a2) United States Patent
`US 8,921,375 B2
`(0) Patent No.:
`Dec. 30, 2014
`(45) Date of Patent:
`Batheet al.
`
`US008921375B2
`
`(54) POLYMORPHIC FORMSOF1-[4-(5-
`CYANOINDOL-3-YL)BUTYL]-4-(2-
`CARBAMOYLBENZOFURAN-5-YL)
`PIPERAZINE HYDROCHLORIDE
`
`(71) Applicant: Merck Patentgesellschaft, Darmstadt
`(DE)
`
`(72)
`
`Inventors: Andreas Bathe, Darmstadt (DE); Bernd
`Helfert, Ober-Ramstadt (DE); Steffen
`Neuenfeld, Messel (DE); Heike Kniel,
`Heppenheim (DE); Matthias Bartels,
`4/1995
`0648767 Al
`EP
`Darmstadt (DE); Susanne Rudolph,
`10/1996
`0738722 Al
`EP
`Dieburg (DE); Henning Bottcher,
`12/2000
`00/72832 A2
`WO
`Darmstadt (DE)
`
`WO 02/102794 A2=12/2002
`
`5,977,112 A
`7,381,726 B2
`7,834,020 B2
`7,981,894 B2
`8,193,195 B2
`8,236,804 B2
`8,318,744 B2
`8,673,921 B2
`2011/0183994 Al
`2011/0294824 Al
`2013/0102616 Al
`
`11/1999 Batheet al.
`6/2008 Batheetal.
`11/2010 Bathe etal.
`7/2011 Batheetal.
`6/2012 Batheetal.
`8/2012 Batheetal.
`11/2012 Bathe etal.
`3/2014 Batheetal.
`7/2011 Bathe etal.
`12/2011 Batheetal.
`4/2013 Batheet al.
`
`FOREIGN PATENT DOCUMENTS
`
`(73) Assignee: Merck Patentgesellschaft, Darmstadt
`(DE)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 14/291,931
`
`(22)
`
`Filed:
`
`May30, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2014/0275115 Al
`
`Sep. 18, 2014
`
`Related U.S. Application Data
`
`(60) Continuation of application No. 13/658,088, filed on
`Oct. 23, 2012, which is a continuation of application
`No. 13/085,117, filed on Apr. 12, 2011, now Pat. No.
`8,318,744, which is a continuation of application No.
`12/566,835, filed on Sep. 25, 2009, now Pat. No.
`7,981,894, which is a division of application No.
`12/110,704, filed on Apr. 28, 2008, now Pat. No.
`7,834,020, which is a division of application No.
`10/481,270,filed as application No. PCT/EP02/06153
`on Jun. 5, 2002, now Pat. No. 7,381,726.
`
`OTHER PUBLICATIONS
`
`Summary ofFacts Regarding US ClinicalTrials Prior to Jun. 5, 2001.
`Sorbera, L.A. et al. “Vilazodone Hydrochloride. Antidepressant
`5-HT .sub.1A Partial Agonist 5-HT Reuptake Inhibitor” Drugsofthe
`Future 2001, 26(3):247-252. (Mar. 2001).
`Remington Farmacia Tomo 2 19.sup.a edicion. (1998).
`Farmacotecnia TeoricaY Practica TomoiV, Dr. Jose Helman. (1980).
`Hungarian Search Report of May 10, 2010, citing HU P0201275
`which corresponds to WO 00/72832.
`Office Action for U.S. Appl. No. 12/945,260, date ofmailing Aug. 17,
`2011.
`Office Action for U.S. Appl. No. 12/945,272, date ofmailing Aug. 17,
`2011.
`Office Action for U.S. Appl. No. 13/100,911, date of mailing Nov.9,
`2011.
`Office Action for U.S. Appl. No. 13/085,117, date of mailing Jan. 13,
`2012.
`Notice of Allowance for U.S. Appl. No. 12/945,272, date of mailing
`Mar. 19, 2012.
`
`(Continued)
`
`Primary Examiner — Samantha Shterengarts
`(74) Attorney, Agent, or Firm — McCarter & English, LLP;
`Danielle L. Herritt; Jin Wang
`
`(30)
`
`Foreign Application Priority Data
`
`(57)
`
`ABSTRACT
`
`Jun. 19,2001
`
`(EP) eee ceeeeneeecenee 01113674
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`AGIK 31/496
`CO7D 403/14
`CO7D 405/14
`(52) U.S. CL.
`CPC vicccccsssectetseenscneetees C07D 405/14 (2013.01)
`USPC iecesesesctsesseesenstetscnssenees 514/254.09; 544/373
`(58) Field of Classification Search
`USPC iecesesesctsesseesenstetscnssenees 514/254.09; 544/373
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`5,521,241 A
`5,532,241 A
`5,723,614 A
`
`5/1996 Wu
`7/1996 Bottcheret al.
`3/1998 Bathe etal.
`
`The invention relates to new crystalline modifications of the
`hydrochloride of 1-[4-(5-cyanoindol-3-yl)butyl|-4-(2-car-
`bamoyl-benzofuran-5-yl)-piperazine, crystalline modifica-
`tion of the dihydrochloride of 1-[4-(5-cyanoindol-3-yl)bu-
`tyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`and
`amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride which are suit-
`able in particular for the preparation of solid medicaments for
`the treatment or prevention of depressive disorders, anxiety
`disorders, bipolar disorders, mania, dementia, substance-re-
`lated disorders, sexual dysfunctions, eating disorders, obe-
`sity, fibromyalgia, sleeping disorders, psychiatric disorders,
`cerebral infarct, tension, for the therapy of side-effects in the
`treatment of hypertension, cerebral disorders, chronic pain,
`acromegaly, hypogonadism, secondary amenorrhea, premen-
`strual syndrome and undesired puerperallactation.
`
`11 Claims, 23 Drawing Sheets
`
`Merck 2020
`Argentum v. Merck
`IPR2018-00423
`
`Merck 2020
`Argentum v. Merck
`IPR2018-00423
`
`

`

`US 8,921,375 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Corrected Notice of Allowance for U.S. Appl. No. 12/945,272, date
`of mailing Apr. 3, 2012.
`Office Action for U.S. Appl. No. 13/100,911, date ofmailing Mar. 23,
`2012.
`Office Action for U.S. Appl. No. 13/100,911, date ofmailing Aug. 17,
`2012.
`Office Action for U.S. Appl. No. 13/085,117, date of mailing Apr. 3,
`2012.
`Notice of Allowance for U.S. Appl. No. 13/085,117, date of mailing
`Aug. 17, 2012.
`
`Office Action for U.S. Appl. No. 13/100,948, date ofmailing Nov. 18,
`2011.
`Office Action for U.S. Appl. No. 13/100,948, date ofmailing Mar. 27,
`2012.
`Notice of Allowance for U.S. Appl. No. 13/100,948, date of mailing
`Jun. 4, 2012.
`Morissette et al. Advanced Drug Delivery Reviews, 2004, 56:275-
`300.
`Notice of Allowance for U.S. Appl. No. 14/032,183, date of mailing
`Dec. 13, 2013.
`Office Action for U.S. Appl. No. 13/658,088, date ofmailing May 23,
`2013.
`Office Action for U.S. Appl. No. 13/658,088, date of mailing Dec. 2,
`2013.
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
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`Sheet 1 of 23
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`US 8,921,375 B2
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`U.S. Patent
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`Dec.30, 2014
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`U.S. Patent
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`Dec. 30, 2014
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`

`U.S. Patent
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`Dec. 30, 2014
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`Sheet 4 of 23
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`US 8,921,375 B2
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`U.S. Patent
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`Dec. 30, 2014
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`US 8,921,375 B2
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`U.S. Patent
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`U.S. Patent
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`U.S. Patent
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`Dec. 30, 2014
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`U.S. Patent
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`U.S. Patent
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`US 8,921,375 B2
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`U.S. Patent
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`U.S. Patent
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`
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`78.04J/g 1.324J/g 107.5J/g0- 145
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`Fig. 28
`
`

`

`U.S. Patent
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`Sheet 15 of 23
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`US 8,921,375 B2
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`
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`TEMPERATURE(°C)
`EMD 68843 FORM II (THF SOLVATE)
`Fig. 29
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`
`150
`
`140
`
`130
`
`120
`
`g
`110 &
`5
`100 5
`=
`
`90
`
`80
`
`70
`
`Exo Up
`
`5 TtrTyp errr y retry er ery eee yp tty trey tee eee tty etre ry rrr] 60
`50
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`TEMPERATURE (°C)
`UNIVERSALV2.4F TA
`EMD 68843 FORM III
`INSTRUMENTS
`Fig. 30
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 16 of 23
`
`US 8,921,375 B2
`
`150
`1-9
`“|
`235.88°C 288.30°C
`|
`5.192J/g 133.1/g7 140
`05
`onnnnTotette r
`44
`242.91°C
`ME
`+130
`vf
`4
`i
`|
`L
`B24
`ti
`P120
`=]
`|
`Laan
`= -34
`{|
`-110
`S|
`g
`i -44
`+100 =
`ke
`5]
`= -5-
`
`
`
`U
`|
`y
`
`
`
`
`290.59°C
`
`50
`
`75
`
`100
`
`125
`
`150
`
`60
`175 200 225 250 275 300 325 350
`
`TEMPERATURE(°C)
`EMD 68843 FORM IV
`Fig. 31
`
`UNIVERSALV2.4F TA
`INSTRUMENTS
`
`L90
`
`L80
`
`70
`
`-64
`
`-7-
`
`-8
`
`Exo Up
`
`0
`
`230.61°C 395.62°C
`9829113.2479
`239.96°C “7h
`\
`
`1
`|
`
`|I
`1
`
`170
`
`160
`150
`140
`130
`S
`120 —
`
`45.55°C
`
`321.0)/g-——-—bo
`athe
`\
`iS/
`\
`\
`
`2
`
`
`
`|
`\
`\I
`\172.44°C
`
`3.655%
`(0.3225mg)
`
`FLOW(W/g) w 60HEAT
`
`50
`
`75
`
`100
`
`Exo Up
`
`125
`
`150
`175 200 225 250 275 300 325 350
`TEMPERATURE(°C)
`UNIVERSAL V2.4F TA
`EMD 68843 FORM V (MONOHYDRATE)
`INSTRUMENTS
`Fig. 32
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 17 of 23
`
`US 8,921,375 B2
`
`146.73°C
`548.10°C
`h
`57.94°C
`05
`0.8866J/g 17Bio
`|
`AX
`atied
`1
`pea141.45°C Mbt
`38.27J)/g
`254.12°C \i
`95.29°C
`S
`1
`=
`6.190%
`\
`|
`=
`5 = (0.1924mg)
`|
`
`re
`Ut
`4
`i
`5
`=
`
`q
`
`108.4J/
`
`-4
`
`|
`
`°
`
`
`
`|
`288.78°C
`
`
`
`150
`
`140
`
`130
`----7F 120
`S
`110 =
`&
`100 3
`Wo
`>
`
`90
`80
`
`70
`
`T Tire TT TTT T Tre T TTT T TIrre T Tire TT TTT T TITTrr 60
`-6 Tire TT TTT T TTT T Tree T TIrrel
`50
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`
`Exo Up
`
`
`
`
`
`1
`
`TEMPERATURE(°C)
`EMD 68843 FORM VI(1.75 HYDRATE)
`Fig. 33
`
`eon TA
`
`
` 60
`
`288.65°C
`|
`111.4J/g
`0
`|--—=nnnnn+ HF
`it
`wit
`Hy
`i
`!
`t
`}
`M
`\
`
`
`
`-15
`
`3
`= 2
`=
`=
`|
`ir 3
`<<
`uu
`4
`x
`
`-44
`
`-5+4
`
`Exo Up
`
`°,
`290.96°C
`
`50
`
`75
`
`100
`
`125
`
`150
`175 200 225 250 275 300 325 350
`TEMPERATURE(°C)
`UNIVERSAL V2.4F TA
`EMD 68843 FORM VII
`INSTRUMENTS
`Fig. 34
`
`
`
`150
`
`140
`130
`
`120
`
`&
`110 na
`x
`100 5
`=
`
`90
`
`80
`
`70
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 18 of 23
`
`US 8,921,375 B2
`
`160
`
`150
`
`130
`
`274.92°C
`
`8.e97evg
`72°C
`267.93vc
`64.80°C
`__
`[-h----~ OI ~ 1
`A
`Nth pp“
`°
`ae
`~s
`90.69°C
`\
`
`\i\
`
`\\
`
`+
`
`288.81°C
`
`80
`
`I!4
`
`
` 60
`
`
`
`HEATFLOW(W/g)
`
`S
`=
`=
`E
`i.
`is
`=
`
`5 TYrTyTtTTrTyrtrrrryrrrryrrrryrirre Trtrry@triret
`TITTrr TYrTrytrrrytrrryrre
`70
`50
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`TEMPERATURE (°C
`UNIVERSALV2.4F TA
`vO)
`INSTRUMENTS
`EMD 68843 FORM VIII (HEMIHYDRATE)
`Fig. 35
`
`Exo Up
`
`0
`
`150
`
`275.21°C
`
`140
`
`130
`
`120
`
`g
`110 ra
`5
`100 3
`=
`
`287.81°C
`
`90
`
`80
`
`70
`
`50
`
`75
`
`100
`
`125
`
`Exo Up
`
`150
`175 200 225 250 275 300 325 350
`TEMPERATURE(°C)
`UNIVERSAL V2.4F TA
`EMD 68843 FORM IX
`INSTRUMENTS
`Fig. 36
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 19 of 23
`
`US 8,921,375 B2
`
`150
`3
`05
`
`| 332.13°C—-288.32°C126.34°C
`
`99.42)/g
`6.804/g
`—'II7.Vig
`140
`oe+----5StrenHyyectotbs.
`|
`ft
`\
`|
`238.79°C
`\ i
`|
`5
`7
`i
`S|
`tl
`1
`= |
`|
`|
`5
`|
`i
`!
`°
`9
`V
`i
`i 4
`}130.71 C
`f
`<
`. 6.288%
`!
`|
`
`Te
`\
`(0.2979mg)
`-54
`tt
`|
`
`“65
`
`To
`
`'
`290.93°C
`
`Exo Up
`
`
`TOIT TTT TT rrr yt
`TTT
`TT a 60
`50.
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`TEMPERATURE (°C)
`UNIVERSALV2.4F TA
`EMD 68843 FORM XI (METHANOLSOLVATE)
`'NSTRUMENTS
`Fig. 37
`
`
`
`
`
`130
`120
`g
`110~
`FE
`100 2
`w
`
`90
`
`80
`
`70
`
`110
`
`=
`&
`E
`100 =
`oo
`=
`
`90
`
`/
`/
`240.45°C 281.89°C ov
`0
`1.441J/g 110.0J/g7
`109.35°C
`|_-------qt NpI?
`100.93°C
`251.73°C \} |
`6.825J/g
`wot
`I
`Lot
`7
`I
`|
`lf
`'
`Vi
`i
`tf
`
`
`
`1.367%
`(0.09074mg)
`
`289.06°C
`
`Exo Up
`
`TTT T TIrrr
`TT
`TT
`T
`TT
`TIere
`TTT T Tre’ T TTI TT TTT T TITre TT TTT
`50.75.
`100
`125
`150
`175 200 225 250 275 300 325 350
`TEMPERATURE (°C
`UNIVERSAL V2.4F TA
`vc)
`INSTRUMENTS
`EMD 68843 FORM XIV (n-heptane solvate)
`Fig. 38
`
`
`
`
`-8
`
`0.5
`
`35
`
`-3.5
`
`|
`
`0.5-
`Ss
`=
`—
`3
`=1-1.5
`kK
`a
`I
`
`
`
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 20 of 23
`
`US 8,921,375 B2
`
`114.50°C
`71.71/g
`~.
`4-7
`139.84°C
`
`ao
`
`ov
`
`225.63°C
`12.46)/g
`|
`eo t--------- hp
`235.04°C
`
`287.04°C
`
`
`
`
`
`HEATFLOW(W/gq)
`
`50
`
`75
`
`Exo Up
`
`2.0
`
`FORM XIV
`
`(1.044mqg) 60
`
`
`13.55%
`
`100
`
`125
`
`150
`175 200 225 250 275 300 325 350
`TEMPERATURE(°C)
`UNIVERSAL V2.4F
`EMD 68843 FORM XV (THF SOLVATE)
`—/®!NSTRUMENTS
`Fig. 39
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`WAVENUMBER cm-1
`
`Fig. 40
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 21 of 23
`
`US 8,921,375 B2
`
`FORM XI
`
`2.0+
`
`1.54
`
`1.04
`
`|
`
`
`
`
`|
`0.54
`0odiI_. Ji wyAl’Niidne
`
`.
`
`T
`T
`T
`T
`T
`T
`T
`
`3500
`3000
`2500
`2000
`1500
`1000
`500
`
`|
`
`|i
`
`a
`
`| |
`
`WAVENUMBER cm-1
`
`Fig. 41
`
`FORMV
`
`i
`
`|
`
`2.05
`
`1.54
`
`1.04
`
`|
`|
`05+
`i,
`A AG
`|
`|
`|
`bla
`WNun
`0.0aceeJee: “lp Tyhyhaatbbodnat
`
`
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`WAVENUMBER cm-1
`
`Fig. 42
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 22 of 23
`
`US 8,921,375 B2
`
`15
`
`FORM TV
`
`2.0
`
`
`
`0.0 be J
`
`1.0
`
`0.5
`
`2.0
`
`15
`
`1.0
`
`0.5
`
`0.0
`
` Ny
`
`2000
`
`1500
`
`1000
`
`500
`
`
`
`3500
`
`3000
`
`2500
`
`WAVENUMBER cm-1
`
`Fig. 43
`
`FORM III
`
`
`
`
`T
`T
`T
`T
`T
`T
`T
`3500
`3000
`2500
`2000
`1500
`1000
`500
`
`i
`
`WAVENUMBER cm-1
`
`Fig. 44
`
`

`

`U.S. Patent
`
`Dec. 30, 2014
`
`Sheet 23 of 23
`
`US 8,921,375 B2
`
`2.0
`
`15
`
`FORM I
`
`0.5
`0.0 A |!
`
`|
`
`Ml
`
`
`
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`WAVENUMBER cm-1
`
`Fig. 45
`
`2.0
`
`FORM |
`
`0.5 |
`
`tL_Aye .
`
`
`3500
`3000
`2500
`2000
`1500
`1000
`WAVENUMBER cm-1
`
`|
`1
`Nynant |
`
`Fig. 46
`
`

`

`US 8,921,375 B2
`
`1
`POLYMORPHIC FORMSOF1-[4-(65-
`CYANOINDOL-3-YL)BUTYL]-4-@-
`CARBAMOYLBENZOFURAN-5-YL)
`PIPERAZINE HYDROCHLORIDE
`
`RELATED APPLICATIONS
`
`This application is a continuation application of U.S.
`patent application Ser. No. 13/658,088, filed on Oct. 23,
`2012; which is a continuation of U.S. patent application Ser.
`No. 13/085,117, filed Apr. 12, 2011, now USS. Pat. No. 8,318,
`744, issued Nov. 27, 2012; which is a continuation applica-
`tion ofU.S. patent application Ser. No. 12/566,835, filed Sep.
`25, 2009, now U.S. Pat. No. 7,981,894, issued Jul. 19, 2011;
`which is a divisional application of U.S. patent application
`Ser. No. 12/110,704, filed Apr. 28, 2008, now U’S. Pat. No.
`7,834,020, issued Nov. 16, 2010; which is a divisional appli-
`cation of U.S. patent application Ser. No. 10/481,270, filed
`Dec. 19, 2003, now U.S. Pat. No. 7,381,726, issued Jun. 3,
`2008; which is a national phase application of International
`Application No. PCT/EP2002/006153, filed Jun. 5, 2002;
`which claims priority to European Patent Application No.
`01113647.0, filed Jun. 19, 2001. The entire contents of each
`of the foregoing applications and patents are hereby incorpo-
`rated in their entirety by reference.
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel compounds, to pro-
`cesses for preparing them andtotheir use in treating medical
`disorders.
`
`BACKGROUND OF THE INVENTION
`
`1-[4-(5-Cyanoindol-3-yl)butyl]-4-(2-carbamoy]-benzofu-
`ran-5-yl)-piperazine,
`its physiologically acceptable salts
`thereof (U.S. Pat. No. 5,532,241, column 7, lines 30 to 58), a
`process (U.S. Pat. No. 5,532,241, Example 4) by which
`it/they can be prepared andtheirusein treating certain medi-
`cal disorders are known from U.S. Pat. No. 5,532,241 and
`WO 00/72832.
`Example 4 of U.S. Pat. No. 5,532,241 describes the prepa-
`ration of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride by reacting 1-[4-
`(5-cyanoindol-3-yl)butyl]-4-(2-carboxybenzofuran-5-yl)
`piperazine
`at
`first with
`2-chloro-1-methylpyridinium
`methanesulfonate in N-methylpyrrolidine andthen with dried
`NH,. Customary working up gives the free base 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carboxybenzofuran-5-yl)pip-
`erazine. 700 mgofthe base are dissolved in 30 ml 2-propanol
`under heating and then treated with 0.1 n 2-propanolic HCL-
`solution (Merck-Art. No. 1.00326) until precipitation of
`hydrochloride is complete. The precipitate wasfiltered off
`and washed with diethylether and dried at room temperature
`to yield 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoy]-ben-
`zofuran-5-yl)-piperazine hydrochloride having a melting
`point of 269-272° C. There is no clear teaching elsewhere in
`the documentof any alternative route or modification to the
`process which would generate new crystal modifications of
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoy]-benzofuran-
`5-yl)-piperazine hydrochloride or new solvates or hydrates of
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoy]-benzofuran-
`5-yl)-piperazine hydrochloride in different crystal modifica-
`tions.
`
` 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoy]-
`Former
`benzofuran-5-yl)-piperazine hydrochloride having a melting
`point of 269-272° C. was a mixture of amorphous 1-[4-(5-
`
`25
`
`40
`
`45
`
`2
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-
`piperazine hydrochloride, crystallized 1 -[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoy]-benzofuran-5-yl)-piperazine
`hydrochloride and the free base 1-[4-(5-cyanoindol-3-yl)bu-
`tyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine.
`Certain crystalline, i.e. morphological forms of pharma-
`ceutical compounds maybeofinterest to those involvedin the
`development of a suitable dosage form because if the mor-
`phological form is not held constant during clinical andsta-
`bility studies, the exact dosage used or measured may not be
`comparable from onelot to the next. Once a pharmaceutical
`compoundis producedforuse, it is important to recognize the
`morphological form delivered in each dosage form to assure
`that the production process use the same form and that the
`same amountof drug is included in each dosage. Therefore, it
`is imperative to assurethat either a single morphological form
`or some known combination of morphological forms is
`present.In addition, certain morphological forms may exhibit
`enhanced thermodynamicstability and may be moresuitable
`than other morphological forms for inclusion in pharmaceu-
`tical formulations.
`
`SUMMARY OF THE INVENTION
`
`Methodsfor preparing pure crystals of 1-[4-(5-cyanoindol-
`3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride have now been found. Furthermore, surpris-
`ingly,
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-ben-
`zofuran-5-yl)-piperazine dihydrochloride, six (five+dihydro-
`chloride XII) new formsof 1-[4-(5-Cyanoindol-3-yl)buty]]-
`4-(2-carbamoy]-benzofuran-5-yl)-piperazine hydrochloride,
`three new forms of 1-[4-(5-cyanoindol-3-yl)buty]|-4-(2-car-
`bamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrate,
`six new formsofsolvates of 1-[4-(5-cyanoindol-3-yl)buty]]-
`4-(2-carbamoy]-benzofuran-5-yl)-piperazine hydrochloride
`and pure amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride have
`been found as have processes for their preparation. These
`forms are hereinafter referred to as I, II, II, IV, V, VI, VU,
`VI, IX, X, XI, XI, XIV, XV and XVI respectively.
`Throughout the specification, the term “Form”is generally
`used as a synonym for the term “modification”or “crystalline
`modification.”
`
`Accordingly, the present invention provides solvates of
`1-[4-(5-cyanoindol-3-yl)buty]]-4-(2-carbamoyl-benzofuran-
`5-yl)-piperazine hydrochloride in crystalline modifications
`and their use for the treatment and prevention of depressive
`disorders, anxiety disorders, bipolar disorders, mania,
`dementia, substance-related disorders, sexual dysfunctions,
`eating disorders, obesity, fibromyalgia, sleeping disorders,
`psychiatric disorders, cerebral infarct, tension, for the therapy
`of side-effects in the treatment of hypertension, cerebral dis-
`orders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperal
`lactation.
`The present invention furthermore provides 1-[4-(5-cy-
`anoindo]-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-pip-
`erazine hydrochloride hydrates in crystalline modifications
`and their use for the treatment and prevention of depressive
`disorders, anxiety disorders, bipolar disorders, mania,
`dementia, substance-related disorders, sexual dysfunctions,
`eating disorders, obesity, fibromyalgia, sleeping disorders,
`psychiatric disorders, cerebral infarct, tension, for the therapy
`of side-effects in the treatment of hypertension, cerebral dis-
`orders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperal
`lactation.
`
`

`

`US 8,921,375 B2
`
`3
`The present invention also provides 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoy]-benzofuran-5-yl)-piperazine
`hydrochloride anhydrates in crystalline modifications and
`their use for the treatment and prevention of depressive dis-
`orders, anxiety disorders, bipolar disorders, mania, dementia,
`substance-related disorders, sexual dysfunctions, eating dis-
`orders, obesity, fibromyalgia, sleeping disorders, psychiatric
`disorders, cerebral infarct, tension, for the therapy of side-
`effects in the treatment of hypertension, cerebral disorders,
`chronic pain, acromegaly, hypogonadism, secondary amen-
`orrhea, premenstrual syndrome and undesired puerperal lac-
`tation.
`
`The present invention relates additionally to 1-[4-(5-cy-
`anoindol]-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-pip-
`erazine dihydrochloride in its crystalline modification andits
`use for the treatment and prevention of depressive disorders,
`anxiety disorders, bipolar disorders, mania, dementia, sub-
`stance-related disorders, sexual dysfunctions, eating disor-
`ders, obesity, fibromyalgia, sleeping disorders, psychiatric
`disorders, cerebral infarct, tension, for the therapy of side-
`effects in the treatment of hypertension, cerebral disorders,
`chronic pain, acromegaly, hypogonadism, secondary amen-
`orrhea, premenstrual syndrome and undesired puerperal lac-
`tation.
`
`The present invention relates additionally to pure amor-
`phous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoy]-ben-
`zofuran-5-yl)-piperazine hydrochloride and its use for the
`treatment and prevention of depressive disorders, anxiety
`disorders, bipolar disorders, mania, dementia, substance-re-
`lated disorders, sexual dysfunctions, eating disorders, obe-
`sity, fibromyalgia, sleeping disorders, psychiatric disorders,
`cerebral infarct, tension, for the therapy of side-effects in the
`treatment of hypertension, cerebral disorders, chronic pain,
`acromegaly, hypogonadism, secondary amenorrhea, premen-
`strual syndrome and undesired puerperallactation.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`
`1 is an IR absorption spectra of Form I
`2 is an IR absorption spectra of Form II
`3 is an IR absorption spectra of Form XV
`4 is an IR absorption spectra of Form XI
`5 is an IR absorption spectra of Form XIV
`6 is an IR absorption spectra of Form V
`7 is an IR absorption spectra of Form VI
`8 is an IR absorption spectra of Form VIII
`9 is an IR absorption spectra of Form IV
`10 is an IR absorption spectra of Form III
`11 is an IR absorption spectra of Form VII
`12 is an x-ray diffractogram of Form I
`13 is an x-ray diffractogram of Form I
`14 is an x-ray diffractogram of Form XV
`15 is an x-ray diffractogram of Form X
`16 is an x-ray diffractogram of Form XI
`17 is an x-ray diffractogram of Form XIV
`FIG. 18 is an x-ray diffractogram of Form V
`FIG. 19 is an x-ray diffractogram of Form VI
`FIG.20 is an x-ray diffractogram of Form VIII
`FIG.21 is an x-ray diffractogram of Form IV
`FIG. 22 is an x-ray diffractogram of Form III
`FIG.23 is an x-ray diffractogram of Form VII
`FIG. 24 is an x-ray diffractogram of Form IX
`FIG.25 is an x-ray diffractogram of Form XIII
`FIG.26 is an x-ray diffractogram of Form XVI
`FIG. 27is an energy/temperature diagram of FormsIT, TV
`and VII
`
`FIG.28 is a diagram of thermalanalysis of Form I
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`
`4
`29 is a diagram of thermal analysis of Form II
`30 is a diagram of thermal analysis of Form III
`31 is a diagram of thermal analysis of Form IV
`32 is a diagram of thermal analysis of Form V
`33 is a diagram of thermal analysis of Form VI
`34 is a diagram of thermal analysis of Form VII
`35 is a diagram of thermal analysis of Form VIII
`36 is a diagram of thermal analysis of Form IX
`37 is a diagram of thermal analysis of Form XI
`38 is a diagram of thermal analysis of Form XIV
`39 is a diagram of thermal analysis of Form XV
`40 is a Ramanspectra of Form XIV
`41 is a Ramanspectra of Form XI
`42 is a Raman spectra of Form V
`43 is a Ramanspectra of Form IV
`44 is a Raman spectra of Form III
`45 is a Raman spectra of Form II
`46 is a Ramanspectra of Form I
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Ithas been foundthat1 -[4-(5-cyanoindol-3-yl)buty]]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride
`is
`able to form solvates in crystalline modifications. Examples
`of such solvates include solvates from water, solvates from
`alcohols such as methanol, ethanol, propan-1-ol or propan-
`2-ol; solvates from organic esters such as ethyl acetate; sol-
`vates from nitriles such as acetonitrile; solvates from ketones
`such as acetone and butanone; solvates from ethers such as
`tetrahydrofuran and solvates from chlorinated hydrocarbons
`such as chloroform and solvates of hydrocarbons such as
`n-heptane or toluene. Preferred solvates are formed with
`polar solvents, preferably water, alcohols, organic esters,
`nitriles, ketones and ethers.
`Preferably, 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbam-
`oyl-benzofuran-5-yl)-piperazine hydrochloride forms sol-
`vates with acetone, tetrahydrofuran, methanol, ethyl acetate
`or n-heptane in crystalline modifications that means the
`bound solvent together with 1-[4-(5-cyanoindol-3-yl)butyl]-
`4-(2-carbamoy]-benzofuran-5-yl)-piperazine hydrochloride
`build the crystal structure. The molar ratio of the solvent to
`1-[4-(5-cyanoindol-3-yl)buty]]-4-(2-carbamoyl-benzofuran-
`5-yl)-piperazine hydrochloride could vary as known to
`skilled persons in the art. Preferably,
`the molar ratio is
`between 0.25:1 to 2.5:1, more preferably between 0.5:1 to
`1:1, most preferably 1:1. (n-heptan solvate 1/15:1)
`It should be understood that the present solvates of the
`invention may contain unbound water that is to say water
`whichis other than water of crystallization.
`Preferred forms of solvates of 1-[4-(5-cyanoindol-3-yl)
`butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydro-
`chloride include:
`
`a) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzo-
`furan-5-yl)-piperazine hydrochloride
`solvate with
`acetone in Form J; (as hereinafter defined),
`b) 1-[4-(5-cyanoindol-3-yl)buty1]-4-(2-carbamoyl-benzo-
`furan-5-yl)-piperazine hydrochloride solvate with tet-
`rahydrofuran in Form II; (as hereinafter defined),
`c) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzo-
`furan-5-yl)-piperazine hydrochloride solvate with tet-
`rahydrofuran in Form XV;(as hereinafter defined),
`d) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzo-
`furan-5-yl)-piperazine hydrochloride solvate with tet-
`rahydrofuran in Form X; (as hereinafter defined),
`e) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzo-
`furan-5-yl)-piperazine hydrochloride
`solvate with
`methanol in Form XI]; (as hereinafter defined), and
`
`

`

`US 8,921,375 B2
`
`m 2
`
`m wa
`
`6
`5
`Alternatively, Form I can be prepared according to a pro-
`f) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoy]-benzo-
`cess which comprises:
`furan-5-yl)-piperazine hydrochloride
`solvate with
`(1) suspending Form IIIof 1-[4-(5-cyanoindol-3-yl)buty]]-
`n-heptane in Form XIV;(as hereinafter defined).
`
`Generally, the specific crystalline forms of the present 4-(2-carbamoy]-benzofuran-5-yl)-piperazine—_hydro-
`5
`chloride, which will be described later in detail,
`in
`invention have certain advantages over the product obtained
`acetone,
`according to U.S. Pat. No. 5,532,241.
`Amongothers, the most important advantages are:
`(2) stirring at room temperature between a few hours or
`reduced hygroscopicity,
`days, preferably 10 to 20 days, and
`better compressibility during the tablating process,
`(3) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)
`prolonged shelf life,
`butyl]-4-(2-carbamoy]-benzofuran-5-yl)-piperazine
`better thermodynamic stability, i.e. stability against heat
`hydrochloride solvate with tetrahydrofuran byfiltration,
`and humidity,
`and drying in vacuo at room temperature.
`better resistance to sunlight, i.e. UV-light,
`Form II according to the invention hasthe characteristic IR
`increased bulk density,
`absorption spectra as shown in FIG.2 and the characteristic
`improved solubility,
`X-ray diffraction pattern as shown in FIG. 13. XRD pattern
`bioavailability characteristics which are constant from one
`were recorded using a x-ray powderdiffractometer (Bruker
`batch to the other,
`AXS D5000) in transmission mode (Cu K alpha 1, PSD).
`better flow and handling propertiesin the tableting process,
`IR absorption spectra were measuredin the spectral range
`4000-400 cm™' on a Bruker IFS48.Spectral resolution was 2
`improvedcolorstability, and
`cm™'. Thespectra as shown in the figures were convertedto
`better filtration properties in the production process.
`transmission.
`Therefore, by use of the crystalline forms of the present
`Form II can be further characterized with the aid ofthermal
`invention, it is possible to obtain galenic formulations having
`improved homogenicity, stability, purity and uniformity from
`one batch to the other.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`Form I according to the invention has the characteristic IR
`absorption spectra as shown in FIG. 1 and the characteristic
`X-ray diffraction pattern as shown in FIG. 12. XRD pattern
`were recorded using a x-ray powderdiffractometer (Bruker
`AXS D5000) in transmission mode (Cu K alpha 1, PSD).
`IR absorption spectra were measuredin the spectral range
`4000-400 cm7' on a Bruker IFS48. Spectral resolution was 2
`cm”’. Sample preparation was performed generally as KBr
`disk. The spectra contains additionally a specific acetone
`absorption band at 1709 em7’.
`Form I can be further characterized with the aid of thermal
`
`analysis measured in the range of 30° to 350° C. FIG. 29
`shows the DSC (TA Instruments DSC 2920) and TGA (TA
`Instruments TGA 2950) measurements. Form IJ showsa des-
`olvation process between 120° C. and 180° C. Analysis by
`thermogravimetry showedthe presence of 13 weight-% to 14
`weight-% ofTHF(theory of 1:1 solvate 13.11 weight-%). The
`DSC measurement gives a phase transition to form VII
`between 200° C. and 260° C. The