Biocidal benzylbiphenyl derivatives

专利摘要:
The present invention provides compounds of formula (I) having biocidal properties, stereochemically isomeric forms thereof, acid or base addition salts thereof, N-oxides, or quaternary ammonium derivatives thereof, preparations thereof, compositions containing them and biocides It relates to its use as a zero: Where The dashed line is any bond; X is a direct bond when the dotted line represents a bond, or When the dotted line does not represent a bond, it is hydrogen or hydroxy, R 1 , R 2 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, —SO 3 H, and the like; R 3 and R 4 are each independently from the group consisting of hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkyloxy, nitro, amino, cyano, trifluoromethyl, or trifluoromethoxy Selected; Is of the formula Is a radical of; From here, A 1 is a direct bond or C 1-6 alkanediyl; A 2 is C 2-6 alkanediyl; R 7 to R 11 are hydrogen, C 1-6 alkyl, aminoC 1-6 alkyl and the like.
公开号:KR20010042084A
申请号:KR1020007010439
申请日:1999-03-25
公开日:2001-05-25
发明作者:미르포엘리벤；반데르플라스마르크아르투르요세파；반데르베켄루이스요제프엘리자베쓰；히레스얀
申请人:디르크 반테；얀센 파마슈티카 엔.브이.；
IPC主号:

专利说明:

Biocidal benzylbiphenyl derivatives
Microorganisms are extremely useful and even necessary, for example, in alcoholic fermentation, cheese ripening, baking, penicillin production, waste liquid purification and biogas production. However, microorganisms can also be harmful or very dangerous by causing infectious diseases, forming toxic or carcinogenic metabolites, attacking valuable substances, disrupting the production process, or damaging product quality.
Biocides are a broad and diverse group of compounds that can kill or inhibit the growth of microorganisms. Biocides may be classified into bactericides, fungicides, agroicides, insecticides, acaricides, chelators, herbicides and the like. Well-known biocides are, for example, formaldehyde releasing compounds, phenol derivatives, salicylanilide, carbanide, and quaternary ammonium salts. An overview of biocides is shown in Microbiocides for the protection of materials, by Wilfried Paulus, Chapman & Hall, 1st edition, 1993.
An important group of biocides is biocides. Since bacteria occur everywhere, their destructive activity (biodeterioration) is essentially inevitable. Nevertheless, substances can be protected with the help of compounds that kill them or inhibit their growth, thus preventing the growth of bacteria in the site of concern.
The present invention provides novel compounds of formula (I) which have unexpected biocidal activity. In particular, the compound of formula (I) has bactericidal activity.
Structurally related compounds with fungicidal activity are described in EP-0,219,756-A1, published April 29, 1987.
The compounds of the present invention differ from the prior art compounds by the nature of the L moiety.
The present invention relates to novel compounds of formula (I) having biocidal properties. The present invention also relates to a process for preparing such novel compounds, to compositions and materials containing such novel compounds and to their use as biocides for plant protection applications.
The present invention relates to compounds of formula (I), stereochemically isomeric forms thereof, acid or base addition salts thereof, N-oxides thereof, or quaternary ammonium derivatives thereof:

Where
The dashed line is any bond;
X is a direct bond when the dotted line represents a bond, or
When the dotted line does not represent a bond, it is hydrogen or hydroxy,
R ¹ and R ² are each independently hydrogen, halo, hydroxy, C _1-4 alkyl, C _1-4 alkyloxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, C _1-6 Alkylcarbonyl, hydroxycarbonyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, di (C _1-4 alkyl) aminocarbonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, Aminosulfonyl, di (C _1-4 alkyl) aminosulfonyl, or —SO ₃ H;
R ³ and R ⁴ are each independently from the group consisting of hydrogen, halo, hydroxy, C _1-4 alkyl, C _1-4 alkyloxy, nitro, amino, cyano, trifluoromethyl, or trifluoromethoxy Selected;
R ⁵ and R ⁶ are each independently hydrogen, halo, hydroxy, C _1-4 alkyl, C _1-4 alkyloxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, C _1-6 Alkylcarbonyl, hydroxycarbonyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, di (C _1-4 alkyl) aminocarbonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, Aminosulfonyl, di (C _1-4 alkyl) aminosulfonyl, or —SO ₃ H;
Is the following chemical formula





Is a radical of;
From here,
A ¹ is a direct bond or C _1-6 alkanediyl;
A ² is C _2-6 alkanediyl;
R ⁷ is hydrogen, C _1-4 alkyl, phenyl or benzyl;
R ⁸ and R ⁹ are each independently hydrogen, C _1-6 alkyl, aminoC _1-6 alkyl or mono- or di (C _1-4 alkyl) aminoC _1-6 alkyl;
R ¹⁰ is hydrogen, C _1-6 alkyl, aminoC _1-6 alkyl or mono- or di (C _1-4 alkyl) aminoC _1-6 alkyl,
R ¹¹ is hydrogen, C _1-6 alkyl, amino, aminoC _1-6 alkyl or mono- or di (C _1-4 alkyl) aminoC _1-6 alkyl.
As used in the above definitions, halo is a generic name for fluoro, chloro, bromo and iodo; C _1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 2-methylpropyl and the like; C _1-6 alkyl includes C _1-4 alkyl and its higher homologs containing 5 or 6 carbon atoms such as 2-methylbutyl, pentyl, hexyl and the like; C _1-6 alkanediyl is a divalent straight and branched chain hydrocarbon radical having 1 to 6 carbon atoms, for example methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1 , 5-pentanediyl, 1,6-hexanediyl and side chain isomers thereof, and C _2-6 alkanediyl is a divalent straight or branched chain hydrocarbon having 2 to 6 carbon atoms; For example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and side chain isomers thereof are defined.
The term "stereochemically isomeric form" as used above defines all possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise stated or indicated, the chemical nomenclature of compounds refers to mixtures of all possible stereochemically isomeric forms, which mixtures include all diastereomers and enantiomers of the basic molecular structure. More particularly, stereogenic centers can have an R- or S-configuration, and substituents on bivalent cyclic (partially) saturated radicals can have cis- or trans-configuration. Compounds containing a double bond may have an E or Z-stereochemistry at the double bond. Stereochemically isomeric forms of the compounds of formula (I) are expressly included within the scope of this invention.
The present invention relates to compounds of formula (I) in which organic or inorganic bases such as amines, alkali metal bases and earth metal bases, or quaternary ammonium bases, or organic or inorganic acids such as mineral acids, Also included are salts that may form with acids containing phonic acid, carboxylic acid or phosphorus.
Examples of mineral acids which form salts are hydrofluoric acid, hydrochloric acid, hydrobromic acid hydroiodic acid, sulfuric acid, nitric acid, hydrochloric acid, perchloric acid or phosphoric acid. Salt-forming sulfonic acids are toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid or trifluoromethane sulfonic acid. Salt-forming carboxylic acids are formic acid, acetic acid, propanoic acid, butanoic acid and the like. Salt-forming dicarboxylic acids are oxalic acid, malonic acid, succinic acid, glutaric acid and the like. Salt-forming hydroxy acids are glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, mandelic acid and the like. Other salt-forming carboxylic acids are trifluoroacetic acid, benzoic acid, chloroacetic acid, phthalic acid, maleic acid and malonic acid. Phosphorus containing acids are various phosphonous acids, phosphonic acids, and phosphinic acids.
Particular addition salts may be used to prepare the base form of the compound of formula (I) with suitable acidic biocides such as 1,2-benzisothiazolone (BIT), 5-chloro-1,2-benzisothiazolone, 6-chloro -1,2-benzisothiazolone, 5-fluoro-1,2-benzisothiazolone, 5-methyl-3 (2H) -isothiazolone, or 4-bromo-5-methyl-3-iso Acid addition salts obtained by treatment with thiazolol. These addition salts may have different stereochemistry such as (1: 1), (1: 2), (1: 3), (2: 1), (3: 1), (2: 3) and the like.
Preferred salt-forming alkali metal hydroxides and earth metal hydroxides are hydroxides of lithium, sodium, potassium, magnesium or calcium, most preferably sodium or potassium hydroxides. Examples of suitable salt-forming amines are primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, four butylamine isomers, dimethylamine, diethylamine, Diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidin, pyridine, quinoline and Isoquinoline. Preferred amines are ethylamine, propylamine, diethylamine or triethylamine, with isopropylamine, diethanolamine and 1,4-diazabicyclo [2.2.2] octane being most preferred. Examples of quaternary ammonium bases are generally cations of haloammonium, for example tetramethylammonium cations, trimethylbenzylammonium cations, triethylbenzylammonium cations, and also ammonium cations.
The term, salt form also includes metal complexes which the compounds of formula (I) can form. The aforementioned metal complex consists of a complex formed between the compound of formula (I) and one or more organic or inorganic metal salts or salts. Examples of such organic or inorganic salts are halogenide, nitrate, sulfate, phosphate, acetate, trifluoroacetate, trichloroacetate, propionate, tartrate, sulfonate, for example methylsulfonate, 4-methylphenylsulfonate Salts of salicylates, benzoates and second main group metals of the periodic table, for example magnesium or calcium salts, salts of third or fourth main group metals, for example aluminum, tin, lead and the first to third 8 transition groups such as salts of chromium, manganese, iron, cobalt, nickel, copper, zinc and the like. Preference is given to metals belonging to the transition element of the fourth cycle. Metals may be present in each of their possible valences. Metal ions may also be present at their possible valences, with the most preferred metal copper being most advantageously used in the divalent form Cu (II). Suitable copper compounds are copper sulfate, copper acetate, copper hydroxide, copper oxide, copper borate, copper fluoride and especially copper hydroxide carbonate Cu (OH) ₂ CuCO ₃ . The complex may be mono- or multinucleated and may contain one or more portions of organic molecules as ligands.
As used herein, the term addition salts also includes solvates that a compound of formula (I) and salts thereof may form. Such solvates are, for example, hydrates, alcoholates and the like.
Interesting compound groups consist of compounds of formula (I) to which one or more of the following limitations apply.
a) R ¹ and R ² are each independently selected from hydrogen, halo, or -SO ₃ H;
b) R ³ and R ⁴ are hydrogen;
c) R ⁵ and R ⁶ are each independently selected from hydrogen, halo, hydroxy, C _1-4 alkyl, C _1-4 alkyloxy or —SO ₃ H;
d) R ⁷ is hydrogen or C _1-4 alkyl;
e) R ⁸ and R ⁹ are each independently hydrogen, C _1-4 alkyl, or aminoC _1-6 alkyl;
f) R ¹⁰ is hydrogen, C _1-6 alkyl, or di (C _1-4 alkyl) aminoC _1-6 alkyl;
g) R ¹¹ is hydrogen, C _1-6 alkyl, amino, aminoC _1-6 alkyl or di (C _1-4 alkyl) aminoC _1-6 alkyl;
h) A ¹ is a direct bond or C _2-4 alkanediyl;
g) A ² is C _2-4 alkanediyl.
More interesting compounds are those in which L is of formula (a-1), (a-2), (a-3), (a-5), (a-7), (a-8), or (a-10) And a radical wherein R ¹⁰ is hydrogen, C _1-6 alkyl, or di (C _1-4 alkyl) aminoC _1-6 alkyl.
Other more interesting compounds are those in which L is a radical of formula (a-3) or (a-9), wherein R ¹¹ is hydrogen, C _1-6 alkyl, amino, aminoC _1-6 alkyl or di (C _{1) -4} alkyl) aminoC _1-6 alkyl.
Also more interesting compounds are those in which L is a radical of formula (a-4) or (a-6), wherein R ⁸ and R ⁹ are each independently hydrogen, C _1-4 alkyl, or aminoC _1-6 alkyl Is a compound of formula (I).
Particular compounds are those of formula (I), wherein L is a radical of formula (a-1) and R ¹⁰ is hydrogen.
Other particular compounds include compounds of formula (I), wherein L is a radical of formula (a-4), wherein A ² is C _2-4 alkanediyl and R ⁹ and R ⁹ are each independently hydrogen, C _1-4 alkyl ) Compound.
Further particular compounds are those in which L is a radical of formula (a-6), wherein A ¹ and A ² are C _2-4 alkanediyl, R ⁷ is hydrogen or C _1-4 alkyl, R ⁸ and R ⁹ are each independently a compound of formula (I), which is hydrogen or C _1-4 alkyl.
Preferred compounds are 4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] (1,4'-bipiperidine);
4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] -1-piperidinepropanamine; And
N- [3-[(1,1'-biphenyl) -4-yl] -3-phenylpropyl] -1,3-propanediamine; And
Their acid or base addition salts, stereoisomeric forms, N-oxides, or quaternary ammonium derivatives thereof.
Another preferred compound is an acid addition salt obtained by treating the base form of the compound of formula (I) with a suitable acidic biocide such as 1,2-benzisothiazolone (BIT).
Particularly preferred acid addition salts are
4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] (1,4'-bipiperidine),
4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] -1-piperidinepropanamine, and
BIT salts of N- [3-[(1,1'-biphenyl) -4-yl] -3-phenylpropyl] -1,3-propanediamine or stereoisomeric forms of these latter compounds, N-oxides, or BIT salt of quaternary ammonium derivatives.
A compound of formula (Ia), defined as a compound of formula (I), wherein X is hydroxy and the dashed line does not represent a bond, is a compound of formula (II), wherein halo 'is chloro, bromo or iodine Organometallic derivatives of the intermediates of the present invention can be prepared by reacting with intermediates of the general formula (III). Organometallic derivatives of intermediates of the general formula (II) are for example converted into intermediates (II) to their corresponding Grignard analogues using magnesium in a reaction-inert solvent such as diethyl ether or tetrahydrofuran. It can manufacture. In the case of compounds of the formula (la), wherein the radical L has a radical of the formula R ⁸ and R ⁹ and R ¹⁰ are hydrogen, depending on the reaction conditions, for example R ⁸ , R ⁹ or R ¹⁰ It may be advisable to temporarily protect R ⁸ , R ⁹ or R ¹⁰ by converting it into an appropriate protecting group such as C _1-6 alkyloxycarbonyl.

Compounds of formula (Ia) are dehydrated above compounds of formula (Ia) under reaction conditions known in the art, for example, as illustrated in Example B.3, where compounds of formula (I) Direct bond and dotted line represents a bond).

The compound of formula (Ib) may be hydrogenated to convert the compound of formula (Ia) to a compound of formula (Ic) wherein the compound of formula (I), wherein X is hydrogen and the dashed line does not represent a bond have.

Formula (Ic), wherein L ¹ represents a radical of the formulas (a-2), (a-3), (a-6) to (a-10), wherein A ¹ is a direct bond Compounds of formula (Ic-1), defined as compounds of formula (I), may comprise intermediates of formula (V) with intermediates of formula (IV), wherein W is an appropriate leaving group such as halo, for example fluoro, chloro, Suitable leaving groups such as bromo, iodo, and in some cases W may also be a sulfonyl oxy group, for example methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy and similar reactive leaving groups Can be prepared by alkylation. The reaction can be carried out in a reaction-inert solvent such as acetonitrile and optionally in the presence of a suitable base such as sodium carbonate, potassium carbonate or triethylamine. In the case of compounds of formula (Ic-1), wherein L ¹ has a radical of the formula R ⁸ , R ⁹ or R ¹⁰ which is hydrogen, depending on the reaction conditions R ⁸ , R ⁹ or R ¹⁰ , for example C It may be advisable to temporarily protect R ⁸ , R ⁹ or R ¹⁰ by conversion to an appropriate protecting group such as _1-6 alkyloxycarbonyl.

Formula (I) wherein L ² represents a radical of formula (a-6) to (a-10), wherein A ¹ is an alkanediyl of C _1-6 The compound of Id) can be prepared by N-alkylating the intermediate of formula (VII) with the intermediate of formula (VI), wherein W is a leaving group as defined above.

The intermediate of formula (VII) has one of the following structures:



In the case of an intermediate of formula (VII), in which R ⁷ , R ⁸ , R ⁹ or R ¹⁰ is hydrogen, depending on the reaction conditions, R ⁷ , R ⁸ , R ⁹ or R ¹⁰ may for example be C _1-6 alkyl It may be advisable to temporarily protect R ⁷ , R ⁸ , R ⁹ or R ¹⁰ by conversion to an appropriate protecting group such as oxycarbonyl.
A compound of formula (Ie), defined as a compound of formula (I), wherein L ³ represents formula (a-2) or (a-4), represents an intermediate of formula (VIII) Or reductively N-alkylates with an intermediate of (X-1); Such intermediates of formula (VIII) may be prepared by N-alkylation with intermediates of formula (IX-2) or (X-2).

The intermediate of formula (IX) or (X) has the following structure.


In the case of intermediates of formula (IX) or (X), wherein formula R ⁸ , R ⁹ or R ¹⁰ is hydrogen, R ⁸ , R ⁹ or R ¹⁰ may be C _1-6 alkyloxycarbonyl depending on the reaction conditions. It may be advisable to temporarily protect R ⁸ , R ⁹ or R ¹⁰ by switching to the appropriate protection group such as.
The compounds of formula (I) may also be converted to one another via reactions or functional group transformations known in the art. For example, a compound of formula (I), wherein R ¹⁰ or R ¹¹ is hydrogen, can be prepared using N-alkylation procedures known in the art, wherein R ¹⁰ or R ¹¹ Is C _1-6 alkyl).
Intermediates of formula (IV) may be prepared as described in working examples A.7, and intermediates of formula (VI) may be prepared as described in working examples A.5 and A.6. Intermediates of VIII) can be prepared as described in Working Examples A.2 and A.3.
Some of the starting materials and intermediates are known compounds, are commercially available and can be prepared according to conventional reaction procedures generally known in the art.
The compounds of formula (I) prepared in the process described above can be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another according to the cleavage procedures known in the art. The racemic compound of formula (I) can be converted to the corresponding diastereomeric salt form by reaction with a suitable chiral acid. The diastereomeric salt forms can then be separated, for example by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali. Another method of separation of enantiomeric forms of compounds of formula (I) involves liquid chromatography using chiral stationary phases. The pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials if the reaction takes place stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by stereospecific methods of preparation. These methods advantageously utilize enantiomerically pure starting materials.
The biocidal properties of the compounds of formula (I) are illustrated in the biological section C below. In particular, the compounds of formula (I) have biocidal properties as demonstrated in Examples C.1 and C.2.
In addition, the compounds of formula (I) were found to be active against certain yeasts as demonstrated in Example C.3.
Many compounds of formula (I) also have algicidal properties.
The compounds of the present invention are active against a wide range of bacteria, including gram-positive and gram-negative bacteria. Examples of such Gram-positive bacteria include Micrococcus flavus, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus picalis faecalis) may be mentioned. Examples of such Gram-negative bacteria include Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri, Pseudomonas cepacia, Pseudomonas cepacia fluorenosmonas fluoresmonas ), Pseudomonas species, Proteus vulgaris, Proteus morganii, Escherichia coli, Klebsiella aerogenes, Enterobacter cloacae, Enterobacter cloacae, Salmonella typhimurium, Serratia marcescens and the like can be mentioned. Experiments have shown that Gram-negative bacteria (which are further protected by the outer membrane as compared to Gram-positive bacteria), in particular Pseudomonas, are more resistant to Gram-positive bacteria than to Gram-positive bacteria ("Microbiocides for the protection"). of materials ", by Wilfried Paulus, Chapman & Hall, 1st edition, 1993). Therefore, compounds having Salbacteria properties against Gram-negative bacteria, in particular Pseudomonas, are highly preferred.
Compounds of formula (I) can be used in a variety of applications:
Industrial aqueous process fluids such as cooling water, pulp and paper mill water and suspensions, secondary oil recovery systems, spinning fluids, metal working, etc.
Aqueous functional fluids such as polymer emulsions, water based paints and adhesives, glues, starch slurries, thickener solutions, gelatin, wax emulsions, inks, varnishes, pigments and mineral slurries, rubber latexes, concrete additives, drilling muds, cosmetics / In tank protection such as oils, aqueous cosmetic preparations, pharmaceutical preparations
-Finally anti-microbial treatment of materials with little or no glassy water, for example paint and adhesive films, textiles, paper, cardboard, plastic, hoses, strings, rubber products, leather, wood, timber materials,
-Sterilization of inanimate surfaces (eg hospitals, households, animal cages, food industry) and devices.
Compounds of formula (I) may be used for the protection of plants and plant derived materials from degradation by phytopathogenic bacteria. Examples of such phytopathogenic bacteria include Xanthomonas Campestris fib. Paseoli (Xanthomonas campestris pv.phaseoli), Pseudomonas syringa fib. Pseudomonas syringae pv.phaseolicola, Erwinia amylovora, Agrobacterium tumefaciens, Clavibacter michiganense, Erwinia carotovora carotovora caroto ), Erwinia tracheiphila, Pseudomonas pisi, Pseudomonas solanacearum, Streptomyces scabies, Xylella pastidiosa, etc. This may be mentioned. Therefore, the compounds of formula (I) have advantageous healing, prevention and systemic biocidal activity to protect plants, especially cultured plants. The compound of formula (I) is a plant or part of a plant that is infected, harmed or destroyed by microorganisms, for example, fruit, fruit trees, flowers, leaves, stems, roots, tubers or culture plants of plants. It can be used to protect the plant, whereby the part of the plant that grows later is protected against these microorganisms.
The compounds of formula (I) can also be used to treat seed sterilization (fruit, tubers, grain kernels) and plant crops and to control phytopathogenic microorganisms occurring in the soil.
Examples of a wide variety of cultivated plants in which the compounds of the present invention can be used are, for example, cereals, for example wheat, barley, rye, oats, rice, sorghuam, etc. fodder beet); Pome and stone fruits and berries, such as apples, pears, western oats, peaches, almonds, cherries, strawberries, raspberries and blackberries; Leguminous plants, such as beans, lentils, peas, soy beans; Oily plants such as rape, mustard, poppy, olives, sunflowers, coco fruit, castor oil, cocoa, pea beans; Gourds such as pumpkin, gerkins, melons, cucumbers and squashes; Fibrous plants, such as cotton, flax, hemp, jute, citrus fruits, for example oranges, lemons, grapes, mandarins, vegetables, for example brassica, such as spinach, lettuce, asparagus, cabbage and turnips ), Carrots, onions, tomatoes, potatoes, hot and sweet pepper; Laurel plants such as avocados, cinnamon, camphor trees; Or plants such as corn, tobacco, nuts, coffee, sugar cane, tea, vines, hops, bananas, gums, and evergreens such as decorative plants such as flowers, shrubs, deciduous trees and conifers. Enumeration of cultivated plants is for the purpose of illustrating the present invention and is not intended to limit the present invention thereto.
Compounds of formula (I) and compositions containing one or more of these compounds may also be used to prevent the formation of biofilms. Biofilms are made up of millions of microorganisms (bacteria, fungi, algae, and protozoa) that accumulate on the surface in aqueous environments (Science, vol. 273, p. 1795-1797, 1996). These film-forming microorganisms secrete substances of adhesive substances that cling them to materials such as metals, plastics, tissues, and solid particles. Once attached to the surface, the biofilm microorganisms perform various harmful or beneficial reactions depending on the environmental conditions. Some of the problems associated with biofilm formation include biocontamination (dirty or contaminated with microbial activity), bioerosion (especially industrial pipes), oil field souring (reduction of sulfates by soil microbes) and host tissues. And infections caused by biofilms growing in medical grafts. Bio-film-related problems are spent billions of dollars industrially by corrosion of pipes, reduction of heat transfer or water pressure in industrial cooling systems, blockage of water injection jets, and blockage of water filters. In addition, biofilms cause major medical problems through infection of host tissues, settlement of bacteria contaminating drinking water, causing rejection of medical transplantation, and contamination of medical devices ranging from contact lenses, urinary catheter to artificial heart.
Compounds of formula (I) are stable compounds and do not require any precautionary measures to deal with them.
In view of the biological activity of the compounds of formula (I) as demonstrated in Examples C.1 to C.4, the compounds are useful for regulating, i.e. preventing, inhibiting, eliminating, saving or eradicating microorganisms.
The invention also relates to biocidal compositions which contain a biocidal effective amount of a compound of formula (I) as defined above as one or more inert carriers and, if desired, other adjuvants and active ingredients. The present invention also relates to a method for controlling microorganisms, in particular bacteria, by applying the novel compounds to the microorganisms.
In the method of controlling microorganisms according to the present invention, the compound of formula (I) is used in unmodified form or preferably with adjuvant commonly used in the field of formulation. They are therefore formulated according to procedures known in the art into emulsifiable concentrates, directly sprayable or dilutable solutions, dilute emulsions, wettable powders, soluble powders, powders, granules and capsules, for example into polymeric materials. Depending on the nature of the composition, the method of application, such as spraying, spraying, spraying, watering or pouring, is selected according to the intended purpose and the main environment.
Formulations, ie compositions, preparations or mixtures containing a compound of formula (I) (active ingredient) and, where appropriate, solid or liquid auxiliaries, are known in the art, for example, active ingredients may be added to extenders such as solvents, solids. It is prepared by mixing and / or grinding homogeneously with a carrier and, if appropriate, with a surfactant.
Suitable solvents are aromatic hydrocarbons, preferably fractions containing 8 to 12 carbon atoms, for example alkylbenzene mixtures, for example dimethylbenzene mixtures or alkylated naphthalenes, aliphatic or cycloaliphatic hydrocarbons, for example paraffin, cyclohexane or Tetrahydronaphthalene, alcohols such as ethanol, propanol or butanol, glycols and their ethers and esters such as propylene glycol or dipropylene glycol ethers, ketones such as cyclohexanone, isophorone or diacetone alcohol, strong Polar solvents such as N-methyl-2-pyrrolidone, dimethylsulfoxide or water, vegetable oils and their esters such as rapeseed oil, castor oil or soybean oil, possibly silicone oils.
For example, solid carriers for powder and dispersible powders are common mineral fillers such as calcite, talcum powder, kaolin, montmorillonite or attapulgite. In order to improve the physical properties, it is also possible to add highly disperse silicic acid or highly disperse adsorption polymers. Suitable granulating adsorption carriers are porous, for example pumice, crushed bricks, vesicles or bentonite; Suitable nonadsorbent carriers are materials such as calcite or sand. A large number of inorganic or organic pregranulating materials, in particular dolomite or ground plant residues, can be used.
Depending on the nature of the compound of formula (I) to be formulated, suitable surfactants are nonionic, cationic and / or nonionic surfactants having emulsifying, dispersing and wetting properties. The term "surfactant" should also be understood to include mixtures of surfactants.
Suitable nonionic surfactants can be water soluble soaps and water soluble synthetic surfactant compounds.
Suitable soaps are sodium metal salts of high fatty acids (C ₁₀ -C ₂₂ ), alkaline earth metals or unsubstituted or substituted ammonium salts, for example sodium of natural fatty acid mixtures obtained from oleic or stearic or coco coconut oil or iron oil. Or potassium salts. Fatty acid methyltaurine salts may also be mentioned.
More frequently, however, so-called synthetic surfactants, in particular fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates are used.
Fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium, and also contain C _8-22 alkyl comprising an alkyl moiety of an acyl radical, for example lignosulfonic acid, or dode Sodium or calcium salts of fatty alcohol mixtures obtained from silsulfates or natural fatty acids. These compounds also include sulfate esters of fatty alcohols / ethylene oxide adducts and salts of sulfonic acids. The sulfonated benzimidazole derivatives preferably contain two sulfonic acid groups and one fatty acid radical containing 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzene sulfonic acid, dibutylnaphthalenesulfonic acid or naphthalenesulfonic acid / formaldehyde condensation products. Also suitable are salts of phosphate esters or phospholipids of adducts of p-nonylphenols with the corresponding phosphates, for example 4 to 14 moles of ethylene oxide.
The nonionic surfactants are preferably aliphatic or cycloaliphatic alcohols, or polyglycol ether derivatives of saturated or unsaturated fatty acids and alkyl phenols, which derivatives are 8 to 20 at 3 to 10 glycol ether groups and (aliphatic) hydrocarbon sites. Carbon atoms and alkyl moieties of alkylphenols containing from 6 to 18 carbon atoms.
Suitable nonionic surfactants are also water-soluble adducts of polyethylene oxide with polypropylene glycol having 1 to 10 carbon atoms in the alkyl chain, ethylenediaminopropylene glycol, which adducts include 20 to 250 ethylene glycol ether groups and It contains 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per unit of propylene glycol.
Representative examples of nonionic surfactants are nonylphenolpolyethoxyethanol, castor oil polyglycol ether, polypropylene / polyethylene oxide adduct, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxypolyethoxyethanol.
Fatty acid esters of polyethylene sorbitan, such as polyoxyethylene sorbitan trioleate, are also suitable nonionic surfactants.
Cationic surfactants are preferably quaternary ammonium salts containing at least one C ₈ -C ₂₂ alkyl radical as an N-substituent and a lower alkyl, benzyl or hydroxy-lower alkyl radical which is unsubstituted or halogenated as an additional substituent. to be. The salt is preferably in the form of a halide, methylsulfate or ethylsulfate, for example stearyl-trimethylammonium chloride or benzyldi (2-chloroethyl) ethylammonium bromide.
Surfactants commonly used in the field of formulations are described, for example, in the literature:
McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood, New Jersey, 1981; H. Stache, "Tensid-Taschenbuch", 2nd Edition, C. Hanser Verlag, Munich & Vienna, 1981, M. and J. Ash, "Encyclopedia of Surfactants", Vol. I-III, Chemical Publishing Co., New York, 1980-81.
Compositions containing a compound of formula (I) may further contain other active ingredients, for example other biocides, in particular fungicides, bactericides, for example to broaden the range of action or to prevent resistance from being made. And acaricides, nematicides, insecticides or herbicides. In many cases, this creates a synergistic effect. That is, the activity of the mixture exceeds the activity of the individual components.
As biocides which can be used in combination with the compounds of the invention, products of the following classes can be considered:
Fungicides:
2-aminobutane; 2-anilino-4-methyl-6-cyclopropyl-pyrimidine; 2 ', 6'-dibromo-2-methyl-4'-trifluoromethoxy-4'-trifluoro-methyl-1,3-thiazole-5-carboxanilide; 2,6-di-chloro-N- (4-trifluoromethylbenzyl) benzamide; (E) -2-methoxyimino-N-methyl-2- (2-phenoxyphenyl) -acetamide; 8-hydroxyquinoline sulfate; Methyl (E) -2- {2- [6- (2-cyanophenoxy) -pyrimidin-4-yloxy] -phenyl} -3-methoxyacrylate; Methyl (E) -methoxyimino [alpha- (o-tolyl] acetate; 2-phenylphenol (OPP), aldimorph, ampropyl force, anilazine, azaconazole, benalacyl, benodanil, benomil, Binapacryl, Biphenyl, Vitertanol, Blastisidin-S, Bromuconazole, Buprimate, Butiobate, Calcium Polysulfide, Captapol, Captan, Carbendazim, Carboxin, Quinomethionate , Chloroneb, chloropicrine, chlorothalonil, clozolinat, cupraneb, cymoxanyl, cyproconazole, cyprofuram, dichlorophene, diclobutrazole, diclofloanid, diclomezin, di Chloran, dietofencarb, difenokazole, dimethymolol, dimethomorph, diconazole, dinocap, diphenylamine, dipyrithione, ditalimphos, dithianon, dodine, dragoxolone, edifene Phos, epoxyconazole, etirimole, ethriazole, phenarimol, fenbuconazole, fenfuram, phenytropane, fenpi Clonil, fenpropidine, fenpropimod, fentin acetate, fentin hydroxide, perbam, perimzone, fluazinam, fludioxosonyl, fluoride, fluquinconazole, flusilazole, flusulfa Mead, plutoranyl, flutriafol, polpet, pocetyl-aluminum, phthalide, fuberidazole, fururaxyl, purmecyclox, guazanthin, hexachlorobenzene, hexaconazole, hymexazole, imazaryl, Imibenconazole, iminooctadine, ifprobenfos (IBP), iprodione, isoprothiolane, kasugamycin, copper preparations such as copper hydroxide, copper naphthenate, copper oxychloride, copper sulfate, copper oxide, Auxin-copper and Bordeaux mixtures, mancopers, mancozebs, manebs, mepanipyrim, mepronil, metallaxyl, metconazole, metasulfocarb, metfuroxam, metiram, metsulfobox, Michaelobutanyl, nickel dimethyldithiocarbame Nitrate, nitrotal-isopropyl, noarimol, opuras, oxadixyl, oxamocarb, oxycarboxine, pepurazoate, fenconazole, pensicuron, phosphodiphene, fimaricin, piperaline, polyoxine , Probenazole, prochloraz, procmidone, propamocarb, propiconazole, propineb, pyrazophos, pyriphenox, pyrimethanyl, pyroquilon, quintogen (PCNB), sulfur and sulfur Formulations, Tebuconazole, Teclophthalam, Tecnazen, Tetraconazole, Tiabendazole, Thiathiophene, Thiophanate-methyl, Thiram, Tollclofos-methyl, Tolylufluoride, Triadimefon, Triadione Menol, triazoxide, triclamid, tricyclazole, tridemorph, triflumizole, tripolin, triticazole, validamycin A, vinclozoline, geneb, zelam. Specific fungicides include thiabendazole; Isothia and benzisothiazolone derivatives such as 1,2-benzisothiazolone (BIT); Oxathiazines such as bentozin (ie, 3- (benzo [b] thien-2-yl) -5,6-dihydro-1,4,2-oxathiazine, 4-oxide); And fungicidally active triazoles such as azaconazole, bromuconazole, cyproconazole, difenocazole, epoxyconazole, fenbuconazole, hexaconazole, metconazole, fenconazole, propicozol Nazol, tebuconazole or triticazole.
Salbacterase:
Bronopol, dichlorophene, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octylinone, furancarboxylic acid, oxytetracycline, probenazole, streptomycin, teclophthalam, copper sulfate and other copper agents.
Pesticides / Acaricides / Nematicides:
Abamectin, AC 303 630, Acetate, Acrinatrin, Alanicab, Aldicarb, Alphamethrin, Amitraz, Avermectin, AZ 60541, Azadirachtin, Ajinfoss A, Ajinfoss M, Azocyclo Tin, Bacillus thuringiensis, bendiocarb, benfuracarb, benzaltope, betacyfluthrin, bifenthrin, BPMC, brofenprox, bromophos A, bufencarb, buprofezin, butokacsin, butyl Pyidabene, kadusafos, cabaril, cabofuran, cabofennotion, cabosulphan, katop, CGA 157 419, CGA 184699, cloetocarb, chlorethoxyphosphate, chlorfenbinfos, chlorofluazuron, cliorum Force, Chlorpyriphos, Chlorpyriphos M, Cis-Resmethrin, Closightin, Clofentezin, Cyanophosph, Cycloprotrin, Cyfluthrin, Cyhalothrin, Cyhexatin, Cypermethrin, Cylo Margin, Deltamethrin, Demetone-M, Demetone-S, Demetone-S-methyl, Dia Pentiuron, diazinon, diclopention, dichlorboth, diclifoss, dicrotophos, diethione, diflubenzuron, dimethatoate, dimethylbinfoss, dioxation, disulfotone, ediffenfoss, emma Mectin, Espenvalate, Ethiophene Carb, Ethion, Etofenprox, Etopro Force, Etrim Force, Phenamifoss, Penazaquine, Penbutatin Oxide, Phenytrothion, Phenobucarb, Phenothiocarb , Phenoxycarb, phenpropartin, fenpyrad, fenpyroximate, pention, fenvalrate, fipronil, fluazinam, flucycloxanthone, flucitalinate, flufenoxuron, flufenprox , Fluvalinate, phonophos, formitol, phosphthiazate, fufenfenx, furathiocarb, HCH, heptenophos, hexaflumuron, hexiax, imidacloprid, isprobenfos, isazofoss , Isopenfoss, isoprocarb, isoxation, two Vermectin, lambda-cyhalothrin, lufenuron, malathion, mecarbam, merbinforce, mesulfenfos, metaldehyde, methacryphos, metamidofos, metidathione, methiocarb, metomile, Metolcarb, Milvemectin, Monoclotophos, Moxidecin, Naled, NC 184, NI 25, Nitenpyram, Ometoate, Oxamyl, Oxidemetone M, Oxidedefoss, Parathion A, Parathion M, Permethrin, Pentoate, forate, posalon, phosmet, phosphamdone, bombardment, pyrimicab, pyrimifos M, pyrimifos A, propenophos, promecarb, propaphos, propoxur, prothiophos , Protoate, pymetrozine, pyraclophos, pyridapention, pyresmethrin, pyrethrum, pyridaben, pyrimidipene, pyriproxyfen, quinalforce, RH 5992, salityon, cebufoss, silafluorophene , Sulfothep, sulfprophos, tebufenozide, tebufenpyrad, tebupyrimifoss, teple Rubenzuron, Tefluthrin, Temefos, Terbam, Terbufos, Tetrachlorbinfos, Thiaphenox, Thiodicarb, Thiopanox, Thiomethone, Tionazine, Turingiencin, Tralomethrin, Triara Ten, triazofoss, triazuron, trichlorphone, triflumuron, trimetacarb, tamidothion, XMC, xylylcarb, zetamethrin
Other biocides that can be used in combination with the compounds of the present invention can be considered products of the following classes: phenol derivatives such as 3,5-dichlorophenol, 2,5-dichlorophenol, 3,5-di Bromophenol, 2,5-dibromophenol, 2,5 (resp. 3,5) -dichloro-4-bromophenol, 3,4,5-trichlorophenol, chlorinated hydrodiphenylether, for example For example, 2-hydroxy-3 ', 2', 4'-trichloro-diphenylether, phenylphenol, 4-chloro-2-phenylphenol, 4-chloro-2-benzylphenol, dichlorophene, hexachlorophene , Aldehydes such as formaldehyde, glutaraldehyde, salicylicaldehyde; Alcohols such as phenoxyethanol; Antimicrobial active carboxylic acids and their derivatives, organometallic compounds such as tributyltin compounds; Iodine compounds such as iodophor, iodonium compounds; Mono-di- and polyamines such as dodecylamine or 1,10-di (n-heptyl) -1,10-diaminodecane; Sulfonium- and phosphonium compounds; Mercapto compounds and their alkali, alkaline earth and heavy metal salts such as 2-mercaptopyridine-N-oxide and its sodium and zinc salts, 3-mercaptopyridazine-2-oxide, 2-mercaptoquinoxaline- 1-oxides, 2-mercaptoquinoxaline-di-N-oxides, and symmetric disulfides of the mercapto compounds; Ureas such as tribromo- or trichlorocarvanide, dichlorotrifluoromethyl-diphenylurea; Tribromosalicylanilide; 2-bromo-2-nitro-1,3-dihydroxypropane; Dichlorobenzoxazolone; And chlorohexidine.
The biocidal compositions preferably used in the process of the invention are usually from 0.1 to 99%, preferably from 0.1 to 95% of the compound of formula (I), from 1 to 99% of solid or liquid auxiliaries, and from 0 to 25%, Preferably from 0.1 to 25% surfactant. Commercially available forms of biocidal compositions are advantageously concentrates which can be easily diluted by the end user.
The composition may also contain further additives, for example stabilizers, for example optionally epoxidized vegetable oils (epoxylated coconut oil, rapeseed oil or soybean oil), antifoams such as silicone oils, preservatives, viscosity modifiers, binders, fillers And medicaments or other substances for special purposes.
The invention also relates to a composition containing a compound of formula (I) in an amount which shows a synergistic effect and another active ingredient and carrier as listed above. In particular, synergistic compositions of compounds of formula (I) with another bactericide and / or another fungicide are foreseen.
Preferred formulations especially consist of the following components (% = weight percent):
Emulsifiable composition
Active ingredient: 1 to 9%, preferably 2 to 5%
Suspending agent: 5-30%, preferably 10-20%
Liquid carrier: 5 to 94%, preferably 70 to 85%
Powder
Active ingredient: 0.1 to 10%, preferably 0.1 to 1%
Solid carrier: 99.9 to 90%, preferably 99.9 to 99%
Suspension Concentrate
Active ingredient: 5 to 75%, preferably 10 to 50%
Water: 94-24%, preferably 88-30%
Suspending agent: 1-40%, preferably 2-30%
Wettable powder
Active ingredient: 0.5 to 90%, preferably 1 to 80%
Suspending agent: 0.5-20%, preferably 1-15%
Solid carrier: 5 to 95%, preferably 15 to 90%
Granules
Active ingredient: 0.5 to 30%, preferably 3 to 15%
Solid carrier: 99.5 to 70%, preferably 97 to 85%
The following examples are intended to illustrate the invention.
Experimental part
The following abbreviations have been used in the procedures described below: “ACN” refers to acetonitrile; "THF" refers to tetrahydrofuran; "DCM" represents dichloromethane; "DIPE" refers to diisopropyl ether; "EtOAc" refers to ethyl acetate; "NH ₄ OAc" refers to ammonium acetate; "HOAc" refers to acetic acid; "MIK" refers to methyl isobutyl ketone.
For some chemicals, chemical formulas were used. For example, NaOH represents sodium hydroxide, K ₂ CO ₃ represents potassium carbonate, H ₂ represents hydrogen gas, MgSO ₄ represents magnesium sulfate, CuO.Cr ₂ O ₃ represents copper chromite, N ₂ represents nitrogen gas, CH ₂ Cl ₂ represents dichloromethane, CH ₃ OH represents methanol, NH ₃ represents ammonia, HCl represents hydrochloric acid, NaH represents sodium hydride; CaCO ₃ represents calcium carbonate, CO represents carbon monoxide, and KOH represents potassium hydroxide.
Of some compounds of formula (I), absolute stereochemical configuration has not been determined experimentally. In these cases, the first isolated stereochemically isomeric form is labeled "A" and the second is labeled "B" without reference to the actual stereochemical configuration.
A. Preparation of Intermediates
Example A.1
a) (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride (1: 1) (0.38 mole) and 4-oxo-1-piperidinecarboxylic acid, ethyl ester in methanol (700 ml) 0.38 mole) was hydrogenated at 50 ° C. with palladium on activated carbon (5 g) as catalyst in the presence of potassium acetate (50 g) and thiophene solution (5 ml). After absorbing hydrogen (2 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in DCM, washed with H ₂ O, dried, filtered and the solvent was evaporated. The residue was triturated in 2-propanol, filtered and dried to yield 78 g of (4-fluorophenyl) (4-piperidinyl) methanone hydrochloride (Intermediate 1).
b) A solution of 4-bromo-1,1'-biphenyl (0.1 mol) in THF (200 ml) was added dropwise to a mixture of magnesium (0.1 mol) in THF (50 m @). Grinard complex was formed. The mixture was stirred and refluxed for 30 minutes. A solution of Intermediate 1 (0.05 mol) in THF (50 ml) was added dropwise. The mixture was stirred and refluxed for 6 hours, then cooled, poured into NH ₄ Cl solution and extracted with toluene. The organic layer was separated, washed with H ₂ O, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH 99/1). The pure fractions were combined and the solvent evaporated to give 31 g of (±) -ethyl 4-[[((1,1-biphenyl) -4-yl] (4-fluorophenyl) hydroxymethyl] (1,4 '). -Bipiperidine) -1'-carboxylate (intermediate 2) was obtained.
Example A.2
a) 12.5 g of acetyl-4-piperidinecarbonyl chloride was added 10 g of 4-fluoro-1,1'-biphenyl, 17.5 g of aluminum (III) chloride and 60 g of 1,2-dichloroethane It was added portionwise to the mixture of. Upon completion, stirring was carried out at reflux for 1 hour. The reaction mixture was poured into a mixture of crushed ice and hydrochloric acid. The product was extracted with DCM. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered and dried to give 15 g (80.8%) of 1-acetyl-4-[(4'-fluoro- [1,1'-biphenyl] -4-yl] carbonyl] pyridine ( Intermediate 3) was obtained.
b) A mixture of 15 g of intermediate (3) and HCl solution (6N, 100 ml) was stirred at reflux for 3 hours. After cooling, the precipitated product was filtered and suspended in water. The base was liberated with sodium hydroxide in a conventional manner and extracted with dichloromethane. The extract was dried, filtered and evaporated to give 11 g (84.3%) of (4-fluoro- [1,1'biphenyl] -4-yl) (4-piperidinyl) -methanone (Intermediate 4). Obtained.
c) 5 g of ethylcarbonochlorate was added dropwise to a stirred mixture of 11 g of intermediate (4), 4.5 g of N, N-diethylethanamine and 150 g of trichloromethane. After complete addition, stirring was continued at reflux for 1 hour. After cooling, the reaction mixture was washed with water, dried, filtered and evaporated to 13 g (91.4%) of 4-[(4'-fluoro- [1,1'-biphenyl] -4-yl) carbo Nil] -1-piperidine-carboxylate (intermediate 5) was obtained.
d) A solution of bromobenzene (0.118 mol) in THF (50 ml) was added dropwise to a mixture of magnesium (0.118 mol) in THF (10 ml). The mixture was stirred and refluxed for 30 minutes, then cooled. A solution of intermediate 5 (0.059 mol) in THF (140 ml) was added dropwise. The mixture was stirred and refluxed overnight, then cooled, poured into saturated NH ₄ Cl solution and extracted with toluene. The organic layer was separated, washed with H ₂ O, dried and filtered to evaporate the solvent. The residue was purified on silica gel (eluent: CH ₂ Cl ₂ 100%) on a glass filter. The pure fractions were combined and the solvent evaporated to 27 g (100%) of (±) -ethyl 4-[[4'-fluoro (1,1'-biphenyl) -4-yl] hydroxyphenylmethyl]- 1-piperidinecarboxylate (intermediate 6) was obtained.
e) A mixture of intermediate 6 (0.062 mol) in HBr (48%, 250 ml) was stirred and refluxed for 4 hours. The solvent was evaporated. The residue was dissolved in DCM, alkalized with NH ₄ OH and extracted with DCM. The organic layer was separated, washed with H ₂ O, dried, filtered and the solvent evaporated to 19 g (89%) of 4-[[4-fluoro (1,1′-biphenyl) -4-yl. ] Phenylmethylene] piperidine (intermediate 7) was obtained.
f) A mixture of intermediate (7) (0.055 mol) and 4-oxo-1-piperidinecarboxylic acid, ethyl ester (0.055 mol) in methanol (250 ml) was activated carbon as catalyst in the presence of thiophene solution (1 ml). Palladium on phase (2 g) was hydrogenated at 50 ° C. After absorbing hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated to give 25.5 g (90%) of ethyl 4-[[4'-fluoro (1,1'-biphenyl) -4-yl] phenyl -Methylene] (1,4'-bipiperidine) -1'-carboxylate (intermediate 8) was obtained.
Example A.3
A mixture of 1,1'-biphenyl (0.3 mol) and aluminum (III) chloride (0.6 mol) in 1,2-dichloroethane (500 ml) was stirred. A mixture of ethyl 4- (chlorocarbonyl) -1-piperidinecarboxylate (0.3 mol) in 1,2-dichloroethane (100 ml) was added dropwise over 30 minutes (the exothermic temperature rose to 30 ° C). . The mixture was stirred at rt for 90 min, poured into ice and HCl and extracted with DCM. CH ₃ OH was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH 99/1). Pure fractions were combined and the solvent was evaporated. The residue was determined by DIPE. The precipitate was filtered off and dried to give 42 g of ethyl 4- (4-phenylbenzoyl) -1-yl piperidine-carboxylate (Intermediate 9).
b) A mixture of 1-bromo-4-methoxybenzene (0.053 mol) in THF (150 ml) was added to a stirred mixture of magnesium (0.053 mol) and several crystals of I ₂ in THF (50 ml) under nitrogen flow. Added dropwise. The mixture was stirred for 1 hour and refluxed. A mixture of intermediate 9 (0.044 mol) in THF (300 ml) was added dropwise. The mixture was refluxed with stirring for 1 hour, poured into saturated NH ₄ Cl solution (300 ml) and extracted three times with DCM. The organic layers were combined, washed once with H ₂ O and once with saturated NaCl solution, dried, filtered and the solvent was evaporated. This fraction was crystallized with CH ₃ OH / DIPE. The precipitate was filtered off and dried to allow 13.2 g (67%) of (±) -ethyl 4-[[(1,1'-biphenyl) -4-yl] (4-methoxyphenyl) hydroxymethyl] -1 Piperidine carboxylate (intermediate 10) was obtained.
c) A mixture of intermediate 10 (0.029 mol) in methanol (250 ml) was hydrogenated at 50 ° C. with palladium (2 g) on activated carbon as a catalyst. After absorbing hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated to 12.5 g (100%) of (±) -ethyl 4-[[(1,1'-biphenyl) -4-yl] (4- Methoxyphenyl) -methyl] -1-piperidinecarboxylate (intermediate 11) was obtained.
d) A mixture of potassium hydroxide (20 g) and intermediate 11 (0.029 mol) in 2-propanol (200 ml) was stirred at reflux for 4 hours and then cooled. The solvent was evaporated. The residue was dissolved in H ₂ O (250 ml) and the mixture was extracted three times with DCM. The combined organic layers were washed twice with H ₂ O and once with saturated NaCl solution, dried, filtered and the solvent was evaporated. Column residue on silica gel (eluent 1: CH ₂ Cl ₂ / CH ₃ OH 100/0 to 95/5, eluent 2: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 90/10 Purified). Collect the desired fractions and evaporate the solvent to give 8.2 g (79%) of (±) -4-[[(1,1'-biphenyl) -4-yl] (4-methoxyphenyl) methyl] piperi Dean (Intermediate 12) was obtained.
Example A.4
a) A mixture of bromobenzene (0.2 mol) in diethyl ether (200 ml) was added dropwise to a mixture of magnesium (0.2 mol) in diethyl ether (20 ml). The mixture was stirred at reflux for 1 hour. A mixture of intermediate 9 (0.1 mol) in diethyl ether (800 ml) was added dropwise. The mixture was stirred at reflux for 1 hour, cooled, poured into NH ₄ Cl solution and extracted with toluene. The organic layer was separated, washed, dried, filtered and the solvent evaporated. The residue was triturated in DIPE, filtered and dried to give 30 g of (±) -ethyl 4-[[((1,1'-biphenyl) -4-yl] hydroxyphenylmethyl] -1-piperi Dean carboxylate (intermediate 13) was obtained.
b) A mixture of intermediate 13 (0.0722 moles) in a mixture of 2-propanol and HCl (50 ml) and toluene (500 ml) was stirred at reflux for 4 hours using a water separator. The solvent was evaporated. The residue was dissolved in DCM. The organic solution is washed, dried, filtered and the solvent is evaporated, 31 g of ethyl 4-[[((1,1'-biphenyl) -4-yl] phenylmethylene] -1-piperidinecarboxylate (Intermediate 14) was obtained.
c) A mixture of intermediate 14 (0.078 moles) in methanol (250 ml) was hydrogenated at 50 ° C. for 2 days with palladium (2 g) on activated carbon as a catalyst. After absorbing hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated to 27 g of (±) -ethyl 4-[[((1,1'-biphenyl) -4-yl] phenylmethyl] -1 -Piperidine-carboxylate (intermediate 15) was obtained.
d) A mixture of sodium hydrogen sulfite (1 g) and intermediate 15 (0.023 mol) in hydrobromic acid (48%) (250 ml) is stirred and refluxed for 6 hours and then cooled to crystallize. The precipitate was filtered off and dried to give 5.29 g (69%) of product. This fraction was separated into its enantiomer by HPLC (eluent: hexane / ethanol 40/60; column: CHIRALPAK AD 5 cm). Two pure fractions were combined and their solvents were evaporated to yield 2.4 g of fraction 1 and 2.2 g of fraction 2.
Fraction 1 was dissolved in HBr solution (0.5 ml). The solvent was evaporated. Toluene was added twice and evaporated again. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried to give (-)-4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] piperidine; [α] ²⁰ _D = -7.62 ° (c = 0.5% in CH ₃ OH) (intermediate 16) was obtained. Fraction 2 was dissolved in HBr solution (0.5 ml). The solvent was evaporated. Toluene was added twice and evaporated again. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried to give (+)-4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] piperidine; [α] ²⁰ _D = + 6.22 ° (0.5% in c = CH ₃ OH) (intermediate 26).
e) a mixture of intermediate 16 (0.0046 mol) and 4-oxo-1-piperidinylcarboxylic acid, 1,1-dimethylethyl ester (0.0048 mol) in methanol (150 ml) was added with potassium acetate (2 g) and methanol Hydrogenated at room temperature with palladium on activated carbon (10%) (1 g) as catalyst in the presence of a thiophene solution (4%) in water. After absorbing hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was converted to free base and purified by column chromatography on silica gel (eluant: CH ₂ Cl ₂ / CH ₃ OH 100/0 to 98/2). The pure fractions were combined and the solvent evaporated to 1 g of 1,1-dimethylethyl (A) -4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] (1,4'-BP Ferridine) -1'-carboxylate (intermediate 17) was obtained.
Example A.5
The sodium hydride dispersion in mineral oil (60%) (0.22 moles) was treated with hexanes under N ₂ stream to remove the oil and then partitioned into THF (100 ml) under N ₂ stream. Ethyl (diethylphosphono) acetate (0.22 mol) was added dropwise. The mixture was stirred for 30 minutes until gas evolution ceased. A mixture of (1,1'-biphenyl) -4-ylphenylmethanone (0.2 mol) in THF (100 ml) was added dropwise at room temperature. The mixture was stirred at rt for 1 h, then stirred and refluxed for 17 h, cooled, poured into 10% HCl and ice and extracted three times with DCM. The combined organic layers were washed once with saturated K ₂ CO ₃ solution, twice with H ₂ O and once with saturated NaCl solution, then dried and filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / EtOAc / hexanes 1/1/98). Two pure fractions were combined and their solvents evaporated. Fraction 2 was crystallized from 2-propanol. The precipitate was filtered off and dried. The mother layer was evaporated and combined with fraction 1 yielded 45 g of ethyl 3-[(1,1'-biphenyl) -4-yl] -3-phenyl-2-propenoate (intermediate 18). .
b) Mixture of intermediates 18 (0.137 mol) in methanol (500 ml) with palladium (10%) on activated carbon as catalyst in the presence of thiophene solution in DIPE (1 ml) at room temperature at 1 atmosphere Hydrogenated. After hydrogen was absorbed (1 equiv), the catalyst was filtered off and the filtrate was evaporated. This fraction was crystallized from CH ₃ OH. The precipitate was filtered off and dried to give 28 g (62%) of (±) -ethyl 3-[(1,1'-fiphenyl) -4-yl] -3-phenyl-propanoate (Intermediate 19). Obtained.
c) Lithium aluminum hydride (0.057 mol) in THF (200 ml) was stirred at reflux temperature. A solution of intermediate 19 (0.057 mol) in THF (300 ml) was added dropwise and the resulting reaction mixture was stirred and refluxed for 3 hours and then stirred at room temperature overnight. The mixture was digested with water (5 ml) and then acidified with 4 NH ₂ SO ₄ . The reaction mixture is filtered and the filtrate is evaporated. The residue was purified on silica gel (eluent: CH ₂ Cl ₂ ) on a glass filter. The desired fractions were combined and the solvent was evaporated to yield 14 g of (±) -γ-phenyl (1,1'-biphenyl) -4-propanol (intermediate 20).
A mixture of intermediate 20 (0.048 mol) in DCM (150 ml) and pyridine (150 ml) was stirred at room temperature. Methanesulfonyl chloride (0.06 mol) was added dropwise and the resulting reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ ). The desired fractions were combined and the solvent was evaporated. The residue was triturated under DIPE and dried to give 5.5 g of (±) -γ-phenyl (1,1'-biphenyl) -4-propanol methanesulfonate (ester) (intermediate 21).
Example A., 6
A mixture of ((1,1'-biphenyl) -4-phenylmethanone (0.01 mol) in THF (200 ml) was stirred at a room temperature under a N ₂ stream. Vinylmagnesium chloride (0.011 mol; 1 M solution in THF The mixture was stirred at rt for 1 h HCl (150 ml) was added The mixture was stirred at rt for 1 h and extracted with DIPE The organic layer was separated and saturated K ₂ CO ₃ solution Washed once, twice with H ₂ O and once with saturated NaCl solution, dried, filtered and the solvent was evaporated This fraction was subjected to column chromatography on silica gel (eluent: CH ₂ Cl ₂ / hexanes). / EtOAc 50/30/20) Two pure fractions were combined and their solvents evaporated to 8.8 g (29%) of 4- (3-chloro-1-phenyl-1-propenyl) (1,1 '-Biphenyl) (intermediate 22) was obtained.
Example A.7
A mixture of bromobenzene (0.3 mol) in THF (300 ml) was added dropwise to a mixture of magnesium (0.32 mol) in THF (20 ml). The mixture was stirred for 1 hour and refluxed. A mixture of 4-biphenylcarboxyaldehyde (0.3 mol) in THF (500 ml) was added dropwise. The mixture was stirred and refluxed for 2 h, stirred at rt overnight, poured into saturated NH ₄ Cl solution and extracted with DCM. The organic layer was separated, washed three times, dried and filtered to evaporate the solvent. The residue was triturated in hexane, filtered and purified on silica gel (eluent: CH ₂ Cl ₂ 100%) on a glass filter. Pure fractions were combined and the solvent was evaporated. The residue was triturated in DIPE, filtered and dried to give 31 g of (±) -α-phenyl (1,1'-biphenyl) -4-methanol (intermediate 23).
b) A mixture of hydrochloric acid (50 ml) and intermediate 23 (0.08 mol) in DCM (200 ml) was stirred at rt overnight. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was crystallized from hexanes. The precipitate was filtered and dried to afford 20 g of (±) -4- (chloro-phenylmethyl) (1,1'-biphenyl) (intermediate 24).
Example A.8
Intermediate 16 was converted to the free base and acrylonitrile (0.02 mol) in methanol (50 ml) was stirred at reflux overnight. Acrylonitrile (0.09 mol) was added. The mixture was stirred at reflux overnight. K ₂ CO ₃ was added. The mixture was stirred and refluxed for 2 hours. The solvent was evaporated. The residue was dissolved in DCM. The organic solution was washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH 98/2). Pure fractions were combined and the solvent was evaporated. The residue was crystallized from 2-propanol. The precipitate was filtered off and dried to give 1.8 g of (A) -4-[([1,1'-biphenyl] -4-yl) phenylmethyl] -1-piperidine-propanenitrile (Intermediate 25, [α ²⁰ _D = -8.29 ° (c = 24.73 mg / DMF in 5 ml), melting point 106 ° C.) was obtained. Similarly, however, starting from intermediate 26, (B) -4-[([1,1'-biphenyl] -4-yl) -phenylmethyl] -1-piperidinepropanenitrile (Intermediate 27, [ α] ²⁰ _D = + 8.23 ° (c = 24.923 mg / DMF in 5 ml), melting point 92 ° C.).
B. Preparation of Final Compound
Example B.1
The mixture of intermediate 2 (0.06 mol) in hydrobromic acid (48%) (250 ml) was stirred and refluxed for 4 hours and then cooled. The precipitate was filtered off and dried to give 25.2 g of product. A portion of this fraction (5 g) was converted to the free base and purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / CH ₃ OH 95/5). Pure fractions were combined and the solvent was evaporated. The residue was dissolved in 2-propanol and converted from 2-propanol / HCl to hydrochloride (1: 2). The precipitate was filtered off and dried to produce 4.2 g of 4-[[((1,1'-biphenyl) -4-yl] (4-fluorophenyl) methylene] (1,4'-bipiperidine) dihydrochloride 2-propanolate (1: 1) (Compound 2) was obtained.
Example B.2
A mixture of intermediate 8 (0.051 mol) and potassium hydroxide (40 g) in 2-propanol (400 ml) was stirred and refluxed for 5 hours. The mixture was cooled and the solvent evaporated. The residue was dissolved in H ₂ O (500 ml) and extracted three times with DCM. The combined organic layers were washed once with NH ₄ Cl (10%), twice with H ₂ O and once with saturated NaCl solution, then dried, filtered and the solvent was evaporated to give 19 g (87%) of 4- [. [4'-Fluoro- (1,1'-biphenyl) -4-yl] phenyl-methylene] (1,4'-bipiperidine) (Compound 4) was obtained.
Example B.3
A mixture of compound 4 (0.029 mol) in acetic acid (250 ml) was hydrogenated at 20 ° C. with palladium (2 g) on activated carbon as a catalyst. After uptake of hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated. Saturated K ₂ CO ₃ solution (100 ml) was added. The mixture was extracted three times with DCM. The combined organic layers were washed twice with H ₂ O and once with saturated NaCl solution, dried, filtered and the solvent was evaporated. This fraction was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ / (CH ₃ OH / NH ₃ ) 95/5). Two fractions were combined and their solvents were evaporated to yield 3.5 g of fraction 1 and 3.5 g of fraction 2. Fraction 2 was converted from 2-propanol / HCl to hydrochloride (1: 2). The precipitate was filtered off and dried to give (±) -4-[[4'-fluoro (1,1'-biphenyl) -4-yl] phenylmethyl] (1,4'-bipiperidine) dihydrochloride Monohydrate (Compound 7) was obtained.
Example B.4
A mixture of ethyl 4-[[(1,1'-biphenyl) -4-yl] phenylmethylene] (1,4-bipiperidine) -1'-carboxylate (0.0083 mol) in methanol (150 ml) Hydrogenated to palladium on carbon (10%, 2 g) as catalyst. After absorbing hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated. A mixture of potassium hydroxide in 2-propanol (200 ml) was added to the residue. The mixture was stirred and refluxed for 4 hours. The solvent was evaporated. The residue was dissolved in DCM (500 ml). The mixture was washed three times with H ₂ O and once with saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was converted to hydrochloride (1: 2) with 2-propanol / HCl. The precipitate was filtered off and dried to give 2.7 g (69.7%) of (±) -4-[[(1,1'-biphenyl) -4-yl] phenyl-methyl] (1,4'-bipiperidine) Dihydrochloride monohydrate (compound 20) was obtained.
Example B.5
Palladium or platinum (0.100 g, as catalyst) on activated carbon was stirred in methanol (2 ml) under N ₂ atmosphere. A thiophene solution in methanol (1 ml) was added. Potassium acetate (0.100 g) was added. Butanal (0.100 g, ± 0.0003 moles) was added. Compound 20 (0.0003 mol) in methanol (3 ml) was added and the reaction mixture was hydrogenated at 50 ° C. over the weekend. After absorbing hydrogen (1 equiv), the catalyst was filtered off. The desired compound was Kromasil Spherical silica Si 60 (100 g, 5 μm; eluent gradient: CH ₂ Cl ₂ / (CH ₂ Cl ₂ / CH ₃ OH 9/1) / CH ₃ OH (0 min) 100/0/0, Prochrom DAC-column (ID) with (10.31 min) 0/100/0, (10.32 min) 50/0/50, (13.02 min) 0/0/100, (13.33-18.32 min) 100/0/0) : Purified by high performance liquid chromatography on 5 cm). Collect the desired fractions and evaporate the solvent to afford 0.040 g of (±) -4-[[(1,1'-4-[[(1,1'-biphenyl) -4-yl] phenyl-methyl] -1 '-Butyl (1,4'-bipiperidine) (compound 14) was obtained.
Example B.6
A mixture of intermediate 21 (0.00027 mol), N, N, N'-trimethyl-1,3-propanediamine (0.100 g) and sodium carbonate (0.100 g) in N, N-dimethylformamide (1 ml) Stir overnight at 90 ° C. The desired compound was transferred to Hyperprep 'BDS' HS C18 (55 g, 8 μm, 100 μs; eluent gradient: [0.5% NH ₄ OAc in H ₂ O) / CH ₃ CN 90/10] / CH ₃ OH / CH ₃ CN Separation by high performance liquid chromatography on (0 min) 75/25/0, (10.31 min) 0/50/50, (16.32 min) 0/0/100, (16.33 min-final) 75/25/0) And purified. Collect the desired fractions and evaporate the solvent to afford 0.020 g of (±) -N- [3-[(1,1'-biphenyl) -4-yl] -3-phenylpropyl] -N, N ', N '-Trimethylpropanediamine (compound 38) was obtained.
Example B.7
A mixture of N, N'-dimethyl-N-[(3-methylamino) propyl] -1,3-propanediamine (0.0248 mol) in DMF (75 ml) was stirred at 60 ° C. A mixture of intermediate 24 (0.01 mol) in DMF (75 ml) was added dropwise. The mixture was stirred at 60 ° C. for 6 hours and at room temperature overnight. The solvent was evaporated. H ₂ O (100 ml) was added and the mixture was extracted three times with DCM. The organic layers were combined, washed twice with H ₂ O and once with saturated NaCl solution, then dried, filtered and the solvent was evaporated. The residue was purified by HPLC (eluent: CH ₂ Cl ₂ / CH ₃ OH / (CH ₃ OH / NH ₃ ) 92/4/4) on silica gel. Pure fractions were combined and the solvent was evaporated. The residue was converted to hydrochloride (1: 3) with 2-propanol / HCl. The precipitate was filtered off and dried to give (±) -N-[[(1,1'-biphenyl) -4-yl] phenylmethyl] -N, N'-dimethyl-N '-[3- (methylamino) Propyl] -1,3-propanediamine trichloride (Compound 52) was obtained.
Example B.8
The Grignard reaction was started with several ml of a mixture of 4-bromobiphenyl (0.08 mol) in magnesium (0.08 mol) and THF (150 ml). Then the remainder of the mixture of 4-bromobiphenyl in THF was added dropwise. The resulting reaction mixture was stirred and refluxed for 1 hour and then cooled. 1- (2,4-dichlorophenyl) -3- [4- [2- (dimethylamino) ethyl] -1-piperidinyl] -1-propaneone.dihydro dissolved in diethyl ether (50 ml) Chloride (0.023 mol) was added dropwise. The mixture was stirred and refluxed for 1 hour and then cooled, digested with NH ₄ Cl 10% and stirred. Dilute aqueous HCl solution was added. The mixture was stirred for a while. The organic layer was separated, washed with H ₂ O, dried and filtered. The filtrate was saturated with HCl / 2-propanol. The precipitate was filtered off and crystallized from CH ₃ OH and diethyl ether. The precipitate was filtered off and dried to give 1.05 g (7.8%) of (±) -α-[(1,1'-biphenyl) -4-yl] -α- (2,4-dichlorophenyl) -4- [ 2- (dimethylamino) ethyl] -1-piperidine-propanol. Dihydrochloride (Compound 34) was obtained.
Example B.9
(±) -N- [3- (1,1'-biphenyl] -4-yl) -3-phenylpropyl] -N'-methyl-N '-(phenylmethyl) -1 in methanol (150 ml) A mixture of, 2-ethanediamine (0.006 mol) was hydrogenated with palladium on carbon (19%, 1 g) as catalyst at room temperature. After absorbing hydrogen (1 equiv), the catalyst is filtered off and the filtrate is evaporated to give a residue, which is converted to hydrochloride (1: 2) with HCl / 2-propanol to give 2.76 g of (±) -N- [3-([1,1'-biphenyl] -4-yl) -3-phenylpropyl] -N'-methyl-1,2-ethanediamine dihydrochloride (Compound 56) was obtained.
Example B.10
A mixture of intermediate 25 (0.003 mol) in a mixture of methanol saturated with NH ₃ (200 ml) was hydrogenated overnight at 20 ° C. with Raney Ni (1 g) as catalyst. After absorbing hydrogen (2 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in 2-propanol and converted to hydrochloride (1: 2) with 2-propanol / HCl. The solvent was evaporated. The residue was triturated in diethyl ether, filtered and dried to 1.4 g of (A) -4-[([1,1'-biphenyl] -4-yl) phenylmethyl] -1-piperidinepropane Amine dihydrochloride tetrahydrate (Compound 78) was obtained.
Tables F-1 to F-5 list compounds prepared according to one of the above examples. The following abbreviations are used in the table: .C ₄ H ₆ O ₅ represents 2-hydroxybutanedioic acid salt (maleate), .C ₂ H ₂ O ₄ represents ethanedioate salt, and .C ₄ H ₆ O ₄ represents a butanedioate salt, .C ₄ H ₆ O ₆ represents [R- (R ^* , R ^* )]-2,3-dihydroxy-butanedioate (L-tartaric acid salt) ,. (E) -C ₄ H ₄ O ₄ represents (E) -2-butenedioate (fumaric acid salt),. (Z) -C ₄ H ₄ O ₄ represents (Z) -2-butenedioate (Maleic acid salt), .C ₆ H ₈ O ₇ represents .2-hydroxy-1,2,3-propanetricarboxylate (citric acid salt), and .BIT represents 1,2-benzisothiazoline 3-one salt is shown.
TABLE F-1


TABLE F-2


TABLE F-3


Table F-4


Table F-5


C. Biological Examples
C.1. Primary Bacteria Screening
Stock solutions with test compounds were pipetted into multiple wells to reach test compound concentrations of 500 μMol and mixed with warm trytose broth agar (2.6%). Allow the medium to cool and then inoculate the bacteria. The wells were placed in an incubator at 27 ° C. and 70% relative humidity. After sufficient growth of untreated culture, test compounds were evaluated.
Pseudomonas aeruginosa
Escherichia coli
Score system
3: complete inhibition of bacterial growth
2: partially rescued bacterial growth
1: bacterial growth comparable to untreated
Table C.1:

C.2 Secondary Bacteria Screening
Numerous compounds of formula (I) were tested in secondary screening for various bacteria. Test conditions are as described in Biological Example C.1. The concentration of the test compound is also 500 μmol and the system used is also the same.
Test bacteria:
bacteria number bacteria number Pseudomonas alcaligenes One Pseudomonas testosteroni 10 Bacillus cereus mycodes 2 Brevibacterium ammoniagenes 11 Flavobacterium sp. 3 Cellulomonas flavigena 12 Streptomyces albus 4 Corynebacterium oortii 13 Shewanella putrefaciens 5 Pseudomonas stutzeri 14 Pseudomonas fluorescens 6 Proteus vulgaris 15 Pseudomonas oleovorans 7 Klebsiella pneumoniae 16 bacteria number bacteria number Alcaligenes faecalis 8 Providencia rettgeri 17 Citrobacteria freundii 9 Pseudomonas putida 18
Table C.2:


C.3 Screening for Yeast
Many compounds of formula (I) were also tested in screening for specific yeasts. Test conditions are as described in Biological Example C.1. The concentration of the test compound is also 500 μmol and the scoring system used is also the same.
Test Yeast:
Debaryomyces hansenii (19)
Rhodotorula rubra (20)
Sprobolomyces roseus (21)
Table C.3:


C.4 Synergy with BIT
Biocidal activity against bacterial / yeast growth was determined by poison plate analysis. In order to obtain the desired concentration of test compound, a calculated amount of stock solution (DMSO) was pipetted into a multi-well plate. Trytoz agar (other than Rhododourula: PDA) was aseptically added and shaken to obtain a uniform distribution. Each plate was inoculated with a bacterial / yeast suspension. After incubation at 27 ° C. and 70% relative humidity for a sufficient time period to allow full growth of the control, the percentage of activity was scored compared to the control.
Possible synergism was investigated using Limpel's formula (Richter, D.L., Pestic. Sci. 1987, 19: 309-315):

Where Ec is the expected addition reaction or calculated activity, X is the percentage of control observed when Compound A is applied alone, and Y is the percentage of control observed when compound B is applied alone. It was believed that synergism occurred when the observed effect of the combination of both compounds, or the measured activity was greater than the corresponding Ec value.
Tables C.4 to C.6 below show BIT and compounds 20, 42 and 40 when tested as a single test compound or as a combination against Rhodotorula rubra or Cellulomonas flavigena. List the measured and calculated activities. BIT (1,2-benzisothiazol-3 (2H) -one) is a well known bactericidal agent and tested at concentrations of 25 and 50 μmol. Compounds 20, 40 and 42 were tested at concentrations of 25, 50 and 75 μmol. When a synergistic effect is observed, "measured" activity and "calculated" activity are indicated in bold.
Table C.4: BIT, percent activity of compound 20 and combinations thereof
(The concentrations of BIT and compound number 20 are expressed in μmol)

Table C.5: BIT, percent activity of compound 42 and combinations thereof
(The concentrations of BIT and compound number 42 are expressed in μmol)

Table C.6: BIT, percent activity of compound 40 and combinations thereof
(The concentrations of BIT and compound number 40 are expressed in μmol)


Tables C.7 to C.8 below list the measured and calculated activities of BAC and compounds 20, 42, and 40 when used as a single test compound or as a combination against Providevidia rettgeri. . BAC (benzalkonium chloride) is a well known bactericidal agent and tested at concentrations of 40 and 80 μmol. Compounds 20, 40 and 42 were tested at concentrations of 10, 20, 40, 80 and 160 μmol. When synergistic effects are observed, "measured" activity and "calculated activity" are indicated in bold.
Table C.7: Activity percentages of BAC, Compound No. 20 or 40 and combinations thereof
(Concentrations of BAC and compound number 20 or 40 are expressed in μmol)

Table C.8: Percent activity of BAC, Compound No. 42 and combinations thereof
(Concentrations of BAC and compound number 42 are expressed in μmol)

权利要求:
Claims (14)
[1" claim-type="Currently amended] Compounds of formula (I), stereochemically isomeric forms thereof, acid or base addition salts thereof, N-oxides thereof, or quaternary ammonium derivatives thereof:

Where
The dashed line is any bond;
X is a direct bond when the dotted line represents a bond, or
When the dotted line does not represent a bond, it is hydrogen or hydroxy,
R ¹ and R ² are each independently hydrogen, halo, hydroxy, C _1-4 alkyl, C _1-4 alkyloxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, C _1-6 Alkylcarbonyl, hydroxycarbonyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, di (C _1-4 alkyl) aminocarbonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, Aminosulfonyl, di (C _1-4 alkyl) aminosulfonyl, or —SO ₃ H;
R ³ and R ⁴ are each independently from the group consisting of hydrogen, halo, hydroxy, C _1-4 alkyl, C _1-4 alkyloxy, nitro, amino, cyano, trifluoromethyl, or trifluoromethoxy Selected;
R ⁵ and R ⁶ are each independently hydrogen, halo, hydroxy, C _1-4 alkyl, C _1-4 alkyloxy, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, C _1-6 Alkylcarbonyl, hydroxycarbonyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, di (C _1-4 alkyl) aminocarbonyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, Aminosulfonyl, di (C _1-4 alkyl) aminosulfonyl, or —SO ₃ H;
Is the following chemical formula





Is a radical of;
From here,
A ¹ is a direct bond or C _1-6 alkanediyl;
A ² is C _2-6 alkanediyl;
R ⁷ is hydrogen, C _1-4 alkyl, phenyl or benzyl;
R ⁸ and R ⁹ are each independently hydrogen, C _1-6 alkyl, aminoC _1-6 alkyl or mono- or di (C _1-4 alkyl) aminoC _1-6 alkyl;
R ¹⁰ is hydrogen, C _1-6 alkyl, aminoC _1-6 alkyl or mono- or di (C _1-4 alkyl) aminoC _1-6 alkyl,
R ¹¹ is hydrogen, C _1-6 alkyl, amino, aminoC _1-6 alkyl or mono- or di (C _1-4 alkyl) aminoC _1-6 alkyl.
[2" claim-type="Currently amended] The compound of claim 1, wherein L is formula (a-1), (a-2), (a-3), (a-5), (a-7), (a-8), or (a-10) Radacal, wherein R ¹⁰ is hydrogen, C _1-6 alkyl, or di (C _1-4 alkyl) aminoC _1-6 alkyl.
[3" claim-type="Currently amended] The compound of claim 1, wherein L is a radical of formula (a-3) or (a-9), wherein R ¹¹ is hydrogen, C _1-6 alkyl, amino, aminoC _1-6 alkyl or di (C _1-4 alkyl) aminoC _1-6 alkyl.
[4" claim-type="Currently amended] The compound of claim 1, wherein L is a radical of formula (a-4) or (a-6), wherein R ⁸ and R ⁹ are each independently hydrogen, C _1-4 alkyl, or aminoC _1-6 Compounds that are alkyl.
[5" claim-type="Currently amended] The method of claim 1,
4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] (1,4'-bipiperidine);
4-[[(1,1'-biphenyl) -4-yl] phenylmethyl] -1-piperidinepropanamine; And
N- [3-[(1,1'-biphenyl) -4-yl] -3-phenylpropyl] -1,3-propanediamine; And
Their acid or base addition salts, stereoisomeric forms, N-oxides, or quaternary ammonium derivatives.
[6" claim-type="Currently amended] 6. The compound of claim 5, wherein the acid addition salt is a 1,2-benzisothiazolone (BIT) salt.
[7" claim-type="Currently amended] A biocidal composition comprising at least one inert carrier and, if desired, another adjuvant and a biocidal effective amount of the compound according to claim 1 as an active ingredient.
[8" claim-type="Currently amended] 8. The biocidal composition of claim 7, further comprising at least one other component selected from the group consisting of bactericides, fungicides, insecticides, acaricides, nematicides, and herbicides.
[9" claim-type="Currently amended] A process for preparing the biocidal composition according to claim 7, wherein the active ingredient is intimately mixed with the carrier.
[10" claim-type="Currently amended] Use for controlling microorganisms of a compound according to any one of claims 1 to 6.
[11" claim-type="Currently amended] A method of controlling microorganisms by applying at least one compound according to any one of claims 1 to 6 to a microorganism.
[12" claim-type="Currently amended] A composition comprising the compound according to any one of claims 1 to 6, and another active ingredient, and a carrier in an amount exhibiting a synergistic effect.
[13" claim-type="Currently amended] 13. The composition of claim 12, wherein the other active ingredient is a fungicide or bactericide.
[14" claim-type="Currently amended] a) A compound of formula (Ia) defined as a compound of formula (I) in which an organometallic derivative of the intermediate of formula (II) is reacted with an intermediate of formula (III), where X is hydroxy and the dotted line shows no bond To obtain
b) N-alkylation of the intermediate of formula (V) with the intermediate of formula (IV) in a reaction-inert solvent and optionally in the presence of a suitable base so that X is hydrogen and the dashed line shows no bond, and L ¹ represents formula (a- 2), (a-3), radicals of (a-6) to (a-10), wherein A ¹ is a compound of formula (Ic-1) defined as a compound of formula (I) To obtain a compound
c) Intermediates of formula (IV) in reaction inert solvents



Reacted with an intermediate of formula (VII) having one of L ² represents a radical of formulas (a-6) to (a-10), wherein A ¹ is an alkanediyl of C _1-6 To obtain a compound of formula (Id) as defined by a compound of
d) converting the compounds of formula (I) to each other according to transformation methods known in the art; Converting the compound of formula (I) to a pharmaceutically acceptable acid addition salt if desired, or conversely converting the acid addition salt of formula (I) to an alkali free base form and, if desired, preparing its stereochemically isomeric form Way:



Where
Halo 'represents chloro, bromo or iodo,
L, R ¹ to R ¹⁰ are as defined in claim 1,
W is an appropriate exit group.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1998-04-02|Priority to EP98201043.1

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1998-04-02|Priority to EP98201043

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1999-03-25|Application filed by 디르크 반테, 얀센 파마슈티카 엔.브이.

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2001-05-25|Publication of KR20010042084A

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2006-03-22|Application granted

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2006-03-22|Publication of KR100563146B1

优先权:

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申请号 | 申请日 | 专利标题

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EP98201043.1|1998-04-02|

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EP98201043|1998-04-02|