ANTICIPATED CLASSIFICATION OF
`THIS APPLICATION:
`
`CLASS
`
`SUBCLASS
`
`PRIOR APPLICATION:
`
`JAB 600
`
`EXAMINER: R. Travers
`
`ART UNIT: 125
`
`The Hon. Commissioner of Patents and Trademarks
`‘Washington, D. C. 20231
`
`Dear Sir:
`
`This is a request for filing a
`
`[X] Continuation
`
`f ] Divisional
`application, under 37 CFR 1.60, of pending prior application Serial No.
`325,181, filed on March 16, 1989, of Raymond Mathieu Xhonneux et al.
`‘
`H
`(Date)
`(Inventor)
`METHOD OF LOWERING THE BLOOD PRESSURE
`(Title of Invention)
`
`for-
`
`1.
`
`Enclosed is a copy of the prior application,
`the oath or Declaration as originally filed.
`
`including
`
`I hereby verify that the attached papers are a true copy
`of prior application serial No. 325,181, as originally
`filed on March 16. 1989,
`and further that this statement was made with the
`knowledge that willful false statements and the like so
`made are punishable by fine or imprisonment,
`or both, under Section 1001 of Title 18 of the United
`"states Code, and that such willful false statements may
`jeopardize the validity of the application or any patent
`issuing thereon.
`
`2.
`
`[X]
`
`The filing fee is calculated below:
`
`Claims as filed in the prior application,
`»
`any claims added or canceled by amendment below
`For--
`No.
`No.
`Filed
`Extra
`
`Rate
`
`including
`
`Fee
`
`Total Claims .............8 - 20
`Independent Claims .......2 -
`3
`Basic fee (minimum
`amount required) ....................................
`
`...0..L.. X $20
`...0..... x $12
`
`..$000.00.
`..$000,00.
`
`§690.00
`
`Total Filing Fee .....................;...............
`
`§69o.00
`
`3.
`
`[X]
`
`The Commissioner is hereby authorized to charge any fees which
`may he required, or credit any overpayment,
`to Account No.
`10-750/JAB 775/CJM. Three copies of this sheet are enclosed.
`
`'1
`
`Petitioner
`Exhibit 1002 - 001
`
`

`
`A check in the amount of $
`
`is enc1osed,
`
`Cancel in this application original Claims 2-17 of the prior
`application before calculating the filing fee. "(At least one
`original independent claim must be retained for filing
`purposes.)
`
`insertin before the first line the
`Amend the specific
`sentence‘
`-— This is a [X] con nuation,
`[
`) division, of application
`1989. --
`
`Transfer the drawings from the prior application to this
`application and abandon said prior application as of the filing
`date accorded this application.
`A duplicate copy of this sheet
`is enclosed for filing in the prior application file.
`
`New formal drawings'are enclosed.
`
`, filed on
`Priority of application Serial No.
`in
`(Country)
`is claimed under 35 U.S.C. 119.
`
`The certified copy of the priority application has been filed in
`prior application serial No.
`, filed
`.
`
`'The prior application is assigned to JANSSEN PHARMACEUTICA Ny.
`
`The power of attorney in the prior application is to Robert L.
`Minier (Reg. #20,083), Audley AL Ciamporcero, Jr.
`(Reg.
`#26,051), Steven P. Berman (Reg. #24,772), Wayne R. Eberhardt
`(Reg. #2Z,804), Jason Lipow (Reg. #25,509), Donal B. Tobin (Reg.-
`#25,711), and David J. Levy (Reg. #27,655), Johnson & Johnson,
`one Johnson & Johnson Plaza, New Brunswick, New Jersey
`08933-7003.
`
`The power appears in the original papers in the prior
`application.
`
`Since the power does not appear in the original papers, a copy
`of the power in the prior application is enclosed.
`
`[X] Address all future communications to Robert L. Minier (Reg.
`#20,083), Johnson 8 Johnson, One Johnson & Johnson Plaza, New
`Brunswick, NJ 08933-7003.
`
`10.
`
`[X ] A Preliminary Amendment is enclosed.
`
`January 24, 1992
`(Date)
`
`.
`
`~
`Charles J Metz
`Reg. No. 20, 359
`
`Address of Signer:
`Johnson & Johnson
`one Johnson & Johnson Plaza
`New Brunswick, NJ 08933
`
`Inventor(s)
`Assignee of complete interest
`Attorney or agent of record
`Filed under Section 1.34(a)
`
`908-524-2814
`
`Petitioner
`Exhibit 1002 - 002
`
`

`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`DOCKET NO. JAB-775
`
`Applicant
`
`Raymond Mathieu Xhonneux et al.
`
`For
`
`METHOD OF LOWERING THE BLOOD PRESSURE
`
`Express Mail Certificate
`
`"Express Mail" mailing number RB759706376
`
`Date of Deposit
`
`January 24, 1992
`
`I hereby certify that
`
`this request
`
`for filing a _Continuation
`
`application under 37 CFR 1.60 of prior application Serial No.
`
`325,181 (JAB-600), copy of prior application, Declaration (2) and
`
`Preliminary Amendment and Information Disclosure Statement and
`
`reference are being deposited with the United States Postal Service
`
`"Express Mail Post Office to Addressee" service under 37 CFR 1.10
`
`on the date indicated above and is addressed to the Commissioner of
`
`Patent and Trademarks, Washington, D.C. 20231.
`
`Charles J. Metz
`
`(Typed or printed name of person mailing paper or fee)
`
`(Signature of person ma
`
`Petitioner
`Exhibit 1002 - 003
`
`

`
`'45? METHOD OF LOWERING TH
`
`E BLOOD PRESSURE
`
` .¢___
`
`I ven ion
`No. 4.654.362 there are described 2,2'—iminobisethanol
`In U.S. Pat.
`It now has been
`es having B adrenergic blocking properties.
`s of said bisethanol derivatives
`a certain class of isomer
`found that
`ure reducing agents.
`potentiate the activity of blood press
`
`derivativ
`
`Description gf the Invengigg
`rned with a group of compounds capable
`said
`The present invention is conce
`e effects of blood pressure reducing agents,
`of potentiating th
`compounds being represented by the formula
`
`20
`
`25
`
`Petitioner
`Exhibit 1002 - 004
`
`

`
`or the pharmaceutically acceptable acid addition salts thereof, wherein
`1
`2 each independently are hydrogen or C1_6
`R
`and R
`6
`R3, R4, R5, R , R7, R8, R9 and R10 each independently are hydrogen,
`halo, C1_6alkyl, C1_6alkyloxy, hydroxy, cyano, carboxy or
`8
`C1_6a1kyloxycarbonyl;
`or two vicinal radicals of R3, R4. R5, R6, R7, R , R9 and R
`—CH=CH—CE=CH— or -(CH2)4- radical.
`
`alkyl:
`
`10
`
`taken
`
`"together may form a
`
`10
`
`15
`
`definitions the term halo is generic to
`As used in the foregoing
`bromo and iodo;
`the term "C1_6alky1" defines straight
`fluoro, chloro,
`n radicals having from 1 to 6
`and branch chained saturated hydrocarbo
`uch as, for example, methyl,
`carbon atoms s
`2—methylpropyl, butyl, p
`
`ethyl,
`
`l—methylethyl.
`entyl, hexyl and the
`
`l,l—dimethylethyl, propyl,
`like.
`
`The descriptors R and S a
`the absolute configuration at the r
`1 has the R configuration,
`atom bearing R
`bearing the hydroxy functions and the carbo
`S configuration.
`
`s used in the above formula (I) indicate
`espective carbon atoms. The carbon
`whereas the carbon atoms
`n atoms bearing R2 have the
`
`Preferred compounds of formula (I) are those wherein R3, R4,
`I
`R6 R7, R8.‘RE'and R10 are hydrogen.
`Particularly preferred are those preferred compounds wherein R
`particularly fluoro.
`and R9 are hydrogen or halo,
`u'S]-a.a'—[imino-
`eferred compound is [2R.uS,2‘S,
`The most pr
`1-benzopyran-2-methanol] or a
`fluoro—3.4-dihydro—2§—
`able acid addition salt thereof.
`
`bismethy1ene]bis[6—
`
`pharmaceutically accept
`
`5
`
`The compounds of formula (1)
`es described in U.S. Pat. No.
`obtaining th
`e compounds of formula (I) wil
`
`can be prepared following the
`4,654,362. Some particular ways of
`1 be described hereinafter in
`
`procedur
`
`some more detail.
`
`(I) can be prepared by reacti
`The compounds of formula
`—a) or (II-b) with an amine of formula (III—a) or
`
`of formula (II
`
`ng an oxirane
`(III—b).
`
`30
`
`35‘
`
`Petitioner
`Exhibit 1002 - 005
`
`

`
`(III-a)
`
`on R1
`|
`P—NH—CH2—CI-I
`S
`
`+
`
`'
`
`R3
`
`5
`
`R4
`5
`R
`
`>
`
`(1)
`
`‘
`
`;"”—’_&
`
`15
`
`20
`
`30
`
`(II-b)
`
`(III-b)
`n or an appropriate
`
`or in particular P may be
`ith (II—a) and
`ons to prepare
`
`inert solvent
`
`.
`o
`In (III-a) and (III-b), P 15 either hydroge
`for example an allyl group,
`protecting group,
`—NH2 may be reacted w
`a benzyl group. Or, a reagent P
`dure.
`The above described reacti
`(II—b)
`in a one-pot proce
`e conducted in a reaction-
`a compound of formula (I) may b
`benzene or
`an aromatic hydrocarbon, e.g.
`a ketone,
`such as, for example,
`methanol, ethanol, propanol;
`1,4-dioxane,
`ether, e.g.
`
`methylbenzene; an alkanol, e.g.
`4-methyl—2—pentanone: an
`
`e.g. 2—propanone,
`
`aprotic solvent, e.g.
`l,l'—oxybisethane; a dipolar
`N.E—dimethylacetamide and the like solvents. In
`E,§—dimethylformamide or _
`certain instances,
`in or
`
`tetrahydrofuran,
`
`ion mixture.
`
`For
`
`derivat
`
`example, where P i
`
`ch
`
`ives of formula (I) are obtained wherefrom the compounds of
`formula (I) th
`a deprotection reaction.
`emselves can be obtained by
`propriate noble metal
`s allyl,
`by reaction with an ap
`nzyl,
`r Rh[P(C6H5)3]Cl, or where P is be
`compound such as PdCl2 o
`platinum on
`by a catalytic hydrogenation procedure,
`e.g. palladium or
`l,4—dioxane,
`arcoal in a suitable solvent such as an ether, e.g.
`methanol, ethanol, an alkoxyalkanol.
`tetrahydrofuran, an alkanol. e.g.
`e.g. methoxyethanol and the like.
`The intermediates of formula (III-a) or (III-b) are obtained by the
`
`Petitioner
`Exhibit 1002 - 006
`
`

`
`-4-
`
`reaction of the amine P-NR2 with (II-b) or (II-a) or, by reacting a
`reagent PZNH, for example dibenzylamine, with (II-b) or (II-a) and
`subsequently selectively removing one of the P-groups, e.g. when P is
`
`benzyl by a catalytic hydrogenation procedure using one equivalent
`
`‘hydrogen. The afore described reactions to prepare (III—a) or (III-b)
`are conducted following the same procedures as described hereinabove for
`
`the preparation of the compounds (I).
`
`The starting materials (II-a) are obtained by an oxiraneformation
`
`reaction from an aldehyde of formula (IV-a» e.g. by reaction of the
`
`latter with a trimethylsulfoxonium halide, or from an ethylene of
`formula (V-a) by reaction of the latter with a peroxide, e.g. a
`
`haloperbenzoic acid. In the same way,
`
`the intermediate (II—b) is
`
`obtained from the corresponding S-isomers (IV-b) or (V-b). The oxiranes
`
`‘of formula (IV-a-1) obtained in the aforementioned oxirane—formation
`
`reaction are separated in their stereoisomers, e.g. by HPLC or selective
`
`crystallization.
`
`separation
`
`peroxide
`
`/‘
`
`(V-a)
`
`The compounds of formula (IV—a),
`
`(IV-b),
`
`(V-a) or (V-b) are obtained by
`
`35
`
`a suitable separation procedure. i.e. by HPLC. or by a reduction
`
`Petitioner
`Exhibit 1002 - 007
`
`

`
`reaction of the c
`
`(IV-a) or (IV—b) ca
`reaction.
`obtained by conventiona
`ation with an opticall
`form
`crystallization procedure or
`
`n be converted to (V-a
`
`) or (V
`active acids in turn c
`by salt or amide
`i.e.
`1 separation techniques,
`y active reagent and a selective
`a HPLC separation.
`
`an be
`
`ave basic properties and, consequently,
`n-toxic acid
`eutically active no
`
`10
`
`unds of formula (I) h
`The compo
`they may be converted to their therap
`addition salt forms by treatment with ap
`such as hydrohalic acid,
`inorganic acids.
`nitric acid,
`drobromic and the like. and sulfuric acid,
`for example, acetic,
`ethane-
`acid and the like;
`such as,
`or organic acids,
`2—hydroxypropanoic,
`hydroxyacetic,
`(z)—2-butenedioic,
`butanedioic.
`2-hydroxy—1,2,3—propane—
`2,3—dihydroxybutanedioic,
`benzenesulfonic,
`ethanesulfonic.
`2—hydroxybenzoic.
`
`phosphoric
`
`2—oxop opanoic,
`(E)-2-butenedioic.
`
`propanoic,
`l5 dioic, propanedioic,
`2—hydroxybutanedioic,
`thanesulfonic,
`' tricarboxylic, me
`cyclohexanesulfamic,
`onic,
`ic and the like acids.
`
`4—methylbenzenesulf
`
`4—amino-2—hydroxybenzo
`Conversely,
`
`into the free base form.
`
`) with the exception of
`The compounds of formula (I
`-benzopyran-
`—dihydro-2§—1
`(RSSS)—c.a'-[iminobis(methylene)bis(3.4
`unds and
`2—methano1]
`ethanedioate(1:1) are deem
`itional feature to the
`constitute in an add
`
`ed to be novel compo
`present invention.
`
`duction of the
`
`reducing agents. In particula
`blood pressure and of the heart r
`ressure reducing agents of which the activity is
`As blood p
`
`ate .
`
`'c and/or
`
`25
`
`30
`
`potentiated ther
`In particular suc
`vasodilating activity.
`3,663,607 and 3,
`Pat. Nos.
`
`35 mentioned in U.S.
`
`h agents may be the com
`in particular
`836,671,
`
`pounds
`
`Petitioner
`Exhibit 1002 - 008
`
`

`
`. ‘
`
`.
`
`atenolol: U.S.
`
`Pat. Nos.
`Pat.
`
`-5-
`
`3.337.628 and
`
`3,873,600,
`
`in particular
`3.520.919,
`particular metoprolol; U.S.
`in
`2,484,029.
`
`in
`
`methylene]bis[6—fluoro
`of active ingredient
`tive examples but no
`
`groups
`
`representa
`
`10
`
`15
`
`20
`
`propranolol: U.S.
`Pat. No. 3,511,336,
`in
`ticular hydralazine;Pat. No. 2,503,059,
`in particular phentolamine; U.S.
`par
`ular verapamil; U.S.
`No. 3,485,847 in
`guanethidine; U.S.
`3,261,859,
`in partic
`rticular carteolol;
`Pat. No.
`Pat.
`No. 3,910,924,
`in pa
`celiprolol. A
`nifedipine; U.S.
`458.625,
`in particular
`particular
`German Pat. Nos. 2,458,624 and 2.
`educing compounds are the compounds
`ula (I) and
`p of blood pressure r
`the compounds of form
`particular grou
`i.e. the
`4,654,362 other than
`ounds of formula (I),
`of U.S. Pat. No.
`antiomers of the comp
`a‘—[iminobis-
`2‘R;u'R]—u,
`in particular the en
`ular compound is [2S,uR.
`A partic
`SRRR—isomers.
`-benzopyran—
`—3,4—dihydro—2§—l
`purpose of providing
`s are listed with the
`restricting the
`t with the purpose of
`and the said
`present invention.
`The said SRRR isomers
`scope of the
`d following the same pr
`ound can be prepare
`on of the compounds of formula
`particular"comp
`bed for the preparati
`II—a),
`previously descri
`rom the enantiomers of the intermediates (
`nantiomers in turn can be
`(I). but starting f
`The latter e
`(II—b) and (III-b).
`paration of (II—a),
`(III-a).
`ereinabove
`m the enantiomers of (IV-a)
`obtained as described h
`—b). but starting fro
`(II-b) and (III
`propriate stereoisomers in stereochemical
`(III-3) I
`or (V—a) and isolating'the ap
`nantiomers of (IV-a) and (V-a)
`in the same
`on procedures.
`separati
`The e
`obtained as described for the preparation
`way can be
`tiomeric starting mat
`m the appropriate enan
`starting fro
`rs in stereochemical
`propriate stereoisome
`e acid addition salt
`of formula (I) and th
`the administration of
`re,
`during or after
`be administered befo
`ime of the administra
`provided that the t
`ressure reducing agent
`the administration of
`(I) in relation to
`nd of formula (I) to be
`he compounds of formula
`ent allows the«compou
`pressure reducing
`pressure reducing ag
`blood
`e effects of the blood
`effective in potentiating th
`erably the compound
`the blood pressure
`t are administered in
`
`Pat.
`
`2—methanol. These
`
`ocedures as
`
`for the pre
`
`of (IV-a) and (V—a)
`erials and/or
`A
`
`separations.
`s thereof may
`
`the blood
`
`tion of
`the
`
`ining a
`
`or simultaneous,
`Such products may
`
`7
`
`isolating the ap
`The compounds
`
`P t
`
`agent. Pref
`reducing agen
`
`Petitioner
`Exhibit 1002 - 009
`
`

`
`.
`
`‘ ‘
`
`-7-
`a kit comprising a container with a suitable
`d another container
`compound of formula (I) an
`h a blood pressure reducin
`that the physician wishing t
`select. based on the diagnosis of
`ate amounts of both components
`
`Such
`g agent.
`o administer
`
`for example comprise
`composition containing a
`containing a composition wit
`product may have the advantage
`sure reducing therapy can
`blood pres
`o be treated.
`the appropri
`of administration.
`and the sequence
`n of the blood pressure
`d during the administratio
`When administere
`sition containing both the blood pressure reducing
`a compo
`dient of formula (I) may particularly be
`
`the patient t
`
`reducing agent,
`ent and the active ingre
`
`ag
`
`ovided a
`
`GCCS Of
`
`hereinabove and
`
`convenient.
`a further aspect of the present invention there is pr
`In
`able of potentiating the eff
`composition comprising an amount cap
`ound of formula (I) as defined
`e reducing agents of a comp
`blood pressur
`In the said composition,
`gent.
`a blood pressure reducing a
`(I) and the blood
`en the compound of formula
`the molar ratio betwe
`but in particular may be
`pressure reducing agent may be other than 1:1.
`ive ingredient of formula (I) in such
`1:1.
`The amount of the act
`e~effects of the
`potentiating effect on th
`composition will be so that a
`the amount of the blood
`obtained;
`a blood
`
`In particular.
`
`1:50,
`
`10
`
`15
`
`25
`
`at when potentiated,
`pressure re
`n administration.
`pressure reducing effect is obtained upo
`the compound of formula (I)
`it is contemplated that the molar ratio of
`situated between 50:1 and
`reducing compound may be
`to the blood pressure
`or betwe
`en 20:1 and 1:20.
`en 10:1 and 1:10. or
`1:2.
`in particular betwe
`ticularly between 2:1 and
`more par
`hose wherein the blood pre
`ertaining to the patents c
`ents specifically mentioned
`
`between 5:1 and 1:5.
`ar such compositions are t
`Particul
`nt is one of the agents p
`and more particularly the ag
`
`reducing age
`
`hereinabove,
`
`30
`
`hereinabove.
`
`ion also provides a composition comprising a
`ingredient an amount
`e carrier and as active
`educing agents of
`ffects of blood pressure r
`pharmaceutically acce
`
`ptable
`
`The present invent
`pharmaceutically acceptabl
`able of potentiating the e
`cap
`ompound of formula (I) or a
`a novel c
`as defined hereinabove.
`n salt thereof.
`an effective amount of
`itions.
`uch pharmaceutical compos
`in has
`und or compounds.
`redient or active ingredie
`harmaceutically acceptab
`
`35
`
`acid-additio
`
`To prepare s
`
`the particular compo
`form. as the active ing
`intimate admixture with a p
`
`<e
`
`e or acid-addition salt
`nts is combined in
`le carrier,
`
`Petitioner
`Exhibit 1002 - 010
`
`

`
`carrier may
`
`-3-
`
`g on the form of
`eutical compositions
`
`y of forms dependin
`sired for administration. These pharmac
`preferably, for
`suitable.
`For example.
`unitary dosage form
`rectally or by par
`
`enteral injection.
`form.
`any of the usual
`
`ions in oral dosage
`
`for example. Vater,
`ral liquid
`
`kaolin.
`
`lutions: or
`binders,
`lubricants,
`pills,
`tablets
`
`preparation de
`are desirably in
`administration orally,
`paring the composit
`in pre
`ployed. such as,
`ical media may be em
`ke in the case of o
`alcohols and the li
`as suspensions, syrups,
`elixirs and so
`s starches, sugars.
`e of powders.
`d the'like in the cas
`dministration.
`e of their ease in a
`sage unit form,
`advantageous oral do
`employed. For
`iers are obviously
`sterile
`ll usually comprise
`for example,
`r ingredients.
`for example. may
`
`pharmaceut
`glycols, oils.
`preparations such
`solid carriers such a
`disintegrating agents an
`and tablets. Becaus
`represent the most
`pharmaceutical carr
`the carrier vi
`though othe
`
`in
`
`to
`
`Injectable solutions.
`'
`solution, glucose
`
`In the
`
`e may be employed.
`nistration,
`the carrier
`ent and/or a suitable
`dditives of any nature
`
`gnificant
`
`capsules
`
`and capsules
`
`be prepare
`
`solution or a
`
`20
`
`optionall
`wetting agent.
`
`in minor propor
`
`which case solid
`parenteral compositions.
`at least in large part.
`15 water,
`aid solubility,
`d in which the carri
`mixture of saline and
`so be prepared in
`suspensions may al
`gents and the lik
`suspending a
`carriers.
`percutaneous admi
`compositions suitable for
`tration enhancing ag
`y comprises a pene
`ned with suitable a
`optionally combi
`ves do not cause a si
`which additi
`tions.
`t to the skin.
`ate the
`additives may facilit
`Said
`helpful for preparin
`skin and/or may be
`
`deletorious effec
`administration to the
`desired compositions.
`as a transdermal p
`of (1) due to thei
`are obviousl
`
`ways, e.g..
`
`addition salts
`corresponding base form,
`queous compositions.
`
`r increased water sol
`y more suitable in the
`
`ubility over the
`
`preparation
`
`iformity of dosage.
`claims herein refer
`
`pharmaceut
`tration and un
`specification and
`suitable as unitary do
`y of active ingredi
`effect in association with the required pharmaceutical
`quantit
`therapeutic
`
`s to physically dis
`ntaining a predeter
`
`crete units
`mined
`
`Q
`
`Petitioner
`Exhibit 1002 - 011
`
`

`
`carrier. Examples of
`scored or coated tablets)
`
`-9-
`such dosage unit forms are tablets (including
`ckets. wafers,
`pills. powder pa
`. capsules.
`tablespoonfuls and
`
`nsions,
`
`teaspoonfuls,
`
`like.
`
`s thereof.
`
`The pres
`
`s a method of potentiating the
`ent invention also concern
`n warm-blooded animals in
`pressure reducing agents i
`effects of blood
`said method comprising
`need of blood pressure reducing medication,
`ffective amount of a
`administering to said warm-blooded animals of an e
`ent and a compound of formula (I) as defined
`blood pressure reducing ag.
`hereinabove.
`
`d of lowering
`
`10
`
`15
`
`20
`
`the present invention concerns a metho
`Or alternatively,
`mals suffering therefrom, said
`essure in warm-blooded ani
`rm-blooded animals of an
`g administering to said wa
`gent and a compound of
`f a blood pressure reducing a
`ereinabove.
`
`the blood pr
`
`method comprisin
`
`effective amount 0
`formula (I) as defined h
`
`pressur
`
`results pre
`
`Those of skill in treating subjects suffering from anuincreased blood
`e could easily determine th
`In gene
`sented hereinafter.
`y dose of the compounds of f
`effective dail
`addition salts would b
`tically acceptable acid-
`articular from 0.1 mg/kg t
`mg/kg body weight,
`in p
`g to 1 mg/kg body weight.
`and preferably from 0.1 mg/k
`
`ormula (I) or their pharmaceu-
`e from 0.01 mg/kg to 59
`o 10 mg/kg body weight
`
`All above cited references are i
`
`ncorporated herein by reference.
`
`The following
`
`examples are intended to illustrate and not to limit
`Unless otherwise
`ent invention in all its aspects.
`
`the scope of the pres
`stated all parts therein are by weight.
`
`30
`
`ng examples
`Whenever used in the followi
`which was first isolated and
`"B" to the one
`
`"A" refers to the isomer
`
`which was subsequently
`
`isolated.
`
`Petitioner
`Exhibit 1002 - 012
`
`

`
`—fluoro—4—oxo-4g-1—benzopy
`as hydrogenated at normal pressure
`arts of acetic acid w
`1 catalyst
`lic acid and 400 p
`alladium—on-charcoa
`re with 3 parts of p
`the catalyst
`and at room temperatu
`n was taken up.
`stirred
`ed amount of hydroge
`10%.
`After the calculat
`filtrate was evaporated. The residue was
`and dried in vacuo at
`filtered off and the
`ct was filtered off
`The produ
`1—benzopyran—
`oleumether.
`—3,4—dihydro—2§-
`of 6—fluoro
`lding 49 parts (83%)
`c acid (int. 1).
`d solution of 9.75 p
`e added l6 parts of
`s at 60°C. The react
`twice in 45 parts o
`The residue was ta
`
`was
`
`in petr
`
`10
`
`70°C, yie
`
`2-carboxyli
`
`b) To a stirre
`
`methylbenzene wer
`
`stirred for 2 hour
`
`l5 residue was taken up
`wa
`5 evaporated each time.
`There were
`
`ran—2-carboxy—
`
`arts of intermediate 1 in 90 parts of
`The mixture was
`thionyl chloride.
`rated. The
`ion mixture was evapo
`e latter
`f methylhenzene and th
`ken up in 90 parts of
`ts of
`E.§—diethylethan-
`9.lO;l0a-octa-
`
`added first 10.5 par
`f 14.25 parts of (+)
`-phenanthren
`
`—1,2;3,4,4a,
`emethanamine
`After stirring
`
`water, dried,
`arts of warm ethanol.
`yielding 6.6
`from ethanol,
`-2§—l—benzopyran-
`E-[dehydroabiethyl]
`ntermediate 2,
`e of 6.8 parts of i
`c) A mixtur
`oric acid was stirre
`oncentrated hydrochl
`was poured into
`the reaction mixture
`After cooling,
`-oxybisethane. The extract was
`ted with l,l'
`The residue was
`filtere
`d and evaporated.
`olution
`a sodium hydroxide s
`thane
`tak
`en up in trichlorome
`The
`d solution 10%.
`yielding l.l parts of
`
`methylbenzene.
`d then a solution o
`amine an
`—methylethyl)-1
`a-dimethyl—7—(l
`parts of methylbenze
`abiethylamine] in 45
`s washed successively with water, a
`e organic layer wa
`ochloric acid solution 10% and
`solution 10%,
`a hydr
`The residue was taken up in 120
`lized
`ered off and crystal
`—6—fluoro-3.4-dihydro-
`
`hydro-1,4
`
`[(+)—dehydro
`
`for 2 hours,
`
`th
`
`sodium hydroxide
`filter
`
`P
`
`20
`
`25
`
`ed and evaporated.
`The product was filt
`parts (28.4%) of (A)
`2-carboxamide
`
`d for 24 hours at
`
`36 parts of c
`
`reflux temperature.
`water. The product was extrac
`ater, dried.
`washed twice with w
`5 Parts of
`taken up in l,l'
`-oxybisethane.
`was filtered off,
`wet
`e added. The product
`of a hydrochloric aci
`and tr
`eated with 50 parts
`ered and evaporated.
`35 organic layer was dried. filt
`
`Petitioner
`Exhibit 1002 - 013
`
`

`
`-11-
`
`-carboxylic acid;
`
`ture and cooled to
`lpropy1)]aluminum
`period of 20
`20 minutes at
`
`as poured into
`
`The extract was
`water and a
`
`—3,4—dihydro-25-1
`4).
`
`ith
`
`29
`
`tetrahy
`
`wash
`
`yieldin
`
`pyran-2—c
`
`e) 6.3 Part
`
`15
`
`parts of intermedia
`dro
`pwise and upon comp
`The r
`eaction mixture was
`
`-3,A—dihydro—2fl—l—benzopyran-2
`(+)—(S)—6—£luoro2
`1% in DMF) (int. 3).
`termediate 3 in 180 parts of
`99.1°c [a.]D5 =+14.88° (c=
`mp.
`n of 22.5 parts of in
`‘
`midazole].
`a stirred solutio
`d) To
`d 18.7 parts of 1.1‘-
`droturan were adde
`hour at room tempera
`e was stirred for l
`The whol
`ution of [bis(2-methy
`136 Parts of a 25% sol
`—70°C.
`ed dropwise during a
`lbenzene were add
`hydride in methy
`minutes. Upon completion. stirring was continued for
`d and the mixture w
`£ methanol were adde
`-70°C. 40 Parts o
`as extracted with 1,l'—oxybisethane.
`The product w
`10 water.
`cid solution 10%.
`ed successively with a hydrochloric a
`dried,
`te solution,
`um hydrogen carbona
`sodi
`) of (+)—(S)-6-fluoro
`g 12 parts (57.9%
`n oily residue (int.
`were washed twice w
`arboxaldehyde as a
`ide dispersion 50%
`up in 250 parts of
`s of a sodium hydr
`dimethyl sulfoxide.
`g a period of 30
`er and then taken
`ide were added durin
`petroleum eth
`Parts of trimethylsulfoxonium iod
`A solution of 12
`r 20 minutes.
`tinued fo
`e was added
`ing was con
`te 4 in 10 parts of dimethyl sulfoxid
`e was stirred for 30 minutes.
`the mixtur
`letion,
`s extracted
`and the product wa
`poured into water
`ed three times with water.
`The extract was wash
`purified by column
`ed. The residue was
`ture of methylbenzene
`ica gel using a mix
`) as eluent. The pure fractions were
`parts (9.8%) of
`ated. yielding 2.1
`an as an oily
`
`with
`
`l,l'-oxybisethane.
`ltered and evaporat
`dried, ii
`chromatography (BPLC) over sil
`ate (90:10 by volume
`and ethyl acet
`collected and th
`
`(+)—[S(S)]—6-fluoro
`
`25
`
`'
`
`—2§—l-benzopyr
`
`residue (int. 5).
`
`30
`
`a)In the
`
`of the compoun
`yran—2-carboxamide (int.
`) A mixture of 6.l parts of interm
`rated hydrochlori
`36 parts of concent
`
`Pb
`
`35
`
`ample lb) 6.1 parts (26.3%)
`l—benzo-
`; -dihydro—fi—[dehydroabiethyl]-23-
`obtained as a residue.
`of acetic acid and
`75 parts
`ediate 6,
`or 24 hours at
`c acid was stirred f
`
`Petitioner
`Exhibit 1002 - 014
`
`

`
`reflux temperature.
`
`ater I
`
`'nto water. The
`
`twice with w
`
`eum ether.
`
`o—3,4—dihydro—2§—1-benzo—
`d from petrol
`1% in
`)—(R)-%—f1uor
`0.9 parts of (-102.5°C [ulgs = -13.39° (c=
`s of intermediate 1 in
`The mixture
`
`tion of 36 part
`
`10 was fur
`was evap
`
`uxed for 4 hours.
`n up in 1.1'—o
`
`15
`
`oxylate as an o
`6 and cooled
`
`pyran—2—carb
`d)-To a stirre
`8 in 450 parts of me
`solution of [bis(2—methy1prop
`under nitrogen atmosphere.
`
`evaporated,
`9.6 Parts of a
`s with petrole
`44 par
`
`three time
`dimethyl sulfoxide.
`and after comple
`
`umether and then taken up in 500 parts of
`
`25
`
`ion. stirring
`
`The whole w
`
`as poured
`The
`
`Petitioner
`Exhibit 1002 - 015
`
`

`
`-13-
`
`(24.8%)
`
`elding 8.2 parts
`s evaporated. yi
`d the eluent wa
`-23-l—benzopyran as a
`were collected an
`-3.4—dihydro—2—oxiranyl
`of (-)—[R(S)]—6—fluoro
`parts of intermediate 9 and 20 parts of benzene-
`
`off and cry:
`
`tallized from ac
`
`dried.
`
`10 u-[[(phenylme
`
`yielding
`thyl)amino]methyl]
`
`itated product wa
`product was filt
`]-6—fluoro—3.4
`—methanol (int.
`
`s filtered
`
`ered off and
`—dihydro-
`10).
`
`etonitrile. The
`3.1‘) of (—)—[R(S)
`-23-l—benzopyran-2
`
`Pre at
`
`ion E.
`
`e
`
`inal
`
`m
`
`phenylmethyl)im
`
`ino]bismethylene]bis-
`
`of intermediate
`
`s hydrogenated a
`char
`alladium-on-
`
`t normal pressur
`coal catalyst 10%.t was
`the catalys
`
`f and the
`
`filtered of
`,in trichloromethane
`
`filtrate was ev
`and purified by c
`
`aporated.
`olumn chromatogr
`
`off and dried, yi
`
`elding 1.2 parts
`e]bis[6-fluoro-3.4
`' mp. 142.7°C (compound 1).
`
`(42%) of
`—dihydro—
`
`Example 4
`
`enylmethy1)imino]bis—
`S,sS)-a.a'-[[(ph
`prepared as
`9.4 parts of (R —benzopyran-2-methanol],
`A mixture of 1
`(methylene)bis[3,4—dihydro-23-1
`—4,654.362 (see c
`described in US
`"A_B+
`the latter: the designation
`
`35
`
`Petitioner
`Exhibit 1002 - 016
`
`

`
`5
`
`10
`
`-14-
`
`-methox
`yethanol was hydrog
`th 2 parts of palladium—on
`unt of hydrogen was t
`iatomaceous earth an
`yieldin
`cetonitrile.
`
`enated at normal pressure and at
`0%.
`—charcoal catalyst 1
`the reaction
`aken up,
`The residue
`
`d evaporated.
`g 6.8 parts (43.8%) of
`-2g—1—benzopyran—
`
`]bis[3.4—dihydro
`
`was crys
`
`(RS,SS)-G.
`
`243 parts of 2
`room temperature wi
`Aft
`er the calculated amo
`re was filtered over d
`mixtu
`tallized twice from a
`u’-[iminobis(methylene)]
`136.1°C (compound 2).
`
`2—methanol]; mp.
`
`of intermediate 10,
`A mixture of 6 parts
`prepared as desc
`1—benzopyran,
`e 53,
`the designation
`thanol was refluxed f
`and the residue was
`
`Example 5
`
`2—oxiranyl—2H-
`654,362 (intermediat
`US—4,
`) and 119 parts of e
`ixture was evaporated
`
`SS—isomer
`
`reaction m
`
`5 parts of (SS)-3,4-dihydro—
`ribed in example 17 of
`"B+" referring to the
`
`or 18 hours. The
`
`added to 275 parts
`e and at room
`
`t 10%. After
`
`um—on—charcoal catalys
`the catalys
`aken up,
`
`temperature wi
`
`th 2 parts of palladi
`unt of hydrogen was t
`The residue was cryst
`the calculated amo
`trate was evaporated.
`3%) of (RSS5)-u-[[[2-(3.4-
`red off and the £il
`lding 3.8 parts (49.
`amino]methyl]-6-f1uoro—3,4-
`from acetonitrile. yie
`-hydroxyethyl]
`dro—2fl—1-benzopyran-2-yl)-2
`dihy
`154.2°C (compound 3).
`-methanol; mp.
`dihydro-2§—1—benzopyran-2
`
`t was filte-
`
`allized
`
`20
`
`25
`
`30
`
`escribed in example 5 and starting
`
`Ex
`1
`Following the same procedures as d
`from (SS)—6-fluoro—3,4-dihydro—u—[[(
`the reaction of interm
`-methanol (obtained from
`-henzopyran
`benzopyran-2
`o-2-oxiranyl—2g-1
`) and (s3) -3 ,4—dihydr
`und 52 of US-4.354.362;
`benzenemethanamine
`d in example 17, compo
`there was also prepared
`(obtained as describe
`ing to the SR isomer)
`“A7” referr
`—yl)-2—hydroxyethyl]amino]-
`designation
`-Zfl-1-benzopyran-2
`—dihydro
`mp. 14o.7°c
`(SSSR)-u-[[[2—(3,4
`o—2g—l—benzopyran-2-methanol;
`-6-fluoro-3,4-dihydr
`methyl]
`
`ediate 5 with
`
`(compound 4).
`
`Q. Pharmacological examples
`Adult spontaneous hypertensive rats (
`
`6 months of age) were
`
`Petitioner
`Exhibit 1002 - 017
`
`

`
`anesthetized by ether inhalation.
`
`-15-
`
`femoral artery was dissected and
`
`blood
`
`'
`
`cannulated,
`
`pr
`essure transducer.
`ained and the systoli
`restr
`usly recorded.
`stration of the test
`n 20% polypropylene gl
`ation of the test dru
`
`continuo
`
`the admini
`
`dissolved i
`
`After administr
`
`when the animals were
`c and diastolic art
`servation period of a
`All test c
`compound.
`ycol and injected in
`g the systolic and
`
`fully awake,
`
`they were
`
`erial blood pressure w
`t least 30 min preceded
`ompounds were
`
`traperitoneally.
`diastolic
`
`arterial blood pr
`The average blood press
`ined at various time
`
`of 120 minutes.
`
`from the results obta
`
`ure and heart rate was calculated
`nistration
`intervals after admi
`e between
`trates the differenc
`
`treated and untreated animals expressed as a percentage (As)
`pressure and the heart rate.
`systolic and diastolic blood
`
`in the
`
`10
`
`15
`
`A\ Changes (av
`
`and in heart rate
`,.._.§..
`
`in sy
`erage 120 min)
`(HR)
`in spontaneou
`
`stolic and diastolic
`s hypertensive rats
`
`Guanethidine
`
`2.5 sup}: + '5'
`1.25
`
`Petitioner
`Exhibit 1002 - 018
`
`

`
`Prazosin
`
`0.01 mpk
`
`Ptazosin
`
`0.01 mpk
`
`+ *
`
`2.5
`
`u‘—[iminobismethy1ene]bis[
`dihydro-2fl—1—benzopyran-2-methanol].
`(compound 1).
`
`Gpfluoro-3,4-
`
`_/3"
`
`Petitioner
`Exhibit 1002 - 019
`
`

`
`What is claimed is .
`
`ntiating the effects 0
`als in need of blood
`
`e reducing
`f blood press
`pressure reducing
`d warm—blooded
`
`of a blood pressure
`
`educing agent and a
`I
`
`. A method of pote
`agents in warm—blooded anim
`said method compr
`medication,
`animals of an effective amount
`compound which is represented by the formula
`
`fl%E>
`
`.;
`
`ptable —'id addition thereof, wherein
`-
`J
`pharmaceutically acce
`are hydrogen or C1_6alkyl:
`R1 and R2 each independentl
`ently are hydrogen.
`:. and R10 each independ
`R3, R4,
`5 R6, R7, R8,
`alkyl. C1_6alkyl~xy. hydroxyfi cyano, carboxy or
`halo, C1_6
`C
`alkyloxycarbonyl:
`-
`,
`3
`4
`-'5
`6
`7
`3
`9
`1'6
`adic--s of R , R ¢’R , R , R , R , R
`and R
`or two vicinal r
`together may form .
`r -(CH2)4- radical.
`-cH=cu—cH=cg; o
`.
`,wa€?é;n R3, R4, R6, R
`/I
`g to claim l
`
`ora
`
`/
`
`7
`
`"
`- me 'od accordin
`Re, R9 and R10 are hydrog‘-.
`
`taken
`
`10
`
`7
`
`.
`
`wherein the compound is [2R,aS,—
`ng to claim 1
`o—2fl-1-
`is[6-fluoro-3,4-dihydr
`
`3. A method accor-
`
`2 ‘ S,a.' S]-a.,a.' -[imin‘is hylene]b
`
`benzopyran—2
`
`—meth--ol].
`
`4. A pharm ceutic
`
`al composition comprising an amount,
`ducing agents, of a
`s of blood pressure re
`
`capable.of
`
`Petitioner
`Exhibit 1002 - 020
`
`

`
`-13-
`
`or-a
`
`able acid addition thereof,
`pharmaceutically accept
`Galkyl;
`y are hydrogen or C1_
`R1 and R2 each independentl
`10 each independently
`R7. R8, R9 and R
`halo, C1_6a1ky1, C1_6a1ky1oxy, hydroxy.
`C
`alkyloxycarbonylt
`1'5
`3
`4
`a1 radicals of R , R .
`or two vicin
`-CK=CH-CB=CH— 0
`together may form a
`t of a b1ood‘pressure reducing gent.
`effective amoun
`
`cyano. carboxy
`
`15
`
`20
`
`5. A composition according to claim 4
`R7. R8. R9 and R10 are hydrogen.
`’
`
`6. A composition according to cl im
`formula (I) is [2R,uS,2'S,a'S]—a,u —[im
`I
`l—benzopyr n-2-m anol].
`f1uoro—3.4-dihydro-2g-
`
`/G§;:;:; the compound of
`
`his bthy1ene]bis[6-
`
`to claim 4 wherein the blood pressure
`ol, metoprolol,
`propranol
`rom atenolol.
`nifedipine,
`
`prazosin, hydralazine, gu nethidine, phentolamine. verapamil,
`, I
`
`cart
`
`eolol, celiprolol.
`
`g to claim‘? iiherein th
`a’-[iminobismethy1ene]bis-
`-methanol].
`
`9. A compo ition according to cl
`both active '
`'
`'
`'
`
`10. A composition according to claim/
`
`aim 8 wherein the molar ratio of
`/
`
`8/:h;:;in’the molar ratio of
`
`ound of formula
`
`37
`
`Petitioner
`Exhibit 1002 - 021
`
`

`
`-19-
`
`I<i’(
`
`n thereof, wherein
`