Carbazole compounds and therapeutic uses of the compounds

{
  "publication_number": "US10137109B2",
  "country": "US",
  "kind": "B2",
  "title": "Carbazole compounds and therapeutic uses of the compounds",
  "abstract": "Compounds of the general structural formula (I) and (II) and use of the compounds and salts and hydrates thereof, as therapeutic agents are disclosed. Treatable diseases and conditions include cancers, inflammatory diseases and conditions, and immunodeficiency diseases. (I), (II).",
  "claims": [
    "1. A method for treating melanoma, comprising intraarterially administering to a patient in need thereof an effective amount of a compound of a structural formula: wherein R a is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e, N(R e) 2, and SR e; alternatively, either R a and R 1 or NR e and R 1 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic or heterocyclic ring; R b is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e, N(R e) 2, and SR e, alternatively, either R b and R 6 or NR e and R 6 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring or a five or six-membered aliphatic carbocyclic or heterocyclic ring; R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e, or R c and R d are taken together to form a five, six, or seven-membered aliphatic ring, optionally containing an oxygen atom; R d is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e, or R d and R 7 together with the atoms to which they are attached form a five or six-membered aliphatic ring; R e, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two R e groups taken together with a nitrogen to which they are attached to form a five or six-membered aliphatic ring; R 1, R 2, R 3, R 4, R 5, and R 6, independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, OR e, C(═O)R e, C(═O)OR e, OC(═O)R e, C(═O)N(R e) 2, C(═O)NR e SO 2 R e, N(R e) 2, NR e C(═O)R e, NR e C(═O)N(R e) 2, CN, NO 2, CF 3, OCF 3, SR e, SOR e, SO 2 N(R e) 2, and OSO 2 CF 3; R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and n is 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt or hydrate thereof and wherein the intraarterial administration is intraarterial infusion.",
    "2. The method of claim 1, wherein the compound is:",
    "3. The method of claim 1, wherein the melanoma is malignant melanoma.",
    "4. The method of claim 3, wherein the malignant melanoma is metastatic.",
    "5. The method of claim 1, wherein the intraarterial administering occurs at a frequency of one to four times per day.",
    "6. The method of claim 5, wherein the intraarterial administering occurs at a frequency of one time per day.",
    "7. The method of claim 1, wherein the intraarterial administering occurs at a frequency of one time per week.",
    "8. A method for treating metastatic colon cancer, comprising intraarterially administering to a patient in need thereof an effective amount of a compound of a structural formula: wherein R a is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e, N(R e) 2, and SR e; alternatively, either R a and R 1 or NR e and R 1 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic or heterocyclic ring; R b is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e, N(R e) 2, and SR e, alternatively, either R b and R 6 or NR e and R 6 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring or a five or six-membered aliphatic carbocyclic or heterocyclic ring; R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e, or R c and R d are taken together to form a five, six, or seven-membered aliphatic ring, optionally containing an oxygen atom; R d is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e, or R d and R 7 together with the atoms to which they are attached form a five or six-membered aliphatic ring; R e, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two R e groups taken together with a nitrogen to which they are attached to form a five or six-membered aliphatic ring; R 1, R 2, R 3, R 4, R 5, and R 6, independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, OR e, C(═O)R e, C(═O)OR e, OC(═O)R e, C(═O)N(R e) 2, C(═O)NR e SO 2 R e, N(R e) 2, NR e C(═O)R e, NR e C(═O)N(R e) 2, CN, NO 2, CF 3, OCF 3, SR e, SOR e, SO 2 N(R e) 2, and OSO 2 CF 3; R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and n is 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt or hydrate thereof and wherein the intraarterial administration is intraarterial infusion.",
    "9. The method of claim 8, wherein the compound is:",
    "10. The method of claim 8, wherein the colon cancer has metastasized to the liver.",
    "11. The method of claim 8, wherein the intraarterial administering occurs at a frequency of one to four times per day.",
    "12. The method of claim 11, wherein the intraarterial administering occurs at a frequency of one time per day.",
    "13. The method of claim 8, wherein the intraarterial administering occurs at a frequency of one time per week.",
    "14. A method for treating metastatic breast cancer, comprising intraarterially administering to a patient in need thereof an effective amount of a compound of a structural formula: wherein R a is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e, N(R e) 2, and SR e; alternatively, either R a and R 1 or NR e and R 1 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic or heterocyclic ring; R b is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, OR e, N(R e) 2, and SR e, alternatively, either R b and R 6 or NR e and R 6 together with the carbon atoms to which they are attached form a five or six-membered aliphatic carbocyclic ring or a five or six-membered aliphatic carbocyclic or heterocyclic ring; R c is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e, or R c and R d are taken together to form a five, six, or seven-membered aliphatic ring, optionally containing an oxygen atom; R d is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and C(═O)R e, or R d and R 7 together with the atoms to which they are attached form a five or six-membered aliphatic ring; R e, independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, or two R e groups taken together with a nitrogen to which they are attached to form a five or six-membered aliphatic ring; R 1, R 2, R 3, R 4, R 5, and R 6, independently, are selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, OR e, C(═O)R e, C(═O)OR e, OC(═O)R e, C(═O)N(R e) 2, C(═O)NR e SO 2 R e, N(R e) 2, NR e C(═O)R e, NR e C(═O)N(R e) 2, CN, NO 2, CF 3, OCF 3, SR e, SOR e, SO 2 N(R e) 2, and OSO 2 CF 3; R 7 is selected from the group consisting of hydrogen, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and n is 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt or hydrate thereof and wherein the intraarterial administration is intraarterial infusion.",
    "15. The method of claim 14, wherein the compound is:",
    "16. The method of claim 14, wherein the breast cancer has metastasized to the liver.",
    "17. The method of claim 14, wherein the intraarterial administering occurs at a frequency of one to four times per day.",
    "18. The method of claim 17, wherein the intraarterial administering occurs at a frequency of one time per day.",
    "19. The method of claim 14, wherein the intraarterial administering occurs at a frequency of one time per week."
  ],
  "description_excerpt": "This invention relates to carbazole compounds, to methods of preparing the compounds, to pharmaceutical compositions containing the compounds, and to their use as therapeutic agents. In particular, the invention relates to carbazole compounds and their use in a variety of therapeutic areas, including the treatment of cancers.\n\nThe frequency of cancer in humans has increased in the developed world as the population has aged. For some types of cancers and the stage of disease at diagnosis, morbidity and mortality rates have not improved significantly in recent years despite extensive research. Induction of cell death is one of the most attractive cancer treatment strategies. There is a significant need to identify agents that are capable of inducing cell death in tumor cells and/or that potentiate chemotherapeutic and radiation therapies.\n\nThe present invention is directed to compounds and compositions that induce cell death, and to therapeutic uses of the compounds in the treatment of a cancer and other conditions in individuals in need of such treatment. The present invention also is directed to methods of preparing the therapeutic compounds.\n\nMore particularly, the present invention is directed to compounds and methods of treating diseases and conditions such as cancers, inflammatory diseases, microbial infections, viral infections, and protozoan infections. The compounds are useful in a method comprising administering a therapeutically effective amount of a compound of structural formula (I) to an individual in need thereof.",
  "cpc": [
    "A61K 31/403",
    "A47C 13/005",
    "A47C 15/002",
    "A47C 17/045",
    "A47C 31/003",
    "A47C 4/028",
    "A47C 7/18",
    "A47C 7/20",
    "A61K 31/439",
    "A61K 31/454",
    "A61K 31/506",
    "A61K 31/5377",
    "A61K 31/55",
    "A61K 9/0019",
    "A61P 17/00",
    "A61P 17/02",
    "A61P 17/06",
    "A61P 19/02",
    "A61P 19/10",
    "A61P 29/00",
    "A61P 31/00",
    "A61P 33/00",
    "A61P 33/02",
    "A61P 33/06",
    "A61P 35/00",
    "A61P 35/02",
    "A61P 35/04",
    "A61P 9/10",
    "C07D 209/86",
    "C07D 209/88",
    "C07D 401/04",
    "C07D 487/04",
    "F16B 1/00",
    "F16B 12/00",
    "F16B 2200/81",
    "F16B 2200/83",
    "Y02A 50/30",
    "Y10T 29/49826",
    "Y10T 403/7164",
    "Y10T 403/7176"
  ],
  "ipc": [
    "A61K 31/403",
    "A61K 31/439",
    "A61K 31/454",
    "A61K 31/506",
    "A61K 31/5377",
    "A61K 31/55",
    "A61K 9/00",
    "C07D 209/86",
    "C07D 209/88",
    "C07D 401/04",
    "C07D 487/04"
  ],
  "assignees": [
    "Incuron Inc"
  ],
  "inventors": [
    "John Tucker",
    "Sergey Sviridov",
    "Leonid Brodsky",
    "Catherine Burkhart",
    "Andrei Purmal",
    "Katerina Gurova",
    "Andrei Gudkov"
  ],
  "filing_date": "2016-12-21",
  "publication_date": "2018-11-27",
  "grant_date": "2018-11-27",
  "priority_date": "2008-10-06",
  "application_number": "US-201615386020-A",
  "family_id": "41503680",
  "cited_by_count": 0,
  "citations": [
    "DE2715680A1",
    "WO2004035580A1",
    "US20050143442A1",
    "US7169802B2",
    "WO2008008155A2",
    "US20110305661A1",
    "US20150045406A1",
    "US9169207B2"
  ]
}