THEREOF

Technical Field

The present invention relates to a novel drug molecules, a novel method for use in preparation of said drug molecules and use of said drug molecules for preparation of a pharmaceutical composition for use in treatment of viral, bacterial and neoplastic diseases.

State of the Art

Bacterial, viral and neoplastic diseases affect a significant part of the world population and play an important role in determining parameters such as average human life, quality of life, etc. Such diseases cause economic burden due to both significant loss in workforce and the cost of treatment.

There are agents for the treatment of bacterial, viral, parasitic and neoplastic diseases in the known art, but there is still a need for specific agents to provide effective treatment and high-yielding methods for use in their production.

Common types of parasitic diseases include malaria and trypanosoma .Leishmaniasis that is another parasitic disease, is caused by protozoan parasites of the Leishmania class .Female sandflies play a role in the spread of these parasites .Leishmaniasis can be on the skin, under the skin, or in visceral form. Visceral leishmaniasis begins with skin wounds and has effects such as fever, low red blood cell count, and gall bladder and liver growth.

Approximately 2 million new cases of Leishmaniasis occur each year, resulting in approximately 70000 deaths. The large number of Leishmania parasites and also the large number of sandfly species that play a role in parasite spread cause many subtypes of the disease to develop, which requires a complicated treatment.

Leishmaniasis is often present in communities where poverty, urban regeneration, forest destruction and inadequate nutrition are seen. In order to prevent the disease, vaccine development studies have been carried out however a safe vaccine providing adequate protection has not been developed.

Pentavalent antimony compounds are proposed by the World Health Organization for use in the treatment of Leishmaniasis. Examples of such compounds are sodium stibogluconate and meglumin antimony. However, a disadvantage of these drugs is that they are treated with parenteral administration under medical supervision because of the high toxicity of the drugs.

In addition, during treatment, resistance develops in the patients and it is necessary to increase the dosage and prolong the duration of the treatment so that the desired effect can be seen.

The other Leishmaniasis medicine recommended by the World Health Organization is pentamidine .This drug, which is thought to be effective in patients who first developed resistance to pentavalent antimony, has an effect that diminishes over time. This suggests that resistance develops against this medication too. Additionally, the drug has caused serious side effects such as low blood pressure, low blood sugar, nephrotoxicity, irreversible diabetes mellitus and even death, leading to the complete cessation of the use of the drug in some parts of the world.

Amphotericin B is another known active agent having antileishmania activity. Because this active substance has toxic effects like the other active substances mentioned above, it is given to the patients under medical supervision.

Another known active agent in the treatment of Leishmania is miltephosin. This active ingredient is considered to be superior to the other known active agents in terms of providing the adaptation to treatment since it allows oral administration.However, the teratogenic nature of the agent makes it impossible to use this medicine in pregnant patiens.

As can be seen, the inadequate number of drugs available in the known state of the technique, the need for medical observation and serious adverse effects of the administration methods make it difficult to treat this disease, which necessitates the development of new agents. One of the studies made for this purpose is published in the application number WO2008007262 .This application discloses various bisnaphthalimidopropyl derivatives and their efficacy in treating Leishmaniasis and cancer, a neoplastic disease .However, the low solubility of the molecules in question reduces the bioavailability of these molecules. It is also not suitable for large-scale industrial production because the synthesis method of the molecules consist of a large number of complex steps and the yield is low.

Aim of the invention

The invention aims to develop alternative active agents which can be used in the treatment of bacterial, viral, parasitic and neoplastic diseases.

The inventors are also aiming to develop active agents which are safe to use as they do not have serious side effects.

Another object of the invention is the development of active agents with high solubility.

In another aspect, the inventors are aiming to develop active agents having enhanced bioavailability.

The inventors also aim to develop a production method comprising a small number of highly efficient steps that can be used in the synthesis of molecules suitable for use in the treatment of bacterial, viral, parasitic and neoplastic diseases .In this way, the inventors are attempting to make a greater amount of the drug available to public by reducing the production cost of the active ingredients .

Working for realizing the abovementioned aims, the inventors of the present invention have developed molecules shown with formula I and a production method which can be used in the production of molecules of the formula I which are suitable for use in the treatment of bacterial, viral, neoplastic and parasitic diseases such as Leishmania .

Detailed Description of the Invention

The present invention relates to molecules shown with Formula I.

wherein;

R _A = C i -C 5 alkane, C i -C 5 alkene or C ₁ -C ₅ alkyne

X = CI, F, Br or I

R _B = -X, -NH 2, -COORs, -CH ₂ CHNH ₂ COOR ₈ , -NR ₈ R 9 and L = R R ₂ , R ₃ , R4, R ₅ , R6, R7 or

R _B = -H and L = ¾ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ ;

R ₂ = -NHCONH-Rg -NHCONH- ;

R ₃ = -OCOHN-R _s -NHOCO-;

R ₄ = -NHCOO-R ₈ -OOCNH-;

R ₅ = -NHCO-Rs-CONH

R ₆ = -CONH-R ₈ -NHOC-

R7 is=-NH-R ₈ -NH- and

R _g and R9 are independently selected from Ci -C ₁₀ alkane, alkene, alkyne.

The term "alkane" as used in the present invention refers to straight or branched saturated hydrocarbon chains.

The term "alkene" as used in the present invention refers to straight or branched hydrocarbon chains containing at least one carbon-carbon double bond.

The term "alkyne" as used in the present invention refers to straight or branched hydrocarbon chains containing at least one carbon-carbon triple bond. In an embodiment of the invention, R _{8 ls} ; is selected from a group comprising C\ alkane, C ₂ alkane, alkane, C ₄ alkane, C ₅ alkane, C6 alkane, C? alkane, C ₈ alkane, C alkane or Cio alkane .

In an embodiment of the invention R is selected from a group comprising d alkane, C ₂ alkane, C3 alkane, C ₄ alkane, C5 alkane, C(, alkane, C ₇ alkane, C ₈ alkane, C9 alkane or do alkane .

As shown here, RB may be attached to any carbon on the benzene ring. Also, in both rings, different RB groups may be present as attached to any carbon atom on these two rings. As shown in the document, which was published by IUPAC in 2008, entitled "Graphical representation standard for chemical structure diagrams" , any hydrogen atom on the ring may be replaced by the group RB as defined herein. In a preferred embodiment of the invention, the active ingredients according to the present invention are represented by Formula I

RA = C3 alkane

RB = H

Ri = -OCOO-Rg-OOCO-;

R ₂ = -NHCONH-R ₈ -NHCONH- ; R ₃ = -OCOHN-Rs-NHOCO;

R4 = -NHCOO-Rs-OOCNH-;

R ₅ = -NHCO-R ₈ -CONH R ₆ = -CONH-R ₈ -NHOC- R = C] - o alkane. In another preferred embodiment of the invention, the active ingredients according to the present invention are represented by Formula I and

R _A = C ₃ alkane

R _B = C1

L = Ri , R ₂ , R ₃ , R4 , R ₅ , R ₆ , R?

Ri = -OCOO-Rs-OOCO-;

R ₂ = -NHCONH-R ₈ -NHCONH- ;

R ₃ = -OCOHN-Rg-NHOCO-;

R ₄ = -NHCOO-Rg-OOCNH-;

R ₅ = -NHCO-Rg -CONH

R ₆ = -CONH-Rs-NHOC-

R ₇ = -NH-R ₈ -NH

R ₈ = C1-C10 alkane.

In another preferred embodiment of the invention, the active ingredients according to the present invention are represented by Formula I wherein

R _A = C ₃ alkane

R _B = -COOR ₈

L - Ri , R ₂ , R ₃ , R4 , R5 , R ₆ , R ₇ Ri = -OCOO-Rg-OOCO-;

R ₂ = -NHCONH-Rs-NHCONH- ;

R ₃ = -OCOHN-Rs-NHOCO-;

R ₄ = -NHCOO-Rg-OOCNH-;

R ₅ = -NHCO-Rg-CONH

R ₆ = -CONH-R ₈ -NHOC-

R ₈ = Ci -Cio alkane.

In another preferred embodiment of the invention, the active ingredients according to the present invention are represented by Formula I wherein

RA = C ₃ alkane

L = Ri , R ₂ , R ₃ , R4 , R5 , R6 , R7

Ri = -OCOO-R ₈ -OOCO-;

R ₂ = -NHCONH-R ₈ -NHCONH- ;

R ₃ = -OCOHN-R ₈ -NHOCO-;

R4 = -NHCOO-Rg-OOCNH-;

R ₅ = -NHCO-Rs-CONH

R ₆ = -CONH-R ₈ -NHOC-

R ₇ = -NH-Rg-NH

R ₈ = Ci -Cio alkane. In another preferred embodiment of the invention, the active agents according to the present invention are represented by Formula I wherein

RA = C3 alkane

R _B = -NR ₈ R ₉

L = Ri, R2, R ₃ , R4 , R5 , e , R?

Ri = -OCOO-Rs-OOCO-;

R ₂ = -NHCONH-Rs-NHCONH- ;

R ₃ = -OCOHN-Rg-NHOCO-;

R4 = -NHCOO-Rs-OOCNH-;

R ₅ = -NHCO-Rg-CONH

R ₆ = -CONH-R ₈ -NHOC-

R 7 = -NH-Rg-NH

Rg = Ci -Cio alkane

Rg is Ci -Cio alkaryl.

In a preferred embodiment of the invention, the compound represented by formula I is Ni, Ng-bis (3-(l,3-dioxo-lH-benzo[de]isoquinolin-2(3H)-yl)propyl) octanediamide and shown by formula la. In a preferred embodiment of the invention, the compound represented by formula I is 1 , 1 '-(butane- 1 ,4-diyl)bis(3-(3-( 1 ,3-dioxo- 1 H-benzo[de]isoquinoline-2(3H)yl)propylurea) and shown with formula lb .

In a preferred embodiment of the invention, the compound represented by formula I is butane-l,4-diylbis((3-(l,3-dioxo-lH-benzo[de]isoquinoline-2( 3H)-yl)propyl)carbamate) and shown with formula Ic.

In a preferred embodiment of the invention the compound represented by formula I is bis (3-(l,3-dioxo-lH-benzo[de]isoquinolin-2(3H)-yl)propyl)butane -l,4-diyldicarbamate and shown with formula Id

In a preferred embodiment of the invention, the compound represented by formula I is butane- 1,4-diyl bis(3-(l,3-dioxo-lH-benzo[de]isoquinoline-2(3H) and shown with formula Ie.

In a preferred embodiment of the invention, the compound represented by formula I is N, N'-(octane-l ,8-diyl)bis(3-(l ,3-dioxo-lH-benzo[de] isoquinoline-2-(3H)-yl)propanamide) and shown with formula If.

The molecules of formula Ia-If whosee chemical structures and specific chemical nomenclature are given above are intended to illustrate the invention and are not to be construed as limiting the invention to these molecules.

In a further aspect, the present invention is directed to methods for use in the preparation of the molecules of formula I according to the invention.

A method which can be used to obtain the active compounds of the formula I according to the invention (Method I) comprises the steps of;

i. Reaction of the compound of formula II with CDI in the presence of a suitable solvent,

Reacting the resulting intermediate product with the agent represented by Formula in the presence of DIEA, and

Formul III

iii. Isolation of final product from reaction mixture

wherein R ₁₀ and Rn are independently selected from the group comprising -OH and - NH ₂ ; RB is selected from -H, -X, -NH ₂ , -COORg , -CH ₂ CHNH ₂ COOR ₈ or -NR ₈ R ₉ ; R ₈ and R9 are independently selected from Ci -C1 ₀ alkane, alkene, alkyne, and n is a natural number from 1 to 10.

A method which can be used to obtain the active compounds of the formula I according to the invention (Method II) comprises the steps of;

i. The dissolution of the compound of formula II in a suitable solvent,

ii. Addition of the compound represented by formula IV to the reaction mixture,

Formul IV

iii. Addition of base to reaction mixture and

iv. Isolation of final product from reaction mixture

Wherein Rio is selected from -OH and -NH ₂ and X is selected from -CI, -Br, -I, -F, R _B , is selected from -H, -X, -NH ₂ , -COOR ₈ , -CH CHNH ₂ COOR ₈ or -NR ₈ R ₉ ; R ₈ and R ₉ are independently selected from Q -C ₁₀ alkane, alkene, alkyne, and n is a natural number from 1 to 10.

The "base" as used herein can be selected from a group comprising 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU), KI / K ₂ C0 ₃ , NaH, N, N-Diisopropylethylamine (DIEA), triethy lamine(TEA) .

A method (Method III) which can be used to obtain the active compounds of Formula I according to the invention comprises the steps of; i. The dissolution of the compound of formula V in a suitable solvent and reacting in the presence of DCC and HOBt,

ii. A of formula III to the reaction mixture,

Formal III

iii. Isolation of final product from reaction mixture

Wherein Rio and Rn are independently selected from the group comprising -OH and -NH2 groups; R _B is selected from -H, -X, -NH , -COOR ₈ , -CH ₂ CHNH ₂ COOR ₈ or -NR _g R ₉ ; R ₈ and R ₉ are independently selected from d -C10 alkane, alkene, alkyne, and n is a natural number from 1 to 10.

As used herein, the term "a solvent" refers to any organic solvent that will dissolve the reagents used during the reaction.

Said organic solvent can be selected from a group comprising acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1 ,2-dichloroethane, diethylene glycol, diethyl ether, diethyl glycol dimethyl ether, l-2,dimethoxyethane (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, glycerine, heptane, hexamethylphosphoramide (HMPA), hexamethyl phosphorous triamide (HMPT), hexane, methanol, methyl butyl ether (MTBE), methylene chloride (DCM), N-methyl-2-pyrrolidone (NMP), nitromethane, pentane, petroleum ether, 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF), toluene, triethyl amine, water, o-xylene, m-xylene, p-xylene.

In a preferred embodiment of the invention, DMF or THF is used as solvent in Method I.

In a preferred embodiment of the invention, DCM and / or DMF is used as solvent in Method II. In one embodiment of the invention, THF is used as the solvent in Method III.

The methods indicated by the methods I, II and III can be carried out at room temperature or at a temperature of 25-40 ^° C.Any step in each method can be performed at a different temperature than the other.

The products obtained by the methods according to the invention can be purified by methods such as filtration, centrifugation, extraction, crystallization, recrystallization, chromatography, distillation.

Herein the chromatography method can be selected from; column chromatography, gas chromatography, liquid chromatography, reverse phase liquid chromatography.

The methods named Method I, Method II and Method III, which can be used to prepare the molecules according to the invention, all outperform the methods used to prepare such molecules in the known state of the art, both in terms of high reaction yield and the less number of synthesis steps involved.

The molecules obtained by Method I, Method II and Method III defined in the present invention are defined by the formula I below;

wherein;

RA = Ci -C ₅ alkane, Ci -C ₅ alkene or Ci -C ₅ alkyne

X = CI, F, Br or I

R B is -H, -X, -NH ₂ , -COORg, -CH ₂ CHNH ₂ COOR _g , -NR ₈ R ₉ and L = Ri, R ₂ , R ₃ , R4, R ₅ , Re, R ₇

Ri = -OCOO-R ₈ -OOCO-;

R ₂ = -NHCONH-R ₈ -NHCONH- ;

R ₃ = -OCOHN-R ₈ -NHOCO-; R4 = -NHCOO-Rg-OOCNH-;

R ₅ = -NHCO-Rs-CONH

R ₆ = -CONH-Rg-NHOC-

R ₈ and R9 are independently selected from Ci -C ₁₀ alkane, alkene, alkyne.

In another aspect, the invention relates to molecules of formula I obtained using Method I, Method II and Method III

wherein;

RA = C1-C5 alkane, C1-C5 alkene or C1-C5 alkyne

X = CI, F, Br or I

R _B is -H, -X, -NH ₂ , -COORg, -CH ₂ CHNH ₂ COOR ₈₎ -NR ₈ R ₉ and L = R _1; R ₂ , R ₃ , R4, R ₅ , R ₆ ,

Ri = -OCOO-R ₈ -OOCO-;

R ₂ = -NHCONH-Rg-NHCONH- ;

R ₃ = -OCOHN-R ₈ -NHOCO-;

R4 = -NHCOO-R ₈ -OOCNH-;

R ₅ = -NHCO-Rg-CONH

R ₆ = -CONH-Rg-NHOC-

Rg and R9 are independently selected from Ci -C10 alkane, alkene, alkyne. The compounds of formula I, as defined above, which are obtained by the method I, method II and method III according to the present invention, are obtained using less reaction steps and with higher yield, and thus the molecules of formula I are obtained in a shorter time.

In another aspect, the invention discloses the use of the compounds of Formula I as medicaments.

In one aspect, the present invention relates to the use of the molecules of Formula I according to the invention in the treatment of parasitic diseases.

As used herein, "parasitic diseases" refers to diseases caused or transmitted by a parasite.

Herein said parasitic diseases can be, schistosomiasis, opistorsiosis, clonorchiasis, dikrosolyoz, fascioliasis, paragonimiasis,fasiolopiasis,Echinococcosis,Taeniasis,cystic ercosis,difilobotrtiasis,sparg anosis,hymenolepiasis,dracunculiasis,onchocerciasis,filarias is,elephantiasis,mansonellosi s,trichinellosis,anchilostomiasis,necatoriasis,anchilostomia sis,ascardiosis

,strongyloidiasis,trichiurosis,enterobiasis,anisachiasis, helmintiasis,tricostrongylosis,angiy ostrongylosis, gnatostomiasis, angiyostrongylosis, syngamiosis, hirudiniasis, akantocefalliasis, gongilonemiasis, metastrongiliasis, telasiasis, pediculosis, pithiriasis, skabiasis, myiasis, tungiasis, trombikulosis, skarabiasis, hirudiniasis, linguatulosis, porosefaliasis, leishmaniasis, trypanosomiasis, malaria caused by Plasmodium falciparum, malaria caused by Plasmodium vivax, malaria caused by Plasmodium malariae, Chagas disease, toxoplasmosis, pneumocystosis, babesiosis, pyroplazmosis, acantamebiasis, naegeriasis and/or microsporidiosis.

In a preferred embodiment of the invention, the molecules of formula I are used in the treatment of Leishmaniasis.

The invention relates preferably to the use of the molecules of formula I in the treatment of leishmaniasis. The Leishmaniasis disease mentioned herein can be cutaneous, mucocutaneous or visceral Leishmaniasis.

In another aspect, the invention provides use of compounds according to present invention shown with formula I for treatment of infectious diseases caused by parasites such as L.Arabica, L. archibaldi, L. aristadesi, L. braziliensis, L. chagasi, L. colombiensis, L. L. infestum, L. equatorensis, L. forattinii, L. garnhami, L. gerbil, L. guyanensis, L. herreri, L. hertigi, L. infantum, L. killicki, L. lainoni, L. major, L. Mexicana, L. naiffi, L. panamensis, L. peruviana, L. pifanoi, L. shawi, L. tarentolae, L. tropica, L. turanica, L. venezuelensis, .

In one aspect, the present invention relates to the use of the molecules of Formula I according to the invention in the treatment of bacterial diseases.

As used herein, the phrase "bacterial diseases" refers to diseases caused by infections caused by the pathogenic bacteria.

Bacterial diseases according to the present invention can be any bacterial disease caused by bacteria belonging to groups of bacillus, bartonella, bordetella, borrelia, brucella, campilobacter, calamidia, Clostridium, corynebacterium, enterococcus, escheria, francisella, hemophilus, helicobacter, legionella, leptospira, lysteria, mycobacteria, mycoplasma, neisseria, pseudomonas, rickettsia, salmonella, shigella, staphylococcus, streptococcus, treponema, ureplasmia, vibrio, yersinia.

Such bacterial diseases include bacterial diseases such as bubonic plague, pneumonic plague, cholera, syphilis, congenital syphilis, post streptococcal glomerulonephritis, ploidy fever, impetigo, serpentine, febrile rheumatism, red fever, streptococcal pharyngitis, sepsis, acute bacterial pneumonia, meningitis, endometritis, neonatal sepsis, neonatal meningitis, neonatal pneumonia, cystitis, osteornyellitis, toxic shock syndrome, staphylococcal food poisoning, shigellosis, salmonella, paratyphoid, typhoid, rocky mountains spotted fever, urinary tract infections, corneal infections, pneumonia, endocarditis, meningitis, gonorrhea, pelvic inflammatory disease, tuberculosis, leprosy, legionary disease, peptic ulcer, upper respiratory system infections, chronic gastritis, bronchitis.septic arthritis, tularemia, bloody diarrhea, urinary tract infections, endocarditis, biliary tract infections, gastrointestinal tract infections, gastroesophageal reflux disease, gonorrhea, pelvic inflammatory disease, tuberculosis, leprosy, listeriosis, leptospirosis, legionnaire disease, peptic ulcer, upper respiratory tract infections , diphtheria, tetanus, parrot fever, trachoma (trachoma), neonatal conjunctivitis, urethritis, epididymitis, prostatitis, lymphogranulomatosis, atypical pneumonia, Guillain-Barre Syndrome, broscellosis, Maltese Fever, Lyme disease.

In one aspect, the present invention relates to the use of molecules of Formula I according to the invention for treatment of viral diseases.

The term "viral diseases" used in the present invention refers to all kinds of diseases that are caused by pathogenic viruses and infectious virus particles (viron) that bind themselves to the cells and enter the cells.

Said viral diseases can be any disease caused by any of the viruses belonging to the the main virus families of Adenoviridae, Herpesviridae, papillomavirida A, polyomavirida A, Poxviridae, heradnavirida, Parvoviridae, Astroviridae, Caliciviridae, Picomaviridae, Coronaviridae, Flaviviridae, Togaviridae, hepevirida A, retroviridae, Orthomyxoviridae, Arenaviridae, Bunyaviridae, filoviridae, paramyxoviridae, rhabdoviridae, and Reoviridae.

Specific examples of such viral diseases include gastroenteritis, glaucoma, keratoconjunctivitis, pharyngytis, croup, pneumonia, cystitis, hand-foot-mouth disease, pleurodnia, septic meningitis, pericarditis, myocarditis, Burkitt's lymphoma, Hodgkin's lymphoma, nasapharyngial carcinoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, tonsillitis, cytomegalic inclusion disease, Kaposi's sarcoma, castleman's disease, influenza, measles, reese's syndrome, mumps, anogenital warts, poliomyelitis, rabies, congenital rubella, rubella, smallpox, shingles, congenital chicken pox syndrome.

In one aspect, the present invention relates to the use of the molecules of Formula I according to the invention in the treatment of neoplastic diseases.

The term "neoplastic diseases" used in the present invention refers to a physiological condition characterized by malignant tumors or uncontrolled cell growth, for example, cancer disease. Within this document the terms "neoplastic disease" and "cancer" can be used interchangeably. Cancer examples include, but are not limited to, carcinoma, lymphoma, blastoma sarcoma, and leukemia.

Carcinoma, as used herein, refers to a cancer type of epithelial cells.

Lymphoma, as used herein, describes a cancer type that develops from lymphocytes. Blastoma, as used herein, refers to a cancer type developed from precursor cells, also known as blast cell.

Sarcoma, as used herein, refers to a cancer type arising from altered cells of mesenchymal origin.

Leukemia, as used herein, refers to a cancer type originating in the bone marrow and causing a high number of abnormal white blood cell formation.

More specific examples of cancer types include breast cancer, prostate cancer, colorectal cancer, skin cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, gastrointestinal cancer, pancreatic cancer, glioblastoma, vulva cancer, cervical cancer, endometrial carcinoma, ovarian cancer, liver cancer, hepatoma, bladder cancer, kidney cancer, salivary gland carcinoma, thyroid cancer and various head and neck cancers. The invention also relates to a pharmaceutical composition comprising as active ingredient the compounds represented by formula I according to the invention.

Said pharmaceutical compositions may comprise at least one further active ingredient in addition to the compounds represented by Formula I.

In another embodiment of the present invention, the compounds of formula I according to the invention can be used in combination with other known active compounds which exhibit antiparasitic, antibacterial, antiviral, antineoplastic and / or cytotoxic and / or antimetastatic action or with binary / ternary combinations thereof .The second active ingredient may be formulated together with the compounds represented by formula I, or may be formulated separately from the compounds according to formula I and sold in packages suitable for combined use.

In a preferred embodiment of the invention, the compounds of formula I are combined with at least one active compound which exhibits antibacterial activity.

The active compounds shown with formula I having antibacterial activity which may be used in combination with the compounds of formula I are selected from the group comprising amikacin, gentamycin, kanamycin, neomycin, netilmicine, tobramycin, paromycin, streptomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem, imipenem, meropenem, cefadroxil, cefazolin cefotaxime, ceftazidime, ceftibuten, ceftizidime, ceftibuten, ceftizidime, cefepime, ceftarolin fosamil, ceftobiprol, teicoplanin, vancomycin, televancin, dalbavancin, oritavancin, cefotaxime, cefixime, cefdinir, cefuroxime, cefixime, cefdmir, cefditoren, cefdinir, cefdinir, clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin, dilithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam, furazolidone, nitrofurantoin, linezolid, posizolid, radezolide, torezolid, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxaciline, mezlocillin, methicillin, nafsilin, ox acylin, penicillin G, penicillin V, piperacillin, temocilin, ticarcillin, clavulanate, sulbactam, tazobactam, simplexin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidinic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfanilimid, sulfasalazine, sulfisoxazole, trometoprim, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, isoniyazid, pyrazinamid, rifampicin, rifabutin, rifapentin, streptomycin, arsfenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin, dalfopristin, thiamphenicol, tigecycline, imidazole, trimethoprim or binary or ternary combinations thereof.

In another preferred embodiment of the invention, the compounds of formula I are combined with at least one active compound which has an antiviral effect.

The active compounds having antiviral activity which can be used in combination with the compounds shown by Formula I can be selected from a group comprising abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, atripla, balavir, cidofovir, combivir, dolutegravir, darunavir, delavirdine, didanosine, docosanol, , interferon type II, interferon type II, interferon type III, interferon, lamivudine, lopinavir, fosivarin, fosampanavir, foscarnet, phosphocetine, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type I , peginterferon alfa-2a, penicyclovir, peramivir, peconaril, podophyllotoxin, protease inhibitor, nucleoside analogs, ralgetavir, ribavirin, rimantadine, ritonavir, pyramidine, nevirapine, nexavir, nitazoxanide, novir, oseltamivir, saquinavir, sofosuvir, stavudine, telaprevir, tenofovir, tipranavir, trifluidine, trizivir, tromantadine, trovada , valaciclovir, valganciclovir, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, or binary or ternary combinations of the listed agents.

In another preferred embodiment of the invention, the compounds of formula I are combined with at least one active compound having antiparasitic effect.

The active compounds which exhibit antiparasitic activity and which can be used in combination with the compounds of formula I are selected from a group comprising nitazoxanide, melarsoprol, eflornithine, metronidazole, tinidazole, miltephosine, mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin, niclosamide, praziquantel, albendazole, rifampin, amphotericin B, fumagillin, furazolidone , nifursemizone, nitacosanide, omidazole, paramomycin sulfate, pentamidine, pyrimethamine, tinidazole, albendazole, mebendazole, thiabendazole, fenbendazole, triclabendazole, flubendazole, abamectin, diethylcarbamazine, ivermektin, suramin, pirantel pamoate, levamisol, niklosamide, nitacoxanide, oxycononazide, monepantel, derquantel , amphotericin B, urea stibamine, sodium stibogluconate, meglumin antimoniate, paromomycin, miltephosine, fluconazole, pentamidine, or binary or ternary combinations thereof.

In another preferred embodiment of the invention, the compounds of formula I are combined with at least one active compound which shows an antineoplastic effect.

The active compounds having antineoplastic activity which may be used in combination with the compounds shown by formula I can be selected from a group comprising cyclophosphamide, ifosfamide, temozolomide, capecitabine, 5-fluorouracil, methotrexate, gemcitabine, pemetrexed, mitomycin, bleomycin, epirubicin, doxorubicin, etoposide, paclitaxel, irinotecan, docetaxel, vincristine, carboplatin, cisplatin, oxaplatin, carbapenetin, cisplatin, oxaliplatin, bevacizumab, cetuximab, gefitinib, imatinib, trastuzumab, denosumab, rituximab, sunitinib, zoledronate, abiraterone, anastrozole, bicalutamide, exemestane, goserelin, medroxyprogesterone, octreotide, tamoxifen, bendamustine, carmustine, chlorambucil, lomustine, melphalan, procarbazine, streptozocin, fludarabine, raltitrexed, actinomycin D, dactinomycin, doxorubicin, mitoxantrone, eribulin, topotecan, vinblastine, vinorelbine, afatinib, aflibcrcept, chrysotinib, dabrafenib, interferon, ipilimumab, lapatinib, nivolumab, panitumumab, pembrolizumab, pertuzumab, sorafenib, trastuzumab emtansin, temsorilimus, vemurafenib, ibandronic acid , pamidronate, bexarotene, buserelin, cyproteronc, degarelix, folinic acid, fulvestrant, lanreotide, lenalidomide, letrozole, leuprorelin, megestro], mesna thalidomide or binary or ternary combinations thereof.

In another embodiment of the invention, at least one further active ingredient may be formulated together with or separately from the compounds of formula I according to the invention, and said at least one further active ingredient may be in the same or different dosage form as the compounds of formula I.

If at least one other active ingredient mentioned above is used in combination with the compounds of formula I according to the invention, the other active ingredients may be administered simultaneously, sequentially or at different times with the compounds of formula I.

The formulations according to the invention may contain at least one excipient in addition to the active substances indicated by formula I.

The dosage range in which the active compounds of the formula I according to the invention can be used is determined according to the needs of the patient, the stage of the disease and the agent to be used. Determining a suitable dose for a given situation is known to the persons skilled in the art .

The invention will now be described by way of example only with reference to the following examples, which are intended to be exemplary only and are not to be construed in any way as limiting the scope of the invention.

EXAMPLES:

Example 1: Synthesis of 2-(3-aminopropyl)-lH-benzo [de] isoquinoline-1,3 (2H)-dione (Formula Ila)

1,4-diaminopropane (1.25 mmol) was added to a suspension of 1,8-naphthalic anhydride (1 mmol) in ethanol . The reaction was refluxed overnight at 75 ° C. The ethylacetate solvent system was used for monitoring the progress of the reaction and purification by column chromatography

Analysis Data: LC-MS: calculated = 254 (M), found = 255 ([M + 1])

Example 2: Synthesis of 2- (3-hydroxypropyl)- lH-benzo[de]isoquinoline-l,3(2H)-dione (Formula lib)

1,8-naphthalic anhydride (1 mmol) was dissolved in DMF. Then, diaminopropane (1 mmol) and DBU (1 mmol) were added. The mixture was stirred for 4 hours. The progress of the reaction was monitored by the DCM / MeOH (40/1) solvent system. The reaction was terminated by precipitation in ice water followed by filtration to give pure product.

Analysis Data: LC-MS: calculated = 255 (M), found = 256 ([M + 1]). LJ

Example 3: Synthesis of 3-(l,3-dioxo-lH-benzo[de]isoquinolin-2(3H)-yl) propanoic acid (Formula Va)

Beta analine (1 mmol) was reacted with DIEA in ACN at 70 [deg.] C. for 1 hour. Subsequently, 1 ,8-naphthalic anhydride (1 mmol) was added to the reaction mixture and the reaction was stirred for 24 hours. The DCM / MeOH (20/1) solvent system was used for monitoring the progress of the reaction and for purification by column chromatography

Analysis Data: LC-MS: calculated = 283 (M), found = 284 ([M+l ]). Example 4: Synthesis of Nl, N8-bis(3-(l ,3-dioxo-lH-benzo [de] isoquinolin-2 (3H)-yl) propyl)octanediamide (Formula la)

Suberic acid (0.4 mmol) was dissolved in DCM and oxalyl chloride (1.6 mmol) was added dropwise to the reaction medium at + 4 ⁰ C. The reaction was brought to room temperature by the addition of 1 -2 drops of DMF. The reaction was stirred at room temperature for 2 hours. The product was obtained in pure form. The obtained product was dissolved in DCM and then added to the reaction flask containing Formula lla .After stirring at room temperature for 10 minutes, triethylaniine (1.2 mmol) was added and the reaction was stirred at room temperature for 2 hours. For purification by column chromatography, the DCM / MeOH (40/1) solvent system was used.

Analysis Data:□ LC-MS: calculated = 646 (M), found = 645 ([M + 1 ]).

EXAMPLE 5: Synthesis of 1,1 *- (Butane- 1 ,4-diyl) bis(3-(3-(l,3-dioxo-lH-benzo[de] isoquinolin-2-(3H)-yl)propyl)urea) (Formula lb)

The compound lla was dissolved in THF under nitrogen atmosphere at room temperature and then treated with a solution of CDI (3 mmol) .The obtained product (4 mmol) was then reacted with 1 ,4-diaminobutane (1 mmol) and DIEA (2.2 mmol) in THF for 16 hours .

Analysis Data:□ LC-MS: calculated = 648 (M), found = 649 ([M + 1 ]). Example 6: Butane- 1,4-diyl bis ((3- (1 ,3-dioxo-lH-benzo [de) isoquinolin-2 (3H) -yl) propyl) carbamate) (Formula Ic)

The compound Ila was dissolved in THF under nitrogen atmosphere at room temperature and then treated with a solution of CDI (3 mmol) .The obtained product (4 mmol) was then reacted with 1 ,4-butanediol (1 mmol) and DIEA (2.2 mmol) in THF for 16 hours .

1H NMR (500 MHz, CDC1 3): δ = 1.64 (t, J = 9.7, 7.8, 5.0 Hz, 4H, 2xCH ₂ ), 1.98 - 1.79 (t, 4H, 2 * CH ₂ ), 3.15 (q, J = 6.3 Hz, 4H, 2xCH ₂ ) _, 4.03 (m, J = 5.4 Hz, 4H 2xCH ₂ ) _, 4.21 (t, J = 6.4 Hz, 4H 2xCH ₂ ) _, 5.50 (br d, J = 6.3 Hz, 2xNH), 7.69 (t, J = 7.7 Hz, 4H, ArH), 8.15 (d, J = 8.2 Hz, 4H, ArH), 8.53 (d, J= 7.3 Hz, 4H, ArH)

¹³ C NMR (125 MHz, CDC1 3): δ = 25.7 (CH ₂ ), 28.3 (CH ₂ ), 37.5 (CH ₂ ), 37.8 (CH ₂ ), 64.4 (0-CH ₂ ) _, 122.4 (C _arom ) 127 (C _arom H), 128.1 (C _arom ) _, 131.4 (C _arom H), 131.3 (C _arom ) _, 134.1 (C _arom H), 1567 (C = O), 164.5 (C = O) ppm.

Analysis data: LC-MS: calculated = 650 (M), found = 651 ([M + 1])

Example 7: bis (3- (1,3-dioxo-lH-benzo [de] isoquinolin-2 (3H) -yl) propyl) butane-1,4- diyldicarbamide (Formula Id)

The compound lib was dissolved in THF at room temperature under nitrogen atmosphere and then treated with a solution of CDI (3 mmol) .The obtained product (4 mmol) was then reacted with 1 ,4-diaminobutane (1 mmol) and DIEA (2.2 mmol) in THF for 16 h .

Analysis Data: 1 H NMR (500 MHz, CDC1 3): δ = 1 :55 to 1 :36 (m, 4H, CH2), 2.03 (dd, J = 48.2, 12.6 Hz, 4H, NHCH2), 3:27 to 3:01 (m, 4H, NCH2 ), 4:33 to 4:04 (m, 4H, OCH2), 7.67 (dd, J= 16.4, 8.4 Hz, 4H, Ar H), 8.12 (d, J= 8.2 Hz, 4H, Ar H), 8.50 (d, J = 7.1 Hz, 4H, ArH), ppm.

LC-MS: calculated = 650 (M), found = 651 ([M + 1])

Example 8: Butane- 1,4-diyl bis(3-(l,3) dioxo-lH-benzo [de] isoquinolin-2 (3H) -yl) propyl) bis (carbonate) (Formula Ie)

The compound lib was dissolved in THF at room temperature under nitrogen atmosphere and then treated with a solution of CDI (3 mmol) .The obtained product (4 mmol) was reacted with 1,4-butanediol (1 mmol) and DIEA (2.2 mmol) in DMF at 80 ⁰ C for 5 days.

LC-MS: calculated = 652 (M), found = 653 ([M + 1]).

Example 9: Synthesis of N, N '- (octane- 1, 8 -diyl) bis (3- (1,3-dioxo-lH-benzo [de] isoquinolin-2 (3H) -yl) propanamide)

After dissolving Formula V (2.4 mmol) in THF under nitrogen atmosphere, DCC and HOBt (0.92 mmol) were added respectively, and the reaction was allowed to proceed at 0 ° C for 1 hour, after which 1,8-diamino octane (0.92 mmol) was added and the reaction mixture was stirred for 24 hours. The obtained product was purified by column chromatography with ethylacetate / hexane (8/1) system .

EXAMPLE 10: Synthesis of N, N '- (octane- 1,8-diyl) bis (3- (1 ,3-dioxo-lH-benzo [de] isoquinolin-2 (3H) -yl) propanamide)

Formula V was dissolved in DCM and reacted with oxalyl chloride in presence of DMF (1-2 drops) as catalyst. The obtained product (4mmol) was reacted with 1 ,8-amino octane (1 mmol) and DIEA (2.2 mmol) in DCM for 3 hours to give compound of formula If.

Analysis Data;

1H NMR (500 MHz, CDC13): δ= 0.89 - 0.74 (m, 2H, CH2), 1.30 - 1.09 (m, 4H, CH 2), 1.50 (brd, 4H, CH 2), 2.81-2.60 (m, 4H, CH 2), 1.30 - 1.09 J = 8.1, 7.4 Hz, 4H, ArH), 8.16 (dd, J = 8.4, 0.9 Hz, 2H), 3.63 (brd, 6H, NCH2), 4.52-4.31 (m, 4H, ArH), 8.54 (dd, J = 7.3, 1.1 Hz, 4H, ArH) ppm.

(13C NMR (125 MHz, CDC13): δ= 32.5 (CH2), 36.1 (CH2), 122.5 (Caro), 126.9 (CaroH), 128.2 (Caro), 131.3 (CaroH), 131.6 (Caro), 134.1 (CaroH), 164 (C=0), 171.7 (C=0) ppm.

LC-MS: calculated = 646 (M), found = 647 ([M + 1]).□

Example 11: Bisnaphthalimidopropyldiamino octane (BNIPDaoct) (formula lg)

Formula Ig

To a methanol solution of the compound shown by Formula Ila , base and 1 ,8-dibromo otane was added and the mixture was refluxed with a condenser. The reaction monitored with TLC and was terminated after 4 hours.

In the reaction; some bases such as DBU, l / K ₂ CO ₃ , NaH, DI EA, TEA were investigated. The activity of DBU was found to be high among the bases used. Analysis Data:

Ή NMR (500 MHz, DMSO-d6): δ= 1.25 (m, 8H, 4xCH ₂ ), 1.56 (m, 4H, 2xCH ₂ ), 2.08 - 1.98 (m, 4H, 2xCH ₂ ), 2.86 (t, J = 7.8 Hz, 4H, 2xNHCH ₂ ), 3.04 - 2.97 (m, 4H, 2xNHCH ₂ ), 4.12 (t, J = 6.7 Hz, 4H, 2xNCH ₂ ) 7.92 - 7.82 (t, 4H, ArH), 8.51 - 8.38 (dd, J = 7.6, 5.9 Hz, 4H, ArH), ppm

¹³ C NMR (125 MHz, CDC1 ₃ ): δ= 24.5 (CH ₂ ), 25.4 (CH ₂ ), 25.8 (CH ₂ ), 28.2 (CH ₂ ), 37.1 (CH ₂ ), 44.8 (CH ₂ ), 46.7 (CH ₂ ), 122.1 (C _aro ), 127.2 (C _aro H), 127.4 (C _aro ), 130.7 (C _aro H), 131.3 (C _aro ), 134.4 (C _aro H), 163.7 (C=0) ppm.

LC-MS: calculated = 218 (M), found = 219 ([M + 1])

Example 12: Novel synthesis method for Bisnaphthalimidopropyldiaminononane (BNIPDanone) (formula Ih)

Formula Ih

A methanol solution of the compound shown by formula Ila was refluxed in the presence of DBU and 1 -9-dibromononane in the reaction mixture. The reaction was monitored by TLC and was terminated at the end of 4 hours.

Analysis Data:

LC-MS: calculated = 632 (M), found = 633 ([M + 1]).