:’i=oRM PTO—l390
`(REV. 1 1.2000)
`*.-
`TRANSMITTAL LETTER TO THE UNITED STATES
`
`us. DEPARTMENT or COMMERCE PATENT AND TRADEMARK OFFICE
`
`
`
`A'['1‘0RNEY’S DOCKET NUMBER
`4 1 94 6/32854
`
`
`
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`CONCERNING A FILING UNDER 35 U.S.C. 371
`INTERNATIONAL APPLICATION NO.
`INTERNATIONAL FILING DATE
`
`PCT/EP00/1 1309
`TITLE OF INVENTION
`
`1
`
`15 NOVEMBER 2000
`
`U.S. APPLICATION NO. (lfknown, sec 37 CFR 1.5)
`N‘’" I0/130271:
`PRIORITY DATE CLAIMED
`16 NOVEMBER 1999
`
`
`
`
`
`
`
`
`STABLE SALTS OF NOVEL DERIVATIVES OF 3,3,—DIPHENYLPROPYLAMINES
`
`APPLICANT(S) FOR DO/EO/US
`MEESE, Claus
`
`Appl-icant herewith submits to the United States Designated/Elected Office (DO/EO/US) the following items and other information:
`This is a FIRST submission ofitems concerning a filing under 35 U.S.C. 371.
`
`This is a SECOND or SUBSEQUENT submission of items concerning a filing under 35 U.S.C. 371.
`
`This is an express request to begin national examination procedures (35 U.S.C. 371(f)). The submission must include
`items (5), (6), (9) and (21) indicated below.
`
`The US has been elected by the expiration of 19 months from the priority date (Article 31).
`
`
`
`
`
`V 3
`7
`
`
`
`EE‘EDIE
`
`A copy of the International Application as filed (35 U.S.C. 371(c)(2))
`a. D is attached hereto (required only if not communicated by the International Bureau).
`b.
`IE has been communicated by the International Bureau.
`c. U is not required, as the application was filed in the United States Receiving Office (RO/US).
`IE Afr English language translation of the International Application as filed (35 U.S.C. 371(c)(2)).
`a. V
`is attached hereto.
`
`6.
`
`7.
`
`b.-‘ D has been previously submitted under 35 U.S.C. 154 (d)(4).
`IE Amendments to the claims of the International Application under PCT Article 19 (35 U.S.C. 371(c)(3))
`a. E] are attached hereto (required only if not communicated by the International Bureau).
`b. D have been communicated by the International Bureau.
`c. E] have not been made; however, the time limit for making such amendments has NOT expired.
`(1.
`IE have not been made and will not be made.
`
`8. D An English language translation of the amendments to the claims under PCT Article 19 (35 U.S.C. 371 (c)(3)).
`9. El An oath or declaration of the inventor(s) (35 U.S.C. 371(c)(4)).
`10. E] An English language translation of the annexes of the International Preliminary Examination Report under PCT
`Article 36 (35 U.S.C. 371(c)(5)).
`
`Items 11 to 20 below concern document(s) or information included:
`.
`1 1. E An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`
`12. IX An assignment document for recording. A separate cover sheet in compliance with 37 CFR 328 and 3.31 is included.
`13.
`[Z] A FIRST preliminary amendment.
`14.
`I___I A SECOND or SUBSEQUENT preliminary amendment.
`15. D A substitute specification.
`16.
`A change of power of attorney and/or address letter.
`17. CI A computer-readable form of the sequence listing in accordance with PCT Rule 13ter.2 and 35 U.S.C. 1.821 — 1.825.
`18. [:1 A second copy of the published international application under 35 U.S.C. 154(d)(4).
`19.
`A second copy of the English language translation of the international application under 35 U.S.C. 154(d)(4).
`I
`.
`IXI Other items or information: Certificate of Express Mailing;
`"
`Postcard
` Statement Under 37 CFR 3.73(b)
`
` page 1 of 2
`
`19000031900003
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0001
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0001
`
`

`
`INTERNATIONAL APPLICATION No
`
`..-.I
`ii’?
`an —~*:.
`:x I:
`J’.
`:
`:a'‘)) ~“-~..
`1‘.
`1)
`“ ‘Ti?!
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`.
`.
`‘'1 ,‘l""'
`.1
`...§I. mull £11‘! BL . IL
`is ‘
`““sl"3I.
`13 $2....
`mlu.
`i<._il
`ii‘ '
`
`JC13 Redd PCT/P10 4 MAY 2002
`A'I'l‘ORNEY’S DOCKET NUMBER
`
`PCT/EP00/11309
`
`,
`
`41946/32854
`CALCULATIONS PTO USE ONLY
`
`BASIC NATIONAL FEE (37 CFR 1.492 (a) (1) — (5)):
`Neither international preliminary examination fee (37 CFR 1.482)
`nor international search fee (37 CFR 1.445(a)(2)) paid to USPTO
`and International Search Report not prepared by the EPO or JPO .................... .. $1000.00
`International preliminary examination fee (37 CFR 1.482) not paid to
`USPTO but International Search Report prepared by the EPO or JPO ............... .. $860.00
`Intemational preliminary examination fee (37 CFR 1.482) not paid to USPTO
`but international search fee (37 CFR 1.445(a)(2)) paid to USPTO ..................... .. $710.00
`International preliminary examination fee (37 CFR 1.482) paid to USPTO
`but all claims did not satisfy provisions of PCT Article 33(l)—(4) ....................... .. $690.00
`International preliminary examination fee (37 CFR 1.482) paid to USPTO
`and all claims satisfied provisions of PCT Article 33(1)-(4) ............................... .. $100.00
`
`ENTER APPROPRIATE BASIC FEE AMOUNT =
`.
`Surcharge of $130.00 for furnishing the oath or declaration later than
`months from the earliest claimed priority date (37 CFR 1.492(e)).
`
`I 20 El 30
`
`86000
`
`NUMBER EXTRAA
`NUMBER FILED
`' CLAIMS '
`I
`10
`x $18.00
`180.00
`30- 20 =
`Total claims
`560.00
`7
`x $80.00
`10- 3 =
`Indeendent claims
`MULTIPLE DEPENDENT CLAIM(S) (if applicable)
`+ $270.00
`»
`TOTAL OF ABOVE CALCULATIONS =
`
`270.00
`
`$ $
`
`$
`$
`
`D Applicant claims small entity status. See 37 CFR 1.27. The fees indicated above
`are reduced by 1/2.
`SUBTOTAL =
`
`+
`
`Processing fee of $130.00 for furnishing the English translation later than I
`I
`months from the earliest claimed priority date (37 CFR 1.492(1)).
`TOTAL NATIONAL FEE =
`
`Fee for recording the enclosed assignment (37 CFR l.21(h)). The assignment must be
`accom anied b an a
`ro riate cover sheet 37 CFR 3.28 3.31 .
`
`$
`
`$
`
`39
`$
`
`a.
`
`IE A check in the amount of $
`
`1910.00
`
`to cover the above fees is enclosed.
`
`b. D Please charge my Deposit Account No.
`A duplicate copy of this sheet is enclosed.
`
`in the amount of $
`
`to cover the above fees.
`
`c.
`
`d.
`
`IZ The Commissioner is hereby authorized to charge any additional fees which may be required, or credit any
`overpayment to Deposit Account No.
`20-0823. A duplicate copy of this sheet is enclosed.
`
`I:I Fees are to be charged to a credit card. WARNING: Information on this form may become public. Credit card
`information should not be included on this form. Provide credit card information and authorization on PTO-2038.
`
`NOTE: Where an appropriate time limit under 37 CFR 1.494 or 1.495 has not been met, a petition to review (37 CFR
`1.137(a) or (b)) must be filed and granted to restore the application to pending st
`s.
`
`/
`
`Signature
`
`Paul A. Lesko
`Name
`
`45,364
`Re istration Number
`
`SEND ALL CORRESPONDENCE TO:
`
`Paul A. Lesko, Esq.
`Thompson Coburn LLP
`One U.S. Bank Plaza
`St. Louis, MO 63101
`Telephone No.: 314.552.6443
`Facsimile No.: 314.552.7000
`
`4
`
`page 2 of2
`
`19000031900003
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0002
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0002
`
`

`
`-1‘.
`nllr
`
`:91.
`«:5
`lid.“ ._§H_.
`
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`
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`21 I.
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`, 73.. ‘“"3i“
`,_.§ill~‘lL_<’l "ail";
`.1013 Rec’d PCT/PTO 1 4 MAY 2002
`
`‘ll
`
`-..‘.L
`
`IN THE UNITED STATES PATENTAND TRADEMARKOFFICE
`
`it
`
`In re Application of: MEESE, Claus et
`al.
`
`Application No.: To be assigned
`
`Filed: Herewith
`
`Title: STABLE SALTS OF NOVEL
`
`DERIVATIVES OF 3,3—
`« DIPHENYLPROPYLAMINES
`
`€€\¥\/%€%€%
`
`Examiner: To be assigned
`
`Group Art Unit: To be assigned
`
`Docket No.: 41946/32854
`
`Commissioner for Patents
`Box PCT
`
`Washington, DC 20231
`
`Sir:
`
`PRELHVIINARY AMENDMENT
`
`Prior to calculation of the filing fee and examination on the merits, kindly amend the
`
`above—identified patent application per the following instructions.
`
`Kindly amend the specification at page one after the title and before the first line of
`
`text, by inserting at that point the following sentence —— This patent application claims the
`
`benefit of priority under 35 U.S.C. § 119 of German Patent Application No. 199 55 190.1,
`
`filed November 16, 1999. German Patent Application No. 199 55 190.1 is incorporated
`
`herein in its entirety by reference.——
`
`The amendments to claims 18-21, 23-25, 27, and 28 are pursuant to an Article 34
`
`amendment made to the PCT application on October 5, 2001.
`
`IN THE CLAI1\/IS
`
`At page 56, amend claims 18-21, 23-25, 27, and 28 as follows:
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0003
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0003
`
`

`
`x1'—':.
`1:1:
`9”?! 3"“ ..n
`.31‘. an
`.‘.*".1. an *—'*m .:'1h f—'":z
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`‘£1, 32."?! ,1?” .-325* llmli £353‘, -Jl.,""-ll‘ m ‘L 3* -:31 “ll. ""15"!-‘J? EC.
`
`18. (once amended) Compound of formula III
`
` Formula TIT
`
`o/\©
`Rx
`/K
`
`‘
`
`
`
`ure cin hi hl stalline and stable form.
`
`
`
`19. (once amended) Compound of formula V
`
`H3C\O
`
`.
`OH
`
`Formula V
`
`
`
`ure cin hi hl stalline and stable form.
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0004
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0004
`
`

`
`20. (once amended) Compound of formula VI
`
`HO 0 OH
`
`0 J\ Formula VI
`1
`
`
`
`
`
`ure cin hi hl stalline and stable form.
`
`'21. (once amended) Use of a compound in accordance with claims 18 to 20 as a highly pure,
`
`crystalline, stable intermediate product in the manufacture of pharmaceutically usefi1l
`
`compounds of formula 1 in accordance with claim 1.
`
`23. (once amended) Compound of formula 3
`
`Formula 3
`
`
`
`ure cin hi hl stalline and stable form.
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0005
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0005
`
`

`
`'1
`‘M ""3 ..::
`“‘“'
`.
`.r"::
`..sx
`-~‘
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`
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`
`24. (once amended) Compound of formula 5
`
`Formula 5
`
`
`
`ure cin hi hl stalline and stable form.
`
`
`
`25. (once amended) Compound of formula 6
`
`Formula 6
`
`
`
`
`
`ure cin hi hl stalline and stable form.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0006
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0006
`
`

`
`27. (once amended) Use of a compound in accordance with claims 23 to 26 as a highly pure,
`
`crystalline, stable intermediate product in the manufacture of pharmaceutically useful
`
`compounds of formula 2 in accordance with claim 3.
`
`28. (once amended) Use of a compound in accordance with claims 23 to 26 as an
`
`intermediate product in the manufacture of phenolic monoesters of general formula 1
`
`Formula 1
`
`in which R denotes Clfigalkyl, C;;Q1_0—cycloa1kyl or unsubstituted or substituted phenyl.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0007
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0007
`
`

`
`..:;
`;§i,”ii:§%
`
`‘*3’ .2“): =~‘
`
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`
`1.
`
`Kindly consider this preliminary amendment and enter it into the record of this
`
`application. Attached is a clean copy of the claims. All correspondence should to be directed
`
`to Paul A. Lesko, Thompson Coburn LLP, One U.S. Bank Plaza, St. Louis, MO 63101,
`
`Telephone No.: 314.552.6443, Facsimile No.: 314.552.7000.
`
`Respectfully submitted,
`
`Pa /A. Lesko
`
`Registration No. 45,364
`Thompson Coburn LLP
`One U.S. Bank Plaza
`
`St. Louis, MO 63101
`
`Telephone: 314.552.6443
`Facsimile: 314.552.7000
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0008
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0008
`
`

`
`.435
`4'“):
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`
`!.l_-
`
`CLEAN COPY OF PARAGRAPH TO BE INSERTED INTO SPECIFICATION
`
`—— This patent application claims the benefit of priority under 35 U.S.C. § 119 of German
`
`Patent Application No. 199 55 190.1, filed November 16, 1999. German Patent Application
`
`No. 199 55 190.1 is incorporated herein in its entirety by reference.—-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0009
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0009
`
`

`
`..s
`
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`
`Claims
`
`18.
`
`Compound of formula III
`
` Formula III
`
`oA©
`N/i\
`/K»
`
`r
`
`in highly pure, crystalline and stable form.
`
`19.
`
`Compound of formula V
`
`.
`OH
`
`Formula V
`
`in highly pure, crystalline and stable form.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0010
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0010
`
`

`
`“Eh, £1.42 !.1§§.k “:22:
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`
`20.
`
`Compound of formula VI
`
`HO O OH
`
`0 J\ Formula VI
`/“L
`
`in highly pure, crystalline and stable form.
`
`21.
`
`Use of a compound in accordance with claims 18 to 20 as a highly pure, crystalline,
`
`stable intermediate product in the manufacture of pharmaceutically useful compounds
`
`of formula 1 in accordance with claim 1.
`
`23.
`
`Compound of formula 3
`
`Formula 3
`
`in highly pure, crystalline and stable form.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0011
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0011
`
`

`
`=
`=v'=- «» "::=* :1.»
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`
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`
`24.
`
`Compound of formula 5
`
`Formula 5
`
`Formula 6
`
`
`
`HO
`
`'
`
`OH a
`
`H3C\
`
`in highly pure, crystalline and stable form.
`
`25. Compound; of formula 6
`
`in highly pure, crystalline and stable form.
`
`27.
`
`Use of a compound in accordance with claims 23 to 26 as a highly pure, crystalline,
`
`stable intermediate product in the manufacture of pharmaceutically useful compounds
`
`of formula 2 in accordance with claim 3.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0012
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0012
`
`

`
`
`
`28. Use of a compound in accordance with claims 23 to 26 as an intermediate product in
`
`the manufacture of phenolic monoesters of general formula 1
`
`in which R denotes C1—C5—alkyl, C3-C10—cycloalkyl or unsubstituted or substituted phenyl.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0013
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0013
`
`

`
`_63_
`
`Figure 1
`
`Reaction diagram 1
`
`(i),
`
`(ii), (iii),
`
`(iv),
`
`(v) stand for:
`
`(i), LiAlH4, (ii),
`
`Raney nickel/H2, (iii), Me2CH—CoCl, Et3N,
`
`(iv),
`
`fumaric acid,
`
`(v), hydrochloric acids; R stands for isopropyl
`
`(iPr)
`
`
`
`(iii)
`
`(iv or V)
`
`—~—~——§- 1
`
`-————~———> 2Ei or 21)
`
`R=i—Pr
`
`’
`
`R=i-Pr
`
`a:X=CfihO4
`
`b:X=Cl
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0014
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0014
`
`

`
`if’ :1
`£1 .31
`
`'3
`
`I§j@1
`
`SPECIFICATION
`
`3’
`
`it
`F
`§”‘Rec'a PCT/PTO 14 MAY 2002
`
`v __1i 1L
`
`Stable salts of novel derivatives of
`
`3,3-diphenylpropylamines
`
`The present
`
`invention concerns highly pure, crystalline,
`
`stable compounds of novel derivatives of 3,3-
`
`diphenylpropylamines in the form of their salts, a method for
`
`manufacturing these and highly pure, stable,
`
`intermediate
`
`products.
`
`From document PCT/EP99/03212 novel derivatives of 3,3-
`
`diphenylproprylamines are known.
`
`These are valuable prodrugs for the treatment of urinary
`
`incontinence and other spasmodic complaints, which overcome
`
`the disadvantage of the active substances available to date,
`
`namely inadequate absorption of the active substance by
`
`biological membranes or the unfavourable metabolism of these.
`
`Furthermore these novel prodrugs have improved
`
`pharmacokinetic characteristics compared with Oxybutynin and
`
`Tolterodin.
`
`Preferred compounds from the group of these novel derivatives
`
`of 3,3—diphenylpropylamines are esters of aliphatic or
`
`aromatic carboxylic acids with the general formula A referred
`
`to below
`
`“Di0
`
`R
`
`0 NA
`
`Formula A
`
`A P
`
`atent Owner, UCB Pharma GmbH — Exhibit 2012 - 0015
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0015
`
`

`
`3.33
`<1‘!
`
`1%‘
`'5‘
`.F':. an ’
`..: 2.:
`‘33~_fi«'
`AL?! #431 if"; ,-XL "‘"-2“
`
`:.
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`:2 31,1’? :31 AL ""'B" 1}, ,El'x-'"I.
`
`in which R denotes C1—C5—alkyl, C3—Cm—cyc1oalkyl or
`
`unsubstituted or substituted phenyl. These can occur in their
`
`optical isomers form as racemic mixtures and in the form of
`
`their individual enantiomers.
`
`Compounds with the structure of formula A do, however, have
`
`low solubility in water. This restricts their oral
`
`bioavailability.
`
`Finally, monoesters of the structure, as shown in formula A,
`
`have a tendency towards intermolecular transesterification.
`
`During long periods of storage,
`
`therefore, as the content of
`
`the Compounds with the structure of general formula A drops
`
`an increase in diesters and free diol can be detected.
`
`Basically salts of the compounds of general formula A can be
`
`obtained if solutions of the compounds of formula A (base
`
`component) are purified with solutions of acids in suitable
`
`solvents, but the salts obtained in the form of solid matter
`
`can prove to be altogether amorphous and/or hygroscopic and
`
`cannot be directly crystallized from the normal solvents
`
`either. Such salts have inadequate chemical stability to be
`
`galenically processed as valuable pharmaceutically active
`
`substances.
`
`Surprisingly, it has now been found that the abovementioned
`
`disadvantages can be avoided if compounds with the structure
`
`of general formula A, once they have been prepared under a
`
`special reaction process, are converted with a
`
`physiologically compatible inorganic or organic acid with
`
`general formula H—X,
`
`in which ‘X represents the respective
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0016
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0016
`
`

`
`.3. =‘.’ x
`ar“).
`...‘.
`-
`1&3. “,3 «ill, 33%:
`
`
`_3_
`
`acid residue,
`
`into their respective salt with general formula
`
`I.
`
`Formula I
`
`The problem for the present invention is therefore to provide
`
`highly pure, crystalline, stable compounds of novel
`
`derivatives of 3,3—diphenylpropylamines in the form of their
`
`salts,
`
`that avoid the stated disadvantages and are well
`
`suited to use in pharmaceutical—technical formulations and
`
`can be processed into these.
`
`A further problem for the present
`
`invention is to provide a
`
`method for manufacturing such highly pure, crystalline,
`
`stable compounds in the form of their salts, as well as
`
`highly pure, stable intermediate products.
`
`The final problem for the invention is to provide a method
`
`for manufacturing the abovementioned compounds with which a
`
`high yield of the products of the process and the respective
`
`intermediate products can be obtained chemo— or
`
`regioselectively.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0017
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0017
`
`

`
`
`
`-4-
`
`This problem is solved in that highly pure, crystalline,
`
`stable compounds of the 3,3—diphenylpropylamines in the form
`
`of their salts with general formula I are provided,
`
`Formula I
`
`in which R denotes Cy4k—alkyl, C3—Cm-cycloalkyl, substituted
`
`or unsubstituted phenyl and X" is the acid residue of a
`
`physiologically compatible inorganic or organic acid.
`
`In accordance with a design of the invention the salts of
`
`general formula I can contain the respective acid residue X’
`
`of the acids mentioned below:
`
`hydrochloric acid, hydrobromic acid, phosphoric acid,
`
`sulphuric acid, nitric acid, acetic acid, propionic acid,
`
`palmitic acid, stearic acid, maleic acid,
`
`fumaric acid,
`
`oxalic acid, succinic acid, DL—malic acid, L—(—)-malic acid,
`
`D—(+)—malic acid, DL-tartaric acid, L—(+)—tartaric acid, D~(—
`
`)—tartaric acid, citric acid, L—aspartic acid, L—(+)—ascorbic
`
`acid, D—(+)—glucuronic acid, 2—oxopropionic acid (pyruvic
`
`acid),
`
`furan—2—carboxylic acid (mucic acid), benzoic acid, 4-
`
`hydroxybenzoic
`
`acid, salicyclic acid, vanillic acid,
`
`4—
`
`hydroxycinammic acid, gallic acid, hippuric acid (N—benzoyl—
`
`glycine), aceturic acid (N—aectylglycine), phloretinic acid
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0018
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0018
`
`

`
`..2‘a
`._._1a
`
`''‘‘‘‘u,.:''‘-. ‘
`.$"‘h m‘.
`2:,
`.:1 at ,:,_u 421421
`
`'3.
`
`.7‘
`II
`-.1-.
`.3,‘ *3)“ m at
`
`
`-5-
`
`(3—(4—hydroxyphenyl)~propionic acid), phthalic acid,
`
`methanesulfonic acid or orotic acid.
`
`In accordance with a further design form of the invention R—
`
`configured compounds with general formula 2 are provided
`
`0
`
`JL O
`
`L+
`NH
`)\
`
`R
`
`X-
`
`Formula 2
`
`in which R denotes C1-C5—alkyl, C3-Cm—cycloalkyl, substituted
`
`or unsubstituted phenyl and X" is the acid residue of a
`
`physiologically compatible inorganic or organic acid.
`
`In accordance with an advantageous design form of the
`
`invention the compounds in the form of their salts of general
`
`formula 2 can contain the respective acid residue X’ of the
`
`acids mentioned below:
`
`hydrochloric acid, hydrobromic acid, phosphoric acid,
`
`sulphuric acid, nitric acid, acetic acid, propionic acid,
`
`palmitic acid, stearic acid, maleic acid,
`
`fumaric acid,
`
`oxalic acid, succinic acid, DL—malic acid, L—(—)—malic acid,
`
`D—(+)—malic acid, DL—tartaric acid, L—(+)—tartaric acid, D—(—
`
`)—tartaric acid, citric acid, L—aspartic acid, L—(+)—ascorbic
`
`acid, D—(+)—glucuronic acid, 2—oxopropionic acid (pyruvic
`
`acid),
`
`furan—2—carboxylic acid (mucic acid), benzoic acid, 4-
`
`hydroxybenzoic
`
`acid, salicyclic acid, vanillic acid, 4-
`
`hydroxycinammic acid, gallic acid, hippuric acid (N—benzoyl—
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0019
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0019
`
`

`
`.95.
`;-4;
`
`“*1-
`..‘n
`.*.“':x
`-31,33 ,-13., LEM
`
`
`
`-6-
`
`glycine), aceturic acid (N—aectylglycine), phloretinic acid
`
`(3—(4—hydroxypheny1)—propionic acid), phthalic acid,
`
`methanesulfonic acid or orotic acid.
`
`Preferred compounds of the present
`
`invention are the salts
`
`—
`
`—
`
`-
`
`R—(+)-2-(3-diisopropylamino—1—phenylpropyl)—4—hydro—
`
`xymethylphenylisobutyrate ester hydrogen fumarate
`
`and
`
`R-(+)-2-(3—diisopropylamino—l—phenylpropy1)—4—hydroXy—
`
`methylphenylisobutyrate ester hydrochloride hydrate.
`
`Furthermore, compounds are preferred in which R stands for
`
`Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4—(1—Cyclo—
`
`propyl—methanoyloxy)—pheny1, 4-(1—cyclobutyl—methanoyloxy)—
`
`phenyl, 4-(1-cyclohexyl—methanoyloxy)-phenyl or 4—(2,2-
`
`dimethyl—propanoyloxy)—phenyl and X'denotes chloride.
`
`Particular preference is for [(R)—3—(2—{1—[4—(l—cyclopropyl—
`
`methanoyloxy)-phenyl]—methanoyloxy}—5—hydroxymethyl—phenyl)—
`
`3—phenylpropyl]—diisopropyl-ammonium chloride,
`
`[(R)~3—(2—{1—
`
`[4-(1-cyclobutyl—methanoyloxy)—phenyl]—methanoyloXy}-5-
`
`hydroxymethyl—pheny1)—3—phenyl—propyl]—diisopropyl—ammonium
`
`chloride,
`
`[(R)-3—(2—{l—[4-(l—cyclohexyl—methanoyloxy)—
`
`phenyl]—methanoyloXy}—5—hydroxymethyl—phenyl)—3—phenyl—
`
`propyl]—diisopropyl—ammonium chloride,
`
`[(R)—3—(2—{1—[4—(2,2—
`
`dimethyl—propanoyloxy)—phenyl]—methanoyloxy}—5—hydroxymethyl—
`
`phenyl)-3-phenyl-propyl]—diisopropyl—ammonium chloride,
`
`{(R)—
`
`3-[2-(l—cyclopropyl—methanoyloxy)—5—hydroxymethyl-phenyl]—3—
`
`phenyl-propyl}—diisopropyl—ammonium chloride,
`
`{(R)—3—[2—(l—
`
`cyclobutyl—methanoyloxy)—5—hydroxymethyl—pheny1]e3—phenyl-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0020
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0020
`
`

`
`
`
`propyl}—diisopropyl—ammonium chloride,
`
`{(R)—3—[2—(l—
`
`cyclopentyl—methanoyloxy)—5—hydroxymethyl—phenyl]-3—phenyl—
`
`propyl}—diisopropyl—ammonium chloride and {(R)—3—[2—(l—
`
`cyclohexyl—methanoyloxy)—5—hydroxymethyl—phenyl]—3—phenyl—
`
`propyl}—diisopropyl—ammonium chloride.
`
`In the compounds of the present
`
`invention the expression
`
`“alkyl” preferably stands for a straight-chain or branched-
`
`chain hydrogen group with between 1 and 6 C—atoms. Special
`
`preference is for methyl, ethyl, propyl,
`
`isopropyl, butyl,
`
`isobutyl, pentyl and hexyl. The expression “cycloalkyl”
`
`designates cyclical hydrogen groups,
`
`that have between 3 and
`
`10 hydrogen atoms,
`
`that may also contain suitable substitutes
`
`in place of the hydrogen atoms.
`
`The expression “phenyl" designates a —Cak—group that may be
`
`substituted or unsubstituted. Suitable substitutes can be,
`
`for example, alkyl, alkoxy, halogen, nitro and amine. The
`
`expression “alkoxy” has, with respect to the alkyl component,
`
`the same meaning as already given above for “alkyl”. Suitable
`
`halogens are fluorine, chlorine, bromine and iodine atoms
`
`The present invention also includes methods for manufacturing
`
`the compounds in accordance with the invention of general
`
`formula I as well as valuable intermediate products.
`
`The method is characterised by chemo— and regioselectivity.
`
`Compounds of general formula I
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0021
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0021
`
`

`
`.
`‘ “ vp.
`
`
`...x
`:.—‘'
`.5 .:
`‘I;
`.1! :3! _.il
`
`:. "-n
`.,
`:1
`5:
`“'H‘1z',4! §‘r'j,:
`
`“°fiL
`
`OR
`
`Formula I
`
`in which R denotes C1—C5—alkyl, C3—Cm—cyc1oalkyl, substituted
`
`or unsubstituted phenyl and X‘ is the acid residue of a
`
`physiologically compatible inorganic or organic acid, are
`
`manufactured in that
`
`a)
`
`a compound of formula III
`
` Formula III
`
`0/\©
`Nk
`/K .
`
`is split with a hydrogenation agent to form a compound
`
`of formula V
`
`Formula V
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012- 0022
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0022
`
`

`
`whereupon
`
`b)
`
`the compound of formula V so obtained is converted with
`
`a reducing agent,
`
`in order to give a compound of formula
`
`Formula VI
`
`
`
`VI
`
`which
`
`C)
`
`is converted with an acylation agent,
`
`in order to obtain
`
`a compound of formula A
`
`“O C it
`
`O
`
`R
`
`E
`
`/j:{\\
`
`
`
`Formula A
`
`in which R has the significance stated above, which
`
`d)
`
`is converted with a physiologically compatible inorganic
`
`or organic acid to form a compound of formula I
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0023
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0023
`
`

`
`u. 1. “L.
`:2 :2
`..z
`IL “"2? H i3»}’:"‘f
`
`
`-10-
`
`Formula I
`
`in which R denotes Cy4g—alkyl, C3—Cm—cycloalkyl,
`
`unsubstituted or substituted phenyl and X— is the acid
`
`residue of a physiologically compatible inorganic or
`
`organic acid.
`
`In accordance with the invention, for the manufacture of the
`
`compounds of general formula I hydrochloric acid, hydrobromic
`
`acid, phosphoric acid, sulphuric acid, nitric acid, acetic
`
`acid, propionic acid, palmitic acid, stearic acid, maleic
`
`acid,
`
`fumaric acid, oxalic acid, succinic acid, DL—malic
`
`acid, L—(—)—malic acid, D—(+)—malic acid, DL—tartaric acid,
`
`L—(+)-tartaric acid, D;(—)—tartaric acid, citric acid, L-
`
`aspartic acid, L—(+)—ascorbic acid, D—(+)—glucuronic acid, 2-
`
`oxopropionic acid (pyruvic acid),
`
`furan—2—carboXylic acid
`
`(mucic acid), benzoic acid, 4—hydroxybenzoic
`
`acid,
`
`salicyclic acid, vanillic acid, 4—hydroxycinammic acid,
`
`gallic acid, hippuric acid (N—benzoyl—glycine), aceturic acid
`
`(N-aectylglycine), phloretinic acid (3—(4-hydroxyphenyl)-
`
`propionic acid), phthalic acid, methanesulfonic acid or
`
`orotic acid are used.
`
`In accordance with an advantageous further development of the
`
`invention a method for the manufacture of R—configured
`
`compounds of the general formula 2 is described,
`
`if Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0024
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0024
`
`

`
`-11-
`
`
`
`O/(l)LR
`
` Formula 2
`
`\L:;...k
`»\
`
`X-
`
`in which R denotes C1—C5—alkyl, C3—Cm—cycloalkyl, substituted
`
`or unsubstituted phenyl and X‘ is the acid residue of a
`
`physiologically compatible inorganic or organic acid,
`
`in that
`
`a)
`
`a compound of formula 3
`
`Formula 3
`
` ow
`
`NJ\
`r_)\
`
`is split with a hydrogenation agent to form a compound
`
`of formula 5
`
`Formula 5
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0025
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0025
`
`

`
`
`
`_]_2_
`
`whereupon
`
`b)
`
`the compound of formula 5 so obtained is converted with
`
`a reducing agent,
`
`in order to give a compound of
`
`formula 6
`
`Formula 6
`
`which
`
`c)is converted with an acylation agent,
`
`in order to obtain
`
`a compound of formula 1
`
`Formula 1
`
`in which R has the significance stated above, which
`
`d)is converted with a physiologically compatible inorganic
`
`or organic acid to form a compound of formula 2
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0026
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0026
`
`

`
`
`
`
`
`-13-
`
`O
`/H\
`
`O
`
`R
`
`Formula 2
`
`
`
`km.
`A x-
`
`in which R denotes Cy{k—alkyl, C3-Cm—cyc1oalkyl,
`
`unsubstituted or substituted phenyl and X— is the acid
`
`residue of a physiologically compatible inorganic or
`
`organic acid.
`
`Advantageously in order to obtain compounds of general
`
`formula 2,
`
`in accordance with the method hydrochloric acid,
`
`hydrobromic acid, phosphoric acid, sulphuric acid, nitric
`
`acid, acetic acid, propionic acid, palmitic acid, stearic
`
`acid, maleic acid,
`
`fumaric acid, oxalic acid, succinic acid,
`
`DL—malic acid, L—(—)—malic acid, D—(+)—malic acid,
`
`DL—tartaric acid, L—(+)—tartaric acid, D—(—)—tartaric acid,
`
`citric acid, L—aspartic acid, L—(+)—ascorbic acid, D—(+)—
`
`glucuronic acid, 2—oxopropionic acid (pyruvic acid),
`
`furan—2—
`
`carboxylic acid (mucic acid), benzoic acid, 4—hydroxybenzoic
`
`acid, salicyclic acid, vanillic acid, 4—hydroxycinammic acid,
`
`gallic acid, hippuric acid (N-benzoyl—glycine), aceturic acid
`
`(N—aectylglycine), phloretinic acid (3—(4—hydroxyphenyl)—
`
`propionic acid), phthalic acid, methanesulfonic acid or
`
`orotic acid are used.
`
`Particular advantageously, on the basis of the crystalline
`
`R—(—)—4—benzyloxy—3—(3—diisopropylamino—1-phenyl-
`
`propyl)benzoic acid methyl ester,
`
`the highly pure,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0027
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0027
`
`

`
`
`
`_:L4_
`
`crystalline intermediate product R-(—)—3—(3—diisopropylamino—
`
`phenyl—propyl)-4-hydroxy—benzoic acid methyl ester is
`
`prepared, which is reduced to R—(+)-2-(3—diisopropylamino—1—
`
`phenylpropyl)—4—hydroxymethylphenol,
`
`is finally acylated in a
`
`suitable manner and is then converted with a physiologically
`
`compatible inorganic or organic acid under spontaneous
`
`crystallisation to the respective highly pure, crystalline,
`
`stable salt.
`
`Depending on the acid chloride used, compounds of general
`
`formula 1 are obtained,
`
`Formula 1
`
`in which R denotes C1—C5—alkyl,
`
`in particular isopropyl, C3-
`
`Cm—cycloalkyl or unsubstituted or substituted phenyl.
`
`In order to obtain the compounds in accordance with the
`
`invention in the form of their salts the special reaction
`
`process via particular intermediate stages and individually
`
`identifiable intermediate products is crucial.
`
`This is explained using reaction diagram 1
`
`(see Figure 1),
`
`in
`
`which the conversions with R—configured compounds are
`
`described, but without this being restrictive.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0028
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0028
`
`

`
`
`
`-15-
`
`In this:
`
`D.)
`
`4
`
`5
`
`5
`
`II
`
`R-(-)-4-benzyloxy-3-(3—diisopropylamino-1—phenyl-
`
`propy1)—benzoic acid— methyl ester
`
`= R-(+)-[4—benzy1oxy—3-(3—diisopropylamino—1—phenyl-
`
`propyl)-phenyl]-methanol
`
`= R—(—)-3-(3—diisopropylamino—phenyl—propy1)—4—hydroxy-
`
`benzoic acid methyl ester
`
`= R—(+)-2-(3—diisopropylamino—1—phenylpropyl)-4-
`
`hydroxymethylphenol
`
`1
`
`= R-(+)-2-(3-diisopropylamino—l—phenylpropyl)-4-
`
`hydroxymethylphenyl-isobutyrate ester
`
`2a = R-(+)-2-(3—diisopropylamino—1—phenylpropyl)—4—hydroxy—
`
`methylphenyl-isobutyrate ester hydrogen fumarate
`
`2b = R—(+)—2—(3—diisopropylamino—1—phenylpropyl)—4—hydro
`
`xymethylphenyl—isobutyrate ester hydrochloride
`
`hydrate
`
`In accordance with the reaction process explained in the
`
`embodiment
`
`the preliminary stage 3
`
`(R—(-)—4—benzyloxy—3—(3—
`
`diisopropylamino—1—phenyl—propyl)—benzoic acid—methylester)
`
`is prepared in crystalline, pure form.
`
`Using normal methods — such as BBr3, AlCl3 — but preferably
`
`by means of hydrogen gas via Raney nickel in methanol as the
`
`solvent at room temperature (RT), preliminary stage 3 is
`
`split into 5
`
`(R—(—)—3-(3-diisopropylamino—phenyl—propyl)-4-
`
`hydroxy—benzoic acid methylester. This develops in highly
`
`pure, crystalline form (melting point 143.7 °C).
`
`Finally, using a suitable reducing agent — such as NaBH4/EtOH
`
`— preferably LiAlH4 5 is reduced into an inert solvent at low
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2012 - 0029
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2012 - 0029
`
`

`
`
`
`-16-
`
`temperature (—78°C to + 10°C) and the compound 6
`
`(R—(+)—2—(3—
`
`diisopropylamino—1—phenylpropyl)—4—hydroxymethylphenol)is
`
`obtained. The compound 6 is obtained in a highly pure state
`
`and can be crystallised from a suitable solvent such as ethyl
`
`acetate. The colourless, compact grained material has a
`
`melting point of 102.3°C. This is surprising in that the
`
`compound 6
`
`in the state of the art is described as an
`
`amorphous solid.
`
`Compound 6 is now acylated with very good yield and regio-
`
`and chemoselectivity,
`
`into a phenolic ester. This reaction is
`
`performed at RT or low temperatures with an equivalent acid
`
`chloride in the presence of a base in a suitable solvent.
`
`Suitable solvents are ethyl acetate, dichloromethane,
`
`tetrahydrofurane, acetonitrile or toluene.
`
`The reaction is preferably performed with isobutyrylchloride
`
`as the acid chloride and triethylamine as the base at the
`
`abov