Substituted benzamides and their use in therapy
阅读说明：本技术 取代的苯甲酰胺及其在疗法中的用途 (Substituted benzamides and their use in therapy ) 是由 A·比约克 G·赫德隆 于 2019-08-15 设计创作，主要内容包括：式(I)的化合物或者其药学上可接受的盐或溶剂化物,以及包含该化合物的药物组合物。该化合物可用于治疗起因于病理性炎症的疾病,例如炎性肠病、银屑病或类风湿性关节炎。(A compound of formula (I))
1. A compound of formula (I)
Or a pharmaceutically acceptable salt or solvate thereof; wherein
R1Selected from C1-C6 alkyl and C3-C6 cycloalkyl;
R2selected from H and C1-C3 alkyl;
R3、R4、R5and R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluoro, chloro, bromo, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluoro;
R7selected from hydrogen and C1-C3 alkyl;
R8and R9Independently selected from C1-C6 alkyl, or
R8And R9Together with the nitrogen atom to which they are both attached form part of formula (II)
；
r is 0 or 1;
R10selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
q is selected from CHR11、NR11And O;
R11selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
R12and R13Independently selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl;
when Q is CHR11When p is 1, 2 or 3; and
when Q is selected from NR11And O, p is 2 or 3;
for use in the treatment of a disease resulting from pathological inflammation, with the proviso that the disease is not acute or chronic respiratory inflammation associated with eosinophil infiltration.
2. A compound or pharmaceutically acceptable salt or solvate thereof for use according to claim 1, wherein
R3、R4、R5And R6Independently selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 alkylthio, fluorine, chlorine, bromine and trifluoromethyl;
R7selected from hydrogen and C1-C3 alkyl; and
R8and R9Independently selected from C1-C6 alkyl.
3. A compound or a pharmaceutically acceptable salt or solvate thereof for use according to claim 1 or 2, wherein
R1Selected from C1-C3 alkyl;
R2、R4、R5、R6and R7Each of which is hydrogen; and
R8and R9Independently selected from C1-C4 alkyl.
4. A compound or pharmaceutically acceptable salt or solvate thereof for use according to any one of claims 1 to 3, wherein the compound is selected from
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide, and
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide,
4-propionylamino-N- [2- (diethylamino) ethyl ] benzamide, and
4-isobutyrylamino-N- [2- (diethylamino) ethyl ] benzamide.
5. The compound or pharmaceutically acceptable salt or solvate thereof for use according to claim 4, wherein the compound is 4-acetamido-3-chloro-N- [2- (diethylamino) ethyl ] -benzamide.
6. The compound or pharmaceutically acceptable salt or solvate for use according to any one of claims 1 to 5 for use in the treatment of a patient for whom anti-TNF- α therapy has failed or is contraindicated.
7. The compound or pharmaceutically acceptable salt or solvate for use according to any one of claims 1 to 6, wherein the disease is selected from inflammatory bowel disease, psoriasis and rheumatoid arthritis.
8. The compound or pharmaceutically acceptable salt or solvate for use according to claim 7, wherein the disease is inflammatory bowel disease.
9. The compound or pharmaceutically acceptable salt or solvate for use according to claim 8, wherein the inflammatory bowel disease is ulcerative colitis.
10. The compound or pharmaceutically acceptable salt or solvate for use according to claim 8, wherein the inflammatory bowel disease is Crohn's disease.
11. A compound of formula (I)
Or a pharmaceutically acceptable salt or solvate thereof; wherein
R1Selected from C1-C6 alkyl and C3-C6 cycloalkyl;
R2selected from H and C1-C3 alkyl;
R3、R4、R5and R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluoro, chloro, bromo, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluoro;
R7selected from hydrogen and C1-C3 alkyl;
R8and R9Independently selected from C1-C6 alkyl, or
R8And R9Together with the nitrogen atom to which they are both attached form part of formula (II)
；
r is 0 or 1;
R10selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
q is selected from CHR11、NR11And O;
R11selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
R12and R13Independently selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl;
when Q is CHR11When p is 1, 2 or 3; and
when Q is selected from NR11And O, p is 2 or 3;
with the proviso that the compound is not:
n- [2- (diethylamino) ethyl ] -4- (propionylamino) benzamide,
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-acetylamino-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide,
4-acetylamino-5-chloro-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide,
n- [2- (diethylamino) ethyl ] -2-methoxy-4- (propionylamino) benzamide,
n- [2- [ di (prop-2-yl) amino ] ethyl ] -2-ethoxy-4- (propionylamino) benzamide,
n- [2- (diethylamino) ethyl ] -2-ethoxy-4- (propionylamino) benzamide,
4- [ acetyl (methyl) amino ] -N- [2- (diethylamino) ethyl ] benzamide,
4- (butyrylamino) -N- [2- (diethylamino) ethyl ] benzamide,
n- [2- (diethylamino) ethyl ] -4- (pentanoylamino) benzamide,
n- [2- (diethylamino) ethyl ] -2-methoxy-4- (4-methylpentanoylamino) benzamide,
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide,
4-propionylamino-2-methoxy-N- (2-morpholin-4-yl-ethyl) -benzamide,
4-acetylamino-N- (2-morpholin-4-yl-ethyl) benzamide,
n- (2-morpholin-4-ylethyl) -4- (pentanoylamino) benzamide,
4-propionylamino-N- (2-diisopropylamino-ethyl) -2-ethoxy-benzamide,
4-propionylamino-N- (2-dibutylamino-ethyl) -2-ethoxy-benzamide,
4-propionylamino-2-methoxy-N- (2-piperidin-1-yl-ethyl) -benzamide, or
4-propionylamino-2-methoxy-N- (2-pyrrolidin-1-yl-ethyl) -benzamide.
12. A compound or pharmaceutically acceptable salt or solvate according to claim 11, wherein
R3、R4、R5And R6Independently selected from hydrogen, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 alkylthio, fluorine, chlorine, bromine and trifluoromethyl;
R7selected from hydrogen and C1-C3 alkyl; and
R8and R9Independently selected from C1-C6 alkyl.
13. A compound or pharmaceutically acceptable salt or solvate according to claim 11 or 12, wherein
R1Selected from C1-C3 alkyl;
R2、R4、R5、R6and R7Each of which is hydrogen; and
R8and R9Independently selected from C1-C4 alkyl.
14. The compound or pharmaceutically acceptable salt or solvate according to any one of claims 11 to 13, wherein the compound is selected from
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide, and
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide.
15. A pharmaceutical composition comprising a compound according to any one of claims 11 to 14 and optionally a pharmaceutically acceptable excipient.
16. A compound of formula (I)
Or a pharmaceutically acceptable salt or solvate thereof; wherein
R1Selected from C1-C6 alkyl and C3-C6 cycloalkyl;
R2selected from H and C1-C3 alkyl;
R3、R4、R5and R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluoro, chloro, bromo, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluoro;
R7selected from hydrogen and C1-C3 alkyl;
R8and R9Independently selected from C1-C6 alkyl, or
R8And R9Together with the nitrogen atom to which they are both attached form part of formula (II)
；
r is 0 or 1;
R10selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
q is selected from CHR11、NR11And O;
R11selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
R12and R13Independently selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl;
when Q is CHR11When p is 1, 2 or 3; and
when Q is selected from NR11And O, p is 2 or 3;
for use in therapy, with the proviso that the compound is not:
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-acetylamino-5-chloro-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide,
n- [2- (diethylamino) ethyl ] -4- (pentanoylamino) benzamide, or
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide.
17. A pharmaceutical composition comprising a compound of formula (I)
Or a pharmaceutically acceptable salt or solvate thereof; wherein
R1Selected from C1-C6 alkyl and C3-C6 cycloalkyl;
R2selected from H and C1-C3 alkyl;
R3、R4、R5and R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluorine, chlorine,Bromo, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluoro;
R7selected from hydrogen and C1-C3 alkyl;
R8and R9Independently selected from C1-C6 alkyl, or
R8And R9Together with the nitrogen atom to which they are both attached form part of formula (II)
；
r is 0 or 1;
R10selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
q is selected from CHR11、NR11And O;
R11selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
R12and R13Independently selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl;
when Q is CHR11When p is 1, 2 or 3; and
when Q is selected from NR11And O, p is 2 or 3;
with the proviso that the compound is not selected from:
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-acetylamino-5-chloro-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide,
n- [2- (diethylamino) ethyl ] -4- (pentanoylamino) benzamide, and
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide.
18. Use of a compound of formula (I) as defined in any one of claims 1 to 5 in the manufacture of a medicament for the treatment of a disease resulting from pathological inflammation.
19. A method for the treatment of a disease resulting from pathological inflammation, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 5, or a salt or solvate thereof.
Technical Field
The present invention relates to compounds useful in the treatment of diseases resulting from pathological inflammation. More particularly, the invention relates to 4-alkanoylaminobenzamide derivatives and their use in therapy, in particular for the treatment of diseases resulting from pathological inflammation. Furthermore, the invention relates to pharmaceutical formulations comprising such compounds.
Background
Throughout this application, various (non-patent) publications are referenced by first author and year of publication. Full citations for these publications are presented in the reference section immediately preceding the claims. The disclosures of these documents and publications referred to herein are hereby incorporated by reference in their entirety into this application in order to more fully describe the state of the art to which this invention pertains.
Diseases resulting from pathological inflammation can be treated by various anti-inflammatory agents, such as corticosteroids, immunomodulators, immunosuppressants and Tumor Necrosis Factor (TNF) inhibitors. TNF is implicated in a variety of 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.
Not all patients treated with anti-TNF drugs respond to such therapies. For example, complete remission is achieved in only about 20% to 35% of IBD patients treated with current biological anti-TNF drugs (Sandborn, 2016). In addition, patients who do not experience complete remission, lose 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 have a rapid onset of action with respect to symptom improvement in IBD patients, there is only a moderate correlation between this improvement and the reduction in mucosal inflammation. Rapid control of symptoms may be due to direct neutralization of circulating TNF, but other mechanisms of action are required to reduce the overall inflammatory burden and induce mucosal healing (Hindryckx, 2018).
Many diseases resulting from pathological inflammation are of a chronic nature, or at least may require long-term treatment. In this case, it is of utmost importance to try to reduce as far as possible any serious side effects resulting from the treatment. For example, although 4-aminobenzamide derivatives, such as procainamide (CAS No. 614-39-1) and dichloropramine (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 this chemical class of compounds may outweigh the potential clinical benefit in long-term therapy (Harrington, 1983; Harron, 1990).
IBD, which consists primarily of Crohn's Disease (CD) and Ulcerative Colitis (UC), is a chronic, frequently progressing condition of the gastrointestinal tract that requires life-long treatment. The natural history of the condition is one of the remission periods interrupted by the recurrence of disease activity. CD and UC are diseases that share many similarities and share many overlapping epidemiological, clinical and therapeutic features, but often differ in the location and how they are managed.
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. Inflammation leads to frequent emptying of the intestine. An ulcer forms, which then bleeds and produces pus and mucus. The hallmark symptom of UC is bloody diarrhea with a feeling of urgency for defecation. Other symptoms include abdominal cramps, loss of appetite, fatigue, weight loss, and fever. Diagnosis of UC is based on a combination of symptoms, endoscopic findings, and histology. Pathogenesis is multifactorial, involving genetic susceptibility, immune response disorders, and environmental factors.
CD is often manifested by abdominal pain, diarrhea, and weight loss. The disease most often begins to develop gradually and may affect only a small portion of the gastrointestinal tract, but it has the potential to progress widely over time. CD can cause inflammation across the intestinal wall, causing fistulas or abscesses. Most commonly, CD affects the onset of the small and large intestine. However, the disease may affect any part of the digestive tract from the mouth to the anus.
Depending on the extent of the disease, patients with UC may be classified as having: 1) ulcerative proctitis affecting only the rectum, 2) left UC affecting the colon distal to the splenic flexure, and 3) extensive UC affecting the colon proximal to the splenic flexure (including total colitis). Symptoms may vary depending on the extent and extent of inflammation. Patients are classified as having mild, moderate, or severe disease activity based on one or more measures of disease severity. UC is more frequently diagnosed between the ages of 15 and 35 and at a second diagnostic peak between the ages of 55 and 65. Median age at diagnosis was 30 years. In 15% of cases, UC is diagnosed in childhood and may be present before school age. Generally, the highest incidence of both CD and UC is found in developed countries in north america and europe. The prevalence was estimated to be 70-500 cases/100.000, with men and women equally affected. CD and UC account for a significant cost to the healthcare system and society.
UC has a significant impact on the quality of life of patients due to early onset and lack of cure. Current medications are moderately effective and adverse effects are a problem. Therefore, there is an urgent need to improve clinical management by establishing new therapeutic strategies. The therapeutic goals are to induce and maintain remission and to prevent complications. Patients with no symptoms and signs or very mild symptoms and signs, with mucosal healing, are considered to be in remission. Effects on the inflammatory process are essential, since even in the presence of symptom control, lack of control of inflammation is associated with poor long-term outcome, with higher risk of early relapse and/or poor long-term outcome, including increased risk of colectomy and colorectal cancer. The extra-intestinal manifestations of UC include primary sclerosing cholangitis, as well as joint, skin and eye manifestations.
Historically, UC medications have been developed primarily for symptom-based treatments, i.e., induction and maintenance of symptom improvement, or at most clinical remission, and prevention of complications without significantly altering the natural course of the disease. In the last decades, the therapeutic goals in both UC and CD patients have largely evolved from focusing only on clinical response to the need to achieve better outcomes associated with mucosal lesion healing. Mucosal Healing (MH) has become a key step in achieving sustained remission in UC (frcoffee 2007; Peyrin-Biroulet 2015), and today regulatory authorities require treatments that show not only improvements in disease symptoms and signs, but also in endoscopic disease activity and ideally healing of the intestinal mucosa (EMA 2016). Implementation of these recommendations in clinical practice has the potential to alter disease progression and restore the quality of life of patients.
Current medications are moderately effective and adverse effects are a problem. Treatment recommendations depend on the location of the disease, severity of the disease, and complications of the disease. For example, the first line treatment in mild to moderate UC is 5-aminosalicylic acid (5-ASA) agent, i.e., mesalamine, sulfasalazine, olsalazine, and balsalazide. Sulfasalazine (SASP) is the parent 5-ASA reagent. For approximately 50% of patients with UC who have failed 5-ASA therapy, the next line of treatment is corticosteroids and/or immunomodulators (thiopurines). SASP provides modest benefit for the treatment of mild to moderate active CD (Lim, 2016).
Biological drugs, such as anti-TNF drugs, are generally indicated for treating patients who have failed conventional therapies. Drawbacks and disadvantages of such medicaments have been discussed herein above.
There is currently no cure for IBD and the goal of treatment is to alleviate symptoms, achieve and maintain remission, and avoid complications as much as possible. Thus, administration may be anti-inflammatory, immunomodulatory, immunosuppressive, anti-diarrheal, etc., to combat various symptoms of the disease.
Some 4-alkanoylaminobenzamides have been described previously, with or without indications of particular use.
Thus, U.S. patent application No. 2011/0027179 discloses 4-acetamido-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide, N- [2- (diethylamino) ethyl ] -2-methoxy-4- (propionylamino) benzamide, N- [2- [ di (prop-2-yl) amino ] ethyl ] -2-ethoxy-4- (propionylamino) benzamide, N- [2- (diethylamino) ethyl ] -2-ethoxy-4- (propionylamino) benzamide, 4-propionylamino-2-methoxy-N- (2-morpholin-4-yl-ethyl) -benzamide, and mixtures thereof, 4-propionylamino-N- (2-diisopropylamino-ethyl) -2-ethoxy-benzamide, 4-propionylamino-N- (2-dibutylamino-ethyl) -2-ethoxy-benzamide, 4-propionylamino-2-methoxy-N- (2-piperidin-1-yl-ethyl) -benzamide and 4-propionylamino-2-methoxy-N- (2-pyrrolidin-1-yl-ethyl) -benzamide. However, U.S. patent application No. 2011/0027179 relates to radiohalobenzamide derivatives and their use in tumor diagnosis and therapy, which means that the disclosed compounds are surmised to be useful as synthetic intermediates.
U.S. patent No. 3,177,252 discloses compounds of the general formula including 4-alkanoylaminobenzamides for the treatment of emesis and behavioral disorders, however, no specific examples of 4-alkanoylaminobenzamides are mentioned.
WO 2014/064229 discloses the use of 4-alkanoylaminobenzamides to enhance protective immunity elicited by an immunogen. 4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide, 4-acetylamino-5-chloro-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide and 4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide are mentioned.
WO 2005/025498 indicates that some 4-alkanoylaminobenzamides cause apoptosis of cells (eosinophils) when delivered locally, and based on this effect, discloses the use of such compounds for the treatment of acute or chronic respiratory inflammation associated with eosinophil infiltration. 4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide and N- [2- (diethylamino) ethyl ] -4- (pentanoylamino) benzamide are mentioned.
WO 99/63987 discloses 4-acetamido-3-chloro-N- [2- (diethylamino) ethyl ] benzamide (N-acetyl chloropramine) and its use for inhibiting or killing tumors or cancer cells, and potentially useful in methods of treating inflammatory disorders.
Acetylcanir (4-acetamido-N- [2- (diethylamino) ethyl ] benzamide; CAS number 32795-44-1) has been used for the treatment or prevention of cardiac arrhythmias.
The compounds 4-acetamido-N- (2-morpholin-4-ylethyl) benzamide and N- (2-morpholin-4-ylethyl) -4- (pentanoylamino) benzamide are commercially available, but no specific use is suggested.
As noted herein above, some patients with inflammatory diseases do not respond to anti-TNF-a therapy or respond weakly to such therapy, and for such patients, other modes of treatment must be provided.
Summary of The Invention
The main object of the present invention is to provide a new method for the treatment of IBD, the final aim of which is to modify the disease course. The present inventors contemplate that more effective treatment of IBD than today's treatments may require drugs that affect not only one Transcription Factor (TF), such as NF κ B, but two or more TFs simultaneously. Combinatorial regulation is a powerful mechanism that enables tight control of gene expression via integration of multiple signaling pathways, inducing different TFs required for promoting the initiation of very specific biological responses, which may involve functional synergy or cooperative interactions 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 exceptionally effective in reducing the symptoms of IBD, and it is contemplated that such excellent efficacy may be based on the multiple effects of the compounds in the cells of a mammal, i.e. inhibition of nfkb and NFAT and enhancement of AP-1 activity. Such combined activity may be the cause of very beneficial effects obtained on e.g. the intestinal mucosa, with abnormally high mucosal healing, as observed by the cessation of rectal bleeding, a reliable symptom score for identifying the level of mucosal inflammation.
Thus, a first aspect is a compound of formula (I)
Or a pharmaceutically acceptable salt or solvate thereof; wherein
R1Selected from C1-C6 alkyl and C3-C6 cycloalkyl;
R2selected from H and C1-C3 alkyl;
R3、R4、R5and R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluoro, chloro, bromo, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluoro;
R7selected from hydrogen and C1-C3 alkyl;
R8and R9Independently selected from C1-C6 alkyl, or
R8And R9Together with the nitrogen atom to which they are both attached form part of formula (II)
；
r is 0 or 1;
R10selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
q is selected from CHR11、NR11And O;
R11selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
R12and R13Independently selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl;
when Q is CHR11When p is 1, 2 or 3; and
when Q is selected from NR11And O, p is 2 or 3;
it is useful for the treatment of a disease resulting from pathological inflammation, provided that the disease is not acute or chronic respiratory inflammation associated with eosinophil infiltration.
A further aspect is a compound of formula (I)
Or a pharmaceutically acceptable salt or solvate thereof; wherein
R1Selected from C1-C6 alkyl and C3-C6 cycloalkyl;
R2selected from H and C1-C3 alkyl;
R3、R4、R5and R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluoro, chloro, bromo, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluoro;
R7selected from hydrogen and C1-C3 alkyl;
R8and R9Independently selected from C1-C6 alkyl, or
R8And R9Together with the nitrogen atom to which they are both attached form part of formula (II)
；
r is 0 or 1;
R10selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
q is selected from CHR11、NR11And O;
R11selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
R12and R13Independently selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl;
when Q is CHR11When p is 1, 2 or 3; and
when Q is selected from NR11And O, p is 2 or 3;
with the proviso that the compound is not selected from:
n- [2- (diethylamino) ethyl ] -4- (propionylamino) benzamide,
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-acetylamino-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide,
4-acetylamino-5-chloro-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide,
n- [2- (diethylamino) ethyl ] -2-methoxy-4- (propionylamino) benzamide,
n- [2- [ di (prop-2-yl) amino ] ethyl ] -2-ethoxy-4- (propionylamino) benzamide,
n- [2- (diethylamino) ethyl ] -2-ethoxy-4- (propionylamino) benzamide,
4- [ acetyl (methyl) amino ] -N- [2- (diethylamino) ethyl ] benzamide,
4- (butyrylamino) -N- [2- (diethylamino) ethyl ] benzamide,
n- [2- (diethylamino) ethyl ] -4- (pentanoylamino) benzamide,
n- [2- (diethylamino) ethyl ] -2-methoxy-4- (4-methylpentanoylamino) benzamide,
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide,
4-propionylamino-2-methoxy-N- (2-morpholin-4-yl-ethyl) -benzamide,
4-acetylamino-N- (2-morpholin-4-yl-ethyl) benzamide,
n- (2-morpholin-4-ylethyl) -4- (pentanoylamino) benzamide,
4-propionylamino-N- (2-diisopropylamino-ethyl) -2-ethoxy-benzamide,
4-propionylamino-N- (2-dibutylamino-ethyl) -2-ethoxy-benzamide,
4-propionylamino-2-methoxy-N- (2-piperidin-1-yl-ethyl) -benzamide, and
4-propionylamino-2-methoxy-N- (2-pyrrolidin-1-yl-ethyl) -benzamide.
A further aspect is a compound of formula (I)
Or a pharmaceutically acceptable salt or solvate thereof; wherein
R1Selected from C1-C6 alkyl and C3-C6 cycloalkyl;
R2selected from H and C1-C3 alkyl;
R3、R4、R5and R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluoro, chloro, bromo, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluoro;
R7selected from hydrogen and C1-C3 alkyl;
R8and R9Independently selected from C1-C6 alkyl, or
R8And R9Together with the nitrogen atom to which they are both attached form part of formula (II)
；
r is 0 or 1;
R10selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
q is selected from CHR11、NR11And O;
R11selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13Substitution;
R12and R13Independently selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl;
when Q is CHR11When p is 1, 2 or 3; and
when Q is selected from NR11And O, p is 2 or 3;
for use in therapy, with the proviso that the compound is not selected from:
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-acetylamino-5-chloro-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide,
n- [2- (diethylamino) ethyl ] -4- (pentanoylamino) benzamide, and
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide.
In some embodiments, there is provided a pharmaceutical formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined herein above, and optionally a pharmaceutically acceptable excipient;
with the proviso that the compound is not selected from:
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-acetylamino-5-chloro-N- [2- (diethylamino) ethyl ] -2-methoxybenzamide,
n- [2- (diethylamino) ethyl ] -4- (pentanoylamino) benzamide, and
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide.
One advantageous aspect is a compound of formula (I) as defined herein for use in the treatment of a disease resulting from pathological inflammation in a mammal for which conventional anti-TNF-alpha therapy (using a TNF-alpha antagonist) is not useful, for example in the treatment of a patient for which conventional anti-TNF-alpha therapy has failed or is contraindicated, provided that the disease is not acute or chronic respiratory inflammation associated with eosinophil infiltration.
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.
In some embodiments, there is provided a compound of formula (I) as defined herein above for use in the treatment of at least one symptom of IBD, for example at least one symptom selected from the group consisting of diarrhoea, rectal bleeding, weight loss, mucosal ulceration, intestinal crypt destruction and leukocyte infiltration into the intestinal mucosa.
In some embodiments, compounds of formula (I) are provided for use in the treatment of mucosal ulcers, e.g., associated with IBD.
In some embodiments, compounds of formula (I) are provided for use in treating refractory injury to the intestinal mucosa, for example in IBD.
A further aspect is a pharmaceutical composition comprising a compound of formula (I) as defined herein in combination with a further therapeutically active ingredient, and optionally a pharmaceutically acceptable excipient. Such compositions may be particularly useful in the treatment of diseases resulting from pathological inflammation, such as IBD or RA.
A further aspect is a kit of parts (kit-of-parts) comprising a combination of a compound of formula (I) as defined herein above and (ii) a further therapeutically active ingredient, wherein each of components (I) and (ii) is formulated optionally in admixture with pharmaceutically acceptable excipients. Such kit of parts may be particularly useful in the treatment of pathological inflammation, such as IBD or RA.
A still further aspect is the use of a compound of formula (I) or a salt or solvate thereof, as defined herein above, in the manufacture of a medicament for the treatment of a disease resulting from pathological inflammation in a mammal for which anti-TNF- α treatment is not useful, with the proviso that the disease is not acute or chronic respiratory inflammation associated with eosinophil infiltration.
A further aspect is a method for treating a disease resulting from pathological inflammation in a mammal for which anti-TNF- α treatment is not useful, provided that the disease is not acute or chronic respiratory inflammation associated with eosinophil infiltration, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I).
Other features and advantages of the present invention will be understood by reference to the following detailed description and examples.
Detailed Description
Definition of
As used herein, and unless otherwise indicated and unless otherwise apparent from the context, each of the following terms shall have the definition set forth below.
The term "Cn alkyl" refers to a straight or branched chain saturated hydrocarbon radical containing n carbon atoms in the chain, i.e., formula CnH2n+1Part (c) of (a).
The term "Cn-Cm alkyl" refers to a straight or branched chain alkyl radical containing a number of carbon atoms in the chain ranging from n to m, where n and m are both integers and m is greater than n.
The term "Cn cycloalkyl" refers to formula CnH2n-1The cyclic hydrocarbon group of (1).
The term "Cn-Cm cycloalkyl" refers to a cyclic hydrocarbyl radical containing a number of carbon atoms in the ring in the range of n to m, where n and m are both integers and m is greater than n.
The term "Cn-Cm alkoxy" refers to a moiety of the formula
Wherein R is Cn-Cm alkyl. For example, methoxy is C1 alkoxy.
The term "Cn-Cm alkylthio" refers to a moiety of the formula
Wherein R is Cn-Cm alkyl. For example, methylthio is C1 alkylthio.
The term "halogen" means F, Cl, Br or I; f, Cl or Br is preferred.
The term "hydroxy" refers to a moiety
。
The term "phenyl" refers to a radical of the formula
The term "benzyl" refers to a radical of the formula
。
As used herein, "AABZ" means a compound of formula (I) as described herein, unless otherwise indicated or apparent from the context. Furthermore, unless otherwise indicated or apparent from the context, the term also includes pharmaceutically acceptable salts or solvates (including hydrates) thereof.
As used herein, in the context of a numerical value or range, "about" means ± 20% of the numerical value or range recited or claimed.
As used herein, the expression "acute or chronic respiratory inflammation associated with eosinophil infiltration" refers to a disease such as disclosed in WO 2005/025498, for example, lung inflammation.
As used herein, "administration," "administering," and the like, means administering, distributing, or applying an agent, drug, or pharmaceutical product to a subject (e.g., a mammalian subject, preferably a human) to alleviate or cure a pathological condition. Oral administration is one way of administering the present compounds to a subject.
As used herein, an "amount" or "dose" of a compound (e.g., AABZ), as measured in milligrams, refers to the number of milligrams of the compound present in the formulation, regardless of the form of the formulation. By "dose of 5.0mg of compound" is meant that the amount of compound in the formulation is 5.0mg, regardless of the form of the formulation. Thus, when in the form of a salt such as the hydrochloride salt, the weight of the salt form required to provide a dose of 5.0mg of the free base compound will be greater than 5.0mg due to the presence of the additional acid.
As used herein, "anti-TNF- α therapy" refers to a therapy intended to reduce TNF- α activity and/or TNF- α production, typically for therapeutic purposes, e.g., for the treatment of inflammatory disorders.
As used herein, "AP-1" means activin-1.
As used herein, "combination" means a collection of compounds for use in therapy by simultaneous or separate (e.g., sequential or concomitant) administration. Simultaneous administration refers to the administration of a blend (whether a true mixture, suspension, emulsion, or other physical combination) of two active ingredients (e.g., AABZ and a further therapeutically active agent). In this case, the combination may be a blend of AABZ and further reagents; or the AABZ and further agents may be provided in separate containers and combined just prior to administration. The separate administrations may be sequential (i.e. sequential) or concomitant (i.e. concurrent).
Separate administration refers to concomitant or sequential administration of AABZ and a further therapeutically active agent as separate formulations, but simultaneously or sufficiently close together in time for the activity relative to either of the AABZ and the further therapeutically active agent alone to be observed, at least additive.
As used herein, "CD" means crohn's disease.
As used herein, "Cpd A" means 4-acetamido-3-chloro-N- [2- (diethylamino) ethyl ] benzamide (N-acetyl chlorophenamine) hydrochloride.
As used herein, "a disease resulting from pathological inflammation" refers to diseases such as inflammatory bowel disease, rheumatic diseases, autoimmune diseases, and further, such diseases in which inflammation plays a major role, such as alzheimer's disease, atherosclerosis, and stroke. More particularly, as used herein, "a disease resulting from pathological inflammation" refers to a disease or disorder 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 a disease selected from ulcerative colitis, crohn's disease, and rheumatoid arthritis.
As used herein, "DSS" means dextran sodium sulfate.
As used herein, "effective" when referring to an amount of a therapeutically active agent, e.g., AABZ, refers to an amount which, when used in the manner of this invention, is sufficient to produce the desired therapeutic response commensurate with a reasonable benefit/risk ratio, without undue adverse side effects (e.g., toxicity, irritation, or allergic response).
As used herein, "excipient" refers to a substance formulated with the active ingredient of a medicament, which is included for purposes such as providing volume to a solid formulation, acting as a carrier and/or diluent, imparting therapeutic enhancement to the active ingredient in the final dosage form, for example, by promoting absorption, reducing viscosity, or increasing solubility, for example, for long-term stabilization. Excipients may also be useful in the manufacturing process, for example, by promoting powder flowability or providing non-stick properties. Examples of excipients are antiadherents, binders, coatings, pigments, disintegrants, flavours, glidants, lubricants, preservatives, adsorbents, sweeteners and vehicles (carriers).
As used herein, "I κ B" means an inhibitor of κ B.
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.
As used herein, "inhibition" of disease progression or disease complication in a subject means preventing or reducing disease progression and/or disease complication in a subject.
As used herein, "MH" means mucosal healing.
As used herein, "mucosal healing" refers to the reduction of mucosal ulceration, e.g., of the intestinal mucosa. Healing may be complete or partial, and may be permanent or not, for example for a period of weeks, months or years. Mucosal healing can be observed by reduction of symptoms such as diarrhea, rectal bleeding, and pain. Mucosal healing can also be determined by endoscopy (colonoscopy).
As used herein, "NFAT" means a nuclear factor that activates T cells.
As used herein, "nfkb" means nuclear factor kb.
As used herein, "patient" or "subject" refers to a mammalian patient or subject selected from animals and humans.
As used herein, "pharmaceutically acceptable" refers to materials that are suitable for use in humans and/or animals, and that are generally safe and non-toxic in normal use, i.e., without undue adverse side effects (such as toxicity, irritation, and allergic response), commensurate with a reasonable benefit/risk ratio.
As used herein, "SASP" means sulfasalazine.
As used herein, "salts thereof" are salts of the present compounds modified by making salts or base salts of the compounds. In this regard, the term "pharmaceutically acceptable salts" refers to the 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 a mineral acid.
As used herein, "solvate" means a physical association of a compound (e.g., a compound of formula (I)) with one or more solvent molecules, e.g., through hydrogen bonding. "solvates" encompasses both solution phases and isolatable 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.
As used herein, "a subject having a disease resulting from pathological inflammation" means a subject clinically diagnosed as having such a disease.
As used herein, "symptoms" associated with a disease resulting from pathological inflammation include any clinical or laboratory manifestations associated with the disease, and are not limited to symptoms that a subject may feel or observe.
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.
As used herein, "TNF" means tumor necrosis factor.
As used herein, "TNF-a" means tumor necrosis factor a.
As used herein, "treating" encompasses, for example, inducing suppression, regression, or stasis of a disease or disorder, such as IBD, or alleviating, lessening, suppressing, inhibiting the symptoms of a disease or disorder, reducing the severity of the symptoms of a disease or disorder, eliminating or substantially eliminating or ameliorating the symptoms of a disease or disorder.
As used herein, "UC" means ulcerative colitis.
A compound of formula (I)
In the compounds of formula (I) as defined herein, R1Selected from C1-C6 alkyl and C3-C6 cycloalkyl. In some embodiments, R1Selected 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, R1Selected from C1-C6 alkyl, such as C1-C5 alkyl or C1-C4 alkyl or C1-C3 alkyl or C1-C2 alkyl. In some embodiments, R1Selected from the group consisting of 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, R1Selected from the group consisting of 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, R1Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and cyclopropyl, such as methyl, ethyl, n-propyl and isopropyl. In some embodiments, R1Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl and neopentyl; such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl; or methyl, ethyl, n-propyl and isopropyl; such as methyl, ethyl and isopropyl. In some embodiments, R1Is methyl or ethyl. In some embodiments, R1Is methyl. In some embodiments, R1Is ethyl. In some embodiments, R1Is isopropyl.
R2Moieties are selected from hydrogen and C1-C3 alkyl. In some embodiments, R2Selected from hydrogen, methyl, ethylAlkyl, n-propyl and isopropyl; such as hydrogen, methyl and ethyl, or hydrogen and methyl. In some embodiments, R2Is hydrogen.
R3、R4、R5And R6The moieties are independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, fluoro, chloro, bromo, phenyl and benzyl, wherein any alkyl is optionally substituted with one or more fluoro. In some embodiments, R3、R4、R5And R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, and fluorine, chlorine, bromine, wherein any alkyl is optionally substituted with one or more fluorine. In some embodiments, R3、R4、R5And R6Independently selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy and fluoro, chloro, bromo, wherein any alkyl is optionally substituted with one or more fluoro. In still other embodiments, R3、R4、R5And R6Independently selected from hydrogen, C1-C3 alkyl, and fluoro, chloro, bromo, wherein any alkyl is optionally substituted with one or more fluoro. In still other embodiments, R3、R4、R5And R6Independently selected from hydrogen, C1-C3 alkoxy and fluoro, chloro, bromo, wherein any alkyl is optionally substituted with one or more fluoro. In still other embodiments, R3、R4、R5And R6Independently selected from hydrogen, C1-C3 alkoxy, C1-C3 alkylthio, and fluoro, chloro, bromo, wherein any alkyl is optionally substituted with one or more fluoro. In still further embodiments, R3、R4、R5And R6Independently selected from hydrogen and fluorine, chlorine, bromine.
When R is3、R4、R5And R6When any one of them is selected from C1-C3 alkyl, it may be selected from methyl and ethyl, for example; in particular, it may be methyl.
When R is3、R4、R5And R6When any of them is selected from C1-C3 alkoxy, it may be selected from methoxy and ethoxy, for example; in particular, it may be methoxy. In some casesIn embodiments, R5And R6Is not a C1-C3 alkoxy group.
When R is3、R4、R5And R6When any one of them is selected from C1-C3 alkylthio, it may be selected from methylthio and ethylthio, for example; in particular, it may be methylthio.
When R is3、R4、R5And R6When any of them is a halogen selected from fluorine, chlorine and bromine, said halogen is selected from chlorine and bromine, in particular, it is chlorine. In some further embodiments, when R3、R4、R5And R6When any of (a) is a halogen selected from fluorine, chlorine and bromine, the halogen is more selected from fluorine and chlorine.
In some embodiments, R3、R4、R5And R6Independently selected from hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, fluoro, chloro, bromo, trifluoromethyl, phenyl and benzyl, for example hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, fluoro, chloro, bromo and trifluoromethyl; or hydrogen, methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo and trifluoromethyl; such as hydrogen, methyl, methoxy, fluoro, chloro, bromo and trifluoromethyl; or hydrogen, methyl, methoxy, chloro and trifluoromethyl, or hydrogen, methyl, methoxy and chloro; or hydrogen, methoxy and chlorine; or hydrogen, methyl and chlorine; such as hydrogen and chlorine.
In some of the above embodiments, R3、R4、R5And R6At least one, more preferably at least two of (a) are hydrogen. In some of the above embodiments, R3、R4、R5And R6Two of which are hydrogen. In some of the above embodiments, R3、R4、R5And R6Three of which are hydrogen. In some of the above embodiments, R3、R4、R5And R6Each of which is hydrogen. In some of the above embodiments, R3、R4、R5And R6At least one of which is different from hydrogen. In the above embodimentIn some of the tables, R3、R4、R5And R6One is different from hydrogen and the other three are hydrogen; for example R3、R4、R5And R6One (e.g. R)3) Is halogen, such as chlorine; and the other three are hydrogen. In some of the above embodiments, R3Is different from hydrogen, and R4、R5And R6Each of which is hydrogen. In some embodiments, R5Is different from hydrogen, and R3、R4And R6Each of which is hydrogen. In some embodiments, R3、R4、R5And R6One (e.g. R)3) Is fluorine, chlorine or bromine, in particular chlorine; and the other three are hydrogen. In some embodiments, R3Is hydrogen or halogen, such as hydrogen or chlorine; and R is4、R5And R6Is hydrogen. In some embodiments, R4And R6Is hydrogen; for example R4And R6Is hydrogen, and R3And R5At least one of which is different from hydrogen, e.g. R3And R5All different from hydrogen. In some embodiments, R4And R5Is hydrogen; for example R4And R5Is hydrogen, and R3And R6At least one of which is different from hydrogen, e.g. R3And R6All different from hydrogen. In some embodiments, R3And R4Is hydrogen; for example R3And R4Is hydrogen, and R5And R6At least one of which is different from hydrogen, e.g. R5And R6All different from hydrogen. In some of the above embodiments, R5And R6Is not methoxy or ethoxy.
R7Moieties are selected from hydrogen and C1-C3 alkyl. In some embodiments, R7Selected from hydrogen, methyl, ethyl, propyl and isopropyl; such as hydrogen, methyl, ethyl and propyl. In some embodiments, R7Selected from hydrogen, methyl and ethyl. In some embodiments, R7Selected from hydrogen and methyl. In some embodiments, R7Is hydrogen.
R8And R9The moieties are independently selected from C1-C6 alkyl, or R8And R9Together with the nitrogen atom to which they are both attached form part of formula (II) as defined herein. In some embodiments, R8And R9Independently selected from C1-C6 alkyl. When R is8And R9Selected from C1-C6 alkyl, R8And R9For example, it may be selected from C1-C5 alkyl groups; or C1-C4 alkyl; or C1-C3 alkyl; such as methyl and ethyl. In some embodiments, when R8And R9Selected from C1-C6 alkyl, R8And R9Are all ethyl groups.
In some embodiments, R8And R9Together with the nitrogen atom to which they are both attached, form part of formula (II) as defined herein, in which case the compound of formula (I) may be represented by formula (Ia)
Wherein R is1-R7、R10Q, p and r are as defined herein.
In the moiety of formula (II), r is 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1.
R10Moieties selected from C1-C3 alkyl and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13And (4) substitution. In some embodiments, R10Selected from methyl, ethyl and cyclopropyl optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13And (4) substitution. In some embodiments, R10Selected from the group consisting of C1-C3 alkyl and C3-C4 cycloalkyl optionally substituted with hydroxy, halogen and cyano; for example C1-C3 alkyl and C3-C4 cycloalkyl substituted by halogen, for example fluorine. In some embodiments, R10Selected from C1-C3 alkyl and C3-C4 cycloalkyl, such as methyl, ethyl and cyclopropyl, especially methyl.
Moiety QSelected from the group consisting of CHR11、NR11And O. In some embodiments, Q is selected from CHR11And NR11. In some embodiments, Q is selected from CHR11And O. In some embodiments, Q is CHR11. In some other embodiments, Q is selected from NR11And O.
R11Moieties selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl; the alkyl and cycloalkyl groups are optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13And (4) substitution. In some embodiments, R11Selected from hydrogen, methyl, ethyl and cyclopropyl, said methyl, ethyl and cyclopropyl being optionally substituted by hydroxy, halogen, cyano, COOR12Or NHR13And (4) substitution. In some embodiments, R11Selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl, said alkyl and cycloalkyl being optionally substituted by hydroxy, halogen or cyano, for example halogen, such as fluorine. In some embodiments, R11Selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl, such as hydrogen, methyl, ethyl and cyclopropyl, or hydrogen, methyl and ethyl; especially hydrogen and methyl. In some embodiments, R11Is hydrogen. In some other embodiments, R11As defined herein above, but is different from hydrogen.
When R is11Is selected from hydroxy, halogen, cyano, COOR12Or NHR13Substituted C1-C3 alkyl or C3-C4 cycloalkyl, the number of such substituents may be one or more, for example 1-3 or 1-2 or 1.
R12Moieties are selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl. In some embodiments, R12Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and cyclopropyl, such as hydrogen, methyl, ethyl, n-propyl and isopropyl; or hydrogen, methyl and ethyl, for example hydrogen and methyl. In some embodiments, R12Selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl. In some embodiments, R12Selected 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, e.g. R12Is methyl. In some other embodiments, R12Is hydrogen.
R13Moieties are selected from hydrogen, C1-C3 alkyl, and C3-C4 cycloalkyl. In some embodiments, R13Selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl and cyclopropyl, such as hydrogen, methyl, ethyl, n-propyl and isopropyl; or hydrogen, methyl and ethyl, for example hydrogen and methyl. In some embodiments, R13Selected from hydrogen, C1-C3 alkyl and C3-C4 cycloalkyl. In some embodiments, R13Selected 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, e.g. R13Is methyl. In some other embodiments, R13Is hydrogen.
In the moiety of formula (II), when Q is CHR11When p is 1, 2 or 3; and when Q is selected from NR11And 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 CHR11And p is 1 or 2. In some embodiments, Q is CHR11And p is 2. In some other embodiments, Q is CHR11And p is 1.
In some embodiments, R1Is C1-C6 alkyl; r2Is hydrogen; r7Is hydrogen; r8And R9Independently selected from C1-C6 alkyl, or R8And R9Together with the nitrogen atom to which they are both attached form a moiety of formula (II) as defined herein; r10Is C1-C3 alkyl; q is CHR11(ii) a And R is11Selected from hydrogen and C1-C3 alkyl. In some embodiments, R1Is C1-C6 alkyl; r2Is hydrogen; r7Is hydrogen; and R is8And R9Independently selected from C1-C6 alkyl. In some of these embodiments, R1、R8And R9Independently selected from C1-C3 alkyl.
In some further embodiments, R1Is C1-C3 alkyl; r2、R4、R5And R7Is hydrogen; and R is8And R9Independently selected from C1-C3 alkyl. In some of these embodiments, R1Selected from methyl, ethyl and isopropyl; and R is8And R9Are identical or different and are selected from the group consisting of methyl, ethyl and n-propyl. In some further embodiments, R1Selected from methyl, ethyl and isopropyl; r2、R4、R5、R6And R7Is hydrogen; and R is8And R9Are identical or different and are selected from the group consisting of methyl, ethyl and n-propyl.
In some embodiments, R2Selected from hydrogen and methyl; r3、R4、R5And R6Independently selected from hydrogen and chlorine; r7Is hydrogen; and R is8And R9Are identical or different and are selected from the group consisting of methyl, ethyl and n-propyl.
In some embodiments, R1Selected from methyl, ethyl and isopropyl; r2Is hydrogen or methyl; r3Is chlorine or hydrogen; r4、R5、R6And R7Is hydrogen; and R is8And R9Are identical or different and are selected from the group consisting of methyl, ethyl and n-propyl. In some embodiments, R1Selected from methyl, ethyl and isopropyl; r2Is hydrogen or methyl; r3Is chlorine or hydrogen; r4、R5、R6And R7Is hydrogen; and R is8And R9Is ethyl. In some embodiments, R1Selected from methyl, ethyl and isopropyl; r2Is hydrogen; r3Is chlorine or hydrogen; r4、R5、R6And R7Is hydrogen; and R is8And R9Are identical or different and are selected from the group consisting of methyl, ethyl and n-propyl. In some embodiments, R1Selected from methyl, ethyl and isopropyl; r2Is hydrogen; r3Is chlorine; r4、R5、R6And R7Is hydrogen; and R is8And R9Are identical or different and are selected from the group consisting of methyl, ethyl and n-propyl.
In some embodiments, a compound of formula (I) as used herein is selected from:
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide,
4-propionylamino-N- [2- (diethylamino) ethyl ] benzamide, and
4-isobutyrylamino-N- [2- (diethylamino) ethyl ] benzamide.
In some embodiments, a compound of formula (I) as used herein is selected from:
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide, and
4-acetylamino-N- [2- (diethylamino) ethyl ] benzamide.
In some embodiments, a compound of formula (I) as used herein is selected from:
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide,
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide, and
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide.
In some embodiments, the compound of formula (I) as used herein as defined is 4-acetamido-3-chloro-N- [2- (diethylamino) ethyl ] benzamide.
In some further embodiments, the compound of formula (I) for use in therapy is selected from:
n- [2- (diethylamino) ethyl ] -4- (propionylamino) benzamide,
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide, and
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide.
In some embodiments, the compound of formula (I) as disclosed herein is selected from:
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide, and
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl ] benzamide.
In some embodiments, the compound of formula (I) is 4-propionylamino-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, AABZ is the hydrochloride salt of the compound of formula (I), e.g., 4-acetamido-3-chloro-N- [2- (diethylamino) ethyl ] benzamide hydrochloride.
The structural formulae of some of the compounds mentioned herein are shown in table 1.
TABLE 1
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzamide derivatives
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzamide derivatives
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzoyl radicalAmines as pesticides
4-acetylamino-N- [2- (diethylamino) ethyl group]Benzamide derivatives
4-propionylamino-N- [2- (diethylamino) ethyl]Benzamide derivatives
4-isobutyrylamino-N- [2- (diethylamino) ethyl group]Benzamide derivatives
Pharmaceutically acceptable salts
AABZ may be provided as a pharmaceutically acceptable salt, e.g., an acid addition salt, of a compound of formula (I). In the preparation of acid or base addition salts, it is preferred to use such acids or bases to form suitable therapeutically acceptable salts. Examples of such acids are hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, aliphatic, cycloaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, for example 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, isethionic acid, halobenzenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid. Base addition salts include those derived from inorganic bases such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and those derived from organic bases such as alkoxides, alkylamides, alkylamines, and arylamines, and the like. Examples of bases useful in preparing the salts of the present invention include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like. In some embodiments, the compound of formula (I) is provided as a hydrochloride salt.
Related teachings regarding salt formulations and methods of making the same as used herein are described, for example, in U.S. patent No. 3,177,252, and such teachings are incorporated herein by reference.
Pharmaceutically acceptable solvates
Any pharmaceutically acceptable solvate is considered possible according to the present invention. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. In some embodiments, the solvate is a hydrate.
Process for preparing compounds of formula (I)
The compounds of formula (I) may be prepared by one 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.
For example, the compounds of formula (I) may be prepared by a process comprising two sequential nucleophilic substitution reactions as shown by the following reaction scheme:
in the above reaction scheme, wherein RaCompound 1, which is, for example, C1-C3 alkyl, is reacted with compound 2, wherein L is a suitable leaving group, such as Cl, to obtain compound 3. Then is used asReacting compound 3 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 compounds of formula (I) may optionally be converted into suitable pharmaceutically acceptable salts or solvates, for example hydrohalide salts.
Use of compounds of formula (I)
A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (hereinafter collectively referred to as AABZ), is useful in treating a disease resulting from pathological inflammation, provided that the disease is not acute or chronic respiratory inflammation associated with eosinophil infiltration.
In some embodiments, the disease resulting from pathological inflammation is as defined herein, but is not respiratory inflammation.
In some embodiments, the disease resulting from pathological inflammation is selected from IBD, psoriasis and RA.
In some embodiments, the disease is an inflammatory disease, such as IBD. In some embodiments, the disease is RA. In some embodiments, the IBD is UC. In some embodiments, the 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.
It would be highly advantageous if AABZ could be used to treat a disease resulting from pathological inflammation in a patient for whom anti-TNF-a therapy is not considered useful, for example because the patient is unable to provide an adequate response to such therapy, or because such therapy is contraindicated for some other reason. Thus, in some embodiments, AABZ is provided for treating a patient for whom anti-TNF-a therapy has failed or is contraindicated. For example, the patient may be one with IBD and for which anti-TNF-a therapy (i.e., treatment with a TNF-a antagonist) does not provide adequate relief of the symptoms of IBD or for some other reason is not treated by such methods.
Symptoms vary according to the severity of the inflammation, and may range from mild to severe.
Signs and symptoms common to both CD and UC include diarrhea, fever and fatigue, abdominal pain and colic, hematochezia, and loss of appetite. Symptoms of RA include joint pain, joint tenderness, joint swelling, joint redness, and joint stiffness.
A particularly advantageous embodiment is AABZ for use in treating a patient with IBD, such as UC or CD, for which anti-TNF-a treatment has failed or is contraindicated.
A further advantageous aspect is AABZ for use in the treatment of mucosal ulcers, for example intestinal mucosal ulcers, for example those associated with IBD.
The advantageous features of AABZ are linked to its low affinity for the dopamine D2 receptor, which substantially reduces the risk of developing adverse dyskinesias such as short-term extrapyramidal disorders and tardive dyskinesias. Thus, one aspect is AABZ, which can be used for long-term treatment of chronic diseases without the negative effects of dopamine D2 receptor blockade.
In some embodiments, AABZ is a pharmaceutically acceptable salt, particularly the hydrochloride salt, of the compound of formula (I).
In some embodiments, AABZ is administered via oral administration. In some embodiments, AABZ is administered in a preferably solid unit formulation, more preferably a tablet.
In some embodiments, AABZ is administered daily.
In some embodiments, the amount of AABZ administered is 0.1-25 mg/kg (mg drug/kg subject body weight) per day (any weight value is based on non-salt, non-solvate form). In other embodiments, the amount of AABZ administered is from 0.3 to 10 mg/kg/day.
In some embodiments, the amount of AABZ administered is from 5.0 to 2000 mg/day or from 10 to 1000 mg/day.
In some embodiments, AABZ is administered once daily. In other embodiments, AABZ is administered twice daily. In other embodiments, AABZ is administered 3 times per day. In still other embodiments, the AABZ is administered four times per day.
In some embodiments, the administration of AABZ lasts for at least 2 weeks. In other embodiments, the administration of AABZ lasts for 3 months or more. In still other embodiments, the administration of AABZ lasts for 12 months or more.
Subject of treatment
The subject treated according to the invention is a mammal, including human and non-human mammals (animals). Examples of non-human mammals are primates, domesticated animals, e.g., farm animals, such as cattle, sheep, pigs, horses, and the like, and pet animals, such as dogs and cats, and the like. 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 horse.
Pharmaceutical composition
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 used to treat a subject having a disease resulting from pathological inflammation, such as IBD, psoriasis, or RA.
AABZ can be administered in admixture with a suitable pharmaceutical diluent, bulking agent or carrier, or any other pharmaceutically acceptable excipient suitably selected with respect to the intended form of administration and in accordance with conventional pharmaceutical practice. Preferred dosage units will be in a form suitable for oral administration. AABZ can be administered alone, but is typically 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 may be readily formulated and may be prepared for ease of swallowing or chewing; other solid forms include granules and bulk powders.
Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents. For example, for oral administration in the form of a dosage unit of a tablet or capsule, 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 and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums (e.g., acacia, tragacanth or sodium alginate), povidone, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate, and the like.
The amount of AABZ in a dosage unit of a formulation (e.g., a tablet or capsule) can be, for example, 5-500 mg (any amount based on the compound of formula (I) in non-salt and non-solvated forms). 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.
In some embodiments, the total amount of AABZ is from 0.1% to 95% by weight of the formulation, e.g., from 0.5% to 50% by weight, or from 1% to 20% by weight, with the remainder comprising, e.g., carriers and any other excipients.
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 salt.
Combined use of AABZ and further therapeutically active ingredients
One aspect herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof (AABZ), as defined herein, for use in combination with at least one further therapeutically active ingredient, for the treatment of a disease resulting from pathological inflammation in a mammal for which TNF-a inhibition is not useful, provided that the disease is not acute or chronic respiratory inflammation associated with eosinophil infiltration.
In some embodiments, the treatment comprises administering to a subject (mammalian patient, e.g., 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 amount of AABZ and further therapeutically active ingredient produces an overall better effect, i.e. a synergistic effect, when administered together to treat a subject, than the sum of simple effects produced when either component is administered alone in the same total amount.
Further therapeutically active ingredients may be selected from, for example, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, cytotoxic drugs, immunosuppressive drugs and antibodies.
In some embodiments, the treatment comprises administering AABZ to a subject (mammalian patient, e.g., human patient) as an additional therapy or in combination with a further therapeutically active ingredient in treating a subject having IBD (e.g., UC or CD) or, e.g., RA. Preferably, the treatment provides for the induction and maintenance of clinical remission in patients with mild to moderate to severe disease activity. In some embodiments, treatment is intended for patients in remission in order to prevent disease recurrence.
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.
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 per day. In still other embodiments, the further therapeutically active ingredient is administered four times per day.
When taken together, the amount of AABZ and the amount of the further therapeutically active ingredient are preferably effective to reduce the symptoms of IBD or RA in the subject.
In some embodiments, the administration of the further therapeutically active ingredient is substantially prior to the administration of the AABZ, i.e., prior to initiating therapy by administering the AABZ, by administering the further therapeutically active ingredient, the subject is receiving therapy.
In some embodiments, the subject is receiving therapy for at least 6 months by administering a further therapeutically active ingredient prior to initiating therapy by administering AABZ. In some embodiments, the subject is receiving therapy for at least 12 months by administering a further therapeutically active ingredient prior to initiating therapy by administering AABZ. In some embodiments, the subject is receiving therapy for at least 24 months by administering a further therapeutically active ingredient prior to initiating therapy by administering AABZ.
In some embodiments, the administration of AABZ and the further therapeutically active ingredient is continued for at least 2 weeks. In other embodiments, the administration of AABZ and a further therapeutically active ingredient lasts for 3 months or more. In still other embodiments, the administration of AABZ and the further therapeutically active ingredient lasts for 12 months or more.
In some embodiments, AABZ and the 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 therapeutically active is in the range of 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, e.g. about 1: 1.
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 ingredient are administered in combination with each other.
A further aspect is AABZ for use as an add-on therapy or in combination with a further therapeutically active ingredient in the treatment of a subject suffering from a disease as mentioned herein, e.g. IBD or RA.
One aspect is a kit of parts comprising a combination of AABZ and a further therapeutically active ingredient, wherein each of the component AABZ and the further therapeutically active ingredient is formulated, optionally in admixture with a pharmaceutically acceptable excipient, e.g., a carrier.
In some embodiments, a kit of parts 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 a further therapeutically active ingredient and a pharmaceutically acceptable carrier; and c) instructions for use of the first pharmaceutical composition and the second pharmaceutical composition together; for example for the treatment of IBD or autoimmune diseases such as RA.
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 treating a subject having IBD or an autoimmune disorder, such as RA.
Generally, a suitable pharmaceutical composition is a pharmaceutical composition as described herein above in association with a pharmaceutical formulation of AABZ, but which composition contains a further therapeutically active ingredient in addition to AABZ.
In some embodiments, the molar ratio of AABZ to further therapeutically active substance 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, e.g. it may be about 1: 1.
In some embodiments, the total amount of AABZ and further therapeutically active ingredient is from 0.1% to 95% by weight of the formulation, e.g., from 0.5% to 50% by weight, or from 1% to 20% by weight, with the remainder comprising, e.g., carriers and any other excipients.
In some embodiments, the pharmaceutical composition comprises AABZ, e.g., 4-acetamido-3-chloro-N- [2- (diethylamino) ethyl ] benzamide, or a pharmaceutically acceptable salt thereof, e.g., the hydrochloride salt, as disclosed herein, and a further therapeutically active ingredient, and optionally a pharmaceutically acceptable excipient.
Specific examples of techniques, pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the invention are described in, for example, EP 1720531B 1. General techniques and compositions for preparing dosage forms useful in the present invention are described in the following references: modern pharmaceuticals, chapters 9 and 10 (Banker & Rhodes, eds., 1979); pharmaceutical Dosage Forms, Tablets (Lieberman et al, 1981); ansel, Introduction to Pharmaceutical Dosage Forms second edition (1976); remington's Pharmaceutical Sciences, 17 th edition (Mack Publishing Company, Easton, Pa., 1985) (and later); advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, ed., 1992); advances in Pharmaceutical Sciences Vol.7 (David Ganderton, Trevor Jones, James McGinity, ed.1995); aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, eds., 1989); Pharmaceutical components Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol.61 (Alain Rolland, Ed., 1993); Drug Delivery to the Pharmaceutical additive track (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J.G. Hardy, S.S. Davis, Clive G. Wilson, Ed.) and model Pharmaceutical compositions for Pharmaceutical Dosage Forms (see, catalog 40, eds., see the entire application for reading and Pharmaceutical Sciences, Vol.40, incorporated herein by reference.
The following examples are intended to illustrate the invention without limiting its scope.
Examples
Intermediate 1
4-acetylamino-3-chlorobenzoic acid ethyl ester
Ethyl 4-amino-3-chlorobenzoate (2.0 g, 10 mmol) and 1.4 g triethylamine were dissolved in 20 mL dichloromethane. 0.9 g of acetyl chloride in 5 mL of dichloromethane was added dropwise at 0 ℃. 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.
Example 1
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzamide hydrochloride
1.5 g 4-acetylamino-3-chlorobenzoic acid ethyl ester (1.5 g, 6.2 mmol) was dissolved in 15 mL N, N-diethylethylenediamine along 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. Drying and evaporation of the solvent gave the free base of the title compound. The residue was dissolved in ethanol-diethyl ether and acidified with ethanolic HCl. The precipitated solid was collected to give the title compound (1.1 g, 3.1 mmol, 50% yield).
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)。
Example 2
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzamide hydrochloride
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 ℃ for 2.5 hours. 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%).
1H NMR (400 MHz, methanol-d 4) 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).
Example 3
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzamide hydrochloride
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. Purity according to HPLC was 99%.
1H NMR (400 MHz, methanol-d 4) 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).
Example 4
4-acetylamino-N- [2- (diethylamino) ethyl group]Benzamide hydrochloride
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. To the suspension was added 10 mL of acetic anhydride. The reaction was slightly exothermic. After 1h, the precipitate was filtered off, washed with ethyl acetate and dried to provide the title compound (2.83 g, 9.0 mmol, 99% yield). The purity according to NMR was 98%.
1H NMR (400 MHz, methanol-d 4) 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).
Biological assay
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 spread of inflammatory responses by releasing proinflammatory mediators, such as TNF- α. Lipopolysaccharide (LPS) is a potent initiator of inflammatory responses. During stimulation with LPS, NF-. kappa.B signaling is activated to regulate transcription of numerous genes involved in immunity and inflammation to produce proinflammatory cytokines, such as TNF-. alpha.. Inhibition of LPS-induced TNF- α production in RAW264.7 macrophages treated with AABZ was investigated by assessing TNF- α production.
Both Dextran Sodium Sulfate (DSS) and trinitrobenzenesulfonic acid (TNBS) -induced colitis are well established animal models of mucosal inflammation that have been used for more than 20 years in studies of IBD pathogenesis and preclinical studies of new therapies. The DSS-induced colitis model has some advantages when compared to other animal models of colitis (Perse 2012) and is therefore selected for analysis of therapeutic effects.
Example 5
Inhibition of LPS-induced TNF-alpha production in macrophages treated with AABZ
RAW264.7 macrophage lines were maintained in DMEM supplemented with 5% FBS at 37 ℃ in a humidified 5% CO2 air environment. RAW264.7 cells were seeded in 96-well plates at a density of 1X 105/ml and a volume of 200. mu.l/well. 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 test substance before addition of LPS (1 μ g/ml). Supernatants were then harvested at various time points and the pro-inflammatory cytokine TNF- α production in culture medium was determined according to the manufacturer's protocol using a commercially available enzyme-linked immunosorbent assay (ELISA) kit.
The effect of some AABZ of the invention at 1 mM on LPS-induced TNF production in RAW264.7 murine macrophages is shown in table 2.
TABLE 2 Effect of AABZ at 1 mM on LPS-induced TNF production in RAW264.7 murine macrophages
Compound (I)
Inhibition of TNF production%
Control of LPS treatment
0
4-acetylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzamide hydrochloride
45
4-propionylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzamide hydrochloride
50
4-isobutyrylamino-3-chloro-N- [2- (diethylamino) ethyl group]Benzamide hydrochloride
63
4-acetylamino-N- [2- (diethylamino) ethyl group]Benzamide hydrochloride
56
* Cpd A
It was observed that different concentrations (0.3, 1.0 and 3.0 mM) of the compound 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 the treatment of diseases resulting from pathological inflammation.
Example 6
Evaluation of the efficacy of AABZ in Dextran Sodium Sulfate (DSS) -induced inflammatory bowel disease in mice.
After one week of acclimation, experiments were performed using 6 to 8 week old female Balb/c mice. 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 food and water. Five days before treatment, mice were randomized into groups and kept 5 to 6 animals per cage. After the adaptation period, acute colitis was induced by administration of a 5% DSS solution (DSS from TdB coultary AB, sweden; MW-40000) via drinking water for five days (day 0 to day 5), which resulted in reproducible colitis characterized by diarrhea, rectal bleeding, weight loss, mucosal ulceration, crypt destruction and leukocyte infiltration. DSS intake was assessed daily. SASP (from Sigma-Aldrich, Sweden) was first dissolved in 0.2M 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, the SASP remained completely dissolved. Cpd A was dissolved in PBS to the desired concentration. All animal groups had free access to 5% DSS in water for the entire test period. Treatment was administered from day 0 to day 5 by gavage orally (SASP) or intraperitoneally (Cpd a), and at an administration volume of 5 ml/kg, twice daily, approximately 8 hours apart. The control group (DSS only) received water (0.2 ml) orally twice daily.
Parameters recorded in the experiment were stool consistency (0, normal; 2, loose stools; 4, watery diarrhea), blood appearance in the stools (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) is calculated by summarizing the scores of these three parameters. Colon length and colon content of Myeloperoxidase (MPO) were also recorded. Data were statistically evaluated using analysis of variance (ANOVA). The least squares means (LS means) and the Standard Error (SE) of the LS means are calculated.
Table 3% inhibition of dextran sodium sulfate disease activity index at day 5 relative to control (100% = complete normalization, 0% = no effect).
Table 4% inhibition on day 5 of dextran sodium sulfate hematochezia score relative to control (100% = complete normalization, 0% = no effect).
5% DSS administration for 5 days resulted in severe acute colitis with diarrhea, hematochezia and weight loss. Diarrhea and hematochezia appeared from day 3 and these symptoms worsened until study termination at day 5. Oral treatment with the optimum dose (40 mg/kg/day, bid) of SASP improved these manifestations of colitis (table 3). From day 3 onwards, there was diarrhea and improvement in hematochezia. On day 3, the diarrhea frequency (stool consistency scores of 2 and 4) totaled 22% in the control group and 8% in the SASP group. On day 5, the corresponding numbers are 98% and 71%, respectively. Comparison of Cpd A100 mg/kg/day bid with SASP 40 mg/kg/day bid treatment resulted in superior improvement of colitis parameters in Cpd A treated animals. Disease Activity Index (DAI) scores were significantly reduced by Cpd a and SASP treatment by 75% and 36%, respectively (table 3), and by Cpd a by 60% relative to SASP treatment (p < 0.016). There was a dramatic decrease in the hematochezia score in the Cpd a 100 mg/kg/day bid group [ (0.1 ± 0.5 relative to 2.4 ± 0.1, p <0.0001 for the control group) and (0.1 ± 0.5 relative to 1.4 ± 0.2, p <0.024 for the SASP group) (table 4).
Example 7
Evaluation of the efficacy of AABZ in collagen-induced arthritis
After a two-week adaptation period, experiments were performed using 9-week-old male DBA/1 mice. 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, mice (10/treatment group) were anesthetized with enflurane and immunized intradermally in the root of the tail with 100 mL of 1:1 emulsion consisting of Freund's complete adjuvant H37Ra (Difco) and 2 mg/mL bovine type II collagen (Elastin Products, Owensville, Mo.) in 0.1M acetic acid. At day 14 post immunization, mice were given ad libitum access to drinking water containing Cpd a, with treatment continuing daily until termination of the experiment (day 49). Cpd a uptake was monitored by weighing the drinking bottles at twice weekly water changes. The control group received water ad libitum.
Mice were monitored three times a week from immunization to day 49 for clinical signs of arthritis. The scoring system (arthritis score) was used as follows: 0 = no arthritis; 1 = arthritis (erythema or swelling) in one of the interphalangeal, metatarsophalangeal or intercarpal/wrist joints; 2 = arthritis in the two joints mentioned above; 3 = arthritis in the three joints mentioned above; 4 = arthritis in the three joints described above, and the mouse could not be supported by the paw. The four measurements for each mouse were summed and the group mean was calculated. Mice with a score >12 were sacrificed. In the scoring protocol, the Last Observation Carried Forward (LOCF) method was used.
The mean day of onset is defined as the mean day of onset in affected mice. The mean arthritis clinical score was defined as the mean score of the experimental group from day 14 to termination of the experiment.
Statistical significance was determined using the mann-whichtwo rank sum test. Treatment with Cpd a resulted in a statistically significant delay in onset of disease and improvement in disease severity. In mice receiving a dose of 200 mg/kg/day Cpd a, 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) compared to the control group.
Example 8
Receptor affinity.
It is well known that pharmaceutical 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, particularly for long-term treatment of chronic diseases. Using in vitro radioligand binding techniques to125I-Spiroperone as a radioligand (Gundlach, 1984) investigated the in vitro affinity of Cpd A and the two prior art compounds metoclopramide and deschloropromide for the dopamine D2 receptor. As shown in table 5, Cpd a exhibits very low affinity for dopamine D2 subtype receptors.
TABLE 5 dopamine D2 receptor affinity.
Compound (I)
IC50（mM）
Metoclopramide
0.07
Dichloropramine
38.6
Cpd
975
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