WO2022119899A1 - A medicament for treating mycobacterial infection characterized by combining a cytochrome bc1 inhibitor with clarithromycin or azithromycin - Google Patents

A medicament for treating mycobacterial infection characterized by combining a cytochrome bc1 inhibitor with clarithromycin or azithromycin Download PDF

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Publication number
WO2022119899A1
WO2022119899A1 PCT/US2021/061365 US2021061365W WO2022119899A1 WO 2022119899 A1 WO2022119899 A1 WO 2022119899A1 US 2021061365 W US2021061365 W US 2021061365W WO 2022119899 A1 WO2022119899 A1 WO 2022119899A1
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Prior art keywords
substituted
unsubstituted
pharmaceutically acceptable
acceptable salt
halogen
Prior art date
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PCT/US2021/061365
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French (fr)
Inventor
Kenzo NISHIGUCHI
Yuya YOSHIOKA
Sayaka HIRUKAWA
Takafumi Hara
William D. CLAYPOOL
Marvin J. Miller
Garrett C. Moraski
Jeffrey S. Schorey
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Shionogi & Co., Ltd.
Hsiri Therapeutics, Inc.
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Publication of WO2022119899A1 publication Critical patent/WO2022119899A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin

Definitions

  • the present invention relates to novel combinations.
  • the invention also relates to such combinations for use as pharmaceuticals, for instance in the treatment of bacterial diseases, including diseased caused by pathogenic mycobacteria such as non-tuberculosis mycobacteria.
  • the present invention relates to a medicament characterized in that a compound having a cytochrome bcl inhibitory activity or its pharmaceutically acceptable salt is combined with clarithromycin or azithromycin or their pharmaceutically acceptable salts, or a medicament characterized in that a compound having a cytochrome bcl inhibitory activity or its pharmaceutically acceptable salt is combined with clarithromycin or azithromycin, and clofazimine, or their pharmaceutically acceptable salts.
  • Genus Mycobacterium has 95 well-characterized species. Over the centuries two well known mycobacterial species, namely, Mycobacterium tuberculosis and M. Leprae have been the known causes of immense human suffering. Most of other mycobacteria are present in the environment and their pathogenic potential has been recognized since the beginning of the last century. These mycobacteria are called non-tuberculous mycobacteria (NTM). Whereas the incidence of tuberculosis (TB) is decreasing, a new health concern has been raised globally by NTM. Pulmonary disease caused by NTM is characterized by progressive, irreversible pulmonary damage and increased mortality. About 80% of pulmonary NTM disease is caused by Mycobacterium avium complex (MAC- M. avium, M.
  • MAC- M. avium, M Mycobacterium avium complex
  • NTM pulmonary disease varies in different regions, ranging from 0.2/100, 000 to 14.7/100,000 with an overall alarming growth rate. The disease is more prevalent after age 60 where the estimated prevalence is from 19.6/100,000 during 1994-1996 to 26.7/100,000 during 2004-2006 in the US.
  • NTM are opportunistic pathogens, causing mostly TB-like pulmonary diseases in immunocompromised patients or patients with preexisting lung conditions, such as cystic fibrosis (CF), bronchiectasis or chronic obstructive pulmonary disease (COPD).
  • CF cystic fibrosis
  • COPD chronic obstructive pulmonary disease
  • post-menopausal women without pre-existing structural pulmonary disease represent another risk group for NTM lung disease. These women, primarily older women of Caucasian or Asian descent, present with nodular bronchiectasis as their NTM lung disease.
  • Patent Documents 1 to 8 disclose a variety of compounds having a cytochrome bc1 inhibitory activity.
  • Patent Document 9 discloses a variety of compounds having a cytochrome bc1 inhibitory activity. For example, the following compound is disclosed.
  • Telacebec This compound is known as Telacebec and is a new clinical candidate for the treatment of tuberculosis.
  • Patent Document 10 discloses a combination of bedaquiline, Telacebec and pyrazinamide.
  • Patent Document 11 discloses a combination of rifabutin, clarithromycin and clofazimine.
  • Non-Patent Document 1 discloses a combination of clarithromycin and clofazimine.
  • Non-Patent Document 2 discloses a combination of a compound having a cytochrome bc1 inhibitory activity and rifampin.
  • Patent Document 1 WO2011/057145
  • Patent Document 2 WO2014/015167
  • Patent Document 3 WO2017/049321
  • Patent Document 4 US2017/0313697
  • Patent Document 5 WO2017/001660
  • Patent Document 6 WO2017/001661
  • Patent Document 7 WO2017/216281
  • Patent Document 8 WO2017/216283
  • Patent Document 9 WO2011/113606
  • Patent Document 10 WO2018/158280
  • Patent Document 11 US2016/0228464
  • Non-Patent Document 1 Antimicrobial Agents and Chemotherapy, February
  • Non-Patent Document 2 Antimicrobial Agents and Chemotherapy, August
  • An object of the present invention is to provide a medicament useful for treating or preventing mycobacterial infections which has few side effects.
  • cytochrome bc1 inhibitor and clarithromycin or azithromycin, or pharmaceutically acceptable salts thereof, or new combinations of a cytochrome bc1 inhibitor, clarithromycin or azithromycin, and clofazimine, or pharmaceutically acceptable salts thereof are particularly effective in the prevention and/or treatment of a mycobacterial infection, especially non-tuberculous mycobacterial infection, as compared to cases where the agents are administered alone.
  • Clarithromycin is one of the macrolides of a combination regimen that the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) recommended as a first-line therapy for MAC disease.
  • Clarithromycin, azithromycin as well is/are the only (single) agents used for treatment of MAC disease for which there is a correlation between in vitro susceptibility and in vivo (clinical) response. Specifically, treatment success correlates with in vitro macrolide susceptibility, while conversely, patients who have MAC isolates that are macrolide resistant do not respond favorably to macrolide-containing regimens. This fundamental relationship has not been established for any other agent in the treatment of MAC lung disease.
  • Clofazimine is an orally administered drug approved for the treatment of leprosy, currently repurposed as an anti-TB drug.
  • a retrospective review reported that a significantly greater proportion of pulmonary disease patients infected by MAC treated with clofazimine converted to negative cultures, although relapse still occurred. In vitro, its MIC ranges from 1-4 ⁇ g/mL against M. avium and is ⁇ 1 ⁇ g/mL against the majority of M. intracellulare isolates.
  • Azithromycin is one of the macrolides of a combination regimen that the ATS/IDSA recommended as a first-line therapy for MAC disease. Since clarithromycin inhibits cytochrome P-450 (CYP) 3A and affects the metabolism of other drugs but azithromycin does not inhibit CYP3A, azithromycin is preferentially used for treatment of MAC disease.
  • CYP cytochrome P-450
  • oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of TB on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents.
  • the cytochrome bc1 complex is one of the validated targets for anti-mycobacteria drug development. The complex is assembled with three subunits, qcrA, qcrB and qcrC. One of the qcrB inhibitors, Telacebec, inhibited the growth of TB not only in vitro but an in vivo mouse model.
  • the cytochrome bc1 inhibitor of the present invention may be a compound of the following general formula (I) :
  • a compound represented by formula (I), or its pharmaceutically acceptable salt has excellent cytochrome bc1 inhibitory activity.
  • a medicament characterized in that (A) a compound represented by formula (I): (I)
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen atom;
  • X is CH or N
  • Y is CH or N
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4;
  • R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; is combined with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
  • a method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt with a compound represented by formula (I) in the above (1), or its pharmaceutically acceptable salt.
  • a method of enhancing the anti-bacterial activity of a compound represented by formula (I) in the above (1), or its pharmaceutically acceptable salt comprising administering the compound represented by formula (I) in the above (1), or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen atom;
  • X is CH or N
  • Y is CH or N
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; and
  • a pharmaceutical composition or kit comprising:
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen atom;
  • X is CH or N
  • Y is CH or N
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; and
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl,
  • Y is CH or N
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; is combined with
  • a method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt with a compound represented by formula (I) in the above (25), or its pharmaceutically acceptable salt.
  • a method of enhancing the anti-bacterial activity of a compound represented by formula (I) in the above (25), or its pharmaceutically acceptable salt comprising administering the compound represented by formula (I) in the above (25), or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt.
  • a method of treating mycobacterial infection comprising administering a combination of
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen atom;
  • X is CH or N
  • Y is CH or N
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
  • (C) clofazimine, or its pharmaceutically acceptable salt in a therapeutically effective amount thereof to an individual in need of treatment for mycobacterial infection.
  • a pharmaceutical composition or kit comprising:
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen atom;
  • X is CH or N
  • Y is CH or N
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
  • a medicament characterized in that (A) a compound defined below , or its pharmaceutically acceptable salt; is combined with
  • a method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt with a compound (A) in the above (49), or its pharmaceutically acceptable salt.
  • a method of enhancing the anti-bacterial activity of a compound (A) in the above (49) , or its pharmaceutically acceptable salt comprising administering the compound (A) in the above (49), or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
  • a pharmaceutical composition or kit comprising:
  • R 1 , R 2 , R 8 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen atom;
  • X is CH or N
  • Y is CH or N
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy,' n is 0, 1, 2, 3 or 4; is combined with
  • a method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt with a compound represented by formula (I) in the above (1') , or its pharmaceutically acceptable salt.
  • a method of enhancing the anti-bacterial activity of a compound represented by formula (I) in the above (1'), or its pharmaceutically acceptable salt comprising administering the compound represented by formula (I) in the above (1'), or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt.
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl,
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
  • (C) clofazimine, or its pharmaceutically acceptable salt in a therapeutically effective amount thereof to an individual in need of treatment for mycobacterial infection.
  • a pharmaceutical composition or kit comprising:
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy;
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen atom;
  • X is CH or N
  • Y is CH or N
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
  • the medicament of the present invention is useful in the treatment of a mycobacterial infection, especially non-tuberculous mycobacterial infection.
  • Figure 1 shows the mean log10 value for CFUs of each lung of the 15 study groups after the end of treatment, as described hereinafter (13 study groups comprise treatment regimens comprising Clarithromycin (CAM) , Clofazimine (CFZ), cytochrome bc1 inhibitors and various combinations, and 2 study groups are control groups) .
  • 13 study groups comprise treatment regimens comprising Clarithromycin (CAM) , Clofazimine (CFZ), cytochrome bc1 inhibitors and various combinations, and 2 study groups are control groups
  • X axis indicates each study groups.
  • Y axis indicates the mean log10 value for CFUs.
  • Figure 2 shows the mean log10 value for CFUs of each lung of the 6 study groups after the end of treatment, as described hereinafter (4 study groups comprise treatment regimens comprising Clarithromycin (CAM) , CFZ, cytochrome bc1 inhibitors and various combinations, and 2 study groups are control groups) .
  • X axis indicates each study groups.
  • Y axis indicates the mean log10 value for CFUs.
  • Figure 3 shows the mean log10 value for CFUs of each lung of the 15 study groups after the end of treatment, as described hereinafter (13 study groups comprise treatment regimens comprising Clarithromycin (CAM) , CFZ, cytochrome bc1 inhibitors and various combinations, and 2 study groups are control groups) .
  • 13 study groups comprise treatment regimens comprising Clarithromycin (CAM) , CFZ, cytochrome bc1 inhibitors and various combinations, and 2 study groups are control groups
  • X axis indicates each study groups.
  • Y axis indicates the mean log10 value for CFUs.
  • Figure 4 shows the mean log10 value for CFUs of each lung of the 6 study groups after the end of treatment, as described hereinafter (4 study groups comprise treatment regimens comprising Azithromycin (AZM) , Rifampicin (RFP), Ethambutol (ETB), CFZ, cytochrome bc1 inhibitor and various combinations, and 2 study groups are control groups) .
  • AZM Azithromycin
  • RFP Rifampicin
  • ETB Ethambutol
  • CFZ cytochrome bc1 inhibitor
  • 2 study groups are control groups
  • X axis indicates each study groups.
  • Y axis indicates the mean log10 value for CFUs.
  • Figure 5 shows the log10 value for CFUs of each of the 12 study groups, as described hereinafter (10 study groups comprise conditions containing either Clarithromycin (CAM) or cytochrome bc1 inhibitors, and 2 study groups are control groups) .
  • X axis indicates each study groups.
  • Y axis indicates the log10 value for CFUs.
  • Figure 6 shows the log10 value for CFUs of each of the 30 study groups, as described hereinafter (28 study groups comprise conditions containing either Clarithromycin (CAM) or combination of CAM and cytochrome bc1 inhibitors, and 2 study groups are control groups) .
  • X axis indicates each study groups.
  • Y axis indicates the log10 value for CFUs.
  • Figure 7 shows the log10 value for CFUs of each of the 11 study groups, as described hereinafter (9 study groups comprise conditions containing either Clarithromycin (CAM) or combination of CAM and cytochrome bc1 inhibitors, and 2 study groups are control groups).
  • X axis indicates each study groups.
  • Y axis indicates the log10 value for CFUs.
  • Figure 8 shows the log10 value for CFUs of each of the 26 study groups, as described hereinafter (24 study groups comprise conditions containing either Clarithromycin (CAM), I-1-3 or combination of CAM and I-1-3, and 2 study groups are control groups).
  • 24 study groups comprise conditions containing either Clarithromycin (CAM), I-1-3 or combination of CAM and I-1-3, and 2 study groups are control groups).
  • X axis indicates each study groups.
  • Y axis indicates the log10 value for CFUs.
  • Figure 9 shows the log10 value for CFUs of each of the 6 study groups, as described hereinafter (4 study groups comprise conditions containing either Clarithromycin (CAM), I-1-3, combination of CAM and Clofazimine (CFZ) or combination of CAM, CFZ and I-1-3, and 2 study groups are control groups) .
  • CAM Clarithromycin
  • I-1-3 combination of CAM and Clofazimine
  • CFZ Clofazimine
  • I-1-3 CFZ and I-1-3
  • 2 study groups are control groups
  • X axis indicates each study groups.
  • Y axis indicates the log10 value for CFUs.
  • Figure 10 shows the mean log10 value for CFUs of each lung of the 6 study groups after the end of treatment, as described hereinafter (6 study groups comprise treatment regimens comprising Clarithromycin
  • CAM CAM
  • Rifampicin Rifampicin
  • ETB Ethambutol
  • CFZ cytochrome bc1 inhibitor and various combinations
  • 2 study groups are control groups
  • X axis indicates each study groups.
  • Y axis indicates the mean log10 value for CFUs of each lung.
  • Figure 11 shows the log10 value for CFUs of each of the 7 study groups, as described hereinafter (5 study groups comprise conditions containing either Clarithromycin (CAM), Clofazimine (CFZ), I-1-3, combination of CAM and CFZ or combination of CAM, CFZ and I-1-3, and 2 study groups are control groups).
  • CAM Clarithromycin
  • CFZ Clofazimine
  • I-1-3 combination of CAM and CFZ or combination of CAM, CFZ and I-1-3
  • 2 study groups are control groups.
  • X axis indicates each study groups.
  • Y axis indicates the log10 value for CFUs.
  • halogen includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a fluorine atom and a chlorine atom are especially preferable.
  • alkyl includes a C1 to C15, preferably C1 to C10, more preferably C1 to C6 and further preferably C1 to C4 linear or branched hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.
  • alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl.
  • a more preferred embodiment is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.
  • alkenyl includes a C2 to C15, preferably a C2 to C10, more preferably a C2 to C6 and further preferably a C2 to C4 linear or branched hydrocarbon group having one or more double bond(s) at any position(s).
  • Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.
  • alkenyl is vinyl, allyl, propenyl, isopropenyl or butenyl.
  • alkynyl includes C2 to C8 straight or branched alkynyl having one or more triple bond(s) in the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Furthermore, an “alkynyl” may have a double bond.
  • alkyloxy means a group wherein the above “alkyl” is bonded to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert'butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, and hexyloxy.
  • alkyloxy is methyloxy, ethyloxy, n- propyloxy, isopropyloxy or tert'butyloxy.
  • alkenyloxy means a group wherein the above “alkenyl” is bonded to an oxygen atom. Examples include vinyloxy, allyloxy, 1-n-propenyloxy, 2- n-butenyloxy, 2-n-pentenyloxy, 2-n-hexenyloxy, 2-n-heptenyloxy, and 2-n-octenyloxy.
  • alkynyloxy means a group wherein the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1 -n-propynyloxy, 2-n- propynyloxy, 2-n-butynyloxy, 2-n-pentynyloxy, 2-n-hexynyloxy, 2-n-heptynyloxy, and 2-n-octynyloxy.
  • substituents of “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy” and “substituted alkynyloxy” include the following substituents.
  • a carbon atom at any positions may be bonded to one or more group(s) selected from the following substituents.
  • a preferable substituent halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfon
  • a more preferable substituent halogen, hydroxy, amino, cyano, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylamino, alkenylamino, and alkynylamino .
  • An especially preferable substituent halogen, hydroxy, amino, cyano, alkyloxy, and alkylamino.
  • haloalkyl includes a group wherein one or more hydrogen atom(s) attached to a carbon atom of the above “alkyl” is replaced with the above "halogen".
  • Examples include monofluoromethyl, monofluoroethyl, monofluoro-n- propyl, 2,2,3, 3, 3-n-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2, 2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1, 2-dibromoethyl, and 1,1,1- trifluoro-n-propan-2-yl.
  • haloalkyl is trifluoromethyl and trichloromethyl.
  • haloalkyloxy means a group wherein the above “haloalkyl” is bonded to an oxygen atom. Examples include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, and trichloroethoxy.
  • haloalkyloxy is trifluoromethoxy and trichloromethoxy.
  • alkylcarbonyl means a group wherein the above “alkyl” is bonded to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec'butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and n- hexylcarbonyl.
  • alkylcarbonyl is methylcarbonyl, ethylcarbonyl and n-propylcarbonyl.
  • alkenylcarbonyl means a group wherein the above “alkenyl” is bonded to a carbonyl group, Examples include vinylcarbonyl, allylcarbonyl and n-propenylcarbonyl.
  • alkynylcarbonyl means a group wherein the above “alkynyl” is bonded to a carbonyl group. Examples include ethynylcarbonyl and n- propynylcarbonyl.
  • alkylamino means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “alkyl” .
  • Examples include methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino, and N-methybN-ethylamino.
  • alkylamino is methylamino and ethylamino.
  • alkenylamino means a group wherein a hydrogen atom attached to a nitrogen atom of an amino group is replaced with the above “alkenyl”. For example, it includes ethylenylamino, propenylamino and the like. Another hydrogen atom attached to the nitrogen atom of the amino group may be replaced with the above “alkyl” .
  • Alkynylamino means a group wherein a hydrogen atom attached to a nitrogen atom of an amino group is replaced with the above “alkynyl”. For example, it includes ethynylamino, propynylamino and the like. Another hydrogen atom attached to the nitrogen atom of the amino group may be replaced with the above "alkyl”.
  • alkylsulfonyl means a group wherein the above “alkyl” is bonded to a sulfonyl group .
  • examples include methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, and sec-butylsulfonyl.
  • alkylsulfonyl is methylsulfonyl and ethylsulfonyl.
  • alkenylsulfonyl means a group wherein the above “alkenyl” is bonded to a sulfonyl group. Examples include vinylsulfonyl, allylsulfonyl, and n- propenylsulfonyl.
  • alkynylsulfonyl means a group wherein the above “alkynyl” is bonded to a sulfonyl group. Examples include ethynylsulfonyl, and n- propynylsulfonyl.
  • alkylcarbonylamino means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “alkylcarbonyl”. Examples include methylcarbonylamino, dimethylcarbonylamino, ethylcarbonylamino, diethylcarbonylamino, n- propylcarbonylamino, isopropylcarbonylamino, N,N-diisopropylcarbonylamino, n- butylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, and sec- butylcarbonylamino. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above "alkyl” .
  • alkenylcarbonylamino means a group wherein a hydrogen atom bonded to a nitrogen atom of an amino group is replaced with the above “alkenylcarbonyl”. For example, it includes ethylenylcarbonylamino, propenylcarbonylamino and the like. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above "alkyl”.
  • alkynylcarbonylamino means a group wherein a hydrogen atom bonded to a nitrogen atom of an amino group is replaced with the above “alkynylcarbonyl”. For example, it includes ethynylcarbonylamino, propynylcarbonylamino and the like. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl” .
  • alkylsulfonylamino means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “alkylsulfonyl”. Examples include methylsulfonylamino, dimethylsulfonylamino, ethylsulfonylamino, diethylsulfonylamino, n- propylsulfonylamino, isopropylsulfonylamino, N,N-diisopropylsulfonylamino, n- butylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, and sec- butylsulfonylamino.
  • alkylsulfonylamino is methylsulfonylamino and ethylsulfonylamino.
  • alkenylsulfonylamino means a group wherein a hydrogen atom bonded to a nitrogen atom of an amino group is replaced with the above “alkenylsulfonyl”. For example, it includes ethylenylsulfonylamino, propenylsulfonylamino and the like. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above "alkyl".
  • alkynylsulfonylamino means a group wherein a hydrogen atom bonded to a nitrogen atom of an amino group is replaced with the above “alkynylsulfonyl”. For example, it includes ethynylsulfonylamino, propynylsulfonylamino and the like. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above “alkyl” .
  • alkylimino means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkyl”. Examples include methylimino, ethylimino, n-propylimino, and isopropylimino.
  • alkenylimino'' means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkenyl”. Examples include ethylenylimino, and n-propenylimino.
  • alkynylimino means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkynyl”. Examples include ethynylimino, and n-propynylimino.
  • alkylcarbonylimino means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkylcarbonyl”. Examples include methylcarbonylimino, ethylcarbonylimino, n- propylcarbonylimino, and isopropylcarbonylimino.
  • alkenylcarbonylimino means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkenylcarbonyl”. Examples include ethylenylcarbonylimino, and n- propenylcarbonylimino.
  • alkynylcarbonylimino means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkynylcarbonyl”. Examples include ethynylcarbonylimino and n* propynylcarbonylimino.
  • alkyloxyimino means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkyloxy”. Examples include methyloxyimino, ethyloxyimino, n-propyloxyimino, and isopropyloxyimino.
  • alkenyloxyimino means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkenyloxy”. Examples include ethylenyloxyimino, and n-propenyloxyimino.
  • alkynyloxy imino means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above “alkynyloxy” .
  • Examples include ethynyloxyimino, and n-propynyloxyimino.
  • alkylcarbonyloxy means a group wherein the above “alkylcarbonyl” is bonded to an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, and secbutylcarbonyloxy.
  • alkylcarbonyloxy is methylcarbonyloxy and ethylcarbonyloxy.
  • alkenylcarbonyloxy means a group wherein the above
  • alkenylcarbonyl is bonded to an oxygen atom. Examples include ethylenylcarbonyloxy and n-propenylcarbonyloxy.
  • alkynylcarbonyloxy means a group wherein the above “alkynylcarbonyl” is bonded to an oxygen atom. Examples include ethynylcarbonyloxy and n-propynylcarbonyloxy.
  • alkyloxycarbonyl means a group wherein the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, n- pentyloxycarbonyl, isopentyloxycarbonyl, and n-hexyloxycarbonyl.
  • alkyloxycarbonyl is methyloxycarbonyl, ethyloxycarbonyl and n-propyloxycarbonyl.
  • alkenyloxycarbonyl means a group wherein the above “alkenyloxy” is bonded to a carbonyl group. Examples include ethylenyloxycarbonyl and n-propenyloxycarbonyl.
  • alkynyloxycarbonyl means a group wherein the above “alkynyloxy” is bonded to a carbonyl group . Examples include ethynyloxycarbonyl and n-propynyloxycarbonyl.
  • alkylsulfanyl means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above “alkyl”. Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, and isopropylsulfanyl.
  • alkenylsulfanyl means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above “alkenyl” .
  • Examples include ethylenylsulfanyl, and n-propenylsulfanyl.
  • alkynylsulfanyl means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above “alkynyl”. Examples include ethynylsulfanyl, and n-propynylsulfanyl.
  • alkylsulfinyl means a group wherein the above “alkyl” is bonded to a sulfinyl group. Examples include methylsulfinyl, ethylsulfinyl, n- propylsulfinyl, and isopropylsulfinyl.
  • alkenylsulfinyl means a group wherein the above “alkenyl” is bonded to a sulfinyl group. Examples include ethylenylsulfinyl, and n- propenylsulfinyl.
  • alkynylsulfinyl means a group wherein the above “alkynyl” is bonded to a sulfinyl group. Examples include ethynylsulfinyl and n* propynylsulfinyl.
  • alkylcarbamoyl means a group wherein a hydrogen atom bonded to a nitrogen atom of a carbamoyl group is replaced with the above “alkyl”. For example, it includes methylcarbamoyl, ethylcarbamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl”.
  • alkenylcarbamoyl means a group wherein a hydrogen atom bonded to a nitrogen atom of a carbamoyl group is replaced with the above “alkenyl”. For example, it includes ethylenylcarbamoyl, propenylcarbamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl".
  • alkynylcarbamoyl means a group wherein a hydrogen atom bonded to a nitrogen atom of a carbamoyl group is replaced with the above “alkynyl”. For example, it includes ethynylcarbamoyl, propynylcarbamoyl and the like.
  • alkylsulfamoyl means a group wherein a hydrogen atom bonded to a nitrogen atom of a sulfamoyl group is replaced with the above “alkyl”. For example, it includes methylsulfamoyl, dimethylsulfamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above “alkyl” .
  • alkenylsulfamoyl means a group wherein a hydrogen atom bonded to a nitrogen atom of a sulfamoyl group is replaced with the above “alkenyl”. For example, it includes ethylenylsulfamoyl, propenylsulfamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl".
  • alkynylsulfamoyl means a group wherein a hydrogen atom bonded to a nitrogen atom of a sulfamoyl group is replaced with the above “alkynyl”. For example, it includes ethynylsulfamoyl, propynylsulfamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl".
  • aromatic carbocyclyl means a cyclic aromatic hydrocarbon group which is monocyclic or polycyclic having two or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl.
  • aromatic carbocyclyl is phenyl
  • aromatic carbocycle means a cyclic aromatic hydrocarbon ring which is monocyclic or polycyclic having two or more rings. Examples include a benzene ring, a naphthalene ring, an anthracene ring, and a phenanthrene ring.
  • aromatic carbocycle is a benzene ring or a naphthalene ring.
  • non-aromatic carbocyclyl means a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group, which is monocyclic or polycyclic having two or more rings.
  • the "non-aromatic carbocyclyl” which is polycyclic having two or more rings includes a fused ring group wherein a non-aromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above "aromatic carbocyclyl”.
  • non-aromatic carbocyclyl also include a group having a bridge or a group to form a spiro ring as follows:
  • the non-aromatic carbocyclyl which is monocyclic is preferably C3 to C 16, more preferably C3 to C 12 and further preferably C4 to C8 carbocyclyl.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
  • non-aromatic carbocyclyl which is polycyclic having two or more rings, include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.
  • non-aromatic carbocycle means a cyclic saturated hydrocarbon ring or a cyclic unsaturated non-aromatic hydrocarbon ring, which is monocyclic or polycyclic having two or more rings.
  • non-aromatic carbocycle which is polycyclic having two or more rings, includes a fused ring wherein the non- aromatic carbocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above "aromatic carbocycle”.
  • non-aromatic carbocycle also include a ring having a bridge or a ring to form a spiro ring as follows ;
  • the non-aromatic carbocycle which is monocyclic is preferably C3 to C 16, more preferably C3 to C 12 and further preferably C4 to C8 carbocyclyl.
  • Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclohexadiene.
  • non-aromatic carbocycle which is polycyclic having two or more rings
  • examples of a non-aromatic carbocycle include indane, indene, acenaphthene, tetrahydronaphthalene, and fluorene.
  • aromatic heterocyclyl means an aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N.
  • aromatic heterocyclyl which is polycyclic having two or more rings, includes a fused ring group wherein an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above "aromatic carbocyclyl”.
  • the aromatic heterocyclyl which is monocyclic, is preferably a 5- to 8- membered ring and more preferably a 5- to 6- membered ring.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl.
  • aromatic heterocyclyl which is bicyclic, include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl.
  • aromatic heterocyclyl which is polycyclic having three or more rings, include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.
  • aromatic heterocycle means an aromatic ring, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N.
  • aromatic heterocycle which is polycyclic having two or more rings, includes a fused ring wherein an aromatic heterocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above "aromatic carbocycle”.
  • the aromatic heterocycle which is monocyclic, is preferably a 5- to 8- membered ring and more preferably a 5- or 6- membered ring.
  • Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophen, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, and thiadiazole.
  • Examples of an aromatic heterocycle which is bicyclic, include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, and thiazolopyridine.
  • Examples of an aromatic heterocycle which is polycyclic having three or more rings, include carbazole, acridine, xanthene, phenothiazine, phenoxathiine, phenoxazine, and dibenzofuran.
  • non-aromatic heterocyclyl means a non-aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N.
  • non- aromatic heterocyclyl which is polycyclic having two or more rings, includes an above-mentioned non-aromatic heterocyclyl fused with a ring of the above "aromatic carbocyclyl", “non-aromatic carbocyclyl” and/or "aromatic heterocyclyl”.
  • non- aromatic heterocyclyl which is polycyclic having two or more rings, includes an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, fused with a ring of the above “non-aromatic carbocyclyl” and/or "aromatic heterocyclyl".
  • non-aromatic heterocyclyl also include a group having a bridge or a group to form a spiro ring as follows:
  • the non-aromatic heterocyclyl which is monocyclic, is preferably a 3- to 8-membered and more preferably a 5- to 6-membered ring.
  • Examples include dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dihydro
  • non-aromatic heterocyclyl which is polycyclic having two or more rings, include indolinyl, isoindolinyl, chromanyl, and isochromanyl.
  • non-aromatic heterocycle means a cyclic non-aromatic ring, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected from O, S and N.
  • non-aromatic heterocycle which is polycyclic having two or more rings, includes an above-mentioned non-aromatic heterocycle fused with a ring of the above "aromatic carbocycle”, “non-aromatic carbocycle” and/or "aromatic heterocycle”.
  • non-aromatic heterocycle also includes a ring having a bridge or a ring to form a spiro ring.
  • the non-aromatic heterocycle which is non-bridged is preferably a 3 to 8-membered ring, more preferably a 4 to 8-membered ring, and further preferably a 5 or 6-membered ring.
  • the non-aromatic heterocycle which is bridged is preferably a 6 to 10- membered ring and more preferably a 8 or 9-membered ring.
  • a number of members mean a number of all annular atoms of a bridged non-aromatic heterocycle.
  • the non-aromatic heterocycle which is monocyclic is preferably a 3 to 8-membered ring, and more preferably a 5 or 6-membered ring.
  • Examples include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, pyridone, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyr
  • non-aromatic heterocycle which is polycyclic having two or more rings, include indoline, isoindoline, chromane, and isochromane.
  • aromatic carbocyclyloxy means a group wherein the "aromatic carbocycle” is bonded to an oxygen atom. Examples include phenyloxy and naphthyloxy.
  • non-aromatic carbocyclyloxy means a group wherein the “non-aromatic carbocycle” is bonded to an oxygen atom, Examples include cyclopropyloxy, cyclohexyloxy, and cyclohexenyloxy.
  • aromatic heterocyclyloxy means a group wherein the "aromatic heterocycle” is bonded to an oxygen atom. Examples include pyridyloxy and oxazolyloxy.
  • non-aromatic heterocyclyloxy means a group wherein the “non-aromatic heterocycle” is bonded to an oxygen atom.
  • examples include piperidinyloxy and tetrahydrofuryloxy.
  • aromatic carbocyclylcarbonyl means a group wherein the "aromatic carbocycle” is bonded to a carbonyl group. Examples include phenylcarbonyl and naphthylcarbonyl.
  • non-aromatic carbocyclylcarbonyl means a group wherein the “non-aromatic carbocycle” is bonded to a carbonyl group. Examples include cyclopropylcarbonyl, cyclohexylcarbonyl, and cyclohexenylcarbonyl.
  • non-aromatic carbocyclylcarbonyloxy means a group wherein the “non-aromatic carbocyclylcarbonyl” is bonded to an oxygen atom. Examples include cyclopropylcarbonyloxy, cyclohexylcarbonyloxy, and cyclohexenylcarbonyloxy.
  • aromatic heterocyclylcarbonyl means a group wherein the "aromatic heterocycle” is bonded to a carbonyl group. Examples include pyridylcarbonyl and oxazolylcarbonyl.
  • non-aromatic heterocyclylcarbonyl means a group wherein the “non-aromatic heterocycle” is bonded to a carbonyl group. Examples include piperidinylcarbonyl, and tetrahydrofurylcarbonyl.
  • aromatic carbocyclyloxycarbonyl means a group wherein the "aromatic carbocyclyloxy” is bonded to a carbonyl group. Examples include phenyloxycarbonyl and naphthyloxycarbonyl.
  • non-aromatic carbocyclyloxycarbonyl means a group wherein the “non-aromatic carbocyclyloxy” is bonded to a carbonyl group. Examples include cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, and cyclohexenyloxycarbonyl.
  • aromatic heterocyclyloxycarbonyl means a group wherein the "aromatic heterocyclyloxy” is bonded to a carbonyl group .
  • aromatic heterocyclyloxycarbonyl examples include pyridyloxycarbonyl and oxazolyloxycarbonyl.
  • non-aromatic heterocyclyloxycarbonyl means a group wherein the “non-aromatic heterocyclyloxy” is bonded to a carbonyl group. Examples include piperidinyloxycarbonyl, and tetrahydrofuryloxycarbonyl.
  • aromatic carbocyclylalkyloxy means an alkyloxy substituted with one or more "aromatic carbocyclyl” described above. Examples include benzyloxy, phenethyloxy, phenybn-propyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, and a group of the following formula:
  • non-aromatic carbocyclylalkyloxy means an alkyloxy substituted with one or more "non-aromatic carbocyclyl" described above.
  • non- aromatic carbocyclylalkyloxy also includes “non-aromatic carbocyclylalkyloxy” wherein the alkyl part is substituted with the above "aromatic carbocyclyl”.
  • Examples include cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopenthylmethyloxy, cyclohexylmethyloxy, and a group of the following formula:
  • aromatic heterocyclylalkyloxy means an alkyloxy substituted with one or more "aromatic heterocyclyl" described above.
  • the "aromatic heterocyclylalkyloxy” also includes “aromatic heterocyclylalkyloxy” wherein the alkyl part is substituted with the above "aromatic carbocyclyl” and/or "non-aromatic carbocyclyl".
  • Examples include pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, and groups of the following formulae :
  • non-aromatic heterocyclylalkyloxy means an alkyloxy substituted with one or more "non- aromatic heterocyclyl” described above.
  • the "non- aromatic heterocyclylalkyloxy” also includes “non-aromatic heterocyclylalkyloxy” wherein the alkyl part is substituted with the above "aromatic carbocyclyl", “non- aromatic carbocyclyl” and/or "aromatic heterocyclyl”. Examples include tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, and groups of the following formulae :
  • aromatic carbocyclylalkyloxycarbonyl means an alkyloxycarbonyl substituted with one or more "aromatic carbocyclyl” described above. Examples include benzyloxycarbonyl, phenethyloxycarbonyl, phenyl-n- propyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, and a group of the following formula:
  • non-aromatic carbocyclylalkyloxycarbonyl means an alkyloxycarbonyl substituted with one or more "non-aromatic carbocyclyl” described above.
  • the "non-aromatic carbocyclylalkyloxycarbonyl” also includes “non-aromatic carbocyclylalkyloxycarbonyl” wherein the alkyl part is substituted with the above “aromatic carbocyclyl” . Examples include cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopenthylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, and a group of the following formula:
  • aromatic heterocyclylalkyloxycarbonyl means an alkyloxycarbonyl substituted with one or more "aromatic heterocyclyl” described above.
  • the "aromatic heterocyclylalkyloxycarbonyl” also include “aromatic heterocyclylalkyloxycarbonyl” wherein the alkyl part is substituted with the above "aromatic carbocyclyl” and/or "non-aromatic carbocyclyl".
  • Examples include pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyloxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, and groups of the following formulae:
  • non-aromatic heterocyclylalkyloxycarbonyl means an alkyloxycarbonyl substituted with one or more "non-aromatic heterocyclyl” described above.
  • the "non-aromatic heterocyclylalkyloxycarbonyl” also includes “non-aromatic heterocyclylalkyloxycarbonyl” wherein the alkyl part is substituted with the above "aromatic carbocyclyl", “non-aromatic carbocyclyl” and/or "aromatic heterocyclyl” .
  • Examples include tetrahydropyranylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, piperazinylmethyloxycarbonyl, and groups of the following formulae:
  • aromatic carbocyclylalkylamino means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "aromatic carbocyclylalkyl". Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, and dibenzylamino.
  • non-aromatic carbocyclylalkylamino means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “non-aromatic carbocyclylalkyl". Examples include cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, and cyclohexylmethylamino.
  • aromatic heterocyclylalkylamino means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "aromatic heterocyclylalkyl".
  • aromatic heterocyclylalkyl examples include pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolylmethylamino, and benzoxazolylmethylamino.
  • non-aromatic heterocyclylalkylamino means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above “non-aromatic heterocyclylalkyl”. Examples include tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, and piperazinylmethylamino.
  • aromatic carbocyclylsulfanyl means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the "aromatic carbocycle”. Examples include phenylsulfanyl and naphthylsulfanyl.
  • non-aromatic carbocyclylsulfanyl means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the "non-aromatic carbocycle". Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, and cyclohexenylsulfanyl.
  • aromatic heterocyclylsulfanyl means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the "aromatic heterocycle”. Examples include pyridylsulfanyl and oxazolylsulfanyl.
  • non-aromatic heterocyclylsulfanyl means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the "non-aromatic heterocycle”. Examples include piperidinylsulfanyl and tetrahydrofurylsulfanyl.
  • non-aromatic carbocyclylsulfonyl means a group wherein the “non-aromatic carbocycle” is bonded to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclohexenylsulfonyl.
  • aromatic carbocyclylsulfonyl means a group wherein the "aromatic carbocycle” is bonded to a sulfonyl group .
  • aromatic carbocyclylsulfonyl examples include phenylsulfonyl and naphthylsulfonyl.
  • aromatic heterocyclylsulfonyl means a group wherein the "aromatic heterocycle” is bonded to a sulfonyl group .
  • aromatic heterocyclylsulfonyl examples include pyridylsulfonyl and oxazolylsulfonyl.
  • non-aromatic heterocyclylsulfonyl means a group wherein the “non-aromatic heterocycle” is bonded to a sulfonyl group.
  • examples include piperidinylsulfonyl and tetrahydrofurylsulfonyl.
  • R 1 , R 2 , R 3 and R 4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy.
  • R 1 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
  • R 1 is a hydrogen atom, halogen or substituted or unsubstituted alkyl.
  • R 1 is a hydrogen atom.
  • R 1 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
  • R 1 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen and the like.
  • R 2 is a hydrogen atom, halogen, cyano or substituted or unsubstituted alkyl.
  • R 2 is a hydrogen atom, halogen or substituted or unsubstituted alkyl.
  • R 2 is a hydrogen atom or halogen.
  • R 2 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
  • R 2 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen and the like.
  • R 3 is a hydrogen atom, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
  • R 3 is a hydrogen atom, halogen or substituted or unsubstituted alkyl.
  • R 3 is a hydrogen atom or halogen.
  • R 3 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
  • R 3 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen and the like.
  • R 4 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
  • R 4 is a hydrogen atom, halogen or substituted or unsubstituted alkyl. Particularly preferably, R 4 is a hydrogen atom.
  • R 4 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
  • R 4 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen and the like.
  • R 5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
  • R 5 is halogen or substituted or unsubstituted alkyl.
  • R 5 is substituted or unsubstituted alkyl.
  • R 5 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
  • R 5 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen and the like.
  • R 6 , R 7 , R 8 and R 9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that
  • R 6 , R 7 , R 8 and R 9 are not simultaneously hydrogen atom.
  • R 6 is a hydrogen atom or halogen. Further preferably, R 6 is a hydrogen atom.
  • R 7 is a hydrogen atom or halogen. Further preferably, R 7 is halogen.
  • R 8 is a hydrogen atom or halogen. Further preferably, R 8 is a hydrogen atom.
  • R 9 is a hydrogen atom or halogen. Further preferably, R 9 is a hydrogen atom.
  • R 6 and R 7 are each independently halogen, and R 8 and R 9 are hydrogen atom are also preferred.
  • R 6 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, alkyloxy and the like.
  • R 6 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen.
  • R 7 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, alkyloxy and the like.
  • R 7 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen.
  • R 8 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, alkyloxy and the like.
  • R 8 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen.
  • R 9 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, alkyloxy and the like.
  • R 9 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen.
  • X is CH or N.
  • Y is CH or N.
  • Embodiments in which X is N, and Y is N are also preferred.
  • Embodiments in which X is CH, and Y is N are also preferred.
  • m is 0, 1, 2, 3 or 4.
  • m is 0, 1 or 2.
  • m is 1 or 2.
  • m is 1.
  • a group represented by formula: in formula (I) is preferably a group represented by formula:
  • a group represented by formula: in formula (I) is preferably a group represented by formula:
  • R 10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
  • R 10 is each independently halogen or substituted or unsubstituted alkyl.
  • R 10 is each independently substituted or unsubstituted alkyl.
  • R 10 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
  • R 11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio.
  • R 11 is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
  • R 11 is substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
  • R 11 is substituted or unsubstituted alkyloxy, including trihaloalkyloxy (like OCFs) .
  • R 11 is a substituted group
  • a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, alkyloxy, alkylamino, non-aromatic carbocyclyl and the like.
  • R 11 is a substituted group
  • a further preferable substituent on said substituted group is selected from halogen and the like.
  • R 12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy.
  • R 12 is each independently halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
  • n is 0, 1, 2, 3 or 4.
  • n is 0, 1 or 2.
  • n is
  • n 0.
  • Preferred combinations of substituents of a compound represented by formula (I) include the following 1) to 6) -
  • R 1 and R 4 are hydrogen atom;
  • R 2 is halogen;
  • R 3 is a hydrogen atom;
  • R 5 is substituted or unsubstituted alkyl;
  • R 6 , R 8 and R 9 are hydrogen atom;
  • R 7 is halogen;
  • X is N;
  • Y is N;
  • m is 1;
  • R 10 is substituted or unsubstituted alkyl;
  • R 11 is substituted or unsubstituted alkyloxy;
  • n is 0;
  • R 1 and R 4 are hydrogen atom; R 2 is halogen; R 3 is a hydrogen atom; R 5 is substituted or unsubstituted alkyl; R 7 , R 8 and R 9 are hydrogen atom; R 6 is halogen; X is CH; Y is N; m is 0; R 11 is substituted or unsubstituted alkyl; n is 0;
  • R 1 and R 4 are hydrogen atom;
  • R 2 is a hydrogen atom;
  • R 3 is halogen;
  • R 5 is substituted or unsubstituted alkyl;
  • R 7 , R 8 and R 9 are hydrogen atom;
  • R 6 is halogen;
  • X is CH;
  • Y is N;
  • m is 0;
  • R 11 is substituted or unsubstituted alkyl; n is 0;
  • R 1 and R 4 are hydrogen atom;
  • R 2 is a hydrogen atom;
  • R 3 is halogen;
  • R 5 is substituted or unsubstituted alkyl;
  • R 6 , R 8 and R 9 are hydrogen atom;
  • R 7 is halogen;
  • X is N;
  • Y is N;
  • m is 1;
  • R 10 is substituted or unsubstituted alkyl;
  • R 11 is substituted or unsubstituted alkyloxy;
  • n is 0;
  • R 1 and R 4 are hydrogen atom; R 2 is halogen; R 3 is a hydrogen atom; R 5 is substituted or unsubstituted alkyl; R 6 , R 8 and R 9 are hydrogen atom; R 7 is halogen; X is N; Y is N; m is 2; R 10 is each independently substituted or unsubstituted alkyl; R 11 is substituted or unsubstituted alkyloxy; n is 0;
  • R 1 and R 4 are hydrogen atom;
  • R 2 is substituted or unsubstituted alkyl;
  • R 3 is hydrogen atom;
  • R 5 is substituted or unsubstituted alkyl;
  • R 6 , R 8 and R 9 are hydrogen atom;
  • R 7 is halogen;
  • X is N;
  • Y is N;
  • m is 1 ;
  • R 10 is substituted or unsubstituted alkyl;
  • R 11 is substituted or unsubstituted alkyloxy;
  • n is 0.
  • any one of more of the compounds of the present invention may be in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts of the compounds include, for example, salts with alkaline metal (e.g. , lithium, sodium or potassium), alkaline earth metal (e.g., calcium or barium), magnesium, transition metal (e.
  • organic bases e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline or quinoline
  • amino acids or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, or hydroiodic acid) or organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid or ethane
  • organic acids e.g., hydroch
  • the compounds of formula (I) are not limited to specific isomers but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, enantiomers, or rotamers), racemates or mixtures thereof. [0157]
  • One or more hydrogen, carbon and/or other atom(s) in the compounds of formula (I) may be replaced with isotopes of hydrogen, carbon and/or other atoms respectively.
  • isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl respectively.
  • the compounds of formula (I) include the compounds replaced with these isotopes.
  • the compounds replaced with the above isotopes are useful as medicines and include all of radiolabeled compounds of the compound of formula (I).
  • a "method of radiolabeling" in the manufacture of the “radiolabeled compounds” is encompassed by the present invention, and the “radiolabeled compounds” are useful for studies on metabolized drug pharmacokinetics, studies on binding assay and/or diagnostic tools.
  • a radiolabeled compound of the compounds of formula (I) can be prepared using well-known methods in this field of the invention.
  • a tritium-labeled compound of formula (I) can be prepared by introducing a tritium to a certain compound of formula (I) through a catalytic dehalogenation reaction using a tritium. This method comprises reacting an appropriately-halogenated precursor of the compound of formula (I) with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absent of a base.
  • an appropriate catalyst such as Pd/C
  • the other appropriate method of preparing a tritium-labeled compound can be referred to "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)".
  • a 14 CTabeled compound can be prepared by using a raw material having 14 C.
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates), co-crystal and/or crystal polymorphs.
  • the present invention encompasses those various solvates, co-crystal and crystal polymorphs.
  • “Solvates” may be those wherein any numbers of solvent molecules (e.g., water molecules) are coordinated with the compounds of formula (I) .
  • the compounds of formula (I) or pharmaceutically acceptable salts thereof When the compounds of formula (I) or pharmaceutically acceptable salts thereof are allowed to stand in the atmosphere, the compounds may absorb water, resulting in attachment of adsorbed water or formation of hydrates. Recrystallization of the compounds of formula (I) or pharmaceutically acceptable salts thereof may produce crystal polymorphs.
  • "Co-crystal” means that a compound of formula (I) or a salt thereof and a counter-molecule exist in the same crystal lattice, and it can be formed with any number of counter-molecules.
  • the compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof may form prodrugs.
  • the present invention also encompasses such various prodrugs.
  • Prodrugs are derivatives of the compounds of the present invention that have chemically or metabolically degradable groups, and compounds that are converted to the pharmaceutically active compounds of the present invention through solvolysis or under physiological conditions in vivo.
  • Prodrugs include compounds that are converted to the compounds of formula (I) through enzymatic oxidation, reduction, hydrolysis or the like under physiological conditions in vivo, compounds that are converted to the compounds of formula (I) through hydrolysis by gastric acid etc., and the like, Methods for selecting and preparing suitable prodrug derivatives are described in, for example, "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs themselves may have some activity.
  • prodrugs include acyloxy derivatives and sulfonyloxy derivatives that are prepared by, for example, reacting compounds having hydroxyl group(s) with suitable acyl halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonyl anhydride and mixed anhydride, or with a condensing agent.
  • they include CH 3 COO-, C 2 H 5 COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH(NH 2 )COO-, CH 2 N(CH 3 ) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p-CH 3 O- PhSO 3 -, PhSO 3 - and p-CH 3 PhSO 3 -.
  • pharmaceutically acceptable means preventively or therapeutically harmless.
  • the compounds represented by Formula (I) of the present invention can be produced according to general procetures as described below. Also, the compounds of the invention can be prepared according to other methods based on the knowledge in organic chemistry.
  • PG is an amino protecting group such as Boc, Cbz and etc.
  • R a1 is halogen, triflate, nonaflate, mesylate or tosylate, the other symbols are as defined above.
  • solvent examples include toluene, DMF, DMA, tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane and the like, and these solvents may be used alone or in combination.
  • Examples of the base include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU and the like.
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a1.
  • the reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
  • the reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
  • Compound a5 can be obtained by reacting with Compound a4 in the presense of Palladium, Ligand and base after reacting Compound a3 with deprotecting agents.
  • reaction solvent for deprotecting reaction examples include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1, 4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
  • Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, methane sulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminium trichloride, bromocatechol borane, trimethylsilyl chloride, trimethylsilyl triflate and the like.
  • the amount of the deprotecting agent may be 1 to 100 mole equivalents, preferably 1 to 50 mole equivalents of Compound a4.
  • Examples of the Palladium include palladium acetate, Pd(PP 3 ) 4 , PdCl 2 ((PPh 3 ) 2 , Pd 2 (dba) 3 and the like.
  • the amount of the Palladium may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a4.
  • Ligand examples include 2-Dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl,Dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) and the like.
  • the amount of the Ligand may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a3.
  • Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like.
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a4.
  • reaction solvent examples include methanol, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
  • the reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
  • the reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
  • Compound a6 can be obtained by reacting with Compound a2 and Compound a4 in the presense of Palladium, Ligand and base.
  • Examples of the Palladium include palladium acetate, Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 and the like.
  • the amount of the Palladium may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a2.
  • Ligand examples include 2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl, dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) and the like.
  • the amount of the Ligand may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a2.
  • Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like.
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a2.
  • reaction solvent examples include methanol, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
  • the reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
  • the reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
  • Compound a5 can be obtained by reacting with Compound al in the presence of the base after reacting Compound a6 with deprotecting agents.
  • reaction solvent for deprotecting reaction examples include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4'dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
  • Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, meth ane sulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminium trichloride, bromocatechol borane, trimethylsilyl chloride, trimethylsilyl triflate and the like.
  • the amount of the deprotecting agent may be 1 to 100 mole equivalents, preferably 1 to 50 mole equivalents of Compound al.
  • solvent examples include toluene, DMF, DMA, dimethyl sulfoxide tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane and the like, and these solvents may be used alone or in combination.
  • Examples of the base include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU and the like.
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound al.
  • the reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
  • the reaction time may be 0. 1 to 24 hours, preferably 1 to 12 hours.
  • Compound a7 can be obtained by reacting Compound a5 with reductants.
  • reaction solvent examples include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1, 4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
  • reductants examples include hydrogen with Pd carbon, hydrogen with Pd(OH) 2 , sodium borohydrodie with NiCl(H 2 O) 6 , lithium aluminumhydride and the like.
  • the amount of the reductants may be 1 to 100 mole equivalents, preferably 1 to 10 mole equivalents of Compound a5.
  • the reaction temperature may be 0°C to 200°C, preferably 0°C to
  • the reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
  • R a2 is halogen, tritiate, nonaflate, mesylate, tosylate, bornic acid or boronate
  • R a3 is triflate, nonaflate, mesylate, tosylate, bornic acid or boronate, the other symbols are as defined above.
  • Examples of the Palladium include palladium acetate, Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 , PdCl 2 (dppf) and the like.
  • the amount of the Palladium may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a8.
  • Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate and the like.
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a8.
  • reaction solvent examples include water, DMF, DMA, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
  • the reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
  • the reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
  • Compound a11 can be obtained by reacting with Compound a10 in the presense of Palladium, ligand and base after reacting Compound a4 with deprotecting agents.
  • reaction solvent for deprotecting reaction examples include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
  • Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, methane sulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminium trichloride, bromocatechol borane, trimethylsilyl chloride, trimethylsilyl triflate and the like.
  • the amount of the deprotecting agent may be 1 to 100 mole equivalents, preferably 1 to 50 mole equivalents of Compound a4.
  • Examples of the Palladium include palladium acetate, Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 and the like.
  • the amount of the Palladium may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a4.
  • Ligand examples include 2-dicyclohexylphosphino-2',6' - diisopropoxy-1,1'-biphenyl,dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) and the like.
  • the amount of the Ligand may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a4.
  • Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert'butoxide, sodium tert'butoxide and the like .
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a4.
  • reaction solvent examples include methanol, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
  • the reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
  • the reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
  • Compound a12 can be obtained by reacting Compound all with reductants.
  • reaction solvent examples include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
  • the reductants includesodium borohydrodie with NiCl 2 (H 2 O) 6 , lithium aluminumhydride, borane tetrahydrofran, borane dimethylsulfide and the like .
  • the amount of the reductants may be 1 to 100 mole equivalents, preferably 1 to 10 mole equivalents of Compound a11.
  • the reaction temperature may be 0°C to 200°C, preferably 0°C to
  • the reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
  • Compound a14 can be obtained by reacting Compound a7 with carbocylic acid (Compound a13) in the presence of condensing agents and base.
  • reaction solvent examples include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1, 4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
  • Examples of the base include triethylamine, potassium tert-biitoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU and the like.
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
  • the condensing agent examples include HATU, WSC, DCC, HOBt and the like.
  • the amount of the condensing agent may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
  • the carboxylic acid may be used in 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a7.
  • the reaction temperature may be under ice-cooling to reflux temperature, preferably room temperature.
  • the reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.
  • Compound a15 can be obtained by reacting Compound a12 with carbocylic acid (Compound a13) in the presence of condensing agents and base.
  • the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1, 4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
  • Examples of the base include triethylamine, potassium tert'butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU and the like.
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
  • the condensing agent examples include HATU, WSC, DCC, HOBt and the like.
  • the amount of the condensing agent may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
  • the carboxylic acid may be used in 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a12.
  • the reaction temperature may be under ice-cooling to reflux temperature, preferably room temperature.
  • the reaction time may be 0. 1 to 24 hours, preferably 1 to 5 hours.
  • Compound a 16 can be obtained by reacting Compound a11 with reductants.
  • reaction solvent examples include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
  • reductants examples include hydrogen with Pd carbon, hydrogen with Pd(OH) 2 , and the like.
  • the amount of the reductants may be 1 to 100 mole equivalents, preferably 1 to 10 mole equivalents of Compound all.
  • the reaction temperature may be 0°C to 200°C, preferably 0°C to
  • the reaction time may be 0. 1 to 24 hours, preferably 1 to 12 hours.
  • Compound a17 can be obtained by reacting Compound al6 with carbocylic acid (Compound a13) in the presence of condensing agents and base.
  • reaction solvent examples include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
  • Examples of the base include triethylamine, potassium tert-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU and the like.
  • the amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
  • the condensing agent examples include HATU, WSC, DCC, HOBt and the like.
  • the amount of the condensing agent may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
  • the carboxylic acid may be used in 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a16.
  • the reaction temperature may be under ice-cooling to reflux temperature, preferably room temperature.
  • the reaction time may be 0. 1 to 24 hours, preferably 1 to 5 hours.
  • the compound represented by formula (I) of the present invention or pharmaceutically acceptable salts thereof are useful in the treatment or prevention of a mycobacterial infection, especially non-tuberculous mycobacterial infection.
  • Such compounds may work by interfering with ATP synthase in pathogenic mycobacteria, with the inhibition of cytochrome bc1 activity as the primary mode of action.
  • the compound represented by formula (I) of the present invention or pharmaceutically acceptable salts thereof have not only the above described activity but also usefulness as a medicine, and have any or all of the following superior features : a) The inhibitory activity for CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and the like) is weak. b) The compound demonstrates good pharmacokinetics, such as a high bioavailability, moderate clearance, high distribution to a targeted tissue and the like. c) The compound has a high metabolic stability.
  • CYP enzymes e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and the like
  • the compound demonstrates good pharmacokinetics, such as a high bioavailability, moderate clearance, high distribution to a targeted tissue and the like.
  • the compound has no irreversible inhibitory effect against CYP enzymes (e.g., CYP3A4) when the concentration is within the range described in the present description as the measurement conditions.
  • CYP enzymes e.g., CYP3A4
  • the compound has no mutagenicity.
  • the compound is associated with a1ow cardiovascular risk.
  • the compound has a high solubility.
  • the compound causes less induction of drug-metabolizing enzyme i) The compound has less risk of phototoxicity, j) The compound has less risk of hepatotoxicity, k) The compound has less risk of kidney toxicity, l) The compound has less risk of gastrointestinal disorders, and m) The compound has intense efficacy.
  • the medicament includes (A) a compound represented by formula (I):
  • the term "medicament characterized by combination” includes an embodiment in which each compound is used as a combination drug, an embodiment in which each compound is used as a kit, an embodiment in which it is administered simultaneously, an embodiment in which it is administered sequentially, an embodiment in which it is administered at intervals and an embodiment in which they are used in combination with other drugs.
  • the term, “simultaneously” means that the compounds (A) and (B) are administered to the subject at the same time, for example in a single dose or bolus.
  • the term, “sequentially” means that the compounds (A) and (B) are administered to the subject in a certain pre-determined sequence within a certain pre-determined time interval of one another.
  • administration sequences of (A)-(B) or (B)-(A) are possible, wherein administration of each is carried out within a few seconds to a few hours of each other.
  • the term administered at “intervals” means that the compounds (A) and (B) are administered to the subject in a certain pre-determined sequence within a certain pre-determined time interval of one another.
  • administration sequences of (A)-(B) or (B)-(A) are possible, wherein administration of each is carried out within a few hours to one day of each other.
  • the compound represented by formula (I), or its pharmaceutically acceptable salt can be used in combination with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt, and it can enhance anti-bacterial effect of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
  • clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt can be used in combination with the compound represented by formula (I), or its pharmaceutically acceptable salt, and it can enhance anti-bacterial effect of the compound represented by formula (I), or its pharmaceutically acceptable salt.
  • the medicament includes (A) a compound represented by formula (I) :
  • the term "medicament characterized by combination” includes an embodiment in which each compound is used as a combination drug, an embodiment in which each compound is used as a kit, an embodiment in which it is administered simultaneously, an embodiment in which it is administered sequentially, an embodiment in which it is administered at intervals and an embodiment in which they are used in combination with other drugs.
  • the term, “simultaneously” means that the compounds (A), (B), and (C) are administered to the subject at the same time, for example in a single dose or bolus.
  • the term, “sequentially” means that the compounds (A), (B), and (C) are administered to the subject in a certain pre- determined sequence within a certain pre-determined time interval of one another.
  • administration sequences of (A)-(B)-(C), (B)-(C)-(A), (C)-(A)-(B), (B)-(A)- (C), (A)-(C)-(B), or (C)-(B)-(A) are possible, wherein administration of each is carried out within a few seconds to a few hours of each other.
  • administered at “intervals” means that the compounds (A), (B), and (C) are administered to the subject in a certain pre-determined sequence within a certain pre-determined time interval of one another.
  • administration sequences of (A)-(B)-(C), (B)- (C)-(A), (C)-(A) -(B), (B)-(A)-(C), (A)-(C)-(B), or (C)-(B)-(A) are possible, wherein administration of each is carried out within a few hours to one day of each other.
  • the compound represented by formula (I) can be used in combination with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt, and it can enhance anti-bacterial effect of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt, and/or (C) clofazimine, or its pharmaceutically acceptable salt.
  • (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt can be used in combination with the compound represented by formula (I) , or its pharmaceutically acceptable salt, and it can enhance anti-bacterial effect of the compound represented by formula (I), or its pharmaceutically acceptable salt.
  • the route of administration of the medicament of the present invention can be administered by either oral or parenteral methods and is not particularly limited to them.
  • oral administration it can be administered by the usual manner in the form of solid preparations for internal use (e .g., tablets, powders, granules, capsules, pills, films), internal solutions (e.g. , suspensions, emulsions, elixirs, syrups, limonade agents, alcoholic agents, fragrance solutions, extracts, decoctions, tinctures), and the like.
  • the tablet may be sugar-coated tablets, film- coated tablets, enteric coated tablets, extended release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets.
  • the powders and granules may be dry syrups.
  • the capsule may be soft capsule, microcapsules or sustained release capsules.
  • any forms of injections, drops, external preparations e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, coating agents, gargles, enemas, ointments, plasters, jellies, creams, patches, cataplasms, external powders, suppositories
  • the injection may be emulsions such as O/W, W/O, O/W/O or W/O/W type.
  • the effective amounts of the compound used in the medicament of the present invention may be mixed as necessary with various pharmaceutical additives such as excipients, binders, disintegrants, and/or lubricants suitable for the dosage form to give the pharmaceutical composition.
  • the pharmaceutical composition can be used for children, the elderly, serious patients or surgery, by appropriately changing the effective amount of the compound used in the medicament of the present invention, the dosage form and/or various pharmaceutical additives.
  • the pediatric pharmaceutical composition is preferably administered to patients aged under 12 years old or 15 years old.
  • the pediatric pharmaceutical composition can also be administered to patients less than 4 weeks after birth, 4 weeks to less than 1 year old after birth, 1 year old to less than 7 years old, 7 years old to less than 15 years old, or 15 years old to 18 years old.
  • the pharmaceutical composition for the elderly is preferably administered to patients over 65 years old.
  • the dose of the medicament of the present invention can be appropriately selected on the basis of the clinically used dosage.
  • the mixing ratio of (A) the compound represented by formula (I) and (B), or the mixing ratio of (A) the compound represented by formula (I), (B) and (C) can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like.
  • the combination drug may be used per 1 part by weight of (A) the compound represented by formula (I).
  • compositions contain the active compound in an effective amount to achieve their intended purpose.
  • a therapeutically effective amount means an amount effective to prevent or inhibit development or progression of a disease characterized by mycobacterial infection or activity in the subject being treated. Determination of the effective amounts is within the capability of those skilled in the art in light of the description provided herein.
  • the medicament of the present invention is suitable for the treatment and/or prevention of diseases and disorders characterized by mycobacterial activity or infection.
  • the mycobacteria may be pathogenic or non- pathogenic.
  • the mycobacteria may be Gram positive or Gram negative.
  • the medicament of the present invention is suitable for the treatment in humans (either or both of immunocompetent and immunocompromised) and animals of tuberculous, lepromatous, and non-tuberculous mycobacteria.
  • tuberculous mycobacteria for example M. tuberculosis, M. bovis, M. africanum, M. microti, M. canetti
  • Lepromatous mycobacteria for example M. leprae, M. Lepromatosis-'
  • Non-tuberculous mycobacteria for example M. abscessus, M. abcessus complex, M. a vium, M.
  • M. avium complex M. kansasii, M. malmoense, M. xenopi, M. malmoense, M. flavences, M. scrofulaceum, M. chelonae, M. peregrinum, M. haemophilum, M. fortuitum, M. marinum, M. ulcerans, M. gordonae, M. haemophilum, M. mucogenicum, M. nonchromogenicum, M. terrae, M. terrae complex, M. asiaticum, M. celatum, M. shimoidei, M. simiae, M. smegmatis, M. szulgai, M. celatum, M. conspicuum, M. genavense, M. immunogenum, M. xenopi. [0190]
  • the medicament of the present invention is suitable for the treatment in humans (both immunocompetent and immunocompromised) and animals of non-mycobacterial infectious diseases. [0191]
  • the subject is known or suspected to need treatment for one or more maladies related to non-pathogenic mycobacterial strain, M. smegmatis, M. vaccae, M. aurum, or combination thereof.
  • the subject is known or suspected to need treatment for one or more maladies related to Gram positive bacteria, S. aureus, M. luteus, or combination thereof.
  • the subject is known or suspected to need treatment for one or more maladies related to Gram negative bacteria, P. aeruginosa, A. baumanii, or combination thereof.
  • the subject is known or suspected to need treatment for one or more maladies related to pathogenic mycobacterial strain, M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M. m ungi, M. pinnipedii, M. leprae, M. avium, myobacterium tuberculosis complex, tuberculosis, or combination thereof.
  • maladies related to pathogenic mycobacterial strain M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M. m ungi, M. pinnipedii, M. leprae, M. avium, myobacterium tuberculosis complex, tuberculosis, or combination thereof.
  • the subject is known or suspected to need treatment for one or more maladies related to non-pathogenic mycobacterial strain, M. smegmatis, M. vaccae, M. a urum, Gram positive bacteria, S. aureus, M. luteus, Gram negative bacteria, P. aeruginosa, A. ba umussi, pathogenic mycobacterial strain, M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M. m ungi, M. pinnipedii, M. avium, myobacterium tuberculosis complex, tuberculosis, or combination thereof.
  • maladies related to non-pathogenic mycobacterial strain M. smegmatis, M. vaccae, M. a urum, Gram positive bacteria, S. aureus, M. luteus, Gram negative bacteria, P.
  • a method which includes killing or inhibiting the growth of a population of one or more of non-pathogenic mycobacterial strain, M. smegmatis, M. vaccae, M. a urum, Gram positive bacteria, S. a ureus, M. luteus, Gram negative bacteria, P. aeruginosa, A. ba umanii, pathogenic mycobacterial strain, M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M mungi, M. pinnipedii, M. a vium, myobacterium tuberculosis complex, tuberculosis, or combination thereof, by contacting one or more member of said population with the compounds used in the present invention or composition.
  • the compound represented by formula (I) used in the present invention (A) can be prepared by reference to WO2011/057145, WO2017/049321, WO2011/113606, WO2021/050708, the entire contents of each of which are hereby incorporated by reference, the same as if set forth at length.
  • HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium; 3- Oxide, hexafluorophosphate
  • Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine) palladium(0)
  • PdCl 2 (PPh 3 ) 2 Bis(triphenylphosphine)palladium chloride
  • RT in the specification means a retention time of LC/MS : liquid chromatography/mass spectrometry, and the measurement conditions are as follows.
  • UV detection wavelength 254nm
  • Mobile phase [A] is 0. 1 % formic acid-containing aqueous solution, and [B] is 0.1% formic acid-containing acetonitrile solution.
  • UV detection wavelength 254nm
  • Mobile phase [A] is 10mM ammonium carbonate-containing aqueous solution, and [B] is acetonitrile.
  • MS(m/z) indicates the value observed in the mass spectrometry.
  • Step 2 To a solution of compound 16 (6.49 g, 19.4 mmol) in THE (100 ml), purged with inert atmosphere, was added 10% Pd(OH) 2 /C (5.44 g, 1.94 mmol) . The reaction mixture was charged with hydrogen gas ( 1 atm). The resulting suspension was vigorously stirred for 6.5 hours. The reaction mixture was purged with an inert atmosphere, filtered through a celite pad. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduce pressure to yield the crude material as an oil. This crude material was used for the next reaction without further purification.
  • the crude material was dissolved in THE (100 ml) and was added to a suspension of LiAlE 4 ( 1.46 g, 38.5 mmol) in THE (100ml) at 0 °C. After stirring for 5 min, to the reaction mixture was added sodium sulfate decahydrate (24.83 g, 77 mmol) and the reaction was stirred for 3 hours. The reaction mixture was filtered through a celite pad. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduce pressure to yield the crude product as an oil. This crude material was used in the next reaction without further purification.
  • a sample of Mycobacterium avium ATCC700898 was taken from 7H9 (5% OADC) agar plate. This was first diluted by CAMHB medium to obtain an optical density of 0.1 at 600 nm wavelength and then diluted 1/20, resulting in an inoculum of approximately 5x 10 exp6 colony forming units per mL. Microtiter plates were filled with 200 ⁇ L of inoculum solution.
  • Test Example 1 The results of Test Example 1 are shown below.
  • a compound of the present invention was reacted for a constant time, a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.
  • a reaction was performed (oxidative reaction) at 37 °C for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes.
  • the compound of the present invention in the supernatant was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and a remaining amount of the compound of the present invention after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%.
  • Test Example 2 The results of Test Example 2 are shown below.
  • Clofazimine (CFZ) loading On the first day, administration dose was 40 mg/kg. after the second day, administration dose was 6 mg/kg. At the beginning of second week, administered at a dose of 15 mg/kg, after this day, administration dose was 6 mg/kg. This dosing mimics the AUG of repetitive administration of 50 mg in human.
  • mice were infected with Mycobacterium avium strain.
  • the clarithromycin sensitive ATCC700898 was thawed at ambient temperat ure and diluted in saline for mouse inoculation. When 0.07 mL of this dilution is inoculated, each mouse receives 10 7 bacteria.
  • the start of dosing was at Day 1.
  • mice were dosed orally with 0.2 mL of the appropriate formulation, except the control groups, which were not treated.
  • CFU colony-forming-units
  • the bactericidal effect of the treatment was defined as a significant decrease of the mean number of CFU in the treated group compared to pre-treatment value.

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Abstract

A medicament characterized in that (A) a compound represented by formula (I):, or its pharmaceutically acceptable salt, wherein R1, R2, R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl or the like; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or the like; R6, R7, R8 and R9 are each independently hydrogen atom, halogen or the like; X is CH or N; Y is CH or N; R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl or the like; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl or the like; R12 is each independently halogen, hydroxy, cyano or the like; n is 0, 1, 2, 3 or 4; is combined with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt; and (C) clofazimine, or its pharmaceutically acceptable salt.

Description

[Document Name] Description
[Title of Invention] A MEDICAMENT FOR TREATING MYCOBACTERIAL
INFECTION CHARACTERIZED BY COMBINING A CYTOCHROME bcl INHIBITOR WITH CLARITHROMYCIN OR AZITHROMYCIN
[TECHNICAL FIELD] [0001]
The present invention relates to novel combinations. The invention also relates to such combinations for use as pharmaceuticals, for instance in the treatment of bacterial diseases, including diseased caused by pathogenic mycobacteria such as non-tuberculosis mycobacteria.
In particular, the present invention relates to a medicament characterized in that a compound having a cytochrome bcl inhibitory activity or its pharmaceutically acceptable salt is combined with clarithromycin or azithromycin or their pharmaceutically acceptable salts, or a medicament characterized in that a compound having a cytochrome bcl inhibitory activity or its pharmaceutically acceptable salt is combined with clarithromycin or azithromycin, and clofazimine, or their pharmaceutically acceptable salts.
[BACKGROUND] [0002]
Genus Mycobacterium has 95 well-characterized species. Over the centuries two well known mycobacterial species, namely, Mycobacterium tuberculosis and M. Leprae have been the known causes of immense human suffering. Most of other mycobacteria are present in the environment and their pathogenic potential has been recognized since the beginning of the last century. These mycobacteria are called non-tuberculous mycobacteria (NTM). Whereas the incidence of tuberculosis (TB) is decreasing, a new health concern has been raised globally by NTM. Pulmonary disease caused by NTM is characterized by progressive, irreversible pulmonary damage and increased mortality. About 80% of pulmonary NTM disease is caused by Mycobacterium avium complex (MAC- M. avium, M. intracellulare, M. chimaera, M. colombiense, M. arosiense, M. vulneris, M. bouchedurhonense, M. timonense, M. marseillense, M. yongonense, M. paraintracellulare and M. lepraem urium).
The annual prevalence of NTM pulmonary disease varies in different regions, ranging from 0.2/100, 000 to 14.7/100,000 with an overall alarming growth rate. The disease is more prevalent after age 60 where the estimated prevalence is from 19.6/100,000 during 1994-1996 to 26.7/100,000 during 2004-2006 in the US.
Different from TB, NTM are opportunistic pathogens, causing mostly TB-like pulmonary diseases in immunocompromised patients or patients with preexisting lung conditions, such as cystic fibrosis (CF), bronchiectasis or chronic obstructive pulmonary disease (COPD). In addition, post-menopausal women without pre-existing structural pulmonary disease represent another risk group for NTM lung disease. These women, primarily older women of Caucasian or Asian descent, present with nodular bronchiectasis as their NTM lung disease.
[0003]
Currently, for most patients with MAC pulmonary disease, a combination therapy is recommended by the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA). For most patients with nodular/bronchiectatic disease, a three-times-weekly regimen of macrolide (clarithromycin or azithromycin), rifampin, and ethambutol is recommended, For patients with fibrocavitary MAC lung disease or severe nodular/bronchiectatic disease, a daily regimen of macrolide (clarithromycin or azithromycin), rifampin or rifabutin, and ethambutol with consideration of three times-weekly amikacin or streptomycin early in therapy is recommended. Patients should be treated until culture negative on therapy for 1 year. Many patients, however, are refractory to the above first-line therapy and do not achieve sustained culture conversion. The limited success of current treatment regimens is in part caused by an insufficient bactericidal activity and challenging compliance due to the frequent occurrence of adverse drug reactions. Therefore, there is a high medical need for new therapies (e.g. combinations) likely to demonstrate activity against drug-resistant mycobacteria, in particular NTM.
[0004]
Patent Documents 1 to 8 disclose a variety of compounds having a cytochrome bc1 inhibitory activity.
Patent Document 9 discloses a variety of compounds having a cytochrome bc1 inhibitory activity. For example, the following compound is disclosed.
Figure imgf000004_0001
This compound is known as Telacebec and is a new clinical candidate for the treatment of tuberculosis.
Patent Document 10 discloses a combination of bedaquiline, Telacebec and pyrazinamide.
Patent Document 11 discloses a combination of rifabutin, clarithromycin and clofazimine.
Non-Patent Document 1 discloses a combination of clarithromycin and clofazimine.
Non-Patent Document 2 discloses a combination of a compound having a cytochrome bc1 inhibitory activity and rifampin.
[PATENT DOCUMENTS] [0005]
Patent Document 1: WO2011/057145
Patent Document 2: WO2014/015167
Patent Document 3: WO2017/049321
Patent Document 4: US2017/0313697
Patent Document 5: WO2017/001660
Patent Document 6: WO2017/001661
Patent Document 7: WO2017/216281 Patent Document 8: WO2017/216283
Patent Document 9: WO2011/113606
Patent Document 10: WO2018/158280
Patent Document 11 : US2016/0228464
[NON-PATENT DOCUMENT]
[0006]
Non-Patent Document 1 : Antimicrobial Agents and Chemotherapy, February
2016, Volume 60, Number 2, 1097- 1105
Non-Patent Document 2: Antimicrobial Agents and Chemotherapy, August
2016, Volume 60, Number 8, 5018-5022
[DISCLOSURE OF INVENTION]
[PROBLEMS TO BE SOLVED BY THE INVENTION] [0007]
An object of the present invention is to provide a medicament useful for treating or preventing mycobacterial infections which has few side effects.
[MEANS FOR SOLVING THE PROBLEMS] [0008]
As a result of intensive studies in order to solve the above problems, the present inventors have newly found that new combinations of a cytochrome bc1 inhibitor, and clarithromycin or azithromycin, or pharmaceutically acceptable salts thereof, or new combinations of a cytochrome bc1 inhibitor, clarithromycin or azithromycin, and clofazimine, or pharmaceutically acceptable salts thereof are particularly effective in the prevention and/or treatment of a mycobacterial infection, especially non-tuberculous mycobacterial infection, as compared to cases where the agents are administered alone.
[0009]
Clarithromycin is one of the macrolides of a combination regimen that the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) recommended as a first-line therapy for MAC disease. Clarithromycin, azithromycin as well, is/are the only (single) agents used for treatment of MAC disease for which there is a correlation between in vitro susceptibility and in vivo (clinical) response. Specifically, treatment success correlates with in vitro macrolide susceptibility, while conversely, patients who have MAC isolates that are macrolide resistant do not respond favorably to macrolide-containing regimens. This fundamental relationship has not been established for any other agent in the treatment of MAC lung disease.
[0010]
Clofazimine is an orally administered drug approved for the treatment of leprosy, currently repurposed as an anti-TB drug. A retrospective review reported that a significantly greater proportion of pulmonary disease patients infected by MAC treated with clofazimine converted to negative cultures, although relapse still occurred. In vitro, its MIC ranges from 1-4 μg/mL against M. avium and is < 1 μg/mL against the majority of M. intracellulare isolates.
[0011]
Azithromycin is one of the macrolides of a combination regimen that the ATS/IDSA recommended as a first-line therapy for MAC disease. Since clarithromycin inhibits cytochrome P-450 (CYP) 3A and affects the metabolism of other drugs but azithromycin does not inhibit CYP3A, azithromycin is preferentially used for treatment of MAC disease.
[0012]
Recently, with the advent of bedaquiline for treatment of multidrug- resistant tuberculosis, oxidative phosphorylation has been validated as an important target and a vulnerable component of mycobacterial metabolism. Exploiting the dependence of TB on oxidative phosphorylation for energy production, several components of this pathway have been targeted for the development of new antimycobacterial agents. The cytochrome bc1 complex is one of the validated targets for anti-mycobacteria drug development. The complex is assembled with three subunits, qcrA, qcrB and qcrC. One of the qcrB inhibitors, Telacebec, inhibited the growth of TB not only in vitro but an in vivo mouse model.
[0013]
The cytochrome bc1 inhibitor of the present invention may be a compound of the following general formula (I) :
(I)
Figure imgf000006_0001
A compound represented by formula (I), or its pharmaceutically acceptable salt has excellent cytochrome bc1 inhibitory activity.
For instance, it is described in WO2021/050708 that the following compounds which fall within formula (I) have excellent cytochrome bc1 inhibitory activity:
Figure imgf000007_0001
[BRIEF DESCRIPTION OF SEVERAL EMBODIMENTS OF THE INVENTION] [0014]
(1) A medicament characterized in that (A) a compound represented by formula (I): (I)
Figure imgf000008_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom;
X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4;
R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; is combined with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
(2) The medicament according to the above (1), wherein R1 and R4 are hydrogen atom.
(3) The medicament according to the above (1) or (2), wherein R2 is hydrogen atom, halogen or substituted or unsubstituted alkyl.
(4) The medicament according to any one of the above (1) to (3), wherein R3 is hydrogen atom or halogen. (5) The medicament according to any one of the above (1) to (4), wherein R5 is substituted or unsubstituted alkyl.
(6) The medicament according to any one of the above (1) to (5), wherein R6 , R8 and R9 are hydrogen atom, and R7 is halogen.
(7) The medicament according to any one of the above (1) to (6), wherein X is N.
(8) The medicament according to any one of the above (1) to (7), wherein Y is N.
(9) The medicament according to any one of the above (1) to (8), wherein m is 1.
(10) The medicament according to the above (9), wherein R10 is substituted or unsubstituted alkyl.
(11) The medicament according to any one of the above (1) to (10), wherein R11 is substituted or unsubstituted alkyloxy.
(12) The medicament according to any one of the above (1) to (11), wherein n is 0.
(13) The medicament according to the above (1), wherein (A) is the compound selected from the group consisting of
Figure imgf000010_0001
, or its pharmaceutically acceptable salt.
(14) The medicament according to any one of the above (1) to (13), wherein (B) is clarithromycin or its pharmaceutically acceptable salt. (15) The medicament according to any one of the above (1) to (14), wherein (A) and (B) ; are simultaneously, sequentially or at intervals administered.
(16) The medicament according to any one of the above (1) to (14), wherein the medicament is combination drugs.
(17) The medicament according to any one of the above (1) to (16), wherein the medicament is used for the treatment or prevention of mycobacterial infection.
(18) A method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt, comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt with a compound represented by formula (I) in the above (1), or its pharmaceutically acceptable salt.
(19) A method of enhancing the anti-bacterial activity of a compound represented by formula (I) in the above (1), or its pharmaceutically acceptable salt, comprising administering the compound represented by formula (I) in the above (1), or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
(20) The method according to the above (18), wherein the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of the compound represented by formula (I) in the above (1), or its pharmaceutically acceptable salt.
(21) The method according to the above (19), wherein the compound represented by formula (I) in the above (1), or its pharmaceutically acceptable salt, is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
(22) A method of treating mycobacterial infection comprising administering a combination of
(A) a compound represented by formula (I) :
(I)
Figure imgf000011_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom;
X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; and
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt, in a therapeutically effective amount thereof to an individual in need of treatment for mycobacterial infection.
(23) The method according to the above (22), wherein (A) a compound represented by formula (I), or its pharmaceutically acceptable salt and (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt are administered simultaneously, sequentially or at intervals.
(24) A pharmaceutical composition or kit, comprising:
(A) a compound represented by formula (I) :
(I)
Figure imgf000012_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom;
X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; and
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
(25) A medicament characterized in that (A) a compound represented by formula (I) :
(I)
Figure imgf000013_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom; X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; is combined with
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt; and
(C) clofazimine, or its pharmaceutically acceptable salt.
(26) The medicament according to the above (25), wherein R1 and R4 a e eydrogen atom.
(27) The medicament according to the above (25) or (26), wherein R2 is hydrogen atom, halogen or substituted or unsubstituted alkyl.
(28) The medicament according to any one of the above (25) to (27), wherein R3 is hydrogen atom or halogen.
(29) The medicament according to any one of the above (25) to (28), wherein R5 is substituted or unsubstituted alkyl.
(30) The medicament according to any one of the above (25) to (29), wherein R6 , R8 and R9 are hydrogen atom, and R7 is halogen.
(31) The medicament according to any one of the above (25) to (30), wherein X is N.
(32) The medicament according to any one of the above (25) to (31), wherein Y is N.
(33) The medicament according to any one of the above (25) to (32), wherein m is 1.
(34) The medicament according to the above (33) , wherein R10 is substituted or unsubstituted alkyl.
(35) The medicament according to any one of the above (25) to (34), wherein R11 is substituted or unsubstituted alkyloxy.
(36) The medicament according to any one of the above (25) to (35), wherein n is 0.
(37) The medicament according to the above (25) , wherein (A) is the compound selected from the group consisting of
Figure imgf000015_0001
, or its pharmaceutically acceptable salt.
(38) The medicament according to any one of the above (25) to (37), wherein (B) is clarithromycin or its pharmaceutically acceptable salt.
(39) The medicament according to any one of the above (25) to (38), wherein (A), (B) and (C) are simultaneously, sequentially or at intervals administered.
(40) The medicament according to any one of the above (25) to (38), wherein the medicament is combination drugs.
(41) The medicament according to any one of the above (25) to (40), wherein the medicament is used for the treatment or prevention of mycobacterial infection.
(42) A method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt, comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt with a compound represented by formula (I) in the above (25), or its pharmaceutically acceptable salt.
(43) A method of enhancing the anti-bacterial activity of a compound represented by formula (I) in the above (25), or its pharmaceutically acceptable salt, comprising administering the compound represented by formula (I) in the above (25), or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt.
(44) The method according to the above (42), wherein the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt is/are administered simultaneously, sequentially or at intervals with a therapeutically effective amount of the compound represented by formula (I) in the above (25), or its pharmaceutically acceptable salt.
(45) The method according to the above (43), wherein the compound represented by formula (I) in the above (25), or its pharmaceutically acceptable salt, is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt.
(46) A method of treating mycobacterial infection comprising administering a combination of
(A) a compound represented by formula (I) : (I)
Figure imgf000017_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom;
X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and
(C) clofazimine, or its pharmaceutically acceptable salt, in a therapeutically effective amount thereof to an individual in need of treatment for mycobacterial infection.
(47) The method according to the above (46), wherein (A) a compound represented by formula (I) , or its pharmaceutically acceptable salt, (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt, are administered simultaneously, sequentially or at intervals.
(48) A pharmaceutical composition or kit, comprising:
(A) a compound represented by formula (l) : (I)
Figure imgf000018_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom;
X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt; and
(C) clofazimine, or its pharmaceutically acceptable salt.
(49) A medicament characterized in that (A) a compound defined below
Figure imgf000018_0002
, or its pharmaceutically acceptable salt; is combined with
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
(50) The medicament according to the above (49), wherein (B) is clarithromycin or its pharmaceutically acceptable salt.
(51) The medicament according to the above (49) or (50), wherein (A) and (B) are simultaneously, sequentially or at intervals administered.
(52) The medicament according to the above (49) or (50), wherein the medicament is combination drugs.
(53) The medicament according to any one of the above (49) to (52), wherein the medicament is used for the treatment or prevention of mycobacterial infection.
(54) A method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt, comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt with a compound (A) in the above (49), or its pharmaceutically acceptable salt.
(55) A method of enhancing the anti-bacterial activity of a compound (A) in the above (49) , or its pharmaceutically acceptable salt, comprising administering the compound (A) in the above (49), or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
(56) The method according to the above (54), wherein the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of the compound (A) in the above (49), or its pharmaceutically acceptable salt.
(57) The method according to the above (55), wherein the compound (A) in the above (49), or its pharmaceutically acceptable salt, is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
(58) A method of treating mycobacterial infection comprising administering a combination of
(A) a compound defined below
Figure imgf000020_0001
, or its pharmaceutically acceptable salt; and
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt, in a therapeutically effective amount thereof to an individual in need of treatment for mycobacterial infection.
(59) The method according to the above (58), wherein the compound (A), or its pharmaceutically acceptable salt and (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt are administered simultaneously, sequentially or at intervals.
(60) A pharmaceutical composition or kit, comprising:
(A) a compound defined below
Figure imgf000020_0002
, or its pharmaceutically acceptable salt; and
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
(1') A medicament characterized in that (A) a compound represented by formula (I):
(I)
Figure imgf000020_0003
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R8 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom;
X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy,' n is 0, 1, 2, 3 or 4; is combined with
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt; and
(C) clofazimine, or its pharmaceutically acceptable salt.
(2') The medicament according to the above (1'), wherein R1 and R4 are hydr aorgeen atom.
(3') The medicament according to the above (I'), wherein R2 is hydrogen atom, halogen or substituted or unsubstituted alkyl.
(4') The medicament according to the above (1') , wherein R3 is hydrogen atom or halogen.
(5') The medicament according to the above (1'), wherein R5 is substituted or unsubstituted alkyl.
(6') The medicament according to the above (1') , wherein R6 , R8 and R9 are hydrogen atom, and R7 is halogen.
(7') The medicament according to the above (1'), wherein X is N.
(8') The medicament according to the above (1'), wherein Y is N.
(9') The medicament according to the above (1'), wherein m is 1.
(10') The medicament according to the above (9'), wherein R10 is substituted or unsubstituted alkyl.
(11') The medicament according to the above (1'), wherein R11 is substituted or unsubstituted alkyloxy.
(12') The medicament according to the above (1'), wherein n is 0.
(13') The medicament according to the above (1'), wherein (A) is the compound selected from the group consisting of
Figure imgf000023_0001
, or its pharmaceutically acceptable salt.
(14') The medicament according to the above (1'), wherein (B) is clarithromycin or its pharmaceutically acceptable salt. (15') The medicament according to the above (1'), wherein (A), (B) and (C) are simultaneously, sequentially or at intervals administered.
(16') The medicament according to the above (1'), wherein the medicament is combination drugs.
(17') The medicament according to the above (1'), wherein the medicament is used for the treatment or prevention of mycobacterial infection.
(18') A method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt, comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt with a compound represented by formula (I) in the above (1') , or its pharmaceutically acceptable salt.
(19') A method of enhancing the anti-bacterial activity of a compound represented by formula (I) in the above (1'), or its pharmaceutically acceptable salt, comprising administering the compound represented by formula (I) in the above (1'), or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt.
(20') The method according to the above ( 18'), wherein the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt is/are administered simultaneously, sequentially or at intervals with a therapeutically effective amount of the compound represented by formula (I) in the above (1'), or its pharmaceutically acceptable salt.
(21') The method according to the above (19'), wherein the compound represented by formula (I) in the above (1'), or its pharmaceutically acceptable salt, is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt.
(22') A method of treating mycobacterial infection comprising administering a combination of
(A) a compound represented by formula (I) : (I)
Figure imgf000025_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom; X is CH or N; Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and
(C) clofazimine, or its pharmaceutically acceptable salt, in a therapeutically effective amount thereof to an individual in need of treatment for mycobacterial infection.
(23') The method according to the above (22'), wherein (A) a compound represented by formula (I), or its pharmaceutically acceptable salt, (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt, are administered simultaneously, sequentially or at intervals.
(24') A pharmaceutical composition or kit, comprising:
(A) a compound represented by formula (I): (I)
Figure imgf000026_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom;
X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt; and
(C) clofazimine, or its pharmaceutically acceptable salt.
[EFFECT OF THE INVENTION] [0015]
The medicament of the present invention is useful in the treatment of a mycobacterial infection, especially non-tuberculous mycobacterial infection.
[BRIEF DESCRIPTION OF DRAWINGS] [0016]
[Figure 1] Figure 1 shows the mean log10 value for CFUs of each lung of the 15 study groups after the end of treatment, as described hereinafter (13 study groups comprise treatment regimens comprising Clarithromycin (CAM) , Clofazimine (CFZ), cytochrome bc1 inhibitors and various combinations, and 2 study groups are control groups) . X axis indicates each study groups. Y axis indicates the mean log10 value for CFUs.
[Figure 2] Figure 2 shows the mean log10 value for CFUs of each lung of the 6 study groups after the end of treatment, as described hereinafter (4 study groups comprise treatment regimens comprising Clarithromycin (CAM) , CFZ, cytochrome bc1 inhibitors and various combinations, and 2 study groups are control groups) . X axis indicates each study groups. Y axis indicates the mean log10 value for CFUs.
[Figure 3] Figure 3 shows the mean log10 value for CFUs of each lung of the 15 study groups after the end of treatment, as described hereinafter (13 study groups comprise treatment regimens comprising Clarithromycin (CAM) , CFZ, cytochrome bc1 inhibitors and various combinations, and 2 study groups are control groups) . X axis indicates each study groups. Y axis indicates the mean log10 value for CFUs.
[Figure 4] Figure 4 shows the mean log10 value for CFUs of each lung of the 6 study groups after the end of treatment, as described hereinafter (4 study groups comprise treatment regimens comprising Azithromycin (AZM) , Rifampicin (RFP), Ethambutol (ETB), CFZ, cytochrome bc1 inhibitor and various combinations, and 2 study groups are control groups) . X axis indicates each study groups. Y axis indicates the mean log10 value for CFUs.
[Figure 5] Figure 5 shows the log10 value for CFUs of each of the 12 study groups, as described hereinafter (10 study groups comprise conditions containing either Clarithromycin (CAM) or cytochrome bc1 inhibitors, and 2 study groups are control groups) . X axis indicates each study groups. Y axis indicates the log10 value for CFUs.
[Figure 6] Figure 6 shows the log10 value for CFUs of each of the 30 study groups, as described hereinafter (28 study groups comprise conditions containing either Clarithromycin (CAM) or combination of CAM and cytochrome bc1 inhibitors, and 2 study groups are control groups) . X axis indicates each study groups. Y axis indicates the log10 value for CFUs.
[Figure 7] Figure 7 shows the log10 value for CFUs of each of the 11 study groups, as described hereinafter (9 study groups comprise conditions containing either Clarithromycin (CAM) or combination of CAM and cytochrome bc1 inhibitors, and 2 study groups are control groups). X axis indicates each study groups. Y axis indicates the log10 value for CFUs.
[Figure 8] Figure 8 shows the log10 value for CFUs of each of the 26 study groups, as described hereinafter (24 study groups comprise conditions containing either Clarithromycin (CAM), I-1-3 or combination of CAM and I-1-3, and 2 study groups are control groups). X axis indicates each study groups. Y axis indicates the log10 value for CFUs.
[Figure 9] Figure 9 shows the log10 value for CFUs of each of the 6 study groups, as described hereinafter (4 study groups comprise conditions containing either Clarithromycin (CAM), I-1-3, combination of CAM and Clofazimine (CFZ) or combination of CAM, CFZ and I-1-3, and 2 study groups are control groups) . X axis indicates each study groups. Y axis indicates the log10 value for CFUs.
[Figure 10] Figure 10 shows the mean log10 value for CFUs of each lung of the 6 study groups after the end of treatment, as described hereinafter (6 study groups comprise treatment regimens comprising Clarithromycin
(CAM) , Rifampicin (RFP), Ethambutol (ETB), CFZ, cytochrome bc1 inhibitor and various combinations, and 2 study groups are control groups) . X axis indicates each study groups. Y axis indicates the mean log10 value for CFUs of each lung.
[Figure 11] Figure 11 shows the log10 value for CFUs of each of the 7 study groups, as described hereinafter (5 study groups comprise conditions containing either Clarithromycin (CAM), Clofazimine (CFZ), I-1-3, combination of CAM and CFZ or combination of CAM, CFZ and I-1-3, and 2 study groups are control groups). X axis indicates each study groups. Y axis indicates the log10 value for CFUs.
[DETAILED DESCRIPTION OF SEVERAL EMBODIMENTS OF THE INVENTION] [0017]
Each term used in this description will be described below. In this description, even when each term is used individually or used together with other terms, the term has the same meaning.
The term, "consisting of means having only the recited components or elements.
The term, "comprising" means not restricting with components and not excluding undescribed factors.
The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." [0018]
The compound represented by formula (I) in (A), or its pharmaceutically acceptable salt is described hereinabove and below. [0019]
The term "halogen" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A fluorine atom and a chlorine atom are especially preferable.
[0020]
The term "alkyl" includes a C1 to C15, preferably C1 to C10, more preferably C1 to C6 and further preferably C1 to C4 linear or branched hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.
A preferred embodiment of "alkyl" is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. A more preferred embodiment is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.
[0021]
The term "alkenyl" includes a C2 to C15, preferably a C2 to C10, more preferably a C2 to C6 and further preferably a C2 to C4 linear or branched hydrocarbon group having one or more double bond(s) at any position(s). Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl.
A preferred embodiment of "alkenyl" is vinyl, allyl, propenyl, isopropenyl or butenyl. [0022]
The term "alkynyl” includes C2 to C8 straight or branched alkynyl having one or more triple bond(s) in the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Furthermore, an “alkynyl” may have a double bond.
[0023]
The term "alkyloxy" means a group wherein the above "alkyl" is bonded to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert'butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, and hexyloxy.
A preferred embodiment of "alkyloxy" is methyloxy, ethyloxy, n- propyloxy, isopropyloxy or tert'butyloxy.
[0024]
The term "alkenyloxy" means a group wherein the above "alkenyl" is bonded to an oxygen atom. Examples include vinyloxy, allyloxy, 1-n-propenyloxy, 2- n-butenyloxy, 2-n-pentenyloxy, 2-n-hexenyloxy, 2-n-heptenyloxy, and 2-n-octenyloxy. [0025]
The term "alkynyloxy" means a group wherein the above "alkynyl" is bonded to an oxygen atom. Examples include ethynyloxy, 1 -n-propynyloxy, 2-n- propynyloxy, 2-n-butynyloxy, 2-n-pentynyloxy, 2-n-hexynyloxy, 2-n-heptynyloxy, and 2-n-octynyloxy.
[0026]
The substituents of “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy” and “substituted alkynyloxy” include the following substituents. A carbon atom at any positions may be bonded to one or more group(s) selected from the following substituents.
A substituent: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylcarbamoyl, alkenylcarbamoyl, alkynylcarbamoyl, alkylsulfamoyl, alkenylsulfamoyl, alkynylsulfamoyl, aromatic carbocyclyl, non-aromatic carbocyclyl, aromatic heterocyclyl, non-aromatic heterocyclyl, aromatic carbocyclyloxy, non-aromatic carbocyclyloxy, aromatic heterocyclyloxy, non-aromatic heterocyclyloxy, aromatic carbocyclylcarbonyl, non-aromatic carbocyclylcarbonyl, aromatic heterocyclylcarbonyl, non-aromatic heterocyclylcarbonyl, aromatic carbocyclyloxycarbonyl, non-aromatic carbocyclyloxycarbonyl, aromatic heterocyclyloxycarbonyl, non-aromatic heterocyclyloxycarbonyl, aromatic carbocyclylalkyloxy, non-aromatic carbocyclylalkyloxy, aromatic heterocyclylalkyloxy, non-aromatic heterocyclylalkyloxy, aromatic carbocyclylalkyloxycarbonyl, non- aromatic carbocyclylalkyloxycarbonyl, aromatic heterocyclylalkyloxycarbonyl, non- aromatic heterocyclylalkyloxycarbonyl, aromatic carbocyclylalkylamino, non-aromatic carbocyclylalkylamino, aromatic heterocyclylalkylamino, non-aromatic heterocyclylalkylamino, aromatic carbocyclylsulfanyl, non-aromatic carbocyclylsulfanyl, aromatic heterocyclylsulfanyl, non-aromatic heterocyclylsulfanyl, non-aromatic carbocyclylsulfonyl, aromatic carbocyclylsulfonyl, aromatic heterocyclylsulfonyl, and non-aromatic heterocyclylsulfonyl.
A preferable substituent: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, alkenylamino, alkynylamino, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkylcarbamoyl, alkenylcarbamoyl, alkynylcarbamoyl, alkylsulfamoyl, alkenylsulfamoyl, and alkynylsulfamoyl.
A more preferable substituent: halogen, hydroxy, amino, cyano, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylamino, alkenylamino, and alkynylamino .
An especially preferable substituent: halogen, hydroxy, amino, cyano, alkyloxy, and alkylamino.
[0027]
The term "haloalkyl" includes a group wherein one or more hydrogen atom(s) attached to a carbon atom of the above "alkyl" is replaced with the above "halogen". Examples include monofluoromethyl, monofluoroethyl, monofluoro-n- propyl, 2,2,3, 3, 3-n-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2, 2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1, 2-dibromoethyl, and 1,1,1- trifluoro-n-propan-2-yl.
A preferred embodiment of "haloalkyl" is trifluoromethyl and trichloromethyl.
[0028]
The term "haloalkyloxy" means a group wherein the above "haloalkyl" is bonded to an oxygen atom. Examples include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, and trichloroethoxy.
A preferred embodiment of "haloalkyloxy" is trifluoromethoxy and trichloromethoxy.
[00291
The term "alkylcarbonyl" means a group wherein the above "alkyl" is bonded to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec'butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and n- hexylcarbonyl.
A preferred embodiment of "alkylcarbonyl" is methylcarbonyl, ethylcarbonyl and n-propylcarbonyl.
[0030]
The term "alkenylcarbonyl" means a group wherein the above "alkenyl" is bonded to a carbonyl group, Examples include vinylcarbonyl, allylcarbonyl and n-propenylcarbonyl.
[0031]
The term "alkynylcarbonyl" means a group wherein the above "alkynyl" is bonded to a carbonyl group. Examples include ethynylcarbonyl and n- propynylcarbonyl.
[0032]
The term "alkylamino" means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "alkyl" . Examples include methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N,N-diisopropylamino, and N-methybN-ethylamino.
A preferred embodiment of "alkylamino" is methylamino and ethylamino.
[0033]
The term "alkenylamino" means a group wherein a hydrogen atom attached to a nitrogen atom of an amino group is replaced with the above "alkenyl". For example, it includes ethylenylamino, propenylamino and the like. Another hydrogen atom attached to the nitrogen atom of the amino group may be replaced with the above "alkyl" .
[0034]
The term "Alkynylamino" means a group wherein a hydrogen atom attached to a nitrogen atom of an amino group is replaced with the above "alkynyl". For example, it includes ethynylamino, propynylamino and the like. Another hydrogen atom attached to the nitrogen atom of the amino group may be replaced with the above "alkyl".
[0035]
The term "alkylsulfonyl" means a group wherein the above "alkyl" is bonded to a sulfonyl group . Examples include methylsulfonyl, ethylsulfonyl, n- propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, and sec-butylsulfonyl.
A preferred embodiment of "alkylsulfonyl" is methylsulfonyl and ethylsulfonyl.
[0036]
The term "alkenylsulfonyl" means a group wherein the above "alkenyl" is bonded to a sulfonyl group. Examples include vinylsulfonyl, allylsulfonyl, and n- propenylsulfonyl.
[0037]
The term "alkynylsulfonyl" means a group wherein the above "alkynyl" is bonded to a sulfonyl group. Examples include ethynylsulfonyl, and n- propynylsulfonyl.
[0038]
The term "alkylcarbonylamino" means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "alkylcarbonyl". Examples include methylcarbonylamino, dimethylcarbonylamino, ethylcarbonylamino, diethylcarbonylamino, n- propylcarbonylamino, isopropylcarbonylamino, N,N-diisopropylcarbonylamino, n- butylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, and sec- butylcarbonylamino. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above "alkyl" .
[0039]
The term "alkenylcarbonylamino" means a group wherein a hydrogen atom bonded to a nitrogen atom of an amino group is replaced with the above "alkenylcarbonyl". For example, it includes ethylenylcarbonylamino, propenylcarbonylamino and the like. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above "alkyl".
[0040]
The term "alkynylcarbonylamino" means a group wherein a hydrogen atom bonded to a nitrogen atom of an amino group is replaced with the above "alkynylcarbonyl". For example, it includes ethynylcarbonylamino, propynylcarbonylamino and the like. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above "alkyl" .
[0041]
The term "alkylsulfonylamino" means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "alkylsulfonyl". Examples include methylsulfonylamino, dimethylsulfonylamino, ethylsulfonylamino, diethylsulfonylamino, n- propylsulfonylamino, isopropylsulfonylamino, N,N-diisopropylsulfonylamino, n- butylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, and sec- butylsulfonylamino.
A preferred embodiment of "alkylsulfonylamino" is methylsulfonylamino and ethylsulfonylamino.
[0042]
The term "alkenylsulfonylamino" means a group wherein a hydrogen atom bonded to a nitrogen atom of an amino group is replaced with the above "alkenylsulfonyl". For example, it includes ethylenylsulfonylamino, propenylsulfonylamino and the like. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above "alkyl".
[0043]
The term "alkynylsulfonylamino" means a group wherein a hydrogen atom bonded to a nitrogen atom of an amino group is replaced with the above "alkynylsulfonyl". For example, it includes ethynylsulfonylamino, propynylsulfonylamino and the like. Another hydrogen atom bonded to the nitrogen atom of the amino group may be replaced with the above "alkyl" .
[0044]
The term "alkylimino" means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkyl". Examples include methylimino, ethylimino, n-propylimino, and isopropylimino. [0045]
The term "alkenylimino'' means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkenyl". Examples include ethylenylimino, and n-propenylimino. [0046]
The term "alkynylimino" means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkynyl". Examples include ethynylimino, and n-propynylimino.
[0047]
The term "alkylcarbonylimino" means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkylcarbonyl". Examples include methylcarbonylimino, ethylcarbonylimino, n- propylcarbonylimino, and isopropylcarbonylimino.
[0048]
The term "alkenylcarbonylimino" means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkenylcarbonyl". Examples include ethylenylcarbonylimino, and n- propenylcarbonylimino.
[0049]
The term "alkynylcarbonylimino" means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkynylcarbonyl". Examples include ethynylcarbonylimino and n* propynylcarbonylimino.
[0050]
The term "alkyloxyimino" means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkyloxy". Examples include methyloxyimino, ethyloxyimino, n-propyloxyimino, and isopropyloxyimino.
[0051]
The term "alkenyloxyimino" means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkenyloxy". Examples include ethylenyloxyimino, and n-propenyloxyimino.
[0052]
The term "alkynyloxy imino" means a group wherein a hydrogen atom attached to a nitrogen atom of an imino group is replaced with the above "alkynyloxy" . Examples include ethynyloxyimino, and n-propynyloxyimino.
[0053]
The term "alkylcarbonyloxy" means a group wherein the above "alkylcarbonyl" is bonded to an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, and secbutylcarbonyloxy.
A preferred embodiment of "alkylcarbonyloxy" is methylcarbonyloxy and ethylcarbonyloxy.
[0054]
The term "alkenylcarbonyloxy" means a group wherein the above
"alkenylcarbonyl" is bonded to an oxygen atom. Examples include ethylenylcarbonyloxy and n-propenylcarbonyloxy.
[0055]
The term "alkynylcarbonyloxy" means a group wherein the above "alkynylcarbonyl" is bonded to an oxygen atom. Examples include ethynylcarbonyloxy and n-propynylcarbonyloxy.
[0056]
The term "alkyloxycarbonyl" means a group wherein the above "alkyloxy" is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, n- pentyloxycarbonyl, isopentyloxycarbonyl, and n-hexyloxycarbonyl.
A preferred embodiment of "alkyloxycarbonyl" is methyloxycarbonyl, ethyloxycarbonyl and n-propyloxycarbonyl.
[0057]
The term "alkenyloxycarbonyl" means a group wherein the above "alkenyloxy" is bonded to a carbonyl group. Examples include ethylenyloxycarbonyl and n-propenyloxycarbonyl.
[0058]
The term "alkynyloxycarbonyl" means a group wherein the above "alkynyloxy" is bonded to a carbonyl group . Examples include ethynyloxycarbonyl and n-propynyloxycarbonyl.
[0059]
The term "alkylsulfanyl" means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above "alkyl". Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, and isopropylsulfanyl.
[0060]
The term "alkenylsulfanyl" means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above "alkenyl" . Examples include ethylenylsulfanyl, and n-propenylsulfanyl.
[0061]
The term "alkynylsulfanyl" means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the above "alkynyl". Examples include ethynylsulfanyl, and n-propynylsulfanyl.
[0062]
The term "alkylsulfinyl" means a group wherein the above "alkyl" is bonded to a sulfinyl group. Examples include methylsulfinyl, ethylsulfinyl, n- propylsulfinyl, and isopropylsulfinyl.
[0063]
The term "alkenylsulfinyl" means a group wherein the above "alkenyl" is bonded to a sulfinyl group. Examples include ethylenylsulfinyl, and n- propenylsulfinyl.
[0064]
The term "alkynylsulfinyl" means a group wherein the above "alkynyl" is bonded to a sulfinyl group. Examples include ethynylsulfinyl and n* propynylsulfinyl.
[0065]
The term "alkylcarbamoyl" means a group wherein a hydrogen atom bonded to a nitrogen atom of a carbamoyl group is replaced with the above "alkyl". For example, it includes methylcarbamoyl, ethylcarbamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl".
[0066]
The term "alkenylcarbamoyl" means a group wherein a hydrogen atom bonded to a nitrogen atom of a carbamoyl group is replaced with the above "alkenyl". For example, it includes ethylenylcarbamoyl, propenylcarbamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl".
[0067]
The term "alkynylcarbamoyl" means a group wherein a hydrogen atom bonded to a nitrogen atom of a carbamoyl group is replaced with the above "alkynyl". For example, it includes ethynylcarbamoyl, propynylcarbamoyl and the like.
Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl".
[0068]
The term "alkylsulfamoyl" means a group wherein a hydrogen atom bonded to a nitrogen atom of a sulfamoyl group is replaced with the above "alkyl". For example, it includes methylsulfamoyl, dimethylsulfamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the sulfamoyl group may be replaced with the above "alkyl" .
[0069]
The term "alkenylsulfamoyl" means a group wherein a hydrogen atom bonded to a nitrogen atom of a sulfamoyl group is replaced with the above "alkenyl". For example, it includes ethylenylsulfamoyl, propenylsulfamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl".
[0070]
The term "alkynylsulfamoyl" means a group wherein a hydrogen atom bonded to a nitrogen atom of a sulfamoyl group is replaced with the above "alkynyl". For example, it includes ethynylsulfamoyl, propynylsulfamoyl and the like. Another hydrogen atom bonded to the nitrogen atom of the carbamoyl group may be replaced with the above "alkyl".
[0071]
The term "aromatic carbocyclyl" means a cyclic aromatic hydrocarbon group which is monocyclic or polycyclic having two or more rings. Examples include phenyl, naphthyl, anthryl, and phenanthryl.
A preferred embodiment of "aromatic carbocyclyl" is phenyl.
[0072]
The term "aromatic carbocycle" means a cyclic aromatic hydrocarbon ring which is monocyclic or polycyclic having two or more rings. Examples include a benzene ring, a naphthalene ring, an anthracene ring, and a phenanthrene ring.
A preferred embodiment of "aromatic carbocycle" is a benzene ring or a naphthalene ring.
[0073]
The term "non-aromatic carbocyclyl" means a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group, which is monocyclic or polycyclic having two or more rings. The "non-aromatic carbocyclyl" which is polycyclic having two or more rings includes a fused ring group wherein a non-aromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above "aromatic carbocyclyl".
In addition, examples of the "non-aromatic carbocyclyl" also include a group having a bridge or a group to form a spiro ring as follows:
Figure imgf000036_0001
The non-aromatic carbocyclyl which is monocyclic is preferably C3 to C 16, more preferably C3 to C 12 and further preferably C4 to C8 carbocyclyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclohexadienyl.
Examples of non-aromatic carbocyclyl, which is polycyclic having two or more rings, include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.
[0074]
The term "non-aromatic carbocycle" means a cyclic saturated hydrocarbon ring or a cyclic unsaturated non-aromatic hydrocarbon ring, which is monocyclic or polycyclic having two or more rings. The "non-aromatic carbocycle", which is polycyclic having two or more rings, includes a fused ring wherein the non- aromatic carbocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above "aromatic carbocycle".
In addition, examples of the "non-aromatic carbocycle" also include a ring having a bridge or a ring to form a spiro ring as follows;
Figure imgf000036_0002
The non-aromatic carbocycle which is monocyclic is preferably C3 to C 16, more preferably C3 to C 12 and further preferably C4 to C8 carbocyclyl. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclohexadiene.
Examples of a non-aromatic carbocycle, which is polycyclic having two or more rings, include indane, indene, acenaphthene, tetrahydronaphthalene, and fluorene.
[0075]
The term "aromatic heterocyclyl" means an aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N. The "aromatic heterocyclyl", which is polycyclic having two or more rings, includes a fused ring group wherein an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above "aromatic carbocyclyl".
The aromatic heterocyclyl, which is monocyclic, is preferably a 5- to 8- membered ring and more preferably a 5- to 6- membered ring. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, and thiadiazolyl.
Examples of aromatic heterocyclyl, which is bicyclic, include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, and thiazolopyridyl.
Examples of aromatic heterocyclyl, which is polycyclic having three or more rings, include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, and dibenzofuryl.
[0076]
The term "aromatic heterocycle" means an aromatic ring, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N.
The "aromatic heterocycle", which is polycyclic having two or more rings, includes a fused ring wherein an aromatic heterocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above "aromatic carbocycle".
The aromatic heterocycle, which is monocyclic, is preferably a 5- to 8- membered ring and more preferably a 5- or 6- membered ring. Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophen, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, and thiadiazole.
Examples of an aromatic heterocycle, which is bicyclic, include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, and thiazolopyridine.
Examples of an aromatic heterocycle, which is polycyclic having three or more rings, include carbazole, acridine, xanthene, phenothiazine, phenoxathiine, phenoxazine, and dibenzofuran.
[0077]
The term "non-aromatic heterocyclyl" means a non-aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected independently from O, S and N. The "non- aromatic heterocyclyl", which is polycyclic having two or more rings, includes an above-mentioned non-aromatic heterocyclyl fused with a ring of the above "aromatic carbocyclyl", "non-aromatic carbocyclyl" and/or "aromatic heterocyclyl". The "non- aromatic heterocyclyl", which is polycyclic having two or more rings, includes an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, fused with a ring of the above "non-aromatic carbocyclyl" and/or "aromatic heterocyclyl".
In addition, examples of the "non-aromatic heterocyclyl" also include a group having a bridge or a group to form a spiro ring as follows:
Figure imgf000038_0001
The non-aromatic heterocyclyl, which is monocyclic, is preferably a 3- to 8-membered and more preferably a 5- to 6-membered ring. Examples include dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl, aziridinyl, dioxolynyl, oxepanyl, thiolanyl, thiinyl, and thiazinyl.
Examples of non-aromatic heterocyclyl, which is polycyclic having two or more rings, include indolinyl, isoindolinyl, chromanyl, and isochromanyl.
[0078]
The term "non-aromatic heterocycle" means a cyclic non-aromatic ring, which is monocyclic or polycyclic having two or more rings, containing one or more, same or different heteroatom(s) selected from O, S and N.
The "non-aromatic heterocycle", which is polycyclic having two or more rings, includes an above-mentioned non-aromatic heterocycle fused with a ring of the above "aromatic carbocycle", "non-aromatic carbocycle" and/or "aromatic heterocycle".
In addition, the "non-aromatic heterocycle" also includes a ring having a bridge or a ring to form a spiro ring.
The non-aromatic heterocycle which is non-bridged is preferably a 3 to 8-membered ring, more preferably a 4 to 8-membered ring, and further preferably a 5 or 6-membered ring.
The non-aromatic heterocycle which is bridged is preferably a 6 to 10- membered ring and more preferably a 8 or 9-membered ring. Herein, a number of members mean a number of all annular atoms of a bridged non-aromatic heterocycle.
The non-aromatic heterocycle which is monocyclic is preferably a 3 to 8-membered ring, and more preferably a 5 or 6-membered ring. Examples include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, pyridone, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxoline, oxepane, thiolane, thiine, and thiazine.
Examples of a non-aromatic heterocycle, which is polycyclic having two or more rings, include indoline, isoindoline, chromane, and isochromane.
[0079]
The term "aromatic carbocyclyloxy" means a group wherein the "aromatic carbocycle" is bonded to an oxygen atom. Examples include phenyloxy and naphthyloxy.
[0080]
The term "non-aromatic carbocyclyloxy" means a group wherein the "non-aromatic carbocycle" is bonded to an oxygen atom, Examples include cyclopropyloxy, cyclohexyloxy, and cyclohexenyloxy.
[0081]
The term "aromatic heterocyclyloxy" means a group wherein the "aromatic heterocycle" is bonded to an oxygen atom. Examples include pyridyloxy and oxazolyloxy.
[0082]
The term "non-aromatic heterocyclyloxy" means a group wherein the "non-aromatic heterocycle" is bonded to an oxygen atom. Examples include piperidinyloxy and tetrahydrofuryloxy.
[0083]
The term "aromatic carbocyclylcarbonyl" means a group wherein the "aromatic carbocycle" is bonded to a carbonyl group. Examples include phenylcarbonyl and naphthylcarbonyl.
[0084]
The term "non-aromatic carbocyclylcarbonyl" means a group wherein the "non-aromatic carbocycle" is bonded to a carbonyl group. Examples include cyclopropylcarbonyl, cyclohexylcarbonyl, and cyclohexenylcarbonyl.
[0085]
The term "non-aromatic carbocyclylcarbonyloxy" means a group wherein the "non-aromatic carbocyclylcarbonyl" is bonded to an oxygen atom. Examples include cyclopropylcarbonyloxy, cyclohexylcarbonyloxy, and cyclohexenylcarbonyloxy.
[0086]
The term "aromatic heterocyclylcarbonyl" means a group wherein the "aromatic heterocycle" is bonded to a carbonyl group. Examples include pyridylcarbonyl and oxazolylcarbonyl.
[0087]
The term "non-aromatic heterocyclylcarbonyl" means a group wherein the "non-aromatic heterocycle" is bonded to a carbonyl group. Examples include piperidinylcarbonyl, and tetrahydrofurylcarbonyl.
[0088]
The term "aromatic carbocyclyloxycarbonyl" means a group wherein the "aromatic carbocyclyloxy" is bonded to a carbonyl group. Examples include phenyloxycarbonyl and naphthyloxycarbonyl.
[0089]
The term "non-aromatic carbocyclyloxycarbonyl" means a group wherein the "non-aromatic carbocyclyloxy" is bonded to a carbonyl group. Examples include cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, and cyclohexenyloxycarbonyl. [0090]
The term "aromatic heterocyclyloxycarbonyl" means a group wherein the "aromatic heterocyclyloxy" is bonded to a carbonyl group . Examples include pyridyloxycarbonyl and oxazolyloxycarbonyl.
[0091]
The term "non-aromatic heterocyclyloxycarbonyl" means a group wherein the "non-aromatic heterocyclyloxy" is bonded to a carbonyl group. Examples include piperidinyloxycarbonyl, and tetrahydrofuryloxycarbonyl.
[0092]
The term "aromatic carbocyclylalkyloxy" means an alkyloxy substituted with one or more "aromatic carbocyclyl" described above. Examples include benzyloxy, phenethyloxy, phenybn-propyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, and a group of the following formula:
Figure imgf000040_0001
[0093]
The term "non-aromatic carbocyclylalkyloxy" means an alkyloxy substituted with one or more "non-aromatic carbocyclyl" described above. The "non- aromatic carbocyclylalkyloxy" also includes "non-aromatic carbocyclylalkyloxy" wherein the alkyl part is substituted with the above "aromatic carbocyclyl".
Examples include cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopenthylmethyloxy, cyclohexylmethyloxy, and a group of the following formula:
Figure imgf000040_0002
[0094]
The term "aromatic heterocyclylalkyloxy" means an alkyloxy substituted with one or more "aromatic heterocyclyl" described above. The "aromatic heterocyclylalkyloxy" also includes "aromatic heterocyclylalkyloxy" wherein the alkyl part is substituted with the above "aromatic carbocyclyl" and/or "non-aromatic carbocyclyl". Examples include pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy, pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, and groups of the following formulae :
Figure imgf000040_0003
[0095]
The term "non-aromatic heterocyclylalkyloxy" means an alkyloxy substituted with one or more "non- aromatic heterocyclyl" described above. The "non- aromatic heterocyclylalkyloxy" also includes "non-aromatic heterocyclylalkyloxy" wherein the alkyl part is substituted with the above "aromatic carbocyclyl", "non- aromatic carbocyclyl" and/or "aromatic heterocyclyl". Examples include tetrahydropyranylmethyloxy, morpholinylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, and groups of the following formulae :
Figure imgf000041_0001
[0096]
The term "aromatic carbocyclylalkyloxycarbonyl" means an alkyloxycarbonyl substituted with one or more "aromatic carbocyclyl" described above. Examples include benzyloxycarbonyl, phenethyloxycarbonyl, phenyl-n- propyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, and a group of the following formula:
Figure imgf000041_0002
[0097]
The term "non-aromatic carbocyclylalkyloxycarbonyl" means an alkyloxycarbonyl substituted with one or more "non-aromatic carbocyclyl" described above. The "non-aromatic carbocyclylalkyloxycarbonyl" also includes "non-aromatic carbocyclylalkyloxycarbonyl" wherein the alkyl part is substituted with the above "aromatic carbocyclyl" . Examples include cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopenthylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, and a group of the following formula:
Figure imgf000041_0003
[0098]
The term "aromatic heterocyclylalkyloxycarbonyl" means an alkyloxycarbonyl substituted with one or more "aromatic heterocyclyl" described above. The "aromatic heterocyclylalkyloxycarbonyl" also include "aromatic heterocyclylalkyloxycarbonyl" wherein the alkyl part is substituted with the above "aromatic carbocyclyl" and/or "non-aromatic carbocyclyl". Examples include pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyloxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, and groups of the following formulae:
Figure imgf000042_0001
[0099]
The term "non-aromatic heterocyclylalkyloxycarbonyl" means an alkyloxycarbonyl substituted with one or more "non-aromatic heterocyclyl" described above. The "non-aromatic heterocyclylalkyloxycarbonyl" also includes "non-aromatic heterocyclylalkyloxycarbonyl" wherein the alkyl part is substituted with the above "aromatic carbocyclyl", "non-aromatic carbocyclyl" and/or "aromatic heterocyclyl" . Examples include tetrahydropyranylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, piperazinylmethyloxycarbonyl, and groups of the following formulae:
Figure imgf000042_0002
[0100]
The term "aromatic carbocyclylalkylamino" means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "aromatic carbocyclylalkyl". Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, and dibenzylamino.
[0101]
The term "non-aromatic carbocyclylalkylamino" means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "non-aromatic carbocyclylalkyl". Examples include cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, and cyclohexylmethylamino.
[0102]
The term "aromatic heterocyclylalkylamino" means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "aromatic heterocyclylalkyl". Examples include pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino, pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolylmethylamino, and benzoxazolylmethylamino.
[0103]
The term "non-aromatic heterocyclylalkylamino" means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is(are) replaced with the above "non-aromatic heterocyclylalkyl". Examples include tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, and piperazinylmethylamino.
[0104]
The term "aromatic carbocyclylsulfanyl" means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the "aromatic carbocycle". Examples include phenylsulfanyl and naphthylsulfanyl. [0105]
The term "non-aromatic carbocyclylsulfanyl" means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the "non-aromatic carbocycle". Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, and cyclohexenylsulfanyl.
[0106]
The term "aromatic heterocyclylsulfanyl" means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the "aromatic heterocycle". Examples include pyridylsulfanyl and oxazolylsulfanyl. [0107]
The term "non-aromatic heterocyclylsulfanyl" means a group wherein a hydrogen atom attached to a sulfur atom of a sulfanyl group is replaced with the "non-aromatic heterocycle". Examples include piperidinylsulfanyl and tetrahydrofurylsulfanyl.
[0108]
The term "non-aromatic carbocyclylsulfonyl" means a group wherein the "non-aromatic carbocycle" is bonded to a sulfonyl group. Examples include cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclohexenylsulfonyl.
[0109]
The term "aromatic carbocyclylsulfonyl" means a group wherein the "aromatic carbocycle" is bonded to a sulfonyl group . Examples include phenylsulfonyl and naphthylsulfonyl.
[0110]
The term "aromatic heterocyclylsulfonyl" means a group wherein the "aromatic heterocycle" is bonded to a sulfonyl group . Examples include pyridylsulfonyl and oxazolylsulfonyl.
[0111]
The term "non-aromatic heterocyclylsulfonyl" means a group wherein the "non-aromatic heterocycle" is bonded to a sulfonyl group. Examples include piperidinylsulfonyl and tetrahydrofurylsulfonyl.
[0112]
Preferred embodiments of R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8 , R9 ,
R10, R11 , R12 , X , Y , m and n in the compound represented by formula (I) are described below. A compound having any possible combination of those described below is preferable.
[0113]
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy.
[0114]
Preferably, R1 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
Further preferably, R1 is a hydrogen atom, halogen or substituted or unsubstituted alkyl.
Particularly preferably, R1 is a hydrogen atom.
[0115]
When R1 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
When R1 is a substituted group, a further preferable substituent on said substituted group is selected from halogen and the like.
[0116]
Preferably, R2 is a hydrogen atom, halogen, cyano or substituted or unsubstituted alkyl.
Further preferably, R2 is a hydrogen atom, halogen or substituted or unsubstituted alkyl.
Particularly preferably, R2 is a hydrogen atom or halogen.
[0117]
When R2 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
When R2 is a substituted group , a further preferable substituent on said substituted group is selected from halogen and the like.
[0118]
Preferably, R3 is a hydrogen atom, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
Further preferably, R3 is a hydrogen atom, halogen or substituted or unsubstituted alkyl.
Particularly preferably, R3 is a hydrogen atom or halogen.
[0119]
When R3 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
When R3 is a substituted group, a further preferable substituent on said substituted group is selected from halogen and the like.
[0120]
Preferably, R4 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
Further preferably, R4 is a hydrogen atom, halogen or substituted or unsubstituted alkyl. Particularly preferably, R4 is a hydrogen atom.
[0121]
When R4 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
When R4 is a substituted group, a further preferable substituent on said substituted group is selected from halogen and the like.
[0122]
R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
Preferably, R5 is halogen or substituted or unsubstituted alkyl.
Further preferably, R5 is substituted or unsubstituted alkyl.
[0123]
When R5 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
When R5 is a substituted group, a further preferable substituent on said substituted group is selected from halogen and the like.
[0124]
R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that
R6 , R7 , R8 and R9 are not simultaneously hydrogen atom. [0125]
Preferably, R6 is a hydrogen atom or halogen. Further preferably, R6 is a hydrogen atom.
[0126]
Preferably, R7 is a hydrogen atom or halogen. Further preferably, R7 is halogen.
[0127]
Preferably, R8 is a hydrogen atom or halogen. Further preferably, R8 is a hydrogen atom.
[0128]
Preferably, R9 is a hydrogen atom or halogen. Further preferably, R9 is a hydrogen atom.
[0129]
Embodiments in which R7 is halogen, and R6 , R8 and R9 are hydrogen atom are also preferred. [0130]
Embodiments in which R6 is halogen, and R7 , R8 and R9 are hydrogen atom are also preferred.
[0131]
Embodiments in which R7 and R8 are each independently halogen, and R6 and R9 are hydrogen atom are also preferred. [0132]
Embodiments in which R6 and R7 are each independently halogen, and R8 and R9 are hydrogen atom are also preferred.
[0133] Embodiments in which R7 and R9 are each independently halogen, and R6 and R8 are hydrogen atom are also preferred.
[0134]
When R6 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, alkyloxy and the like.
When R6 is a substituted group, a further preferable substituent on said substituted group is selected from halogen.
[0135]
When R7 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, alkyloxy and the like.
When R7 is a substituted group, a further preferable substituent on said substituted group is selected from halogen.
[0136]
When R8 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, alkyloxy and the like.
When R8 is a substituted group, a further preferable substituent on said substituted group is selected from halogen.
[0137]
When R9 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, alkyloxy and the like.
When R9 is a substituted group, a further preferable substituent on said substituted group is selected from halogen.
[0138]
X is CH or N.
[0139]
Y is CH or N.
[0140]
Embodiments in which X is N, and Y is N are also preferred.
[0141]
Embodiments in which X is N, and Y is CH are also preferred.
[0142]
Embodiments in which X is CH, and Y is N are also preferred.
[0143] m is 0, 1, 2, 3 or 4. Preferably, m is 0, 1 or 2. Further preferably, m is 1 or 2. Particularly preferably, m is 1.
[0144]
In case that m is 1, a group represented by formula:
Figure imgf000046_0001
in formula (I) is preferably a group represented by formula:
Figure imgf000046_0002
[0145] In case that m is 2, a group represented by formula:
Figure imgf000047_0002
in formula (I) is preferably a group represented by formula:
Figure imgf000047_0001
[0146]
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
Preferably, R10 is each independently halogen or substituted or unsubstituted alkyl.
Further preferably, R10 is each independently substituted or unsubstituted alkyl.
[0147]
When R10 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, cyano, alkyloxy, alkylamino and the like.
[0148] R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio. Preferably, R11 is halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
Further preferably, R11 is substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
Particularly preferably, R11 is substituted or unsubstituted alkyloxy, including trihaloalkyloxy (like OCFs) .
[0149]
When R11 is a substituted group, a preferable substituent on said substituted group is selected from halogen, hydroxy, amino, alkyloxy, alkylamino, non-aromatic carbocyclyl and the like.
When R11 is a substituted group, a further preferable substituent on said substituted group is selected from halogen and the like.
[0150]
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy.
Preferably, R12 is each independently halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
[0151]
When R12 is a substituted group, a preferable substituent on said substituted group is selected from halogen and the like. [0152] n is 0, 1, 2, 3 or 4. Preferably, n is 0, 1 or 2. Further preferably, n is
0 or 1. Particularly preferably, n is 0. [0153]
Preferred combinations of substituents of a compound represented by formula (I) include the following 1) to 6) -
1) a compound wherein R1 and R4 are hydrogen atom; R2 is halogen; R3 is a hydrogen atom; R5 is substituted or unsubstituted alkyl; R6 , R8 and R9 are hydrogen atom; R7 is halogen; X is N; Y is N; m is 1; R10 is substituted or unsubstituted alkyl; R11 is substituted or unsubstituted alkyloxy; n is 0;
2) a compound wherein R1 and R4 are hydrogen atom; R2 is halogen; R3 is a hydrogen atom; R5 is substituted or unsubstituted alkyl; R7 , R8 and R9 are hydrogen atom; R6 is halogen; X is CH; Y is N; m is 0; R11 is substituted or unsubstituted alkyl; n is 0;
3) a compound wherein R1 and R4 are hydrogen atom; R2 is a hydrogen atom; R3 is halogen; R5 is substituted or unsubstituted alkyl; R7 , R8 and R9 are hydrogen atom; R6 is halogen; X is CH; Y is N; m is 0; R11 is substituted or unsubstituted alkyl; n is 0;
4) a compound wherein R1 and R4 are hydrogen atom; R2 is a hydrogen atom; R3 is halogen; R5 is substituted or unsubstituted alkyl; R6 , R8 and R9 are hydrogen atom; R7 is halogen; X is N; Y is N; m is 1; R10 is substituted or unsubstituted alkyl; R11 is substituted or unsubstituted alkyloxy; n is 0;
5) a compound wherein R1 and R4 are hydrogen atom; R2 is halogen; R3 is a hydrogen atom; R5 is substituted or unsubstituted alkyl; R6 , R8 and R9 are hydrogen atom; R7 is halogen; X is N; Y is N; m is 2; R10 is each independently substituted or unsubstituted alkyl; R11 is substituted or unsubstituted alkyloxy; n is 0;
6) a compound wherein R1 and R4 are hydrogen atom; R2 is substituted or unsubstituted alkyl; R3 is hydrogen atom; R5 is substituted or unsubstituted alkyl; R6 , R8 and R9 are hydrogen atom; R7 is halogen; X is N; Y is N; m is 1 ; R10 is substituted or unsubstituted alkyl; R11 is substituted or unsubstituted alkyloxy; n is 0.
[0154]
A compound represented by formula (I) :
(I)
Figure imgf000048_0001
, or its pharmaceutically acceptable salt is particularly preferably the compound selected from the group consisting of
Figure imgf000049_0001
, or its pharmaceutically acceptable salt.
[0155]
If desired, any one of more of the compounds of the present invention (a compound represented by formula (I), clarithromycin, azithromycin or clofazimine) may be in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of the compounds include, for example, salts with alkaline metal (e.g. , lithium, sodium or potassium), alkaline earth metal (e.g., calcium or barium), magnesium, transition metal (e. g., zinc or iron), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline or quinoline) or amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, or hydroiodic acid) or organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid). Especially, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are included. These salts can be formed by the usual methods. [0156]
The compounds of formula (I) are not limited to specific isomers but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, enantiomers, or rotamers), racemates or mixtures thereof. [0157]
One or more hydrogen, carbon and/or other atom(s) in the compounds of formula (I) may be replaced with isotopes of hydrogen, carbon and/or other atoms respectively. Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 123I and 36Cl respectively. The compounds of formula (I) include the compounds replaced with these isotopes. The compounds replaced with the above isotopes are useful as medicines and include all of radiolabeled compounds of the compound of formula (I). A "method of radiolabeling" in the manufacture of the "radiolabeled compounds" is encompassed by the present invention, and the "radiolabeled compounds" are useful for studies on metabolized drug pharmacokinetics, studies on binding assay and/or diagnostic tools.
[0158]
A radiolabeled compound of the compounds of formula (I) can be prepared using well-known methods in this field of the invention. For example, a tritium-labeled compound of formula (I) can be prepared by introducing a tritium to a certain compound of formula (I) through a catalytic dehalogenation reaction using a tritium. This method comprises reacting an appropriately-halogenated precursor of the compound of formula (I) with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absent of a base. The other appropriate method of preparing a tritium-labeled compound can be referred to "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". A 14CTabeled compound can be prepared by using a raw material having 14C.
[0159]
The compounds of formula (I) or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates), co-crystal and/or crystal polymorphs. The present invention encompasses those various solvates, co-crystal and crystal polymorphs. "Solvates" may be those wherein any numbers of solvent molecules (e.g., water molecules) are coordinated with the compounds of formula (I) . When the compounds of formula (I) or pharmaceutically acceptable salts thereof are allowed to stand in the atmosphere, the compounds may absorb water, resulting in attachment of adsorbed water or formation of hydrates. Recrystallization of the compounds of formula (I) or pharmaceutically acceptable salts thereof may produce crystal polymorphs. "Co-crystal" means that a compound of formula (I) or a salt thereof and a counter-molecule exist in the same crystal lattice, and it can be formed with any number of counter-molecules.
[0160]
The compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof may form prodrugs. The present invention also encompasses such various prodrugs. Prodrugs are derivatives of the compounds of the present invention that have chemically or metabolically degradable groups, and compounds that are converted to the pharmaceutically active compounds of the present invention through solvolysis or under physiological conditions in vivo. Prodrugs include compounds that are converted to the compounds of formula (I) through enzymatic oxidation, reduction, hydrolysis or the like under physiological conditions in vivo, compounds that are converted to the compounds of formula (I) through hydrolysis by gastric acid etc., and the like, Methods for selecting and preparing suitable prodrug derivatives are described in, for example, "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs themselves may have some activity.
[0161]
When the compounds of formula (I) or pharmaceutically acceptable salts thereof have hydroxyl group(s), prodrugs include acyloxy derivatives and sulfonyloxy derivatives that are prepared by, for example, reacting compounds having hydroxyl group(s) with suitable acyl halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonyl anhydride and mixed anhydride, or with a condensing agent. For example, they include CH3COO-, C2H5COO-, tert-BuCOO-, C15H31COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3O- PhSO3-, PhSO3- and p-CH3PhSO3-.
[0162]
The term “pharmaceutically acceptable” means preventively or therapeutically harmless.
[0163]
General procedures for the synthesis of the compounds of the present invention are described below. Starting materials and reaction reagents used in such synthesis are commercially available or can be synthesized according to methods well known in the art using compounds commercially available. Further, extraction, purification and the like may be performed in accordance with the methods carried out in the art.
In the following all steps, when a substituent which impedes a reaction, e.g. hydroxy, mercapto, amino, formyl, carbonyl, carboxy, is possessed, the substituent is protected by the method described in Protective Groups in organic Synthesis, and Theodora W Greene (John Wiley & Sons, hereinafter referred to as literature A) in advance, and the protecting group may be removed at a desirable stage. In addition, in the all steps, an order of steps to be implemented may be appropriately changed, and each intermediate may be isolated, and used in a next step . All of reaction time, reaction temperature, solvents, reagents, protecting groups, etc. are mere exemplification and not limited as long as they do not cause an adverse effect on a reaction.
[0164]
For example, the compounds represented by Formula (I) of the present invention can be produced according to general procetures as described below. Also, the compounds of the invention can be prepared according to other methods based on the knowledge in organic chemistry.
[0165]
Preparation of Compound a3
Figure imgf000052_0001
wherein
PG is an amino protecting group such as Boc, Cbz and etc., Ra1 is halogen, triflate, nonaflate, mesylate or tosylate, the other symbols are as defined above.
Compound a1 is reacted with Compound a2 in the presence of the base to obtain Compound a3.
Examples of the solvent include toluene, DMF, DMA, tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane and the like, and these solvents may be used alone or in combination.
Examples of the base include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU and the like. The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a1.
The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
[0166]
Preparation of Compound a5
Figure imgf000052_0002
wherein each symbol is as defined above.
Compound a5 can be obtained by reacting with Compound a4 in the presense of Palladium, Ligand and base after reacting Compound a3 with deprotecting agents.
Examples of the reaction solvent for deprotecting reaction include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1, 4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, methane sulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminium trichloride, bromocatechol borane, trimethylsilyl chloride, trimethylsilyl triflate and the like. The amount of the deprotecting agent may be 1 to 100 mole equivalents, preferably 1 to 50 mole equivalents of Compound a4.
Examples of the Palladium include palladium acetate, Pd(PP3)4, PdCl2((PPh3)2, Pd2(dba)3 and the like. The amount of the Palladium may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a4.
Examples of the Ligand include 2-Dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl,Dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) and the like. The amount of the Ligand may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a3.
Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a4.
Examples of the reaction solvent include methanol, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1, 4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
[0167]
Preparation of Compound a6
Figure imgf000053_0001
wherein each symbol is as defined above.
Compound a6 can be obtained by reacting with Compound a2 and Compound a4 in the presense of Palladium, Ligand and base.
Examples of the Palladium include palladium acetate, Pd(PPh3)4 , PdCl2(PPh3)2, Pd2(dba)3 and the like. The amount of the Palladium may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a2.
Examples of the Ligand include 2-dicyclohexylphosphino-2',6'- diisopropoxy-1,1'-biphenyl, dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) and the like. The amount of the Ligand may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a2.
Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide and the like. The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a2.
Examples of the reaction solvent include methanol, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
[0168]
Preparation of Compound a5
Figure imgf000054_0001
wherein each symbol is as defined above.
Compound a5 can be obtained by reacting with Compound al in the presence of the base after reacting Compound a6 with deprotecting agents.
Examples of the reaction solvent for deprotecting reaction include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4'dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, meth ane sulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminium trichloride, bromocatechol borane, trimethylsilyl chloride, trimethylsilyl triflate and the like. The amount of the deprotecting agent may be 1 to 100 mole equivalents, preferably 1 to 50 mole equivalents of Compound al.
Examples of the solvent include toluene, DMF, DMA, dimethyl sulfoxide tetrahydrofuran, ethanol, water, toluene, acetonitrile, 1,4-dioxane and the like, and these solvents may be used alone or in combination.
Examples of the base include potassium tert-butoxide, sodium hydride, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, DBU and the like. The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound al.
The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
The reaction time may be 0. 1 to 24 hours, preferably 1 to 12 hours.
[0169]
Preparation of Compound a?
Figure imgf000055_0001
wherein each symbol is as defined above.
Compound a7 can be obtained by reacting Compound a5 with reductants.
Examples of the reaction solvent include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1, 4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
Examples of the reductants include hydrogen with Pd carbon, hydrogen with Pd(OH)2, sodium borohydrodie with NiCl(H2O)6, lithium aluminumhydride and the like. The amount of the reductants may be 1 to 100 mole equivalents, preferably 1 to 10 mole equivalents of Compound a5.
The reaction temperature may be 0°C to 200°C, preferably 0°C to
100°C.
The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
[0170]
Preparation of Compound alO
Figure imgf000055_0002
wherein
Ra2 is halogen, tritiate, nonaflate, mesylate, tosylate, bornic acid or boronate, Ra3 is triflate, nonaflate, mesylate, tosylate, bornic acid or boronate, the other symbols are as defined above.
The compound a8 is reacted with a9 in the presence of the Palladium and base to obtain Compound a10.
Examples of the Palladium include palladium acetate, Pd(PPh3)4, PdCl2(PPh3)2, Pd2(dba)3, PdCl2(dppf) and the like. The amount of the Palladium may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a8.
Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate and the like. The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a8.
Examples of the reaction solvent include water, DMF, DMA, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
[0171]
Preparation of Compound a11
Figure imgf000056_0001
wherein each symbol is as defined above.
Compound a11 can be obtained by reacting with Compound a10 in the presense of Palladium, ligand and base after reacting Compound a4 with deprotecting agents.
Examples of the reaction solvent for deprotecting reaction include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
Examples of the deprotecting agent include hydrochloric acid / ethyl acetate, methane sulfonic acid, trifluoroacetic acid, sulfuric acid, iodotrimethylsilane, aluminium trichloride, bromocatechol borane, trimethylsilyl chloride, trimethylsilyl triflate and the like. The amount of the deprotecting agent may be 1 to 100 mole equivalents, preferably 1 to 50 mole equivalents of Compound a4.
Examples of the Palladium include palladium acetate, Pd(PPh3)4, PdCl2(PPh3)2, Pd2(dba)3 and the like. The amount of the Palladium may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a4.
Examples of the Ligand include 2-dicyclohexylphosphino-2',6' - diisopropoxy-1,1'-biphenyl,dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane, (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphane) and the like. The amount of the Ligand may be 0.01 to 5 mole equivalents, preferably 0.01 to 1 mole equivalents of Compound a4.
Examples of the base include cesium carbonate, potassium carbonate, sodium carbonate, potassium tert'butoxide, sodium tert'butoxide and the like . The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a4.
Examples of the reaction solvent include methanol, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
The reaction temperature may be room temperature to 200°C, preferably 50°C to 150°C, and the reaction can be conducted in seeled tube as required.
The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours. [0172]
Preparation of Compound a 12
Figure imgf000057_0001
wherein each symbol is as defined above.
Compound a12 can be obtained by reacting Compound all with reductants.
Examples of the reaction solvent include ethyl acetate, water, dicloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
Examples of the reductants includesodium borohydrodie with NiCl2(H2O)6, lithium aluminumhydride, borane tetrahydrofran, borane dimethylsulfide and the like . The amount of the reductants may be 1 to 100 mole equivalents, preferably 1 to 10 mole equivalents of Compound a11.
The reaction temperature may be 0°C to 200°C, preferably 0°C to
100°C.
The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.
[0173]
Preparation of Compound a14
Figure imgf000057_0002
wherein each symbol is as defined above.
Compound a14 can be obtained by reacting Compound a7 with carbocylic acid (Compound a13) in the presence of condensing agents and base.
Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1, 4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
Examples of the base include triethylamine, potassium tert-biitoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU and the like. The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
Examples of the condensing agent include HATU, WSC, DCC, HOBt and the like. The amount of the condensing agent may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
The carboxylic acid may be used in 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a7.
The reaction temperature may be under ice-cooling to reflux temperature, preferably room temperature.
The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.
[0174]
Preparation of Compound a15
Figure imgf000058_0001
wherein each symbol is as defined above.
Compound a15 can be obtained by reacting Compound a12 with carbocylic acid (Compound a13) in the presence of condensing agents and base. Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1, 4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
Examples of the base include triethylamine, potassium tert'butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU and the like. The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
Examples of the condensing agent include HATU, WSC, DCC, HOBt and the like. The amount of the condensing agent may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
The carboxylic acid may be used in 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a12.
The reaction temperature may be under ice-cooling to reflux temperature, preferably room temperature.
The reaction time may be 0. 1 to 24 hours, preferably 1 to 5 hours.
[0175]
Preparation of Compound a16
Figure imgf000058_0002
wherein each symbol is as defined above.
Compound a 16 can be obtained by reacting Compound a11 with reductants.
Examples of the reaction solvent include ethyl acetate, water, dichloromethane, N,N-dimethylformamide, ethanol, tetrahydrofuran, methanol, acetic acid, 1,4-dioxane, acetonitrile, toluene and the like, and these solvents may be used alone or in combination.
Examples of the reductants include hydrogen with Pd carbon, hydrogen with Pd(OH)2, and the like. The amount of the reductants may be 1 to 100 mole equivalents, preferably 1 to 10 mole equivalents of Compound all.
The reaction temperature may be 0°C to 200°C, preferably 0°C to
100°C.
The reaction time may be 0. 1 to 24 hours, preferably 1 to 12 hours.
[0176]
Preparation of Compound a17
Figure imgf000059_0001
wherein each symbol is as defined above.
Compound a17 can be obtained by reacting Compound al6 with carbocylic acid (Compound a13) in the presence of condensing agents and base.
Examples of the reaction solvent include N,N-dimethylformamide, ethanol, water, dichloromethane, tetrahydrofuran, methanol, 1,4-dioxane, acetonitrile, toluene, ethyl acetate and the like, and these solvents may be used alone or in combination.
Examples of the base include triethylamine, potassium tert-butoxide, potassium carbonate, cesium carbonate, diisopropylethylamine, DBU and the like. The amount of the base may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
Examples of the condensing agent include HATU, WSC, DCC, HOBt and the like. The amount of the condensing agent may be 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a13.
The carboxylic acid may be used in 1 to 10 mole equivalents, preferably 1 to 5 mole equivalents of Compound a16.
The reaction temperature may be under ice-cooling to reflux temperature, preferably room temperature.
The reaction time may be 0. 1 to 24 hours, preferably 1 to 5 hours.
[0177]
The compound represented by formula (I) of the present invention or pharmaceutically acceptable salts thereof are useful in the treatment or prevention of a mycobacterial infection, especially non-tuberculous mycobacterial infection. Such compounds may work by interfering with ATP synthase in pathogenic mycobacteria, with the inhibition of cytochrome bc1 activity as the primary mode of action. The compound represented by formula (I) of the present invention or pharmaceutically acceptable salts thereof have not only the above described activity but also usefulness as a medicine, and have any or all of the following superior features : a) The inhibitory activity for CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and the like) is weak. b) The compound demonstrates good pharmacokinetics, such as a high bioavailability, moderate clearance, high distribution to a targeted tissue and the like. c) The compound has a high metabolic stability. d) The compound has no irreversible inhibitory effect against CYP enzymes (e.g., CYP3A4) when the concentration is within the range described in the present description as the measurement conditions. e) The compound has no mutagenicity. f) The compound is associated with a1ow cardiovascular risk. g) The compound has a high solubility. h) The compound causes less induction of drug-metabolizing enzyme i) The compound has less risk of phototoxicity, j) The compound has less risk of hepatotoxicity, k) The compound has less risk of kidney toxicity, l) The compound has less risk of gastrointestinal disorders, and m) The compound has intense efficacy.
[0178]
In embodiments, the medicament includes (A) a compound represented by formula (I):
(I)
Figure imgf000060_0001
wherein each symbol has the same meaning as above
, or its pharmaceutically acceptable salt, is combined with
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
The term "medicament characterized by combination" includes an embodiment in which each compound is used as a combination drug, an embodiment in which each compound is used as a kit, an embodiment in which it is administered simultaneously, an embodiment in which it is administered sequentially, an embodiment in which it is administered at intervals and an embodiment in which they are used in combination with other drugs.
Referring to administration, the term, “simultaneously" means that the compounds (A) and (B) are administered to the subject at the same time, for example in a single dose or bolus. The term, “sequentially” means that the compounds (A) and (B) are administered to the subject in a certain pre-determined sequence within a certain pre-determined time interval of one another. For example, administration sequences of (A)-(B) or (B)-(A) are possible, wherein administration of each is carried out within a few seconds to a few hours of each other. The term administered at “intervals” means that the compounds (A) and (B) are administered to the subject in a certain pre-determined sequence within a certain pre-determined time interval of one another. For example, administration sequences of (A)-(B) or (B)-(A) are possible, wherein administration of each is carried out within a few hours to one day of each other.
[0179]
The compound represented by formula (I), or its pharmaceutically acceptable salt can be used in combination with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt, and it can enhance anti-bacterial effect of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt.
Also, (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt can be used in combination with the compound represented by formula (I), or its pharmaceutically acceptable salt, and it can enhance anti-bacterial effect of the compound represented by formula (I), or its pharmaceutically acceptable salt.
[0180]
In embodiments, the medicament includes (A) a compound represented by formula (I) :
(I)
Figure imgf000061_0001
wherein each symbol has the same meaning as above
, or its pharmaceutically acceptable salt, is combined with
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt.
The term "medicament characterized by combination" includes an embodiment in which each compound is used as a combination drug, an embodiment in which each compound is used as a kit, an embodiment in which it is administered simultaneously, an embodiment in which it is administered sequentially, an embodiment in which it is administered at intervals and an embodiment in which they are used in combination with other drugs.
Referring to administration, the term, “simultaneously" means that the compounds (A), (B), and (C) are administered to the subject at the same time, for example in a single dose or bolus. The term, “sequentially" means that the compounds (A), (B), and (C) are administered to the subject in a certain pre- determined sequence within a certain pre-determined time interval of one another. For example, administration sequences of (A)-(B)-(C), (B)-(C)-(A), (C)-(A)-(B), (B)-(A)- (C), (A)-(C)-(B), or (C)-(B)-(A) are possible, wherein administration of each is carried out within a few seconds to a few hours of each other. The term administered at “intervals” means that the compounds (A), (B), and (C) are administered to the subject in a certain pre-determined sequence within a certain pre-determined time interval of one another. For example, administration sequences of (A)-(B)-(C), (B)- (C)-(A), (C)-(A) -(B), (B)-(A)-(C), (A)-(C)-(B), or (C)-(B)-(A) are possible, wherein administration of each is carried out within a few hours to one day of each other. [0181]
The compound represented by formula (I) , or its pharmaceutically acceptable salt can be used in combination with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt, and it can enhance anti-bacterial effect of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt, and/or (C) clofazimine, or its pharmaceutically acceptable salt.
Also, (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt can be used in combination with the compound represented by formula (I) , or its pharmaceutically acceptable salt, and it can enhance anti-bacterial effect of the compound represented by formula (I), or its pharmaceutically acceptable salt.
[0182]
The route of administration of the medicament of the present invention can be administered by either oral or parenteral methods and is not particularly limited to them.
[0183]
In the case of oral administration, it can be administered by the usual manner in the form of solid preparations for internal use (e .g., tablets, powders, granules, capsules, pills, films), internal solutions (e.g. , suspensions, emulsions, elixirs, syrups, limonade agents, alcoholic agents, fragrance solutions, extracts, decoctions, tinctures), and the like. The tablet may be sugar-coated tablets, film- coated tablets, enteric coated tablets, extended release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets. The powders and granules may be dry syrups. The capsule may be soft capsule, microcapsules or sustained release capsules.
[0184]
In the case of parenteral administration, any forms of injections, drops, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, infusions, coating agents, gargles, enemas, ointments, plasters, jellies, creams, patches, cataplasms, external powders, suppositories) which are usually used can be suitably administered. The injection may be emulsions such as O/W, W/O, O/W/O or W/O/W type.
[0185]
Optionally, the effective amounts of the compound used in the medicament of the present invention may be mixed as necessary with various pharmaceutical additives such as excipients, binders, disintegrants, and/or lubricants suitable for the dosage form to give the pharmaceutical composition. Furthermore, the pharmaceutical composition can be used for children, the elderly, serious patients or surgery, by appropriately changing the effective amount of the compound used in the medicament of the present invention, the dosage form and/or various pharmaceutical additives. The pediatric pharmaceutical composition is preferably administered to patients aged under 12 years old or 15 years old. The pediatric pharmaceutical composition can also be administered to patients less than 4 weeks after birth, 4 weeks to less than 1 year old after birth, 1 year old to less than 7 years old, 7 years old to less than 15 years old, or 15 years old to 18 years old. The pharmaceutical composition for the elderly is preferably administered to patients over 65 years old.
[0186]
The dose of the medicament of the present invention can be appropriately selected on the basis of the clinically used dosage. The mixing ratio of (A) the compound represented by formula (I) and (B), or the mixing ratio of (A) the compound represented by formula (I), (B) and (C) can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like. For example, when the subject to be administered is a human, 0.01 to 400 parts by weight of (B) and/or (C) the combination drug may be used per 1 part by weight of (A) the compound represented by formula (I).
[0187]
Generally, pharmaceutical compositions contain the active compound in an effective amount to achieve their intended purpose. In one embodiment, a therapeutically effective amount means an amount effective to prevent or inhibit development or progression of a disease characterized by mycobacterial infection or activity in the subject being treated. Determination of the effective amounts is within the capability of those skilled in the art in light of the description provided herein.
[0188]
In some embodiments, the medicament of the present invention is suitable for the treatment and/or prevention of diseases and disorders characterized by mycobacterial activity or infection. The mycobacteria may be pathogenic or non- pathogenic. The mycobacteria may be Gram positive or Gram negative.
[0189]
In some embodiments, the medicament of the present invention is suitable for the treatment in humans (either or both of immunocompetent and immunocompromised) and animals of tuberculous, lepromatous, and non-tuberculous mycobacteria. Non-limiting examples of these include but not limited to the following species and strains: Tuberculous mycobacteria, for example M. tuberculosis, M. bovis, M. africanum, M. microti, M. canetti; Lepromatous mycobacteria, for example M. leprae, M. Lepromatosis-', Non-tuberculous mycobacteria, for example M. abscessus, M. abcessus complex, M. a vium, M. intracellulare, M. avium complex, M. kansasii, M. malmoense, M. xenopi, M. malmoense, M. flavences, M. scrofulaceum, M. chelonae, M. peregrinum, M. haemophilum, M. fortuitum, M. marinum, M. ulcerans, M. gordonae, M. haemophilum, M. mucogenicum, M. nonchromogenicum, M. terrae, M. terrae complex, M. asiaticum, M. celatum, M. shimoidei, M. simiae, M. smegmatis, M. szulgai, M. celatum, M. conspicuum, M. genavense, M. immunogenum, M. xenopi. [0190]
In some embodiments, the medicament of the present invention is suitable for the treatment in humans (both immunocompetent and immunocompromised) and animals of non-mycobacterial infectious diseases. [0191]
In some embodiments, the subject is known or suspected to need treatment for one or more maladies related to non-pathogenic mycobacterial strain, M. smegmatis, M. vaccae, M. aurum, or combination thereof.
[0192]
In some embodiments, the subject is known or suspected to need treatment for one or more maladies related to Gram positive bacteria, S. aureus, M. luteus, or combination thereof.
[0193]
In some embodiments, the subject is known or suspected to need treatment for one or more maladies related to Gram negative bacteria, P. aeruginosa, A. baumanii, or combination thereof.
[0194]
In some embodiments, the subject is known or suspected to need treatment for one or more maladies related to pathogenic mycobacterial strain, M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M. m ungi, M. pinnipedii, M. leprae, M. avium, myobacterium tuberculosis complex, tuberculosis, or combination thereof.
[0195]
In some embodiments, the subject is known or suspected to need treatment for one or more maladies related to non-pathogenic mycobacterial strain, M. smegmatis, M. vaccae, M. a urum, Gram positive bacteria, S. aureus, M. luteus, Gram negative bacteria, P. aeruginosa, A. ba umanii, pathogenic mycobacterial strain, M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M. m ungi, M. pinnipedii, M. avium, myobacterium tuberculosis complex, tuberculosis, or combination thereof.
[0196]
In some embodiments, a method is provided, which includes killing or inhibiting the growth of a population of one or more of non-pathogenic mycobacterial strain, M. smegmatis, M. vaccae, M. a urum, Gram positive bacteria, S. a ureus, M. luteus, Gram negative bacteria, P. aeruginosa, A. ba umanii, pathogenic mycobacterial strain, M. tuberculosis, M. bovis, M. marinum, M. kansasaii, H37Rv, M. africanum, M. canetti, M. caprae, M. microti, M mungi, M. pinnipedii, M. a vium, myobacterium tuberculosis complex, tuberculosis, or combination thereof, by contacting one or more member of said population with the compounds used in the present invention or composition.
[EXAMPLES]
[0197]
The present invention is explained in more detail below by Examples, but the present invention is not limited to them.
[0198]
The compound represented by formula (I) used in the present invention (A) can be prepared by reference to WO2011/057145, WO2017/049321, WO2011/113606, WO2021/050708, the entire contents of each of which are hereby incorporated by reference, the same as if set forth at length.
[0199]
Besides, abbreviations used herein have the following meanings:
Me: methyl Et: ethyl
Bu: butyl
Ph: phenyl
PPh3: triphenylphosphine
Ac: acetyl
EtOAc: ethyl acetate
DMF: N,N-dimethylformamide
DMA: N,N-dimethylacetoamide
TEA: trifluoroacetic acid
DMSQ: dimethyl sulfoxide
THF: tetrahydrofuran
WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium; 3- Oxide, hexafluorophosphate
DCC: N,N'-Dicyclohhexylcarbodiimide
HOBt: hydrxybenzotriazole
Boc: t-butoxycarbonyl t: tertially
Cbz: benzyloxycarbonyl dppf: 1,1'-Bis(diphenylphosphino)ferrocene
Pd2(dba)3: Tris(dibezylideneacetone)dipalladium
PdCl2(dppf) : [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride
Pd(PPh3)4: Tetrakis(triphenylphosphine) palladium(0)
PdCl2(PPh3)2 : Bis(triphenylphosphine)palladium chloride
[0200]
NMR analysis of each example was performed by 400 MHz using deuterated dimethyl sulfoxide (d6-DMSO) or deuterochloroform (CDCl3). In the case of indicating NMR data, there are cases in which not all measured peaks are described.
"RT" in the specification means a retention time of LC/MS : liquid chromatography/mass spectrometry, and the measurement conditions are as follows. (Method A)
UHPLC/MS data of the compounds were measured under the following condition. Column: ACQUITY UPLC®BEH C18 (1.7μm i.d.50x2.1mm) (Waters) Flow rate: 0.8 mL/min
UV detection wavelength: 254nm
Mobile phase: [A] is 0. 1 % formic acid-containing aqueous solution, and [B] is 0.1% formic acid-containing acetonitrile solution.
Gradient: Linear gradient of 5% to 100% solvent [B] for 3.5 minutes was performed, and 100% solvent [B] was maintained for 0.5 minute."
(Method B)
UHPLC/MS data of the compounds were measured under the following condition.
Column: ACQUITY UPLC®BEH C18 (1.7pmi.d.50x2.1mm) (Waters)
Flow rate : 0.8 mL/min
UV detection wavelength: 254nm
Mobile phase : [A] is 10mM ammonium carbonate-containing aqueous solution, and [B] is acetonitrile.
Gradient: Linear gradient of 5% to 100% solvent [B] for 3.5 minutes was performed, and 100% solvent [B] was maintained for 0.5 minute.
Hereinafter, MS(m/z) indicates the value observed in the mass spectrometry.
[Example 1]
[0201]
Preparation of Compound I-1-3
Figure imgf000066_0001
Step 1
To a solution of Compound 1 (1 g, 7.19mmol) in DMA (5mL) were added K2CO3 (1.49g, 10.78mmol) and Compound 2 (0.792g, 7.91mmol), and the solution was stirred at 100°C for 4.5 hours. After the reaction solution was poured into water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried with sodium sulfate and filtered. After the organic layer was concentrated under reduced pressure, the residue was washed with hexanes to yield Compound 3 (1.01g, yield: 64%) as a solid.
1H-NME (CDC13) δ: 7.38-7.33 (1H, m), 7.27 (1H, dd, J = 12.9, 1.9 Hz), 6.91 (1H, t, J = 8.2 Hz), 3.50-3.41 (2H, m), 3. 12-2.98 (3H, m), 2.88-2.77 (1H, m), 2.52-2.44 (1H, m), 1. 12 (3H, d, J = 6.0 Hz).
Step. 2
To a solution of Compound 3 (510mg, 2.33mmol) in toluene (5.0mL) were added l-bromo- 4-(trifluoromethyl)benzene 4 (576mg, 2.56mmol), Pd(OAc)2 (52.2mg, 0.233 mmol), 2 -dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (217mg, 0.465mmol) and sodium t'butoxide (447mg, 4.65mmol), the solution was stirred at 100°C for 1 hour. To the reaction solution were added water and ethyl acetate. The oranic layer was washed with water and brine, dried with anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure, the residue was purified by silica gel chromatography (hexanes / ethyl acetate) to yield Compound 5 (543mg, yield: 64%) as a yellow solid.
1H-NMR (CDC13) δ: 7.39 (1H, dd, J = 8.4, 1.9 Hz), 7.30 (1H, dd, J = 12.5, 1.9 Hz), 7.14 (2H, d, J = 8.3 Hz), 6.95 (1H, t, J = 9.2 Hz), 6.92 (2H, d, J = 8.3 Hz), 3.99-3.90 (1H, m), 3.55-3.50 (1H, m), 3.42-3.40 (1H, m), 3.35 3.26 (3H, m), 3.20 3.11 (1H, m), 1. 16 (3H, d, J = 6.4 Hz)
Step.3
To a solution of Compound 5 (546 mg, 1.50mmol) in MeOH (15mL) were added 5% Pd-C (320g, 0.150mmol) and Conc.HCl (1.5mL), and the solution was stirred at room temperature for 5 hours under hydrogen atomosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure. To the reaction mixture were added aqueous NaOH solution and ethyl acetate. The oranic layer was washed with water and brine, dried with anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure to yield Compound 6 (440mg, yield: 80%) as a yellow solid.
1H-NMR (CDC13) δ: 7.16'7. 10 (2H, m), 7.07'7.00 (2H, m), 6.98'6.88 (3H, m), 3.99'3.91 (1H, m), 3.86-3.80 (2H, m), 3.40-3.21 (4H, m), 3.17-3. 10 (1H, m), 3.05'2.99 ( 1H, m), 1.19 (3H, d, J = 6.4 Hz) .
Step.4
To a solution of Compound 6 (80mg, 0.209mmol) in acetonitrile (2.0mL) were added Compound 7 (52mg, 0.230mmol), triethylamine (0.087mL, 0.626mmol), 3 -(((ethylimino) me thylene) amino) -N,N-dimethylprop an- 1 -amine (48.6mg, 0.313mmol) and HOBt (28.2mg, 0.209mmol), the solution was stirred at 80°C for 1 hour. To the reaction solution was added water, and extracted with ethyl acetate. The oranic layer was washed with brine, dried with anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure, the residue was purified by silica gel chromatography (CHCl3 / methanol) to yield Compound I-1-' 3 (55mg, yield: 45%) as a white solid.
LC/MS Method A: m/z=590.2. [M+H]+, retention time: 3.0 min
[Example 2]
[0202]
Preparation of Compound 8
Figure imgf000067_0001
To a solution of Compound 7 (20g, 89mmol) in acetonitrile (200mL) were added N-methylmorpholine (19.6mL, 178mmol), 3- (((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride ( 18.8g, 98mmol) and HOBt (18.01g, 98mmol), the solution was stirred at room temperature for over 15 hours. To the reaction solution was added water, and the reaction mixture was filtered. The residue was washed with water and dried under reduced pressure to yield Compound 8 (19.4g, yield: 64%) as a solid.
1H-NMR (CDC13) δ: 9.26 (1H, d, J = 1.3 Hz), 8. 14 (1H, d, J = 8.4 Hz), 7.74 (1H, d, J = 9.4 Hz), 7.62-7.44 (4H, m), 3.37 (2H, q, J = 7.5 Hz), 1.53 (3H, t, J = 7.5 Hz).
[Example 3]
[0203]
Preparation of Compound 10
Figure imgf000068_0001
To a solution of Compound 9 (4.9g, 23.7mmol) in acetonitrile (99mL) were added N-methylmorpholine (2.86mL, 26mmol), 3- (((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (4.04g, 26mmol) and HOBt (3.2g, 23.7mmol), the solution was stirred at room temperature for over 22 hours. To the reaction solution was added water, and the reaction mixture was filtered. The residue was washed with water and dried under reduced pressure to yield Compound 10 (5.09g, yield: 66%) as a white solid.
1H-NMR (CDC13) δ: 9. 18 (1H, dd, J = 7.5, 5.4 Hz), 8.14 ( 1H, dt, J = 8.4, 0.9 Hz), 7.59 (1H, dd, J = 16. 1, 8.0 Hz), 7.54-7.40 (3H, m), 6.98 (1H, td, J = 7.5, 2.7 Hz), 3.35 (2H, q, J = 7.5 Hz), 1.52 (3H, t, J = 7.5 Hz).
[Example 4]
[0204]
Preparation of Compound I-1-38
Figure imgf000068_0002
To a solution of Compound 6 (70mg, 0.183mmol) in acetonitrile (1.0mL) were added Compound 9 (41.8mg, 0.201mmol), triethylamine (0.051mL, 0.365mmol), 3 - (((ethylimino) methylene) amino) -N,N-dimethylprop an- 1 -amine hydrochloride (52.5mg, 0.274mmol) and HOBt (24.7mg, 0.183mmol), the solution was stirred at 50°C for 1 hour. To the reaction solution was added saturated aqueous NaHCO3 solution, and extracted with ethyl acetate. The oranic layer was washed with water and brine, and dried with anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure, the residue was purified by silica gel chromatography (hexane /ethyl acetate) to yield Compound I-1-38 (78mg, yield: 75%) as a white solid.
1H-NMR (CDCl3) δ: 9.44 ( 1H, t, J = 5.6 Hz), 7.22 (1H, s), 7. 14-7.07 (4H, m), 6.97-6.92 (3H, m), 6.80 (1H, t, J = 7.3 Hz), 6.06 (1H, s), 4.63 (2H, d, J = 3.8 Hz), 3.95 (1H, d, J = 2.0 Hz), 3.38-3.27 (4H, m), 3.17-3.14 (1H, m), 3.06'2.95 (3H, m), 1.44' 1.40 (3H, m), 1.19 (3H, d, J = 4.5 Hz).
LC/MS Method B: m/z=574.25 [M+H]+, retention time : 2.99 min
[Example 5]
[0205]
Preparation of Compound I-1-2
Figure imgf000069_0001
To a solution of Compound 6 (1.5g, 3.91mmol) in dichloromethane ( l.OmL) were added Compound 11 (1.32g, 4.3mmol) and triethylamine (0.814mL, 5.87mmol), the solution was stirred at room temperature for 15 hours. The reaction solution was purified by aminosilica gel and silica gel chromatography (CHCl3 /methanol) to yield Compound I-1-2 (1.76g, yield: 81%) as a white solid.
LC/MS Method A: m/z=574.25 [M+H]+, retention time : 2.99 min
[Example 6]
[0206]
Preparation of Compound I-1-25
Figure imgf000070_0001
To a solution of Compound 6 (50mg, 0. 130mmol) in dichloromethane (0.8mL) were added Compound 13 (29.8g, 0.156mmol), triethylamine (0.054mL, 0.391mmol), 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine (30.4mg, 0. 196mmol) and HOBt (8.8mg, 0.065mmol), the solution was stirred at room temperature for 15 hours. To the reaction solution was added saturated aqueous NaHCO3 solution, and extracted with dichloromethane. The oranic layer was washed with water and brine, and dried with anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl3 /methanol) to yield Compound I-1-25 (47mg, yield: 74.5%) as a white solid.
LC/MS Method A: m/z=556.3 [M+H]+, retention time: 2.73 min
[Example 7]
[0207]
Preparation of Compound I-1-1
Figure imgf000071_0001
Step 1
To a solution of Compound 14 (5.05 g, 21.7 mmol) in 1,4-dioxane (76mL) were added compound 15 (7.37 g, 23.8mmol), PdCl2(Ph3)2 ( 1.52 g, 2.17 mmol) and 2M Na2CO3 aqueous solution (32.5 ml, 65 mmol) . The reaction mixture was stirred at 100 °C for 1.5 hours. After the reaction solution was poured into water, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes-EtOAc) to yield compound 16 (6.59 g, 19.7 mmol, 91%) as a white solid.
1H-NMR (400 MHz, CDC13) δ: 7.78 (dd, 1H, J = 7.8, 1.3 Hz), 7.70 (dd, 1H, 1 1.6, 1.3 Hz), 6.04 (m, 1H), 4.15-4.05 (m, 2H), 3.92 (s, 3H), 3.62 (t, 2H, 5.4), 2.56-2.46 (m, 2H), 1.48 (s, 9H)
Step 2 To a solution of compound 16 (6.49 g, 19.4 mmol) in THE (100 ml), purged with inert atmosphere, was added 10% Pd(OH)2/C (5.44 g, 1.94 mmol) . The reaction mixture was charged with hydrogen gas ( 1 atm). The resulting suspension was vigorously stirred for 6.5 hours. The reaction mixture was purged with an inert atmosphere, filtered through a celite pad. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduce pressure to yield the crude material as an oil. This crude material was used for the next reaction without further purification. The crude material was dissolved in THE (100 ml) and was added to a suspension of LiAlE4 ( 1.46 g, 38.5 mmol) in THE (100ml) at 0 °C. After stirring for 5 min, to the reaction mixture was added sodium sulfate decahydrate (24.83 g, 77 mmol) and the reaction was stirred for 3 hours. The reaction mixture was filtered through a celite pad. The filter cake was washed with EtOAc, and the filtrate was concentrated under reduce pressure to yield the crude product as an oil. This crude material was used in the next reaction without further purification. To a solution of the crude material in dichloromethane (100 ml) were added Et3N (7.93 ml, 57.2 mmol) and methansulfonyl chloride (3.28 g, 28.6 mmol) at -78 °C. To the reaction solution was added H2O, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude material as an oil. This crude material was used in the next reaction without further purification. To a solution of the crude material in DMF (60 ml) was added NaN3 (2.47 g, 37.9 mmol) and the mixture was stirred at 80 °C for 1 hour. To the reaction solution was added H2O, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude material as an oil. This crude product was used to the next reaction without further purification. To a solution of the crude product in THE (50 ml) were added PPh3 (5.55 g, 21.2 mmol) and H2O (3.18 ml, 176 mmol) and the mixture was stirred at reflux for 2 hours. The mixture was then concentrated under reduced pressure, the residue was purified by silica gel column chromatography (EtOAc-CHCl3-MeOH) to yield compound 17 (4.11 g, 13.3 mmol, 69% for 5 steps) as a white solid.
1H-NMR (400 MHz, CDCl3) δ: 7.15 (t, 1H, J = 7.7 Hz), 7.04 (d, 1H, J = 7.9 Hz), 7.00 (d, 1H, J = 11.3 Hz), 4,24 (s, 2H), 3.84 (s, 2H), 2.98-2.89 (m, 1H), 2.84-2.70 (m, 2H), 1.83- 1.75 (m, 2H), 1.68- 1.55 (4H, m) , 1.48 (s, 9H)
LC/MS Method: A, LC-MS: m/z=253. [M+H]+, retention time: 1.67min
Step 3
To a solution of compound 17 ( 1.84 g, 5.97 mmol) in dichloromethane (20 ml) were added compound 1 1 (2.02 g, 6.56 mmol) and Et3N (1.24 ml, 8.95 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was purified by silica gel chromatography (CHCl3 /MeOH) to yield compound 18 (2.83 g, 5.89 mmol, 99%) as a white solid.
LC/MS Method: A, LC-MS : m/z=481. [M+H]+, retention time: 2.17 min
Step 4
To a solution of compound 18 (2.44 g, 5.08 mmol) in dichloromethane (20 ml) was added TEA (3.91 ml, 50.8 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was purified by amino silica gel chromatography (CHCl3 /MeOH) to yield compound 19 ( 1.83 g, 4.81 mmol, 95%) as a off-white amorphous. LC/MS Method: A, LC-MS: m/z=381. [M+H] + , retention time : 1.00 min
Step 5
To a solution of compound 19 (100 mg, 0.263 mmol) in THF were added compound 4 (95 mg, 0.394 mmol), Pd2(dba)3 (24. 1 mg, 0.0026 mmol), 2* dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (49. ling, 0.105 mmol) and NaOtBu (0.789 mmol), and then the reaction was stirred at 60 °C for 1 hour. To the reaction solution was added H2O, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexanes /EtOAc) to yield compound I-1-1 (81.7 mg, 0.151 mmol, 57.5%) 1H-NMR (400 MHz, CDC13) δ: 9.32 (d, 1H, J = 7.5 Hz), 7.33 (s, 1H), 7.28-7.22 (m, 1H), 7.15*7.04 (m, 4H) , 6.94 (d, 2H, J = 7.9 Hz), 6.77 (d, 1H, J = 6.5 Hz), 6.06 (s, 1H), 4.67 (d, 2H, J = 5.3 Hz), 3.80-3.72 (m, 2H), 3.05- 2.95 (m, 1H), 2.90-2.80 (m, 2H), 2.69 (s, 3H), 2.43 (s, 3H), 1.95- 1.83 (m, 4H)
LC/MS Method: A, LC-MS : m/z=541. [M+H]+, retention time: 2.42 min
[0208]
The following Compounds were obtained in accordance with the general synthetic methods and Examples. The chemical structures and the physical properties(LC/MS data) of Compounds are described below.
[0209]
[Table 1]
Figure imgf000074_0001
[0210]
[Table 2]
Figure imgf000075_0001
[0211]
[Table 3]
Figure imgf000076_0001
[0212]
[Table 4]
Figure imgf000077_0001
[0213]
[Table 5]
Figure imgf000078_0001
[0214]
[Table 6]
Figure imgf000079_0001
[0215]
[Table 7]
Figure imgf000080_0001
[0216]
[Table 8]
Figure imgf000081_0001
[0217]
[Table 9]
Figure imgf000082_0001
[0218]
[Table 10]
Figure imgf000083_0001
[0219]
[Table 11]
Figure imgf000084_0001
[0220]
[Table 12]
Figure imgf000085_0001
[0221]
[Table 13]
Figure imgf000086_0001
[0222]
[Table 14] O H -N y-N //
Cl
-^N X HCI
Figure imgf000087_0001
[0223]
[Table 15]
Figure imgf000088_0001
[0224]
[Table 16]
Figure imgf000089_0001
[0225]
[Table 17]
Figure imgf000090_0001
[0226]
[Table 18]
Figure imgf000091_0001
[0227]
[Table 19]
Figure imgf000092_0001
[0228]
[Table 20]
Figure imgf000093_0001
[0229]
[Table 21]
Figure imgf000094_0001
[0230]
Pharmacological examples
(Test Example 1)
Determination of IC85 for testing compounds against M. avium.
Preparation
One μL of DMSO stock solutions (200 x final concentration) of experimental compounds were added to round-bottom, sterile 96 well microtiter plates. Serial 4-fold dilutions (from 8 to 0.0000076 μM) were made directly in the microtiter plates from column 1 to 11. Untreated control samples with and without inoculum were included in column 12 in each plate.
A sample of Mycobacterium avium ATCC700898 was taken from 7H9 (5% OADC) agar plate. This was first diluted by CAMHB medium to obtain an optical density of 0.1 at 600 nm wavelength and then diluted 1/20, resulting in an inoculum of approximately 5x 10 exp6 colony forming units per mL. Microtiter plates were filled with 200 μL of inoculum solution.
Plates were incubated at 37°C in a stainless-steel bat to prevent evaporation. After 3 days of incubation, resazurin was added to all wells. One day later, fluorescence was measured on EnVision Microplate Reader with 543 excitation and 590 nm emission wavelengths and calculated IC85 values.
[0231]
The results of Test Example 1 are shown below.
[0232]
[Table 22]
Figure imgf000095_0001
[0233]
(Test Example 2) Metabolic stability test
Using a commercially available pooled human liver microsomes, a compound of the present invention was reacted for a constant time, a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.
A reaction was performed (oxidative reaction) at 37 °C for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes. After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol/acetonitrile = 1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and a remaining amount of the compound of the present invention after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%.
[0234]
The results of Test Example 2 are shown below.
[0235]
[Table 23]
Figure imgf000097_0001
[0236]
Biological Example - COMBINATIONS
Protocol
The compounds employed were as follows:
• Clarithromycin - “CAM”
• Azithromycin - “AZM”
• Rifampicin - “RFP”
• Ethambutol - “ETB”
• Clofazimine - “CFZ”
• The following “bc1 inhibitors”:
Figure imgf000098_0001
[0237]
Design of the study
(Test Example 3)
There were 15 study groups and 4 mice per group
[Table 24]
Figure imgf000099_0001
Generally, as can be seen from the table above, the following doses of the relevant compounds and formulation concentrations were given:
• Clarithromycin (CAM) - administered at a dose of 200 mg/kg in mice as a clinical dose of 600 mg in human; the formulation concentration being 20 mg/mL
• Clofazimine (CFZ) loading — On the first day, administration dose was 40 mg/kg. after the second day, administration dose was 6 mg/kg. At the beginning of second week, administered at a dose of 15 mg/kg, after this day, administration dose was 6 mg/kg. This dosing mimics the AUG of repetitive administration of 50 mg in human.
[0238]
Methods
All treatments were evaluated on Mycobacterium avium ATCC700898.
All formulations prepared in 0.5% (w/v) Methylcellulose.
All formulations were solutions and prepared once in a week.
Time Schedule, after mice were infected.
Necropsy Control 1 Day 1
Start Treatment Day 1
Last treatment Day 7
Necropsy Control 2 Day 8
Necropsy Treatment Groups Day 8 The mice were infected with Mycobacterium avium strain.
The clarithromycin sensitive ATCC700898 was thawed at ambient temperat ure and diluted in saline for mouse inoculation. When 0.07 mL of this dilution is inoculated, each mouse receives 107 bacteria.
48 female 8-weeks old BALB/c mice, Charles River, were inoculated intran asally with 0.07 mL of a bacterial suspension containing ± 107 colony forming u nits (CFU).
[0239]
Dosing
The start of dosing was at Day 1.
• Body weight of all mice were regarded as around 20 g.
• All mice were dosed orally with 0.2 mL of the appropriate formulation, except the control groups, which were not treated.
• All groups were treated once daily on working days for a week (5 doses/treatments in total) .
• The last doses/treatments were given on Day 7. [0240]
Necropsy
At day 1 after the infection, 4 control mice were sacrificed, and the lung was collected in homogenization tubes.
At day 8 after the infection, 4 control mice and 40 treated mice were sacrificed, and the lung was collected in homogenization tubes.
[0241]
Assessment of infection and treatment
The effectiveness of treatments was assessed by counting the numbers of colony-forming-units (CFU) in the lungs.
• 1.8 mL Mueller Hinton Broth (MHB) was added to each homogenization tube containing lung.
• Lungs were homogenized, and four 10-fold serial dilutions were made in MHB.
• From each individual lung, 100 μL of the undiluted suspension and four serial 10-fold dilutions, were plated on 7H10 agar plates.
• CFU's were counted after incubation at 35°C for 3 weeks.
• The bactericidal effect of the treatment was defined as a significant decrease of the mean number of CFU in the treated group compared to pre-treatment value.
[0242] Preparation of Media 7H10 agar + 5% OADC
• dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water.
• add 5 mL glycerol
• autoclave at 121°C for 10 min and cool to 55°C
• add 50 mL Middlebrook OADC Enrichment (BD 212240)
• keep at 55°C
• pipette 20 mL agar solution/dish
• store at 4°C until ready to use after coagulation
[0243]
Results
[Table 25]
Figure imgf000101_0001
The results above can be seen with reference to Figure 1, which shows each the mean log10 value for CFUs of each of the 15 study groups. It also shows a “cut off value of 2.00, which is essentially the value at which the CFUs (or the bacterial infection) is so low that it cannot accurately be measured, or the CFUs are below the detectable level.
• double combinations of clarithromycin + clofazimine resulted the effect causing drop to the mean log10 of 5.49
• triple combinations of clarithromycin + clofazimine + I-1-3 showed potent efficacy by I-1-3 dose dependent manner
• triple combinations of clarithromycin + clofazimine + I-1-149 showed potent efficacy by I-1-149 dose dependent manner
• triple combinations of clarithromycin + clofazimine + I-1-144 showed potent efficacy by I-1-144 dose dependent manner
• triple combinations of clarithromycin + clofazimine + I-1-43 showed potent efficacy by I-1-43 dose dependent manner
[0244]
(Test Example 4)
There were 6 study groups and 4 mice per group
[Table 26]
Figure imgf000102_0001
Almost protocol was the same as the protocol described in the above Test Example 3.
[0245]
Results
Table 27]
Figure imgf000102_0002
The results above can be seen with reference to Figure 2, which shows each the mean log10 value for CFUs of each of the 6 study groups. It also shows a “cut off" value of 2.00, which is essentially the value at which the CFUs (or the bacterial infection) is so low that it cannot accurately be measured, or the CFUs are below the detectable level.
It can be seen that, compared to the control groups :
• double combinations of clarithromycin + clofazimine resulted the effect causing drop to the mean log10 of 5.69
• triple combinations of clarithromycin + clofazimine + I-2-6 showed potent efficacy by I-2-6 dose dependent manner
[0246]
(Test Example 5)
There were 15 study groups and 4 mice per group
[Table 28]
Figure imgf000103_0001
Almost protocol was the same as the protocol described in the above Test Example 3.
[0247] Results [Table 29]
Figure imgf000104_0001
The results above can be seen with reference to Figure 3, which shows each the mean log10 value for CFUs of each of the 15 study groups. It also shows a “cut off value of 2.00, which is essentially the value at which the CFUs (or the bacterial infection) is so low that it cannot accurately be measured, or the CFUs are below the detectable level.
It can be seen that, compared to the control groups:
• double combinations of clarithromycin + clofazimine resulted the effect causing drop to the mean log10 of 4.97
• triple combinations of clarithromycin + clofazimine + I-1-25 showed potent efficacy by I-1-25 dose dependent manner
• triple combinations of clarithromycin + clofazimine + I-1-42 showed potent efficacy by I-1-42 dose dependent manner
• triple combinations of clarithromycin + clofazimine + I-1-29 showed potent efficacy by I-1-29 dose dependent manner
• triple combinations of clarithromycin + clofazimine + I-1-39 showed potent efficacy by I-1-39 dose dependent manner
[0248]
(Test Example 6) There were 6 study groups and 4 mice per group
[Table 30]
Figure imgf000105_0001
Almost protocol was the same as the protocol described in the above Test Example 3 except for the bacterial load and the period of treatment.
• 24 female 8-weeks old BALB/c mice, Charles River, were inoculated intranasally with 0.07 mL of a bacterial suspension containing ± 106 colony forming units (CFU).
• All groups were treated once daily on working days for 2 consecutive weeks (5 times/week, 10 doses/treatments in total).
• The last doses/treatments were given on Day 14.
[0249]
Results [Table 31]
Figure imgf000105_0002
The results above can be seen with reference to Figure 4, which shows each the mean log10 value for CFUs of each of the 6 study groups. It also shows a “cut off value of 2.00, which is essentially the value at which the CFUs (or the bacterial infection) is so low that it cannot accurately be measured, or the CFUs are below the detectable level.
It can be seen that, compared to the control groups:
• Clinical standard therapy of azithromycin + rifampicin + ethambutol resulted the effect causing drop to a mean log10 of 0. 1 CFU from control 2 (mean log10 of 5.93)
• double combinations of azithromycin + clofazimine resulted the effect causing drop to the mean log10 of 5.47
• triple combinations of clarithromycin + clofazimine + I-1-3 showed surprising reduction in CFU (mean log10 of 3.71)
[0250]
Biological Example - COMBINATIONS Protocol
The compounds employed were as follows:
• Clarithromycin - “CAM”
• The following “bc1 inhibitors”:
Figure imgf000106_0002
[0251]
Design of the study
(Test Example 7)
There were 12 study groups.
[Table 32]
Figure imgf000106_0001
[0252]
Methods
All treatments were evaluated on Mycobacterium avium ATCC7008
98.
All compound solutions were prepared in 7H9 medium containing
5% OADC.
The assay buffer was also used 7H9 medium containing 5% OADC.
The clarithromycin sensitive ATCC700898 was cultured 7 days at
37°C in 7H9 medium containing 5% OADC. And then, glycerol was mixed with the culture solution to a final concentration of 20% glycerol and stored at -80°C.
Determination of colony forming units (CFU) of the stock solution was perform ed by counting the numbers of colonies grown in 7H10 agar plates containing 5 % OADC. The bactericidal studies were performed using the medium in 96 well plate (final volume was 200 μl/well). The stock solution was diluted by the med ium to a final concentration of approximately 1.0 x 105 CFU/ml. All CAM and bc1 inhibitors were dissolved in DMSO to make a 1 mg/mL solution. And then, t he solutions were diluted with the medium to a final concentration as shown in Table 32. The assay plates were incubated at 37°C for 3 days.
[0253]
Sampling point
At day 0 after starting the assay, determination of CFU was conducted only in the control group for calculating initial number of CFU.
At day 3 after starting the assay, determination of CFU was conducted in all tested groups.
[0254]
Assessment of infection and treatment
The effectiveness of treatments was assessed by counting the numbers of colony-forming-units (CFU) in the lungs.
• The cultures of each groups were serially diluted 10-fold with saline.
• From each individual group, 100 μL of these diluents were applied to the 7H10 agar containing 5% OADC.
• CFU's were counted after incubation at 35°C for 2 weeks.
• The bacteriostatic and bactericidal effect of the treatment was defined as comparing with Control CFU at day0 and/or day3.
• When the number of CFU in maximum diluent were exceeded 3000 CFU, 3000 CFU was adopted as the upper limit of detection.
[0255]
Preparation of Media
7H9 medium + 5% OADC
• dissolve 2.35 g Middlebrook 7H9 medium (BD 262710) in 475 mL distilled water
• add 2.5 mL glycerol
• autoclave at 121°C for 10 min and cool to around room temperature
• add 25 mL Middlebrook OADC Enrichment (BD 212240)
• store at 4°C until ready to use 7H10 agar + 5% OADC
• dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water.
• add 5 mL glycerol
• autoclave at 121°C for 10 min and cool to 55°C
• add 50 mL Middlebrook OADC Enrichment (BD 212240)
• keep at 55°C
• pipette 20 mL agar solution/dish
• store at 4°C until ready to use after coagulation
[0256] Results [Table 33]
Figure imgf000108_0001
The results above can be seen with reference to Figure 5, which shows each the log10 value for CFUs of each of the 12 study groups. It also shows a “upper limit' value of 7.48, which is essentially the value at which the CFUs is so high that it cannot accurately be measured.
All bc1 inhibitors revealed bacteriostatic effect as the log10 CFU of 5.38 to 5.76.
[0257]
(Test Example 8)
There were 30 study groups.
[Table 34]
Figure imgf000109_0001
Almost protocol was the same as the protocol described in the above Test Example 7.
[0258]
Results
[Table 35]
Figure imgf000110_0001
The results above can be seen with reference to Figure 6, which shows each the log10 value for CFUs of each of the 30 study groups. It also shows a “upper limit' value of 8.48, which is essentially the value at which the CFUs is so high that it cannot accurately be measured.
It can be seen that, compared to the control groups:
• double combinations of clarithromycin 1 μg/ml + bc1 inhibitors 10 μg/ml resulted the effect causing drop to the log10 of 3.90 to 4.26.
• double combinations of clarithromycin 1 μg/ml + several bc1 inhibitors (I-1-144, I-1-149 and 1-2-6) revealed concentration correlation.
[0259]
(Test Example 9)
There were 11 study groups and 4 mice per group [Table 36]
Figure imgf000111_0001
Methods
All treatments were evaluated on Mycobacterium a vium ATCC7008
97.
The clarithromycin resistant ATCC700897 was cultured 7 days at 37°C in 7H9 medium containing 5% OADC. And then, glycerol was mixed with the culture solution to a final concentration of 20% glycerol and stored at -80°C.
Determination of colony forming units (CFU) of the stock solution was perform ed by counting the numbers of colonies grown in 7H10 agar plates containing 5 % OADC.
Almost protocol was the same as the protocol described in the above Test Example 7 except for using strain.
[0260]
Results
[Table 37]
Figure imgf000111_0002
The results above can be seen with reference to Figure 7, which shows each the log10 value for CFUs of each of the 11 study groups. It also shows a “upper limit' value of 6.48, which is essentially the value at which the CFUs is so high that it cannot accurately be measured. It can be seen that, compared to the control groups: double combinations of clarithromycin + bc1 inhibitors revealed bacteriostatic effect as the log10 CFU of 4.71 to 4.98, despite no bacteriostatic effect with clarithromycin alone.
[0261]
(Test Example 10)
There were 26 study groups.
Table 38]
Figure imgf000112_0001
Almost protocol was the same as the protocol described in the above Test Example 9.
[0262] Results [Table 39]
Figure imgf000113_0001
The results above can be seen with reference to Figure 8, which shows each the log10 value for CFUs of each of the 26 study groups. It also shows a “upper limit' value of 6.48, which is essentially the value at which the CFUs is so high that it cannot accurately be measured.
It can be seen that, compared to the control groups :
Regardless of the concentration of clarithromycin, and even in the absence of clarithromycin, I-1-3 revealed a clear bacteriostatic effect at a concentration of 3 μg/ml or more as the log10 CFU of 5.49 to 5.78. I-1-3 at a concentration of 1 μg/ml also revealed bacteriostatic effect as t he log10 CFU of 5.86 to 6.05.
[0263]
Biological Example - COMBINATIONS
Protocol
The compounds employed were as follows :
• Clarithromycin - “CAM”
• Clofazimine - CFZ
• The following “bc1 inhibitor” :
V I-1-3 [0264]
Design of the study
(Test Example 11)
There were 6 study groups.
[Table 40]
Figure imgf000114_0001
[0265]
Methods
All treatments were evaluated on Mycobacterium intracellulare
ATCC 13950.
All compound solutions were prepared in 7H9 medium containing 5%
OADC.
The assay buffer was also used 7H9 medium containing 5% OADC.
The clarithromycin susceptable ATCC 13950 was cultured 7 days at 37°C in 7H9 medium containing 5% OADC. And then, glycerol was mixed with the culture solution to a final concentration of 20% glycerol and stored at -80°C. Determination of colony forming units (CFU) of the stock solution was performed by counting the numbers of colonies grown in 7H10 agar plates containing 5% OADC. The bactericidal studies were performed using the medium in 96 well plate (final volume was 200 μl/well). The stock solution was diluted by the medium to a final concentration of approximately 2.0 x 105 CFU/ml. All CAM, CFZ and bc1 inhibitor were dissolved in DMSO to make a 1 mg/mL solution. And then, the solutions were diluted with the medium to a final concentration as shown in Table 40. The assay plates were incubated at 37°C for 1 day.
[0266]
Sampling point
At day 0 after starting the assay, determination of CFU was conducted only in the control group for calculating initial number of CFU.
At day 1 after starting the assay, determination of CFU was conducted in all tested groups.
[0267]
Assessment of infection and treatment
The effectiveness of treatments was assessed by counting the numbers of colony-forming-units (CFU) in the lungs.
• The cultures of each groups were serially diluted 10-fold with saline.
• From each individual group, 100 p.L of these diluents were applied to the 7H10 agar containing 5% OADC. CFU's were counted after incubation at 35°C for 2 weeks.
The bacteriostatic and bactericidal effect of the treatment was defined as comparing with Control CFU at day 0 and/or day 1.
When the number of CFU in maximum diluent were exceeded 500 CFU, 500 CFU was adopted as the upper limit of detection.
[0268]
Preparation of Media
7H9 medium + 5% OADC
• dissolve 2.35 g Middlebrook 7H9 medium (BD 262710) in 475 mL distilled water
• add 2.5 mL glycerol
• autoclave at 121°C for 10 min and cool to around room temperature
• add 25 mL Middlebrook OADC Enrichment (BD 212240)
• store at 4°C until ready to use
7H10 agar + 5% OADC
• dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water.
• add 5 mL glycerol
• autoclave at 121°C for 10 min and cool to 55°C
• add 50 mL Middlebrook OADC Enrichment (BD 212240)
• keep at 55°C
• pipette 20 mL agar solution/ dish
• store at 4°C until ready to use after coagulation
[0269]
Results
[Table 41]
Figure imgf000115_0001
The results above can be seen with reference to Figure 9, which shows each the log10 value for CFUs of each of the 6 study groups. It also shows a “upper limit' value of 5.70, which is essentially the value at which the CFUs is so high that it cannot accurately be measured.
• Only group 4 revealed clearly bactericidal effect as the log l O CFU of 4.54 at day
1.
[0270]
(Test Example 12)
There were 6 study groups and 4 mice per group [Table 42]
Figure imgf000116_0001
Generally, as can be seen from the table above, the following doses of the relevant compounds and formulation concentrations were given-
• CFZ loading - On the first day, administration dose was 60 mg/kg. after the second day, administration dose was 9 mg/kg. At the beginning of second week, administered at a dose of 20 mg/kg, after this day, administration dose was 9 mg/kg. This dosing mimics the Cmax of repetitive administration of 50 mg in human.
[0271]
Methods
All treatments were evaluated on Mycobacterium avium ATCC 13950.
All formulations prepared in 20% Tween20, 80% aq. (20% 2-Hydroxypropyl- beta-cyclodextrin and 0.6% Hydroxypropyl Methylcellulose, pH3).
All formulations were solutions and prepared once in a week.
Time Schedule, after mice were infected.
Figure imgf000116_0002
The mice were infected with Mycobacterium intracellulare strain.
The clarithromycin sensitive ATCC 13950 was thawed at ambient temperature and diluted in saline for mouse inoculation. When 0.07 mL of this dilution is inoculated, each mouse receives 107 bacteria.
48 female 8-weeks old BALB/c mice, Charles River, were inoculated intranasally with 0.07 mL of a bacterial suspension containing ± 107 colony forming units (CFU).
[0272]
Dosing
The start of dosing was at Day 22.
• Body weight of all mice were regarded as around 20 g.
• All mice were dosed orally with 0.2 mL of the appropriate formulation, except the control groups, which were not treated. All groups were treated once daily on working days for a week (5 doses/treatments in total) .
The last doses/treatments were given on Day 45.
[0273]
Necropsy
At day 22 after the infection, 4 control mice were sacrificed, and the lung was collected in homogenization tubes.
At day 46 after the infection, 4 control mice and 40 treated mice were sacrificed, and the lung was collected in homogenization tubes.
[0274]
Assessment of infection and treatment
The effectiveness of treatments was assessed by counting the numbers of colony-forming-units (CFU) in the lungs.
• 1.8 mL Mueller Hinton Broth (MHB) was added to each homogenization tube containing lung.
• Lungs were homogenized, and four 10-fold serial dilutions were made in MHB.
• From each individual lung, 100 p.L of the undiluted suspension and four serial 10-fold dilutions, were plated on 7H10 agar plates.
• CFU's were counted after incubation at 35°C for 3 weeks.
• The bactericidal effect of the treatment was defined as a significant decrease of the mean number of CFU in the treated group compared to pre-treatment value.
[0275]
Preparation of Media 7H10 agar + 5% OADC
• dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water.
• add 5 mL glycerol
• autoclave at 121°C for 10 min and cool to 55°C
• add 50 mL Middlebrook OADC Enrichment (BD 212240)
• keep at 55°C
• pipette 20 mL agar solution/dish
• store at 4°C until ready to use after coagulation
[0276] Results [Table 43]
Figure imgf000118_0001
The results above can be seen with reference to Figure 10, which shows each the mean log10 value for CFUs of each of the 6 study groups. It also shows a “cut off value of 2.00, which is essentially the value at which the CFUs (or the bacterial infection) is so low that it cannot accurately be measured, or the CFUs are below the detectable level.
It can be seen that, compared to the control groups:
• triple combinations of clarithromycin + Rifampicin + Ethambutol resulted the effect causing drop to the mean log10 of 5.23.
• double combinations of clarithromycin + clofazimine showed the effect causing drop to the mean log10 of 4.96
• triple combinations of clarithromycin + clofazimine + I-1-3 showed surprising reduction in CFU (mean log10 of 2.05 in Study Group 3, under the cut off value in Study Group 4)
[0277]
Biological Example - COMBINATIONS
Protocol
The compounds employed were as follows:
• Clarithromycin - “CAM”
• Clofazimine - CFZ
• The following “bc1 inhibitor” :
V I-1-3
[0278]
Design of the study
(Test Example 13)
There were 7 study groups.
[Table 44]
Figure imgf000119_0001
[0279]
Methods
All treatments were evaluated on Mycobacterium avium ATCC700897.
All compound solutions were prepared in 7H9 medium containing 5%
OADC.
The assay buffer was also used 7H9 medium containing 5% OADC.
The clarithromycin resistant ATCC700897 was cultured 7 days at 37°C in 7H9 medium containing 5% OADC. And then, glycerol was mixed with the culture solution to a final concentration of 20% glycerol and stored at -80°C. Determination of colony forming units (CFU) of the stock solution was performed by counting the numbers of colonies grown in 7H10 agar plates containing 5% OADC. The bactericidal studies were performed using the medium in 96 well plate (final volume was 200 μl/well). The stock solution was diluted by the medium to a final concentration of approximately 2.0 x 105 CFU/ml. All CAM, CFZ and bc1 inhibitor were dissolved in DMSO to make a 1 mg/mL solution. And then, the solutions were diluted with the medium to a final concentration as shown in Table 44. The assay plates were incubated at 37°C for 2 days.
[0280]
Sampling point
At day 0 after starting the assay, determination of CFU was conducted only in the control group for calculating initial number of CFU.
At day 2 after starting the assay, determination of CFU was conducted in all tested groups.
[0281]
Assessment of infection and treatment
The effectiveness of treatments was assessed by counting the numbers of colony-forming-units (CFU) in the lungs.
• The cultures of each groups were serially diluted 10-fold with saline.
• From each individual group, 100 μL of these diluents were applied to the 7H10 agar containing 5% OADC.
• CFU's were counted after incubation at 35°C for 2 weeks.
• The bacteriostatic and bactericidal effect of the treatment was defined as comparing with Control CFU at day0 and/or day2.
• When the number of CFU in maximum diluent were exceeded 500 CFU, 500 CFU was adopted as the upper limit of detection. [0282]
Preparation of Media
7H9 medium + 5% OADC
• dissolve 2.35 g Middlebrook 7H9 medium (BD 262710) in 475 mL distilled water
• add 2.5 mL glycerol
• autoclave at 121°C for 10 min and cool to around room temperature
• add 25 mL Middlebrook OADC Enrichment (BD 212240)
• store at 4°C until ready to use 7H10 agar + 5% OADC
• dissolve 19 g Middlebrook 7H10 agar (BD 262710) in 950 mL distilled water.
• add 5 mL glycerol
• autoclave at 121°C for 10 min and cool to 55°C
• add 50 mL Middlebrook OADC Enrichment (BD 212240)
• keep at 55°C
• pipette 20 mL agar solution/dish
• store at 4°C until ready to use after coagulation
[0283]
Results .Table 45]
Figure imgf000120_0001
The results above can be seen with reference to Figure 11, which shows each the log10 value for CFUs of each of the 7 study groups. It also shows a “upper limit' value of 5.70, which is essentially the value at which the CFUs is so high that it cannot accurately be measured.
• Only group 5 revealed bactericidal effect as the log10 CFU of 4.90.
[0284]
Based on the above test results, the medicament of the present invention can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with mycobacteria.
[02851
Usefulness as a medicament can be examined by the following tests, etc.
[0286]
Test Example 14: CYP inhibition test
Using commercially available pooled human liver microsomes, an inhibitory degree of each metabolite production amount by the compound of the present invention was assessed as marker reactions of human main five CYP isoforms (CYP1A2, 2C9, 2C19, 2D6, and 3A4), 7-ethoxyresorufin O-deethylation (CYP1A2) , tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C 19), dextromethorphan O-demethylation (CYP2D6), and terfenedine hydroxylation (CYP3A4).
[0287]
The reaction conditions were as follows: substrate, 0.5 pmol/L ethoxyresorufin (CYP 1A2), 100 pmol/L tolbutamide (CYP2C9), 50 pmol/L S- mephenytoin (CYP2C 19), 5 pmol/L dextromethorphan (CYP2D6), 1 pmol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37°C; enzyme, pooled human liver microsomes 0.2 mg protein/mLi concentration of the compound of the present invention, 1.0, 5.0, 10, 20 pmol/L (four points). [02881
Each of five kinds of substrates, human liver microsomes, or the compound of the present invention in 50 mmol/L Hepes buffer were added to a 96-well plate at the composition as described above, and NADPH, as a cofactor was added to initiate metabolism reactions. After the incubation at 37°C for 15 minutes, a methanol/acetonitrile = 1/1 (V/V) solution was added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter or LC/MS/MS and hydroxytolbutamide (CYP2C9 metabolite), 4' hydroxymephenytoin (CYP2C19 metabolite), dextrorphan(CYP2D6 metabolite), and terfenadine alcohol metabolite (CYP3A4 metabolite) were quantified by LC/MS/MS.
[0289]
The sample obtained by adding only DMSO that was a solvent dissolving a compound instead of the compound of the present invention to a reaction mixture was adopted as a control (100%). Remaining activity (%) was calculated at each concentration of the compound of the present invention compared to control, and IC50 was calculated by reverse presumption by a1ogistic model using a concentration and an inhibition rate.
[0290]
Test Example 15 : CYP3A4 (MDZ) MBI test
The CYP3A4(MDZ) MBI test is a test of investigating Mechanism based inhibition (MBI) potential on CYP3A4 inhibition of the compound of the present invention by the enhancement of the inhibitory effect caused by a metabolic reaction of the compound of the present invention. CYP3A4 inhibition was evaluated using pooled human liver microsomes by 1-hydroxylation reaction of midazolam (MDZ) as a marker reaction.
[0291]
The reaction conditions were as follows : substrate, 10 pmol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolic reaction time, 2 minutes; reaction temperature, 37°C; protein content of pooled human liver microsomes, at pre-reaction 0.5 mg/mL, at reaction 0.05 mg/mL (at 10-fold dilution) ; concentrations of the compound of the present invention, 1, 5, 10, 20 pmol/L or 0.83, 5, 10, and 20 pmol/L (four points) .
[0292]
Pooled human liver microsomes and a solution of the compound of the present invention in K-Pi buffer (pH 7.4) as a pre-reaction solution were added to a 96'well plate at the composition of the pre-reaction. A part of pre-reaction solution was transferred to another 96-well plate, and 1/10 diluted by K-Pi buffer containing a substrate. NADPH as a cofactor was added to initiate a reaction as a marker reaction (Preincubation 0 min). After a predetermined time of a marker reaction, a solution of methanol/acetonitrile = 1/1 (V/V) was added to stop the reaction. In addition, NADPH was added to a remaining pre-reaction solution to initiate a pre- reaction (Preincubation 30 min). After a predetermined time of a pre-reaction, a part was transferred to another 96-well plate, and 1/10 diluted by K-Pi buffer containing a substrate to initiate a reaction as a marker reaction. After a predetermined time of a marker reaction, a solution of methanol/acetonitrile = 1/1 (V/V) was added to stop the reaction. After centrifuged at 3000 rpm for 15 minutes, 1-hydroxymidazolam in the supernatant was quantified by LC/MS/MS.
[0293]
The sample obtained by adding only DMSO that was a solvent dissolving a compound instead of the compound of the present invention to a reaction mixture was adopted as a control (100%). Remaining activity (%) was calculated at each concentration of the compound of the present invention compared to control, and IC value was calculated by reverse-presumption by a1ogistic model using a concentration and an inhibition rate. Shifted IC value was calculated as "IC of preincubation 0 min/ IC of preincubation 30 min". When a shifted IC was 1.5 or more, this was defined as positive . When a shifted IC was 1.0 or less, this was defined as negative.
[0294]
Test Example 16: BA test
Materials and Methods for experiments to evaluate oral absorption
(1) Animals : rats were used
(2) Breeding conditions : The mice or rats were allowed to freely take solid food and sterilized tap water.
(3) Dose and grouping: orally or intravenously administered at a predetermined dose; grouping was as follows (Dose depends on the compound)
Oral administration: 2 to 60 pmol/kg or 1 to 30 mg/kg (n = 2 to 3) Intravenous administration: 1 to 30 pmol/kg or 0.5 to 10 mg/kg (n = 2 to 3)
(4) Preparation of dosing solution: for oral administration, in a solution or a suspension state; for intravenous administration, in a solubilized state
(5) Administration method: in oral administration, forcedly administered into ventriculus with oral probe; in intravenous administration, administer from caudal vein with a needle-equipped syringe
(6) Evaluation items: blood was collected over time, and the plasma concentration of drug was measured by LC/MS/MS
(7) Statistical analysis: regarding the transition of the plasma concentration of the compound of the present invention, the area under the plasma concentration-time curve (AUG) was calculated by non-linear least squares program WinNonlin (Registered trade name) , and the bioavailability (BA) was calculated from the AUCs of the oral administration group and intravenous administration group.
[0295]
Test Example 17 : Fluctuation Ames Test
Mutagenicity of the compound of the present invention was evaluated. A 20 μL of freezing-stored Salmonella typhim urium (TA98 strain, TA100 strain) was inoculated on 10 mL of a1iquid nutrient medium (2.5% Oxoid nutrient broth No.2), and this was incubated at 37°C for 10 hours under shaking. The 7.70 to 8.00 mL of TA98 culture medium was centrifuged (2000 x g, 10 minutes). Bacteria were suspended in a Micro F buffer (K2HPO4: 3.5 g/L, KH2PO4 1 g/L, (NH4)2SO4 1 g/L, trisodium citrate dihydrate: 0.25 g/L, and MgSO4 ° 7H2O: 0.1 g/L) with the same volume as that of the culture medium used for centrifugation. The suspension was added to 120 mL of Exposure medium (Micro F buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, and glucose: 8 mg/mL) . The 3.10 to 3.42 mL of TA100 culture medium strain was mixed with 120 to 130 mL Exposure medium.
Each 12 μL of DMSO solution of the compound of the present invention (several stage dilution from maximum dose 50 mg/mL at 2 to 3 fold ratio), DMSO as a negative control, and 50 μg/mL of 4-nitroquinoline 1-oxide DMSO solution for the TA98 strain and 0.25 μg/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain in the assay without metabolic activation, 40 μg/mL of 2- aminoanthracene DMSO solution for the TA98 strain and 20 μg/mL of 2- aminoanthracene DMSO solution for the TA100 strain in the assay with metabolic activation as a positive control, and 588 μL of the test bacterial suspension (498 μL and 90 μL of S9 mixture in the case of metabolic activation assay) was mixed, and this was incubated at 37°C for 90 minutes under shaking. 460 μL of the mixture was mixed with 2300 μL of Indicator medium (Micro F buffer containing 8 μg/mL biotin, 0.2 μg/mL histidine, 8 mg/mL glucose, 37.5 μg/mL bromocresol purple), each 50 μL was dispensed to microplate 48 wells/dose, and this was incubated at 37°C for 3 days. Since the wells containing the bacteria which gained growth ability by point mutation in amino acid (histidine) synthesizing enzyme gene turns from purple to yellow due to a pH change, the number of yellow wells in 48 wells was counted per dose, and was compared with the negative control group. (-) and (+) means negative and positive in mutagenicity respectively.
[0296]
Test Example 18: hERG Test
For the purpose of assessing risk of an electrocardiogram QT interval prolongation of the compound of the present invention, effects of the compound of the present invention on delayed rectifier K+ current (IKr) , which plays an important role in the ventricular repolarization process, was studied using CHO cells expressing human ether-a-go-go related gene (hERG) channel.
After a cell was retained at a membrane potential of -80 mV by whole cell patch clamp method using an automated patch clamp system (QPatch; Sophion Bioscience A/S) and gave a1eak potential of -50 mV, IKr induced by depolarization pulse stimulation at +20 mV for 2 seconds and, further, repolarization pulse stimulation at -50 mV for 2 seconds, was recorded. Extracellular solution (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCh: 2 mmol/L, MgCl2: 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)- 1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)- 1- piperazineethanesulfonic acid) : 10 mmol/L, pH = 7.4) adjusted to contain 0. 1% dimethylsulfoxide was used as a medium. The extracellular solution in which the medium and the compound of the present invention had been dissolved at each objective concentration was applied to the cell for 7 minutes or more at room temperature. From the recording IKr, an absolute value of the tail peak current was measured based on the current value at the resting membrane potential using analysis software (QPatch Assay software; Sophion Bioscience A/S). Further, the tail peak current after application of the compound of the present invention relative to the tail peak current after application of the medium was calculated as a % inhibition to assess the influence of the compound of the present invention on IKr. [0297]
Test Example 19: Solubility test
The solubility of the compound of the present invention was determined under 1% DMSO addition conditions. 10 mmol/L solution of the compound was prepared with DMSO. 2 μL of the solution of the compound of the present invention was respectively added to 198 μL of JP-1 fluid or JP-2 fluid. The mixture was left shaking at room temperature for 1 hour, and the mixture was vacuum-filtered. The filtrate was 10- or 100-fold diluted with methanol/water = 1/1 (v/v) or acetonitrile/methanol/water = 1/1/2 (v/v/v), and the compound concentration in the filtrate was measured with LC/MS or Solid-Phase Extraction (SPE) /MS by the absolute calibration method.
[0298]
The composition of the JP-1 fluid was as below.
Water was added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL.
The composition of the JP-2 fluid was as below.
1 volume of water was added to 1 volume of the solution in which 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate were dissolved in water to reach 1000 mL. [0299] Test Example 20: Powder solubility test
Appropriate quantity of the compound of the present invention was put in suitable containers. 200 μL of JP-1 fluid (water was added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL), 200 μL of JP-2 fluid (1 volume of water was added to 1 volume of the solution which 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolve in water to reach 1000 mL) or 20 mmol/L sodium taurocholate (TCA)/JP-2 fluid (JP-2 fluid was added to 1.08 g of TCA to reach 100 mL) was independently added to each container. When total amount was dissolved after adding the test reagent, the compound of the present invention was added appropriately. After sealing and shaking at 37°C for 1 hour, the solution was filtered and lOOμL of methanol was added to 100 μL of each filtrate to dilute two-fold. The dilution rate was changed as necessary. After checking that there is no bubble and precipitate, the container was sealed and shaken. The compound of the present invention was measured using HPLC by absolute calibration curve method.
[0300]
Test Example 21 : P-gp substrate test
The compound of the present invention is added to one side of Transwell (registered trademark, CORNING) where human MDRl-expressing cells or parent cells have been monolayer-cultured. The cells are reacted for a constant time. The membrane permeability coefficients from the apical side toward the basolateral side (A → B) and from the basolateral side toward the apical side (B → A) are calculated for the MDRl-expressing cells or the parent cells, and the efflux ratio (ER; ratio of the membrane permeability coefficients of B → A and A → B) values of the MDRl-expressing cells and the parent cells are calculated. The efflux ratio (ER) values of the MDR1-expressing cells and the parent cells are compared to confirm whether or not the compound of the present invention would be a P-gp substrate. [0301]
Formulation Example
The following Formulation Examples are only exemplified and not intended to limit the scope of the invention.
[0302]
Formulation Example 1: Tablets
The compounds used in the present invention, lactose, and calcium stearate were mixed. The mixture was crushed, granulated and dried to give a suitable size of granules. Next, calcium stearate was added to the granules, and the mixture was compressed and molded to give tablets.
[0303]
Formulation Example 2: Capsules
The compounds used in the present invention, lactose, and calcium stearate were mixed uniformly to obtain powder medicines in the form of powders or fine granules. The powder medicines were filled into capsule containers to give capsules.
[0304]
Formulation Example 3: Granules
The compounds used in the present invention, lactose and calcium stearate are mixed uniformly and the mixture is compressed and molded. Then, it is crushed, granulated and sieved to give suitable sizes of granules.
[0305]
Formulation Example 4: Orally disintegrated tablets
The compounds used in the present invention and crystalline cellulose are mixed, granulated and tablets are made to give orally disintegrated tablets.
[0306]
Formulation Example 5: Dry syrups
The compounds used in the present invention and lactose are mixed, crushed, granulated and sieved to give suitable sizes of dry syrups.
[0307]
Formulation Example 6: Injections
The compounds used in the present invention and phosphate buffer are mixed to give injection.
[0308]
Formulation Example 7: Infusions
The compounds used in the present invention and phosphate buffer are mixed to give injection.
[0309]
Formulation Example 8: Inhalations
The compounds used in the present invention and lactose are mixed and crushed finely to give inhalations.
[0310]
Formulation Example 9: Ointments
The compounds used in the present invention and petrolatum are mixed to give ointments.
[0311]
Formulation Example 10: Patches
The compounds used in the present invention and base such as adhesive plaster or the like are mixed to give patches. [Industrial Applicability] [0312]
The medicament of the present invention can be a medicine useful as a therapeutic and/or prophylactic agent for symptoms and/or diseases induced by infection with mycobacteria.

Claims

[Document Name] Claims
1. A medicament characterized in that (A) a compound represented by formula (I) :
(I)
Figure imgf000127_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom; X is CH or N; Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4; is combined with
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt; and
(C) clofazimine, or its pharmaceutically acceptable salt.
2. The medicament according to claim 1, wherein R1 and R4 are hydrogen atom.
3. The medicament according to claim 1, wherein R2 is hydrogen atom, halogen or substituted or unsubstituted alkyl.
4. The medicament according to claim 1, wherein R3 is hydrogen atom or halogen.
5. The medicament according to claim 1, wherein R5 is substituted or unsubstituted alkyl.
6. The medicament according to claim 1, wherein R6 , R8 and R9 are hydrogen atom, and R7 is halogen.
7. The medicament according to claim 1, wherein X is N.
8. The medicament according to claim 1, wherein Y is N.
9. The medicament according to claim 1, wherein m is 1.
10. The medicament according to claim 9, wherein R10 is substituted or unsubstituted alkyl.
11. The medicament according to claim 1, wherein R11 is substituted or unsubstituted alkyloxy.
12. The medicament according to claim 1, wherein n is 0.
13. The medicament according to claim 1, wherein (A) is the compound selected from the group consisting of
Figure imgf000129_0001
, or its pharmaceutically acceptable salt.
14. The medicament according to claim 1, wherein (B) is clarithromycin or its pharmaceutically acceptable salt.
15. The medicament according to claim 1, wherein (A), (B) and (C) are simultaneously, sequentially or at intervals administered.
16. The medicament according to claim 1, wherein the medicament is combination drugs.
17. The medicament according to claim 1, wherein the medicament is used for the treatment or prevention of mycobacterial infection.
18. A method of enhancing the anti-bacterial activity of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt, comprising administering the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt with a compound represented by formula (I) in claim 1, or its pharmaceutically acceptable salt.
19. A method of enhancing the anti-bacterial activity of a compound represented by formula (I) in claim 1, or its pharmaceutically accep table salt, comprising administering the compound represented by formula (I) in claim 1, or its pharmaceutically acceptable salt with (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt.
20. The method according to claim 18, wherein the (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt is/are administered simultaneously, sequentially or at intervals with a therapeutically effective amount of the compound represented by formula (I) in claim 1, or its pharmaceutically acceptable salt.
21. The method according to claim 19, wherein the compound represented by formula (I) in claim 1, or its pharmaceutically acceptable salt, is administered simultaneously, sequentially or at intervals with a therapeutically effective amount of (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and/or (C) clofazimine, or its pharmaceutically acceptable salt.
22. A method of treating mycobacterial infection comprising administering a combination of
(A) a compound represented by formula (I) : (I)
Figure imgf000131_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom; X is CH or N; Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R13 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and
(C) clofazimine, or its pharmaceutically acceptable salt, in a therapeutically effective amount thereof to an individual in need of treatment for mycobacterial infection.
23. The method according to claim 22, wherein (A) a compound represented by formula (I), or its pharmaceutically acceptable salt, (B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt and (C) clofazimine, or its pharmaceutically acceptable salt, are administered simultaneously, sequentially or at intervals.
24. A pharmaceutical composition or kit, comprising:
(A) a compound represented by formula (I) : (I)
Figure imgf000132_0001
, or its pharmaceutically acceptable salt, wherein
R1 , R2 , R3 and R4 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; R5 is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; R6 , R7 , R8 and R9 are each independently hydrogen atom, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, with the proviso that R6 , R7 , R8 and R9 are not simultaneously hydrogen atom; X is CH or N;
Y is CH or N;
R10 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; m is 0, 1, 2, 3 or 4; R11 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy or pentafluorothio;
R12 is each independently halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy; n is 0, 1, 2, 3 or 4;
(B) clarithromycin or its pharmaceutically acceptable salt, or azithromycin or its pharmaceutically acceptable salt; and
(C) clofazimine, or its pharmaceutically acceptable salt.
PCT/US2021/061365 2020-12-02 2021-12-01 A medicament for treating mycobacterial infection characterized by combining a cytochrome bc1 inhibitor with clarithromycin or azithromycin WO2022119899A1 (en)

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