SUBSTITUTED AROMATIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF
20240043372 ยท 2024-02-08
Inventors
Cpc classification
C07C235/34
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
C07C215/68
CHEMISTRY; METALLURGY
C07C39/11
CHEMISTRY; METALLURGY
A61K31/045
HUMAN NECESSITIES
A61P17/02
HUMAN NECESSITIES
A61K31/165
HUMAN NECESSITIES
C07C59/52
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
International classification
C07C235/34
CHEMISTRY; METALLURGY
C07C39/11
CHEMISTRY; METALLURGY
C07C215/68
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
A61P17/02
HUMAN NECESSITIES
Abstract
Compounds of Formula I or II, methods of preparation and of use thereof. Formula I has a core aromatic group with substituents as follows: Formula (I) wherein G.sub.1 is (CH.sub.2).sub.nC(R.sub.1)(R.sub.2)OH, (CH.sub.2).sub.n; CHO, (CH.sub.2).sub.nC(O)NR.sub.1R.sub.2, (CH.sub.2).sub.nCH (R.sub.1)NR.sub.1R.sub.2, (CH.sub.2).sub.nC(O)OR.sub.3, (CH.sub.2).sub.nCH(R.sub.1)OR.sub.3, or (CH.sub.2).sub.nC(O)R.sub.3; G.sub.2 and G.sub.4 are independently H, OH, F, or Cl, where G.sub.2 can also be NH.sub.2; G.sub.3 and G.sub.5 are independently (H, F, Cl, OH, (CH.sub.2).sub.n-optionally substituted heterocycle, (CH.sub.2).sub.n-optionally substituted phenyl, (CH.sub.2).sub.nC.sub.3H.sub.5, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, C(O)R.sub.3, or CH(OH)R.sub.3; and G.sub.6 is H, F, Cl, OH, (CH.sub.2).sub.n-optionally substituted heterocycle, (CH.sub.2).sub.n-optionally substituted phenyl, or (CH.sub.2).sub.nCOOH, wherein ?n is an integer selected from 0 to 5, ?R.sub.1 and R.sub.2 are independently selected from H and optionally substituted C.sub.1-C.sub.6 alkyl group, and ?R.sub.3 is an optionally substituted C.sub.1-C.sub.6 alkyl group or when present on G.sub.1 forms a lactone with the core aromatic group, or a pharmaceutically acceptable salt thereof.
##STR00001##
Claims
1. A compound according to Formula I having a core aromatic group with substituents as follows: ##STR00070## wherein G.sub.1 is (CH.sub.2).sub.nC(R.sub.1)(R.sub.2)OH, (CH.sub.2).sub.nCHO, (CH.sub.2).sub.nC(O)NR.sub.1R.sub.2, (CH.sub.2).sub.nCH (R.sub.1)NR.sub.1R.sub.2, (CH.sub.2).sub.nC(O)OR.sub.3, (CH.sub.2).sub.nCH(R.sub.1)OR.sub.3, or (CH.sub.2).sub.nC(O)R.sub.3; G.sub.2 is H, NH.sub.2, OH, F, or Cl; G.sub.3 is H, F, Cl, OH, (CH.sub.2).sub.n-optionally substituted heterocycle, (CH.sub.2).sub.n-optionally substituted phenyl, (CH.sub.2).sub.nC.sub.3H.sub.5, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, C(O)R.sub.3, and CH(OH)R.sub.3; G.sub.4 is H, OH, F or Cl; G.sub.5 is H, OH, F, Cl, (CH.sub.2).sub.n-optionally substituted heterocycle, (CH.sub.2).sub.n-optionally substituted phenyl, (CH.sub.2).sub.nC.sub.3H.sub.5, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6 alkenyl, C(O)R.sub.3, or CH(OH)R.sub.3; and G.sub.6 is H, F, Cl, OH, (CH.sub.2).sub.n-optionally substituted heterocycle, or (CH.sub.2).sub.n-optionally substituted phenyl, wherein n is an integer selected from 0 to 5; R.sub.1 and R.sub.2 are independently selected from H and optionally substituted C.sub.1-C.sub.6 alkyl group, and R.sub.3 is an optionally substituted C.sub.1-C.sub.6 alkyl group or when present on G.sub.1 forms a lactone with the core aromatic group, or a pharmaceutically acceptable salt thereof.
2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.3 is C.sub.5 alkyl, C.sub.5 alkenyl, C(O)(CH.sub.2).sub.3CH.sub.3 or CH(OH)(CH.sub.2).sub.3CH.sub.3.
3. The compound or pharmaceutically acceptable salt thereof of claim 1 wherein G.sub.3 is C.sub.6 alkyl, C.sub.6 alkenyl, C(O)(CH.sub.2).sub.4CH.sub.3 or CH(OH)(CH.sub.2).sub.4CH.sub.3.
4. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.3 is C.sub.5 alkyl, C.sub.6 alkyl, C.sub.5 alkenyl, or C.sub.6 alkenyl.
5. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.3 is C.sub.5 alkyl or C.sub.5 alkenyl.
6. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.3 is C.sub.5 alkyl or C.sub.6 alkyl.
7. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.3 is C.sub.5 alkyl.
8. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.3 is (CH.sub.2).sub.n-optionally substituted phenyl.
9. The compound or pharmaceutically acceptable salt thereof of claim 8, wherein the phenyl is substituted with an optionally substituted C.sub.1-C.sub.6 alkyl.
10. The compound or pharmaceutically acceptable salt thereof of claim 9, wherein G.sub.3 is CH.sub.3(CH.sub.2).sub.xC.sub.6H.sub.4(CH.sub.2).sub.y wherein x+y=4 or 5, and wherein y is an integer selected from 0 to 5.
11. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.3 is (CH.sub.2).sub.n-optionally substituted heterocycle.
12. The compound or pharmaceutically acceptable salt thereof of claim 11, wherein the heterocycle has from 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.
13. The compound or pharmaceutically acceptable salt thereof of claim 11, wherein the heterocycle is a non-aromatic monocyclic or polycyclic ring.
14. The compound or pharmaceutically acceptable salt thereof of claim 11, wherein the heterocycle is an aromatic ring.
15. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.5 is H, OH, F, CH.sub.2Phe, CH.sub.2C.sub.3H.sub.5, C.sub.4-C.sub.6 alkyl, (CH.sub.2).sub.nCH?CH, or CH?CH(CH.sub.2), wherein n is 2 or 3.
16. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.1 is (CH.sub.2).sub.nCH(CH.sub.3)OH; (CH.sub.2).sub.nCH.sub.2OCH.sub.3; (CH.sub.2).sub.nCH(O)NH.sub.2; (CH.sub.2).sub.nC(O)R.sub.3; C(CH.sub.3).sub.2OH; CH(F)OH; CF.sub.2OH; C(O)CH.sub.3; CH.sub.2C(O)OR.sub.3; or (CH.sub.2).sub.nC(O)R.sub.3; or pharmaceutically acceptable salt thereof.
17. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.1 is (CH.sub.2).sub.nC(R.sub.1)(R.sub.2)OH.
18. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.1 is (CH.sub.2).sub.nCHO.
19. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.1 is (CH.sub.2).sub.nC(O)NR.sub.1R.sub.2.
20. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.1 is (CH.sub.2).sub.nCH (R.sub.1)NR.sub.1R.sub.2.
21. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.1 is (CH.sub.2).sub.nC(O)OR.sub.3.
22. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.1 is (CH.sub.2).sub.nCH(R.sub.1)OR.sub.3.
23. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein G.sub.1 is (CH.sub.2).sub.nC(O)R.sub.3.
24. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is: 2-(2-hydroxypropyl)-4,6-dipentylphenol; 4-benzyl-2-(2-hydroxypropyl)-6-pentylphenol; 2,4-dibenzyl-6-(2-hydroxypropyl)phenol; 2-benzyl-6-(2-hydroxypropyl)-4-pentylphenol; 2,4-bis(3-cyclopropylpropyl)-6-(2-hydroxypropyl)phenol; 2-(2-hydroxy-3,5-dipentylphenyl)acetamide; 2-(5-benzyl-2-hydroxy-3-pentylphenyl)acetamide; 2-(3,5-dibenzyl-2-hydroxyphenyl)acetamide; 2-(3-benzyl-2-hydroxy-5-pentylphenyl)acetamide; 2-(3,5-bis(3-cyclopropylpropyl)-2-hydroxyphenyl)acetamide; 2-(2-hydroxy-3,5-dipentylphenyl)acetaldehyde; 2-(5-benzyl-2-hydroxy-3-pentylphenyl)acetaldehyde; 2-(3,5-dibenzyl-2-hydroxyphenyl)acetaldehyde; 2-(3-benzyl-2-hydroxy-5-pentylphenyl)acetaldehyde; 2-(3,5-bis(3-cyclopropylpropyl)-2-hydroxyphenyl)acetaldehyde; 1-(2-hydroxy-3,5-dipentylphenyl)propan-2-one; 1-(5-benzyl-2-hydroxy-3-pentylphenyl)propan-2-one; 1-(3,5-dibenzyl-2-hydroxyphenyl)propan-2-one; 1-(3-benzyl-2-hydroxy-5-pentylphenyl)propan-2-one; 1-(3,5-bis(3-cyclopropylpropyl)-2-hydroxyphenyl)propan-2-one; methyl 2-(2-hydroxy-3,5-dipentylphenyl)acetate; methyl 2-(5-benzyl-2-hydroxy-3-pentylphenyl)acetate; methyl 2-(3,5-dibenzyl-2-hydroxyphenyl)acetate; methyl 2-(3-benzyl-2-hydroxy-5-pentylphenyl)acetate; methyl 2-(3,5-bis(3-cyclopropylpropyl)-2-hydroxyphenyl)acetate; 2-(2-methoxypropyl)-4,6-dipentylphenol; 4-benzyl-2-(2-methoxypropyl)-6-pentylphenol; 2,4-dibenzyl-6-(2-methoxypropyl)phenol; 2-benzyl-6-(2-methoxypropyl)-4-pentylphenol; or 2,4-bis(3-cyclopropylpropyl)-6-(2-methoxypropyl)phenol, or pharmaceutically acceptable salt thereof.
25. The compound or pharmaceutically acceptable salt thereof of claim 1, which is: ##STR00071## or pharmaceutically acceptable salt thereof.
26. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the pharmaceutically acceptable salt of said compound is an organic or inorganic salt.
27. The compound or pharmaceutically acceptable salt thereof of claim 26, wherein the salt is a sodium, potassium, lithium, ammonium, calcium, magnesium, manganese, zinc, iron, or copper salt.
28. The compound or pharmaceutically acceptable salt thereof of claim 26, wherein the salt is an acetate, benzoate, besylate, bromide, carbonate, citrate, edisylate, estolate, fumarate, gluconate, hippurate, iodide, maleate, mesylate, methylsulfate, napsylate, oxalate, pamoate, phosphate, stearate, succinate, sulfate, tartrate, tosylate, or chloride salt.
29.-43. (canceled)
44. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutical acceptable carrier, diluent or carrier.
45. A method for treatment or prevention of cancer, inflammatory-related disease, oxidative stress, pain, metabolic disorder or a fibrotic-related disease in a subject, comprising administering a therapeutically effective amount of the compound of claim 1 to the subject.
46. (canceled)
47. (canceled)
48. The method of claim 45, wherein the treatment of cancer includes inhibition of tumor growth, cell proliferation, tumor cell migration or metastasis in a subject suffering from the cancer.
49. (canceled)
50. (canceled)
51. (canceled)
52. The method of claim 45, wherein the compound of claim 1 is administered in combination with an anticancer agent.
53. The method of claim 52, wherein the anticancer agent is temozolomide, abraxane, decarbazine, doxorubicin, daunorubicin, cyclophosphamide, busulfex, busulfan, bleomycin, alectinib, melphalan, pamidronate, bevacizumab, carbozantinib, vinblastine, docetaxel, prednisolone, ifosphamide, dexamethasone, vincristine, bleomycin, etoposide, topotecan, mitomycine, irinotecan, taxotere, taxol, 5-fluorouracil, folfirinox, methotrexate, gemcitabine, cisplatin, carboplatin, chlorambucil, beribucin, or tyrosine kinase inhibitors.
54. The method of claim 45, wherein the cancer is bladder cancer, breast cancer, colorectal cancer, kidney cancer, melanoma, non-Hodgkin's lymphoma, lung, liver, leukemia, glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer or uterine cancer.
55. The method of claim 45, wherein the cancer is glioblastoma or melanoma, and wherein the compound is administered in combination with chitosan for in situ treatment of recurrence of cancer.
56. The method of claim 45, for treating or preventing a fibrotic-related disease.
57. (canceled)
58. (canceled)
59. (canceled)
60. The method of claim 45, wherein the subject is a human.
Description
BRIEF DESCRIPTION OF FIGURES
[0139] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. A detailed description of specific exemplary embodiments is provided herein below with reference to the accompanying figures in which:
[0140]
[0141]
[0142]
[0143]
[0144]
[0145]
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[0148]
[0149] In the figures, exemplary embodiments or results are illustrated by way of example. It is to be expressly understood that the description and figures are only for the purpose of illustrating certain embodiments and are an aid for understanding. They are not intended to be a definition of the limits of the invention.
DETAILED DESCRIPTION
[0150] A detailed description of one or more embodiments of the present disclosure is provided below along with accompanying figures that illustrate principles of the present disclosure. The invention is described in connection with such embodiments, but the invention is not limited to any embodiment. The scope of the present disclosure is limited only by the claims. Numerous specific details are set forth in the following description in order to provide a thorough understanding of the present disclosure. These details are provided for the purpose of non-limiting examples and the invention may be practiced according to the claims without some or all these specific details. For the purpose of clarity, technical material that is known in the technical fields related to the invention has not been described in detail so that the invention is not unnecessarily obscured.
[0151] The present inventor has through R&D work surprisingly and unexpectedly discovered that alcohol, aldehyde, amine, amide, ester, ether, lactone and/or ketone forms of substituted aromatic compounds (i.e., herein described Formula I) as well as acceptable salt thereof are particularly suited for commercial pharmaceutical applications.
[0152] For example, such pharmaceutical applications include manufacturing of pharmaceutical compositions, therapeutic uses and methods thereof, for example for preventing and/or treating cancer, inflammatory-related disease, oxidative stress, pain, metabolic disorder or fibrotic-related diseases. For example, it has been discovered that the herein described compounds demonstrated at least one or more of the following advantageous characteristics: improved pharmacokinetics, improved half-life, improved toxicity and/or reduction of undesirable metabolites relative to known structures.
[0153] Without being bound by any theory, it is believed that the herein described G.sub.1 group and/or the herein described G.sub.2-G.sub.6 substituents on the aromatic core, affords one or more of the herein described advantageous characteristics to the compounds of the present disclosure. Such advantageous characteristics were unexpected and surprising in view of the known art. For instance, it is believed that the herein described G.sub.1 group afford to the compounds of the present disclosure superior pharmacokinetic/safety profile compared to similar compounds but having a carboxylic acid at G.sub.1, for example leading to less formation of glucuronide metabolites, which represents an advantageous commercial realization at least because such metabolites, and especially the acyl-glucoronide, are known to induce idiosyncratic adverse events and are therefore not well regarded by health agencies and regulators. For instance, it is believed that the herein described G.sub.1 group afford to the compounds of the present disclosure superior biological activity compared to similar compounds but having a carboxylic acid at G.sub.1. This was surprising, unexpected and counter-intuitive at least because, the carboxylic acid functional group plays a cardinal role in drug design and this functional group is often part of the pharmacophore of diverse classes of therapeutic agents (Hajduk et al., J. Med. Chem. 2000; 43:3443-3447). Indeed, a large number (>450) of carboxylic acid-containing drugs have been marketed worldwide, including widely used nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, anticoagulants, and cholesterol-lowering statins, among others. The acidity, combined with the ability to establish relatively strong electrostatic interactions and hydrogen bonds, is often brought up as being the reasons this functional group is believed to be a key determinant in drug-target interactions.
A) Compounds
[0154] In a broad aspect, the present disclosure relates to a compound of Formula I having a core aromatic group with substituents as follows:
##STR00004##
wherein [0155] G.sub.1 is (CH.sub.2).sub.nC(R.sub.1)(R.sub.2)OH, (CH.sub.2).sub.nCHO, (CH.sub.2).sub.nC(O)NR.sub.1R.sub.2, (CH.sub.2).sub.nCH (R.sub.1)NR.sub.1R.sub.2, (CH.sub.2).sub.nC(O)OR.sub.3, (CH.sub.2).sub.nCH(R.sub.1)OR.sub.3, or (CH.sub.2).sub.nC(O)R.sub.3; [0156] G.sub.2 is H, OH, NH.sub.2, F, or Cl, preferably H, NH.sub.2, or OH; [0157] G.sub.3 is H, F, Cl, OH, (CH.sub.2).sub.n-optionally substituted heterocycle, (CH.sub.2).sub.n-optionally substituted phenyl, (CH.sub.2).sub.nC.sub.3H.sub.5, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6alkenyl, C(O) [0158] R.sub.3, and CH(OH)R.sub.3; preferably optionally substituted C.sub.5 alkyl, optionally substituted C.sub.5 alkenyl, C(O)(CH.sub.2).sub.nCH.sub.3 or CH(OH)(CH.sub.2).sub.nCH.sub.3 wherein n is 3; more preferably optionally substituted C.sub.6 alkyl, optionally substituted C.sub.6 alkenyl, C(O)(CH.sub.2).sub.nCH.sub.3 or CH(OH)(CH.sub.2).sub.nCH.sub.3 wherein n is 4; even more preferably optionally substituted C.sub.5 alkyl, optionally substituted C.sub.6 alkyl, optionally substituted C.sub.5 alkenyl, optionally substituted C.sub.6 alkenyl; yet even more preferably optionally substituted C.sub.5 alkyl or optionally substituted C.sub.5 alkenyl; particularly preferably optionally substituted C.sub.5 alkyl or optionally substituted C.sub.6 alkyl; more particularly preferably optionally substituted C.sub.5 alkyl; [0159] G.sub.4 is H, OH, F or Cl, preferably H or OH, more preferably OH; [0160] G.sub.5 is H, OH, F, Cl, (CH.sub.2).sub.n-optionally substituted heterocycle, (CH.sub.2).sub.n-optionally substituted phenyl, (CH.sub.2).sub.nC.sub.3H.sub.5, optionally substituted C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.2-C.sub.6alkenyl, C(O)R.sub.3, or CH(OH)R.sub.3; preferably optionally substituted C.sub.5 alkyl, optionally substituted C.sub.5 alkenyl, C(O)(CH.sub.2).sub.nCH.sub.3 or CH(OH)(CH.sub.2).sub.nCH.sub.3 wherein n is 3; more preferably optionally substituted C.sub.6 alkyl, optionally substituted C.sub.6 alkenyl, C(O)(CH.sub.2).sub.nCH.sub.3 or CH(OH)(CH.sub.2).sub.nCH.sub.3 wherein n is 4; even more preferably optionally substituted C.sub.5 alkyl, optionally substituted C.sub.6 alkyl, optionally substituted C.sub.5 alkenyl, optionally substituted C.sub.6 alkenyl; yet even more preferably optionally substituted C.sub.5 alkyl or optionally substituted C.sub.5 alkenyl; particularly preferably optionally substituted C.sub.5 alkyl or optionally substituted C.sub.6 alkyl; more particularly preferably optionally substituted C.sub.5 alkyl; and [0161] G.sub.6 is H, F, Cl, OH, (CH.sub.2).sub.n-optionally substituted heterocycle, (CH.sub.2).sub.n-optionally substituted phenyl, or (CH.sub.2).sub.nCOOH,
wherein [0162] n is an integer selected from 0 to 5, preferably 1 to 5, more preferably 1 to 3; [0163] R.sub.1 and R.sub.2 are independently selected from H and optionally substituted C.sub.1-C.sub.6 alkyl group, and [0164] R.sub.3 is an optionally substituted C.sub.1-C.sub.6 alkyl group or when present on G.sub.1 forms a lactone with the core aromatic group, [0165] or a pharmaceutically acceptable salt thereof.
[0166] In particular, the functional group at position G.sub.1 does not include a carboxylic acid.
[0167] The term optionally substituted heterocycle refers to a cyclic compound that has atoms of at least two different elements as members of its ring(s). Preferably, the heterocycle is a five- or six-membered ring. Preferably, the heterocycle has from 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. The heterocycle may be an heterocycloalkyl, i.e., a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, or may be an heteroaromatic, i.e., an aromatic ring containing at least one heteroatom as part of the aromatic ring. Examples of heterocycloalkyl groups include but without being limited to aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. Examples of heteroaromatic groups include but without being limited to pyridine, furan, tiophene, cytosine, and indole. The heterocycle can be unsubstituted or substituted with one or two suitable substituents, for example with an optionally substituted C.sub.1-C.sub.6 alkyl.
[0168] Non-limitative examples of a (CH.sub.2).sub.n-optionally substituted heterocycle may include a group where the heterocycle is substituted with an optionally substituted C.sub.1-C.sub.6 alkyl. In a non-limiting example, the (CH.sub.2).sub.n-optionally substituted heterocycle may include a group such as CH.sub.3(CH.sub.2).sub.x-heterocycle-(CH.sub.2).sub.y where x+y=3, 4 or 5, and where y is an integer selected from 0 to 5, preferably 1 to 5, more preferably 1 to 4. Non-limiting examples where y is an integer of from 0 to 5 may include any one of the following (where (CH.sub.2).sub.y is on the far right of the illustrated structures and is shown connected to the rest of Formula I with the wavy bond):
##STR00005##
(i.e., where y is 0 and x+y is 3),
##STR00006##
(i.e., where y is 0 and x+y is 3), and the like.
[0169] The (CH.sub.2).sub.n-optionally substituted phenyl may include a group where the phenyl is substituted with an optionally substituted C.sub.1-C.sub.6 alkyl. In a non-limiting example, the (CH.sub.2).sub.n-optionally substituted phenyl may include a (CH.sub.2).sub.n-substituted phenyl group such as CH.sub.3(CH.sub.2).sub.xC.sub.6H.sub.4(CH.sub.2).sub.y where x+y=3, 4 or 5, and where y is an integer selected from 0 to 5, preferably 1 to 5, more preferably 1 to 4. Non-limiting examples where y is an integer of from 0 to 5 may include any one of the following (where (CH.sub.2).sub.y is on the far right of the illustrated structures and is shown connected to the rest of Formula I with the wavy bond):
##STR00007##
(i.e., where y is 3 and x+y is 3);
##STR00008##
(i.e., where y is 2 and x+y is 3);
##STR00009##
(i.e., where y is 1 and x+y is 3); or
##STR00010##
(i.e., where y is 0 and x+y is 3), and the like.
[0170] In cases where the phenyl is substituted with a substituted C.sub.1-C.sub.6 alkyl, non-limiting examples may include a C.sub.1-C.sub.6 alkyl substituted with a phenyl (where the bond to the remaining Formula I molecule is on the far right of the illustrated structures and is shown connected to the rest of Formula I with the wavy bond):
##STR00011##
and the like.
[0171] In particular, compounds of Formula I with the groups and substituents as set forth below with respect to G.sub.1 may be used for the prevention and/or treatment of cancer: [0172] (CH.sub.2).sub.nOH wherein n is 1 or 2, or n is preferably 1; [0173] (CH.sub.2).sub.nCH(CH.sub.3)OH wherein n is 1 or 2, or n is preferably 1; [0174] (CH.sub.2).sub.nOCH.sub.3 wherein n is 1 or 2, or n is preferably 1; [0175] (CH.sub.2).sub.n(O)NH.sub.2 wherein n is 1 or 2, or n is preferably 1; [0176] CH.sub.2COH; [0177] CH(CH.sub.3)OH; [0178] (CH.sub.2).sub.nC(O)R.sub.3; [0179] C(CH.sub.3).sub.2OH; [0180] CH(F)OH; [0181] CF.sub.2OH; [0182] C(O)CH.sub.3 [0183] C(O)R.sub.3; [0184] CH.sub.2C(O)OR.sub.3; [0185] (CH.sub.2).sub.nC(O)R.sub.3.
[0186] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable alcohol at position G.sub.1.
[0187] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable aldehyde at position G.sub.1.
[0188] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable ketone at position G.sub.1.
[0189] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable amine at position G.sub.1.
[0190] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable amide at position G.sub.1.
[0191] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable ester at position G.sub.1.
[0192] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable ether at position G.sub.1.
[0193] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable lactone at position G.sub.1.
[0194] According to a particular embodiment, the compounds are provided as the pharmaceutically acceptable ketone at position G.sub.1.
[0195] Non-limiting examples of compounds of Formula I include alcohol, aldehyde, amine, amide, ester, ether, lactone or ketone (at position G.sub.1) forms of any of the compounds listed in Table 1 hereinafter (shown as the alcohol form), where position G.sub.2 can be preferably H, NH.sub.2, or OH. In a preferred embodiment, the compound is represented by the alcohol, aldehyde, lactone or ketone (at position G.sub.1) form of any one of the following compounds. Where relevant, one or more of the following compounds can be a pharmaceutical salt form (for example a sodium salt thereof):
TABLE-US-00001 TABLE 1 Compound Structure 1a
[0196] Non-limiting examples of compounds of Formula I also include alcohol, aldehyde, amine, amide, ester, ether, lactone or ketone (at position G.sub.1) forms of any of the compounds listed in Table 2 hereinafter, where position G.sub.2 can be preferably H, NH.sub.2, or OH. In a preferred embodiment, the compound is represented by the alcohol, lactone, aldehyde or ketone (at position G.sub.1) form of any one of the following compounds. Where relevant, one or more of the following compounds can be a pharmaceutical salt form (for example a sodium salt thereof):
TABLE-US-00002 TABLE 2 Compound Structure 2a
[0197] In some embodiments, the compound of Formula I also includes an alcohol, aldehyde, amine, amide, ester, ether or ketone (at position G.sub.1) forms of any of the compounds listed in Table 3 hereinafter, where position G.sub.2 can be preferably H, NH.sub.2, or OH. In a preferred embodiment, the compound is represented by the alcohol, aldehyde, lactone or ketone (at position G.sub.1) form of any one of the following compounds. Where relevant, one or more of the following compounds can be a pharmaceutical salt form (for example a sodium salt thereof):
TABLE-US-00003 TABLE 3 Compound Structure Name 3a
Salts
[0198] As used herein, the term pharmaceutically acceptable salt is intended to mean base addition salts. Example of pharmaceutically acceptable salts are also described, for example, in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 66, 1-19 (1977). Pharmaceutically acceptable salts may be synthesized from the parent agent that contains an acidic moiety, by conventional chemical methods. Generally, such salts and are prepared by reacting the free acid forms of these agents with a stoichiometric amount of the appropriate base in water or in an organic solvent, or in a mixture of the two. Likewise, when the parent agent contains a group such as NH.sub.2, the pharmaceutically acceptable salts may be synthesized from the parent agent by conventional chemical methods by reacting the free NH.sub.3.sup.+ with an anionic source in a suitable solvent.
[0199] Salts may be prepared in situ, during the final isolation or purification of the compound or by separately reacting a purified compound of the present disclosure with the desired corresponding base, and isolating the salt thus formed. For example, this approach may be implemented with the alcohol form of some of the compounds of the present disclosure (such as the alcohol form of at least some of the compounds of any one of Tables 1-3) or with the free acid form of some of the compounds of the present disclosure (such as the free acid form present on a substituent at a position other than G.sub.1 of at least some of the compounds of any one of Tables 1-3).
[0200] The pharmaceutically acceptable salt of the compounds of the present disclosure may be selected from the group consisting of organic or inorganic salts.
[0201] For example, the pharmaceutically acceptable salt may include a sodium, potassium, calcium, magnesium, lithium, ammonium, manganese, zinc, iron, olamine, meglumine, lysine, tromethamine, or copper salt, when the compounds are amenable to be such salts. In preferred embodiments, the pharmaceutically acceptable salt of the compounds of the present disclosure may be the sodium, potassium, calcium, magnesium or lithium salt, when the compounds are amenable to be such salts. More preferably the pharmaceutically acceptable salt is sodium, when the compounds are amenable to be such salts.
[0202] For example, the pharmaceutically acceptable salt may include an acetate, benzoate, besylate, bromide, carbonate, citrate, edisylate, estolate, fumarate, gluconate, hippurate, iodide, maleate, mesylate, methylsulfate, napsylate, oxalate, pamoate, phosphate, stearate, succinate, sulfate, tartrate, tosylate, or chloride salt, when the compounds are amenable to be such salts.
[0203] In some embodiments, the compounds are the sodium salts of at least some of the compounds listed in Tables 1-3 hereinbefore, which are amenable to be such salts.
[0204] All alcohol, salt and other ionic and non-ionic forms of the compounds described are included when referring to a given compound, where applicable. For example, if a compound is shown as an alcohol herein, the salt forms of the compound are also included, when the compounds are amenable to be such salts. Likewise, if a compound is shown as a salt herein, then the alcohol forms are also included. The same is also applicable to a compound having an aromatic group in one of the substituent groups, where such aromatic group on the substituent group may include a free form of a carboxylic acid. In such case, when the compound is shown as a salt herein, then the carboxylic acid free form is also included. Likewise, when the aromatic group on the substituent group is shown with a free form of a carboxylic acid, then the salt forms of the compound are also included, when the compounds are amenable to be such salts.
Prodrugs
[0205] In certain embodiments, the compounds of the present disclosure may also include all pharmaceutically acceptable salts, isosteric equivalents such as tetrazole and prodrug forms thereof. Examples of the latter include the pharmaceutically acceptable esters or amides of the compounds of the present disclosure.
Chirality
[0206] The compounds of the present disclosure, their pharmaceutically acceptable salts, or prodrugs thereof, may contain one or more asymmetric centers, chiral axes and chiral planes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms and may be defined in terms of absolute stereochemistry, such as (R)- or (S)-. The present disclosure is intended to include all such possible isomers, as well as, their racemic and optically pure forms. Optically active (+) and (?), (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC. The racemic mixtures may be prepared and thereafter separated into individual optical isomers or these optical isomers may be prepared by chiral synthesis. The enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may then be separated by crystallization, gas-liquid or liquid chromatography, selective reaction of one enantiomer with an enantiomer specific reagent. It will also be appreciated by those skilled in the art that where the desired enantiomer is converted into another chemical entity by a separation technique, an additional step is then required to form the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents or by converting one enantiomer to another by asymmetric transformation.
[0207] Certain compounds of the present disclosure may exist in Zwitterionic form and the present disclosure includes Zwitterionic forms of these compounds and mixtures thereof.
Hydrates
[0208] In addition, the compounds of the present disclosure also may exist in hydrated and anhydrous forms. Hydrates of any of the formulas described herein may thus exist as a monohydrate or in the form of a polyhydrate.
B) Methods of Preparation
[0209] In general, the compounds of the present disclosure may be prepared by any conventional methods, using readily available and/or conventionally preparable starting materials, reagents and conventional synthesis procedures. Of particular interest is the work of Hundertmark, et al., Org. Lett. 2000, 12, pp. 1729-1731 and WO 2014/138906.
[0210] The exemplification section hereinafter provides general schemes and specific, but non limitative, examples for the synthesis of representative compounds of Formula I.
C) Pharmaceutical Applications
[0211] As indicated and exemplified herein, the compounds of the present disclosure may have beneficial pharmaceutical properties and these compounds may have useful pharmaceutical applications in subjects. Medical and pharmaceutical applications contemplated by the inventor include, but are not limited to, prevention and/or treatment of various cancers, oxidative stress associated conditions, inflammatory-related disease, pain, metabolic disorder, and/or fibrosis and fibrosis-related diseases.
[0212] In one aspect, the medical and pharmaceutical application is prevention and/or treatment of various cancers. In one embodiment. the cancer is selected from bladder, breast, colorectal, kidney, melanoma, non-Hodgkin's lymphoma, leukemia, ovarian, pancreatic, prostate and uterine cancers.
[0213] In another embodiment, the cancer is selected from glioblastoma, heart, esophageal, liver and bile duct, pancreas, lung, gallbladder, mesothelioma, diffuse intrinsic pontine glioma, and acute myelomonocytic leukemia, and fibrosarcoma.
[0214] In another embodiment, the cancer is selected from glioblastoma, breast, colorectal, leukemia, melanoma and pancreatic cancers.
[0215] In another embodiment, the cancer is selected from brain and skin cancers.
[0216] In some embodiments, the pharmaceutical application may include a method of preventing or treating a cancer as defined herein, where the method may include administering to the patient a therapeutically effective amount of the compound of as defined herein, for example, to the proximity of the cancer or in situ at cancer site after removal or not of the primary tumor, in other words peri-tumoral, or pre/post surgical resection of a tumor. In some cases, such administration may occur in the context of inoperable tumors.
[0217] In some embodiments, the compound of the present disclosure may be formulated into a slow or controlled release composition, for example for local delivery of the compound at a target site. Slow or controlled release compositions are known in the art (e.g., thermogel) and for conciseness' sake will not be further described here.
[0218] Reference herein to treatment extends to prophylaxis as well as therapy of an established cancer. Accordingly, at least some of the compounds of the present disclosure could be used after surgical removal of the primary tumor, prior to surgery, prior or after aggressive chemotherapy, radiotherapy, immunotherapy or other targeted therapy or even when the patient is in remission. These at least some of the compounds of the present disclosure are expected to have a relative lack of toxicity when compared to standard cancer therapies thereby allowing for a more liberal prophylactic use than would be advisable with standard therapies.
[0219] In one aspect, the medical and pharmaceutical application is prevention and/or treatment of fibrosis and fibrosis-related diseases. In one embodiment, the compounds of the present disclosure are for use in monotherapy for the treatment of fibrosis and fibrosis-related diseases. For example, the compounds may be used for reducing proliferation or progression of fibrotic tissue in fibrotic-related diseases. In other embodiments, the compounds of the present disclosure are used in combination with one or more already approved anti-fibrosis and anti-fibrosis-related diseases agents such as pirfenidone, nintedanib or other preclinical compounds such as PPAR agonists/antagonists, fezagepras, kinase inhibitors, mTOR inhibitors, and the like.
[0220] For example, the fibrotic disease can be pulmonary fibrosis. In this embodiment, the therapeutically effective amount is preferably between about 1 to about 50 mg/kg, and preferably between about 1 to about 20 mg/kg. The compound is preferably administered orally. The subject is preferably a human. According to a preferred embodiment, the pulmonary fibrosis is idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary hypertension.
[0221] For example, the fibrotic disease can be liver fibrosis. In this embodiment, the therapeutically effective amount is preferably between about 1 to about 50 mg/kg. The compound is preferably administered orally. The subject is preferably human. According to a preferred embodiment, the liver fibrosis is resulting from a chronic liver disease, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, alcoholic liver disease or non-alcoholic steatohepatitis, obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins.
[0222] For example, the fibrotic disease can be skin fibrosis. In this embodiment, the compound is preferably administered topically or orally. When administered topically, the therapeutically effective amount of the compound of the present disclosure is preferably between about 0.01 to about 10% (w/w). The subject is preferably human. When administered orally, the therapeutically effective amount of the compound of the present disclosure is preferably between about 1 to about 50 mg/kg and the subject is human. According to a preferred embodiment of the disclosure, the skin fibrosis is scarring, hypertrophic scarring, keloid scarring, dermal fibrotic disorder, wound healing, delayed wound healing, psoriasis or scleroderma. Said scarring may derived from a burn, a trauma, a surgical injury, a radiation or an ulcer. Said ulcer can be a diabetic foot ulcer, a venous leg ulcer or a pressure ulcer.
[0223] For example, the fibrotic disease can be cardiac fibrosis. In this embodiment, the therapeutically effective amount is preferably between about 1 to about 50 mg/kg, and preferably between about 1 to about 20 mg/kg. The compound is preferably administered orally. The subject is preferably a human. According to a preferred embodiment, the cardiac fibrosis is resulting from coronary artery and vascular diseases, myocardial infarction, heart failure, atherosclerosis, angina, arrhythmia.
[0224] For example, the fibrotic disease can be renal fibrosis. In this embodiment, the therapeutically effective amount is preferably between about 1 to about 50 mg/kg, and preferably between about 1 to about 20 mg/kg. The compound is preferably administered orally. The subject is preferably a human. According to a preferred embodiment, the renal fibrosis may result from chronic kidney diseases (CKD), acute kidney diseases (AKD), diabetic kidney diseases (DKD), polycystic kidney diseases (PKD), or other rare or genetic diseases.
[0225] In addition to the previous embodiments of dosages, for all above mentioned fibrotic diseases, when the compound of the present disclosure is topically administered to a human, the therapeutically effective amount of a compound corresponds to preferably between about 0.01 to about 10% (w/w), or between about 0.1 to 10% (w/w), or between about 1.0 to about 10% (w/w), between about 0.1 to about 5% (w/w), or between about 1.0 to about 5% (w/w). In all above-mentioned fibrotic diseases, when the compound of the present disclosure is orally administered to a human, the therapeutically effective amount of a compound corresponds preferably between about 1 to about 50 mg/kg, or between about 1 to 25 mg/kg, or between about 1 to about 10 mg/kg, between about 5 to about 25 mg/kg, or between about 10 to about 20 mg/kg.
[0226] In one aspect, the medical and pharmaceutical application is prevention and/or treatment of an oxidative stress related disorder. The term oxidative stress related disorder refers to any disease in which there is an imbalance between the production of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. Examples of such diseases include, but are not limited to, cardiovascular diseases, cancer, diabetes, arthritis, atherosclerosis, Parkinson's disease, heart failure, myocardial infarction, Alzheimer's disease, chronic fatigue syndrome and autoimmune diseases.
[0227] In one aspect, the medical and pharmaceutical application is prevention and/or treatment of inflammatory-related diseases. The term inflammatory-related disease refers to any and all abnormalities associated with inflammatory-related disease, including chronic and acute inflammatory diseases, including but not limited to immune mediated inflammatory diseases (IMID) and autoimmune diseases arthritis, ITP, glomerulonephritis, vasculitis, psoriatic arthritis, systemic lupus erythematosus (SLE), idiopathic thrombocytopenic purpura (ITP), psoriasis, Crohn's disease, inflammatory bowel disease, ankylosing spondylitis, Sjogren's syndrome, Still's disease (macrophage activation syndrome), uveitis, scleroderma, myositis, Reiter's syndrome, and Wegener's syndrome. For example, the inflammatory-related disease may include rheumatoid arthritis, oedema, dermatitis, colitis and others. In general, prophylactic and therapeutic uses comprise the administration of a compound as described herein to a subject, preferably a human patient in need thereof. The compounds of the present disclosure may be administered with any conventional treatments. In order to evaluate, assess, and/or confirm the efficacy of the method, compounds and/or compositions of the disclosure, serial measurements can be determined. Quantitative methods and techniques for the assessment of inflammatory-related disease are well known in the art.
[0228] In one aspect, the medical and pharmaceutical application is prevention and/or treatment of metabolic diseases or disorders. Some of the symptoms that can occur with metabolic disorders are lethargy, weight loss, jaundice and seizures. It is believed that the principal classes of metabolic disorders are: acid-base imbalance, metabolic brain diseases, disorders of calcium metabolism, DNA repair-deficiency disorders, glucose metabolism disorders, hyperlactatemia, iron metabolism disorders, lipid metabolism disorders, malabsorption syndromes, metabolic syndrome X, inborn error of metabolism, mitochondrial diseases, phosphorus metabolism disorders, porphyrias, proteostasis deficiencies, metabolic skin diseases, wasting syndrome, or water-electrolyte imbalance. For example, the metabolic diseases or disorders may include diabetes type 1, II or Ill, triglyceridemia, cholesterolemia, and others.
[0229] In some embodiments, the compounds of the present disclosure pharmaceutically acceptable salt thereof are for use in monotherapy for the treatment of cancer.
[0230] In other embodiments, the compound of the present disclosure or pharmaceutically acceptable salt thereof is used in combination with one or more already approved anticancer therapy, such as but without being limited to chemotherapeutic agents, cytokines, radiation therapy agents, immunotherapy, monoclonal antibodies, targeted therapy, etc. Examples of anticancer agents which may be used in combination with the compounds of the present disclosure include, but are not limited to, temozolomide, abraxane, decarbazine, doxorubicin, daunorubicin, cyclophosphamide, busulfex, busulfan, bleomycin, alectinib, melphalan, pamidronate, bevacizumab, carbozantinib, vinblastine, docetaxel, prednisolone, ifosphamide, dexamethasone, vincristine, bleomycin, etoposide, topotecan, mitomycine, irinotecan, taxotere, taxol, 5-fluorouracil, folfirinox, methotrexate, gemcitabine, cisplatin, carboplatin, chlorambucil, beribucin and tyrosine kinase inhibitors.
[0231] In some embodiments, a method of treatment or prevention according to the present disclosure may also include co-administration of the at least one compound according to the present disclosure, or a pharmaceutically acceptable salt thereof together with the administration of another therapeutically effective agent. Therefore, an additional aspect of the present disclosure relates to methods of concomitant therapeutic treatment of a subject, comprising administering to a subject in need thereof an effective amount of a first agent and a second agent, wherein the first agent is as defined in Formula I or other listed compounds, and the second agent is for the prevention or treatment of any one of disorder or disease as defined hereinbefore. As used herein, the term concomitant or concomitantly as in the phrases concomitant therapeutic treatment or concomitantly with includes administering a first agent in the presence of a second agent. A concomitant therapeutic treatment method includes methods in which the first, second, third or additional agents are co-administered. A concomitant therapeutic treatment method also includes methods in which the first or additional agents are administered in the presence of a second or additional agents, wherein the second or additional agents, for example, may have been previously administered. A concomitant therapeutic treatment method may be executed stepwise by different actors. For example, one actor may administer to a subject a first agent and as a second actor may administer to the subject a second agent and the administering steps may be executed at the same time, or nearly the same time, or at distant times, so long as the first agent (and/or additional agents) are after administration in the presence of the second agent (and/or additional agents). The actor and the subject may be the same entity (e.g., a human).
[0232] Accordingly, the present disclosure also relates to a method for preventing, reducing or eliminating a symptom or complication or metastasis of any one of the above-mentioned diseases or conditions. The method comprises administering, to a subject in need thereof, a first pharmaceutical composition comprising at least one compound of the present disclosure and a second pharmaceutical composition comprising one or more additional active ingredients, wherein all active ingredients are administered in an amount sufficient to inhibit, reduce, or eliminate one or more symptoms or complications of the disease or condition to be treated. In one aspect, the administration of the first and second pharmaceutical composition is temporally spaced apart by at least about two minutes. Preferably the first agent is a compound of Formula I or other listed compounds as defined herein, or a pharmaceutically acceptable salt thereof, e.g., sodium salt, when the compounds are amenable to be such salts. The second agent may be selected from the list of compounds given hereinbefore but not limited thereto.
D) Pharmaceutical Compositions and Formulations
[0233] As indicated hereinbefore, at least some of the compounds of the present disclosure may have one or more potential therapeutic applications. Therefore, the disclosure is also concerned with pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds of the present disclosure and a pharmaceutically acceptable carrier, diluent or excipient. For example, such pharmaceutical compositions may include a compound of Formula I, such as the alcohol, aldehyde, ester, ketone forms of those compounds described in any one of the aforementioned Tables.
[0234] A related aspect of the present disclosure concerns pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds of the present disclosure. As indicated hereinbefore, the pharmaceutical compositions of the present disclosure may be useful in prevention and/or treatment of one or more cancers in subjects.
[0235] The composition of the present disclosure may include one or more compounds of Formula I or other listed compounds, as defined herein or pharmaceutically acceptable derivatives, salts prodrugs, analogues and isomers, or enantiomers thereof. Formulations of the active compound may be prepared so as to provide a pharmaceutical composition in a form suitable for enteral (such as taken orally in the form of liquids, capsules, tablets, or chewable tablets), mucosal (including sublingual, nasally, breathed into the lungs, usually through the mouth (by inhalation) or mouth and nose (by nebulization), vaginal and rectal), parenteral (including intramuscular, intradermal, intrathecally, subcutaneous and intravenous) or topical (including ointments, creams or lotions) administration. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well-known in the art of pharmaceutical formulation. All methods include the step of bringing together the active pharmaceutical ingredient with liquid carriers or finely divided solid carriers or both as the need dictates.
[0236] When appropriate, the above-described formulations may be adapted to provide sustained release of the active pharmaceutical ingredient. Sustained release formulations well-known to the art include the use of a bolus injection, continuous infusion, biocompatible polymers, chitosan or liposomes. The herein described compound(s) may also be administered in situ at the site of the primary cancer, as depot.
E) Kits
[0237] The compound(s) of the present disclosure may be packaged as part of a kit, optionally including a container (e.g., packaging, a box, a vial, etc.). The kit may be commercially used according to the methods described herein and may include instructions for use in a method of the present disclosure. Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives, or metal chelators. The additional kit components are present as pure compositions, or as aqueous or organic solutions that incorporate one or more additional kit components. Any or all of the kit components optionally further comprise buffers.
[0238] The compound(s) of the present disclosure may or may not be administered to a patient at the same time or by the same route of administration. Therefore, the methods of the present disclosure encompass kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of two or more active ingredients to a patient.
[0239] A typical kit of the present disclosure comprises a unit dosage form of at least one compound according to the disclosure as defined by Formula I, or a pharmaceutically acceptable salt thereof, and a unit dosage form of at least one additional active ingredient. Examples of additional active ingredients that may be used in conjunction with the compounds of the present disclosure include, but are not limited to, any of the anticancer agents indicated hereinbefore that could be used in combination with the compound(s) of the present disclosure. The kit may further include instructions for the use as described herein, on a suitable media such as but without being limited to a paper insert, a computer readable media, and the like.
[0240] Kits of the present disclosure can further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles are provided herein before.
Definitions
[0241] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention pertains. As used herein, and unless stated otherwise or required otherwise by context, each of the following terms shall have the definition set forth below.
[0242] As used herein, the term therapeutically effective amount means the amount of compound that, when administered to a subject for treating or preventing a particular disorder, disease or condition, is sufficient to effect such treatment or prevention of that disorder, disease or condition. As used herein, the term therapeutically effective amount further means the amount of compound that induces regression of established tumors and/or primary solid tumors; inhibits cell proliferation, cancer cell migration, and metastasis. Dosages and therapeutically effective amounts may vary for example, depending upon a variety of factors including the activity of the specific agent employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination, if applicable, the effect which the practitioner desires the compound to have upon the subject (e.g., total or partial response as evidenced by factors which include reduction in tumor burden and/or tumor size as well as increase in survival time and/or quality of life which is associated with a reduction in amount and/or duration of treatment with standard but more toxic anticancer agents), the properties of the compounds (e.g., bioavailability, stability, potency, toxicity, etc.), and the particular disorder(s) the subject is suffering from. In addition, the therapeutically effective amount may depend on the subject's blood parameters (e.g., lipid profile, insulin levels, glycemia), the severity of the disease state, organ function, or underlying disease or complications. Such appropriate doses may be determined using any available assays including the ex-ovo (chorioallantoic membrane) assays described herein. When one or more of the compounds of the present disclosure is to be administered to humans, a physician may for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained. The dose to be administered will ultimately be at the discretion of the oncologist. In general, however, the dose will be in the range from about 1 to about 100 mg/kg per day when administered orally; and in the range from about 0.01 to about 10 mg/kg per day when administered intravenously or subcutaneously.
[0243] As used herein, the term pharmaceutically acceptable carrier, pharmaceutically acceptable diluent or pharmaceutically acceptable excipient is intended to mean, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, such as a liposome, sodium decanoate, triglyceride, cyclodextrins, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in subjects, preferably humans. It preferably refers to a compound or composition that is approved or approvable by a regulatory agency of the Federal or State government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans. The pharmaceutically acceptable vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Additional examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Prevention of the action of microorganisms can be achieved by addition of antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic agents are included, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate, chitosan or gelatin.
[0244] As used herein, the terms treatment or treating of a subject relates to the application or administration of a compound of the present disclosure to a subject (or application or administration of a compound of the present disclosure to a cell or tissue from a subject) with the purpose of delaying, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition. The term treating refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being. In some embodiments, the term treating can include increasing a subject's life expectancy and/or delay before additional treatments are required (e.g., dialysis or kidney transplantation for a patient having kidney cancer).
[0245] As used herein, the term preventing or prevention is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or disorder or metastasis (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians.
[0246] As used herein, the term subject includes living organisms in which cancers can occur, or which are susceptible to such disease. The term subject includes animals such as mammals or birds. Preferably, the subject is a mammal. More preferably, the subject is a human. Most preferably, the subject is a human patient in need of treatment.
[0247] As used herein, the term alkyl is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms in a linear or branched arrangement, for example, C.sub.1-C.sub.8 as in C.sub.1-C.sub.8 alkyl is defined as including groups having 1, 2, 3, 4, 5, 6, 7 or 8 in a linear or branched arrangement. Examples of C.sub.1-C.sub.8 alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl and octyl. In preferred embodiments, the alkyl groups are linear alkyl groups.
[0248] As used herein, the term, alkenyl is intended to mean unsaturated straight or branched chain hydrocarbon groups having the specified number of carbon atoms therein, and in which at least two of the carbon atoms are bonded to each other by a double bond, and having either E or Z regiochemistry and combinations thereof. For example, C.sub.2-C.sub.6 as in C.sub.2-C.sub.6 alkenyl is defined as including groups having 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, at least two of the carbon atoms being bonded together by a double bond. Examples of C.sub.2-C.sub.6 alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl. In preferred embodiments, the alkenyl groups are linear alkenyl groups.
[0249] As used herein, the term optionally substituted refers to groups substituted with from 1 to 5 substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8 heterocycloalkyl, C.sub.1-C.sub.6 alkyl aryl, C.sub.1-C.sub.6 alkyl heteroaryl, C.sub.1-C.sub.6 alkyl cycloalkyl, C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.8heterocycloalkyl, amino, aminosulfonyl, ammonium, acyl amino, amino carbonyl, aryl, heteroaryl, sulfinyl, sulfonyl, alkoxy, alkoxy carbonyl, carbamate, sulfanyl, halogen, trihalomethyl, cyano, hydroxy, mercapto and nitro. Preferably, to groups substituted with from 1 to 5 substituents selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.3-cycloalkyl, C.sub.3-C.sub.8 heterocycloalkyl, C.sub.1-C.sub.6 alkyl aryl, C.sub.1-C.sub.6 alkyl heteroaryl, C.sub.1-C.sub.6 alkyl cycloalkyl, and C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.8 heterocycloalkyl.
[0250] As used herein, the term subject denotes a non-human mammal or a human. Preferred non-human mammals include primates, rodents, such as mouse or rat, feline, canine, bovine and ovine. More particularly, the subject is a human, in particular a child, an adult, a woman or a man.
[0251] As used herein, the term lactones refers to cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (C(O)O), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are usually formed by intramolecular esterification of the corresponding hydroxycarboxylic acids, which takes place spontaneously when the ring that is formed is five- or six-membered.
EXAMPLES
[0252] The following examples describe some exemplary modes of making and practicing certain compositions that are described herein. These examples are for illustrative purposes only and are not meant to limit the scope of the compositions and methods described herein.
[0253] The examples set forth herein below provide exemplary methods for the preparation of certain representative compounds encompassed by Formula I. Some Examples provide exemplary uses of certain representative compounds of Formula I. Also provided are exemplary methods for assaying representative compounds of Formula I for in vitro, ex ovo and/or in vivo efficacy.
[0254] In these examples, the following compounds will be referred in terms of Representative Compound x where x is a number from 1 to 5 as per the following
##STR00058##
Instrumentation:
[0255] All HPLC chromatograms and mass spectra were recorded on an HP 1100 LC-MS Agilent instrument using an analytical C18 column (250?4.6 mm, 5 microns) with a gradient over 3 min of 50-99% CH.sub.3CNH.sub.2O with 0.01% TFA as the eluant followed by isocratic over 3 min and a flow of 2 mL/min.
Example 1: Experimental Procedures for the Preparation of Certain Representative Compounds
A) Representative Compound 2
[0256] The following procedure was used to prepare Representative Compound 2:
##STR00059##
[0257] Step-1: To a solution of (2-Hydroxy-phenyl)-acetic acid (1 equiv.), in ACN was added NBS lotwise (2.2 equiv.) at 0? C., then slowly brought the RM for room temperature (rt) then stirred for 16 h at room temperature (rt) (TLC control). The RM was concentrated to remove ACN then digested in Water for 1 h, then filtered and dried the collected solid. The solid was taken in Toluene heated up to 100? C. to dissolve then slowly brought to rt and filtered to get pure compound.
[0258] Step-2: To a solution from Step-1 (1 equiv.) in DMF (5 V), was added K.sub.2CO.sub.3 (5 equiv.) and Benzylbromide (2.2 equiv.) dropwise and stirred the RM for 4 h at 80? C. (TLC control). The RM was quenched into water and extracted with Methyl tert-butyl ether (MTBE), washed the MTBE layer with water and dried then concentrated under reduced pressure to get crude.
[0259] Step-3: To a solution from Step-2 (1 equiv.), Olefinic Boronic ester derivative (2.2 equiv.) and Na.sub.2CO.sub.3 (5 equiv.) in DME (10 V) and H.sub.2O (1 V) was degassed with argon then added Pd(PPh.sub.3).sub.4 (0.1 equiv.), then stirred for 18 h at 90? C. Work-Up: The reaction mixture was filtered through Celite then filtrate was diluted with EtOAc and washed with Water, dried the organic layer then concentrated to get crude as dark brown viscous oil. The crude was purified through CombiFlash? to get pure compound.
[0260] Step-4: To a solution from Step-3 (1 equiv.) in Dry THF (10 V) was cooled to 0? C. then added LAH (1.2 equiv.) dropwise under argon atmosphere then brought to rt and stirred for 1 h at rt. The RM was quenched with aq.Math.Na.sub.2SO.sub.4 sol at 0? C. then extracted with EtOAc, dried the organic layer and concentrated under reduced pressure to get crude. The crude was purified through column chromatography.
[0261] Step-5: To a solution from Step-4 (1 equiv.) in EtOAc (10 V) was added Pd(OH).sub.2 (50% w/w) then stirred at rt in autoclave under 10 bar H.sub.2 pressure (TLC control). The RM was filtered through Celite and the filtrate was concentrated to get crude. This crude was subjected to reverse phase CombiFlash purification to obtain the desired product in high purity Purification condition: SiliaSep? C18, 80 g cartridge was used, with eluent: Gradient elution of MeCN in water (0.1% HCO.sub.2H). Purity was assessed by LCMS and identity confirmed with .sup.1H nuclear magnetic resonance (.sup.1H NMR).
B) Representative Compound 1
[0262] The following procedure was used to prepare Representative Compound 1:
##STR00060##
[0263] Step 5a: To a solution of Representative Compound 2 (1 equiv.) in Toluene (20 V), was added p-Toluenesulfonic acid (p-TSA) (0.1 equiv.), then heated the RM to 120-130? C. for 16 h using Dean-Stark condenser. The RM was concentrated to get crude. The crude was purified through column chromatography.
[0264] Step-6a: To a solution from Step-5a (1 equiv.) in THF (10 V) was cooled to ?20? C., then purged in ammonia gas for 10 min and stirred for 16 h at 80? C. (TLC control). The RM was concentrated to get crude compound. Crude weight?225 mg; purity by LCMS?81%. The crude was recrystallized using hexanes to get the desired compound
C) Representative Compound 3
[0265] The following procedure was used to prepare Representative Compound 3.
##STR00061##
[0266] Step-1: To a solution of Int-1 (1 equiv.) in dry THF (10 V) was cooled to 0? C. then added BH.sub.3. THF (1.5 equiv.) dropwise under argon atmosphere then brought to rt and stirred for 16 h at room temperature (rt). The RM was quenched with water at 0? C. then diluted with EtOAc and washed with water, dried the organic layer and concentrated under reduced pressure to get crude. The crude was purified through CombiFlash to get pure compound.
[0267] Step-2: To a solution from Step-1 (1 equiv.) in MeOH (10 V) was added Pd/C (20% w/w) then stirred for 16 h at rt under 5 bar H.sub.2 (TLC control). Work-Up: The RM was filtered through Celite and the filtrate was concentrated under reduced pressure to get crude. The crude was purified through column chromatography.
[0268] Step-3: To a solution from Step-2 (1 equiv.) in THF (10 V), was added NBS (2.5 equiv.) at 0? C. then stirred for 16 h at rt under (TLC control). Work-Up: The RM was quenched in to sat sodium thiosulfate and extracted with EtOAc, dried the organic layer and concentrated under reduced pressure to get crude. The crude was purified through column chromatography.
[0269] Step-4: To a solution from Step-3 (1 equiv.), Olefinic Boronic ester derivative (2.2 equiv.), and Na.sub.2CO.sub.3 (5 equiv.) in 1,4-Dioxane (10 V) and H.sub.2O (1 V) was degassed with argon then added Pd(PPh.sub.3).sub.4 (0.2 equiv.), then stirred for 18 h at 90? C. Work-Up: The reaction mixture was filtered through Celite then filtrate was diluted with EtOAc and washed with Water, dried the organic layer then concentrated to get crude as dark brown viscous oil. The crude was purified through column chromatography to get pure compound.
[0270] Step-5: To a solution from Step-4 (1 equiv.) in MeOH (10 V) was added Pd(OH).sub.2 (20% w/w), then stirred for 16 h at rt under 5 bar H.sub.2 (TLC control). Work-Up: The RM was filtered through Celite and the filtrate was concentrated under reduced pressure to get crude. The crude was purified through column chromatography to get pure compound. Purity was assessed by LCMS and identity confirmed with .sup.1H nuclear magnetic resonance (.sup.1H NMR).
D) Representative Compound 4
[0271] The following procedure was used to prepare Representative Compound 4
##STR00062##
[0272] Step-1: To a solution of (3-Bromophenyl)acetic acid methylester (1 equiv.), Olefinic Boronic ester derivative (1.1 equiv.), and Na.sub.2CO.sub.3 (3 equiv.), in 1,4-Dioxane (10 V), and H.sub.2O (1 V), was degassed with Argon for 15 min then added Pd(PPh.sub.3).sub.4 (0.01 equiv.), then stirred for 18 h at 90? C. Work-Up: The reaction mixture was filtered through Celite then filtrate was diluted with EtOAc and washed with Water, dried the organic layer then concentrated to get crude as dark brown viscous oil.
[0273] Step-2: To a solution from Step-1 (1 equiv.) in EtOH (20 V), was added Pd(OH).sub.2 (20% w/w) then stirred at rt in autoclave under 5 bar H.sub.2 pressure (TLC control). The RM was filtered through Celite and the filtrate was concentrated to get crude. The crude was purified through combi-flash to get pure compound
[0274] Step-3: To a solution from Step-2 (1 equiv.) in dry THF (10 V), was cooled to 0? C. then added lithium aluminum hydride (LAH) (1.2 equiv.) dropwise under argon atmosphere then brought to rt and stirred for 1 h at rt. The RM was quenched with aq. Na.sub.2SO.sub.4 sol at 0? C. then diluted with EtOAc then filtered through celite the filtrate layers, dried the organic layer and concentrated under reduced pressure to get crude. The crude was purified through CombiFlash to get pure compound. Purity was assessed by LCMS and identity confirmed with .sup.1H nuclear magnetic resonance (.sup.1H NMR).
E) Representative Compound 5
[0275] The following procedure was used to prepare Representative Compound 5.
##STR00063##
[0276] Step-1: To a solution of Int-1 (1 equiv.) in THF (10 V) cooled to 0? C. was added Phenyl magnesium bromide (5 equiv.) (2.0 M in THF) dropwise then stirred for 16 h at rt. (TLC control). Work-Up: The RM was quenched with sat NH4Cl sol then extracted with EtOAc, dried the organic layer and concentrated under reduced pressure to get crude.
[0277] Step-2: To a solution from Step-1 (1 equiv.) in dichloromethane (DCM) (10 V) cooled to 0? C. was added Triethylsilane (2.5 V) and Trifluoroacetic acid (TFA) (5 V), dropwise then stirred for 20 h at rt. (TLC control). The RM was diluted with DCM and washed with water, dried the organic layer and concentrated under reduced pressure to get crude. The crude was purified through column chromatography to get pure product.
[0278] Step-3: To a solution from Step-2 (1 equiv.), CuBr.sub.2 (2 equiv.) and Dimethylmalonate (2.2 equiv.) in 1,4-Dioxane (10 V), cooled to 0? C. then added NaH (2.0 equiv.) and stirred for 16 h at 100? C. (TLC control). Work-Up: The RM was filtered through Celite and washed the bed with EtOAc the filtrate was concentrated and purified by column chromatography to get pure product.
[0279] Step-4: To a solution from Step-3 (1 equiv.) in ethanol (10 V), was added NaOH (2.2 equiv.), at rt then stirred for 16 h at 60? C. (TLC control). Work Up: The RM was diluted with water and washed with MTBE then the aqueous layer was acidified with 1.5 N HCl then extracted with EtOAc, washed the organic layer with water then dried and concentrated under reduced pressure.
[0280] Step-5a: To a solution from Step-4 (1 equiv.) in THF (10 V) cooled to 0? C. was added LAH (5 equiv.) (2.0 M in THF) dropwise then stirred for 2 h at rt. (TLC control). Work-Up: The RM was quenched with water then extracted with EtOAc, dried the organic layer and concentrated under reduced pressure to get crude. Purity was assessed by LCMS and identity confirmed with .sup.1H nuclear magnetic resonance (.sup.1H NMR).
Example 2: Antitumor Effect of Compounds on Avatar CAM Assay
[0281] In this example, representative compounds of the present disclosure were tested for their respective effect on tumors using a model of Avatar Chick Chorioallantoic Membrane (CAM) assay. CAM assays have been widely used to study angiogenesis and tumor invasion of colorectal, prostate and brain cancers, as well as for studying patient-derived xenograft for potential personalized medicine.
[0282] The present inventor has tested representative compounds from the present disclosure or a Positive Control (PCtrl: sodium 2-(2-hydroxy-3,5-dipentylphenyl)acetate) as per the following. Fertilized eggs from white leghorn chicken were used and incubated in an Ova-Easy egg incubator at 37? C. with 60% humidity. At day 3, eggs were cracked. At day 9, U87 (human glioblastoma) cell suspensions (1?10.sup.6 cells), or Caki cells or patient-derived xenograph (glioblastoma fragment) were mixed (1:1) with growth factor reduced Matrigel? in a total volume of 20 ?l for cell lines and POX-patient fragments were placed directly on top of the CAM and were returned to the incubator. Intravenous injection at day 11 or topical administration (Day 11 to Day 16) with or without the compounds. At day 16, chick embryos were killed by decapitation. Tumours were removed and tumour volumes were calculated using the formula: (Dd.sup.2/3).
[0283] Table 4 summarizes the anticancer activity of these representative compounds on human glioblastoma U87 cell, human renal carcinoma Caki cell lines, glioblastoma from patient derived xenograft (POX) and human fibrosarcoma HT1080 cell. As shown, alcohol derivatives strongly improve anticancer activity relatively to their respective positive control compound (Pctrl or Setogepram).
TABLE-US-00004 TABLE 4 Anticancer Activity PDX Compound Structure U87 (Glioblastoma) Caki HT1080 PCtrl
[0284]
[0285]
[0286]
Example 3: Antiproliferative Effect of Compounds on Cancer Cells
[0287] Antiproliferative activity of representative compounds on cancer cells was also undertaken by using PC-3 cells (human prostate cancer cells). PC-3 cells were cultured for 24 hours in 96-well plates with or without Compounds or Positive Control (PCtrl: sodium 2-(2-hydroxy-3,5-dipentylphenyl)acetate) or Setogepram CAS No.: 1002101-19-0 from MedChemExpress LLC, USA) at various concentrations. The last four hours of incubation, 50 ?l of a freshly made solution of MTT at 2 mg/ml in PBS were added. Cells were harvested, 150 ?l of DMSO were added to solubilize the formazan crystal formed and the plates were read the plate at 570 nm.
[0288] Table 5 summarizes the percentage of inhibition of PC-3 cells proliferation by representative compounds. As shown, alcohol derivatives strongly improve antiproliferative/anticancer activity relatively to the positive control compound.
TABLE-US-00005 TABLE 5 Cpd4 Setogepram PCtrl Cpd1 Cpd2 Cpd3 Cpd5 % of inhibition of Concentration % of inhibition of Proliferation Concentration Proliferation 200 uM 20.0 0.0 66.3 65.8 53.0 1000 uM 70.4 0.0 100 uM 0.0 0.0 72.2 62.1 72.2 500 uM 72.9 0.0 50 uM 0.0 0.0 70.0 67.4 70.6 250 uM 74.2 10.4 25 uM 0.0 0.0 63.6 39.1 42.8 125 uM 30.3 5.7 12.5 uM 0.0 0.0 0.0 0.0 1.7 62.5 uM 26.1 16.8
Example 4: Antifibrotic Effect of Compounds on Patient-Derived Xenograft IPF Lungs
[0289] Avatar CAM model was also used to determine the antifibrotic activity of the representative compounds. Briefly, fertilized eggs from white leghorn chicken were used and incubated in an Ova-Easy egg incubator at 37? C. with 60% humidity. At day 3, eggs were cracked. At day 9, PDX-fragments from IPF lungs were grafted on top of the CAM and were returned to the incubator. Treatment by intravenous injection of compounds was performed at day 11 and at day 16, chick embryos were killed by decapitation. IPF-PDX fragments were removed and volumes were calculated using the formula: (Dd.sup.2/3). Fibrosis was determined by a Masson's trichrome staining.
[0290] Table 6 shows antifibrotic activity of preferred compounds on PDX-IPF as shown by a reduction of the volume growth of the PDX-IPF-fragments. Results are compared to setogepram, a well-known antifibrotic compound and it shows that the alcohol derivative (Representative Compound 4) shows unexpected greater antifibrotic activity. As illustrated in
[0291] As illustrated in
TABLE-US-00006 TABLE 6 Antifibrotic Activity Compound PDX (IPF lungs) Representative XXXX compound 4 Representative XX compound 5 Setogepram XX
Example 5: Anti-Inflammatory/Antifibrotic/Metabolic/Analgesic Effect of Representative Compounds Determined by Cytokine Release from Human Peripheral Blood Mononuclear Cells (PBMC)
[0292] The anti-inflammatory/antifibrotic/metabolic and analgesic activity of Representative Compounds was undertaken with the analysis of cytokine releases under inflammatory conditions in LPS-stimulated PBMC.
[0293] It is well known that IL-6, MCP1, TNF? and IL-1? are pleiotropic cytokines involved in inflammation, fibrosis, metabolism and pain. Human peripheral blood mononuclear cells were isolated from venous blood of healthy volunteers by dextran sedimentation followed by centrifugation over Ficoll-Hypaque, according to the manufacturer's protocol. Freshly isolated human PBMC (4?10.sup.6 cells/mL suspended in RPMI-1640) were stimulated with or without LPS or Representative Compounds or Positive Control (PCtrl: sodium 2-(2-hydroxy-3,5-dipentylphenyl)acetate) or Setogepram (a well-know anti-inflammatory/antifibrotic agent) at various concentration and incubated for 4 and 24 h. After incubation, supernatants were collected and IL-6, MCP1, TNF? and IL-1? were measured by ELISA, as recommended by the manufacturer's protocol.
IL-6
[0294] II-6 is a pleiotropic cytokine and functions as a proinflammatory factor as well as a profibrotic factor. Inflammatory/fibrotic models of chronic diseases and clinical observations identify also IL-6 activity as detrimental in autoimmunity and cancer. IL-6 plays also an important role in various metabolic processes as an autocrine and/or paracrine actions of adipocyte function. At present, accumulating evidence has demonstrated that IL-6 is closely linked to metabolic disorders such as MS and type 2 diabetes. IL-6 is also involved in the process of pathological pain.
[0295]
MCP-1
[0296] CCL2 is produced by many cell types, including endothelial, fibroblasts, epithelial, smooth muscle, mesangial, astrocytic, monocytic, and microglial cells. These cells are important for antiviral immune responses in the peripheral circulation and in tissues. However, monocyte/macrophages are found to be the major source of CCL2. CCL2 regulates the migration and infiltration of monocytes, memory T lymphocytes, and natural killer (NK) cells. CCL2 has been shown to be a potential intervention point for the treatment of various inflammatory and fibrotic diseases (IPF), as well as multiple sclerosis (Sorensen et al., Chemokine CCL2 and chemokine receptor CCR2 in early active multiple sclerosis. Eur J Neurol. 2004; 11:445-449), rheumatoid arthritis, atherosclerosis, and insulin-resistant diabetes.
[0297]
TNF?
[0298] TNF? plays an important role in proinflammatory response and cell-to-cell communication. TNF? signaling is closely associated with various autoimmune and inflammatory diseases. Until now, five drugs targeting TNF have been developed: infliximab, etanercept, adalimumab, glomumab, and certolizumab pegol. The indications of these TNF-targeting drugs have been approved for rheumatoid arthritis, psoriatic arthritis, psoriasis, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn's disease, and ulcerative colitis. TNF-? is also involved in the evolution of lung and liver fibrosis. Furthermore, TNF? seems to be increased in obese subjects, suggesting its role as a proinflammatory cytokine to insulin resistance and metabolic abnormalities in obesity.
[0299]
IL-1?
[0300] IL-1? is an inducible cytokine and is not generally expressed in healthy cells or tissue; however, full-length IL-1? is rapidly induced in cells by activation of pattern recognition receptors (PRRs) such as TLRs by pathogen products or factors released by damaged cells, leading to intracellular accumulation of the protein. IL-1? is released by lung macrophages, and stimulates fibroblasts to synthesize collagen and produce fibrin. IL-1? is also involved in inflammatory, fibrotic, metabolic syndrome and pathological pain and related diseases.
[0301]
[0302] Other examples of implementations will become apparent to the reader in view of the teachings of the present description and as such, will not be further described here.
[0303] The present results have shown that alcohol, aldehyde, amine, amide, ester, ether, lactone and/or ketone forms of substituted aromatic compounds (i.e., Formula I) as well as acceptable salt thereof provide compounds having advantageous properties. In particular, alcohol forms have demonstrated superior biological activity in the tests described herein compared to carboxylic acid forms (or acceptable salt thereof) of such substituted aromatic compounds.
[0304] Note that titles or subtitles may be used throughout the present disclosure for convenience of a reader, but in no way these should limit the scope of the present disclosure. Moreover, certain theories may be proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the present disclosure so long as the invention is practiced according to the present disclosure without regard for any particular theory or scheme of action.
[0305] All references cited throughout the specification are hereby incorporated by reference in their entirety for all purposes.
[0306] Reference throughout the specification to some embodiments, and so forth, means that a particular element (e.g., feature, structure, and/or characteristic) described in connection with the invention is included in at least one embodiment described herein, and may or may not be present in other embodiments. In addition, it is to be understood that the described inventive features may be combined in any suitable manner in the various embodiments.
[0307] It will be understood by those of skill in the art that throughout the present specification, the term a used before a term encompasses embodiments containing one or more to what the term refers. It will also be understood by those of skill in the art that throughout the present specification, the term comprising, which is synonymous with including, containing, or characterized by, is inclusive or open-ended and does not exclude additional, un-recited elements or method steps.
[0308] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In the case of conflict, the present document, including definitions will control.
[0309] As used in the present disclosure, the terms around, about or approximately shall generally mean within the error margin generally accepted in the art. Hence, numerical quantities given herein generally include such error margin such that the terms around, about or approximately can be inferred if not expressly stated.
[0310] Although various embodiments of the disclosure have been described and illustrated, it will be apparent to those skilled in the art in light of the present description that numerous modifications and variations can be made. The scope of the present invention is defined more particularly in the appended claims.