmaceutical composition specifically suitable to the antivirally active pharmaceutical ingredients involved, for oral administration.

[00 54] Further subject matter of the present invention are drugs that contain at least one variant of the active ingredient combinations pursuant to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, as well as their use for the aforementioned purposes.

[00155] As already noted, a medical person skilled in the art is already aware that the administration forms cited are not to be regarded as static. Thus, it may be necessary to diverge from the cited quantities, depending on body weight, application route, individual behavior with regard to the active ingredient, type of preparation and time or interval at which the application is to take piace. Thus in certain cases less than the aforementioned minimum quantity may suffice, while in other cases the aforementioned upper limit must be exceeded. In the case of the application of larger quantities starting from more than 30 mg/kg body weight, it may be recommended to divide these into several single doses over the course of the day,

[00156] A further aspect of the present invention concerns a process for the treatment of patients suffering from a viral infection and the diseases induced by it, including the administration of active pharmaceutical ingredient combinations pursuant to the invention in accordance with the subject matter of the invention detailed above.

[00157] In particular, a further aspect of the invention concerns a process for the treatment of patients suffering from a virat infection and the diseases induced by it, comprising the administration of a) at least one antivirally active pharmaceutical ingredient of the compound according to Formula (I)

in which

X stands for N or CH and R1 stands for a halogen substituent and R2 stands for H or CH3,

or one of its physiologically acceptable salts, solvates or any of the solvates of the salts thereof, and b) at least one antivirally active pharmaceutical ingredient different from a), selected from a group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors and combinations thereof, as well as physiologically acceptable salts, solvates or any of the solvates of the salts thereof.

[00158] A further aspect of the present invention concerns a process for the treatment of patients suffering from a viral infection and the diseases induced by it, comprising the administration of a) at least one antivirally active pharmaceutical ingredient of the compound according to Formula

in which

X stands for N or CH and

R1 stands for a halogen substituent and

R2 stands for H or CH3, or one of its physiologically acceptable salts, solvates or any of the solvates of the salts thereof, and b) at least one antivirally active pharmaceutical ingredient different from a) selected from a group comprising nucleoside and nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors and combinations thereof, as well as physiologically acceptable salts, solvates or the solvates of the salts thereof, wherein the active ingredient combinations act so effectively that a synergistic antiviral effect is produced in the patient.

[00159] A further aspect of the present invention concerns a process for the treatment of patients pursuant to the subject matter described above, wherein said viral infection is an infection with HIV-1 and said disease induced by it is AIDS.

[00160] A further aspect of the present invention concerns a process for the treatment of patients pursuant to the subject matter described above, wherein the patients suffer from an infection with multi-resistant viruses, particularly an infection with resistant HI viruses and the diseases induced thereby.

[00161] A further aspect of the present invention concerns a process for the treatment of patients pursuant to the subject matter described above, wherein the patients suffer from an infection with multi-resistant viruses, particularly an infection with multi-resistant HI viruses and the diseases induced thereby.

[00162] A further aspect that is essential to the invention is, given the entire above-cited context, the combined use of antivirally active pharmaceutical ingredients pursuant to the invention in the prevention and/or treatment of viral infections and of diseases caused by them; particularly the combined use in the prevention and/or treatment of specific patient groups (comprising specific individuals), namely those that suffer either from an infection with mono-resistant or multi-resistant viruses.

[00163] Consequently, particularly preferred variants of this invention are those embodiments numbered below, which are depending on one another:

[00164] 1.) An antivirally active pharmaceutical ingredient a) pursuant to the compound according to Formula (I)

in which

X stands for N or CH and

R1 stands for a halogen substituent and

R2 stands for H or CH3,

or one of its physiologically acceptable salts, solvates or a solvate of the salts thereof, for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein the use of the antivirally active pharmaceutical ingredients a) is combined with the use of at least one antivirally active pharmaceutical ingredients b) that is different from a, selected from a group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors as well as combinations thereof and physiologically acceptable salts, solvates or solvates of the salts thereof.

[00 65] 2.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to Embodiment 1 , wherein under a) in the compound according to Formula (I)

X stands for N or CH and R1 stands for fluorine, bromine, chlorine or iodine, R2 stands for H or CH3.

[00166] 3.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to Embodiment 1 or 2, wherein under a) in the compound according to Formula (I)

X stands for N or CH and

R1 stands for fluorine or chlorine,

R2 stands for H or CH3.

[00167] 4.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of Embodiments 1 to 3, wherein under a) the compound according to Formula (I) is a compound of Formula (II)

or one of its physiologically acceptable salts, solvates or any solvate of the salts thereof.

[00168] 5.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of Embodiments 1 to 3, wherein under a) the compound according to Formula (I) is a compound of Formula (III)

[00169] 6.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of Embodiments 1 to 3, wherein under a) the compound according to Formula (I) is a compound of Formula (IV)

[00170] 7.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to the above-numbered embodiments, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is a nucleoside or nucleotide reverse transcriptase inhibitor, selected from a group comprising Zidovudine (AZT), Lamivudine (3TC), Didanosine (dd!), Zaicitabine (ddC), Stavudine (d4T), Abacavir (ABC), Tenofovir (TDF or TAF), Emtricitabine (FTC), Amdoxovir (DAPD), Apricitabine (dOTC), Racivir (RCV), Elvucitabine (ACH-126,443) and Festinavir (4'Ed4T) as well as combinations thereof and physiologically innocuous salts, solvates or solvates of the salts thereof.

[00171] 8.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to the above-numbered embodiments, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is a non-nucleoside reverse transcriptase inhibitor, selected from a group comprising Efavirenz (EFV), Etravirine (ETV), Nevirapine (NVP), Rifpivirine (RPV), Delavirdine (DLV), Doravirine (DOR), VM-1500 and Lersivirine (LER) as well as combinations thereof and physiologically acceptable salts, solvates or solvates of the salts thereof.

[00172] 9.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to the above-numbered embodiments, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is a protease inhibitor, selected from a group comprising Saquinavir (SQV), Indinavir (!DV), Ritonavir (RTV), Neifinavir (NFV), Amprenavir (APV), Lopinavir (LPV), Atazanavir (ATV), Fosamprenavir (FPV), Tipranavir (TPV) and Darunavir (DRV) as well as combinations thereof and physiologically innocuous salts, solvates or solvates of the salts thereof.

[00173] 10.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to the above-numbered embodiments, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is an entry inhibitor, selected from a group comprising Maraviroc (MVC), Enfuvirtide (T-20), Cenicriviroc (TAK-652, TBR-652), Ibalizumab (TMB-355), PRO-140, AMD-070 and INCB9471 as well as combinations thereof and

physiologically acceptable salts, solvates or solvates of the salts thereof.

[00174] 11.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to the above-numbered embodiments, wherein under b) the at least one antivirally active pharmaceutical ingredient different from a) is an integrase inhibitor, selected from a group comprising Raltegravir (RAL), Elvitegravir (EVG), Dolutegravir (DTG) and GSK- 265744 as well as combinations thereof and physiologically acceptable salts, solvates or solvates of the salts thereof.

[00175] 12.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to the above-numbered embodiments, wherein under b) each of two or three or four of the antivirally active pharmaceutical ingredients specifically cited in Embodiments 7 to 1 may be combined with one another, wherein each of two or three or four specific antivirally active pharmaceutical ingredients to be combined, of embodiments 7 to 1 1 , belong to different drug action classes.

[00176] 13.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to the above-numbered embodiments, wherein the antivirally active pharmaceutical ingredient a) and the at least one antivirally active pharmaceutical ingredient b) that is different from a) are present in a synergistic antiviral combination, wherein the antivirally active pharmaceutical ingredients cited under b) are selected from a group comprising nucleoside and nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors as well as combinations thereof and physiologically acceptable salts, solvates or solvates of the salts thereof.

[00177] 14.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 13, wherein said synergistic antiviral combination is characterised in that there exists a synergistic increase in antiviral effectiveness of the combinations of the antivirally active pharmaceutical ingredients a) and b) as compared with the antiviral effectiveness of the individual active pharmaceutical ingredients a) and b), which extends beyond the total effectiveness of the two active pharmaceutical ingredients a) and b) used individually.

[00178] 15.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiments 13 and 14, wherein the at least one antivirally active pharmaceutical ingredient different from a) is a nucleoside and nucleotide reverse transcriptase inhibitor, selected from a group comprising Stavudine (d4T), Zidovudine (AZT), Tenofovir (TDF or TAF), Lamivudine (3TC), Abacavir (ABC) and Didanosine (ddl) as well as combinations thereof and physiologically acceptable salts, solvates or solvates of the salts thereof. [00179] 16.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of Embodiments 13 to 15, wherein the at least one antivirally active pharmaceutical ingredient b) different from a) is a protease inhibitor, selected from a group comprising Nelfinavir (NFV), Atazanavir (ATV) and Darunavir (DRV) as well as combinations thereof and physiologically acceptable salts, solvates or solvates of the salts thereof.

[00180] 17.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of embodiments 13 to 16, wherein the at least one antivirally active pharmaceutical ingredient b) different from a) is an entry inhibitor, selected from a group comprising araviroc (MVC) and Enfuvirtide (T-20) as well as combinations thereof and physiologically acceptable salts, solvates or solvates of the salts thereof. [00181] 18.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of embodiments 13 to 17, wherein the at least one antivirally active pharmaceutical ingredient b) different from a) is an integrase inhibitor, selected from a group comprising Raltegravir (RAL), Elvitegravir (EVG), Dolutegravir (DTG) and GSK-1265744 as well as combinations thereof or a physiologically acceptabe salt, solvate or any solvate of the salt thereof.

[00182] 19.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of embodiments 13 to 18, wherein under b) each of two or three or four of the antivirally active pharmaceutical ingredients specifically cited in embodiments 15 to 18 may be combined with one another, wherein each of the two or three or four specific antivirally active pharmaceutical ingredients to be combined, of embodiments 15 to 18, belong to different drug action classes. [00183] 20.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of the above-enumerated embodiments, wherein the antivirally active pharmaceutical ingredient a) is administered in a daily dose of 0.1 - 30 mg/kg body weight, preferably in a daily dose of 0.1 - 25 mg/kg body weight, further preferred in a daily dose of 0.1 - 20 mg/kg body weight, further preferred in a daily dose of 0.1 - 5 mg/kg body weight, further preferred in a daily dose of 0.1 - 10 mg/kg body weight, further preferred in a daily dose of 0.1 - 5 mg/kg body weight and as a function of which the at least one antivirally active pharmaceutical ingredient b) different from a) and each further antivirally active pharmaceutical ingredient b) is administered in a daily dose of 0.1 - 30 mg/kg body weight, preferably in a daily dose of 0.1 - 25 mg/kg body weight, further preferred in a daily dose of 0.1 -20 mg/kg body weight, further preferred in a daily dose of 0.1 - 15 mg/kg body weight, further preferred in a daily dose of 0.1 - 10 mg/kg body weight, further preferred in a daily dose of 0.1 - 5 mg/kg body weight.

[00184] 21 .) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of the above-enumerated embodiments, wherein the antivirally active pharmaceutical ingredient a) is administered in a single dose of 0.1 -15 mg/kg body weight, preferably in a single dose of 0.1 - 12.5 mg/kg body weight, further preferred in a single dose of 0.1 - 10 mg/kg body weight, further preferred in a single dose of 0.1 - 7.5 mg/kg body weight, further preferred in a single dose of 0.1 -5 mg/kg body weight, further preferred in a single dose of 0.1 -2.5 mg/kg body weight and as a function of which the at least one antivirally active pharmaceutical ingredient b) different from a) and each further antivirally active pharmaceutical ingredient b) is administered in a single dose of 0.1 - 15 mg/kg body weight, preferably in a single dose of 0.1 - 12.5 mg/kg body weight, further preferred in a single dose of 0.1 -1 0 mg/kg body weight, further preferred in a single dose of 0.1 - 7.5 mg/kg body weight, further preferred in a single dose of 0.1 - 5 mg/kg body weight, further preferred in a single dose of 0.1 - 2.5 mg/kg body weight.

[00185] 22.) The antiviraliy active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of the above-enumerated embodiments, wherein the antivirally active pharmaceutical ingredient a) is present in a single dose of 0.1 - 1000 mg, preferably of 1 - 800 mg, further preferred of 1 - 600 mg, further preferred of 1 - 400 mg, further preferred of 1 - 200 mg per dose unit and as a function of which the at least one antivirally active pharmaceutical ingredient b) different from a) and each further antivirally active pharmaceutical ingredient b) is administered in a single dose of 0.1 - 1000 mg, preferably of 1 - 800 mg, further preferred of 1 - 600 mg, further preferred of 1 - 400 mg, further preferred of 1 - 200 mg per dose unit.

[00186] 23.) Pharmaceutical compound for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, comprising an antivirally active pharmaceutical ingredient a) pursuant to any of embodiments 1 to 22 and at least one antivirally active pharmaceutical ingredient b) different from a) pursuant to any of embodiments 1 to 22 and at least one inert, non-toxic, pharmaceutically suitable excipient therefore. [00 87] 24.) Pharmaceutical compound for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 23, wherein said pharmaceutical compound may be administered with at ieast one pharmaceutically suitable carrier via an oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, or otic route or as an implant or stent. [00188] 25.) Combination preparation for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual comprising an antivirally active pharmaceutical ingredient a) pursuant to embodiments 1 to 22, wherein the antivirally active pharmaceutical ingredient a) is present separately in a pharmaceutical administration form suitable to it, and at least one active pharmaceutical ingredient b) different from a) pursuant to one of embodiments 1 to 22, wherein the antivirally active pharmaceutical ingredient b) is present separately in a pharmaceutical administration form suitable to it, and for the separate administration form, in each case at least one inert, non-toxic pharmaceutical excipient. [00189] 26.) Combination preparation for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 25, wherein said administration form suitable to it may be selected for each of antivirally active pharmaceutical ingredients a) and b) independently of one another from a group comprising capsules, tablets, active ingredient patches, liquids.

[00190] 27.) Combination preparation for use in the prevention and/or treatment of viral infections and of diseases caused by in an individual pursuant to one of embodiments 25 and 26, wherein the antivirally active pharmaceutical ingredients a) and b) in their suitable administration forms pursuant to embodiment 26 may be administered simultaneously or sequentially.

[00191] 28.) Combination preparation for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 27, wherein the sequential administration is carried out with a delay of no more than 24 hours, preferably of no more than 2 hours, preferably of no more than 10 hours, further preferred of no more than 8 hours, even more preferred of no more than 6 hours, even more preferred of no more than 4 hours, most preferred of no more than 1 hour.

[00192] 29.) Combination preparation for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of embodiments 25 to 28, wherein said suitable administration form for the antivirally active pharmaceutical ingredients a) and b) may in each case be administered independent of one another with at least one pharmaceutically suitable carrier via an oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, or otic route or as an implant or stent. [00193] 30.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of embodiments 1 to 22, wherein said individual suffers from a viral infection that is a retroviral infection.

[00194] 31 .) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 30, wherein said retroviral infection is an HIV-1 retroviral infection. [00195] 32.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 31 , wherein said retroviral infection in an individual is caused by a mono-resistant retrovirus, which is a mono-resistant HIV-1 retrovirus. [00196] 33.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 32, wherein the infection caused by a mono-resistant retrovirus in an individual is characterised in that the individual does not respond to an antivirally active pharmaceutical ingredient from a drug action class selected from the group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease- Inhibitors, entry inhibitors and integrase inhibitors, and wherein the proof of a simple resistant retrovirus may be provided by a genotypic resistance test of the viral genome.

[00197] 34.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 31 , wherein said infection with retroviruses in an individual is induced by a multi-resistant retrovirus which is a multi-resistant HIV-1.

[00198] 35.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 34, wherein the infection caused by a multi-resistant retrovirus in an individual is characterised in that the individual does not respond to at least two different antivirally active pharmaceutical ingredients from a drug action class selected from the group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors, and wherein the proof of a multi-resistant retrovirus may be provided by a genotypic resistance test of the viral genome. [00199] 36.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 31 , wherein said infection with retroviruses in an individual is induced by a multi-resistant retrovirus which is a multi-resistant H!V-1 retrovirus.

[00200] 37.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to embodiment 36, wherein the infection caused by multi-resistant retroviruses in an individual is characterised in that the individual does not respond to at least two different antivirally active pharmaceutical ingredients from at least two different drug action classes selected from the group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors and also does not respond to combinations thereof, and wherein the proof of a multi-resistant retrovirus may be provided by a genotypic resistance test of the viral genome.

[00201] 38.) The antivirally active pharmaceutical ingredient a) for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual pursuant to any of embodiments 31 to 37, wherein the disease caused by the HIV-1 virus is selected from a group comprising HIV infection, AIDS, ARC, LAS and impaired immunity, and encephalopathy caused by the HIV-1 viruses.

[00202] Unless otherwise specified, the percentages in the following tests and examples are given as percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration readings of liquid/liquid solutions refer in each case to the volume. The notation "w/v" means "weight/volume". Thus for example "10% w/v": means 100 ml solution or suspension contains 10 g substance.

Examples

Abbreviations

AZT Zidovudine

RIL / RPV Rilpivirine

LER Lersivirine

EFV Efavirenz

ETR Etravirine

NVP Nevirapine

ATV Atazanavir

RTV Ritonavir

TPV Tipranavir

DRV Darunavir

DOR Doravirine

LPV Lopinavir

d4T Stavudine

4'Ed4T Festinavir

PTC Emtricitabine

RBV Ribavirin

ABC Abacavir

IDV Indinavir

NFV Nelfinavir

SQV Saquinavir

3TC Lamivudine

TDF Tenofovir disoproxil fumarate TAF Tenofovir alafenamide

RAL Raltegravir ddl Didanosine

AIDS acquired immune deficiency syndrome

CC₅₀ cytotoxic concentration 50%

CPE cytopathic effect

DHHS U.S. Department of Health and Human Services

EC₅₀ effective concentration 50%

ED₅₀ effective dose 50%

FCS fetal calf serum cART combined a nti retroviral therapy

HIV human immunodeficiency virus

HAART highly active anti retroviral therapy ll(s) integrase inhibitor(s)

MTP microtiter plate

NRTI(s) nucleoside reverse transcriptase inhibitor(s)

NNRTI(s) non-nucleoside reverse transcriptase inhibitor(s)

Pl(s) protease inhibitor(s)

RT reverse transcriptase

RTI Reverse transcriptase inhibitor(s)

SD standard deviation

TCID5₀ tissue culture infectious dose 50%

CPE cytopathic effect

DMSO Dimethyl sulfoxide

ED₅₀ Average effective concentration GADPH glycerinaldehyde-3-phosphate- dehydrogenase

PBS phosphate buffered saline

MOI multiplicity of infection

ELISA enzyme-linked immunosorbent assay bs broad singlet (in NMR) d doublet (in NMR) dd doublet of doublet (in NMR) dt doublet of triplet (in NMR) eq. equivalent(s)

ESI electrospray-ionisation (in MS) h hour(s)

HPLC high-pressure-, high performance liquid chromatography

LC-MS liquid chromatography-mass spectrometry

LHMDS lithium bis(trimethylsilyl)amide

m multiplet (in NMR)

min minute(s)

MS mass spectrometry

NMR nuclear magnetic resonance

RT room temperature

Rt retention time (in HPLC) s singlet (in NMR)

TFA trifluoroacetic acid

THF tetrahydrofuran A. LC-MS and HPLC methods

The methods to be applied for LC-MS and HPLC are described below exemplari!y:

LC-MS:

[00203] Instrument: Waters ACQUITY SQD UPLC System; Column: Waters Acquity

UPLC HSS T3 1 ,8μ 50 mm x 1 mm; Eluent A: 1 I water + 0.25 ml 99% formic acid, Eluent B: 1 I acetonitrile + 0.25 ml 99% formic acid; Gradient: 0.0 min 90% A→ 1.2 min 5% A→ 2.0 min 5% A; Heater: 50°C; Flow rate: 0.40 ml/min; UV detection: 210-400 nm.

HPLC:

[00204] When purifying compounds by preparative HPLC according to the method described above, wherein the eluent contains additives, such as formic acid, the compounds in accordance with the invention can arise in salt form, such as formate salt, if the compounds contain sufficient basic functionality. Such a salt can be converted into the corresponding free base by methods known to one skilled in the art.

B. Synthesis of precursors of exemplary Formula (I) compounds from a): The synthesis of precursors of the Formula (I) compounds from a) is described below as an example:

[00205] The (hetero)arylhydrazine and methyl-(hetero)arylketone used are

commercially available or were synthesised using methods familiar from the literature.

[00206] The following references on synthesis of the (hetero)arylhydrazine are cited as examples: K. H. Pilgram, Synthetic Communications, 985, 15 (8), 697- 706; M. T. Makhija, Bioorganic & Medicinal Chemistry, 2004, 12 (9), 23 7-2333; A. Reisinger, Organic &

Biomolecular Chemistry, 2004, 2 (2), 246-256; V. S. Padalkar, Synthetic Communications, 201 1 _» 41 (6), 925-938; H. Y. Lo, Bioorganic & Medicinal Chemistry Letters, 2010, 20 (22), 6379-6383; M. G. C. Kahn, Bioorganic & Medicinal Chemistry Letters, 2006, 16 (13), 3454-3458; WO

2007/064872; WO 2009/068617; US 2005/0215577; WO 2008/034008; WO 2011/033018.

[00207] The following references on synthesis of the methyl-(hetero)arylketone are cited as examples: D. B. Bolstad, Journal of Medicinal Chemistry, 2008, 51 (21 ), 6839-6852; D. Xu, Tetrahedron Letters, 2008, 49 (42), 6104-6107; M. A. Chowdhury, Journal of Medicinal Chemistry, 2009, 52 (6), 1525-1529; J. Zheng, Chemical Communications, 2007, 48, 5149-5151 ; US 2009/0209529; WO 2007/064553; WO 2007/03 440; WO 2009/077954. Example 1A

Lithium-1 -(3-fluoro-5-trifluoromethoxyphenyl)-4-ethoxy-3,4-dioxobut-1 -en-1 -olate

[00208] A solution of LHMDS, (1 N in THF, 3.1 1 ml, 3.116 mmol) is diluted with diethylether ( 0 m!) and cooled to -78°C. A solution of 3-fluoro-5-trifluoromethoxy- acetophenone (0.60 g, 2.70 mmol) in diethylether (5 ml) is added and the reaction mixture is stirred for 45 min at -78°C. Next, diethyloxalate (0.44 ml, 3.24 mmol) is added by drops at -78°C and the resulting solution is warmed to RT and stirred at RT overnight. The title compound results after removing the solvent under vacuum and is used in the next step without further purification.

[00209] LC-MS (Method 1 ): Rt = 1 .19 min; MS (ESIpos): m/z = 321 [M-Li+2H]+,

Example 2A

Lithium-1 -{3-chloro-5-trif luoromethoxyphenyl)-4-ethoxy-3,4-dioxobut-1 -en-1 -olate

[00210] The title compound is produced from 3-ch!oro-5-trifluoromethoxyacetophenone

(1 .00 g, 3.56 mmol) and diethyloxalate (0.58 ml, 4.28 mmol) in an manner analogous to the synthesis of the compound from Example 1 A. The title compound is used in the next step without further purification. Example 3A

5-(3-fluoro-5-trifluoromethoxyphenyl)-1 - ridine-3-yl)-1 H-pyrazole-3-carboxylic acid

[00211] A solution of the compound from Example 1A (1.82 g, 4.71 mmol) and 1.03 g (7.07 mmol) 3-pyridylhydrazine hydrochloride in 10 ml ethanol is stirred for 3 h at RT. The ethanol is removed under vacuum and the residue is dissolved in 10 ml glacial acetic acid. The solution is stirred for 2 h under reflux and the solvent is then removed under vacuum. The residue is dissolved in a mixture of methanol / acetonitrile / water and purified using preparative HPLC (developing solvent: methanol / Milli-Q water / trifluoroacetic acid (anhydrous) 5:80:5). [00212] The intermediate is dissolved in 30 ml THF and 10 ml water, and 0.91 g (21.72 mmol) lithiumhydroxide monohydrate is added. The reaction mixture is stirred at RT overnight, acidified with 1 N hydrochloric acid and extracted using dichloromethane. The organic phase is washed with water, dried using sodium sulfate, filtered and evaporated under vacuum. The residue is stirred together with ether/pentane, filtered and dried. This produces 1.12 g (65% of theory) of the title compound.

[00213] 1 H-NMR (400 MHz, DMSO-d6): δ = 7.03 (s, 1 H), 7.32 (s, 1 H), 7.41 (d, 1 H), 7.48 (d, 1 H), 7.55 (dd, 1 H), 7.83-7.89 (m, 1 H), 8.58 (d, 1H), 8.67 (dd, 1 H), 13.20 (bs, 1 H).

[00214] LC-MS (Method 1 ): Rt = 0.87 min; MS (ESIpos): m/z = 368 [M+H]+.

Example 4A

5-(3-chloro-5-trifluoromethoxyphenyl)-1-(pyridine-3-yl)-1 H-pyrazole-3-carboxylic acid

[00215] 500 mg ( 1.23 mmol) of the compound from Example 2A is reacted with 197 mg (1.36 mmol) 3-pyridylhydrazine hydrochloride in a manner analogous to the synthesis of the compound from Example 3A. Following hydrolysis, 203 mg (43% of theory) of the title compound is produced.

[00216] 1 H-N R {400 MHz, DMSO-d6); δ = 7.16 (s, 1 H), 7.34 (s, 1 H), 7.55 (dd, 1 H), 7.58-7.61 (m, 2H), 7.64 (s, 1 H), 7.86 (dt, 1 H), 8.67 (dd, 1 H), 13.19 (bs, 1 H).

[00217] LC-MS (Method 3): Rt = 0.98 min; MS (ESIpos): m/z = 384 [M+H]+.

Example 5A

4-chloro-2,3-dihydro-1 H-pyrrolo[3,4-c]pyridine-1 -on

[00218] 1.50 g (7.51 mmol) 2-chloro-3-methyl-4-pyridinecarboxylic acid ethyl-ester,

1.74 g (9.77 mmol) N-bromosuccinimide and 0.1 1 g (0.68 mmol)

2,2'-azobis-2-methyl-proprionitrile are dissolved in carbon tetrachloride and stirred for 5 h under reflux. The resulting solid is filtered off and discarded. The filtrate is washed with water, the aqueous phase is extracted using dichloromethane, and the combined organic phases are evaporated using a rotary evaporator. The raw product is separated by column chromatography using silica gel (dichloromethane→ dichloromethane / methanol 99:1 ). This produces 2.11 g (94% of theory, 93% purity) of the brominated intermediate. [00219] 1 .50 g (5.39 mmol, 93% purity) of the brominated intermediate is dissolved in

20 ml acetonitrile, and mixed with 15 ml of a 20% solution of ammonia and water, and the reaction mixture is stirred for 2 h at RT. The fine precipitate is filtered off and dried under high vacuum. After unifying both fractions, 1 .36 g of the title compound is produced (quantitative yield, contaminated by ammonium bromide salt).

[00220] 1 H-NMR (400 MHz, DMSO-d6): δ = 4.47 (s, 2H), 7.72 (d, 1 H), 8.57 (d, 1 H), 9.18 (s, 1 H). [00221 ] LC-MS (Method 1 ): Rt = 0.38 min; MS (ESIpos): m/z = 169 [M+H]+.

Synthesis of examplary Formula (I) compounds from a) The synthesis of Formula (I) compounds according to a) is shown below exemplarilv:

[00222] The described pyrazole carboxylic acid intermediates are converted into the target compounds using a four-step sequence. The following synthesis diagram shows the exemplary conversion.

Example 1

4-{5-[3-fluoro-5-(trifluoromethoxy)phenyl]-1-(pyridine-3-yl)-1 H-pyrazole-3-yl}-2,3-dihydro-IH- pyrrolo[3,4-c]pyridine-1 -one

Step 1 [00223] A solution of 1.47 g (4.00 mmol) of the pyrazole carboxylic acid from Example

3A in 38 ml dioxane is mixed with 1.72 ml (8.00 mmol) diphenyl phosphorazidate and 840 μΙ (6.00 mmol) of triethylamine, and the reaction mixture is stirred for 1 h at 50°C. After adding 2.87 ml (20.00 mmol) 2-(trimethylsilyl)ethanol, the reaction mixture is stirred for 2 h under reflux, mixed with water and extracted twice using ethyiacetate. The combined organic phases are dried using sodium sulfate, filtered and evaporated under vacuum until dryness. The residue is crystallised using ether/pentane, the solid is filtered off and dried. This produces 1.55 g (80% of theory) of trimethylsilyl ethyl carbamate.

Step 2

[00224] 1.55 g (3.21 mmol) of the product from Step 1 is dissolved in 38 ml tetrahydrofuran and mixed with tetra-n-butylammonium fluoride (1 in THF, 6.43 ml, 6.43 mmol). The reaction mixture is stirred for 3 h at 50°C, the solvent is removed under vacuum and the residue is absorbed in ethyl acetate and washed with water. The organic phase is dried using sodium sulfate, filtered and evaporated under vacuum. The residue is crystallised using ether/pentane, the solid is filtered off and dried. This produces 1.03 g (95% of theory) of aminopyrazole.

[00225] Using an analogous approach, (1.20 g, 2.49 mmol) of the product from Step 1 is converted to 0.78 g (93% of theory) of trimethylsilyl ethyl carbamate.

Step 3 [00226] A solution of 0.66 g (4.57 mmol) copper(l)bromide, 760 pi (5.72 mmol) n-pentyl nitrite and 5 mg (0.02 mmol) copper(ll)bromide in 67 ml acetonitrile is combined with a solution of 1.29 g (3.81 mmol) of the compound from Step 2 in 33 ml acetonitrile. The reaction mixture is stirred overnight at RT, combined with water, the phases are separated and the aqueous phase is extracted three times using ethyl acetate. The combined organic phases are dried using sodium sulfate, filtered and evaporated under vacuum until dryness. The residue is dissolved in a small amount of acetonitrile, filtered accordingly and separated using preparative HPLC (solvent: acetonitrile-water gradient). This produces 0.45 g (29% of theory) of bromopyrazole.

Step 4

[00227] In three parallel mixtures, each of three 00 mg (0.25 mmol) portions of the product from Step 3 is dissolved in 5 ml dioxane in each case and each is combined with 76 mg (0.30 mmol) of bis-pinakolato-diboron, 73 mg (0.75 mmol) potassium acetate and 12 mg (0.017 mmol) [1 , 1 -bis-(diphenyl-phosphino)ferrocene] -dichloropalladium dichloromethane complex. The reaction mixtures are stirred for 1 h in the microwave at 120°C and cooled to RT, then combined with 50 mg (0.30 mmol) of the compound from Example 5A, 250 μΙ (2 N in water, 0.50 mmol) sodium carbonate solution and 10 mg (0.013 mmol)

[1 ,1 -bis-(diphenylphosphino)ferrocene]-dichloropalladium dichloromethane complex and stirred for 2 h at 120X. The reaction mixtures are combined. The suspension is diluted with acetonitrile, filtered accordingly and separated using preparative HPLC (solution: acetonitrile-water gradient). After crystallisation of the resulting sediment from acetonitrile, this produces 174 mg (51 % of theory) of the title compound.

[00228] 1 H-NMR (400 MHz, DMSO-d6): δ = 4.81 (s, 2H), 7.1 1 (s, 1 H), 7.46-7.59 (m,

4H), 7.70 (d. 1 H), 7.87-7.93 (m, 1 H), 8.66 (dd, 1 H), 8.70 (d, 1 H), 8.83 (d, 1 H), 9.07 (s, 1 H).

[00229] LC-MS (Method 1 ): Rt = 1.02 min; MS (ESIpos): m/z = 456 [M+H]+

Example 2

The com ound in accordance with Formula II), namely

[00230] A solution of 2.50 g (6,52 mmol) of the pyrazole carboxylic acid from Example 4A in 46 ml dioxane is combined with 2.81 ml (13.03 mmol) diphenyl phosphorazidate and 1.36 ml (9.77 mmol) triethylamine, and the reaction mixture is stirred for 1 h at 50°C. After adding 4.67 ml (32.58 mmol) 2-(trimethylsilyl)ethanol, the reaction mixture is stirred for 2 h under reflux, combined with water and extracted twice using ethyl acetate. The combined organic phases are dried using sodium sulfate, filtered and evaporated under vacuum until dryness. The residue is crystallised with ether/pentane and the sediment is filtered out and dried. This produces 2.50 g (77% of theory) of trimethylsilyl ethyl carbamate.

Step 2

[00231] 2.55 g (5.1 1 mmol) of the product from Step 1 is dissolved in 60 ml

tetrahydrofuran and combined with tetra-n-butylammonium fluoride ( in THF, 10.22 ml, 10.22 mmol). The reaction mixture is stirred for 3 h at 50°C, the solvent is removed under vacuum, and the residue is absorbed in ethyl acetate and washed with water. The organic phase is dried using sodium sulfate, filtered and evaporated under vacuum until dryness. The residue is crystallised with ether/pentane, the sediment is filtered out and dried. This produces 1.60 g (88% of theory) of amino pyrazole.

Step 3

[00232] A solution of 775 mg (5.40 mmol) copper(l)bromide, 900 μΙ (6.75 mmol) n-pentylnitrite and 7.9 mg (0.04 mmol) copper(ll)bromide in 80 ml acetonitrile is combined, by dropwise addition, with a solution of 1.60 g (4.50 mmol) of the compound from Step 2 in 40 ml acetonitrile. The reaction mixture is stirred at T overnight, combined with water and extracted three times using ethyl acetate. The combined organic phases are dried using sodium sulfate, filtered and evaporated under vacuum until dryness. The residue is dissolved in a small amount of acetonitrile, filtered accordingly and separated using preparative HPLC (solvent:

acetonitrile-water gradient). This produces 701 mg (37% of theory) of bromopyrazole. Step 4

[00233] In four parallel procedures, four portions of 175 mg (0.42 mmol) of the product from Step 3 are each dissolved in 5 ml dioxane and combined with 128 mg (0.50 mmol) of bis-pinakolatodiborane, 123 mg (1.26 mmol) potassium acetate and 21 mg (0.025 mmol)

[1 ,1-bis-(diphenyl-phosphino)ferrocene]-dichloropalladium-dichloro-methane complex. Each reaction mixture is stirred in the microwave for 1 h at 120°C, cooled to RT, combined with 85 mg (0.50 mmol) of the compound from Example 5A, 0.42 ml (2 N in water, 0.84 mmol) of a sodium carbonate solution and 17 mg (0.02 mmol)

[1 ,1-bis-(diphenylphosphino)ferrocene]-dichloropalladium-dichloromethane complex and stirred for 2 h at 120°C. The reaction mixtures are combined. The suspension is diluted with acetonitrile, filtered accordingly and separated using preparative HPLC (solvent: acetonitrile-water gradient). Once the resulting sediment has crystallised out of the acetonitrile, this produces 286 mg (36% of theory) of the title compound.

[00234] 1 H-NMR (400 MHz, DMSO-d6): δ = 4.80 (s, 2H), 7.24 (s, 1 H), 7.53- 7.60 (m,

2H), 7.65-7.68 (m, 2H). 7.70 (d, 1 H), 7.87-7.93 (m, 1 H), 8.66 (dd, 1H), 8.71 (d, 1 H), 8.83 (d, 1 H), 9.08 (s, 1 H).

[00235] LC-MS (Method 1 ): Rt = 1.03 min; MS (ESIpos): m/z = 472 [M+H]+.

[00236] The following compounds were synthesised in a manner analogous to the examples described above:

Example 3

The compound in accordance with Formula (III), namely

{"<>- [00237] LC-MS (Method 1 ): Rt =1 .02 min; MS (ESIpos): m/z = 473 [M+H]+.

[00238] 1 H-NMR (400 MHz, DMSO-d6): d = 4.80 (s, 2H), 7.25 (s, 1H), 7.57 - 7.59 (m,

1 H), 7.6 -7.72 (m, 3H), 7.91 (d, 1 H), 8.68 - 8.73 (m, 2H), 9.45 (s, 2H). Example 4

The compound in accordance with Formula IV), namely

[00239] LC-MS (Method ): Rt = 1.07 min; MS (ESIpos): m/z = 487 [M+H]+.

[00240] 1 H-NMR (400 MHz, DMSO-d6): d = 2.81 (s, 3H), 4.73 (s, 2H), 7.25 (s, 1 H),

7.50-7.61 (m, 1H), 7.61-7.75 (m, 3H), 7.91 (d, 1 H), 8.60-8.78 (m, 2H), 9.38 (s, 1 H).

D. Assessment of physiological effectiveness

[00241] The effectiveness of the combinations of pharmaceutical active ingredients for treatment of diseases caused by retroviruses, diseases caused by HIV-1 in particular, can be demonstrated in the assay systems described below.

[00242] The assay systems referred to below are to be regarded as examples and can be varied by one skilled in the art, by making modifications, or replaced by other suitable assay systems known to one skilled in the art for investigating the pharmaceutical compositions in accordance with the invention against the background of retroviral diseases, especially against the background of diseases caused by HIV-1.

Materials for in-vitro assays

Viruses, cells and cell cultures

[00243] HIV-1 (strain LAI (BRU)) and MT-4 cells were obtained from the NIH AIDS Research and Reference Reagent Program. The HIV-1 LAI virus stock was expanded by subculturing in MT-4 cells and the TCID₅₀ value was determined by end-point titration using an AlamarBlue cell viability assay (Invitrogen GmbH, Karlsruhe, Germany). The MT-4 cells were kept in an RPMI-1640 medium with 10% FCS, 2 mM L-glutamine and 1% penicillin/streptomycin at 37°C and 5% C0_2, and subcultured in a ratio of 1 :3 every three to four days. On the day before performing the assay, the cells were divided in a ratio of 1 :2 to ensure that the cells would be in an exponential growth phase at the time of infection. In addition to the wild type virus, variants of HIV-1 LAI virus with defined resistance mutations (single or multiple) in the reverse transcriptase gene or in other gene regions of the HI virus can be used to assess the combinations of active ingredients. Resistance mutations against non-nucleoside inhibitors of reverse transcriptase include the following, which are cited only as an example: Y181 C; K103N; L100I-K103N;

L100I-K103N-Y181C; V179F-Y181C; K103N-Y181C or G190A. The corresponding recombinant virus mutations are generated using the methods of in-vitro mutagenesis of proviral DNA (Plasm id pLAI.2) (Peden et al. Virology, 185: 661-672, 1991 ), which are familiar to one skilled in the art, and the subsequent transfection of adherent 293T cells (DuBridge et al. Mol. Cell. Biol. 7: 379-387, 1987) with the recombinant proviral DNA using Lipofectamine reagent in accordance with the manufacturer's instructions (Invitrogen, Karlsruhe, Germany). The 293T cells transfected in this manner then secrete the viruses with the desired resistance mutations into the culture medium. The virus stocks obtained in this manner can be used like the HIV-LAI wild type virus.

Compounds with antiviral effect

[00244] The compound from Example 2 (4-{5-[3-chloro-5-

(trifluoro-methoxy)phenyl]-1-(pyridine-3-yl)-1 H-pyrazole-3-yl}-2,3-dihydro-1 H-pyrrolo[3,4- c]pyridine-1-on) and Zidovudine (AZT) were obtained from Bayer Healthcare AG (Leverkusen, Germany). Rilpivirine (RIL; RPV) and Lersivirine (LER) were obtained from Medicilon Inc. (China). Efavirenz (EFV), Etravirine (ETR), Nevirapine (NVP), Atazanavir (ATV), Ritonavir (RTV), Tipranavir (TPV), Darunavir (DRV) and Lopinavir (LPV) were acquired in the form of preparations available on the market and purified. Stavudine (d4T), Emtricitabine (FTC) and Ribavirin (RBV) were obtained from AK Scientific Inc. (USA). Abacavir (ABC), Indinavir (IDV), Nelfinavir (NFV) and Saquinavir (SQV) were obtained from Atomole Scientific Co. Ltd. (China). Lamivudine (3TC) and Tenofovir (TDF) were obtained from Beta Pharma Co. Ltd. (China). Raltegravir (RAL) and Elvitegravir (EVG) were obtained from Selleck Chemicals LLC (USA). Didanosine (ddl) was obtained from TCI Deutschland GmbH (Germany). For in-vitro use, all compounds were stored as DMSO stock solutions and were diluted immediately before use with cell culture medium.

Active ingredient combination assay [00245] The active ingredients were tested in combinations of two in 96-well MTPs. The starting concentration of each active ingredient was selected based on its EC₅₀ value such that the EC₅₀ value was approximately in the middle of the dilution series (EC₅₀ value determined using AiamarBlue cell viability assay). The tests were performed using serial three-fold dilutions.

[00246] Each active ingredient compound being tested was first diluted in a separate 96-well MTP before the dilutions were mixed with one another. The dilution coefficient of "stock solution to final concentration in the well" was 1 ,000 for the vertically diluted Compound A and 100 for the horizontally diluted Compound B. To avoid edge effects, the wells along the edges of the MTP were not used for substance dilutions. All wells of MTP A, except all wells of the horizontal Row B, were filled with 20 μΙ DMSO. The latter were filled with 30 μΙ of Compound A. Starting with horizontal Row B, three-fold dilutions of 10 μ I each were performed through to horizontal Row F. All wells were filled with 180 μΙ RPMI-1640 medium. In MTP B, all wells except wells in the vertical Rows 9, 10 and 1 1 were filled with 20 μΙ DMSO. The wells of Rows 10 and 1 were filled with 22 μΙ DMSO and 178 μΙ RPMI-1640 medium (virus and cell controls). The wells of Row 9 were filled with 30 μΙ of Compound B. Starting from vertical Row 9, three-fold dilutions of 10 μΙ each were performed through to vertical Row 3. From vertical Row 2 in MTP A, 20 μΙ were added horizontally to each of the wells in vertical Rows 2 to 9 in MTP B. This resulted in the generation of ten different active ingredient combination plates from one MTP A by using all vertical rows of MTP A. The pipette tips were replaced every dilution step and the DMSO final concentration in each well was kept at 1 .1 %. Finally, all wells from vertical Row 2 to vertical Row 9 were filled with 160 μΐ of RPMI-1640 medium and the final assay MTPs ( 10 μ[ per well) were produced from MTP B using a CyBi®-well Vario (CyBio AG, Jena, Germany).

[00247] Combinations of the compound from Example 2 (4-{5-[3-chioro-5- (trifluoromethoxy)phenyl]-1 -(pyridine-3-yl)-1 H-pyrazole-3-yl} -2,3-dihydro-1 H-pyrrolo[3,4- c]pyridine-1 -on) with various known anti-HIV active ingredients (see Tables A-C, below) were tested in MT4 cells against HIV-1 LAI (wild type virus or corresponding variants with resistance mutations) by means of the AlamarBlue cell viability assay. For this purpose, 4 million MT4 cells (for each checkerboard titration (micro)plate) were centrifuged at 350 x g for five minutes and resuspended in 9 ml culture medium with 2% FCS. 90 μΙ of this suspension was placed in each well of vertical Row 1 1 (cell control) of the previously described checkerboard titration (micro)plate (4 x 10⁶ cells per ml). The remaining cell suspension was mixed with the suitable quantity of HIV-1 LAI virus (e.g. MOI 0.01 ) and 90 μΙ of this cell/virus suspension was added to each remaining well. Vertical Row 10 was used as an untreated virus control. The MTPs were incubated at 37°C and 5% CO2 for five days before the virus-induced cytopathic effect (CPE) was measured by using the AlamarBlue cell viability assay. For this purpose, 10 μΙ of AlamarBlue solution were added to each well and the fluorescence signal was measured after three hours using a SpectraFluor Plus fluorescence reader (excitation 550 nm, emission 595 nm) (TECAN Deutschland GmbH, Crailsheim, Germany). In parallel, the active ingredient combinations were tested for synergistic cytotoxicity by using checkerboard titration (micro)plates and non-infected MT4 cells.

[00248] Each combination (see Tables A, Al, A2, B, B1 , B2, below) was tested five times in at least four independent experiments. The control combinations for the assays were AZT-AZT for additive effects, RBV-D4T for antagonistic effects and RBV-DDI for synergistic effects. The raw data were analyzed using the procedure of Prichard and Shipman, using MacSynergy II software with a confidence interval of 95 %. According to the MacSynergy II manual and the publication of Lai and colleagues (Lai et al., Antimicrob Agents Chemother. 2009 Jun; 53(6):2424-31 ), the synergy volumes (μΜ ² %) of active ingredient combinations is defined as follows: values less than - 00 display strong antagonistic effect, values in the range of -100 to -50 display moderate antagonistic effect, values between -50 and 50 are regarded as indicating an additive effect (see Tables A2 and B2 for details). Synergy volumes of 50 to 100 and greater than 100 are regarded as moderate and strong synergies, respectively (see Tables A1 and B1 for details).

[00249] In an analogous manner, the antiviral activity data for the active ingredient combinations consisting of active ingredient a) and b) could also be analyzed at constant concentration ratios (diagonal rows on the checkerboard titration (micro )plate) by means of an alternative method of Chou & Talalay ("median-effect principle," Chou TC, Pharmacol Rev. 2006 Sep; 58(3):621-81) using CalcuSyn 2. -Software (Biosoft Cambridge UK). A combination index (CI) was calculated for every active ingredient combination at ED₅₀, ED₇₅ und ED₉₀ and, since specifically in chemotherapy, high effectiveness values are more important than lower ones, the CI value was defined as a weighted CI (WCI) = [Cl₅₀ + 2CI₇₅ + 3CI₉₀)]/6. Average CI values of less than 0.85, from 0.95 to 1.2, and of greater than 1.2 could respectively indicate synergistic, additive and antagonistic effects of two active ingredients. Only CI values with an R value greater than 0.85 were included to calculate the WCI.

[00250] The antiviral activity data obtained in these tests and assessed using MacSynergy II software is shown below in Tables A, A1 , A2, B, B1 and B2. None of the tested active ingredient combinations was cytotoxic within the concentration range tested nor were any antagonistic effects detected.

[00251] Table A: Antiviral activity of a compound according to Formula (II) as per Example 2 in combination with an additional antivirally active pharmaceutical ingredient of a different compound (determined using MacSynergy II)

Combinations with compounds as per Formula (II); overall test

Substance class Mean volume (uM²%) ± SD^a Antiviral

and substance Synergistic Antagonistic Effect

NRTIs

d4T 105.0 ± 36.6 -5.3 ± 10.0 Synergistic

AZT 191.0 ± 14.3 -1.0 ± 0.9 Synergistic

TDF 156.9 ± 45.7 -1.4 ± 2.9 Synergistic

3TC 120.2 ± 28.9 -4.6 ± 8.5 Synergistic

ABC 133.1 ± 55.1 -1 1.7 ± 11.2 Synergistic

FTC 64.2 ± 25.7 -5.9 ± 5.3 Additive

ddl 36.1 ± 16.6 -4.7 ± 6.6 Additive

N NRTIs

EFV 67.2 ± 30.5 -4.3 ± 8.0 Additive

ETR 45.2 ± 12.5 -10.0 ± 8.9 Additive

NVP 34.9 ± 13.0 -1.5 ± 2.0 Additive

RPV 41.2 ± 38.4 -20.6 + 29.5 Additive

LER 45.1 ± 17.8 -16.7 ± 28.8 Additive

Pis

ATV 107.6 ± 44.4 -0.7 ± 0.9 Synergistic

DRV 105.1 ± 44.8 -2.1 ± 2.1 Synergistic

NFV 95.7 ± 22.9 -1.8 ± 2.0 Synergistic

RTV 129.5 ± 82.5 -2.7 ± 5.6 Additive / Synergistic

SQV 1 15.2 ± 46.1 -2.3 ± 3.0 Additive / Synergistic

LPV 80.9 ± 44.2 -1.7 ± 3.4 Additive / Synergistic

IDV 68.2 ± 28.1 -1 .2 ± 1.6 Additive / Synergistic

TPV 71.0 ± 47.7 -1 .8 ± 2.5 Additive / Synergistic lis

RAL 161.0 ± 94.2 -7.3 ± 5.8 Synergistic

Controls

RBV/ddl 240.0 ± 76.6 -5.4 ± 7.8 Synergistic

RBV/d4T 22.8 ± 21.0 -329.3 ± 153.3 Antagonistic

AZT/ AZT 9.6 ± 1 1.0 -8.9 ± 17.7 Additive [00252] Regarding Table A: The antiviral activity of the active ingredient combinations shown above was determined in a checkerboard titration (micro)plate using an AlamarB!ue cell viability assay. Each of the combinations listed was tested five times (n=5) in at least four separate and independent experiments. The superscripted "a" refers to a synergistic effect with a 95% confidence interval, calculated using MacSynergy II software. The antiviral synergy data from the various experiments was combined and the arithmetic mean was calculated individually for each combination of active ingredients. The positive and negative values obtained were added individually in order to illustrate the mean values of the volumes ± the standard deviation (SD) in the synergistic interactions. The antiviral effect was assessed as per the Mac Synergy II manual and the publication by Lai and colleagues (2009) (Lai et al., Antimicrobial Agents Chemother. 53: 2424-2431 ). The assessment "Additive / Synergistic" refers to cases in which the synergy volume was in the threshold area between "Additive" and "Synergistic" once the SD had been taken into account. Table A1 : Synergistic antiviral activity of a compound according to Formula (II) as per Example 2 in combination with an additional antivirally active pharmaceutical ingredient of a different compound (determined using MacSynergy II) Combinations with compounds as per Formula (II): Synergistic effect only

Substance class Mean volume (uM²%) ± SD^e Antiviral

and substance Synergistic Antaaonistic Effect

NRTIs

d4T 105.0 ± 34.5 -5.3 ± 10.0 Synergistic

AZT 191.0 ± 14.3 -1.0 ± 0.8 Synergistic

TDF 156.9 ± 45.7 -1.4 ± 2.9 Synergistic

3TC 120.2 ± 28.9 -4.6 ± 8.5 Synergistic

ABC 133.1 ± 55.1 -1 1.7 ± 1 1.2 Synergistic

Pis

ATV 107.6 ± 44.4 -0.7 ± 0.9 Synergistic

DRV 105.1 ± 44.6 -2.1 ± 2.1 Synergistic

NFV 95.7 ± 22.9 -1.8 ± 2.0 Synergistic

lis

RAL 161 .0 ± 94.2 -7.3 ± 5.8 Synergistic

Controls

RBV/ddl 240.0 ± 78.6 -5.4 ± 7.8 Synergistic

RBV/d4T 22.8 ± 21.0 -329.3 ± 153.3 Antagonistic

AZT/AZT 9.6 ± 1 1.0 -8.9 ± 17.7 Additive

[00253] Regarding Table A1 : The antiviral activity of the active ingredient combinations shown above was determined in a checkerboard titration (micro)plate using an AlamarB!ue cell viability assay. Each of the combinations listed was tested five times (n=5) in at least four separate and independent experiments. The superscripted "a" refers to a synergistic effect with a 95% confidence interval, calculated using MacSynergy II software. The antiviral synergy data from the various experiments were combined and the arithmetic mean was calculated individually for each combination of active ingredients. The positive and negative values obtained were added individually in order to then illustrate the mean values of the volumes ± the standard deviation (SD) in the synergistic interactions.

Table A2: Additive antiviral activity of a compound according to Formula (II) as per Example 2 in combination with an additional antivirally active pharmaceutical ingredient of a different compound (determined using MacSynergy II)

Combinations with compounds as per Formula (II): Additive effect only

Substance class Mean volume (uM²%) ± SD^a Antiviral

and substance Synergistic Antagonistic Effect

NRTIs

FTC 64.2 ± 25.7 -5.9 ± 5.3 Additive

ddl 36.1 ± 16.6 -4.7 ± 6.6 Additive

NNRTIs

EFV 67.2 ± 30.5 -4.3 ± 8.0 Additive

ETR 45.2 ± 12.5 -10.0 ± 8.9 Additive

NVP 34.9 ± 13.0 -1.5 ± 2.0 Additive

RPV 41.2 ± 38.4 -20.6 ± 29.5 Additive

LER 45.1 ± 17.8 -16.7 ± 28.8 Additive

EFV 67.2 ± 30.5 -4.3 ± 6.0 Additive

Pis

RTV 129.5 ± 82.5 -2.7 ± 5.6 Additive / Synergistic

SQV 115.2 ± 46.1 -2.3 ± 3.0 Additive / Synergistic

LPV 80.9 ± 44.2 -1.7 ± 3.4 Additive / Synergistic

IDV 68.2 ± 28.1 -1.2 ± 1.6 Additive / Synergistic

TPV 71.0 ± 47.7 -1.8 ± 2.5 Additive / Synergistic

Controls

RBV/ddl 240.0 ± 78.6 -5.4 ± 7.8 Synergistic

RBV/d4T 22.8 ± 21.0 -329.3 ± 153.3 Antagonistic

AZT/AZT 9.6 ± 1 1.0 -8.9 ± 17.7 Additive

Regarding Table A2: The antiviral activity of the active ingredient combinations shown above was determined in a checkerboard titration (micro)plate using an AlamarBlue cell viability assay (see Table A2, above). Each of the combinations listed was tested five times (n=5) in at least three separate and independent experiments. The superscripted "a" refers to a synergistic effect with a 95% confidence interval, calculated using MacSynergy II software. The antiviral additive effect data from the various experiments were combined and the arithmetic mean was calculated individually for each combination of active ingredients. The positive and negative values obtained were added individually in order to then illustrate the mean values of the volumes ± the standard deviation (SD) in the synergistic interactions. The antiviral effect was assessed as per the Mac Synergy II manual and the publication by Lai and colleagues (2009) (Lai et al., Antimicrobial Agents Chemother. 53: 2424-2431). The assessment "Additive / Synergistic" refers to cases in which the synergy volume was in the threshold area between "Additive" and "Synergistic" once the SD had been taken into account.

Table B: Antiviral activity of a compound according to Formula (III) as per Example 2 in combination with an additional antivirally active pharmaceutical ingredient of a different compound (determined using MacSynergy II)

Combinations with compounds as per Formula (III); overall test

Substance class Mean volume (μΜ %) ± SD^a Antiviral

and substance Synergistic Antagonistic Effect

NRTIs

d4T 55 + 36 -7.4 ± 7.1 Additive

AZT 82 ± 49 -23 ± 16 Additive

TDF 64 ± 30 -24 ± 33 Additive

3TC 42 ± 43 -5 ± 4.2 Additive

ABC 29 ± 8.7 -6.4 ± 1.2 Additive

FTC 44 ± 34 -19 ± 19 Additive

ddl 120 ± 65 -11 ± 19 Synergistic

N NRTIs

EFV 90 ± 74 -27 ± 24 Additive

ETR 39 ± 12 -7.7 ± 1 1 Additive

NVP 67 ± 30 -6.3 ± 13 Additive

RIL 77 ± 100 -21 ± 14 Additive

38 ± 24 -6.6 ± 5.4 Additive

Pis

ATV 43 ± 34 -38 ± 27 Additive

DRV 41 ± 37 -20 ± 26 Additive

FV 65 ± 39 -13 ± 22 Additive

RTV 82 ± 19 -1.7 ± 3 Additive

SQV 63 ± 45 -5 ± 7.7 Additive

LPV 43 ± 33 -7.3 ± 6,2 Additive

IDV 67 ± 72 -0.59 ± 0.7 Additive

TPV 51 + 21 -5.1 ± 5.9 Additive

lis

RAL 70 ± 43 -1 ± 9,2 Additive

EVG 59 ± 30 -7.6 ± 9.4 Additive

Controls

RBV/ddl 290 ± 130 -14 ± 17 Synergistic

RBV/d4T 0.26 ± 0.49 -620 ± 290 Antagonistic

AZT/AZT 10 ± 1 1 -8.1 + 9.1 Additive [00254] Regarding Table B: The antiviral activity of the active ingredient combinations shown above was determined in a checkerboard titration (micro )plate using an AlamarBlue cell viability assay. Each of the combinations listed was tested five times (n=5) in at least three separate and independent experiments. The superscripted "a" refers to a synergistic effect with a 95% confidence interval, calculated using MacSynergy II software. The antiviral synergistic effect data from the various experiments were combined and the arithmetic mean was calculated individually for each combination of active ingredients. The positive and negative values obtained were added individually in order to then illustrate the mean values of the volumes ± the standard deviation (SD) for the synergistic interactions.

Table B1 : Synergistic antiviral activity of a compound according to Formula (III) as per Example 3 in combination with an additional antivirally active pharmaceutical ingredient of a different compound (determined using MacSynergy II)

Combinations with compounds as per Formula (III): Synergistic effect only

Substance class Mean volume (u ²%^ ± SD^a Antiviral

and substance Synergistic Antagonistic Effect

NRTIs

ddl 120 ± 85 -11 ± 19 Synergistic

Controls

RBV/ddl 290 ± 130 -14 ± 17 Synergistic

RBV/d4T 0.26 ± 0.49 -620 ± 290 Antagonistic

AZT/AZT 10 ± 11 -8.1 ± 9,1 Additive [00255] Regarding Table B1 : The antiviral activity of the active ingredient

combinations shown above was determined in a checkerboard titration (micro)plate using an AlamarBlue cell viability assay. Each of the combinations listed was tested five times (n=5) in at least three separate and independent experiments. The superscripted "a" refers to a synergistic effect with a 95% confidence interval, calculated using MacSynergy II software. The antiviral synergistic effect data from the various experiments were combined and the arithmetic mean was calculated individually for each combination of active ingredients. The positive and negative values obtained were added individually in order to then emphasise the mean values of the volumes ± the standard deviation (SD) for the synergistic interactions. Table B2: Additive antiviral activity of a compound according to Formula (III) as per Example 3 in combination with an additional antivirally active pharmaceutical ingredient of a different compound (determined using MacSynergy II)

Combinations with compounds as per Formula (III): Additive effect

Substance class and Mean volume fuM²%) ± SD^S Antiviral

substance Synergistic Antaqonistic Effect

NRTls

d4T 55 ± 36 -7.4 ± 7.1 Additive

AZT 82 ± 49 -23 ± 16 Additive

TDF 64 ± 30 -24 ± 33 Additive

3TC 42 ± 43 -5 ± 4.2 Additive

ABC 29 + 8.7 -6.4 ± 1.2 Additive

FTC 44 ± 34 -19 ± 19 Additive

± 74 -27 ± 24 Additive

ETR 39 ± 12 -7.7 ± 1 1 Additive

NVP 67 ± 30 -6.3 ± 13 Additive

RIL 77 ± 100 -21 ± 14 Additive

38 ± 24 -6.8 + 5.4 Additive

Pis

ATV 43 ± 34 -38 ± 27 Additive

DRV 41 ± 37 -20 ± 26 Additive

NFV 65 ± 39 -13 + 22 Additive

RTV 82 ± 19 -1.7 ± 3 Additive

SQV 63 ± 45 -5 ± 7.7 Additive

LPV 43 ±33 -7.3 ± 6.2 Additive

IDV 67 ± 72 -0.59 ± 0.7 Additive

TPV 51 ± 21 -5.1 ± 5.9 Additive

Ms

RAL 70 ± 43 -11 ± 9.2 Additive

EVG 59 ± 30 -7.6 ± 9.4 Additive

Controls

RBV/ddl 290 ± 130 -14 ± 17 Synergistic

RBV/d4T 0.26 ± 0.49 -620 ± 290 Antagonistic

AZT/AZT 10 ± 1 1 -8.1 ± 9.1 Additive

[00256] Regarding Table B2: The antiviral activity of the active ingredient combinations shown above was determined in a checkerboard titration (micro)plate using an AlamarBlue cell viability assay (see Table C, above). Each of the combinations listed was tested five times (n=5) in at least three separate and independent experiments. The superscripted "a" refers to a synergistic effect with a 95% confidence interval, calculated using MacSynergy II software. The antiviral additive effect data from the various experiments were combined and the arithmetic mean was calculated individually for each combination of active ingredients. The positive and negative values obtained were added individually in order to then emphasise the mean values of the volumes ± the standard deviation (SD) for the synergistic interactions.

[00257] It is clearly evident from Tables A, A1 and B, B1 that the compound according to Formula (I) as per Example 2 (Formula II) and/or Example 3 (Formula III) has synergistic effects with a large number of compounds that are antiretroviral active ingredients found in the various drug action classes that are different to NNRTIs.

[00258] In another aspect, the present invention supplies active ingredient combinations with purely additive effects, from a compound according to Formula (I) as per a) with at least one other already known antivirally active pharmaceutical ingredient as per b). This also includes the use of a compound according to Formula (I) as per a) with another already known antivirally active pharmaceutical ingredient as per b), which latter can also belong to the NNRTI action class. One skilled in the art would be aware that in cases in which the combinations in accordance with the invention primarily result in an additive effect, one can nevertheless assume that it is advantageous with regard to use against resistant and, especially,

multidrug-resistant strains of HIV - which therefore also already display resistances against previously known individual and combination therapies - as one of the problems the invention aims to solve is to provide an effective antiretroviral therapy against multidrug-resistant forms of viruses, especially HI viruses.

[00259] In this regard, it is therefore clearly evident from Tables A, A2 and B, B2 that the compound according to Formula (I) as per Example 2 (Formula II) and/or Example 3 (Formula III) has additive antiretroviral effects with a large number of different compounds that are antiretroviral active pharmaceutical ingredients and that these effects can be beneficial to affected patients in terms of overcoming resistant, especially multidrug-resistant, forms of HIV.

[00260] A matrix of active ingredients is shown below in Table C with examples of dosing quantities for possible combination partners for the compounds in accordance with the invention in accordance with Formula (I) as per a). Table C: Sample matrix of active ingredients of possible combination partners that could be combined with compounds according to

Formula (I) as per a). The possible single dose quantities for the compounds according to Formula (I) are described above and reference should be made to them.

Daily Acti

Class of Dose of Class of Dose of Dose of Class of

Compound as Active dose of Active Active Class of ve

Active Active Active Active Active Active Imped, per Formula (1) single dose/combination Ingred. 1 Active Ingred.2 Ingred.3 Active Ingred.3 Ingr

Ingred.1 Ingred.2 Ingred.2 Ingred.3 -" ingred.4

Ingred.1

In combination with 2 150 NRHs/Nt Tl 2 x 300 NRTIs NtRTl

Combination of 3TC AZT

additional→ mg Is mg Is

In combination with

Combination of 3TC x600 NRTIs/NtRT]

additional-_* 1 x 300 NRTIs/ tRTl ABC 1

mg Is mg Is

2 x 300

In combination with Is/NtRTIs

Combination of 3TC 2x 150 NRTIs/NtRTl ABC 2x300 NRTIs NtRT AZT mg NRT

additional

mg Is mg Is

In combination with 1 245 NRTIs/NtRTl

Combination of FTC 1 x 200mg NRTIs/NtRTj TDF

additional-* mg Is

Is

In combination with

Single dose of 3TC 2 x 150 NRTIs/NtRTl

additional -+

mg Is

In combination with

Single dose of ABC 2 x300 NRTIs NtRTl

additional-^

mg Is

In combination with

Single dose of A2T 2 x250 NRTIs/NtRTl

additional-_*

mg Is

In combination with

Single dose of FTC 1 x 200

additional→ NRTIs/NtRT

mg Is

In combination with

Single dose of TDF 1 x245 NRTIs/NtRTl

additional→

mg is

1 x600

In combination with

Single dose of EFV mg NNRTI

additional- 3x200

mg

In combination with additional— _* in combination with addttional-_*

In combination with additional— »

In combination with additional > in combination with additional-*

In combination with additional-*

in combination with additional-*

in combination with additional→

In combination with additional-*

In combination with additional—_*

In combination with additional-*

In combination with 1x200 N Tb/ t Tl 1x300 NRTls/NtRTl 1x800

Combination of FTC TDF EFV NNRTI

additional-* mg Is rung Is mg

In combination with 1x200 NRTlsNtRTl 1 x245

Combination of FTC RIL 1 x25mg NNRTI TDF NRTlsNtRTIs

additional ► mg Is mg

in combination with x200 NRTls/NtRTl 1x150 1x150 1 245

Combination of FTC EVG Cobicistat TDF NRTIs/NtRTIs additional- mg Is mg mg mg

Claims

Patent Claims

1. An antivirally active pharmaceutical ingredient a)

according to the compound as per Formula (I),

wherein

X stands for N or CH and

R1 stands for a halogen substituent and

R2 stands for H or CH3,

or one of their physiologically acceptable salts, solvates or one of the solvates of their salts, for use in the prevention or treatment of viral infections, and diseases caused by them in an individual, where the use of the antivirally active pharmaceutical ingredient a) is combined with the use of at least one antivirally active pharmaceutical ingredient b) that is different from a), to be selected from a group encompassing nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

2. The antivirally active pharmaceutical ingredient a) according to claim 1 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein under a) in the compound according to Formula (I) X stands for N or CH and

R1 stands for fluorine, bromine, chlorine or iodine,

R2 stands for H or CH3.

3. The antivirally active pharmaceutical ingredient a) according to claim 1 or 2 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein under a) in the compound according to Formula (I)

X stands for N or CH and

R1 stands for fluorine or chlorine, R2 stands for H or CH3.

4. The antivirally active pharmaceutical ingredient a) according to one of claims 1 to 3 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where under a) the compound according to Formula (I) is a compound of Formula (II)

or one of its physiologically acceptable salts, solvates or a solvate of its salts.

5. The antivirally active pharmaceutical ingredient a) according to one of claims 1 to 3 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein under a) the compound according to Formula (I) is a compound of Formula (III)

(Hi) or one of its physiologically acceptable salts, solvates or a solvate of its salts.

6. The antivirally active pharmaceutical ingredient a) according to one of claims 1 to 3 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein under a) the compound according to Formula (I) is a compound of Formula (IV)

or one of its physiologically innocuous salts, solvates or a solvate of its salts.

7, The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where under b) the one or more antivirally active pharmaceutical ingredient(s) that is/are different from a) is a nucleoside or nucleotide reverse

transcriptase inhibitor, selected from a group consisting of Zidovudine (AZT), Lamivudine (3TC), Didanosine (ddl), Zalcitabine (ddC), Stavudine (d4T), Abacavir (ABC), Tenofovir (TDF or TAF), Emtricitabine (FTC), Amdoxovir (DAPD), Apricitabine (dQTC), Racivir (RCV), Elvucitabine (ACH- 126,443) and Festinavir (4'Ed4T) as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

8. The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where under b) the one or more antivirally active pharmaceutical ingredient(s) that is/are different from a) is a non-nucleoside reverse transcriptase inhibitor, selected from a group consisting of Efavirenz (EFV), Etravirine (ETV),

Nevirapine (NVP), Rilpivirine (RPV), Delavirdine (DLV), Doravirine (DOR), VM-1500 and Lersivirine (LER) as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

9. The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where under b) the one or more antivirally active pharmaceutical ingredient(s) that is/are different from a) is a protease inhibitor selected from a group consisting of Saquinavir (SQV), Indinavir (IDV), Ritonavir (RTV), Nelfinavir (NFV), Amprenavir (APV), Lopinavir (LPV), Atazanavir (ATV), Fosamprenavir (FPV), Tipranavir (TPV) and Darunavir (DRV) as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

10. The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where under b) the one or more antivirally active pharmaceutical ingredient(s) that is/are different from a) is an entry inhibitor, selected from a group consisting of Maraviroc (MVC), Enfuvirtide (T-20), Cenicriviroc (TAK-652, TBR-652), Ibalizumab (TMB-355), PRO-140, AMD-070 and INCB9471 as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts. 1 1. The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where under b) the one or more antivirally active pharmaceutical ingredient(s) that is/are different from a) is an integrase inhibitor, selected from a group consisting of Raltegravir (RAL), Eivitegravir (EVG), Dolutegravir (DTG) and GSK-1265744 as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

12. The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where under b) two or three or four of the antivirally active pharmaceutical ingredients specifically referred to in claims 7 to 11 can be combined with one another, where the two or three or four specific antivirally active pharmaceutical ingredients to be combined, according to claims 7 to 11 , belong to different drug action classes.

13. The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein the antivirally active pharmaceutical ingredient a) and the one or more antivirally active pharmaceutical ingredient(s) b) that is/are different from a) is present in a combination having a synergistic antiviral effect, wherein the antivirally active pharmaceutical ingredients specified under b) are selected from a group consisting of nucleoside and nucleotide reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors, as well as combinations thereof and their

physiologically acceptable salts, solvates or the solvates of their salts.

14. The antivirally active pharmaceutical ingredient a) according to claim 13 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where said combination having a synergistic antiviral effect is characterised in that there exists a synergistic increase of the antiviral effectiveness of the combinations of antivirally active pharmaceutical ingredients a) and b) compared to the antiviral effectiveness of the individual active pharmaceutical ingredients a) and b) alone, which increase exceeds the sum of the effectiveness of the two active pharmaceutical ingredients a) and b) used individually.

15. The antivirally active pharmaceutical ingredient a) according to claims 13 and 14 for use in the prevention and/or treatment of viral infections, and the diseases caused by them in an individual, where the one or more antivirally active pharmaceutical ingredient(s) b) that is/are different from a) is a nucleoside and nucleotide reverse transcriptase inhibitor selected from a group consisting of Stavudine (d4T), Zidovudine (AZT), Tenofovir (TDF or TAF), Lamivudine (3TC), Abacavir (ABC) and Didanosine (ddl), as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

16. The antiviral pharmaceutical ingredient a) according to any of claims 13 to 15 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where the one or more antivirally active pharmaceutical ingredient(s) b) that is/are different from a) is a protease inhibitor selected from a group consisting of Nelfinavir (NFV), Atazanavir (ATV) and Darunavir (DRV), as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

17. The antiviral pharmaceutical ingredient a) according to any of claims 13 to 16 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where the one or more antivirally active pharmaceutical ingredient(s) b) that is/are different from a) is/are an entry inhibitor selected from a group consisting of Maraviroc (MVC) and Enfuvirtide (T-20), as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

18. The antiviral pharmaceutical ingredient a) according to any of claims 13 to 17 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where the one or more antivirally active pharmaceutical ingredient(s) b) that is/are different from a) is/are an integrase inhibitor selected from a group consisting of Raltegravir (RAL), Elvitegravir (EVG), Dolutegravir (DTG) and GSK-1265744, as well as combinations thereof and their physiologically acceptable salts, solvates or the solvates of their salts.

19. The antivirally active pharmaceutical ingredient a) according to any of claims 3 to 18 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, where under b) two or three or four of the antivirally active pharmaceutical ingredients specifically referred to in claims 15 to 18 can be combined with one another, where the two or three or four specific antivirally active pharmaceutical ingredients to be combined, according to claims 15 to 18, belong to different drug action classes.

20. The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections, and of the diseases caused by them in an individual, wherein the antivirally active pharmaceutical ingredient a) is administered in a daily dose of 0.1 - 30 mg/kg of body weight, preferably in a daily dose of 0.1 - 25 mg/kg of body weight, more preferred in a daily dose of 0.1 - 20 mg/kg of body weight, yet more acceptable in a daily dose of 0.1 - 15 mg/kg of body weight, yet more acceptable in a daily dose of 0.1 - 10 mg/kg of body weight, yet more acceptable in a daily dose of 0.1 - 5 mg/kg of body weight and depending on the former, the one or more antivirally active pharmaceutical ingredient(s) b) that is/are different from a) is administered in a daily dose of 0.1 -30 mg/kg of body weight, preferably in a daily dose of 0.1 - 25 mg/kg of body weight, more preferred in a daily dose of 0.1 - 20 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 15 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 0 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 5 mg/kg of body weight.

21 , The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections, and of the diseases caused by them in an individual, wherein the antivirally active pharmaceutical ingredient a) is administered in a daily dose of 0.1 - 15 mg/kg of body weight, preferably in a daily dose of 0.1 - 12.5 mg/kg of body weight, more preferred in a daily dose of 0.1 - 20 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 7.5 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 5 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 2.5 mg/kg of body weight and depending on the former, the one or more antivirally active pharmaceutical ingredient(s) b) that is/are different from a) is administered in a daily dose of 0.1-15 mg/kg of body weight, preferably in a daily dose of 0.1 - 12.5 mg/kg of body weight, more preferred in a daily dose of 0.1 - 0 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 7.5 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 5 mg/kg of body weight, yet more preferred in a daily dose of 0.1 - 2.5 mg/kg of body weight.

22. The antivirally active pharmaceutical ingredient a) according to any of the above claims for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein the antiviral pharmaceutical ingredient a) is administered in a single dose of 0.1 - 1000 mg, preferably of 1 - 800 mg, yet more preferred of 1 - 600 mg, yet more preferred of 1 - 400 mg, yet more preferred of 1 - 200 mg per dose unit and, depending on the former, the one or more antivirally active pharmaceutical ingredient(s) b) that is/are different from a) and every additional antivirally active pharmaceutical ingredient b) is provided in a single dose of 0.1 - 1000 mg, preferably of 1 - 800 mg, yet more preferred of 1 - 600 mg, yet more preferred of 1 - 400 mg, yet more preferred of 1 - 200 mg per dose unit.

23. A pharmaceutical composition for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, comprising an antivirally active pharmaceutical ingredient a) according to any of claims 1 to 22, and one or more antivirally active pharmaceutical ingredient(s) b) according to any of claims 1 to 22 that is/are different from a), and one or more inert, non-toxic, pharmaceutically suitable excipient.

24. Pharmaceutical composition according to claim 23 for use in the prevention and/or

treatment of viral infections and of diseases caused by them in an individual, where said pharmaceutical composition, along with one or more pharmaceutically suitable substrate(s), can be administered in an oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctiva! or otic manner, or as an implant or stent.

25. A combination preparation for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, comprising

an antivirally active pharmaceutical ingredient a) according to any of claims 1 to 22, wherein the antivirally active pharmaceutical ingredient a) is provided separately in a dosage form pharmaceutically suited to it, and one or more antivirally active pharmaceutical ingredient(s) b) according to any of claims 1 to 22 that is/are different from a), wherein the antivirally active pharmaceutical ingredient b) is provided separately in a dosage form pharmaceutically suited to it, and one or more inert, non-toxic, pharmaceutically suitable excipient(s) is/are provided for the separate dosage forms.

26. The combination preparation according to claim 25 for use in the prevention and/or

treatment of viral infections and of diseases caused by them in an individual, wherein said dosage form specifically suitable for the antivirally active pharmaceutical ingredients a) and b) can be chosen separately for each of a) and b) from a group consisting of capsules, tablets, transdermal patches, fluids.

27. Combination preparation according to claims 25 and 26 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein the antivirally active pharmaceutical ingredients a) and b) in the dosage forms specifically suited to them can be administered simultaneously or sequentially.

28. Combination preparation according to claim 27 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein sequential dosing is performed with a delay of not more than 24 hours, preferably not more than 12 hours, preferably not more than 10 hours, more preferred not more than 8 hours, yet more preferred not more than 6 hours, yet more preferred not more than 4 hours, most preferred not more than 1 hour.

29. Combination preparation according to claims 25 to 28 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein said dosage form specifically suitable for the antivirally active pharmaceutical ingredients a) and b) can be administered with at least one pharmaceutically suitable carrier in an oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic manner, or as an implant or stent. 30. The antivirally active pharmaceutical ingredient a) according to any of the above claims 1 to 22 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, said individual suffering from a viral infection which is a retroviral infection. 31. The antivirally active pharmaceutical ingredient a) according to claim 30 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, said retroviral infection being an HIV-1 retroviral infection.

32. The antivirally active pharmaceutical ingredient a) according to claim 31 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, said retroviral infection in an individual being caused by a mono-resistant retrovirus, which is a mono-resistant HIV-1 retrovirus.

33. The antivirally active pharmaceutical ingredient a) according to claim 32 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein the infection in an individual caused by a mono-resistant retrovirus is characterised in that the individual does not respond to an antivirally active

pharmaceutical ingredient from a drug action class selected from the group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors, and wherein the presence of a mono-resistant retrovirus can be documented using a genotypic resistance test of the viral genome.

34. The antivirally active pharmaceutical ingredient a) according to claim 31 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein said retroviral infection in an individual is caused by a

multidrug-resistant retrovirus, which is a multidrug-resistant HIV-1 retrovirus.

35. The antivirally active pharmaceutical ingredient a) according to claim 34 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein the infection in an individual caused by a multidrug-resistant retrovirus is characterised in that the individual does not respond to two or more different antivirally active pharmaceutical ingredients from a drug action class selected from the group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors, and wherein the presence of a multidrug-resistant retrovirus can be

documented using a genotypic resistance test of the viral genome.

36. The antivirally active pharmaceutical ingredient a) according to claim 31 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein said retroviral infection in an individual is caused by a

37. The antivirally active pharmaceutical ingredient a) according to claim 36 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein the infection in an individual caused by a multidrug-resistant retrovirus is characterised in that the individual does not respond to two or more different antivirally active pharmaceutical ingredients from two or more drug action classes selected from the group comprising nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, entry inhibitors and integrase inhibitors, nor to combinations thereof, and wherein the presence of a multidrug-resistant retrovirus can be documented using a genotypic resistance test of the viral genome.

38. The antivirally active pharmaceutical ingredient a) according to any of claims 31 to 37 for use in the prevention and/or treatment of viral infections and of diseases caused by them in an individual, wherein the disease caused by the HIV-1 retrovirus is among the group comprising acute HIV infection, AIDS, ARC, LAS as well as immunodeficiency and encephalopathy caused by the said HIV-1 retrovirus.