Case 1:15-cv-01078-GMS Document 4 Filed 11/23/15 Page 1 of 1 PagelD #: 222
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`UNITED STATES PATENT AND TRADEMARKOFFICE
`
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`APPLICATION NO.
`
`: 8,673,921 B2
`: 14/032183
`
`DATED
`INVENTOR(S)
`
`: March 18, 2014
`: Andreas Batheet al.
`
`Page 1 of 1
`
`It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shownbelow:
`
`Title Page, under “Foreign Application Priority Data,” item (30), left column, replace
`
`“Jun. 19, 2001
`
`(EP) wees 01113674” with
`
`--Jun. 19,2001
`
`(EP) wee 01113647--
`
`Signed and Sealed this
`First Day of March, 2016
`
`Wiirbtl. Ko Lea
`
`Michelle K. Lee
`
`Director ofthe United States Patent and Trademark Office
`
`Page 2
`
`Page 2
`
`

`

`UNITED STATES PATENT AND TRADEMARKOFFICE
`CERTIFICATE OF CORRECTION
`
`PATENTNO.:
`
`8673921
`
`Page 1 of
`
`1
`
`DATED:
`
`March 18, 2014
`
`INVENTOR(S):
`
`Andreas Bathe etal.
`
`
`
`
`
`It is certified that error appears in the above-identified patent and that said
`Letters Patent is hereby corrected as shown below:
`
`On page 1, under "Foreign Application Priority Data,” item (30), left column, replace
`
`"Jun. 19, 2001 (EP)............ 01113674" with
`-- Jun. 19, 2001 (EP)... 01113647--
`
`U.S. Patent and Trademark Office
`PTO-1050
`
`Page 3
`
`/Joseph K. McKane/
`Supervisory Patent Examiner, Art Unit 1626
`
`Page 3
`
`

`

`(PATENT)
`
`Docket No.: 120140-00110
`
`| hereby certify that this paper (along with any paperreferred to as being
`attached or enclosed) is being transmitted via the Office electronic filing system
`in accordancewith § 1.6(a)(4).
`
`Dated: November 24, 2015
`Electronic Signature for Jin Wang, Esq., J.D.:_/Jin Wang/
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`In re Application of:
`Andreas Batheetal.
`
`U.S. Patent No.:
`
`8,673,921
`
`Issued:
`
`March 18, 2014
`
`Confirmation No.:
`
`2870
`
`Art Unit:
`
`1626
`
`Application No.:
`
`14/032,183
`
`Examiner: Samantha L. Shterengarts
`
`Filing Date:
`
`September 19, 2013
`
`For: POLYMORPHIC FORMSOF1-[4-(5-
`CYANOINDOL-3-YL)BUTYL]-4-(2-
`CARBAMOYLBENZOFURAN-5-YL)
`PIPERAZINE HYDROCHLORIDE
`
`Attention: Certificate of Correction Branch
`Commissionerfor Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`REQUEST FOR CERTIFICATE OF CORRECTION
`PURSUANTTO 37 C.E.R.§
`1.323
`
`Dear Sir:
`
`Upon reviewing the above-identified patent, Patentee noted a typographicalerror on the
`
`patent which should be corrected.
`
`On the cover page of the patent, in the left-hand column under item (30) “Foreign
`
`Application Priority Data,” the foreign priority is incorrectly shown as “Jun. 19, 2001
`
`(EP) 01113674.”
`
`The foreign priority should be corrected to show:
`
`-- Jun. 19, 2001
`
`(EP) 01113647--
`
`ME! 18810129v.1
`
`Page 4
`
`Page 4
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`

`

`Patent No.: 8,673,921
`
`Docket No.: 120140-00110
`
`Transmitted herewith is a proposed Certificate of Correction effecting such amendment.
`
`Patentees respectfully solicit the granting of the requested Certificate of Correction.
`
`Please charge the fee of $100.00 as required under 37 C.F.R § 1.20(a) from our Deposit
`
`Account No. 50-4876, under Order No. 120140-00110 from which the undersignedis authorized
`
`to draw.
`
`Dated: November 24, 2015
`
`Respectfully submitted,
`
`Electronic signature: / Jin Wang/
`Jin Wang, Esq.
`Registration No.: 66,467
`McCARTER & ENGLISH, LLP
`265 Franklin Street
`Boston, Massachusetts 02110
`(617) 449-6580
`(617) 607-9200 (Fax)
`Attorney for Patentee
`
`MEI 18810129v.1
`
`Page 5
`
`Page 5
`
`

`

`(PATENT)
`
`Docket No.: 120140-00110
`
`| hereby certify that this paper (along with any paperreferred to as being
`attached or enclosed) is being transmitted via the Office electronic filing system
`in accordancewith § 1.6(a)(4).
`
`Dated: November 24, 2015
`Electronic Signature for Jin Wang, Esq., J.D.:_/Jin Wang/
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`In re Application of:
`Andreas Batheetal.
`
`U.S. Patent No.:
`
`8,673,921
`
`Issued:
`
`March 18, 2014
`
`Confirmation No.:
`
`2870
`
`Art Unit:
`
`1626
`
`Application No.:
`
`14/032,183
`
`Examiner: Samantha L. Shterengarts
`
`Filing Date:
`
`September 19, 2013
`
`For: POLYMORPHIC FORMSOF1-[4-(5-
`CYANOINDOL-3-YL)BUTYL]-4-(2-
`CARBAMOYLBENZOFURAN-5-YL)
`PIPERAZINE HYDROCHLORIDE
`
`MS Petition
`Commissionerfor Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`PETITION TO ACCEPT UNINTENTIONALLY DELAYED CLAIM FOR
`FOREIGN PRIORITY PURSUANT TO 37 C.F.R.§ 1.55(e)
`
`Dear Sir:
`
`Patentee requests correction of the foreign priority, as stated on the above-identified
`
`patent. The foreign priority, as shown on the cover page of the patent, in the left-hand column
`
`under item (30) “Foreign Application Priority Data,” is incorrectly shown as “Jun. 19, 2001
`
`(EP) 01113674.”
`
`The foreign priority should be corrected to show:
`
`-- Jun. 19, 2001
`
`(EP) 01113647--
`
`Patentee submits that the entire delay between the date the priority claim was due under
`
`37 C.F.R. § 1.55(d) and the date the priority claim was filed was unintentional. Specifically,
`
`the Applicant Data Sheetfiled in this patent contains an inadvertent typographicalerror of the
`
`ME! 20117231v.1
`
`Page 6
`
`Page 6
`
`

`

`Patent No.: 8,673,921
`
`Docket No.: 120140-00110
`
`foreign priority application number,i.e. (EP) 01113674, which should be (EP) 01113647.
`
`However, Patentee notes that the correct priority information is shown on page 2 of the
`
`Preliminary Amendmentunder “Related Applications” submitted on September 19, 2013 during
`
`prosecution of this patent. In addition, it is indicated on the Notice of Allowability mailed on
`
`December13, 2013 that “fa/cknowledgement is made of a claim for foreign priority under 35
`
`U.S.C. §119(a)-(d) or (f)” and that “fall certified copies of the priority documents have been
`
`received [by the Patent Office].” Furthermore, Patentee submits that all parent patents, US
`
`8,318,744 issued on November 27, 2012 , US 7,981,894 issued on July 19, 2011, US 7,834,020
`
`issued on November16, 2010, and US 7,381,726 issued on June 3, 2008, which are relied upon
`
`in this patent for an earlier filing date under 35 U.S.C. 120, 121, 365(c), or 386(c), have all
`
`claimed the correct foreign priority application number European Patent Office (EPO)
`
`01113647.0. Therefore, the priority claim was unintentionally delayed.
`
`A certified copy of the foreign application EP 01113647.0 wasfiled in the prior-filed
`
`nonprovisional application 10/481,270, now U.S. Patent No. 7,381,726, which the instant patent
`
`claims a benefit under 35 U.S.C. 120, 121, 365(c), or 386(c). However, for the convenience of
`
`the Office, Patentee enclose herewith a certified copy of the foreign priority application
`
`EP 01113647.0
`
`Applicant additionally requests that all pertinent U.S. Patent and Trademark Office
`
`records relating to the subject application be changedto reflect this correction.
`
`Please charge the fee of $1,700.00 as required under 37 C.F.R § 1.17(m) from our
`
`Deposit Account No. 50-4876, under Order No. 120140-00110 from which the undersigned is
`
`authorized to draw.
`
`Dated: November 24, 2015
`
`Respectfully submitted,
`
`Electronic signature: / Jin Wang/
`Jin Wang, Esq.
`Registration No.: 66,467
`McCARTER & ENGLISH, LLP
`265 Franklin Street
`Boston, Massachusetts 02110
`(617) 449-6580
`(617) 607-9200 (Fax)
`Attorney for Patentee
`
`ME! 20117231v.1
`
`Page 7
`
`Page 7
`
`

`

`PTO/SB/44 (09-07)
`Approvedfor use through 08/31/2013. OMB 0651-0033
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Underthe Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unlessit displays a valid OMB control number.
`(Also Form PTO-1050)
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`
`:
`
`8,673,921
`
`
`
`APPLICATION NO.—: 14/032,183
`
`ISSUE DATE
`
`INVENTOR(S)
`
`:
`
`:
`
`March 18, 2014
`
`Andreas Bathe etal.
`
`(EP) ........ ee. 01113647--
`
`It is certified that an error appears or errors appear in the above-identified patent and that said
`Letters Patent is hereby corrected as shown below:
`
`On page 1, under “Foreign Application Priority Data,” item (30), left column, replace
`
`“Jun. 19, 2001 (EP)... ee. 01113674” with
`
`-- Jun. 19, 2001
`
`MAILING ADDRESS OF SENDER (Please do not use customer number below):
`Jin Wang
`MCCARTER & ENGLISH, LLP
`265 Franklin Street
`
`1
`
`Boston, Massachusetts 02110
`
`ME1 18809901v.1
`
`Page 8
`
`Page 8
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`
`2Frie—
`European
`Office européen
`Europdisches
`Patent Office
`des brevets
`
`©
`
`‘
`
`0)
`
`Patentamt
`
`PCTEP 02/06155
`
`REC'D 88 AUG 2002
`
`Bescheinigung
`
`Certificate
`
`Attestation
`
`Die angehefteten Unterla-
`gen stimmen mit der
`ursprGnglich eingereichten
`Fassung der auf dem nach-
`sten Blatt bezeichneten
`europadischen Patentanmel-
`dung Gberein.
`
`Les documentsfixés a
`The attached documents
`cette attestation sont
`are exact copies of the
`European patent application conformes a ia version
`described on the following
`_initialement déposée de
`page, as originallyfiled.
`la demande de brevet
`européen spécifiée a la
`page suivante.
`
`Patentanmeldung Nr.
`
`Patent application No. Demande de brevet n°
`
`01113647.0
`
`Der Prasident des Europdischen Patentamts;
`Im Auftrag
`
`For the President of the European Patent Office
`
`Le Président de Office européen des brevets
`p.o,
`
`R C van Dijk
`
`PRIORITY DOCUMENT |!
`SUBMITTED OR TRANSMITTED IN
`COMPLIANCE WITH
`|
`RULE 17.1(a) OR (b)
`:
`|
`EPA/EPO/JOEB Form 1014=-02:1
`
`DEN HAAG, DEN
`THE HAGUE,
`LA HAYE, LE
`
`25/01/02
`
`Page 1
`
`Page 10
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`

`

`Enea
`
`"
`
`‘
`
`©
`
`cn
`
`0)
`
`Europaisches
`
`Patentamt
`
`European
`
`Patent Office
`
`Blatt 2 der Bescheinigung
`Sheet 2 of the certificate
`Page 2 de Il’attestation
`
`Office européen
`
`g
`des brevets
`
`
`
`01113647.0
`
`Anmaldung Nr.:
`Application no.:
`Demande n*:
`Anmelder:
`Applicant(s):
`Demandeur(s):
`Merck Patent GmbH
`64293 Darmstadt
`GERMANY
`
`Anmeldetag:
`Date of filing:
`Date de dépét:
`
`.
`19/06/01
`
`Bezeichnung der Erfindung:
`Title of the invention:
`Titre de I’invention:
`Polymorphic forms of 1-(4-(5-cyanoindol—3-y1)buty] )-4—( 2-carbamoy1 benzofuran-5-y] ) piperazine
`hydrochloride
`
`tn Anspruch genommenePrioridt(en) / Priority(ies) claimed / Priorité(s) revendiquée(s)
`Staat:
`Tag:
`Aktenzeichen:
`State:
`Date:
`File no.
`Pays:
`Date:
`Numéro de dépéot:
`
`Internationale Patentklassifikation:
`International Patent classification:
`Classification Internationale des brevets:
`
`/
`
`Am Anmeldatag benannte Vertragstaaten:
`Contracting states designated at date offiling: AT/BE/CH/CY/DE/DK/ES/FV/FR/GB/GR/IE/IT/LI/LU/MC/NL/PT/SE/TR
`Etats contractants désignés lors du depot:
`Bemerkungen:
`Remarks:
`Remarques:
`
`EPA/EPO/OEB Form
`
`1012
`
`- 11.00
`
`Page 11
`g
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`Page 11
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`

`

`
`
`
`
`:
`
`
`
`EPO - Munich
`19 Juni 2001
`
`67
`
`Merck Patent Gesellschaft
`mit beschrankter Haftung
`
`64271 Darmstadt
`
`Polymorphic formsof 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoylbenzofuran-5-
`yl)piperazine hydrochloride
`
`Druckdatum: 18.06.2001
`Speicherdatum: 13.06.2001
`
`Peeteaban
`
`Page 12
`
`

`

`
`
`
`ey
`ceil
`9
`-1-
`
`areas
`We
`ia Hs cl
`19, Juni 2001
`
`
`
`Polymorphic forms of 4-[4-(5-cyanoindol-3-yl)butyl}-4-(2-
`carbamoylbenzofuran-5-yl)piperazine hydrochloride
`
`FIELD OF THE INVENTION
`The presentinvention relates to novel compounds,to processes for
`preparing them andto their usein treating medical disorders.
`
`BACKGROUND OF THE INVENTION
`1{4-{6-Cyanoindol-3-y!)butyl|4-(2-carbamoyl-benzofuran-6-y))-piperazine,
`its physiologically acceptable salts thereof (US 5,532,241, column7,lines
`30 to 58), a process (US 5,532,241, Example 4) by which it/they can be
`prepared and their use in treating certain medical disorders are known from
`U.S. Patent US 5,532,241 and WO 00/72832.
`Example 4 of US 5,532,241 describes the preparation of 4-[4-(5-
`eyanoindol-3-yi)butyll-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochioride by reacting 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carboxybenzofuran-5-yl)piperazine atfirstwith 2-chioro-1-methylpyridinium
`methanesulfonate in N-methylpyrrolidine and then with dried NHs.
`Customary working up gives the free base 4-[4-(5-cyanoindol-3-yl)butyl]-4-
`(2-carboxybenzofuran-5-yl)piperazine. 700 mg ofthe base are dissolved in
`30 mi 2-propanol under heating and then treated with 0.1n 2-propanolic
`HCL-solution (Merck-Art. No. 4.00326) until precipitation of hydrochloride is
`complete. The precipitate was filtered off and washed with diethylether and
`dried at room temperature to yield 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-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 4-{4-(-cyanoindol-3-yl)butyl]-4-(2-carbamoyt-
`benzofuran-5-yl)-piperazine hydrochloride or new solvates or hydrates of 1-
`14-(6-cyanoindol-3-y))butyl-4-(2-carbamoy!-benzofuran-6-y)-piperazine
`hydrochloride in different crystal modifications.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`
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`Page 13
`
`

`

` 10
`
`15
`
`20
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`25
`
`30
`
`
`
`
`
`Former 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-
`piperazine hydrochloride having a melting point of 269-272°C was a mixture
`of amorphous 1-[4-(5-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)butyl]-4-(2-carbamoy!-benzofuran-5-yl)-piperazine.
`
`Methodsfor preparing pure crystals of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride has now been found.
`Furthermore, surprinsingly, 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine dihydrochloride,five (four + dihydrochloride
`XIN) 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-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride hydrate, six new forms of solvates of 1-[4-(5-cyanoindol-3-
`yl)buty!]-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 processesfor their
`preparation. These forms are hereinafter referred to as |,Il, III, 1V, V, VI, VIL,
`VII, IX, X, XI, XH, XIV, XV and XVI respectively.
`
`..
`
`SUMMARYOFTHE INVENTION
`
`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, psypsychiatric disorders, cerebralinfarct,
`tension, for the therapy of side-effects in the treatment of hypertension,
`cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperallactation.
`
`reefFBHaDane
`
`Page 14
`
`

`

`
`
` The present invention furthermore provides 4-[4-(5-cyanoindol-3-yl)butyl}-4-
`
`(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride hydrates in
`crystalline modifications andtheir 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, psypsychiatric disorders, cerebralinfarct,
`tension, for the therapy of side-effects in the treatment of hypertension,
`cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperallactation.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`The presentinvention also provides 1- 4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride anhydratesin
`crystalline modifications andtheir 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, psypsychiatric disorders, cerebralinfarct,
`tension,for the therapy of side-effects in the treatment of hypertension,
`cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperal lactation.
`The present inventionrelates additionally to 4-[4-(5-cyanoindol-3-yl)butyl}-4-
`(2-carbamoyl-benzofuran-5-yl)-piperazine dihydrochlorideinits crystalline
`modification andits usefor the treatment and prevention of depressive
`disorders, anxiety disorders, bipolar disorders, mania, dementia,
`substance-related disorders, sexual dysfunctions, eating disorders, obesity,
`fibromyalgia, sleeping disorders, psypsychiatric disorders, cerebralinfarct,
`tension, for the therapy of side-effects in the treatment of hypertension,
`cerebral disorders, chronic pain, acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired puerperal lactation.
`
`
`
`
`
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`The present invention relates additionally to amorphous 1-[4-(5-cyanoindol-
`3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride andits
`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, psypsychiatric disorders, cerebral infarct, tension, for the therapy
`of side-effects in the treatment of hypertension, cerebral disorders, chronic
`pain, acromegaly, hypogonadism, secondary amenorrhea, premenstrual
`syndrome and undesired puerperal lactation.
`|
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`BRIEF DESCRIPTION OF THE FIGURES
`Fig. 1 is a IR absorption spectra of Form |
`Fig. 2 is a IR absorption spectra of Form Il
`Fig. 3 is a IR absorption spectra of Form XV
`Fig. 4 is a IR absorption spectra of Form XI!
`Fig. 5 is a IR absorption spectra of Form XIV
`Fig. 6 is a IR absorption spectra of Form V
`Fig. 7 is a IR absorption spectra of Form VI
`Fig. 8 is a IR absorption spectra of Form VIII
`Fig. 9 is a IR absorption spectra of Form IV
`Fig. 10 is a 1R absorption spectra of Form Ill
`Fig. 11 is alR absorption spectra of Form VII
`Fig. 12 is an x-ray diffractogram for Form |
`Fig. 13 is an x-ray diffractogram for Form Il
`Fig. 14 is an x-ray diffractogram for Form XV
`Fig. 15 is an x-ray diffractogram for Form X
`Fig. 16 is an x-ray diffractogram for Form Xl
`Fig. 17 is an x-ray diffractogram for Form XIV
`Fig. 18 is an x-ray diffractogram for Form V
`Fig. 19 is an x-ray diffractogram for Form VI
`Fig. 20 is an x-ray diffractogram for Form VIiil
`Fig. 21 is an x-raydiffractogram for Form IV
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`Fig. 31 is a diagram of thermal analysis from Form IV
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`Fig. 22 is an x-ray diffractogram for FormIll
`Fig. 23 is an x-ray diffractogram for Form VII
`Fig. 24 is an x-ray diffractogram for Form IX
`Fig. 25 is an x-ray diffractogram for Form XIlt
`Fig. 26 is an x-ray diffractogram for amorphous hydrochloride (Form XVI)
`Fig. 27 is an energy/temperature diagram
`Fig. 28 is a diagram of thermal analysis from Form |
`Fig. 29 is a diagram of thermal analysis from Formil
`Fig. 30 is a diagram of thermalanalysis from Form Il!
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`Fig. 32 is a diagram of thermal analysis from Form V
`Fig. 33 is a diagram of thermal analysis from Form Vi
`Fig. 34 is a diagram of thermal analysis from Form VII
`Fig. 35 is a diagram of thermal analysis from Form Vill
`Fig. 36 is a diagram of thermal analysis from Form IX
`Fig. 37 is a diagram ofthermal analysis from Form XI
`Fig. 38 is a diagram of thermal analysis from Form XIV
`Fig. 39 is a diagram of thermal analysis from Form XV
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`DETAILED DESCRIPTION OF THE INVENTION
`
`it has been found that 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoy!-
`benzofuran-5-yl)-piperazine hydrochloride is able to form solvatesin
`crystalline modifications. Examples of such solvates include solvates from
`alcohols such as methanol, ethanol, propan-1-ol or propan-2-ol; solvates
`from organic esters such as ethyl acetate; solvates 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-
`heptaneor toluene.
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`Preferably, 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-
`piperazine hydrochloride forms solvates with acetone, tetrahydrofuran,
`methanol, ethyl acetate or n-heptanein 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 ratio of the solvent to 1-[4-(5-cyanoindol-3-yl)butyi]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride could vary as known
`for skilled personsin the art. Preferably, the 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 understoodthat the present solvates of the invention may
`contain unbound waterthat is to say water which is other than waterof
`
`crystallization.
`
`Preferred forms ofsolvates of 1-[4-(5-cyanoindol-3-y!)butyl]-4-42-carbamoyi
`a) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`
`benzofuran-5-yl)-piperazine hydrochloride include:
`
`hydrochloride solvate with acetone in Form I; (as hereinafter defined)
`b) 1-[4-(5-cyanoindol-3-y!)buty!]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride solvate with tetrahydrofuran in Form I; (as hereinafter
`defined)
`
`c) 1-[4-(5-cyanoindol-3-y!)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride solvate with tetrahydrofuran in Form XV; (as hereinafter
`defined)
`
`d) 1-[4-(5-cyanoindol-3-y!)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride solvate with tetrahydrofuran in Form X; (as hereinafter
`defined)
`e) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride solvate with methanol in Form XI; (as hereinafter defined)
`f) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride solvate with n-heptane in Form XIV;(as hereinafter defined).
`
`Wonaanan
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`PSD).
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`Form | according to the invention has the characteristic IR absorption
`spectra as shown in Fig. 1 and the charasteristic X-ray diffraction pattern as
`shownin Fig. 12. XRD pattern were recorded using a x-ray powder
`diffractometer (Bruker AXS 15000)in transmission mode (Cu K alpha 1,
`IR absorption spectra were measured in the spectral range 4000 - 400 cm"
`on a BrukerIFS48. Spectral resolution was 2 cm". The spectra as shown in
`the figures were converted to transmission. Sample preparation was
`performed generally as KBr disk. The spectra contains additionally a
`specific acetone absoption band at 4709cm".
`Form | can be further characterized with the aid of thermal analysis
`measuredin the range of 30° to 350 °C. Fig. 28 shows the DSC (TA
`Instruments DSC 2920) and TGA (TA instruments TGA 2950)
`measurements. Form | shows a desolvation process between 50°C and
`180°C. Analysis by thermogravimetry showed the presence of 10 % to 11
`% of acetone (theory of 1: 1 solvate 10.82 %). The DSC measurement
`gives a phase transition to form Vil between 200°C and 260°C. The
`thermoanalytically resulting form Vil melts between 280°C and 290°C.
`The ratio of acetone to 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoy!-
`benzofuran-5-yl)-piperazine hydrochloride in said crystal modification is 1:1,
`that means the compoundofthe invention in crystal modification of Form |
`is 1|4-(6-cyanoindol-3-y))butyl|-4-(2-carsamoyl-benzofuran-6-y/)-piperazins
`hydrochloride monoacetonate.
`The invention also provides a process for preparing the above Form |
`according to the invention, which comprises:
`(1) dispersing 1-[4-(6-cyanoindol-3-y))butyl]-4-(2-carbamoyl-benzofuran-S-
`yl)-piperazine in acetone
`(2) converting the 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine base, by addition of 1N hydrochloric acid
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`into the hydrochloride salt at temperatures between 30°C and the
`boiling point of acetone, preferably between 40° C and 50°C
`(3) precipitation of Form | at room temperature
`(4) recovering the precipitated 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride acetonate by
`filtration, and drying in vacuo at room temperature.
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`Alternatively, Form | can be prepared according to a process which ~
`comprises:
`(1) suspending Form Ill of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride, whichwill be described later
`in detail, in acetone
`(2) stirring at room temperature between a few hours or days, preferably
`10 to 20 days,
`(3) recovering the precipitated 1-[4-(5-cyanoindol-3-y!)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate with
`tetrahydrofuranbyfiltration, and drying in vacuo at room temperature.
`
`Form Il according to the invention has the charasteristic IR absorption
`spectra as shownin Fig. 2 and the charasteristic X-ray diffraction pattern as
`shownin Fig. 13. XRD pattern were recorded using a x-ray powder
`diffractometer (Bruker AXS D5000)in transmission mode (Cu K alpha1,
`PSD).
`:
`IR absorption spectra were measured in the spectral range 4000 - 400 cm"
`on a BrukerIFS48. Spectral resolution was 2 cm. The spectra as shownin
`the figures were converted to transmission.
`Form II can be further characterized with the aid of thermal analysis
`measuredin the range of 30° to 350°C.Fig. 29 shows the DSC (TA
`instruments DSC 2920) and TGA (TA Instruments TGA 2950)
`measurements. Form II shows a desolvation process between 120°C and
`180°C. Analysis by thermogravimetry showed the presence of 13 % to 14
`% of THE (theory of 1 : 1 solvate 13.11 %). The DSC measurement gives a
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`phasetransition to form Vil between 200°C and 260°C. The
`thermoanalytically resulting form VII melts between 280°C and 292°C.
`Theratio of tetrahydrofuran to 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride in said crystal
`modification is 1:1, that means the compound of the invention in crystal
`modification of Form !I is a monosolvate of 1-[4-(5-cyanoindol-3-y!)buty!]-4-
`(2-carbamoyl-benzofuran-5-yl)-piperazine hydrochloride with
`tetrahydrofuran.
`
`The invention also provides a process for preparing the above Form li
`according to the invention, which comprises:
`(1) dispersing 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazinein tetrahydrofuran
`(2) converting the 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine base, by addition of 1N hydrochloric acid
`into the hydrochloride salt at temperatures between 10°C and 60°C,
`preferably between 20° C and 30°C
`(3) precipitation of Form it between -10°C and 10°C
`(4) recovering the precipitated 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride solvate with
`tetrahydrofuranbyfiltration, and drying in vacuo at room temperature.
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`Alternatively, Form II can be prepared according to a process which
`comprises:
`.
`(1) suspending Form ill of 4-[4-(5-cyanoindol-3-yl)butyl}-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride, which will be described later
`in detail, in tetrahydrofuran
`(2) stirring at room temperature between a few hours or days, preferably
`15 to 30 days,
`(3) recovering the precipitated 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride acetonate by
`filtration, and drying in vacuo at room temperature.
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`Form XV according to the invention has the charasteristic IR absorption
`spectra as shownin Fig. 3 and the charasteristic X-ray diffraction pattern as
`‘shownin Fig. 14. 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 measuredin the spectral range 4000 - 400 cm"
`on a Bruker IFS48. Spectral resolution was 2 cm”. The spectra as shownin
`the figures were converted to transmission.
`Form XV canbefurther characterized with the aid of thermal analysis
`measured in the range of 30° to 350 °C. Fig. 39 shows the DSC (TA
`Instruments DSC 2920) and TGA(TAInstruments TGA 2950)
`measurements. Form XV shows a desolvation process between 75°C and
`180°C. Analysis by thermogravimetry showed the presenceof 13 % to 14
`% of THF (theory of 1: 1 solvate 13.11 %). The DSC measurementgives a
`phasetransition to form VII between 200°C and 260°C. The
`thermoanalytically resulting form VII melts between 280°C and 290°C. The
`ratio of tetrahydrofuran to 1-[4-(5-cyanoindol--3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride in said crystal modification is 1:1,
`that means the compoundofthe invention in crystal modification of Form
`XV is a monosolvate of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride with tetrahydrofuran.
`
`The invention also provides a process for preparing the above Form XV
`according to the invention, which comprises:
`(1) dispersing 4-[4-(5-cyanoindol-3-y!)buty!]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine in tetrahydrofuran
`(2) converting the 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine base, by addition of 1N hydrochloric acid
`into the hydrochloride salt at temperatures between -10°C and 10°C,
`preferably between -5° C and +5°C
`(3) precipitation of Form XV at room temperature
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`000) in transmission mode (Cu K
`
`5-cyanoindol-3-yl)butyl]-4-(2-
`(4) recovering the precipitated 1-[4-(
`-yl)-piperazine hydrochloride solvate with
`carbamoyl-benzofuran-5
`\tration, and drying in vacuo at room temperature.
`tetrahydrofuranbyfi
`
`Form X according to the invention has the charasteristic X-ray diffraction
`pattern as shown in Fig. 15. XRD pattern were recorded using a x-ray
`powder.diffractometer (Bruker AXS D5
`alpha 1, PSD).
`
`Theratio of tetrahydrofuranto 4-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`5-yl)-piperazine hydrochloride in said crystal
`carbamoyl-benzofuran-
`modification is 0,5:1, that means the compound of the invention in crystal
`ate of 4-[4-(5-cyanoindol-3-yl)butyl]-4-
`modification of Form Il is a hemisolv
`-yl)-piperazine hydrochloride with
`(2-carbamoyl-benzofuran-5
`tetrahydrofuran.
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`the above Form X
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`The invention also provides a process for preparing
`according to the invention, which comprises:
`-yl)butyl]-4-(2-carbamoy!-benzofuran-5-
`(1) dispersing 4-[4-(5-cyanoindol-3
`yl)-piperazine in tetrahydrofuran
`(2-carbamoyl-
`(2) converting the 4-[4-(5-cyanoindol-3-yl)butyl]-4-
`benzofuran-5-yl)-piperazine base, by addition of 1N hydrochloric acid
`into the hydrochloride salt at temperatures between 40°C and 40°C,
`preferably between 90° C and 30°C
`precipitation of Form