UNITED STATES PATENT AND TRADEMARK OFFICE
`
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`1
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`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`DX 1450
`P.O. Bo
`dria, Virginia 22313-1450
`Alexan
`to.gov
`www.usp
`
`APPLICATION NO.
`
`FILING DATE
`
`FIRST NAMED INVENTOR
`
`ATTORNEY DOCKET NO. CONFIRMATION NO.
`
`11/720,205
`
`05/25/2007
`
`John M. Kovarik
`
`34053-US-PCT
`
`5868
`
`1095
`7590
`12/21/2011
`NOVARTIS
`
`CORPORATE INTELLECTUAL PROPERTY
`ONE HEALTH PLAZA 101/2
`EAST HANOVER, NJ 07936-1080
`
`EXAMINER
`
`BLAKELY III, NELSON CLARENCE
`
`ART UNIT
`
`PAPER NUMBER
`
`1629
`
`MAIL DATE
`
`12/21/2011
`
`DELIVERY MODE
`
`PAPER
`
`Please find below and/or attached an Office communication concerning
`
`this application or proceeding.
`
`The time period for reply,
`
`if any, is
`
`set
`
`in
`
`the
`
`attached
`
`communication.
`
`PTOL-90A (Rev. 04/07)
`
`0001
`
`APOTEX - EXHIBIT 1014
`
`

`

`Examiner-Initiated Interview Summary
`
`Application No.
`
`Applicant(s)
`
`11/720,205
`Examiner
`
`KOVARIK ET AL.
`Art Unit
`
`NELSON BLAKELY
`
`III
`
`1629
`
`All participants
`
`(applicant,
`
`applicant's
`
`representative,
`
`PTO
`
`personnel):
`
`
`
`
`
`III (1) Nelson C Blakelv (Examiner).
`
`(2) Karen DeBenedictis
`
`(Attorney).
`
`(3).
`
`(4).
`
`Date of Interview: 13 December 2011.
`Type: Kl Telephonic • Video Conference
`
`• Personal [copy given to: • applicant • applicant's representative]
`
`Exhibit shown or demonstration
`If Yes, brief description:
`.
`
`conducted: • Yes • No.
`
`Issues Discussed dlOl 0112 0102 DlOS dOthers
`(For each of the checked box(es)
`above,
`please
`describe
`below
`
`the
`
`issue
`
`and
`
`detailed
`
`Claim(s) discussed:
`
`Identification of prior art discussed:
`
`Substance of Interview
`(For each issue
`discussed,
`reference or a
`portion
`
`provide
`thereof,
`
`a
`claim
`
`detailed
`interpretation,
`
`description reached. Some and
`
`proposed
`
`
`
`topics may
`
`
`indicate include: identification or clarification if
`
`amendments,
`arguments
`
`of
`
`
`agreement a
`of
`
`In a voicemail message on 12/13/2011. Attorney
`the Office.
`
`of
`
`Record
`
`DeBenedictis
`
`confirmed
`
`
`
`that filed with
`
`no
`
`Applicant recordation instructions: It is not necessary for applicant to provide a
`
`
`
`separate record of the substance of interview.
`
`
`
`Examiner recordation instructions: Examiners must summarize the substance of any interview of record.
`
`A complete and proper recordation of
`the substance of an interview should include the items listed
`in MPEP 713.04 for complete and proper recordation including
`the
`
`identification of the
`other pertinent matters discussed regarding patentability and the
`general thrust of each argument or issue discussed, a
`
`general indication of any
`general results or outcome of the interview, to include an indication as to whether or not agreement was reached on the issues raised.
`
`• Attachment
`
`/Nelson C Blakely III/
`Examiner, Art Unit 1629
`
`/Jeffrey S. Lundgren/
`Supervisory Patent Examiner, Art Unit 1629
`
`U.S. Patent
`and
`Trademark
`PTOL-413B (Rev. 8/11/2010)
`
`Office
`
`Interview Summary
`
`Paper No. 20111214
`
`0002
`
`

`

`Notice of Abandonment
`
`11/720,205
`Examiner
`
`KOVARIK ET AL.
`Art Unit
`
`Application No.
`
`Applicant(s)
`
`— The MAILING DATE of this communication
`
`NELSON BLAKELY
`appears
`on
`
`III
`the
`
`1629
`cover
`
`sheet
`
`with
`
`the
`
`correspondence
`
`This application
`
`is abandoned
`
`in view of:
`
`
`
`the expiration the
`
`of
`
`a
`
`at
`
`
`
`timely
`to
`failure
`1. ^ Applicant's
`the 25
`
`proper Office letter mailed reply to on
`
`
`
`a
`file
`2011.
`May
`received
`(a) • A reply was
`on
`), which is after
`
`
`or (with a Certificate of Mailing Transmission dated
`period for reply
`(including
`a
`total
`
`extension time of
`of
`on
`month(s)) which expired
`on
`(b) • A proposed
`reply was
`received
`under (a) to the final rejection.
`
`
`, but it does not constitute
`a
`proper
`reply 37 CFR 1.113
`
`to a
`final
`rejection
`consists
`only
`of:
`(1)
`(A proper reply under 37 CFR 1.113
`application
`in condition
`
`for allowance; (2) a
`timely
`filed
`
`of Notice Appeal (with appeal
`
`fee);
`
`(3) or a timely filed Request
`for
`
`Continued Examination
`(RCE)
`in
`compliance
`with 1.114).
`
`37
`CFR
`but it does not constitute
`
`proper a reply, or a bona
`
`fide
`attempt
`(c) • A reply was received on
`final rejection. See 37 CFR 1.85(a)
`and
`
`1.111. (See explanation
`in
`box
`7
`below).
`(d) ^ No reply has been received.
`
`
`
`a the non-proper
`
`and
`fee
`the pay required issue
`
`
`timely
`to
`failure
`2. • Applicant's
`
`
`Notice the of Allowance
`(PTOL-85).
`of
`from the mailing date
`(a) • The issue fee and publication fee, if applicable, was received on
`.), which is after the expiration
`
`of the statutory period
`for
`Allowance (PTOL-85).
`(b) • The submitted
`fee of $ is insufficient. A balance of $.
`is due.
`if fee, required by 37 CFR 1.18(d),
`
`The issue fee
`required
`by
`
`37 is $
`
`
`1.18 CFR . The publication
`
`(c) • The issue
`fee and
`publication
`
`fee, applicable, has not been if
`
`received.
`
`
`
`
`
`fee, publication applicable, within
`
`if
`
`the
`
`statutory
`
`period
`
`of
`
`three
`
`(with a Certificate of Mailing or Transmission dated
`payment
`
`
`the of fee (and publication issue
`
`fee)
`
`set in the Notice of
`
`is
`
`$.
`
`timely
`
`to
`failure
`30 Applicant's
`Allowability (PTO-37).
`(a) • Proposed corrected
`drawings
`of
`the
`after the expiration
`(b) • No corrected drawings
`have
`
`file
`
`corrected
`
`drawings
`
`as
`
`required
`
`
`
`by, Notice of
`
`and
`
`were
`
`period reply.
`been
`
`on received (with a Certificate of Mailing or Transmission
`
`
`
`
`for
`received.
`
`dated J, which is
`
`4. • The letter of express abandonment which
`the applicants.
`5. D The letter of express abandonment which
`is
`1.34(a)) upon
`the
`
`
`of filing a continuing application.
`
`is
`
`signed
`
`by
`
`
`
`the of record, the assignee of the entire attorney or
`
`
`
`
`
`
`
`
`
`agent interest, all of
`
`or
`
`signed
`
`by
`
`an
`
`
`
`attorney a representative capacity or
`
`
`
`under
`
`
`
`agent 37
`
`CFR
`
`the Board
`6. • The decision by
`of the decision has expired and
`
`Interference
`Patent of Appeals and
`
`
`there
`
`
`no are allowed claims.
`
`rendered
`
`
`
`on and because
`
`the period
`
`for
`
`seeking
`
`court
`
`7. • The reason(s) below:
`
`See attached
`
`Interview Summary.
`
`/Jeffrey S. Lundgren/
`Supervisory Patent Examiner,
`
`
`
`Art Unit 1629
`
`Petitions to revive under 37 CFR 1.137(a) or (b), or
`minimize any negative effects on patent term.
`U.S. Patent
`and
`Trademark
`Office
`PTOL-1432 (Rev. 04-01)
`
`requests to withdraw the holding of abandonment under 37 CFR 1.181, should be promptly filed to
`
`Notice of Abandonment
`
`Part of Paper No. 20111214
`
`0003
`
`

`

`CASE PAT034053-US-PCT
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Art Unit: 1614
`IN RE PCT NATIONAL STAGE APPLICATION OF
`Examiner: Blakely III, Nelson
`Kovarik, John M. et al.
`INTERNATIONAL APPLICATION NO: PCT/US2005/43044
`FILED: November 28, 2005
`U.S. APPLICATION NO: 11/720205
`35 USC §371 DATE: May 25, 2007
`FOR: Dosage Regimen of an S1P Receptor Agonist
`
`Commissioner for Patents
`PO Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`PETITION FOR EXTENSION OF TIME
`
`The Office Action of May 25, 2011 has a
`25, 2011. A three-month extension is hereby
`
`to expire on August
`shortened statutory time set
`requested pursuant to 37 CFR §1.136(a).
`
`The response to said Office Action is a request for
`above-identified application.
`
`filing a continued application of
`
`the
`
`in the amount of
`Please charge Deposit Account No. 19-0134 in the name of Novartis
`$1270 for payment of the extension fee.
`The Commissioner is hereby authorized to charge any
`
`
`additional fees under 37 CFR §1.17 which may be required, or credit any overpayment, to
`Account No. 19-0134 in the name
`of Novartis,
`
`Novartis Pharmaceuticals Corporation
`One Health Plaza, Bldg. 101
`East Hanover, NJ 07936
`+1 862 7793785 „
`Date:
`//,
`'/J
`
`Respectfully su bmitted,
`
`Karen DeBenedictis
`Attorney for Applicant
`Reg. No. 32,977
`
`0004
`
`

`

`Electronic Patent Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`11720205
`
`25-May-2007
`
`Title of Invention:
`
`
`
`DOSAGE REGIMEN OF AN P RECEPTOR AGONIST SI
`
`
`
`First Named
`
`Inventor/Applicant Name:
`
`John M. Kovarik
`
`Filer:
`
`Karen DeBenedictis/Denise
`
`Cooper
`
`Attorney Docket Number:
`
`34053-US-PCT
`
`Filed as Large Entity
`
`U.S. National Stage under 35 USC 371 Filing Fees
`
`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total in
`USD($)
`
`Basic Filing:
`
`Pages:
`
`Claims:
`
`Miscellaneous-Filing:
`
`Petition:
`
`Patent-Appeals-and-lnterference:
`
`Post-Allowance-and-Post-lssuance:
`
`Extension-of-Time:
`
`Extension
`
`- 3 months
`
`with
`
`$0
`
`paid
`1253
`
`1
`
`1270
`
`1270
`
`0005
`
`

`

`Description
`
`Fee Code
`
`Quantity
`
`Amount
`
`Sub-Total in
`USD($)
`
`Miscellaneous:
`
`Total in USD ($)
`
`1270
`
`0006
`
`

`

`Electronic Acknowledgement Receipt
`
`EFSID:
`
`Application Number:
`
`11468721
`
`11720205
`
`International Application Number:
`
`Confirmation Number:
`
`5868
`
`Title of Invention:
`
`
`
`DOSAGE REGIMEN OF AN P RECEPTOR AGONIST SI
`
`
`
`First Named
`
`Inventor/Applicant Name:
`
`John M. Kovarik
`
`Customer Number:
`
`1095
`
`Filer:
`
`Karen DeBenedictis/Denise
`
`Cooper
`
`Filer Authorized By:
`
`Karen DeBenedictis
`
`Attorney Docket Number:
`
`34053-US-PCT
`
`Receipt Date:
`
`Filing Date:
`
`Time Stamp:
`
`22-NOV-2011
`
`25-MAY-2007
`
`17:31:39
`
`Application Type:
`
`U.S. National
`
`Stage
`
`under
`
`35
`
`USC 371
`
`Payment information:
`
`Submitted with Payment
`
`Payment Type
`
`Payment was successfully
`
`
`
`received in RAM
`
`RAM confirmation Number
`
`Deposit Account
`
`Authorized User
`
`yes
`
`Deposit Account
`
`$1270
`
`4664
`
`190134
`
`The Director of the USPTO is hereby authorized to charge indicated fees and credit any overpayment as follows:
`
`Charge any Additional
`
`Fees
`
`required
`
`
`
`under 1.21 (Miscellaneous
`
`
`
`37 fees
`
`and
`
`
`
`C.F.R. Section charges)
`
`0007
`
`

`

`File Listing:
`
`Document
`Number
`
`Document Description
`
`File Name
`
`File Size( Bytes)/
`Message Digest
`
`Multi
`Part /.zip
`
`Pages
`(ifappl.)
`
`46255
`
`1
`
`Extension of
`
`Time
`
`34053_Ext.pdf
`
`no
`
`1
`
`Warnings:
`
`Information:
`
`C67b4ee934e5b58a2f5bb35da182fa550d2
`9156a
`
`30356
`
`2
`
`Fee Worksheet
`
`(SB06)
`
`fee-info.pdf
`
`no
`
`2
`
`dd1ffe169f0b908e08292596a2f790a2f65ce
`cac
`
`Warnings:
`
`Information:
`
`Total Files Size (in bytes):
`
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`
`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO of the indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New Applications Under 35 U.S.C. 111
`includes the necessary components for a filing date (see 37 CFR
`If a new application is being filed and the application
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this
`
`Acknowledgement Receipt will establish the filing date of the application.
`
`National Stage of an International Application under 35 U.S.C. 371
`is compliant with the conditions of 35
`If a timely submission to enter the national stage of an international application
`U.S.C. 371 and other applicable requirements a Form PCT/DO/EO/903
`indicating acceptance of the application as a
`national stage submission under 35 U.S.C. 371 will be issued in addition to
`the Filing Receipt, in due course.
`
`New International Application Filed with the USPTO as a Receiving Office
`is being filed and the international application includes the necessary components for
`If a new international application
`
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/RO/105) will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of
`the application.
`
`0008
`
`

`

`PTO/SB/OSa (07-09)
`through 07/31/2012.
`OMB
`Approved for use
`
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`
`0651-0031
`
`Substitute for form 1449/PTO
`
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`(Use as many sheets as necessary)
`
`Sheet
`
`1
`
`of
`
`Complete if Known
`Application Number
`11/720205
`November 28, 2005
`Filing Date
`Kovarik, John M. et al.
`First Named Inventor
`Art unit
`1614
`Blakely III, Nelson
`Examiner Name
`Attome^Do^^^umber PAT034053-US-PCT
`
`Examiner
`Initials''
`
`Cite
`No.'
`
`Document Number
`Number-Kind Code2"'"™™'
`
`U.S. PATENT DOCUMENTS
`Name of Patentee or
`Publication Date
`Applicant of Cited Document
`MM-DD-YYYY
`
`Pages, Columns, Lines, Where
`Relevant Passages or Relevant
`Figures Appear
`
`US-
`US-
`US-
`US-
`US-
`us-
`us-
`us-
`us-
`us-
`us-
`us-
`us-
`us-
`
`Examiner
`Initials'
`
`Cite
`No.'
`
`FOREIGN PATENT DOCUMENTS
`Publication Date
`Name of Patentee or
`MM-DD-YYYY
`Applicant of Cited Document
`
`Foreign Patent Document
`Country Code3 Number4 Kind Code5"*""1
`EP 1431275 Al
`EP 1431284 A1
`WO 2004/103306
`EP 0627406 Al
`
`06-23-2004
`06-23-2011
`12-02-2004
`12-07-1994
`
`Kyorin Pharmaceutical Co., Ltd.
`Kyorin Pharmaceutical Co., Ltd.
`IRM LLC
`Yoshitomi Pharmaceutical
`Industries. Ltd.
`
`Pages, Columns, Lines,
`Where Relevant Passages or
`Relevant Figures Appear
`
`T* •
`•
`•
`•
`•
`
`•
`—
`
`Date
`Examiner
`Signature
`Considered
`*EXAMINER: Initial if reference considered, whether or not citation is in conformance with MPEP 609. Draw a line through citation if not in conformance
`and not considered. Include copy of
`this
`
`
`form with the next communication to applicant. 1 Applicant's unique citation designation number
`(optional).
`2
`See Kind Codes of USPTO Patent Documents at www.uspto.gov or MPEP 901.04. 3 Enter Office that issued the document, by the two-letter code (WIPO
`Standard ST.3). 4 For Japanese patent documents, the indication of the year of the reign of the
`Emperor must
`precede
`the
`serial
`
`document. 5 Kind of document by the appropriate symbols as indicated on the document under WIPO Standard ST. 16 if possible. 6 Applicant is
`to place
`a check mark here if English language Translation is attached.
`1.97 37 CFR The information is 1.98. and required obtain or retain a benefit to by the public which Is to file
`
`
`
`
`
`
`
`This collection of information
`is
`required
`by
`
`(and by the USPTO to process) an application. Confidentiality is
`
`governed by 35 U.S.C. 122 and 37 CFR 1.14. This collection is estimated to take 2
`hours to complete, including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon the
`individual case. Any comments on
`the
`
`of amount time you require to complete this form and/or suggestions for reducing this burden, should be sent to the
`
`Chief Information Officer, U.S. Patent and Trademaric Office, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED
`FORMS TO THIS ADDRESS. SEND TO: Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1460.
`If you need assistance
`in completing
`the
`
`
`call form, 1-800-PTO-9199
`(1-800-786-9199)
`
`
`
`
`select and option 2.
`
`number
`
`0009
`
`

`

`PTO/SB/O8b (07-09)
`Approved for use through 07/31/2012. OMB 0651-0031
`U.S. Patent and Trademark Office; U.S. DEPARTMENT OF COMMERCE
`Underth^apeiwori^educjroi^te^M995^ionersan^r^equire{U^esgoncH^icollecto
`
`Substitute for form 1449/PTO
`
`INFORMATION DISCLOSURE
`STATEMENT BY APPLICANT
`(Use as manys/ieets as necessary)
`
`Sheet
`
`2
`
`I of
`
`2
`
`Complete if Known
`Application Number
`11/720205
`Filing Date
`November 28, 2005
`First Named Inventor
`Kovarik, John M.
`et al.
`Art unit
`1614
`Examiner Name
`Blakely II), Nelson
`Attorney Docket Number
`PAT034053-US-PCT
`
`Examiner
`initials*
`
`Cite
`No.'
`
`NON PATENT LITERATURE DOCUMENTS
`Include name of the author (in CAPITAL LETTERS), title of the article (when appropriate), title of
`the item (book, magazine, journal, serial, symposium,
`catalog, etc.), date, page(s), volume-issue number(s), publisher, city and/or
`country where published.
`A.N. Okoto" Lechenie autoimunnogo tireoditida" (Treatment of autoimmune thryroiditis). Vitebsk, 1998. Found 06 May
`2011 http://rustamsamedov.narod.ru/physlib/thyreotditauto, html.
`G.L. Vyshkovski. Index of Pharmaceuticals. Annual Index, 5, 2003, OOO
`I.B. Mikhailov. "Osnovi ratsionalnoi farmakoterapii" (Theory of
`pharmacotherapy. Tutorial on clinical
`rational
`pharmacotherapy for students of pediatric and medical departments of institutions of higher education. St. Petersburg
`"Foliant". P.32 1999
`
`"RLS-2003". P.1016.
`
`T2
`
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`•
`
`Examiner
`Date
`Signature
`Considered
`•EXAMINER: Initial if reference considered, whether or not citation is
`in conformance with MPEP 609. Draw a line through citation
`if not
`in conformance
`and not considered. Include copy of
`this
`form with the next communication to applicant.
`1 Applicant's unique citation designation number (optional). 2 Applicant is to place a check mark here if English language Translation is attached.
`This collection of
`information
`is required by 37 CFR 1.98. The information is required to obtain or
`retain a benefit by the public which is to file (and by the
`USPTO to process) an application. Confidentiality is governed by 35 U.S.C. 122 and 37 CFR 1.14, This collection is estimated to take 2 hours to
`complete, including gathering, preparing, and submitting the completed application form to the USPTO. Time will vary depending upon
`the individual
`case. Any comments on
`the amount of
`time
`to complete this form and/or suggestions
`you
`require
`for
`reducing this
`should be sent to
`burden,
`the Chief
`Information Officer, U.S. Patent and Trademark Office, P.O. Box 1450, Alexandria, VA 22313-1450. DO NOT SEND FEES OR COMPLETED FORMS TO
`THIS ADDRESS. SEND TO: Commissioner for Patents,
`P.O. Box 1450, Alexandria, VA 22313-1460.
`
`0010
`
`

`

`3
`
`(19)
`
`(12)
`
`Europaisches Patentamt
`European Patent Office
`Office europeen des brevets
`
`EP 1 431 275 A1
`EUROPEAN PATENT APPLICATION
`published
`in
`accordance
`with
`EPC
`Art.
`
`(11)
`
`158(3)
`
`(43) Date of publication:
`23.06.2004 Bulletin 2004/26
`
`(21) Application number: 02768056.0
`
`(22) Date of filing: 25.09.2002
`
`(51) Intel.7: C07C 217/34, C07C 217/56,
`C07C 217/64, C07C 255/54,
`C07C 317/22, C07C 323/20,
`C07D 213/30, A61K 31/137,
`A61K 31/138, A61K 31/277,
`A61K 31/4409, A61P 11/02,
`A61P 11/06, A61P 17/00,
`A61P 17/16, A61P 27/14,
`A61P 29/00, A61P 37/06,
`A61P 37/08
`
`(86) International application number:
`PCT/J P2002/009864
`
`number:
`(87) International publication
`WO 2003/029184
`(10.04.2003 Gazette
`
`2003/15)
`
`(84) Designated Contracting States:
`AT BE BG CH CY CZ DE DK
`
`SE IE IT LI LU MC NL PT SK TR
`
`Designated Extension States:
`AL LT LV MK RO SI
`
`EE
`
`ES
`
`Fl
`
`• ANDO, Naoki
`FR GB
`GR
`Oura-gun, Gunma 374-0112
`• TANASE, Takahiro
`Shimotsuga-gun, Tochigi
`• KURIYAMA, Kazuhiko
`Oyama-si, Tochigi 329-0214
`• IWANAMI, Satoru
`Sashima-gun,
`Ibaraki 306-0236
`• KUDOU, Shinji
`Shimotsuga-gun, Tochigi
`
`(JP)
`
`329-0101
`
`(JP)
`
`(JP)
`
`329-0101
`
`(JP)
`
`(JP)
`
`Ltd.
`
`(74) Representative: VOSSIUS & PARTNER
`Siebertstrasse 4
`81675 Munchen (DE)
`
`(30) Priority: 27.09.2001 JP 2001297400
`25.07.2002 JP 2002216191
`
`(71) Applicant: Kyorin Pharmaceutical Co.,
`Tokyo 101-8311
`(JP)
`
`(72) Inventors:
`• KOHNO, Yasushi
`Oyama-si, Tochigi 323-0820
`
`(JP)
`
`(54) DIARYL ETHER DERIVATIVE,
`
`ADDITION
`
`SALT
`
`THEREOF,
`
`AND
`
`IMMUNOSUPPRESSANT
`
`The present invention provides diaryl ether derivatives that exhibit significant
`
`
`(57)
`less side effects.
`
`
`The diaryl derivatives of the present invention are
`
`represented
`
`by
`
`the
`
`immunosuppressive effects with
`
`following
`
`general
`
`formula
`
`<
`LO
`r-
`CM
`
`CO
`"3"
`
`Q_
`LU
`
`R1
`
`R3
`
`%
`
`NH2
`
`A
`*
`
`2
`
`»H
`
`(D
`
`H
`
`one example is 2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl)propyl-1,3-propanediol.
`
`Printed by Jouve, 75001 PARIS
`
`(FR)
`
`0011
`
`

`

`EP 1 431 275 A1
`
`Description
`
`TECHNICAL FIELD
`
`5
`
`[0001] The present invention relates to dlaryl ether derivatives, salts and hydrates thereof that are useful as an
`immunosuppressive agent.
`
`TECHNICAL BACKGROUND
`
`as
`in
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`[0002]
`Immunosuppressive agents are widely used as a treatment for autoimmune diseases such as rheumatoid
`arthritis, nephritis, osteoarthritis
`such
`
`and systemic lupus erythematosus,
`chronic
`inflammatory
`diseases
`
`tory bowel disease, and allergic diseases
`such
`as
`asthma
`and
`
`dermatitis. has led to an increase Progress
`in the number of tissue and organ transplantations performed each year. In such a situation of modern medicine, having
`as much control as possible
`over
`the
`rejection
`
`
`
`following a key to successful transplantation transplantation. is
`
`Immu­
`nosuppressive agents also play
`
`significant end.
`role
`to
`this
`a
`[0003] Among immunosuppressors
`commonly used in organ transplantation are antimetabolites, such as azathio-
`prine and mycophenolate mofetil, calcineurin inhibitors, such as cyclosporin A and tacrolimus, and corticosteroid, such
`as prednisolone. Some of these drugs are not effective enough while others require continuous monitoring of the blood
`drug level to avoid renal failure and other serious side effects. Thus,
`
`none of conventional
`immunosuppressive agents
`are satisfactory
`in view of efficacy and potential
`side
`effects.
`[0004] Multiple drug combined-therapy, in which different immunosuppressive
`drugs with different mechanisms of
`action are used, is becoming increasingly common with the aims of alleviating the side effects of the drugs and achieving
`sufficient immunosuppressive
`effects.
`Also,
`
`development of new types of immunosuppressive agents
`that
`have
`pletely different mechanisms
`of action is sought.
`[0005]
`a conducted search for new
`
`inventors
`In an effort to respond
`
`to such demands, the present
`
`nosuppressive agents with main
`emphasis
`on
`
`2-amino-1,3-propanediol derivatives.
`[0006] While the use of 2-amino-1,3-propanediol derivatives
`been disclosed in
`
`
`as immunosuppressive agents has
`PCT publication WO94/08943
`(YOSHITOMI PHARMACEUTICAL
`INDUSTRIES,
`Ltd.,
`
`TAITO Co., Ltd.) and in Japa­
`nese Patent Publication No. Hei 9-2579602 (YOSHITOMI PHARMACEUTICAL
`INDUSTRIES,
`Ltd.,
`
`known that 2-amino-1,3-propanediol
`it has not been previously
`derivatives
`having
`a
`
`diaryl which are sub­ether
`
`jects of the present invention,
`can
`serve
`as an
`effective
`immunosuppressor.
`
`com­
`
`types of immu­
`
`TAITO
`group,
`
`Co.,
`
`DISCLOSURE OF THE
`
`INVENTION
`
`[0007] Accordingly, it is an objective of the present invention to provide a diaryl ether derivative that exhibits significant
`immunosuppressive effects with
`little
`side
`effects.
`[0008]
`from
`
`In the course of studies on immunosuppressive agents that have different mechanisms of action
`tabolites and calcineurin inhibitors, the present inventors discovered
`that novel diaryl ether derivatives that have a
`different structure
`from
`conventional
`
`immunosuppressors exhibit strong
`immunosuppressive
`effects.
`Specifically,
`compounds aresuch that one of the aryl groups includes, at its para-position, acarbon chain with an aminopropanediol
`group and the other aryl
`
`group includes a substituent at
`its meta-position.
`
`
`
`
`This led the present discovery inventors to
`devise the present
`invention.
`[0009] The present invention
`as
`containing
`agent
`immunosuppressive
`is an
`thus
`a diaryl ether derivative, a pharmaceutically acceptable salt and hydrate thereof, the diaryl ether derivative represented
`by the following general
`formula
`(1):
`
`an
`
`antime­
`
`the
`
`active
`
`RI
`
`V*. +
`
`2
`
`R3
`
`<6
`
`NHa
`
`« 0)
`
`H
`
`wherein R1 is halogen, trihalomethyl, hydroxy, lower alkyl having 1 to 7 carbon atoms, substituted or unsubstituted
`
`phenyl, aralkyl, lower alkoxy having 1 to 4 carbon atoms, trifluoromethyloxy, phenoxy, cyclohexylmethyloxy
`substituted
`or unsubstituted aralkyloxy, pyridylmethyloxy, cinnamyloxy, naphthylmethyloxy, phenoxymethyl, hydroxymethyl, hy-
`
`2
`
`0012
`
`

`

`EP 1 431 275 A1
`
`having 1 to4carbon atoms, loweralkylsulfinyl having 1 to4carbon atoms, loweralkylsulfonyl
`
`droxyethyl, loweralkylthio
`atoms,
`
`benzylthio, acetyl, nitro, or cyano; R2 is hydrogen, halogen, trihalomethyl,
`lower alkoxy
`having 1
`to 4
`carbon
`having 1 to 4 carbon atoms,
`
`lower alkyl having 1 to 7 carbon atoms, phenethyl, or benzyloxy; R3 is hydrogen,
`halogen,
`trifluoromethyl,
`
`lower alkoxy having 1 to 4 carbon atoms, hydroxy, benzyloxy.
`lower alkyl having 1 to 7
`carbon
`atoms,
`phenyl, lower alkoxymethyl having 1 to 4 carbon atoms, or
`lower
`
`
`having alkylthio 1 to 4 carbon atoms; and X is-(CH2)n-
`(n is an integerfrom 1
`
`to 4), -OCHgCHg-, or -ChkCHCHj-.
`[0010] More specifically,
`an active
`as
`the present invention
`
`is an immunosuppressive agent containing
`least one of a diaryl ether derivative, a pharmaceutically acceptable salt and hydrate thereof, the diaryl ether derivative
`represented by
`the
`following
`
`general formula (1 a):
`
`ingredient
`
`F3C,
`
`i
`
`%
`
`I
`
`R3
`
`NH2
`
`X
`
`H
`
`2
`
`M
`
`(la)
`
`wherein Rg, R3, and X are the same as defined
`above.
`[0011] Furthermore, the present invention
`is an immunosuppressive agent containing as an active ingredient at least
`
`one of a diaryl ether derivative, a pharmaceutically acceptable salt and hydrate thereof, the diaryl ether derivative
`represented by
`the
`following
`
`general formula (1 b):
`
`R4
`
`I
`
`+
`
`•2
`
`I
`
`R3
`
`NH2
`
`X
`
`iH
`
`H
`
`(lb)
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`wherein Rg, R3, and X are the same as defined above; and R4 is hydrogen, halogen, trifluoromethyl, lower alkoxy
`
`or having 1 to 4 carbon atoms, lower alkyl having 1
`
`to 7
`carbon
`atoms.
`
`BRIEF DESCRIPTION OF THE
`
`DRAWINGS
`
`40
`
`[0012]
`
`45
`
`50
`
`55
`
`Fig. 1 is a graph showing activities of a test compound
`Fig. 2 is a graph showing activities of a test compound
`Fig. 3 is a graph showing activities of a test compound
`Fig. 4 is a graph showing activities of a test compound
`Fig. 5 is a graph showing activities of a test compound
`Fig. 6 is a graph showing activities of a test compound
`Fig. 7 is a graph showing activities of a test compound
`Fig. 8 is a graph showing activities of a test compound
`
`in a mouse
`in a mouse
`in a mouse
`in a mouse
`in a mouse
`in a mouse
`in a mouse
`in a mouse
`
`skin
`skin
`skin
`skin
`skin
`skin
`skin
`skin
`
`graft model.
`graft model.
`graft model.
`graft model.
`graft model.
`graft model.
`graft model.
`graft model.
`
`BEST MODE FOR CARRYING OUT
`
`THE
`
`INVENTION
`
`[0013] The compounds of the general formulae
`of the pharma­
`
`(1a) and (1b) are novel compounds. Examples
`
`(1),
`formula
`
`(1) include acid salts, such
`as hydrochloride, hyd-
`
`ceutically acceptable salt of the compound of the general
`robromide, acetate,
`trifluoroacetate,
`methanesulfonate,
`citrate,
`and
`tartrate.
`[0014]
`In the general formula (1), the term 'halogen atom'
`
`includes fluorine, chlorine, bromine,
`
`and iodine atom. The
`term 'trihalomethyl group' includes trifluoromethyl and trichloromethyl. The phrase
`'lower alkyl group having 1 to 7
`carbon atoms' includes straight-chained
`
`
`
`or branched hydrocarbons having 1 to 7 carbon atoms, such as methyl, ethyl,
`
`3
`
`0013
`
`

`

`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EP 1 431 275 A1
`
`'substituted or unsubstituted phenoxy group1
`propyl, isopropyl, butyl; t-butyl, pentyl, hexyL and heptyl. The phrase
`ring,
`a
`
`atom, halogen chlorine, bromine and
`
`such
`includes those that have, at any position
`of its
`benzene
`1 to
`4 lower
`alkoxy having
`4
`carbon
`iodine, trifluoromethyl,
`lower
`alkyl
`
`1 to having carbon atoms, or
`
`
`
`'aralkyl group" as in
`
`'aralkyl group' or'aralkyloxy
`group'
`includes
`
`benzyl, diphenylmethyl, phenethyl,
`and phenylpropyl.
`
`
`1 The term 'lower alkyl group' as used in 'lower alkoxyl group having to 4 carbon atoms," 'lower alkylthio group having
`
`
`1 to 4 carbon atoms,' 'lower alkylsulfinyl group having
`
`
`4 1 to carbon atoms," or
`'lower
`alkylsulfonyl
`
`having
`group 1 to 4
`includes straight-chained or branched hydrocarbons having 1 to 4 carbon atoms, such as methyl, ethyl,
`carbon atoms,'
`propyl, isopropyl, and
`butyl.
`The
`phrase
`'substituted
`or
`
`
`unsubstituted includes those that
`
`
`aralkyl have, at
`position of its benzene ring, a halogen atom, such as fluorine, chlorine, bromine and iodine, trifluoromethyl, lower alkyl
`having 1 to 4
`carbon atoms,
`or
`lower
`alkoxy
`having
`1
`to
`4
`[0015] According to the present invention, the compounds of the general formula (1)can be produced in the following
`pathways:
`
`any
`
`carbon
`
`atoms.
`
`group"
`
`Synthetic pathway 1
`
`Rl^>
`.
`
`Jf
`
`(2)
`
`Step 1 Ri.
`
`i :
`I
`P)
`
`NHBoc
`
`JOjRs
`
`Step 2 R1
`
`I
`
`»
`(4)
`
`12
`
`NHBoc
`
`IH
`
`Step 3
`
`Rt
`
`I'
`
`W NHj
`
`'2 0)
`
`Synthetic pathway 2
`
`xt
`
`Ph^
`
`(5)
`
`-y
`
`Step4 _
`
`I
`(6)
`
`NHBoc
`O^Rg
`
`.Step 5 PhNHBdO
`-
`
`02RS
`
`Step 6 _
`
`I
`<8)
`
`NHBoc Step 7 ^ HO.
`
`;3 NHBoc
`
`Step 8
`
`>*1
`
`(9)
`
`-R7
`
`Ri
`
`rl
`
`n
`
`* (10)
`
`Ra
`
`NHBoc
`
`Step 9'^
`
`Ri
`
`fet
`
`I
`
`'2
`
`(1)
`
`Ra
`
`Nl
`
`'H
`
`w
`
`[0016] The compound appearing
`
`in
`
`the
`
`synthetic
`
`pathway
`
`1
`
`and
`
`represented
`
`R,
`
`II
`
`fa
`
`NHBoc
`Rs(3)
`
`'2
`
`>2*5
`
`(wherein R5
`is lower alkyl having 1
`
`as described above) can
`be
`
`carbon to 4 atoms; Boc is t-butoxycarbonyl; and Rg, R3, and X are the same
`
`
`prepared
`
`
`
`by a compound of the reacting following general
`formula
`(2):
`
`4
`
`0014
`
`

`

`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EP 1 431 275
`
`A1
`
`Rl
`
`,0,
`i :
`2
`
`+
`
`Ra
`
`%
`
`X
`X
`
`(2)
`
`(wherein Y is chlorine, bromine, or iodine; and R-,, R2, R3, and X are as described above) with a compound of the
`following general
`formula
`(11):
`
`O2R5 < (11)
`
`BocHN
`
`O2R5
`
`(wherein R5 and Boc are as described
`presence a base (Step 1).
`of
`
`the
`in
`above)
`[0017] This reaction can be
`1,4-dioxane, as (DMSO), N.
`
`
`such
`a reaction
`solvent
`out using
`carried
`
`
`ethanol or a reaction temperature of CO to reflux temperature, at
`
`N-dimethylformamide
`(DMF),
`tetrahydrofuran
`(THF).
`
`preferably at a temperature of 80oC to 100°C. in the presence of an inorganic base such as sodium hydride, potassium
`hydride, sodium alkoxide, and
`potassium
`alkoxide.
`[0018] The compound appearing
`in the
`synthetic
`
`pathway
`
`1
`
`and
`
`represented
`
`by
`
`dimethylsulfoxide
`
`the
`
`Rl
`
`R3
`*
`
`'X
`
`NHBoc
`H W
`
`iH
`
`a
`
`(wherein R^ R2, R3, R4, X, and Boc are as described above) can be prepared by the
`the general formula
`(3) (Step
`2).
`[0019] This reaction can be carried out at a reaction temperature of 0°C to reflux temperature, preferably at room
`temperature, using an alkylborane derivative, such as borane (BHg) and 9-borabicyclo[3.3.1)nonane (9-BBN), or a
`metal hydride complex, such as diisobutylaluminum
`
`hydride ((iBu)2AIH), sodium borohydride
`(NaBH4) and lithium alu­
`
`minum hydride (UAIH4), preferably lithium borohydride (LiBh^), and using a reaction solvent such as THF, ethanol and
`methanol.
`[0020] The compound appearing
`
`in the
`
`synthetic
`
`pathway
`
`1
`
`and
`
`represented
`
`
`
`reduction of the compound of
`
`by
`
`the
`
`R1
`
`2
`
`NH2
`
`•H
`
`(1)
`
`Rg, R3, and
`(wherein Ri,
`formula (4) (Step 3).
`[0021] This reaction can be carried out at a reaction temperature in the range of 0oC to room temperature in an
`inorganic or organic acid, such as acetic acid, hydrochloric acid, hydrobromic
`acid,
`methanesulfonic
`oacetic acid, or in a mixed solvent with an organic solvent such as methanol, ethanol, THF, 1,4-dioxane, and ethyl
`acetate.
`[0022] The compound appearing
`
`
`
`described prepared by the acidolysis of the above) can
`
`
`
`X
`
`are
`
`as
`
`
`
`
`
`be compound
`
`of the general
`
`in the
`
`synthetic
`
`pathway
`
`2
`
`and
`
`represented
`
`acid
`
`and
`
`by
`
`the
`
`5
`
`0015
`
`

`

`EP 1 431 275
`
`A1
`
`5
`
`OjRs (6)
`
`10
`
`(wherein R3, R5, X, and Boc are as described
`following general
`formula
`(5):
`
`above)
`
`can
`
`be
`
`prepared
`
`by
`
`reacting
`
`the
`
`15
`
`Ph^O
`
`XX-
`
`(5)
`Y
`
`20
`
`(wherein R3, X, and Y are as described above) with
`
`the
`
`compound
`
`of the
`
`(11):
`
`general
`
`formula
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`BocHN
`
`CO2R5
`
`OjRs
`
`(11)
`
`(wherein R5, and Boc are
`presence a base (Step 4). of
`
`
`in the
`as described above)
`
`[0023] This reaction can be
`THF, or
`DMF,
`DMSO,
`
`carried
`
`
`a using out reaction solvent such as 1,4-dioxane,
`
`to 100°C, in the presence of an
`at a reaction temperature
`in
`the
`
`of range 0oC to reflux temperature, preferably 80oC
`
`inorganic base such as sodium
`hydride,
`
`potassium sodium alkoxide, and potassium hydride,
`
`alkoxide.
`[0024] The compound appearing
`in the
`synthetic
`pathway
`2
`