Substituted 3-(biphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one

Patent metadata

Field	Value
Publication number	US-9278925-B2
Application number	US-201214236279-A
Country	US
Kind code	B2
Filing date	Jul 31, 2012
Priority date	Aug 4, 2011
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

The invention relates to substituted 3-(biphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-ones, in particular for therapeutic purposes, to pharmaceutical compositions and to their use in therapy, in particular for the prophylaxis and therapy of neoplastic disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
R 1 represents a trifluoromethyl or methoxymethyl group and
R 2 represents hydrogen or fluorine,
or a salt thereof.

2. A compound selected from
(5r,8r)-3-(4′-chloro-3′-fluoro-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-8-(methoxymethyl)-1-azaspiro[4.5]dec-3-en-2-one;
(5r,8r)-3-(4′-chloro-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-8-(methoxymethyl)-1-azaspiro[4.5]dec-3-en-2-one;
(5r,8r)-3-(4′-chloro-3′-fluoro-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-8-(trifluoromethyl)-1-azaspiro[4.5]dec-3-en-2-one; and
(5r,8r)-3-(4′-chloro-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-8-(trifluoromethyl)-1-azaspiro[4.5]dec-3-en-2-one.

3. A pharmaceutical formulation comprising a compound according to claim 1 in combination with a further active compound, wherein the further active compound includes at least one of afinitor, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BCG or tice-BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulphate, broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidin, chlorambucil, cisplatin, cladribin, clodronic acid, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunoxome, decadron, decadron phosphate, delestrogen, denileukin diftitox, depomedrol, deslorelin, dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine, doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend, epirubicin, epoetin-alfa, epogen, eptaplatin, ergamisol, estrace, estradiol, estramustine sodium phosphate, ethinylestradiol, ethyol, etidronic acid, etopophos, etoposide, fadrozole, farstone, filgrastim, finasteride, fligrastim, floxuridine, fluconazole, fludarabin, 5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU), fluoxymesterone, flutamide, formestane, fosteabine, fotemustine, fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel, goserelin, granisetron hydrochloride, histrelin, hycamtin, hydrocortone, erythro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, interferon-alpha, interferon-alpha-2, interferon-alpha-2.alpha., interferon-alpha-2.beta., interferon-alpha-n1, interferon-alpha-n3, interferon-beta, interferon-gamma-1.alpha., interleukin-2, intron A, iressa, irinotecan, kytril, lapatinib, lentinan sulphate, letrozole, leucovorin, leuprolide, leuprolide acetate, levamisole, levofolic acid calcium salt, levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrol acetate, melphalan, menest, 6-mercaptopurine, mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, modrenal, myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide, nolvadex, NSC-631570, OCT-43, octreotide, ondansetron hydrochloride, orapred, oxaliplatin, paclitaxel, pediapred, pegaspargase, pegasys, pentostatin, picibanil, pilocarpine hydrochloride, pirarubicin, plicamycin, porfimer sodium, prednimustine, prednisolone, prednisone, premarin, procarbazine, procrit, raltitrexed, RDEA119, rebif, rhenium-186 etidronate, rituximab, roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine, sizofiran, sobuzoxane, solu-medrol, streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin, tasonermin, tastolactone, taxoter, teceleukin, temozolomide, teniposide, testosterone propionate, testred, thioguanine, thiotepa, thyrotropin, tiludronic acid, topotecan, toremifen, tositumomab, tastuzumab, teosulfan, tretinoin, trexall, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizin, zinecard, zinostatin-stimalamer, zofran; ABI-007, acolbifen, actimmune, affinitak, aminopterin, arzoxifen, asoprisnil, atamestane, atrasentan, BAY 43-9006 (sorafenib), avastin, CCI-779, CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate, decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin, eflornithine, exatecan, fenretinide, histamine dihydrochloride, histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanine, L-651582, lanreotide, lasofoxifen, libra, lonafarnib, miproxifen, minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin, neovastat, nolatrexed, oblimersen, onko-TCS, osidem, paclitaxel polyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549, raloxifen, ranpirnas, 13-cis-retic acid, satraplatin, seocalcitol, T-138067, tarceva, taxoprexin, thymosin-alpha-1, tiazofurin, tipifarnib, tirapazamine, TLK-286, toremifen, transMID-107R, valspodar, vapreotide, vatalanib, verteporfin, vinflunin, Z-100, and zoledronic acid.

4. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

5. A method for the treatment of breast carcinomas, colorectal carcinomas, prostate carcinomas or non-small-cell bronchial carcinomas comprising administering to a human or other mammal in need thereof a therapeutically effective amount of a compound according to claim 1 .

6. A method for the treatment of hormone receptor-positive breast carcinomas or androgen receptor-negative prostate carcinomas comprising administering to a human or other mammal in need thereof a therapeutically effective amount of a compound according to claim 1 .

7. A method for the treatment of breast carcinomas, colorectal carcinomas, prostate carcinomas or non-small-cell bronchial carcinomas comprising administering to a human or other mammal in need thereof a therapeutically effective amount of a compound according to claim 2 .

8. A method for the treatment of hormone receptor-positive breast carcinomas or androgen receptor-negative prostate carcinomas comprising administering to a human or other mammal in need thereof a therapeutically effective amount of a compound according to claim 2 .

Assignees

• Liu Ningshu
• Thede Kai
• Mönning Ursula
• Scholz Arne
• Hilger Christoph-Stephan
• Bömer Ulf
• Fischer Reiner
• Bayer Ip Gmbh

Inventors

• Liu Ningshu
• Thede Kai
• Mönning Ursula
• Scholz Arne
• Hilger Christoph-Stephan
• Bömer Ulf
• Fischer Reiner

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D209/54 Primary

  Spiro-condensed · CPC title

• A61K31/403

  condensed with carbocyclic rings, e.g. carbazole · CPC title