(12) United States Patent
`Xhonneux et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,545,040 B1
`Apr. 8, 2003
`
`US006545040B1
`
`METHOD OF LOWERING THE BLOOD
`PRESSURE
`
`Inventors: Raymond Mathieu Xhonneux,
`Vlimmeren (BE); Guy Rosalia Eugene
`Van Lommen, Berlaar (BE)
`
`Assignee: J anssen Pharmaceutica N.V. (BE)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`Appl. No.:
`
`Filed:
`
`07/825,488
`Jan. 24, 1992
`
`Ritter, J .M., A Study to Investigate the Mechanism of the
`Vasodilator Effect of Nebivolol Isomers on Forearm Blood
`FloW in Healthy Volunteers, J RD, Clinical Research Report,
`NEB—GBR—29, N106922, 1994.
`
`Ritter, J .M., et al., A Study to Investigate the Vasodilator
`Action of Nebivolol in Patient Volunteers With Essential
`Hypertension, JRF Clinical Research Report, Jan. 1998.
`
`Ritter, J.M., et al., A Study to Compare the Effect of
`Nebivolol and Atenolol on Forearm Blood FloW in Healthy
`Volunteers, JRF, Clinical Research Report on NEB—
`GBR—27, (N 107424), Oct. 1993.
`
`Robertson, J.I.S., Janssen Research Foundation, Clinical
`Expert Report, Jan. 1995, 1—47.
`
`Related US. Application Data
`
`Rousseau, M.F. et al., Perfusion 10/97, p. 367—375.
`
`(54)
`
`(75)
`
`(73)
`(*)
`
`(21)
`(22)
`
`(63)
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`Continuation of application No. 07/325,181, ?led on Mar.
`16, 1989, now abandoned, which is a continuation-in-part of
`application No. 07/172,747, ?led on Mar. 23, 1988, now
`abandoned.
`
`Int. Cl.7 .................... .. A61K 31/35; A61K 31/335;
`A61K 31/18
`US. Cl. ...................... .. 514/451; 514/452; 514/602
`Field of Search ............................... .. 514/451, 452,
`514/602
`
`References Cited
`
`US. PATENT DOCUMENTS
`
`4,654,362 A
`
`3/1987 Van Lommen et al.
`
`514/452
`
`OTHER PUBLICATIONS
`
`Van de Water et al. 109 CA:16771g 1988*
`Van de Water 110 CA:50943v 1988*
`Kakoki, M., et al. Effects of Vasodilatory[3—Adrenoceptor
`Antagonists on Endotheliurn—Derived Nitric Oxide Release
`in Rat Kidney. Hyptertension, 1999, 33 [part II] 467—471.
`LaCourciere, Y. et al., Comparative Assessment of Antihy
`pertensive Ef?cacy of DL—Nebivolol and D—Nebivolol in
`Patients With Con?rmed Mild to Moderate Hypertension,
`Journal of Cardiovascular Pharmacology, 25 :619—624,
`1995, Raven Press, Ltd., NeW York.
`Parenti, A., et al., Inositol Phosphate Metabolism and Nitri
`c—Oxide Synthase Activity in Endothelial Cells Are
`Involved in the Vasorelaxant Activity of Nebivolol. J. Phar
`macology and Experimental Therapeutics, 292:698—703
`(2000).
`PauWels, P.J., et al., The Receptor Binding Pro?le of the
`NeW Antihypertensive Agent Nebivolol and Its Stereoiso
`mers Compared With Various [3—Adrenergic Blockers,
`Molecular Pharmacology, 34:843—851, 1988.
`Pouleur, M.D., Effects of d—nebivolol and I—nebivolol on
`Left Ventricular Systolic and Diastolic Function, Janssen
`Research Foundation, NEB—BEL—41, 1991.
`Ritter, J ., et al., AStudy to Investigate the Vasodilator Effect
`of fNebivolol Racemate & Isomers on Forearm Blood FloW
`in Healthy Volunteers, JRF, Clinical Research Report, Trial
`NEB—GBR—31, Jul. 1997.
`Ritter, J ., et al., A Study to Investigate the Possible Vasodi
`lator Effect of Nebivolol on Forearm Blood FloW in Healthy
`Volunteers, NEB—GBR—23, Aug. 16, 1992—Aug. 27, 1992.
`
`Rousseau, M.F., et al., Long—term Effects of Nebivolol on
`Ischaemic Left Ventricular Dysfunction, Janssen Research
`Foundation, Oct. 1994.
`
`Rousseau, M.F., et al., Medium—term Effects of Beta—block
`ade on Left Ventricular Mechanics: A Double—blind, Place
`bo—controlled Comparison of Nebivolol and Atenolol in
`Patients Wit Ischemic Left Ventricular Dysfunction, Journal
`of Cardiac Failure, vol. 2, No. 1, 1996.
`
`Stoleru, L. et al., Effects of d—Nebivolol and L—Nebivolol on
`Left Ventricular Systolic and Diastolic Function: Compari
`son With D—L—Nebivolol and Atenolol, Journal of Cardio
`vascular Pharmacology, 22:183—190, 1993, Raven Press,
`Ltd., NeW York.
`
`Stoleru, L., et al., Bene?cial Effect of (d—I) Nebivolol on the
`Left Ventricular Systolic and Diastolic Function, European
`Heart Journal 13 (Suppl), p. 21, 1992.
`
`Van de Water, A., et al., Cardiovascular Effects of dl—nebiv
`0101 and its enantiomers—a Comparison With Those of
`Atenolol, Eur. J. Pharmacol, 1988 Abstract.
`Van de Water, A., et al., Pharmacological and Hemodynamic
`Pro?le of Nebivolol, A Chemmically Novel, Potent, and
`Selective [31—adrenergic Antagonist, J. Cardiovase. Pharma
`col, 1988 Abstract.
`
`Van de Water, A., et al., The Cardiac and Haemodynamic
`Effects of Cumulative Intravenous Injections of R 65 825 in
`Closed—Chest AnaesthetiZed Mongrel Dogs, Janssen
`Research Products Information Service, Mar. 1985.
`
`(List continued on next page.)
`
`Primary Examiner—Russell Travers
`
`(57)
`
`ABSTRACT
`
`A method of potentiating the effects of blood pressure
`reducing agents in Warm-blooded animals, said method
`comprising administering to said Warm-blooded animals of
`an effective amount of a blood pressure reducing agent and
`a 2,2‘-iminobisethanol derivative.
`
`6 Claims, N0 Drawings
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1001-1
`IPR2016-00379
`
`

`
`US 6,545,040 B1
`Page 2
`
`OTHER PUBLICATIONS
`
`Van de Water, A., et al., The Cardiac and Haemodynamic
`Effects of Intravenous Injections of R 65 824 in Closed—
`Chest AnaesthetiZed Mongrel Dogs, J anssen Research Prod
`ucts Information Service, R 65 824/1, Apr. 1985.
`Van de Water, A., et al., The Comparison of the Cardiac and
`Haemodynamic Effects of Cumulative Intravenous Injec
`tions of R 65 824 and Those of R 65 825 With Those of
`Propranolol in C1osed—Chest AnaesthetiZed Mongrel Dogs,
`J anssen Research Products Information Service, R 65 824/3,
`R 65 825/3, Jul. 1985.
`Van de Water, A., et al., The In Vivo Beta—Adrenergic
`Blocking Properties of an Intravenous Administration of R
`65 825 in C1osed—Chest AnaesthetiZed Mongrel Dogs, Jan
`ssen Research Products Information Service, R 65 825/2,
`Mar. 1985.
`Van de Water, A., et al., The In Vivo Beta—Adrenergic
`Blocking Properties of an Intravenous Administration of R
`65 824 in C1osed—Chest AnaesthetiZed Mongrel Dogs, Jan
`ssen Research Products Information Service, R 65 824/2,
`May 1985.
`Van Nueten, J .M., et al., In Vitro Pharmacological Pro?le of
`R 65 824, APotent and Selective [31—adrenergic Antagonist,
`J anssen Research Products Information Service, Nov. 1985.
`Van Nueten, L. et al., Nebivolol: Comparison of the Effects
`of dl—Nebivolol, d—Nebivolol, I—Nebivolol, Atenolol, and
`Placebo on Exercise—Induced Increases in Heart Rate and
`Systolic Blood Pressure, Cardiovascular Drugs and Therapy,
`1998, 12:339—344, Kluwer Academic Publisher, Boston.
`Van Rooy, P, Determination of the Acute and Subacute
`[3—sympthiocolytic Activity of d—, I—and dl—nebivolol Com
`pared to Atenolol and Placebo, in Inhibiting Exercise—In
`duced Tachycardia, NEB—BEL—20, J anssen Research Foun
`dation, 1989.
`Wisenbaugh, Thomas MD, et al., Long—Term (3—month)
`Effects of a NeW Beta—Blocker (Nebivolol) on Cardiac
`Performance in Dilated Cardiomyopathy, JACC, vol. 21,
`No. 5, Apr. 1993:1094—1100.
`Xhonneux, R., et al., The I—enantiomer of Nebivolol Poten
`tiates the Blood Pressure LoWering Effect of the d—enanti
`omer, European Journal of Pharmacology, 181, 1990,
`261—265, Elsevier Science Publishers.
`BoWman, AJ et al., Nitric Oxide Mediated Venodilator
`Effects of Nebivolol, Br J Clin Pharmacology, 1994, 38:
`199—204.
`Cockcroft, J .R., et al., Effect of Racemic Nebivolol on
`Forearm Blood FloW in Healthy Volunteers, British Journal
`of clinical Pharmacology 35 (5) p. 542p—543p, 1993.
`Cockcroft, J.R., et al., Nebivolol Causes Vasodilation in
`Human Forearm Vasculature: Evidence for an L—arginine/no
`Dependent MechanismAmerican Journal of Hypertension 7
`(4) Part 2, 1183, p. 23A, 1994.
`Cockcroft, J .R., et al., Nebivolol Induced Vasodilation in the
`Human Forearm May be Mediated by the L—ARG/N O
`PathWay, Third International Meeting on the Biology of
`Nitric Oxide, Cologne, Germany, Oct. 3—6, 1993.
`Cockcroft, J.R., et al., Perfusion 11/97, p. 414—420.
`Crockcroft, J .R., et al., Nebivolol Vasodilates Human Fore
`arm Vasculature: Evidence for an—I—Arginine/NO—Depen
`dent Mechanism, The Journal of Pharmacology and Experi
`mental Therapeutics, 1995, 274:1067—1071.
`DaWes, M., et al., The Vasodilator Action of Nebivolol in
`Forearm Vasculature of Subjects With Essential Hyperten
`sion, Br. J. Clinical Pharmacology 48, 460—463, 1999.
`
`De Crée, J. et al., Non—invasive Cardiac Haemodynamics of
`Nebivolol in Men, Acta AntWerpiensa 6 (2), 1989.
`De Cree, J ., Comparison of the Hemodynamic Effects of
`Nebivolol and Atenolol, JRF, clinical Research Report 33,
`Jan. 1989 (N 65577) 6:2—21.
`De Cree, J ., et al., Cardiac Haemodynamic Effects of d—, I—,
`dl—nebivolol and Atenolol During a 7—day Double—blind
`Cross—over Study in Healthy Volunteers, J anssen Research
`Products Information Services, Clinical Research Report,
`Mar. 1989.
`De Cree, J ., et al., Double—blind Fplacebo—controlled
`Cross— over Study Evaluating the Acute Haemodynamic
`Effects of dl—nebivolol 5 mg, d—nebivolol 2.5 mg and
`I—nebivolol 2.5 mg in Healthy Volunteers, Janssen Research
`Products Information Services, Clinical Research Report,
`Feb. 1989.
`De Cree, J., et al., Double—blind Study Comparing the
`Subacute Hemodynamic Effects in Men at Rest and During
`Exercise of the 2 Enantiomers of dl—nebivolol, d—nebivolol
`(R 67138) and I—nebivolol (R 67145), Janssen Research
`Products Information Service, Clinical Research Report,
`Mar. 1988.
`De Cree, J ., et al., Effects of Isometric Handgrip on Blood
`Pressure and Heart Rate During a 7—day Double—Blind
`Cross—over Treatment With dl—, d—and 1—nebivolol and
`Atenolol, J anssen Research Products Information Services,
`Clinical Research Report, Jan. 1989.
`E. Snook et al., JRF, Comparative Pharmacokinetics of
`Nebivolol after a Single Oral Dose of 7.5mg d—nebivolol,
`7.5 mg I—nevivolol and 15 mg of the Racemate Nebivolol in
`4 Extensive and 2 Poor Metabolisers of Debrisoquine,
`NEB—BEL—22, Oct. 1994.
`G. Cheymol et al., Pharmacokinetic Study and Cardiovas
`cular Monitoring of Nebivolol in Normal and Obese Sub
`jects, Eur. J. Clin. Pharmacol, 1997, 51:493—498.
`Gao, Y., et al., Nebivolol Induces Endothelium—Dependent
`relaxations of Canine Coronary Arteries, Journal of Cardio
`vascular Pharmacology, 17:964—969, 1991, Raven Press,
`Ltd., NeW York.
`Goldstein, M. et al., Administration of Nebivolol after
`Coronary Artery Bypass in Patients With Altered Left Ven
`tricular Function, Journal of Cardiovascular Pharmacology,
`22:253—258, 1993, Raven Press, Ltd., NeW York.
`Himmelmann, A. et al., Haemodynamic Effects and Phar
`macokinetics of Oral d—and I—nebivolol in Hypertensive
`Patients, Eur, J. Clin Pharmacol, 1996, 51: 259—264.
`JRF, A Study to Investigate the Mechanism of the Vasodi
`lator Effect of Nebvivolol on Forearm Blood FloW in
`Healthy Volunteers, NEB—GBR—25, 1993, Ritter.
`JRF, A Study to Investigate the Mechanism of the Vasodi
`lator Effect of Nebivolol on Forearm Blood FloW in Healthy
`Volunteers, NEB—GBR—28, 1993, Ritter.
`JRF, Double—blind, Placebo—controlled Phase—II Study of
`di—Nebivolol and its d—and I—enantiomers in Patients With
`Mild to Moderate Hypertension, Clinical Research Report
`NEB—GER—9, I 1993 (N 106 599).
`JRF, Effect of Nebivolol and its Enantiomers in Hyperten
`sive Patients, Comparison With Placebo and Atenolol, Clini
`cal Research Report NEB—INT—4, Jun. 1993 (N 92909).
`J RF, Synoptic Clinical Research Report NEB—BEL—26, Sep.
`1994, De Meirleir.
`J RF, Synoptic Clinical Research Report NEB—BEL—42, Jan.
`1994 (N 106563), Goldstein.
`* cited by examiner
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1001-2
`IPR2016-00379
`
`

`
`US 6,545,040 B1
`
`1
`METHOD OF LOWERING THE BLOOD
`PRESSURE
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of our application Ser.
`No. 07/325,181, ?led on Mar. 16, 1989, (noW abandoned)
`Which in turn Was a continuation-in-part of application Ser.
`No. 07/172,747, ?led on Mar. 23, 1988 noW abandoned.
`
`BACKGROUND OF THE INVENTION
`
`In US. Pat. No. 4,654,362 there are described 2,2‘
`iminobisethanol derivatives having [3 adrenergic blocking
`properties. It noW has been found that a certain class of
`isomers of said bisethanol derivatives potentiate the activity
`of blood pressure reducing agents.
`
`DESCRIPTION OF THE INVENTION
`
`The present invention is concerned With a group of
`compounds capable of potentiating the effects of blood
`pressure reducing agents, said compounds being represented
`by the formula
`
`R
`
`R5
`
`or the pharmaceutically acceptable acid addition salts
`thereof, Wherein
`R1 and R2 each independently are hydrogen or C1_6alkyl;
`R3, R4, R5, R6, R7, R8, R9 and R10 each independently are
`hydrogen, halo, C1_6alkyl, C1_6alkyloxy, hydroxy,
`cyano, carboxy or C1_6alkyloxycarbonyl; or tWo vicinal
`radicals of R3, R4, R5, R6, R7, R8, R9 and R10 taken
`together may form a —CH=CH—CH=CH— or
`—(CH2)4— radical.
`As used in the foregoing de?nitions the term halo is
`generic to ?uoro, chloro, bromo and iodo; the term “C1_
`salkyl” de?nes straight and branch chained saturated hydro
`carbon radicals having from 1 to 6 carbon atoms such as, for
`example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl,
`propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.
`The descriptors R and S as used in the above formula (I)
`indicate the absolute con?guration at the respective carbon
`atoms. The carbon atom bearing R1 has the R con?guration,
`Whereas the carbon atoms bearing the hydroxy functions and
`the carbon atoms bearing R2 have the S con?guration.
`Preferred compounds of formula (I) are those Wherein R3,
`R4, R6, R7, R8, and R10 are hydrogen.
`Particularly preferred are those preferred compounds
`Wherein R5 and R9 are hydrogen or halo, particularly ?uoro.
`The most preferred compound is [2R,otS,2‘S,(xS]-ot,(x‘
`[iminobismethylene]bis[6-?uoro-3,4-dihydro-2H-1
`benZopyran-2-methanol] or a pharmaceutically acceptable
`acid addition salt thereof.
`The compounds of formula (I) can be prepared folloWing
`the procedures described in US. Pat. No. 4,654,362. Some
`particular Ways of obtaining the compounds of formula (I)
`Will be described hereinafter in some more detail.
`
`2
`The compounds of formula (I) can be prepared by react
`ing an oxirane of formula (II-a) or (II-b) With an amine of
`formula (III-a) or (III-b).
`
`(II-a)
`
`OH R,
`
`P—NH—CH2—CH
`s
`
`5
`
`O
`
`R7
`
`(III-a)
`
`R2
`
`(II-b)
`
`OH R1
`
`P—NH—CH2—CH
`s
`
`R
`
`O
`
`R7
`
`R10
`
`+
`
`R3
`
`R6
`
`R8 —> (I)
`
`R9
`
`R4 —> (I)
`
`R5
`
`(III-b)
`
`In (III-a) and (III-b), P is either hydrogen or an appropriate
`protecting group, for example an allyl group, or in particular
`P may be a benZyl group. Or, a reagent P—NH2 may be
`reacted With (II-a) and (II-b) in a one-pot procedure. The
`above described reactions to prepare a compound of formula
`(I) may be conducted in a reaction-inert solvent such as, for
`example, an aromatic hydrocarbon, e.g. benZene or methyl
`benZene; an alkanol, e.g. methanol, ethanol, propanol; a
`ketone, e.g. 2-propanone, 4-methyl-2-pentanone; an ether,
`e.g. 1,4-dioxane, tetrahydrofuran, 1,1‘-oxybisethane; a dipo
`lar aprotic solvent, e.g. N,N-dimethylformamide or N,N
`dimethylacetamide and the like solvents. In certain
`instances, in order to increase the reaction rate, it may be
`appropriate to heat the reaction mixture.
`If in the above reactions P is other than hydrogen, the
`N-protected derivatives of formula (I) are obtained Where
`from the compounds of formula (I) themselves can be
`obtained by a deprotection reaction. For example, Where P
`is allyl, by reaction With an appropriate noble metal com
`pound such as PdCl2 or Rh[P(C6H5)3]Cl, or Where P is
`benZyl, by a catalytic hydrogenation procedure, e.g. palla
`dium or platinum on charcoal in a suitable solvent such as
`an ether, e.g. 1,4-dioxane, tetrahydrofuran, an alkanol, e.g.
`methanol, ethanol, an alkoxyalkanol, e.g. methoxyethanol
`and the like.
`The intermediates of formula (II-a) or (III-b) are obtained
`by the reaction of the amine P-KH2 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, eg when P is benZyl by a catalytic
`
`20
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1001-3
`IPR2016-00379
`
`

`
`US 6,545,040 B1
`
`4
`3
`The compounds of formula (I) With the exception of
`hydrogenation procedure using one equivalent hydrogen.
`(RSSS)-ot,0t‘-[irninobis(rnethylene)bis(3,4-dihydro-2H-1
`The afore described reactions to prepare (III-a) or (III-b) are
`benZopyran-2-rnethanol] ethanedioate(1:1) are deemed to be
`conducted following the same procedures as described here-
`novel compounds and constitute in an additional feature to
`inabove for the preparation of the compounds
`The starting materials (II-a) are obtained by an oxirane 5 the present invention.
`forrnation reaction from an aldehyde of formula (IV-a), eg
`The compounds of formula (I) and the pharrnaceutically
`by reaction of the latter With a trirnethylsulfoxoniurn halide,
`acceptable acid addition salts thereof potentiate the activity
`or from an ethylene of formula (V-a) by reaction of the latter
`of blood pressure reducing agents. In particular they poten
`With a peroxide, e. g. a haloperbenZoic acid. In the same Way,
`tiate the reduction of the blood pressure and of the heart rate.
`the intermediate (II-b) is obtained from the corresponding 10
`As blood pressure reducing agents of Which the activity is
`S-isorners (IV-b) or (V-b). The oxiranes of formula (IV-a-1)
`potentiated there may be mentioned agents having adrener
`obtained in the aforementioned oxirane-forrnation reaction
`gic and/or vasodilating activity. In particular such agents
`are separated in their stereoisorners, eg by HPLC or selec-
`may be the compounds mentioned in US. Pat. Nos. 3,663,
`tive crystalliZation.
`607 and 3,836,671, in particular atenolol; US. Pat. Nos.
`
`R1
`
`o
`
`cH=o +
`
`+
`(CH3)3SO r —>
`
`R
`
`separation
`
`peroxide
`
`(1H1)
`
`R1
`cH=cH2
`
`o
`
`+
`
`R
`
`R4
`
`R5
`
`R4
`
`R5
`
`R3
`
`R6
`(IV-a)
`
`R3
`
`R6
`(V-a)
`
`3,337,628 and 3,520,919, in particular propranolol; US. Pat.
`The compounds of formula (IV-a), (IV-b), (V-a) or (V-b)
`No. 3,873,600, in particular rnetoprolol; U.S. Pat. No. 3,511,
`are obtained by a suitable separation procedure, ie by
`HPLC, or by a reduction reaction of the corresponding 45 836, in particular praZosin; U.S. Pat. No. 2,484,029, in
`optically active racernic acids Whereas (IV-a) or (IV-b) can
`particular hydralaZine; US. Pat. No. 2,928,829 in particular
`be Converted to (V-a) 0r (V-b) by a Wittig reaction- The said
`guanethidine; US. Pat. No. 2,503,059, in particular phen
`Corresponding Optically active acids in turn can be Obtained
`tolarnine; US. Pat. No. 3,261,859, in particular veraparnil;
`by Conventional Separation techniques> i~e~ by salt or amide
`US. Pat. No. 3,485,847 in particular nifedipine; US. Pat.
`formation with an optically active reagent and a selective 50 NO_ 3,910,924, in particular Carteolol; German Pat NOS_
`crystalhzanon procedure or a HPLC sepafanon'
`_
`2,458,624 and 2,458,625, in particular celiprolol. Aparticu
`The Compounds of formula (I) have baslc propemes, and’
`lar group of blood pressure reducing compounds are the
`consequently, they may be converted to the1rtherapeut1cally
`Compounds of Us‘ Pat‘ NO‘ 4,654,362 other than the
`active non-tox1c acid addition salt forms by treatment With
`Compounds of formula (I) and in particular the enan?omers
`appropriate acids, such as, for example, inorganic acids, 55
`.
`.
`-
`-
`-
`-
`of the compounds of formula (I), 1.e. the SRRR-isomers. A
`such as hydrohal1c acid, e.g.hydrochlor1c, hydrobrornic and
`particular Compound is [2S,OLR,2,R,OUR]_OL,OU_
`the like, and sulfuric acid, nitric acid, phosphoric acid and
`_
`_
`_
`_
`_
`the like; or organic acids, such as, for example, acetic,
`[lmlnoblsmethylen?blsw'?uOrO'3’4'd1hydrO'2H'1'
`prop anoic, hydroxyacetic , 2_hydrOXyprOp ano 1C,
`benZopyran-2-rnethanol. These groups of' active ingredients
`2-oxopropanoic, ethanedioic, propanedioic, butanedioic,
`are hsted Wlth th? Purpose of provldlng representatlve
`(Z) _g_butenedioic,
`_z_butenedioic, 60 examples but not With the purpose ofrestr1ct1ng the scope of
`2_hydr0Xybutanedi0iC, 2,3_dihydroxybutanedioic,
`the present invention. The said SRRR isorners and the said
`2-hydroXy-1,2,3-propane-tricarboxylic, methanesulfonic,
`particular compound can be prepared folloWing the same
`ethanesulfonic, benZenesulfonic, 4-rnethylbenZenesulfonic,
`procedures as previously described for the preparation of the
`cyclohexanesulfarnic, 2-hydroxybenZoic, 4-arnino-2-
`compounds of formula (I), but starting from the enantiorners
`hydroxybenZoic and the like acids.
`65 of the intermediates (II-a), (III-a), (II-b) and (III-b). The
`Conversely, the salt form can be converted by treatment
`latter enantiorners in turn can be obtained as described
`With alkali into the free base forrn.
`hereinabove for the preparation of (II-a), (III-a), (II-b) and
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1001-4
`IPR2016-00379
`
`

`
`US 6,545,040 B1
`
`5
`(III-b), but starting from the enantiomers of (IV-a) or (V-a)
`and isolating the appropriate stereoisomers in stereochemi
`cal separation procedures. The enantiomers of (IV-a) and
`(V-a) in the same Way can be obtained as described for the
`preparation of (IV-a) and (V-a) starting from the appropriate
`enantiomeric starting materials and/or isolating the appro
`priate stereoisomers in stereochemical separations.
`The compounds of formula (I) and the acid addition salts
`thereof may be administered before, during or after the
`administration of the blood pressure reducing agent pro
`vided that the time of the administration of the compounds
`of formula (I) in relation to the administration of the blood
`pressure reducing agent alloWs the compound of formula (I)
`to be effective in potentiating the effects of the blood
`pressure reducing agent. Preferably the compound of for
`mula (I) and the blood pressure reducing agent are admin
`istered in the form of suitable compositions. Said composi
`tions are meant to also comprise products containing a
`compound of formula (I) as de?ned hereinabove and a
`blood-pressure reducing agent as a combined preparation for
`simultaneous, separate or sequential use in blood-pressure
`reducing therapy. Such products may for example comprise
`a kit comprising a container With a suitable composition
`containing a compound of formula (I) and another container
`containing a composition With a blood pressure reducing
`agent. Such product may have the advantage that the phy
`sician Wishing to administer blood pressure reducing therapy
`can select, based on the diagnosis of the patient to be treated,
`the appropriate amounts of both components and the
`sequence of administration.
`When administered during the administration of the blood
`pressure reducing agent, a composition containing both the
`blood pressure reducing agent and the active ingredient of
`formula (I) may particularly be convenient.
`In a further aspect of the present invention there is
`provided a composition comprising an amount capable of
`potentiating the effects of blood pressure reducing agents of
`a compound of formula (I) as de?ned hereinabove and a
`blood pressure reducing agent. In the said composition, the
`molar ratio betWeen the compound of formula (I) and the
`blood pressure reducing agent may be other than 1:1, but in
`particular may be 1:1. The amount of the active ingredient
`of formula (I) in such composition Will be so that a poten
`tiating effect on the effects of the blood-pressure reducing
`agent is obtained; the amount of the blood pressure reducing
`agent Will be so that When potentiated, a blood pressure
`reducing effect is obtained upon administration. In
`particular, it is contemplated that the molar ratio of the
`compound of formula (I) to the blood pressure reducing
`compound may be situated betWeen 50:1 and 1:50, in
`particular betWeen 20:1 and 1:20, or betWeen 10:1 and 1:10,
`or betWeen 5:1 and 1:5, more particularly betWeen 2:1 and
`1:2. Particular such compositions are those Wherein the
`blood pressure reducing agent is one of the agents pertaining
`to the patents cited hereinabove, and more particularly the
`agents speci?cally mentioned hereinabove.
`The present invention also provides a composition com
`prising a pharmaceutically acceptable carrier and as active
`ingredient an amount capable of potentiating the effects of
`blood pressure reducing agents of a novel compound of
`formula (I) or a pharmaceutically acceptable acid-addition
`salt thereof, as de?ned hereinabove.
`To prepare such pharmaceutical compositions, an effec
`tive amount of the particular compound or compounds, in
`base or acid-addition salt form, as the active ingredient or
`active ingredients is combined in intimate admixture With a
`pharmaceutically acceptable carrier, Which carrier may take
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`6
`a Wide variety of forms depending on the form of prepara
`tion desired for administration. These pharmaceutical com
`positions are desirably in unitary dosage form suitable,
`preferably, for administration orally, rectally or by parenteral
`injection. For example, in preparing the compositions in oral
`dosage form, any of the usual pharmaceutical media may be
`employed, such as, for example, Water, glycols, oils, alco
`hols and the like in the case of oral liquid preparations such
`as suspensions, syrups, elixirs and solutions; or solid carriers
`such as starches, sugars, kaolin, lubricants, binders, disin
`tegrating agents and the like in the case of poWders, pills,
`capsules and tablets. Because of their ease in administration,
`tablets and capsules represent the most advantageous oral
`dosage unit form, in Which case solid pharmaceutical car
`riers are obviously employed. For parenteral compositions,
`the carrier Will usually comprise sterile Water, at least in
`large part, though other ingredients, for example, to aid
`solubility, may be included. Injectable solutions, for
`example, may be prepared in Which the carrier comprises
`saline solution, glucose solution or a mixture of saline and
`glucose solution. Injectable suspensions may also be pre
`pared in Which case appropriate liquid carriers, suspending
`agents and the like may be employed. In the compositions
`suitable for percutaneous administration, the carrier option
`ally comprises a penetration enhancing agent and/or a suit
`able Wetting agent, optionally combined With suitable addi
`tives of any nature in minor proportions, Which additives do
`not cause a signi?cant deletorious effect to the skin. Said
`additives may facilitate the administration to the skin and/or
`may be helpful for preparing the desired compositions.
`These compositions may be administered in various Ways,
`e.g., as a transdermal patch, as a spot-on, as an ointment.
`Acid addition salts of (I) due to their increased Water
`solubility over the corresponding base form, are obviously
`more suitable in the preparation of aqueous compositions.
`It is especially advantageous to formulate the aforemen
`tioned pharmaceutical compositions in dosage unit form for
`ease of administration and uniformity of dosage. Dosage
`unit form as used in the speci?cation and claims herein
`refers to physically discrete units suitable as unitary
`dosages, each unit containing a predetermined quantity of
`active ingredient calculated to produce the desired therapeu
`tic effect in association With the required pharmaceutical
`carrier. Examples of such dosage unit forms are tablets
`(including scored or coated tablets), capsules, pills, poWder
`packets, Wafers, injectable solutions or suspensions,
`teaspoonfuls, tablespoonfuls and the like, and segregated
`multiples thereof.
`The present invention also concerns a method of poten
`tiating the effects of blood pressure reducing agents in
`Warm-blooded animals in need of blood pressure reducing
`medication, said method comprising administering to said
`Warm-blooded animals of an effective amount of a blood
`pressure reducing agent and a compound of formula (I) as
`de?ned hereinabove.
`Or alternatively, the present invention concerns a method
`of loWering the blood pressure in Warm-blooded animals
`suffering therefrom, said method comprising administering
`to said Warm-blooded animals of an effective amount of a
`blood pressure reducing agent and a compound of formula
`(I) as de?ned hereinabove.
`Those of skill in treating subjects suffering from an
`increased blood pressure could easily determine the effective
`amount from the test results presented hereinafter. In general
`it is contemplated that an effective daily dose of the com
`pounds of formula (I) or their pharmaceutically acceptable
`acid-addition salts Would be from 0.01 mg/kg to 50 mg/kg
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1001-5
`IPR2016-00379
`
`

`
`US 6,545,040 B1
`
`7
`body Weight, in particular from 0.1 mg/kg to 10 mg/kg body
`Weight and preferably from 0.1 mg/kg to 1 mg/kg body
`Weight.
`All above cited references are incorporated herein by
`reference.
`The following examples are intended to illustrate and not
`to limit the scope of the present invention in all its aspects.
`Unless otherWise stated all parts therein are by Weight.
`Whenover used in the folloWing examples “A” refers to
`the isomer Which Was ?rst isolated and “B” to the one Which
`Was subsequently isolated.
`
`Experimental Part
`A. Preparation of the Intermediates
`
`EXAMPLE 1
`
`a) A mixture of 63.4 parts of 6-?uoro-4-oxo-4H-1
`benZopyran-2-carboxylic acid and 400 parts of acetic acid
`Was hydrogenated at normal pressure and at room tem
`perature With 3 parts of palladium-on-charcoal catalyst
`10%. After the calculated amount of hydrogen Was taken
`up, the catalyst Was ?ltered off and the ?ltrate Was
`evaporated. The residue Was stirred in petroleumether.
`The product Was ?ltered off and dried in vacuo at 70° C.,
`yielding 49 parts (83%) of 6-?uoro-3,4-dihydro-2H-1
`benZopyran-2-carboxylic acid (int. 1).
`b) To a stirred solution of 9.75 parts of intermediate 1 in 90
`parts of methylbenZene Were added 16 parts of thionyl
`chloride. The mixture Was stirred for 2 hours at 60° C. The
`reaction mixture Was evaporated. The residue Was taken
`up tWice in 45 parts of methylbenZene and the latter Was
`evaporated each time. The residue Was taken up in 90
`parts of methylbenZene. There Were added ?rst 10.5 parts
`of N,N-diethylethanamine and then a solution of 14.25
`parts of (+)-1,2,3,4,4a,9,10,10a-octa-hydro-1,4a
`dimethyl-7-(1-methylethyl)-1-phenanthrenemethanamine
`[(+)-dehydroabiethylamine] in 45 parts of methylben
`Zene. After stirring for 2 hours, the organic layer Was
`Washed successively With Water, a sodium hydroxide
`solution 10%, a hydrochloric acid solution 10% and
`Water, dried, ?ltered and evaporated. The residue Was
`taken up in 120 parts of Warm ethanol. The product Was
`?ltered off and crystalliZed from ethanol, yielding 6.6
`parts (28.4%) of (A)-6-?uoro-3,4-dihydro-N
`[dehydroabiethyl]-2H-1-benZopyran-2-carboxamide (int.
`2).
`c) Amixture of 6.8 parts of intermediate 2, 75 parts of acetic
`acid and 36 parts of concentrated hydrochloric acid Was
`stirred for 24 hours at re?ux temperature. After cooling,
`the reaction mixture Was poured into Water. The product
`Was extracted With 1,1‘-oxybisethane. The extract Was
`Washed tWice With Water, dried, ?ltered and evaporated.
`The residue Was taken up in 1,1‘-oxybisethane. 5 Parts of
`a sodium hydroxide solution Were added. The product Was
`?ltered off, taken up in trichloromethane and treated With
`50 parts of a hydrochloric acid solution 10%. The organic
`layer Was dried, ?ltered and evaporated, yielding 1.1 parts
`of (+)-(S)-6-?uoro-3,4-dihydro-2H-1-benZopyran-2
`carboxylic acid; mp. 99.7° C. [a1D25=+14.88° (c=1% in
`DMF) (int. 3).
`d) To a stirred solution of 22.5 parts of intermediate 3 in 180
`parts of tetrahydrofuran Were added 18.7 parts of 1,1‘
`carbonylbis[1H-imidaZole]. The Whole Was stirred for 1
`hour at room temperature and cooled to —70° C. 136 Parts
`of a 25% solution of [bis(2-methylpropyl)]aluminum
`hydride in methylbenZene Were added dropWise during a
`period of 20 minutes. Upon completion, stirring Was
`
`8
`continued for 20 minutes at —70° C. 40 Parts of methanol
`Were added and the mixture Was poured into Water. The
`product Was extracted With 1,1‘-oxybisethane. The extract
`Was Washed successively With a hydroch