>
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`(19) 0
`
`E"'°"“'s°““”“‘°"“"“‘
`
`European Patent Office
`Office européen des brevets
`
`11111111111111111111H11111111111111llllllllll11111111111111
`
`(11)
`
`0
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`(12)
`
`EUROPEAN PATENT APPLICATION
`
`(43) 1381901 Publicationi
`17.11.1999 Bulletin 1999/46
`
`(21) Application number: 98108608.5
`__
`
`(51) Int. CL5: C07C 1/00, C07C 217/62,
`C07C 217/48, C07C 219/28,
`
`C07C 219/22; C0713 207/06,
`C07D 295/06, C07C 271/08,
`
`A61 K 31/135, A61 K 31/325,
`
`A61 K 31/40, A61 K 31/435
`
`(84) Designated Contracting States:
`AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU
`MC NL PT SE
`Designated Extension States:
`AL LT LV MK RO SI
`
`(72) Inventors:
`- Sparf, Bengt Ph. D.
`14265 Trangsund (SE)
`- Meese, Claus 0., Dr. rer. nat.
`40789 Monheim (DE)
`
`(71) Applicant: SCHWARZ PHARMA AG
`40789 Monheim (DE)
`
`(54)
`
`Novel derivatives of 3,3-diphenylpropylamines
`
`The invention concerns novel derivatives of
`(57)
`3,3-diphenylpropylamines, methods tor their prepara-
`tion, pharmaceutical compositions containing the novel
`compounds, and the use of the compounds for prepar-
`ing drugs. More particularly the invention concerns to
`provide novel prodrugs of antimuscarinic agents with
`superior pharmacokinetic properties
`compared to
`present drugs as oxybutynin and tolterodine, methods
`
`for preparing thereof, pharmaceutical compositions
`containing them, a method 01 using said compounds
`and compositions for the treatment oi urinary inconti-
`nence, gastrointestinal hyperactivity (irritable bowel
`syndrome) and other smooth muscle contractile condi-
`tions.
`
`FDRMATION OF THE ACTIVE METABOLITE FROM DIFFERENT PRUDRUGS BY HUMAN LIVER S 9 (96)
`
`IN 1h
`
`Table 1
`
`100,0
`
`90,0
`
`80,0-
`
`70,07’
`
`60,0
`
`50,0-V
`
`40,0
`
`30,0 »
`
`20,0 --
`
`10,0 »
`
`0,0 7
`
`
`
`
`
`[%]oflheor.possibletum-over
`
`A00-I-OAG
`
`HO-I-OBut
`
`HOIOnfiut
`
`iButO-/-OiBut
`
`Buto-/-OBut
`
`HO-/-OProp
`
`HO-/-0Ac
`
`Prop0—lDProp
`
`prodrugs
`
`EP0957073A1
`
`Printed by Xerox (UK) Business Services
`2.16.7/3 6
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 1
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 1
`
`

`
`Description
`
`EP 0 957 073 A1
`
`[0001] The present invention relates to novel derivatives of 3,3-diphenylpropylamines, methods for their preparation,
`pharmaceutical compositions containing the novel compounds, and the use of the compounds for preparing drugs. A
`further object oi the invention is to provide novel prodrugs of anti muscarinic agents with superior pharmacokinetic prop-
`erties compared to present drugs as oxybutynin and tolterodine, methods for preparing thereof, pharmaceutical com-
`positions containing them, a method of using said compounds and compositions for the treatment of urinary
`incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile conditions.
`[0002] More particularly, the present invention relates to certain prodrugs of 3,3-diphenylpropylamines while avoiding
`on administration to a mammal a high variation in bioavailability and formation of active metabolites which can result in
`a substantial variation in response - too low efficacy or too much side effects - for the subjects on the suggested therapy.
`[0003]
`In man, normal urinary bladder contractions are mediated mainlythrough cholinergic muscarinic receptor stim-
`ulation. There is reason to believe that muscarinic receptors mediate not only normal bladder contractions but also the
`main part of the contractions in the overactive bladder resulting in symptoms as urinary frequency, urgency and urge
`incontinence. For this reason antimuscarinic drugs have been instituted as a treatment of bladder over activity.
`[0004] Among the antimuscarinic drugs available on the market, oxybutynin is currently regarded as the gold standard
`for pharmacological treatment of urge incontinence and other symptoms related to bladder over activity. The effective-
`ness of oxybutynin has been demonstrated in several clinical studies but the clinical usefulness of oxybutynin is limited
`due to antimuscarinic side effects. Dryness of the mouth is the must common experienced side effect which may be
`severe enough to result in poor compliance or discontinuation of treatment (Andersson, K.-E., 1988, Current concepts
`in the treatment of disorders of micturition, Drugs 35, 477-494; Kelleher et al. 1994).
`[0005] Tolterodine is a new, potent and competetive, muscarinic receptor antagonist intended for the treatment of uri-
`nary urge incontinence and detrusor hyperactivity. Preclinical pharmacological data show that tolterodine exhibits a
`favourable tissue selectivity in vivo for the urinary bladder over the effect on the salivation (Nilvebrant et al, 1997, Tol-
`derodine - a new bladderselective antimuscarinic agent, Eur. J. Pharmacol. 327 (1997), 195-207), whereas oxybutynin
`exhibits the reversed selectivity. Tolterodine is equipotent to oxybutynin at urinary bladder muscarinic receptors and the
`favourable tissue selectivity of tolterodine demonstrated in the preclinical studies has been confirmed in clinical studies.
`Thus a good clinical efficacy has been combined with a very low number of incidences of dry mouth and antimuscarinic
`side effects.
`
`[0006] A major metabolite of tolterodine, the 5-hydroxymethyl derivative is also a potent muscarinic receptor antago-
`nist and the pharmacological in vitro and in vivo profiles of this metabolite is almost identical to those of tolterodine (Nil-
`vebrant et al, 1997, Eur. J. Pharmacol. 327 (1997), 195-207). Combined pharmacological and pharmacokinetic data
`indicate that it is most likely that the metabolite give a major contribution to the clinical effect in most patients.
`[0007] The document WO 94/11337 discloses that the active metabolite of tolterodine is suggested as a new drug for
`urge incontinence. Administration of the active metabolite directly to patients has the advantage compared to tolterod-
`ine that only one active principle (compound) has to be handled by the patient which normally should result in a lower
`variation in efficacy and side effects between patients and lower risk of interaction with other drugs.
`[0008] However, the introduction of an additional hydroxy group in the tolterodine results in an increased hydrophilic
`property of the new compounds (3,3-diphenylpropylamines) compared to the parent compounds which normally results
`in a lower absorption/bioavailability. In a method to circumvent this disadvantage different prodrugs of the metabolite
`have been synthetized and tested for their absorption/bioavailability data.
`[0009]
`It is an object of the present invention to provide novel derivatives of 3,3-diphenylpropylamines. It is an further
`object of the present invention to provide new derivatives of 3,3-diphenylpropylamines which will be more useful as pro-
`drugs for treatment of urinary incontinence and other spasmogenic conditions that are caused by muscarinic mecha-
`nisms while avoiding the disadvantage of a too low absorption/bioavailability after oral administration of the drugs or an
`unfavourable metabolism.
`
`[0010] The novel compounds of the present invention are represented by the general Formula (I)
`
`(l)
`
`2
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 2
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 2
`
`

`
`wherein R indepently signifies:
`
`EP 0 957 073 A1
`
`a) R‘ represents the residues hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, benzyl or allyl;
`or
`
`b) R2 represents the residues formyl, acetyl, propionyl, isobutyryl, butyryl, valeroyl, pivaloyl, benzoyl; or
`
`c) R3 represents the residues CH3OCO-, CZH5-OCO-, C3H7OCO-, (CH3)3COCO-, benzoylacyl, benzoylglycyl, gly-
`cyl, valyl, Ieucyl, isoleucyl, phenylalanyl, prolyl, seryl, threonyl, methionyl, hydroxyprolyl; or
`
`d) a group consisting
`
`R‘
`\
`
`R5/
`
`of wherein R4 and R5 indepently represent the residues hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
`pentyl, hexyl, benzyl, phenoxyalkyl wherein the alkyl residue means methyl, ethyl, propyl, isopropyl, butyl, isobutyl
`and wherein R4 and R5 may form a ring together with the amine nitrogen; or
`
`e) a group consisting
`
`R5
`3
`R7/
`
`N-SOz-
`
`isobutyl, pentyl,
`of wherein R6 and R7 indepently represent the residues methyl, ethyl, propyl, isopropyl, butyl,
`hexyl, benzyl, phenoxyalkyl wherein the alkyl residue means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,
`hexyl; or
`
`f) an ester of inorganic acids such as sulfuric acid, phosphoric acid;
`
`X represents a tertiary amino group of Formula la
`
`wherein R8 and R9 signify non-aromatic hydrocarbyl groups, which may be the same or different and which
`together contain at least three carbon atoms, and wherein R8 and R9 may form a ring together with the amine
`nitrogen, R‘ represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, benzyl, alkyl,
`phenoxyalkyl wherein the alkyl residue means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, if R is hydrogen
`R‘ will not represent hydrogen or methyl
`and
`
`their salts with physiologically acceptable acids and, when the compounds can be in the form of optical iso-
`mers, the racemic mixture and the individual enantiomers.
`
`[0011] The compounds of Formula (I) can form salts with physiologically acceptable acids, organic and inorganic. Fur-
`thermore the aforementioned compounds comprise the free bases as well as the salts thereof. Examples of such acid
`
`3
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 3
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 3
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`

`
`EP 0 957 073 A1
`
`addition salts include the hydrochloride, hydrobromide and the like.
`
`[0012] When the novel compounds are in the form of optical isomers, the invention comprises the racemic mixture as
`well as the individual isomers as such.
`
`5
`
`Preferably each of R8 and R9 independently signifies a saturated hydrocarbyl group, especially saturated
`[0013]
`aliphatic hydrocarbyl groups such as C1_g-alkyl, especially C1_6-alkyl, or adamantyl, R8 and R9 together comprising at
`least three, preferably at least four carbon atoms.
`[0014] According to an other embodiment of the invention at least one of R8 and R9 comprises a branched carbon
`chain.
`
`[0015]
`
`Presently preferred tertiary amino groups X in Formula I include the following groups a) to h):
`
`a)
`
`- CH(CH3)2
`
`—N<cH(cH )
`
`3 2
`
`b)
`
`_N/
`
`\
`
`CH3
`
`C(CHa)a
`
`/CH3
`
`-—N
`
`\C(CH3)gCH2C}-I3
`
`[0016]
`
`Preferred compounds according to the present invention are:
`
`A) Phenolic monoesters represented by the general Formulae II and II’
`
`4
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 4
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 4
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`

`
`EP 0 957 073 A1
`
`Formula II
`
`Formula II‘
`
`Formic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`Acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`Propionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`n-Butyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`lsobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`2,2-Dimethylpropionic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`Benzoic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`Malonic acid bis—[2-(3—diisopropy|amino-1—pheny|propyl)—4—hydroxymethy|—pheny|] ester
`Succinic acid bis-[2-(3-diisopropy|amino-1-phenylpropyl)-4-hydroxymethyl-phenyl] ester
`Pentanedioic acid bis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl] ester
`Hexanedioic acid bis-[2-(3-diisopropy|amino-1-phenylpropyl)-4-hydroxymethylphenyl] ester
`
`B) Identical diesters represented by the general Formula Ill
`
`Formula III
`
`Formic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester
`Acetic acid 4-acetoxy-3-(3-diisopropy|amino-1-phenylpropyl)-benzyl ester
`Propionic acid 2-(3-diisopropylamino-1—pheny|propy|)—4—propiony|oxymethy|phenyl ester
`n-Butyric acid 4-n-butyryloxymethyl-2-(3-diisopropy|amino-1-phenylpropyl)-phenyl ester
`lsobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-isobutyryloxymethylphenyl ester
`2,2-Dimethylpropionic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-(2,2-dimethylpropionyloxy)-benzyl ester
`Benzoic acid 4-benzoyloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester
`
`5
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 5
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 5
`
`

`
`C) Mixed diesters represented by the general Formula IV
`
`EP 0 957 073 A1
`
`RZYO
`
`Acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester
`Benzoic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester
`lsobutyric acid 4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester
`2,2-Dimethylpropionic acid 4-acetoxy-3-(3-diisopropy|amino-1-pheny|propy|)benzy| ester
`2,2-Dimethylpropionic acid 4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester
`
`D) Benzylic monoesters represented by the general Formula V
`
`Formula V
`
`Formic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`Acetic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`Propionic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`Butyric acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`lsobutyric acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`2,2-Dimethylpropionic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`Benzoic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`
`E) Ethers and silyl ethers represented by the general Formula VI
`
`R4
`l
`
`6
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 6
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 6
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`

`
`EP 0 957 073 A1
`
`2-(3-Diisopropylamino-1-phenylpropyl)-4-methoxymethylphenol
`
`2-(3-Diisopropylamino-1-phenylpropyl)-4-ethoxymethylphenol
`2-(3-Diisopropylamino-1-phenylpropyl)-4-propoxymethylphenol
`2-(3-Diisopropylamino-1-phenylpropyl)-4-isopropoxymethylphenol
`2-(3-Diisopropylamino-1-phenylpropyl)-4-butoxymethylphenol
`Acetic acid 2-(3-Diisopropylamino-1-phenylpropyl)-4-methoxymethylphenyl ester
`Acetic acid 2-(3-Diisopropylamino-1-phenylpropyl)-4-ethoxymethylphenyl ester
`2-(3-Diisopropylamino-1-phenylpropyl)-4-trimethylsilanyloxymethylphenol
`Diisopropyl-[3-phenyl-3-(2-trimethylsilanyloxy-5-trimethylsilanyloxymethylpheny|)propy|]-amine
`[3-(3-Diisopropylamino-1-phenylpropyl)-4-trimethylsilanyloxyphenyl]-methanol
`Diisopropyl-[3-(5-methoxymethyl-2-trimethylsilanyloxyphenyl)-3-phenylpropylamine
`Diisopropyl-[3-(5-ethoxymethyl-2-trimethylsilanyloxyphenyl)-3-phenylpropylamine
`(4-(tert.-Butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-pheny|]methano|
`Acetic acid 4—(tert.—buty|-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester
`4-(tert.-Butyl-dimethylsiIanyloxy)-3-(3-diisopropy|amino-1-phenylpropyl)-phenol
`Acetic acid 4-(tert.-butyl-dimethylsilanyloxy)-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester
`{3-[2-(tert.-Butyl-dimethylsilanyloxy)-5-(tert.-butyl-dimethylsi|any|oxymethy|)phenyl]-3-pheny|propy|}-diisopro-
`pylamine
`[4-(tert.-Butyl-diphenylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]methanol
`Acetic acid 4-(tert.-butyl-diphenylsilanyloxymethyl)-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester
`4-(tert.-Butyl-diphenylsiIany|oxymethy|)-2-(3-diisopropy|amino-1-pheny|propy|)pheno|
`{3-[2-(tert.—Buty|—diphenylsi|any|oxy)—5-(tert.-butyl-diphenylsi|any|oxymethy|)phenyl]—2—pheny|propyl}-diisopro—
`pylamine
`Acetic acid 4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester
`Benzoic acid 4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester
`Isobutyric acid 4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester
`
`F) Carbonates and carbamates represented by the general Formulae VII and VII‘
`
`0
`
`Y
`Y\R6
`0 Y
`
`R5’° 0 NY
`
`HO 0 0 A
`
`A
`Y
`O
`%CH2)n
`Di
`Y
`
`0 Y
`NY
`
`HO
`
`Formula VII
`
`I
`
`Formula VII’
`
`N-Ethylcarbamic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`N-Phenylcarbamic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester
`N-Ethylcarbamic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-N-ethylcarbamoyloxybenzyl ester
`
`7
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 7
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 7
`
`

`
`EP 0 957 073 A1
`
`N-Phenylcarbamic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-N-phenylcarbamoyloxybenzyl ester
`
`{4-[2-(3-Diisopropy|amino-1-phenylpropyl)-4-hydroxymethyl-phenoxycarbonylamino]-butyl}-carbamic acid 2-
`(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyl ester
`Carbonic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester ethyl ester
`Carbonic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester phenyl ester
`Carbonic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-ethoxycarbonyloxymethylphenyl ester ethyl ester
`Carbonic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-phenoxycarbonyloxymethylphenyl ester phenyl ester
`
`10
`
`[0017] The compounds of formula (I) may, in accordance with the present invention be prepared by per se conven-
`tional methods. Methods for preparing substituted 3,3-diphenylpropylamines as disclosed by this invention may be syn-
`thesized according to methods as described in the document PCT/SE93/00927.
`[0018] The invention will be further illustrated by the following non-limiting examples and pharmacological tests.
`[0019] The following starting materials and preffered Examples illustrate the invention:
`
`I. Experimental
`
`1. General
`
`All compounds were fully characterized by ‘H and 13C NMR spectroscopy. The chemical shifts reported (‘3C
`[0020]
`NM Fl, ppm) refer to the solvents CDCI3 (77.10 ppm), CD3OD (49.00 ppm) or hexadeuterio dimethylsulphoxide (DMSO-
`d6, 39.70 ppm) respectively. Thin-layer chromatography (tlc, Rf values reported) was conducted on precoated 5x10 cm
`E. Merck silica gel plates (60F254), spots were visualized by fluorescence quenching or spaying with alkaline potas-
`sium permanganate solution. Solvent systems: (1), ethyl acetate/n-hexane (30fl0, v/v-%); (2), to|uene/acetone/metha-
`nol/acetic
`acid
`(70/5/20/5,
`v/v-%);
`(3),
`n-hexane/acetone/diethylamine
`(70/20/10,
`v/v-%);
`(4),
`n-
`hexane/acetone/diethylamine (70/20/10, v/v-%); (5), ethyl acetate/n-hexane/2-propanol/triethylamine (60/40/20/1, v/v-
`%); (6), ethyl acetate/triethylamine (90/10, v/v-%). Gas chromatography-mass spectrometry (GC-MS): spectra (m/z val-
`ues and relative abundance reported) were recorded on a Finnigan TSQ 700 triple mass spectrometer in the positive
`(P-Cl) or negative (N-Cl) chemical ionization mode using methane or ammonia as reactant gas. Hydroxylic compounds
`were analyzed as their trimethylsilyl ether derivatives.
`
`2. Synthesis of Intermediates A and B
`
`[0021] An icecooled solution of 4-bromophenol (69.2g) and cinnamoyl chloride (66.8g) in dichloromethane (150ml)
`was treated with triethylamine (40.6g). After stirring for 18h at room temperature the mixture was washed with water
`(250ml), 1M aqueous HCI, and dried over anhydrous sodium sulphate. Evaporation in vacuum left solid 3—pheny/acry/ic
`acid 4—bromophenyI ester (121.0g, 99.8% yield), m.p. 113.3 °C, tlc (1) 0.83. NMR(CDCl3): 116.85, 118.87, 123.49,
`128.38, 129.06, 130.90, 132.49, 134.02, 147.07, 149.84, 165.06.
`[0022] A portion of the ester (60.0g) was dissolved in a mixture of acetic acid (60ml) und concentrated sulphuric acid
`(18ml) and refluxed for 2h. After cooling, the reaction mixture was poured into ice water and the product was was iso-
`lated by extraction with ethyl acetate. Evaporation of the solvent and recrystallization of the residue from boiling I etha-
`nol (150ml) yielded 26.3g (43.8% yield) of pure, crystalline 6—bromo—4—pheny/chroman—2—one, m.p. 117.8 °C, tlc (1)
`0.67. NMR (CDCI3): 36.56, 40.51, 117.29, 118.87, 127.47, 127.89. 128.33, 129.32, 131.07, 131.79, 139.42, 150.76,
`166.84.
`
`A suspension consisting of 6-bromo-4-phenylchroman-2-one (85.0g), anhydrous potassium carbonate
`[0023]
`(46.7g), sodium iodide (20.5g) and benzyl chloride (40.6g) in methanol (350m|) and acetone (350m|) was refluxed for
`3h. After evaporation of the solvents the residue was extracted with diethyl ether (2 x 300ml) and the extract was
`washed with water (2 x 200ml) and aqueous sodium carbonate. Drying (Na2SO4) and rotoevaporation left 121.8g
`(102.1 % crude yield) of 3-(2-benzy/oxy—5-bromophenyl)—3—phen)/mropionic acid methyl ester as a light yellow oil, tlc (1)
`0.77. NMR (CDCI3): 39.22, 40.53, 51.63, 70.16, 113.10, 113.77,126.46, 126.92, 127.88, 128.08, 128.34, 128.45,
`130.31, 130.55, 134.41, 136.44, 142.37, 154.94, 172.08.
`[0024] A solution of the propionate (121 .0g) in 350ml of dry tetrahydrofuran was slowly added under an atmosphere
`of nitrogen to a suspension of lithium aluminiumhydride (7.9g) in tetrahydrofuran (350m|). After stirring at room temper-
`ature for 18h, 20% aqueous HCI was added dropwise and the product was isolated by repeated extraction with diethyl
`ether. The combined extracts were gradually washed with hydrochloric acid, sodium hydroxide solution, distilled water,
`and then dried (Na2SO4) to give a light yellow viscous oil (108.8g, 96.3% yield) after evaporation which gradually crys-
`tallized, m.p. 73.8 °C, tlc (1) 0.47, 3—(2—benzy/oxy—5—brom0phenyU—3—phenymropan—1-0/. NMR (CDCI3): 37.52, 39.52,
`60.84, 70.54, 113.54, 113.83, 126.29, 127.30, 127.51, 129.99, 128.24, 128.38, 129.99, 130.88, 135.69, 136.40,
`143.53, 155.12.
`
`8
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`
`EP 0 957 073 A1
`
`[0025] A cooled (5 °C) solution of 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropan-1-ol (108.0g) in dichloromethane
`(300ml) war treated with pyridine (79.4ml) and than p-toluenesulphonyl chloride (60.6g) in dichloromethane (200ml).
`After 18h at room temperature the solvent was removed in vacuum and the residue extracted diethyl ether. The extract
`was washed with hydrochloric acid, water, and dried over anhydrous sodium sulphate to give to/uene-4—su/phonic acid
`3-(2—benzy/oxy—5—bromophenyD—3—phen)/wropyl ester as a light yellow oil after concentration under reduced pressure
`(140.3g, 93.6% yield), tlc (1) 0.66. NMR (CDCI3): 21.67, 33.67, 39.69, 68.58, 70.28, 113.21, 113.76, 126.47, 127.84,
`128.10, 128.25, 128.41, 128.51, 129.81, 130.26, 130.42, 132.91, 134.39, 136.41, 142.16, 155.07.
`
`A solution of the toluenesulphonate (139.3g) in acetonitrile (230m|) and N,N-diisopropylamine (256g) was
`[0026]
`refluxed for 97h. The reaction mixture was then evaporated to dryness and the residue thus formed was partitioned
`between diethyl ether (500ml) and aqueous sodium hydroxide (2M, 240ml). The organic phase was washed twice with
`water (250ml) and then extracted with 1M sulphuric acid. The aqueous phase was adjusted to about pH 12-13 and reex-
`tracted with ether (500m|). The organic phase was washed with water, dried (Na2SO4) and evaporated to provide [3—(2—
`benzy/oxy—5—bromopheny/)—3—phenyipropyU—diisopropy/amine as a brown and viscous syrup (94.5g, 77.9% yield), tlc (2)
`0.49. NMR (CDCI3): 20.65, 20.70. 36.70, 41.58, 43.78, 48.77, 70.24, 113.52, 126.02, 127.96, 128.20, 128.36, 129.82,
`130.69, 136.34, 136.76, 144.20, 155.15.
`
`[0027] An ethereal Grignard solution, prepared from the above amine (22.8g), ethyl bromide (17.4g) and magnesium
`(6.1g) under an atmosphere of nitrogen was diluted with dry tetrahydrofuran (200ml) and then cooled to -60 °C. Pow-
`dered solid carbon dioxide (ca. 50g) was the added in small portions and the green reaction mixture was warmed at
`room temperature. After the addition of an aqueous solution of ammonium chloride (200ml, 10%) and adjustment of the
`aqueous phase to pH 0.95, a white solid was recovered by filtration to provide 4-benzy/oxy—3-(3—diisopropy/amino—1-
`phenylpropy/)benzoic acid hydrochloride (14.7g, 64.3% yield), m.p. 140 °C (dec.), tlc (2) 0.33. NMR (CD3OD): 17.07,
`18.77, 33.55, 43.27, 56.50, 71.50, 112.89, 124.10, 127.94, 129.07, 129.25, 129.34, 129.59, 129.66, 130.18, 131.60,
`132.78, 137.60, 143.30, 161.11, 169.70.
`[0028] The hydrochloride was converted into its methyl ester (MeOH, trace sulphuric acid, 6h reflux) and the free base
`thus obtained (28g) was dissolved in dry diethyl ether (230ml). This solution was slowly (2h) dropped under an nitrogen
`atmosphere to a suspension of lithium aluminium hydride (1 .8g) in ether (140ml). After stirring for 18h, the reaction was
`quenched by the addition of water (4.7ml). The organic phase was dried over anhydrous sodium sulphate, filtered and
`evaporated to dryness to provide [4—benzy/oxy-3—(3diisopropy/amino—1—phenymrop)/0—phenyU—methano/ (26g, 98.9%
`yield), as an oil which gradually crystallized, m.p. 86.4 °C. tlc (2) 0.32, Intermediate A. NMFl (CDCI3): 20.53, 20.61,
`36.87, 41.65, 44.14, 48.82, 65.12, 70.09, 111.80, 125.77, 125.97, 126.94, 127.55, 128.08, 128.37, 128.44, 133.27,
`134.05, 134.27, 137.21, 144.84.
`
`(intermediate A)
`
`A solution of Intermediate A (9.1g) in methanol (100m|) was hydrogenated over Flaney-nickel (4.5g) under
`[0029]
`ambient conditions. After 5h thin layer chromatography indicated complete hydrogenolysis. The catalyst was filtered off
`and the solution evaporated to dryness to leave an oil (6.95g, 96.5% yield) which gradually solidified, 2-(3-diisopro—
`py/amino—1—pheny(0ropyD—4—h)/droxymethylpiveno/, m.p. 50 °C.
`tlc (2) 0.15, Intermediate B. NMR (CDCI3): 19.42,
`19.83, 33.22, 39.62, 42.27, 48.27, 65.19, 118.32, 126.23, 126.55, 127.47, 128.33, 132.50, 144.47, 155.38. Hydrochlo-
`ride: colourless crystalls, m.p. 187-190 °C (with decomposition)
`
`9
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`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 9
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 9
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`

`
`EP 0 957 073 A1
`
`(Intermediate 8)
`
`3. Examples
`
`a) Phenolic monoesters
`
`aa) General Procedure
`
`A stirred solution of 2—(3—diisopropy/amino-1-phenymrop)/0-4—hydroxymethyioheno/ (Intermediate B, 1.71g,
`[0030]
`5.01 mmol) and acid chloride (5.00 mmol carboxylic acid monochloride ior compounds of Formila II, 2.50 mmol for com-
`pounds of Formula II‘) in 60 ml of dichloromethane was cooled to 0 °C and then triethylamine (0.502g,4.96 mmol for
`compounds of Formula II, 1.05g, 9.92 mmol for compounds of Formula II‘), dissolved in 10 ml oi dichloromethane, was
`added dropwise during 5-10 mm. Stirring was continued for 18h at room temperature, and then the mixture was washed
`successively with water (25 ml), aqueous sodium hydrogen carbonate (5%, 25 ml), and water (25 ml). The organic
`phase was then dried (sodium sulphate) and evaporated under reduced pressure and a low temperature. The oily res-
`idues thus formed were finally exposed to high vacuum (2-4 hrs.) to remove traces of residual solvents. The esters of
`Formula II or II’ were obtained as viscous colourless to light yellow syrups in purities between 90% and 99% (tlc, HPLC,
`NM Ft).
`
`bb) Salt formation (Example hydrochloride)
`
`[0031] A cooled (0 °C) solution of 4.94 mmol amino base in 30 ml oi dry diethyl ether was treated under an atmos-
`phere oi nitrogen with 4.70 mmol (monoamines oi Formula II) or 9.4 mmol (diamines of Formula II‘) ethereal ( 1M)
`hydrochloric acid. The oily precipitation was washed repeatedly with dry ether and then evaporated in high vacuum. The
`residual product solidificated in most cases as an amorphous ioam. The highly hygroscopic solids show a wide melting
`range above 100 °C (with decomposition).
`
`Acetic acid 2-(3—diisopropy/amino—1—phenyioropyD-4—hydroxymethyioheny/ ester, Rf 0.47 (4), NMR (CDCI3): 20.36,
`20.68, 20.97, 36.59, 42.35, 43.83, 48.76, 64.58, 122.69, 125.61, 126.22, 126.71, 127.96, 128.34, 136.82, 138.97,
`
`143.73, 147.77, 169.24; GC-MS/P-Cl (ammonia, trimethylsilyl derivative): 456.8 (100%), 398.4 (4%)
`
`Propionic acid 2—(3—diisopropy/amino—1—pheny/propyD-4—hydroxymethy/pheny/ ester, Rf 0.52 (4); NMR (CDCI3):
`20.44, 20.64, 27.67, 36.67, 42.21, 43.87, 48.78, 64.70, 122.71, 125.62, 126.52, 126.78, 127.97, 128.53, 136.86,
`138.82, 143.82, 147.86, 172.68; GC-MS/P-Cl (ammonia, trimethylsilyl derivative): 470.38 (100%), 398.4 (4%)
`
`n-Butyric acid 2-(3-diisopropy/amino—1-phenyiorop)/0-4Jvydroxymethyiohenyl ester, Rf 0.43 (4); NMR (CDCI3):
`13.77, 18.40, 20.43, 20.51, 20.59, 36.15, 36.82, 42.16, 43.90, 48.83, 49.20, 64.58, 122.66, 125.98, 126.17, 126.74,
`127.33, 127.94, 128.33, 136.79, 138.91, 143.82, 171.88; GC-MS/N-Cl (methane, trimethylsilyl derivative): 482.3
`(20%), 412.3 (100%), 340.1 (33%), 298.1 (89%), 234.7 (15%); GC-MS/P-Cl (methane, trimethylsilyl derivative):
`484.5 (100%), 468.4 (62%), 394.3 (22%); ; GC-MS/P-Cl (ammonia, trimethylsilyl derivative): 484.4 (100%), 398.4
`(3%)
`
`lsobutyric acid 2-(3—diisopropyIamino—1—phenyioropy0—4—hydroxymethy/pheny/ ester, Ft, 0.43(4); NMR (CDCI3):
`18.99, 19.11, 20.54, 34.21, 36.88, 41.84, 43.91, 48.78, 64.61, 122.54, 125.57, 126.14, 126.81, 127.94, 128.34,
`136.84, 138.84, 143.89, 147.85, 175.36:
`
`2,2—Dimethy/propionic acid 2—(3—diisopropy/amino—1—pheny/propyD—4—hydroxymethy/pheny/ ester, Rf 0.49 (1); NMR
`(CDCI3): 20.46, 20.66, 26.53, 27.34, 37.12, 39.21, 41.46, 43.98, 48.81, 64.65, 122.42, 125.58, 126.16, 126.92,
`
`10
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`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1069 — Page 10
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`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1069 - Page 10
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`

`
`EP 0 957 073 A1
`
`128.37, 134.27, 136.92, 138.82, 143.97, 148.02, 176.97; ;GC-MS/P-Cl (ammonia, trimethylsilyl derivative): 498.8
`(100%), 482.5 (10%), 398.4 (4%)
`
`Benzoic acid 2—(3—diisopropy/amino—1—pheny/propyD-4-hydroxymethymhenyl ester, Rf 0.52 (4); NMR (CDCI3):
`20.42, 20.62, 36.95, 41.72, 42.27, 48.23, 64.83, 122.74, 125.33, 127.36, 127.89, 127.97, 128.38, 129.34, 130.64,
`131.15, 131.83, 136.87, 138.90, 143.82, 147.74, 164.77
`
`Ma/onic acid bis-[2-(3-diisopropy/amino—1-p/1eny#3ropyD-4—hydroXymethy/-phenyfl ester, F), 0.38 (4); NM R (CDCI3):
`20.52, 20.62, 20.69, 36.95, 41.84, 42.82, 43.89, 48.23, 64.83, 123.37, 127.36, 127.97, 128.42, 128.38, 129.06,
`131.55, 137.50, 138.90, 148.23, 148.32, 160.54
`
`Succinic acid bis—[2—(3—diisopropy/amino—1—phenymropy0—4—hydroxymethy/—phenyU ester, Rf 0.40 (4)
`NMR (CDCI3): 20.54, 20.63, 20.73, 30.69, 36.91, 41.80, 43.92, 48.20, 64.81, 122.60, 127.41, 127.93, 128.39,
`129.31, 131.80, 136.73, 138.92, 143.82, 148.17, 168.01
`
`Pentanedioic acid bis—[2—{3—diisopropy/amin0—1—phenymropyD—4—hydrox)/methy/—phenyU ester, R, 0.43; NMR
`(CDCI3): 20.47, 20.60, 32.87, 36.93, 41.82, 43.90, 48.22, 64.81, 64.83, 122.85, 122.85, 127.39, 127.99, 128.35,
`129.31, 131 .84, 136.98, 138.94, 143.80, 147.40, 147.40, 169.05
`
`Ft, 0.43; NMR
`Hexanedioic acid bis—[2—(3—diisopropy/amino-1—p/1eny/propy0—4—I1ydroxymethy/—phenyU ester,
`(CDCI3): 20.64, 23.40, 34.37, 36.95, 41.84, 43.88, 48.25, 64.87, 122.88, 127.34, 127.97, 128.39, 129.33, 131.80,
`136.99, 138.94, 143.82, 147.65, 168.72
`
`b) Identical diesters
`
`Identical diesters (Formula III) were prepared and worked-up as described above with the exeption that 2.4
`[0032]
`mmol of both triethylamine and acyl chloride (R1-COCI) were used. The physical properties were similar to the bases
`and salts described above.
`
`Formic acid 2—(3—diisopropy/amino—1—pheny/propyD—4—formy/oxymethy/phenyl ester, Rf 0.65 (4) This diester was
`prepared trom mixed formic acetic anhydride and Intermediate B as described tor other substrates previously (F:
`Reber, A. Lardon, T. Reichstein, He/v. Chim. Acta 37: 45 - 58 [1954])
`
`Acetic acid 4—acetoxy—3—(3—diisopropyIamino—1—phenymropy0—benzy/ ester, Rf 0.76 (4);; GC~MS/P-Cl (ammonia):
`426.3 (100%), 368.3 (22%); GO-MS/P-CI (methane, trimethylsilyl derivative): 426.4 (64%), 410.3 (16%), 366.3
`(100%); hydrochloride, NMR (DMSOd5): 16.50, 16.76, 18.05, 20.94, 21.04, 27.02, 31.39, 41.28, 45.26,
`53.80,65.21,123.39, 126.84, 127.61, 127.85, 128.70, 134.41, 135.49, 142.68, 148.20, 169.32, 170.42
`
`Fl, 0.82 (4); NMR
`Propionic acid 2-(3-diisopropylamino-1—pheny(oropy0-4-propiony/oXymethy(oheny/ ester,
`(CDCI3): 20.53, 20.73, 21.14, 27.66, 36.73, 42.10, 43.68, 48.65, 65.75, 122.65, 126.10, 127.01, 127.70, 128.34,
`128.78, 133.73, 136.81, 143.76, 148.45, 172.45, 174.21; ; GO-MS/P-Cl (ammonia): 454.8 (100%), 438.5 (9%),
`382.4 (27%)
`
`Ft, 0.86 (4); NMR
`n-But)/ric acid 4-n—butj/ryloxymethy/-2-(3-diisopropy/amino-1-phenyloropyfl-phenyl ester,
`(CDCI3): 13.70, 13.76, 18.44, 20.53, 20.69, 21.13, 36.14, 36.76, 37.09, 42.08, 43.73, 48.71, 65.64, 122.81, 125.97,
`126.97, 127.92, 128.35, 128.77, 133.78, 136.99, 143.76, 148.41, 171.68, 173.40; ; GC-MS/P-Cl (ammonia): 482.8
`(100%), 396.4 (67%)
`
`lsobutyric acid 2—(3-diisopropy/amino—1—pheny/propy0—4-isobutyryloxymethy(oheny/ ester, R, 0.83 (4); NMR
`(CDCI3): 18.97, 19.10, 20.64, 20.67, 34.01, 34.23, 36.98, 41.72, 43.70, 48.65, 65.61, 122.50, 126.18, 126.73,
`127.92, 128.13, 128.36, 133.90, 137.01, 143.85, 148.41, 175.17, 176.81; GC-MS/N-CI (methane,): 480.3 (15%);
`GC-MS/P-Cl (methane): 482.5 (63%), 466.4 (18%), 394.3 (100%