PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`
`
`(51) International PatentClassification © ;
`(11) International Publication Number:
`WO 95/33754
`
`C07F 5/02, AOIN 55/00, CO9D 5/14,
`
`
`(43) International Publication Date:
`14 December 1995 (14.12.95)
`CO8K 5/55
`
`
`
`PCT/GB95/01206|(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`(21) International Application Number:
`CN, CZ, DE, DK, EE, ES, Fl, GB, GE, HU, IS, JP, KE,
`
` (22) Internationa! Filing Date:
`KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN,
`26 May 1995 (26.05.95)
`
`
`MW,Mx,NO, NZ, PL, PT, RO, RU, SD, SE, SG,SI, SK,
`
`TJ, TM, TT, UA, UG, US, UZ, VN, European patent (AT,
`
`
`BE, CH, DE, DK, ES, FR, GB, GR,IE, IT, LU, MC, NL,
` (30) Priority Data:
`GB
`
`PT, SE), OAPI patent (BF, BJ, CF, CG, C], CM, GA, GN,
`9411587.0
`9 June 1994 (09.06.94)
`ML,MR, NE, SN, TD, TG), ARIPO patent (KE, MW,SD,
`
`SZ, UG).
` (71) Applicant (for all designated States except US): ZENECA
`
`LIMITED [GB/GB]; 15 Stanhope Gate, London W1Y 6LN
`
` Published
`(GB).
`
`With international search report.
`
` (72) Inventors; and
`
`(75) Inventors/Applicants (for US only): AUSTIN, Peter, William
`
`[GB/GB]; 45 Randale Drive, Bury, Lancashire BL9 8NF
`(GB). KNEALE,Christopher, Juan [GB/GB]; 8 Dalefields,
`Delph, Oldham, Lancashire OL3 5HZ (GB). CROWLEY,
`Patrick, Jelf [GB/GB]; 56 Ellis Road, Crowthorne, Berkshire
`RG11 6PT (GB). CLOUGH, John, Martin [GB/GB]; 7
`Gypsy Lane, Marlow, Buckinghamshire SL7 3JT (GB).
`
`
`
`Intellectual Property
`FAWKES, David, Melville;
`(74) Agents:
`Group, Zeneca Specialties, P.O. Box 42, Hexagon House,
`Blackley, Manchester M9 8ZS (GB)et al.
`
`
`
`
`
`
`
`
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`
`
`(54) Title) OXABOROLES AND SALTS THEREOF, AND THEIR USE AS BIOCIDES
`
`(57) Abstract
`
`The use of oxaboroles and salts thereof as industrial biocides especially fungicides for the protection of plastics materials such as
`plasticised PVC. Preferred compounds are 5- and 6-fluoro or bromo- 1,3-dihydro-1-hydroxy-2,1-benzoxaborole including O-esters thereof.
`
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`1vaHe
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`MYLAN - Ex. 1007, p. 1
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`MYLAN - Ex. 1007, p. 1
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`

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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of
`applications under the PCT.
`
`pamphlets publishing international
`
`
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`Viet Nam
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`MYLAN- Ex. 1007,'p. 2
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`AT
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`KR
`KZ
`LI
`LK
`LU
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`MC
`MD
`MG
`ML
`MN
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`United Kingdom
`Austria
`Georgia
`Australia
`Guinea
`Barbados
`Greece
`Belgium
`Hungary
`Burkina Faso
`Ireland
`Bulgaria
`Italy
`Benin
`Japan
`Brazil
`Kenya
`Belarus
`Kyrgystan
`Canada
`Democratic People’s Republic
`Central African Republic
`of Korea
`Congo
`
`Republic of Korea
`Switzerland
`Kazakhstan
`Cate d'Ivoire
`Liechtenstein
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`Cameroon
`Sri Lanka
`China
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`Luxembourg
`Czechoslovakia
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`Latvia
`Czech Republic
`Monaco
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`Germany
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`Republic of Moldova
`Denmark
`Madagascar
`Spain
`Mali
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`Finland
`Mongolia
`France
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`Gabon
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`MYLAN - Ex. 1007, p. 2
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`

`

`WO 95/33734
`
`PCT/GB93/01206
`
`OXABOROLES AND SALTS THEREOF, AND THEIR USE AS BIOCIDES
`
`The present invention relates to the use of oxaboroles and
`salts thereof as industrial biocides, especially fungicides, biocidal
`compositions containing the oxaboroles including their salts and certain
`oxaboroles .
`
`No single industrial biocide is ideal for all applications
`and new biocides are constantly being sought with better activity
`against individual spoilage micro-organisms, wider spectrum of activity,
`improved compatibility with the medium in which they are used and
`improved persistence in use. Safety in use is another important
`consideration.
`A small number of compounds containing an oxaborole ring
`(hereinafter "oxaborole") have already been described in the literature.
`These are N- (1,3-dihydro-1-hydroxy-2,1-benzoxaborol -6-yl) -succinamic
`acid (CA 55 23423c); 4-(1,3-dihydro-1-hydroxy-2,1-benzoxaborol-6-ylazo) -
`2-naphthoic acid (CA §5 23423c); 1,3-dihydro-1-hydroxy-6-nitro-2,1-
`benzoxaborole (CA 55 23423b); 6-amino-1,3-dihydro-1-hydroxy-2,1-
`benzoxaborole and its hydrochloride (CA 55 23423c); 1,3-dihydro-1-
`hydroxy-7-methyl-2,1-benzoxaborole (CA 55 6473f); 1- (benzyloxy) -1,3-
`dihydro-2,1-benzoxaborole (CA 6] 16084f); 1,3-dihydro-1-hydroxy-N,N-
`dimethyl-2,1-benzoxaborol-6-amine (CA 103(3) 22633f); 4-bromo-1,3-
`dihydro-1-hydroxy-2,1-benzoxaborole (CA 103(3) 22633f); 1,1'-oxybis [4-
`romo-1,3-dihydro-2,1-benzoxaborole (CA 103(3) 22633f); 1-
`(cyclohexyloxy) -1,3-dihydro-2,1-benzoxaborole (CA 61 16084f); 1-ethoxy-
`1,3-dihydro-2,1-benzoxaborole (CA 61 16084f); 3,7-dihydro-1,5-dihydroxy-
`1E, 3H-benzo[1,2-c: 4,5-c']bis[1,2]oxaborole (CA 61 14698a); 1,3-dihydro-
`1-hvdroxy-6-methyl-2,1-benzoxaborole (CA 61 14698b); 5-bromo-1,3-
`dihydro-1-hydroxy-2,1-benzoxaborole-6-methanol
`(CA 51 14698b); 1,1'-
`oxybis [1,3-dihydro-2,1-benzoxaborole] (CA 103(3) 22633f); and
`boronophthalide (CA 116(13) 129587q).
`French certificate of utility No
`73 29370 discloses boronophthalide (1-hydroxy-3H-1,2-benzoxaborole) and
`this is the only citation known which discloses that an oxaborole is
`biologically active.
`It is disclosed as being useful in inhibiting the
`growth of micro organisms in aviation fuels. However, at least 100ppm
`of the boronophthalide is required to protect the fuel.
`It has now been found that compounds containing an oxaborole
`ring are particularly effective against micro-organisms such as
`bacteria, algae, yeasts and particularly fungi, especially fungi which
`cause degradation of plastics materials.
`The level of microbiological
`activity now found is surprising in the light of the disclosure in the
`above utility certificate.
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`

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`WO95/33734
`
`PCT/GB935/01206
`
`According to the present invention there is provided a method
`for the protection of a medium susceptible to microbial attack by the
`treatment of the medium with an effective amount of an oxaborole of
`general formula (1)
`
`xo
`
`.
`
`or a salt thereof
`wherein
`
`A
`.
`A and D are each independently, hydrogen, optionally
`substituted C,,,-alkyl, aralkyl, aryl, or heterocyclyl or where A and D
`together with the carbon atoms to which they are attached form a 5,6 or
`7-membered fused ring which itself may be substituted;
`independently,
`X is a group -CR'R? wherein R* and R’ are each,
`hydrogen, optionally substituted C,..-alkyl, nitrile, nitro, aryl or
`aralkyl or R' and R* together with the carbon atom to which they are
`attached form an alicyclic ring;
`R is hydrogen, optionally substituted C,-y,-alkyl, aralkyl,
`aryl, heteroaryl, cycloalkyl or a radical of formula (2)
`
`wherein A, D and X are as hereinbefore defined except where the medium
`is aviation fuel and the only oxaborole is boronophthalide.
`When A and/or D is alkyl, it may be linear or branched and is
`preferably C,.,,-, more preferably C,..- and especially C,_,-alkyl.
`When A and/or D is substituted alkyl,
`the substituent may be
`C,.<-alkoxy, hydroxy, halogen, nitrile, amino, substituted amino, carboxy,
`acyl, aryloxy or carbonylamino optionally substituted by C,.,-alkyl.
`When A and/or D is alkyl the alkyl group or groups are
`preferably unsubstituted.
`.
`When A and/or D is aryl, it is preferably phenyl which may
`itself be substituted.
`When A and/or D is aralkyl, it is preferably benzyl or
`2-ethylphenyl, where the phenyl ring may be substituted.
`When the phenyl ring is substituted,
`the substituents include
`C,.e-alkyl, Cy.,-alkoxy, aryloxy, hydroxy, halogen, nitro, carbonamido,
`sulphonamido,
`trifluoromethyl or amino optionally substituted by one or
`more C,.,-alkyl groups.
`Aryloxy is preferably phenoxy.
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`MYLAN- Ex. 1007, p. 4
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`

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`WO 95/33754
`
`PCT/GB95/01206
`
`When A and D together with the two carbon atoms to which they
`are attached form a fused ring the ring may be alicyclic as in
`cyclopentene, cyclohexene or cycloheptene or it may be aromatic such as
`phenyl, pyridyl,
`thienyl or furanyl.
`The fused ring may also carry
`substituents as described hereinbefore for substituted phenyl and
`substituted alkyl.
`The fused ring may also contain more than one ring
`system, for example, a naphthyl or quinolinyl ring system or the fused
`ring may also link two oxaborole rings as for example in 1H, 3H-
`benzo[1,2-c: 4,5-c']bis [1,2] oxaborole.
`When R! and/or R? is aryl it is preferably phenyl.
`When R! and/or R? is aralkyl it is preferably benzyl.
`Preferably, at least one of R' and R? is hydrogen and it is
`especially preferred that both are hydrogen.
`When R is alkyl it may be linear or branched and is
`preferably C,..- and especially C,_.-alkyl.
`When R is substituted alkyl,
`the substitutent may be
`Cyg-aunoxy, Cy..-alkylthio, hydroxy, amino, substituted amino, carboxy,
`aryl, aryloxy, carbonamido optionally substituted by C,.,-alkyl, aryl such
`as phenyl and aralkyl such as benzyl.
`When R is aralkyl it is preferably benzyl or 2-ethylphenyl .
`When R is aryl it is preferably phenyl.
`When R is heteroaryl it is preferably quinclinyl and
`particularly quinolin-8-yl.
`When R is cycloalkyl it is preferably cyclohexyl.
`When the substituent is halogen, it is preferably bromine,
`chlorine and especially fluorine.
`One preferred class «.£ oxaborole is a benzoxaborole of
`formula 1 wherein A and D together with the carbon atoms to which they
`are attached form a fused phenyl, naphthyl or thienyl ring.
`When the fused ring is phenyl,
`the oxaborole is a
`benzoxaborole and the substituent or substituents may be in any of
`positions 4,5,6 or 7 of the benzoxaborole. Preferably the substituent
`or substituents is/are in the 5 and/or 6 position. Preferred
`substituents are amino, alkyl, alkoxy, phenyl, phenoxy, sulphonamide,
`carbonamide, each of which may be substituted, and also trifluoromethyl,
`chlorine, bromine and especially fluorine.
`the other fused phenyl ring
`When the fused ring is naphthyl,
`is attached to the benzoxaborole ring system in either the 4,5- or 5,6-
`position.
`
`In one preferred class of oxaborole, R is hydrogen.
`Another preferred class of oxaboroles for use in the present
`invention is where R is substituted alkyl, especially where the
`substituent is a primary, secondary or tertiary amino group and
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`WO 95/33754
`
`PCT/GB935/01206
`
`particularly wherein the alkylene amino group forms a 5-, 6- or 7-
`membered ring together with the boron atom and the oxygen atom to which
`the group R is attached.
`Such compounds are esters containing a
`tetrahedral boron atom as for example in formula (3) below
`
`A
`
`D7
`
`xTeme
`SB=N'RER!
`°°
`\
`
`8
`
`wherein
`
`A,D and X are as defined hereinbefore;
`R? and R‘ are each independently, hydrogen, optionally
`substituted C,.,,-alkyl or optionally substituted phenyl or R’ together
`with Y or part of Y forms a 5- or 6- or 7- membered optionally
`substituted ring containing the nitrogen atom; and
`Y is an optionally substituted divalent alkylene linking
`group containing up to 18 carbon atoms.
`R? and R' are preferably optionally substituted C,_,,-alkyl,
`more preferably optionally substituted C,.,-alkyl and especially
`substituted C,.,-alkyl.
`It is preferred that when R’ and/or R' is alkyl the alkyl
`group is unsubstituted.
`The alkylene group represented by Y may be linear or
`
`branched.
`
`When Y is substituted alkylene the substituent is preferably
`phenyl, C,.,-alkoxy, C,..-alkylthio or carbonyl alkylene as for example a
`-COCH,- group.
`When Y or part of Y forms a 5-, 6- or 7~- membered optionally
`substituted ring the substituent may be a fused ring which may itself be
`substituted.
`
`Preferably Y is unsubstituted alkylene.
`When R? together with Y forms a 6-membered optionally
`substituted ring the ring is preferably a quinolinyl ring as obtainable,
`for example,
`from 8-hydroxyquinoline.
`When R? together with part of Y forms a 5-membered ring the
`ring is preferably pyrrolidin-2-yl.
`It is preferred that A and D together with the carbon atoms
`to which they are attached form an aromatic ring or ring system such as
`for example a fused phenyl,
`thienyl or naphthyl ring which ring or ring
`system may be substituted as defined hereinbefore for substituted phenyl
`and substituted alkyl.
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`WO 95/33754
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`PCT/GB95/01206
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`When A and D together with the carbon atoms to which they are
`attached form a fused phenyl ring which is substituted,
`the oxaborole
`may be a 1H, 3H-benzo [1,2-¢:4,5-c'] bis {1,2] oxaborole containing an
`ester group attached to each boron atom.
`A particularly preferred class of oxaborole of formula 3 is
`that of formula 4
`
`AN
`
`EX\
`
`IL »,
`me
`(eye6
`
`Ds.
`O
`\
`
`.
`
`(4)
`
`Rey
`
`wherein
`
`A, D and X are as defined hereinbefore;
`nisi, 2 or 3;
`R? is hydrogen, optionally substituted C,..,-alkyl or
`optionally substituted phenyl;
`R® and R® are each independently, hydrogen, optionally
`substituted alkyl containing up to a total of 16 carbon atoms or
`optionally substituted phenyl.
`independently, optionally
`Preferably R° and R® are each,
`substituted C,.,- and especially optionally substituted C,.,7alkyl.
`Preferably two of R?, R° and R* are hydrogen.
`It is
`especially preferred that R° and R® are both hydrogen.
`Preferably n is 1 or 2 and especially 1.
`When A and/or D and/or R is a group which is or contains
`halogen the halogen may be fluorine, chlorine, bromine or iodine. When
`A and/or D is alkyl substituted by halogen, it may contain more than one
`halogen atom as in trifluoromethyl.
`When A and D together with the two carbon atoms to which they
`are attached form a fused ring, any substituent in the fused ring is
`preferably attached to a carbon atom other than that adjacent to the
`oxaborole ring.
`Thus in the case of 1,2-dihydro-2,1-benzoxaboroies the
`substituent or substituents are preferably in the 5 and/or 6 position.
`When the oxaborole of formula 1 is a salt,
`the group
`-OR attached to the boron atom is ionic as in -O-R* where R* is an alkali
`metal such as lithium, potassium or sodium or R’ is an amine salt or
`quaternary ammonium cation.
`In the latter case the quaternary ammonium
`ion may itself be microbiologically active.
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`MYLAN- Ex. 1007, p. 7
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`

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`WO 93/33754
`
`PCT/GB95/01206
`
`When A and/or D is amino or substituted amino, or when A
`and/or D and/or R contains amino or substituted amino the salt of the
`oxaborole of formula I may be the salt of an organic or inorganic acid.
`Examples of such acids are acetic and hydrochloric acids.
`Particularly useful effects have been obtained in plastics
`materials and paint films where the compound containing an oxaborole
`ring is benzoxaborole or the 6-chloro-, 5-chloro-, 5-fluoro- or 5-bromo-
`derivative thereof and the oxaborole esters obtainable therefrom by
`reaction with alkanoamines such as ethanolamine, 3-aminopropanol and
`4-aminobutanol.
`
`The oxaborole may be used in undiluted form but is preferably
`formulated in a composition together with a carrier. Thus, as a further
`aspect of the invention there is provided a composition comprising a
`carrier and an oxaborole of general formula (1) or a salt thereof
`(hereinafter "biocide composition") with the proviso that when
`boronophthalide is the only oxaborole present the carrier is not an
`aviation fuel.
`
`The carrier may be a material which shows little, if any,
`antimicrobial activity and may be, or include, a medium which is
`susceptible to the growth of micro-organisms, such as bacteria or fungi.
`The carrier may be a solid but is preferably a liquid medium and the
`biocide composition is preferably a solution, suspension or emulsion of
`the oxaborole in a liquid medium.
`The carrier is generally selected so that the biocide
`composition is compatible with the medium to be protected. Thus, for
`example, if the medium to be protected is a solvent-based paint,
`lacquer
`or varnish the carrier is preferably a solvent, especially a non-polar
`solvent such as white spirits.
`the
`If the medium to be protected is a plastics material,
`carrier is preferably a plasticiser or stabiliser typically used in the
`fabrication of plastics articles such as dioctylphthalate,
`dioctyladipate or epoxidised soya bean oil.
`If the medium to be
`protected is an aquecus medium,
`the carrier is preferably water or a
`water-miscible organic solvent or mixture thereof. Examples of suitable
`water-miscible organic solvents are acetic acid, N,N-dimethylformamide,
`dimethylsulphoxide, N-methyl-2-pyrrolidine, alcohols such as ethanol or
`glycols such as ethylene glycol, propylene glycol and dipropylene glycol
`and lower C,.,-alkyl carbitols such as methyl carbitol.
`If the carrier is
`a solid,
`the composition may be a dry solid as described in EP 407024.
`If the biocide composition is in the form of a suspension or
`emulsion, it preferably also contains a surface active agent to produce
`a stable dispersion or to maintain the non-continuous phase uniformly
`distributed throughout the continuous phase. Any surface active agent
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`WO 95/33754
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`PCT/GB95/01206
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`which does not adversely affect the biocidal activity of the compound of
`formula I may be used, for example alkylene oxide adducts of fatty
`alcohols, alkyl phenols, amines such as ethylene diamine and anionic
`surfactants such as adducts of naphthol sulphonates and formaldehyde.
`The concentration of the oxaborole in the biocide composition
`is preferably up to a level at which the biocide composition is stable
`under the conditions of storage or transportation and is preferably from
`1 to 50%, especially from 5 to 30% and more especially from 10 to 20% by
`weight relative to the total weight of the biocide composition.
`As noted hereinbefore, many of the oxaboroles are new.
`According to a further aspect of the invention there is
`provided a compound of formula (1)
`
`\ie
`
`ol,
`-
`or a salt thereof
`wherein A, D, X and R are all as hereinbefore defined except
`for N- (1, 3-dihydro-1-hydroxy-2, 1-benzoxaborol-6-yl) -succinamic acid; 6-
`nitro-, 6-amino-, 7-methyl-, 6-(NN-dimethylamino) -,
`5-(NN-dimethylamino)-, 4-bromo-, 6-methyl-, 5-bromo-6-methylol-1,3-
`dihydro-1-hydroxy-2,1-benzoxaborole; boronophthalide; 1-benzyloxy-,
`1-cyclohexyloxy-, 1-ethoxy-1, 3-dihydro-2,1-benzoxaborole;
`1,1'-oxybis [1, 3-dihydro-2,1-benzoxaborole] ; 1,1'-oxybis [4-bromo-1,3-
`dihydro-2,1-benzoxaborole] and 3,7-dihydro-1,5-dihydroxy-1H, 3H-
`benzo[1,2-c: 4,5-c']bis[1,2]oxaborole.
`Preferably A and D together with the carbon atoms to which
`they are attached form a fused phenyl ring which may itself be
`substituted as defined hereinbefore and preferably R is hydrogen or
`alkyl substituted by amino.
`It is also preferred that X is -CH,-.
`Preferably the fused phenyl ring contains a halogen atom in
`the 5 and/or 6 position of a benzoxaborole ring system, especially in
`the 5-position. Preferred halogens are fluorine and chlorine. Examples
`include 5-chloro and especially 5-fluoro benzcxaborole.
`Other preferred oxaboroles are the O-esters obtainable by
`reacting the oxaborole with an aminoaliphatic carboxylic acid such as
`glycine or an alkanolamine such as ethanolamine, 3-aminopropanol or
`4-aminobutanol .
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`WO 95/33754
`
`PCT/GB95/01206
`
`According to a further aspect of the invention there is
`provided a compound of formula 3
`
`AL
`
`UXTie
`
`< BONRR!
`Ds.
`O
`\
`
`0
`
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`
`wherein
`
`A,D and X are as defined hereinbefore;
`R? and R‘ are each,
`independently, hydrogen, optionally
`substituted C,,,-alkyl or optionally substituted phenyl or R’ together
`with Y or part of Y forms a 5-, 6- or 7-membered ring containing the
`nitrogen atom; and
`Y is an optionally substituted divalent alkylene linking
`group containing up to 18 carbon atoms.
`The oxaboroles may be made by any method known to the art.
`the 1,3-dihydro-1-hydroxy-2,1-benzoxaboroles may be made by
`Thus,
`reacting an ortho-toluidine under Sandmeyer conditions to obtain an
`o- substituted halogeno toluene which is then reacted with magnesium or
`alkyl lithium such as butyl lithium in an inert solvent and the Grignard
`reagent or aryl lithium so formed is reacted with a borate ester such as
`tributyl borate to obtain a toluene boronic acid. This boronic acid is
`then reacted with a brominating agent such as N-bromosuccinimide in an
`inert solvent such as carbon tetrachloride to give a bromomethylbenzene
`boronic acid which is hydrolysed in alkali to give the hydroxymethyl
`analogue which is finally cyclised to give the benzoxaborole under acid
`conditions. This is method A.
`The preparation of
`o-bromomethylbenzeneboronic acids is described in JACS 1958 80 835.
`Alternatively, an appropriate benzaldehyde is reacted with
`p-toluenesulphonylhydrazide in an inert solvent such as dry
`dichloromethane and the product is subsequently reacted with boron
`tribromide in the presence of a catalyst such as ferric or aluminium
`chloride and then cyclised to give a 1,2-dihydro-1-hydroxy-2- (4-
`methylpheny1-sulphonyl) -2,3,1-benzodiazaborine. This is subsequently
`hydrolysed under alkaline conditions and then converted to the
`benzoxaborole under acid conditions.
`It is generally not necessary to
`isolate the intermediate diazaborine. This is method B and is described
`in Liebigs Ann. Chem. 1985 683.
`Oxaboroles containing a fused aromatic ring can be made by
`reacting an aromatic compound containing a -CH,OH group with alkyl or
`aryl lithium and an organoborate in a dry inert organic liquid.
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`MYLAN- Ex. 1007, p. 10
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`MYLAN - Ex. 1007, p. 10
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`

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`WO95/33754
`
`PCT/GB95/01206
`
`According to a still further aspect of the invention there is
`provided a process for making an oxaborole containing a fused aromatic
`ring which comprises reacting an aromatic compound containing a -CH,OH
`group with alkyl or aryl-lithium and an organo-borate in a dry inert
`organic liquid.
`Preferably the fused aromatic ring is a fused phenyl ring and
`the aromatic compound containing 4 -CH,OH group is an optionally
`substituted benzyl alcohol.
`Preferably the aromatic compound containing a -CH,OH group
`also contains one or more further substitutents which are ortho-
`lithiation activating groups since these allow for reaction under milder
`conditions.
`Such activating groups are preferably located in a
`position(s) other than ortho to the -CH,OH group. Examples of activating
`groups are C,,-alkoxy, halogen such as chlorine and fluorine, substituted
`alkyl such as -CH,OCH,,
`-CH,NTI2,
`-CH,CH,NT,, substituted amino such as -NTI},
`-NHCOT,
`-NHCO,T and amides such as -SO,NHT,
`-SO.NT,,
`-CONHT and -CONT,
`where T is aryl or alkyl. Preferably when T is aryl it is phenyl, and
`it is preferred that when T is alkyl it is C,,-alkyl.
`An alkyl lithium compound is preferred which may be linear or
`branched and is preferably C,.,-alkyl and especially C,.,-alkyl such as
`butyl lithiun.
`The organic liquid is preferably an alkyl ether such as
`diethylether or preferably a cyclic-ether such as tetrahydrofuran.
`The reaction may be carried out at temperatures up to the
`boiling point of the organic liquid. However, when the aromatic
`compound containing a -CH,OH group also contains an ortho-lithiation
`activating group the reaction is preferably carried out below o°c and
`more preferably below -50°C.
`It is especially preferred that the
`reaction is carried out between -70 and -100°C.
`The aromatic compound containing a -CH,OH group may also
`carry further substitutents which do not react with the alkyl or aryl
`lithium compound.
`The organo-borate is preferably an alkyl borate which may be
`linear or branched, more preferably 4 C,.,-alkyl and especially a G.4-
`alkyl borate.
`sec-Butyl lithium and n-butyl borate are preferred.
`The reaction between the aromatic compound containing a
`-CH,OH group and alkyl or aryl lithium is preferably carried out in the
`presence of a chelating agent.
`The preferred chelating agent is
`tetramethyleneethylenediamine.
`Oxaboroles containing a fused aromatic ring can also be made
`by reacting an aromatic compound containing a -CH,OH group and an ortho
`jodo or bromo group with alkyl or aryl lithium and an organo-borate.
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`MYLAN- Ex. 1007, p. 11
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`MYLAN - Ex. 1007, p. 11
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`WO 95/33754
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`PCT/GB95/01206
`
`10
`
`According to a still further aspect of the invention there is
`provided a process for making an oxaborole containing a fused aromatic
`ring comprising reacting an aromatic compound containing a -CH,OH group
`and an ortho iodo or bromo group with alkyl or aryl lithium and an
`organo-borate in an inert organic liquid.
`Preferred reaction conditions are as defined for the aromatic
`compound containing a -CH,OH group.
`The boron esters of the oxaborole are typically made by
`reaction of an oxaborole of formula 1 where R is hydrogen with an
`appropriate amino-aliphatic carboxylic acid or preferably an
`alkanolamine in an inert solvent at 25-125°C when the boron ester is
`formed almost instantaneously. Preferably the inert solvent forms an
`azeotrope with water to facilitate removal of water formed when the
`alkanolamine is reacted with the oxaborole.
`It is especially preferred
`that the solvent is toluene. This is method C.
`The oxaborole or compositions containing the oxaborole can be
`used for the treatment of various media to inhibit the growth of micro-
`organisms and are especially effective in providing anti-fungal
`activity.
`
`As a further aspect of the present invention there is
`provided a method for inhibiting the growth of micro-organisms on, or
`in, a medium which comprises treating the medium with an oxaborole or a
`biocide composition containing an oxaborole.
`The oxaborole can be used in conditions in which micro-
`organisms grow and cause problems.
`Systems in which micro-organisms
`cause problems include liquid, particularly aqueous, systems such as
`cooling water liquors, paper mill liquors, metal working fluids,
`geological drilling lubricants, polymer emulsions and especially surface
`coating compositions such as paints, varnishes and lacquers and more
`especially solid materials such as wood, plastics materials and leather.
`The oxaboroles have been found particularly effective in
`inhibiting microbial degradation of plastics materials such as
`plasticised PVC and urethanes since they are not significantly adversely
`affected by the high temperatures commonly used in the fabrication of
`such articles.
`In this respect the benzoxazoles have been found
`especially effective, particularly those containing one or more halogen
`substituents in the fused phenyl ring of the benzoxaborole.
`The oxaborole can be included in such materials to provide an
`anti-microbial effect.
`The amount of the compound is typically in the
`range from 0.00001 to 2.0% preferably from 0.0001 to 1% and especially
`from 0.0002 to 0.5% by weight of the compound relative to the system to
`which it is added.
`In certain cases, microbial inhibition has been
`obtained with from 0.0005% to 0.01% by weight of the oxaborole. Thus,
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`MYLAN- Ex. 1007, p. 12
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`MYLAN - Ex. 1007, p. 12
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`WO 95/33754
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`PCT/GB95/01206
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`11
`
`in the case of plastics materials the oxaboroles have been found to
`inhibit microbial growth at an applied concentration of less than 0.05%,
`particularly less than 0.01% and especially less than 0.005% and more
`especially less than 0.001%.
`The oxaborole may be the only antimicrobial compound used to
`protect the medium or it may be used together with one or more different
`oxaboroles or with one or more other compounds having antimicrobial
`activity.
`A mixture of anti-microbial compounds hereinafter referred to
`as a "biocide mixture" often has a broader anti-microbial spectrum and
`hence is more generally effective than the components of the mixture.
`The other antimicrobial compound or compounds may possess anti-
`bacterial, anti-fungal, anti-algal or other antimicrobial activity.
`biocide mixture typically contains from 1 to 99% by weight, and
`preferably from 40 to 60% by weight, of an oxaborole relative to the
`total weight of an antimicrobially active compound,
`in the biocide
`mixture.
`
`The
`
`Examples of other antimicrobial compounds which may be used,
`together with the oxaborole are quaternary ammonium compounds such as
`N,N-diethyl -N-dodecyl-N-benzylammonium chloride;
`N, N-dimethyl-N-octadecyl-N- (dimethylbenzyl) ammonium chloride;
`N,N-dimethyl-N,N-didecylammonium chloride;
`N,N-dimethyl-N, N-didodecylammonium chloride;
`N,N,N-trimethyl-N-tetradecylammonium chloride;
`N-benzyl-N,N-dimethyl-N (C,.-C,g-alkyl) ammonium chloride;
`N- (dichlorobenzyl) -N,N-dimethyl-N-dodecylammonium chloride;
`N-hexadecylpyridinium chloride; N-hexadecylpyridinium bromide;
`N-hexadecyl-N,N,N-trimethylammonium bromide; N-dodecylpyridinium
`chloride; N-dodecylpyridinium bisulphate; N-benzyl-N-dodecyl-N, N-
`bis (beta-hydroxyethyl) ammonium chloride; N-dodecyl-N-benzyl-N, N-
`dimethylammonium chloride; N-benzyl-N,N-dimethyl-N- (Cy.-Cya-
`alkyl) ammonium chloride; N-dodecyl-N,N-dimethyl-N-ethylammonium
`ethylsulphate; N-dodecyl-N,N-dimethyl-N- (1-naphthylmethyl) ammonium
`chloride; N-hexadecyl-N,N-dimethyl-N-benzylammonium chloride; N-dodecyl-
`N,N-dimethyl-N-benzylammonium chloride and 1- (3-chloroallyl) -3,5,7-
`triaza-l-azonia-adamantane chloride; urea derivatives such as 1,3-
`bis (hydroxymethyl) -5,5-dimethylhydantoin; bis (hydroxymethyl) urea; 3-
`(3,4-dichlorophenyl) -1,1-dimethylurea; 3- (4-isopropylphenyl) -1,1-
`dimethylurea; tetrakis (hydroxy-methyl) acetylene diurea; 1-
`(hydroxymethyl) -5,5-dimethylhydantoin and imidazolidinylurea; amino
`compounds such as 1,3-bis(2-ethyl-hexyl) -5-methyl-5-amino-
`hexahydropyrimidine; hexamethylenetetramine; 1,3-bis(4-amino-
`phenoxy) propane; and 2- [ (hydroxymethyl) -amino]ethanol;
`imidazole
`derivatives such as 1[2-(2,4-dichloro-phenyl) -2- (2-propenyloxy) ethyl] -
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`MYLAN- Ex. 1007, p. 13
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`MYLAN - Ex. 1007, p. 13
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`WO 95/33754
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`PCT/GB95/01206
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`12
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`1H-imidazole; 2-(methoxycarbonyl-amino) -benzimidazol; 1-decyl-3-dodecyl-
`2-methylimidazolium bromide; dodecylbis (1-decyl-2-methyl -imidazolium) -
`dibromide; nitrile compounds such as 2-bromo-2-bromomethyl-
`glutaronitrile, 2-chloro-2-chloromethylglutaronitrile; 2,4,5,6-tetra-
`chloroisophthalodinitrile;
`thiocyanate derivatives such as
`methylene (bis) thiocyanate; tin compounds or complexes such as
`tributyltinoxide, chloride, naphthoate, benzoate or 2-hydroxybenzoate;
`isothiazolin-3-ones such as 4,5-trimethylene-4-isothiazolin-3-one, 2-
`methyl-4, 5-trimethylene-4-isothiazolin-3-one, 2-methylisothiazolin-3-
`one, 5-chloro-2-methyl-isothiazolin-3-one, benzisothiazolin-3-one; 2-
`methylbenzisothiazolin-3-one, 2-octylisothiazolin-3-one, 4,5-dichloro-2-
`octylisothiazolin-3-one; N- (2-ethylbutyl)benzisothiazolin-3-one); N-(n-
`hexyl) benzisothiazolin-3-one;
`thiazole derivatives such as 2-
`(thiocyanomethylthio) -benzthiazole and mercaptobenzthiazole; nitro
`compounds such as tris (hydroxymethyl)nitromethane; 5-bromo-5-nitro-1,3-
`dioxane and 2-bromo-2-nitropropane-1,3-diol;
`iodine compounds such as
`iodo propynyl butyl carbamate and tri-iodo allyl alcohol; aldehydes and
`derivatives such as glutaraldehyde (pentanedial), p-chlorophenyl-3-
`iodopropargyl hemiformal,
`formaldehyde and glyoxal; amides such as
`chloracetamide; N,N-bis (hydroxymethyl) chloracetamide; N-hydroxymethyl-
`chloracetamide and dithio-2,2-bis(benzmethyl amide); guanidine
`derivatives such as poly (hexamethylenebiguanide) and 1,6-hexamethylene-
`bis [5- (4-chlorophenyl) biguanide];
`imidazolium halides such as N,N'-
`didecyl-2-methylimidazolium bromide and 1,12-bis- (N-decyl-2-
`methylimidazolium) -dodecyl dibromide;
`thiones such as 3,5-
`dimethyltetrahydro-1,3,5-2H-thiodiazine-2-thione; triazine derivatives
`such as hexahydrotriazine and 1,3,5-tri- (hydroxyethyl) -1,3,5-
`hexahydrotriazine, 6-chloro-2,4-diethylamino-s-triazine and 4-
`cyclopropylamino-2-methylthio-6-t-butylamino-s-triazine; oxazolidine and
`derivatives thereof such as bis-oxazolidine; furan and derivatives
`thereof such as 2,5-dihydro-2,5-dialkoxy-2,5-dialkylfuran; carboxylic
`acids and the salts and esters thereof such as sorbic acid and 4-
`hydroxybenzoic acid and their salts and esters; phenol and derivatives
`thereof such as 5-chloro-2-(2,4-dichloro-phenoxy) phenol; thio-bis (4-
`chlorophenol) and 2-phenylphenol; sulphone derivatives such as
`diiodomethyl-paratclyl sulphone; 2,3,5,6-tetrachloro-4-
`(methylsulphonyl) pyridine and hexachlorodimethyl sulphone;
`such as dimethyldithiocarbamate and its metal complexes,
`ethylenebisdithiocarbamate and its metal complexes, and 2-
`mecaptopyridine-N-oxide and its metal complexes and imides such as
`trichloromethylmercaptophthalimide,
`fluorodichlor