Patent Application
20180199575
The invention relates to the use of substituted oxotetrahydroquinolinylphosphin- and -phosphonamides or salts thereof for enhancing stress tolerance in plants to abiotic stress, and for enhancing plant growth and/or for increasing plant yield.
It is known that particular aryl- and heteroaryl-substituted sulfonamides can be used as active compounds to counter abiotic plant stress (cf. WO2011/113861). The action of particular aryl-, heteroaryl- and benzylsulfonamidocarboxylic acids, -carboxylic esters, -carboxamides and -carbonitriles against abiotic plant stress is described in WO 2012/089721 and WO 2012/089722.
The preparation of sulfamidoalkanecarboxylic acids and sulfamidoalkanecarbonitriles is described in DE847006. The use of selected arylsulfonamides having alkylcarboxyl substituents as growth regulators especially for limiting the longitudinal growth of rice and wheat plants with the aim of minimizing weather-related lodging is described in DE2544859, while the fungicidal action of certain N-cyanoalkylsulfonamides is described in EP176327. It is also known that substituted N-sulfonylaminoacetonitriles can be used to control parasites in warm-blooded animals (cf. WO2004/000798). The use of 1-(4-methylphenyl)-N-(2-oxo-1-propyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamide to counter drought stress in Arabidopsis thaliana and soya is described in Proc. Natl. Acad. Sci. 2013, 110(29), 12132-12137. Further 1-aryl-N-(2-oxo-1-alkyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamides having an unbranched or branched alkyl group, but without further substitution, in the N-tetrahydroquinolinyl moiety are described in WO2013/148339, whereas WO2014/201555 describes corresponding 1-aryl-N-(2-oxo-1-alkenyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamides and 1-aryl-N-(2-oxo-1-alkynyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamides. WO2013/148339 and WO2014/201155 likewise describe the agonistic effect of the substances in question on abscisic acid receptors. Moreover, it is known that substituted dihydrooxindolylsulfonamides can be used as active compounds to counter abiotic plant stress (cf. WO2015/049351).
Substituted 1-aryl-N-(2-oxo-1-alkyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamides having a substituted alkyl group in the N-tetrahydroquinolinyl moiety and their action for increasing tolerance in plants to abiotic stress are described in WO2015/155154. Furthermore, it is known that certain specifically substituted N-(2-oxo-1-alkyl-1,2,3,4-tetrahydroquinolin-6-yl)methanesulfonamides (cf. WO2016022910) and specifically substituted 6-sulfonylaminoquinolines (cf. WO2016022915) can be used as growth regulators and for germination inhibition.
It is likewise known that particular substituted benzoxazinylsulfonamides can be used as pharmaceutically active compounds, for example as regulators of mineralocorticoid receptors (cf. JP2009051830, WO2007/089034). The use of amidinophenylpropionyl-substituted tetrahydroquinolines as active antithrombotic ingredients is described in DE19727117. The use of 2-oxoquinoline derivatives as active immunomodulating ingredients has likewise been described (cf. JP07252228). Furthermore, it is known that oxotetrahydroquinolinylsulfonamides can be used as Rho kinase inhibitors (cf. Eur. J. Med. Chem. 2008, 43, 1730).
It is also known that certain substituted phenylphosphinic acid derivatives can be used as active compounds to counter abiotic plant stress, for example in oilseed rape, wheat and barley (cf. WO2011/124553). Phosphinamides and their preparation are described in WO2009/110609 and WO2008/111371. Substituted oxotetrahydroquinolinylphosphin- and -phosphonamides or their salts and their use for increasing stress tolerance in plants, however, have hitherto not been described.
It is known that plants can react with specific or unspecific defense mechanisms to natural stress conditions, for example cold, heat, drought stress (stress caused by aridity and/or lack of water), injury, pathogenic attack (viruses, bacteria, fungi, insects) etc., but also to herbicides [Pflanzenbiochemie [Plant Biochemistry], p. 393-462, Spektrum Akademischer Verlag, Heidelberg, Berlin, Oxford, Hans W. Heldt, 1996.; Biochemistry and Molecular Biology of Plants, p. 1102-1203, American Society of Plant Physiologists, Rockville, Md., eds. Buchanan, Gruissem, Jones, 2000].
Numerous proteins in plants, and the genes that code for them, which are involved in defense reactions to abiotic stress (for example cold, heat, drought, salt, flooding) are known. Some of these form part of signal transduction chains (e.g. transcription factors, kinases, phosphatases) or cause a physiological response of the plant cell (e.g. ion transport, deactivation of reactive oxygen species). The signaling chain genes of the abiotic stress reaction include inter alia transcription factors of the DREB and CBF classes (Jaglo-Ottosen et al., 1998, Science 280: 104-106). Phosphatases of the ATPK and MP2C type are involved in the reaction to salt stress. In addition, in the event of salt stress, the biosynthesis of osmolytes such as proline or sucrose is frequently activated. This involves, for example, sucrose synthase and proline transporters (Hasegawa et al., 2000, Annu Rev Plant Physiol Plant Mol Biol 51: 463-499). The stress defense of the plants to cold and drought uses some of the same molecular mechanisms. There is a known accumulation of what are called late embryogenesis abundant proteins (LEA proteins), which include the dehydrins as an important class (Ingram and Bartels, 1996, Annu Rev Plant Physiol Plant Mol Biol 47: 277-403, Close, 1997, Physiol Plant 100: 291-296). These are chaperones which stabilize vesicles, proteins and membrane structures in stressed plants (Bray, 1993, Plant Physiol 103: 1035-1040). In addition, there is frequently induction of aldehyde dehydrogenases, which deactivate the reactive oxygen species (ROS) which form in the event of oxidative stress (Kirch et al., 2005, Plant Mol Biol 57: 315-332). Heat shock factors (HSF) and heat shock proteins (HSP) are activated in the event of heat stress and play a similar role here as chaperones to that of dehydrins in the event of cold and drought stress (Yu et al., 2005, Mol Cells 19: 328-333).
A number of signaling substances which are endogenous to plants and are involved in stress tolerance or pathogenic defense are already known. Mention should be made here, for example, of salicylic acid, benzoic acid, jasmonic acid or ethylene [Biochemistry and Molecular Biology of Plants, p. 850-929, American Society of Plant Physiologists, Rockville, Maryland, eds. Buchanan, Gruissem, Jones, 2000]. Some of these substances or the stable synthetic derivatives and derived structures thereof are also effective on external application to plants or in seed dressing, and activate defense reactions which cause elevated stress tolerance or pathogen tolerance of the plant [Sembdner, and Parthier, 1993, Ann. Rev. Plant Physiol. Plant Mol. Biol. 44: 569-589].
It is also known that chemical substances can increase the tolerance of plants to abiotic stress. Such substances are applied either by seed dressing, by leaf spraying or by soil treatment. For instance, an increase in the abiotic stress tolerance of crop plants by treatment with elicitors of systemic acquired resistance (SAR) or abscisic acid derivatives is described (Schading and Wei, WO2000/28055; Abrams and Gusta, U.S. Pat. No. 5,201,931; Abrams et al., WO97/23441, Churchill et al., 1998, Plant Growth Regul 25: 35-45). In addition, effects of growth regulators on the stress tolerance of crop plants have been described (Morrison and Andrews, 1992, J Plant Growth Regul 11: 113-117, RD-259027). In this context, it is likewise known that a growth-regulating naphthylsulfonamide (4-bromo-N-(pyridin-2-ylmethyl)naphthalene-1-sulfonamide) influences the germination of plant seeds in the same way as abscisic acid (Park et al. Science 2009, 324, 1068-1071). Furthermore, in biochemical receptor tests a naphthylsulfamidocarboxylic acid (N-[(4-bromo-1-naphthyl)sulfonyl]-5-methoxynorvaline) shows a mode of action comparable to 4-bromo-N-(pyridin-2-ylmethyl)naphthalene-1-sulfonamide (Melcher et al. Nature Structural & Molecular Biology 2010, 17, 1102-1108). It is also known that a further naphthylsulfonamide, N-(6-aminohexyl)-5-chloronaphthalene-1-sulfonamide, influences the calcium level in plants which have been exposed to cold shock (Cholewa et al. Can. J. Botany 1997, 75, 375-382).
Similar effects are also observed on application of fungicides, especially from the group of the strobilurins or of the succinate dehydrogenase inhibitors, and are frequently also accompanied by an increase in yield (Draber et al., DE3534948, Bartlett et al., 2002, Pest Manag Sci 60: 309). It is likewise known that the herbicide glyphosate in low dosage stimulates the growth of some plant species (Cedergreen, Env. Pollution 2008, 156, 1099).
In the event of osmotic stress, a protective effect has been observed as a result of application of osmolytes, for example glycine betaine or the biochemical precursors thereof, e.g. choline derivatives (Chen et al., 2000, Plant Cell Environ 23: 609-618, Bergmann et al., DE4103253). The effect of antioxidants, for example naphthols and xanthines, for increasing abiotic stress tolerance in plants has also already been described (Bergmann et al., DD277832, Bergmann et al., DD277835). However, the molecular causes of the antistress action of these substances are largely unknown.
It is also known that the tolerance of plants to abiotic stress can be increased by a modification of the activity of endogenous poly-ADP-ribose polymerases (PARP) or poly-(ADP-ribose) glycohydrolases (PARG) (de Block et al., The Plant Journal, 2004, 41, 95; Levine et al., FEBS Lett. 1998, 440, 1; WO2000/04173; WO2004/090140).
It is thus known that plants possess several endogenous reaction mechanisms which can bring about an effective defense against a wide variety of different harmful organisms and/or natural abiotic stress. Since the environmental and economic demands on modern plant treatment compositions are increasing constantly, for example with respect to their toxicity, selectivity, application rate, formation of residues and favorable manufacture, there is a constant need to develop novel plant treatment compositions which have advantages over those known, at least in some areas.
It was therefore an object of the present invention to provide compounds which further increase tolerance to abiotic stress in plants, bring about invigoration of plant growth and/or contribute to an increase in plant yield. In this context, tolerance to abiotic stress is understood to mean, for example, tolerance to cold, heat and drought stress (stress caused by drought and/or lack of water), salts and flooding.
Surprisingly, it has now been found that substituted oxotetrahydroquinolinylphosphin- and -phosphonamides can be used to enhance stress tolerance in plants to abiotic stress, and to enhance plant growth and/or to increase plant yield.
The present invention accordingly provides substituted oxotetrahydroquinolinylphosphin- and -phosphonamides of the general formula (I) or salts thereof
where
The compounds of the general formula (I) can form salts by addition of a suitable inorganic or organic acid, for example mineral acids, for example HCl, HBr, H2SO4, H3PO4 or HNO3, or organic acids, for example carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic acid, lactic acid or salicylic acid or sulfonic acids, for example p-toluenesulfonic acid, onto a basic group, for example amino, alkylamino, dialkylamino, piperidino, morpholino or pyridino. In such a case, these salts will comprise the conjugate base of the acid as the anion. Suitable substituents in deprotonated form, for example sulfonic acids, particular sulfonamides or carboxylic acids, are capable of forming internal salts with groups, such as amino groups, which are themselves protonatable. Salts may also be formed by action of a base on compounds of the general formula (I). Examples of suitable bases are organic amines such as trialkylamines, morpholine, piperidine and pyridine, and the hydroxides, carbonates and hydrogencarbonates of ammonium, alkali metals or alkaline earth metals, especially sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate. These salts are compounds in which the acidic hydrogen is replaced by an agriculturally suitable cation, for example metal salts, especially alkali metal salts or alkaline earth metal salts, in particular sodium and potassium salts, or else ammonium salts, salts with organic amines or quaternary ammonium salts, for example with cations of the formula [NRaRbRcRd]+ in which Ra to Rd are each independently an organic radical, especially alkyl, aryl, aralkyl or alkylaryl. Also suitable are alkylsulfonium and alkylsulfoxonium salts, such as (C1-C4)-trialkylsulfonium and (C1-C4)-trialkylsulfoxonium salts.
The compounds of the formula (I) according to the invention and salts thereof are referred to hereinafter as “compounds of the general formula (I)”.
Preference is given to compounds of the general formula (I) in which
Particular preference is given to compounds of the general formula (I) in which
Very particular preference is given to compounds of the general formula (I) which are described by the formulae (Iaa) to (Ibf) in which, here and later on in the description,
corresponds, for example, to a methyl radical,
to an ethyl radical and
to an n-propyl radical,
and in which
Especially preferred are compounds of the general formula (I) described by the formulae (Iaa) to (Ibf) below
where
Very especially preferred are compounds of the general formula (I) described by the formulae (Iaa) to (Iau) below
where
The abovementioned general or preferred radical definitions apply both to the end products of the general formula (I) and, correspondingly, to the starting materials or the intermediates required in each case for the preparation. These radical definitions can be combined with one another as desired, i.e. including combinations between the given preferred ranges.
With regard to the compounds according to the invention, the terms used above and further below will be elucidated. These are familiar to the person skilled in the art and especially have the definitions elucidated hereinafter:
According to the invention, “arylsulfonyl” denotes optionally substituted phenylsulfonyl or optionally substituted polycyclic arylsulfonyl, here especially optionally substituted naphthylsulfonyl, for example substituted by fluorine, chlorine, bromine, iodine, cyano, nitro, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, alkylcarbonylamino, dialkylamino or alkoxy groups.
According to the invention, “cycloalkylsulfonyl”—alone or as part of a chemical group—represents optionally substituted cycloalkylsulfonyl, preferably having 3 to 6 carbon atoms, for example cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl or cyclohexylsulfonyl.
According to the invention, “alkylsulfonyl”—alone or as part of a chemical group—refers to straight-chain or branched alkylsulfonyl, preferably having 1 to 8 or 1 to 6 carbon atoms, for example (but not limited to) (C1-C6)-alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, 1-methylethylsulfonyl, butylsulfonyl, 1-methylpropylsulfonyl, 2-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl, 2-methylbutylsulfonyl, 3-methylbutylsulfonyl, 1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl, 2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl, 3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl, 1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl, 1-ethyl-1-methylpropylsulfonyl and 1-ethyl-2-methylpropylsulfonyl.
According to the invention, “heteroarylsulfonyl” denotes optionally substituted pyridylsulfonyl, pyrimidinylsulfonyl, pyrazinylsulfonyl or optionally substituted polycyclic heteroarylsulfonyl, here in particular optionally substituted quinolinylsulfonyl, for example substituted by fluorine, chlorine, bromine, iodine, cyano, nitro, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, alkylcarbonylamino, dialkylamino or alkoxy groups.
According to the invention, “alkylthio”—alone or as part of a chemical group—denotes straight-chain or branched S-alkyl, preferably having 1 to 8 or 1 to 6 carbon atoms, such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkylthio, for example (but not limited to) (C1-C6)-alkylthio such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio, 1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio and 1-ethyl-2-methylpropylthio.
According to the invention, alkenylthio denotes an alkenyl radical bonded via a sulfur atom, alkynylthio denotes an alkynyl radical bonded via a sulfur atom, cycloalkylthio denotes a cycloalkyl radical bonded via a sulfur atom, and cycloalkenylthio denotes a cycloalkenyl radical bonded via a sulfur atom.
According to the invention, alkylsulfinyl (alkyl-S(═O)—), unless defined differently elsewhere, denotes alkyl radicals which are bonded to the skeleton via —S(═O)—, such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkylsulfinyl, for example (but not limited to) (C1-C6)-alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, 1-methylethylsulfinyl, butylsulfinyl, 1-methylpropylsulfinyl, 2-methylpropylulfinyl, 1,1-dimethylethylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl, 2-methylbutylsulfinyl, 3-methylbutylsulfinyl, 1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl, 2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl, 1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl, 4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl, 1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl, 1-ethyl-1-methylpropylsulfinyl and 1-ethyl-2-methylpropylsulfinyl.
Analogously, alkenylsulfinyl and alkynylsulfinyl are defined in accordance with the invention respectively as alkenyl and alkynyl radicals bonded to the skeleton via —S(═O)—, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenylsulfinyl or (C3-C10)-, (C3-C6)- or (C3-C4)-alkynylsulfinyl.
Analogously, alkenylsulfonyl and alkynylsulfonyl are defined in accordance with the invention respectively as alkenyl and alkynyl radicals bonded to the skeleton via —S(═O)2—, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenylsulfonyl or (C3-C10)-, (C3-C6)- or (C3-C4)-alkynylsulfonyl.
“Alkoxy” denotes an alkyl radical bonded via an oxygen atom, for example (but not limited to) (C1-C6)-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy. Alkenyloxy denotes an alkenyl radical attached via an oxygen atom, and alkynyloxy denotes an alkynyl radical attached via an oxygen atom, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenoxy and (C3-C10)-, (C3-C6)- or (C3-C4)-alkynoxy.
“Cycloalkyloxy” denotes a cycloalkyl radical attached via an oxygen atom and cycloalkenyloxy denotes a cycloalkenyl radical attached via an oxygen atom.
According to the invention, “alkylcarbonyl” (alkyl-C(═O)—), unless defined differently elsewhere, represents alkyl radicals bonded to the skeleton via —C(═O)—, such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkylcarbonyl. Here, the number of the carbon atoms refers to the alkyl radical in the alkylcarbonyl group.
Analogously, “alkenylcarbonyl” and “alkynylcarbonyl”, unless defined differently elsewhere, in accordance with the invention, respectively represent alkenyl and alkynyl radicals bonded to the skeleton via —C(═O)—, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenylcarbonyl and (C2-C10)-, (C2-C6)- and (C2-C4)-alkynylcarbonyl. Here, the number of the carbon atoms refers to the alkenyl or alkynyl radical in the alkenyl or alkynyl group.
Alkoxycarbonyl (alkyl-O—C(═O)—), unless defined differently elsewhere: alkyl radicals bonded to the skeleton via —O—C(═O)—, such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkoxycarbonyl. Here, the number of the carbon atoms refers to the alkyl radical in the alkoxycarbonyl group.
Analogously, “alkenyloxycarbonyl” and “alkynyloxycarbonyl”, unless defined differently elsewhere, in accordance with the invention, respectively represent alkenyl and alkynyl radicals bonded to the skeleton via —O—C(═O)—, such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenyloxycarbonyl and (C3-C10)-, (C3-C6)- and (C3-C4)-alkynyloxycarbonyl. Here, the number of the carbon atoms refers to the alkenyl or alkynyl radical in the alkenyloxycarbonyl or alkynyloxycarbonyl group.
According to the invention, the term “alkylcarbonyloxy” (alkyl-C(═O)—O—), unless defined differently elsewhere, represents alkyl radicals bonded to the skeleton via the oxygen of a carbonyloxy group (—C(═O)—O—), such as (C1-C10)-, (C1-C6)- or (C1-C4)-alkylcarbonyloxy. Here, the number of the carbon atoms refers to the alkyl radical in the alkylcarbonyloxy group.
Analogously, “alkenylcarbonyloxy” and “alkynylcarbonyloxy” are defined in accordance with the invention respectively as alkenyl and alkynyl radicals bonded to the skeleton via the oxygen of (—C(═O)—O—), such as (C2-C10)-, (C2-C6)- or (C2-C4)-alkenylcarbonyloxy or (C2-C10)-, (C2-C6)- or (C2-C4)-alkynylcarbonyloxy. Here, the number of the carbon atoms refers to the alkenyl or alkynyl radical in the alkenyl- or alkynylcarbonyloxy group respectively.
The term “aryl” denotes an optionally substituted mono-, bi- or polycyclic aromatic system having preferably 6 to 14, especially 6 to 10, ring carbon atoms, for example phenyl, naphthyl, anthryl, phenanthrenyl and the like, preferably phenyl.
The term “optionally substituted aryl” also embraces polycyclic systems, such as tetrahydronaphthyl, indenyl, indanyl, fluorenyl, biphenylyl, where the bonding site is on the aromatic system. In systematic terms, “aryl” is generally also encompassed by the term “optionally substituted phenyl”. Preferred aryl substituents here are, for example, hydrogen, halogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, halocycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkoxyalkyl, alkylthio, haloalkylthio, haloalkyl, alkoxy, haloalkoxy, cycloalkoxy, cycloalkylalkoxy, aryloxy, heteroraryloxy, alkoxyalkoxy, alkynylalkoxy, alkenyloxy, bis-alkylaminoalkoxy, tris-[alkyl]silyl, bis-[alkyl]arylsilyl, bis-[alkyl]alkylsilyl, tris-[alkyl]silylalkynyl, arylalkynyl, heteroarylalkynyl, alkylalkynyl, cycloalkylalkynyl, haloalkylalkynyl, heterocyclyl-N-alkoxy, nitro, cyano, amino, alkylamino, bis-alkylamino, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, alkoxycarbonylalkylamino, arylalkoxycarbonylalkylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl, bis-alkylaminocarbonyl, heteroarylalkoxy, arylalkoxy.
A heterocyclic radical (heterocyclyl) contains at least one heterocyclic ring (=carbocyclic ring in which at least one carbon atom has been replaced by a heteroatom, preferably by a heteroatom from the group of N, O, S, P) which is saturated, unsaturated, partly saturated or heteroaromatic and may be unsubstituted or substituted, in which case the bonding site is localized on a ring atom. If the heterocyclyl radical or the heterocyclic ring is optionally substituted, it may be fused to other carbocyclic or heterocyclic rings. In the case of optionally substituted heterocyclyl, polycyclic systems are also included, for example 8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[2.2.2]octanyl or 1-azabicyclo[2.2.1]heptyl. In the case of optionally substituted heterocyclyl, spirocyclic systems are also included, for example 1-oxa-5-azaspiro[2.3]hexyl. Unless defined otherwise, the heterocyclic ring preferably contains 3 to 9 ring atoms, in particular 3 to 6 ring atoms, and one or more, preferably 1 to 4, in particular 1, 2 or 3 heteroatoms in the heterocyclic ring, preferably from the group N, O and S, where, however, two oxygen atoms must not be directly adjacent to one another, for example having one heteroatom from the group consisting of N, O and S 1- or 2- or 3-pyrrolidinyl, 3,4-dihydro-2H-pyrrol-2- or -3-yl, 2,3-dihydro-1H-pyrrol-1- or -2- or -3- or -4- or -5-yl, 2,5-dihydro-1H-pyrrol-1- or -2- or -3-yl, 1- or 2- or 3- or 4-piperidinyl; 2,3,4,5-tetrahydropyridin-2- or -3- or -4- or -5-yl or -6-yl; 1,2,3,6-tetrahydropyridin-1- or -2- or -3- or -4- or -5- or -6-yl; 1,2,3,4-tetrahydropyridin-1- or -2- or -3- or -4- or -5- or -6-yl; 1,4-dihydropyridin-1- or -2- or -3- or -4-yl; 2,3-dihydropyridin-2- or -3- or -4- or -5- or -6-yl, 2,5-dihydropyridin-2- or -3- or -4- or -5- or -6-yl, 1- or 2- or 3- or 4-azepanyl, 2,3,4,5-tetrahydro-1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl, 2,3,4,7-tetrahydro-1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl, 2,3,6,7-tetrahydro-1H-azepin-1- or -2- or -3- or -4-yl; 3,4,5,6-tetrahydro-2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl, 4,5-dihydro-1H-azepin-1- or -2- or -3- or -4-yl, 2,5-dihydro-1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl, 2,7-dihydro-1H-azepin-1- or -2- or -3- or -4-yl, 2,3-dihydro-1H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl, 3,4-dihydro-2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 3,6-dihydro-2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 5,6-dihydro-2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4,5-dihydro-3H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 1 H-azepin-1- or -2- or -3- or -4- or -5- or -6- or -7-yl; 2H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 3H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4H-azepin-2- or -3- or -4- or -5- or -6- or -7-yl, 2- or 3-oxolanyl (=2- or 3-tetrahydrofuranyl); 2,3-dihydrofuran-2- or -3- or -4- or -5-yl; 2,5-dihydrofuran-2- or -3-yl, 2- or 3- or 4-oxanyl (=2- or 3- or 4-tetrahydropyranyl); 3,4-dihydro-2H-pyran-2- or -3- or -4- or -5- or -6-yl; 3,6-dihydro-2H-pyran-2- or -3-or -4- or -5- or -6-yl; 2H-pyran-2- or -3- or -4- or -5- or -6-yl; 4H-pyran-2- or -3- or -4-yl, 2- or -3- or -4-oxepanyl; 2,3,4,5-tetrahydrooxepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,4,7-tetrahydrooxepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,6,7-tetrahydrooxepin-2- or -3- or -4-yl; 2,3-dihydrooxepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4,5-dihydrooxepin-2- or -3- or -4-yl; 2,5-dihydrooxepin-2- or -3- or -4- or -5- or -6- or -7-yl; oxepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2- or 3-tetrahydrothiophenyl; 2,3-dihydrothiophen-2- or -3- or -4- or -5-yl; 2,5-dihydrothiophen-2- or -3-yl; tetrahydro-2H-thiopyran-2- or -3- or -4-yl; 3,4-dihydro-2H-thiopyran-2- or -3- or -4- or -5- or -6-yl; 3,6-dihydro-2H-thiopyran-2- or -3- or -4- or -5- or -6-yl; 2H-thiopyran-2- or -3- or -4- or -5- or -6-yl; 4H-thiopyran-2- or -3- or -4-yl. Preferred 3-membered and 4-membered heterocycles are, for example, 1- or 2-aziridinyl, oxiranyl, thiiranyl, 1- or 2- or 3-azetidinyl, 2- or 3-oxetanyl, 2- or 3-thietanyl, 1,3-dioxetan-2-yl. Further examples of “heterocyclyl” are a partially or fully hydrogenated heterocyclic radical having two heteroatoms from the group consisting of N, O and S, for example 1- or 2- or 3- or 4-pyrazolidinyl, 4,5-dihydro-3H-pyrazol-3- or -4- or -5-yl; 4,5-dihydro-1H-pyrazol-1- or -3- or -4- or -5-yl; 2,3-dihydro-1H-pyrazol-1- or -2- or -3- or -4- or -5-yl, 1- or 2- or 3- or 4- imidazolidinyl; 2,3-dihydro-1H-imidazol-1- or -2- or -3- or -4-yl, 2,5-dihydro-1H-imidazol-1- or -2- or -4- or -5-yl, 4,5-dihydro-1H-imidazol-1- or -2- or -4- or -5-yl, hexahydropyridazin-1- or -2- or -3- or -4-yl, 1,2,3,4-tetrahydropyridazin-1- or -2- or -3- or -4- or -5- or -6-yl; 1,2,3,6-tetrahydropyridazin-1- or -2- or -3- or -4- or -5- or -6-yl; 1,4,5,6-tetrahydropyridazin-1- or -3- or -4- or -5- or -6-yl; 3,4,5,6-tetrahydropyridazin-3- or -4- or -5-yl; 4,5-dihydropyridazin-3- or -4-yl; 3,4-dihydropyridazin-3- or -4- or -5- or -6-yl; 3,6-dihydropyridazin-3- or -4-yl; 1,6-dihydropyridazin-1- or -3- or -4- or -5- or -6-yl; hexahydropyrimidin-1- or -2- or -3- or -4-yl; 1,4,5,6-tetrahydropyrimidin-1- or -2- or -4- or -5- or -6-yl, 1,2,5,6-tetrahydropyrimidin-1- or -2- or -4- or -5- or -6-yl; 1,2,3,4-tetrahydropyrimidin-1- or -2- or -3- or -4- or -5- or -6-yl; 1,6-dihydropyrimidin-1- or -2- or -4- or -5- or -6-yl; 1,2-dihydropyrimidin-1- or 2- or 4- or 5- or 6-yl; 2,5-dihydropyrimidin-2- or 4- or 5-yl; 4,5-dihydropyrimidin-4- or 5- or -6-yl; 1,4-dihydropyrimidin-1- or -2- or -4- or -5- or -6-yl; 1- or 2- or 3-piperazinyl; 1,2,3,6-tetrahydropyrazin-1- or -2- or -3- or -5- or -6-yl; 1,2,3,4-tetrahydropyrazin-1- or -2- or -3- or -4- or -5- or -6-yl; 1,2-dihydropyrazin-1- or -2- or -3- or -5- or -6-yl, 1,4-dihydropyrazin-1- or -2- or -3-yl, 2,3-dihydropyrazin-2- or -3- or -5- or -6-yl; 2,5-dihydropyrazin-2- or -3-yl; 1,3-dioxolan-2- or -4- or -5-yl; 1,3-dioxo1-2- or -4-yl; 1,3-dioxan-2- or -4- or -5-yl; 4H-1,3-dioxin-2- or -4- or -5- or -6-yl; 1,4-dioxan-2- or -3- or -5- or -6-yl; 2,3-dihydro-1,4-dioxin-2- or -3- or -5- or -6-yl; 1,4-dioxin-2- or -3-yl; 1,2-dithiolan-3- or -4-yl; 3H-1,2-dithio1-3- or -4- or -5-yl; 1,3-dithiolan-2- or -4-yl; 1,3-dithiol-2- or -4-yl, 1,2-dithian-3- or -4-yl, 3,4-dihydro-1,2-dithiin-3- or -4- or -5- or -6-yl, 3,6-dihydro-1,2-dithiin-3- or -4-yl; 1,2-dithiin-3- or -4-yl; 1,3-dithian-2- or -4- or -5-yl; 4H-1,3-dithiin-2- or -4- or -5- or -6-yl; isoxazolidin-2- or -3- or -4- or -5-yl; 2,3-dihydroisoxazol-2- or -3- or -4- or -5-yl, 2,5-dihydroisoxazol-2- or -3- or -4- or -5-yl, 4,5-dihydroisoxazol-3- or -4- or -5-yl; 1,3-oxazolidin-2- or -3- or -4- or -5-yl; 2,3-dihydro-1,3-oxazol-2- or -3- or -4- or -5-yl; 2,5-dihydro-1,3-oxazol-2- or -4- or -5-yl; 4,5-dihydro-1,3-oxazol-2- or -4- or -5-yl; 1,2-oxazinan-2- or -3- or -4- or -5- or -6-yl; 3,4-dihydro-2H-1,2-oxazin-2- or -3- or -4- or -5- or -6-yl; 3,6-dihydro-2H-1,2-oxazin-2- or -3- or -4- or -5- or -6-yl; 5,6-dihydro-2H-1,2-oxazin-2- or -3- or -4- or -5- or -6-yl; 5,6-dihydro-4H-1,2-oxazin-3- or -4- or -5- or -6-yl; 2H-1,2-oxazin-2- or -3- or -4- or -5- or -6-yl; 6H-1,2-oxazin-3- or -4- or -5- or -6-yl; 4H-1,2-oxazin-3- or -4- or -5- or -6-yl; 1,3-oxazinan-2- or -3- or -4- or -5- or -6-yl; 3,4-dihydro-2H-1,3-oxazin-2- or -3- or -4- or -5- or -6-yl; 3,6-dihydro-2H-1,3-oxazin-2- or -3- or -4- or -5- or -6-yl; 5,6-dihydro-2H-1,3-oxazin-2- or -4- or -5- or -6-yl; 5,6-dihydro-4H-1,3-oxazin-2- or -4- or -5- or -6-yl; 2H-1,3-oxazin-2- or -4- or -5- or -6-yl; 6H-1,3-oxazin-2- or -4- or -5- or -6-yl; 4H-1,3-oxazin-2- or -4- or -5- or -6-yl; morpholin-2- or -3- or -4-yl, 3,4-dihydro-2H-1,4-oxazin-2- or -3- or -4- or -5- or -6-yl, 3,6-dihydro-2H-1,4-oxazin-2- or -3- or -5- or -6-yl; 2H-1,4-oxazin-2- or -3- or -5- or -6-yl; 4H-1,4-oxazin-2- or -3-yl; 1,2-oxazepan-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,4,5-tetrahydro-1,2-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,4,7-tetrahydro-1,2-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,6,7-tetrahydro-1,2-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,5,6,7-tetrahydro-1,2-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4,5,6,7-tetrahydro-1,2-oxazepin-3- or -4- or -5- or -6- or -7-yl; 2,3-dihydro-1,2-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,5-dihydro-1,2-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,7-dihydro-1,2-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4,5-dihydro-1,2-oxazepin-3- or -4- or -5- or -6- or -7-yl; 4,7-dihydro-1,2-oxazepin-3- or -4- or -5- or -6- or -7-yl; 6,7-dihydro-1,2-oxazepin-3- or -4- or -5- or -6- or -7-yl; 1,2-oxazepin-3- or -4- or -5- or -6- or -7-yl; 1,3-oxazepan-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,4,5-tetrahydro-1,3-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,4,7-tetrahydro-1,3-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,6,7-tetrahydro-1,3-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,5,6,7-tetrahydro-1,3-oxazepin-2- or -4- or -5- or -6- or -7-yl; 4,5,6,7-tetrahydro-1,3-oxazepin-2- or -4- or -5- or -6- or -7-yl; 2,3-dihydro-1,3-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,5-dihydro-1,3-oxazepin-2- or -4- or -5- or -6- or -7-yl; 2,7-dihydro-1,3-oxazepin-2- or -4- or -5- or -6- or -7-yl; 4,5-dihydro-1,3-oxazepin-2- or -4- or -5- or -6- or -7-yl; 4,7-dihydro-1,3-oxazepin-2- or -4- or -5- or -6- or -7-yl; 6,7-dihydro-1,3-oxazepin-2- or -4- or -5- or -6- or -7-yl; 1,3-oxazepin-2- or -4- or -5- or -6- or -7-yl; 1,4-oxazepan-2- or -3- or -5- or -6- or -7-yl; 2,3,4,5-tetrahydro-1,4-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,4,7-tetrahydro-1,4-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3,6,7-tetrahydro-1,4-oxazepin-2- or -3- or -5- or -6- or -7-yl; 2,5,6,7-tetrahydro-1,4-oxazepin-2- or -3- or -5- or -6- or -7-yl; 4,5,6,7-tetrahydro-1,4-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 2,3-dihydro-1,4-oxazepin-2- or -3- or -5- or -6- or -7-yl, 2,5-dihydro-1,4-oxazepin-2- or -3- or -5- or -6- or -7-yl; 2,7-dihydro-1,4-oxazepin-2- or -3- or -5- or -6- or -7-yl; 4,5-dihydro-1,4-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 4,7-dihydro-1,4-oxazepin-2- or -3- or -4- or -5- or -6- or -7-yl; 6,7-dihydro-1,4-oxazepin-2- or -3- or -5- or -6- or -7-yl; 1,4-oxazepin-2- or -3- or -5- or -6- or -7-yl; isothiazolidin-2- or -3- or -4- or -5-yl; 2,3-dihydroisothiazol-2- or -3- or -4- or -5-yl, 2,5-dihydroisothiazol-2- or -3- or -4- or -5-yl, 4,5-dihydroisothiazol-3- or -4- or -5-yl; 1,3-thiazolidin-2- or -3- or -4- or -5-yl; 2,3-dihydro-1,3-thiazol-2- or -3- or -4- or -5-yl; 2,5-dihydro-1,3-thiazol-2- or -4- or -5-yl; 4,5-dihydro-1,3-thiazol-2- or -4- or -5-yl; 1,3-thiazinan-2- or -3- or -4- or -5- or -6-yl; 3,4-dihydro-2H-1,3-thiazin-2- or -3- or -4- or -5- or -6-yl; 3,6-dihydro-2H-1,3-thiazin-2- or -3- or -4- or -5- or -6-yl; 5,6-dihydro-2H-1,3-thiazin-2- or -4- or -5- or -6-yl; 5,6-dihydro-4H-1,3-thiazin-2- or -4- or -5- or -6-yl; 2H-1,3-thiazin-2- or -4- or -5- or -6-yl; 6H-1,3-thiazin-2- or -4- or -5- or -6-yl; 4H-1,3-thiazin-2- or -4- or -5- or -6-yl. Further examples of “heterocyclyl” are a partly or fully hydrogenated heterocyclic radical having 3 heteroatoms from the group of N, O and S, for example 1,4,2-dioxazolidin-2- or -3- or -5-yl; 1,4,2-dioxazol-3- or -5-yl; 1,4,2-dioxazinan-2- or -3- or -5- or -6-yl; 5,6-dihydro-1,4,2-dioxazin-3- or -5- or -6-yl; 1,4,2-dioxazin-3- or -5- or -6-yl; 1,4,2-dioxazepan-2- or -3- or -5- or -6- or -7-yl; 6,7-dihydro-5H-1,4,2-dioxazepin-3- or -5- or -6- or -7-yl; 2,3-dihydro-7H-1,4,2-dioxazepin-2- or -3- or -5- or -6- or -7-yl; 2,3-dihydro-5H-1,4,2-dioxazepin-2- or -3- or -5- or -6- or -7-yl; 5H-1,4,2-dioxazepin-3- or -5- or -6- or -7-yl; 7H-1,4,2-dioxazepin-3- or -5- or -6- or -7-yl. Structural examples of heterocycles which are optionally substituted further are also listed below:
The heterocycles listed above are substituted at one or more positions, preferably at one position, for example in the case of a plurality of substituents by identical or different radicals selected from the group of hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkoxy, aryloxy, alkoxyalkyl, alkoxyalkoxy, cycloalkyl, halocycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, alkenyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, hydroxycarbonyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, alkoxycarbonylalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, alkynyl, alkynylalkyl, alkylalkynyl, trisalkylsilylalkynyl, nitro, amino, cyano, haloalkoxy, haloalkylthio, alkylthio, hydrothio, hydroxyalkyl, oxo, heteroarylalkoxy, arylalkoxy, heterocyclylalkoxy, heterocyclylalkylthio, heterocyclyloxy, heterocyclylthio, heteroaryloxy, bisalkylamino, alkylamino, cycloalkylamino, hydroxycarbonylalkylamino, alkoxycarbonylalkylamino, arylalkoxycarbonylalkylamino, alkoxycarbonylalkyl(alkyl)amino, aminocarbonyl, alkylaminocarbonyl, bisalkylaminocarbonyl, cycloalkylaminocarbonyl, hydroxycarbonylalkylaminocarbonyl, alkoxycarbonylalkylaminocarbonyl, arylalkoxycarbonylalkylaminocarbonyl.
When a base structure is substituted “by one or more radicals” from a list of radicals (=group) or a generically defined group of radicals, this in each case includes simultaneous substitution by a plurality of identical and/or structurally different radicals.
In the case of a partly or fully saturated nitrogen heterocycle, this may be joined to the remainder of the molecule either via carbon or via the nitrogen.
Suitable substituents for a substituted heterocyclic radical are the substituents specified further down, and additionally also oxo and thioxo. The oxo group as a substituent on a ring carbon atom is then, for example, a carbonyl group in the heterocyclic ring. As a result, lactones and lactams are preferably also included. The oxo group may also occur on the ring heteroatoms, which may exist in different oxidation states, for example in the case of N and S, and in that case form, for example, the divalent —N(O)—, —S(O)— (also SO for short) and —S(O)2— (also SO2 for short) groups in the heterocyclic ring. In the case of —N(O)— and —S(O)— groups, both enantiomers in each case are included.
According to the invention, the expression “heteroaryl” refers to heteroaromatic compounds, i.e. fully unsaturated aromatic heterocyclic compounds, preferably 5- to 7-membered rings having 1 to 4, preferably 1 or 2, identical or different heteroatoms, preferably O, S or N. Inventive heteroaryls are, for example, 1H-pyrrol-1-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, furan-2-yl; furan-3-yl; thien-2-yl; thien-3-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-pyrazol-1-yl, 1 H-pyrazol-3-yl; 1H-pyrazol-4-yl; 1H-pyrazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-4-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,5-oxadiazol-3-yl, azepinyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,3-triazin-4-yl, 1,2,3-triazin-5-yl, 1,2,4-, 1,3,2-, 1,3,6- and 1,2,6-oxazinyl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, oxepinyl, thiepinyl, 1,2,4-triazolonyl and 1,2,4-diazepinyl, 2H-1,2,3,4-tetrazol-5-yl, 1H-1,2,3,4-tetrazol-5-yl, 1,2,3,4-oxatriazol-5-yl, 1,2,3,4-thiatriazol-5-yl, 1,2,3,5-oxatriazol-4-yl, 1,2,3,5-thiatriazol-4-yl. The heteroaryl groups according to the invention may also be substituted by one or more identical or different radicals. If two adjacent carbon atoms are part of a further aromatic ring, the systems are fused heteroaromatic systems, such as benzofused or polyannulated heteroaromatics. Preferred examples are quinolines (e.g. quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl); isoquinolines (e.g. isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, isoquinolin-8-yl); quinoxaline; quinazolines cinnoline; 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, 2,6-naphthyridine; 2,7-naphthyridine; phthalazine; pyridopyrazines; pyridopyrimidines; pyridopyridazines; pteridines; pyrimidopyrimidines. Examples of heteroaryl are also 5- or 6-membered benzofused rings from the group of 1H-indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1-benzofuran-2-yl, 1-benzofuran-3-yl, 1-benzofuran-4-yl, 1-benzofuran-5-yl, 1-benzofuran-6-yl, 1-benzofuran-7-yl, 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl, 1H-indazol-1-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1 H-indazol-5-yl, 1H-indazol-6-yl, 1 H-indazol-7-yl, 2H-indazol-2-yl, 2H-indazol-3-yl, 2H-indazol-4-yl, 2H-indazol-5-yl, 2H-indazol-6-yl, 2H-indazol-7-yl, 2H-isoindol-2-yl, 2H-isoindol-1-yl, 2H-isoindol-3-yl, 2H-isoindol-4-yl, 2H-isoindol-5-yl, 2H-isoindol-6-yl; 2H-isoindol-7-yl, 1 H-benzimidazol-1-yl, 1 H-benzimidazol-2-yl, 1H-benzimidazol-4-yl, 1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl, 1 H-benzimidazol-7-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzoxazol-7-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-4-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3-benzothiazol-7-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1,2-benzisoxazol-6-yl, 1,2-benzisoxazol-7-yl, 1,2-benzisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothiazol-5-yl, 1,2-benzisothiazol-6-yl, 1,2-benzisothiazol-7-yl.
The term “halogen” denotes, for example, fluorine, chlorine, bromine or iodine. If the term is used for a radical, “halogen” denotes, for example, a fluorine, chlorine, bromine or iodine atom.
According to the invention, “alkyl” denotes a straight-chain or branched open-chain, saturated hydrocarbon radical which is optionally mono- or polysubstituted. Preferred substituents are halogen atoms, alkoxy, haloalkoxy, cyano, alkylthio, haloalkylthio, amino or nitro groups, particular preference being given to methoxy, methyl, fluoroalkyl, cyano, nitro, fluorine, chlorine, bromine or iodine. The prefix “bis” also includes the combination of different alkyl radicals, e.g. methyl(ethyl) or ethyl(methyl).
“Haloalkyl”, “-alkenyl” and “-alkynyl” respectively denote alkyl, alkenyl and alkynyl partly or fully substituted by identical or different halogen atoms, for example monohaloalkyl such as CH2CH2Cl, CH2CH2Br, CHClCH3, CHCl, CH2F; perhaloalkyl such as CCl3, CClF2, CFCl2, CF2CClF2, CF2CClFCF3; polyhaloalkyl such as CH2CHFCl, CF2CClFH, CF2CBrFH, CH2CF3; the term perhaloalkyl also encompasses the term perfluoroalkyl.
Partly fluorinated alkyl denotes a straight-chain or branched, saturated hydrocarbon which is mono- or polysubstituted by fluorine, where the fluorine atoms in question may be present as substituents on one or more different carbon atoms of the straight-chain or branched hydrocarbon chain, for example CHFCH3, CH2CH2F, CH2CH2CF3, CHF2, CH2F, CHFCF2CF3.
Partly fluorinated haloalkyl denotes a straight-chain or branched, saturated hydrocarbon which is substituted by different halogen atoms with at least one fluorine atom, where any other halogen atoms optionally present are selected from the group consisting of fluorine, chlorine or bromine, iodine. The corresponding halogen atoms may be present as substituents on one or more different carbon atoms of the straight-chain or branched hydrocarbon chain. Partly fluorinated haloalkyl also includes full substitution of the straight or branched chain by halogen including at least one fluorine atom.
Haloalkoxy is, for example, OCF3, OCHF2, OCH2F, OCF2CF3, OCH2CF3 and OCH2CH2Cl; the situation is equivalent for haloalkenyl and other halogen-substituted radicals.
The expression “(C1-C4)-alkyl” mentioned here by way of example is a brief notation for straight-chain or branched alkyl having one to 4 carbon atoms according to the range stated for carbon atoms, i.e. encompasses the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl or tert-butyl radicals. General alkyl radicals with a larger specified range of carbon atoms, e.g. “(C1-C6)-alkyl”, correspondingly also encompass straight-chain or branched alkyl radicals with a greater number of carbon atoms, i.e. according to the example also the alkyl radicals having 5 and 6 carbon atoms.
Unless stated specifically, preference is given to the lower carbon skeletons, for example having from 1 to 6 carbon atoms, or having from 2 to 6 carbon atoms in the case of unsaturated groups, in the case of the hydrocarbyl radicals such as alkyl, alkenyl and alkynyl radicals, including in composite radicals. Alkyl radicals, including in composite radicals such as alkoxy, haloalkyl, etc., are, for example, methyl, ethyl, n-propyl or i-propyl, n-, i-, t- or 2-butyl, pentyls, hexyls such as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyls such as n-heptyl, 1-methylhexyl and 1,4-dimethylpentyl; alkenyl and alkynyl radicals are defined as the possible unsaturated radicals corresponding to the alkyl radicals, where at least one double bond or triple bond is present. Preference is given to radicals having one double bond or triple bond.
The term “alkenyl” also includes, in particular, straight-chain or branched open-chain hydrocarbon radicals having more than one double bond, such as 1,3-butadienyl and 1,4-pentadienyl, but also allenyl or cumulenyl radicals having one or more cumulated double bonds, for example allenyl (1,2-propadienyl), 1,2-butadienyl and 1,2,3-pentatrienyl. Alkenyl denotes, for example, vinyl which may optionally be substituted by further alkyl radicals, for example (but not limited thereto) (C2-C6)-alkenyl such as ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.
The term “alkynyl” also includes, in particular, straight-chain or branched open-chain hydrocarbon radicals having more than one triple bond, or else having one or more triple bonds and one or more double bonds, for example 1,3-butatrienyl or 3-penten-1-yn-1-yl. (C2-C6)-Alkynyl is, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl.
The term “cycloalkyl” refers to a carbocyclic saturated ring system having preferably 3-8 ring carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which optionally has further substitution, preferably by hydrogen, alkyl, alkoxy, cyano, nitro, alkylthio, haloalkylthio, halogen, alkenyl, alkynyl, haloalkyl, amino, alkylamino, bisalkylamino, alkoxycarbonyl, hydroxycarbonyl, arylalkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylaminocarbonyl. In the case of optionally substituted cycloalkyl, cyclic systems with substituents are included, also including substituents with a double bond on the cycloalkyl radical, for example an alkylidene group such as methylidene. In the case of optionally substituted cycloalkyl, polycyclic aliphatic systems are also included, for example bicyclo[1.1.0]butan-1-yl, bicyclo[1.1.0]butan-2-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[1.1.1]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, bicyclo[2.1.0]pentan-5-yl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[3.2.1]octan-2-yl, bicyclo[3.2.2]nonan-2-yl, adamantan-1-yl and adamantan-2-yl, but also systems such as 1,1′-bi(cyclopropyl)-1-yl, 1,1′-bi(cyclopropyl)-2-yl, for example. The term “(C3-C7)-cycloalkyl” is a brief notation for cycloalkyl having three to 7 carbon atoms, corresponding to the range specified for carbon atoms.
In the case of substituted cycloalkyl, spirocyclic aliphatic systems are also included, for example spiro[2.2]pent-1-yl, spiro[2.3]hex-1-yl, spiro[2.3]hex-4-yl, 3-spiro[2.3]hex-5-yl, spiro[3.3]hept-1-yl, spiro[3.3]hept-2-yl.
“Cycloalkenyl” denotes a carbocyclic, nonaromatic, partly unsaturated ring system having preferably 4-8 carbon atoms, e.g. 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, or 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1,3-cyclohexadienyl or 1,4-cyclohexadienyl, also including substituents with a double bond on the cycloalkenyl radical, for example an alkylidene group such as methylidene. In the case of optionally substituted cycloalkenyl, the elucidations for substituted cycloalkyl apply correspondingly.
The term “alkylidene”, also, for example, in the form (C1-C10)-alkylidene, means the radical of a straight-chain or branched open-chain hydrocarbon radical which is attached via a double bond. Possible bonding sites for alkylidene are naturally only positions on the base structure where two hydrogen atoms can be replaced by the double bond; radicals are, for example, ═CH2, ═CH—CH3, ═C(CH3)—CH3, ═C(CH3)—C2H5 or ═C(C2H5)—C2H5 Cycloalkylidene denotes a carbocyclic radical attached via a double bond.
Depending on the nature of the substituents and the manner in which they are attached, the compounds of the general formula (I) may be present as stereoisomers. The formula (I) embraces all possible stereoisomers defined by the specific three-dimensional form thereof, such as enantiomers, diastereomers, Z and E isomers. If, for example, one or more alkenyl groups are present, diastereomers (Z and E isomers) may occur. If, for example, one or more asymmetric carbon atoms are present, enantiomers and diastereomers may occur. Stereoisomers can be obtained from the mixtures obtained in the preparation by customary separation methods. The chromatographic separation can be effected either on the analytical scale to find the enantiomeric excess or the diastereomeric excess, or else on the preparative scale to produce test specimens for biological testing. It is likewise possible to selectively prepare stereoisomers by using stereoselective reactions with use of optically active starting materials and/or auxiliaries. The invention thus also relates to all stereoisomers which are embraced by the general formula (I) but are not shown in their specific stereomeric form, and to mixtures thereof.
Synthesis of oxotetrahydroquinolinylphosphin- and -phosphonamides:
The oxotetrahydroquinolinylphosphin- and -phosphonamides of the general formula (I) according to the invention, optionally with further substitution, can be prepared by known processes. The synthesis routes used and examined proceed from commercially available or easily preparable oxotetrahydroquinolinylsulfonamides and the corresponding sulfonyl chlorides. Oxotetrahydroquinolinylamines optionally having further substitution (A) can be prepared proceeding from correspondingly substituted anilines (scheme 1). In this case, an aniline optionally having further substitution can be coupled with an appropriate halopropionyl halide using a suitable base in a suitable polar-aprotic solvent and, in the subsequent step, reacted with a suitable Lewis acid in a Friedel-Crafts alkylation to give correspondingly substituted oxotetrahydroquinolines in which, in further reaction steps, first the CR1R9R10 radical, where R1, R9 and R10 are as defined further up, is introduced with the aid of a suitable base (e.g. sodium hydride, potassium carbonate or cesium carbonate) in a suitable polar-aprotic solvent (e.g. acetonitrile or N,N-dimethylformamide, also corresponding to the abbreviation DMF), the product is nitrated with a suitable nitrating acid (e.g. conc. nitric acid) and then the nitro group is converted to the corresponding amino group with the aid of a suitable reducing agent (e.g. tin(II) chloride dihydrate, iron in acetic acid or hydrogen over palladium on charcoal). In this way, the desired illustrative substituted oxotetrahydroquinolinylamines (A) are obtained (cf. US2008/0234237, J. Med. Chem. 1986, 29(12), 2433 and Eur. J. Med. Chem. 2008, 43, 1730, J. Med. Chem. 2011, 54, 5562). Alternatively, a nitro-substituted oxotetrahydroquinoline can be obtained via a tandem reaction, mediated by tributyltin hydride and azobis(isobutyronitrile) (corresponding to the abbreviation AIBN), of an alkyl acrylate optionally having further substitution with an o-haloaniline optionally having further substitution (cf. Tetrahedron 2009, 65, 1982; B. Giese et al. Org. React. 1996, 48). This mode of cyclization can also be conducted by electrocatalytic or photochemical means (cf. J. Org. Chem. 1991, 56, 3246; J. Am. Chem. Soc. 2009, 131, 5036; Photochem. & Photobiol. Sci. 2009, 8, 751). A further alternative for preparation of nitro-substituted oxotetrahydroquinolines is the Beckmann rearrangement of indanooximes optionally having further substitution. Scheme 1 shows this reaction sequence for preparation of optionally substituted oxotetrahydroquinolinylamines (A) by way of example but without restriction with R2, R3, R4, R7, R8=hydrogen and X and Y═H, and R1, R9 and R10 are as defined above.
Oxotetrahydroquinolinylamines in which the CR1R9R10 radical where R1, R9 and R10 are as defined further up can be introduced only with difficulty, if at all, by simple alkylation can be prepared via alternative synthesis routes. By way of example, but without restriction, some of these routes are described hereinafter. When CR1R9R10=bis-cyclopropylmethyl, the synthesis proceeds at first via Pd-mediated coupling of an aryl bromide with bis-cyclopropylmethylamine using suitable Pd catalysts (e.g. Pd2(dba)3) and phosphorus-containing ligands (e.g. BINAP, t-BuXPhos) (cf. Tetrahedron 2001, 57, 2953, WO2012/168350, Angew. Chem. Int. Ed. 2012, 51, 222; Tetrahedron 2001, 57, 2953), by copper(II) chloride-mediated coupling or by copper acetate-mediated reaction of bis(cyclopropylmethyl)amine with triphenylbismuth (cf. Chem. Commun. 2011, 47, 897; J. Med. Chem. 2003, 46, 623) are prepared. The abbreviation ‘dba’ stands for dibenzylideneacetone, BINAP stands for 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, while t-BuXPhos stands for 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl. Thereafter, the N-bis(cyclopropylmethyl)aniline optionally having further substitution can be coupled with an appropriate halopropionyl halide using a suitable base in a suitable polar-aprotic solvent and, in the subsequent step, reacted with a suitable Lewis acid (e.g. aluminum trichloride or titanium tetrachloride) in a Friedel-Crafts alkylation to give a corresponding N-[bis(cyclopropylmethyl)]-substituted oxotetrahydroquinoline, which can be converted by nitration with nitric acid and subsequent reduction with a suitable reducing agent (e.g. tin(II) chloride hydrate, iron in acetic acid or hydrogen with palladium on charcoal) to the desired N-[bis(cyclopropylmethyl)]-substituted oxotetrahydroquinolinylamine (B) optionally having further substitution. Scheme 2 shows this reaction sequence by way of example but without restriction with R2, R3, R4=hydrogen, and R7, R8, X and Y═H and R1, R9=cyclopropyl and R10═H.
When R1=haloalkyl, the synthesis of the N-haloalkylmethyl-substituted oxotetrahydroquinolinylamines optionally having further substitution proceeds, by way of example but without restriction, via an alkylation using a suitable haloalkyl trifluoromethanesulfonate and a suitable base (e.g. sodium hydride) in a suitable polar-aprotic solvent (e.g. N,N-dimethylformamide or acetonitrile). Thereafter, the N-haloalkylmethyl-substituted nitrooxotetrahydroquinoline can be converted by reduction with a suitable reducing agent (e.g. tin(II) chloride hydrate, iron in acetic acid or hydrogen with palladium on charcoal) to the desired N-haloalkylmethyl-substituted oxotetrahydroquinolinylamine (C) optionally having further substitution. Scheme 3 shows this reaction sequence by way of example but without restriction with difluoroethyl trifluoromethanesulfonate as reagent, R2, R3, R4=hydrogen, and R7, R8, X and Y═H and R1═CHF2 and R9, R10═H.
For spiro[3.3]hept-2-yl and bicyclo[1.1.1]pent-1-yl as N-cycloalkyl radicals in the 1-cycloalkyl-2-oxotetrahydroquinolinylphosphin- and -phosphonamides according to the invention (with R2, R3, R4═H, W═O), the synthesis proceeds, by way of example but without restriction, first via a reaction of a suitable substituted (2E)-3-(2-fluorophenyl)acrylate with the appropriate cycloalkylamine using a suitable amine base (e.g. triethylamine or diisopropylethylamine) in a suitable polar aprotic solvent (e.g. N,N-dimethylformamide, dioxane) at elevated temperature. In the subsequent step, the corresponding substituted 3-[2-(cycloalkylamino)-5-nitrophenyl]acrylate is converted with the aid of hydrogen and a suitable transition metal catalyst, e.g. (Ph3P)3RhCl, in a suitable polar protic solvent (e.g. methanol, ethanol) to the corresponding substituted 3-[2-(cycloalkylamino)-5-nitrophenyl]propanoate. The substituted 3-[2-(cycloalkylamino)-5-nitrophenyl]propanoate thus obtained is then converted with a suitable base (e.g. sodium hydride) in a suitable polar aprotic solvent (e.g. diethyl ether, tetrahydrofuran) to the corresponding substituted 1-cycloalkyl-2-oxotetrahydroquinoline. By reduction of the nitro group of the corresponding substituted 1-cycloalkyl-2-oxotetrahydroquinoline with a suitable reducing agent (e.g. tin(II) chloride hydrate, iron in acetic acid or hydrogen with palladium on charcoal), it is possible to obtain, for example, the optionally further-substituted 6-amino-1-(spiro[3.3]hept-2-yl)-3,4-dihydroquinolin-2(1H)-one (D) or, correspondingly, the optionally further-substituted 6-amino-1-(bicyclo[1.1.1]pent-1-yl)-3,4-dihydroquinolin-2(1H)-one (E) (scheme 4). R1, R9, R10, R11, R12, R13 and R14 and the corresponding cycloalkyl skeleton are depicted by way of example but without restriction in scheme 4 below with n=1, by a spiro[3.3]hept-2-yl and bicyclo[1.1.1]pent-1-yl group. R2, R3, R4 are represented by way of example but without restriction by H, and W is represented by way of example but without restriction by O.
In the same way, it is also possible, for example, to prepare 6-amino-1-[1,1′-bi(cyclopropyl)-2-yl]-3,4-dihydroquinolin-2(1H)-one (F) or, correspondingly, the optionally further-substituted 6-amino-1-[1,1′-bi(cyclopropyl)-1-yl]-3,4-dihydroquinolin-2(1H)-one (G) (scheme 5). R1, R11, R12, R13 and R14 and the corresponding cycloalkyl skeleton are depicted by way of example but without restriction in scheme 4 below with n=0, by a 1,1′-bi(cyclopropyl)-2-yl and 1,1′-bi(cyclopropyl)-1-yl group. R2, R3, R4 are represented by way of example but without restriction by H, and W is represented by way of example but without restriction by O.
Substituted phosphonyl chloride and phosphinyl chloride precursors can be prepared, for example, stepwise starting with the reaction of a correspondingly substituted benzyl halide with a correspondingly substituted phosphorus compound such as, for example, sodium diethylphosphite, triethyl phosphite, or a correspondingly substituted diethylalkyl phosphonite according to Arbuzov in a suitable polar-aprotic solvent (e.g. N,N-dimethylformamide or diethyl ether). Alternatively, using a suitable base (e.g. sodium hydroxide) at elevated temperature, the phosphonic and phosphinic esters can be converted into the corresponding acid intermediates (I) (second reaction in Scheme 6). In the next step, the intermediates (H) and (J) obtained in this manner can be converted into the corresponding phosphonyl chloride and phosphinyl chloride precursors (K) (Scheme 6) (cf. Org. Lett. 2005, 7, 4919; US2008/0008682, DE10206117; JP63218684; DE3400509; J. Org. Chem. 1992, 57, 4292). Coupling of the corresponding substituted phosphonyl chloride and phosphinyl chloride precursors with the appropriate oxotetrahydroquinolinylamines optionally having further substitution with the aid of a suitable base (e.g. triethylamine, pyridine) in a suitable solvent (e.g. tetrahydrofuran, acetonitrile, DMSO or dichloromethane) (cf. J. Med. Chem. 1990, 33, 2912; Aust. J. Chem. 1984, 37, 1009) affords the oxotetrahydroquinolinylphosphin- and -phosphonamides according to the invention which are optionally substituted further (for example, but without restriction, in Scheme 6 subclass (Iaa)). In Scheme 6 below, R1, R2, R3, R4, R9, R10 and R11 are each as defined above. R7, R8, X and Y are represented by way of example but without restriction by H. In an exemplary but not limiting manner, R5 is represented by p-chlorobenzyl and by p-methylbenzyl. In the second reaction, in an exemplary but not limiting manner, R11 is represented by methyl.
Selected detailed synthesis examples for the compounds of the general formula (I) according to the invention are given below. The example numbers mentioned correspond to the numbering scheme in Tables A1 to E4 below. The 1H NMR, 13C-NMR and 19F-NMR spectroscopy data reported for the chemical examples described in the sections which follow (400 MHz for 1H-NMR and 150 MHz for 13C-NMR and 375 MHz for 19F-NMR, solvent CDCl3, CD3OD or d6-DMSO, internal standard: tetramethylsilane δ=0.00 ppm), were obtained on a Bruker instrument, and the signals listed have the meanings given below: br=broad; s=singlet, d=doublet, t=triplet, dd=doublet of doublets, ddd=doublet of a doublet of doublets, m=multiplet, q=quartet, quint=quintet, sext=sextet, sept=septet, dq=doublet of quartets, dt=doublet of triplets, tt=triplet of triplets. In the case of diastereomer mixtures, either the significant signals for each of the two diastereomers are reported or the characteristic signal of the main diastereomer is reported. The abbreviations used for chemical groups are defined as follows: Me=CH3, Et=CH2CH3, t-Hex=C(CH3)2CH(CH3)2, t-Bu=C(CH3)3, n-Bu=unbranched butyl, n-Pr=unbranched propyl, c-Hex=cyclohexyl.
No. A9-156: Methyl N-[1-(n-propyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(2,4-dimethylbenzyl)phosphonamidate
3,4-Dihydroquinolin-2(1H)-one (20.0 g, 136.05 mmol) was added to conc. sulfuric acid (200 ml) and cooled to −20° C., and fuming nitric acid (4 ml, 95.24 mmol) was then added carefully over a period of 30 minutes. The resulting reaction mixture was stirred at −20° C. for 2 h and at room temperature for a further 2 h and then slowly diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-nitro-3,4-dihydroquinolin-2(1H)-one (20.0 g, 76% of theory) was isolated as a colorless solid. 6-Nitro-3,4-dihydroquinolin-2(1H)-one (8.52 g, 44.38 mmol) was dissolved under argon in abs. N,N-dimethylformamide (150 ml), the mixture was cooled to 0° C. and fine potassium carbonate powder (7.40 g, 52.26 mmol) was added. After 15 min of stirring at a temperature of 0° C., n-propyl iodide (2 equiv, 88.771 mmol) was added. The resulting reaction mixture was stirred at room temperature for 24 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), gave 6-nitro-1-propyl-3,4-dihydroquinolin-2(1H)-one (8.40 g, 87% of theory) as a colorless solid. In the next step, 6-nitro-1-propyl-3,4-dihydroquinolin-2(1H)-one (5.0 g, 24.27 mmol) was dissolved in an ethanol/water mixture (ratio 1:1, 50 ml), and ammonium chloride (12.96 g, 242.72 mmol) and iron powder (4.07 g, 72.82 mmol) were added. The resulting reaction mixture was stirred at a temperature of 80° C. for 2 h and, after cooling to room temperature, concentrated. Ethyl acetate and water were added to the residue and the aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (4.0 g, 94% of theory) as a colorless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 6.79 (d, 1H), 6.45 (m, 1H), 6.42 (m, 1H), 4.85 (br. s, 2H, NH2), 3.75 (m, 2H), 2.68 (m, 2H), 2.43 (m, 2H), 1.52 (m, 2H), 0.85 (t, 3H). Trimethyl phosphite (1 equiv, 8.07 mmol) and 2,4-dimethylbenzyl bromide (1 equiv, 8.07 mmol) were added to a multi-necked flask which had been dried by heating and then stirred together under continuous nitrogen flow at a temperature of 100° C. for 10 h. After complete conversion, without further purification, distilled POCl3 (1 equiv) was added to the resulting crude product and the mixture was stirred under argon at a temperature of 60° C. for 1.5 h. After complete conversion, the methyl (2,4-dimethylbenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. In a round-bottom flask which had been dried by heating, under argon, 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (668 mg, 3.27 mmol) was dissolved in abs. tetrahydrofuran (2 ml) and slowly added dropwise under argon to a solution, cooled to −20° C., of methyl (2,4-methylbenzyl)phosphonochloridate (1065 mg, 3.27 mmol) in abs. tetrahydrofuran (10 ml) in a round-bottom flask which had been dried beforehand by heating. The resulting reaction mixture was stirred at −20° C. for 10 minutes, triethylamine (0.91 ml, 6.54 mmol) was then added and the mixture was subsequently stirred at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave methyl N-[1-(n-propylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(2,4-dimethylbenzyl)phosphonamidate (57 mg, 4% of theory) as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.00 (m, 1H), 6.95 (m, 1H), 6.88 (m, 1H), 6.85-6.83 (m, 2H), 6.80 (m, 1H), 6.69 (m, 1H), 4.88 (br. s, 1H, NH), 3.86 (m, 2H), 3.76 (d, 3H), 3.32/3.26 (d, 2H), 2.83-2.78 (m, 2H), 2.64-2.59 (m, 2H), 2.26/2.13 (s, 6H), 1.71-1.63 (m, 2H), 0.96 (t, 3H).
No. A10-152: Ethyl N-[1-(n-propyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(4-methylbenzyl)phosphonamidate
Triethyl phosphite (2.00 g, 12.04 mmol) and 4-methylbenzyl bromide (15.65 mmol) were added to a microwave vessel which had been dried by heating and then stirred together in the microwave under nitrogen at a temperature of 140° C. for 1 h. After complete conversion, the resulting crude product was purified by column chromatography (heptane/ethyl acetate gradient), distilled POCl3 (4.43 mmol) was then added to a partial amount of the resulting purified intermediate (4.43 mmol) and the mixture was stirred under argon at a temperature of 60° C. for 1.5 h. After complete conversion, the reaction mixture was concentrated carefully and the ethyl (4-methylbenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. In a round-bottom flask which had been dried by heating, under argon, 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (904 mg, 4.43 mmol) was dissolved in abs. tetrahydrofuran (2 ml) and slowly added dropwise under argon to a solution, cooled to −20° C., of ethyl (4-ethylbenzyl)phosphonochloridate (1030 mg, 4.43 mmol) in abs. tetrahydrofuran (8 ml) in a round-bottom flask which had been dried beforehand by heating. The resulting reaction mixture was stirred at −20° C. for 10 minutes, triethylamine (1.23 ml, 8.86 mmol) was then added and the mixture was subsequently stirred at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave ethyl N-[1-(n-propylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(4-methylbenzyl)phosphonamidate (224 mg, 12% of theory) as a colorless solid. 1H-NMR (600 MHz, CDCl3 δ, ppm) 7.16-03 (m, 4H), 6.87 (m, 1H), 6.81 (m, 1H), 6.72 (m, 1H), 5.00 (br. m, 1H, NH), 4.24-4.17 (m, 1H), 4.08-4.00 (m, 1H), 3.90-3.84 (m, 2H), 3.27/3.02 (d, 2H), 2.83-2.78 (m, 2H), 2.63-2.59 (m, 2H), 2.30 (s, 3H), 1.71-1.63 (m, 2H), 1.33 (t, 3H), 0.96 (t, 3H).
No. A10-156: Ethyl N-[1-(n-propyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(2,4-dimethylbenzyl)phosphonamidate
Triethyl phosphite (2.00 g, 12.04 mmol) and 2,4-dimethylbenzyl bromide (3.12 g, 15.65 mmol) were added to a microwave vessel which had been dried by heating and then stirred together under nitrogen at a temperature of 140° C. in the microwave for 1 h. After complete conversion, the resulting crude product was purified by column chromatography (heptane/ethyl acetate gradient), distilled POCl3 (0.36 ml, 3.90 mmol) was then added to a partial amount of the resulting purified intermediate (1.00 g, 3.90 mmol) and, under argon, the mixture was stirred at a temperature of 60° C. for 1.5 h. After complete conversion, the reaction mixture was concentrated carefully, the ethyl (2,4-dimethylbenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. In a round-bottom flask which had been dried by heating, under argon, 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (797 mg, 3.90 mmol) was dissolved in abs. tetrahydrofuran (2 ml) and slowly added dropwise under argon to a solution, cooled to −20° C., of ethyl (2,4-methylbenzyl)phosphonochloridate (3.90 mmol) in abs. tetrahydrofuran (8 ml) in a round-bottom flask which had been dried beforehand by heating. The resulting reaction mixture was stirred at −20° C. for 10 minutes, triethylamine (1.09 ml, 7.80 mmol) was then added and the mixture was subsequently stirred at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), ethyl N-[1-(n-propylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(2,4-dimethylbenzyl)phosphonamidate (39 mg, 2% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.00 (m, 1H), 6.95 (m, 1H), 6.90 (m, 1H), 6.85-6.83 (m, 2H), 6.80 (m, 1H), 6.69 (m, 1H), 4.83 (br. m, 1H, NH), 4.23-4.18 (m, 1H), 4.06-3.99 (m, 1H), 3.86 (m, 2H), 3.31 (d, 1H), 3.26 (d, 1H), 2.82-2.78 (m, 2H), 2.64-2.59 (m, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 1.71-1.63 (m, 2H), 1.32 (t, 3H), 0.95 (t, 3H).
No. A11-151: P-Benzyl-P-methyl-N-(2-oxo-1 -propyl-1,2,3,4-tetrahydroquinolin-6-yl)phosphinamide.
3,4-Dihydroquinolin-2(1H)-one (20.0 g, 136.05 mmol) was added to conc. sulfuric acid (200 ml) and cooled to −20° C., and fuming nitric acid (4 ml, 95.24 mmol) was then added dropwise carefully over a period of 30 minutes. The resulting reaction mixture was stirred at −20° C. for 2 h and at room temperature for a further 2 h and then carefully diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-nitro-3,4-dihydroquinolin-2(1H)-one (20.0 g, 76% of theory) was isolated as a colorless solid. 6-Nitro-3,4-dihydroquinolin-2(1H)-one (8.52 g, 44.38 mmol) was dissolved under argon in abs. N,N-dimethylformamide (150 ml), the mixture was cooled to 0° C. and fine potassium carbonate powder (7.40 g, 52.26 mmol) was added. After 15 min of stirring at a temperature of 0° C., n-propyl iodide (2 equiv, 88.771 mmol) was added. The resulting reaction mixture was then stirred at room temperature for 24 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 6-nitro-1-propyl-3,4-dihydroquinolin-2(1H)-one (8.40 g, 87% of theory) as a colorless solid. In the next step, 6-nitro-1-propyl-3,4-dihydroquinolin-2(1H)-one (5.0 g, 24.27 mmol) was dissolved in an ethanol/water mixture (ratio 1:1, 50 ml), and ammonium chloride (12.96 g, 242.72 mmol) and iron powder (4.07 g, 72.82 mmol) were added. The resulting reaction mixture was stirred at a temperature of 80° C. for 2 h and, after cooling to room temperature, concentrated. Ethyl acetate and water were added to the residue and the aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (4.0 g, 94% of theory) as a colorless solid. 1H-NMR (400 MHz, d6-DSMO δ, ppm) 6.79 (d, 1H), 6.45 (m, 1H), 6.42 (m, 1H), 4.85 (br. s, 2H, NH2), 3.75 (m, 2H), 2.68 (m, 2H), 2.43 (m, 2H), 1.52 (m, 2H), 0.85 (t, 3H). Methyldiethyl phosphite (1 equiv, 8.07 mmol) and benzyl bromide (1.54 ml, 8.07 mmol) were added to a multi-necked flask which had been dried by heating and then stirred together under continuous nitrogen flow at a temperature of 100° C. for 10 h. After complete conversion, without further purification, distilled POCl3 (1 equiv) was added to the resulting crude product and the mixture was stirred under argon at a temperature of 60° C. for 1.5 h. After complete conversion, the benzyl(methyl)phosphine chloride obtained was, without further purification, directly reacted in the next step. Under argon, 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (1 equiv., 4.13 mmol) was dissolved together with benzyl(methyl)phosphine chloride (1 equiv., 4.13 mmol) in abs. tetrahydrofuran (10 ml) in a round-bottom flask which had been dried by heating, the mixture was cooled to a temperature of −20° C., then triethylamine (1.2 ml, 8.26 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure, dil. HCl and dichloromethane were added to the residue that remained and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave P-benzyl-P-methyl-N-(2-oxo-1-propyl-1,2,3,4-tetrahydroquinolin-6-yl)phosphinamide (103 mg, 7% of theory) as a colorless solid.1H-NMR (400 MHz, CDCl3 δ, ppm) 7.37-7.26 (m, 6H), 6.83 (m, 1H), 6.61 (m, 1H), 6.45 (br. s, 1H, NH), 3.75 (m, 2H), 3.35-3.30 (m, 2H), 2.81 (m, 2H), 2.62 (m, 2H), 1.52 (m, 2H), 0.85 (t, 3H).
No. A25-152: Methyl N-[1-(cyclopropylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(4-methylbenzyl)phosphonamidate
3,4-Dihydroquinolin-2(1H)-one (770 mg, 3.83 mmol) was added to conc. acetic acid (5 ml), and fuming nitric acid (0.21 ml, 5.06 mmol) was then added carefully. The resulting reaction mixture was stirred at room temperature for 2 h and then diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 68% of theory) was isolated as a colorless solid. 6-Nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol) was dissolved under argon in abs. N,N-dimethylformamide and admixed with fine potassium carbonate powder (1.08 mg, 7.81 mmol). After stirring at room temperature for 5 min, chloromethylcyclopropane (306 mg, 3.38 mmol) and potassium iodide (6 mg, 0.04 mmol) were added. The resulting reaction mixture was stirred at 120° C. for 2 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(cyclopropylmethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (600 mg, 94% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.17 (dd, 1H), 8.08 (d, 1H), 7.22 (d, 1H), 3.91 (d, 2H), 3.04 (m, 2H), 2.73 (m, 2H), 1.12 (m, 1H), 0.55 (m, 2H), 0.45 (m, 2H). In the next step, 1-(cyclopropylmethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (600 mg, 2.44 mmol) was added together with tin(II) chloride dihydrate (2.19 g, 9.75 mmol) to abs. ethanol and the mixture was stirred under argon at a temperature of 80° C. for 5 h. After cooling to room temperature, the reaction mixture was poured into ice-water and then adjusted to pH 12 with aqueous NaOH. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-amino-1-(cyclopropylmethyl)-3,4-dihydroquinolin-2(1H)-one (481 mg, 91% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.94 (d, 1H), 6.58 (dd, 1H), 6.53 (d, 1H), 3.83 (d, 3H), 2.81 (m, 2H), 2.61 (m, 2H), 1.12 (m, 1H), 0.47 (m, 2H), 0.39 (m, 2H). Trimethyl phosphite (1 equiv, 8.07 mmol) and 4-methylbenzyl bromide (1 equiv, 8.07 mmol) were added to a multi-necked flask which had been dried by heating and then stirred together under continuous nitrogen flow at a temperature of 100° C. for 10 h. After complete conversion, without further purification, distilled POCl3 (1 equiv) was added to the resulting crude product and the mixture was stirred under argon at a temperature of 60° C. for 1.5 h. After complete conversion, the methyl (4-methylbenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. In a round-bottom flask which had been dried by heating, under argon, 6-amino-1-cyclopropylmethyl-3,4-dihydroquinolin-2(1H)-one (960 mg, 4.57 mmol) was dissolved in abs. tetrahydrofuran (2 ml) and slowly added dropwise under argon to a solution, cooled to −20° C., of methyl (4-methylbenzyl)phosphonochloridate (1000 mg, 4.57 mmol) in abs. tetrahydrofuran (10 ml) in a round-bottom flask which had been dried beforehand by heating. The resulting reaction mixture was stirred at −20° C. for 10 minutes, triethylamine (1.27 ml, 9.15 mmol) was then added and the mixture was subsequently stirred at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), methyl N-[1-(cyclopropylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(4-methylbenzyl)phosphonamidate (209 mg, 10% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.09-7.04 (m, 4H), 7.02 (m, 1H), 6.83 (m, 1H), 6.73 (m, 1H), 5.01 (br. s, 1H, NH), 3.84 (d, 2H), 3.76/3.53 (d, 3H), 3.25/3.00 (d, 2H), 2.87-2.82 (m, 2H), 2.65-2.61 (m, 2H), 2.32/2.30 (s, 3H), 1.13 (m, 1H), 0.53-0.48 (m, 2H), 0.45-0.41 (m, 2H).
No. A26-152: Ethyl N-{1-[1,1′-bi(cyclopropyl)-1-yl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}-P-(4-methylphenyl)phosphonamidate
Triethyl phosphite (1 equiv, 8.07 mmol) and 4-methylbenzyl bromide (1 equiv, 8.07 mmol) were added to a multi-necked flask which had been dried by heating and then stirred together under continuous nitrogen flow at a temperature of 100° C. for 10 h. After complete conversion, without further purification, distilled POCl3 (1 equiv) was added to the resulting crude product and the mixture was stirred under argon at a temperature of 60° C. for 1.5 h. After complete conversion, the ethyl (4-methylbenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. In a round-bottom flask which had been dried by heating, under argon, 6-amino-1-cyclopropylmethyl-3,4-dihydroquinolin-2(1H)-one (890 mg, 4.11 mmol) was dissolved in abs. tetrahydrofuran (2 ml) and slowly added dropwise under argon to a solution, cooled to −20° C., of ethyl (4-methylbenzyl)phosphonochloridate (957 mg, 4.11 mmol) in abs. tetrahydrofuran (8 ml) in a round-bottom flask which had been dried beforehand by heating. The resulting reaction mixture was stirred at −20° C. for 10 minutes, triethylamine (1.15 ml, 8.23 mmol) was then added and the mixture was subsequently stirred at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), ethyl N-[1-(cyclopropylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(4-methylbenzyl)phosphonamidate (236 mg, 9% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.17-7.03 (m, 4H), 7.00 (m, 1H), 6.83 (m, 1H), 6.72 (m, 1H), 5.03 (br. m, 1H, NH), 4.24-4.19 (m, 1H), 4.12-4.01 (m, 1H), 3.87 (m, 2H), 3.27/3.02 (d, 2H), 2.87-2.82 (m, 2H), 2.65-2.61 (m, 2H), 2.32/2.30 (s, 3H), 1.33 (t, 3H), 1.13 (m, 1H), 0.53-0.48 (m, 2H), 0.45-0.39 (m, 2H).
No. A26-169: Ethyl N-[1-(cyclopropylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(2,4-dichlorobenzyl)phosphonamidate
3,4-Dihydroquinolin-2(1H)-one (770 mg, 3.83 mmol) was added to conc. acetic acid (5 ml), and fuming nitric acid (0.21 ml, 5.06 mmol) was then added carefully. The resulting reaction mixture was stirred at room temperature for 2 h and then diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 68% of theory) was isolated as a colorless solid. 6-Nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 2.60 mmol) was dissolved under argon in abs. N,N-dimethylformamide and admixed with fine potassium carbonate powder (1.08 mg, 7.81 mmol). After stirring at room temperature for 5 min, chloromethylcyclopropane (306 mg, 3.38 mmol) and potassium iodide (6 mg, 0.04 mmol) were added. The resulting reaction mixture was stirred at 120° C. for 2 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(cyclopropylmethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (600 mg, 94% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.17 (dd, 1H), 8.08 (d, 1H), 7.22 (d, 1H), 3.91 (d, 2H), 3.04 (m, 2H), 2.73 (m, 2H), 1.12 (m, 1H), 0.55 (m, 2H), 0.45 (m, 2H). In the next step, 1-(cyclopropylmethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (600 mg, 2.44 mmol) was added together with tin(II) chloride dihydrate (2.19 g, 9.75 mmol) to abs. ethanol and the mixture was stirred under argon at a temperature of 80° C. for 5 h. After cooling to room temperature, the reaction mixture was poured into ice-water and then adjusted to pH 12 with aqueous NaOH. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 6-amino-1-(cyclopropylmethyl)-3,4-dihydroquinolin-2(1H)-one (481 mg, 91% of theory) as a colorless solid, 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.94 (d, 1H), 6.58 (dd, 1H), 6.53 (d, 1H), 3.83 (d, 3H), 2.81 (m, 2H), 2.61 (m, 2H), 1.12 (m, 1H), 0.47 (m, 2H), 0.39 (m, 2H). Triethyl phosphite (1 equiv, 8.07 mmol) and 2,4-dichlorobenzyl bromide (1 equiv, 8.07 mmol) were added to a multi-necked flask and then stirred together under continuous nitrogen flow at a temperature of 100° C. for 10 h. After complete conversion, without further purification, distilled POCl3 (1 equiv) was added to the resulting crude product and the mixture was stirred under argon at a temperature of 60° C. for 1.5 h. After complete conversion, the ethyl (2,4-dichlorobenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. 6-Amino-1-cyclopropylmethyl-3,4-dihydroquinolin-2(1H)-one (53 mg, 0.24 mmol) was dissolved, under argon, together with ethyl (2,4-dichlorobenzyl)phosphonochloridate (105 mg, 0.37 mmol) in abs. acetonitrile (5 ml) in a round-bottom flask which had been dried by heating, then pyridine (0.4 ml, 0.49 mmol) and dimethyl sulfoxide (0.01 ml, 0.15 mmol) were added and the mixture was stirred at room temperature for 8 h. The reaction mixture was then concentrated under reduced pressure, dil. HCl and dichloromethane were added to the residue that remained and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), ethyl N-[1-(cyclopropylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(2,4-dichlorobenzyl)phosphonamidate (29 mg, 24% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.48 (m, 1H), 7.23 (m, 1H), 7.18 (br. s, 1H, NH), 7.03-6.95 (m, 2H), 6.77 (m, 1H), 6.68 (m, 1H), 3.87 (m, 2H), 3.15-3.06 (m, 2H), 2.84-2.80 (m, 2H), 2.66-2.61 (m, 4H), 1.28 (m, 3H), 1.13 (m, 1H), 0.52 (m, 2H), 0.44 (m, 2H).
No. A45-152: Methyl N-{1-[1,1′-bi(cyclopropyl)-1-yl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}-P-(4-methylphenyl)phosphonamidate
Ethyl (2E)-3-(2-fluoro-5-nitrophenyl)acrylate (1000 mg, 4.18 mmol) and 1,1′-bi(cyclopropyl)-1-amine (508 mg, 3.80 mmol) were dissolved under argon in abs. N,N-dimethylformamide (10 ml), and then N,N-diisopropylethylamine (1.32 ml, 7.60 mmol) was added. The resulting reaction mixture was stirred at a temperature of 50° C. for a total of 16 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave ethyl (2E)-3-{2-[1,1′-bi(cyclopropyl)-1-ylamino]-5-nitrophenyl}acrylate (570 mg, 43% of theory) as a colorless solid, 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.27 (d, 1H), 8.16 (m, 1H), 7.63 (d, 1H), 7.18 (d, 1H), 6.46 (d, 1H), 5.19 (br. s, 1H, NH), 4.29 (q, 2H), 1.35 (t, 3H), 1.33-1.27 (m, 1H), 0.78 (m, 4H), 0.49 (m, 2H), 0.18 (m, 2H). Ethyl (2E)-3-{2-[1,1′-bi(cyclopropyl)-1-ylamino]-5-nitrophenyl}acrylate (570 mg, 1.80 mmol) was then dissolved in abs. ethanol (10 ml), and (Ph3P)3RhCl (167 mg, 0.18 mmol) was added. After stirring at room temperature for 5 min, hydrogen was introduced into the reaction solution with a constant gas flow via a gas introduction apparatus for about 9 h. The progress of the reaction was monitored by LC-MS. On completion of conversion, the reaction solution was concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave ethyl 3-{2-[1,1′-bi(cyclopropyl)-1-ylamino]-5-nitrophenyl}propanoate (200 mg, 35% of theory) as a colorless solid, 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.07 (m, 1H), 7.94 (d, 1H), 7.11 (d, 1H), 5.40 (br. s, 1H, NH), 4.18 (q, 2H), 2.77 (m, 2H), 2.64 (m, 2H), 1.30-1.24 (m, 4H), 0.76 (m, 4H), 0.46 (m, 2H), 0.17 (m, 2H). Ethyl 3-{2-[1,1′-bi(cyclopropyl)-1-ylamino]-5-nitrophenyl}propanoate (200 mg, 0.63 mmol) was dissolved in abs. tetrahydrofuran (8 ml) and, under argon, added dropwise to a suspension, cooled to 0° C., of sodium hydride (38 mg, 0.94 mmol, 60% suspension in oil) in abs. tetrahydrofuran (5 ml). The resulting reaction mixture was stirred at 0° C. for 1 h, and then water was added cautiously, followed by ethyl acetate after stirring for 5 min. The aqueous phase was then extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 1-[1,1′-bi(cyclopropyl)-1-yl]-6-nitro-3,4-dihydroquinolin-2(1H)-one (90 mg, 53%) as a colorless solid, 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.16 (m, 1H), 8.04 (m, 1H), 7.53 (d, 1H), 2.93 (m, 2H), 2.78-2.58 (m, 2H), 1.44 (m, 1H), 1.23 (m, 1H), 1.03 (m, 1H), 0.91-0.82 (m, 2H), 0.60-0.45 (m, 3H), 0.28 (m, 1H). In the next step, 1-[1,1′-bi(cyclopropyl)-1-yl]-6-nitro-3,4-dihydroquinolin-2(1H)-one (90 mg, 0.33 mmol) was, together with tin(II) chloride dihydrate (298 mg, 1.32 mmol), added to abs. ethanol (5 ml) and stirred under argon at a temperature of 80° C. for 5 h. After cooling to room temperature, the reaction mixture was poured into ice-water and then adjusted to pH 12 with aqueous NaOH. The aqueous phase was then extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 6-amino-1-[1,1′-bi(cyclopropyl)-1-yl]-3,4-dihydroquinolin-2(1H)-one (70 mg, 87% of theory) as a highly viscous foam, 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.18 (m, 1H), 6.58 (m, 1H), 6.48 (d, 1H), 2.78 (m, 2H), 2.59 (m, 2H), 1.47 (m, 1H), 1.08 (m, 1H), 0.98 (m, 1H), 0.90-0.81 (m, 2H), 0.60-0.43 (m, 3H), 0.28 (m, 1H). Trimethyl phosphite (1 equiv, 8.07 mmol) and 4-methylbenzyl bromide (1 equiv, 8.07 mmol) were added to a multi-necked flask which had been dried by heating and then stirred together under continuous nitrogen flow at a temperature of 100° C. for 10 h. After complete conversion, without further purification, distilled POCl3 (1 equiv) was added to the resulting crude product and the mixture was stirred under argon at a temperature of 60° C. for 1.5 h. After complete conversion, the methyl (4-methylbenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. In a round-bottom flask which had been dried by heating, under argon, 6-amino-1-[1,1′-bi(cyclopropyl)-1-yl]-3,4-dihydroquinolin-2(1H)-one (1108 mg, 4.57 mmol) was dissolved in abs. tetrahydrofuran (2 ml) and slowly added dropwise under argon to a solution, cooled to −20° C., of methyl (4-methylbenzyl)phosphonochloridate (1000 mg, 4.57 mmol) in abs. tetrahydrofuran (10 ml) in a round-bottom flask which had been dried beforehand by heating. The resulting reaction mixture was stirred at −20° C. for 10 minutes, triethylamine (1.27 ml, 9.15 mmol) was then added and the mixture was subsequently stirred at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), gave methyl N-{1-[1,1′-bi(cyclopropyl)-1-yl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}-P-(4-methylphenyl)phosphonamidate (243 mg, 11% of theory) as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.28-7.22 (m, 2H), 7.13 (m, 1H), 7.10-7.04 (m, 2H), 6.81 (m, 1H), 6.68 (m, 1H), 5.11 (br. s, 1H, NH), 3.72/3.52 (d, 3H), 3.30-2.90 (m, 2H), 3.25/3.00 (d, 2H), 2.82-2.53 (m, 2H), 2.32/2.27 (s, 3H), 1.47 (m, 1H), 1.09 (m, 1H), 0.99 (m, 1H), 0.78-0.70 (m, 1H), 0.59-0.42 (m, 4H), 0.27 (m, 1H).
No. A46-152: Ethyl N-{1-[1,1′-bi(cyclopropyl)-1-yl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}-P-(4-methylphenyl)phosphonamidate
Triethyl phosphite (1 equiv, 8.07 mmol) and 4-methylbenzyl bromide (1 equiv, 8.07 mmol) were added to a multi-necked flask which had been dried by heating and then stirred together under continuous nitrogen flow at a temperature of 100° C. for 10 h. After complete conversion, without further purification, distilled POCl3 (1 equiv) was added to the resulting crude product and the mixture was stirred under argon at a temperature of 60° C. for 1.5 h. After complete conversion, the ethyl (4-methylbenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. In a round-bottom flask which had been dried by heating, under argon, 6-amino-1-[1,1′-bi(cyclopropyl)-1-yl]-3,4-dihydroquinolin-2(1H)-one (1042 mg, 4.29 mmol) was dissolved in abs. tetrahydrofuran (2 ml) and slowly added dropwise under argon to a solution, cooled to −20° C., of ethyl (4-methylbenzyl)phosphonochloridate (1000 mg, 4.29 mmol) in abs. tetrahydrofuran (10 ml) in a round-bottom flask which had been dried beforehand by heating. The resulting reaction mixture was stirred at −20° C. for 10 minutes, triethylamine (1.19 ml, 8.54 mmol) was then added and the mixture was subsequently stirred at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave ethyl N-{1-[1,1′-bi(cyclopropyl)-1-yl]-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}-P-(4-methylphenyl)phosphonamidate (196 mg, 9% of theory) as a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.28-7.23 (m, 2H), 7.13 (m, 1H), 7.11-7.02 (m, 2H), 6.82 (m, 1H), 6.68 (m, 1H), 5.04-4.91 (br. s, 1H, NH), 4.23-3.78 (m, 4H), 3.25/3.00 (d, 2H), 2.86-2.58 (m, 2H), 2.31/2.28 (s, 3H), 1.47 (m, 1H), 1.33/1.22 (m, 3H), 1.09 (m, 1H), 0.99 (m, 1H), 0.78-0.70 (m, 1H), 0.59-0.42 (m, 4H), 0.27 (m, 1H).
No. A57-152: Methyl N-[2-oxo-1-(spiro[3.3]hept-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-P-(4-methylphenyl)phosphonamidate
Ethyl (2E)-3-(2-fluoro-5-nitrophenyl)acrylate (1000 mg, 4.18 mmol) and spiro[3.3]hept-2-ylamine (561 mg, 3.80 mmol) were dissolved under argon in abs. N,N-dimethylformamide, and then N,N-diisopropylethylamine (1.32 ml, 7.60 mmol) was added. The resulting reaction mixture was stirred at a temperature of 50° C. for 10 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave ethyl (2E)-3-[5-nitro-2-(spiro[3.3]hept-2-ylamino)phenyl]acrylate (500 mg, 36% of theory) as a colorless solid, 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.26 (d, 1H), 8.11 (m, 1H), 7.67 (d, 1H), 6.51 (m, 1H), 6.47 (d, 1H), 4.82 (br. m, 1H, NH), 4.29 (q, 2H), 3.88 (m, 1H), 2.60 (m, 2H), 2.12 (m, 2H), 2.01 (m, 2H), 1.95-1.85 (m, 4H), 1.37 (t, 3H). Ethyl (2E)-3-[5-nitro-2-(spiro[3.3]hept-2-ylamino)phenyl]acrylate (500 mg, 1.51 mmol) was then dissolved in abs. ethanol (8 ml), and (Ph3P)3RhCl (70 mg) was added. After stirring at room temperature for 5 min, hydrogen was introduced into the reaction solution with a constant gas flow via a gas introduction apparatus for 10 h. The progress of the reaction was monitored by LCMS. On completion of conversion, the reaction solution was concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave ethyl 3-[5-nitro-2-(spiro[3.3]hept-2-ylamino)phenyl]propanoate (490 mg, 97% of theory) as a colorless solid, 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.04 (dd, 1H), 7.94 (d, 1H), 6.43 (d, 1H), 5.11 (br. m, 1H, NH), 4.28 (q, 2H), 3.87 (m, 1H), 2.81 (m, 2H), 2.67 (m, 2H), 2.58 (m, 2H), 2.11 (m, 2H), 2.00 (m, 2H), 1.92-1.85 (m, 4H), 1.28 (t, 3H). Ethyl 3-[5-nitro-2-(spiro[3.3]hept-2-ylamino)phenyl]propanoate (490 mg, 1.47 mmol) was dissolved in abs. tetrahydrofuran (8 ml) and, under argon, added dropwise to a suspension, cooled to 0° C., of sodium hydride (88 mg, 2.21 mmol, 60% suspension in oil) in abs. tetrahydrofuran (5 ml). The resulting reaction mixture was stirred at 0° C. for 1 h, and then water was added cautiously, followed by ethyl acetate after stirring for 5 min. The aqueous phase was then extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 6-nitro-1-(spiro[3.3]hept-2-yl)-3,4-dihydroquinolin-2(1H)-one (180 mg, 43%) as a colorless solid, 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.11-8.07 (m, 2H), 6.84 (d, 1H), 4.29 (m, 1H), 2.92 (m, 2H), 2.74 (m, 2H), 2.61 (m, 2H), 2.12 (m, 2H), 2.07 (m, 2H), 1.94-1.83 (m, 4H). In the next step, 6-nitro-1-(spiro[3.3]hept-2-yl)-3,4-dihydroquinolin-2(1H)-one (180 mg, 2.44 mmol) was, together with tin(II) chloride dihydrate (567 mg, 2.52 mmol), added to abs. ethanol and stirred under argon at a temperature of 80° C. for 5 h. After cooling to room temperature, the reaction mixture was poured into ice-water and then adjusted to pH 12 with aqueous NaOH. The aqueous phase was then extracted repeatedly with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 6-amino-1-(spiro[3.3]hept-2-yl)-3,4-dihydroquinolin-2(1H)-one (151 mg, 94% of theory) as a highly viscous foam, 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.59-6.53 (m, 3H), 4.32-3.80 (br. s, 2H, NH2), 4.21 (m, 1H), 2.72 (m, 2H), 2.67 (m, 2H), 2.48 (m, 2H), 2.12-2.06 (m, 4H), 1.93-1.80 (m, 4H). Trimethyl phosphite (1 equiv, 8.07 mmol) and 4-methylbenzyl bromide (1 equiv, 8.07 mmol) were added to a multi-necked flask which have been dried by heating and then stirred together under continuous nitrogen flow at a temperature of 100° C. for 10 h. After complete conversion, a partial amount of the resulting crude product (170 mg) was, without further purification, taken up in aqueous NaOH (10% strength, 5 ml), and the mixture was stirred under reflux conditions for 2 hours. After cooling to room temperature, dil. hydrochloric acid was added carefully, followed by thorough extraction with dichloromethane and water. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Without further purification, the resulting crude product (109 mg, 0.54 mmol) was initially charged into abs. N,N-dimethylformamide (2 ml) and cooled to 0° C. After 5 minutes of stirring at 0° C., oxalyl chloride (0.12 ml, 1.63 mmol) was added and the reaction mixture obtained was stirred at room temperature for one and a half hours and then concentrated under reduced pressure. The resulting methyl (4-methylbenzyl)phosphonochloridate was taken up in abs. dichloromethane (5 ml) and cooled to a temperature of −20° C., and a solution of 6-amino-1-(spiro[3.3]hept-2-yl)-3,4-dihydroquinolin-2(1H)-one (167 mg, 0.65 mmol) mmol) in abs. dichloromethane (2 ml) was added. This was followed by the dropwise addition of N-ethyldiisopropylamine (0.17 ml, 1.19 mmol). The resulting reaction mixture was stirred at −20° C. for 10 minutes and then at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with dichloromethane and the filtrate was concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave methyl N-[2-oxo-1-(spiro[3.3]hept-2-yl)-1,2,3,4-tetrahydroquinolin-6-yl]-P-(4-methylphenyl)phosphonamidate (10 mg, 4% of theory) as a highly viscous foam. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.15-7.11 (m, 2H), 7.09-7.05 (m, 2H), 6.99 (m, 1H), 6.83 (m, 1H), 6.68-6.65 (m, 1H), 5.15 (br. s, 1H, NH), 4.24-4.19 (m, 1H), 3.65/3.43 (m, 3H), 3.14/3.03 (d, 2H), 2.73-2.69 (m, 2H), 2.67-2.63 (m, 2H), 2.52-2.46 (m, 2H), 2.32 (s, 3H), 2.15-2.03 (m, 4H), 1.85-1.70 (m, 4H).
The compounds listed below are obtained analogously to the preparation examples given above and referred to at the appropriate place and taking into account the general information regarding the preparation of substituted oxotetrahydroquinolinylphosphin- and -phosphonamides of the general formula (I).
A1. Compounds A1-1 to A1-650 of the general formula (Iaa1) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions (Nos 1 to 650; corresponding to Compounds A1-1 to A1-650) in Table 1 below. An arrow in any of the definitions of R5, R6 listed in table 1 represents, by way of example, but not by way of limitation, a bond of the radical in question to the core structure (Iaa1).
A2. Compounds A2-1 to A2-650 of the general formula (Iaa2) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A2-1 to A2-650).
A3. Compounds A3-1 to A3-650 of the general formula (Iaa3) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A3-1 to A3-650).
A4. Compounds A4-1 to A4-650 of the general formula (Iaa4) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A4-1 to A4-650).
A5. Compounds A5-1 to A5-650 of the general formula (Iaa5) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A5-1 to A5-650).
A6. Compounds A6-1 to A6-650 of the general formula (Iaa6) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A6-1 to A6-650).
A7. Compounds A7-1 to A7-650 of the general formula (Iaa7) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A7-1 to A7-650).
A8. Compounds A8-1 to A8-650 of the general formula (Iaa8) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A8-1 to A8-650).
A9. Compounds A9-1 to A9-650 of the general formula (Iaa9) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A9-1 to A9-650).
A10. Compounds A10-1 to A10-650 of the general formula (Iaa10) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A10-1 to A10-650).
A11. Compounds A11-1 to A11-650 of the general formula (Iaa11) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A11-1 to A11-650).
A12. Compounds A12-1 to A12-650 of the general formula (Iaa12) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A12-1 to A12-650).
A13. Compounds A13-1 to A13-650 of the general formula (Iaa13) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A13-1 to A13-650).
A14. Compounds A14-1 to A14-650 of the general formula (Iaa14) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A14-1 to A14-650).
A15. Compounds A15-1 to A15-650 of the general formula (Iaa15) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A15-1 to A15-650).
A16. Compounds A16-1 to A16-650 of the general formula (Iaa16) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A16-1 to A16-650).
A17. Compounds A17-1 to A17-650 of the general formula (Iaa17) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A17-1 to A17-650).
A18. Compounds A18-1 to A18-650 of the general formula (Iaa18) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A18-1 to A18-650).
A19. Compounds A19-1 to A19-650 of the general formula (Iaa19) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A19-1 to A19-650).
A20. Compounds A20-1 to A20-650 of the general formula (Iaa20) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A20-1 to A20-650).
A21. Compounds A21-1 to A21-650 of the general formula (Iaa21) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A21-1 to A21-650).
A22. Compounds A22-1 to A22-650 of the general formula (Iaa22) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A22-1 to A22-650).
A23. Compounds A23-1 to A23-650 of the general formula (Iaa23) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A23-1 to A23-650).
A24. Compounds A24-1 to A24-650 of the general formula (Iaa24) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A24-1 to A24-650).
A25. Compounds A25-1 to A25-650 of the general formula (Iaa5) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A25-1 to A25-650).
A26. Compounds A26-1 to A26-650 of the general formula (Iaa26) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A26-1 to A26-650).
A27. Compounds A27-1 to A27-650 of the general formula (Iaa27) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A27-1 to A27-650).
A28. Compounds A28-1 to A28-650 of the general formula (Iaa28) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A28-1 to A28-650).
A29. Compounds A29-1 to A29-650 of the general formula (Iaa29) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A29-1 to A29-650).
A30. Compounds A30-1 to A30-650 of the general formula (Iaa30) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A30-1 to A6-63).
A31. Compounds A31-1 to A31-650 of the general formula (Iaa31) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A31-1 to A31-650).
A32. Compounds A32-1 to A32-650 of the general formula (Iaa32) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A32-1 to A32-650).
A33. Compounds A33-1 to A33-650 of the general formula (Iaa33) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A33-1 to A33-650).
A34. Compounds A34-1 to A34-650 of the general formula (Iaa34) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A34-1 to A34-650).
A35. Compounds A35-1 to A35-650 of the general formula (Iaa35) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A35-1 to A35-650).
A36. Compounds A36-1 to A36-650 of the general formula (Iaa36) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A36-1 to A36-650).
A37. Compounds A37-1 to A37-650 of the general formula (Iaa37) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A37-1 to A37-650).
A38. Compounds A38-1 to A38-650 of the general formula (Iaa6) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A38-1 to A38-650).
A39. Compounds A39-1 to A39-650 of the general formula (Iaa39) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A39-1 to A39-650).
A40. Compounds A40-1 to A40-650 of the general formula (Iaa40) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A40-1 to A40-650).
A41. Compounds A41-1 to A41-650 of the general formula (Iaa41) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A41-1 to A41-650).
A42. Compounds A42-1 to A42-650 of the general formula (Iaa42) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A42-1 to A42-650).
A43. Compounds A43-1 to A43-650 of the general formula (Iaa43) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A43-1 to A43-650).
A44. Compounds A44-1 to A44-650 of the general formula (Iaa44) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A44-1 to A44-650).
A45. Compounds A45-1 to A45-650 of the general formula (Iaa45) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A45-1 to A45-650).
A46. Compounds A46-1 to A46-650 of the general formula (Iaa46) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A46-1 to A46-650).
A47. Compounds A47-1 to A47-650 of the general formula (Iaa47) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A47-1 to A47-650).
A48. Compounds A48-1 to A48-650 of the general formula (Iaa48) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A48-1 to A48-650).
A49. Compounds A49-1 to A49-650 of the general formula (Iaa49) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A49-1 to A49-650).
A50. Compounds A50-1 to A50-650 of the general formula (Iaa50) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A50-1 to A50-650).
A51. Compounds A51-1 to A51-650 of the general formula (Iaa51) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A51-1 to A51-650).
A52. Compounds A52-1 to A52-650 of the general formula (Iaa52) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A52-1 to A52-650).
A53. Compounds A53-1 to A53-650 of the general formula (Iaa53) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A53-1 to A53-650).
A54. Compounds A54-1 to A54-650 of the general formula (Iaa54) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A54-1 to A54-650).
A55. Compounds A55-1 to A55-650 of the general formula (Iaa55) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A55-1 to A55-650).
A56. Compounds A56-1 to A56-650 of the general formula (Iaa56) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A56-1 to A56-650).
A57. Compounds A57-1 to A57-650 of the general formula (Iaa57) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A57-1 to A57-650).
A58. Compounds A58-1 to A58-650 of the general formula (Iaa58) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A58-1 to A58-650).
A59. Compounds A59-1 to A59-650 of the general formula (Iaa59) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A59-1 to A59-650).
A60. Compounds A60-1 to A60-650 of the general formula (Iaa60) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A60-1 to A60-650).
A61. Compounds A61-1 to A61-650 of the general formula (Iaa61) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A61-1 to A61-650).
A62. Compounds A62-1 to A62-650 of the general formula (Iaa62) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A62-1 to A62-650).
A63. Compounds A63-1 to A63-650 of the general formula (Iaa63) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A63-1 to A63-650).
A64. Compounds A64-1 to A64-650 of the general formula (Iaa64) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A64-1 to A64-650).
A65. Compounds A65-1 to A65-650 of the general formula (Iaa65) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A65-1 to A65-650).
A66. Compounds A66-1 to A66-650 of the general formula (Iaa66) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A66-1 to A66-650).
A67. Compounds A67-1 to A67-650 of the general formula (Iaa67) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds A67-1 to A67-650).
B1. Compounds B1-1 to B1-650 of the general formula (Iab1) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B1-1 to B1-650).
B2. Compounds B2-1 to B2-650 of the general formula (Iab2) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B2-1 to B2-650).
B3. Compounds B3-1 to B3-650 of the general formula (Iab3) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B3-1 to B3-650).
B4. Compounds B4-1 to B4-650 of the general formula (Iab4) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B4-1 to B4-650).
B5. Compounds B5-1 to B5-650 of the general formula (Iab5) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B5-1 to B5-650).
B6. Compounds B6-1 to B6-650 of the general formula (Iab6) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B6-1 to B6-650).
B7. Compounds B7-1 to B7-650 of the general formula (Iab7) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B7-1 to B7-650).
B8. Compounds B8-1 to B8-650 of the general formula (Iab8) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B8-1 to B8-650).
B9. Compounds B9-1 to B9-650 of the general formula (Iab9) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B9-1 to B9-650).
B10. Compounds B10-1 to B10-650 of the general formula (Iab10) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B10-1 to B10-650).
B11. Compounds B11-1 to B11-650 of the general formula (Iab11) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B11-1 to B11-650).
B12. Compounds B12-1 to B12-650 of the general formula (Iab12) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B12-1 to B12-650).
B13. Compounds B13-1 to B13-650 of the general formula (Iab13) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B13-1 to B13-650).
B14. Compounds B14-1 to B14-650 of the general formula (Iab14) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B14-1 to B14-650).
B15. Compounds B15-1 to B15-650 of the general formula (Iab15) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B15-1 to B15-650).
B16. Compounds B16-1 to B16-650 of the general formula (Iab16) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B16-1 to B16-650).
B17. Compounds B17-1 to B17-650 of the general formula (Iab17) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B17-1 to B17-650).
B18. Compounds B18-1 to B18-650 of the general formula (Iab18) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B18-1 to B18-650).
B19. Compounds B19-1 to B19-650 of the general formula (Iab19) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B19-1 to B19-650).
B20. Compounds B20-1 to B20-650 of the general formula (Iab20) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B20-1 to B20-650).
B21. Compounds B21-1 to B21-650 of the general formula (Iab21) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B21-1 to B21-650).
B22. Compounds B22-1 to B22-650 of the general formula (Iab22) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B22-1 to B22-650).
B23. Compounds B23-1 to B23-650 of the general formula (Iab23) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B23-1 to B23-650).
B24. Compounds B24-1 to B24-650 of the general formula (Iab24) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B24-1 to B24-650).
B25. Compounds B25-1 to B25-650 of the general formula (Iab25) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B25-1 to B25-650).
B26. Compounds B26-1 to B26-650 of the general formula (Iab26) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B26-1 to B26-650).
B27. Compounds B27-1 to B27-650 of the general formula (Iab3) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds B27-1 to B27-650).
C1. Compounds C1-1 to C1-650 of the general formula (Ias1) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds C1-1 to B1-650).
C2. Compounds C2-1 to C2-650 of the general formula (Ias2) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds C2-1 to C2-650).
C3. Compounds C3-1 to C3-650 of the general formula (Ias3) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds C3-1 to C3-650).
C4. Compounds C4-1 to C4-650 of the general formula (Ias4) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds C4-1 to C4-650).
D1. Compounds D1-1 to D1-650 of the general formula (Iat1) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds D1-1 to D1-650).
D2. Compounds D2-1 to D2-650 of the general formula (Iat2) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds D2-1 to D2-650).
D3. Compounds D3-1 to D3-650 of the general formula (Iat3) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds D3-1 to D3-650).
D4. Compounds D4-1 to D4-650 of the general formula (Iat4) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds D4-1 to D4-650).
E1. Compounds E1-1 to E1-650 of the general formula (Iaul) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds E1-1 to E1-650).
E2. Compounds E2-1 to E2-650 of the general formula (Iau2) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds E2-1 to E2-650).
E3. Compounds E3-1 to E3-650 of the general formula (Iau3) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds E3-1 to E3-650).
E4. Compounds E4-1 to E4-650 of the general formula (Iau4) in which R2, R3 and R4 represent hydrogen and W, R5, R6 correspond to the definitions for the respective individual compound in the radical definitions cited in table 1 (Nos 1 to 650; corresponding to compounds E4-1 to E4-650).
Spectroscopic data of selected table examples:
The spectroscopic data listed hereinafter for selected table examples were evaluated via conventional 1H NMR interpretation.
Example No. A1-151:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.42-7.25 (m, 8H), 7.22 (m, 1H), 3.70 (m, 2H), 3.31 (s, 3H), 3.09 (m, 2H), 2.63 (m, 2H), 1.36 (d, 3H).
Example No. A1-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.08-7.03 (m, 4H), 6.87-6.79 (m, 2H), 6.72 (m, 1H), 5.14 (br. s, 1H, NH), 3.73/3.52 (d, 3H), 3.33 (s, 3H), 3.27/3.02 (d, 2H), 2.85-2.82 (m, 2H), 2.65-2.62 (m, 2H), 2.30 (s, 3H).
Example No. A2-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.12-7.02 (m, 4H), 6.87-6.81 (m, 2H), 6.73 (m, 1H), 4.80 (br. m, 1H, NH), 4.24-4.19 (m, 1H), 4.08-4.00 (m, 1H), 3.33 (s, 3H), 3.27/3.02 (d, 2H), 2.85-2.81 (m, 2H), 2.66-2.61 (m, 2H), 2.31 (s, 3H), 1.33 (t, 3H).
Example No. A3-153:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.20 (m, 1H), 7.08-7.02 (m, 3H), 6.98 (m, 1H), 6.79 (m, 1H), 6.58-6.52 (m, 1H), 3.39-3.23 (m, 2H), 3.29 (s, 3H), 2.86-2.77 (m, 2H), 2.63-2.57 (m, 2H), 1.52 (d, 3H).
Example No. A3-158:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.16 (m, 2H), 7.02 (m, 2H), 6.93 (m, 2H), 6.86 (m, 1H), 4.54 (m, 1H), 3.44-3.23 (m, 2H), 3.33 (s, 3H), 2.86 (m, 2H), 2.63 (m, 2H), 1.51 (d, 3H).
Example No. A3-159:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.28 (m, 1H), 6.99-6.93 (m, 4H), 6.90-6.82 (m, 2H), 4.54 (m, 1H), 3.42-3.24 (m, 2H), 3.32 (s, 3H), 2.86 (m, 2H), 2.63 (m, 2H), 1.53 (d, 3H).
Example No. A3-165:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.28 (m, 2H), 7.12 (m, 2H), 6.92 (m, 2H), 6.86 (m, 1H), 4.54 (m, 1H), 3.35-3.26 (m, 2H), 3.32 (s, 3H), 2.86 (m, 2H), 2.64 (m, 2H), 1.52 (d, 3H).
Example No. A3-181:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.61 (m, 2H), 7.32 (m, 2H), 6.94 (m, 2H), 6.85 (m, 1H), 4.56 (m, 1H), 3.42-3.25 (m, 2H), 3.32 (s, 3H), 2.87 (m, 2H), 2.64 (m, 2H), 1.52 (d, 3H).
Example No. A5-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.12-7.00 (m, 4H), 6.89 (m, 1H), 6.81 (m, 1H), 6.70 (m, 1H), 5.08 (br. s, 1H, NH), 3.97-3.92 (m, 2H), 3.75 (d, 3H), 3.43/3.23 (d, 2H), 2.83-2.78 (m, 2H), 2.63-2.58 (m, 2H), 2.30 (s, 3H), 1.26-1.22 (t, 3H).
Example No. A6-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.12-7.04 (m, 4H), 6.89 (m, 1H), 6.81 (m, 1H), 6.73 (m, 1H), 4.73 (br. m, 1H, NH), 4.24-4.18 (m, 1H), 4.08-3.99 (m, 1H), 3.97-3.92 (m, 2H), 3.27/3.12 (d, 2H), 2.83-2.78 (m, 2H), 2.63-2.59 (m, 2H), 2.31 (s, 3H), 1.33 (t, 3H), 1.26-1.21 (t, 3H).
Example No. A9-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.07-7.03 (m, 4H), 6.88 (m, 1H), 6.80 (m, 1H), 6.72 (m, 1H), 4.90 (br. s, 1H, NH), 3.87 (m, 2H), 3.73/3.68 (d, 3H), 3.27/3.02 (d, 2H), 2.83-2.78 (m, 2H), 2.65-2.60 (m, 2H), 2.32 (s, 3H), 1.71-1.63 (m, 2H), 0.96 (t, 3H).
Example No. A9-165:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.47 (m, 2H), 7.34 (m, 2H), 6.90 (m, 1H), 6.81 (m, 1H), 6.69 (m, 1H), 4.93 (br. s, 1H, NH), 3.87 (m, 2H), 3.73/3.68 (d, 3H), 3.27/3.02 (d, 2H), 2.83-2.78 (m, 2H), 2.64-2.58 (m, 2H), 2.33 (s, 3H), 1.70-1.61 (m, 2H), 0.98 (t, 3H).
Example No. A11-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.13 (m, 2H), 7.07 (m, 2H), 6.92 (m, 2H), 6.86 (m, 2H), 3.86 (m, 2H), 3.39-3.21 (m, 2H), 2.83 (m, 2H), 2.62 (m, 2H), 2.32 (s, 3H), 1.68-1.58 (m, 2H), 1.51 (d, 3H), 0.95 (t, 3H).
Example No. A11-158:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.15 (m, 2H), 7.02 (m, 2H), 6.92 (m, 2H), 6.87 (m, 2H), 4.54 (m, 1H), 3.86 (m, 2H), 3.35-3.23 (m, 2H), 2.84 (m, 2H), 2.62 (m, 2H), 1.68-1.59 (m, 2H), 1.52 (d, 3H), 0.95 (t, 3H).
Example No. A11-159:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.33 (m, 1H), 7.01-6.95 (m, 4H), 6.93-6.88 (m, 3H), 6.87 (m, 2H), 3.89 (m, 2H), 3.44-3.27 (m, 2H), 2.87 (m, 2H), 2.65 (m, 2H), 1.72-1.60 (m, 2H), 1.56 (d, 3H), 0.98 (t, 3H).
Example No. A11-165:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.28 (m, 2H), 7.13 (m, 2H), 6.91 (m, 2H), 6.85 (m, 2H), 3.86 (m, 2H), 3.35-3.23 (m, 2H), 2.83 (m, 2H), 2.62 (m, 2H), 1.68-1.59 (m, 2H), 1.52 (d, 3H), 0.95 (t, 3H).
Example No. A61-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.14-7.05 (m, 4H), 6.88 (m, 1H), 6.81 (m, 1H), 6.72 (m, 1H), 5.02 (br. m, 1H, NH), 3.92-3.88 (m, 2H), 3.73/3.55 (d, 3H), 3.27/3.02 (d, 2H), 2.83-2.78 (m, 2H), 2.63-2.58 (m, 2H), 2.33-2.28 (m, 3H), 1.65-1.58 (m, 2H), 1.43-1.36 (m, 2H), 0.97 (t, 3H).
Example No. A65-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.14-7.04 (m, 4H), 6.99 (m, 1H), 6.78 (m, 1H), 6.71 (m, 1H), 4.85 (br. m, 1H, NH), 4.49-4.64 (m, 1H), 3.73/3.54 (d, 3H), 3.26/3.02 (d, 2H), 2.88-2.82 (m, 2H), 2.56-2.52 (m, 2H), 2.30 (s, 3H), 1.51 (d, 6H).
Example No. A66-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.14-7.04 (m, 4H), 7.00 (m, 1H), 6.79 (m, 1H), 6.71 (m, 1H), 4.76 (br. m, 1H, NH), 4.68-4.62 (m, 1H), 4.24-4.16 (m, 1H), 4.09-4.00 (m, 1H), 3.27/3.12 (d, 2H), 2.76-2.72 (m, 2H), 2.56-2.51 (m, 2H), 2.32 (s, 3H), 1.50 (d, 6H), 1.33 (t, 3H).
Example No. B2-152:
1H-NMR (400 MHz, CDCl3 δ, ppm) 7.16-7.08 (m, 4H), 7.03 (m, 1H), 6.88-6.83 (m, 2H), 4.88 (br. m, 1H, NH), 4.23-4.16 (m, 1H), 4.12-3.99 (m, 1H), 3.93-3.87 (m, 2H), 3.27/3.12 (d, 2H), 2.47 (s, 2H), 2.32 (m, 3H), 1.71-1.63 (m, 2H), 1.33 (t, 3H), 1.27-1.22 (m, 6H), 0.98 (t, 3H).
The present invention further provides for the use of at least one substituted oxotetrahydroquinolinylphosphin- or -phosphonamide of the general formula (I), alone or in combination with further agrochemically active compounds, for example fungicides, insecticides, herbicides, plant growth regulators or safeners, for increasing the resistance of plants to abiotic stress factors, preferably drought stress, and for enhancing plant growth and/or for increasing plant yield.
The present invention further provides a spray solution for treatment of plants, comprising an amount, effective for increasing the resistance of plants to abiotic stress factors, of at least one compound selected from the group consisting of at least one of the oxotetrahydroquinolinylphosphin- and -phosphonamides of the general formula (I) having substitution in accordance with the invention. The abiotic stress conditions which can be relativized may include, for example, heat, drought, cold and aridity stress (stress caused by aridity and/or lack of water), osmotic stress, waterlogging, elevated soil salinity, elevated exposure to minerals, ozone conditions, strong light conditions, limited availability of nitrogen nutrients, limited availability of phosphorus nutrients.
In one embodiment, it may, for example, be the case that one or more of the compounds for use in accordance with the invention, i.e. the appropriate substituted oxotetrahydroquinolinylphosphin- and -phosphonamides of the general formula (I) having substitution in accordance with the invention, are applied by spray application to plants or plant parts to be treated correspondingly. The compounds of the general formula (I) or salts thereof are used preferably with a dosage between 0.00005 and 3 kg/ha, more preferably between 0.0001 and 2 kg/ha, especially preferably between 0.0005 and 1 kg/ha, specifically preferably between 0.001 and 0.25 kg/ha.
The term “resistance to abiotic stress” is understood in the context of the present invention to mean various kinds of benefits for plants. Such advantageous properties are manifested, for example, in the following improved plant characteristics: improved root growth with regard to surface area and depth, increased stolon or tiller formation, stronger and more productive stolons and tillers, improvement in shoot growth, increased lodging resistance, increased shoot base diameter, increased leaf area, higher yields of nutrients and constituents, for example carbohydrates, fats, oils, proteins, vitamins, minerals, essential oils, dyes, fibers, better fiber quality, earlier flowering, increased number of flowers, reduced content of toxic products such as mycotoxins, reduced content of residues or disadvantageous constituents of any kind, or better digestibility, improved storage stability of the harvested material, improved tolerance to disadvantageous temperatures, improved tolerance to drought and aridity, and also oxygen deficiency as a result of waterlogging, improved tolerance to elevated salt contents in soil and water, enhanced tolerance to ozone stress, improved compatibility with respect to herbicides and other plant treatment compositions, improved water absorption and photosynthesis performance, advantageous plant properties, for example acceleration of ripening, more homogeneous ripening, greater attractiveness to beneficial animals, improved pollination, or other advantages well known to a person skilled in the art.
More particularly, the use of one or more compounds of the general formula (I) according to the invention exhibits the advantages described in spray application to plants and plant parts. In addition, the combined use of oxotetrahydroquinolinylphosphin- and -phosphonamides of the general formula (I) having substitution in accordance with the invention with genetically modified cultivars with a view to increased tolerance to abiotic stress is likewise possible.
The further various benefits for plants mentioned above can be combined in a known manner in component form, and generally applicable terms can be used to describe them. Such terms are, for example, the following names: phytotonic effect, resistance to stress factors, less plant stress, plant health, healthy plants, plant fitness, plant wellness, plant concept, vigor effect, stress shield, protective shield, crop health, crop health properties, crop health products, crop health management, crop health therapy, plant health, plant health properties, plant health products, plant health management, plant health therapy, greening effect or regreening effect, freshness, or other terms with which a person skilled in the art is entirely familiar.
In the context of the present invention, a good effect on resistance to abiotic stress is understood to mean, without limitation,
The present invention further provides a spray solution for treatment of plants, comprising an amount, effective for enhancement of the resistance of plants to abiotic stress factors, of at least one compound from the group of the substituted oxotetrahydroquinolinylphosphin- and -phosphonamides of the general formula (I) having substitution in accordance with the invention. The spray solution may comprise other customary constituents, such as solvents, formulation auxiliaries, especially water. Further constituents may include active agrochemical ingredients which are described in more detail below.
The present invention further provides for the use of corresponding spray solutions for increasing the resistance of plants to abiotic stress factors. The remarks which follow apply both to the use of one or more compounds of the general formula (I) according to the invention per se and to the corresponding spray solutions.
It has additionally been found that the application, to plants or in their environment, of one or more compounds of the general formula (I) according to the invention in combination with at least one fertilizer as defined further below is possible.
Fertilizers which can be used in accordance with the invention together with the compounds of the formula (I) according to the invention elucidated in detail above are generally organic and inorganic nitrogen compounds, for example ureas, urea/formaldehyde condensation products, amino acids, ammonium salts, ammonium nitrates, potassium salts (preferably chlorides, sulfates, nitrates), salts of phosphoric acid and/or salts of phosphorous acid (preferably potassium salts and ammonium salts). In this context, particular mention should be made of the NPK fertilizers, i.e. fertilizers which contain nitrogen, phosphorus and potassium, calcium ammonium nitrate, i.e. fertilizers which additionally contain calcium, or ammonium sulfate nitrate (general formula (NH4)2SO4NH4NO3), ammonium phosphate and ammonium sulfate. These fertilizers are generally known to the person skilled in the art; see also, for example, Ullmann's Encyclopedia of Industrial Chemistry, 5th edition, Vol. A 10, pages 323 to 431, Verlagsgesellschaft, Weinheim, 1987.
The fertilizers may additionally comprise salts of micronutrients (preferably calcium, sulfur, boron, manganese, magnesium, iron, boron, copper, zinc, molybdenum and cobalt) and of phytohormones (for example vitamin B1 and indole-(III)-acetic acid) or mixtures of these. Fertilizers used in accordance with the invention may also contain other salts such as monoammonium phosphate (MAP), diammonium phosphate (DAP), potassium sulfate, potassium chloride, magnesium sulfate. Suitable amounts for the secondary nutrients or trace elements are amounts of 0.5% to 5% by weight, based on the overall fertilizer. Further possible constituents are crop protection agents, insecticides, fungicides, safeners or growth regulators or mixtures thereof. Further details of these are given further down.
The fertilizers can be used, for example, in the form of powders, granules, prills or compactates. However, the fertilizers can also be used in liquid form, dissolved in an aqueous medium. In this case, dilute aqueous ammonia can also be used as a nitrogen fertilizer. Further possible ingredients for fertilizers are described, for example, in Ullmann's Encyclopedia of Industrial Chemistry, 5th edition, 1987, volume A 10, pages 363 to 401, DE-A 41 28 828, DE-A 19 05 834 and DE-A 196 31 764. The general composition of the fertilizers, which, in the context of the present invention, may take the form of straight and/or compound fertilizers, for example composed of nitrogen, potassium or phosphorus, may vary within a wide range. In general, a content of 1% to 30% by weight of nitrogen (preferably 5% to 20% by weight), of 1% to 20% by weight of potassium (preferably 3% to 15% by weight) and a content of 1% to 20% by weight of phosphorus (preferably 3% to 10% by weight) is advantageous. The microelement content is usually in the ppm range, preferably in the range from 1 to 1000 ppm.
In the context of the present invention, the fertilizer and one or more compounds of the formula (I) according to the invention may be administered simultaneously. However, it is also possible first to apply the fertilizer and then one or more compounds of the formula (I) according to the invention, or first to apply one or more compounds of the general formula (I) and then the fertilizer. In the case of nonsynchronous application of one or more compounds of the general formula (I) and the fertilizer, the application in the context of the present invention is, however, effected in a functional relationship, especially within a period of generally 24 hours, preferably 18 hours, more preferably 12 hours, specifically 6 hours, more specifically 4 hours, even more specifically within 2 hours. In very particular embodiments of the present invention, one or more compounds of the formula (I) according to the invention and the fertilizer are applied within a time frame of less than 1 hour, preferably less than 30 minutes, more preferably less than 15 minutes.
Preference is given to the use of compounds of the general formula (I) according to the invention on plants from the group of the useful plants, ornamentals, turfgrass types, commonly used trees which are used as ornamentals in the public and domestic sectors, and forestry trees. Forestry trees include trees for the production of timber, cellulose, paper and products made from parts of the trees. The term useful plants as used here refers to crop plants which are used as plants for obtaining foods, animal feeds, fuels or for industrial purposes.
The useful plants include, for example, the following types of plants: triticale, durum (hard wheat), turf, vines, cereals, for example wheat, barley, rye, oats, rice, corn and millet; beet, for example sugar beet and fodder beet; fruits, for example pome fruit, stone fruit and soft fruit, for example apples, pears, plums, peaches, almonds, cherries and berries, for example strawberries, raspberries, blackberries; legumes, for example beans, lentils, peas and soybeans; oil crops, for example oilseed rape, mustard, poppies, olives, sunflowers, coconuts, castor oil plants, cocoa beans and peanuts; cucurbits, for example pumpkin/squash, cucumbers and melons; fiber plants, for example cotton, flax, hemp and jute; citrus fruits, for example oranges, lemons, grapefruit and tangerines; vegetables, for example spinach, lettuce, asparagus, cabbage species, carrots, onions, tomatoes, potatoes and bell peppers; Lauraceae, for example avocado, Cinnamomum, camphor, or also plants such as tobacco, nuts, coffee, eggplant, sugar cane, tea, pepper, grapevines, hops, bananas, latex plants and ornamentals, for example flowers, shrubs, deciduous trees and coniferous trees. This enumeration does not constitute a limitation.
The following plants are considered to be particularly suitable target crops for the application of the method of the invention: oats, rye, triticale, durum, cotton, eggplant, turf, pome fruit, stone fruit, soft fruit, corn, wheat, barley, cucumber, tobacco, vines, rice, cereals, pears, pepper, beans, soybeans, oilseed rape, tomato, bell pepper, melons, cabbage, potatoes and apples.
Examples of trees which can be improved by the method of the invention include: Abies sp., Eucalyptus sp., Picea sp., Pinus sp., Aesculus sp., Platanus sp., Tilia sp., Acer sp., Tsuga sp., Fraxinus sp., Sorbus sp., Betula sp., Crataegus sp., Ulmus sp., Quercus sp., Fagus sp., Salix sp., Populus sp.
Preferred trees which can be improved by the method of the invention include: from the tree species Aesculus: A. hippocastanum, A. pariflora, A. carnes; from the tree species Platanus: P. aceriflora, P. occidentalis, P. racemosa; from the tree species Picea: P. abies; from the tree species Pinus: P. radiate, P. ponderosa, P. contorta, P. sylvestre, P. elliottii, P. montecola, P. albicaulis, P. resinosa, P. palustris, P. taeda, P. flexilis, P. jeffregi, P. baksiana, P. strobes; from the tree species Eucalyptus: E. grandis, E. globulus, E. camadentis, E. nitens, E. oblique, E. regnans, E. pilularus.
Particularly preferred trees which can be improved by the method of the invention are: from the tree species Pinus: P. radiate, P. ponderosa, P. contorta, P. sylvestre, P. strobes; from the tree species Eucalyptus: E. grandis, E. globulus and E. camadentis.
Particularly preferred trees which can be improved by the method of the invention are: horse chestnut, Platanaceae, linden tree and maple tree.
The present invention can also be applied to any desired turfgrasses, including cool-season turfgrasses and warm-season turfgrasses. Examples of cool-season turfgrasses are bluegrasses (Poa spp.), such as Kentucky bluegrass (Poa pratensis L.), rough bluegrass (Poa trivialis L.), Canada bluegrass (Poa compressa L.), annual bluegrass (Poa annus L.), upland bluegrass (Poa glaucantha Gaudin), wood bluegrass (Poa nemoralis L.) and bulbous bluegrass (Poa bulbosa L.); bentgrasses (Agrostis spp.) such as creeping bentgrass (Agrostis palustris Huds.), colonial bentgrass (Agrostis tenuis Sibth.), velvet bentgrass (Agrostis canina L.), South German Mixed Bentgrass (Agrostis spp. including Agrostis tenius Sibth., Agrostis canina L., and Agrostis palustris Huds.), and redtop (Agrostis alba L.);
fescues (Festuca spp.), such as red fescue (Festuca rubra L. spp. rubra), creeping fescue (Festuca rubra L.), chewings fescue (Festuca rubra commutata Gaud.), sheep fescue (Festuca ovina L.), hard fescue (Festuca longifolia Thuill.), hair fescue (Festuca capillata Lam.), tall fescue (Festuca arundinacea Schreb.) and meadow fescue (Festuca elanor L.);
ryegrasses (Lolium spp.), such as annual ryegrass (Lolium multiflorum Lam.), perennial ryegrass (Lolium perenne L.) and Italian ryegrass (Lolium multiflorum Lam.);
and wheatgrasses (Agropyron spp.), such as fairway wheatgrass (Agropyron cristatum (L.) Gaertn.), crested wheatgrass (Agropyron desertorum (Fisch.) Schult.) and western wheatgrass (Agropyron smithii Rydb.).
Examples of further cool-season turfgrasses are beachgrass (Ammophila breviligulata Fern.), smooth bromegrass (Bromus inermis Leyss.), cattails such as Timothy (Phleum pratense L.), sand cattail (Phleum subulatum L.), orchardgrass (Dactylis glomerata L.), weeping alkaligrass (Puccinellia distans (L.) Parl.) and crested dog's-tail (Cynosurus cristatus L.).
Examples of warm-season turfgrasses are Bermudagrass (Cynodon spp. L. C. Rich), zoysiagrass (Zoysia spp. Willd.), St. Augustine grass (Stenotaphrum secundatum Walt Kuntze), centipedegrass (Eremochloa ophiuroides Munro Hack.), carpetgrass (Axonopus affinis Chase), Bahia grass (Paspalum notatum Flugge), Kikuyugrass (Pennisetum clandestinum Hochst. ex Chiov.), buffalo grass (Buchloe dactyloids (Nutt.) Engelm.), Blue gramma (Bouteloua gracilis (H.B.K.) Lag. ex Griffiths), seashore paspalum (Paspalum vaginatum Swartz) and sideoats grama (Bouteloua curtipendula (Michx. Torr.)). Cool-season turfgrasses are generally preferred for the use according to the invention. Particular preference is given to bluegrass, bentgrass and redtop, fescues and ryegrasses. Bentgrass is especially preferred.
Particular preference is given to using the compounds of the formula (I) according to the invention to treat plants of the respective commercially available or commonly used plant cultivars. Plant cultivars are understood to mean plants which have new properties (“traits”) and which have been obtained by conventional breeding, by mutagenesis or with the aid of recombinant DNA techniques. Crop plants may thus be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the transgenic plants and including the plant cultivars which are protectable or non-protectable by plant breeders' rights.
The treatment method according to the invention can thus also be used for the treatment of genetically modified organisms (GMOs), e.g. plants or seeds. Genetically modified plants (or transgenic plants) are plants in which a heterologous gene has been stably integrated into the genome. The expression “heterologous gene” essentially means a gene which is provided or assembled outside the plant and when introduced into the nuclear, chloroplastic or hypochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing (an)other gene(s) which is/are present in the plant (using for example antisense technology, cosuppression technology or RNAi technology [RNA interference]). A heterologous gene that is located in the genome is also called a transgene. A transgene that is defined by its specific presence in the plant genome is called a transformation or transgenic event.
Plants and plant varieties which are preferably treated with the compounds of the general formula (I) according to the invention include all plants which have genetic material which imparts particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means or not).
Plants and plant varieties which can likewise be treated with the compounds of the general formula (I) according to the invention are those plants which are resistant to one or more abiotic stress factors. Abiotic stress conditions may include, for example, heat, drought, cold and aridity stress, osmotic stress, waterlogging, increased soil salinity, increased exposure to minerals, ozone conditions, strong light conditions, limited availability of nitrogen nutrients, limited availability of phosphorus nutrients or shade avoidance.
Plants and plant cultivars which can likewise be treated with the compounds of the formula (I) according to the invention are those plants which are characterized by enhanced yield characteristics. Enhanced yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation. Yield can also be affected by improved plant architecture (under stress and non-stress conditions), including but not limited to early flowering, flowering control for hybrid seed production, seedling vigor, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance. Further yield traits include seed composition, such as carbohydrate content, protein content, oil content and oil composition, nutritional value, reduction in antinutritional compounds, improved processibility and better storage stability.
Plants that may also be treated with the compounds of the general formula (I) according to the invention are hybrid plants that already express the characteristics of heterosis, or hybrid effect, which results in generally higher yield, higher vigor, better health and better resistance towards biotic and abiotic stress factors. Such plants are typically produced by crossing an inbred male-sterile parent line (the female crossbreeding parent) with another inbred male-fertile parent line (the male crossbreeding parent). Hybrid seed is typically harvested from the male-sterile plants and sold to growers. Male-sterile plants can sometimes (for example in corn) be produced by detasseling (i.e. mechanical removal of the male reproductive organs or male flowers); however, it is more typical for male sterility to be the result of genetic determinants in the plant genome. In that case, and especially when seed is the desired product to be harvested from the hybrid plants, it is typically beneficial to ensure that male fertility in hybrid plants, which contain the genetic determinants responsible for male sterility, is fully restored. This can be accomplished by ensuring that the male crossbreeding parents have appropriate fertility restorer genes which are capable of restoring the male fertility in hybrid plants that contain the genetic determinants responsible for male sterility. Genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) were for instance described for Brassica species (WO 92/005251, WO 95/009910, WO 98/27806, WO 2005/002324, WO 2006/021972 and U.S. Pat. No. 6,229,072). However, genetic determinants for male sterility can also be located in the nuclear genome. Male-sterile plants can also be obtained by plant biotechnology methods such as genetic engineering. A particularly useful means of obtaining male-sterile plants is described in WO 89/10396 in which, for example, a ribonuclease such as a barnase is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored by expression in the tapetum cells of a ribonuclease inhibitor such as barstar (e.g. WO 91/002069).
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated with the compounds of the formula (I) according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
Herbicide-tolerant plants are for example glyphosate-tolerant plants, i.e. plants made tolerant to the herbicide glyphosate or salts thereof. Thus, for example, glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Examples of such EPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonella typhimurium (Comai et al., Science (1983), 221, 370-371), the CP4 gene of the bacterium Agrobacterium sp. (Barry et al., Curr. Topics Plant Physiol. (1992), 7, 139-145), the genes encoding a petunia EPSPS (Shah et al., Science (1986), 233, 478-481), a tomato EPSPS (Gasser et al., J. Biol. Chem. (1988), 263, 4280-4289) or an Eleusine EPSPS (WO 2001/66704). It can also be a mutated EPSPS, as described, for example, in EP-A 0837944, WO 2000/066746, WO 2000/066747 or WO 2002/026995.
Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxidoreductase enzyme as described in U.S. Pat. No. 5,776,760 and U.S. Pat. No. 5,463,175. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate acetyl transferase enzyme as described, for example, in WO 2002/036782, WO 2003/092360, WO 2005/012515 and WO 2007/024782. Glyphosate-tolerant plants can also be obtained by selecting plants containing naturally occurring mutations of the abovementioned genes, as described, for example, in WO 01/024615 or WO 2003/013226.
Other herbicide-resistant plants are for example plants that are made tolerant to herbicides inhibiting the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate. Such plants can be obtained by expressing an enzyme detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition. One example of such an effective detoxifying enzyme is an enzyme encoding a phosphinothricin acetyltransferase (such as the bar or pat protein from Streptomyces species). Plants expressing an exogenous phosphinothricin acetyltransferase are described, for example, in U.S. Pat. No. 5,561,236; U.S. Pat. No. 5,648,477; U.S. Pat. No. 5,646,024; U.S. Pat. No. 5,273,894; U.S. Pat. No. 5,637,489; U.S. Pat. No. 5,276,268; U.S. Pat. No. 5,739,082; U.S. Pat. No. 5,908,810 and U.S. Pat. No. 7,112,665.
Further herbicide-tolerant plants are also plants that have been made tolerant to the herbicides inhibiting the enzyme hydroxyphenylpyruvate dioxygenase (HPPD). Hydroxyphenylpyruvate dioxygenases are enzymes that catalyze the reaction in which para-hydroxyphenylpyruvate (HPP) is converted to homogentizate. Plants tolerant to HPPD inhibitors can be transformed with a gene encoding a naturally occurring resistant HPPD enzyme, or a gene encoding a mutated HPPD enzyme according to WO 96/038567, WO 99/024585 and WO 99/024586. Tolerance to HPPD inhibitors can also be obtained by transforming plants with genes encoding certain enzymes enabling the formation of homogentisate despite inhibition of the native HPPD enzyme by the HPPD inhibitor. Such plants and genes are described in WO 99/034008 and WO 2002/36787. Tolerance of plants to HPPD inhibitors can also be improved by transforming plants with a gene encoding a prephenate dehydrogenase enzyme in addition to a gene encoding an HPPD-tolerant enzyme, as described in WO 2004/024928.
Other herbicide-resistant plants are plants which have been rendered tolerant to acetolactate synthase (ALS) inhibitors. Known ALS inhibitors include, for example, sulfonylurea, imidazolinone, triazolopyrimidines, pyrimidinyloxy(thio)benzoates, and/or sulfonylaminocarbonyltriazolinone herbicides. Different mutations in the ALS enzyme (also known as acetohydroxy acid synthase, AHAS) are known to confer tolerance to different herbicides and groups of herbicides, as described, for example, in Tranel nd Wright, Weed Science (2002), 50, 700-712, and also in U.S. Pat. No. 5,605,011, U.S. Pat. No. 5,378,824, U.S. Pat. No. 5,141,870 and U.S. Pat. No. 5,013,659. The production of sulfonylurea-tolerant plants and imidazolinone-tolerant plants has been described in U.S. Pat. No. 5,605,011; U.S. Pat. No. 5,013,659; U.S. Pat. No. 5,141,870; U.S. Pat. No. 5,767,361; U.S. Pat. No. 5,731,180; U.S. Pat. No. 5,304,732; U.S. Pat. No. 4,761,373; U.S. Pat. No. 5,331,107; U.S. Pat. No. 5,928,937; and U.S. Pat. No. 5,378,824; and also in the international publication WO 96/033270. Further imidazolinone-tolerant plants have also been described, for example, in WO 2004/040012, WO 2004/106529, WO 2005/020673, WO 2005/093093, WO 2006/007373, WO 2006/015376, WO 2006/024351 and WO 2006/060634. Further sulfonylurea- and imidazolinone-tolerant plants have also been described, for example, in WO 2007/024782.
Further plants tolerant to ALS-inhibitors, in particular to imidazolinones, sulfonylureas and/or sulfamoylcarbonyltriazolinones can be obtained by induced mutagenesis, by selection in cell cultures in the presence of the herbicide or by mutation breeding, as described, for example, for soybeans in U.S. Pat. No. 5,084,082, for rice in WO 97/41218, for sugarbeet in U.S. Pat. No. 5,773,702 and WO 99/057965, for lettuce in U.S. Pat. No. 5,198,599 or for sunflower in WO 2001/065922.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated with the compounds of the formula (I) according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
In the present context, the term “insect-resistant transgenic plant” includes any plant containing at least one transgene comprising a coding sequence encoding the following:
1) an insecticidal crystal protein from Bacillus thuringiensis or an insecticidal portion thereof, such as the insecticidal crystal proteins compiled by Crickmore et al., Microbiology and Molecular Biology Reviews (1998), 62, 807-813, updated by Crickmore et al. (2005) in the Bacillus thuringiensis toxin nomenclature (online at: http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/), or insecticidal portions thereof, for example proteins of the Cry protein classes Cry1Ab, Cry1Ac, Cry1F, Cry2Ab, Cry3Ae or Cry3Bb or insecticidal portions thereof; or
2) a crystal protein from Bacillus thuringiensis or a portion thereof which is insecticidal in the presence of a second other crystal protein from Bacillus thuringiensisor a portion thereof, such as the binary toxin made up of the Cy34 and Cy35 crystal proteins (Moellenbeck et al., Nat. Biotechnol. (2001), 19, 668-72; Schnepf et al., Applied Environm. Microb. (2006), 71, 1765-1774); or
3) a hybrid insecticidal protein comprising parts of two different insecticidal crystal proteins from Bacillus thuringiensis, such as a hybrid of the proteins of 1) above or a hybrid of the proteins of 2) above, for example the Cry1A.105 protein produced by maize event MON98034 (WO 2007/027777); or
4) a protein of any one of points 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation, such as the Cry3Bb1 protein in maize events MON863 or MON88017, or the Cry3A protein in maize event MIR 604; or
5) an insecticidal secreted protein from Bacillus thuringiensis or Bacillus cereus, or an insecticidal portion thereof, such as the vegetative insecticidal proteins (VIPs) listed under the following link, for example proteins from the VIP3Aa protein class: http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/vip.html, or
6) a secreted protein from Bacillus thuringiensis or Bacillus cereus which is insecticidal in the presence of a second secreted protein from Bacillus thuringiensis or B. cereus, such as the binary toxin made up of the VIP1A and VIP2A proteins (WO 94/21795); or
7) a hybrid insecticidal protein comprising parts from different secreted proteins from Bacillus thuringiensis or Bacillus cereus, such as a hybrid of the proteins in 1) or a hybrid of the proteins in 2) above; or
8) a protein of any one of points 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation (while still encoding an insecticidal protein), such as the VIP3Aa protein in cotton event COT 102.
Of course, the insect-resistant transgenic plants, as used herein, also include any plant comprising a combination of genes encoding the proteins of any one of the above classes 1 to 8. In one embodiment, an insect-resistant plant contains more than one transgene encoding a protein of any one of the above classes 1 to 8, to expand the range of the target insect species affected or to delay insect resistance development to the plants, by using different proteins insecticidal to the same target insect species but having a different mode of action, such as binding to different receptor binding sites in the insect.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated with the compounds according to the invention of the general formula (I) are tolerant to abiotic stress factors. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Particularly useful stress-tolerant plants include:
a. plants which contain a transgene capable of reducing the expression and/or the activity of the poly(ADP-ribose)polymerase (PARP) gene in the plant cells or plants, as described in WO 2000/004173 or EP 04077984.5 or EP 06009836.5;
b. plants which contain a stress tolerance-enhancing transgene capable of reducing the expression and/or the activity of the PARG-encoding genes of the plants or plant cells, as described, for example, in WO 2004/090140;
c. plants which contain a stress tolerance-enhancing transgene encoding a plant-functional enzyme of the nicotinamide adenine dinucleotide salvage biosynthesis pathway, including nicotinamidase, nicotinate phosphoribosyltransferase, nicotinic acid mononucleotide adenyltransferase, nicotinamide adenine dinucleotide synthetase or nicotinamide phosphoribosyltransferase, as described, for example, in EP 04077624.7 or WO 2006/133827 or PCT/EP07/002433.
Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated with the compounds of the formula (I) according to the invention show altered quantity, quality and/or storage stability of the harvested product and/or altered properties of specific ingredients of the harvested product such as, for example:
1) Transgenic plants which synthesize a modified starch which, in its physicochemical characteristics, in particular the amylose content or the amylose/amylopectin ratio, the degree of branching, the average chain length, the side chain distribution, the viscosity behavior, the gelling strength, the starch granule size and/or the starch granule morphology, is changed in comparison with the synthesized starch in wild-type plant cells or plants, so that this modified starch is better suited to specific applications. These transgenic plants synthesizing a modified starch are described, for example, in EP 0571427, WO 95/004826, EP 0719338, WO 96/15248, WO 96/19581, WO 96/27674, WO 97/11188, WO 97/26362, WO 97/32985, WO 97/42328, WO 97/44472, WO 97/45545, WO 98/27212, WO 98/40503, WO 99/58688, WO 99/58690, WO 99/58654, WO 2000/008184, WO 2000/008185, WO 2000/28052, WO 2000/77229, WO 2001/12782, WO 2001/12826, WO 2002/101059, WO 2003/071860, WO 2004/056999, WO 2005/030942, WO 2005/030941, WO 2005/095632, WO 2005/095617, WO 2005/095619, WO 2005/095618, WO 2005/123927, WO 2006/018319, WO 2006/103107, WO 2006/108702, WO 2007/009823, WO 2000/22140, WO 2006/063862, WO 2006/072603, WO 2002/034923, EP 06090134.5, EP 06090228.5, EP 06090227.7, EP 07090007.1, EP 07090009.7, WO 2001/14569, WO 2002/79410, WO 2003/33540, WO 2004/078983, WO 2001/19975, WO 95/26407, WO 96/34968, WO 98/20145, WO 99/12950, WO 99/66050, WO 99/53072, U.S. Pat. No. 6,734,341, WO 2000/11192, WO 98/22604, WO 98/32326, WO 2001/98509, WO 2001/98509, WO 2005/002359, U.S. Pat. No. 5,824,790, U.S. Pat. No. 6,013,861, WO 94/004693, WO 94/009144, WO 94/11520, WO 95/35026 and WO 97/20936.
2) Transgenic plants which synthesize non-starch carbohydrate polymers or which synthesize non-starch carbohydrate polymers with altered properties in comparison to wild-type plants without genetic modification. Examples are plants producing polyfructose, especially of the inulin and levan type, as described in EP 0663956, WO 96/001904, WO 96/021023, WO 98/039460 and WO 99/024593, plants producing alpha-1,4-glucans, as described in WO 95/031553, US 2002/031826, U.S. Pat. No. 6,284,479, U.S. Pat. No. 5,712,107, WO 97/047806, WO 97/047807, WO 97/047808 and WO 2000/14249, plants producing alpha-1,6-branched alpha-1,4-glucans, as described in WO 2000/73422, and plants producing alternan, as described in WO 2000/047727, EP 06077301.7, U.S. Pat. No. 5,908,975 and EP 0728213.
3) Transgenic plants which produce hyaluronan, as for example described in WO 06/032538, WO 2007/039314, WO 2007/039315, WO 2007/039316, JP 2006/304779 and WO 2005/012529.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated with the compounds of the formula (I) according to the invention are plants, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such altered fiber characteristics and include:
a) plants, such as cotton plants, which contain an altered form of cellulose synthase genes, as described in WO 98/000549;
b) plants, such as cotton plants, which contain an altered form of rsw2 or rsw3 homologous nucleic acids, as described in WO 2004/053219;
c) plants, such as cotton plants, with an increased expression of sucrose phosphate synthase, as described in WO 2001/017333;
d) plants, such as cotton plants, with an increased expression of sucrose synthase as described in WO 2002/45485;
e) plants, such as cotton plants, wherein the timing of the plasmodesmatal gating at the basis of the fiber cell is altered, for example through downregulation of fiber-selective β-1,3-glucanase as described in WO 2005/017157;
f) plants, such as cotton plants, which have fibers with altered reactivity, for example through expression of the N-acetylglucosamine transferase gene including nodC and chitin synthase genes, as described in WO 2006/136351.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated with the compounds of the formula (I) according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such altered oil characteristics and include:
a) plants, such as oilseed rape plants, which produce oil having a high oleic acid content, as described, for example, in U.S. Pat. No. 5,969,169, U.S. Pat. No. 5,840,946 or U.S. Pat. No. 6,323,392 or U.S. Pat. No. 6,063,947;
b) plants, such as oilseed rape plants, which produce oil having a low linolenic acid content, as described in U.S. Pat. No. 6,270,828, U.S. Pat. No. 6,169,190 or U.S. Pat. No. 5,965,755;
c) plants, such as oilseed rape plants, which produce oil having a low level of saturated fatty acids, as described, for example, in U.S. Pat. No. 5,434,283.
Particularly useful transgenic plants which may be treated with the compounds of the formula (I) according to the invention are plants containing transformation events, or a combination of transformation events, and that are listed for example in the databases of various national or regional regulatory agencies.
Particularly useful transgenic plants which may be treated with the compounds of the general formula (I) according to the invention are, for example, plants which comprise one or more genes which encode one or more toxins and are the transgenic plants available under the following trade names: YIELD GARD® (for example corn, cotton, soybeans), KnockOut® (for example corn), BiteGard® (for example corn), BT-Xtra® (for example corn), StarLink® (for example corn), Bollgard® (cotton), Nucotn® (cotton), Nucotn 33B® (cotton), NatureGard® (for example corn), Protecta® and NewLeaf® (potato). Examples of herbicide-tolerant plants include are corn varieties, cotton varieties and soya bean varieties which are available under the following trade names: Roundup Ready® (tolerance to glyphosates, for example corn, cotton, soybeans), Liberty Link® (tolerance to phosphinothricin, for example oilseed rape), IMI® (tolerance to imidazolinone) and SCS® (tolerance to sulfonylurea), for example corn. Herbicide-resistant plants (plants bred in a conventional manner for herbicide tolerance) which may be mentioned include the varieties sold under the name Clearfield® (for example corn).
The compounds of the formula (I) to be used in accordance with the invention can be converted to customary formulations, such as solutions, emulsions, wettable powders, water- and oil-based suspensions, powders, dusts, pastes, soluble powders, soluble granules, granules for broadcasting, suspoemulsion concentrates, natural compounds impregnated with active ingredient, synthetic substances impregnated with active ingredient, fertilizers, and also microencapsulations in polymeric substances. In the context of the present invention, it is especially preferred when the compounds of the general formula (I) are used in the form of a spray formulation.
The present invention therefore additionally also relates to a spray formulation for enhancing the resistance of plants to abiotic stress. A spray formulation is described in detail hereinafter:
The formulations for spray application are produced in a known manner, for example by mixing the compounds of the general formula (I) according to the invention to be used with extenders, i.e. liquid solvents and/or solid carriers, optionally with use of surfactants, i.e. emulsifiers and/or dispersants and/or foam formers. Further customary additives, for example customary extenders and solvents or diluents, dyes, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, stickers, gibberellins and also water, can optionally also be used. The formulations are produced either in suitable facilities or else before or during application.
The auxiliaries used may be those substances which are suitable for imparting, to the composition itself and/or to preparations derived therefrom (for example spray liquors), particular properties such as particular technical properties and/or else special biological properties. Typical auxiliaries include: extenders, solvents and carriers.
Suitable extenders are, for example, water, polar and nonpolar organic chemical liquids, for example from the classes of the aromatic and nonaromatic hydrocarbons (such as paraffins, alkylbenzenes, alkylnaphthalenes, chlorobenzenes), the alcohols and polyols (which, if appropriate, may also be substituted, etherified and/or esterified), the ketones (such as acetone, cyclohexanone), esters (including fats and oils) and (poly)ethers, the unsubstituted and substituted amines, amides, lactams (such as N-alkylpyrrolidones) and lactones, the sulfones and sulfoxides (such as dimethyl sulfoxide).
If the extender utilized is water, it is also possible to use, for example, organic solvents as auxiliary solvents. Useful liquid solvents essentially include: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic hydrocarbons such as cyclohexane or paraffins, for example petroleum fractions, mineral and vegetable oils, alcohols such as butanol or glycol and also their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethyl sulfoxide, and also water.
It is possible to use colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian blue, and organic colorants such as alizarin colorants, azo colorants and metal phthalocyanine colorants, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.
Suitable wetting agents which may be present in the formulations which can be used in accordance with the invention are all substances which promote wetting and which are conventionally used for the formulation of agrochemical active substances. Preference is given to using alkyl naphthalenesulfonates, such as diisopropyl or diisobutyl naphthalenesulfonates.
Suitable dispersants and/or emulsifiers which may be present in the formulations which can be used in accordance with the invention are all nonionic, anionic and cationic dispersants conventionally used for the formulation of active agrochemical ingredients. Preference is given to using nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants. Suitable nonionic dispersants include in particular ethylene oxide/propylene oxide block polymers, alkylphenol polyglycol ethers and tristyrylphenol polyglycol ethers, and the phosphated or sulfated derivatives thereof. Suitable anionic dispersants are especially lignosulfonates, polyacrylic acid salts and arylsulfonate-formaldehyde condensates.
Antifoams which may be present in the formulations usable in accordance with the invention are all foam-inhibiting substances customary for the formulation of agrochemically active compounds. Silicone antifoams and magnesium stearate can be used with preference.
Preservatives which may be present in the formulations usable in accordance with the invention are all substances usable for such purposes in agrochemical compositions. Examples include dichlorophene and benzyl alcohol hemiformal.
Secondary thickeners which may be present in the formulations usable in accordance with the invention are all substances usable for such purposes in agrochemical compositions. Preferred examples include cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica.
Stickers which may be present in the formulations usable in accordance with the invention include all customary binders usable in seed-dressing products. Preferred examples include polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose. Suitable gibberellins which may be present in the formulations which can be used in accordance with the invention are preferably the gibberellins A1, A3 (=gibberellic acid), A4 and A7; gibberellic acid is especially preferably used. The gibberellins are known (cf. R. Wegler “Chemie der Pflanzenschutz- and Schädlingsbekämpfungsmittel”, vol. 2, Springer Verlag, 1970, pp. 401-412).
Further additives may be fragrances, mineral or vegetable, optionally modified oils, waxes and nutrients (including trace nutrients), such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc. Additionally present may be stabilizers, such as cold stabilizers, antioxidants, light stabilizers or other agents which improve chemical and/or physical stability.
The formulations contain generally between 0.01 and 98% by weight, preferably between 0.5 and 90%, of the compound of the general formula (I).
The compounds of the general formula (I) according to the invention may be present in commercially available formulations, and also in the use forms, prepared from these formulations, in a mixture with other active compounds, such as insecticides, attractants, sterilizing agents, bactericides, acaricides, nematicides, fungicides, growth-regulating substances, herbicides, safeners, fertilizers or semiochemicals.
In addition, the described positive effect of the compounds of the formula (I) on the plants' own defenses can be supported by an additional treatment with active insecticidal, fungicidal or bactericidal compounds.
Preferred times for the application of compounds of the general formula (I) according to the invention or salts thereof for enhancing resistance to abiotic stress are treatments of the soil, stems and/or leaves with the approved application rates.
The compounds of the general formula (I) according to the invention or salts thereof may generally additionally be present in their commercial formulations, and in the use forms prepared from these formulations, in mixtures with other active ingredients, such as insecticides, attractants, sterilants, acaricides, nematicides, fungicides, bactericides, growth regulators, substances which influence plant maturity, safeners or herbicides.
The invention is to be illustrated by the biological examples which follow, but without restricting it thereto.
In Vitro Analyses
Effects of the phytohormone abscisic acid (ABA) on the behavior of plants under abiotic stress and the mechanism of action of ABA are described in the literature (cf. Abrams et al., WO97/23441, Park et al. Science, 2009, 324, 1068; Grill et al. Science, 2009, 324, 1064; Tanokura et al. Biophysics, 2011, 7, 123; Schroeder et al. Plant J. 2010, 61, 290). Therefore, it is possible with the aid of a suitable in vitro test system to derive a correlation between the action of ABA and the stress response of a plant under abiotic stress. In the event of water deficiency (drought stress), plants form the phytohormone abscisic acid (ABA). This binds, along with a co-regulator (Regulatory Component of ABA-Receptor=RCAR according to Grill et al. Science, 2009, 324, 1064 or PYR/PYL according to Cutler et al. Science, 2009, 324, 1068), to a phosphatase (e.g. ABI1, a type 2C protein phosphatase, also abbreviated to PP2C) and inhibits its activity. As a result, a “downstream” kinase (e.g. SnRK2) is no longer dephosphorylated. This kinase, which is thus active, via phosphorylation of transcription factors (e.g. AREB/ABF, cf. Yoshida et al., 2010, 61, 672), switches on a genetic protection program to increase drought stress tolerance.
The assay described hereinafter utilizes the inhibition of the phosphatase ABI1 via the co-regulator RCAR11/PYR1 aus Arabidopsis thaliana. For the determination of activity, the dephosphorylation of 4-methylumbelliferyl phosphate (MUP) was measured at 460 nm. The in vitro assay was conducted in Greiner 384-well PS microplates F-well, using two controls: a) 0.5% dimethyl sulfoxide (DMSO) and b) 5 μM abscisic acid (ABA). The assay described here was generally conducted with substance concentrations of the appropriate chemical test substances in a concentration range of 0.1 μM to 100 μM in a solution of DMSO and water. The substance solution thus obtained, if necessary, was stirred with esterase from porcine liver (EC 3.1.1.1) at room temperature for 3 h and centrifuged at 4000 rpm for 30 min. A total volume of 45 μl was introduced into each cavity of the microplate, having the following composition:
Enzyme buffer mix and substrate mix were made up 5 minutes prior to the addition and warmed to a temperature of 35° C. On completion of pipetting of all the solutions and on completion of mixing, the plate was incubated at 35° C. for 20 minutes. Finally, a relative fluorescence measurement was made at 35° C. with a BMG Labtech “POLARstar Optima” microplate reader using a 340/10 nm excitation filter and a 460 nm emission filter. The efficacy of the compounds of the general formula (I) is reported in the table which follows using abscisic acid (5 μM) as comparative substance (abscisic acid, No. 10) according to the following classification: ++++ (inhibition≥90%), +++ (90%>inhibition≥70%), ++ (70%>inhibition≥50%), + (50%>inhibition≥30%).
Effects of selected compounds of the general formula (I) in the above-described in vitro assay at a concentration of 5 μM of the substance of the general formula (I) in question in a solution of DMSO and water:
In Vivo Analyses
Seeds of monocotyledonous and dicotyledonous crop plants were sown in sandy loam in plastic pots, covered with soil or sand and cultivated in a greenhouse under good growth conditions. The test plants are treated at the early leaf stage (BBCH10-BBCH13). To assure uniform water supply before commencement of stress, the potted plants were supplied with water by dam irrigation prior to substance application.
The compounds according to the invention were first formulated as wettable powders (WP) or dissolved in a solvent mixture. The further dilution was effected with water supplemented with 0.2% wetting agent (e.g. agrotin). The finished spray liquor was sprayed onto the green parts of the plant at an equivalent water application rate of 600 l/ha. Substance application was followed immediately by stress treatment of the plants.
Drought stress was induced by gradual drying out under the following conditions:
“Day”: 14 hours with illumination at −26-30° C.
“Night”: 10 hours without illumination at −18-20° C.
The duration of the respective stress phases was guided mainly by the condition of the stressed control plants. It was ended (by re-irrigating and transfer to a greenhouse with good growth conditions) as soon as irreversible damage was observed on the stressed control plants.
The end of the stress phase was followed by an about 4-7-day recovery phase, during which the plants were once again kept under good growth conditions in a greenhouse. The duration of the recovery phase was guided mainly by when the trial plants had attained a state which enabled visual scoring of potential effects, and was therefore variable.
Once this juncture had been reached, the appearance of the plants treated with test substances was recorded in comparison to the stressed control plants by the following categories:
In order to rule out any influence on the effects observed by any fungicidal or insecticidal action of the test compounds, it was additionally ensured that the tests proceeded without fungal infection or insect infestation.
The values reported in tables B-1 and B-2 below are mean values of the results from at least three repeats.
Effects of selected compounds of the general formula (I) under drought stress according to the following tables B-1 and B-2:
In the above tables:
BRSNS=Brassica napus
TRZAS=Triticum aestivum
Similar results were also achievable with further compounds of the general formula (I), even on application to different plant species.
| Number | Date | Country | Kind |
|---|---|---|---|
| 15176810.8 | Jul 2015 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2016/066499 | 7/12/2016 | WO | 00 |
