EP2675789A1 - Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie und halogensubstituierte spirocyclische ketoenole - Google Patents

Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie und halogensubstituierte spirocyclische ketoenole

Info

Publication number
EP2675789A1
EP2675789A1 EP12703559.0A EP12703559A EP2675789A1 EP 2675789 A1 EP2675789 A1 EP 2675789A1 EP 12703559 A EP12703559 A EP 12703559A EP 2675789 A1 EP2675789 A1 EP 2675789A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compounds
alkoxy
substituted
chlorine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12703559.0A
Other languages
German (de)
English (en)
French (fr)
Inventor
Thomas Bretschneider
Reiner Fischer
Stefan Lehr
Elmar Gatzweiler
Ulrich Görgens
Isolde HÄUSER-HAHN
Ines Heinemann
Arnd Voerste
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer CropScience AG
Original Assignee
Bayer Intellectual Property GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE102011080405A external-priority patent/DE102011080405A1/de
Application filed by Bayer Intellectual Property GmbH filed Critical Bayer Intellectual Property GmbH
Priority to EP12703559.0A priority Critical patent/EP2675789A1/de
Publication of EP2675789A1 publication Critical patent/EP2675789A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/36—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings
    • A01N43/38—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom five-membered rings condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
    • A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
    • A01N43/06—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings
    • A01N43/12—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom five-membered rings condensed with a carbocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins

Definitions

  • the present invention relates to substituted 3- (biphenyl-3-yl) -SS-di-fluoro-4-hydroxy-1-azaspiro [4.5] dec-3-en-2-ones of the formula (Ia) for therapeutic purposes, pharmaceutical agents containing the compounds according to the invention and their use in therapy, in particular for the prophylaxis and / or therapy of tumor diseases.
  • Acetyl-CoA carboxyiases (ACCs) play a key role in cellular fatty acid homeostasis.
  • ACCs are biotin-containing enzymes that catalyze the carboxylation of acetyl-CoA to Maionyi-CoA in an ATP-dependent manner (Kim, 1997, Harwood, 2005, Tong, 2005).
  • This reaction which proceeds as two half reactions, a biotin-carboxyiase (BC) reaction and a carboxyl transferase (CT) reaction, is the first preliminary step in fatty acid biosynthesis and is the first
  • ACCl and ACC2 Two human ACC isoforms are known, ACCl and ACC2, which are encoded by two different genes (LuTFI ABU-ELHEIGA et al, 1995, Jane WIDMER, et al., 1996).
  • ACCl is expressed in lipogenic tissue (liver, adipose tissue), localized in the cytosol, and fills the Maionyi-CoA pool, which is a C2 unit donor for the de novo synthesis of long-chain fatty acids by FASN and
  • ACC2 is primarily expressed in oxidative tissues (liver, heart, skeletal muscle) (Bianchi et al., 1990; Kim, 1997), associated with the mitochondria, and regulates a second pool of malonyl-CoA. This controls fatty acid oxidation by inhibiting carnitine palmitate transferase I, the enzyme that facilitates the entry of long-chain fatty acids into the mitochondria for ⁇ -oxidation (Milgraum LZ, et al., 1997, Widmer J. et al., 1996). Both enzymes show a very large sequence homology and are similarly regulated by a combination of
  • ACC activity is strictly controlled by a number of dietary, hormonal, and other physiological mechanisms such as forward allosteric
  • ACCl knockout mice are embryonic lethal (Swinnen, et al., 2006, Abu-Elheiga, et al., 2005). ACC2
  • Knockout mice show reduced malonyl-CoA levels in skeletal and cardiac muscle, increased
  • Fatty acid oxidation in muscle decreased liver fat levels, decreased levels of total body fat, increased levels of UCP3 in skeletal muscle (as a sign of increased energy expenditure), decreased body weight, decreased levels of plasma free fatty acids, decreased plasma Glucose levels, decreased levels of glycogen in tissues, and are protected from diet-induced diabetes and obesity (Abu-Elheiga et al., 2001, 2003, Oh et al., 2005).
  • Tumor cells (Swinnen, et al., 2004, Heemers, et al., 2000, Swinnen, et al., 2002, Rossi, et al., 2003, Milgraum, et al., 1997, Yahagi, et al., 2005 ). This phenotype is very likely to contribute
  • EP0454782 and US5759837 protect the use of fatty acid synthesis inhibitors to inhibit tumor cell growth. Cyclic ketoenoie are not revealed.
  • PCT Patent Application PCT EP99 / 01787 published as WO 99/48869 corresponding to European Patent EP 1 066 258 B1, relates to novel arylphenyl-substituted cyclic ketoenoie, to a majority of the processes for their preparation and their use as Pesticides and herbicides.
  • EP-A-0 262 399 and GB-A-2 266 888 disclose similarly structured compounds (3-arylpyrrolidine-2,4-diones), but of which no herbicidal, insecticidal or acaricidal activity has become known.
  • Unsubstituted, bicyclic 3-aryl-pyrrolidine-2,4-dione derivatives are known having herbicidal, insecticidal or acaricidal activity (EP-A-355 599, EP-A-415 21 1 and J PA-1 2-053 670) and substituted monocyclic 3-aryl-pyrrolidine-2,4-dione derivatives (EP-A-377 893 and EP-A-442 077).
  • EP-A-442 073 Polycyclic 3-arylpyrrolidine-2,4-dione derivatives (EP-A-442 073) and also 1,1-arylpyrrolidinone-dione derivatives are also known (EP-A-456 063, EP-A-521 334, EP-A) A-596 298, EP-A-613 884, EP-A-613 885, WO 95/01 971, WO 95/26 954, WO 95/20 572, EP-A-0 668 267, WO 96/25 395 , WHERE
  • ketalsubstituted 1 -H-arylpyrrolidine-2,4-diones from WO 99/16748 and (spiro) - ketalsubstituted N-alkoxy-alkoxy-substituted aryl-pyrrolidindione from JP-A-14 205 984 and Ito M. et al. Bioscience, Biotechnology and Biochemistry 67, 1230-1238, (2003).
  • WO 06/024411 discloses herbicidal compositions containing ketoenols.
  • WO 2005/0891 18 and WO2007 / 039286 disclose generically nitrogenous bicyclic structures for therapy, wherein 5 '-biphenyl-substituted cyclic ketoenol are not specifically mentioned. It has now surprisingly been found that a specific subgroup of the aryl-substituted cyclic ketoenols described in the prior art also inhibit human ACC and are suitable for the therapy of diseases.
  • the Anmeiderin is not known that in the prior art 3 - (B ipheny 1-3 -yl) -8, 8-difluoro-4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one of the formula (Ia) according to the present invention are described for the therapy of diseases, in particular not for the therapy of tumor diseases.
  • the object of the present invention is to provide structures for the treatment of diseases available.
  • Tumors are suitable and have advantages over known in the art structures. Particularly interesting are compounds which have a selectivity against human ACC2, ie inhibit human ACCI stronger than human ACC2.
  • structures are provided for the therapy of diseases which strongly inhibit human ACC1.
  • the structures sought thereby inhibit human ACCl more than human ACC2, i. have a selectivity against human ACC2.
  • structures are provided for the therapy of diseases which additionally also possess one, more preferably several, or even all, of the following properties: they inhibit human ACCI after single measurement or better on average from several measurements with an IC50 of less than 300 nM, better of less than 200 nM, even better less than 100 nM in the described assay, they inhibit human ACC2 after single measurement or better in the mean of several measurements with an IC50 of more than 0.5 ⁇ , better of more than 1.5 ⁇ , even better than 2 ⁇ in the described assay, the ratio of the IC50 for the inhibition of human ACC2 to IC50 for the inhibition of human ACCI after single measurement or better in the mean of several measurements is at least a factor 8, better at least a factor 15, even better at least a factor of 20, they inhibit tumor cell proliferation of MCF7 cells n after single measurement or better in the mean of several measurements with an IC50 of less than 250 nM, better less than 100 nM, even better less than 50 nM in the described assay, they have an IC50 of
  • the estimated daily human dose is less than 2 g, better under 1 g per patient.
  • R la represents a methyl group or a chlorine atom
  • R 2a represents a hydrogen atom or a methyl group
  • R 3a is a hydrogen or a fluorine atom
  • R 4a represents a chlorine or fluorine atom
  • the compounds of formula (la) have surprisingly highlighted by a good enzyme inhibition of the human ACC's.
  • the compounds of the invention have an increased selectivity against ACC2 and inhibit especially ACCl. This property was unpredictable and qualifies the compounds of the invention for reduced therapy
  • Physiologically acceptable salts of the compounds according to the invention of the formula (Ia) also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium)
  • Potassium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, Dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
  • alkaline earth stabilizers eg calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, Dimethyl
  • compositions containing the compounds of the invention according to the formula (Ia) and at least one or more further active ingredients, in particular for the prophylaxis and / or therapy of tumor diseases.
  • the compounds according to the invention of the formula (Ia) can act systemically and / or locally.
  • a suitable manner e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivai, otic or as an implant or stent.
  • the compounds of the invention according to the formula (Ia) can be administered in suitable forms of administration.
  • Soft gelatin capsules Soft gelatin capsules
  • dragees granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intraiumbal) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
  • a resorption step e.g., intravenous, intraarterial, intracardiac, intraspinal, or intraiumbal
  • absorption e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal.
  • Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines including powder inhalers, Nebuiizers
  • nasal drops solutions, sprays
  • lingual, sublingual or buccal tablets to be applied
  • films / wafers or capsules films / wafers or capsules
  • suppositories ear or ophthalmic preparations
  • vaginal capsules aqueous suspensions (lotions, shake mixtures)
  • lipophilic suspensions ointments
  • creams transdermal therapeutic systems (such as patches)
  • transdermal therapeutic systems such as patches
  • milk Pastes, foams, scattering powders, implants or stents.
  • the compounds according to the invention of the formula (Ia) can be converted into the mentioned application forms. This can be done in a conventional manner by mixing with inert,
  • Non-toxic, pharmaceutically suitable excipients happen. These adjuvants include, among others.
  • Carriers e.g., microcrystalline cellulose, lactose, mannitol
  • solvents e.g., liquid
  • Polyethylene glycols emulsifiers and dispersing or wetting agents (for example sodium dodecylsulfate,
  • binders e.g., polyvinylpyrrolidone
  • synthetic and natural polymers e.g., albumin
  • stabilizers e.g., antioxidants such as
  • dyes e.g., inorganic pigments such as iron oxides
  • dyes e.g., inorganic pigments such as iron oxides
  • Flavor and / or odor remedies Flavor and / or odor remedies.
  • the formulation of the compounds of the formula (Ia) according to the invention into pharmaceutical preparations is carried out in a manner known per se, by converting the active substance (s) into the desired formulation with the auxiliaries customary in Gaienik.
  • auxiliaries may, for example, vehicles, fillers, disintegrants, binders, humectants, lubricants, Ab- and Adsorptionsmitte !, diluents, solvents,
  • Cosolvents for changing the osmotic pressure or buffers are used.
  • the pharmaceutical formulations can be any suitable pharmaceutical formulations.
  • auxiliaries for the purposes of the invention may be, for example, salts, saccharides (mono-, di-, tri-, oligo-, and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils, hydrocarbons and derivatives thereof, the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.
  • the auxiliaries may be of natural origin or synthetically or partially synthetically obtained.
  • tablets, dragees, capsules, pills, powders, granules, troches, suspensions, emulsions or solutions are particularly suitable.
  • the present invention relates to the compounds according to the invention of the formula (Ia).
  • They can be used for the prophylaxis and treatment of human diseases, in particular tumors.
  • the compounds according to the invention of the formula (Ia) according to the invention can be used in particular to inhibit or reduce the cell proliferation and / or the cell division and / or to induce apoptosis.
  • the compounds according to the invention of the formula (Ia) are particularly suitable for the prophylaxis and / or therapy of hyper-proliferative diseases such as, for example
  • Keioids and other skin-related hyperplasias are Keioids and other skin-related hyperplasias
  • BPH benign prostate hyperplasia
  • tumors for example, tumors treat the breast, the breast
  • Genitourinary tract eye, liver, skin, head and neck, thyroid, parathyroid gland, bone, connective tissue and metastases of these tumors.
  • hematological tumors are treatable
  • breast tumors are treatable:
  • tumors of the respiratory tract are treatable.
  • tumors of the brain are treatable.
  • tumors of the male reproductive organs are treatable: prostate cancers,
  • Penis cancer For example, tumors of the female reproductive organs are treatable:
  • tumors of the gastrointestinal tract are treatable:
  • tumors of the urogenital tract are treatable:
  • tumors of the eye are treatable:
  • Intraocular melanomas Intraocular melanomas
  • liver tumors are treatable:
  • tumors of the skin are treatable:
  • tumors of the head and neck are treatable:
  • treatment bars are:
  • treatment can be:
  • leukemias are treatable:
  • the compounds of the invention according to the formula (Ia) can be used for the prophylaxis and / or therapy of:
  • Pancreatic carcinoma renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-cancerous bronchial carcinoma, endometrial carcinoma,
  • the compounds of the invention according to the formula (Ia) can be used to particular advantage for the prophylaxis and / or therapy of breast cancers, in particular hormone receptor-positive mammary carcinomas, colorectal carcinomas, prostate carcinomas, in particular Androgen receptor-negative prostate carcinomas or non-small cell lung carcinomas.
  • Another object of the present application are the compounds of the invention according to the formula (Ia) for use as medicaments, in particular for the prophylaxis and / or therapy of tumor diseases.
  • a further subject of the present application are the compounds of the invention according to the formula (Ia) for the prophylaxis and / or therapy of breast carcinomas, pancreatic carcinomas,
  • Renal cell carcinoma hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell bronchial carcinoma, endometrial carcinoma, colorectal carcinoma or prostate carcinoma.
  • Another object of the present application are the compounds of the invention according to the formula (Ia) for the prophylaxis and / or treatment of breast cancer, in particular
  • Hormone receptor-positive breast cancers colorectal carcinomas, prostate cancers, especially androgen receptor-negative prostate carcinomas or non-small cells
  • Another object of the invention is the use of the compounds of the invention according to the formula (Ia) for the preparation of a medicament.
  • Another object of the present application is the use of the compounds of the invention according to the formula (Ia) for the manufacture of a medicament for the prophylaxis and / or therapy of tumor diseases.
  • Another object of the present application is the use of the invention
  • Bronchial carcinoma, endometrial carcinoma, colorectal carcinoma or prostate cancer Bronchial carcinoma, endometrial carcinoma, colorectal carcinoma or prostate cancer.
  • Another object of the present application is the use of the compounds of the invention according to the formula (Ia) for the manufacture of a medicament for the prophylaxis and / or therapy of breast cancer, in particular hormone receptor-positive breast carcinomas, colorectal carcinomas, prostate cancer, especially androgen receptor-negative
  • Prostate carcinoma or non-small cell lung carcinoma are Prostate carcinoma or non-small cell lung carcinoma.
  • Another object of the present application is the use of the compounds of the invention according to the formula (Ia) for the prophylaxis and / or therapy of tumor diseases.
  • Another object of the present application is the use of the compounds of the invention according to the formula (Ia) for the prophylaxis and / or treatment of breast carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cell lung carcinoma, endometrial carcinoma, colorectal carcinoma or prostate cancer.
  • a further subject matter of the present application is the use of the compounds according to the invention of the formula (Ia) for the prophylaxis and / or therapy of breast cancers, in particular hormone receptor-positive breast carcinomas, colorectal carcinomas,
  • Prostate carcinomas especially androgen receptor-negative prostate carcinomas or non-small cell bronchial carcinomas.
  • Another object of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention according to the formula (Ia) for the prophylaxis and / or treatment of breast carcinoma, pancreatic carcinoma, renal cell carcinoma, hepatocellular carcinoma, malignant melanoma and other skin tumors, non-small cells Bronchial carcinoma, endometrial carcinoma, colorectal carcinoma or prostate cancer.
  • Another object of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds of the invention according to the formula (Ia)
  • Prophylaxis and / or therapy of breast cancers in particular hormone receptor-positive breast carcinomas, colorectal carcinomas, prostate carcinomas, in particular androgen receptor-negative prostate carcinomas or non-cancerous bronchial carcinomas.
  • Another object of the invention is the use of the compounds of the invention according to the formula (Ia) for the treatment of diseases associated with proliferative processes.
  • Compound of the invention and one or more further active ingredients, in particular for the prophylaxis and / or therapy of the aforementioned diseases.
  • the compounds of the invention according to the formula (Ia) can be combined with known anti-hyperpropriiferative, cytostatic or cytotoxic substances for the treatment of cancer.
  • Suitable combination active ingredients are: afmitor, aldesleukin, alendronic acid, alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasine, 5-azacytidine , Azathioprine, BCG or tice-BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bieomycin sulfate, broxuridine, bortezomib, busuifan, caicitonin, campath, capecitabine, carbopiatine, casodex, cefeson, celmoleukin, cerubidine,
  • Rhenium-186-etidronate rituximab, roferon-A, romurtide, saiagen, sandostatin, sargramostim, semustin, sizofiran, souzoxan, solu-medrol,
  • Valrubicin Vesnarinone, Vinblastine, Vincristine, Vindesine, Vinorelbine, Virulizine, Zinecard, Zinostatin Stimalamer, Zofran; ABI-007, Acolbifen, Actimmun, Affmitak, Aminopterin, Arzoxifen, Asoprisnil, Atamestan, Atrasentan, BAY 43-9006 (Sorafenib), Avastin, CCI-779, CDC-501, Celebrex, Cetuximab, Crisnatol, cyproterone acetate, decitabine, No. 101.
  • the compounds according to the invention can be combined with anti-hyperproliferative agents, which can be given by way of example-without this enumeration being conclusive: Aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, coiaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, 2 ', 2'-difluorodetoxycytidine, docetaxel, Doxorubicin (adamyrincin), epirubicin, epothilone and its derivatives, erythro-hydroxynonyladenine, ethinyl estradiol, etoposide, fudarabine phosphate, 5-fluor
  • the compounds of the invention of formula (Ia) may also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
  • biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
  • the compounds of the invention according to the formula (Ia) can also achieve positive effects in combination with other anti-angiogenic therapies, such as Avastin, axitinib, regorafenib, recentin, sorafenib or sunitinib. Combinations with inhibitors of the
  • Proteasomes and mTOR as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.
  • the compounds of the formula (Ia) according to the invention can be prepared with the synthesis routes A and / or B.
  • the Suzuki couplings are generally carried out in inert solvents, in the presence of a catalyst, optionally in the presence of an additional reagent, preferably in a temperature range from room temperature to 130 ° C at atmospheric pressure.
  • the reactions can also be carried out in a closed vessel with heating in the microwave.
  • catalysts are conventional palladium catalysts for Suzuki reaction conditions, preferably catalysts such as e.g. Dichlorobis (triphenylphosphine) palladium,
  • a ligand such as dicyclohexyl [2 ', 4', 6'-tri (propan-2-yl) biphenyl-2-yl] phosphine.
  • Additional reagents are, for example, potassium or cesium acetate, cesium, potassium or sodium carbonate, potassium tert-butylate, cesium fluoride, potassium phosphate or sodium or potassium hydroxide.
  • additional reagents such as cesium carbonate and / or aqueous sodium hydroxide solution.
  • Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone, or alkyl sulfoxides, such as dimethyl sulfoxide, or mixtures of the solvents with alcohols, such as methanol or ethanol and / or water, preferably 1, 2-dimethoxyethane.
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene or toluene
  • carboxamides such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone
  • alkyl sulfoxides such as dimethyl sulfoxide
  • solvents such as
  • the compound of the formula (IIa) can be prepared by reacting the compounds of the formula (IVa)
  • R 1a and R 2a have the abovementioned meanings
  • B a is Ci-Ce-alkyl, preferably ethyl or methyl, is reacted under conditions of Dieckmann condensation.
  • the Dieckmann condensations are generally carried out in inert solvents in the presence of a base, preferably in a temperature range from room temperature to 130 ° C at atmospheric pressure.
  • bases are alkali metal or alkaline earth metal alkoxides, such as sodium or potassium tert-butoxide, sodium methoxide or ethoxide, potassium tert-butoxide being preferred.
  • Inert solvents are, for example, ethers, such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons, such as benzene, xylene or toluene, or carboxamides, such as dimethylformamide.
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene or toluene
  • carboxamides such as dimethylformamide.
  • the compounds of the formula (IVa) can be prepared by reacting compounds of the formula (Va) or a salt of compounds of the formula (Va)
  • reaction inert solvents, by reacting the compounds of the formula (Via) first with thionyl chloride or an equivalent reagent known to those skilled in the art and in the second stage with compounds of the formula (Va) or a salt of the compounds of the formula (Va) in Presence of a base such. B. triethylamine or potassium carbonate are reacted.
  • the reaction in inert solvents, in the presence of a dehydrating reagent, optionally in the presence of a base, preferably in a temperature range of -30 ° C to 50 ° C at atmospheric pressure.
  • Inert solvents are, for example, halogenated hydrocarbons, such as dichloromethane or trichloromethane, hydrocarbons, such as benzene or toluene, nitromethane, tetrahydrofuran, 1,4-dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of the solvents. Particularly preferred are acetonitrile, dichloromethane, dimethylformamide, tetrahydrofuran or Toiuoi.
  • Bases are, for example, alkali metal carbonates, e.g. Sodium or potassium carbonate or bicarbonate or organic bases such as trialkylamines, e.g. Triethylamine, iV-methylmorpholine, ⁇ -methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali metal carbonates e.g. Sodium or potassium carbonate or bicarbonate
  • organic bases such as trialkylamines, e.g. Triethylamine, iV-methylmorpholine, ⁇ -methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • Suitable dehydrating here for example, carbodiimides such as A r, A r 'diethyl, N, N,' -Dipropyi-, N, N'-diisopropyl, iV.iV'-dicyclohexylcarbodiimide, N- suitable (3-dimethylaminoisopropyl) -N ethylcarbodiimide hydrochloride (EDC), A r -cyclohexylcarbodiimide-JV'-propyloxymethyl-polystyrene (PS-
  • carbodiimides such as A r, A r 'diethyl, N, N,' -Dipropyi-, N, N'-diisopropyl, iV.iV'-dicyclohexylcarbodiimide, N- suitable (3-dimethylaminoisopropyl) -N ethylcarbodiimide hydroch
  • Carbodiimid) or carbonyl compounds such as Carbonyidiimidazoi, or 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazoiium-3-suuifat or 2-ter / -Butyi-5-methyl-isoxazoIium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl, or bis- (2-oxo-3-oxazolidinyl) -phosphoryichloride, or ( ) - (benzotriazol-1-yn) -NNN 'N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) -1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or 0- (7-
  • Benzotriazole-1-ylxytris (dimethylamino) -phosphonium hexafluorophosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or A r -hydroxysuccinimide, or mixtures thereof, with bases.
  • the condensation is carried out with PyBOP, TBTU or with EDC in the presence of HOBt.
  • the compounds of the formula (Ia) according to the invention can be prepared by reacting a compound of the formula (VIIa)
  • R 1a , R 2a , R 3a , R 4a and B a have the meanings given above, under the conditions given above in a Dieckmann condensation reaction.
  • the compounds of the formula (VIIa) can be prepared by reacting compounds of the formula (Va) or a salt of compounds of the formula (Va) in which B has the abovementioned meaning, with compounds of the formula (VIII)
  • the compounds of the formula (VIIIa) can be prepared by reacting the compounds of the formula (IVa) in which R 1a and R 2a have the meanings mentioned above in a Suzuki reaction under the abovementioned conditions with compounds of the formula (IIIa ), in
  • R 3a, R 4a and A a have the meanings given above.
  • the compounds of the forms required for synthesis route A and B! (Va) or salts of compounds of the forms! (Va), in which B a has the meaning given above, can be prepared by mixing the compound of the forms! (IXa) or a salt of the compound of the forms! (IXa)
  • the compound of the formula (Xa) can be prepared by reacting the compound of the formula (XIa)
  • ⁇ -NM R 400MHz, DMSO-d 6 : ⁇ fppm j 1.09 - 1.27 (m, 1H), 1.30 - 1.41 (m, 2H), 1.51 - 1.72 (m, 51 1).
  • the cooled reaction mixture was poured onto 800 ml of ice water and acidified with aqueous hydrochloric acid.
  • the crude product was filtered off, dried and purified by chromatography on silica gel (hexane / ethyl acetate gradient). Evaporation gave 4.1 g (69% of theory) of the titer compound.
  • V.2-b Example ⁇ -1-alS of WO03 / 059065
  • the product was taken up in methylene chloride, extracted with 50 ml of 1N aqueous sodium hydroxide solution, the aqueous phase acidified with aqueous 1 N hydrochloric acid, filtered off with suction, washed with water, slurried with 25 ml of hot acetonitrile on the ultrasonic bath, filtered off with suction, washed and dried. 5.70 g (55% of theory) of the title compound were obtained.
  • Example 1-6 3- (3 ', 4'-Difluoro-4-methylbiphenyl-3-yl) -8,8-difluoro-4-hydroxy-1-azaspiro [4.5] dec-3-en-2-one
  • the hACC 1 inhibitory activity of the substances of this invention was measured in the hACC 1 assay described in the following paragraphs.
  • enzyme activity is measured by quantifying the adenosine di-phosphate (ADP) formed as a by-product of the enzyme reactions using the ADP-Gio TM detection system from Promega.
  • ADP adenosine di-phosphate
  • ATP adenosine triphosphate
  • ADP-GLO reagent an adenylate cyclase
  • kinase detection reagent is then converted the formed ADP into ATP and converted this in an iuciferase-based reaction into a glow luminescence signal.
  • Carboxylase alpha transcript variant 1 (GenBank Accession No. NM l 98834) (amino acids 39 end), expressed in baculovirus-fixed insect lines (Hi5) and purified by anti-FLAG affinity chromatography.
  • the reaction was stopped by adding 2.5 ⁇ L of the "ADP-GLO reagent" (diluted 1: 1 to 5 L) and the resulting mixture incubated for 1 h at 22 ° C to fully add the unreacted ATP to cAMP Subsequently 2.5 ⁇ of the "Kinase Detection Reagent" (1.2 times more concentrated than indicated by the manufacturer) were added, the resulting mixture incubated for 1 h at 22 ° C and then the luminescence with a suitable instrument (Viewlux or Topcount from Perkin -Elmer or Pherastar from BMG Labtechnologies). The amount of light emitted was taken as a measure of the amount of ADP formed and thus of the enzyme activity of the liACCl.
  • test substance was incubated on the same microtiter plates at 10 different concentrations in the range from 20 ⁇ to 1 nM (20 ⁇ , 6.7 ⁇ , 2.2 ⁇ , 0.74 ⁇ , 0.25 ⁇ , 82 ⁇ , 27 ⁇ , 9.2 ⁇ , 3.1 M and 1 nM, the
  • Serial dilutions were assayed at the level of 10X concentrated solution prior to assay by serial 1: 3 dilutions) in duplicate values for each concentration and IC 50 values were calculated using a 4-parameter fit using in-house software.
  • the hACC2 inhibitory activity of the substances of this invention was measured in the hACC2 assay described in the following paragraphs.
  • enzyme activity is measured by quantifying the adenosine di-phosphate (ADP) formed as a by-product of the enzyme reactions using the ADP-Gio TM detection system from Promega.
  • ADP adenosine di-phosphate
  • ATP adenosine triphosphate
  • ADP-GLO reagent an adenylyceyciase
  • kinase detection reagent is then converted the formed ADP into ATP and converted this in an iuciferase-based reaction into a glow luminescence signal.
  • the enzyme used was recombinant C-terminal FLAG-tagged human ACC2 (acetyl-coenzyme A carboxylase 2, GenBank Accession No. NP 001084) (amino acids 27- end) expressed in bacillus irus-fixed insect cells (Hi5) and purified by anti -FLAG-affinity chromatography.
  • test substance was incubated on the same microtiter plates at 10 different concentrations ranging from 20 ⁇ to 1 nM (20 ⁇ , 6.7 ⁇ , 2.2 ⁇ , 0.74 ⁇ , 0.25 ⁇ , 82 ⁇ , 27 ⁇ , 9.2 ⁇ , 3.1 ⁇ M and 1 ⁇ M).
  • Serial dilutions were prepared prior to assay concentrated at the level of 1 OOfach solution by serial 1: 3 dilutions) in duplicate values for each concentration and IC 5 0- values were calculated by a 4 parameter fit using an inhouse software was used ,
  • the substances were tested in Zeii-based assays, that is, the ability of the substances to tumor cell proliferation after 96 hours
  • Luminescence values for the t 0 samples determined.
  • the dose plates for the t 96 hour time points were treated with substances diluted in growth medium.
  • the cells were then incubated at 37 ° C for 96 hours, then the luminescence values were determined for the t 96 Sumden samples.
  • Trizol RNA extraction reagent (Invitrogen) was used and purification was performed using the RNeasy Mini Kit (Qiagen).
  • DNase I (Qiagen) digestion was performed to eliminate genomic DNA.
  • total RNA analysis was performed using an RNA LabChip on an Agiient Bioanaiyzer 2100 Piatform (Agiient Technologies) and RNA concentration determined using the Peqiab NanoDrop System.
  • the "one-cycle eukaryotic target labeling assay" from Affymetrix was used and the array was subsequently read on an Affymetrix GeneChip 3000 scanner (Affymetrix)
  • the partition coefficient octanoi / water P or D is a key parameter for the estimation of membrane penetration and permeability. It is defined as the ratio of the equilibrium concentrations of a substance in the two-phase system octanoi / water.
  • c octanol concentration of the substance in the octanoi phase
  • the logP describes the distribution behavior of a substance that exists exclusively in its neutral form.
  • the logD describes the distribution behavior of a substance at a certain pH value; depending on the ionization pKa of the substance, it may be a part of the substance in ionic, some in neutral form.
  • the nine reference substances were individually dissolved in methanol. The concentration is shown in Table 1. Each ⁇ of the stock solutions were added together in an HPLC-Viai and mixed with 300 .mu.l of water. Tab. 1
  • a formamide solution was used. To this end, 7 mg of formamide were dissolved in 10 ml of methanol. ⁇ ⁇ of this stock solution was mixed with 500 ⁇ l Methanoi and 200 ⁇ l water.
  • TRANSIL Intestinal Absorption & ISA Binding Combined Assay Kit was used. This is a 96-well microtiter plate (96 well-MTP) filled with transil, which is capable of binding to MA transii and HSA transii for every eight drugs. For each drug, a series of 12 welis is available on the Transii plate. Two wells serve as reference and are filled only with buffer pH 7.4. Five more wells contain MA transii in varying increasing concentrations, the remaining five contain HSA transii in varying increasing concentrations.
  • the active ingredients were delivered in a 96 well MTP.
  • This plate is called a mother plate.
  • Per well 30 ⁇ 1 of a 10 mmol drug solution in DMSO (dimethyl sulfoxide) were included.
  • DMSO dimethyl sulfoxide
  • Warfarin whose membrane affinity and binding to HSA is known, serves to verify the accuracy of the measurement.
  • From the mutation plate was made a daughter plate with the dilution 1 to 4000 with a mixture buffer pH 7.4 and DMSO in the ratio 1 + 1 produced.
  • the active ingredient concentration per well was 2.5 ⁇ / liter, the volume per well was 400 ⁇ .
  • the 96 active ingredients from the daughter plate were distributed to a total of 12 Transii plates. Twelve times 20 ⁇ l were taken from each well of the daughter plate. The concentration in each case in the transil plate was 0.25 ⁇ / 3 ⁇ 6 ⁇ , corresponding to a dilution of 1 to 10. The content of DMSO was 5%.
  • the filled Transii plates were resuspended for two minutes each, then allowed to stand at room temperature for at least two minutes and then centrifuged at 600 rpm for five minutes. Subsequently, 20 ⁇ of supernatant was taken from each pipette of the transil plate by the pipetting robot and transferred to a separate microtiter plate. In each case, the supernatants of four Transii plates in a microtiter plate were pooled ("pooled"), so that at the end of three pooite microtiter plates each with 80 ⁇ 1 solution and an active compound concentration of 62.5 nM were present per well.
  • the pipetting robot prepared a dilution of 1 to 10 000 000 in an acetonitrile-water mixture in the ratio 8 + 2 in a separate microtiter plate from the mother plate.
  • This microtiter plate was measured using the Discovery Quant Optimize software from AB Sciex on the HPLC-MS.
  • the three gepooiten microtiter plates were measured with the software Discovery Quant Anaiyze the company AB Sciex on the HPLC-MS.
  • the binding of test substances to piasm proteins is determined by equilibrium dialysis with the aid of the Teflon Ht-Diaiysis apparatus (96well) and a semipermeable membrane (regenerated cellulose, MWCO 12-14K). This separates 150 ⁇ each of a plasma and a buffer side (50 mM phosphate buffer). The pnif substance is added to the piasm side in 2 concentrations (usually 3 and 0.3 ⁇ ) and binds to piasm proteins. The unbound portion of the test substance passes through the membrane and spreads on both sides until equilibrium is established (about 6-8 h at 37 ° C). The substance concentration on the buffer and piasm side was determined by LC-MS analysis.
  • both sides are brought to dilution with buffer or plasma on the same matrix (10% plasma) and then precipitated with methanol. From the quotient of the buffer and plasma concentration, the free (unbound) fraction (fu) is calculated.
  • the controls will be accompanied by stability samples and recovery samples.
  • the substance is diaiysed in buffer against buffer to check the non-specific binding to the apparatus and membrane and the adjustment of the equilibrium. Since dilution of the plasma occurs during the incubation by the osmotic pressure of the piasm proteins (Voiumenshift), this possible error is determined by weighing empty plasma samples and included in the calculation of the fu.
  • the equilibrium and plasma stability should not be less than 80% and at least 30% recovery.
  • a free fraction of ⁇ 1% is called high, between 1 and 10% as moderate and> 10% as low piasmaprotein binding. 3.6 Pharmacokinetic parameters
  • test substances were applied in dissolved form both for intravenous and intragastric administration, using compatible solubilizers such as PEG400 and / or ethanol in a tolerated amount.
  • test substances were applied at a dose of 0.1 -1 mg / kg.
  • the application took place in the male rat as a boius injection, in the female dog as an infusion (15 min).
  • about 100-100 l of blood samples were taken via a jugular vein catheter (rat) or from the saphenous vein (dog) After centrifuging the samples for 15 min at 3000 rpm, an aliquot of ⁇ was taken from the supernatant (plasma) and added by addition of 400 ⁇ , cold ACN or methanol (absolute).
  • the precipitated samples were frozen overnight at 20 ° C, then centrifuged again at 3000 rpm for 15 min before removing 10 ⁇ l of the clear supernatant for concentration determination, and assayed by an Agilent 1200 HPLC system with attached L CMS / MS detection.
  • test substances were intragastrically administered as a bolus to fasting male rats or female dogs at a dose of 0.3-1 mg / kg by means of a probe. At various times after application, about 100 - 1 50 ⁇ ⁇ .
  • Blood samples were taken from a juguiaris (rat) or saphenous vein (dog) catheter. The blood samples were mixed with lithium-1 leparin as anticoagulant and kept refrigerated until further processing (refrigerator). After centrifuging the samples for 15 min at 3000 rpm, an aliquot of ⁇ ⁇ was taken from the supernatant (plasma) and added by addition of 400 ⁇ . cold ACN or methanol (absolute) like.
  • the precipitated samples were frozen overnight at -20 ° C, then centrifuged for 15 min at 3000 rpm, before 1 ⁇ ⁇ of the clear supernatant was removed for concentration determination.
  • the analysis was carried out by an Agiient 1200 HPLC system with connected LCMS / MS detection
  • AUCnorm extrapolated area under the plasma concentration time profile from time zero to infinity divided by the body weight normalized dose (in kg * L / h);
  • AUC (0-tn) norm integrated area under the piasma concentration time profile from time zero to the last time a plasma concentration was measurable, divided by the body weight normalized dose (in kg * L / h);
  • Cmax Maximaie Concentration of the test chemical in plasma (in ⁇ g / L);
  • Cmax, norm maximum concentration of test chemical in plasma divided by body weight normalized dose (in kg / L);
  • tl / 2 half-life within a specified interval (here: terminal tl / 2, in h);
  • Fobs% observed oral bioavailability, AUC (0-tn) norm after i.g. Gabe divided by AUC (0-tn) norm to i.v. Administration, tmax: Time at which the maximum concentration of the test substance in the plasma is also measured.
  • the AUC (0-tn) norm is divided after administration of a microcrystalline substance suspension by the AUC (0-tn) norm after administration of a substance solution.
  • the maximum tolerable dose was determined according to the following protocol: Female nude mice (NMRI-nude (nu / nu) mice, Taconic M & B A / S) received daily a defined dose of the test substance over a period of 3 weeks observed daily for mortality and body weight. As defined in the MTD, the highest dose that could be administered was that no animal died during the treatment phase and that it did not decrease by more than 10%
  • Test substances were added to their MTD or, if this was previously not zuittein, at the highest formuierbaren in the standard vehicle dose and partly in lower dosages.
  • a prostatectominal model with hormone-independent human PC-3 cells in male nude mice (NMRI-nude (nu / nu) mice, Taconic M & B A / S) was used primarily.
  • 3 million tumor cells (suspended in medium + Matrigel) 1: 1, final 0.1 ml) were injected subcutaneously into the flank per animal. When the tumors reached 20-30 mm 2 tumor area, the mice were placed in the
  • the T / C value was calculated based on the effect on the final tumor weight: mean of the tumor weights in the treatment group divided by the mean of the tumor weights in the vehicle group. 4. Results
  • Enzyme assays together. For accurate determination of selectivity, measurements of inhibition of ACCl and ACC2 (IC50 determinations) were compared in pairs using copies of the same series of dilutions in both assays. If either the ACCl or the ACC2-IC50 determination was not evaluated due to lack of data quality, both measurements were left unconsidered and were not listed in the table. The selectivity of the inhibition of ACCl versus the inhibition of ACC2 was then determined as the average of the selectivities observed in the individual measurements.
  • Example MNM Ne s sn gr e ss n gr uu .. IC50 IC50 ACC2 / ACC1
  • ACCl expression in tumor and corresponding norma tissue was determined by microarray (FIG. 1). The expression of ACCl was significantly upregulated compared to
  • Pancreatic carcinomas 4.4 Octanol-water partition coefficients (! OgP / D), membrane affinity (log VIA) and protein binding to human serum albumin (Ka USA)
  • Table 4 shows the determined logP / D, logMA and Ka I ISA values.
  • the evaluation of the HPLC peaks was carried out via Discovery Quant Analyze. The calculation of
  • Table 5 shows the binding determined by gravity analysis to human, mouse and rat plasma proteins.
  • Table 6 shows the pharmacokinetic parameters from the rat.
  • Example 1 - 1 was applied to female nude mice (NMR! Nu / nu):
  • the MTD for a daily treatment of 100 mg daily is above 100 mg / kg
  • the MTD for a 2-day treatment with twice daily administration is above 50 mg / kg.
  • the present invention also relates to novel hair-substituted spirocyclic ketoenols of the formula (I), to a plurality of processes for their preparation and to their use as pesticides and / or herbicides and / or fungicides.
  • the invention also relates to selective herbicidal compositions which contain halogen-substituted spirocyclic ketoenols on the one hand and a compound which improves crop-surface compatibility on the other hand.
  • the present invention further relates to the enhancement of the action of pesticides containing in particular halogen-substituted spirocyclic ketoenols, by the addition of ammonium or phosphonium salts and optionally penetration promoters, the corresponding agents, processes for their preparation and their use in crop protection as insecticides and / or acaricides and / or nematicides and / or fungicides and / or for the prevention of undesired plant growth.
  • EP-A-0 262 399 and GB-A-2 266 888 disclose similarly structured compounds (3-arylpyrrolidine-2,4-diones), but of which no herbicidal, insecticidal or acaricidal activity has become known.
  • Unsubstituted, bicyclic 3-arylpyrrolidine-2,4-dione derivatives are known having herbicidal, insecticidal or acaricidal activity (EP-A-355 599, EP-A-415 21 1 and J-A-12-053 670) and substituted monocyclic 3-arylpyrrolidine-2,4-dione derivatives (EP-A-377 893, EP-A-442 077 and WO 10/066780).
  • EP-A-442 073 polycyclic 3-arylpyrrolidine-2,4-dione derivatives
  • EP-A-456 063, EP-A-521 334, EP-A A-596 298, EP-A-613 884, EP-A-613 885, WO 95/01 971, WO 95/26 954, WO 95/20 572, EP-A-0 668 267, WO 96/25 395 , WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97/36 868, WO 97/43275, WO 98/05638, WO 98/06721, WO 98/25928, WO 99/24437, WO 99/43649, WO 99/48869, WO 99/55673, WO 01/17972, WO 01/23354, WO 01/74770, WO 03/013249, WO
  • ketalsubstituted 1-H-arylpyrrolidine-2,4-diones from WO 99/16748 and (spiro) - ketal-substituted N-alkoxy-alkoxy-substituted aryl-pyrrolidinediones are known from JP-A-14 205 984 and Ito M. et al .. Bioscience, Biotechnology and Biochemistry 67, 1230-1238, (2003).
  • the addition of safeners to etoenols is also known in principle from WO 03/013249.
  • WO 06/024411 discloses herbicidal compositions containing ketoenoie. With pharmaceutical effect are so far known WO 2011/098433, DE-A-102010008642, DE-A-102010008643 and DE-Anmeidetechnisch 102010008640.
  • 3-aryl-A 3 -dihydrofuronone derivatives having herbicidal, acaricidal and insecticidal properties are known from EP-A-528 1 56, EP-A-647 637, WO 95/26 954, WO 96/20 196, WO 96/25 395, WO 96/35 664, WO 97/01 535, WO 97/02 243, WO 97/36 868, WO 98/05 638, WO 98/06 721, WO 99/16748, WO 98 / 25 928, WO 99/43 649, WO 99/48 869, WO 99/55 673, WO 01/23354, WO 01/74 770, WO 01/17972, WO 04/024 688, WO 04/080 962 , WO 04/1 1 1042, WO 05/092 897, WO 06/000 355, WO 06/029 799, WO 07/048545
  • W is hydrogen, halogen, Aikyi, alkenyl, alkynyl, optionally substituted cycloalkyl, aikoxy, alkenyloxy, haloalkyl, haloalkoxy or cyano,
  • Y and Z independently of one another represent hydrogen, aikyl, alkenyl, alkynyl, optionally substituted cycloalkyl, aikoxy, halogen, haloalkyl, haloalkoxy, cyano, nitro or in each case optionally substituted aryl or hetaryl,
  • A is halogen
  • B is halogen or a bond to the adjacent carbon atom, with the proviso that A and B are in the 3 ' and / or 4' position,
  • D is Nl or oxygen
  • G is hydrogen (a) or one of the groups
  • E is a metal ion or an ammonium ion
  • L is oxygen or sulfur
  • M is oxygen or sulfur
  • R l is in each case optionally halogen or cyano-substituted alkyl, alkenyl, alkoxyalkyl, alkylthioalkyl or polyalkoxyalkyl or in each case optionally by halogen, alkyl or Aikoxy substituted cycloalkyl or heterocyclyl or is in each case optionally substituted phenyl, phenylalkyl, hetaryi, phenoxyalkyl or hetaryloxyalkyl
  • R 2 is in each case optionally substituted by halogen or cyano alkyl, alkenyl, alkoxyalkyl or polyalkoxyalkyl or individually optionally substituted cycloalkyl, phenyl or benzyl .
  • R ⁇ R.4 and independently of one another are each optionally halogen-substituted alkyl, aikoxy, alkylamino, dialkylamino, alkylthio, alkenyithio or cycloalkylthio or each optionally substituted phenyl, benzyl, phenoxy or phenylthio, and R 'independently of one another represent hydrogen, for in each case optionally substituted by halogen or cyano-substituted alkyl, cycloalkyl, alkenyl, Aikoxy, alkoxyalkyl, in each case optionally substituted phenyl or benzyl, or together with the N-atom to which they are attached, an optionally oxygen or sulfur-containing and optionally substituted Cycius form.
  • the compounds of the formula (I) can also be present in different compositions as optical isomers or mixtures of isomers, which can optionally be separated in a customary manner. Both the pure isomers and the mixtures of isomers, their preparation and use and agents containing them are the subject of the present invention. In the following, however, for the sake of simplicity, reference is always made to compounds of the formula (I), although both the pure compounds and, if appropriate, mixtures with different proportions of isomeric compounds are meant.
  • A, B, E, L, M, W, X, Y, Z, R 1 . R 2 . R 3 , R 4 . R 5 , R 6 and R 7 have the meanings given above. Including the different meanings (a), (b), (c), (d), (e), (f) and (g) of the group G, the following main structures (1-2 -a) to ( ⁇ -2-g), when D is oxygen,
  • A, B, E, LM W, X, Y, Z, RR 2 . R 3 , R 4 . R 5 , R 6 and R 7 have the abovementioned meaning.
  • A, B, W, X, Y and Z have the meanings given above, if one
  • A, B. W, X, Y and Z have the meanings given above, and
  • R 8 is alkyl (preferably C j -Cg-alkyl), in the presence of a diluent and in the presence of a base intramolecularly condensed.
  • Hal is halogen (in particular chlorine or bromine) or ⁇ ) with carboxylic anhydrides of the formula (V)
  • R ' has the abovementioned meaning, if appropriate in the presence of a diluent and if appropriate in the presence of an acid binder;
  • R ⁇ and M have the meanings given above, if appropriate in the presence of a diluent and if appropriate in the presence of an acid binder;
  • M and R have the meanings given above, if appropriate in the presence of a diluent and if appropriate in the presence of an acidifier,
  • R ' has the abovementioned meaning, if appropriate in the presence of a diluent and if appropriate in the presence of an acid binder,
  • Hal is halogen (in particular chlorine or bromine), if appropriate in the presence of a diluent and if appropriate in the presence of an acid binder,
  • Me is a monovalent or divalent metal (preferably an alkali or alkaline earth metal such as lithium, sodium, potassium, magnesium or calcium), t is the number 1 or 2 and
  • R 'R' R '' independently of one another are hydrogen or alkyl (preferably C j -Cg -alkyl), if appropriate in the presence of a diluent,
  • OH OH or its ester in the presence of a solvent, in the presence of a catalyst (eg Pd complexes) and in the presence of a base (for example sodium carbonate, potassium phosphate),
  • a catalyst eg Pd complexes
  • a base for example sodium carbonate, potassium phosphate
  • Y-ol (XV) in the presence of a solvent in the presence of a copper (e.g., Cu-I-J) and in the presence of a base (e.g., potassium tert -butylate, sodium hydride) exchanges the bromine or iodine atom.
  • novel compounds of the formula (I) have very good activity as pesticides, preferably as insecticides, acaricides, nematicides, fungicides and herbicides, moreover, in particular, in particular to crop plants, are very well plant-tolerated and / or over favorable toxicological and / or environmental properties feature.
  • the invention also relates to selective herbicidal compositions containing an effective content of a combination of active substances comprising as components a ') at least one compound of formula (1) in which A, B, D, G, W, X, Y and Z are the above have meaning indicated and
  • the safeners are preferably selected from the group consisting of:
  • RA is halogen, (Ci-C 4 ) Alkyi, (Ci-C 4 ) Aikoxy, Nitro or (Ci-C 4 ) Haloalkyi;
  • W A m A is 0 or 1;
  • R A 2 is OR A 3 , SR A 3 or NR A 3 R A 4 or a saturated or unsaturated 3- to 7-membered heterocycle having at least one N atom and up to 3 heteroatoms, preferably from the group O and S, which is connected via the N-atom with the carbonyl group in (S l) and unsubstituted or substituted by radicals from the group (Ci-G alkyl, (Ci-C4) alkoxy or optionally substituted phenyl, preferably a radical of the formula OR A 3 , NHRA 4 or N (CH 3 ) 2 , in particular of the formula ORA 3 ;
  • R A 3 is hydrogen or an unsubstituted or substituted aliphatic hydrocarbon radical, preferably having a total of 1 to 18 C atoms;
  • R A 4 is hydrogen, (Ci-CejAlkyi, (Ci-CöjAlkoxy or substituted or unsubstituted phenyl;
  • R A 5 is I (Ci-Cs) alkyl, (Ci-C 8 ) haloaikyl, (Ci-C 4 ) alkoxy (Ci-C 8 ) alkyl, cyano or COOR A 9 , where R A 9 hydrogen, Ci-C 8) alkyl, (Ci-C 8) haloalkyl, (Ci-C 4) alkoxy (Ci-C 4) alkyl, (Ci-C 6) hydroxyalkyl, (C3-Ci2) -cycloalkyl or tri- (C 1 -C 4 ) -alkyl-silyl;
  • R A 6 , R A 7 , R A 8 are identical or different hydrogen, (Ci-C 8 ) alkyl, (Ci-Cs) haloalkyl, (C 3 -C 12) cycloalkyl or substituted or unsubstituted phenyl; preferably: a) compounds of the type of dichlorophenylpyrazoline-3-carboxylic acid (S l a ), preferably compounds such as 1- (2,4-dichlorophenyl) -5-ethoxycarbonyl) -5-methyl-2-pyrazolinyl-3-carboxylic acid, l - (2,4-Dichloiphenyl) -5-ethoxycarbonyl) -5-methyl-2-pyrazoline-3-carboxylic acid ethyl ester (S l -1) ("Mefenpyr-diethyl”), and related compounds, as described in WO -A-91/07874; b) derivatives of Dichlor
  • 5-Diphenyipyrazoi-3-carboxylic acid (S l c ), preferably compounds such as ethyl 1- (2,4-dichlorophenyl) -5-phenyl-pyrazole-3-carboxylate (S 1 -5), l - (2-chlorophenyl) -5 phenylpyrazole-3-carboxylic acid methyl ester (S l -6) and related compounds as described, for example, in EP-A-268554; d) compounds of the type of the triazolecarboxylic acids (S l d ), preferably compounds such as fenchlorazole (ethyl ester), ie 1- (2,4-dichlorophenyl) -5-trichloromethyl- (III) -1,4,4-triazole-3 -carboxylic acid ethyl ester (S l -7), and related compounds as described in EP-A-174 562 and EP-A-346 620;
  • RB 1 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, nitro or (C 1 -C 4 ) haloalkyl;
  • n is a natural number of 0 to 5, preferably 0 to 3;
  • RB 2 is OR B 3 , SR b 3 or NR B 3 R B 4 or a saturated or unsaturated 3- to 7-g lower heterocycle having at least one N atom and to to 3 heteroatoms, preferably from the group O and S, which is connected via the N-atom with the carbonyl group in (S2) and unsubstituted or by radicals from the group (Ci-C4) alkyl, (Ci-G alkoxy or optionally substituted Phenyi is substituted, preferably a radical of the formula ORB 3 , Ni l RH 4 or N (CH 3) 2, in particular the formula
  • RH ' is hydrogen or an unsubstituted or substituted aliphatic hydrocarbon radical, preferably having a total of 1 to 18 carbon atoms;
  • RH 4 is hydrogen, (C 1 -C 6) alkyl, (C 1 -C 6 -alkoxy or substituted or unsubstituted phenyl;
  • TB is a (Ci or C2) alkanediyl chain which is unsubstituted or substituted by one or two (Ci-C4) alkyl radicals or by [(Ci-C3) alkoxy] carbonyl; preferably: a) Compounds of the 8-quinolinoxyacetic acid (S2 a), preferably (5-chloro-8-quinolinoxy) acetic acid (1 -methylhexyl) ester ( "cloquintocet-mexyl”) (S2-1), (5- Chloro-8-quinolinoxy) acetic acid (l, 3-dimethyl-but-1-yl) ester
  • Rc 1 is (Ci-C 4) alkyl, (Ci-C 4) Haioalkyl, (C 2 -C 4) alkenyl, (C 2 -C 4) haloalkenyl,
  • Rc 2 , Rc 3 are identical or different hydrogen, (Ci-C 4 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, (Ci-C 4 ) haloalkyl, (C 2 -C 4) haloalkenyl, (Ci-C4) alkylcarbamoyl (Ci-C4) alkyl, (C 2 - C 4) Alkenylcarbamoyl- (Ci-C 4) alkyl, (Ci-C 4) alkoxy (Ci-C 4 ) alkyl, dioxolanyl- (C 1 -C 4 ) alkyl, thiazolyl, furyl, furylalkyl, thienyl, piperidyl, substituted or unsubstituted phenyl, or R c 2 and R c 3 together form a substituted or unsubstituted heterocyclic ring,
  • R-29148 (3-dichloroacetyl-2,2,5-trimethyl-1,3-oxazolidine) from Stauffer (S3-2), "R-28725" (3-dichloro-acetyl-2,2, -dimethyl- 1,3-oxazolidine) from Stauffer (S3-3), "Benoxacor” (4-dichloroacetyl-3,4-dihydro-3-methyl-2H-1,4-benzoxazine) (S3-4),
  • PPG-1 292 N-allyl-N - [(1,3-dioxolan-2-yl) -methyl] -dichloroacetamide
  • TI-35 (1-dichloroacetyl-azepane) from TRI Chemical RT (S3-8),
  • R D 2 is halogen, (Ci-C 4) haloalkyl, (Ci-C 4) haloalkoxy, nitro, (Ci-C 4) alkyl, (Ci-C 4) alkoxy, (Ci-C 4) alkylsulfonyl, (C -C 4 ) alkoxycarbonyl or (Ci-C 4 ) alkylcarbonyl;
  • R D 3 is hydrogen, (Ci-C 4) alkyl, (C 2 -C 4) alkenyl or (C 2 -C 4) alkynyl;
  • R D 4 is halogen, nitro, (Ci-C 4) alkyl, (Ci-C 4) haloalkyl, (Ci-C 4) haloalkoxy, (C 3 -C 6) cycloalkyl, phenyl, (Ci-C 4) alkoxy , cyano, (Ci-C 4) alkylthio, (Ci-C 4) alkyl sulfmyl, (C i -C 4) alky Isulfony 1, (Ci-C 4) alkoxycarbonyl or (Ci-C 4) alkylcarbonyl;
  • R D 5 is hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 5 -C 6 ) cycloalkenyl, phenyl or 3- to 6-membered heterocyciyl containing VD heteroatoms from the group nitrogen, Sauersioff and sulfur, wherein the seven latter radicals by v D substituents from the group halogen, (Ci-CejAlkoxy, (Ci
  • R D 6 is hydrogen, (C 1 -C 6 ) -alkyl, (C 2 -C 6 ) -alkenyl or (C 2 -C 6 ) -alkynyl, where the three latter radicals are represented by v D radicals from the group consisting of halogen, hydroxy, C 4 ) alkyl,
  • RD 7 is hydrogen, (Ci-C 4 ) alkylamino, di- (Ci-C 4 ) alkylamino, (Ci-C 6 ) alkyl, (C 3 -C 6 ) Cycioaikyi, wherein the latter two radicals by VD substituents from the
  • Rn is (Ci-C6) AlkyL (C3-C6) cycloalkyl, where the 2 latter radicals by v D substituents from the group halogen, (Ci-C4) alkoxy, (Ci-C6) haloalkoxy and (Ci-C4) alkylthio and in the case of cyclic radicals also (Ci-C4) alkyl and (Ci-C4) haloalkyl are substituted;
  • RD 4 is halogen, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, CF 3; m D 1 or 2; v D is 0, 1, 2 or 3 means: as well
  • Acylsulfamoylbenzoeklareamide for example, the following formula (S4 b ), for example, are known from WO-A-99/16744,
  • RD 8 and RD 9 independently of one another are hydrogen * , (C 1 -C 6 -alkyl, (C 3 -C 8 ) -cycloalkyl, (C 3 -C 4 ) -alkenyl, (C 3 -C 6 ) -alkynyl,
  • RD 4 is halogen, (Ci-C) alkyl, (Ci-C 4 ) alkoxy, CF 3 m D I or 2; for example, l - [4- (N-2-methoxybenzoylsulfamoyl) phenyl] -3-methylurea,
  • Carboxylic acid derivatives (S5) e.g.
  • Ethyl 3,4,5-triacetoxybenzoate 3,5-dimethoxy-4-hydroxybenzoic acid, 3,5-dihydroxybenzoic acid, 4-hydroxysalicylic acid, 4-fluorosalicyclic acid, 2-hydroxycinnamic acid, 1, 2-dihydro-2-oxo-6- trifluoromethylpyridine-3-carboxamide, 2,4-dichlorobenzoic acid, as described in WO-A-2004/084631, WO-A-2005/015994, WO-A-2005/016001.
  • RE 1 , RI 1 are each independently halogen, (Ci-C4) alkyl, (Ci-C4) aikoxy, (Ci-C4) haloalkyl, (Ci-C4) alkylamino, di- (Ci-C4) alkylamino, nitro;
  • a E is COORE 3 or COSR E 4
  • RE 3 , RE 4 are independently hydrogen, (C 1 -C 4 ) alkyl, (C 2 -C 6) alkenyl, (C 2 -C 4) alkynyl, cyanoalkyl, (C 1 -C 4) haloalkyl, phenyl, nitrophenyl, benzyl, halobenzyl , Pyridinylalkyl and alkylammonium,
  • ⁇ ! is 0 or 1 n E 2 , n E 3 are independently 0, 1 or 2, preferably:
  • N is an integer from 0 to 4 and in the case that Xi is, I, an integer from 0 to 5,
  • RF 2 is hydrogen or (Ci-C 4 ) alkyl
  • RF 3 is hydrogen, (Ci-C 8 ) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, or aryl, wherein each of the aforementioned C-containing radicals unsubstituted or by one or more, preferably is substituted for three identical or different radicals from the group consisting of halogen and alkoxy, or their salts, preferably compounds wherein nF is an integer from 0 to 2,
  • RF 3 is hydrogen, (Ci-Cs) alkyl, (C 2 -C 4 ) alkenyl, (C 2 -C 4 ) alkynyl, or aryl, wherein each of the aforementioned C-Haitigen radicals unsubstituted or by one or more, preferably up to three identical or different radicals from the group consisting of halogen and alkoxy substituted, mean, or their salts.
  • S9 Agents from the class of 3- (5-tetrazoicarbonyi) -2-quinolones (S9), e.g. 1,2-dihydro-4-hydroxy-1-ethyl-3- (5-tetrazolylcarbonyl) -2-quinolone (CAS reference no.
  • Halogen (C 1 -C 4 ) alkyl, methoxy, nitro, cyano, CF 3 , OCF 3 independently of one another O or S, an integer from 0 to 4,
  • RG 2 (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 3 -C 6 ) cycloalkyl, aryl; Benzyl, halobenzyl, RG 3 is hydrogen or (Ci-C6) alkyl, S il) active ingredients of the type of oxyimino compounds (S il), which are known as Saatbeizmittei such.
  • S il active ingredients of the type of oxyimino compounds
  • Fluorofenim (1- (4-chlorophenyl) -2,2,2-trifluoro-1-ethanone-0- (1,3-dioxolan-2-ylmethyl) oxime) (S1-l-2), which was used as a Seed pickling safener for millet is known against damage from Metolachior, and
  • Cyometrinil or “CGA-43089” ((Z) -cyanomethoxyimino (phenyl) acetonitrile) (S1-l3), which is known as a seed dressing safener for millet against damage to Metolachior.
  • S 12 active ingredients from the class of isothiochromanones (S 12), such as e.g. Methyi - [(3-oxo-1H-2-benzothiopyran-4 (3H) -ylidene) methoxy] acetate (CAS No. 205121-04-6) (S12-1) and related compounds of WO-A -1998 / 13361.
  • S 13 One or more compounds from group (S 13):
  • Naphthalene anhydride (1,8-naphthalenedicarboxylic anhydride) (S 13-1), which is known as a seed safener for maize against thiocarbamate herbicide damage
  • Fenclorim (4,6-dichloro-2-phenylpyrimidine) (S 13-2), known as safener for pretilachlor in sown rice
  • MG 191 (CAS Reg. No. 96420-72-3) (2-dichloromethyl-2-methyl-1,3-dioxolane) (S 13-5) from Nitrokemia, which is known as a safener for corn,
  • CSB (1-Bromo-4- (chloromethylsulfonyl) benzene) from Kumiai, (CAS Registry No. 54091-06-4), which is known as a safener against damage of some herbicides in rice.
  • R H ' is a (Ci-C6) haloalkyl radical
  • RH ' is hydrogen or halogen
  • R 3 , R 4 independently of one another denote hydrogen, (C 1 -C 16) alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkynyl, where each of the last-mentioned 3 radicals is unsubstituted hydroxy, cyano, (Ci-C4) alkoxy, (Ci-C4) Haloaikoxy, (Ci-C4) alkylthio, (Ci-C 4) alkylamino, di [(Ci-C 4) alkyl] -amino, [(Ci- C 4 ) alkoxy] carbonyl, [(C 1 -C 4 ) haloalkoxy] carbonyl, (C 1 -C 6) cycloalkyl which is unsubstituted or substituted, phenyl which is unsubstituted or substituted, and heterocyclyl which is unsubstituted or substituted , or (Ca-CejC
  • RH 3 (C 1 -C 4 ) alkoxy, (C 2 -C 4 ) alkenyloxy, (C 2 -C 6) aikynyloxy or (C 2 -C 4 ) haloalkoxy and
  • crop plant compatibility-improving compound [component (b ')]
  • cioquintocetmexyl, fenchlorazole ethyl ester, isoxadifenethyi, mefenpyr-diethyi, fenciorim, cumyluron, s4-1 and s4-5 are most preferred, with cloquintocet- mexyl and Mefenpyr-diethyi are particularly emphasized.
  • W preferably represents hydrogen, halogen, Cj -CG alkyl, C2-C6-alkenyl, C2-Cg-alkynyl, optionally mono- or disubstituted by C 'i -CVAlkyl. ' i - alkoxy. Fluorine, chlorine, trifluoromethyl or C 3 -C 9 -cycloalkyl-substituted C 3 -C 9 -cycloalkyl, C 1 -C -alkoxy, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy or cyano,
  • X is preferably halogen, C ' ] -Cg-alkyl.
  • CVQ j Al kenyl.
  • Y and Z are preferably each independently hydrogen, halogen, C1-Cg-alkyl, VCg-alkenyl, (VCg-alkynyl, optionally mono- to disubstituted by Cj-C2-alkyl, C 1 -C -alkoxy, fluorine, chlorine, trifluoromethyl or C 3 -C 6 -cycloalkyl-substituted C 3 -C 9 -cycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 9 -halogenoalkyl, C 1 -C 4 -haloalkoxy, cyano or for one of the (het) -aryl radicals
  • V 1 is preferably hydrogen, halo, C 1 -C 12 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, C 1 -C 4 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 4 -alkaloalkyl.
  • A is preferably halogen
  • B is preferably halogen or a bond which is bonded to the same carbon atom as A, with the proviso that A and B are in the 3 ' and / or 4 ' position,
  • D is preferably NH or oxygen
  • G is preferably hydrogen (a) or one of the groups in which
  • E is a metal ion or an ammonium ion
  • L is oxygen or sulfur and M is oxygen or sulfur
  • R l is preferably each optionally halogen or cyano-substituted C j - C 2 ß-alkyl, C 2 -C 2 o Alkenyl, C 1 -C 8 alkoxy-C 1 -CG -alkyl, C 1 -Cg -alkylthio-C ⁇ -C 8 -alkyl or poly-C 1 -C -alkoxy-C 1 -C 6 -alkyl or optionally C 1 -C 9 -cycloalkyl which is substituted by halogen, C 1 -C 6 -cyclo or C 1 -C 4 -alkoxy and in which optionally one or two not directly adjacent methylene groups are replaced by oxygen and / or sulfur, optionally substituted by halogen, cyano, nitro, Ci-Cg-alkyl, C j -
  • Halogeno-saccharoxy, cyano or nitro-substituted phenyl or benzyl, and R 1 independently of one another preferably represent in each case halogen-substituted C 1 -C 6 -alkyl, C 1 -C -alkoxy, C 1 -C 6 -alkylamino, and di- (C 1 -C 6 -alkyl) amino, Cj -Cg-alkylthio or C3-Cg-alkenylthio or in each case optionally by halogen, nitro, cyano, C
  • Cj ⁇ alkylthio, Cj-C4 haloalkylthio, i -C '4-A lkyl or C] -C4-I lalogenalkyl substituted phenyl, phenoxy or phenylthio, and R'"independently of one another preferably represent hydrogen, represent in each case optionally C 1 -C 6 -alkyl substituted by halogen or cyano, C 3 -C 9 -cycloalkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -alkyl or C 1 -C 6 -alkoxy-C 2 -C 6 -alky 1, each being optionally halogen, Cj -Cg-alkyl, C
  • halogen is fluorine, chlorine, bromine and iodine, in particular fluorine, chlorine and bromine.
  • W is particularly preferably hydrogen, chlorine, bromine, C] - ' 4-alkyl.
  • X is particularly preferably chlorine, bromine, iodine, C] - ' 4-A! Kyl.
  • Y and Z are particularly preferably independently of one another hydrogen, fluorine, chlorine, bromine, iodine, C 1 -C 4 -alkyl.
  • V ' is particularly preferably hydrogen, fluorine, chlorine, bromine, C] -Cg-alkyl, C] -C ' 4-alkoxy.
  • V are particularly preferably independently of one another hydrogen, fluorine, chlorine, bromine,
  • D is particularly preferably NH or oxygen
  • G is particularly preferably hydrogen (a) or one of the groups
  • E is a metal ion or an ammonium ion
  • L is oxygen or sulfur
  • M is oxygen or sulfur
  • I particularly preferably represents in each case optionally monosubstituted to trisubstituted by fluorine or chlorine C ' i -C] 6 -A!
  • C] -C -l-lalogenalkyl C] -C3-I lalogenalkoxy.
  • R ⁇ particularly preferably represents in each case optionally mono- to trisubstituted by fluorine or chlorine-substituted Cj -Cig-AlkyL CVC
  • R ' is particularly preferably optionally mono- to trisubstituted by fluorine or chlorine j -CG alkyl or in each case optionally mono- to disubstituted by fluorine, chlorine, bromine,' i - ( '4-alkyl, i -C' 4-alkoxy, C 1 -C 2 haloalkoxy, cyano or nitro, substituted phenyl or benzyi,
  • R ⁇ and R ⁇ are, independently of one another particularly preferably represent hydrogen, represent in each case optionally mono- to trisubstituted by fluorine or chlorine Cj -CG alkyl, '3-Cg cycloalkyl, Cj-Cg-alkoxy, C3-Cg alkenyl, or Cj -Cg-alkoxy-C2-Cg-alkyl, each optionally optionally mono- to trisubstituted by fluorine, chlorine, bromine, j -C j -I lalogenalkyl.
  • halogen is fluorine, chlorine and bromine, in particular fluorine and chlorine.
  • W is very particularly preferably hydrogen, chlorine, bromine, methyl, ethyl, vinyl, ethynyl, propynyl, cyclopropyl, methoxy, ethoxy or trifluoromethyl,
  • X is very particularly preferably chlorine, bromine, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, cyclopropyl, methoxy, ethoxy, trifluoromethyl, difluoromethoxy,
  • Trifluoromethoxy or cyano, Z are very particularly preferably, independently of one another, hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, vinyl, ethynyl, propynyl, cyclopropyl, methoxy, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, cyano or a phenyl radical,
  • radicals Y or Z may be phenyl, very particularly preferably represents hydrogen, fluorine or chlorine,
  • V 2 very particularly preferably represents hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl. Methoxy, ethoxy or trifluoromethyl,
  • a very particularly preferably represents fluorine
  • B very particularly preferably represents fluorine or a bond which is bonded to the same carbon atom as A
  • D is most preferably NU. or oxygen, very particularly preferably represents hydrogen (a) or one of the groups
  • E is a metaiiion or an ammonium ion
  • M is oxygen or sulfur
  • R 1 very particularly preferably represents in each case optionally monosubstituted to trisubstituted by fluorine or chlorine, C 1 -C 1 -alkyl, C 2 -C 1 2-alkenyl, C 1 -C 4 -alkoxy C 1 -C 4 -CValkyl.
  • C 1 -C 4 -alkylthio-C 1 -C 2 -alkyl or C 3 -C 6 -cycloalkyl which is optionally monosubstituted by fluorine, chlorine, methyl, ethyl or methoxy, where appropriate once to twice by fluorine, chlorine, bromine, cyano, nitro, methyl, Ethyl, n-propyl, i-propyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy-substituted phenyl, in each case optionally monosubstituted by chlorine, bromine or methyl, furanyl, thienyl or pyridyl,
  • R ⁇ very particularly preferably represents in each case optionally mono- to trisubstituted by fluorine or chlorine -substituted C 1 -C 10 -alkyl, C 1 -C 4 ((-alkenyl or C 1 -C 4 -alkoxy-C 1 -alkyl) for cyclopentyl or cyclohexyl or for each optionally mono- to disubstituted by fluorine, chlorine, cyano, nitro, methyl, ethyl, methoxy, trifluoromethyl or trifluoromethoxy substituted phenyl or benzyl, is very particularly preferably each optionally monosubstituted to trisubstituted by fluorine or chlorine methyl, ethyl, propyl or iso-propyl, or in each case optionally monosubstituted by fluorine, chlorine, bromine, methyl, ethyl, isopropyl, tert-butyl, me
  • R ⁇ and R ⁇ are, independently of one another very particularly preferably represent C i - '4-alkoxy or 1-C4 alkylthio AI or in each case optionally monosubstituted by fluorine, chlorine, bromine, nitro, cyano, methyl, methoxy, trifluoromethyl or trifluoromethoxy
  • phenyl, phenoxy or phenylthio, and R ⁇ independently of one another very particularly preferably represent hydrogen, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, C 3 -C 4 -alkenyl or C 1 -C 4 -alkyl -Alkoxy- -C ⁇ alkyL optionally for once to twice by fluorine, chlorine, bromine, methyl, methoxy or
  • Trifluoromethyl-substituted phenyl or together for a C5 -Cg-alkylene radical, in which optionally a methylene group is replaced by oxygen or sulfur.
  • W is particularly preferably hydrogen, chlorine, bromine, methyl, ethyl or methoxy, (highlighted for hydrogen, methyl or ethyl),
  • X is particularly preferably chlorine, bromine, methyl, ethyl, methoxy or ethoxy (highlighted for chlorine, methyl or ethyl)
  • Y and Z are particularly preferably independently of one another hydrogen, chlorine, bromine, methyl, Trifluoroethoxy or for the rest
  • V 1 particularly preferably represents fluorine or chlorine
  • V 2 particularly preferably represents hydrogen, fluorine or chlorine, (highlighted for hydrogen, likewise highlighted for fluorine), V
  • Z stands for hydrogen, bromine, A particularly preferably represents fluorine, B particularly preferably represents fluorine or a bond, where A and B are bonded to the same carbon atom in the 4 'position, D is particularly preferably NH or oxygen, G is particularly preferably hydrogen ( a) or for one of the groups (G stands for groups (a), (b) or (c)), in soft
  • E is a metal ion or an ammonium ion
  • R ' is particularly preferred for Ci-Cj Q alkyl, C ⁇ -C 4 -alkoxy-C ⁇ -C 2 alkyl, CSS-Cg-cycloalkyl, optionally unsubstituted or chlorine-substituted phenyl or thienyl, (highlighted for Cj -C ⁇ alkyl), is particularly preferably C] -C] Q-alkyl, CVC ' i Q-alkenyl or benzyi, (highlighted for C ⁇ -C ⁇ Q-alkyl).
  • G is hydrogen.
  • Saturated or unsaturated hydrocarbon radicals such as alkyl, alkanediyl or alkenyl may also be used in conjunction with heteroatoms, e.g. in alkoxy, as far as possible, in each case straight-chain or branched.
  • optionally substituted radicals may be monosubstituted or polysubstituted, with multiple substituents the substituents being the same or different.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Plant Pathology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Furan Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP12703559.0A 2011-02-17 2012-02-14 Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie und halogensubstituierte spirocyclische ketoenole Withdrawn EP2675789A1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12703559.0A EP2675789A1 (de) 2011-02-17 2012-02-14 Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie und halogensubstituierte spirocyclische ketoenole

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161443852P 2011-02-17 2011-02-17
EP11154805 2011-02-17
DE102011080405A DE102011080405A1 (de) 2011-08-04 2011-08-04 Substituierte 3-(Biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur Therapie
EP12703559.0A EP2675789A1 (de) 2011-02-17 2012-02-14 Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie und halogensubstituierte spirocyclische ketoenole
PCT/EP2012/052521 WO2012110519A1 (de) 2011-02-17 2012-02-14 Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie und halogensubstituierte spirocyclische ketoenole

Publications (1)

Publication Number Publication Date
EP2675789A1 true EP2675789A1 (de) 2013-12-25

Family

ID=46671961

Family Applications (2)

Application Number Title Priority Date Filing Date
EP12703559.0A Withdrawn EP2675789A1 (de) 2011-02-17 2012-02-14 Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie und halogensubstituierte spirocyclische ketoenole
EP12703558.2A Withdrawn EP2675788A1 (de) 2011-02-17 2012-02-14 Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP12703558.2A Withdrawn EP2675788A1 (de) 2011-02-17 2012-02-14 Substituierte 3-(biphenyl-3-yl)-8,8-difluor-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-one zur therapie

Country Status (7)

Country Link
US (2) US8946124B2 (enExample)
EP (2) EP2675789A1 (enExample)
JP (2) JP5905908B2 (enExample)
CN (2) CN103492367B (enExample)
BR (1) BR112013021021A2 (enExample)
CA (1) CA2827398A1 (enExample)
WO (2) WO2012110519A1 (enExample)

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3670496A3 (en) 2013-10-17 2020-09-30 Shionogi&Co., Ltd. Acc2 inhibitors
WO2016022520A1 (en) * 2014-08-05 2016-02-11 Kyung-An Han Composition and methods for modulation of the octopamine receptor and its homologs
IL313498A (en) 2014-10-06 2024-08-01 Vertex Pharma Modulators of the cystic fibrosis transmembrane conductance regulator
CN106674323B (zh) * 2015-11-05 2019-10-22 苏州博创园生物医药科技有限公司 具有acc1蛋白调控作用的五环三萜类化合物及其用途
KR102671723B1 (ko) 2016-01-15 2024-06-04 바이엘 크롭사이언스 악티엔게젤샤프트 치환된 2-아릴에탄올의 제조 방법
EP3436446B1 (en) 2016-03-31 2023-06-07 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11220511B2 (en) 2016-08-04 2022-01-11 Bayer Cropscience Aktiengesellschaft Process for preparing spiroketal-substituted cyclic ketoenols
HRP20211683T1 (hr) 2016-09-30 2022-03-04 Vertex Pharmaceuticals Incorporated Modulator transmembranskog regulatora provodljivosti cistične fibroze, farmaceutski pripravci, postupci liječenja, i postupak za pripravu modulatora
MX2021013639A (es) 2016-12-09 2022-09-30 Vertex Pharma Forma cristalina del compuesto 1, un modulador del regulador de conductancia transmembrana de fibrosis quística, procesos para su preparación, composiciones farmacéuticas del compuesto 1, y su uso en el tratamiento de fibrosis quística.
CN108721304B (zh) * 2017-04-17 2020-10-16 北京大学 用于治疗肿瘤的药物组合物及其用途
AU2018279646B2 (en) 2017-06-08 2023-04-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
AU2018304168B2 (en) 2017-07-17 2023-05-04 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
TWI799435B (zh) 2017-08-02 2023-04-21 美商維泰克斯製藥公司 製備化合物之製程
US10743535B2 (en) 2017-08-18 2020-08-18 H&K Solutions Llc Insecticide for flight-capable pests
WO2019079760A1 (en) 2017-10-19 2019-04-25 Vertex Pharmaceuticals Incorporated CRYSTALLINE FORMS AND COMPOSITIONS OF CFTR MODULATORS
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
TWI810243B (zh) 2018-02-05 2023-08-01 美商維泰克斯製藥公司 用於治療囊腫纖化症之醫藥組合物
MA52187A (fr) * 2018-04-13 2021-02-17 Bayer Ag Formulation solide de melanges insecticides
WO2019200246A1 (en) 2018-04-13 2019-10-17 Alexander Russell Abela Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
CN112770742A (zh) 2018-07-27 2021-05-07 阿佩塔生物科学有限公司 用于治疗蠕形螨引起的眼部和面部疾病的多杀菌素制剂
TWI767148B (zh) 2018-10-10 2022-06-11 美商弗瑪治療公司 抑制脂肪酸合成酶(fasn)
CN118164897B (zh) * 2024-03-11 2024-11-15 南开大学 一种螺环特胺酸类化合物及其制备方法和应用
CN119842724B (zh) * 2025-03-24 2025-07-15 浙江农林大学 台湾乳白蚁Or-43884基因及其在防治白蚁中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060292073A1 (en) * 2005-06-23 2006-12-28 Emory University Stereoselective Synthesis of Amino Acid Analogs for Tumor Imaging

Family Cites Families (212)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2842476A (en) 1953-04-23 1958-07-08 Mclaughlin Gormley King Co Insecticidal compositions
US4272417A (en) 1979-05-22 1981-06-09 Cargill, Incorporated Stable protective seed coating
US4245432A (en) 1979-07-25 1981-01-20 Eastman Kodak Company Seed coatings
DE3008186A1 (de) 1980-03-04 1981-10-15 Hoechst Ag, 6000 Frankfurt Synergistische kombinationen von phosphinothricin
US4362682A (en) 1980-08-21 1982-12-07 Badische Corporation Chip-free staple fiber process
MA19709A1 (fr) 1982-02-17 1983-10-01 Ciba Geigy Ag Application de derives de quinoleine a la protection des plantes cultivees .
DE3382743D1 (de) 1982-05-07 1994-05-11 Ciba Geigy Verwendung von Chinolinderivaten zum Schützen von Kulturpflanzen.
EP0106258A3 (de) 1982-10-09 1985-05-15 Heinz Dipl.-Ing. Hölter Verfahren zur kontinuierlichen Nutzung von Abfall, vorzugsweise Müll und Klärschlamm
EP0131624B1 (en) 1983-01-17 1992-09-16 Monsanto Company Plasmids for transforming plant cells
BR8404834A (pt) 1983-09-26 1985-08-13 Agrigenetics Res Ass Metodo para modificar geneticamente uma celula vegetal
JPS6087254A (ja) 1983-10-19 1985-05-16 Japan Carlit Co Ltd:The 新規尿素化合物及びそれを含有する除草剤
DE3525205A1 (de) 1984-09-11 1986-03-20 Hoechst Ag, 6230 Frankfurt Pflanzenschuetzende mittel auf basis von 1,2,4-triazolderivaten sowie neue derivate des 1,2,4-triazols
BR8600161A (pt) 1985-01-18 1986-09-23 Plant Genetic Systems Nv Gene quimerico,vetores de plasmidio hibrido,intermediario,processo para controlar insetos em agricultura ou horticultura,composicao inseticida,processo para transformar celulas de plantas para expressar uma toxina de polipeptideo produzida por bacillus thuringiensis,planta,semente de planta,cultura de celulas e plasmidio
EP0191736B1 (de) 1985-02-14 1991-07-17 Ciba-Geigy Ag Verwendung von Chinolinderivaten zum Schützen von Kulturpflanzen
EP0221044B1 (en) 1985-10-25 1992-09-02 Monsanto Company Novel plant vectors
ATE57390T1 (de) 1986-03-11 1990-10-15 Plant Genetic Systems Nv Durch gentechnologie erhaltene und gegen glutaminsynthetase-inhibitoren resistente pflanzenzellen.
DE3773384D1 (de) 1986-05-01 1991-10-31 Honeywell Inc Verbindungsanordnung fuer mehrere integrierte schaltungen.
JPS638302A (ja) 1986-06-27 1988-01-14 Kao Corp 殺生剤用効力増強剤
JPH0618761B2 (ja) 1986-07-14 1994-03-16 花王株式会社 粒状農薬の製造方法
IL83348A (en) 1986-08-26 1995-12-08 Du Pont Nucleic acid fragment encoding herbicide resistant plant acetolactate synthase
US5013659A (en) 1987-07-27 1991-05-07 E. I. Du Pont De Nemours And Company Nucleic acid fragment encoding herbicide resistant plant acetolactate synthase
US4925868A (en) 1986-08-29 1990-05-15 Takeda Chemical Industries, Ltd. 4-Hydroxy-3-pyrrolin-2-ones and treatment of circulatory disorders therewith
DE3633840A1 (de) 1986-10-04 1988-04-14 Hoechst Ag Phenylpyrazolcarbonsaeurederivate, ihre herstellung und verwendung als pflanzenwachstumsregulatoren und safener
US5078780A (en) 1986-10-22 1992-01-07 Ciba-Geigy Corporation 1,5-diphenylpyrazole-3-carboxylic acid derivatives for the protection of cultivated plants
US4808430A (en) 1987-02-27 1989-02-28 Yazaki Corporation Method of applying gel coating to plant seeds
DE3733017A1 (de) 1987-09-30 1989-04-13 Bayer Ag Stilbensynthase-gen
US5689046A (en) 1987-09-30 1997-11-18 Bayer Aktiengesellschaft Stilbene synthase gene
DE3808896A1 (de) 1988-03-17 1989-09-28 Hoechst Ag Pflanzenschuetzende mittel auf basis von pyrazolcarbonsaeurederivaten
GB8810120D0 (en) 1988-04-28 1988-06-02 Plant Genetic Systems Nv Transgenic nuclear male sterile plants
DE3817192A1 (de) 1988-05-20 1989-11-30 Hoechst Ag 1,2,4-triazolderivate enthaltende pflanzenschuetzende mittel sowie neue derivate des 1,2,4-triazols
US4985063A (en) 1988-08-20 1991-01-15 Bayer Aktiengesellschaft 3-aryl-pyrrolidine-2,4-diones
US5215570A (en) 1988-10-20 1993-06-01 Ciba-Geigy Corporation Sulfamoylphenylureas
ATE84302T1 (de) 1988-10-20 1993-01-15 Ciba Geigy Ag Sulfamoylphenylharnstoffe.
DE58907411D1 (de) 1989-01-07 1994-05-11 Bayer Ag 3-Aryl-pyrrolidin-2,4-dion-Derivate.
ATE151882T1 (de) 1989-01-17 1997-05-15 Univ Johns Hopkins Karzinomverwandtes haptoglobin (hpr)
US5759837A (en) 1989-01-17 1998-06-02 John Hopkins University Chemotherapy for cancer by inhibiting the fatty acid biosynthetic pathway
DE3929087A1 (de) 1989-09-01 1991-03-07 Bayer Ag 3-aryl-pyrrolidin-2,4-dion-derivate
DE4014420A1 (de) 1989-09-23 1991-04-04 Bayer Ag 5h-furan-2-on-derivate
DE3939010A1 (de) 1989-11-25 1991-05-29 Hoechst Ag Isoxazoline, verfahren zu ihrer herstellung und ihre verwendung als pflanzenschuetzende mittel
DE3939503A1 (de) 1989-11-30 1991-06-06 Hoechst Ag Neue pyrazoline zum schutz von kulturpflanzen gegenueber herbiziden
US5700758A (en) 1989-11-30 1997-12-23 Hoechst Aktiengesellschaft Pyrazolines for protecting crop plants against herbicides
DE4032090A1 (de) 1990-02-13 1991-08-14 Bayer Ag Polycyclische 3-aryl-pyrrolidin-2,4-dion-derivate
DE4004496A1 (de) 1990-02-14 1991-08-22 Bayer Ag 3-aryl-pyrrolidin-2,4-dion-derivate
ATE241007T1 (de) 1990-03-16 2003-06-15 Calgene Llc Dnas, die für pflanzliche desaturasen kodieren und deren anwendungen
JPH0747523B2 (ja) 1990-04-16 1995-05-24 花王株式会社 殺生剤効力増強剤
DE4107394A1 (de) 1990-05-10 1991-11-14 Bayer Ag 1-h-3-aryl-pyrrolidin-2,4-dion-derivate
EP0536293B1 (en) 1990-06-18 2002-01-30 Monsanto Technology LLC Increased starch content in plants
DE69132939T2 (de) 1990-06-25 2002-11-14 Monsanto Technology Llc Glyphosattolerante pflanzen
DE4107396A1 (de) 1990-06-29 1992-01-02 Bayer Ag Stilbensynthase-gene aus weinrebe
EP0539588A1 (en) 1990-07-05 1993-05-05 Nippon Soda Co., Ltd. Amine derivative
DE59108636D1 (de) 1990-12-21 1997-04-30 Hoechst Schering Agrevo Gmbh Neue 5-Chlorchinolin-8-oxyalkancarbonsäurederivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Antidots von Herbiziden
SE467358B (sv) 1990-12-21 1992-07-06 Amylogene Hb Genteknisk foeraendring av potatis foer bildning av staerkelse av amylopektintyp
US5811374A (en) 1991-02-07 1998-09-22 Bayer Aktiengesellschaft 3-aryl-pyrrolidine-2,4-dione derivatives
DE4104782B4 (de) 1991-02-13 2006-05-11 Bayer Cropscience Gmbh Neue Plasmide, enthaltend DNA-Sequenzen, die Veränderungen der Karbohydratkonzentration und Karbohydratzusammensetzung in Pflanzen hervorrufen, sowie Pflanzen und Pflanzenzellen enthaltend dieses Plasmide
US5352674A (en) 1991-03-25 1994-10-04 Valent U.S.A. Chemically stable granules containing insecticidal phosphoroamidothioates
DE4121365A1 (de) 1991-06-28 1993-01-14 Bayer Ag Substituierte 1-h-3-aryl-pyrrolidin-2,4-dion-derivate
DE4216814A1 (de) 1991-07-16 1993-01-21 Bayer Ag 3-aryl-4-hydroxy-(delta)(pfeil hoch)3(pfeil hoch)-dihydrofuranon- und 3-aryl-4-hydroxy-(delta)(pfeil hoch)3(pfeil hoch)-dihydrothiophenon-derivate
US5462912A (en) 1991-10-09 1995-10-31 Kao Corporation Agricultural chemical composition enhancer comprising quaternary di(polyoxyalkylene) ammonium alkyl sulfates
GB9210393D0 (en) 1992-05-15 1992-07-01 Merck Sharp & Dohme Therapeutic agents
TW259690B (enExample) 1992-08-01 1995-10-11 Hoechst Ag
DE4236400A1 (de) 1992-10-28 1994-05-05 Bayer Ag N-Phenylacetaminonitrile
AU666040B2 (en) 1992-10-28 1996-01-25 Bayer Aktiengesellschaft Substituted 1-H-3-aryl-pyrrolidine-2,4-dione derivatives
MY111077A (en) 1992-11-13 1999-08-30 Kao Corp Agricultural chemical composition
DE4306257A1 (de) 1993-03-01 1994-09-08 Bayer Ag Substituierte 1-H-3-Phenyl-5-cycloalkylpyrrolidin-2,4-dione, ihre Herstellung und ihre Verwendung
DE4306259A1 (de) 1993-03-01 1994-09-08 Bayer Ag Dialkyl-1-H-3-(2,4-dimethylphenyl)-pyrrolidin-2,4-dione, ihre Herstellung und ihre Verwendung
ES2130431T3 (es) 1993-07-05 1999-07-01 Bayer Ag Aril-cetoenolheterociclos substituidos.
DE4331448A1 (de) 1993-09-16 1995-03-23 Hoechst Schering Agrevo Gmbh Substituierte Isoxazoline, Verfahren zu deren Herstellung, diese enthaltende Mittel und deren Verwendung als Safener
EP0647637B1 (de) 1993-09-17 1999-01-27 Bayer Ag 3-Aryl-4-hydroxy-3-dihydrofuranon-Derivate
CN1112846C (zh) 1993-12-28 2003-07-02 花王株式会社 农药增效剂组合物和农药组合物
DE4401542A1 (de) 1994-01-20 1995-07-27 Hoechst Schering Agrevo Gmbh Synergistische Kombinationen von Ammoniumsalzen
DE4425617A1 (de) 1994-01-28 1995-08-03 Bayer Ag 1-H-3-Aryl-pyrrolidin-2,4-dion-Derivate
DE4431730A1 (de) 1994-02-09 1995-08-10 Bayer Ag Substituierte 1H-3-Aryl-pyrrolidin-2,4-dion-Derivate
CN1075060C (zh) 1994-04-05 2001-11-21 拜尔公司 用作除草剂和农药的烷氧基－烷基取代的1－h－3－芳基－吡咯烷－2,4－二酮
DE4416303A1 (de) 1994-05-09 1995-11-16 Bayer Ag Schaumarmes Netzmittel und seine Verwendung
ES2190790T3 (es) 1994-12-23 2003-08-16 Bayer Cropscience Ag Derivados del acido 3-aril-tetronico, su obtencion y su empleo como agentes pesticidas.
JP4036470B2 (ja) 1995-02-13 2008-01-23 バイエル・アクチエンゲゼルシヤフト 除草剤および有害生物防除剤としての２−フェニル置換複素環式１，３−ケトエノール
ES2275275T3 (es) 1995-04-20 2007-06-01 Basf Aktiengesellschaft Productos resistentes a herbicidas diseñados sobre la base de la estructura.
BR9608229A (pt) 1995-05-09 1998-12-29 Bayer Ag Cetoenóis alquil-dihalogenofenil-substituídos
RU2195449C2 (ru) 1995-06-28 2002-12-27 Байер Акциенгезельшафт 2,4,5-тризамещенные фенилкетоенолы, промежуточные соединения для их получения, способ и средство для борьбы с насекомыми и паукообразными на их основе
ES2189877T3 (es) 1995-06-30 2003-07-16 Bayer Cropscience Ag Cetoenoles dialquil-halogenofenilsubstituidos para el empleo como herbicidas y pesticidas.
US5808146A (en) * 1995-11-09 1998-09-15 Emory University Amino acid analogs for tumor imaging
CA2250417A1 (en) 1996-04-02 1997-10-09 Bayer Aktiengesellschaft Substituted phenyl keto enols as pesticides and herbicides
CN1156470C (zh) 1996-05-10 2004-07-07 拜尔公司 新的取代的吡啶基酮烯醇
DE19621522A1 (de) 1996-05-29 1997-12-04 Hoechst Schering Agrevo Gmbh Neue N-Acylsulfonamide, neue Mischungen aus Herbiziden und Antidots und deren Verwendung
US5876739A (en) 1996-06-13 1999-03-02 Novartis Ag Insecticidal seed coating
DK1277734T3 (da) 1996-08-05 2007-06-04 Bayer Cropscience Ag 2- og 2,5-substituerede phenylketoenoler
DE19632126A1 (de) 1996-08-09 1998-02-12 Bayer Ag Phenylsubstituierte cyclische Ketoenole
DE69707907T2 (de) 1996-09-26 2002-05-16 Syngenta Participations Ag, Basel Herbizid wirkende zusammensetzung
DE19651686A1 (de) 1996-12-12 1998-06-18 Bayer Ag Neue substituierte Phenylketoenole
DE19652961A1 (de) 1996-12-19 1998-06-25 Hoechst Schering Agrevo Gmbh Neue 2-Fluoracrylsäurederivate, neue Mischungen aus Herbiziden und Antidots und deren Verwendung
GB9703054D0 (en) 1997-02-14 1997-04-02 Ici Plc Agrochemical surfactant compositions
US6071856A (en) 1997-03-04 2000-06-06 Zeneca Limited Herbicidal compositions for acetochlor in rice
DE19727410A1 (de) 1997-06-27 1999-01-07 Hoechst Schering Agrevo Gmbh 3-(5-Tetrazolylcarbonyl)-2-chinolone und diese enthaltende nutzpflanzenschützende Mittel
DE19742492A1 (de) 1997-09-26 1999-04-01 Bayer Ag Spirocyclische Phenylketoenole
DE19742951A1 (de) 1997-09-29 1999-04-15 Hoechst Schering Agrevo Gmbh Acylsulfamoylbenzoesäureamide, diese enthaltende nutzpflanzenschützende Mittel und Verfahren zu ihrer Herstellung
DE19749720A1 (de) 1997-11-11 1999-05-12 Bayer Ag Neue substituierte Phenylketoenole
DE19808261A1 (de) 1998-02-27 1999-10-28 Bayer Ag Arylphenylsubstituierte cyclische Ketoenole
DE19813354A1 (de) 1998-03-26 1999-09-30 Bayer Ag Arylphenylsubstituierte cyclische Ketoenole
DE19818732A1 (de) * 1998-04-27 1999-10-28 Bayer Ag Arylphenylsubstituierte cyclische Ketoenole
JP2000053670A (ja) 1998-08-10 2000-02-22 Ube Ind Ltd アルコキシメチルフラノン誘導体及び有害生物防除剤
US6503904B2 (en) 1998-11-16 2003-01-07 Syngenta Crop Protection, Inc. Pesticidal composition for seed treatment
DE19857963A1 (de) 1998-12-16 2000-06-21 Bayer Ag Agrochemische Formulierungen
CA2382435C (en) 1999-09-07 2009-02-03 Syngenta Participations Ag Novel herbicidally active phenyl-substituted heterocycles
DE19946625A1 (de) 1999-09-29 2001-04-05 Bayer Ag Trifluormethylsubstituierte spirocyclische Ketoenole
DE10016544A1 (de) 2000-04-03 2001-10-11 Bayer Ag C2-phenylsubstituierte Ketoenole
JP2002205984A (ja) 2000-05-11 2002-07-23 Sankyo Co Ltd Ｎ−置換スピロジヒドロピロール誘導体
DE10032587A1 (de) 2000-07-05 2002-01-17 Bayer Ag 4-Alkoxy-cyclohexan-1-amino-carbonsäureester und Verfahren zu ihrer Herstellung
US6660690B2 (en) 2000-10-06 2003-12-09 Monsanto Technology, L.L.C. Seed treatment with combinations of insecticides
AR031027A1 (es) 2000-10-23 2003-09-03 Syngenta Participations Ag Composiciones agroquimicas
US20020134012A1 (en) 2001-03-21 2002-09-26 Monsanto Technology, L.L.C. Method of controlling the release of agricultural active ingredients from treated plant seeds
ATE536345T1 (de) 2001-05-31 2011-12-15 Nihon Nohyaku Co Ltd Substituierte anilidderivate, deren zwischenprodukte, chemikalien für die landwirtschaft und den gartenbau und deren verwendung
DE10139465A1 (de) 2001-08-10 2003-02-20 Bayer Cropscience Ag Selektive Herbizide auf Basis von substituierten, cayclischen Ketoenolen und Safenern
DE10201239A1 (de) 2002-01-15 2003-07-24 Bayer Cropscience Ag Fungizide biphenylsubstituierte cyclische Ketoenole
HUP0402592A2 (hu) 2002-01-22 2005-04-28 Syngenta Participations Ag Herbicidekként hasznosítható fenil-szubsztituált heterociklusos vegyületek
US6645914B1 (en) 2002-05-01 2003-11-11 Ndsu-Research Foundation Surfactant-ammonium sulfate adjuvant composition for enhancing efficacy of herbicides
US20030224939A1 (en) 2002-05-31 2003-12-04 David Miles Adjuvant for pesticides
GB0213715D0 (en) 2002-06-14 2002-07-24 Syngenta Ltd Chemical compounds
DE10231333A1 (de) 2002-07-11 2004-01-22 Bayer Cropscience Ag Cis-Alkoxysubstituierte spirocyclische 1-H-Pyrrolidin-2,4-dion-Derivate
DE10239479A1 (de) 2002-08-28 2004-03-04 Bayer Cropscience Ag Substituierte spirocyclische Ketoenole
US6984662B2 (en) 2003-11-03 2006-01-10 The Hartz Mountain Corporation High concentration topical insecticide containing insect growth regulator
US7132448B2 (en) 2002-09-12 2006-11-07 The Hartz Mountain Corporation High concentration topical insecticide containing insect growth regulator
DE10301804A1 (de) 2003-01-20 2004-07-29 Bayer Cropscience Ag 2,4-Dihalogen-6-(C2-C3-alkyl)-phenyl substituierte Tetramsäure-Derivate
DE10311300A1 (de) 2003-03-14 2004-09-23 Bayer Cropscience Ag 2,4,6-Phenylsubstituierte cyclische Ketoenole
UA90844C2 (ru) 2003-03-26 2010-06-10 Байер Кропсайенс Аг Применение гидроксиароматических соединений в качестве сафенеров, способ защиты культурных или полезных растений от фитотоксичного побочного влияния агрохимикатов и средство для защиты растений
TWI312272B (en) 2003-05-12 2009-07-21 Sumitomo Chemical Co Pyrimidine compound and pests controlling composition containing the same
DE10326386A1 (de) 2003-06-12 2004-12-30 Bayer Cropscience Ag N-Heterocyclyl-phenylsubstituierte cyclische Ketoenole
DE10335725A1 (de) 2003-08-05 2005-03-03 Bayer Cropscience Gmbh Safener auf Basis aromatisch-aliphatischer Carbonsäuredarivate
DE10335726A1 (de) 2003-08-05 2005-03-03 Bayer Cropscience Gmbh Verwendung von Hydroxyaromaten als Safener
UA79404C2 (en) 2003-10-02 2007-06-11 Basf Ag 2-cyanobenzenesulfonamide for controlling pests
DE10351646A1 (de) 2003-11-05 2005-06-09 Bayer Cropscience Ag 2-Halogen-6-alkyl-phenyl substituierte spirocyclische Tetramsäure-Derivate
DE10351647A1 (de) 2003-11-05 2005-06-09 Bayer Cropscience Ag 2-Halogen-6-alkyl-phenyl substituierte Tetramsäure-Derivate
DE10354629A1 (de) 2003-11-22 2005-06-30 Bayer Cropscience Ag 2-Ethyl-4,6-dimethyl-phenyl substituierte spirocyclische Tetramsäure-Derivate
DE10354628A1 (de) 2003-11-22 2005-06-16 Bayer Cropscience Ag 2-Ethyl-4,6-dimethyl-phenyl-substituierte Tetramsäure-Derivate
GB0329744D0 (en) 2003-12-23 2004-01-28 Koninkl Philips Electronics Nv A beverage maker incorporating multiple beverage collection chambers
DE102004001433A1 (de) 2004-01-09 2005-08-18 Bayer Cropscience Ag cis-Alkoxyspiro-substituierte Tetramsäure-Derivate
CA2553715C (en) 2004-02-18 2012-08-28 Ishihara Sangyo Kaisha, Ltd. Anthranilamide compounds, process for their production and pesticides containing them
US7388027B2 (en) 2004-03-04 2008-06-17 Bristol-Myers Squibb Company Bicyclic compounds as modulators of androgen receptor function and method
JP4883296B2 (ja) 2004-03-05 2012-02-22 日産化学工業株式会社 イソキサゾリン置換ベンズアミド化合物及び有害生物防除剤
DE102004014620A1 (de) 2004-03-25 2005-10-06 Bayer Cropscience Ag 2,4,6-phenylsubstituierte cyclische Ketoenole
DE102004023332A1 (de) 2004-05-12 2006-01-19 Bayer Cropscience Gmbh Chinoxalin-2-on-derivate, diese enthaltende nutzpflanzenschützende Mittel und Verfahren zu ihrer Herstellung und deren Verwendung
DE102004030753A1 (de) 2004-06-25 2006-01-19 Bayer Cropscience Ag 3'-Alkoxy spirocyclische Tetram- und Tretronsäuren
DE102004041529A1 (de) 2004-08-27 2006-03-02 Bayer Cropscience Gmbh Herbizid-Kombinationen mit speziellen Ketoenolen
DE102004044827A1 (de) 2004-09-16 2006-03-23 Bayer Cropscience Ag Jod-phenylsubstituierte cyclische Ketoenole
WO2006043635A1 (ja) 2004-10-20 2006-04-27 Kumiai Chemical Industry Co., Ltd. ３－トリアゾリルフェニルスルフィド誘導体及びそれを有効成分として含有する殺虫・殺ダニ・殺線虫剤
TWI360539B (en) * 2004-10-28 2012-03-21 Shionogi & Co 3-carbamoyl-2-pyridone derivatives
DE102004053191A1 (de) 2004-11-04 2006-05-11 Bayer Cropscience Ag 2,6-Diethyl-4-methyl-phenyl substituierte Tetramsäure-Derivate
DE102004053192A1 (de) 2004-11-04 2006-05-11 Bayer Cropscience Ag 2-Alkoxy-6-alkyl-phenyl substituierte spirocyclische Tetramsäure-Derivate
ES2347806T3 (es) 2004-11-26 2010-11-04 Basf Se Compuestos de 2-ciano-3-(halo)alcoxi-bencenosulfonamida novedosos para combatir plagas de animales.
DE102005008021A1 (de) 2005-02-22 2006-08-24 Bayer Cropscience Ag Spiroketal-substituierte cyclische Ketoenole
DE602006019560D1 (de) 2005-03-24 2011-02-24 Basf Se 2-cyanobenzolsulfonamidverbindungen zur behandlung von samen
JPWO2007023719A1 (ja) 2005-08-22 2009-02-26 クミアイ化学工業株式会社 薬害軽減剤及び薬害が軽減された除草剤組成物
EP1917360A2 (en) 2005-08-24 2008-05-07 Pioneer Hi-Bred International Inc. Compositions providing tolerance to multiple herbicides and methods of use thereof
WO2007023764A1 (ja) 2005-08-26 2007-03-01 Kumiai Chemical Industry Co., Ltd. 薬害軽減剤及び薬害が軽減された除草剤組成物
MX2008002802A (es) 2005-08-31 2008-04-07 Monsanto Technology Llc Secuencias nucleotidicas que codifican proteinas insecticidas.
JP2009510150A (ja) 2005-10-06 2009-03-12 ノバルティス アクチエンゲゼルシャフト Ｌｆａ−１メディエーターとしてのテトラヒドロ−ピロリジノン化合物
WO2007040280A1 (ja) 2005-10-06 2007-04-12 Nippon Soda Co., Ltd. 環状アミン化合物および有害生物防除剤
DE102005051325A1 (de) 2005-10-27 2007-05-03 Bayer Cropscience Ag Alkoxyalkyl spirocyclische Tetram- und Tetronsäuren
WO2007057407A2 (en) 2005-11-21 2007-05-24 Basf Se Insecticidal methods using 3-amino-1,2-benzisothiazole derivatives
DE102005059471A1 (de) 2005-12-13 2007-07-12 Bayer Cropscience Ag Herbizide Zusammensetzungen mit verbesserter Wirkung
DE102005059469A1 (de) 2005-12-13 2007-06-14 Bayer Cropscience Ag Insektizide Zusammensetzungen mit verbesserter Wirkung
DE102005059892A1 (de) 2005-12-15 2007-06-28 Bayer Cropscience Ag Alkylthio-spirocyclische Tetramsäuren
DE102005059891A1 (de) 2005-12-15 2007-06-28 Bayer Cropscience Ag 3'-Alkoxy-spirocyclopentyl substituierte Tetram- und Tetronsäuren
TW200803740A (en) 2005-12-16 2008-01-16 Du Pont 5-aryl isoxazolines for controlling invertebrate pests
DE102006007882A1 (de) 2006-02-21 2007-08-30 Bayer Cropscience Ag Cycloalkyl-phenylsubstituierte cyclische Ketoenole
WO2007101369A1 (fr) 2006-03-09 2007-09-13 East China University Of Science And Technology Méthode de préparation et utilisation de composés présentant une action biocide
DE102006015467A1 (de) 2006-03-31 2007-10-04 Bayer Cropscience Ag Substituierte Enaminocarbonylverbindungen
DE102006015470A1 (de) 2006-03-31 2007-10-04 Bayer Cropscience Ag Substituierte Enaminocarbonylverbindungen
DE102006015468A1 (de) 2006-03-31 2007-10-04 Bayer Cropscience Ag Substituierte Enaminocarbonylverbindungen
DE102006018828A1 (de) 2006-04-22 2007-10-25 Bayer Cropscience Ag Alkoxyalkyl-substituierte cyclische Ketoenole
DE102006025874A1 (de) 2006-06-02 2007-12-06 Bayer Cropscience Ag Alkoxyalkyl-substituierte cyclische Ketoenole
TWI381811B (zh) 2006-06-23 2013-01-11 Dow Agrosciences Llc 用以防治可抵抗一般殺蟲劑之昆蟲的方法
DE102006033154A1 (de) 2006-07-18 2008-01-24 Bayer Cropscience Ag Wirkstoffkombinationen mit insektiziden und akariziden Eigenschaften
DE102006033572A1 (de) 2006-07-20 2008-01-24 Bayer Cropscience Ag N'-Cyano-N-halogenalkyl-imidamid Derivate
DE102006039912A1 (de) 2006-08-25 2008-03-20 Bayer Healthcare Ag Substituierte Spirotetronsäuren und ihre Verwendung
DE102006050148A1 (de) 2006-10-25 2008-04-30 Bayer Cropscience Ag Trifluormethoxy-phenylsubstituierte Tetramsäure-Derivate
JP5047588B2 (ja) 2006-10-31 2012-10-10 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 キノリン誘導体およびそれを含んでなる農園芸用殺虫剤
US8202890B2 (en) 2006-11-30 2012-06-19 Meiji Seika Pharma Co., Ltd. Pest control agent
DE102006057037A1 (de) 2006-12-04 2008-06-05 Bayer Cropscience Ag cis-Alkoxyspirocyclische biphenylsubstituierte Tetramsäure-Derivate
DE102006057036A1 (de) * 2006-12-04 2008-06-05 Bayer Cropscience Ag Biphenylsubstituierte spirocyclische Ketoenole
DE102007001866A1 (de) 2007-01-12 2008-07-17 Bayer Cropscience Ag Spirocyclische Tetronsäure-Derivate
KR20090116821A (ko) 2007-03-01 2009-11-11 바스프 에스이 아미노티아졸린 화합물을 포함하는 살충 활성 혼합물
EP1987718A1 (de) 2007-04-30 2008-11-05 Bayer CropScience AG Verwendung von Pyridin-2-oxy-3-carbonamiden als Safener
EP1987717A1 (de) 2007-04-30 2008-11-05 Bayer CropScience AG Pyridoncarboxamide, diese enthaltende nutzpflanzenschützende Mittel und Verfahren zu ihrer Herstellung und deren Verwendung
EP1992614A1 (de) 2007-05-16 2008-11-19 Bayer CropScience Aktiengesellschaft 3-(2-Alkoxy-phenyl)-substituierte Tetramate
EP2020413A1 (de) 2007-08-02 2009-02-04 Bayer CropScience AG Oxaspirocyclische-spiro-substituierte Tetram- und Tetronsäure-Derivate
EP2045240A1 (de) 2007-09-25 2009-04-08 Bayer CropScience AG Halogenalkoxyspirocyclische Tetram- und Tetronsäure-Derivate
GB0720126D0 (en) 2007-10-15 2007-11-28 Syngenta Participations Ag Chemical compounds
EP2103615A1 (de) 2008-03-19 2009-09-23 Bayer CropScience AG 4'4'-Dioxaspiro-spirocyclisch substituierte Tetramate
WO2010005692A2 (en) 2008-06-16 2010-01-14 E. I. Du Pont De Nemours And Company Insecticidal cyclic carbonyl amidines
JP5268461B2 (ja) 2008-07-14 2013-08-21 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Ｐｆ１３６４物質、その製造方法、生産菌株、及び、それを有効成分とする農園芸用殺虫剤
AU2009271634A1 (en) * 2008-07-14 2010-01-21 Cropsolution, Inc. Modulators of acetyl-coenzyme a carboxylase and methods of use thereof
MX2011000477A (es) 2008-07-17 2011-03-15 Bayer Cropscience Ag Compuestos heterociclicos como pesticidas.
GB0820344D0 (en) 2008-11-06 2008-12-17 Syngenta Ltd Herbicidal compositions
TW201031335A (en) 2008-12-02 2010-09-01 Syngenta Participations Ag Chemical compounds
US8389443B2 (en) 2008-12-02 2013-03-05 Bayer Cropscience Ag Geminal alkoxy/alkylspirocyclic substituted tetramate derivatives
TWI396627B (zh) 2008-12-05 2013-05-21 Bobst Sa 在用於處理平板元件之機器中的校準方法
MX2011005795A (es) 2008-12-12 2011-06-20 Syngenta Participations Ag N-oxipiperidinas espiroheterociclicas como pesticidas.
KR101687743B1 (ko) 2008-12-18 2016-12-19 바이엘 인텔렉쳐 프로퍼티 게엠베하 살해충제로서의 테트라졸 치환된 안트라닐산 아미드
ES2589007T3 (es) 2008-12-26 2016-11-08 Dow Agrosciences, Llc Composiciones estables de insecticida de tipo sulfoximina
BRPI0923702B8 (pt) 2008-12-26 2022-10-11 Dow Agrosciences Llc Composições inseticidas estáveis compreendendo spinosin e uma mistura esteroisomérica de sulfoxaflor, e seu método de produção
CN103641709B (zh) 2009-03-11 2017-08-25 拜耳知识产权有限责任公司 被卤代烷基亚甲基氧基苯基取代的酮烯醇
WO2010113831A1 (ja) 2009-03-31 2010-10-07 東レ株式会社 発光素子材料前駆体およびその製造方法
ES2525014T3 (es) 2009-05-19 2014-12-17 Bayer Cropscience Ag Derivados de ácido tetrónico espiroheterocíclicos herbicidas
EP2435440A4 (en) 2009-05-26 2013-01-02 Syngenta Participations Ag NEW SPIROHETEROCYCLIC FURANO AND THIOFURANDION DERIVATIVES
GB0921346D0 (en) 2009-12-04 2010-01-20 Syngenta Participations Ag Chemical compounds
GB0921343D0 (en) 2009-12-04 2010-01-20 Syngenta Participations Ag Chemical compounds
GB0921344D0 (en) 2009-12-04 2010-01-20 Syngenta Participations Ag Chemical compounds
WO2011098443A1 (de) 2010-02-10 2011-08-18 Bayer Cropscience Ag Spiroheterocyclisch-substituierte tetramsäure-derivate
EP2534133B1 (de) 2010-02-10 2018-09-05 Bayer CropScience Aktiengesellschaft Biphenylsubstituierte cyclische ketoenole
DE102010008644A1 (de) 2010-02-15 2011-08-18 Bayer Schering Pharma Aktiengesellschaft, 13353 Zyklische Ketoenole zur Therapie
DE102010008642A1 (de) 2010-02-15 2011-08-18 Bayer Schering Pharma Aktiengesellschaft, 13353 Zyklische Ketoenole zur Therapie
DE102010008643A1 (de) 2010-02-15 2011-08-18 Bayer Schering Pharma Aktiengesellschaft, 13353 Zyklische Ketoenole zur Therapie

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060292073A1 (en) * 2005-06-23 2006-12-28 Emory University Stereoselective Synthesis of Amino Acid Analogs for Tumor Imaging

Also Published As

Publication number Publication date
US20140011853A1 (en) 2014-01-09
WO2012110519A1 (de) 2012-08-23
JP2014508752A (ja) 2014-04-10
WO2012110518A1 (de) 2012-08-23
US9000026B2 (en) 2015-04-07
US20140045696A1 (en) 2014-02-13
CA2827398A1 (en) 2012-08-23
CN103649049A (zh) 2014-03-19
CN103492367A (zh) 2014-01-01
BR112013021021A2 (pt) 2016-08-02
CN103492367B (zh) 2015-04-01
EP2675788A1 (de) 2013-12-25
US8946124B2 (en) 2015-02-03
JP5905908B2 (ja) 2016-04-20
JP2014506886A (ja) 2014-03-20
CN103649049B (zh) 2016-06-29
HK1193091A1 (en) 2014-09-12

Similar Documents

Publication Publication Date Title
US9000026B2 (en) Substituted 3-(biphenyl-3-yl)-8,8-difluoro-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-ones for therapy
EP2534147B1 (de) Spiroheterocyclisch-substituierte tetramsäure-derivate
EP2681191B1 (de) 2-acyloxy-pyrrolin-4-one
EP2534133B1 (de) Biphenylsubstituierte cyclische ketoenole
EP2742030B1 (de) 1,2,4-triazolyl-substituierte ketoenole zum einsatz im pflanzenschutz
EP2373619A1 (de) Geminal alkoxy/alkylspirocyclisch-substituierte tetramsäure-derivate
BRPI1011208B1 (pt) Compostos herbicidas e praguicidas derivados do ácido tetrônico espiroheterocíclico, método para a fabricação dos compostos, agentes para o controle de pragas e/ou do crescimento indesejado de plantas, método para o controle de pragas animais e/ou do crescimento indesejado de plantas, uso dos compostos, método para a fabricação dos agentes e uso dos agentes
HK1193091B (en) Substituted 3-(biphenyl-3-yl)-8,8-difluoro-4-hydroxy-1-azaspiro[4.5]dec-3-en-2-ones for therapy
BR112014003203B1 (pt) compostos cetoenóis substituídos com 1,2,4-triazolilo, composição, utilização da mesma, e métodos para o controle de vegetação indesejada

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20130917

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20140818

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: BAYER CROPSCIENCE AKTIENGESELLSCHAFT

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

INTG Intention to grant announced

Effective date: 20190311

INTC Intention to grant announced (deleted)
GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20190516

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20190927