Substituted benzamides and their use in therapy

Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical composition comprising the compound. The compound can be used for treating diseases caused by pathological inflammation, such as inflammatory bowel disease, psoriasis or rheumatoid arthritis.

Description

Field of the Invention

[0001] The present invention relates to compounds that can be used for the treatment of diseases caused by pathological inflammation. More specifically, the present invention relates to 4-alkanoylaminobenzamide derivatives and their use in therapy, particularly for the treatment of diseases caused by pathological inflammation. In addition, the present invention relates to pharmaceutical formulations comprising such compounds. Background of the Invention

[0003] Throughout this application, various (non-patent) publications are referred to by the first author and the year of publication. The complete citations for these publications are presented in the reference section immediately preceding the claims. The disclosures of these documents and publications mentioned herein are hereby incorporated by reference in their entirety into this application to more fully describe the state of the art to which the present invention pertains.

[0004] Diseases caused by pathological inflammation can be treated with various anti-inflammatory agents, such as corticosteroids, immunomodulators, immunosuppressants, and tumor necrosis factor (TNF) inhibitors. TNF is involved in various inflammatory, autoimmune, and immune-mediated disorders, such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and psoriasis, and this forms the basis for the use of TNF inhibitors (anti-TNF drugs) in the treatment of such diseases. However, there are some important side effects associated with anti-TNF drugs, including an increased risk of lymphoma and skin cancer, an increased risk of serious infections including tuberculosis and fungal infections, and injection site reactions.

[0005] Not all patients treated with anti-TNF drugs respond to such therapy. For example, among IBD patients treated with current biologic anti-TNF drugs, only about 20% to 35% of patients achieve complete remission (Sandborn, 2016). Additionally, patients who do not experience complete remission, lose their response over time, or do not respond to anti-TNF therapy also have a substantially reduced response rate when treated with a second anti-TNF drug (Sands, 2014). Furthermore, although anti-TNF drugs may act rapidly in terms of symptom improvement in IBD patients, there is only a moderate correlation between such improvement and a reduction in mucosal inflammation. The rapid control of symptoms may be due to the direct neutralization of circulating TNF, but other mechanisms of action are needed to reduce the overall inflammatory burden and induce mucosal healing (Hindryckx, 2018).

[0006] Many diseases resulting from pathological inflammation are of a chronic nature or at least may require long-term treatment. In such cases, it is of utmost importance to try to minimize any serious side effects resulting from the treatment. For example, although 4-aminobenzamide derivatives such as procainamide (CAS No. 614-39-1) and dimetindene (CAS No. 891-60-1) have been proposed as potential therapeutic agents for the treatment of IBD (Kim, 2016; Ivanenkov, 2011), the well-known neurological and cardiovascular side effects associated with compounds of this chemical class may outweigh the potential clinical benefits in long-term treatment (Harrington, 1983; Harron, 1990).

[0007] IBD, which consists mainly of Crohn's disease (CD) and ulcerative colitis (UC), is a chronic, frequently progressive condition of the gastrointestinal tract that requires lifelong treatment. The natural history of the condition is one of remission interrupted by relapses of disease activity. CD and UC are diseases with many similarities and share many overlapping epidemiological, clinical, and therapeutic features, but often differ in terms of location and how to manage them.

[0008] UC is a disease in which the innermost lining of the colon and rectum becomes inflamed. Histologically, UC is characterized by the presence of both acute and chronic inflammation. The inflammation causes the intestine to empty frequently. Ulcers form, which then bleed and produce pus and mucus. The hallmark symptom of UC is bloody diarrhea accompanied by a sense of urgency to defecate. Other symptoms include abdominal cramps, loss of appetite, fatigue, weight loss, and fever. The diagnosis of UC is based on a combination of symptoms, endoscopic findings, and histology. The pathogenesis is multifactorial and involves genetic susceptibility, dysregulation of the immune response, and environmental factors.

[0009] CD typically presents with abdominal pain, diarrhea, and weight loss. The disease most often starts gradually and may affect only a small part of the gastrointestinal tract, but it has the potential to progress widely over time. CD can cause inflammation that penetrates the intestinal wall, causing fistulas or abscesses. Most commonly, CD affects the small intestine and the beginning of the large intestine. However, the disease can affect any part of the digestive tract from the mouth to the anus.

[0010] Depending on the extent of the disease, UC patients can be classified as having: 1) ulcerative proctitis involving only the rectum, 2) left-sided UC of the colorectum involving the distal splenic flexure, and 3) extensive UC of the colon involving the proximal splenic flexure (including pancolitis). Symptoms may vary depending on the degree and extent of inflammation. Patients are classified as having mild, moderate, or severe disease activity according to one or more measures of disease severity. UC is more frequently diagnosed between 15 and 35 years of age and there is a second peak of diagnosis between 55 and 65 years of age. The median age at diagnosis is 30 years. In 15% of cases, UC is diagnosed in childhood and may be present pre-school. Generally, the highest incidence rates of both CD and UC are found in the developed countries of North America and Europe. The prevalence is estimated at 70 - 500 cases per 100,000, with men and women equally affected. CD and UC account for a substantial cost to the healthcare system and society.

[0011] Due to the early onset and lack of cure, UC has a significant impact on the quality of life of patients. Current medications are moderately effective and adverse effects are a problem. Therefore, there is an urgent need to improve clinical management by establishing new treatment strategies. The treatment goals are to induce and maintain remission and prevent complications. Patients without symptoms and signs or with very mild symptoms and signs, along with mucosal healing, are considered to be in remission. Control of the inflammatory process is essential because even in the presence of symptom control, lack of control of inflammation is associated with poor long-term outcomes, with a higher risk of early recurrence and / or poor long-term outcomes, including an increased risk of colectomy and colorectal cancer. Extraintestinal manifestations of UC include primary sclerosing cholangitis, as well as joint, skin, and eye manifestations.

[0012] Historically, UC medications have been developed mainly for symptom-based treatment, i.e., inducing and maintaining symptom improvement, or at most clinical remission, and preventing complications, without significantly altering the natural course of the disease. In the last few decades, the treatment goals in both UC and CD patients have evolved greatly from focusing only on clinical response to the need to achieve better outcomes related to mucosal lesion healing. Mucosal healing (MH) has become a key step in achieving sustained remission in UC (Frøslie 2007; Peyrin-Biroulet 2015), and nowadays, regulatory agencies require treatments to show not only improvement in disease symptoms and signs, but also improvement in endoscopic disease activity and ideally healing of the intestinal mucosa (EMA 2016). The implementation of these recommendations in clinical practice has the potential to change the disease course and restore the quality of life of patients.

[0013] Current medications are moderately effective, and adverse effects are a problem. Treatment recommendations depend on disease location, disease severity, and disease complications. For example, the first-line treatment in mild to moderate UC is 5-aminosalicylic acid (5-ASA) agents, namely mesalazine, sulfasalazine, olsalazine, and balsalazide. Sulfasalazine (SASP) is the parent 5-ASA agent. For approximately 50% of UC patients who fail 5-ASA therapy, the next line of treatment is corticosteroids and / or immunomodulators (thioguanine). SASP provides moderate benefit in treating mild to moderate active CD (Lim, 2016).

[0014] Biological drugs, such as anti-TNF drugs, are generally indicated for treating patients who fail conventional therapies. The drawbacks and disadvantages of such drugs have been discussed above in this article.

[0015] There is currently no cure for IBD, and the aim of treatment is to relieve symptoms, achieve and maintain remission, and avoid complications as much as possible. Therefore, medications can be anti-inflammatory, immunomodulatory, immunosuppressive, antidiarrheal, etc., to combat the various symptoms of the disease.

[0016] Some 4-alkanoylaminobenzamides have been previously described, with or without indication of specific uses.

[0017] Thus, US Patent Application No. 2011 / 0027179 discloses 4-acetamido-N-[2-(diethylamino)ethyl]-2-methoxybenzamide, N-[2-(diethylamino)ethyl]-2-methoxy-4-(propionamido)benzamide, N-[2-[bis(propan-2-yl)amino]ethyl]-2-ethoxy-4-(propionamido)benzamide, N-[2-(diethylamino)ethyl]-2-ethoxy-4-(propionamido)benzamide, 4-propionamido-2-methoxy-N-(2-morpholin-4-yl-ethyl)-benzamide, 4-propionamido-N-(2-diisopropylamino-ethyl)-2-ethoxy-benzamide, 4-propionamido-N-(2-dibutylamino-ethyl)-2-ethoxy-benzamide, 4-propionamido-2-methoxy-N-(2-piperidin-1-yl-ethyl)-benzamide, and 4-propionamido-2-methoxy-N-(2-pyrrolidin-1-yl-ethyl)-benzamide. However, US Patent Application No. 2011 / 0027179 relates to radiohalobenzamide derivatives and their use in tumor diagnosis and tumor treatment, which means that the disclosed compounds are presumably used as synthetic intermediates.

[0018] US Patent No. 3,177,252 discloses general formula compounds including 4-alkanoylaminobenzamides for treating vomiting and behavioral disorders. However, no specific examples of 4-alkanoylaminobenzamides are mentioned.

[0019] WO 2014 / 064229 discloses the use of 4-acylaminobenzamides to enhance protective immunity elicited by an immunogen. 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-acetamido-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide, and 4-acetamido-N-[2-(diethylamino)ethyl]benzamide are mentioned.

[0020] WO 2005 / 025498 indicates that, when delivered locally, some 4-acylaminobenzamides cause apoptosis of cells (eosinophils), and based on this effect, the use of such compounds for the treatment of acute or chronic respiratory inflammation associated with eosinophil infiltration is disclosed. 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide and N-[2-(diethylamino)ethyl]-4-(valeramido)benzamide are mentioned.

[0021] WO 99 / 63987 discloses 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide (N-acetyl dechlorpromazine) and its use for inhibiting or killing tumors or cancer cells and potentially for use in methods for treating inflammatory disorders.

[0022] Acetcainide (4-acetamido-N-[2-(diethylamino)ethyl]benzamide; CAS No. 32795-44-1) has been used for the treatment or prevention of arrhythmia.

[0023] The compounds 4-acetamido-N-(2-morpholin-4-ylethyl)benzamide and N-(2-morpholin-4-ylethyl)-4-(valeramido)benzamide are commercially available but no specific use has been proposed.

[0024] As noted above herein, some patients suffering from inflammatory diseases do not respond to anti-TNF-α treatment or respond weakly to such treatment, and for such patients, other treatment modalities must be provided. Summary of the Invention

[0026] The main object of the present invention is to provide a new method for treating IBD, the ultimate aim being to modify the disease course. The inventors considered that a more effective treatment of IBD than current treatments might require a drug that affects not only one transcription factor (TF) such as NFκB, but two or more TFs simultaneously. Combinatorial regulation is a powerful mechanism that enables tight control of gene expression by integrating multiple signaling pathways, inducing different TFs required for the initiation of very specific biological responses, which initiation may involve functional synergy or cooperative interaction between two or more different TFs. Without wishing to be bound by any theory, the inventors have found that the compounds of formula (I) are particularly effective in alleviating the symptoms of IBD, and considering that such excellent potency may be based on the multiple effects of the compounds in mammalian cells, namely inhibition of NFκB and NFAT and enhancement of AP-1 activity. Such combinatorial activity may be the cause of the very favorable effects obtained, for example, on the intestinal mucosa, with abnormally high mucosal healing, as observed by the cessation of rectal bleeding, which is a reliable symptom score for assessing the level of mucosal inflammation.

[0027] Accordingly, a first aspect is a compound of formula (I)

[0028]

[0029] or a pharmaceutically acceptable salt or solvate thereof; wherein

[0030] R 1 is selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0031] R 2 is selected from H and C1-C3 alkyl;

[0032] R 3 、R 4 、R 5 and R 6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, bromine, phenyl and benzyl, wherein any alkyl is optionally substituted by one or more fluorines;

[0033] R 7 is selected from hydrogen and C1-C3 alkyl;

[0034] R 8 and R 9 are independently selected from C1-C6 alkyl, or

[0035] R 8 and R 9 together with the nitrogen atom to which they are both attached form a moiety of formula (II)

[0036] ;

[0037] r is 0 or 1;

[0038] R 10 is selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 ;

[0039] Q is selected from CHR 11 , NR 11 and O;

[0040] 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 ;

[0041] R 12 and R 13 are independently selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl;

[0042] when Q is CHR 11 , p is 1, 2 or 3; and

[0043] when Q is selected from NR 11 and O, p is 2 or 3;

[0044] It is used for treating diseases caused by pathological inflammation, provided that the disease is not an acute or chronic respiratory inflammation associated with eosinophil infiltration.

[0045] A further aspect is a compound of formula (I)

[0046]

[0047] or a pharmaceutically acceptable salt or solvate thereof; wherein

[0048] R 1 is selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0049] R 2 is selected from H and C1-C3 alkyl;

[0050] R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, bromine, phenyl and benzyl, wherein any alkyl is optionally substituted by one or more fluorines;

[0051] R 7 is selected from hydrogen and C1-C3 alkyl;

[0052] R 8 and R 9 are independently selected from C1-C6 alkyl, or

[0053] R 8 and R 9 together with the nitrogen atom to which they are both attached form a moiety of formula (II)

[0054] ;

[0055] r is 0 or 1;

[0056] R 10 is selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 ;

[0057] Q is selected from CHR 11 、NR 11 and O;

[0058] 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 ;

[0059] R 12 and R 13 are independently selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl;

[0060] when Q is CHR 11 , p is 1, 2 or 3; and

[0061] when Q is selected from NR 11 and O, p is 2 or 3;

[0062] provided that the compound is not selected from:

[0063] N-[2-(diethylamino)ethyl]-4-(propionylamino)benzamide,

[0064] 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0065] 4-acetamido-N-[2-(diethylamino)ethyl]-2-methoxybenzamide,

[0066] 4-Acetamido-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide,

[0067] N-[2-(Diethylamino)ethyl]-2-methoxy-4-(propionamido)benzamide,

[0068] N-[2-[Bis(prop-2-yl)amino]ethyl]-2-ethoxy-4-(propionamido)benzamide,

[0069] N-[2-(Diethylamino)ethyl]-2-ethoxy-4-(propionamido)benzamide,

[0070] 4-[Acetyl(methyl)amino]-N-[2-(diethylamino)ethyl]benzamide,

[0071] 4-(Butyramido)-N-[2-(diethylamino)ethyl]benzamide,

[0072] N-[2-(Diethylamino)ethyl]-4-(valeramido)benzamide,

[0073] N-[2-(Diethylamino)ethyl]-2-methoxy-4-(4-methylvaleramido)benzamide,

[0074] 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide,

[0075] 4-Propionamido-2-methoxy-N-(2-morpholin-4-yl-ethyl)benzamide,

[0076] 4-Acetamido-N-(2-morpholin-4-yl-ethyl)benzamide,

[0077] N-(2-Morpholin-4-ylethyl)-4-(valeramido)benzamide,

[0078] 4-Propionamido-N-(2-diisopropylamino-ethyl)-2-ethoxy-benzamide,

[0079] 4-Propionamido-N-(2-dibutylamino-ethyl)-2-ethoxy-benzamide,

[0080] 4-Propionamido-2-methoxy-N-(2-piperidin-1-yl-ethyl)-benzamide, and

[0081] 4-Propionamido-2-methoxy-N-(2-pyrrolidin-1-yl-ethyl)benzamide.

[0082] A further aspect is a compound of formula (I)

[0083]

[0084] or a pharmaceutically acceptable salt or solvate thereof; wherein

[0085] R 1 is selected from C1-C6 alkyl and C3-C6 cycloalkyl;

[0086] R 2 is selected from H and C1-C3 alkyl;

[0087] R 3 、R 4 、R 5 and R 6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, bromine, phenyl and benzyl, wherein any alkyl is optionally substituted by one or more fluorines;

[0088] R 7 is selected from hydrogen and C1-C3 alkyl;

[0089] R 8 and R 9 are independently selected from C1-C6 alkyl, or

[0090] R 8 and R 9 together with the nitrogen atom to which they are both attached form a moiety of formula (II)

[0091] ;

[0092] r is 0 or 1;

[0093] R 10 is selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 ;

[0094] Q is selected from CHR 11 、NR 11 and O;

[0095] 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 ;

[0096] R 12 and R 13 are independently selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl;

[0097] When Q is CHR 11When p is 1, 2 or 3; and

[0098] When Q is selected from NR 11 and O, p is 2 or 3;

[0099] It is used in therapy, provided that the compound is not selected from:

[0100] 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0101] 4-Acetamido-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide,

[0102] N-[2-(Diethylamino)ethyl]-4-(valeramido)benzamide, and

[0103] 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide.

[0104] In some embodiments, there is provided a pharmaceutical formulation comprising a compound of formula (I) as defined above herein, or a pharmaceutically acceptable salt or solvate thereof, and optionally a pharmaceutically acceptable excipient;

[0105] Provided that the compound is not selected from:

[0106] 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0107] 4-Acetamido-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide,

[0108] N-[2-(Diethylamino)ethyl]-4-(valeramido)benzamide, and

[0109] 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide.

[0110] An advantageous aspect is a compound of formula (I) as defined herein, which is used for treating a disease in a mammal resulting from pathological inflammation, for which conventional anti-TNF-α therapy (using a TNF-α antagonist) is of no use in the mammal, such as for treating a patient for whom conventional anti-TNF-α therapy has failed or is contraindicated, provided that the disease is not an acute or chronic respiratory inflammation associated with eosinophil infiltration.

[0111] In some embodiments, the disease resulting from pathological inflammation is a disease selected from IBD, psoriasis and RA. In some embodiments, the disease resulting from pathological inflammation is IBD or RA. In some embodiments, the disease resulting from pathological inflammation is IBD.

[0112] In some embodiments, there is provided a compound of formula (I) as defined above herein for treating at least one symptom of IBD, such as at least one symptom selected from diarrhea, rectal bleeding, weight loss, mucosal ulceration, intestinal crypt destruction, and leukocyte infiltration into the intestinal mucosa.

[0113] In some embodiments, there is provided a compound of formula (I) for treating mucosal ulceration, such as that associated with IBD.

[0114] In some embodiments, there is provided a compound of formula (I) for treating refractory damage to the intestinal mucosa, such as in IBD.

[0115] A further aspect is a pharmaceutical composition comprising a compound of formula (I) as defined herein and a further therapeutically active ingredient, and optionally a combination of pharmaceutically acceptable excipients. Such compositions may be particularly useful for treating diseases resulting from pathological inflammation, such as IBD or RA.

[0116] A further aspect is a kit-of-parts comprising a compound of formula (I) as defined above herein and (ii) a combination of further therapeutically active ingredients, wherein components (i) and (ii) are each optionally formulated by admixing with pharmaceutically acceptable excipients. Such kits-of-parts may be particularly useful for treating pathological inflammation, such as IBD or RA.

[0117] A still further aspect is the use of a compound of formula (I) as defined above herein, or a salt or solvate thereof, in the manufacture of a medicament for treating a disease in a mammal resulting from pathological inflammation, for which anti-TNF-α therapy is of no use, provided that the disease is not an acute or chronic respiratory inflammation associated with eosinophil infiltration.

[0118] A further aspect is a method for treating a disease in a mammal resulting from pathological inflammation, for which anti-TNF-α therapy is of no use, provided that the disease is not an acute or chronic respiratory inflammation associated with eosinophil infiltration, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).

[0119] Other features and advantages of the invention will be understood by reference to the following detailed description and examples. DETAILED DESCRIPTION OF THE INVENTION

[0121] Definition

[0122] As used herein, and unless otherwise stated and unless otherwise apparent from the context, the following terms shall each have the definitions set forth below.

[0123] The term "Cn alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group containing n carbon atoms in the chain, i.e., the moiety of the formula C n H 2n+1 .

[0124] The term "Cn-Cm alkyl" refers to a straight-chain or branched-chain alkyl group containing from n to m carbon atoms in the chain, where n and m are both integers and m is greater than n.

[0125] The term "Cn cycloalkyl" refers to a cyclic hydrocarbon group of the formula C n H 2n-1 .

[0126] The term "Cn-Cm cycloalkyl" refers to a cyclic hydrocarbon group containing from n to m carbon atoms in the ring, where n and m are both integers and m is greater than n.

[0127] The term "Cn-Cm alkoxy" refers to the moiety of the formula

[0128]

[0129] where R is a Cn-Cm alkyl. For example, methoxy is a C1 alkoxy.

[0130] The term "Cn-Cm alkylthio" refers to the moiety of the formula

[0131]

[0132] where R is a Cn-Cm alkyl. For example, methylthio is a C1 alkylthio.

[0133] The term "halogen" refers to F, Cl, Br or I; preferably F, Cl or Br.

[0134] The term "hydroxy" refers to the moiety

[0135] .

[0136] The term "phenyl" refers to the group of the formula

[0137]

[0138] The term "benzyl" refers to the group of the formula

[0139] .

[0140] As used herein, "AABZ" means a compound of formula (I) as described herein, unless otherwise specified or obvious from the context. In addition, unless otherwise specified or obvious from the context, the term also includes its pharmaceutically acceptable salts or solvates (including hydrates).

[0141] As used herein, in the context of a numerical value or range, "about" means ±20% of the recited or claimed numerical value or range.

[0142] As used herein, the expression "acute or chronic respiratory inflammation associated with eosinophil infiltration" refers to diseases disclosed, for example, in WO 2005 / 025498, such as pulmonary inflammation.

[0143] As used herein, "administration", "administering", etc. mean the giving, dispensing or imposing of an agent, drug or medicine to a subject (such as a mammalian subject, preferably a human) to relieve or cure a pathological condition. Oral administration is one way of administering the present compound to a subject.

[0144] As used herein, the "amount" or "dose" of a compound (such as AABZ) measured in milligrams refers to the number of milligrams of the compound present in a 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 the form of a salt, such as a hydrochloride salt, the weight of the salt form required to provide a dose of 5.0 mg of the free base compound will be greater than 5.0 mg due to the presence of the additional acid.

[0145] As used herein, "anti-TNF-α therapy" refers to a therapy aimed at reducing TNF-α activity and / or TNF-α production, and is typically used for therapeutic purposes, such as for treating inflammatory disorders.

[0146] As used herein, "AP-1" means activator protein-1.

[0147] As used herein, "combination" means a collection of compounds for use in therapy by simultaneous or separate (such as sequential or concomitant) administration. Simultaneous administration refers to the administration of an admixture (whether a true mixture, suspension, emulsion or other physical combination) of two active ingredients (such as AABZ and a further therapeutic active agent). In this case, the combination can be an admixture of AABZ and a further reagent; or AABZ and the further reagent can be provided in separate containers and combined immediately prior to administration. Separate administration can be sequential (i.e., consecutive) or concomitant (i.e., occurring simultaneously).

[0148] Separate administration refers to the concomitant or sequential administration of AABZ and a further therapeutic active agent as separate formulations, but simultaneously or close enough in time together for an activity to be observed that is at least additive relative to either AABZ or the further therapeutic active agent alone.

[0149] As used herein, "CD" means Crohn's disease.

[0150] As used herein, "Cpd A" means 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide (N-acetyl-dechlorpromazine) hydrochloride.

[0151] As used herein, "disease caused by pathological inflammation" refers to diseases such as inflammatory bowel disease, rheumatic disease, autoimmune disease, and further, such diseases in which inflammation plays a major role, such as Alzheimer's disease, atherosclerosis, and stroke. More particularly, as used herein, "disease 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 particularly refers to diseases selected from ulcerative colitis, Crohn's disease, and rheumatoid arthritis.

[0152] As used herein, "DSS" means dextran sodium sulfate.

[0153] As used herein, when referring to the amount of a therapeutic agent such as AABZ, "effective" refers to such an amount that, when used in the manner of the present invention, is sufficient to produce the desired therapeutic response commensurate with a reasonable benefit / risk ratio without undue adverse side effects (such as toxicity, irritation, or allergic response).

[0154] As used herein, "excipient" refers to a substance formulated together with the active ingredient of a medicament and included for purposes such as long-term stabilization, providing volume to a solid preparation, acting as a carrier and / or diluent, imparting therapeutic enhancement to the active ingredient in the final dosage form, such as by promoting absorption, reducing viscosity, or increasing solubility. Excipients can also be useful during the manufacturing process, such as by promoting powder flowability or providing non-stick properties. Examples of excipients are anti-adhesives, binders, coatings, pigments, disintegrants, flavorings, glidants, lubricants, preservatives, adsorbents, sweeteners, and vehicles (carriers).

[0155] As used herein, "IκB" means inhibitor of κB.

[0156] As used herein, "inflammatory bowel disease" or "IBD" refers to intestinal diseases associated with inflammation and / or ulceration, and includes, for example, Crohn's disease and ulcerative colitis.

[0157] As used herein, "inhibition" of disease progression or disease complications in a subject means preventing or reducing disease progression and / or disease complications in the subject.

[0158] As used herein, "MH" means mucosal healing.

[0159] As used herein, "mucosal healing" refers to, for example, the alleviation of mucosal ulcers of the intestinal mucosa. Healing can be complete or partial, and can be permanent or not permanent, for example, over a period of weeks, months, or years. Mucosal healing can be observed by the alleviation of symptoms such as diarrhea, rectal bleeding, and pain. Mucosal healing can also be determined by endoscopy (colonoscopy).

[0160] As used herein, "NFAT" means nuclear factor of activated T cells.

[0161] As used herein, "NFκB" means nuclear factor κB.

[0162] As used herein, "patient" or "subject" refers to mammalian patients or subjects selected from animals and humans.

[0163] As used herein, "pharmaceutically acceptable" refers to a substance that is suitable for use in humans and / or animals, is generally safe and non-toxic under normal use, i.e., has no excessive adverse side effects (such as toxicity, irritation, and allergic responses), and is commensurate with a reasonable benefit / risk ratio.

[0164] As used herein, "SASP" means sulfasalazine.

[0165] As used herein, "its salts" are salts of the present compounds modified by preparing the salts of the compounds or the base salts. In this regard, the term "pharmaceutically acceptable salts" refers to relatively non-toxic, inorganic and organic acid or base addition salts of the compounds of the present invention. For example, one means of preparing such salts is by treating the compounds of the present invention with inorganic acids.

[0166] As used herein, "solvate" means the physical association of a compound (such as a compound of formula (I)) with one or more solvent molecules, for example, through hydrogen bonding. "Solvate" encompasses both the solution phase and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are generally known to those of ordinary skill in the art.

[0167] As used herein, "a subject suffering from a disease caused by pathological inflammation" means a subject clinically diagnosed as suffering from such a disease.

[0168] 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 a subject can feel or observe.

[0169] As used herein, "TF" means a transcription factor, which is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA.

[0170] As used herein, "TNF" means tumor necrosis factor.

[0171] As used herein, "TNF-α" means tumor necrosis factor α.

[0172] As used herein, "treatment" encompasses, for example, inducing inhibition, regression, or stasis of a disease or disorder such as IBD, or alleviating, mitigating, suppressing, or inhibiting the symptoms of a disease or disorder, reducing the severity of the symptoms of a disease or disorder, eliminating or substantially eliminating or improving the symptoms of a disease or disorder.

[0173] As used herein, "UC" means ulcerative colitis.

[0174] Compound of formula (I)

[0175] In the compounds of formula (I) as defined herein, R 1 is selected from C1-C6 alkyl and C3-C6 cycloalkyl. In some embodiments, R 1 is selected from C1-C5 alkyl and C3-C5 cycloalkyl, such as C1-C4 alkyl and C3-C4 cycloalkyl, or C1-C3 alkyl and C3 cycloalkyl. In some embodiments, R 1 is selected from C1-C6 alkyl, such as C1-C5 alkyl or C1-C4 alkyl or C1-C3 alkyl or C1-C2 alkyl. In some embodiments, R 1 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; such as 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, R 1 is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and cyclobutyl, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. In some embodiments, R 1 is selected from methyl, ethyl, n-propyl, isopropyl, and cyclopropyl, such as methyl, ethyl, n-propyl, and isopropyl. In some embodiments, R 1Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, and neopentyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl; or methyl, ethyl, n-propyl, and isopropyl; for example, methyl, ethyl, and isopropyl. In some embodiments, R 1 is methyl or ethyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is isopropyl.

[0176] R 2 is selected from hydrogen and C1-C3 alkyl. In some embodiments, R 2 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl; for example, hydrogen, methyl, and ethyl, or hydrogen and methyl. In some embodiments, R 2 is hydrogen.

[0177] R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine, bromine, phenyl, and benzyl, wherein any alkyl is optionally substituted by one or more fluorines. In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and fluorine, chlorine, bromine, wherein any alkyl is optionally substituted by one or more fluorines. In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, and fluorine, chlorine, bromine, wherein any alkyl is optionally substituted by one or more fluorines. In still other embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, C1-C3 alkyl, and fluorine, chlorine, bromine, wherein any alkyl is optionally substituted by one or more fluorines. In still other embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, C1-C3 alkoxy, and fluorine, chlorine, bromine, wherein any alkyl is optionally substituted by one or more fluorines. In still other embodiments, R 3 , R4 , R 5 and R 6 are independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkylthio, and fluorine, chlorine, bromine, wherein any alkyl is optionally substituted by one or more fluorines. In a further embodiment, R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen and fluorine, chlorine, bromine.

[0178] When any one of R 3 , R 4 , R 5 and R 6 is selected from C1-C3 alkyl, it can be selected from methyl and ethyl, for example; in particular, it can be methyl.

[0179] When any one of R 3 , R 4 , R 5 and R 6 is selected from C1-C3 alkoxy, it can be selected from methoxy and ethoxy, for example; in particular, it can be methoxy. In some embodiments, R 5 and R 6 are not C1-C3 alkoxy.

[0180] When any one of R 3 , R 4 , R 5 and R 6 is selected from C1-C3 alkylthio, it can be selected from methylthio and ethylthio, for example; in particular, it can be methylthio.

[0181] When any one of R 3 , R 4 , R 5 and R 6 is a halogen selected from fluorine, chlorine and bromine, the halogen is selected from chlorine and bromine, in particular, it is chlorine. In some further embodiments, when any one of R 3 , R 4 , R 5 and R 6 is a halogen selected from fluorine, chlorine and bromine, the halogen is more selected from fluorine and chlorine.

[0182] In some embodiments, R 3 , R 4 , R 5 and R 6Independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, fluorine, chlorine, bromine, trifluoromethyl, phenyl, and benzyl, such as hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, fluorine, chlorine, bromine, and trifluoromethyl; or hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine, and trifluoromethyl; such as hydrogen, methyl, methoxy, fluorine, chlorine, bromine, and trifluoromethyl; or hydrogen, methyl, methoxy, chlorine, and trifluoromethyl, or hydrogen, methyl, methoxy, and chlorine; or hydrogen, methoxy, and chlorine; or hydrogen, methyl, and chlorine; such as hydrogen and chlorine.

[0183] In some of the above embodiments, R 3 、R 4 、R 5 and R 6 At least one of them, more preferably at least two, is hydrogen. In some of the above embodiments, R 3 、R 4 、R 5 and R 6 Two of them are hydrogen. In some of the above embodiments, R 3 、R 4 、R 5 and R 6 Three of them are hydrogen. In some of the above embodiments, R 3 、R 4 、R 5 and R 6 Each of them is hydrogen. In some of the above embodiments, R 3 、R 4 、R 5 and R 6 At least one of them is different from hydrogen. In some of the above embodiments, R 3 、R 4 、R 5 and R 6 One of them is different from hydrogen, and the other three are hydrogen; for example, R 3 、R 4 、R 5 and R 6 One of them (for example, R 3 ) is a halogen, such as chlorine; and the other three are hydrogen. In some of the above embodiments, R 3 is different from hydrogen, and R 4 、R 5 and R 6 Each of them is hydrogen. In some embodiments, R 5 is different from hydrogen, and R 3 、R 4 and R 6 Each of them is hydrogen. In some embodiments, R 3 、R 4 、R5 and R 6 One of them (e.g., R 3 ) is fluorine, chlorine or bromine, especially chlorine; and the other three are hydrogen. In some embodiments, R 3 is hydrogen or a halogen, such as hydrogen or chlorine; and R 4 , R 5 and R 6 are hydrogen. In some embodiments, R 4 and R 6 are hydrogen; for example, R 4 and R 6 are hydrogen, and at least one of R 3 and R 5 is different from hydrogen, such as both R 3 and R 5 are different from hydrogen. In some embodiments, R 4 and R 5 are hydrogen; for example, R 4 and R 5 are hydrogen, and at least one of R 3 and R 6 is different from hydrogen, such as both R 3 and R 6 are different from hydrogen. In some embodiments, R 3 and R 4 are hydrogen; for example, R 3 and R 4 are hydrogen, and at least one of R 5 and R 6 is different from hydrogen, such as both R 5 and R 6 are different from hydrogen. In some of the above embodiments, R 5 and R 6 are not methoxy or ethoxy.

[0184] R 7 moieties are selected from hydrogen and C1-C3 alkyl. In some embodiments, R 7 is selected from hydrogen, methyl, ethyl, propyl and isopropyl; for example, hydrogen, methyl, ethyl and propyl. In some embodiments, R 7 is selected from hydrogen, methyl and ethyl. In some embodiments, R 7 is selected from hydrogen and methyl. In some embodiments, R 7 is hydrogen.

[0185] R 8 and R 9 moieties are independently selected from C1-C6 alkyl, or R 8 and R 9 , 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 R 9 are independently selected from C1-C6 alkyl. When R 8 and R 9 are selected from C1-C6 alkyl, R 8 and R 9 may for example be selected from C1-C5 alkyl; or C1-C4 alkyl; or C1-C3 alkyl; for example methyl and ethyl. In some embodiments, when R 8 and R 9 are selected from C1-C6 alkyl, R 8 and R 9 are both ethyl.

[0186] In some embodiments, R 8 and R 9 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) may be represented by formula (Ia)

[0187]

[0188] wherein R 1 -R 7 、R 10 、Q, p and r are as defined herein.

[0189] In the moiety of formula (II), r is 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1.

[0190] The R 10 moiety is selected from C1-C3 alkyl and C3-C4 cycloalkyl; said alkyl and cycloalkyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 In some embodiments, R 10 is selected from methyl, ethyl and cyclopropyl, said methyl, ethyl and cyclopropyl being 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 C1-C3 alkyl and C3-C4 cycloalkyl substituted by halogen, for example fluorine. In some embodiments, R 10 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, for example methyl, ethyl and cyclopropyl, especially methyl.

[0191] The Q moiety is selected from CHR 11 、NR 11 and O. In some embodiments, Q is selected from CHR 11and 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.

[0192] R 11 moieties are selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; said alkyl and cycloalkyl are optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 substituents. In some embodiments, R 11 is selected from hydrogen, methyl, ethyl, and cyclopropyl, said methyl, ethyl, and cyclopropyl being optionally substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 substituents. In some embodiments, R 11 is selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl, said alkyl and cycloalkyl being optionally substituted by hydroxy, halogen, or cyano, such as halogen, such as fluorine. In some embodiments, R 11 is selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl, such as hydrogen, methyl, ethyl, and cyclopropyl, or hydrogen, methyl, and ethyl; particularly hydrogen and methyl. In some embodiments, R 11 is hydrogen. In some other embodiments, R 11 is as defined above herein but different from hydrogen.

[0193] When R 11 is a C1-C3 alkyl or C3-C4 cycloalkyl substituted by hydroxy, halogen, cyano, COOR 12 or NHR 13 substituents, the number of such substituents can be one or more, such as 1-3 or 1-2 or 1.

[0194] R 12 moieties are selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl. In some embodiments, R 12 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl, such as hydrogen, methyl, ethyl, n-propyl, and isopropyl; or hydrogen, methyl, and ethyl, such as hydrogen and methyl. In some embodiments, R 12 is selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl. In some embodiments, R 12 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, such as methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; methyl, ethyl, n-propyl, and isopropyl; or methyl and ethyl, such as R 12 is methyl. In some other embodiments, R 12 is hydrogen.

[0195] R 13 is selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl. In some embodiments, R 13 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl, such as hydrogen, methyl, ethyl, n-propyl, and isopropyl; or hydrogen, methyl, and ethyl, such as hydrogen and methyl. In some embodiments, R 13 is selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl. In some embodiments, R 13 is selected from C1-C3 alkyl and C3-C4 cycloalkyl, such as methyl, ethyl, n-propyl, isopropyl, and cyclopropyl; methyl, ethyl, n-propyl, and isopropyl; or methyl and ethyl, such as R 13 is methyl. In some other embodiments, R 13 is hydrogen.

[0196] In the moiety of formula (II), when Q is CHR 11 , 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.

[0197] In some embodiments, R 1 is C1-C6 alkyl; R 2 is hydrogen; R 7 is hydrogen; R 8 and R 9 are independently selected from C1-C6 alkyl, or R 8 and R 9 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 is selected from hydrogen and C1-C3 alkyl. In some embodiments, R 1 is C1-C6 alkyl; R 2 is hydrogen; R 7 is hydrogen; and R 8 and R 9 are independently selected from C1-C6 alkyl. In some of these embodiments, R 1 , R 8 and R 9 are independently selected from C1-C3 alkyl.

[0198] In some further embodiments, R 1 is a C1-C3 alkyl group; R 2 , R 4 , R 5 and R 7 are hydrogen; and R 8 and R 9 are independently selected from C1-C3 alkyl groups. In some of these embodiments, R 1 is selected from methyl, ethyl, and isopropyl; and R 8 and R 9 are the same or different and are selected from methyl, ethyl, and n-propyl. In some further embodiments, R 1 is selected from methyl, ethyl, and isopropyl; R 2 , R 4 , R 5 , R 6 and R 7 are hydrogen; and R 8 and R 9 are the same or different and are selected from methyl, ethyl, and n-propyl.

[0199] In some embodiments, R 2 is selected from hydrogen and methyl; R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen and chlorine; R 7 is hydrogen; and R 8 and R 9 are the same or different and are selected from methyl, ethyl, and n-propyl.

[0200] In some embodiments, R 1 is selected from methyl, ethyl, and isopropyl; R 2 is hydrogen or methyl; R 3 is chlorine or hydrogen; R 4 , R 5 , R 6 and R 7 are hydrogen; and R 8 and R 9 are the same or different and are selected from methyl, ethyl, and n-propyl. In some embodiments, R 1 is selected from methyl, ethyl, and isopropyl; R 2 is hydrogen or methyl; R 3 is chlorine or hydrogen; R 4 , R 5 , R 6 and R 7 are hydrogen; and R 8 and R 9 are ethyl. In some embodiments, R1 Selected from methyl, ethyl and isopropyl; R 2 is hydrogen; R 3 is chlorine or hydrogen; R 4 、R 5 、R 6 and R 7 are hydrogen; and R 8 and R 9 are the same or different and are selected from methyl, ethyl and n-propyl. In some embodiments, R 1 is selected from methyl, ethyl and isopropyl; R 2 is hydrogen; R 3 is chlorine; R 4 、R 5 、R 6 and R 7 are hydrogen; and R 8 and R 9 are the same or different and are selected from methyl, ethyl and n-propyl.

[0201] In some embodiments, the compounds of formula (I) as used herein are selected from:

[0202] 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0203] 4-Propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0204] 4-Isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0205] 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide,

[0206] 4-Propionamido-N-[2-(diethylamino)ethyl]benzamide, and

[0207] 4-Isobutyramido-N-[2-(diethylamino)ethyl]benzamide.

[0208] In some embodiments, the compounds of formula (I) as used herein are selected from:

[0209] 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0210] 4-Propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0211] 4-Isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, and

[0212] 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide.

[0213] In some embodiments, the compounds of formula (I) as used herein are selected from:

[0214] 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide,

[0215] 4-Propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, and

[0216] 4-Isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

[0217] In some embodiments, the compound of formula (I) as used herein is 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

[0218] In some further embodiments, the compounds of formula (I) for use in therapy are selected from:

[0219] N-[2-(Diethylamino)ethyl]-4-(propionamido)benzamide,

[0220] 4-Propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, and

[0221] 4-Isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

[0222] In some embodiments, the compounds of formula (I) as disclosed herein are selected from:

[0223] 4-Propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, and

[0224] 4-Isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide.

[0225] 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-isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide. In some embodiments, AABZ is the hydrochloride salt of the compound of formula (I), such as 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride.

[0226] The structural formulas of some of the compounds mentioned herein are shown in Table 1.

[0227] Table 1

[0228] 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Propionamido-N-[2-(diethylamino)ethyl]benzamide #timg# 4-Isobutyramido-N-[2-(diethylamino)ethyl]benzamide #timg#

[0229] Pharmaceutically acceptable salts

[0230] AABZ can be provided as a pharmaceutically acceptable salt of the compound of formula (I), such as an acid addition salt. When preparing acid or base addition salts, such acids or bases that form suitably therapeutically acceptable salts are preferably used. 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, 2-hydroxyethanesulfonic acid, halobenzenesulfonic 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 those derived from organic bases such as alcoholates, alkylamides, alkylamines and arylamines, etc. Examples of bases that can be used to prepare the salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, etc. In some embodiments, the compound of formula (I) is provided as a hydrochloride.

[0231] For example, relevant teachings related to salt formulations and their preparation methods as used herein are described in U.S. Patent No. 3,177,252, and such teachings are hereby incorporated by reference into the present application.

[0232] Pharmaceutically acceptable solvates

[0233] According to the present invention, any pharmaceutically acceptable solvate is considered possible. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates and isopropanolates. In some embodiments, the solvate is a hydrate.

[0234] Process for preparing the compound of formula (I)

[0235] The compound of formula (I) can be prepared by those of ordinary skill in the art, for example, by following the general procedures of U.S. Patent Application No. 2011 / 0027179 and WO 2005 / 025498.

[0236] For example, the compound of formula (I) can be prepared by a method comprising two consecutive nucleophilic substitution reactions as shown by the following reaction scheme:

[0237]

[0238] In the above reaction scheme, wherein R aCompound 1, which is, for example, a C1-C3 alkyl, reacts with Compound 2 in which L is a suitable leaving group such as Cl to obtain Compound 3. Subsequently, Compound 3 is reacted with a secondary amine 4 in the presence of ammonium chloride as a catalyst for the reaction to obtain a compound of formula (I) as defined herein. The compound of formula (I) can optionally be converted into a suitable pharmaceutically acceptable salt or solvate, such as a hydrohalide salt.

[0239] Use of the compound of formula (I)

[0240] The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (collectively hereinafter referred to as AABZ in this text) can be used for treating diseases resulting from pathological inflammation, provided that the disease is not an acute or chronic respiratory inflammation associated with eosinophil infiltration.

[0241] In some embodiments, the disease resulting from pathological inflammation is as defined herein, but is not a respiratory inflammation.

[0242] In some embodiments, the disease resulting from pathological inflammation is selected from IBD, psoriasis, and RA.

[0243] In some embodiments, the disease is an inflammatory disease, such as IBD. In some embodiments, the disease is RA. In some embodiments, IBD is UC. In some embodiments, IBD is CD. In some embodiments, the disease is IBD or RA. In some embodiments, the disease is UC, CD, or RA. In some embodiments, the disease is UC or CD.

[0244] Very advantageously, AABZ can be used for treating a disease resulting from pathological inflammation in a patient for whom anti-TNF-α treatment is not considered useful, for example because the patient cannot provide a sufficient response to such treatment, or because such treatment is contraindicated for some other reason. Accordingly, in some embodiments, AABZ is provided for treating a patient for whom anti-TNF-α treatment has failed or is contraindicated. For example, the patient may be a patient suffering from IBD, and for whom anti-TNF-α treatment (i.e., treatment using a TNF-α antagonist) cannot provide sufficient relief of IBD symptoms, or cannot be administered to the patient by such means for some other reason.

[0245] The symptoms vary according to the severity of the inflammation and can range from mild to severe.

[0246] The signs and symptoms common to both CD and UC include diarrhea, fever and fatigue, abdominal pain and cramps, blood in the stool, and loss of appetite. The symptoms of RA include joint pain, joint tenderness, joint swelling, joint redness, and joint stiffness.

[0247] One particularly advantageous embodiment is AABZ for treating patients suffering from IBD such as UC or CD, for whom anti-TNF-α therapy has failed or is contraindicated.

[0248] A further advantageous aspect is AABZ for treating mucosal ulcers, such as intestinal mucosal ulcers, such as those associated with IBD.

[0249] The advantageous properties of AABZ are associated with its low affinity for the dopamine D2 receptor, which substantially reduces the risk of developing adverse movement disorders such as acute extrapyramidal disorders and tardive dyskinesia. Accordingly, one aspect is AABZ which can be used for the long-term treatment of chronic diseases without the negative effects of dopamine D2 receptor blockade.

[0250] In some embodiments, AABZ is a pharmaceutically acceptable salt of a compound of formula (I), particularly the hydrochloride salt.

[0251] In some embodiments, AABZ is administered via oral administration. In some embodiments, AABZ is administered in preferably solid unit dosage forms, more preferably tablets.

[0252] In some embodiments, AABZ is administered daily.

[0253] In some embodiments, the dosage of AABZ is 0.1 - 25 mg / kg (mg of drug / kg of subject body weight) / day (any weight value is based on the non-salt, non-solvate form). In other embodiments, the dosage of AABZ is 0.3 - 10 mg / kg / day.

[0254] In some embodiments, the dosage of AABZ is 5.0 - 2000 mg / day or 10 - 1000 mg / day.

[0255] In some embodiments, AABZ is administered once daily. In other embodiments, AABZ is administered twice daily. In other embodiments, AABZ is administered three times daily. In still other embodiments, AABZ is administered four times daily.

[0256] In some embodiments, the administration of AABZ continues for at least 2 weeks. In other embodiments, the administration of AABZ continues for 3 months or longer. In still other embodiments, the administration of AABZ continues for 12 months or longer.

[0257] Subject to be treated

[0258] Subjects treated according to the invention are mammals, including humans and non-human mammals (animals). Examples of non-human mammals are primates, domesticated animals such as farm animals, e.g., cows, 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.

[0259] Pharmaceutical composition

[0260] One aspect is a pharmaceutical composition comprising an amount of AABZ, and optionally (but preferably) at least one pharmaceutically acceptable excipient such as a carrier. In some embodiments, the pharmaceutical composition is for treating a subject having a disease resulting from a pathological inflammation, such as IBD, psoriasis or RA.

[0261] AABZ can be administered in admixture with a suitable pharmaceutical diluent, extender or carrier, or any other pharmaceutically acceptable excipient, which is appropriately selected in view of the intended form of administration and in accordance with conventional pharmaceutical practice. The preferred dosage unit will be in a form suitable for oral administration. AABZ can be administered alone, but is generally mixed with a pharmaceutically acceptable carrier and administered in the form of 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 prepared to be easy to swallow or chew; other solid forms include granules and bulk powders.

[0262] Tablets can contain suitable binders, lubricants, disintegrants, colorants, flavorants, flow-inducing agents and melting agents. For example, for oral administration in the form of dosage units of tablets or capsules, AABZ can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier 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 β-lactose, corn starch, natural and synthetic gums (such as gum arabic, tragacanth or sodium alginate), polyvinylpyrrolidone, carboxymethylcellulose, polyethylene glycol, waxes, etc. Lubricants used in 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, croscarmellose sodium, sodium starch glycolate, etc.

[0263] The amount of AABZ in a dosage unit of the pharmaceutical formulation (such as a tablet or a capsule) can be, for example, 5 - 500 mg (any amount is based on the compound of formula (I) in non - salt and non - solvated form). In some 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.

[0264] In some embodiments, the total amount of AABZ is from 0.1% to 95% by weight of the pharmaceutical formulation, for example, from 0.5% to 50% by weight, or from 1% to 20% by weight, the remainder comprising, for example, a carrier and any other excipients.

[0265] In some embodiments, the pharmaceutical composition comprises 4 - acetamido - 3 - chloro - N - [2 - (diethylamino)ethyl]benzamide or a pharmaceutically acceptable salt thereof such as the hydrochloride.

[0266] Combined use of AABZ and further therapeutically active ingredients

[0267] One aspect of the present invention is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof (AABZ), for use in combination with at least one further therapeutically active ingredient for the treatment of a disease in a mammal that is caused by pathological inflammation for which TNF - α inhibition is not useful, provided that the disease is not an acute or chronic respiratory inflammation associated with eosinophil infiltration.

[0268] In some embodiments, the treatment comprises administering to a subject (a mammalian patient, such as a human patient) an amount of AABZ and a further therapeutically active ingredient, wherein the amounts, when taken together, are effective to treat the subject. In some embodiments, the total amounts of AABZ and the further therapeutically active ingredient produce an overall better effect, i.e., a synergistic effect, when administered together to treat the subject compared to the simple sum of the effects produced when either component is administered alone in the same total amount.

[0269] The further therapeutically active ingredient can be selected from, for example, non - steroidal anti - inflammatory drugs (NSAIDs), corticosteroids, cytotoxic drugs, immunosuppressive drugs, and antibodies.

[0270] In some embodiments, the treatment comprises administering AABZ to a subject (a mammalian patient, such as a human patient) as an adjunctive therapy or in combination with a further therapeutically active ingredient in treating a subject having IBD (such as UC or CD) or, for example, RA. Preferably, in patients with mild to moderate to severe disease activity, the treatment provides induction and maintenance of clinical remission. In some embodiments, the treatment is contemplated for patients in remission in order to prevent disease recurrence.

[0271] In some embodiments, the further therapeutically active ingredient is administered via oral administration. In still other embodiments, the further therapeutically active ingredient is administered via rectal administration.

[0272] In some embodiments, the further therapeutically active ingredient is administered once daily. In other embodiments, the further therapeutically active ingredient is administered twice daily. In other embodiments, the further therapeutically active ingredient is administered three times daily. In still other embodiments, the further therapeutically active ingredient is administered four times daily.

[0273] When taken together, the amount of AABZ and the amount of the further therapeutically active ingredient are preferably effective in alleviating the symptoms of IBD or RA in the subject.

[0274] In some embodiments, the administration of the further therapeutically active ingredient is substantially prior to the administration of AABZ, i.e., the subject is receiving therapy by administering the further therapeutically active ingredient prior to initiating therapy with AABZ.

[0275] In some embodiments, the subject is receiving therapy by administering the further therapeutically active ingredient for at least 6 months prior to initiating therapy with AABZ. In some embodiments, the subject is receiving therapy by administering the further therapeutically active ingredient for at least 12 months prior to initiating therapy with AABZ. In some embodiments, the subject is receiving therapy by administering the further therapeutically active ingredient for at least 24 months prior to initiating therapy with AABZ.

[0276] In some embodiments, the administration of AABZ and the further therapeutically active ingredient continues for at least 2 weeks. In other embodiments, the administration of AABZ and the further therapeutically active ingredient continues for 3 months or longer. In still other embodiments, the administration of AABZ and the further therapeutically active ingredient continues for 12 months or longer.

[0277] In some embodiments, AABZ and a further therapeutically active ingredient are administered in combination with each other (simultaneously, or separately and concomitantly or sequentially), wherein the molar ratio of AABZ to the further therapeutic agent ranges from 1:100 to 100:1, 1:50 to 50:1, 1:20 to 20:1, 1:10 to 10:1, 1:5 to 5:1 or 1:2 to 2:1, for example about 1:1.

[0278] In some embodiments, 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide or a pharmaceutically acceptable salt thereof such as the hydrochloride salt and a further therapeutic component are administered in combination with each other.

[0279] A further aspect is AABZ for use as an adjunctive therapy or in combination with a further therapeutically active ingredient in the treatment of a subject suffering from a disease as mentioned herein such as IBD or RA.

[0280] One aspect is a kit of parts comprising a combination of AABZ and a further therapeutically active ingredient, wherein each of the components AABZ and the further therapeutically active ingredient is optionally formulated in admixture with a pharmaceutically acceptable excipient such as a carrier.

[0281] In some embodiments, a kit of parts is provided, which comprises: a) a first pharmaceutical composition comprising an amount of AABZ and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising an amount of a further therapeutically active ingredient and a pharmaceutically acceptable carrier; and c) instructions for the combined use of the first pharmaceutical composition and the second pharmaceutical composition; for example for the treatment of IBD or an autoimmune disease such as RA.

[0282] One aspect is a pharmaceutical composition comprising an amount of AABZ, an amount of a further therapeutically active ingredient, and optionally at least one pharmaceutically acceptable excipient such as a carrier. In some embodiments, the pharmaceutical composition is for the treatment of a subject suffering from IBD or an autoimmune disorder such as RA.

[0283] Generally, a suitable pharmaceutical composition is a pharmaceutical composition as described above herein in association with a pharmaceutical formulation of AABZ, but in addition to AABZ, the composition further contains a further therapeutically active ingredient.

[0284] In some embodiments, the molar ratio of AABZ to the further therapeutically active agent in the pharmaceutical composition ranges from 1:100 to 100:1, 1:50 to 50:1, 1:20 to 20:1, 1:10 to 10:1, 1:5 to 5:1 or 1:2 to 2:1, for example it can be about 1:1.

[0285] In some embodiments, the total amount of AABZ and further therapeutically active ingredients is from 0.1% to 95% by weight of the preparation, for example, from 0.5% to 50% by weight, or from 1% to 20% by weight, the remainder comprising, for example, a carrier and any other excipients.

[0286] In some embodiments, the pharmaceutical composition comprises AABZ as disclosed herein, such as 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, or a pharmaceutically acceptable salt thereof such as the hydrochloride, and a further therapeutically active ingredient, and optionally a pharmaceutically acceptable excipient.

[0287] Specific examples of techniques, pharmaceutically acceptable carriers, and excipients that can be used to formulate the oral dosage forms of the present invention are described, for example, in EP 1 720 531 B1.General techniques and compositions for preparing dosage forms useful in the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & 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 Volume 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 Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Volume 61 (Alain Rolland, ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Volume 40 (Gilbert S. Banker, Christopher T. Rhodes, eds.).These references are hereby incorporated by reference in their entirety into this application.

[0288] The following examples are expected to illustrate the invention without limiting its scope. Example

[0289] Intermediate 1

[0290] Ethyl 4-acetamido-3-chlorobenzoate

[0291] 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 give 2.0 g of the title product.

[0292] Example 1

[0293] 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride

[0294] 1.5 g of ethyl 4-acetamido-3-chlorobenzoate (1.5 g, 6.2 mmol) together with a catalytic amount of ammonium chloride were dissolved in 15 mL of N,N-diethylethylenediamine. The reaction mixture was refluxed for 3 hours. Dichloromethane was added and the mixture was washed 4 times with water to remove the excess diamine. Drying and evaporation of the solvent gave the free base of the title compound. The residue was dissolved in ethanol-ether and acidified with ethanolic HCl. The precipitated solid was collected to give the title compound (1.1 g, 3.1 mmol, 50% yield).

[0295] 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).

[0296] Example 2

[0297] 4-Propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride

[0298] 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 h. The volatiles were then removed using a rotary evaporator. Water (5 mL) was added and evaporated. The residue was lyophilized from water and the title compound was obtained (0.6 g, 100% yield, HPLC purity 98%).

[0299] 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).

[0300] Example 3

[0301] 4-Isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride

[0302] The compound 4-isobutyrylamino-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride was obtained in substantially the same manner by using isobutyric anhydride instead of propionic anhydride. The purity according to HPLC was 99%.

[0303] 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 (hept, J = 6.8 Hz, 1H), 1.36 (t, J = 7.3 Hz, 6H), 1.24 (d, J = 6.9 Hz, 6H).

[0304] Example 4

[0305] 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide hydrochloride

[0306] A suspension of 4-amino-N-[2-(diethylamino)ethyl]benzamide hydrochloride (2.5 g, 9.1 mmol) in 20 mL of anhydrous pyridine was stirred. 10 mL of acetic anhydride was added to the suspension. The reaction was slightly exothermic. After 1 hour, the precipitate was filtered off, washed with ethyl acetate and dried to afford the title compound (2.83 g, 9.0 mmol, 99% yield). The purity according to NMR was 98%.

[0307] 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).

[0308] Biological assay

[0309] UC is an inflammatory disease characterized by 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 pro-inflammatory mediators such as TNF-α. Lipopolysaccharide (LPS) is a potent inducer of the inflammatory response. During LPS stimulation, NF-κB signaling is activated to regulate the transcription of numerous genes involved in immunity and inflammation to produce pro-inflammatory cytokines such as TNF-α. The inhibition of LPS-induced TNF-α production in RAW264.7 macrophages treated with AABZ was investigated by assessing the production of TNF-α.

[0310] Both dextran sulfate sodium (DSS)- and trinitrobenzenesulfonic acid (TNBS)-induced colitis are well-established animal models of mucosal inflammation that have been used in the study of the pathogenesis of IBD and preclinical studies of new therapies for over 20 years. The DSS-induced colitis model has several advantages when compared to other animal models of colitis (Perse 2012) and was therefore selected for the analysis of treatment effects.

[0311] Example 5

[0312] Inhibition of LPS-induced TNF-α production in macrophages treated with AABZ

[0313] The RAW264.7 macrophage cell line was maintained in DMEM supplemented with 5% FBS in a humidified air environment of 5% CO2 at 37°C. The RAW264.7 cells were seeded in 96-well plates at a density of 1×105 / ml and a volume of 200 μl / well. The cells were incubated in medium supplemented with 10% FBS for 24 hours and then pre-incubated for 2 hours with or without the indicated concentrations of the test substance before adding LPS (1 μg / ml). Subsequently, the supernatants were harvested at various time points and the production of the pro-inflammatory cytokine TNF-α in the medium was determined using a commercially available enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's protocol.

[0314] The effect of some AABZs of the present invention at 1 mM on LPS-induced TNF production in RAW264.7 murine macrophages is shown in Table 2.

[0315] Table 2. Effect of AABZ at 1 mM on LPS-induced TNF production in RAW264.7 murine macrophages

[0316] Compound % Inhibition of TNF production LPS-treated control 0 4-Acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride * 45 4-Propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride 50 4-Isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride 63 4-Acetamido-N-[2-(diethylamino)ethyl]benzamide hydrochloride 56

[0317] * Cpd A

[0318] It was observed that compared with the LPS-treated control group, different concentrations (0.3, 1.0, and 3.0 mM) of the compound significantly reduced the expression level of TNF. These results support the usefulness of the compounds as disclosed herein for treating diseases caused by pathological inflammation.

[0319] Example 6

[0320] Evaluation of the efficacy of AABZ in dextran sulfate sodium (DSS)-induced inflammatory bowel disease in mice.

[0321] After a one-week acclimation period, experiments were performed using female Balb / c mice aged 6 to 8 weeks. Mice weighing 18 - 25 g were purchased from Taconic (Denmark) and maintained in a temperature- and light-controlled facility with free access to standard rodent chow and water. Five days before the start of treatment, the mice were randomly assigned to groups and 5 to 6 animals were housed per cage. After the acclimation period, acute colitis was induced by administering a 5% DSS solution (DSS from TdB Consultary AB, Sweden; MW ~40,000) via the drinking water for five days (days 0 to 5), which resulted in reproducible colitis characterized by diarrhea, rectal bleeding, weight loss, mucosal ulceration, crypt destruction, and leukocyte infiltration. DSS intake was evaluated daily. Sulfasalazine (from Sigma-Aldrich, Sweden) was first dissolved in 0.2 M sodium hydroxide (NaOH) at a concentration higher than 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, sulfasalazine remained completely dissolved. Compound A was dissolved in PBS to the desired concentration. For the entire test period, all animal groups had free access to a 5% aqueous DSS solution. From day 0 to day 5, treatment was administered by gavage either orally (sulfasalazine) or intraperitoneally (Compound A), and at a dosing volume of 5 ml / kg, twice daily, approximately 8 hours apart. The control group (DSS only) received water (0.2 ml) orally twice daily.

[0322] Parameters recorded during the experiment were fecal consistency (0, normal; 2, soft stools; 4, watery diarrhea), presence of blood in the feces (0, normal; 2, Hemoccult+; 4, visible 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 summing the scores of these three parameters. Colon length and the colonic content of myeloperoxidase (MPO) were also recorded. The data were statistically evaluated using analysis of variance (ANOVA). The least-squares means (LS means) and the standard error of the LS means (SE) were calculated.

[0323] Table 3. Percent inhibition of dextran sulfate sodium disease activity index on day 5 relative to control (100% = complete normalization, 0% = no effect).

[0324]

[0325] Table 4. Percent inhibition of dextran sulfate sodium fecal blood score on day 5 relative to control (100% = complete normalization, 0% = no effect).

[0326]

[0327] Administration of 5% DSS for 5 days resulted in severe acute colitis, accompanied by diarrhea, bloody stools, and weight loss. Diarrhea and bloody stools appeared from day 3, and these symptoms worsened until the study was terminated on day 5. Oral treatment with the optimal dose (40 mg / kg / day, bid) of SASP improved these manifestations of colitis (Table 3). Improvement in diarrhea and bloody stools was present starting from day 3. At day 3, the frequency of diarrhea (stool consistency scores of 2 and 4) was 22% in total in the control group and 8% in total in the SASP group. At day 5, the corresponding figures were 98% and 71%, respectively. Comparison of treatment with Cpd A at 100 mg / kg / day bid and SASP at 40 mg / kg / day bid led to excellent improvement in colitis parameters in the animals treated with Cpd A. The disease activity index (DAI) scores were significantly reduced by 75% and 36% by treatment with Cpd A and SASP, respectively (Table 3), and were significantly reduced by 60% with Cpd A treatment relative to SASP treatment (p<0.016). There was a sharp decrease in the bloody stool score in the group treated with Cpd A at 100 mg / kg / day bid [(0.1±0.5 vs. 2.4±0.1 in the control group, p<0.0001) and (0.1±0.5 vs. 1.4±0.2 in the SASP group, p<0.024)] (Table 4).

[0328] Example 7

[0329] Evaluation of the efficacy of AABZ in collagen-induced arthritis

[0330] After a two-week acclimation period, experiments were performed using 9-week-old male DBA / 1 mice. The mice were purchased from B&M (Denmark) and maintained in a temperature- and light-controlled facility with free access to standard rodent food and water. After the acclimation period, the mice (10 per treatment group) were anesthetized with enflurane and immunized intradermally at the base of the tail with 100 mL of a 1:1 emulsion consisting of Freund's complete adjuvant H37Ra (Difco) in 0.1 M acetic acid and 2 mg / mL bovine type II collagen (Elastin Products, Owensville, MO). On day 14 after immunization, the mice were given free access to drinking water containing Cpd A, and the treatment was continued daily until the end of the experiment (day 49). Cpd A intake was monitored by weighing the drinking bottles when the water was changed twice a week. The control group received water ad libitum.

[0331] From immunization to day 49, the clinical signs of arthritis in the mice were monitored three times a week. The following scoring system (arthritis score) was used: 0 = no arthritis; 1 = arthritis (erythema or swelling) in one of the interphalangeal, metatarsophalangeal or intercarpal / carpal joints; 2 = arthritis in two of the above joints; 3 = arthritis in three of the above joints; 4 = arthritis in three of the above joints and the mouse was unable to support itself on its paws. The four measurements for each mouse were summed and the group mean was calculated. Mice with a score > 12 were sacrificed. In the scoring scheme, the last observation carried forward (LOCF) method was used.

[0332] The mean onset day was defined as the mean onset day in the affected mice. The mean arthritis clinical score was defined as the mean score of the experimental group from day 14 to the end of the experiment.

[0333] The Mann-Whitney rank sum test was used to determine statistical significance. Treatment with Cpd A resulted in a statistically significant delay in disease onset and an improvement in disease severity. Compared with the control group, in the mice receiving a dose of 200 mg / kg / day of Cpd A, the mean disease onset was delayed by 5.8 days (p = 0.02), and the severity of the arthritis score was reduced by 1.6 (p = 0.05).

[0334] Example 8

[0335] Receptor affinity.

[0336] It is well known that drug compounds with affinity for striatal dopamine D2 may cause adverse side effects such as short-term extrapyramidal disorders and tardive dyskinesia. Such adverse effects have been observed, for example, for metoclopramide, which reduces its utility especially for the long-term treatment of chronic diseases. Using in vitro radioligand binding techniques, with 125 I-spiperone as the radioligand (Gundlach, 1984), the in vitro affinity of Cpd A and two prior art compounds, metoclopramide and dechlorpromazine, for the dopamine D2 receptor was investigated. As shown in Table 5, Cpd A exhibits very low affinity for the dopamine D2 subtype receptor.

[0337] Table 5. Dopamine D2 receptor affinity.

[0338] Compound IC50 (mM) Metoclopramide 0.07 Domperidone 38.6 Cpd 975

[0339] References

[0340] Frøslie KF et al., Gastroenterology. 2007 133:412–422.

[0341] Gundlach AL et al., Life Sciences 1984 35 1981-1988.

[0342] Harrington RA et al., Drugs 1983 25:451-94.

[0343] Harron DWG et al., Drugs 1990 39: 720-740.

[0344] Hindryckx P et al., J Crohns Colitis. 2018 12 105-119.

[0345] Ivanenkov YA et al., Mini Rev Med Chem. 2011 1:55-78.

[0346] Kim W et al., Mol Pharm. 2016 13:2126-35.

[0347] Lim WC et al., Cochrane Database Syst Rev. 2016 7:CD008870.

[0348] Peyrin-Biroulet L et al., Am J Gastroenterol. 2015 110:1324-38.

[0349] Perše M et al., J Biomed Biotechnol. 2012 2012:718617.

[0350] Sandborn WJ. Gastroenterol Hepatol (N Y). 2016 12:438-41.

[0351] Sands BE et al., Gastroenterology. 2014 147:618-627.

[0352] Vowinkel T et al., Dig Dis Sci. 2004 49 556-64。

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of inflammatory bowel disease or rheumatoid arthritis; wherein R 1 selected from C1-C3 alkyl; R 2 、R 4 、R 5 、R 6 and R 7 each of which is hydrogen; R 3 selected from hydrogen, C1-C3 alkyl, fluorine, chlorine and bromine; and R 8 and R 9 are independently selected from C1-C4 alkyl groups.

2. Use according to claim 1, wherein R 3 is selected from hydrogen, C1-C2 alkyl, fluorine, chlorine and bromine.

3. Use according to claim 1, wherein R 3 is selected from hydrogen and chlorine.

4. The use according to claim 1, wherein the compound is selected from 4-acetamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-propionamido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-isobutyramido-3-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-acetamido-N-[2-(diethylamino)ethyl]benzamide, 4-propionamido-N-[2-(diethylamino)ethyl]benzamide, and 4-isobutyramido-N-[2-(diethylamino)ethyl]benzamide.

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

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

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

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

9. The use according to any one of claims 1 to 8, wherein the medicament is for the treatment of patients for whom treatment with a TNF-α antagonist has failed or is contraindicated.

10. The use according to any one of claims 1 to 8, wherein the medicament is for the treatment of inflammatory bowel disease.

11. The use according to claim 10, wherein the inflammatory bowel disease is ulcerative colitis.

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

13. The use according to any one of claims 1 to 8, wherein the medicament is for the treatment of rheumatoid arthritis.

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