USOO8921375B2
`
`(12) United States Patent
`US 8,921,375 B2
`(10) Patent N0.:
`Bathe et al.
`
`(45) Date of Patent: Dec. 30, 2014
`
`(54) POLYMORPHIC FORMS OF 1-[4-(5-
`CYANOINDOL-3-YL)BUTYL]-4-(2-
`CARBAMOYLBENZOFURAN-S-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,
`Darmstadt (DE); Susanne Rudolph,
`Dieburg (DE); Henning Bottcher,
`Darmstadt (DE)
`
`(73) Assignee: Merck Patentgesellschaft, Darmstadt
`(DE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl.No.: 14/291,931
`
`(22)
`
`Filed:
`
`May 30, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2014/0275115A1
`
`Sep. 18,2014
`
`Related US. 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 ,2,70 filed as application No. PCT/EP02/06153
`on Jun. 5, 2002, now Pat. No. 7, 381 7.26
`
`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 A1
`2011/0294824 A1
`2013/0102616 A1
`
`11/1999 Bathe et a1.
`6/2008 Bathe et a1.
`11/2010 Bathe et a1.
`7/2011 Bathe et a1.
`6/2012 Bathe et a1.
`8/2012 Bathe et a1.
`11/2012 Bathe et a1.
`3/2014 Bathe et a1.
`7/2011 Bathe et a1.
`12/2011 Bathe et a1.
`4/2013 Bathe et a1.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`WO
`WO
`
`0648767 A1
`0738722 A1
`00/72832 A2
`02/102794 A2
`
`4/1995
`10/1996
`12/2000
`12/2002
`
`OTHER PUBLICATIONS
`
`Summary ofFacts Regarding US Clinical Trials Prior to Jun. 5, 2001.
`Sorbera, L.A. et a1. “Vilazodone Hydrochloride. Antidepressant
`5-HT .sub.1A Partial Agonist 5-HT Reuptake Inhibitor” Drugs ofthe
`Future 2001, 26(3):247-252. (Mar. 2001).
`Remington Farmacia Tomo 2 19.sup.a edicion. (1998).
`Farmacotecnia TeoricaY Practica Tomo iV, Dr. Jose Helman. (1980).
`Hungarian Search Report of May 10, 2010, citing HU P0201275
`which corresponds to W0 00/72832.
`Office Action for U. S. Appl. No. 12/945 ,260, date ofmailing Aug. 17,
`201 1.
`Office Action f0rU.S.App1.N0. 12/945,272, date ofmailing Aug. 17,
`2011.
`Office Action for U.S.App1.N0. 13/100,911, date ofmailing Nov. 9,
`2011.
`Office Action for US. Appl. No. 13/085,117, date ofmailing Jan. 13,
`2012.
`Notice ofAllowance for US. Appl. No. 12/945,272, date ofmailing
`Mar. 19, 2012.
`
`(Continued)
`
`Primary Examiner 7 Samantha Shterengarts
`(74) Attorney, Agent, or Firm 7 McCarter & English, LLP;
`Danielle L. Herritt; Jin Wang
`
`(30)
`
`Foreign Application Priority Data
`
`(57)
`
`ABSTRACT
`
`Jun. 19, 2001
`
`(EP) ..................................... 01113674
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 31/496
`C07D 403/14
`C07D 405/14
`(52) US. Cl.
`CPC .................................... C07D 405/14 (2013.01)
`USPC ...................................... 514/254.09; 544/373
`(58) Field of Classification Search
`USPC ...................................... 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 Bottcheretal.
`3/1998 Bathe et a1.
`
`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, hypogonadi sm, secondary amenorrhea, premen-
`strual syndrome and undesired puerperal lactation.
`
`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 US. Appl. No. 12/945,272, date
`ofmailing Apr. 3, 2012.
`Office Action forU.S. Appl. No. 13/100,911, date ofmailing Mar. 23,
`2012.
`Office Action for US. Appl. No. 13/100,911, date ofmailing Aug. 17,
`2012.
`Office Action for US. Appl. No. 13/085,117, date ofmailing Apr. 3,
`2012.
`Notice ofAllowance for US. Appl. No. 13/085,117, date ofmailing
`Aug. 17,2012.
`
`Office Action for U.S.Appl. No. 13/100,948, date ofmailing Nov. 18,
`2011.
`Office Action for US. Appl. No. 13/100,948, date ofmailing Mar. 27,
`2012.
`Notice ofAllowance for US. Appl. No. 13/100,948, date ofmailing
`Jun. 4, 2012.
`Morissette et al. Advanced Drug Delivery Reviews, 2004, 56:275-
`300.
`Notice ofAllowance for US. Appl. No. 14/032,183, date ofmailing
`Dec. 13, 2013.
`Office Action forU.S. Appl. No. 13/658,088, date ofmailing May 23,
`2013.
`Office Action for US. Appl. No. 13/658,088, date ofmailing Dec. 2,
`2013.
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 1 of 23
`
`US 8,921,375 B2
`
`
`
`0.1—
`
`0.0—
`4000
`
`FormI
`
`I
`3500
`
`I
`3000
`
`|
`2500
`
`I
`2000
`
`|
`1500
`
`|
`1000
`
`|
`500
`
`WAVENUMBER cm-1
`
`Fig. 1
`
`
`
`
`0.0
`4000
`
`I
`3000
`
`3500
`
`2500
`
`\MJ
`2000
`
`1500
`
`WAVENUMBER cm-1
`
`Fig. 2
`
`Form 11
`
`I
`1000
`
`500
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 2 of 23
`
`US 8,921,375 B2
`
`0.14—
`
`
`UNITSOOOOOOOO—\—\4r3°|°ca5
`ABSORBANCE
`
`0.02—
`000 .33]
`
`
`3500
`3000
`2500
`2000
`1500
`1000
`500
`
`1
`
`FormXV
`
`E;
`WIM”at;
`
`E
`\E WE
`fl'
`\E\jhm..~kfi j
`
`.
`
`E;
`
`u“
`
`E
`
`_.
`
`E
`
`E
`E
`E’
`
`E
`
`E01
`
`-
`E
`_
`fl
`}5
`\E v
`EEEEH
`El
`:
`EEEEEEEXKVEU
`
`WAVENUMBERcm-1
`
`Fig. 3
`
`E
`
`Form XI
`
`
`
`0ow4>||
`
`
`
`ABSORBANCEUNITS
`
`
`
`«I;"W”
`
`W...
`
`”.5
`
`E
`E
`
`..
`EEE EEK.
`EEEEE
`“E
`
`00% NE;
`
`EEE
`E
`EEE E
`
`E
`E5 E EEEW’
`E \\\_K WE
`E‘E
`
`E
`‘
`
`.E
`E EEEEEE gLEjEE
`
`E/E
`
`
`
`'
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`WAVENUMBER cm-1
`
`Fig. 4
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 3 of 23
`
`US 8,921,375 B2
`
`0-14‘
`
`Form XIV ABSORBANCE
`0.02—
`UNITS.0.0.0.0.0OOO—‘d4%an9°<91’
`
`0.00
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`WAVENUMBERcm-1
`
`Fig.5
`
`2.04
`
`Form V
`
`‘PH“
`
`
`
`ABSORBANCEUNITS
`
`.0 ‘f‘
`
` I
`
`I
`3000
`
`I
`2500
`
`I
`2000
`
`3500
`
`I
`1500
`
`I
`1000
`
`I
`500
`
`0.0
`
`WAVENUMBER cm-1
`
`Fig. 6
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 4 of 23
`
`US 8,921,375 B2
`
`
`
`ABSORBANCEUNITS
`
`0.5
`
`
`
`.0.C'.C'Nw.b
`
`.0 a
`
`0.0
`
`0.25
`
`0.20
`
`O '_I U'I
`
`0.00
`
`Form VI
`
`I
`3000
`
`I
`2500
`
`3500
`
`\
`
`I
`2000
`
`\F"
`
` I
`
`I
`1500
`
`I
`1000
`
`I
`500
`
`FormVIII
`
`WAVENUMBER cm-1
`
`Fig. 7
`
`
`
`j
`
`I
`I
`
`'I
`
`I
`I;I
`
`
`ABSORBANCEUNITS .0 S
`0.05
`
` |
`
`|
`3000
`
`|
`2500
`
`I
`2000
`
`3500
`
`1500
`
`1000
`
`500
`
`WAVENUM BER cm-1
`
`Fig. 8
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 5 of 23
`
`US 8,921,375 B2
`
`Form IV
`
`0.4—
`
`0.3—
`
`0.2—
`
`0.1—
`
`
`0'0_
`I
`I
`I
`I
`I
`I
`I
`4000
`3500
`3000
`2500
`2000
`1500
`1000
`500
`
`WAVENUMBER cm-I
`
`Fig. 9
`
`
`
`ABSORBANCEUNITS
`
`ABSORBANCEUNITS
`
`Form 111
`
`s:-‘f‘
`
`s:-4?
`
`0.3—
`
`0.2—
`
`0.1—
`
`
`
`0.0
`4000
`
`I
`3500
`
`I
`3000
`
`I
`2500
`
`"
`I
`2000
`
`I
`1500
`
`I
`1000
`
`I
`500
`
`WAVENUMBER cm-1
`
`Fig. 10
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 6 of 23
`
`US 8,921,375 B2
`
`0.20
`
`5
`
`Form VII
`
`0 '_\ U'l
`
`0.05
`
`0.00 "w“
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`WAVENUMBERcm-1
`
`Fig.11
`
`Forml
`
`8000—
`
`
`
`ABSORBANCEUNITS
`
`+2:5
`
`
`
`@4000—
`.E_l
`
` 1
`
`IIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIlIlIIIIIIIIIIIIIIIIIIIIl‘
`1O
`20
`3O
`4O
`50
`6O
`
`2-Theta - Scale
`
`Fig. 12
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 7 of 23
`
`US 8,921,375 B2
`
`8000—
`
`Form 11
`
`7000—
`
`j/
`
`.
`
`W._
`' 3000— ‘J
`
`1000—
`
`6000—
`
`U1 0Oc?
`
`4000—
`
`InCounts)
`
`V —
`
`2000—
`
`2-Theta - Scale
`
`Fig. 13
`
`Form XV
`
`
`
`2-Theta - Scale
`
`Fig. 14
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 8 of 23
`
`US 8,921,375 B2
`
`Form X
`
`‘
`
`
`
`8000-
`
`17?
`E:5
`
`o E.
`
`E —
`
`' 4000—
`
`0
`
`MMVW
`
`
`1
`10
`20
`30
`40
`50
`60
`
`2-Theta - Scale
`
`Fl 9. 1 5
`
`Form XI
`
`6000
`
`E 4000
`
`C:
`
`5o 9
`
`,
`.E_l
`
`2000
`
`MW
`
` 1
`
`1O
`
`20
`
`3O
`
`4O
`
`50
`
`60
`
`2-Theta - Scale
`
`Fig. 16
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 9 of 23
`
`US 8,921,375 B2
`
`Form XIV
`
`8000
`
`A
`
`0
`
`.E_l
`
`g
`84000—
`
`'
`
`_
`
`1%“
`
`M)
`
`”WW
`
`.fr
`“W
`
`.
`
`0,
`
`«‘WN’W‘V’WMM/H’,
`W’WW’WM‘WWMMM
`0 IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`1
`1O
`20
`3O
`40
`50
`60
`
`
`
`,
`
`W
`
`2-Theta - Scale
`
`Fig. 17
`
`FormV
`
`8000
`
`6000
`
`.5oO O
`
`Lin(Counts)
`
` 1
`
`30
`
`40
`
`50
`
`60
`
`10
`
`20
`
`2-Theta - Scale
`
`Fig. 18
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 10 of 23
`
`US 8,921,375 B2
`
`12000—
`
`Form V1
`
`11000:
`
`10000:
`
`9000:
`358000:
`g 7000;
`&£6000—
`
`E 50003
`
`
`3k
`w
`4000:
`3000— M W W
`
`
`
`‘AAAMnKfiMWANdwwmwwx‘m
`
`1O
`
`20
`
`3O
`
`4O
`
`50
`
`6O
`
`2-Theta - Scale
`
`Fig. 19
`
`Form VIII
`
` 1
`
`1000—
`o
`
`17000—
`16000—
`15000—
`14000—
`13000—
`12000—
`
`cg1ooo-
`E10000—
`8 9000—
`Ei 8000—
`5 7000—
`6000—
`5000—
`
`
`
`4000i
`
`3333'VU‘W[WLJ
`
`1000-
`
`O
`"'A 7‘.
`60
`1
`10
`20
`3O
`4O
`5O
`
`m mAMUMMWVNMWMMv A
`
`2-Theta - Scale
`
`Fig. 20
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 11 of 23
`
`US 8,921,375 B2
`
`Form IV
`
`
`
`k‘MWMMMVAMWMwflwww
`
`IIIIIIIIIIIIIIIIII IIIIIIIII
`3O
`4O
`50
`6O
`
`2-Theta - Scale
`
`Fig. 21
`
`Form III
`
`
`
`
`O-
`
`1
`
`Viv—7v
`IIIIIIIIIIIIIIIIIIIIIIIIIIIllIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`1O
`20
`3O
`40
`50
`6O
`
`WV\V\JI~\JWKM
`
`2-Theta - Scale
`
`Fig. 22
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 12 of 23
`
`US 8,921,375 B2
`
`Form Vll
`
`
`
`2-Theta - Scale
`
`Fig. 23
`
`Form IX
`
`
`
`
`
`1O
`
`20
`
` 1
`
`3O
`
`40
`
`50
`
`6O
`
`2-Theta - Scale
`
`Fig. 24
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 13 of 23
`
`US 8,921,375 B2
`
`Form XIII
`
` MM
`
`
`0IIII||||III|IIII||IIIIIIIIIIIIII ||I|I||
`1
`10
`20
`30
`40
`
`W50
`
`III|IIII_
`60
`
`2-Theta - Scale
`
`Hg. 25
`
`FormXVI
`
`3000
`
`l
`
`h
`
`MW
`
`KMM
`
`L K}
`MJMNWkW‘MkaJLWM’WMWWW
`
`1000—
`_
`
` 1
`
`1O
`
`20
`
`3O
`
`40
`
`50
`
`6O
`
`2-Theta - Scale
`
`Fig. 26
`
`E 2000—
`8
`8
`_l
`
`_
`
`E
`
`
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 14 of 23
`
`US 8,921,375 B2
`
`ENERGY/TEMPERATURE DIAGRAM (SCHEMATIC)
`
`,
`
`ENERGY
`
`V”
`
`I”
`
`TIII—Vll TIV—VIITmlll
`
`
`TIII—IV
`
`Fig. 27
`
`1 j
`
`0-
`
`
`
`HEATFLOW(W/g)
`
`'2 —
`
`
`
`247.27°C 283.88°C
`161.92°C
`1.324J/g 107.5J/g
`78.04J/g
`
`
`243.22°C
`
`234.93°C
`
`
`4.600(3.276)J/g
`1 70.89°C
`
`
`
`
`
`
`i
`
`_ 10.60%
`(0.1639mg)
`
`
`
`
`
`
`170
`
`145
`
`95
`
`70
`
`290.28°C
`
`
` 45
`
`20
`75 100 125 150 175 200 225 250 275 300 325 350 375 400
`
`5O
`
`TEMPERATURE (°C)
`EMD 68843 FORM | (ACETONE SOLVATE)
`
`Fig. 28
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 15 of 23
`
`US 8,921,375 B2
`
`
`
`
`
`1
`
`
`
`150
`
`_
`142.30°C
`223.470C
`291.61%:
`0‘
`73_40_I/g
`1.966J/g
`107.4J/g
`
`
`'
`-1—
`233.33°C
`
`
`A 2 '
`154.20°C
`
`
`é”
`o
`E -3
`
`113529656
`)
`0
`d _4_
`(
`.
`mg
`I;
`_
`”f _5_
`—
`-6—
`
`-
`
`'7‘
`
`293.31°C
`
`
`
`140
`
`130
`
`120
`110 E
`100 '—
`6
`90 g
`8O
`7o
`
`60
`
`50
`
`_8IlllIllIIIllIIIIIIIIIIIIIllllIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII4O
`50
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`
`Exo Up
`
`TEMPERATURE (°C)
`EMD 68843 FORM 11 (THF SOLVATE)
`Hg. 29
`
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`
`
`224.59°C
`288.02°C
`
`1.631J/g
`131.2J/g
`|
`
`234.31 C
`
`
`
`
`60
`I
`I
`I
`I
`I
`I
`I
`I
`I
`|
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`|
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`50
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`
`289.78°C
`
`
`
`150
`
`140
`
`130
`
`120
`
`:«v‘
`110 I:
`5
`100 m
`E
`
`90
`
`80
`
`7o
`
`0
`
`-1
`
`3"
`5
`E '2
`9
`I:
`<
`w -3
`I
`
`-4
`
`'5
`
`Exo Up
`
`TEMPERATURE (°C)
`EMD 68843 FORM 111
`
`UNIVERSAL V2.4F TA
`'NSTRUIVIENTS
`
`Fig. 30
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 16 of 23
`
`US 8,921,375 B2
`
`1-:
`
`E150
`
`235.88°C 288.30°C
`_
`5.192J/g
`133.1J/g
`0‘
`‘——————————————————————————————————_1——-+\l/__1__1TW/
`II
`-1-
`242.91°C
`\‘5 1
`_
`1:1
`H
`1‘;
`E:
`1
`H
`H
`1
`:1
`
`A
`9-2-
`E 3'
`_ _
`E
`'
`1... -4-
`E
`-
`:1: —5—
`
`
`
`-6-
`
`-7-
`
`-8
`
`
`
`
`/”'
`440
`-
`—130
`_
`
`—120 ,3
`-
`E,
`—110 I
`-
`9
`—100 L;
`-
`—90
`
`—so
`
`—7o
`
`290.59°C
`
`5o
`
`75
`
`100
`
`125
`
`150
`
`60
`175 200 225 250 275 300 325 350
`
`Exo Up
`
`o
`
`TEMPERATURE (°C)
`EMD 68843 FORM IV
`Fig. 31
`
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`45.55°C
`321 .OJ/g/,,,,,,,,F-----
`
`230.61°C 28562°C
`-
`51%?311+1;33”g
`
`170
`
`160
`
`HEAT
`
`FLOW(W/g)
`
`3.655%
`
`(0.3225mg)
`
`50
`
`75
`
`100
`
`125
`
`150
`
`175 200 225 250 275 300 325 350
`
`Exo Up
`
`TEMPERATURE (°C)
`EMD 68843 FORM V (MONOHYDRATE)
`
`UNIVERSAL V2.4F TA
`'NSTRUMENTS
`
`Fig. 32
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 17 of 23
`
`US 8,921,375 B2
`
`j
`
`146.73°C
`A
`1
`41’, ‘\
`141.45°C
`38.27J/g
`
`1
`
`248 10°C
`-
`o
`0.8866J/g 55555;:
`H‘H;\\|
`/+__‘_
`254-12C \5
`,1
`.‘
`,I'
`1
`I
`.
`,1'
`.‘
`
`288.78 C
`
`
`
`150
`
`140
`
`130
`
`‘—————’ 120
`
`’3
`110 95
`E
`g
`100 Lu
`3
`
`9o
`
`80
`
`70
`
`6.190%
`(0.1924mg)
`
`
`
`57.94°C
`0-
`108.4J/
`xE~~44\g
`“\1——/”’
`95.29°C
`
`3.3
`i
`g '2‘
`0
`'fi
`_1
`I:
`5
`I
`
`_
`
`-4-
`
`'
`
`
`
`
`
`'6 I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`|
`I
`I
`| 60
`50
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`
`Exo Up
`
`
`
`
`
`1
`
`-
`o-
`
`-1—
`
`3"
`E ‘2‘
`E
`'
`9
`E _3_
`<
`LIJ
`_
`I
`
`-4-
`
`_5_
`
`288.65°C
`111.4J/g
`———————————————————————————————————————————————————+—— \
`,
`\i v'
`\I
`I
`\ii
`I I
`I
`‘1'!
`I:
`1:
`:1
`II
`II
`
`
`
`TEMPERATURE (°C)
`EMD 68843 FORM VI (1.75 HYDRATE)
`
`IIEII/REEIIAAEII‘IEAF TA
`
`Hg. 33
`
`
`
`150
`
`14o
`
`130
`
`120
`A
`110 §
`1—
`g
`100 E
`E
`
`90
`
`80
`
`70
`
`0
`290.96 C
`
`
`50
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`
`Exo Up
`
`TEMPERATURE (°C)
`EMD 68843 FORM VII
`
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`Fig. 34
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 18 of 23
`
`US 8,921,375 B2
`
`1—3
`
`64-80°C
`0'
`59.00J/
`'--1-—————L\ g
`
`274.92°C
`I8.976J/g
`I 284.72°C
`$3753};
`9 31197149”
`7"" ----------------------------“fl-[Lt‘k7L ) /g
`'
`
`160
`
`15o
`
`140
`
`130
`
`3‘
`120 1:
`3
`110 E
`E
`
`100
`
`90
`
`so
`
`I
`
`I
`
`I
`
`I
`I
`50
`
`I
`
`I
`
`I
`
`I
`I
`75
`
`I
`
`I
`
`I
`
`I
`I
`I
`100
`
`I
`
`I
`I
`I
`125
`
`I
`
`I
`
`I
`
`I
`
`I
`I
`I
`150
`
`70
`|
`I II |
`I
`|
`|
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`175 200 225 250 275 300 325 350
`
`_5
`
`EXO Up
`
`
`
`
`
`o
`
`3
`E
`g
`9
`LL
`LIJ
`'2:
`I
`
`3.,
`5
`g
`9
`LL
`E
`I
`
`
`
`
`TEMPERATURE (°C)
`EMD 68843 FORM VIII (HEMIHYDRATE)
`Fig. 35
`
`UNIVERSAL V2.4F TA
`'NSTRUMENTS
`
`275.21°c
`
`40.86J/g ‘1
`
`-
`
`287.81°C
`
`150
`
`14o
`
`130
`
`120
`
`3‘
`110 11’
`3
`100 E
`E
`
`90
`
`80
`
`7o
`
`50
`
`75
`
`100
`
`125
`
`150
`
`60
`175 200 225 250 275 300 325 350
`
`EXO Up
`
`TEMPERATURE (°C)
`EMD 68843 FORM IX
`
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`Fig. 36
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 19 of 23
`
`US 8,921,375 B2
`
`o
`288. 32 C
`23; 13°C
`126.34°C
`I 171J/g/
`6804J/g
`99.42J/g
`—————————1——————\
`1
`I,——+——————————————————Hy,’+-—|-~\
`I
`,1,
`I
`238. 79°C
`\i ,1'
`\
`,1
`III
`‘I
`II
`I
`I
`11
`11
`II
`1.
`0
`II
`III
`I13o.71 C
`II
`_ 6.288%
`I
`
`(0.2979mg)
`I
`1
`I
`290.93°C
`
`;
`
`0:1
`_
`
`-1—
`-
`_2_
`_
`
`:61
`E 3
`' '
`E
`'
`LL _4_
`E
`_
`I _5_
`_
`
`'6‘
`
`'7‘
`
`150
`
`140
`
`130
`
`120
`”a
`110 35
`E
`100 g
`g
`
`90
`
`80
`
`7o
`
`'8
`
`60
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII||II
`50
`75
`100
`125
`150
`175 200 225 250 275 300 325 350
`
`TEMPERATURE (°C)
`EMD 68843 FORM XI (METHANOL SOLVATE)
`Hg. 37
`
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`Exo Up
`
`
`
`
`
`0.5
`
`-
`
`-0-5-
`a
`E
`V
`g
`:15
`1—
`<
`§
`
`-2.5—
`
`24o.45°C 281 .89°C
`a
`1 4411/9 110.OJ/g ,/
`109/35 C
`—————————————-I-—‘I
`‘\__I_______-____————————————-H-~—|/H‘—I'7"
`100.93°C
`251 73°C \I 1"
`6.825J/g
`\i
`1'
`I
`I
`I
`I
`I
`I
`I
`I
`'
`1
`'1
`
`
`
`1.367%
`(0.09074mg)
`
`
`
`
`//
`II
`/"~’
`
`110
`
`A
`g
`:
`100 g
`E
`5
`
`90
`
`l I
`
`289.06°C
`
`
`
`_3-5
`
`I
`
`I
`
`I
`
`I
`
`I
`I
`I
`50
`
`I
`
`I
`I
`75
`
`I
`
`I
`
`I
`
`I
`
`I
`I
`I
`100
`
`I
`I
`I
`125
`
`I
`
`I
`
`I
`
`I
`
`I
`I
`I
`150
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`175 200 225 250 275 300 325 350
`
`Exo Up
`
`TEMPERATURE °C
`)
`(
`EMD 68843 FORM XIV (n-heptane solvate)
`
`UNIVERSALV2.4F TA
`INSTRUMENTS
`
`Fig. 38
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 20 of 23
`
`US 8,921,375 B2
`
`
`
`1 14.50°C
`
`225.63°C
`
`287.04°C
`
`
`
`HEATFLOW(W/g)
`
`13.55%
`
`71 .71J/g
`\
`————————————1—~\_/+\
`
`/
`
`109.1J/g
`12.46J/g
`/--+--——T'T“+"*\1—\--————+
`235.o4°c
`
`“W”
`1 39.84°C
`
`(1 .044mg)
`
`5o
`
`75
`
`100
`
`125
`
`150
`
`175 200 225 250 275 300 325 350
`
`TEMPERATURE (oc)
`EMD 68843 FORM XV (THF SOLVATE)
`Fig. 39
`
`UNIVERSAL V2.4F
`TA 'NSTRU’V‘ENTS
`
`Exo Up
`
`2.0
`
`FORM XIV
`
`
`
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`WAVENUMBER cm-1
`
`Fig. 40
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 21 of 23
`
`US 8,921,375 B2
`
`2.04
`
`FORM XI
`
`1.5—
`
`1.0—
`
`
`
`J,
`0.5—
`
`1.00W,_,MJJW’M»N- ,,,,,WJM MWWl/WZW
`
`
`
`3500
`
`3000
`
`|
`2500
`
`1500
`2000
`WAVENUMBER cm-1
`
`1000
`
`3 i
`
`i
`
`Fl 9. 41
`
`-
`
`1
`
`FORM V
`
`2.04
`
`1.5—
`
`1.0—
`
`g
`:3;
`iii
`
`2
`
`J
`‘
`
`
`
`0.5-
`
`E
`i:
`:5
`‘
`O 0 mm» W)”jfleNRbA‘AJ‘U‘(4_H__________”fak— “$212.1":
`
`
`
`3U
`i
`{
`i
`ii
`I
`i L
`=
`~11
`\Jflfl‘vli‘E‘Léibr“WW“jaigxu’g‘h’mgflj
`
`~
`
`WAVENUMBER cm-1
`
`Fig. 42
`
`' H—l—l—l—I—I—l—
`3500
`3000
`2500
`200
`1500
`1000
`500
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 22 of 23
`
`US 8,921,375 B2
`
`2.0
`
`15
`
`FORM IV
`
`1.0
`
`0.5
`
`
`
` 111.111....
`
`
`
`
`0.0 MW
`3500
`
`3000
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`WAVENUMBER cm-1
`
`Hg. 43
`
`FORM III
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0'0
`
`
`
`
`|
`|
`|
`|
`|
`|
`|
`3500
`3000
`2500
`2000
`1500
`1000
`500
`
`W
`
`WAVENUMBER cm-1
`Fig. 44
`
`

`

`US. Patent
`
`Dec. 30, 2014
`
`Sheet 23 of 23
`
`US 8,921,375 B2
`
`2.0
`
`15
`
`FORM 11
`
`1.0
`
`0.5
`
`I
`
`
`|
`|
`|
`I
`I
`I
`I
`3500
`3000
`2500
`2000
`1500
`1000
`500
`
`0'0
`
`WAVENUMBER cm-1
`
`Hg. 45
`
`FORM 1
`
`2.0
`
`1.5
`
`1.0
`
`.
`
`0.5
`kw“?
`0 0 “5..”ij
`\AWVW
`I
`'
`3500
`3000
`2500
`
`i
`
`I
`5
`
`
`
`1000
`
`I
`500
`
`:
`
`g
`I
`i
`waUI)
`
`I
`1500
`2000
`WAVENUMBER cm-1
`
`Fig. 46
`
`

`

`1
`POLYMORPHIC FORMS OF 1-[4-(5-
`CYANOINDOL-3-YL)BUTYL]-4-(2-
`CARBAMOYLBENZOFURAN-S-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. 13/085,1 17, filedApr. 12, 201 1, now U.S. 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.
`011136470, filed Jun. 19, 2001. The entire contents of each
`of the foregoing applications and patents are hereby incorpo-
`rated in their entirety by reference.
`
`10
`
`15
`
`20
`
`25
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel compounds, to pro-
`cesses for preparing them and to their use in treating medical
`disorders.
`
`30
`
`BACKGROUND OF THE INVENTION
`
`1- [4-(5-Cyanoindol-3 -yl)butyl] -4-(2-carbamoyl-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 and their use in treating certain medi-
`cal disorders are known from U.S. Pat. No. 5,532,241 and
`WO 00/72832.
`
`Example 4 ofU.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 and then with dried
`NH3. Customary working up gives the free base 1-[4-(5-
`cyanoindol-3 -yl)butyl] -4-(2-carboxybenzofuran-5 -yl)pip-
`erazine. 700 mg of the 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 was filtered off
`and washed with diethylether and dried at room temperature
`to yield 1-[4-(5-cyanoindol-3 -yl)butyl]-4-(2-carbamoyl-ben-
`zofuran—5-yl)-piperazine hydrochloride having a melting
`point of 269-2720 C. There is no clear teaching elsewhere in
`the document of any alternative route or modification to the
`process which would generate new crystal modifications of
`1-[4-(5 -cyanoindol-3-yl)butyl] -4-(2-carbamoyl-benzofi1ran-
`5-yl)-piperazine hydrochloride or new solvates or hydrates of
`1-[4-(5 -cyanoindol-3-yl)butyl] -4-(2-carbamoyl-benzofi1ran-
`5-yl)-piperazine hydrochloride in different crystal modifica-
`tions.
`
`1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`Former
`benzofuran—5-yl) -piperazine hydrochloride having a melting
`point of 269-2720 C. was a mixture of amorphous 1-[4-(5-
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`US 8,921,375 B2
`
`2
`
`cyanoindol-3 -yl)butyl] -4-(2-carbamoyl-benzofuran-5-yl)-
`piperazine hydrochloride, crystallized 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride and the free base 1-[4-(5 -cyanoindol-3 -yl)bu-
`tyl] -4-(2-carbamoyl-benzofi1ran-5 -yl) -piperazine.
`Certain crystalline, i.e. morphological forms of pharma-
`ceutical compounds may be ofinterest to those involved in the
`development of a suitable dosage form because if the mor-
`phological form is not held constant during clinical and sta-
`bility studies, the exact dosage used or measured may not be
`comparable from one lot to the next. Once a pharmaceutical
`compound is produced foruse, 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 amount of drug is included in each dosage. Therefore, it
`is imperative to assure that either a single morphological form
`or some known combination of morphological forms is
`present. In addition, certain morphological forms may exhibit
`enhanced thermodynamic stability and may be more suitable
`than other morphological forms for inclusion in pharmaceu-
`tical formulations.
`
`SUMMARY OF THE INVENTION
`
`Methods for 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 XIII) new forms of 1 -[4-(5 -Cyanoindol-3 -yl)butyl]-
`4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride,
`three new forms of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-car-
`bamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrate,
`six new forms of solvates of 1-[4-(5-cyanoindol-3-yl)butyl]-
`4-(2-carbamoyl-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, III, IV, V, VI, VII,
`VIII,
`IX, X, XI, XIII, 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)butyl] -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-
`anoindol-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-carbamoyl-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-benzofi1ran—5 -yl) -pip-
`erazine dihydrochloride in its crystalline modification and its
`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-carbamoyl-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, hypogonadi sm, secondary amenorrhea, premen-
`strual syndrome and undesired puerperal lactation.
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`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 II
`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
`18 is an x-ray diffractogram of FormV
`19 is an x-ray diffractogram of Form VI
`20 is an x-ray diffractogram of Form VIII
`21 is an x-ray diffractogram of Form IV
`22 is an x-ray diffractogram of Form III
`23 is an x-ray diffractogram of Form VII
`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. 27 is an energy/temperature diagram of Forms III, IV
`and VII
`
`FIG. 28 is a diagram of thermal analysis of Form I
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`FIG.
`
`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 Raman spectra of Form XIV
`41 is a Raman spectra of Form XI
`42 is a Raman spectra of Form V
`43 is a Raman spectra of Form IV
`44 is a Raman spectra of Form III
`45 is a Raman spectra of Form II
`46 is a Raman spectra of Form I
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`It has been found that 1-[4-(5 -cyanoindol-3-yl)butyl]-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-S-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-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride
`build the crystal structure. The molar ratio of the solvent to
`1-[4-(5 -cyanoindol-3-yl)butyl] -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 25:1, 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
`which is 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 I; (as hereinafter defined),
`b) 1-[4-(5-cyanoindol-3-yl)butyl]-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
`
`5
`f) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzo-
`furan-5-yl)-piperazine hydrochloride
`solvate with
`n-heptane in Form XIV; (as hereinafter defined).
`Generally, the specific crystalline forms of the present
`invention have certain advantages over the product obtained
`according to US. Pat. No. 5,532,241.
`Among others, the most important advantages are:
`reduced hygroscopicity,
`better compressibility during the tablating process,
`prolonged shelf life,
`better thermodynamic stability, i.e. stability against heat
`and humidity,
`better resistance to sunlight, i.e. UV-light,
`increased bulk density,
`improved solubility,
`bioavailability characteristics which are constant from one
`batch to the other,
`better flow and handling properties in the tableting process,
`improved color stability, and
`better filtration properties in the production process.
`Therefore, by use of the crystalline forms of the present
`invention, it is possible to obtain galenic formulations having
`improved homogenicity, stability, purity and uniformity from
`one batch to the other.
`
`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 powder diffractometer (Bruker
`AXS D5000) in transmission mode (Cu K alpha 1, PSD).
`IR absorption spectra were measured in the spectral range
`4000-400 cm‘1 on a Bruker IFS48. Spectral resolution was 2
`cm'l. Sample preparation was performed generally as KBr
`disk. The spectra contains additionally a specific acetone
`absorption band at 1709 cm‘l.
`Form I can be further characterized with the aid of thermal
`
`analysis measured in the range of 30° to 350° C. FIG. 28
`shows the DSC (TA Instruments DSC 2920) and TGA (TA
`Instruments TGA 2950) measurements. Form I shows a des-
`olvation process between 50° C. and 180° C. Analysis by
`therrnogravimetr