ii
`
`.
`
`rap 0 957 073 A1
`
`Benzoic acid 4-benzoyloxymetiryl-2-(3-diisopropylamino-1-phenymropyfl-phenyi ester. H.069 (4); NMR (CDCIS):
`' 20.62,36.95, 41.72, 43.89, 48.23..66.76, 122.22.125.33, 127.36, 127.62, 127.89. 127.89,'127.97, 128.38, 129.49,
`130.52. 130.64. 131.15, 131.22, 131.98, 136.38, 137.66, 143.82, 148.95.164.77,‘ 166.6(_1,?;=‘.,_
`y
`K.
`‘
`I
`diesters
`C)
`4
`-
`9
`’
`‘:'
`.
`4
`_V
`[0033] Mixed diesters (Formula IV) were prepared by acylation of the respective benzylic r§r‘pVl_ienolic;a;i‘n‘_§ri_oesters.
`‘Workup and physical properties corresponded to the bases and salts described above.
`. " 1“
`'
`*
`
`’
`
`_.
`
`‘'
`
`
`
`'13]
`
`E
`
`‘Acetic acid 2-(3-diisopropyIamino-1-phenykaropyl)-4-iormyloxymetiiykahenyl ester,‘ R, 0.76 (4); NMR (cocr5)£
`20.52. 20.91. 33.25. 42.20, 4223, 48.23, 70.71. 122.95, 127.35, 127.97, 128.38, 123.73, rszoa 135.41, 137.11,
`143.31, 149.35, 161.34.168.95
`
`5
`
`ra
`
`15
`
`_
`
`Benzoic acid 2—(3-diisopropylaminol1-phenymropyo-4-iormyloxymethyiohenyl ester, R} 0.74 (4); NMR (CD013):
`20.60, 36.93. 41.72, 43.89, 48.23‘. 70.71, 122.50, 125.33. 127.30, 127.89, 127.97, 128.36, 129.57, 130.65, 131.13,
`132.05, 135.41. 135.66, 143.80, 149.15, 161.35, 164.78
`
`-
`
`»
`
`'
`
`_
`
`'
`
`_
`
`i
`V
`I
`
`i
`
`Isobutyric acid 4-acetoxymethyl-2-(3—dirsopropyIamino-1-phenybropyp-phenyl ester, R, 0.77 (4); NMFl (CDCI3):
`18.99, -19.12,=20.65. 421.05, 34.24, 37.02, 41.79, 43.79, 48.72, 65.98, 122.75,-126.76, 127.-14, 127.94, 128.39.
`128.84, 133.55, 137.04.143.84. 148.56, 170.84, 175.18;
`,.
`‘
`'
`'
`
`20
`
`2,2-Dimethylpropionic acid 4-acetoxy-3-(3-diisopropylamino-1-phenylpropyb-benzyl ester, R, 0.80 I (4); NMR
`(CDCI3): 20.63, 20.93, 27.19, 33.25, 37.49, 42.21. 42.25. 48.22, 67.37, 123.18, 127.36, 127.84, 128.39, 131.16,
`’ _.137.34, 143.84, 148.29, 168.93, 178.40.
`4
`,
`.
`_(
`"
`'
`.
`’
`'
`'
`
`.
`
`0.81 (4): NMR
`_2,2-Dimethymropiorric acid 4-acetoxymethyl-2~(.3-diisopropyIamino—1-phenyIprbpy0phenyI ester.
`(GDCI3): 20.60, 20.79. 27.09, 36.93, 37.35, 41.85, 42.29, 48.25, 65.91, 122.36, 127.37, 127.99, 128.39, 129.38,
`132.69.136.00, 136.85, 143.80. 170.45. 176.60
`'
`‘
`.
`.
`
`30
`
`d) Benzylic monoesters'
`
`35
`
`'
`45
`
`A
`50
`
`55
`
`[0034] A mixture consisting of Intermediate B (80 mg, 0.23 rnrnol), vinyl ester (0.4 ml), tert.-butyl methylether (18 ml),
`and lipase enzyme (1.0 g) was gently shaken at room temperature. Benzylic tormate. acetate. and n-butyrate were pre-
`pared from the corresponding vinyl ester donors using SAM Ilipase (Amano Pharmaceutical Co.). Benzcylation was
`achieved with vinyl benzoate in the presence of Lipozym IM 20 (Novo -Nordisk), vmereas pivalates and isobutyrates
`were obtained from the corresponding vinylesters under catalysis of Novozy'm SP 435 (Novo Nordisk). Tic analysis
`indicated after 2 - 24 h complete-disappearance otthe starting material (R, = 0.45 (3). The mixture was filtered and then
`evaporated under high vacuum (< 40 PC) to give the car’ooxylic.acid.(R‘-COZH) salts otthe respective benzylic
`monoesters as colourless to light yellowoils- ‘
`_
`»
`'
`
`-
`
`Formic acid 3-(3—diisopropylamino-:1-phenymropyv-4-hydroxybenzyl ester, R, 0.25 (2); NMR (CDCI3): 119.43, 33.24,
`39.61. 42.25, 48.21, 68.44, 118.09. 127.34, 127.66, 128.31, 128.39, 133.97, 144.47, 156.63, 161.32
`
`"Acetic acid 3-(3-dirsopropyiamirro-1—phenylpropyD-4-hydroxybenzyl ester, R, 0.26 (2); NMR (CDCIS): 19.45.20.96.
`33.26, 39.63. 42.27, 48.23, 48.23, 63.59, 118.00, 127.36, 128.33. 128.33, 128.48, 128.48, 128.53, 129.13. 131.59,
`133.88. 144.49, 155.74, 170.44
`'
`.
`’
`.
`‘
`
`-
`
`Propionic acid 3-(3—dirsopropyIamino'—1-phenylpropyu-4-hydraxybenzyl ester. R, 0.45 (2); NMR (CDCI3): 19.02, _
`19.43, 27.58, 33.20. 39.61, 42.25, 48.21, 64.08, 118.30, 125.30, 127.03, 127.39. 128.31, 130.12, 134.22, 144.51,
`155.64, 173.22
`1
`~
`'
`
`Buiyric acid 3-(aaiisopropylamino-1-phenylpropyv-4—hydroxybenzyI ester, R, 0.54 (2); NMR (CDCI3): 13.58, 18.40,
`19.45, 33.29, 35.88. 39.65, 42.23, 48.25, 63.96, 118.32, 124.55, 126.20, 127.35, 128.32, 129.91, 134.22, 144.50,
`155.60, 169.05
`'
`
`/sobuiyric acid 3—(3—diisopropyIamino71-pheny/propy0-4-hydroxybenzy/ ester, R, 0.56 (4); NMR (CDCI3): 19.09,
`19.45, 33.28, 33.59.139.65. 42.29, 48.25, 64.63, 118.35, 125.35. 127.03, 127.38, 128.35, 128.49, 129.79, 134.22,
`144.52, 155.65, 175.48
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 834
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 834
`
`

`
`{'
`.
`EP0957073 A1
`if
`2,2—DimethyIpropionic acid 3-(3-diisopropyIamino-1-phenywropyb-4-hydroxybenayl ester. R, 0.61 (4); NMR
`(CDCI3): 19.41, 27.15, 33.24, 37.46, 39.61. 42.25, 4821, 65.10, 118.30.125.32, 127200, 127.34. 128.31, 129.42.
`134.18. 144.47, 155.61, 178.39
`'
`,,
`V
`‘I-3-
`_./.
`_
`‘_
`,
`,‘
`.7
`7
`‘
`'
`7
`‘
`'.."‘
`Benzaic acid .3-(3-diisopropy/amino-1-phenybmpyy-4-hydmxybenzxl ester. R, 0.77‘ (4);‘ NMR (pDCl3):18.Q1.
`19.40. 33.24, 39.60, 42.40, 48.20, 66.93. 117.13. 127.18. 127.81, 1281.33. 129.98, 130.17. 132.96, 183.58. 142.33,
`155.95, 166.60
`.
`I”
`it
`
`'
`
`‘
`
`r
`
`-
`
`,'_ .
`
`
`
`e) Ethers and silyl ethers
`
`[0035] A mixture of Intermediate B (3.4g, 10 mmol). methanesulphonic acid (2 ml, 31 mmol). and alcohol R3-OH,.(50
`- _150 ml) was stirred at room temperature until no starting material was detectable (2 - 24h). After evaporation to dry-
`ness (< 35 °C) the residue was redissolved in aqueous sodium hydrogen carbonate solution (100 - 200 ml, 5 ‘)6. wlv)
`and the solution was extracted with ethyl acetate (75 ml). The organic phase was separated, dried (Na-2804). filtered
`and evaporated to give bases of Fomlula VI (R‘ = H) as colourless to light yellow oils
`-
`«
`-[0036] Mixed ester ether derivatives. e-.g. of Intermediate A. were prepared by benzylic acylation of phenolic ethers.
`‘ such as Intermediate A. according to the procedure described for Examples of the structure of Formula l\/.
`
`15
`
`l-lydrochlcrides:
`
`-
`
`[0037] Molar equivalents of bases of Formula Vl (H4 = H). dissolved__ in tert.=butyl_ rn_e_t_hyle_ther._and ethereal hydrochlo-
`_ric acid were combined at room temperature. Oilyprecipitates were separated and dried in vacuum, crystalline hydro- '
`chlorides were isolated and recrystallized from acetonitrile to give colourless crystalline material.
`
`__
`
`25.
`
`2-(3-Diisoproply/amino-1-phenymropyo-4-methoxymethywhenol, R. 0.61 (4); GC-MS/P-Cl (methane, trimethylsilyi
`derivative): 428.4_(100%). 412.3 (49%). 396.3 (52%); hydrochloride: amorphous hygroscopic colourless solid; in.
`_- p. 161 ‘C; NMR (CD3OD): 17.39/18.75 (broad signals). 33.79. 43.13. 56.47. 58.00, 75.59, 116.19, 120.79. ‘1 27.62,
`129.04. 129.14. 129.42, 129.55. 130.43, 144.32. 155.85
`.
`'
`
`'
`
`2—(3-Diisopropylarnino-1-phenykaropyp-4-ethoxymerizylphenol, R, 0.72 (4); GC-MS/P-GI (ammonia. trimethylsilyl
`derivative): 444.8 (100%), 398.4 (6%); hydrochloride m. p 158 - 161 °C. NMR (CD300): 15.43, 17.12. 18.82,
`33.80. 56.49, 66.49. 73.62, 116.19. 127.63. 128.99. 129.13. 129.36.129.55, 130.58, 1_30_.75. 144.32.155.77
`
`f2-(3-Di:sopropyIamino-1—phenywropy0-4-prapoxymethyI—phenol, NMR (CDC|3)i 18.62, 19.44. 23.10, 33.24. 39.61,
`-442.26, 48.22. 71.87. 73.94, 117.78. 124.95. 127.35. 127.57, 128.32, 128.47, 133.66. 134.23. 144.48, 155.25
`
`2-(3—DirsopropyIamino-1—phenyk)ropy0¥4-isopropoxymethyl-phenol. ‘NMR (C0CI3): 19.44, 122.32. 33.27,_ 39.65,
`42.29, 48.25. 69.28, 72.10, 117.90, 127.38, 128.03, 128.41 , 131.10, 133.76, 134.37, 144.51. 154.65
`
`2-(3-Diisopropylamino-1-pheny0Jropy04-butoxymethyl-phenol,(NMR (CDCl§): 13.75, 19.44, 19.75, 3224, 33.28,
`39.60. 42.20. 48.20, 72.45, 117.87,‘ 125.50. 127.29. 128.39, 133.70, 134.30, 144.47, 155.36
`
`I
`
`"Acetic acid 2-{3—DiisopropyIamino-14-phenylpropy0—4-methoxymethyI-pheny/ ester. NMR (CDCI3): 19.99, 20.62,
`20.90, 33.33, 42.30. 48.21, 58.41, 75.94, 122.92, 127.37, 127.95, 128.35, 131.85, 136.99, 138.81. 143.88. 147.88,
`168.95
`~
`.
`.
`'
`
`Acetic acid 2-(3-Dirsopmpylamino—1-phenymropy0-4-ethoxymetI;v/-pheny/ ester, NMR (CDCI3): 15.49, 19.94.
`20.95. 33.23, 42.25, 48.25, 65.70, 73.73, 122.63, 127.46, 127.95, 128.36, 131.65, 136.79, 139.71. 143.80, 147.66,
`168.99
`.
`~
`.
`.
`
`2~(3—Diisopropyiamino-1-phenybropy0-4-trimethylsi/anyloxyrnethymhenol, NMR (CDCI3): 0.10, 0.10. 19.40, 19.43.
`33.25, 39.65, 42.25. 48.20. 64.93, 117.90, 124.90, 126.60, 127.35, 128.35. 128.48, 133.80. 137.15.144.49.
`155.28
`-
`-
`
`Diisopropyl-[3-phenyl-3-(2—trimethylsilanyloxy-5-rrimethylsi/anyloxymethylphenyu-propyflamine, NMR (CDCI3):
`0.10, 0.10, 0.29, 0.29, 19.40. 19.53. 33.28, 41.19, 42.27, 48.25. 66.40, 121.37, 127.36, 128.25, 128.50, 136.42,
`144.10, 154.98
`'
`»
`
`45
`
`50
`
`55
`
`13
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 835
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 835
`
`

`
`;
`EP0957073A1
`,
`i
`[3-(3-Diisopropy/amino?1-phenymropyD¥4-trimethylsilany/oxyphenyfl-methano/.1hlixlllil (CD013): 0.29. 0.33. 19.40.
`19.53. 33.27. 41.16. 42.27, 48.23. 65.22. 118.04. 124.99. 126.52. 127.30. 128.25. 134.15.136.80. 144.14 155.05
`
`DI7sopr0pyl-[3-(5~methoxymethyl-2-trimethylsilanyloxyphenyb-3-phenybropylamine._ NMB{ (C_DC|3): 0.28. 0.32.
`19.39. 19.43. 33.28. 41.22. 42.33, 48.19. 58.40, 75.95, 117.68. 124.92. 126.60, 127.35. 128.25. 128.$. 134.00.
`' 136.47. 144.15. 155.09
`1
`'
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`1
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`
`5-
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`.
`»
`-
`l
`‘
`*7
`
`Drisopropyl-[3-(5-ethoxymethyI—2-trimethylsilanylaxyphenyu-3-phenykampylamine. NMR = (GDCI3): 0.28. 0.31,
`15.50. 19.42, 19.58, 33.29. 41.17, 4225, 48.20. 65.70. 72.48.117.50. 124.75.126.39. 127.39. 128.25. 128.50.
`4 134.99.136.28,144.19. 154.28
`-
`«
`'
`.
`
`.2.”
`
`.
`
`.
`
`.1,
`4
`__
`.
`'1;
`
`[4-(tert-Butyl-dimethylsiIanyIoxy)-3—(3-cfiisopropy!amino-1-phenylpropyb-phenyljmethanol.
`
`0.65 (3)
`
`.
`
`Acetic acid 4-(tert—butyI-dimethylsilanyloxy)-3-(3-diisopropyIamino-1-phenywropy0-behzy/ ester. NMR (CDCI3): -
`‘ 4.92. -5.00, 19.40. 19.49._ 20.40. 20.83. 23.49. 33.25. 41.22. 42.25. 48.25. 72.55..81.55. 121.24. 124.88. 127.40,-
`128.26..128.48. 128.44. 133.37.135.74. 144.11. 155.20
`:
`-
`
`4-(tert.-Butyl-dimethylsilany/oxyrnethyD-2-(3-wisopropyIamin0—1-phenyloropyb-phenol. Fl. 0.70 (3): GC-MSIN-Cl
`(methane, trimethylsilyl derivative): 526.5 (59%). 454.3 (100%). 4122 (14%). 340.1 (42%); GC-MSIP-Cl (methane.
`‘ trimethylsilyl derivative): 528.6 (100%). 512.5 (85). 470.43 (10%). 396.3 (31%)
`
`Acetic acid 4-(tert-bury/1-dimethyisilanyloxy)-2-(3-dfisopropylamino-1-phenymropyyphenyl ester, NMR (CDCI3): -
`4.77. -4.88, 19.15. 20.65.‘ 20.93. 24.77, 33.25. 42.20. 48.20. 67.90. 122.79. 125.15. 127.44. _127.90. 128.41.
`136.99. 140.55, 143.85. 147.86. 168.95
`.
`v
`-
`
`(3-[2e(tert.-Butyl-cflmethylsllanyloxy)-5-(tart.-butyl-dimethylsilanyloxyrnethy0—pi1enyI]-3-phenylpmpyo-
`1 dirsopropylamine. Ft,.0.94 (3); GC-MSIN-Cl (methane): 568.6 (62%), 454.3 (100%), 4382 (10%), 340.2 (58%).
`324.8 (16%). 234.7 (78%): GC-MS/P-Cl (methane): 570.6 (70%). 554.5 (52%). 5125 (18%). 438.4 (24%)
`
`' Acetic acid 4-benéyloxy-3-(3-dirsopropylamino—1-phenylpropya-benzyl ester. R. 0.56 (5); GO-MSIP-Cl (ammonia):
`474.4 (100%). 416.4 (54%); NMR (CDCl3): 20.44, 20.56. 21.07, 36.73. 41.53, 44.01, 48.79, 66.43. 70.00, 111.61.
`125.75. 127.34, 127.55. 127.76, 127.90. 128.03. 128.27, 128.39. 133.98. 136.98, 144.63, 156.05. 170.94 '
`_
`
`V
`
`'Benzoic acid 4-benzyloxy-3-(3-diisopropy/amino—1-phenykaropyp-benzyl ester, R,'0.87 (4); NMR (CDCl3):20.'54.
`20.60. 36.80. 41.51, 43.95, 48.67. 66.83. 70.04. 111.66. 125.76. 127.35. 127.45. 127.78. 128.06.128.27. 128.30,
`128.42. 128.85. 129.66, 130.55. 132.86. 134.05.137.03, 144.75. 156.08. 166.46; GC-MS/P-CI (ammonia): 536.5
`(100%). 416.4 (42%)
`_
`-
`A
`
`lsobutyric acid 4-benzyIoxy-3»(3-¢fiisapropy/amino-1-phenylpropyo-benzyl ester. R, 0.77 (4); NMR. (CDOla): 19.01,
`20.62. 20.65, 34.04, 36.85. 41.54. 43.97. 48.71. 66.15. 70.06. 111.62. 125.79. 4125.96. 126.97. 127.24. 127.55.
`127.81. 128.08. 123.34, 128.45, 134.05, 137.10, 144.79. 156.00. 177.01); GC-MS/P-Cl (ammonia): 502.4 (100%),
`416.4_(49%)‘
`,
`A
`-
`'
`
`'
`
`f) Carbamates and Carbonates
`
`[0038] A solution of 4.0 mmol of lntermecfiate B or benzylic ether (Formula Vl. R‘ = H) in dichloromethane (20 ml)was
`treated at room temperature for 16 h with isocyanate (4.8 mmol) or diisocyanate (22 mmol). After washing with 10 ml
`aqueous sodium hydrogen carbonate (5%. wlv). drying (Na2SO4) and evaporation the oily residue was redissolved in '
`tetrahydrofuran (10 ml). Addition of ethereal hydrochloric acid and evaporation to dryness in high vacuum gave crystal-
`line or amorphous carbamate hydrochlorides. Bis-carbarnates were prepared in fike manner using lntermediate B and
`excess isocyanate'(4.8 mmol) and toluene as solvent at 65 “C over 18 h.
`Carbonates were prepared and worked-up according to the methods described for the preparation of compounds of
`Fomula II to N. Alkyl chlorotormates were used as acylation reagents.
`
`N-Ethy/carbamic acid 2-(3—diisopropyIamino-1-phenylpropyv-4-hydroxymethyI-pheny/ ester. R, 0.38 (4); GC-MSIP-
`Cl (ammonia. trimethylsilyl derivative): 486.8 (100%). 413.4 (5%). 398.4 (6%); hydrochloride: m. p. 64 "C (with
`decomposition); NMR (DMSO-d5): 15.16. 16.68. 18.05. 18.13, 25.33. 31.26, 35.46, 53.94. 62.65. 67.22, 123.04.
`125.70, 126.72, 127.86, 128.67. 135.42. 136.02. 140.07, 142.98. 147.53, 154.52
`
`i‘
`
`1
`‘
`
`>
`l_.:~ ,-
`
`’
`
`4.
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 836
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 836
`
`

`
`1
`'
`
`E
`I
`i
`3
`I
`5
`
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`
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`
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`
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`'
`EP 0 957 "073 A1.
`tr‘
`’ N-PhenyIcarbamic acid 2-{.’.3diis.opropylamino—1-phenymropyy4-iyrdmxymelhgvi-phenyl ester. NMR (CDCI3):
`20.52. 20.61, 36.91, 39:44, 42.25. 48.22, 62.66, 118.36. 119.46, 123.50, 125.32, 127,11, 127.99, 130.15, 132.63,
`139.65,141.33, 145.16, 152.21. 156.00
`'
`
`~
`I
`N-Ethyicarbamic acid3-(3-diisopropylamino-1-phenywropyv-4-N-ethyiE;atbamoyloxyl§énzy/ ester. Fl,p.36lt3), NNJR 1
`(CDCI3): 15.00, 1923.19.40. 3326. 36.00.139.62, 42.35.48.12,65.95,-118.30, 125.45, 127.08, $3.33. 130.37
`134.24,144.44,155.44, 157.74
`.
`_
`,3)’
`—
`1*
`er.
`5-
`
`
`
`an‘.
`
`acid 2-(3-‘
`(4-[2-(3-DiisopmpyIamino-1-phenylpropyi)-4—hydro,\ymetI;yl-phenoxycarbonylaminojbutjfl/-carbamic
`diisopropy/amino-1-phenyIpropy04-hydmxymethyI—phenyl ester. ( Formula Vll', X = Y = NH. n = 4) R, 0.§0 (6); ‘i:
`-dinydrochloridez m. p. 142.5 - 145.6 ‘C
`A
`'
`'
`
`_
`
`_
`
`' 5
`
`‘1a
`
`’ Carbonic acid 2-(36-diisopmpylaminw1-phenymropy0—4-hydmxymethylohenyl ester ethyl ester, R, 0.67 (4)
`Carbonic acid2-(3-diisopmpyIamino-1-phenymropyl)-4-ethoxycarbanyloxymethywhenyl ester ethyl ester. R, 0.87
`(4)
`.
`.
`
`15
`
`_
`
`20
`
`ab
`
`as
`
`4. The respective prodrugs (Formula I) or pharmaceulically acceptable salts thereof were prepared also from lnterrne-b
`diate A or Intermediate 8 by the following methods:
`‘
`‘
`
`'
`
`[0039]
`
`'
`
`R-O
`
`..
`
`
`
`Y
`N
`7/
`
`.
`
`:
`
`Fonnula l,
`
`a) Phenolic ‘monoesters
`
`1
`(R' =’ benzyl: lnlermedate A)
`ta’ = H: Intermediate 3)
`i
`
`‘
`
`40 «
`
`[0040] Treatment of Intermediate 8 with an equivalent of an acylating agent ( e.g. acyl halogenide or acyl anhydride)
`in an inert solvent and in the presence of an condensating agent (e.g. amine) provides phenolic monoeslers of Forrnula_
`llor Formula II‘ (n = 0-12), respectively. if polytunctional acylating agents (e.g. acid chlorides of dicaiboxylic acids) are 5
`used.
`'
`.
`'
`'
`
`50
`
`55
`
`15
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 837
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 837
`
`

`
`i
`
`-
`
`EP 0 957 073 A1
`
`3
`
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`I , ’
`
`
`
`.Formuta|l'.
`
`[0041] Allemalively. structures of Formula II or ll‘ may be obtained by regioselective deprotection of a protected ben-
`zylic hydroxy group (chemically or enzyrnatically: T. W. Greene, _P. G. M. Wuts,
`.Protective Groups in O/yanio
`ChemIshy", 2nd Ed, J. Wily & Sons,-New York 1991).
`'
`'
`
`b)‘jldentica| cfiesters
`
`
`
`Di-acyl "compounds are readily accessible if an at least two molar excess of eoylalion agent is used in the
`[004§]
`above-mentioned conversions of Intermediates A or B or. more general. on treatment of compounds of Formula I with
`‘ acylating agents in the presence of suitable catalysts
`
`Formula lll
`
`'
`
`_c) Mixed diesters
`
`[0043] A Acylation of compounds of the general Formula lwherein R and R‘ are diflerent substituents selected from the
`group consisting of hydrogen, aoyl residues or protecting groups that are cleavable under the acylation reaction condi-
`tions yields mixed diesters ol Formula l\/, where R‘ and R2 are diflerent.
`
`‘IS
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 838
`
`20
`
`25
`
`30
`
`1,
`
`.
`
`40
`
`45
`
`50
`
`55
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 838
`
`

`
`EP 0 957 073 A1
`
`.-
`
`
`
`1a,
`
`Formula I
`
`'_ Formula lV
`
`15
`
`20
`
`d) Benzylic monoesters
`
`[0044] Moreover. the invention refers to the preparation of phenols with para acyloxymethyl substituents (Formula
`f These compounds can be prepared in several chemical _s_teps from intermediates such as Formula l,-where R repre-
`sents hydrogen and R'- is hydrogen or any suitable-protective group which can be removed by known methods (T. W.
`Greene; P. G. M: Wuts. ,,Protective Groups in Organic Chemistry‘. and Ed.. J. Vlfily & Sons, New York 1991) in the pres-
`ence of the newly introduced substituent R‘CO. It was found. however, in the present invention that the benzylic sub-
`stituent Fl‘CO can be introducedmore conveniently and in only one step -if intermediate B is treated at-room
`temperature and under anhydrous ooncfitions with activated esters (e.g. vinyl acylates. isopropenyl acylates) in the
`_ presence of enzymes such as lipases or esterases.
`
`'
`
`30
`
`35
`
`40
`
`45
`
`.50
`
`55
`
`on" Y
`
`R‘l\([3rO 8
`.
`H
`V 0
`
`H
`
`I
`I
`I Forrnulav
`
`e) Ethers and silanyl esters
`
`[0045] Regioselective modification of the benzylic hydroxy groups is achieved either by acid or base treatment of hen-
`zylic acylates in thepresence at suitable hydroxy reagents (e.g. alcohols) or by catalytic ether formation as described
`in theliterature for other benzylic _substrates (J. M. Saa, A. Uobera. A. Garcia-Raso. A Costa. P. M. Deya; J. Org. Chem.
`53: 4263-4273 [1988]). Both free benzylic alcohols such as Intermediates A and B or Formulas II or VI (in which R3
`hydrogen) or Formula VII (in which R5 is hydrogen) as well as benzylic acylates such as Formula lll. l\/. V may serve as
`starting materials for the preparation of benzylic ethers (B. Loubinoux, J. Miazirnbakana, P. Gerardin; Tetrahedron Lett.
`. 30: 1939-1 942 [1989]).
`Likewise the phenolic hydroxy groups are readfly transformed into phenyl ethers (R‘ = alkyl) using alkylating agents
`such as e_.g. alkyl halogenides. alkyl sulphates. alkyl triflates or employing Mitsunobu type reaction conditions (Synthe-
`sis 1981. 1-28). Similarly, both phenolic and alcoholic rnonosilyl ethers are obtained by regioselective silylation or by
`desilylation oi bis-silyl ethers of -lntennediate B as described torother compounds in the literature (J. Paladino, C.
`Guyard. C. Thurieau, J.—L Fauchere. Helv. Chim. Acta 76: 2465-2472 [1993]; Y. Kawazoe, M. Nomura. Y. Kondo. K.
`Kohda. Tetrahedron Leti. 26: 4307-4310 [1987]).
`-
`‘
`~
`
`17
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 839
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 839
`
`

`
`EP 0 957 073 A1
`
`4-,
`
`I \ '. 0 Y ‘
`/
`/\
`.~..
`,
`
`.
`
`-,o.
`
`'
`
`.
`
`2
`
`.
`
`"A
`
`
`
`4
`
`*3"
`~ //
`
`-
`
`-'3;
`:
`
`.,
`
`‘
`
`~
`
`Formula VI
`
`'
`
`l
`
`f) Carbamates and Carbonates
`
`[D046]. Other reactive reagents which can be used in the reaction of the hydroxy groups of Intermediates A or B, For-
`mulas II. II‘, V. or VI (R3 or R‘ = hydrogen) shown above are, for example, other activated carbonyl compounds or car-
`bonyl precursor reagents.
`-
`'
`Preferably. haloformates, ketenes..activated esters. mixed anhydrides of organic or inorganic acids. isocyanates, isothi- I
`ocyanates can be: used. The coupling reactions can be carried out in inert solvents over periods-of several hours at tern-
`peratures from -10 "C to the refluxing temperature of the solvent or reagent used to provide compounds of the general
`Fomiula VII where R5 represents hydrogen, alkyl, aliphatic or aromatic awl. or carbamoyl, and Y and R5 represent 0.‘
`S, NH and alkyl or aryl, respectively.
`.
`.
`-
`‘
`Polylunctional reagents give the conesponding derivatives. For example, diisocyarntes or di-carbonylchlorides provide
`compounds of Formula VII‘ where X, Y have the meaning of O, S, or NH and n is zero to twelve
`-
`~
`
` Fomula VII
`
`[0047] The compounds of formula (I) can be used as pharmaceutically active substances, especially as anfimuscan;
`nic agents.
`-
`[0048]
`. The compounds of formula (I) can be used for preparing pharmaceutical formulations containing at least one
`of said compounds.
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page84O
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 840
`
`

`
`ll. Phamtaceuticalcomposition of the present invention
`
`I‘
`
`EP0957073A1
`
`In-accordance with the present invention, the compounds of formula (l), in the form of tree bases or salts with
`[0049]
`i
`
`physiologically acceptable acids, can be brought into suitable galenic formsgsuch as corrip'tisifions for oral use;tor injec-3;
`tion, for nasal spray administration or the like, in accordance with acceptedpharmaceuticai procedures. ,Such-pharnrfa’
`‘
`
`ceulical compositions according to the invention comprise an effective amount oi the compounds o§‘iormula (i),'ir
`'._
`association with compatible pharmaceutically acceptable carrier materials, or diluents. as is-well lmoiyrfih the art The 1;
`1
`carriers may be any inert material, organic or inorganic, suitable for enteral, percutaneousor parernetjafiadnfinisuafion,
`such as: water, gelatin, gum arabicum, lactose, microcrystalline cellulose starch, sodiu'rrr§’tarch glycolate, calcium 75..
`hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such compositions may also ‘
`:-
`contain other pharmaceutically active agents, and conventional additives. such as stabilizers. wetting agents, emulsifi-
`ers, flavouring agents. buffers, and the like.
`'
`_
`.
`_
`"
`.
`[0050] The composition according to the invention can e.g. be made up in solid or liquid form for oral administration,
`such as tablets. capsules, powders, syrups. elixirs and the like, in the form of sterile solutions, suspensions or emul-
`sions for parenteral adntinistration, and the like.
`-
`4
`
`10'
`
`15
`
`[0051] The compounds according to the invention may be used in a patch formulation. The compounds can be admin-
`istered transdermally with a reduced incidence of side effects and improved individual compliance.
`[0052] The compounds and compositions can. as mentioned above, be used for the treatment of urinary incontinence
`and other spasmogenic conditions that are caused by muscarinic mechanisms The dosage of the specific compound
`will vary depencfing on its potency. the mode of administration, the age and weight of the patient and the severity ofthe
`condition to be treated. The daily dosage may, for example, range from about 0.01 mg to about 5 mg, adminstered sin-
`gly or multiply in doses eg. from about 0.05 mg to about 200 g each.
`'
`'
`'
`
`‘
`
`Ill. lncubations of different compounds of the invention with ‘human Iiever S 9-fraction. ‘
`
`,
`
`30
`
`35
`
`. my
`
`50
`
`55
`
`_ A pooled human liver S 9-preparation was used to show the in-vitro metabolism of different compounds of the
`[0053]
`invention and to prove the generation of the active metabolite by enzymatic process.
`'
`[0054] The pooled human liver S 9-preparation was delivered by Gentest, Wobum,'MA, USA
`[0055]
`‘The analysis was performed by a routine High Pressure Liquid Crornatography (HPLC) method with UV-‘detec-V
`tion.
`v
`-
`' [0056] The incubation results expressed in ($6) of theoretical tum—over are presented in Table 1.
`- [0057] They ranged from 96 to 63,2 _%. The formation of the active metabolite is dependem on the substituents both
`. at the benzylic and phenofic side of the respective compounds.
`.
`
`Explanation:
`
`[0058] The prodrugs introduced" in the assay show the following chemical structure:
`
`
`
`chemical structure X-/-Y '
`
`AcO-/—OAc
`
`means
`
`acetate
`
`means
`HO-/-OBut
`means
`HO-/-OiBut
`iButO-/-OiBut means
`ButO-/eOBut
`means
`Propo-/-OProp means
`HO-/-OProp
`means
`' HO-/-OAc
`means
`
`hydroxy and butyrate
`hydroxy and iso-butyrate
`iso-butyrate
`'
`butyrate
`propyrate‘
`hydroxy and propyrate
`hydroxy and acetate
`
`19
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 841
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 841
`
`

`
`Claims
`
`-
`
`1. 3,3-Diphenylpropylamines 01 Formula I:
`1
`
`EP0957073 A1
`_
`
`‘
`
`-
`
`5
`
`J1
`
`.
`.(|)
`
`‘
`
`.
`
`’//'
`
`I
`
`
`
`--t
`
`,
`
`
`,‘
`
`.
`
`‘
`
`R-O X
`.
`I
`
`I
`
`E
`
`-
`
`i
`|
`J
`
`:
`|
`.
`I
`2
`
`wherein Fl indepently signifies:
`
`a) R‘ represents the residues hydrogen. methyl. ethyl. propyl, isopropvl. butyl. isobutyl, pentyl. haiyl, benzyl or
`allyl; or
`~
`_
`..
`.
`'
`
`p
`
`.
`V
`_
`b) R2 represents the residues tormyl. acetyi, propionyl, isobutyryl. butyryl, valeroyl. pivaloyl, benzoyl; or
`
`c-T‘???
`
`c) R3 represents the residues C»H3OC0-. CgH5"0CO', C3H-,OCO-. (CH3)3COCO-. benzoylacyl. benzoylglycyl,
`glycyl. valyi, Ieucyl, isoleucyl. phenylalanyl, prolyi, seryl. threonyl, methionyl, hydroxyprolyl; or’
`'
`.
`_'
`d) a group consisting of
`
`.
`
`-
`
`-
`
`‘
`
`4
`
`'
`
`»
`
`4
`
`« N-CO-
`5/.
`
`.
`
`A
`
`4
`
`R
`A
`
`R
`
`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. iso-
`butyl and wherein R‘ and R5 may form a ring together with the amine nitrogen; v
`or
`4
`-
`
`|._
`
`..
`
`N-SOT
`
`6
`
`.e
`
`R
`
`e) a group consisting of
`
`wherein R5 and R7 indepently represent the residues methyl, ethyl, propyl, isopropyl. butyl. isobutyl. pentyl,
`hexyl. benzyl, phenoxyalkyl wherein the alkyl residue means methyl, ethyl, propyl, isopropyl. butyl. isobutyl,
`pentyl. hexyl; or
`'
`
`' -
`
`:
`
`'
`
`‘
`
`f) an ester 01 inorganic acids such as sulfuric acid, phosphoric acid;
`
`X represents a tertiary amino group of Formula la
`
`an
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 842
`
`5
`
`1o
`
`15
`
`20
`
`25
`
`.
`
`an
`
`.
`
`as
`
`.
`
`.
`
`45
`
`50
`
`55
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 842
`
`

`
`EP 0 957 073 A1» ,
`
`/-~._
`
`Re
`
`‘
`
`1
`
`_ N
`
`\\ 9
`.
`R
`
`H
`
`f
`
`ii"
`=
`
`'=,
`
`_
`
`’
`
`‘(*' /.r ‘
`' ,/
`
`,.
`
`
`
`:2
`1.
`
`3
`
`10
`
`15
`
`wherein R°_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 H9 may form a ring together with the
`amine nitrogen. Fl‘ represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, ben-
`. zyi, alkyl. phenoxyalkyl wherein the alkyl _residue means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, if
`R is hydrogen R‘ will not represent hydrogen or methyl
`-
`I
`and
`’
`.
`
`2a.
`
`2.
`
`their salts with physiologically acceptable acids, their free bases and. when the compounds
`in" the
`form of optical isomers, the racemic mixture and the individual enantiomers.
`A
`_
`3,3-Diphenylpropylamines according to "claim 1. wherein each of R3 and R9 independently signifies a saturated
`hydrocarbyl-group, especially saturated afiphatic hydrocarbyl groups such as C1_8-alkyl. especially CH;-alkyl, or
`adamantyl, R5 and R9 together comprising at least three, preferably at least four carbon atoms.
`'
`
`_
`
`,
`
`‘
`
`,
`Q
`
`A
`
`_
`
`25
`
`3.
`
`3,3-Diphenylpropylamines according to claim 1 or 2. wherein at least one of R5 and R9 comprises a branched car-
`bon chain.
`-
`-
`-
`'
`
`4.
`
`3,3-Diphenylpropylamines accorcfing to any one of claims 1 to 3, wherein X signifiesany ol the following groups a)
`to h):
`V
`~
`
`30
`
`as
`
`,45
`
`'50
`
`55
`
`21
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 843
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 843
`
`

`
`10
`
`15
`
`'80
`
`35
`
`50
`
`55
`
`EPO957073 A1
`
`/CH<CH3)2
`a) —N\
`cg-1(r_'.1-1s).‘.
`
`b)
`
`/SE3
`._
`:‘ ——N \_?7"‘-
`'
`'F(CHa)a ;,
`
`
`
`C)
`
`'_' /CH3
`N\
`
`, ca,
`
`Hac
`' -N
`
`.
`
`d)
`
`i
`
`‘
`
`A
`
`CH3
`
`Hsc
`c) —N
`
`CH.
`
`I-13C
`
`CH3
`
`‘
`
`i
`
`TH“.
`'—N
`
`f)
`
`2)
`
`h)
`
`5.
`
`3.3-diphenylpropylamines. their salts with physiologically acceptable acids. their
`mates and individual enantiomeis thereof which are detinied as
`'
`
`tree bases or salts thereof, race-
`
`Formic acid 2-(3-diisopropylamino-1-pheriylpropyl)-4-hydroxymethytphenyl ester
`Acetic acid 2-(3-diisopropylamino—1-phenylpropyl)-4-hydroxymethylphenyl ester
`Propionic acid 2-(3-dfisopropylamino-1-phenylpropyl)-4-hydroxymethyiphenyl 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-hydroxy-methylphenyl ester
`Benzoic acid 2-(3-diisopropylamino-1—phenylpropyl)-4-hydroxymethylphenyl ester
`Malonic acid bis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl] ester
`Succinic acid bis-[2-(3diisopropylamino-1-phenylpropyl)-4-hydroxymethy-phenyl] ester
`Pentanedioic acid bis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl] ester _
`Hexanedioic acid bis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl] ester
`Formic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester
`
`an
`
`Petitioner Mylan Pharmaceuticals Inc. — Exhibit 1002 — Page 844
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1002 - Page 844
`
`

`
`5 '
`
`"
`
`‘
`
`*3
`
`
`
`V EP0957073A1
`Acetic acid 4-acetoxy~3—(i3-diisopropylamino-1-phenylpropyl)-benzyl ester
`Propionic acid 2—(3-diisopropylamino-1-phenyipropyl)Arpropionyloxymethylphenyl ester
`n-Butyric acid 4-n-butyryloxymethyl-2-(3-dfisopropylamino-1-phenylpropyl)-phenyl ester
`V’
`-.7
`,-
`A lsobutyric_acid 2-(3-diisopropylamino-1-phenylpropyl)-4-isobutyryloxymethylpheiiyl ester
`2,2-Dimethylpropionic acid 3-(3-dfisopropylamino-1-phenylpropyl)-21-(2.2-dimethyipropionyloxyfiberizyl estei?
`Benzoic acid 4-benzoyioxymethyi-2-(3~o’iisopropyiamino-1-pu'1eny‘t§7ro,7y1)-phenyi ester
`fl‘
`, Acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester."/«
`Benzoic acid 2-(3-cfiisopropylamino-1-phenylpropyl)-Honnyloxymethylphenyl est’e‘r/;-
`A lsobutyric acid 4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-ghenyl ester
`2,2-Dimethylpropionicacid 4-acetoxy-3-(3-diisopropylamino-1-phenylprocyl)-benzyl ester
`2,2-Dimethylpropionic acid 4-acetoxymethyl-2-(3-diisopropylarnind1-phenylpropyl)-phenyl ester
`Formic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`a
`Acetic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester
`Propionic acid 3-(3-dfisopropylamino-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-disopropylamino-1-phenyipropyl)-4-hydroxybenzyl ester
`Benzoic acid 3-(3-diisopropylarnino-1-phenylpropyl)-4»hydroxybenzyl ester
`2-(3-Diisopropylamino-1-phenylpropyl)-4-methoxymethylphenol
`2-(3-Diisopropylamino-1-phenylpropyl)-4-ethoxyrnethylphenol
`2-(3-Diisopropylamino-1 -phenylpropyl)-4-propoxymethylphenol
`2-(3-Diisopropylamino-1 -phenylpropyl)-4-isopropaxymetliylphenol
`-2-(3-Diisopropy|amino—1 -phenylpropyl)-4-butoxymethylphenol
`Acetic acid 2-(3-Diisopropylamino-1-phenylpropyl)g4-methcxymethylphenyl ester
`Acetic acid 2-(3-Diisopropyla_mino_-1-phenylpropyl)-4-ethoxymethylphenyl ester
`.' 2—(3-Diisopropylamino-1-pheriylpropyl)-4—trimethylsiIanyloxymethylphenoI
`Diisopropyl-[3-phenyl-3-(2-trimethyisilanyloxy-5-trimethylsilanyloxymethylphenyl)propyl]-amine
`[3-(3-Dfisopropylamino-1-phenylpropyl)-4-trimethylsilanyloxyphenyl]-methanol
`Drisoprcpyl-[3-(5-methoxymethyl-2-trimethylsilanyloxyphenyi)-3-phenylpropylarnine
`Diisopropyl-[3-(5-ethoxymethyl-2-trimethylsilanyloxyphenyl)-3-phenylpropylamine
`-[4-(tert.-Butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol I
`Acetic acid 4-(tert.-butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester
`4-(tert-Butyl-dimethylsilanyloxy)-37(3-dfisopropylamino-1 -phenylpropyl)-phenol
`-
`Acetic acid '4~(tert.butyl-dimethylsilanyloxy)—2-(3-diisopropylamino-1—phenylpropyl)-phenyl ester .
`{3—[2-(tert.-Butyl-dimethyisilanylaxy)-5-(tert-butyl-dimethylsilanyloxymethybphenyll-3-phenylpropyl}-aiisopro
`pylamine
`A
`'
`_
`-
`_
`[4-(tert-Butyl-diphenylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-rnethanol
`Acetic acid 4-(tert-butyl-diphenylsilanyloxymethyl)-2-(3-disopropylamino-1-phenylpropyl)-phenyl ester
`4-(tert.-Butyl-diphenylsilanyloxymethyl)-2-(3-diisopropylamino-1 -phenylpropyl)-phenol
`~
`{3-[2—(tert.-Butyldiphenylsilanyloxy)-5-(tart-butyi-diphenylsilanyloxymefltyophenyl]-2-phenylpropyl}-diisopro-
`pylamine
`-
`‘
`'
`'
`
`_
`
`Acetic acid 4-benzyloxy-3-(3-disopropylamino-1-phenylpropyl)-beniyl ester
`Benzoic acid 4—ben2yloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester
`lsobutyric acid 4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester
`N-Ethylcarbamic acid 2-(3-diisopropylamino-1-phenylpropyl)-4—hydroxymethylphenyl ester
`N-Phenylcarbamic acid 2-(3-cfiisopropylamino-1-phenylpropyl)-4-hydroxymethylp