WO2018189566A1

WO2018189566A1 - Use of a chemical compound as a therapeutic agent

Info

Publication number: WO2018189566A1
Application number: PCT/IB2017/000748
Authority: WO
Inventors: Dorian Bevec; Andreas Christian HOCKE; Stefan HIPPENSTIEL; Katja ZSCHEPPANG
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-04-10
Filing date: 2017-04-10
Publication date: 2018-10-18
Anticipated expiration: 2019-10-10

Abstract

The present invention relates to a novel medical use of the compound 4- (Cyclopropylamino)-2-((4-(4-(ethanesulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine- 5-carboxamide as a therapeutic agent for the prophylaxis and/or treatment of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury. A preceding IAV infection of the human alveolus leads to an IFN type I and III dependent modulation of the early cytokines IL-1b _and GM-CSF, which are key for orchestrating an adequate innate immune response against S. pneumoniae. Their suppression may result in impaired bacterial clearance and alveolar repair. The selective inhibition of IFNR I and III associated Tyk2 can fully restore the impaired immune activation. A pharmacological Tyk2 inhibition is sufficient as treatment for viral-bacterial co-infection in human pneumonia.

Description

Use of a chemical compound as a therapeutic agent

Specification The present invention is directed to the use of the compound 4-(Cyclopropylamino)- 2-((4-(4-(ethanesulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide as a therapeutic agent for the prophylaxis and/or treatment of an infection, viral- bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co- infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury.

Background of the invention

The identification of a therapeutic compound effective for the prophylaxis and/or treatment of a disease can be based on the activity of the compound in a biological assay. A biological assay that mimics a disease causative mechanism can be used to test the therapeutic activity of a candidate chemical entity.

The causative mechanism of many diseases is the over activity of a biological pathway. A chemical entity that can reduce the activity of the biological pathway can be effective in the prophylaxis and/or treatment of the disease caused by the over activity of the biological pathway. Similarly the causative mechanism of many diseases is the over production of a biological molecule. A chemical entity that can reduce the production of the biological molecule or block the activity of the over produced biological molecule can be effective in the prophylaxis and/or treatment of the disease caused by the over production of the biological molecule.

Conversely, the causative mechanism of many diseases is the under activity of a biological pathway. A chemical entity that can increase the activity of the biological pathway can be effective in the prophylaxis and/or treatment of the disease caused by the under activity of the biological pathway. Also similarly the causative mechanism of many diseases is the under production of a biological molecule. A chemical entity that can increase the production of the biological molecule or mimic the biological activity of the under produced biological molecule can be effective in the prophylaxis and/or treatment of the disease caused by the under production of the biological molecule.

It is the object of the present invention to provide a chemical entity compound for the prophylaxis and/or treatment of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury.

The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, and the examples of the present application.

Description of the invention

infectious diseases

The immune system in higher vertebrates represents the first line of defense against various antigens that can enter the vertebrate body, including microorganisms such as bacteria, fungi and viruses that are the causative agents of a variety of diseases.

Despite large immunization programs, viral infections, such as influenza A virus (IAV), remain a serious source of morbidity and mortality throughout the world and a significant cause of illness and death among people with immune-deficiency associated with aging or different clinical conditions. Although antiviral chemotherapy with compounds such as amantadine and rimantadine have been shown to reduce the duration of symptoms of clinical infections (i.e., IAV infection), major side effects and the emergence of drug-resistant variants have been described. New classes of antiviral agents designed to target particular viral proteins such as influenza neuraminidase are being developed. However, the ability of viruses to mutate the target proteins represents an obstacle for effective treatment with molecules, which selectively inhibit the function of specific viral polychemical entitys. Thus, there is need for new therapeutic strategies to prevent and treat viral infections. Additionally, there is a need for new therapies for the prevention and treatment of bacterial infections, especially bacterial infections caused by multiple drug resistant bacteria. Currently, bacterial infections are treated with various antibiotics. Although antibiotics have and can be effective in the treatment of various bacterial infections, there are a number of limitations to the effectiveness and safety of antibiotics. For example, some individuals have an allergic reaction to certain antibiotics and other individuals suffer from serious side effects. Moreover, continued use of antibiotics for the treatment of bacterial infections contributes to formation of antibiotic-resistant strains of bacteria.

Furthermore, the severity and lethality in influenza A virus (IAV) infections is frequently aggravated by secondary bacterial pneumonia. However, mechanisms in human lung tissue provoking this increase in fatality are unknown.

Severe pneumonia causes high mortalities worldwide which has remained almost unchanged since the introduction of antibiotics. IAV and Streptococcus pneumoniae (S. pneumoniae), especially in subsequent co-infections, account for a majority of the fatal outcome. Considering the fatality resulting from secondary bacterial pneumonia, the threat of future IAV outbreaks, and the increasing bacterial resistance towards antibiotics, it is pivotal to apprehend the molecular interplay between viruses, bacteria, and pulmonary target cells to enable for innovative adjunctive therapies beyond pathogen-directed clinical approaches.

Previous studies with mice indicate that mechanisms accounting for increased severity of secondary bacterial co-infection include IAV induced alterations of phagocyte functions, epithelial damage increasing bacterial adherence, or alteration of immune system components. In particular, lAV-induced type I and II interferons (IFN) are suspected to modulate innate immune responses in secondary bacterial infections.

Data indicate decreased neutrophil recruitment due to impaired production of the chemokines CXCL1 and CXCL2, reduced numbers of IL-17 producing gdT cells, or diminished bacterial clearance by alveolar macrophages (AM). However, the interference of IAV induced IFN with recognition of secondary bacterial pathogens in human lung tissue is completely unknown. In vitro studies on monocytes and macrophages revealed that IFN might interfere with central pro-inflammatory cytokine pathways such as the inflammasome thereby inhibiting IL-1 b production. In turn, IL-1 b seems to be critical for survival in S. pneumoniae infection or in post-IAV Staphylococcus aureus (S. aureus) pneumonia in mice. However, the cellular source, molecular mechanism, and its role for induction of subsequent cytokine responses in human lungs are still unknown.

Besides IL-1 b, IFN alter the production of another central factor for pulmonary inflammation control, the granulocyte macrophage-colony stimulating factor (GM- CSF). In mice infected with IAV, GM-CSF enhanced the amount and resistance of AM as well as the recruitment and activation of dendritic cells, both significantly contributing to survival rates. Likewise, in mice mortality rates were improved due to enhanced bacterial killing by AM of S. pneumoniae or group B streptococci and even infection with gram-negative Klebsiella pneumoniae showed less apoptosis and alveolar leakage after GM-CSF treatment. Moreover, clinical trials using GM-CSF for adjunctive treatment in acute lung injury or adult respiratory distress syndrome (ARDS) underscore the therapeutic potential ascribed to this molecule.

Pharmaceutical compositions

Still another aspect of the present invention relates to the use of a chemical entity as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents for the manufacture of a pharmaceutical composition for the treatment and/or prophylaxis of of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury.

Such pharmaceutical compositions comprise a chemical entity as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient, binders, disintegrates, glidents, diluents, lubricants, coloring agents, sweetening agents, flavoring agents, preservatives or the like. The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluents and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way. Preferably the chemical entity is suitable for intravenous administration or suitable for oral administration or suitable for administration by inhalation.

Administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, liposomal formulations, micro- and nano-formulations, powders and deposits. Furthermore, the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, which preparations in addition to typical vehicles and/or diluents contain a chemical entity according to the present invention.

The chemical entity of the invention forms pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such acid addition salt formation are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, sulfonic acid, phosphonic acid, perchloric acid, nitric acid, formic acid, propionic acid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid, nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid, camphersulfonic acid, china acid, mandelic acid, o-methylmandelic acid, hydrogen-benzenesulfonic acid, picric acid, adipic acid, D-o-tolyltartaric acid, tartronic acid, a-toluic acid, (o, m, p)- toluic acid, naphthylamine sulfonic acid, and other mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The pharmaceutical compositions according to the present invention will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, aerosol preparations consistent with conventional pharmaceutical practices. Other suitable formulations are gels, elixirs, dispersible granules, syrups, suspensions, creams, lotions, solutions, emulsions, suspensions, dispersions, and the like. Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices. The pharmaceutical compositions may be comprised of 5 to 95% by weight of the chemical entitys.

As pharmaceutically acceptable carrier, excipient and/or diluents can be used lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules).

Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl-cellulose, polyethylene glycol and waxes. Among the lubricants that may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration. The term capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.

Tablet means compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction well known to a person skilled in the art.

Powders for constitution refer to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices. One example for such an oral administration form for newborns, toddlers and/or infants is a human breast milk substitute which is produced from milk powder and milk whey powder, optionally and partially substituted with lactose. Suitable diluents are substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn rice and potato, and celluloses such as microcrystalline cellulose. The amount of diluents in the composition can range from about 5 to about 95% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, and most preferably from about 40 to 50% by weight.

The term disintegrants refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches, "cold water soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose, microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of disintegrant in the composition can range from about 1 to about 40% by weight of the composition, preferably 2 to about 30% by weight of the composition, more preferably from about 3 to 20% by weight of the composition, and most preferably from about 5 to about 10% by weight.

Binders characterize substances that bind or "glue" powders together and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluents or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropyl-methylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 1 to 30% by weight of the composition, preferably from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight. Lubricant refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.05 to about 15% by weight of the composition, preferably 0.2 to about 5% by weight of the composition, more preferably from about 0.3 to about 3%, and most preferably from about 0.3 to about 1.5% by weight of the composition.

Glidents are materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0.01 to 10% by weight of the composition, preferably 0.1% to about 7% by weight of the total composition, more preferably from about 0.2 to 5% by weight, and most preferably from about 0.5 to about 2% by weight.

Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.01 to 10% by weight of the composition, preferably from about 0.05 to 6% by weight, more preferably from about 0.1 to about 4% by weight of the composition, and most preferably from about 0.1 to about 1%.

The term buffer, buffer system, buffer solution and buffered solution, when used with reference to hydrogen-ion concentration or pH, refers to the ability of a system, particularly an aqueous solution, to resist a change of pH on adding acid or alkali, or on dilution with a solvent. Preferred buffer systems can be selected from the group consisting of formate (pKa=3.75), lactate (pKa=3.86), benzoic acid (pKa=4.2) oxalate (pKa=4.29), fumarate (pKa=4.38), aniline (pKa=4.63), acetate buffer (pKa=4.76), citrate buffer (pKa2=4.76,pKa3=6.4), glutamate buffer (pKa=4.3), phosphate buffer (pKa=7.20), succinate (pKa1=4.93;pKa2=5.62), pyridine (pKa=5.23), phthalate (pKa=5.41); histidine (pKa=6.04), MES (2-(N-morpholino)ethanesulphonic acid; pKa=6.15); maleic acid (pKa=6.26); cacodylate (dimethylarsinate, pKa=6.27), carbonic acid (pKa=6.35), ADA (N-(2-acetamido)imino-diacetic acid (pKa=6.62); PIPES (4-piperazinebis-(ethanesulfonic acid; BIS-TRIS-propane (1 ,3- bis[tris(hydroxymethyl)methylamino]-propane), pKa=6.80), ethylendiamine (pKa=6.85), ACES 2-[(2-amino-2-oxoethyl)amino]ethanesulphonic acid; pKa=6.9), imidazole (pKa=6.95), MOPS (3-(N-morphin)-propansulfonic acid; pKa=7.20), diethylmalonic acid (pKa=7.2), TES (2-[tris (hydroxymethyl) methyl] amino ethanesulphonic acid; pKa=7.50) and HEPES (N-2-hydroxylethylpiperazin-N^'-2- ethansulfonic acid; pKa=7.55) buffers or other buffers having a pKa between 3.8 to 7.7.

Preferred is the group of carboxylic acid buffers such as acetate and carboxylic diacid buffers such as fumarate, tartrate and phthalate and carboxylic triacid buffers such as citrate. Another group of preferred buffers is represented by inorganic buffers such as sulfate, borate, carbonate, oxalate, calcium hydroxyde and phosphate buffers. Another group of preferred buffers are nitrogen containing buffers such as imidazole, diethylenediamine, and piperazine.

Also preferred are sulfonic acid buffers such as TES, HEPES, ACES, PIPES, [(2- hydroxy-1 ,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid (TAPS), 4-(2- hydroxyethyl)piperazine-1-propanesulfonic acid (EPPS), 4-

Morpholinepropanesulfonic acid (MOPS) and N,N-bis(2-hydroxyethyl)-2- aminoethanesulfonic acid (BES).

Another group of preferred buffers are glycine buffers such as glycine, glycyl-glycine, glycyl-glycyl-glycine, N,N-bis(2-hydroxyethyl)glycine and N-[2-hydroxy-1 , 1- bis(hydroxy-methyl)ethyl]glycine (Tricine).

Preferred are also amino acid buffers such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophane, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, cysteine, methionine, proline, 4-hydroxyproline, Ν,Ν,Ν-trimethyllysine, 3-methylhistidine, 5-hydroxylysine, O- phosphoserine, γ-carboxyglutamate, ε-Ν-acetyllysine, ω-Ν-methylarginine, citrulline, ornithine and derivatives thereof.

Also preferred are the following buffers:

effective pH range pKa 25°C buffer

2.7-4.2 3.40 malate (pK1 )

3.0-4.5 3.75 formate

3.0-6.2 4.76 citrate (pK2)

3.2-5.2 14.21 succinate (pK1 )

3.6-5.6 [4.76 acetate

3.8-5.6 [4.87 propionate

4.0-6.0 5.13 malate (pK2)

4.9-5.9 5.23 pyridine

5.0-6.0 5.33 piperazine (pK1 )

5.0-7.4 6.27 cacodylate

Preferred are the buffers having an effective pH range of from 2.7 to 8.5, and more preferred of from 3.8 to 7.7. The effective pH range for each buffer can be defined as pKa - 1 to pKa + 1 , where Ka is the ionization constant for the weak acid in the buffer and pKa = - log K.

Most preferred are buffers suitable for pharmaceutical use e.g. buffers suitable for administration to a patient such as acetate, carbonate, citrate, fumarate, glutamate, lactate, phosphate, phthalate, and succinate buffers. Particularly preferred examples of commonly used pharmaceutical buffers are acetate buffer, citrate buffer, glutamate buffer and phosphate buffer. Also most preferred is the group of carboxylic acid buffers. The term "carboxylic acid buffers" as used herein shall refer to carboxylic mono acid buffers and carboxylic diacid buffers as well as carboxylic triacid buffers. Of course also combinations of buffers, especially of the buffers mentioned herein are useful for the present invention.

Some suitable pharmaceutical buffers are a citrate buffer (preferably at a final formulation concentration of from about 20 to 200 mM, more preferably at a final concentration of from about 30 to 120 mM) or an acetate buffer (preferably at a final formulation concentration of about 20 to 200 mM) or a phosphate buffer (preferably at a final formulation concentration of about 20 to 200 mM).

The preferred dosage concentration for either intravenous, oral, or inhalation administration is between 1 to 100 pmole/ml, and more preferably is between 10 to 50 mole/ml.

Method of treatment

Another aspect of the present invention relates to a method of prophylaxis and/or treatment of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury, comprising administering to a patient in need thereof a pharmaceutical composition comprising a chemical entity according to the present invention.

Accordingly, the terms "prophylaxis" or "treatment" includes the administration of the chemical entity of the present invention to prevent, inhibit, or arrest the symptoms of an infectious disease, an infection, viral-bacterial co-infection, pulmonary viral- bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury. In some instances, treatment with the chemical entity of the present invention will be done in combination with other protective compounds to prevent, inhibit, or arrest the symptoms of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury.

The term "active agent" or "therapeutic agent" as used herein refers to an agent that can prevent, inhibit, or arrest the symptoms and/or progression of an infection, viral- bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co- infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury.

The term "therapeutic effect" as used herein, refers to the effective provision of protection effects to prevent, inhibit, or arrest the symptoms and/or progression of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury. The term "a therapeutically effective amount" as used herein means a sufficient amount of one or more of the chemical entitys of the invention to produce a therapeutic effect, as defined above, in a subject or patient in need of treatment.

The terms "subject" or "patient" are used herein mean any mammal, including but not limited to human beings, including a human patient or subject to which the compositions of the invention can be administered. The term mammals include human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals. The chemical entity of the present invention can be used for the prophylaxis and/or treatment of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury, in combination administration with another therapeutic compound. As used herein the term "combination administration" of a compound, therapeutic agent or known drug with a chemical entity of the present invention means administration of the drug and the one or more compounds at such time that both the known drug and the chemical entity will have a therapeutic effect. In some cases this therapeutic effect will be synergistic. Such concomitant administration can involve concurrent (i.e. at the same time), prior, or subsequent administration of the drug with respect to the administration of a chemical entity of the present invention. A person of ordinary skill in the art would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and chemical entitys of the present invention.

Definition of chemical entity activity

A chemical entity is deemed to have therapeutic activity if it demonstrated any one of the following activities listed in a) to g). a) The chemical entity could inhibit the activity of an over active biological pathway. b) The chemical entity could inhibit the production of an over produced biological molecule. c) The chemical entity could inhibit the activity of an over produced biological molecule. d) The chemical entity could increase the activity of an under active biological pathway. e) The chemical entity could increase the production of an under produced biological molecule. f) The chemical entity could mimic the activity of an under produced biological molecule. g) The chemical entity could prevent, inhibit, or arrest the symptoms and/or progression of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury.

As used herein "inhibition" is defined as a reduction of the activity or production of a biological pathway or molecule activity of between 10 to 100%. More preferably the reduction of the activity or production of a biological pathway or molecule activity is between 25 to 100%. Even more preferably the reduction of the activity or production of a biological pathway or molecule activity is between 50 to 100%.

As used herein "increase" is defined as an increase of the activity or production of a biological pathway or molecule of between 10 to 100%. More preferably the increase of the activity or production of a biological pathway or molecule activity is between 25 to 100%. Even more preferably the increase of the activity or production of a biological pathway or molecule activity is between 50 to 100%.

Chemical entity

The following chemical entity was tested for the activity as a therapeutic agent for the prophylaxis and/or treatment of an infection, viral-bacterial co-infection, pulmonary viral-bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, and/or Acute Lung Injury: 4-(Cyclopropylamino)-2-((4-(4-(ethanesulfonyl)piperazin-1- yl)phenyl)amino)pyrimidine-5-carboxamide, also known as Cerdulatinib.

Furthermore the present invention relates to the use of the above-mentioned chemical entity as pharmaceutically active agent in medicine, i.e. as medicament.

As used herein, the term "chemical entity" or "chemical entity of the invention" shall also refer to salts, enantiomers, diastereomers, racemates, prodrugs and hydrates of the above-mentioned chemical entity. EXAMPLES

The chemical entity as listed above was tested for activity using the assays described in Examples 1 to 5.

EXAMPLE 1 :

Human lung tissue model for ex vivo co-infection of IAV and S. pneumoniae

A prerequisite for the analysis and interpretation of cytokine regulation during coinfection in ex vivo cultivated human lung tissue is the establishment and characterization of the model. Fresh lung explants were obtained from 78 patients suffering from bronchial carcinoma, who underwent lung resection at local thoracic surgeries. The study was approved by the ethics committee at the Charite clinic (projects EA2/050/08 and EA2/023/07) and written informed consent was obtained from all patients. Tumor-free peripheral lung tissue was first dissected into smaller pieces by scalpel, afterwards stamped into small cylinders (3 x 8 x 8 mm) using a biopsy punch (diameter 8 mm). Finally generated lung tissue pieces were weighted and incubated overnight in RPMI 1640 medium at 37°C with 5% CO2 to wash off clinically applied antibiotics. The following infection experiments were done in RPMI 1640 medium supplemented with 0.3% bovine serum albumin and 2 mM L-glutamine at 37°C with 5% C0₂.

The human seasonal influenza H3N2 virus A/Panama/2007/1999 (Pan/99[H3N2]) strain was provided by T. Wolff (RKI, Berlin, Germany) and propagated using MDCK cells. Virus stocks were aliquoted, stored at -80 °C and titrated on MDCK cells by a standard plaque assay.

Two strains of S. pneumoniae were used, the encapsulated D39 serotype 2 (NCTC7466) (gift from S. Hammerschmidt, University of Greifswald, Germany) and a clinical isolate of S. pneumonia serotype 3 (ST3, SN35209) (donated by Dr. Mark van der Linden, National Reference Center for Streptococci, Aachen, Germany).

Human lung tissue was inoculated with control medium or Pan/99(H3N2) for 24 h. Additional samples were subsequently challenged with S. pneumoniae strain D39 for further 16h. As expected, exclusively AEC II were infected by IAV as indicated by pro-SP-C co-localization. S. pneumoniae D39 was detected closely attached to the cell surface of AEC I and AEC II as well as AM independent of prior IAV infection. Viral growth was next measured after 1 , 16, 24, and 48h to determine the highest amount of viral load under the conditions used.

Growth peak was reached after 24h with around 1 x 10⁶ PFU/ml, which was used for co-infection in all following experiments. Challenging the tissue with either S. pneumoniae alone or in combination with Pan/99 IAV (H3N2) strain demonstrated that growth of pneumococcal strains D39 or the clinical ST3 isolate remained unaffected by IAV. Measurement of LDH release during tissue infection did not indicate significant differences in cytotoxicity compared to controls. These data assure that hypothesized differences of cytokine regulation will not result from different pathogen growth or a higher extent of cell death.

EXAMPLE 2:

IAV induced type I, II, and III IFN show unchanged expression during co- infection with S. pneumoniae

IFN are assumed to play a major role towards susceptibility to secondary bacterial infection; however, this is still unexamined for human lung tissue. The secretion of different IFN types after single and co-infection in the lung supernatants was anlysed. Pan/99(H3N2) significantly induced the release of IFNa2 and IFNb (type I), IFNg (type II), and IFNI1 (type III) whereas S. pneumoniae D39 showed no IFN induction at all. The secretion pattern of all IFN remained unchanged in viral and bacterial co- infection, demonstrating that S. pneumoniae has no effect on IFN regulation, which might pave the way for a compromised secondary host defense against the bacteria.

EXAMPLE 3:

IAV and IFN interfere with S. pneumoniae induced IL-1 b - GM-CSF axis in human lungs

The induction of cytokines and chemokines plays an important role for the initiation of innate immune responses to control viral and bacterial infections, and studies in mice revealed that induction of type I and II IFN during primary non-lethal influenza virus infection complicates the defense against a range of bacterial pathogens.

The role of cytokines and chemokines, with regard to human lung co-infection is so far unknown. The influence of IAV on the regulation of typical pneumococcal induced factors in human lung supernatants was examined. S. pneumoniae D39 infection significantly induced all tested cytokines, but no changes in presence of IAV were found in co-infection for IL-6, IL-8, IL-10, and TNFa. However, the preceding IAV infection significantly reduced S. pneumoniae D39 induction of IL-1 b and GM-CSF, which was confirmed for the clinical ST3 isolate. Since in vitro studies indicate that IFN might interfere with IL-1 b and GM-CSF induction, it was tested, if IFN in human lung tissue can mimic IAV induced suppression of IL-1 b and GM-CSF. Next to single and co-infection with Pan/99(H3N2) and S. pneumoniae D39, IAV was replaced by IFNb and IFNg treatment for the same time course and compared the liberated amount of IL-1 b and GM-CSF. In line with IAV infection, IFN significantly blocked S. pneumonia induced IL-1 b and GM-CSF synthesis to a similar amount.

The expression of GM-CSF is depended on IL-1 b instead of TNFa. Pre-treatment of human lungs with IL-1 receptor antagonist Anakinra (4 h) prior to 16h S. pneumoniae D39 infection or IL-1 b stimulation significantly reduced GM-CSF expression. In contrast, TNFa stimulation of human lungs was not sufficient for induction of GM- CSF. The induction of COX-2 in the same lungs served as a positive control for effective TNFa stimulation. In order to underscore direct dependency of GM-CSF liberation on IL-1 β production, the time course of both factors in S. pneumoniae infected human lung tissue was determined. Direct comparison of expression patterns revealed a time-shifted secretion beginning with considerable amounts of IL- 1 b after 4 to 6h, followed by GM-CSF after 8 to 16h. The release of GM-CSF in human lungs is mainly dependent on IL-1 β, rather than on TNFa.

EXAMPLE 4:

AEC II derived IFN blocks IL-1 b of AM leading to suppression of AEC II expressed GM-CSF

IAV induced IFN blocked IL-1 β release, finally leading to loss of GM-CSF production in human lungs. To further investigate the underlying cellular interplay of this cytokine regulation in viral and bacterial co-infection, AM and AEC II were isolated from fresh human lung tissue. Phenotype characterization by immunofluorescence staining showed isolated AM positive for CD68, AEC II for pancytokeratin, and pro-SP-C. The release of IFN by IAV infected AEC II and AM demonstrates that AEC II are a major cellular source of IFN in the human alveolar compartment. In contrast, AEC II are negative for release of IL-1 b after infection with S. pneumoniae D39, but showed significant release of GM-CSF after IL-1 b treatment. In line with stimulation of intact human lung tissue, S. pneumoniae failed to directly induce GM-CSF secretion in AEC II. S. pneumoniae infection of AM led to a strong release of IL-1 b but failed to induce GMCSF expression. Simultaneous treatment of AM with type I and II IFN was sufficient to suppress IL-1 b production, while TNFa was not reduced in the same samples, mirroring the results obtained in intact lung tissue. Supernatants of AM infected with S. pneumoniae were used for stimulation of GM-CSF in AEC II in presence or absence of Anakinra to provide evidence for the dependence of epithelial GM-CSF on IL-1 b released by AM. However, the inhibition of epithelial GMCSF expression seems not restricted to IL-1 b suppression in AM alone, instead IFN may also directly inhibit GMCSF after IL-1 b stimulation.

EXAMPLE 5:

Tyk2 inhibition restores IAV induced type I and III IFN mediated suppression of IL-1 β - GM-CSF axis

To clarify the cellular level, the responsible IFN type, and the mechanism of S. pneumoniae induced IL-1 b suppression after IAV infection, isolated AM from fresh human lung tissue were challenged with bacteria in absence or presence of type I IFNb, type II IFNg, or type III IFNA1. No differences have been found on the transcriptional level for IL-1 b mRNA expression. Surprisingly, the compound 4- (Cyclopropylamino)-2-((4-(4-(ethanesulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine- 5-carboxamide in AM and human lungs completely restored IFNb mediated IL- 1 b suppression in AM as well as IAV induced suppression of S. pneumonia triggered IL-1 b and GM-CSF production in human lungs.

Claims

Use of the single chemical entity 4-(Cyclopropylamino)-2-((4-(4- (ethanesulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide for the manufacture of a medicament for the treatment of patients suffering from infection, viral-bacterial co-infection, pulmonary viral-bacterial co- infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury.

The use according to claim 1 wherein the chemical entity is suitable for intravenous administration, or for oral administration, or for administration by inhalation.

Use of the chemical entity of claim 1 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluents for the manufacture of a pharmaceutical composition for the treatment and/or prophylaxis of an infection, viral-bacterial co-infection, pulmonary viral- bacterial co-infection, influenza bacterial co-infection, influenza and Streptococcus pneumoniae co-infection, viral infection, bacterial infection, lung infection, community acquired pneumonia, Adult Respiratory Distress Syndrome, Acute Lung Injury.

Pharmaceutical formulation/composition containing 4-(Cyclopropylamino)-2- ((4-(4-(ethanesulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide together with at least one pharmaceutically acceptable carrier, excipient and/or diluents. The pharmaceutical formulation/composition according to claims 1-4, wherein the pharmaceutical composition is suitable for intravenous administration or for oral administration or for administration by inhalation.

6. The pharmaceutical formulation/composition according to any one of claims 1- 5, wherein the pharmaceutical formulation is in the form of a lyophilised chemical entity accodring to claim 1 together with at least one cryo- / lyoprotectant or in form of a physiologically acceptable liquide buffer solution of a chemical entity according to claim 1 or in form of a lyophilised chemical entity accodring to claim 1 taken up in a physiologically acceptable liquide buffer solution.