`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`(21) International Application Number:
`
`Published
`With international search report.
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
` WO 95/33754
`(51) International Patent Classification 6 :
`(11) International Publication Number:
`C07F 5/02, A01N 55/00, C09D 5/14,
`
`14 December 1995 (14.12.95)
`(43) International Publication Date:
`
`
`C08K 5/55
`
`PCT/GB 95/0 1 206
`
`(81) Designated States: AM, AT, AU, BB, BG, BR, BY, CA, CH,
`CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IS, JP, KE,
`
`KG, KP, KR, KZ, LK, LR, LT, LU, LV, MD, MG, MN,
` (22) International Filing Date:
`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:
`
`941 15 87.0
`
`
`
`PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN,
`9 June 1994 (09.06.94)
`GB
`
`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 WlY 6LN
`
`(GB).
` (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, Crowthome, Berkshire
`
`RG11 6PT (GB). CLOUGH, John, Martin [GB/GB]; 7
`
`Gypsy Lane, Marlow, Buckinghamshire SL7 SJT (GB).
`
`
`
`Intellectual Property
`FAWKES, David, Melville;
`(74) Agents:
`Group, Zeneca Specialties, P.O. Box 42, Hexagon House,
`Blackley, Manchester M9 828 (GB) et a1.
`
`
`
`
`
`
` (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,l-benzoxaborole including O—esters thereof.
`
`MYLAN - EX. 1007, p. 1
`
`MYLAN - Ex. 1007, p. 1
`
`
`
`
`
`Codes used to identify States party to the PCT on the front pages of
`applications under the PCT.
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`pamphlets publishing international
`
`AT
`AU
`BB
`BE
`BF
`BG
`3.]
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`ES
`FI
`FR
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`Austria
`
`
`Australia
`
`Barbados
`
`Belgium
`Burkina Faso
`
`Bulgaria
`Benin
`
`
`Brazil
`Belarus
`
`Canada
`
`Central African Republic
`
`Congo
`
`Switzerland
`Cate d’lvoirc
`
`Cameroon
`
`China
`
`Czechoslovakia
`
`Czech Republic
`
`Germany
`
`Denmark
`
`Spain
`
`Finland
`France
`
`Gabon
`
`
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People’s Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NB
`NL
`NO
`NZ
`PL
`
`R0
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`
`UA
`US
`UZ
`VN
`
`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
`
`
`
`"ta
`
`MYLAN - EX. 1007,‘p. 2
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`MYLAN - Ex. 1007, p. 2
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`
`
`WO 95/33754
`
`PCT/GB9S/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-(l,3—dihydro-l—hydroxy—2,1—benzoxaborol—6—yl)—succinamic
`
`acid (CA 55 23423c); 4—(l,3—dihydro—l—hydroxy-2,l—benzoxaborol-G-ylazo)-
`
`l,3—dihydro—l—hydroxy-G—nitro—Z,l—
`2—naphthoic acid (CA 55 23423c);
`benzoxaborole (CA 55 23423b); 6—amino—l,3—dihydro—l-hydroxy—2,l—
`
`benzoxaborole and its hydrochloride (CA 55 23423c); 1,3—dihydro—l—
`
`hydroxy—7-methyl—2,l—benzoxaborole (CA 55 6473f);
`
`l—(benzyloxy)-l,3—
`
`dihydro—Z,l-benzoxaborole (CA 51 16084f);
`
`l,3—dihydro—l-hydroxy—N,N—
`
`dimethyl—Z,l—benzoxaborol—S—amine (CA l91(3) 22633f); 4—bromo-l,3-
`
`dihydro—l—hydroxy—Z,l—benzoxaborole (CA 1Q3(3) 22633f);
`
`l,l'—oxybis[4—
`
`romo-l,3—dihydro-2,l—benzoxaborole (CA ;Q3(3) 22633f);
`
`l—
`
`(cyclohexyloxy)—l,3—dihydro-2,l—benzoxaborole (CA El 16084f);
`
`l—ethoxy—
`
`1,3—dihydro—2,l—benzoxaborole (CA 5; l6084f); 3,7—dihydro—l,5—dihydroxy—
`lH,3H—benzo[l,2—c: 4,5-c']bis[l,2]oxaborole (CA 5; 14698a); 1,3—dihydro—
`
`l—hydroxy—G—methyl—Z,l—benzoxaborole (CA 5; 14698b); 5-bromo—1,3—
`
`dihydro—l—hydroxy—Z,l—benzoxaborole-S~methanol
`
`(CA 5; l4698b);
`
`l,l'—
`
`oxybis[1,3—dihydro-2,l—benzoxaborole](CA 191(3) 22633f); and
`
`boronophthalide (CA 115(13)
`
`l29587q).
`
`French certificate of utility No
`
`73 29370 discloses boronophthalide (l—hydroxy—BH-l,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 lOOppm
`
`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
`baCCeria, 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.
`
`10
`
`15
`
`20
`
`25
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`30
`
`35
`
`40
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`MYLAN - EX. 1007, p. 3
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`MYLAN - Ex. 1007, p. 3
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`
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`WO 95/33754
`
`PCT/GB95/01206
`
`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)
`
`'
`
`or a salt thereof
`wherein
`
`I“
`‘"
`A and D are each independently, hydrogen, optionally
`substituted Chm-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 —CRH¥ wherein R1 and R2 are each,
`hydrogen, optionally substituted CPS—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 Gym—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 Chm-, more preferably CLB- and especially Chg-alkyl.
`When A and/or D is substituted alkyl,
`the substituent may be
`CPS-alkoxy, hydroxy, halogen, nitrile, amino, substituted amino, carboxy,
`acyl, aryloxy or carbonylamino optionally substituted by CLE—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
`Cl.5-al}cyl, C1_6-alkoxy, aryloxy, hydroxy, halogen, nitro, carbonamido,
`sulphonamido,
`trifluoromethyl or amino optionally substituted by one or
`more Che—alkyl groups.
`Aryloxy is preferably phenoxy.
`
`MYLAN - EX. 1007, p. 4
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`40
`
`MYLAN - Ex. 1007, p. 4
`
`
`
`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[l,2—c: 4,5—c']bis[l,2]oxaborole.
`When Rland/or RF is aryl it is preferably phenyl.
`When R} and/or R? is aralkyl it is preferably benzyl.
`Preferably, at least one of PE and.P? is hydrogen and it is
`especially preferred that both are hydrogen.
`When R is alkyl it may be linear or branched and is
`
`preferably CLH— and especially Chg—alkyl,
`When R is substituted alkyl,
`the substitutent may be
`CPS—aLaoxy, Cbfi—alkylthio, hydroxy, amino, substituted amino, carboxy,
`aryl, aryloxy, carbonamido optionally substituted by Chg—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 quinolinyl and
`
`particularly quinolin-B-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 cf 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
`
`10
`
`15
`
`25
`
`3O
`
`35
`
`40
`
`MYLAN - EX. 1007, p. 5
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`MYLAN - Ex. 1007, p. 5
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`
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`WO 95/33754
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`PCT/GB95/01206
`
`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
`
`Such compounds are esters containing a
`the group R is attached.
`tetrahedral boron atom as for example in formula (3) below
`
`A
`
`x
`
`,
`/
`B—N R3R4
`
`I_
`
`D‘.
`o
`k,
`
`wherein
`
`A,D and X are as defined hereinbefore;
`
`R? and R5 are each independently, hydrogen, optionally
`
`substituted Gide-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.
`
`R3 and.FF are preferably optionally substituted Chm-alkyl,
`
`more preferably optionally substituted Che—alkyl and especially
`substituted CPS-alkyl.
`
`It is preferred that when P? and/or R“ is alkyl the alkyl
`
`group is unsubstituted.
`
`branched.
`
`The alkylene group represented by Y may be linear or
`
`When Y is substituted alkylene the substituent is preferably
`
`phenyl, Chg—alkoxy, CLG-alkylthio or carbonyl alkylene as for example a
`—COCH2— 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 R3 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 R3 together with part of Y forms a 5—membered ring the
`
`ring is preferably pyrrolidin—Z—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.
`
`MYLAN - EX. 1007, p. 6
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`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`40
`
`MYLAN - Ex. 1007, p. 6
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`
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`WO 95/33754
`
`PCT/GB95/01206
`
`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—c: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
`
`10
`
`15
`
`2O
`
`25
`
`3O
`
`35
`
`40
`
`A
`
`D
`
`x\
`
`a
`
`(4)
`
`I ,0B—-+NHR3
`0
`i
`\
`<$HjCH—R°
`
`.
`
`6
`
`R
`
`n
`
`wherein
`
`A, D and X are as defined hereinbefore;
`n is l, 2 or 3;
`E? is hydrogen, optionally substituted Chm-alkyl or
`
`optionally substituted phenyl;
`FF and F? are each independently, hydrogen, optionally
`substituted alkyl containing up to a total of 16 carbon atoms or
`optionally substituted phenyl.
`independently, optionally
`Preferably RF and RF are each,
`substituted Chs— and especially optionally substituted qu—alkyl.
`Preferably two of PP, PP and F? are hydrogen.
`It is
`especially preferred that F? and FF are both hydrogen.
`Preferably n is l 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,l—benzoxaboroles 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 —OT? where F? is an alkali
`metal such as lithium, potassium or sodium or Rf is an amine salt or
`quaternary ammonium cation.
`In the latter case the quaternary ammonium
`ion may itself be microbiologically active.
`
`MYLA_N - EX. 1007, p. 7
`
`MYLAN - Ex. 1007, p. 7
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`
`
`WO 95/33754
`
`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—, S—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
`
`fonnulated 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.
`
`If the medium to be protected is a plastics material,
`
`the
`
`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
`
`the carrier is preferably water or a
`protected is an aqueous medium,
`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 Cb4—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
`
`10
`
`15
`
`2O
`
`25
`
`30
`
`35
`
`40
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`MYLAN - EX. 1007, p. 8
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`MYLAN - Ex. 1007, p. 8
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`WO 95/33754
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`PCT/GB95/01206
`
`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)
`
`\I
`
`’
`
`'IP
`A
`or a salt thereof
`wherein A, D , X and R are all as hereinbefore defined except
`for N-(l,3—dihydro—l—hydroxy—2,l—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-l-hydroxy—Z,l—benzoxaborole; boronophthalide;
`l—benzyloxy—,
`l-cyclohexyloxy-,
`l—ethoxy—l,3—dihydro—2,l—benzoxaborole;
`1,1'-oxybis[1,3—dihydro—2,l—benzoxaborole];
`l,l'-oxybis[4—bromo—l,3—
`dihydro—Z,l—benzoxaborole] and 3,7-dihydro—l,5-dihydroxy—1H,3H—
`benzo[1,2—c: 4,5—c']bis[l,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 —C}g-.
`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 benzoxaborole.
`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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`MYLAN - EX. 1007, p. 9
`
`MYLAN - Ex. 1007, p. 9
`
`
`
`WO 95/33754
`
`PCT/GB95/01206
`
`According to a further aspect of the invention there is
`
`provided a compound of formula 3
`
`A
`
`D
`
`x
`
`I \o
`
`'Bl—N+R3R4
`c
`
`C
`k/
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`40
`
`wherein
`
`A,D and X are as defined hereinbefore;
`
`R? and R3 are each,
`
`independently, hydrogen, optionally
`
`substituted CIJB—alkyl or optionally substituted phenyl or R9 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—l-hydroxy-2,l—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 fig 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—l—hydroxy—2—(4-
`methylphenyl—sulphonyl)—2,3,l—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 —C}QOH group with alkyl or
`aryl lithium and an organoborate in a dry inert organic liquid.
`
`MY’LAN - Ex. 1007, p. 10
`
`MYLAN - Ex. 1007, p. 10
`
`
`
`WO 95/33754
`
`PCT/G395/01206
`
`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 —C$gOH
`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 a —C}§OH group is an optionally
`substituted benzyl alcohol.
`Preferably the aromatic compound containing a —C}gOH 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 —C}gOH group. Examples of activating
`groups are Che—alkoxy, halogen such as chlorine and fluorine, substituted
`alkyl such as -C}hOCH3, —CHJ¢T2,
`-C}gCEgNT2, substituted amino such as —NT2,
`—NHCOT, —NHCO§T and amides such as —SOJ®TT, —SO§YT2, —CONHT and —CONT2
`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 Che—alkyl.
`An alkyl lithium compound is preferred which may be linear or
`branched and is preferably Che—alkyl and especially Cb4—alkyl such as
`
`butyl lithium.
`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 —C}gOH group also contains an ortho—lithiation
`activating group the reaction is preferably carried out below 0°C and
`more preferably below -50°C.
`It is especially preferred that the
`reaction is carried out between —70 and -lOO°C.
`The aromatic compound containing a -ClgOH 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 a Clg—alkyl and especially a Cb4—
`
`alkyl borate.
`sec-Butyl lithium and n-butyl borate are preferred.
`The reaction between the aromatic compound containing a
`4JQOH 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§3H group and an ortho
`iodo or bromo group with alkyl or aryl lithium and an organo—borate.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`_
`
`30
`
`35
`
`40
`
`MYLAN - Ex. 1007, p. 11
`
`MYLAN - Ex. 1007, p. 11
`
`
`
`WO 95/33754
`
`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 —CI§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 -C}§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,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`MYLAN - Ex. 1007, p. 12
`
`MYLAN - Ex. 1007, p. 12
`
`
`
`WO 95/33754
`
`PCT/GB95/01206
`
`ll
`
`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
`
`A mixture of anti—microbial compounds hereinafter referred to
`activity.
`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(Cm—Cm—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-(Cu—Cw—
`alkyl)ammonium chloride; N—dodecyl—N,N-dimethyl—N-ethylammonium
`ethylsulphate; N-dodecyl-N,N—dimethyl—N-(l-naphthylmethyl)ammonium
`chloride; N—hexadecyl-N,N—dimethyl-N—benzylammonium chloride; N—dodecyl—
`N,N-dimethyl-N—benzylammonium chloride and l-(3—chloroallyl)—3,5,7—
`triaza—l-azonia—adamantane chloride; urea derivatives such as 1,3—
`
`bis(hydroxymethyl)—5,5—dimethylhydantoin; bis(hydroxymethyl)urea;
`(3,4—dichlorophenyl)—l,l—dimethylurea; 3—(4—isopropylphenyl)—1,1—
`dimethylurea; tetrakis (hydroxy-methyl)acetylene diurea; l-
`(hydroxymethyl)-5,5—dimethylhydantoin and imidazolidinylurea; amino
`compounds such as l,3—bis(2—ethyl—hexyl)-5—methyl—S-amino—
`hexahydropyrimidine; hexamethylenetetramine;
`l,3—bis(4—amino—
`phenoxy)propane; and 2—[(hydroxymethyl)—amino]ethanol;
`imidazole
`derivatives such as l[2—(2,4—dichloro—phenyl)—2—(2-propenyloxy)ethyl]—
`
`3—
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
`
`40
`
`u
`
`MYLAN - Ex. 1007, p. 13
`
`MYLAN - Ex. 1007, p. 13
`
`
`
`WO 95/33754
`
`PCT/GB95/01206
`
`12
`
`lH—imidazole; 2—(methoxycarbonyl-amino)—benzimidazol;
`
`l—decyl—B—dodecyl-
`
`2-methylimidazolium bromide; dodecylbis(l—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,S—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—B-one;
`
`2—
`
`methylbenzisothiazolin—3—one, 2—octylisothiazolin—3—one, 4,5—dichloro—2—
`
`octylisothiazolin—B—one; N—(2~ethylbutyl)benzisothiazolin-B—one); N—(n—
`
`hexyl)benzisothiazolin—B-one;
`
`thiazole derivatives such as 2-
`
`(thiocyanomethylthio)—benzthiazole and mercaptobenzthiazole; nitro
`
`compounds such as tris(hydroxymethyl)nitromethane; 5—bromo—5—nitro—l,3—
`
`dioxane and 2—bromo—2—nitropropane—l,3—diol;
`
`iodine compounds such as
`
`iodo propynyl butyl carbamate and tri—iodo allyl alcohol; aldehydes and
`
`derivatives such as glutaraldehyde (pentanedial), p—chlorophenyl—B-
`
`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-l,3,5—2H-thiodiazine—2-thione; triazine derivatives
`
`such as hexahydrotriazine and 1,3,5—tri-(hydroxyethyl)—l,3,5—
`
`hexahydrotriazine, 6—chloro—2,4—diethylamino—s—triazine and 4—
`
`cyclopropylamino—Z—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,S—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—paratolyl sulphone; 2,3,5,6—tetrachloro—4—
`(methylsulphonyl)pyridine