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EP2670408A1 - (5s,8s)-3-(4'-chlor-3'-fluor-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-on (verbindung a) zur therapie - Google Patents

(5s,8s)-3-(4'-chlor-3'-fluor-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-on (verbindung a) zur therapie

Info

Publication number
EP2670408A1
EP2670408A1 EP12704386.7A EP12704386A EP2670408A1 EP 2670408 A1 EP2670408 A1 EP 2670408A1 EP 12704386 A EP12704386 A EP 12704386A EP 2670408 A1 EP2670408 A1 EP 2670408A1
Authority
EP
European Patent Office
Prior art keywords
compound
carcinoma
prophylaxis
hydroxy
azaspiro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12704386.7A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ningshu Liu
Kai Thede
Philip Lienau
Arne Scholz
Christoph-Stephan Hilger
Ulf Bömer
Maher MAJJAR
Knut Eis
Reiner Fischer
Wahed Ahmed Moradi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Intellectual Property GmbH
Original Assignee
Bayer Intellectual Property GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE102011011040A external-priority patent/DE102011011040A1/de
Application filed by Bayer Intellectual Property GmbH filed Critical Bayer Intellectual Property GmbH
Publication of EP2670408A1 publication Critical patent/EP2670408A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Acetyl-CoA carboxylases play a key role in cellular fatty acid homeostasis.
  • ACCs are biotin-containing enzymes that catalyze the carboxylation of acetyl-CoA to malonyl-CoA in an ATP-dependent manner (Kim, 1997, Harw ood., 2005; Tong., 2005).
  • This reaction which runs as two half reactions, a biotin carboxylase (BC) reaction and a carboxyl transferase (CT) reaction, is the first preliminary step in fatty acid biosynthesis and is the rate-limiting step for the pathway.
  • BC biotin carboxylase
  • CT carboxyl transferase
  • ACC1 and ACC2 encoded by two different genes (LuTFI ABU-ELHEIGA et al, 1995, Jane WIDMER, et al., 1996).
  • ACC I is expressed in lipogenic tissue (liver, adipose tissue), localized in the cytosol, and fills the malonyl-CoA pool, which serves as a C2 unit donor for the de novo synthesis of long-chain fatty acids by FASN and subsequent chain extension.
  • ACC2 is mainly expressed in oxidative tissues (liver, heart, skeletal muscle) (Bianchi et al., 1990; Kim. 1997), associated with the mitochondria, and regulates a second pool of malonyl-CoA.
  • ACC activity is strictly controlled by a variety of dietary, hormonal, and other physiological mechanisms, such as forward allosteric activation by citrate. a feedback inhibition by long-chain fatty acids, reversible phosphorylation and / or inactivation or modulation of the
  • ACC I knockout mice are embryonic lethal (Swinnen, et al., 2006, Abu-Elheiga, et al., 2005).
  • ACC2 knockout mice show reduced malonyl-CoA levels. in skeletal and cardiac muscle, increased fatty acid oxidation in muscle, decreased liver fat levels, decreased levels of total body fat, increased levels of UCP3 in skeletal muscle (as a sign of increased energy expenditure), decreased body weight, decreased levels of plasma free fatty acids, decreased plasma Glucose levels, decreased levels of glycogen in tissues and are protected from diet-induced diabetes and obesity (Abu-Elheiga et al, 2001, 2003, Oh et al., 2005).
  • EP0454782 and US5759837 protect the use of fatty acid synthesis inhibitors to inhibit tumor cell growth. Cyclic ketoenols are not revealed.
  • PCT Patent Application PCT / EPP99 / 01787 published as WO 99/48869 corresponding to European Patent EP 1 066 258 B1, relates to novel arylphenyl-substituted cyclic ketoenols, a majority of the processes for their preparation and their use as pesticides and herbicides.
  • EP-A-0 262 399 and GB-A-2 266 888 disclose similarly structured compounds (3-arylpyrrolidine-2,4-diones), of which, however, no herbicidal, insecticidal or acaricidal activity has become known , Unsubstituted, bicyclic 3-arylpyrrolidine-2,4-dione derivatives are known (EP-A-355 599, EP-A-415 21 1 and JP-A-12-053.) With herbicidal, insecticidal or acaricidal activity 670) and substituted monocyclic 3-arylpyrrolidine-2,4-dione derivatives (EP-A-377 893 and EP-A-442 077).
  • EP-A-442 073 polycyclic 3-arylpyrrolidine-2,4-dione derivatives
  • I H-Aiylpyrrolidin-dione derivatives EP-A-456 063, EP-A-521 334, EP-A -596 298, EP-A-613 884, EP-A-613 885, WO 95/01 971, WO 95/26 954, WO 95/20 572, EP-A-0 668 267, WO 96/25 395, WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97/36868, WO 97/43275, WO 98/05638, WO 98/06721, WO 98/25928, WO 99/24437, WO 99/43649, WO 99/48869, WO 99/55673,
  • WO 06/02441 1 discloses herbicidal compositions containing ketoenols.
  • Tetronic acid derivatives (such as 3- (2-methyl-phenyl) -4-hydroxy-5- (4-fluoro-phenyl) - ⁇ -dihydrofuranone (2)) are also described in DE-A-4 014 420.
  • Structure compounds without indication of insecticidal and / or acaricidal activity are known from the publication Campbell et al. J.
  • Derivatives having herbicidal, acaricidal and insecticidal properties are known from: EP-A-528 156, EP-A-647 637. WO 95/26 954. WO 96/20 196, WO 96/25 395.
  • WO 96/35 664 WO 97/01 535, WO 97/02 243, WO 97/36 868, WO 98/05 638, WO 98/06 72, WO 99/16748, WO 98/25 928, WO 99/43 649.
  • WO 01/23354
  • Phenyl-pyrone derivatives having herbicidal, acaricidal and insecticidal properties which are substituted in the phenyl ring are described in EP-A-588 137, WO 96/25 395, WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97 / 16,436, WO 97/19941, WO 97/36868, WO 98/05638, WO 99/43649, WO 99/48869, WO 99/55673, WO 01/17972, WO 01/74770, WO 03/013249 , WO 04/080 962, WO 04/1 1 1 042, WO 05/092897, WO 06/029799 and
  • Herbicidal, acaricidal and insecticidal derivatives are described in WO 94/14785,
  • 2- (2,4,6-trimethylphenyl) -l, 3-indanedione is from J. Economic Entomology. 66, (1973), 584 and the published patent application DE-A 2 361 084, with indication of herbicidal and acaricidal effects.
  • WO 96/21 652 WO 99/47525, WO 01/17351, WO 01/17352, WO 01/17353, WO 01/17972, WO 01/17973, WO 03/028 466, WO 03 / 062 244.
  • 4-biphenyl-substituted tetronic acid derivatives are disclosed in WO 2008/022725 for the therapy of viral diseases.
  • WO 2005/0891 18 and WO2007 / 039286 generically disclose nitrogen-containing bicyclic
  • Compound A is specifically disclosed in WO2008 / 067910 (Table 1, page 26, line 4).
  • WO2008 / 067910 does not disclose the suitability of compound A for therapeutic purposes.
  • Compound A Concurrent with the present application of priority, the subject of which is the therapeutic use of compound A alone, i.a. filed a PCT application, the subject has the therapeutic use of numerous cyclic ketoenols and the priority of a German application with the application number DE 102010008644.4 claims.
  • Compound A is Example I-1118 in the PCT application, but was in the
  • Example 11-16 of WO99 / 48869 is also an article in DE 102010008644.4 and the PCT application claiming the priority of DE 102010008644.4 (Example 1-2).
  • Example I-I-a-31 of WO03 / 059065 which differs from the compound A by the replacement of the fluorine atom on the outer phenyl ring of the biphenyl by a chlorine atom.
  • the therapeutic use of Example I-1-a-31 of WO03 / 059065 is also an article in DE 102010008644.4 and the PCT application claiming the priority of DE 102010008644.4 (Example 1-8 1).
  • the object of the present invention is to provide a particularly effective structure for the therapy of diseases.
  • Structures solves the task of the invention particularly well, namely a structure that can be used particularly well in the treatment of human diseases.
  • Compound A has comparable enzyme inhibition data as Example I-I-a-16 of
  • WO99 / 48869 which could be considered structurally closest prior art.
  • the compound A is characterized by a broader therapeutic window in the M C F 7 - X eno ra 11 - M odel I than this prior art, which has no effectiveness in this model at tolerated doses.
  • Compound A has better enzyme inhibition data than Example I-1-a-3 1 of WO03 / 059065, which could also be considered as the structurally closest prior art.
  • Ketoenol surprisingly has highlighted Compound A by better enzyme inhibition and / or better in vivo efficacy at tolerated doses.
  • Physiologically acceptable salts of Compound A also include salts of common bases such as, by way of example and by way of example, alkali metal salts (e.g., sodium and potassium salts), alkaline earth salts (e.g., calcium and magnesium salts), and ammonium salts derived from ammonia or organic acids.
  • alkali metal salts e.g., sodium and potassium salts
  • alkaline earth salts e.g., calcium and magnesium salts
  • Amines having I to 16 ( ' atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
  • Another object of the present invention are pharmaceutical compositions containing compound A and at least one or more other active ingredients, in particular for the prophylaxis and / or therapy of tumor diseases.
  • Compound A can act systemically and / or locally. For this purpose, it may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent. For these routes of administration, compound A can be administered in suitable administration forms.
  • the compound A donating application forms containing the compound A in crystalline and / or amorphised and / or dissolved form such as.
  • Tablets uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), orally disintegrating tablets or films / wafers, films / lyophilisates, capsules in the oral cavity
  • Parenteral administration can be done by bypassing a resorption step (e.g.
  • intravenously, intraarterially, intracardially, intraspinally or intralumbarally) or with the involvement of resorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and
  • Infusion preparations in the form of solutions, suspensions, emulsions. Lyophilisates or sterile powders.
  • Inhalation medicines i.a.
  • Powder inhalers. Nebulizer nose drops, solutions. sprays; lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or
  • Eye preparations vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions. Ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes. Foams, scattering powders, implants or stents.
  • the compound A can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable Excipients happen. These excipients include, inter alia, excipients (for example
  • microcrystalline cellulose lactose, mannitol
  • solvents eg liquid polyethylene glycols
  • emulsifiers and dispersing or wetting agents for example sodium dodecylsuifate, polyoxy sorbitan oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers eg antioxidants such as for example
  • Ascorbic acid Ascorbic acid
  • dyes e.g., inorganic pigments such as iron oxides
  • flavor and / or smell corrigents e.g., inorganic pigments such as iron oxides
  • Another object of the present invention are pharmaceutical compositions containing the compound A, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the formulation of compound A into pharmaceutical preparations is carried out in a manner known per se, by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
  • auxiliaries may, for example, vehicles, fillers, disintegrants, binders, moisturizers, lubricants, adsorbents and adsorbents. Diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants,
  • Preservatives Preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers are used.
  • auxiliaries may be, for example, salts, saccharides (mono-, di-, tri- and oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes. oils
  • Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • oral or oral administration in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question.
  • the present invention relates to the use of the compound A for the prophylaxis and therapy of human diseases, in particular of tumor diseases.
  • compound A can be used to inhibit or reduce cell proliferation and / or cell division and / or to induce apoptosis.
  • the compound A is particularly suitable for the prophylaxis and / or treatment of hyperproliferative diseases such as
  • BPH benign prostatic hyperplasia
  • tumors according to the invention for example, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast, tumors of the breast,
  • Respiratory tract the brain, the reproductive system, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland, the bone and the connective tissue and metastases of these tumors.
  • hematological tumors are treatable
  • treatable as breast tumors are:
  • tumors of the respiratory tract are treatable.
  • tumors of the brain are treatable.
  • tumors of the male reproductive organs are treatable:
  • tumors of the female reproductive organs are treatable:
  • tumors of the gastrointestinal tract are treatable:
  • Gastrointestinal stromal tumors For example, tumors of the urogenital tract are treatable:
  • tumors of the eye are treatable:
  • Intraocular melanomas Intraocular melanomas
  • Treatable as tumors of the liver for example:
  • Tumors of the skin are treatable, for example:
  • Tumors of the head and neck are treatable:
  • sarcomas are treatable:
  • lymphomas are treatable:
  • AIDS-associated lymphomas Treatable as leukemias for example:
  • the compound A can be used for the prophylaxis and / or therapy of:
  • Pank easka rzi nomen Renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma, colorectal carcinoma, gastric carcinoma and prostate carcinoma.
  • the compound A can be used with particular advantage for the prophylaxis and / or therapy of:
  • breast cancers in particular of hormone receptor negative and hormone receptor positives, as well as pancreatic carcinomas, non-small cell lung carcinomas, endometrial carcinomas, colorectal carcinomas, gastric carcinomas and prostate carcinomas.
  • Another object of the present application is the compound A for use as a medicament, in particular for the prophylaxis and / or therapy of tumor diseases.
  • a further subject of the present application is compound A for the prophylaxis and / or therapy of breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, malignant melanomas and other skin tumors, non-small cells,
  • Bronchial carcinoma endometrial carcinoma, colorectal carcinoma, gastric carcinoma or prostate cancer.
  • An advantageous object of the present application is compound A for the prophylaxis and / or therapy of breast cancers, in particular of hormone receptor negative and hormone receptor positives, as well as pancreatic carcinomas, non-small cell lung carcinomas, endometrial carcinomas, colorectal carcinomas, gastric carcinomas and prostate carcinomas.
  • Another object of the invention is the use of the compound A for the preparation of a medicament.
  • Another object of the present application is the use of the compound for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases.
  • Another object of the present application is the use of the compound A for the manufacture of a medicament for the prophylaxis and / or treatment of breast, pancreatic, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cells, bronchial carcinoma, endometrial carcinoma, colorectal carcinoma, gastric carcinoma or prostate cancer.
  • An advantageous subject of the present application is the use of the compound A for the manufacture of a medicament for the prophylaxis and / or therapy of breast cancers, in particular of hormone receptor negative and hormone receptor positives, as well as
  • Pancreatic carcinoma non-small cell lung carcinoma, endometrial carcinoma,
  • Another object of the present application is the use of the compound for the prophylaxis and / or therapy of tumor diseases.
  • Another object of the present application is the use of compound A for the prophylaxis and / or treatment of breast, pancreatic, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cells, bronchial carcinoma, endometrial carcinoma, colorectal carcinoma, gastric carcinoma or prostate cancer.
  • An advantageous subject of the present application is the use of the compound A for the prophylaxis and / or therapy of breast cancers, in particular of hormone receptor negative and hormone receptor positives. as well as pancreatic carcinomas, non-small cells
  • Bronchial carcinoma endometrial carcinoma, colorectal carcinoma, gastric carcinoma and prostate cancer.
  • the present application further relates to pharmaceutical formulations in the form of tablets containing compound A for the prophylaxis and / or therapy of breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, malignant melanomas and other skin tumors, non-small cell carcinomas, bronchial carcinomas, Endometrial carcinoma, colorectal carcinoma, gastric carcinoma or prostate cancer.
  • An advantageous subject of the present application are pharmaceutical formulations in the form of tablets containing compound A for the prophylaxis and / or therapy of
  • breast cancers in particular of hormone receptor negative and hormone receptor positives, as well as pancreatic carcinomas, non-small cell lung carcinomas, endometrial carcinomas, colorectal carcinomas, gastric carcinomas and prostate carcinomas.
  • Another object of the invention is the use of compound A for the treatment of diseases associated with proliferative processes.
  • Compound A can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesirable and unacceptable side effects.
  • Another object of the present invention are therefore pharmaceutical compositions containing compound A and one or more other active ingredients, in particular for the prophylaxis and / or therapy of the aforementioned diseases.
  • compound A may be associated with known anti-hyperproliferative. cytostatic or cytotoxic substances used to treat cancers. The combination of compound A with other substances commonly used for cancer therapy or else with radiotherapy is particularly indicated. Examples of suitable combination active ingredients are:
  • Afmitor Aldesleukin, alendronic acid, alfaferone, alitretinoin. Allopurinol. Aloprim. Aloxi, altretamine, aminoglutethimide. Amifostine, Amrubicin, Amsacrine, Anastrozoi, Anzmet, Aranesp, Arglabin. Arsenic trioxide, Aromasin. 5-azacytidine, azathioprine, BCG or tice-BCG, bestatin. Beta methasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine, bortezomib. Busuifan, calcitonin. Campath, capecitabine, carboplatin. Casodex, cefeson,
  • Celmoleukin Cerubidin, chlorambucil, cisplatin, cladribine, clodronic acid, cyclophosphamide, cytarabine. dacarbazine, dactinomycin. DaunoXome, Decadron. Decadron phosphate. Delicious roe.
  • Denileukin Diftitox Depomedrol, Deslorelin, Dexrazoxane, Diethylstilbestrol, Diflucan, Docetaxel, Doxifluridine, Doxorubicin, Dronabinol, DW-166HC, Eligard, Elitek, Ellence, Einend, Epirubicin, Epoetin-alfa, Epogen, Eptaplatin. Ergamisol, Estrace, Estradiol, Estramustine Sodium Phosphate, Ethinyl Estradiol. Ethyol, etidronic acid, etopophos. Etoposide.
  • Interferon-alpha-2 ⁇ Interferon-alpha-n 1.
  • Interferon-alpha-n3, Intercron-beta Interferon gamma-la, Interleukin-2, Intron A, Iressa.
  • Irinotecan. Kytril, lapatinib, lentinan sulfate, letrozole, leucovorin, leuprolide. Lcuprolid acetate.
  • Levamisole. Levofolic acid calcium salt, levothroid, levoxyl, lomustine, lonidamine, marinol, mechlorethamine, mccobalamin. Medroxyprogcristone acetate, metastol acetate. Melphalan, Menest.
  • 6-mercaptopurine Mesna, methotrexate, metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone, mod renal, myocet, ncdaplatin. Neulasta, Neumega, Neupogen. Nilutamide. Nolvadex, NSC-631570, OCT-43, Octreotide. Ondansetron hydrochloride, Orapred. Oxaliplatin, Paclitaxel, Pcdiapred, Pcgaspargasc. Pegasys. Pcntostatin, Picibanil. Pilocarpine hydrochloride. Pirarubicin. Plicamycin. Porfimer sodium, Prcdnimustin.
  • Prednisolone Prednisone, Premarin, Procarbazine, Procrit. Raltitrexed, RDEA1 19, Rebif. Rhenium 186 etidronate, rituximab, Roferon-A. Ronuirtid. Salagen. Sandostatin, Sargramostim, Seniustin. Sizofirane, sobuzoxan, solu-medrol, streptozocin, strontium-89-chloride, tamoxifen,
  • Vinorelbine Virulizin. Zinecard, Zinostatin Stimalamer, Zofran; ABI-007, Acolbifen, Actimmun. 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. Eflornitliin.
  • Exatecan fenretinide, histamine dihydrochloride, histrelin-hydrogei-implant, holmium-166-DOTMP, ibandronic acid.
  • Interferon-gamma Intron PEG, ixabepilone. Keyhole limpet hemocyanin, L-
  • Taxoprexin thymosin-alpha. Tiazofurin, tipifarnib, tirapazamine, TLK-286, toremi fen. TransMID-107R, Valspodar. Vapreotide. Vatalanib. Verteporfin. Vinflunine. Z-100th zoledronic acid. and combinations thereof.
  • the compound A can be combined with anti-hyperproliferative agents, which may be by way of example-without this enumeration being conclusive: Aminoglutethimide, L-asparaginase, azathioprine, Bleomycin, busiilfan, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine. dacarbazine.
  • anti-hyperproliferative agents which may be by way of example-without this enumeration being conclusive: Aminoglutethimide, L-asparaginase, azathioprine, Bleomycin, busiilfan, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine. dacarbazine.
  • Flutamide Hexamethylmelamine, hydroxyurea, hydroxyprogesterone caproate, idarubicin. Ifosfamide, interferon, irinotecan. Leucovorin, Lomustin.
  • compound A can also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
  • biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
  • Compound A may also be used in combination with other antiangiogenic agents
  • compound A may also be used in conjunction with radiotherapy and / or surgical intervention.
  • Comparative Example V.2 is Example I-1 -a-3 1 of WO03 / 059065.
  • Example I-I-A-31 of WO03 / 059065 is also an article in DE 1020 1 0008644.4 and the PCT application which has the priority of DE 1020 1 0008644.4 in
  • ACC 1 acetyl-CoA carboxylase 1
  • the basic principle of the assay is the measurement of the adenosine diphosphate (ADP) formed as a co-product by means of an HTRF "-based, homogeneous homo-resolved fluorescence assay (HTRF).
  • ADP adenosine diphosphate
  • HTRF homogeneous homo-resolved fluorescence assay
  • a 1 ⁇ 10 fold concentrated solution of the test substance in DMSO is pipetted into a black low-volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany) 2 ⁇ l of a solution of ACC 1 in assay buffer [50 mM HEPES / NaOH pH 7.5 , 1 2mM sodium bicarbonate, 2mM MgC ' h, 2mM potassium citrate, 0.005% (w / v) bovine
  • BSA Serum albiimine
  • the reaction was quenched by successive additions of 2.5 microliters of a solution of d2 labeled ADP (HTRF ® Trans Screener TM ADP kit, Cis biointernational, Marcoule, France) TM in the EDTA-containing HTR F 'Trans Screener ADP-assay buffer (in HTRF Transscreener TM ADP kit contains 50 mM HEPES pH 7.0, 60 mM EDTA, 0.1% (w / v) BSA, 0.02% sodium azide, 400 niM potassium fluoride) and 2.5 ⁇ a solution of europium cryptate-labeled anti-ADP antibody (HTRF ® Trans Screener TM ADP Kit) in HTRF ® Trans Screener TM ADP detection buffer.
  • d2 labeled ADP HTRF ® Trans Screener TM ADP kit, Cis biointernational, Marcoule, France
  • the resulting mixture was incubated for one hour at 22 ° C to allow binding of the europium cryptate-labeled anti-A D P antibody to the ADP formed by the enzyme reaction and the d2-labeled ADP. Subsequently, the amount of the complex of d2-labeled ADP and europium cryptate-labeled anti-ADP antibody was determined by measuring the resonance energy transfer from the europium cryptate to the d2. For this purpose, in an HTRF meter, e.g. a Rubystar or Pherastar (both BMG Labtcchnologics. Offenburg,
  • hACC I inhibitory activity of the substances of this invention was measured in the hACC 1 assay described in the following paragraphs.
  • the enzyme activity is measured by quantifying the adenosine di-phosphate (ADP) formed as a by-product of the enzyme reactions using the ADP-Glo TM detection system of Promega.
  • ADP adenosine di-phosphate
  • ATP adenosine tri-phosphate
  • ADP-GLO reagent an adenylate cyclase
  • the adenylate cyclase is stopped and then (.K i nase Detecti on Reagent "), the ADP formed is then converted into ATP and converted into a glow luminescence signal in a luciferase-based reaction.
  • test substance was incubated on the same microtiter plates at 10 different concentrations ranging from 20 ⁇ to 1 nM (20 ⁇ , 6.7 ⁇ , 2.2 ⁇ , 0.74 ⁇ , 0.25 ⁇ , 82 ⁇ , 27 ⁇ , 9.2 ⁇ , 3.1 nM and I nM, the serial dilutions were assayed at the level of the I OX-fold concentrated solution by serial 1: 3 dilutions) in duplicate for each concentration prior to assay and IC50 values were calculated using a 4-parameter fit using an inhousc software.
  • ACC2 acetyl-CoA carboxylase 2
  • BSA Serum Albumin
  • the concentration of the ACC2 was adjusted to the respective activity of the enzyme and adjusted so that the assay worked in the linear range. Typical concentrations were in the range of 0.6 ng / ⁇ .
  • the reaction urde stopped by successive additions of 2.5 microliters of a solution of d2-labeled ADP (HTRF ® Trans Screener TM ADP kit, Cis biointemational. Marcoulc. France) (in the EDTA-containing HTRF ® Trans Screener TM ADP detection buffer in HTRF ® Trans Screener TM 50mM HEPES pH 7.0, 60mM EDTA, 0.1% (w / v) BSA, 0.02% Natnumazide, 400mM potassium fluoride) and 2.5 ⁇ l of a solution of europium cryptate-labeled anti-ADP Kit.
  • ADP antibody (HTRF ® Transscreener TM ADP Kit) in HTRF * Transscreener TM ADP detection buffer.
  • the resulting mixture was incubated for one hour at 22 ° C to allow binding of the europium-cryptate-labeled anti-ADP antibody to the ADP formed by the enzyme reaction and the d2-labeled ADP. Subsequently, the amount of the complex of d2-labeled ADP and europium cryptate-labeled anti-ADP antibody was determined by measuring the resonance energy transfer from the europium cryptate to the d2. For this purpose, in an HTRF measuring instrument, eg a Rubystar or Pherastar (both BMG Labtechnologies, Offenburg,
  • test substances were incubated on the same microtiter plates at 10 different concentrations in the range of 20 ⁇ to 1 nM (20 ⁇ , 6.7 ⁇ , 2.2 ⁇ , 0.74 ⁇ , 0.25 ⁇ , 82 ⁇ , 27 ⁇ , 9 , 2 ⁇ , 3, 1 ⁇ and 1 nM, the serial dilutions were assayed at the level of 100X concentrated solution by serial 1: 3 dilutions) in duplicate for each concentration before the assay and IC50 values were calculated using a 4-parameter -Fit, for which an inhouse software was used.
  • the hACC2 inhibitory activity of the substances of this invention was measured in the hACC2 assay described in the following paragraphs.
  • the enzyme activity is measured by quantifying the adenosine di-phosphate (ADP) formed as a by-product of the enzyme reactions using the ADP-Glo TM detection system from Promega.
  • ADP adenosine di-phosphate
  • ATP adenosine tri-phosphate
  • ADP-GLO reagent an adenylate cyclase
  • kinase detection reagent is then converted the formed ADP into ATP and converted this into a glow luminescence signal in a luciferase-based reaction.
  • the enzyme used was recombinant C-terminal FLAG-tagged human ACC2 (acetyl-coenzyme A carboxylase 2, Gen Bank Accession No. NP_001084) (amino acids 27-end), expressed in baculovirus-infected insect cells (Hi5) and purified by anti-FLAG affinity chromatography.
  • the reaction was stopped by adding 2.5 ⁇ of the "ADP-GLO reagent” (diluted 1: 1.5 fold) and the resulting mixture incubated at 22 ° C for 1 h to completely exchange the unreacted ATP in cAMP Subsequently, 2.5 ⁇ of the "Kinase Detection Reagent" (1.2 times more concentrated than indicated by the manufacturer) was added, the resulting mixture incubated for 1 h at 22 ° C and then the luminescence with a suitable instrument (Viewlux or Topcount from Perkin -Elmer or Pherastar from BMG Labtechnologies). The amount of light emitted was taken as a measure of the amount of ADP formed and thus of the hACC 2 enzyme activity.
  • a suitable instrument Viewlux or Topcount from Perkin -Elmer or Pherastar from BMG Labtechnologies
  • test substance was incubated on the same microtiter plates at 10 different concentrations ranging from 20 ⁇ to 1 nM (20 ⁇ , 6.7 ⁇ , 2.2 ⁇ , 0.74 ⁇ , 0.25 ⁇ , 82 ⁇ , 27 ⁇ , 9.2 ⁇ , 3.1 ⁇ M and 1 ⁇ M , the serial dilutions were assayed at the level of 100X concentrated solution by serial 1: 3 dilutions) in duplicates for each concentration before assay and IC50 values were calculated using a 4-parameter fit using in-house software has been.
  • the assay was incubated at room temperature in a clear 384-wel! microtiter plate
  • the assay contained 50mM Tris-HCl pH 8.3, 50mM KCl, 2.5mM MgCl. 0.5 m M ATP. 0.8 mM dithiothreitol (DTT). 30 mM NaHCCk 0.1 mM acetyl-CoA, 0.04% bovine serum albumin and 0.4 ⁇ g of partially purified ACCase enzyme in a final volume of 40 ⁇ l. After 45 minutes of incubation, the reaction was stopped with 150 ⁇ M malachite green solution and the absorbance at 620 after 30 Minutes read out.
  • the malachite green (MG) solution was prepared by mixing 3 parts of 0.6 mM MG-HCl solution in distilled water with 1 part of 8.5 mM AMMOKOBDAT in 4 M HCl. The solution was allowed to stand for 30 minutes. After filtration through a 0.45 ⁇
  • Pol tetrafluoroethylene (PTFE) filters were added to 0.1 part of Triton X-100 (1.5%) in distilled water.
  • ACCase enzyme was extracted from oat seedlings harvested 9 days after seeding and partially purified by 0-40% ammonium sulfate precipitation followed by ionic Australian Q-Sepharose chromatography.
  • test substances were tested in a "Mode of action" experiment based on the short-term application of a test substance capable of ACC I and / or ACC2 in the living
  • Organism to inhibit after oral administration, leading to a reduction of Malonvl-CoA in the tumor 2 million human MCF-7 breast cancer cells were experimentally subcutaneously injected into female nude mice (NM RI-nude (nu / nu) mice, Taconic M & B A / S, the day before application of a pellet for the release of estrogen over a period of at least 60 days) injected. Once the tumor had reached an area of about 60-70 mm 2 , the oral administration of the test substance took place over a period of 1-3 days, then the intratumoral content of malonyl-CoA was determined at defined times and compared with the vehicle control. The method is described in Anal Chem. 2008 Aug 1; 80 (15): 5736-42. Epub 2008 Jul 9.). Ce! L assays
  • the substances were tested in cell-based assays, that is, the ability of the substances to tumor cell proliferation after 96 hours
  • Luminescences between substance-treated and control values were used to determine the percent growth inhibition.
  • HEC 1A ATCC endometrial carcinoma
  • Xenograft models were used in immunosuppressed mice to determine antitumoral efficacy in the living organism.
  • MTD maximum tolerable dose
  • Body weight compared to the starting weight came.
  • mice Had reached the tumor area, the mice were randomized into the therapy groups and started the therapy. Therapy was then measured 2-3 times weekly
  • Control group which had received only the vehicle of the test substance, or in one of
  • Treatment groups had reached 120mm 2 . At this time, the experiment was stopped in all groups and the prepared tumors were weighed.
  • the T / C value calculated as the primary success parameter was calculated either on the basis of the effect on the tumor weight or on the tumor area: Mean value of the tumor area / area in the treatment group divided by the average of the tumor weights / areas in the vehicle group. Analysis of ACC1 expression in tumor and normal tissues
  • the ACC I expression was determined by means of a microrray.
  • the RNA was isolated from different tumor tissues and the corresponding normal weights.
  • Trizol RNA extraction reagent (Invitrogen) was used and purification was performed using the RNeasy Mini Kit (Qiagen).
  • DNase I (Qiagen) digestion was performed to eliminate genomic DNA.
  • total RNA analysis was performed using an RNA LabChip on an Agilent Bioanalyzer 2100 Platform (Agilent Technologies) and RNA concentration determined using the Peqlab NanoDrop System.
  • Affymetrix and then the array on an Affymetrix GeneChip 3000 scanner (Affymetrix) read. Evaluation and quality control were performed using the Expressionist Pro 4.0 Refiner (Gene Data) software. 4. Results:
  • Table 1 summarizes the results with respect to compound A and the comparative examples from the enzyme assays.
  • Comparative Example V.1 was applied to female nude mice (NMRI nu / nu):
  • V. 1 20 14 days, twice daily minus 29 2 of 3
  • Vehicle 2 1 day. once a day plus 1 5 0 out of 5
  • the MTD is below 10 mg / kg for a 14-day treatment twice daily.
  • the MTD is less than 15 mg / kg for a 2-day regimen once daily.
  • Comparative Example V.1 was subsequently applied in the MCF-7 breast cancer xenograft model to female nude mice (NMR! Nu / nu):
  • FIG. 2 shows the tumor area as a function of the number of days after implantation of the tumor cells
  • the treatment phase was followed by an observation period of 7 days.
  • the deaths that occurred and the effect on body weight are summarized in Table 4.
  • the MTD for a 2-day treatment at I daily dosing is below 40 mg / kg and above 30 mg / kg.
  • FIG. 3 shows the tumor area as a function of the number of days after implantation of the tumor cells.
  • Comparative Example V.1 shows that no antitumor efficacy is observed for Comparative Example V.1 even at a poorly tolerated dose, while biologically significant and significant antitumoral effects for Compound A are within a tolerable dose range from 20 mg / kg qd to 35 mg / kg qd.
  • ACC 1 in tumor and corresponding normal tissue was determined by microarray (FIG. 1).
  • the expression of ACC1 was significantly upregulated compared to normal breast cancer, colorectal carcinoma, and bronchial carcinoma
  • Tablets were prepared according to the composition of Table 6 containing the compound by direct tabletting.
  • the pharmaceutical formulation can be prepared by any suitable method, in particular powder mixing and direct tabletting in any desired scale.
  • the resulting molding compound was pressed by means of an eccentric tablet press (Kersch EK 2) into biconvex tablets with a diameter of 8 mm and a radius of curvature of 1 2 mm. b) Breaking strength
  • the breaking strength (by means of Schleuniger's breaking strength tester), mass and disintegration time in water at 37 ° C. (using the apparatus described in monograph 2.9.1 European Pharmacopoeia) of the tablets obtained were tested at the beginning, middle and end of the tableting process.
  • the produced tablets were subjected to a short term stability test for 1 month at 25 ° C / 60% relative humidity and at 40 ° C / 75% relative humidity.
  • the tablets were stable under both conditions in terms of content and degradation products, analyzed by HPLC. Characters:

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EP12704386.7A 2011-02-06 2012-02-03 (5s,8s)-3-(4'-chlor-3'-fluor-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-on (verbindung a) zur therapie Withdrawn EP2670408A1 (de)

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PCT/EP2012/051895 WO2012104428A1 (de) 2011-02-06 2012-02-03 (5s,8s)-3-(4'-chlor-3'-fluor-4-methylbiphenyl-3-yl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-on (verbindung a) zur therapie

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US9212140B2 (en) 2015-12-15
PH12013501638A1 (en) 2013-09-16
TN2013000336A1 (en) 2015-01-20
CA2826515A1 (en) 2012-08-09
EA201391084A1 (ru) 2014-02-28
WO2012104428A1 (de) 2012-08-09
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IL227804A0 (en) 2013-09-30
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