WO2018209343A1 - Novel methods, compounds, and compositions: small molecule anticancer agents - Google Patents
Novel methods, compounds, and compositions: small molecule anticancer agents Download PDFInfo
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- WO2018209343A1 WO2018209343A1 PCT/US2018/032547 US2018032547W WO2018209343A1 WO 2018209343 A1 WO2018209343 A1 WO 2018209343A1 US 2018032547 W US2018032547 W US 2018032547W WO 2018209343 A1 WO2018209343 A1 WO 2018209343A1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- 229960002950 novobiocin Drugs 0.000 description 1
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
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- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
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- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 125000004673 propylcarbonyl group Chemical group 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
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- 238000010298 pulverizing process Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 239000002719 pyrimidine nucleotide Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 1
- VXGYRCVTBHVXMZ-UHFFFAOYSA-N quinoline-6-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CC=C21 VXGYRCVTBHVXMZ-UHFFFAOYSA-N 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
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- 230000000391 smoking effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- OOQRRYDVICNJGC-MRVPVSSYSA-N tert-butyl n-[(2s)-1-hydroxy-3-methylbutan-2-yl]carbamate Chemical compound CC(C)[C@@H](CO)NC(=O)OC(C)(C)C OOQRRYDVICNJGC-MRVPVSSYSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- Another aspect of the present invention provides methods of preparing compounds of formula (1), as defined above, and their derivatives, analogs, stereoisomers, pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
- Aryl represents an optionally substituted monocyclic or polycyclic aromatic ring such as phenyl, naphthyl and the like, or optionally substituted 5 or 6 membered heteroaromatic rings containing one or more heteroatoms such as nitrogen, oxygen or sulfur.
- the heteroaromatic ring may form part of a fused, bicyclic ring. Examples of heteroaromatic rings include:
- heteroarylcarbonyl groups include: pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl and the like.
- acyl groups include (Ci-Cio): formyl, acetyl, propionyl, and the like.
- Exemplary 'heteroaralkoxy' groups, heteroaralkyl-O-, include: thienylmethyloxy, pyridylmethyloxy and the like.
- Exemplary 'heteroarylcarbonyl' groups, heteroaryl-CO- include: pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl,
- 'sulfonic acid or its derivatives' may be amides or esters.
- Exemplary sulfonic acid groups include SO2NH2, S0 2 NHMe, S0 2 NMe 2 , S0 2 NHCF 3 , SOOCH 3 , SOOC2H5, SOOC 3 H 7 , and the like. Accordingly, one embodiment of the present invention provides a process for the preparation of compounds of general formula (1) according to Scheme I below:
- compositions of quinazolone derivatives are considered 15 within the scope of compounds of the present invention and are salts with an organic or inorganic acid.
- Preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, or the like.
- Such salts may be synthesized from the compound, or derivative thereof, of the present invention that contains a basic or acidic moiety by conventional chemical methods.
- such salts may be prepared by reacting a free acid or base form of the compound, or derivative thereof, with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Further suitable salts may be found in
- Screening assays for determining those cancers susceptible to treatment using compounds of the present invention include incubating cell line models representing specific cancers as set forth, for example, by the National Cancer Institute, in the presence and absence of such compounds. Viability of cells may be determined by the MTT assay (Promega Corp., Madison, Wis. 53711), or the SRB (sulforhodamine B) assay (Skehan, et al., JNCI, 82: 13,1107,1990). Susceptibility to said compounds exists when viability in the presence of a compound of the present invention is less than viability in the absence of such compound.
- Ovarian cancer OVCAR3, OVCAR4, OVCAR5, OVCAR8, A2780, IGROV1,
- formulations are prepared by uniformly mixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
- a pharmaceutical carrier is selected on the basis of the chosen route of administration and standard pharmaceutical practice. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
- This carrier can be a solid or liquid and the type is generally chosen based on the type of
- Topical applications for administration according to the method of the present invention include ointments, cream, suspensions, lotions, powder, solutions, pastes, gels, spray, aerosol or oil.
- a formulation may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- kits useful for example, for the treatment of cancer or viral infection, that comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention.
- kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A pharmaceutical composition that inhibits the growth of tumors and cancers in mammals that comprises novel hetero cyclic compounds. The compounds can also be used as antibiotics.
Description
Novel Methods, Compounds, and Compositions: Small Molecule anticancer agents Inventors
Rajur, S. B; Kim, H-OK; Neelagiri, V. R; Salgaonkar, P. D; Divakaramenon, S; Chaeho, M; Neelagir M.
Claim of Priority
This application claims priority to U.S. Application 62/505,555 filed on May 12, 2017 the contents of which are herein fully incorporated by reference in its entirety.
Field of the Embodiments
The present invention relates to methods for the treatment of cancer and viral/bacterial infection in mammals, particularly in human and warm blooded animals, using a composition comprising a novel heterocycle, or salt thereof.
Background of the Embodiments
A. Anticancer. Cancers are the leading cause of death in animals and humans. The exact cause of cancer is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of cancers and tumors has been shown by a number of researchers. Many types of chemotherapeutic agents have been shown to be effective against cancers and tumor cells, such as non-small cell lung cancer, melanoma, breast, prostate. The American Cancer Society's estimates that for 2014, there will be 159,260 deaths from lung cancer,1 and close to 90% of lung cancers are NSCLC.2 For most patients with NSCLC, current treatments are not curative for their disease.3 There are nine types of standard treatments currently used: surgery, radiation therapy, chemotherapy, targeted therapy, laser therapy, photodynamic therapy, cryosurgery, electrocautery, and watchful waiting.4 A number of drugs are approved
for the treatment of NSCLC (e.g, methotrexate, paclitaxel, docetaxel, carboplatin, cisp latin, gefitnib, gemcitabine, erlotinib).4 Recent advances have led to expansion beyond cytotoxic chemotherapy to include molecularly targeted therapies (e.g., bevacizumab).4'5 Despite these advances, NSCLC is still associated with a 5-year survival rate of 15%.5 For example, in the treatment of NSCLC with activating epidermal growth factor receptor (EGFR) mutation as a distinct clinical entity, the median response to treatment with EGFR tyrosine kinase inhibitors ranges from 11 to 14 months; acquired resistance ultimately occurs due to a range of mechanism.6 The development of alternative treatments that can be used when resistance develops to the initial treatment is critical to long term patient survival. In spite of the impressive progress in oncology for diagnosis, surgery and therapy that has occurred in the last several decades, the overall cancer mortality is still high, and there exists an ongoing need for new agents with new mechanisms of action.
B. Antibiotics
Bacterial pathogens continue to pose a serious threat to public health as indicated by a worldwide resurgence of bacterial diseases. One aspect of this resurgence appears to be the result of prior widespread, and largely effective, therapeutic and prophylactic use of antibiotics, which, unfortunately, over time has also selected for resistant strains of various bacterial pathogens. Of particular concern to the public health has been the emergence and proliferation of bacterial strains that are resistant to multiple antibiotics in the current arsenal of antimicrobial agents. Such multi-antibiotic resistant ("MAR") bacterial strains include species of Gram positive bacteria, such as, antibiotic resistant strains of Staphylococcus aureus, Enterococcus fecalis, and Enterococcus fecium, which, along with antibiotic resistant Gram negative strains of Escherichia coli, constitute the most frequent etiological agents of nosocomial (hospital-acquired) diseases, such as septicemia, endocarditis, and infections of wounds and the urinary tract. S. aureus is currently the most frequent cause of nosocomial bacteremia and skin or wound infection. Streptococcus pneumoniae causes several serious and life-threatening diseases, including a contagious meningitis, bacteremia, and otitis media. Annual mortality from S. pneumoniae infection alone is estimated at between 3-5 million persons globally. More recently, clinical accounts of highly aggressive skin and tissue infections by "flesh-eating" strains of Group A streptococcus bacteria, such as Streptococcus
pyogenes, has heightened the concern and need for new or improved antibacterial agents.
Recently, a group of organic compounds has been described which are structural analogs of deoxynucleotides, such as N.sup.3 -substituted uracil and isocytosine and 9-substituted guanine and adenine compounds. Such compounds have been classified as "HPUra" (for "6-(p- hydroxyphenylazo)uracil)-like class of anti- microbial compounds or the 6-anilinouracil ("AU") family of compounds, which are non-traditional antibiotics in that they specifically bind and inhibit the bacterial DNA polymerase IIIC ("Pol IIIC") that is required for DNA replication in the "low G-C" eubacteria, which include mycoplasmas and the low G-C, Gram positive bacteria such as Streptococcus, Enterococcus, Staphylococcus, Bacillus, Clostridium, and Listeria (see, e.g., Wright et al., Curr. Opin. Anti- Infective Investig. Drugs, 1: 45-48 (1999); Tarantino et al., J. Med. Chem., 42: 2035-2040 (1999); U.S. Pat. No. 5,516,905). Accordingly, these compounds are antibiotics capable of inhibiting Gram positive bacteria and mycoplasmas (see, e.g., U.S. Pat. No. 5,516,905).
Another approach to developing improved antibiotics has been the synthesis of hybrid molecules, such as the family of hybrid molecules consisting of a fluoroquinolone antibiotic molecule (see, e.g., Domagala et al., J. Med. Chem., 29: 394-404 (1986)) linked to a .beta.- lactam antibiotic molecule (see, e.g., Hamilton-Miller, J. Antimicrobial Chemotherapy, 33: 197-202 (1994)). Such hybrid molecules are "dual-action" antibiotics in that they offer the benefit of a fluoroquinolone component, which can inhibit bacterial type II topoisomerase (Topo II), and a .beta.-lactam component, such as cephalosporins and penicillins, which inhibit bacterial cell wall synthesis (see, e.g, Hamilton-Miller, J. Antimicrobial Chemotherapy, 33: 197-202 (1994)). The fluoroquinolone and .beta.-lactam components may be linked to one another via an ester linkage in a "pro-drug" form, which can undergo hydrolysis after administration to an individual (often catalyzed by esterase) to provide the two active component antibiotics. Alternatively, linkages less susceptible to spontaneous hydrolysis may be used to enhance the half-life of the hybrid molecule after administration. In this latter case, the fluoroquinolone active segment may be released in the presence of a .beta. -lactamase, such as produced by P-lactam resistant bacteria, or when the .beta.-lactam antibiotic is acylated during its mode of action (Id.).
A dual- action antibiotic directed against two different targets in a bacterial cell is an attractive strategy as the probability of the appearance of a resistant strain in a treated bacterial population should be quite low, i.e., equal to the product of the probabilities of occurrence of two, spontaneous and separate, resistant mutations in a single bacterial cell. The impact that currently available, hybrid antibiotics, such as the "cephaloquins" (or "quinocephs"), as described above, will have clinically remains to be determined. Moreover, as is well known, the search and development of a variety of antibiotics will continue to be necessary as it is unlikely that any one class of antibiotics will be effective against a sufficiently wide spectrum of bacteria as to treat all bacterial diseases or to be used in all patients. Thus, in addition to having an antimicrobial action against one or more clinically significant strains of bacterial pathogens, the successful development of any new and useful antibiotic depends not only on the frequency with which resistant strains may arise, but also on an understanding of such pharmaceutically and pharmacologically relevant properties as solubility, potency, patient toxicity, and the susceptibility of the antibiotic to degradation or clearance when administered to a patient by a particular route.
Clearly, needs remain for compounds that can serve as antibiotics against pathogenic bacterial species as well as for compounds that provide the structural foundation for developing future generations of new anti- microbial agents.
Despite advances in the field of cancer treatment the leading therapies to date are surgery, radiation and chemotherapy. Chemotherapeutic approaches are said to fight cancers that are metastasized or ones that are particularly aggressive. Such cytocidal or cytostatic agents work best on cancers with large growth factors, i.e., ones whose cells are rapidly dividing. To date, hormones, in particular estrogen, progesterone and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti-metabolites form the bulk of therapies available to oncologists. Ideally cytotoxic agents that have specificity for cancer and tumor cells while not affecting normal cells would be extremely desirable. Unfortunately, none have been found and instead agents which target especially rapidly dividing cells (both tumor and normal) have been used.
Clearly, the development of materials that would target tumor cells due to some unique specificity for them would be a breakthrough. Alternatively, materials that were cytotoxic to tumor cells while exerting mild effects on normal cells would be desirable.
More specifically, it is an object of this invention to provide an anti-cancer composition comprising a pharmaceutical carrier and a quinolone or aza-quinolone along with a method for treating such cancers. These and other objects will become evident from the following detailed description of this invention.
Summary of the Embodiments
The invention provides a new family of molecules, which are heterocyclic compounds that have antibacterial activity against pathogenic bacterial strains and/or that provide a structural foundation (i.e., are parent molecules) for developing additional new anti-cancer and
antibacterial agents.
The present invention is directed to compounds of general formula (1),
their derivatives, analogs, stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them, which may be useful in the treatment of a variety of diseases.
The present invention further addresses methods of using compounds of formula (I) to treat asthma, chronic and acute inflammatory disease, allergic responses, vascular inflammatory disease, bronchitis, emphysema, chronic obstructive pulmonary disease, atherosclerosis, arthritis, cellular proliferative disorders and other diseases involving dysregulation of cell proliferation or
apoptosis, cancer, neurodegenerative diseases, behavioral and psychological symptoms of dementia such as Alzheimer's disease, and other related diseases.
Another aspect of the present invention provides methods of preparing compounds of formula (1), as defined above, and their derivatives, analogs, stereoisomers, pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
An aspect of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (1), as described above, and their derivatives, analogs, stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and mixtures in combination with suitable carriers, solvents, diluents, binders, coloring agents and other media normally employed in preparing such pharmaceutical compositions.
Another aspect of the present invention relates to preparation of libraries of compounds of formula (1).
Yet another aspect of the present invention is directed to compounds of formula (1), which have use in the treatment of pathological conditions.
The present invention is in the field of medicinal chemistry and relates to novel compound, quinolones of the formula (I), their derivatives, analogs, stereoisomers, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and pharmaceutical compositions containing them. The present invention further relates to methods of using compounds of formula (I) and derivatives thereof for the treatment of cancer.
(I)
In the structure above,
Ri, R2, R4 and X may be the same or different and independently represent hydrogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxyalkyl, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, alkylamino, monoalkylamino, dialkylamino, amino alkyl, aralkyl, aralkoxy, alkenyl, alkenyloxy,
cycloalkenyloxy, alkynyl, aroyl, aralkenyl, aralkynyl, aroyloxy, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroarylcarbonyl, silylalkyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives;
R3 represents hydrogen, or
Z represents, oxygen, sulfur or nitrogen;
" " represents a bond or no bond;
R5 and R6 may be the same or different and independently represent hydrogen, hydroxy, nitro, cyano, amino, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxyalkyl, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, alkylamino, monoalkylamino, dialkylamino, aminoalkyl, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, alkynyl, aroyl, aralkenyl, aralkynyl, aroyloxy, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroarylcarbonyl, silylalkyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives; R5 and R6 together with X, and optionally other atoms, may form a 3 to 7 membered cyclic ring optionally containing one or more hetero atoms selected from oxygen, nitrogen or sulfur, wherein said rings may be substituted.
The substituents on Ri, R2, R4, R5, R6 and cyclic rings formed with R5 and R6 may be selected from hydrogen, halogen, hydroxy, nitro, cyano, amino, oxo (=0), thioxo(=S), substituted or unsubstituted groups selected from alkyl, haloalkyl, cycloalkyl, alkoxy, cycloalkoxy, acyl, acyloxy, aryl, aryloxy, alkylthio, arylthio, aminoalkyl, alkylamino, monoalkylamino, dialkylamino, aralkyl, nitroaralkyl, aralkoxy, alkenyl, alkenyloxy, aroyl, aroyloxy, heteroaryl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, carboxylic acid or its derivatives, or sulfonic acid or its derivatives.
The aryl or alkyl groups of substituents of Ri, R2, R4, Rs, R6 and cyclic rings formed by R5 and R6 may be optionally substituted with halogen, nitro, alkyl, alkoxy, hydroxyl or amino groups. A and W represent carbon, substituted carbon, nitrogen etc.
Y represents
" " represents a bond or no bond;
Wherever substitutions are possible on the above described groups, the substituents may be the same or different and substitution may take place one to three times on said groups.
Detailed Description of the Embodiments
A. The Anti-cancer Compounds
It is to be understood that this invention is not limited to methodology, protocol or reagents described herein. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments and should not be construed as limiting.
The present invention relates to compounds of general formula (I)
(I)
where the detailed descriptions of the symbols are as follows:
"Aryl" represents an optionally substituted monocyclic or polycyclic aromatic ring such as phenyl, naphthyl and the like, or optionally substituted 5 or 6 membered heteroaromatic rings
containing one or more heteroatoms such as nitrogen, oxygen or sulfur. The heteroaromatic ring may form part of a fused, bicyclic ring. Examples of heteroaromatic rings include:
where Zi represents NH, oxygen, or sulfur. Yi, Y2, Y3, Y4 may be the same or different and independently represent nitrogen, oxygen, sulfur or carbon.
For purposes of the present invention, 'halogen' represents fluorine, chlorine, bromine or iodine;
For purposes of the present invention, 'haloalkyl' represents fluoromethyl, chloromethyl, fluoroethyl, trifluoromethyl and the like.
For purposes of the present invention, an 'alkyl' group is a linear or branched Ci-Cio group including: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, iso-pentyl, hexyl, heptyl, octyl and the like.
Exemplary aminoalkyl groups include, amino (Ci-Cio) alkyl: aminomethyl, aminoethyl, aminopropyl, amino butyl and the like.
Exemplary alkylamino groups include, (Ci-Cio) alkyl amino: methylamino, ethylamino, propylamino and the like.
Exemplary mo no alkylamino groups include (Ci-Cio): methylamino, ethylamino, propylamino, isopropylamino and the like.
Exemplary dialkylamino groups include (Ci-Cio): dimethylamino, diethylamino and the like.
Exemplary alkylthio groups include (Ci-Cio): methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio and the like.
Exemplary arylthio groups include: phenylthio, naphthylthio and the like.
Exemplary alkylcarbonyl groups include, optionally substituted (Ci-Cio): methylcarbonyl, ethyl carbonyl, isopropylcarbonyl and the like.
Exemplary alkoxycarbonyl groups include, optionally substituted (Ci-Cio): methoxycarbonyl, ethoxycarbonyl and the like.
Exemplary arylcarbonyl groups include, optionally substituted: phenylcarbonyl,
naphthylcarbonyl and the like.
Exemplary aryloxycarbonyl groups include: phenoxycarbonyl, naphthyloxycarbonyl and the like.
Exemplary aralkoxycarbonyl groups include (Ci-C6): benzyloxycarbonyl, 2- phenethyloxycarbonyl and the like.
Exemplary heteroarylcarbonyl groups include: pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl and the like.
Exemplary silylalkyl groups include optionally substituted (Ci-C6): silylmethyl, silylethyl, silylpropyl, silylisopropyl, silylbutyl, silylisobutyl and the like.
Exemplary cycloalkyl groups include (C3-C7): cyclopropyl, eye lo butyl, eyelopentyl, eyelohexyl, cycloheptyl, cyclooctyl and the like.
Exemplary alkoxy groups include (Ci-Cio): methoxy, ethoxy, propoxy, butoxy, iso-propoxy, iso-butoxy and the like.
Exemplary cycloalkoxy groups include (C3-C6): cyclopropoxy, eye lo butoxy, cyclopentoxy, cyclohexoxy and the like.
Exemplary alkenyl groups include (C2-C6): ethenyl, propenyl, prop-l-enyl, isopropenyl, butenyl, but-l-enyl, isobutenyl, pentenyl, pent-l-enyl, hexenyl, pent-2-enyl, 2-methyl-but-2-ene, 2-methyl-pent-2-enyl and the like.
Exemplary alkynyl groups include (C3-C10): ethenyl, propynyl, prop-l-ynyl, butynyl, but-1- ynyl and the like.
Exemplary cycloalkenyl groups include (C3-C7): cyclopropenyl, eye lo butenyl, cyclopentenyl, cyclohexenyl and the like.
Exemplary alkoxyalkyl groups include (Ci-C6)alkoxy(Ci-Oo)alkyl: methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, isopropoxymethyl isopropoxyethyl, isopropoxypropyl, t-butoxymethyl, t-butoxymethyl, t-butoxypropyl, and the like.
Exemplary alkenyloxy groups include, (C2-C6)alkenyl-0-: ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy and the like.
Exemplary cycloalkenyloxy' groups include, (C3-C7)cycloalkenyl-0: cycloethenyloxy, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy and the like.
Exemplary acyl groups include (Ci-Cio): formyl, acetyl, propionyl, and the like.
Exemplary acyloxy groups include (O-C6)acyl-0-: acetyloxy, propionyloxy, and the like.
Exemplary aryloxy groups include: phenoxy, naphthyloxy and the like.
Exemplary aroyl groups include aryl-CO-: benzoyl, 1-naphthoyl and the like.
Exemplary aroyloxy groups include, aroyl-O-: benzoyloxy, 1-naphthoyloxy and the like.
Exemplary aralkyl groups include, aryl-(Ci-Cio)alkyl: benzyl, ethylphenyl, propylphenyl, butylphenyl, propyl2-phenylethyl and the like.
For purposes of the present invention, aralkenyl' is a aryl-(C2-C6)alkenyl group, wherein aryl and (C2-C6)alkenyl groups are as defined above.
For purposes of the present invention, aralkynyl' is a aryl-(C2-C6)alkynyl group, wherein the aryl and (C2-C6)alkynyl groups are as defined above.
Exemplary 'aralkoxy' groups, aralkyl-O-, include benzyloxy, 2-phenethyloxy and the like. 'Heterocyclyl' is a non-aromatic saturated monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one hetero atom selected from O, S or N. Exemplary heterocyclyl groups include aziridinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl and the like.
'Heterocyclylalkyl' is a non-aromatic saturated monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms having at least one hetero atom selected from O, S or N, attached to an (Ci-Cio)alkyl group, where heterocyclyl and (Ci-Oo)alkyl groups are as defined above.
Exemplary heterocyclylalkyl groups include N-methylpiperidinyl, N-ethylpiperidinyl, N- propylpiperidinyl, N-methylpyrrolidinyl, N-ethylpyrrolidinyl, N-propylpyrrolidinyl and the like. For purposes of the present invention, 'heteroaryl' is an aromatic monocyclic or polycyclic ring system of about 5 to about 10 carbon atoms, having at least one heteroatom selected from O, S or N. Exemplary heteroaryl groups include pyrazinyl, isothiazolyl, oxazolyl, pyrazolyl, pyrrolyl, pyridazinyl, thienopyrimidyl, furanyl, indolyl, isoindolyl, benzo[l,3]dioxolyl, 1,3- benzoxathiole, quinazolinyl, pyridyl, thiophenyl and the like.
For purposes of the present invention, 'heteroaralkyl' is a heteroaryl-(Ci-Cio)alkyl group, wherein the heteroaryl and (Ci-Oo)alkyl groups are as defined above. Exemplary heteroaralkyl groups include pyrrolylmethyl, pyrrolylethtyl, pyrrolylpropyl, furanylmethyl, furanylethyl, furanylpropyl, furanylbutyl, indolylmethyl, indolylethyl, indolylpropyl, indolylbutyl,
benzo[l,3]dioxolylmethyl, benzo[l,3]dioxolylethyl, benzo[l,3]dioxolylpropyl,
benzo[l,3]dioxolylbutyl, thiophenylmethyl, thiophenylethyl, thiophenylpropyl, thiophenyl and the like.
Exemplary 'heteroaryloxy' groups, heteroaryl-O-, include: pyrazinyloxy, isothiazolyloxy, oxazolyloxy, pyrazolyloxy, phthalazinyloxy, indolyloxy, quinazolinyloxy, pyridyloxy, thienyloxy and the like.
Exemplary 'heteroaralkoxy' groups, heteroaralkyl-O-, include: thienylmethyloxy, pyridylmethyloxy and the like.
Exemplary 'alkylcarbonyl' or 'acyl' groups, (Ci-Cio)alkyl-CO-, include: methylcarbonyl, ethylcarbonyl, propylcarbonyl and the like.
Exemplary 'alkoxycarbonyl' groups include: (Ci-Cio)alkyl-O-CO-, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and the like.
Exemplary 'arylcarbonyl' or 'aroyl' groups, aryl-CO-, include: phenylcarbonyl,
naphthylcarbonyl and the like.
Exemplary 'aryloxycarbonyl' groups, aryl-O-CO-, include: phenoxycarbonyl,
naphthyloxycarbonyl and the like.
Exemplary 'aralkoxycarbonyl' groups, aryl-(Ci-C6)alkoxy-CO-, include: benzyloxycarbonyl, 2-phenethyloxycarbonyl and the like.
Exemplary 'heteroarylcarbonyl' groups, heteroaryl-CO-, include: pyrazinylcarbonyl, isothiazolylcarbonyl, oxazolylcarbonyl, pyrazolylcarbonyl, pyrrolylcarbonyl,
pyridazinylcarbonyl, indolylcarbonyl and the like.
For purposes of the present invention, 'carboxylic acid or its derivatives' may be acids, amides or esters. Exemplary carboxylic acid groups include COOH, CONH2, CONHMe, CONMe2, CONHEt, CONEt2, CONHPh, COOCH3, COOC2H5, COOC3H7, and the like.
For purposes of the present invention, 'sulfonic acid or its derivatives' may be amides or esters. Exemplary sulfonic acid groups include SO2NH2, S02NHMe, S02NMe2, S02NHCF3, SOOCH3, SOOC2H5, SOOC3H7, and the like.
Accordingly, one embodiment of the present invention provides a process for the preparation of compounds of general formula (1) according to Scheme I below:
Scheme I
1a
Where R4 = Cyclopropyl or Et; A = N or C; X = H or none; W = CH or N
L = CI or other leaving group or none
R5 = H or CH3 la is converted to I. The solvent used in the reaction may be selected from aromatic solvents such as benzene, toluene, xylene and the like. The temperature of the reaction may be in the range of room temperature (25-40 °C) to 120 °C. The duration of the reaction may be in the range of 0 to 24 hours, preferably 10 to 14 hours.
10 Representative compounds and their derivatives in accordance with the present invention are shown below but are not limited to those presented in Table 1:
Table 1:
Preferred derivatives include:
2A: l-cyclopropyl-6-fluoro-4-oxo-7-(4-(4-(pyridin-3-yl)pyrimidin-2-yl)piperazin-l-yl)-l,4- di ydroquinoline-3-carboxylic acid
2B: l-cyclopropyl-6-fluoro-4-oxo-7-(4-(4-(thiophen-2-yl)pyrimidin-2-yl)piperazin-l-yl)-l,4- di ydroquinoline-3-carboxylic acid
2C: l-ethyl-6-fluoro-4-oxo-7-(4-(4-(thiazol-2-yl)pyrimidin-2-yl)piperazin-l-yl)-l,4- di ydroquinoline-3-carboxylic acid
2D: l-cyclopropyl-6-fluoro-7-(5-fluoro-4-(imidazo[l,2-b]pyridazin-3-yl)pyrimidin-2- ylamino)-4-oxo- 1 ,4-dihydro- 1 ,8-naphthyridine-3-carboxylic acid
IE: l-cyclopropyl-6-fluoro-4-oxo-7-(4-(4-(pyrrolidin- l-yl)pyrimidin-2-yl)piperazin- 1-yl)- l,4-di ydroquinoline-3-carboxylic acid
2F: l-cyclopropyl-6-fluoro-4-oxo-7-(4-(4-(thiazol-2-yl)pyrimidin-2-yl)piperazin-l-yl)-l,4- di ydroquinoline-3-carboxylic acid
2G: l-cyclopropyl-6-fluoro-7-(4-(4-morpholinopyrimidin-2-yl)piperazin- l-yl)-4-oxo- 1,4- di ydroquinoline-3-carboxylic acid
2H: l-cyclopropyl-6-fluoro-7-(4-(4-(furan-2-yl)pyrimidin-2-yl)piperazin-l-yl)-4-oxo-l,4- di ydroquinoline-3-carboxylic acid
21: 7-(4-(4-(lH-imidazol-l-yl)pyrimidin-2-yl)piperazin-l-yl)-l-cyclopropyl-6-fluoro-4-oxo- 1 ,4-di ydroquinoline-3-carboxylic acid
2J: 7-(4-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)piperazin- 1-yl)- l-cyclopropyl-6-fluoro-4- oxo-l,4-di ydro-l,8-naphthyridine-3-carboxylic acid
2L: l-cyclopropyl-6-fluoro-4-oxo-7-(4-(thiazol-2-yl)piperazin- 1-yl)- 1,4-di ydro- 1,8- naphthyridine-3-carboxylic acid
2M: l-cyclopropyl-6-fluoro-4-oxo-7-(4-(l-oxo-l-(4-(pyridin-3-yl)pyrimidin-2- ylamino)propan-2-yl)piperazin- 1-yl)- l,4-di ydroquinoline-3-carboxy lie acid
2N: l-cyclopropyl-6-fluoro-4-oxo-7-(4-(4-(thiazol-2-yl)pyrimidin-2-yl)piperazin- 1-yl)- 1,4- dihydro- 1 ,8-naphthyridine-3-carboxylic acid
2T: 7-(4-(4-butylpyrimidin-2-yl)piperazin- 1-yl)- 1 -eye lopropyl-6-f uoro-4-oxo- 1,4- dihydroquinoline-3-carboxylic acid
2U: l-cyclopropyl-6-fluoro-7-(4-(4-(4-(l-methyl-lH-pyrazol-4-yl)thiazol-2-yl)pyrimidin-2- yl)piperazin-l-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid
2V: methyl 7-(4-((3s,5s,7s)-adamantan-l-ylcarbamoyl)piperazin-l-yl)-l-cyclopropyl-6- fluoro-4-oxo- 1 ,4-dihydroquinoline-3-carboxylate
Accordingly, one embodiment of the present invention provides a process for the preparation of compounds of general formula (I) according to Scheme II below:
Scheme II
1 b
L = CI or other leaving group or none
W = CH or N
la is converted to Id by reaction with lc. The solvent used in the reaction may be selected from aromatic solvents such as benzene, toluene, xylene and the like. The temperature of the reaction may be in the range of room temperature (25-40 °C) to 120 °C. The duration of the reaction may be in the range of 0 to 24 hours, preferably 10 to 14 hours.
Id is converted to le, where "Y" represents a leaving group such as halogen, toloylsulfonyloxy, or methanesulfonyloxy, by reaction with a halogenating agent such as N-bromosuccinimide, benzoyl peroxide, l,3-dibromo-5,5-dimethylhydantoin and the like. Solvent used in the reaction may be selected from carbon tetrachloride, dichloromethane, chloroform, tetrahydrofuran and the like. The temperature of the reaction may be in the range of room temperature (25-40 °C) to 100 °C. The duration of the reaction may be in the range of 2 to 24 hours, preferably 5 to 10 hours, le is converted to 1 by reaction with If, in the presence or absence of a base such as potassium carbonate, sodium carbonate, sodium hydride and the like. Solvent used in the reaction may be selected from tetrahydrofuran, Ν,Ν-dimethylformamide, dimethylacetamide, acetone and the like. The temperature of the reaction may be in the range of room temperature (25-40 °C) to 120 °C. The duration of the reaction may be in the range of 2 to 24 hours, preferably 1 to 3 hours. Representative compounds and their derivatives in accordance with the present invention are shown below but are not limited to those presented in Table 2:
Table 2:
Preferred derivatives include:
3B: 9-fluoro-3-methyl-7-oxo- 10-(4-(4-(thiazol-2-yl)pyrimidin-2-yl)piperazin- l-yl)-3,7-dihydro- 2H-[l,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid
According to another aspect of the present invention, a library of compounds was prepared as per Scheme III to afford compounds of formula (I).
Scheme III
where R independently represent hydrogen, optionally substituted groups selected from alkyl, cycloalkyl, alkoxy, cycloalkoxy, alkoxyalkyl, aryl, aryloxy, alkylthio, arylthio, alkylamino, monoalkylamino, dialkylamino, aminoalkyl, aralkyl, aralkoxy, alkenyl, alkenyloxy, cycloalkenyloxy, alkynyl, aroyl, aralkenyl, aralkynyl, aroyloxy, heteroaryl, heterocyclyl,
heterocyclylalkyl, heterocyclylalkyl, heteroaryloxy, heteroaralkyl, heteroaralkoxy, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heteroarylcarbonyl, silylalkyl, carboxylic acid or its derivatives, or sulfonic acids or its derivatives. "Aryl" (C ring) represents an optionally substituted monocyclic or polycyclic aromatic ring such as phenyl, naphthyl and the like, or optionally substituted 5 or 6 membered heteroaromatic rings containing one or more heteroatoms such as nitrogen, oxygen or sulfur. The heteroaromatic ring may form part of a fused, bicyclic ring. Examples of heteroaromatic rings include:
Representative compounds and their derivatives in accordance with the present invention are shown below but are not limited to those presented in Table 3:
Table 3:
Preferred derivatives include:
5A: ethyl l-cyclopropyl-6-fluoro-4-oxo-7-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-l,4- dihydro- 1 ,8-naphthyridine-3-carboxylate
5B: l-cyclopropyl-6-fluoro-4-oxo-7-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-l,4- dihydroquinoline-3-carboxylic acid
5C: l-cyclopropyl-6-fluoro-3-(4-methylpiperazine-l-carbonyl)-7-(4-(pyridin-3-yl)pyrimidin- 2-ylamino)quinolin-4(lH)-one
Another embodiment of the present invention provides a process for the preparation of compounds of formula (1) where R3 represents -OR7.
Scheme IV
or N
le is converted to I by reaction with lg, where "L" represents a leaving group such as halogen, toloylsulfonyloxy or methanesulfonyloxy, in the presence or absence of a base such as potassium carbonate, sodium carbonate, sodium hydride and the like. Solvent used in the reaction may be selected from tetrahydrofuran, Ν,Ν-dimethylformamide, dimethylacetamide, acetone and the like. The temperature of the reaction may be in the range of room temperature (25-40 °C) to 120 °C. The duration of the reaction may be in the range of 2 to 24 hours, preferably 1 to 3 hours. According to another aspect of the present invention, a library of compounds was prepared as per Scheme IV to afford compounds of formula (1) where R4 = no atom, R3 =OR7, R2 = H, and Ri= H. The design of the compound library was based primarily on structure (5). Various substitutions were made at the hydroxy site of (4), by reaction with R7-L, where L is a leaving group such as halogen, methylsulfonyloxy, tolylsulfonyloxy and the like.
Preferred derivatives include:
6: (R)-2-amino-3-methylbutyl l-cyclopropyl-6-fluoro-4-oxo-7-(4-(4-(thiazol-2- yl)pyrimidin-2-yl)piperazin- l-yl)-l,4-dihydroquinoline-3-carboxylate
5 7: l-cyclopropyl-6-fluoro-7-(4-(4-(thiazol-2-yl)pyrimidin-2-yl)piperazin- l-yl)quinolin-
4(lH)-one
8: methyl l-cyclopropyl-6-fluoro-4-oxo-7-(4-(4-(thiazol-2-yl)pyrimidin-2-yl)piperazin-l- yl)- l,4-dihydroquinoline-3-carboxylate
9: l-cyclopropyl-3-(3 -difluoroazetidine- l-carbonyl)-6-fluoro-7-(4-(4-(thiazol-2- 10 yl)pyrimidin-2-yl)piperazin- l-yl)quinolin-4(lH)-one
10: (E)-N-(l-cyclopropyl-6-fluoro-4-oxo-7-(4-(4-(thiazol-2-yl)pyrimidin-2-yl)piperazin-l- yl)- l,4-dmydroquinolin-3-yl)-4-(dimethylamino)but-2-enamide
[0032] Pharmaceutically acceptable addition salts of quinazolone derivatives are considered 15 within the scope of compounds of the present invention and are salts with an organic or inorganic acid. Preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates,
sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, or the like. Such salts may be synthesized from the compound, or derivative thereof, of the present invention that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting a free acid or base form of the compound, or derivative thereof, with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Further suitable salts may be found in
Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing Company, Easton, Pa., 1995, p. 1457.
[0033] Pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts or the quaternary ammonium salts of the compounds or derivatives formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, or the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, or the like. Preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, or the like.
[0034] Further, included within the scope of the compound, or salts thereof, useful for the present invention are prodrugs. As used herein, a "prodrug" is a drug covalently bonded to a carrier wherein release of the drug occurs in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present invention are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the desired compound. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, is cleaved to form a free hydro xyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of alcohol or amine functional groups in the compounds of the
present invention; phosphate esters, dimethylglycine esters, amino alky lbenzyl esters, aminoalkyl esters or carboxyalkyl esters of alcohol or phenol functional groups in the compounds of the present invention; or the like. [0035] It is believed that these particular materials have the capability of reducing tumors or decreasing their growth significantly because of their ability to inhibit the synthesis of sterols.
[0036] C. Screening Assays [0037] Screening assays for determining those cancers susceptible to treatment using compounds of the present invention include incubating cell line models representing specific cancers as set forth, for example, by the National Cancer Institute, in the presence and absence of such compounds. Viability of cells may be determined by the MTT assay (Promega Corp., Madison, Wis. 53711), or the SRB (sulforhodamine B) assay (Skehan, et al., JNCI, 82: 13,1107,1990). Susceptibility to said compounds exists when viability in the presence of a compound of the present invention is less than viability in the absence of such compound.
[0038] Exemplary cell line models representing specific cancers include, but are not limited to, the following:
[0044] Leukemia: P388, P3888/ADR, CCRFCEM, CCRFSB, K562, MOLT4, L1210,
HL60(TB), RPM18226, SR, or K562/ADR;
Non-small cell lung cancer: A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-, NCI-H522, H460
[0041] Colon cancer: HT29, HCC2998, HCT116, LOVO, SW1116, SW-620, COLO 205,
DLDl, WIDR, COLO 320DM, HCT116, CXF 280, KM 12, KM20L2, COLO 741, CXF 264L,
COLO 746, UABC02, MLI059, CAC02, HT29/PAR, HT29/MDR1, HCT-15, or NB4;
Breast cancer: MCF7, MCF7/ADRRES, ZR751, ZR7530, MDAMB231/ATCC, HS 578T, UISOBCA1, MCF7/ATCC, SKBR3, MDAMB435, MDAN, BT549, T47D, MDAMB231, MAXF 401, BT474, or MDAMB468;
[0043] Ovarian cancer: OVCAR3, OVCAR4, OVCAR5, OVCAR8, A2780, IGROV1,
NCI/ ADR- RES, SKOV3, OVXF 899, A1336, or ES2;
[0045] Fibroblast: IMR90, or CCD19LU;
[0046] Renal cancer: U031, SN12C, SN12S 1, SN12K1, SN12L1, SN12A1, A498, A704, CAKI1, RXF 393, RXF631, 7860, SW156, TK164, 769P, SS78, ACHN, TK10, RXF 486L, UOK57, or UOK57LN;
[0047] Melanoma: LOX IMVI, MALME3M, RPM17951, SKMEL2, SKMEL5, SKMEL28, SKMEL31, UCSD 242L, UCSD 354L, M14, M19MEL, UACC62, UACC257, MDA-MB-435 , MEXF 514L, or UABMEL3;
[0048] Prostate cancer: PC3, PC3M, DU145, LNCAP, 1013L, UMSCP1, WIS, JE, RER, MRM, DHM, AG, RB, RVP, FC, WAE, DB/SMC, JCA1, ND1, WMF, TSUPR1, JECA, GDP, T10, WBW, RVPl, or WLL;
[0049] CNS cancer: SNB7, SNB19, SNB44, SNB56, SNB75, SNB78, U251, TE671, SF268, SF295, SF539, XF 498, SW 1088, SW 1783, U87 MG, SF767, SF763, A172, or SMSKCNY;.
[0050] Bone/muscle: A204/ATCC, OHS, TE85, A673, CHA59, MHM 25, RH18, RH30, or RD; and
[0051] Lymphoma: AS283, HT, KD488, PA682, SUDHL7, RL, DB, SUDHL1, SUDHL4, SUDHL10, NUDUL1, or HUT 102.
[0052] D. Dosage
[0053] Any suitable dosage may be administered in the methods of the present invention. The compound or salt thereof chosen for a particular application, the carrier and the amount will vary widely depending on the species of the warm blooded animal or human, the type of cancer, or the particular viral infection being treated, and depending upon the effective inhibitory concentrations observed in trial studies. The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular compound, salt, or combination and its mode and route of administration; the age, health, or weight of the
subject; the nature and extent of symptoms; the metabolic characteristics of the drug and patient, the kind of concurrent treatment; the frequency of treatment; or the effect desired.
[0054] Generally a dosage of as little as about 1-2 milligram (mg) per kilogram (kg) of body weight is suitable, but preferably as little as 10 mg/kg and up to about 10,000 mg/kg may be used. Preferably, a dosage from 15 mg/kg to about 5000 mg/kg is used. Most preferably, the dose is between 150 mg/kg to about 1000 mg/kg. Doses useful in the treatment of cancer or viral infections are 250 mg/kg, 500 mg/kg, 800 mg/kg, 1000 mg/kg, 1500 mg/kg, 2500 mg/kg, 3500 mg/kg, 4000 mg/kg, 5000 mg/kg, or 6000 mg/kg. Any range of doses can be used. Generally, a compound, salt thereof or combination of the present invention can be administered on a daily basis one or more times a day, or one to four times a week either in a single dose or separate doses during the day. Twice weekly dosing over a period of at least several weeks is preferred, and often dosing will be continued over extended periods of time and possible for the lifetime of the patient. However, the dosage and the dosage regimen will vary depending on the ability of the patient to sustain the desired and effective plasma levels of the compounds of the present invention, or salt thereof, in the blood.
[0055] The compound, salt thereof, or combination, may be micronized or powdered so that it is more easily dispersed and solubilized by the body. Processes for grinding or pulverizing drugs are well known in the art. For example, a hammer mill or similar milling device can be used. The preferred particle size is less than about lOO.mu. and preferably less than 50. mu..
[0056] Intravenously, the most preferred doses may range from about 1 to about 10
mg/kg/minute during a constant rate infusion.
[0057] The compounds and salts thereof of the present invention are generally safe. The
LD.sub.50 is high, about 1500 mg/kg given orally in mice and there are no special handling requirements.
[0058] The compounds and salts thereof of the present invention may be administered in a unit dosage form which may be prepared by any methods known to one of skill in the art in light of the present disclosure. Unit dosages may include from 1 milligram to 1000 milligrams of active ingredient. Preferably the dosage unit will contain from about 10 mg to about 500 mg active ingredient. The active ingredient is generally present in an amount of about 0.5% to about 95% by weight based on the total weight of the dosage unit.
[0059] For intravenous use, preferred dosages may range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
[0060] A dosage unit may comprise a single compound, or mixtures thereof, with other compounds or other cancer- or viral-inhibiting compounds. The dosage unit may comprise diluents, extenders, carriers, liposomes, or the like. The unit may be in solid or gel form such as pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, intravenous injection or parenteral administration or injection into or around the treatment site.
[0061] E. Dosage Delivery Forms
[0062] The compounds of the present invention are typically mixed with a pharmaceutically acceptable carrier. A "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle for delivering a compound of the present invention to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of
administration in mind. A "pharmaceutically acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
[0063] Oral formulations suitable for use in the practice of the present invention include capsules, gels, cachets, tablets, effervescent or non-effervescent powders or tablets, powders or granules; as a solution or suspension in aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion. The compounds of the present invention may also be presented as a bolus, electuary, or paste.
[0064] Generally, formulations are prepared by uniformly mixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. A pharmaceutical carrier is selected on the basis of the chosen route of administration and standard pharmaceutical practice. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. This carrier can be a solid or liquid and the type is generally chosen based on the type of
administration being used. Examples of suitable solid carriers include lactose, sucrose, gelatin, agar and bulk powders. Examples of suitable liquid carriers include water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions, and solution and or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent
granules. Such liquid carriers may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Preferred carriers are edible oils, for example, corn or canola oils. Polyethylene glycols, e.g. PEG, are also preferred carriers.
[0065] The formulations for oral administration may comprise a non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, cyclodextrin, cyclodextrin derivatives, or the like.
[0066] Capsule or tablets can be easily formulated and can be made easy to swallow or chew. Tablets may contain suitable carriers, binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, or melting agents. A tablet may be made by compression or molding, optionally with one or more additional ingredients. Compressed tables may be prepared by compressing the active ingredient in a free flowing form (e.g., powder, granules) optionally mixed with a binder (e.g., gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked
carboxymethyl cellulose) surface- active or dispersing agent. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, or the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, or the like. Disintegrators include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, or the like. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
[0067] The tablets may optionally be coated or scored and may be formulated so as to provide slow- or controlled-release of the active ingredient. Tablets may also optionally be provided with an enteric coating to provide release in parts of the gut other than the stomach.
[0068] Exemplary pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U.S. Pat. No. 3,903,297 to Robert, issued Sep. 2, 1975, incorporated by reference herein. Techniques and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al.,
Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).
[0069] Formulations suitable for topical administration in the mouth wherein the active ingredient is dissolved or suspended in a suitable carrier include lozenges which may comprise the active ingredient in a flavored carrier, usually sucrose and acacia or tragacanth; gelatin, glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
[0070] Topical applications for administration according to the method of the present invention include ointments, cream, suspensions, lotions, powder, solutions, pastes, gels, spray, aerosol or oil. Alternately, a formulation may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
[0071] The topical formulations may desirably include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
[0072] The oil phase of an emulsion used to treat subjects in the present invention may be constituted from ingredients known to one of skill in the art in light of the present disclosure. An emulsion may comprise one or more emulsifiers. For example, an oily phase may comprise at least one emulsifier with a fat or an oil, with both a fat and an oil, or a hydrophilic emulsifier may be included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier(s), with or without stabilizer(s), make up an emulsifying wax, and the wax together with the oil and/or fat make up the emulsifying ointment base that forms the oily dispersed phase of the cream formulations.
[0073] Emulsifiers and emulsion stabilizers suitable for use in the formulation include Tween 60, Span 80, cetosteryl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate, paraffin, straight or branched chain, mono-or dibasic alkyl esters, mineral oil. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, the properties required and compatibility with the active ingredient.
[0074] Compounds of the present invention may also be administered vaginally, for example, as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing appropriate
carriers in addition to the active ingredient. Such carriers are known in the art in light of the present disclosure.
[0075] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
[0076] Formulations suitable for nasal administration may be administered in a liquid form, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer, including aqueous or oily solutions of the active ingredient. Formulations for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, of less than about 100 microns, preferably less than about 50 microns, which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
[0077] Formulations suitable for parenteral administration include aqueous and non-aqueous formulations isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending systems designed to target the compound to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules or vials. Extemporaneous injections solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
[0078] In general, water, a suitable oil, saline, aqueous dextrose (glucose), or related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, buffer substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid salts thereof, or sodium EDTA. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, or chlorobutanol. Suitable pharmaceutical carriers are described in Remington, cited supra.
[0079] The present invention additionally contemplates administering compounds of the herein described invention for use in the form of veterinary formulations, which may be prepared, for example, by methods that are conventional in the art in light of the present disclosure.
[0080] Useful pharmaceutical dosage formulations for administration of the compounds of the present invention are illustrated as follows:
[0081] Capsules: A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
[0082] Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.
[0083] Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings can be applied to increase palatability or delay absorption.
[0084] Injectable: A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
[0085] Suspension: An aqueous suspension is prepared for oral administration so that each 5 ml contains 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 ml of vanillin.
[0086] Compounds of the present invention may be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
[0087] Compounds of the present invention may be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer,
polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
[0088] F. Method of Treatment
[0089] The method of treatment can be any suitable method which is effective in the treatment of the particular cancer or viral infection that is being treated. Treatment includes administering a therapeutically effective amount of the compounds of the present invention in a form described herein above, to a subject in need of treatment.
[0090] Compounds of the present invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body, for example, suitable means including, but not limited to, oral, rectal, nasal, topical (including transdermal, aerosol, buccal or sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous or intradermal), intravesical, or injection into or around the cancer or site of viral infection. They can be administered by any conventional means available for use in conjunction with
pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutics. Preferably, compounds of the present invention are administered as a pharmaceutical formulation comprising at least one compound of the present invention, as defined above, together with one or more pharmaceutically acceptable carriers. It can be co- administered in the form of a tablet or capsule, as an agglomerated powder or in a liquid form or as a liposome.
[0091] The preferred route will vary with the condition and age of the recipient, virus or cancer being treated nature of the disorder, or severity of disorder. It is believed that oral administration, or parenteral treatment is the preferred method of administering the compounds to subjects in need thereof.
[0092] In each of the above-described methods, the administering may be in vivo, or may be ex vivo. In vivo treatment is useful for treating diseases in a mammal, preferably the mammal is a human; and ex vivo treatment is useful for purging body fluids, such as blood, plasma, bone marrow, and the like, for return to the body. The nation's blood supply is currently tested for antibodies to HIV. However, the test is still imperfect and samples that yield negative tests can still contain HIV virus. Treating blood and blood products with the compounds of the present invention can add an extra margin of safety to kill any retrovirus that may have gone undetected. Body tissue may be internal or external to an animal body, or, for example, may be the surface skin of the animal.
[0093] Treatment with a quinolone compound, formulated with an appropriate carrier, and an additional cancer or viral inhibiting compound or compounds or diluent to facilitate application is another embodiment of the method of administering the compounds to warm blooded animals.
[0094] G. Pharmaceutical Kits
[0095] The present invention also includes pharmaceutical kits useful, for example, for the treatment of cancer or viral infection, that comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more
pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
[0096] H. Study of Efficacy of CBI333 and analogs of using NCIH460 Xeniograft model
Tween
80 in
saline
15mg/mL
in 1%
10 QD x
CBI265 Tween SC 150mg/Kg/day 5
mL/Kg >14days
80 in
saline
Twice
5mg/mL 10
CBI 429 IV 50mg/Kg/day weekly x 5
in saline mL/Kg
>14days
A suspension of the compound in 1% Tween 80 in saline (1.5 mL per day per group) should ve prepared fresh each day of dosing using vortexing to created a fine suspension. Asolution of the compound in saline (1.5 mL/day) should be pareared fresh each day of dosing using vortexing to ensure the material is completely dissolved.
[009] Cell preparation Procedure:
NCI-H460 cells was grown and harvested at Toxicon. Animals were inoculated with cells (5 x 106) per animal, tumors were measured after ~2 weeks, once the established tumor reach a mean of calculated weight of at least 100 -200 mg or more, the animals were randomized into 6 group. Animals were treated as described in Table. Following treatment, tumors and the mouse body weight measurement were recorded twice weekly and gross clinical observation was made daily. Animals with tumors that are not palable was considered complete regression. Animals were observed once a day for clinical sign of toxicity. After completion of dosing, the animals were observed for two or more weeks to see re-grown of tumors.
[0097] Dose administration.
The dose administration procedure is described in Table. A sterile disposable polypropylene syringe fitted with the largest bore (smallest gauge) needle acceptable for dosing mice by the intended route of administration was used. [0097] Clinical Observations
Animals were observed for any adverse effects. An usual findings were recorded.
[0097] The following examples are illustrative and are not meant to be limiting to the invention.
[0098] The following examples are illustrative and are not meant to be limiting to the invention.
1) Compounds of Formula I, I A and IB:
Series I: Series IA:
Series IB:
and salts thereof, wherein:
Ri is selected from acid, ester, amide, substituted amide, nitrile, oxime, substituted or un- substituted akly sulfonyl
R is alkyl (n =1-6) or cycloalkyl e.g. cyclopropyl, substituted cycloalkyl, cyclic fused ring between N-R and A-X (eg NCH(CH3)CH2OC) etc
A is carbon, substituted carbon, nitrogen
W is carbon, substituted carbon, nitrogen
X is independently selected from hydrogen, alkyl, OR fused cyclic ring in to nitrogen of the quinolone
Y is independently selected from a group consisting of N, NH, O & S
R2 is independently selected from a group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic.
R3 is independently selected from a group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic.
Heterocycle is any substituted or unsubstituted aryl ring (n=5-7) containing 1,2 or 3 heteroatoms selected from 0,N, and S. The substitutents on the aryl ring as independently selected from a group consisting of hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkyl sulfonyl, aliphatic cyclic, aliphatic heterocyclic, heterocycles, substituted heterocyces and groups thereof.
1) Compounds of Formula II & IV:
Series II:
Series IV:
Ri is selected from acid, ester, amide, substituted amide, nitrile, oxime, substituted or unsubstituted akly sulfonyl
R is alkyl (n =1-6) or cycloalkyl e.g. cyclopropyl, substituted cycloalkyl, cyclic fused ring between N-R and A-X (eg NCH(CH3)CH2OC) etc
A is carbon, substituted carbon, nitrogen
W is carbon, substituted carbon, nitrogen
X is independently selected from hydrogen, alkyl, OR fused cyclic ring in to nitrogen of the quinolone
Y is independently selected from a group consisting of C, CR, NR, NH, O & S
The piperazine moiety is linked to the aryl, heteroaryl moiety independently at 2, 3, 4, 5, 6, or 7 position.
The 2-3 link is saturated or unsaturated
Linker is independently chosen from alkyl, substituted alkly, heteroatom such as NR, NH, O, S, carbonyl, carbamate ester, urea, thiourea, ester, thioester and groups alike. A compound according to the claims selected from claims delineated in Table A and salts thereof:
Table A: We will include the structures from our shipping list. Experimental:
General Procedure I for making compounds of Type - 1 (Table 1, 2 & 3):
The appropriate piperazine derivative (1 eq) and the 6-substituted-2-chloropyrimidine derivative (1 eq) in suitable base was heated in alcohol solvent at 115 °C (conventional heating) for 48 h or microwave heating for 12 h to give the title compounds after filtration.
Compound 2T
MS (ES +ve) 466.2 (M+H); lH NMR (DMSO-d6) δ 8.66 (s, 1H), 8.27 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 13.2 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 6.58 (d, J = 5.1 Hz, 1H), 3.98 (t, J = 4.8 Hz, 4H), 3.83 (m, 1H), 3.41 (t, J = 4.8 Hz, 4H), 1.62 (m, 2H), 1.33 (m, 4H), 1.18 (m, 2H), 0.89 ( t, J = 7.5 Hz, 3H).
MS (ES +ve) 543.1 (M+H); lH NMR (DMSO-d6) δ 8.66 (s, IH), 8.02 (d, J = 6.0 Hz, IH), 7.95 (d, J = 13.5 Hz, IH), 7.61 (d, J = 6.9 Hz, IH), 6.32 (d, J = 6.0 Hz, IH), 4.05 (m, 4H), 3.91 (m, 4H), 3.81 (m, IH), 3.38 (m, 4H), 3.13 (m, 4H), 1.28 (m, 4H).
Compound 2L
DI PEA
35 mg (0.12 mmol) of 1 and 23 mg (0.136 mmol) of 2 was reacted under conditions employed for the synthesis of 2T to obtain 16 mg (32%) of 2L. LC-MS: (416, M+l); ); IH NMR (300 MHz, DMSO-i 6):□ 8.67 (s, IH), 8.17 (d, IH, J=13.5), 7.25 (d, IH, J=3.6 Hz), 6.94 (d, IH, J=3.6 Hz), 4.08 (t, 4H), 3.62-3.41 (m, IH), 3.65 (t, 4H), 1.31-1.21 (m, 2H), 1.19-l. l l(m, 2H).
MS (ES +ve) 476.4 (M+H); lH NMR (DMSO-d6) δ 8.67 (s, IH), 8.46 (m, IH), 7.92 (m, 2H), 7.64 (d, J = 7.2 Hz, IH), 7.33 (m, IH), 6.97 (m, IH), 6.71 (m, IH), 4.03 (t, J = 5.1 Hz, 4H), 3.82 (m, IH), 3.43 (t, J = 5.1 Hz,4H), 1.31 (m, 4H).
Compound 21
MS: (476, M+1); ); IH NMR (300 MHz, OMSO-d6):□ 8.73 (d, 2H, J=8.1 Hz), 8.57 (d, IH, J=5.4 Hz), 8.08 (s, IH), 8.00(s, IH, J=13.2 Hz), 7.67 (d, IH, J= 7.8 Hz), 7.20 (s, IH), 7.13 (d, IH, J=5.4 Hz), 4.10 (t, 4H), 3.87 (m, IH), 3.49 (t, 4H), 1.35 (t, 2H), 1.24 (br s, 2H).
Compound 2J
MS: (512, M+1); ); IH NMR (300 MHz, OMSO-d6):□ 8.67 (s, IH), 8.17 (d, IH, J= 13.2 Hz), 7.17 (s, IH), 7.05 (s, IH), 4.08 (br s, 4H), 3.88 (br s, 4H), 3.77 (m, IH), 1.26 (m, 2H), 1.15 (m, 2H).
Compound 2E
MS (ES +ve) 479.3 (M+H); ¾ NMR (DMSO-d6) δ 8.67 (s, IH), 7.97 (d, J = 13.2 Hz, IH), 7.89 (d, J = 7.2 Hz, IH), 7.60 (d, J = 7.2 Hz, IH), 6.27 (d, J = 7.2 Hz, IH), 4.05 (m, 4H), 3.94 (m, 4H), 3.82 (m, IH), 3.42 (m, 8H), 1.94 (m, 4H), 1.28 (m, 4H).
Compound 2F
MS (ES +ve) 493.2 (M+H); lH NMR (DMSO-d6) δ 8.67 (s, IH), 8.50 (d, J = 5.1 Hz, IH), 8.08 (m, IH), 8.00 (m, IH), 7.97 (d, J = 13.2 Hz, IH), 7.64 (d,J = 7.5 Hz, IH), 7.32 (d, J = 5.1 Hz, IH), 4.04 (m, 4H), 3.82 (m, IH), 3.47 (m, 4H), 1.32 (m, 4H).
MS (ES +ve) 495.3 (M+H); ¾ NMR (DMSO-d6) δ 8.66 (s, IH), 7.96 (m, IH), 7.93 (d, J = 4.5 Hz, IH), 7.59 (d, J = 7.8 Hz, IH), 6.53 (d, J = 6.6 Hz, IH), 3.92-3.47 (m, 17H), 1.29 (m, 4H).
Compound 2C
MS (ES +ve) 481.2 (M+H); lH NMR (DMSO-d6) δ 8.96 (s, IH), 8.59 (d, J = 4.8 Hz, IH), 8.07- 7.98 (m, 2H), 7.94 (s, IH), 7.31 (d, J = 5.1 Hz, IH), 7.27 (d, J = 7.5 Hz, IH), 4.61 (q, J = 7.2 Hz, 2H), 4.03 (m, 4H), 3.45 (m, 4H), 1.41 (t, J = 7.2 Hz, 3H).
General Procedure II for making compounds of Type - 1 (Table 1, 2 & 3):
Synthesis of 2: To a solution of 1 (0.05 g, 0.1778 mmol) in DMSO (2 mL) was added piperazine (0.054 g, 0.6223 mmol) and the reaction mixture heated in a microwave at 100°C for 6h.
Reaction mixture poured over water and filtered to give 2 (0.07 g). LCMS ES (+ve) 349.2 (M+H).
Synthesis of 3: In a general procedure for making compounds of Type - 1 the appropriate piperazine derivative (1 eq) and the 6-substituted-2-chloropyrimidine derivative (1 eq) in suitable base was heated in alcohol solvent at 115 °C (conventional heating) for 48 h or microwave heating for 12 h to give the title compounds after filtration.
Compound 3B
MS (ES +ve) 509.2 (M+H); ¾ NMR (DMSO-d6) δ 8.97 (s, IH), 8.57 (d, J = 4.8 Hz, IH), 8.08 (m, IH), 8.07 (d, J = 3.3 Hz, IH), 7.99 (d, J = 3.0 Hz, IH), 7.64 (d,J = 12.0 Hz, IH), 7.30 (d, J 5.1 Hz, IH), 4.34 (m, IH), 4.63 (m, IH), 4.41 (m, IH), 3.96 (m, 4H), 3.41 (m, 4H), 1.47 (d, J = 6.6 Hz, 3H).
General Procedure III for making compounds of Type - 1 (Table 1, 2 & 3):
Synthesis of 5: To 4 (0.25 g, 1.50 mmol) was added aq. HBr and reaction mixture heated at reflux for 24 h. Reaction mixture was concentrated and residue washed with water to give 0.25 g
of 5 as a tan-colored solid. lH NMR (CDC13) δ 7.78-7.43 (m, 4H), 5.63 (m, 1H), 4.08 (m, 1H), 3.77 (m, 1H).
Synthesis of 6: In a general procedure for making compounds of Type 6 the appropriate piperazine derivative (1 eq) and the bromo derivative (1 eq) in suitable base was heated in alcohol solvent at 115 °C (conventional heating) for 48 h or microwave heating for 12 h to give the title compounds after reverse phase HPLC purification.
Compound 2P
MS (ES +ve) 498.2 (M+H); lU NMR (DMSO-d6) δ 8.65 (s, 1H), 7.92-7.55 (m, 6H), 5.02 (t, J 5.4 Hz, 2H), 3.77 (m, 3H), 3.36 (m, 4H), 2.84 (m, 2H), 2.56 (m, 2H), 1.31- 1.14 (m, 2H).
Compound 2R
MS (ES +ve) 486.2 (M+H); lH NMR (DMSO-d6) δ 8.87 (s, 1H), 7.94 (d, J = 13.5 Hz, 1H), 7.81- 7.62 (m, 4H), 7.20 (d, J = 7.5 Hz, 1H), 5.01 (t, J = 6.3 Hz, 2H), 4.59 (q, J = 6.6 Hz, 2H), 3.73 (m, 2H), 3.35 (m, 4H), 2.80 (m, 2H), 2.54 (m, 2H), 1.40 (t, J = 7.2 Hz, 3H).
General Procedure IV for making compounds of Type - 1 (Table 1, 2 & 3):
Synthesis of 7: To a solution of 4 (0.25 g, 1.50 mmol) in ethanol was added piperazine (0.25 g, 2.90 mmol) and the reaction mixture was heated at 90°C for lh. Solvent was evaporated and the residue was purified by silica gel column chromatography to give the 7 (0.22 g) as a off-white solid. MS (ES +ve) 253.1 (M+H)
Compound 3A: Piperazine derivative 7 (1 eq) and the fluoro derivative (1 eq) in suitable base was heated in alcohol solvent at 115 °C (conventional heating) for 48 h or microwave heating for 12 h to give the title compound 3A after reverse phase HPLC purification. MS (ES +ve) 514.3 (M+H); lH NMR (DMSO-d6) δ 8.97 (s, 1H), 7.81-7.57 (m, 5H), 4.98 (m, 2H), 4.59 (m, 2H), 4.38 (m, 2H), 3.73 (m, 2H), 3.34 (m, 4H), 2.72 (m, 2H), 1.45 (d, J = 6.6 Hz, 3H).
General Procedure V for making compounds of Type - 1 (Table 1, 2 & 3):
In a general procedure for making compounds of type shown above bromo compound (1 eq), amine (1 eq), Pd catalyst (5 mol ), phosphine ligand (10 mol ), base (3 eq) was taken up in degassed dioxane and heated at 100°C for 12h. The crude reaction mixture was filtered and purified by RP-HPLC to give the title compounds.
MS (ES +ve) 418.1 (M+H); lH NMR (DMSO-d6) δ 9.38 (d, J = 2.1 Hz, 1H), 9.34 (d, J = 6.6 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.73 (m, 2H), 8.56 (m, 1H), 8.08 (d, J = 11.1 Hz, 1H), 7.76 (d, J = 5.1 Hz, 1H), 7.58 (m, 1H), 3.83 (m, 1H), 1.31 (m, 4H).
General Procedure VI for making compounds of Type - 1 (Table 1, 2 & 3):
Synthesis fo 10: In a general procedure for making compounds of Type 10; to a solution of amine (3 eq) in THF was added and Me3Al (3 eq) at room temperature and reaction mixture stirred for 15 mins. To the mixture was added ester compound 9 (1 eq) and reaction mixture heated at 60°C overnight. The reaction mixture was quenched by addition of Rochelle salt and diluted with ethyl acetate. The organic layer was washed with brine and dried over Na2S04. Purified by silica gel column chromatography to give the title compound 10.
Synthesis of 11: In a general procedure for making compounds of Type 11 shown above bromo compound 10 (1 eq), amine (1 eq), Pd catalyst (5 mol ), phosphine ligand (10 mol ), base (3 eq) was taken up in degassed dioxane and heated at 100°C for 12h. The crude reaction mixture was filtered and purified by RP-HPLC to give the title compounds.
MS (ES +ve) 500.4 (M+H).
Procedure for Preparation of Target 6
Synthesis of intermediate: To a cooled solution of Compound 2F (1 eq), Boc-Valinol (1.5 eq) and Triphenylphosphine (1.7 eq) in acetonitrile, DIAD(1.7 eq) was added drop wise at 0°C. This reaction mixture was warmed to room temperature and stirred for overnight. This was purified by column chromatography to get intermediate. LCMS (ES+ve)
Synthesis of Compound 6: 4N HCl (20 eq) was added to a solution of intermediate in dioxane at room temperature and stirred for 6 h. Solid precipitate was filtered and washed with EtOAc to get compound 8 as HCl salt. MS (ES+ve) 578.3.
Procedure for Preparation of Target 10
Synthesis of 2F-2: A mixture of 2F (2g) with diphenyl phosphorazidate (10 mL) and t-BuOK (5.4g) in t-BuOH (200 mL) was heated at reflux overnight. After concentration the residue was purified by column chromatography to obtain 2F-1 (1.7g) as a yellow solid. The 2F-1 was subjected to deprotection using 4M HC1 to obtain 2F-2 in quantitative yield.
Synthesis of 10: To a stirred solution of 2F-2 (1.5g) in dichloromethane was added DIEA, followed by dropwise solution of premade 4-(dimethylamino)but-2-enoyl chloride in
dichloromethane at rt. After stirring at rt overnight, the reaction was work-up as usual manner to obtain 10 (420mg) after purification by chromatography. LCMS: tR 2.87, m/e 575.5 (M+l). ¾ NMR (300 MHz, CDC13) d 1.16 and 1.32 (two sets of m, 4H), 2.47 (s, 6H), 3.37(s and m, 7H), 4.15 (dd, 4H), 6.34 (d, 1H), 6.95 (two t, 1H), 7.35 (d, 2H), 7.51 (d, 1H), 7.98 (d, 1H), 8.04 (d, 1H), 8.50 (d, 1H), 8.55 (br, 1H), 9.29 (s, 1H)
Mechanism of action
Ciprofloxacin is a broad- spectrum antibiotic active against both Gram-positive and Gram- negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV enzymes necessary to separate bacterial DNA, thereby inhibiting cell division.
This mechanism can also affect mammalian cell replication. In particular, some congeners of this drug family (for example those that contain the C-8 fluorine)^ display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases and are toxic to
cultured mammalian cells and in vivo tumor models.^ Although quinolones are highly toxic to mammalian cells in culture, its mechanism of cytotoxic action is not known. Quinolone-induced DNA damage was first reported in 1986 (Hussy and others.).^
Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the quinolones and the induction of micro nuclei. Γ971 Γ981 Γ"1 Γ10°1 As such, some fluoroquinolones may cause injury to the chromosome of eukaryotic cells /1011Γ1021Γ1031Γ1041Γ1051Γ1061
There continues to be debate as to whether or not this DNA damage is to be considered one of the mechanisms of action concerning the severe adverse reactions experienced by some patients following fluoroquinolone therapyJ95iriQ7^1Q81
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antibacterial to anticancer agents". Curr Med Chem Anticancer Agents 3 (6): 439-50. doi: 10.2174/1568011033482279. ISSN 1568-0118. PMID 14529452.
http://openurl.ingenta.com/content/nlm?genre=article&issn=1568-
0118&volume=3&issue=6&spage=439&aulast=Sissi. "The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent. Indeed, a distinctive feature of drugs based on the quinolone structure is their remarkable ability to target different type II topoisomerase enzymes. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models."
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^ Gootz TD Barrett JF, Sutcliffe JA, TD (January 1990). "Inhibitory effects of quinolone antibacterial agents on eucaryotic topoisomerases and related test systems". Antimicrob. Agents Chemother. 34 (1): 8-12. doi: 10.1128/AAC.34.1.8. ISSN 0066-4804. PMC 171510. PMID 2158274.
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Λ Elsea SH Osheroff N, Nitiss JL, SH (July 1992). "Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast". J. Biol. Chem. 267 (19): 13150-3. ISSN 0021- 9258. PMID 1320012. http://www.ibc.org/cgi/reprint/267/19/13150.
* Suto MJ, Domagala JM, Roland GE, Mailloux GB, Cohen MA, MJ (December 1992). "Fluoroquinolones: relationships between structural variations, mammalian cell cytotoxicity, and antimicrobial activity". J. Med. Chem. 35 (25): 4745-50.
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* Enzmann H, Wiemann C, Ahr HJ, Schliiter G, H (April 1999). "Damage to mitochondrial DNA induced by the quinolone Bay y 3118 in embryonic turkey liver". Mutat. Res. 425 (2): 213-24. doi: 10.1016/S0027-5107(99)00044-5. ISSN 0027-5107. PMID 10216214.
12. ^ Kashida Y, Sasaki YF, Ohsawa K, Y (October 2002). "Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice". Toxicol. Sci. 69 (2): 317-21. doi: 10.1093/toxsci/69.2.317. ISSN 1096-6080. PMID 12377980.
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Determination of Minimum Inhibitory Concentration (MIC). MICs were determined by the broth microdilution method outlined in the CLSI (formerly NCCLS) guidelines (1) with modifications to incubation conditions. Log-phase bacterial cultures were grown in cation- adjusted Mueller-Hinton broth (MHB). Diluted bacterial cultures from log-phase growth were 5 seeded into 96- well plates at a concentration of 1 x 10s CFU/mL, and plates were incubated at 37°C for 16 to 20h with shaking. Test compound stock solutions in DMSO were diluted into media, to achieve a final concentration of 1% DMSO. Cell growth was determined by measuring optical density (600nm) in a microplate reader (Dynex Technologies, Chantilly, VA). MIC values for antimicrobial compound-treated cultures were calculated as the lowest
10 concentration of drug at which growth was not apparent, as measured by optical density at 600 nm. Values were determined in quadruplicate and the average MIC value was listed as the MIC value in data tables.
MIC ^g/mL)
Cipro
CBI- CBI- CBI- CBI- floxaci Norfl Enrofl Levofl
Bacterial isolate 360 362 349 353 n oxacin oxacin oxacin
MRS A
1234514234 0.25 0.5 0.25 1 0.5 1 0.125 0.125
MRS A
1234522733 8 4 16 32 16 32 4 4
MRS A
1234523542 0.125 0.5 0.25 1 0.25 1 0.125 0.125
MRS A
1234524102 0.125 0.5 0.25 1 0.25 1 0.125 0.125
MRS A
1234524209 0.125 0.5 0.25 1 0.25 1 0.125 0.125
MRS A
1234527687 0.125 0.5 0.25 1 0.25 1 0.125 0.125
MRS A
1234533548 0.25 0.5 0.25 1 0.25 1 0.125 0.125
S. aureus ISP794 (wild-type, S. aureus EN1252a (parC gyrA, Hooper) Hooper)
Fold
MIC MIC MIC MIC Averag resistanc
Compound ^g/mL) ^g/mL) . Average ^g/mL) ^g/mL) e e
Ciprofloxaci i
n 0.31 0.31 j 0.31 20 20 20 64
Norfloxacin 0.5 0.5 ! 0.5 64 64 64 128
Enrofloxacin 0.25 0.25 i 0.25 16 16 16 64
Levofloxacin 0.5 0.25 ! 0.38 8 8 8 21
CBI-333 1 2 ! 1.5 4 8 6 4
CBI-349 0.25 0.25 i 0.25 32 32 32 128
CBI-351 4 4 ! 4 4 4 4 1
CBI-353 1 1 j 1 128 >128 128 128
CBI-354 1 1 i 1 128 128 128 128
CBI-358 2 2 ! 2 >64 >64 >64 >32
CBI-359 1 1 j 1 128 128 128 128
CBI-360 0.25 0.25 i 0.25 32 32 32 128
CBI-361 1 1 ! l 8 8 8 8
CBI-362 1 1 ] 1 8 8 8 8
CBI-363 4 4 i 4 4 4 4 1
CBI-364 2 2 ! 2 128 128 128 64
Summary of antibiotic MICs for S. aureus mutants selected by the compounds
5 Sachin S. Bhagwat, Lakshmi A. Mundkur, Shrikant V. Gupte, Mahesh V. Patel, and Habil F.
Khorakiwala Antimicrob Agents Chemother. Nov 2006; 50(11): 3568-3579.
Claims
1. A method of treating carcinoma susceptible to treatment in a warm blooded mammal comprising administering to said mammal a safe and effective amount of a lH-l,2,4-triazole derivative of the formula: 3wherein Z is an alkylene selected from the group consisting of CH.sub.2-CH.sub.2-, -CH.sub.2-CH.sub.2-CH.sub.2-, ~CH(CH.sub.3)~CH(CH.sub.3)~ and— CH.sub.2— CH(alkyl), wherein said alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl; or a pharmaceutically acceptable salt thereof.
2. A method according to claim 1 wherein said lH-l,2,4-triazole derivative is selected from the group consisting of: l-[2-(2,4-dichlorophenyl)-l,3-d- ioxolan-2-ylmethyl]-lH-l,2,4-triazole; 1- [2-(2,4-dichlorophenyl)-4-methyl- l,3-dioxolan-2-ylmethyl]-lH-l,2,4-triazole, l-[2-(2,4- dichlorophenyl)-4-et- hyl-l,3-dioxolan-2-ylmethyl]-lH-l,2,4-triazole, l-[2-(2,4-dichlorophenyl)- - 4-propyl-l,3-dioxolan-2-ylmethyl]-lH-l,2,4-triazole, l-[2-(2,4-dichlorophenyl)-4-pentyl-l,3- dioxolan-2-ylmethyl]- 1H- 1 ,2,4-tria- zole.
3. A method according to claim 1 wherein said lH-l,2,4-triazole derivative is l-[2-(2,4- dichlorophenyl)-4-propyl- 1 ,3-dioxolan-2-ylmethyl] - 1H- 1 ,2,4-t- riazole.
4. A method according to claim 1 wherein the carcinoma is breast cancer.
5. A method according to claim 1 wherein the carcinoma is head or neck cancer.
6. A method according to claim 1 wherein the carcinoma is melanoma.
7. A method according to claim 1 wherein the carcinoma is ovarian cancer.
8. A method according to claim 1 wherein the carcinoma is colon cancer.
9. A method according to claim 1 wherein the carcinoma is lung cancer.
10. A method according to claim 1 wherein the carcinoma is stomach cancer.
11. A method according to claim 1 wherein the carcinoma is uterine cancer.
12. A method of treating a viral infection susceptible to treatment in a warm blooded mammal comprising administering to said mammal a safe and effective amount of l-[2-(2,4- dichlorophenyl)-4-propyl- 1 ,3-dioxolan-2-ylm- ethyl] - 1H- 1 ,2,4-triazole.
13. A method according to claim 12 wherein the viral infection is an influenza infection.
14. A method according to claim 12 wherein the viral infection is a rhinoviral infection.
15. A pharmaceutical kit comprising a safe and effective amount of a lH-l,2,4-triazole derivative of the formula: 4wherein Z is an alkylene selected from the group consisting of CH.sub.2-CH.sub.2-, -CH.sub.2-CH.sub.2-CH.sub.2-, ~CH(CH.sub.3)~CH(CH.sub.3)~ and— CH.sub.2— CH(alkyl) wherein said alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl; and instruction for use in treating carcinoma susceptible to treatment.
16. A pharmaceutical kit of claim 15 wherein the lH-l,2,4-triazole derivative is l-[2-(2,4- dichlorophenyl)-4-propyl- 1 ,3-dioxolan-2-ylmethyl] - - 1H- 1 ,2,4-triazole.
17. A pharmaceutical kit comprising a safe and effective amount of a lH-l,2,4-triazole derivative of the formula: 5wherein Z is an alkylene selected from the group consisting of CH.sub.2-CH.sub.2-, -CH.sub.2-CH.sub.2-CH.sub.2-, ~CH(CH.sub.3)~CH(CH.sub.3)~ and—CH.sub.2— CH(alkyl) wherein said alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl; and instruction for use in treating a viral infection susceptible to treatment.
18. A pharmaceutical kit of claim 17 wherein the lH-l,2,4-triazole derivative is l-[2-(2,4- dichlorophenyl)-4-propyl- 1 ,3-dioxolan-2-ylmethyl] - - 1H- 1 ,2,4-triazole.
19. A pharmaceutical kit of claim 18 wherein the instructions are for use in treating influenza.
20. A pharmaceutical kit of claim 18 wherein the instructions are for use in treating a rhino viral infection.
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CN111732573A (en) * | 2020-05-16 | 2020-10-02 | 复旦大学 | Quinolone acid-aminopyrimidine compound and preparation method and application thereof |
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CN109942546A (en) * | 2019-04-16 | 2019-06-28 | 西南大学 | Quinolone pyrimidines and its preparation method and application |
CN109942546B (en) * | 2019-04-16 | 2022-04-08 | 西南大学 | Quinolone pyrimidine compound and preparation method and application thereof |
CN111732573A (en) * | 2020-05-16 | 2020-10-02 | 复旦大学 | Quinolone acid-aminopyrimidine compound and preparation method and application thereof |
CN111732573B (en) * | 2020-05-16 | 2022-09-16 | 复旦大学 | Quinolone acid-aminopyrimidine compound and preparation method and application thereof |
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