I 1111111111111111 11111 1111111111 1111111111 1111111111 11111 111111111111111111
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`US008673921B2
`
`c12) United States Patent
`Bathe et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,673,921 B2
`Mar.18,2014
`
`(54) POLYMORPHIC FORMS OF
`1-[ 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,
`Darmstadt (DE); Susanne Rudolph,
`Dieburg (DE); Henning Bottcher,
`Darmstadt (DE)
`
`(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 O days.
`
`(21) Appl. No.: 14/032,183
`
`(22) Filed:
`
`Sep.19,2013
`
`(65)
`
`Prior Publication Data
`
`US 2014/0024658 Al
`
`Jan.23,2014
`
`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.
`
`7,834,020 B2
`7,981,894 B2
`8,193,195 B2
`8,236,804 B2
`8,318,744 B2
`2011/0183994 Al
`2011/0294824 Al
`2013/0102616 Al
`
`11/2010 Bathe et al.
`7/2011 Bathe et al.
`6/2012 Bathe et al.
`8/2012 Bathe et al.
`11/2012 Bathe et al.
`7/2011 Bathe et al.
`12/2011 Bathe et al.
`4/2013 Bathe et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`WO
`WO
`
`0648767 Al
`0738722 Al
`00/72832 A2
`02/102794 A2
`
`4/1995
`10/1996
`12/2000
`12/2002
`
`OTHER PUBLICATIONS
`
`Summary of Facts Regarding US Clinical Trials Prior to Jun. 5, 2001.
`Sorbera, L.A. et al. "Vilazodone Hydrochloride. Antidepressant
`5-HT . sub. lA Partial Agonist 5-HT Reuptake Inhibitor" Drugs of the
`Future 2001, 26(3):247-252. (Mar. 2001).
`Remington Farmacia Torno 2 19.sup.a edicion. (1998).
`Farmacotecnia Teorica Y Practica Torno iV, Dr. Jose Helman. (1980).
`Hungarian Search Report of May 10, 2010, citing HU P0201275
`which corresponds to WO 00/72832.
`OfficeActionforU.S.Appl. No.12/945,260, dateofmailingAug.17,
`2011.
`OfficeActionforU.S.Appl. No.12/945,272, dateofmailingAug.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.
`Corrected Notice of Allowance for U.S. Appl. No. 12/945,272, date
`of mailing Apr. 3, 2012.
`
`(Continued)
`
`Primary Examiner - Samantha Shterengarts
`(74) Attorney, Agent, or Firm - McCarter & English, LLP;
`Danielle L. Herritt, Esq.; Jin Wang, Esq.
`
`(30)
`
`Foreign Application Priority Data
`
`(57)
`
`ABSTRACT
`
`Jun. 19, 2001
`
`(EP) ..................................... 01113674
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311496
`C07D405/14
`(52) U.S. Cl.
`...................................... 514/254.09; 544/373
`USPC
`( 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
`5,977,112 A
`7,381,726 B2
`
`5/1996 Wu
`7 / 1996 Bottcher et al.
`3/ 1998 Bathe et al.
`1111999 Bathe et al.
`6/2008 Bathe et al.
`
`The invention relates to new crystalline modifications of the
`hydrochloride of
`l-[4-(5-cyanoindol-3-yl)butyl]-4-(2-car(cid:173)
`bamoyl-benzofuran-5-yl)-piperazine,
`crystalline modifica(cid:173)
`tion of the dihydrochloride of l-[4-(5-cyanoindol-3-yl)bu(cid:173)
`tyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`and
`amorphous 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl(cid:173)
`benzofuran-5-yl)-piperazine hydrochloride which are suit(cid:173)
`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(cid:173)
`lated disorders, sexual dysfunctions, eating disorders, obe(cid:173)
`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(cid:173)
`strual syndrome and undesired puerperal lactation.
`
`15 Claims, 23 Drawing Sheets Argentum EX1001
`
`Page 1
`
`

`

`US 8,673,921 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`OfficeActionforU.S.Appl. No. 13/100,911, date of mailing Mar. 23,
`2012.
`OfficeActionforU.S.Appl. No. 13/100,911, date of mailing 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.
`OfficeActionforU.S.Appl. No. 13/100,948, dateofmailingNov.18,
`2011.
`Office Action for U.S. Appl. No. 13/ l 00 ,948, date of mailing Mar. 27,
`2012.
`Notice of Allowance for U.S. Appl. No. 13/100,948, date of mailing
`Jun. 4, 2012.
`Office Action for U.S. Appl. No. 13/658,088, date of mailing May 23,
`2012.
`Morissette, et al. Advanced Drug Delivery Reviews, 56, 2004, p.
`275-300.
`
`Page 2
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 1 of 23
`
`US 8,673,921 B2
`
`Form I
`
`0.8
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`
`Page 3
`
`

`

`U.S. Patent
`
`Mar.18,2014
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`Sheet 2 of 23
`
`US 8,673,921 B2
`
`0.14
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`
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`
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`Page 4
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`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 3 of 23
`
`US 8,673,921 B2
`
`0.14
`
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`
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`
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`Page 5
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 4 of 23
`
`US 8,673,921 B2
`
`Form VI
`
`0.5
`
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`
`

`

`U.S. Patent
`
`Mar.18,2014
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`Sheet 5 of 23
`
`US 8,673,921 B2
`
`Form IV
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`
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`
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`
`Page 7
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 6 of 23
`
`US 8,673,921 B2
`
`0.20
`
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`
`Form I
`
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`
`Fig. 12
`
`Page 8
`
`

`

`U.S. Patent
`
`Mar.18,2014
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`Sheet 7 of 23
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`US 8,673,921 B2
`
`Form II
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`

`

`U.S. Patent
`
`Mar.18,2014
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`Sheet 8 of 23
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`US 8,673,921 B2
`
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`Page 10
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`

`

`U.S. Patent
`
`Mar.18,2014
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`Sheet 9 of 23
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`US 8,673,921 B2
`
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`

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`U.S. Patent
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`Mar.18,2014
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`Sheet 10 of 23
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`US 8,673,921 B2
`
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`U.S. Patent
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`Mar.18,2014
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`Sheet 11 of 23
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`US 8,673,921 B2
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`U.S. Patent
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`Mar.18,2014
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`Sheet 12 of 23
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`US 8,673,921 B2
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`Form VII
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`U.S. Patent
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`Mar.18,2014
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`Sheet 13 of 23
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`US 8,673,921 B2
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`

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`U.S. Patent
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`Mar.18,2014
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`Sheet 14 of 23
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`US 8,673,921 B2
`
`ENERGY /TEMPERATURE DIAGRAM (SCHEMATIC)
`
`// HL
`
`ENERGY
`
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`
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`
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`TEMPERATURE (0
`EMD 68843 FORM I (ACETONE SOLVATE)
`Fig. 28
`
`()
`
`Page 16
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`

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`U.S. Patent
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`Mar.18,2014
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`Sheet 15 of 23
`
`US 8,673,921 B2
`
`142.30°(
`73.40J/g
`
`154.20°(
`
`223.47°(
`1.966J/g
`
`233.33°(
`
`13.26%
`(1.595mg)
`
`1
`
`0
`
`-1
`
`cri-2
`~
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`90
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`5
`
`293.31 °C
`
`80
`
`70
`
`60
`
`50
`
`Exo Up
`
`-8 --+-r--~mm~~mm~~mm~~mm~~~~~~~-,-r+--40
`50
`75 100 125 150 175 200 225 250 275 300 325 350
`TEMPERATURE (°C)
`UNIVERSAL V2.4F TA
`EMD 68843 FORM II (THF SOLVATE)
`INSTRUMENTS
`Fig. 29
`
`0
`
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`
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`~
`:s -2
`0
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`
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`
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`1.631J/g
`
`288.02°(
`131.2J/g
`
`234.31 °(
`
`289.78°(
`
`150
`
`140
`
`130
`
`120
`
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`110 ~
`I-
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`$
`
`90
`
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`--+-r--~mm~~mm~~mm~~mm~~mm~~~-,-r+--60
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`50
`
`Exo Up
`
`75 100 125 150 175 200 225 250 275 300 325 350
`TEMPERATURE (°C)
`UNIVERSAL V2.4FTA
`INSTRUMENTS
`EMD 68843 FORM III
`Fig. 30
`
`Page 17
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 16 of 23
`
`US 8,673,921 B2
`
`0
`
`-1
`
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`~ i -3
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`235.88°(
`5.192J/g
`-1---+-i-----t-i
`242.91°(
`
`,,/-
`
`./(cid:173)
`
`288.30°(
`133.1 Jig
`I ,I _-
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`'
`I
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`
`290.59°(
`
`150
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`140
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`120
`
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`
`100 ~
`
`90
`
`80
`
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`
`300 325 350
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`-8--+-r-~rnrn~~~rn~~~rnrn~~~rnrn~~~rn~---r+-60
`50
`75 100 125
`150 175 200 225 250 275
`TEMPERATURE (0()
`EMD 68843 FORM IV
`Fig. 31
`230.61 oc 285.620(
`5-872J/g
`113.2J/ g
`t---l--i---+-+-------1--
`,
`'--,-J
`239.96°(
`\
`I
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`321.0J/g ------+-----
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`3.655%
`(0.3225mg)
`
`170
`
`160
`
`150
`
`140
`
`130
`
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`120 ~
`:r:
`110 ~
`LU
`5
`
`100
`
`90
`
`80
`
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`
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`i' I
`
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`: 289.64°(
`
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`
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`
`-6--+-r-~rn~~m~~m~~mrn~~m~~m~~mrn~.-+-60
`50
`75
`100 125 150 175 200 225 250 275
`TEMPERATURE (0()
`EMD 68843 FORM V (MONOHYDRATE)
`Fig. 32
`
`300 325 350
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`Page 18
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 17 of 23
`
`US 8,673,921 B2
`
`146/30(
`/ \
`'-
`I
`----rl
`-----i------141.45°(
`38.27 Jig
`95.29°(
`
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`108.4J/g
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`
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`248.10°C 282 660(
`130
`O.8866J/g 117 . .SJ/g
`H-H--
`254.120( '\ ! r+-----, ____ _.,
`120
`I I
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`
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`
`-6--+-r-~rn~~m~~~rn~~m~~~rn~~m~~~rn-+-6O
`50
`75
`100 125 150 175 200 225 250 275
`TEMPERATURE (0()
`EMD 68843 FORM VI (1.75 HYDRATE)
`Fig. 33
`
`300 325 350
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`0
`
`--------------------------------------------------i---~
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`
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`~ ~ -2
`$
`9
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`I-: -3
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`111.4J/g
`
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`
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`-6--+-r-m""T""T""m""T""T""m""T""T""m--r-r-m--r-r-..--r-T",--r,..--r-T"rn---.-r-rn""T""T""m""T""T""m""T""T""m--r-r-m""T""TT6O
`50
`75
`100 125 150 175 200 225 250 275
`300 325 350
`TEMPERATURE (0()
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`EMD 68843 FORM VII
`Fig. 34
`
`Page 19
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 18 of 23
`
`US 8,673,921 B2
`
`160
`
`0
`
`oi -1
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`274.92°C
`j8.976J/g
`267.93°C ll 284.72°C
`64.80°C
`I\ 119.7(149.3)J/g
`140
`38.57 Jig
`59.00J/g
`1----r----------------------------~~---,
`-~-----l
`
`~.\i I\ !~------ .... ____ .. ,/
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`130
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`
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`
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`288.81°C
`
`Exo Up
`
`-5-+-,--~m~--~~~m~-~~~~-~~~m~-.---..---r-+-70
`50
`75
`100 125 150 175 200 225 250 275
`TEMPERATURE (°C)
`EMO 68843 FORM VIII (HEMIHYORATE)
`Fig. 35
`
`300 325 350
`UNIVERSAL V2.4F TA
`INSTRUMENTS
`
`- --
`
`-
`
`0
`
`-1
`
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`266.80oc 5.971J/~
`40.86J/g
`:\ 281.54 C
`------------~---~1.1(146.0)J/g
`\!\''-rt-
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`
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`
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`-7-+-r-m~m~~~~~~m~m~m~~~~~~~~m~~6o
`100 125 150 175 200 225 250 275
`50
`75
`300 325 350
`UNIVERSAL V2.4F TA
`TEMPERATURE (°C)
`INSTRUMENTS
`EMO 68843 FORM IX
`Fig. 36
`
`Page 20
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 19 of 23
`
`US 8,673,921 B2
`
`--------+-----
`
`------t----=-------t-
`
`288.32°(
`232.13°(
`126.34°(
`117.1 J/g ~//-
`6.804J/g
`99.42J/g
`I ~--
`I ,--i------------------H,
`-+--t--,
`,,r
`'\
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`I
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`\ l
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`\/
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`Ii l 130.71 °C
`6.288%
`(0.2979mg)
`
`\/
`Ii
`
`290.93°(
`
`0
`
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`
`80
`
`70
`
`-8--+--~m~-~~~-~~~~~~-~m~-~~~~60
`50
`75 100 125 150 175 200 225 250 275
`300 325 350
`UNIVERSAL V2.4F TA
`TEMPERATURE (0
`INSTRUMENTS
`EMO 68843 FORM XI (METHANOL SOLVATE)
`Fig. 3 7
`
`()
`
`Exo Up
`
`0.5
`
`-0.5
`
`240.45°c 281.89°c
`1o935 °c
`1.441 J/g 11 O.OJ/g //
`;~
`''---1------------------------it--1--II
`'\
`------------i--i,.
`!
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`251.73°C \ : I
`100.93°C
`1,
`I
`6.825J/g
`\: I
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`
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`
`;
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`
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`
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`~ LU
`:r:
`
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`
`50
`
`Exo Up
`
`75 100 125 150 175 200 225 250 275 300 325 350
`UNIVERSAL V2.4F TA
`TEMPERATURE (0
`EMD 68843 FORM XIV (n-heptane solvate)
`INSTRUMENTS
`Fig. 38
`
`()
`
`Page 21
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 20 of 23
`
`US 8,673,921 B2
`
`114.50°(
`71.71J/g
`-----------~-------},,
`
`287.04°(
`225.63°(
`109.lJ/g
`12.46J/g
`I ,-r
`,/--+---------+-~'-r-------+,
`''-+---'
`235.04°(
`\: /
`139.84°C
`\: I
`\!:
`I• I I I
`l I
`
`13.55%
`(1.044mg)
`
`1 I
`11
`11
`11
`11
`
`II 11
`ii
`290.24°(
`
`0
`
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`
`90
`
`80
`
`70
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`
`-8-+--,-~~~~~~~~~~~~~~~~~~~~~m~1'-r-+-60
`50
`75
`100 125 150 175 200 225 250 275
`300 325 350
`UNIVERSAL V2.4F
`TEMPERATURE (0
`TA INSTRUMENTS
`EMD 68843 FORM XV (THF SOLVATE)
`Fig. 39
`
`()
`
`FORM XIV
`
`2.0
`
`1.5
`
`1.0
`
`0.5 O.OJ
`
`3000
`
`2500
`
`3500
`
`1500
`2000
`WAVENUMBER cm-1
`
`Fig. 40
`
`1000
`
`500
`
`Page 22
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 21 of 23
`
`US 8,673,921 B2
`
`I\
`
`!
`I
`
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`
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`0.5
`
`FORM XI
`
`3500
`
`3000
`
`2500
`
`1500
`2000
`WAVENUMBER cm-1
`Fig. 41
`
`1000
`
`500
`
`FORMV
`
`3000
`
`2500
`
`1500
`2000
`WAVENUMBER cm-1
`Fig. 42
`
`1000
`
`500
`
`Page 23
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 22 of 23
`
`US 8,673,921 B2
`
`FORM IV
`
`3000
`
`2500
`
`1500
`2000
`WAVENUMBER cm-1
`Fig. 43
`
`1000
`
`500
`
`FORM III
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
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`
`1.5
`
`1.0
`
`0.5
`
`0.0-,____, ___
`3500
`
`~--~--~--~~--~--~--
`3000
`2500
`
`1500
`2000
`WAVENUMBER cm-1
`Fig. 44
`
`1000
`
`500
`
`Page 24
`
`

`

`U.S. Patent
`
`Mar.18,2014
`
`Sheet 23 of 23
`
`US 8,673,921 B2
`
`2.0
`
`FORM II
`
`1.5
`
`3000
`
`2500
`
`1500
`2000
`WAVENUMBER cm-1
`Fig. 45
`
`1000
`
`500
`
`1.0
`
`0.5
`
`2.0
`
`1.5
`
`1.0
`
`FORM I
`
`WAVENUMBER cm-1
`Fig. 46
`
`Page 25
`
`

`

`US 8,673,921 B2
`
`1
`POLYMORPHIC FORMS OF
`1-[ 4-(5-CYANOINDOL-3-YL)BUTYL ]-4-(2-
`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, filedApr. 12, 2011, now U.S. Pat. No. 8,318,744,
`issued Nov. 27, 2012, which is a continuation application of
`U.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(cid:173)
`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(cid:173)
`rated by reference.
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel compounds, to pro(cid:173)
`cesses for preparing them and to their use in treating medical 30
`disorders.
`
`BACKGROUND OF THE INVENTION
`
`1-[ 4-( 5-Cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofu(cid:173)
`ran-5-yl)-piperazine,
`its physiologically acceptable salts
`thereof(U.S. Pat. No. 5,532,241, colunm 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(cid:173)
`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(cid:173)
`ration of 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl(cid:173)
`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
`NH 3 • Customary working up gives the free base l-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carboxybenzofuran-5-yl)pip(cid:173)
`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(cid:173)
`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 l-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-ben(cid:173)
`zofuran-5-yl)-piperazine hydrochloride having a melting
`point of 269-272° 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-y !)butyl ]-4-(2-carbamoy l-benzofuran-
`5-y l)-piperazine hydrochloride or new solvates or hydrates of
`1-[ 4-( 5-cyanoindol-3-y !)butyl ]-4-(2-carbamoy l-benzofuran-
`5-y l)-piperazine hydrochloride in different crystal modifica(cid:173)
`tions.
`Former 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl(cid:173)
`benzofuran-5-yl)-piperazine hydrochloride having a melting
`point of 269-272° C. was a mixture of amorphous l-[4-(5-
`
`5
`
`2
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)(cid:173)
`piperazine hydrochloride, crystallized 1-[ 4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride and the free base l-[4-(5-cyanoindol-3-yl)bu-
`tyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine.
`Certain crystalline, i.e. morphological forms of pharma(cid:173)
`ceutical compounds may be ofinterest to those involved in the
`development of a suitable dosage form because if the mor(cid:173)
`phological form is not held constant during clinical and sta-
`10 bility studies, the exact dosage used or measured may not be
`comparable from one lot to the next. Once a pharmaceutical
`compound is produced for use, 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
`15 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
`20 than other morphological forms for inclusion in pharmaceu(cid:173)
`tical formulations.
`
`SUMMARY OF THE INVENTION
`
`25
`
`Methods for preparing pure crystals of 1-[ 4-( 5-cyanoindol-
`3-y l) butyl ]-4-(2-carbamoy l-benzofuran-5-yl )-piperazine
`hydrochloride have now been found. Furthermore, surpris(cid:173)
`ingly,
`l-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-ben(cid:173)
`zofuran-5-yl)-piperazine dihydrochloride, six (five+dihydro(cid:173)
`chloride XIII) new forms of 1-[ 4-(5-Cyanoindol-3-yl)butyl]-
`4-(2-carbamoy l-benzofuran-5-yl )-piperazine hydrochloride,
`three new forms of l-[4-(5-cyanoindol-3-yl)butyl]-4-(2-car(cid:173)
`bamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrate,
`six new forms of solvates of 1-[ 4-(5-cyanoindol-3-yl)butyl]-
`35 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,
`40 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
`45 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,
`50 eating disorders, obesity, fibromyalgia, sleeping disorders,
`psychiatric disorders, cerebral infarct, tension, for the therapy
`of side-effects in the treatment of hypertension, cerebral dis(cid:173)
`orders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperal
`55 lactation.
`The present invention furthermore provides l-[4-(5-cy(cid:173)
`anoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-pip(cid:173)
`erazine hydrochloride hydrates in crystalline modifications
`and their use for the treatment and prevention of depressive
`60 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-
`65 orders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperal
`lactation.
`
`Page 26
`
`

`

`US 8,673,921 B2
`
`5
`
`10
`
`4
`FIG. 29 is a diagram of thermal analysis of Form II
`FIG. 30 is a diagram of thermal analysis of Form III
`FIG. 31 is a diagram of thermal analysis of Form IV
`FIG. 32 is a diagram of thermal analysis of Form V
`FIG. 33 is a diagram of thermal analysis of Form VI
`FIG. 34 is a diagram of thermal analysis of Form VII
`FIG. 35 is a diagram of thermal analysis of Form VIII
`FIG. 36 is a diagram of thermal analysis of Form IX
`FIG. 37 is a diagram of thermal analysis of Form XI
`FIG. 38 is a diagram of thermal analysis of Form XIV
`FIG. 39 is a diagram of thermal analysis of Form XV
`FIG. 40 is a Raman spectra of Form XIV
`FIG. 41 is a Raman spectra of Form XI
`FIG. 42 is a Raman spectra of Form V
`FIG. 43 is a Raman spectra of Form IV
`FIG. 44 is a Raman spectra of Form III
`FIG. 45 is a Raman spectra of Form II
`FIG. 46 is a Raman spectra of Form I
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`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(cid:173)
`orders, anxiety disorders, bipolar disorders, mania, dementia,
`substance-related disorders, sexual dysfunctions, eating dis(cid:173)
`orders, obesity, fibromyalgia, sleeping disorders, psychiatric
`disorders, cerebral infarct, tension, for the therapy of side(cid:173)
`effects in the treatment of hypertension, cerebral disorders,
`chronic pain, acromegaly, hypogonadism, secondary amen-
`orrhea, premenstrual syndrome and undesired puerperal lac(cid:173)
`tation.
`The present invention relates additionally to l-[4-(5-cy(cid:173)
`anoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-pip(cid:173)
`erazine dihydrochloride in its crystalline modification and its 15
`use for the treatment and prevention of depressive disorders,
`anxiety disorders, bipolar disorders, mania, dementia, sub(cid:173)
`stance-related disorders, sexual dysfunctions, eating disor(cid:173)
`ders, obesity, fibromyalgia, sleeping disorders, psychiatric
`disorders, cerebral infarct, tension, for the therapy of side- 20
`effects in the treatment of hypertension, cerebral disorders,
`chronic pain, acromegaly, hypogonadism, secondary amen(cid:173)
`orrhea, premenstrual syndrome and undesired puerperal lac(cid:173)
`tation.
`The present invention relates additionally to pure amor- 25
`phous
`l-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-ben(cid:173)
`zofuran-5-yl)-piperazine hydrochloride and its use for the
`treatment and prevention of depressive disorders, anxiety
`disorders, bipolar disorders, mania, dementia, substance-re(cid:173)
`lated disorders, sexual dysfunctions, eating disorders, obe- 30
`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(cid:173)
`strual syndrome and undesired puerperal lactation.
`
`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(cid:173)
`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,
`l-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbam-
`oyl-benzofuran-5-yl)-piperazine hydrochloride forms sol(cid:173)
`vates with acetone, tetrahydrofuran, methanol, ethyl acetate
`or n-heptane in crystalline modifications that means the
`bound solvent together with l-[4-(5-cyanoindol-3-yl)butyl]-
`40 4-(2-carbamoy l-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
`45 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
`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(cid:173)
`chloride include:
`a) 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofu(cid:173)
`ran-5-yl)-piperazine hydrochloride solvate with acetone in
`Form I; (as hereinafter defined)
`b) 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofu(cid:173)
`ran-5-yl)-piperazine hydrochloride solvate with tetrahy(cid:173)
`drofuran in Form II; (as hereinafter defined)
`c) 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofu(cid:173)
`ran-5-yl)-piperazine hydrochloride solvate with tetrahy(cid:173)
`drofuran in Form XV; (as hereinafter defined)
`d) 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofu(cid:173)
`ran-5-yl)-piperazine hydrochloride solvate with tetrahy(cid:173)
`drofuran in Form X; (as hereinafter defined)
`65 e) 1-[ 4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofu(cid:173)
`ran-5-yl)-piperazine hydrochloride solvate with methanol
`in Form XI; (as hereinafter defined)
`
`35
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1 is an IR absorption spectra of Form I
`FIG. 2 is an IR absorption spectra of Form II
`FIG. 3 is an IR absorption spectra of Form XV
`FIG. 4 is an IR absorption spectra of Form XI
`FIG. 5 is