New medical treatments for pathological inflammation

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, in combination with a 5-ASA agent, is used to treat a disease caused by pathological inflammation. A combination of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof with a 5-ASA agent, and the use of such a combination. A multi-component kit and a pharmaceutical composition comprising such a combination.

Description

Technical Field

[0001] The present invention relates to compounds for treating diseases caused by pathological inflammation. More specifically, the present invention relates to a combination of 4-alkanoylaminobenzamide derivatives and 5-aminosalicylate (5-ASA) agents for treating inflammatory bowel disease (IBD). In addition, the present invention relates to a combination of 4-alkanoylaminobenzamide derivatives and 5-ASA agents, as well as pharmaceutical preparations and kits-of-parts comprising such combinations. Background Art

[0002] Throughout this application, various (non-patent) publications are mentioned by first author and year of publication. Full citations to these publications are given in the reference section immediately preceding the claims. The disclosures of these documents and publications mentioned herein are incorporated herein by reference in their entirety to more fully describe the state of the art to which the present invention belongs.

[0003] Inflammatory bowel disease (IBD)

[0004] IBD is mainly composed of Crohn's disease (CD) and ulcerative colitis (UC), and is a chronic, often progressive gastrointestinal condition that requires lifelong treatment. The natural history of this condition is one of remission, interrupted by recurrence of disease activity. CD and UC are diseases with many similarities, but often differ in positioning and how to manage. UC is characterized by recurrent and remitted mucosal inflammation that extends from the rectum to the proximal segment of the colon, and its histological characteristics are the presence of both acute inflammation and chronic inflammation. The diagnosis of UC is based on a combination of symptoms, endoscopic findings and histology. Pathogenesis is multifactorial, including genetic susceptibility, immune response disorders and environmental factors. CD can involve any part of the gastrointestinal system. About 60% of CD patients suffer from colon involvement. Half of these patients have diseases limited to the colon (Mills, 2007).

[0005] Based on the extent of the disease, UC patients can be classified as having 1) ulcerative proctitis involving only the rectum, 2) left-sided UC involving the colorectum distal to the splenic flexure, and 3) extensive UC involving the colon proximal to the splenic flexure (including pancolitis). Symptoms can vary depending on the degree and extent of inflammation. Patients are classified as having mild, moderate, or severe disease activity based on one or more measures of disease severity. The hallmark symptom of UC is bloody diarrhea with an urgent need to pass stool. Other symptoms include abdominal cramps, loss of appetite, fatigue, weight loss, and fever. Traditionally, the highest incidence of both CD and UC has been found in developed countries in North America and Europe. The prevalence is estimated to be 70-500 cases per 100,000 people, with men and women being affected equally. People are more often diagnosed with UC between the ages of 15 and 35, with a second, smaller peak between the ages of 55 and 65. The median age at diagnosis is 30 years. In 15% of cases, UC is diagnosed in childhood and may be present before school age. CD and UC impose significant costs on the healthcare system and society.

[0006] UC has a substantial impact on the patient's quality of life due to early onset and lack of cure. Current drugs are moderately effective, and side effects are a problem. Therefore, there is an urgent need to improve clinical management by establishing new treatment strategies. The goals of treatment are to induce and maintain remission and prevent complications. Patients with mucosal healing without or with very mild signs and symptoms are considered to be in remission. The ultimate treatment goal for all UC patients is steroid-free clinical and endoscopic remission. An influence on the inflammatory process is necessary because lack of inflammatory control, even in the presence of symptom control, is associated with poor long-term outcomes. The risk of colectomy and colorectal cancer is increased in patients who do not respond to medical management. Extraintestinal manifestations of UC include primary sclerosing cholangitis, as well as joint, skin, and eye manifestations.

[0007] Treatment of IBD

[0008] Treatment recommendations depend on disease location, disease severity, and disease complications. First-line treatment for mild to moderate UC includes administration of 5-aminosalicylate (5-ASA; mesalamine [CAS No. 89-57-6]) agents. Sulfasalazine (SASP [CAS No. 599-79-1]), an azo-bonded prodrug of 5-ASA, is the parent 5-ASA agent. SASP provides modest benefit for the treatment of mild to moderately active CD (Lim, 2016). Patients who are ineffective or incompletely responsive to 5-ASA drugs can be treated with corticosteroids or immunomodulators (thiopurines). Tumor necrosis factor-α (TNFα) blockers are indicated for the treatment of UC patients with moderate to severe active UC, as well as UC patients who have failed conventional treatment. However, severe side effects limit the use of these types of drugs. Clearly, new drugs with higher efficacy and safety in inducing and then maintaining clinical and endoscopic remission are clearly needed.

[0009] 5-ASA in UC

[0010] The main therapy for mild to moderate UC is 5-ASA agents (Hanauer, 2004). After the introduction of SASP (Svartz 1942), the successful management of UC was very convenient. It is generally believed that 5-ASA represents the therapeutically active part of SASP (Azadkhan 1977; van Hees 1980). Orally ingested SASP is enzymatically decomposed into 5-ASA and sulfapyridine (CAS No. 144-83-2) (Peppercorn 1972) in the colon, thereby releasing 5-ASA that acts locally on the colonic mucosa. Other azo-bonded 5-ASA agents include olsalazine (CAS No. 15722-48-2) and balsalazide (CAS No. 80573-04-2). Other 5-ASA delivery systems use, for example, pH-dependent delayed release formulations to directly release sufficient concentrations of 5-ASA in the colon (Amidon 2015). Both oral therapy and rectal therapy are effective in inducing and maintaining relief. Once daily is the optimal dose, and there is marginal evidence of a significant dose-response effect beyond 2400 mg / day.

[0011] A systematic review and meta-analysis of patients with active mild to moderate UC compared 5-ASA to placebo and showed that 5-ASA was significantly superior to placebo (Wang 2016a; Wang 2016b). 71% of 5-ASA patients failed to enter clinical remission, compared to 83% of placebo patients. 5-ASA was also found to be superior to placebo in terms of maintenance of treatment. 41% of 5-ASA patients relapsed, compared to 58% of placebo patients. No statistically significant difference was found between 5-ASA and SASP in terms of efficacy in inducing remission (Wang 2016a). However, SASP was found to be significantly superior to 5-ASA in maintaining remission (Wang 2016b).

[0012] 5-ASA mechanism of action

[0013] The mechanism by which 5-ASA agents exert their effects is unclear, but a central mechanism explaining the inhibitory effects of 5-ASA on multiple inflammatory pathways may be due to its inhibition of nuclear factor κB (NFκB) activation (MacDermott, 2000). It has been shown that SASP is a potent inhibitor of NFκB activation, capable of inhibiting NFκB-dependent transcription, and capable of preventing the nuclear translocation of NFκB due to inhibition of inhibitory κBα (IκBα) phosphorylation and subsequent degradation (Wahl, 1998; Zhao, 2010). 5-ASA has been shown to inhibit TNFα-stimulated NFκB activation, NFκB nuclear translocation, and degradation of IκBα (Kaiser, 1999).

[0014] Activation of NFκB

[0015] NFκB is considered to be a heterodimer of proteins belonging to the Rel family of transcription factors (TFs). A common feature of the regulation of TFs belonging to the Rel family is that they are sequestered in the cytoplasm as inactive complexes with a class of inhibitory molecules called IκB. Treatment of cells with different inducers (e.g., TNFα) leads to dissociation of the cytoplasmic complex and translocation of free NFκB to the nucleus. There are two main biochemically characterized forms of IκB proteins in mammalian cells—IκBα and IκBβ. The main difference between IκBα and IκBβ lies in their response to different inducers of NFκB activity. One class of inducers causes rapid but transient activation of NFκB by primarily affecting the IκBα complex, while the other class of inducers causes persistent activation of NFκB by affecting both the IκBα complex and the IκBβ complex. Therefore, the overall activation of NFκB consists of two overlapping phases, namely a transition phase mediated by IκBα and a sustained phase mediated by IκBβ. After stimulation, the different behaviors of the two IκBs fulfill the prediction of differential regulation suggested by the existence of multiple IκB isoforms. Although the two major IκB isoforms interact with the same Rel protein, they are activated by different signaling pathways and may cause very different physiological responses. While the IκBα response is used to respond immediately to transient stress states, the sustained response generated by IκBβ can be used in states of chronic inflammation, infection, stress or differentiation (Thompson, 1995).

[0016] 4-Aminobenzamide

[0017] 4-aminobenzamides, including metoclopramide (CAS No. 364-62-5) and procainamide (CAS No. 51-06-9), constitute a class of compounds that have been developed for many clinical indications and screened or used as antiemetics, antiarrhythmics, local anesthetics, anti-inflammatory agents, antitumor agents, and radio / chemosensitizers (Stanley, 1982; Rang, 1995; Pero, 1998 and 1999). The diverse clinical applications of these drugs are paralleled by equally diverse modes of action. U.S. Patent No. 3,177,252 discloses 4-aminobenzamides for the treatment of vomiting and behavioral disorders. Metoclopramide belongs to the class of dopamine antagonists. EP 0 927 030 B1 includes the use of declopramide (CAS No. 891-60-1) to inhibit or kill tumors or cancer cells. Declopramide is listed among many small molecule NFκB inhibitors as a potential therapeutic agent for the treatment of autoimmune diseases, including IBD (Ivanenkov, 2011). Combined 5-ASA and procainamide were used in an attempt to improve the anti-colitis efficacy of 5-ASA. Rectal administration of combined 5-ASA and procainamide caused additive anti-colitis effects in a 2,4,6-trinitrobenzenesulfonic acid-induced rat colitis model (Kim, 2016). Neither rectal administration of combined 5-ASA and procainamide nor oral administration of 5-ASA azo-bonded to procainamide (5-ASA-azo-PA) showed superiority over oral SASP alone.

[0018] The well-known potential for serious neurologic and cardiovascular adverse events and the risk of antinuclear antibody formation may outweigh the potential clinical benefits of using 4-aminobenzamide in long-term treatment (Harrington, 1983; Harron, 1990).

[0019] 4-Alkanoylaminobenzamide

[0020] U.S. Patent No. 3,177,252 discloses 4-alkanoylaminobenzamides for treating vomiting and behavioral disorders. WO 99 / 63987 discloses 4-acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide (N-acetylprocainamide; hereinafter Compound A) and its use in inhibiting or killing tumors or cancer cells and as a potential therapeutic agent for treating inflammatory conditions. N-acetylprocainamide (aceccainide, CAS No. 32795-44-1) has been used to treat or prevent arrhythmias.

[0021] 4-aminobenzamides are known to inhibit NFκB, and these compounds have also been found to induce apoptosis (Liberg, 1999). Acetylation of declopramide, to give compound A, abolished the induction of apoptosis (Liberg 1999; Lindgren 2003), but nonetheless significantly enhanced NFκB inhibition compared to the corresponding 4-aminobenzamide (Liberg, 1999; Lindgren, 2001). While 4-aminobenzamides inhibited both IκBα breakdown and the NFκB rescue pathway, 4-alkanoylaminobenzamide analogs inhibited IκBβ breakdown and did not affect the NFκB rescue pathway (Lindgren, 2003). Summary of the invention

[0022] One aspect is a compound of formula (I) for use in combination with a 5-ASA agent for treating a disease caused by pathological inflammation

[0023]

[0024] or a pharmaceutically acceptable salt or solvate thereof; wherein

[0025] R1 is selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0026] R2 is selected from H and C1-C3 alkyl;

[0027] R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluorine;

[0028] R7 is selected from hydrogen and C1-C3 alkyl;

[0029] R8 and R9 are independently selected from C1-C6 alkyl, or

[0030] R8 and R9 together with the nitrogen atom to which they are both attached form the following moiety:

[0031] Formula (II)

[0032] ;

[0033] r is 0 or 1;

[0034] R 10 Selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxyl, halogen, cyano, COOR 12 or NHR 13 replace;

[0035] Q is selected from CHR 11 NR11 and O;

[0036] R 11 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 replace;

[0037] R 12 and R 13 independently selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl;

[0038] When Q is CHR 11 When , p is 1, 2, or 3; and

[0039] When Q is selected from NR 11 When α is 2 or 3, p is 2 or 3.

[0040] On the one hand, it is a combination of (i) and (ii) below:

[0041] (i) Compound of formula (I)

[0042]

[0043] or a pharmaceutically acceptable salt or solvate thereof; wherein

[0044] R1 is selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0045] R2 is selected from H and C1-C3 alkyl;

[0046] R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluorine;

[0047] R7 is selected from hydrogen and C1-C3 alkyl;

[0048] R8 and R9 are independently selected from C1-C6 alkyl, or

[0049] R8 and R9 together with the nitrogen atom to which they are both attached form the following moiety:

[0050] Formula (II)

[0051] ;

[0052] r is 0 or 1;

[0053] R 10 Selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxyl, halogen, cyano, COOR12 or NHR 13 replace;

[0054] Q is selected from CHR 11 NR 11 and O;

[0055] R 11 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 replace;

[0056] R 12 and R 13 independently selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl;

[0057] When Q is CHR 11 When , p is 1, 2, or 3; and

[0058] When Q is selected from NR 11 and O, p is 2 or 3; and

[0059] (ii) 5-ASA agent.

[0060] Another aspect is a pharmaceutical composition comprising a combination as defined herein and optionally a pharmaceutically acceptable excipient. Said composition is useful for treating pathological inflammation, in particular for treating IBD.

[0061] Another aspect is a kit of parts comprising the combination as defined herein, wherein each of components (i) and (ii) is optionally formulated in admixture with a pharmaceutically acceptable excipient. The kit of parts is useful for treating pathological inflammation, and in particular for treating IBD.

[0062] Yet another aspect of the invention is the use of a compound of formula (I) or a salt or solvate thereof as defined herein in the manufacture of a medicament for the treatment of a disease caused by pathological inflammation, wherein the treatment further comprises the administration of a 5-ASA agent.

[0063] Yet another aspect of the present invention is the use of a compound of formula (I) or a salt or solvate thereof as defined herein in the manufacture of a medicament for the treatment of a disease caused by pathological inflammation, wherein the medicament further comprises a 5-ASA agent.

[0064] Yet another aspect is the use of a compound of formula (I) or a salt or solvate thereof and a 5-ASA agent in the manufacture of a kit of parts for treating pathological inflammation (eg IBD).

[0065] Another aspect is a method of treating a disease caused by pathological inflammation, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a salt or solvate thereof, in combination with administering to said mammal a 5-ASA agent.

[0066] Other features and advantages of the present invention will be understood by reference to the following detailed description and examples. DETAILED DESCRIPTION

[0067] definition

[0068] As used herein, and unless otherwise stated or otherwise obvious from the context, each of the following terms shall have the definitions set forth below.

[0069] The term "Cn alkyl" refers to a straight or branched saturated hydrocarbon group containing n carbon atoms in the chain, i.e., a group of formula C n H 2n+1 part.

[0070] The term "Cn-Cm alkyl" refers to a straight or branched alkyl group containing a number of carbon atoms in the chain ranging from n to m, wherein n and m are both integers and m is higher than n.

[0071] The term "Cn cycloalkyl" refers to a group of the formula C n H 2n-1 of a cyclic hydrocarbon group.

[0072] The term "Cn-Cm cycloalkyl" refers to a cyclic hydrocarbon group containing a number of carbon atoms in the ring ranging from n to m, wherein n and m are both integers and m is higher than n.

[0073] The term "Cn-Cm alkoxy" refers to a moiety of the formula

[0074]

[0075] Wherein R is Cn-Cm alkyl. For example, methoxy is C1 alkoxy.

[0076] The term "Cn-Cm-alkylthio" refers to a moiety of the formula

[0077]

[0078] Wherein R is Cn-Cm alkyl. For example, methylthio is C1 alkylthio.

[0079] The term "halogen" refers to F, Cl, Br or I; preferably F, Cl or Br.

[0080] The term "hydroxy" refers to the moiety

[0081] .

[0082] The term "phenyl" refers to a radical of the formula

[0083] .

[0084] The term "benzyl" refers to a radical of the formula

[0085] .

[0086] As used herein, "AABZ" means a compound of formula (I) as described herein. Unless otherwise indicated or obvious from the context, the term also includes pharmaceutically acceptable salts or solvates (including hydrates) thereof.

[0087] As used herein, "about" in the context of a numerical value or a range means ±20% of the recited or claimed numerical value or range.

[0088] As used herein, "add-on" or "add-on therapy" means that a collection of agents is used in a therapy, wherein a subject receiving the therapy begins a first treatment regimen of one or more agents, and then begins a second treatment regimen of one or more different agents in addition to the first treatment regimen, such that not all agents used in the therapy are started at the same time.

[0089] As used herein, "administration", "administering" and the like means to give, distribute or apply a drug, medicine or therapeutic agent to a subject (eg, a mammalian subject, preferably a human) to alleviate or cure a pathological condition. Oral administration is a way to administer the compounds of the present invention to a subject.

[0090] As used herein, an "amount" or "dose" of a compound (e.g., AABZ) measured in milligrams refers to the number of milligrams of the compound present in the formulation, regardless of the form of the formulation. "A dose of 5.0 mg of the compound" means that the amount of the compound in the formulation is 5.0 mg, regardless of the form of the formulation. Thus, when in salt form (e.g., hydrochloride), the weight of the salt form required to provide a 5.0 mg dose of the free base compound will be greater than 5.0 mg due to the presence of additional acid.

[0091] As used herein, the term "5-ASA agent" means a compound containing a 5-aminosalicylic acid moiety. As used herein, unless otherwise indicated or obvious from the context, the term also includes salts or solvates of the compound.

[0092] As used herein, "combination" means a collection of compounds used for therapy by simultaneous or separate (e.g., sequential or concomitant) administration. Simultaneous administration refers to the administration of a mixture (whether a true mixture, suspension, emulsion, or other physical combination) of two active ingredients (e.g., AABZ and 5-ASA agents). In this case, the combination can be a mixture of AABZ and 5-ASA agents; or AABZ and 5-ASA agents can be provided in separate containers and combined just prior to administration. Separate administration can be sequential (i.e., continuous) or concomitant (i.e., occurring simultaneously).

[0093] Separate administration refers to the AABZ and 5-ASA agents being administered as separate formulations, but simultaneously or together, concomitantly or sequentially, close enough in time to observe at least additive activity relative to the activity of either AABZ or 5-ASA agent alone.

[0094] As used herein, "CD" means Crohn's disease.

[0095] As used herein, "Compound A (Cpd A)" ​​means 4-acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide (N-acetylchlorpromide) hydrochloride.

[0096] As used herein, "DSS" means dextran sulfate sodium.

[0097] As used herein, "effective" when referring to the amount of an AABZ or 5-ASA agent means an amount sufficient to produce the desired therapeutic response without undue adverse side effects (e.g., toxicity, irritation, or allergic response), commensurate with a reasonable benefit / risk ratio, when used in the manner of the present invention.

[0098] As used herein, "excipients" are substances formulated with pharmaceutical active ingredients that are included for purposes such as long-term stability, providing bulk to solid formulations, acting as carriers and / or diluents, imparting therapeutic enhancement to the active ingredient in the final dosage form (e.g., by promoting absorption, reducing viscosity, or enhancing solubility). Excipients may also be used in the manufacturing process, for example, by promoting powder flowability or providing non-sticky properties. Examples of excipients are antiadherents, binders, coatings, colorants, disintegrants, flavorings, glidants, lubricants, preservatives, adsorbents, sweeteners, and vehicles (carriers).

[0099] As used herein, "diseases caused by pathological inflammation" refers to diseases such as inflammatory bowel disease, rheumatic diseases, autoimmune diseases and disorders, and further, such diseases in which inflammation plays a major role, such as Alzheimer's disease, atherosclerosis and stroke. More particularly, as used herein, "diseases caused by pathological inflammation" refers to diseases and disorders selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis, multiple sclerosis and type I diabetes, and in particular, refers to diseases selected from ulcerative colitis and Crohn's disease.

[0100] As used herein, "IBD" means inflammatory bowel disease.

[0101] As used herein, "inhibition" of disease progression or disease complications in a subject refers to preventing or reducing disease progression and / or disease complications in a subject.

[0102] As used herein, "NFκB" means nuclear factor κB.

[0103] As used herein, "IκB" means inhibitor of κB.

[0104] As used herein, "pharmaceutically acceptable" means suitable for use by humans and / or animals, generally safe and non-toxic in normal use, i.e., without excessive adverse side effects (e.g., toxicity, irritation, and allergic response), commensurate with a reasonable benefit / risk ratio.

[0105] As used herein, "SASP" means sulfasalazine.

[0106] As used herein, "salts thereof" are salts of compounds of the invention that have been modified by preparing acid or base salts of compounds of the invention. The term "pharmaceutically acceptable salts" in this regard refers to relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the invention. For example, one method of preparing such salts is to treat a compound of the invention with an inorganic acid.

[0107] As used herein, "solvate" means a physical association of a compound (e.g., a compound of Formula (I)) with one or more solvent molecules, for example, by hydrogen bonding. "Solvate" encompasses both solution-phase solvates and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known to those of ordinary skill in the art.

[0108] As used herein, "a subject suffering from a disease caused by pathological inflammation" means a subject who has been clinically diagnosed as having such a disease.

[0109] As used herein, "symptoms" associated with a disease caused by pathological inflammation include any clinical or laboratory manifestations associated with the disease, and are not limited to symptoms that can be felt or observed by a subject.

[0110] As used herein, "TF" means transcription factor.

[0111] As used herein, "TNF" means tumor necrosis factor.

[0112] As used herein, "TNF-α" means tumor necrosis factor alpha.

[0113] As used herein, "treating" encompasses, for example, inhibiting, regressing or arresting the induction of a disease or disorder (e.g., IBD), or alleviating, reducing, suppressing, inhibiting, reducing the severity of a disease or disorder, eliminating or substantially eliminating, or ameliorating the symptoms of a disease or disorder.

[0114] As used herein, "UC" means ulcerative colitis.

[0115] IBD, including UC and CD, is a chronic, relapsing, and remitting disorder without a definitive cure. Current drugs are moderately effective for inducing and maintaining clinical and endoscopic remission, and side effects are a problem. Therefore, not all IBD patients respond adequately to currently available disease-modifying drugs.

[0116] An important object of the present invention is to provide a new drug and method for treating diseases caused by pathological inflammation (e.g., IBD), with the ultimate goal of modifying the course of the disease. Without wishing to be bound by any theory, the inventors have concluded that more effective treatments for diseases such as these involve not only NFκB inhibition, but also the use of NFκB inhibitors that can exert a dual effect on NFκB activity in combination. By combining NFκB inhibitors that simultaneously inhibit the degradation of the two major forms of IκB proteins (i.e., IκBα and IκBβ), treatments that are superior to existing therapies with 5-ASA alone can be obtained. The inventors unexpectedly and surprisingly found that combining a compound of formula (I) with a 5-ASA agent as defined above in an amount greater than the minimum effective amount produces a synergistically enhanced therapeutic effect with a favorable safety profile.

[0117] Thus, another aspect is AABZ, in combination with a 5-ASA agent, for use in treating a condition (a disease caused by pathological inflammation, such as IBD) that is associated with (e.g., mediated by) NFκB activity. Another aspect is AABZ, in combination with a 5-ASA agent, for use in inhibiting NFκB activity in mammalian (e.g., human) cells to treat a condition (a disease caused by pathological inflammation, such as IBD) that is associated with (e.g., mediated by) NFκB activity. Another aspect is AABZ, in combination with a 5-ASA agent, for use in inhibiting the degradation of IκBα and IκBβ in cells to treat a condition (a disease caused by pathological inflammation, such as IBD) that is associated with (e.g., mediated by) NFκB activity in cells. Another aspect is a method for treating a condition (a disease caused by pathological inflammation, such as IBD) that is associated with (e.g., mediated by) NFκB activity, comprising administering to a mammal in need of such treatment a therapeutically effective amount of AABZ in combination with a therapeutically effective amount of a 5-ASA agent.

[0118] Compound of formula (I)

[0119] In the compounds of formula (I) as defined herein, R1 is selected from C1-C6 alkyl and C3-C6 cycloalkyl. In some embodiments, R1 is selected from C1-C5 alkyl and C3-C5 cycloalkyl, for example, selected from C1-C4 alkyl and C3-C4 cycloalkyl, or selected from C1-C3 alkyl and C3 cycloalkyl. In some embodiments, R1 is selected from C1-C6 alkyl, for example, selected from C1-C5 alkyl or selected from C1-C4 alkyl or selected from C1-C3 alkyl, or selected from C1-C2 alkyl. In some embodiments, R1 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, neopentyl and cyclopentyl; for example, selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl and neopentyl. In some embodiments, R1 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and cyclobutyl, for example, selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In some embodiments, R1 is selected from methyl, ethyl, n-propyl, isopropyl and cyclopropyl, for example, selected from methyl, ethyl, n-propyl and isopropyl. In some embodiments, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl and neopentyl; for example, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; or selected from methyl, ethyl, n-propyl and isopropyl; for example, selected from methyl, ethyl and isopropyl. In some embodiments, R1 is methyl or ethyl. In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is isopropyl.

[0120] The moiety R2 is selected from hydrogen and C1-C3 alkyl. In some embodiments, R2 is selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; for example, selected from hydrogen, methyl and ethyl; or selected from hydrogen and methyl. In some embodiments, R2 is hydrogen.

[0121] The moieties R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, halogen, phenyl and benzyl, wherein any alkyl is optionally substituted by one or more fluorines.

[0122] In some embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio and halogen, wherein any alkyl is optionally substituted by one or more fluorine. In some embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen, wherein any alkyl is optionally substituted by one or more fluorine. In other embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen, wherein any alkyl is optionally substituted by one or more fluorine. In other embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy and halogen, wherein any alkyl is optionally substituted by one or more fluorine. In other embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkyl and halogen, wherein any alkyl is optionally substituted by one or more fluorine. In other embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkoxy and halogen, wherein any alkyl is optionally substituted by one or more fluorine. In other embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkylthio and halogen, wherein any alkyl is optionally substituted by one or more fluorine. In other embodiments, R3, R4, R5 and R6 are independently selected from hydrogen and halogen.

[0123] When any one of R3, R4, R5 and R6 is selected from C1-C3 alkyl, it may be selected from methyl and ethyl, for example; in particular, it may be methyl.

[0124] When any one of R3, R4, R5 and R6 is selected from C1-C3 alkoxy, it may be selected from methoxy and ethoxy, for example; in particular, it may be methoxy.

[0125] When any one of R3, R4, R5 and R6 is selected from C1-C3 alkylthio, it may be selected from methylthio and ethylthio, for example; in particular, it may be methylthio.

[0126] When any one of R3, R4, R5 and R6 is selected from halogen, the halogen, for example, can be selected from fluorine, chlorine and bromine; In particular, the halogen can be chlorine or bromine, such as chlorine. In some other embodiments, when any one of R3, R4, R5 and R6 is selected from halogen, the halogen is more particularly selected from fluorine and chlorine.

[0127] In some embodiments, R3, R4, R5 and R6 are independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, fluorine, chlorine, bromine, trifluoromethyl, phenyl and benzyl, for example selected from hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, fluorine, chlorine, bromine and trifluoromethyl; or selected from hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine and trifluoromethyl; for example selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine and trifluoromethyl; or selected from hydrogen, methyl, methoxy, chlorine and trifluoromethyl, or selected from hydrogen, methyl, methoxy and chlorine; or selected from hydrogen, methoxy and chlorine; or selected from hydrogen, methyl and chlorine; for example selected from hydrogen and chlorine.

[0128] In some of the above embodiments, at least one, more preferably at least two of R3, R4, R5 and R6 are hydrogen. In some of the above embodiments, two of R3, R4, R5 and R6 are hydrogen. In some of the above embodiments, three of R3, R4, R5 and R6 are hydrogen. In some of the above embodiments, each of R3, R4, R5 and R6 is hydrogen. In some of the above embodiments, at least one of R3, R4, R5 and R6 is different from hydrogen. In some of the above embodiments, one of R3, R4, R5 and R6 is different from hydrogen, and the other three are hydrogen; for example, one of R3, R4, R5 and R6 (for example, R3) is halogen, for example, chlorine; and the other three are hydrogen. In some of the above embodiments, R3 is different from hydrogen, and each of R4, R5 and R6 is hydrogen. In some embodiments, R5 is different from hydrogen, and each of R3, R4 and R6 is hydrogen. In some embodiments, one of R3, R4, R5 and R6 (e.g. R3) is fluorine, chlorine or bromine, particularly chlorine; and the other three are hydrogen. In some embodiments, R3 is hydrogen or halogen, hydrogen and chlorine; and R4, R5 and R6 are hydrogen. In some embodiments, R4 and R6 are hydrogen; for example, R4 and R6 are hydrogen, and at least one of R3 and R5 is different from hydrogen, for example, R3 and R5 are different from hydrogen. In some embodiments, R4 and R5 are hydrogen; for example, R4 and R5 are hydrogen, and at least one of R3 and R6 is different from hydrogen, for example, R3 and R6 are different from hydrogen.

[0129] In some embodiments, R3 and R4 are hydrogen; for example, R3 and R4 are hydrogen, and at least one of R5 and R6 is different from hydrogen, for example, both R5 and R6 are different from hydrogen. In some of the above embodiments, R5 and R6 are not methoxy or ethoxy.

[0130] The moiety R7 is selected from hydrogen and C1-C3 alkyl. In some embodiments, R7 is selected from hydrogen, methyl, ethyl, propyl and isopropyl; for example, selected from hydrogen, methyl, ethyl and propyl. In some embodiments, R7 is selected from hydrogen, methyl and ethyl. In some embodiments, R7 is selected from hydrogen and methyl. In some embodiments, R7 is hydrogen.

[0131] The moieties R8 and R9 are independently selected from C1-C6 alkyl, or R8 and R9 together with the nitrogen atom to which they are both attached form a moiety of formula (II) as defined herein. In some embodiments, R8 and R9 are independently selected from C1-C6 alkyl. When R8 and R9 are selected from C1-C6 alkyl, R8 and R9 can, for example, be selected from C1-C5 alkyl; or from C1-C4 alkyl; or from C1-C3 alkyl; for example from methyl and ethyl. In some embodiments, when R8 and R9 are selected from C1-C6 alkyl, both R8 and R9 are ethyl. In some embodiments, R8 and R9 together with the nitrogen atom to which they are both attached form a moiety of formula (II) as defined herein, in which case the compound of formula (I) can be represented by formula (Ia)

[0132]

[0133] Among them, R1-R7, R 10 , Q, p and r are as defined herein.

[0134] In moiety (II), r is 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1.

[0135] The part R 10 Selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxyl, halogen, cyano, COOR 12 or NHR 13 In some embodiments, R 10 is selected from methyl, ethyl and cyclopropyl, wherein the methyl, ethyl and cyclopropyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 In some embodiments, R 10 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, optionally substituted by hydroxy, halogen and cyano; for example substituted by halogen (e.g. fluorine). 10 Selected from C1-C3 alkyl and C3-C4 cycloalkyl, such as methyl, ethyl and cyclopropyl, such as methyl.

[0136] The moiety Q is selected from CHR 11 NR 11 In some embodiments, Q is selected from CHR11 and NR 11 In some embodiments, Q is selected from CHR 11 and O. In some embodiments, Q is CHR 11 In some other embodiments, Q is selected from NR 11 and O.

[0137] The part R 11 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 In some embodiments, R 11 is selected from hydrogen, methyl, ethyl and cyclopropyl, wherein the methyl, ethyl and cyclopropyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 In some embodiments, R 11 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl, the alkyl and cycloalkyl being optionally substituted by hydroxy, halogen or cyano; for example substituted by halogen, such as fluorine. 11 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl, for example hydrogen, methyl, ethyl and cyclopropyl, or hydrogen, methyl and ethyl; in particular hydrogen and methyl. In some embodiments, R 11 In some other embodiments, R 11 As defined above, but different from hydrogen.

[0138] When R 11 For hydroxyl, halogen, cyano, COOR 12 or NHR 13 In the case of substituted C1-C3 alkyl or C3-C4 cycloalkyl, the number of these substituents may be one or more, for example, 1-3 or 1-2 or 1.

[0139] The part R 12 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl. 12 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and cyclopropyl, for example selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; or selected from hydrogen, methyl and ethyl, for example selected from hydrogen and methyl. In some embodiments, R 12 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl. 12 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, for example, selected from methyl, ethyl, n-propyl, isopropyl and cyclopropyl; selected from methyl, ethyl, n-propyl and isopropyl; or selected from methyl and ethyl, for example, R 12In some other embodiments, R 12 For hydrogen.

[0140] The part R 13 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl. 13 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and cyclopropyl, for example selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; or selected from hydrogen, methyl and ethyl, for example selected from hydrogen and methyl. In some embodiments, R 13 is selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl. 13 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, for example, selected from methyl, ethyl, n-propyl, isopropyl and cyclopropyl; selected from methyl, ethyl, n-propyl and isopropyl; or selected from methyl and ethyl, for example, R 13 In some other embodiments, R 13 For hydrogen.

[0141] In formula (II), when Q is CHR 11 When p is 1, 2 or 3; and when Q is selected from NR 11 and O, p is 2 or 3. In some embodiments, p is 2 or 3. In some embodiments, p is 2. In some embodiments, Q is CHR 11 , and p is 1 or 2. In some embodiments, Q is CHR 11 , and p is 2. In some other embodiments, Q is CHR 11 , and p is 1.

[0142] In some embodiments of the compound of formula (I), R1 is C1-C6 alkyl; R2 is hydrogen; R7 is hydrogen; R8 and R9 are independently selected from C1-C6 alkyl, or R8 and R9 together with the nitrogen atom to which they are both attached form a moiety of formula (II) as defined herein; R 10 is C1-C3 alkyl; Q is CHR 11 ; and R 11 Selected from hydrogen and C1-C3 alkyl.

[0143] In some embodiments, R1 is C1-C6 alkyl; R2 is hydrogen; R7 is hydrogen; and R8 and R9 are independently selected from C1-C6 alkyl. In some of these embodiments, R1, R8 and R9 are independently selected from C1-C3 alkyl.

[0144] In some other embodiments, R1 is C1-C3 alkyl; R2, R4, R5 and R7 are hydrogen; and R8 and R9 are independently selected from C1-C3 alkyl. In some of these embodiments, R1 is selected from methyl, ethyl and isopropyl; and R8 and R9 are the same or different and are selected from methyl, ethyl and n-propyl.

[0145] In some additional embodiments, R1 is selected from methyl, ethyl and isopropyl; R2, R4, R5, R6 and R7 are hydrogen; and R8 and R9 are the same or different and are selected from methyl, ethyl and n-propyl.

[0146] In some embodiments, R2 is selected from hydrogen and methyl; R3, R4, R5 and R6 are independently selected from hydrogen and chloro; R7 is hydrogen; and R8 and R9 are the same or different and are selected from methyl, ethyl and n-propyl.

[0147] In some embodiments, R1 is selected from methyl, ethyl and isopropyl; R2 is hydrogen or methyl; R3 is chlorine or hydrogen; R4, R5, R6 and R7 are hydrogen; and R8 and R9 are the same or different and selected from methyl, ethyl and n-propyl. In some other embodiments, R1 is selected from methyl, ethyl and isopropyl; R2 is hydrogen or methyl; R3 is chlorine or hydrogen; R4, R5, R6 and R7 are hydrogen; and R8 and R9 are ethyl. In some other embodiments, R1 is selected from methyl, ethyl and isopropyl; R2 is hydrogen; R3 is chlorine or hydrogen; R4, R5, R6 and R7 are hydrogen; and R8 and R9 are the same or different and selected from methyl, ethyl and n-propyl.

[0148] In some embodiments, R1 is selected from methyl, ethyl, and isopropyl; R2 is hydrogen; R3 is chloro; R4, R5, R6, and R7 are hydrogen; and R8 and R9 are the same or different and are selected from methyl, ethyl, and n-propyl.

[0149] In some embodiments, the compound of formula (I) is selected from:

[0150] 4-Acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0151] 4-Propanylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0152] 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0153] 4-Acetylamino-N-[2-(diethylamino)ethyl]benzamide,

[0154] N-[2-(diethylamino)ethyl]-4-(propionylamino)benzamide, and

[0155] N-[2-(Diethylamino)ethyl]-4-(isobutyrylamino)benzamide.

[0156] In some embodiments, the compound of formula (I) is selected from

[0157] 4-Acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0158] 4-Propanylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0159] 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide, and

[0160] 4-Acetylamino-N-[2-(diethylamino)ethyl]benzamide.

[0161] In some embodiments, the compound of formula (I) is 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide. In some embodiments, the compound of formula (I) is 4-propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide. In some embodiments, the compound of formula (I) is 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide. In some embodiments, the compound of formula (I) is 4-acetamido-N-[2-(diethylamino)ethyl]benzamide. In some embodiments, the compound of formula (I) is N-[2-(diethylamino)ethyl]-4-(propionamido)benzamide. In some embodiments, the compound of formula (I) is N-[2-(diethylamino)ethyl]-4-(isobutyrylamino)benzamide.

[0162] In some embodiments, AABZ is a hydrochloride salt of a compound of formula (I), such as any of the hydrochloride salts of compounds of formula (I) listed above, such as AABZ is

[0163] 4-Acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride.

[0164] The structural formulas of some of the compounds mentioned herein are shown in Table 1.

[0165] Table 1

[0166] 4-Acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Propanylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Acetylamino-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Propanylamino-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Isobutyrylamino-N-[2-(diethylamino)ethyl]benzamide #timg#

[0167] Method for preparing the compound of formula (I)

[0168] The compounds of formula (I) can be readily prepared by one of ordinary skill in the art, for example, by following the general procedures disclosed in U.S. Patent Application Nos. 2011 / 0027179 and WO 2005 / 025498. For example, the compounds of formula (I) can be prepared by a process comprising two consecutive nucleophilic substitution reactions, as shown in the following reaction scheme.

[0169]

[0170] In the above reaction scheme, compound 1 (wherein R a For example, C1-C3 alkyl) is reacted with compound 2 (wherein L is a suitable leaving group, such as Cl) to obtain compound 3. Compound 3 is then reacted with secondary amine 4 in the presence of ammonium chloride as a reaction catalyst to obtain a compound of formula (I) as defined herein. The compound of formula (I) may optionally be converted into a suitable pharmaceutically acceptable salt or solvate, such as a hydrochloride.

[0171] 5-ASA

[0172] Examples of 5-ASA agents according to the present invention are mesalazine, sulfasalazine, olsalazine or balsalazide (which may also be referred to as balsalazine) or pharmaceutically acceptable salts thereof. In Table 2, the structural formulae of some 5-ASA agents are shown.

[0173] Table 2

[0174] 5-ASA Structural formula Mesalazine #timg# Sulfasalazine #timg# Olsalazine #timg# Balsalazide #timg#

[0175] In some embodiments, the 5-ASA agent is mesalamine, sulfasalazine, olsalazine or balsalazide, or a pharmaceutically acceptable salt or solvate of any of these compounds. However, it should be noted that the present invention is not limited to these compounds. Instead, any 5-ASA prodrug or formulation capable of releasing 5-ASA or its salt or solvate in vivo is expected to be useful according to the present invention.

[0176] In some embodiments, the 5-ASA agent is mesalazine or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the 5-ASA agent is sulfasalazine or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the 5-ASA agent is olsalazine or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the 5-ASA agent is balsalazide or a pharmaceutically acceptable salt or solvate thereof.

[0177] In some embodiments, the 5-ASA agent is a colon-specific prodrug of 5-ASA designed to achieve colon delivery. This prodrug comprises a carrier portion connected to 5-ASA via a carboxyl or hydroxyl functional group of 5-ASA. As colon-specific prodrugs of 5-ASA, esters and amides have been reported (Amidon, 2015), and any such prodrug is contemplated for use herein.

[0178] In particular, Amidon et al. (2015) describe criteria for colon-specific drug delivery on page 731. In some embodiments, the 5-ASA agent is a colon-specific prodrug that meets this criteria for colon-specific delivery.

[0179] Additional examples of 5-ASA prodrugs useful herein are disclosed, for example, in U.S. Pat. No. 7,157,444 and Jung (1998) and Jung (2003); for example, 5-aminosalicylic acid-glycine and 5-aminosalicylic acid-taurine.

[0180] In some embodiments, the 5-ASA agent is a formulation that can release 5-ASA or a salt or solvate thereof in vivo (e.g., in the colon), or can release a 5-ASA prodrug. In some embodiments, the 5-ASA agent is a formulation that can delay the release of 5-ASA or a salt thereof (e.g., hydrochloride) in the colon.

[0181] Pharmaceutically acceptable salts

[0182] AABZ can be provided in the form of a pharmaceutically acceptable salt (e.g., an acid addition salt) of a compound of formula (I). Similarly, 5-ASA agents can be provided in the form of a pharmaceutically acceptable salt (e.g., a base addition salt). In the preparation of acid or base addition salts, it is preferred to use an acid or base that forms a suitable therapeutically acceptable salt. Examples of such acids are hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, halogen benzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid. Base addition salts include those derived from inorganic bases, such as ammonium or alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates, etc., and salts derived from organic bases, such as alkoxides, alkylamides, alkyl and arylamines, etc. Examples of bases useful in preparing the salts of this invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.

[0183] In some embodiments, the compound of formula (I) is provided as a hydrochloride salt. In some embodiments, the 5-ASA agent is provided as a salt of a strong base (eg, an alkali metal salt, such as a sodium salt).

[0184] Relevant teachings regarding salt formulations used herein and methods of making the same are described, for example, in U.S. Pat. No. 3,177,252, and such teachings are hereby incorporated by reference into this application.

[0185] Pharmaceutically acceptable solvates

[0186] According to the present invention, it is contemplated that any pharmaceutically acceptable solvate is contemplated to be possible. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. In some embodiments, the solvate is a hydrate.

[0187] Combination use of AABZ and 5-ASA agents

[0188] One aspect is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (AABZ) as defined herein, for use in combination with a 5-ASA agent for the treatment of a disease caused by pathological inflammation.

[0189] In some embodiments, the treatment comprises administering to a subject (mammalian patient, e.g., human patient) an amount of AABZ and a 5-ASA agent greater than the minimum effective amount, wherein these amounts when taken together are effective to treat the subject. In some embodiments, when AABZ and the 5-ASA agent are administered together to treat a subject, the total amount of AABZ and the 5-ASA agent produces an overall better effect, i.e., a synergistic effect, than the simple addition of the effects produced by administering the same total amount of either component alone.

[0190] In some embodiments, the treatment comprises administering AABZ to a subject (mammalian patient, e.g., human patient) as an add-on therapy or in combination with a 5-ASA agent in treating a subject with pathological inflammation, IBD (e.g., UC or CD). Preferably, the treatment provides induction and maintenance of clinical and endoscopic remission in patients with mild to moderate to severe disease activity. In some embodiments, treatment is intended for patients in remission to prevent disease relapse.

[0191] In some embodiments, AABZ is a pharmaceutically acceptable salt of a compound of formula (I), particularly a hydrochloride salt.

[0192] In some embodiments, AABZ is administered orally. In some embodiments, AABZ is administered in a preferably solid unit dosage form, more preferably a tablet.

[0193] In some embodiments, AABZ is administered in an amount of 0.1-25 mg / kg (mg of drug per kg of subject body weight) per day (any weight values ​​are based on non-salt, non-solvate form). In other embodiments, AABZ is administered in an amount of 0.3-10 mg / kg per day.

[0194] In some embodiments, AABZ is administered in an amount of 5.0-2000 mg / day, or 10-1000 mg / day.

[0195] In some embodiments, AABZ is administered daily, such as once a day. In other embodiments, AABZ is administered twice a day. In other embodiments, AABZ is administered three times a day. In yet other embodiments, AABZ is administered four times a day.

[0196] In some embodiments, the 5-ASA agent is administered by oral administration. In yet other embodiments, the 5-ASA agent is administered by rectal administration.

[0197] In some embodiments, the 5-ASA agent is administered daily. In some embodiments, the dosage of the 5-ASA agent is 250 mg / day to 8000 mg / day (any weight value is based on non-salt, non-solvate form). In some embodiments, the dosage of the 5-ASA agent is less than 8000 mg / day. In other embodiments, the dosage of the 5-ASA agent is less than 6750 mg / day. In other embodiments, the dosage of the 5-ASA agent is less than 4000 mg / day. In other embodiments, the dosage of the 5-ASA agent is less than 2000 mg / day.

[0198] In some embodiments, the 5-ASA dose is administered once per day. In other embodiments, the 5-ASA dose is administered twice per day. In other embodiments, the 5-ASA dose is administered three times per day. In yet other embodiments, the 5-ASA dose is administered four times per day.

[0199] The amount of AABZ and the amount of 5-ASA agent, when taken together, are preferably effective to reduce the symptoms of pathological inflammation (e.g., IBD) in a subject. Symptoms vary depending on the severity of the inflammation and can vary from mild to severe. Signs and symptoms common to both CD and UC include diarrhea and urgency, fever and fatigue, abdominal pain and cramping, blood in the stool, and decreased appetite. Symptoms of autoimmune diseases vary with the disease.

[0200] In some embodiments, administration of the 5-ASA agent significantly precedes administration of the AABZ, ie, the subject receives treatment via administration of the 5-ASA agent prior to initiating treatment via administration of the AABZ.

[0201] In some embodiments, the subject is receiving treatment by administration of a 5-ASA agent for at least 6 months prior to initiating treatment by administration of AABZ. In some embodiments, the subject is receiving treatment by administration of a 5-ASA agent for at least 12 months prior to initiating treatment by administration of AABZ. In some embodiments, the subject is receiving treatment by administration of a 5-ASA agent for at least 24 months prior to initiating treatment by administration of AABZ.

[0202] In some embodiments, treatment comprises administration of at least one additional drug, for example selected from nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, cytotoxic drugs, immunosuppressive drugs, and antibodies.

[0203] In some embodiments, the administration of AABZ and 5-ASA agents continues for at least 2 weeks. In other embodiments, the administration of AABZ and 5-ASA agents continues for 3 months or longer. In yet other embodiments, the administration of AABZ and 5-ASA agents continues for 12 months or longer.

[0204] In some embodiments, the AABZ and 5-ASA agents are administered in combination with one another (simultaneously, or separately and concomitantly or sequentially) at a molar ratio of AABZ to 5-ASA of 1:100 to 100:1, e.g., 1:50 to 50:1, or 1:20 to 20:1, or 1:10 to 10:1, or 1:5 to 5:1, or 1:2 to 2:1, e.g., about 1:1.

[0205] In some embodiments, 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide or a pharmaceutically acceptable salt thereof (eg, hydrochloride) and sulfasalazine or a pharmaceutically acceptable salt thereof (eg, sodium salt) are administered in combination with each other.

[0206] AABZ can be administered in admixture with a suitable pharmaceutical diluent, extender or carrier or any other pharmaceutically acceptable excipient appropriately selected according to the intended form of administration and consistent with conventional pharmaceutical practice. The preferred dosage unit will be in a form suitable for oral administration. AABZ can be administered alone, but is usually mixed with a pharmaceutically acceptable carrier and co-administered in tablets or capsules, liposomes, or as an agglomerated powder. Examples of suitable solid carriers include lactose, sucrose, gelatin, and agar. Capsules or tablets can be easily formulated and can be made to be easy to swallow or chew; other solid forms include granules and bulk powders.

[0207] Tablets can contain suitable binders, lubricants, disintegrants, colorants, flavoring agents, flow inducers and melting agents. For example, for oral administration in the dosage unit form of tablets or capsules, active drug components can be combined with oral, nontoxic, pharmaceutically acceptable inert carriers such as lactose, gelatin, agar, starch, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose, etc. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, polyvidone, carboxymethyl cellulose, polyethylene glycol, wax, etc. Lubricants for these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc, etc. Disintegrants include but are not limited to starch, methylcellulose, agar, bentonite, xanthan gum, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, etc.

[0208] Another aspect is AABZ used as an add-on therapy or in combination with a 5-ASA agent for treating a subject suffering from pathological inflammation, such as IBD.

[0209] Another aspect is a 5-ASA agent for use in treating a subject suffering from pathological inflammation (eg, IBD) by administering the 5-ASA agent and AABZ to the subject.

[0210] Subjects treated

[0211] The subject treated according to the present invention is a mammal, including humans and non-human mammals (animals). Examples of non-human mammals are primates, domestic animals, such as livestock, such as cattle, sheep, pigs, horses, etc., and pet animals, such as dogs and cats, etc. In a preferred embodiment, the subject is a human. In some other embodiments, the subject is a non-human mammal, such as a dog or a horse.

[0212] disease

[0213] Diseases treated according to the present invention are diseases caused by pathological inflammation as defined herein. In some embodiments, the disease is IBD. In some embodiments, the disease is UC. In some embodiments, the disease is CD. As mentioned above, CD may affect any part of the gastrointestinal tract. In some embodiments, the CD affects the colon.

[0214] Multi-component pill box

[0215] One aspect is a multi-component kit comprising a combination of AABZ and a 5-ASA agent, wherein each of the components AABZ and 5-ASA agent is optionally formulated in admixture with a pharmaceutically acceptable excipient (e.g., a carrier). In some embodiments, a multi-component kit (e.g., for treating IBD) is provided, comprising: a) a first pharmaceutical composition comprising an amount of AABZ and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising an amount of 5-ASA agent and a pharmaceutically acceptable carrier; and c) instructions for using the first pharmaceutical composition and the second pharmaceutical composition together.

[0216] Pharmaceutical composition

[0217] In one aspect is a pharmaceutical composition comprising an amount of AABZ, an amount of a 5-ASA agent, and optionally (but preferably) at least one pharmaceutically acceptable excipient (eg, carrier). In some embodiments, the pharmaceutical composition is used to treat a subject suffering from IBD.

[0218] Typically, suitable pharmaceutical compositions are those as described above in connection with the pharmaceutical formulation of AABZ, but containing, in addition to AABZ, a 5-ASA agent.

[0219] In some embodiments, AABZ is a pharmaceutically acceptable salt of a compound of formula (I), such as a hydrochloride salt.

[0220] In some embodiments, the amount of AABZ in the composition is 5-500 mg (any amount is based on the non-salt form and non-solvate form of the compound of formula (I)). In other embodiments, the amount of AABZ is 10-100 mg. In other embodiments, the amount of AABZ is 5-25 mg. In one embodiment, the amount of AABZ in the composition is 500 mg. In other embodiments, the amount of AABZ is 25 mg. In other embodiments, the amount of AABZ is 100 mg. In other embodiments, the amount of AABZ is 10 mg. In other embodiments, the amount of AABZ is less than 10 mg.

[0221] In some embodiments, the amount of 5-ASA agent in the composition is 225-1200 mg (any amount is based on the non-salt form and non-solvate form of the compound of formula (I)). In other embodiments, the amount of 5-ASA agent is 500-1000 mg. In other embodiments, the amount of 5-ASA agent is 225-450 mg. In one embodiment, the amount of 5-ASA agent in the composition is 750 mg.

[0222] In some embodiments, the molar ratio of AABZ to 5-ASA in the pharmaceutical composition is 1:100 to 100:1, such as 1:50 to 50:1, or 1:20 to 20:1, or 1:10 to 10:1, or 1:5 to 5:1, or 1:2 to 2:1, for example, the molar ratio can be about 1:1.

[0223] In some embodiments, the total amount of AABZ and 5-ASA agents is 0.1 wt % to 95 wt %, such as 0.5 wt % to 50 wt %, or 1 wt % to 20 wt % of the formulation, with the remainder comprising, for example, carrier and any other excipients.

[0224] In some embodiments, the pharmaceutical composition comprises 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide or a pharmaceutically acceptable salt thereof (eg, hydrochloride) and sulfasalazine or a pharmaceutically acceptable salt thereof (eg, sodium salt).

[0225] Specific examples of techniques, pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms of the present invention are described, for example, in EP 1 720 531 B1.General techniques and compositions for making dosage forms useful in the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker and Rhodes, eds., 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd edition (1976); Remington's Pharmaceutical Sciences, 17th edition (Mack Publishing Company, Easton, Pa., 1985) (and subsequent editions); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, eds., 1992); Advances in Pharmaceutical Sciences, Vol. 7 (David Ganderton, Trevor Jones, James McGinity, eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, ed., 1989); Pharmaceutical Particulates. Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol. 61 (Alain Rolland, 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; JG Hardy, SSDavis, Clive G. Wilson, eds.); and Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, eds.). These references are incorporated herein by reference in their entirety.

[0226] The following examples are intended to illustrate the invention without limiting its scope. Example

[0227] Intermediate 1

[0228] Ethyl 4-acetamido-3-chlorobenzoate

[0229] Ethyl 4-amino-3-chlorobenzoate (2.0 g, 10 mmol) and 1.4 g of triethylamine were dissolved in 20 mL of dichloromethane. 0.9 g of acetyl chloride in 5 mL of dichloromethane was added dropwise at 0°C. The reaction mixture was allowed to reach room temperature, stirred for 3 hours, washed with water, and dried. The solvent was evaporated to yield 2.0 g of the title product.

[0230] Example 1

[0231] 4-Acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride

[0232] 1.5 g of ethyl 4-acetylamino-3-chlorobenzoate (1.5 g, 6.2 mmol) was dissolved in 15 mL of N', N'-diethylethane-1,2-diamine together with a catalytic amount of ammonium chloride. The reaction mixture was refluxed for 3 hours. Dichloromethane was added and washed 4 times with water to remove excess diamine. The solvent was dried and evaporated to produce the free base of the title compound. The residue was dissolved in ethanol-ether and acidified with ethanolic hydrogen chloride solution. The precipitated solid was collected to obtain the title compound (1.1 g, 3.1 mmol, 50% yield).

[0233] 1H NMR (DMSO-d6): δ 1,23 (t, 6H), 2,15 (s, 3H), 3,17-3,23 (6H), 3,65(q, 2H), 7,88 (d, 1H), 7,94 (s, 1H), 8,06 (s, 1H), 9,05 (t, 1H), 9,68 (s,1H), 10,42 (s, 1H).

[0234] Example 2

[0235] 4-Propanylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride

[0236] 4-amino-N-[2-(diethylamino)ethyl]benzamide hydrochloride (0.5 g, 1.6 mmol), pyridine (5.0 mL) and propionic anhydride (5.0 mL) were stirred at 50 °C for 2.5 hours. Volatiles were then removed using a rotary evaporator. Water (5 mL) was added and evaporated. The residue was freeze-dried from water to give the title compound (0.6 g, 100% yield, HPLC purity 98%).

[0237] 1H NMR (400 MHz, methanol-d4) δ 8.07 (d, J = 8.6 Hz, 1H), 8.01 (d, J =2.0 Hz, 1H), 7.83 (dd, J = 8.6, 2.0 Hz, 1H), 3.76 (t, J = 6.2 Hz, 2H), 3.39(t, J = 6.2 Hz, 2H), 3.34 (q, J = 7.3 Hz, 4H), 2.52 (q, J = 7.6 Hz, 2H), 1.36(t, J = 7.3 Hz, 6H), 1.23 (t, J = 7.6 Hz, 3H).

[0238] Example 3

[0239] 4-Isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride

[0240] By using isobutyric anhydride instead of propionic anhydride, the compound 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride was obtained in substantially the same manner. According to HPLC, the purity was 99%.

[0241] 1H NMR (400 MHz, methanol-d4) δ 8.01 (d, J = 2.2 Hz, 1H), 8.00 (d, J =8.5 Hz, 1H), 7.83 (dd, J = 8.5, 2.0 Hz, 1H), 3.76 (t, J = 6.2 Hz, 2H), 3.39(t, J = 6.2 Hz, 2H), 3.34 (q, J = 7.3 Hz, 4H), 2.80 (septet, J = 6.8 Hz, 1H),1.36 (t, J = 7.3 Hz, 6H), 1.24 (d, J = 6.9 Hz, 6H).

[0242] Example 4

[0243] 4-Acetylamino-N-[2-(diethylamino)ethyl]benzamide hydrochloride

[0244] A suspension of 4-amino-N-[2-(diethylamino)ethyl]benzamide hydrochloride (2.5 g, 9.1 mmol) was stirred in 20 mL of anhydrous pyridine. 10 mL of acetic anhydride was added to the suspension. The reaction was slightly exothermic. After 1 hour, the precipitate was filtered out, washed with ethyl acetate, and dried to provide the title compound (2.83 g, 9.0 mmol, 99% yield). According to NMR, the purity was 98%.

[0245] 1H NMR (400 Mhz, methanol-d4) δ 7.84 (d, 2H), 7.68 (d, 2H), 3.74 (t, 2H),3.37 (t, 2H), 3.35 - 3.29 (m, 4H), 2.14 (s, 3H), 1.35 (t, 6H).

[0246] Biological assays

[0247] UC is an inflammatory disease characterized by the infiltration of inflammatory cells (e.g., macrophages) into the diseased colon. Macrophages play a key role in the initiation and propagation of the inflammatory response by releasing proinflammatory mediators (e.g., TNF-α). Lipopolysaccharide (LPS) is a potent initiator of the inflammatory response. During LPS stimulation, NF-κB signaling is activated to regulate the transcription of many genes involved in immunity and inflammation, producing proinflammatory cytokines such as TNF-α. The inhibition of LPS-induced TNF-α production in RAW264.7 macrophages treated with AABZ was studied by evaluating the production of TNF-α. The aim of this study was to evaluate the anti-inflammatory activity of AABZ.

[0248] Colitis induced by both dextran sulfate sodium (DSS) and trinitrobenzene sulfonic acid (TNBS) is an established animal model of mucosal inflammation that has been used for more than two decades in the study of IBD pathogenesis and in preclinical studies of new therapies. The DSS-induced colitis model has some advantages when compared to other colitis animal models (Perse, 2012) and was therefore chosen for analyzing the effects of combined treatments.

[0249] Example 5

[0250] Inhibition of LPS-induced TNF-α production in macrophages treated with AABZ.

[0251] The RAW264.7 macrophage cell line was maintained in DMEM supplemented with 5% FBS at 37°C in a 5% CO2 humidified air environment. RAW264.7 cells were plated at 1×10 5 / ml density and 200 μl / well volume were seeded in 96-well plates. The cells were incubated in medium supplemented with 10% FBS for 24 hours, then pre-incubated for 2 hours with or without the indicated concentrations of the test substances, after which LPS (1 μg / ml) was added. The supernatant was then harvested at different time points and the production of the proinflammatory cytokine TNF-α in the culture medium was determined using a commercially available enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's protocol.

[0252] The effects of some AABZs of the present invention at 1 mM on LPS-induced TNF-α production in RAW264.7 murine macrophages are shown in Table 3.

[0253] Table 3. Effect of 1 mM AABZ on LPS-induced TNF-α production in RAW264.7 mouse macrophages

[0254] Compound % inhibition of TNF production LPS-treated control 0 4-Acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride* 45 4-Propanylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride 50 4-Isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride 63 4-Acetylamino-N-[2-(diethylamino)ethyl]benzamide hydrochloride 56

[0255] * Compound A.

[0256] It was observed that the compound at different concentrations (0.3 mM, 1.0 mM and 3.0 mM) significantly reduced the expression level of TNF compared to the LPS treated control group. These results support the usefulness of the compounds as disclosed herein for treating diseases caused by pathological inflammation.

[0257] Example 6

[0258] The effects of Compound A alone or in combination with SASP on DSS-induced inflammatory bowel disease were evaluated. Effects in Disease

[0259] After the adaptation period of one week, the experiment was performed with female Balb / c mice of 6-8 weeks of age. The mice weighing 18-25 g were purchased from Taconic (Denmark), and maintained in a temperature and light controlled facility, so that they could freely obtain standard rodent food and water. Five days before the start of treatment, mice were randomly divided into each group, and 5 to 6 animals per cage were kept. After the adaptation period, 5% DSS solution (from TdBConsultaryAB, DSS in Sweden; MW~40000) was given by drinking water for five days (the 0th day to the 5th day) to induce acute colitis, which caused the reproducible colitis characterized by diarrhea, rectal bleeding, weight loss, mucosal ulcers, crypt destruction and leukocyte infiltration. DSS intake was assessed every day.

[0260] SASP (from Sigma-Aldrich, Sweden) was first dissolved in 0.2 M sodium hydroxide (NaOH) at a concentration above the desired final concentration. Phosphate buffered saline (PBS) was added to the desired concentration and the pH was adjusted to 7.5-8.0 with NaOH or hydrochloric acid. At this pH, SASP remained completely dissolved. Compound A hydrochloride was dissolved in PBS to the desired concentration.

[0261] All animal groups had free access to a 5% DSS aqueous solution throughout the experiment. From day 0 to day 5, the therapeutic agent was administered orally (SASP) or intraperitoneally (Compound A) by gavage, and the administration volume was 5 ml / kg, twice a day, approximately 8 hours apart. The control group (DSS only) received water (0.2 ml) orally twice a day. The parameters recorded in the experiment were stool consistency (0, normal; 2, loose stools; 4, watery diarrhea), the appearance of blood in the stool (0, normal; 2, occult blood +; 4, severe bleeding), and weight loss (0, none; 1, 1-5%; 2, 5-10%; 3, 10-20%; 4, >20%). The disease activity index (DAI) was calculated by summarizing the scores of these three parameters. Colon length and colon content of myeloperoxidase (MPO) were also recorded. The data were statistically evaluated using analysis of variance (ANOVA). The least squares mean (LS mean) and standard error (SE) of the LS mean were calculated.

[0262] Table 4 shows the percentage inhibition of the effect of sodium dextran sulfate recorded on day 5 (100% = complete normalization, 0% = no effect).

[0263] Table 4. Percent inhibition of dextran sulfate sodium disease activity index on day 5 relative to control

[0264] (100% = perfect normalization, 0% = no effect).

[0265]

[0266] Administration of 5% DSS for 5 days resulted in severe acute colitis with diarrhea, blood in the stool, and weight loss. Diarrhea and blood in the stool appeared from day 3, and these symptoms worsened until the end of the study on day 5. Oral treatment with SASP (40 mg / kg / day, twice a day was found to be the optimal dose) improved some of these manifestations of colitis. From day 3, diarrhea and blood in the stool improved. On day 3, the frequency of diarrhea (stool consistency scores of 2 and 4) was 22% in the control group and 8% in the SASP 40 mg / kg / day, twice a day group. On day 5, the corresponding figures were 98% and 71%, respectively. The combination of Compound A (50 mg / kg / day, twice a day) and SASP (20 mg / kg / day, twice a day) resulted in excellent improvement in colitis parameters (Table 4). The combination of Compound A and SASP was synergistic in improving DSS-induced acute colitis (p<0.008). The combination treatment significantly reduced the Disease Activity Index (DAI) score by 51% compared to the control group (p < 0.0001) and by 47% compared to the SASP (20 mg / kg / day, twice a day) alone group (p < 0.0002).

[0267] References

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Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating inflammatory bowel disease, in R1 is selected from C1-C3 alkyl; Each of R2, R4, R5, R6 and R7 is hydrogen; R3 is selected from hydrogen, C1-C3 alkyl and halogen; R8 and R9 are independently selected from C1-C4 alkyl; wherein the treatment further comprises administering a 5-ASA agent selected from mesalazine, sulfasalazine, olsalazine, balsalazide, 5-aminosalicylic acid-glycine and 5-aminosalicylic acid-taurine or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein R3 is selected from hydrogen and halogen.

3. The method according to claim 2, wherein R3 is selected from hydrogen and chlorine.

4. The use according to claim 1, wherein the compound of formula (I) is selected from 4-Acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-Propanylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-Acetylamino-N-[2-(diethylamino)ethyl]benzamide, N-[2-(diethylamino)ethyl]-4-(propionylamino)benzamide, and N-[2-(Diethylamino)ethyl]-4-(isobutyrylamino)benzamide.

5. The use according to claim 4, wherein the compound of formula (I) is 4-acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

6. The use according to claim 4, wherein the compound of formula (I) is 4-propionylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

7. The use according to claim 4, wherein the compound of formula (I) is 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

8. The use according to claim 4, wherein the compound of formula (I) is 4-acetylamino-N-[2-(diethylamino)ethyl]benzamide.

9. The use according to claim 1, wherein the inflammatory bowel disease is ulcerative colitis.

10. The use according to claim 1, wherein the inflammatory bowel disease is Crohn's disease.

11. A combination of (i) and (ii) below: (i) Compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein R1 is selected from C1-C3 alkyl; Each of R2, R4, R5, R6 and R7 is hydrogen; R3 is selected from hydrogen, C1-C3 alkyl and halogen; R8 and R9 are independently selected from C1-C4 alkyl; and (ii) a 5-ASA agent selected from mesalazine, sulfasalazine, olsalazine, balsalazide, 5-aminosalicylic acid-glycine and 5-aminosalicylic acid-taurine or a pharmaceutically acceptable salt thereof.

12. A combination according to claim 11, wherein R3 is selected from hydrogen and halogen.

13. The combination according to claim 12, wherein R3 is selected from hydrogen and chlorine.

14. A combination according to claim 11, wherein the compound of formula (I) is selected from 4-Acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-Propanylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-Acetylamino-N-[2-(diethylamino)ethyl]benzamide, N-[2-(diethylamino)ethyl]-4-(propionylamino)benzamide, and N-[2-(Diethylamino)ethyl]-4-(isobutyrylamino)benzamide.

15. A combination according to claim 14, wherein the compound of formula (I) is 4-acetylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

16. The combination according to claim 14, wherein the compound of formula (I) is 4-propionylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

17. The combination according to claim 14, wherein the compound of formula (I) is 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

18. The combination according to claim 14, wherein the compound of formula (I) is 4-acetylamino-N-[2-(diethylamino)ethyl]benzamide.

19. A pharmaceutical composition comprising the combination according to any one of claims 11 to 18 and optionally a pharmaceutically acceptable excipient.

20. A multi-component kit comprising the combination according to any one of claims 11 to 18, wherein each of component (i) and component (ii) is optionally formulated in admixture with a pharmaceutically acceptable excipient.

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