FILE HISTORY
`US 6,713,464
`
`6,713,464
`PATENT:
`INVENTORS: Meese, Claus
`Sparf, Bengt
`
`TITLE:
`
`Derivatives of 3,3-diphenylpropylamines
`
`APPLICATION
`NO:
`FILED:
`ISSUED:
`
`US2000700094A
`
`02 JAN 2001
`30 MAR 2004
`
`COMPILED:
`
`17 SEP 2013
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0001
`
`

`
`'Ii
`
`j. i~<'*
`
`*j ~ U.S.C.
`
`U.S. UTILITY PATENT APPLICATION
`-
`PATENT DATE
`0.1
`
`ScANN14AR43L0 200C
`
`APPLICATION NO.
`
`.1 *i~
`
`'
`
`!'I
`
`CONT/PRIOR CLASS
`71) 01.1 1
`
`S)
`
`SUBCLASS
`t El1-
`
`ART UNiT
`
`-
`
`EXAktIER
`
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`1.
`
`CT
`
`PTO-2040
`12dM
`
`LREARED
`
`AND APPROVED FOR ISSUE
`
`OR IGINAL
`SUBCLASS
`CLASS
`75
`6j
`IERNATIONAL CLASSIFICATION
`
`ISSUING CLASSIFICAT1ON
`CROSS REFERENCE(S)
`
`CLASS
`61Y___
`
`SUBCLASS (ONE SUBCLASS PER BLOCK)
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`NOTICE OF ALLOWANCE MAILED
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`Inomillion dsclosed herein may be resticted. Unauthorized dIsWlsure (nay be prohibited by the United States Code Title 36. Sections 122, 181 and 388.
`Possession outside the U.S. Patent A Trwbenwk Office Is restfted to authorized employees and contractors only.
`PT
`Form,
`
`.~ENFL
`
`(LABEL AREA)
`
`(FACE)
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0002
`
`

`
`6.,713.,464
`
`NOVEL DERIVATIVES OF 3.3-DIPHENYLPROPYLAMINES
`
`Transaction History
`
`Transaction Description
`Date
`11/8/2000 Receipt of 371 Request
`11/17/2000 371 Application Preexamnination Docketing
`11/17/2000 Correspondence Address Change
`12/4/2000 371 Application Preexamination Docketing
`12/5/2000 Notice of DO/EQ Missing Requirements Mailed
`1/2/2001 Preliminary Amendment
`1/2/2001 Affidavit(s) (Rule. 131 or 132) or Exhibit(s) Received
`1/2/2001 Applicant 371 Filing Paper Received
`1/2/2001 Applicant 37 1 Filing Paper Received
`1/2/2001 Initial Exam Team nn
`1/16/2001 Released to QIPE
`1/16/2001 Notice of DO/EQ Acceptance Mailed
`1/30/2001 IFW Scan & PACR Auto Security Review
`2/15/2001 Application Dispatched from OIPE
`5/2/2001 Case Docketed to Examiner in GAU
`6/27/2001 Change in Power of Attorney (May Include Associate POA)
`6/27/2001 Correspondence Address Change
`6/27/2001 Change in Power of Attorney (May Include Associate POA)
`8/15/2 001 Information Disclosure Statement (IDS) Filed
`8/15/2001 Information Disclosure Statement (IDS) Filed
`9/7/2001 Mail Restriction Requirement
`9/7/2001 Restriction/Election Requirement
`4/9/2002 Case Docketed to Examiner in GAU
`4/10/2002 Mail Abandonment for Failure to Respond to Office Action
`4/10/2002 Aband. for Failure to Respond to 0. A.
`5/31/2002 Petition Entered
`1/17/2003 Response to Election / Restriction Filed
`1/17/2003 Request for Extension of Time - Granted
`1/17/2003 Mail-Petition to Revive Application - Granted
`1/24/2003 Mail Notice of Rescinded Abandonment
`1/24/2003 Notice of Rescinded Abandonment in TCs
`2/6/2003 Mail Non-Final Rejection
`2/6/2003,Non-Final Rejection
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0003
`
`

`
`2/6/2003 Date Forwarded to Examiner
`2/6/2003 Correspondence Address Change
`4/14/2003 Response after Non-Final Action
`4/24/2003 Date Forwarded to Examiner
`4/28/2003 Workflow - Drawings Finished
`4/28/2003 Workflow - Drawings Matched with File at Contractor
`4/28/2003 Supplemental Response
`5/8/2003 Date Forwarded to Examiner
`5/15/2003 Notice of Allowance Data Verification Completed
`5/15/2003 Case Docketed to Examiner in GAU
`5/16/2003 Mail Notice of Allowance
`5/19/2003 Dispatch to Publication s
`5/22/2003 Workflow - File Sent to Contractor
`5/22/2003 Receipt into Pubs
`7/11/2003 Receipt into Pubs
`8/18/2003 Information Disclosure Statement (IDS) Filed
`8/18/2003 Information Disclosure Statement (IDS) Filed
`8/18/2003 Request for Continued Examination (RCE)
`8/18/2003 Workflow - Request for RCE - Finish
`8/18/2003 Workflow - Request for RCE - Begin
`10/28/2003 Date Forwarded to Examiner
`10/28/2003 Disposal for a RCE / CPA / R129
`11/3/2003 Formal Drawings Required
`11/3/2003 Notice of Allowance Data Verification Completed
`11/4/2003 Mail Notice of Allowance
`11/4/2003 Mail Formal Drawings Required
`12/10/2003 Receipt into Pubs
`1/28/2004 Issue Fee Payment Verified
`1/28/2004 Issue Fee Payment Received
`2/18/2004 Correspondence Address Change
`2/20/2004 Application Is Considered Ready for Issue
`2/25/2004 Receipt into Pubs
`3/11/2004 Issue Notification Mailed
`3/30/2004 Patent Issue Date Used in PTA Calculation
`4/6/2004 Record ation of Patent Grant Mailed
`4/20/2004 Correspondence Address Change
`2/28/2005 Post Issue Communication - Certificate of Correction
`3/7/2006 Correspon dence Address Change
`I 3/8/2006IChange in Power of Attorney (May Include Associate POA)
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0004
`
`

`
`4(OCC)
`
`09700094,
`
`CONTkNT§
`Date received
`(Incl. C. of.M.)
`or
`Date Mailed
`
`INITIALS
`
`Date received
`(Incl. C. of M.)
`or
`Date Mailed
`
`42.
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`43-
`44.-
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`48. -
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`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0005
`
`

`
`SEARCHED
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`SEARCH NOTES
`(INCLUDING SEARCH STRATEGY~
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`INTERFERENCE SEARCHED
`Class
`Sub.
`Date
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`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0006
`
`

`
`(12) United States Patent
`Meese et aW.
`
`(54) DERIVATIVES OF 3,3-
`DIPHENYLPROPYLA,MINES
`
`(75)
`
`Inventors: *Claus Meese, Monheim (DE); Bengt
`Sparf, Trangsund (SE).
`
`(73) Assignee: Schwarz Pharma AG, Monheim (DE)
`
`()Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`09/700,094
`May UI, 1999
`PCT/EP99/03212
`
`(21) Appl. No.:
`(22)
`PCT Filed:
`(86) PCT No.:
`§ 371 (c)(1),
`Jan. 2, 2001
`(2), (4) Date:
`(87) PCT Pub. No.: W099/58478
`PCT Pub. Date: Nov. 18, 1999
`Foreign Application Priority Data
`(30)
`May 12, 1998
`(EP) ................................
`98108608
`Int. Cl.7 . . . . . . . . . . ... A61K 31/215; A61K 31/22;
`(51)
`A61K 31/225; A01N 37/08; A01N 37/02
`(52) U.S. Cl ...............
`514/175; 514/529; 514/530;
`514/546; 514/547; 514/548; 549/269; 560/140;
`560/255; 564/316
`(58) Field of Search .........................
`560/110, 108,
`560/121, 123, 124, 138, 140, 142, 255;
`514/530, 531, 532, 533, 534, 544, 547,
`548, 551, 175, 529; 549/269; 564/316
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`11/2001 Johansson et al ........ 514/277
`6,313,132 BI
`FOREIGN PATENT DOCUMENTS
`7/1989
`*5/1994
`
`wo
`wo
`
`WO 89/06644
`WO 94/11337
`OTHER PUBLICATIONS
`Nilvebrant et al, "Antimuscarinic Potency and Bladder
`Selectivity of PNU-200577, a Major Metabolite of Toltero-
`dine" Pharmacology and Toxicology, vol. 81, pp. 169-172
`(1997).*
`
`11111111111111N11111
`
`
`1111111IIlii11111 11111 liii Ni11liii
`1111111111111111
`
`US006713464Bl
`US 6,713,464 BI
`Mar. 30,2004
`
`(10) Patent No.:
`(45) Date of Patent:
`
`Nilvebrant et al, "Tolterodine-A New Bladder Selective
`Muscarinic Receptor Antagonist: Preclinical Pharmacologi-
`cal and Clinical Data" Life Sciences, vol. 60(13/14), pp.
`1129-1136 (1997).*
`
`Postlind et al, "Tolterodine, A New Muscarinic Receptor
`Antagonist, is Metabolized by Cytochromes P450 and 3A in
`Human Liver Microsomes" Drug Metabolism and Disposi-
`tion, vol. 26(4), pp. 289-293 (1998).*
`
`Andersson et al, "Biotransformation of Tolterodine, A New
`Muscarinic Receptor Antagonist, in Mice, Rats, and Dogs"
`Drug Metabolism and Disposition, vol. 26(6), pp. 528-535
`(1998).*
`
`Brynne et al, "Pharmacokcinetics and pharmacodynamics of
`tolterodine in man: a new drug for the treatment of urinary
`bladder overactivity" J. Clin. Pharm. Ther. vol. 35(7), pp.
`287-295 (1997).*
`
`Nilvebrant et al., European Journal of Pharmacology,
`327(1997) pp. 195-207.
`
`*cited by examiner
`
`Primary Examiner-John M. Ford
`Assistant Examiner-Zachary C. Micker
`(74) Attorney Agent, or Firm-Edwards & Angell, LLP;
`Peter F. Corless; Christine C. O'Day
`
`(57)
`
`ABSTRACT
`
`The invention concerns novel derivatives of 3,3-
`diphenylpropylamnines, methods for their preparation, phar-
`maceutical compositions containing the novel compounds,
`and the use of the compounds for preparing drugs. More
`particularly, the invention relates to novel prodrugs of anti-
`muscarinic agents with superior pharmacokinetic properties
`compared
`to existing drugs such as oxybutynin and
`tolterodine, methods for their preparation, pharmaceutical
`compositions containing
`them, a method of using said
`compounds and compositions for the treatment of urinary
`incontinence, gastrointestinal hyperactivity (irritable bowel
`syndrome) and other smooth muscle contractile conditions.
`
`26.Claims, 1 Drawing Sheet
`
`FORMATION 0OF THE ACTIVE METABOLITE FROM DIF'FERENT PRODRUGS BY HUMAN LIVER SB9(%) IN III
`
`AcO-/-OAcf HO-1-01BUtt BUtO-/-OBUIf H04-OPropI
`H04-OBut
`PropO-I-OProp
`HCq-OAc
`lBuO-/-OlBut
`
`PRODRUGS
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0007
`
`

`
`U.S. Patent
`
`Mar. 30, 2004
`
`US 6,713,464 RI
`
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`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0008
`
`

`
`US 6,713,464 Bl
`
`side effects or interactions due to non-absorbed antimusca-
`rinic drug. In a method to circumvent this disadvantage,
`different prodrugs of the metabolite have been synthesized
`and tested for their antimuscarinic activity, potential absorp-
`tion through biological membranes and enzymatic cleavage.
`
`SUMMARY OF THE INVENTION
`
`It is an object of the present invention to provide novel
`derivatives of 3,3-diphenylpropylamines. It is a further
`object of the present invention to provide new derivatives of
`3,3 -dip henylpropylamnines which will be more useful as
`prodrugs for treatment of urinary incontinence and other
`that are caused by muscarinic
`spasmogenic conditions
`mechanisms while avoiding the disadvantage of a too low
`absorption through biological membranes of the drugs or an
`unfavourable metabolism.
`
`A further object of the invention
`is to provide novel
`prodrugs of antimuscarinic agents with superior pharmaco-
`kinetic properties compared to present drugs as oxybutynin
`and tolterodine, methods for preparing thereof, pharmaceu-
`tical compositions containing them, a method of using said
`compounds and compositions for the treatment of urinary
`incontinence, gastrointestinal hyperactivity (irritable bowel
`syndrome) and other smooth muscle contractile conditions.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the formation of the active metabolite from
`different prodrugs by human liver S 9(%) in 1 hour.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`the present invention, novel 3,3-
`According
`to
`diphenylpropyl amines are provided, which are represented
`by the general formulae I and VII'
`
`O-R'
`
`Formula I
`
`DERIVATIVES OF 39,3-
`DIPHENYLPROPYLAMINES
`
`5
`
`10
`
`BACKGROUND OF THE INVENTION
`The present invention relates to novel derivatives of
`3,3-diphenylpropylamines, methods for their preparation,
`pharmaceutical compositions containing
`the novel
`compounds, and the use of the compounds for preparing
`drugs.
`In man, normal urinary bladder contractions are mediated
`mainly through cholinergic muscarinic receptor stimulation.
`There is reason to believe that muscarinic receptors mediate
`not only normal bladder contractions, but also the main part i
`of the contractions in the overactive bladder resulting in
`symptoms such as urinary frequency, Urgency and urge
`incontinence. For this reason, antimuscarinic drugs have
`been proposed for the treatment of bladder overactivity.
`Among the antimuscarinic drugs available on the market, 2
`oxybutynin is currently regarded as the gold standard for 2
`pharmacological treatment of urge incontinence and other
`symptoms related to bladder overactivity. The effectiveness
`of oxybutynin has been demonstrated in several clinical
`studies, but the clinical usefulness of oxybutynin is limited 2
`due to antimuscarinic side effects. Dryness of the mouth is 2
`the most common experienced side effect which may be
`severe enough to result in poor compliance or discontinua-
`tion of Treatment (Andersson, K.-E., 1988, Current concepts
`in the treatment of disorders of micturition, Drugs 35, 30
`477-494; Kelleher et al. 1994).
`Tolterodine is a new, potent and competitive, muscarinic
`receptor antagonist intended for the treatment of urinary
`urge
`incontinence and detrusor hyperactivity. Preclinical
`pharmacological data show that tolterodine exhibits a 3
`favourable tissue selectivity in vivo for the urinary bladder
`over the effect on the salivation (Nilvebrant et al., 1997,
`Tolterodine-a new bladder-selective antimuscarinic agent,
`Eur. J. Pharmacol. 327 (1997), 195-207), whereas oxybu-
`tynin exhibits the reversed selectivity. Tolterodine is equi- 40
`potent to oxybutynin at urinary bladder muscarinic receptors
`and the favourable tissue selectivity of tolterodine demon-
`strated
`in
`the preclinical studies has been confirmed in
`clinical studies. Thus a good clinical efficacy has been
`combined with a very low number of incidences of dry 45
`mouth and antimuscarinic side effects.
`A major metabolite of tolterodine, the 5-hydroxymethyl
`derivative is also a potent muscarinic receptor antagonist
`and the pharmacological in vitro and in vivo profiles of this
`metabolite are almost identical
`to those of tolterodine 50
`(Nilvebrant et al., 1997, Eur. J. Pharmacol. 327 (1997),
`195-207). Combined pharmacological and.pharmacokinetic
`data indicate that it is most likely that the metabolite gives
`a major contribution to the clinical effect in most patients.
`WO 94/11337 proposes the active metabolite of toltero- 55
`dine as a new drug for urge incontinence. Administration of
`the active metabolite directly to patients has the advantage
`compared
`to tolterodine
`that only one active principle
`(compound) has to be handled by the patient which normally
`should result in a lower variation in efficacy and side effects 60
`between patients and lower risk of interaction with other
`drugs.
`However, the introduction of an additional hydroxy group
`in the tolterodine results in an increased hydrophilic prop-
`erty of the new compounds (3,3-diphenylpropylamineS) 65
`compared to the parent compounds which normally results
`in a lower absorption/bioavailability, leading to pre-systemic
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0009
`
`

`
`US 6,713,464 Bl
`
`-continued
`
`Formula V11'
`
`X represents a tertiary amino group of formula Ia
`
`Formula la
`
`-N
`
`/ R
`
`\R9
`
`wherein R 8 and R9 represent non-aromatic hydrocaryl
`groups, which may be the same or different and which
`together contain at least three carbon atoms, and
`wherein R' and R' may form a ring together with the
`amine nitrogen,
`Y and Z independently represent a single bond between
`the (CH.),,, group and the carbonyl group, 0, S or NH,
`A represents hydrogen ('H) or deuterium ('H),
`n is 0 to 12 and
`their salts with physiologically acceptable acids, their free
`bases and, when the compounds can be in the form of optical
`isomers, the racemic mixture and the individual enanti-
`omners.
`The aforementioned compounds can form salts with
`physiologically acceptable organic and inorganic acids.
`Furthermore, the aforementioned compounds comprise the
`free bases as well as the salts thereof. Examples of such acid
`addition salts include the hydrochloride, hydrobromide and
`the like.
`When the novel compounds are in the form of optical
`isomers, the invention comprises the racemic mixture as
`well as the individual isomers as such.
`Preferably each of R8 and R9 independently signifies a
`saturated hydrocarbyl group, especially saturated aliphatic
`hydrocarbyl groups such as C,-alkyl, especially Cl,-alkyl,
`or adamantyl, R8 and R9 together comprising at least- three,
`preferably at least four carbon atoms.
`According to another embodiment of the invention, at
`least one of R'
`comprie
`rnhed carbon chain.
`d1
`Presently preferred tertiary amino groups X in formula 1
`include the following groups a) to h):
`
`-N
`
`-N
`
`CH(CH3)2
`
`CH(CH3)2
`
`/CH3
`
`C(CH3)3
`
`/CH
`
`-N
`
`C(CH3)2qH2CH3
`
`H3C
`
`CH3
`
`-N
`
`H3C
`
`CH
`
`wherein R and R' are independently selected from
`a) hydrogen, C.1_C 6 alkyl, C37C10 cycloalkyl, substi-
`tuted or unsubstituted benzyl, allyl or carbohydrate; 30
`or
`b) formyl, C,-C 6 alkylcarbonyl, cycloalkylcarbonyl,
`substituted or unsubstituted arylcarbonyl, preferably
`benzoyl; or
`c) C,-C. alkoxycarbonyl, substituted or unsubstituted 3
`aryloxycarbonyl, benzoylacyl, benzoylglycyl, a sub-
`stituted or unsubstituted amino acid residue; or
`
`d)
`
`N-CO-
`
`R5
`
`and R-5 independently represent
`wherein R'
`hydrogen, C,-C 6 alkyl, substituted or unsubstituted
`aryl, preferably substituted or unsubstituted phenyl,
`benzyl or phenoxyalkyl wherein the alkyl iresidue has
`1 to 4 carbon atoms and wherein R' and R' may form
`a ring together with the amine nitrogen; or
`
`45
`
`N S2-
`
`7
`R
`
`wherein R 6 and R 7 independently represent C,-C.,
`alkyl, substituted or unstubstituted aryl, preferably
`substituted or unsubstituted phenyl, benzyl or phe- 60
`noxyalkyl wherein the alkyl residue has 1 to 6 carbon
`atoms; or
`fan ester moiety of inorganic acids,
`g) -- SiR,,R,R,, wherein R, Rb, R,, are independently
`selected from C.1 -C 4 alkyl or aryl, preferably phenYl, 6S
`with the proviso that R' is not hydrogen, methyl or benzyl
`if R is hydrogen,
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0010
`
`

`
`US 6,713,464 Bl
`
`-continued
`
`H3C
`
`CH3
`
`-N
`
`H3C :
`
`CH3
`
`-NC
`
`-N
`
`5
`
`10
`
`20
`
`25
`
`g)
`
`h)
`
`and nitro. As substituted benzoyl groups 4-methylbe'nzoyl,
`2-methylbenzoyl, 4-methoxybenzoyl, 2-methoxybenzoyl,
`4-chlorobenzoyl, 2-chlorobenzoyl, 4-nitrobenzoyl and
`2-nitrobenzoyl may be mentioned.
`
`to a group
`The term "CI-C 6 alkoxycarbonyl" refers
`ROC(=O)- wherein R is an alkyl group as defined here-
`inbefore. Preferred C,-C 6 alkoxycarbonyl groups are
`C2H5-OC(=O)-,
`selected from CH30C(=O)-,
`CAHOC(=O)- and (CH3)3COC(=O)-
`and alicyclic
`alkyloxycarbonyl.
`
`The term "amino acid residue" denotes the residue of a
`naturally occurring or synthetic amino acid. Particularly
`preferred amino acid residues are selected from the group
`consisting of glycyl, valyl, leucyl, isoleucyl, phenylalanyl,
`prolyl, seryl, threonyl, methionyl, hydroxyprolyl.
`
`The amino acid residue may be substituted by a suitable
`group and as substituted amino acid residues, benzoylglycyl
`and N-acetylglycyl may be mentioned.
`
`The term "carbohydrate" denotes the residue of a poly-
`hydroxy aldehyde or polyhydroxy ketone of the formula
`C.H 2,,O,,,, or C.(H20),, and corresponding carbohydrate
`groups are, for example, described
`in Aspinal, The
`Polysaccharides, New York: Academic Press 1982, 1983. A
`preferred carbohydrate group in the compounds according to
`the present invention is a glucuronosyl group,- in particular
`a l[p-D-glucuronosyl group.
`
`The term "LG" as used herein, denotes a leaving group
`selected from halogenides, carboxylates, imidazolides and
`the like.
`
`The term "Bn" as used herein denotes a benzyl group.
`
`Suitable ester moieties of inorganic acids may be derived
`from inorganic acids such as sulfuric acid and phosphoric
`acid.
`
`Preferred compounds according to the present invention
`are:
`
`A) Phenolic monoesters represented by the genera formulae
`II and IF'
`
`Formula IH
`
`R0 0
`
`HON
`
`A
`
`A
`
`40
`
`Group a) is particularly preferred.
`The aforementioned
`tertiary amino groups X are 3
`described in WO 94/11337 and the compounds according to 3
`the present invention can be obtained by using the corre-
`sponding starting compounds.
`In the compounds according to the present invention, the
`term "alkyl" preferably represents a straight-chain or
`branched-chain hydrocarbon group having 1 to 6 carbon 35
`atoms. Such hydrocarbon groups may be selected from
`methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and
`hexyl. The term "cycloalkyl" denotes a cyclic hydrocarbon
`group having 3 to 10 carbon atoms which may be substituted
`conveniently.
`The term "substituted or unsubstituted benzyl" denotes a
`benyl group -CH 2-C 6H. which is optionally substituted
`by one or more substituents on the phenyl ring. Suitable
`substituents are selected from alkyl, alkoxy, halogen, nitro
`and the like. Suitable halogen atoms are fluorine, chlorine 45
`and iodine atoms. Preferred substituted benzyl groups are
`4-methylbenzyl, 2-methylbenzyl, 4-methoxybenzyl,
`2-methoxybenzyl, 4-nitrobenzyl, 2-nitrobenzyl,
`4-chlorobenzyl and 2-chlorobenzyl.
`In the compounds according to the present invention the 50
`term "C,-C,, alkylcarbonyl" denotes a group R-C(=O)-
`wherein R is an alkyl group as defined hereinbefore. Pre-
`ferred C.1 _C6 alkylcarbonyl groups are selected from acetyl,
`propionyl, isobutyryl, butyryl, valeroyl and pivaloyl. The
`term "cycloalkylcarbonyl" denotes a group R-C(==O)-
`wherein R is a cyclic hydrocarbon group as defined herein-
`before. The same counts to the selected carbonyl groups.
`The term "aryl" denotes an aromatic hydrocarbon group
`such as phenyl-(C 6HS--), naphthyl-(ClOH 7 -), anthryl-
`(C,,H-), etc. Preferred aryl groups according
`to the 60
`present invention are phenyl and naphthyl with phenyl being
`particularly preferred.
`The term "benzoyl" denotes an acyl group of the formula
`-CO-C 6H. wherein the phenyl ring may have one or
`more substituents.
`Preferred substituents of the-aryl group and in particular
`of the phenyl group are selected from alkyl, alkoxy, halogen
`
`55
`
`65
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0011
`
`

`
`US 6,713,464 B1.i
`
`-continued
`
`Formula 11'
`
`01'11
`
`N
`
`10
`
`15
`
`20
`
`8
`(±)-4-methoxybenzoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-2-methoxybenzoic acid 2-(3-diisopropylamino-lr
`5 phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-4-nitrobenzoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyl ester,
`(±)-2-nitrobenzoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-malonic acid bis-[2-(3-diisopropylamino-1-
`phenylpropyl)-4-hydroxymethyl-phenyl]ester,
`(±)-succinic acid bis-[2-(3-diisopropylamino-l-
`pbenylpropyl)-4-hydroxymethyl-phenyl]ester,
`(±)-pentanedioic acid bis-[2-(3-diisopropylamino-1-
`*phenylpropyl)-4-hydroxymethyl-phenyl]ester,
`(±)-hexanedioic acid bis-[2-(3-diisopropyl amino-1 -
`phenylpropyl)-4-hydroxymethyl-phenyl]ester.
`B) Identical diesters represented by the general formula
`
`Formula III
`
`wherein R' represents hydrogen, CI-C 6 alkyl or phenyl.
`Particularly preferred phenolic monoesters are listed
`below:
`(±)-formic acid 2-(3-diisopropyl amino- 1-phenylpropyl) -
`4-hydroxymethylphenyl ester,
`(±)-acetic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-
`hydroxymethylphenyl ester,
`(±)-propionic acid 2-(3 -diisopropyl amino-1I-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-n-butyric acid 2-(3-diisopropylamiino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-isobutyric acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`R-(+)-isobutyric acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-2,2-dimethylpropionic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)- 2-ace tamido acetic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-cyclopentanecarboxylic acid 2-(3-diisopropylamino-
`1-phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-cyclohexanecarboxylic acid 2-(3-diisopropylamino-
`1-phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-benzoic acid 2-(3-d iisopropyl amino- 1-phenylpropyl) -
`4-hydroxymethylphenyl ester,
`R-(+)-benzoic acid 2-(3-diisopropylamino-l.-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-4-methylbenzoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-2-methylbenzoic acid- 2-(3 -diisopropyl amino -1-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-2-acetoxybenzoic acid 2-(3-diisopropylamin,o-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-l-naphthoic acid 2-(3-diisopropylamino-1-
`phenylpropyl)-4-hydroxymethylphenyl ester,
`(±)-2-naphthoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(t)-4-chlorobenzoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`
`Rl
`
`011
`
`0A
`
`wherein R' is as defined above.
`Particularly preferred identical diesters are listed below:
`(±)-formic acid 2-(3-diisopropylamino-l-phenylpropyl)-
`4-formyloxymethylphenyl ester,
`(±)-acetic acid 4-acetoxy-3-(3-diisopropylamnino-l-
`phenylpropyl)-benzyl ester,
`(±)-propionic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-propionyloxymethylphenyI ester,
`(±)-n-butyric acid 4-n-butyryloxymethyl-2-(3-
`diisopropylamino-l-phenylpropyl)-phenyI ester,
`(±)-isobutyric acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-isobutyryloxymethylphenyI ester,
`(±)-2,2-dimethylpropionic acid 3-(3-diisopropylamino-1-
`phenylpropyl)-4-(2,2-dimethyl-propionyloxy)-benzyI
`ester,
`(±)-benzoic acid 4-benzoyloxymethyl-2-(3-
`diisopropylamino-l-phenylpropyl)-phenyI ester,
`R-(+)-benzoic acid 4-benzoyloxymethyl-2-(3-
`diisopropylamino-l-phenylpropyl)-phenyI ester,
`(-t)-pent-4-enoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-(pe nt-4-enoy lox ymethyl)-phenyl
`ester,
`cyclic oct-4-ene-1,8-dioate of Intermediate B.
`cyclic octane- 1,8 -dioate of Intermediate B,
`poly-co-DL-lactides of Intermediate B.
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0012
`
`

`
`9
`C)Mixed diesters represented by the general formula IV
`
`Formula IV
`
`R~
`
`R' Y0
`
`XCN
`
`r) AA
`
`20
`
`wherein R' is as defined above and
`R represents hydrogen, CI-C 6 alkyl or phenyl
`with the proviso that R' and R' are not identical.
`Particularly preferred mixed diesters are listed below:
`(±)-acetic acid 2-(3-diisopropylamino-l-phenylpropyl)-4-
`formyloxymethylphenyl ester,
`(±)-benzoic acid 2-(3-diisopropyl amino- 1-phenylpropyl) -
`4-formyloxymethylphenyl, ester,
`(±)-benzoic acid 2-(3-diisopropyl amino- 1-phenylpropyl) - 25
`4-acetoxymethylphenyl ester,
`R-(+)-benzoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-acetoxymethylphenyI ester,
`(±)-isobutyric acid 4-acetoxymethyl-2-(3- 3
`diisopropylamino-l-phenylpropyl)-phenyI ester,
`R-(+)-isobutyric acid 4- ace toxymnethyl -2-(3 -
`diisopropylamino-l-phenylpropyl)-phenyI ester,
`(±)-2,2-dimethylpropionic acid 4-acetoxy-3-(3-
`diisopropylamino-l-phenylpropyl)-benzyI e ster,
`(±)-2,2-dimethylpropionic acid 4-acetoxymethyl-2-(3-
`diisopropylamino-l-phenylpropyl)-phenyI ester,
`(±)-benzoic acid 4-benzyloxy-3-(3-diisopropylamino-l-
`phenylpropyl)-benzyl ester.
`D) Benzylic monoesters represented by the general formula 40
`V
`
`3
`
`Formula V
`
`N. OH
`
`R'Y
`
`0
`
`N
`
`4
`
`50
`
`5
`
`wherein R' is as defined above.
`Particularly preferred benzylic monoesters, are listed
`below:
`(±)-formic acid 3-(3 -d iisopropyl amino- 1-phenylpropyl) -
`4-hydroxybenzyl ester,
`(±)-acetic acid 3-(3-diisopropylamino-l-phenylpropyl)-4- 60
`hydroxybenzyl ester,
`(t)-propionic acid 3-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxybenzyl ester,
`(±)-butyric acid 3-(3-diisopropylamino-l-phenylpropyl)-
`4-hydroxybenzyl ester,
`(±)-isobutyric acid 3-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxybenzyl ester,
`
`65
`
`US 6,713,464 Bl
`
`10
`(±)-2,2-dimethylpropionic acid 3-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxybenzyl ester,
`(±)-benzoic acid 3-(3-diisopropylamino-l-phenylpropyl)-
`4-hydroxybenzyl ester.
`5E) Ethers and silyl ethers represented by the general formula
`vi
`
`Formula VI
`
`N
`
`wherein at least one of R"0 and R" is selected from C.1-C,5
`alkyl, benzyl or --SiR,RbR,, as defined above and the
`other one of R"0 and R" may additionally represent
`hydrogen, Cl-C,, alkylcarbonyl or benzoyl.
`Particularly preferred ethers and silyl ethers are listed
`below:
`(t) -2 -(3 -d i isop ro p ylami no -1 -p hen ylp rop yl) -4 -
`methoxymethylphenol,
`(t) -2 -(3 -d iisop ro p ylIami no- 1 -ph e nyl prop yl) -4 -
`ethoxymethylphenol,
`(t) -2 -(3 -d iisop rop ylIami no -1 -p h enyl prop yl) -4 -
`propoxymethylphenol,.
`()2 -(3-d i iso pro pylIa mi n o- 1 -ph e nylp rop y1) -4 -
`isopropoxymethylphenol,
`(±) -2 -(3 -d i isop ro pylIa mi n o- 1 -ph e n yIp rop y1) -4 -
`butoxymethylphenol,
`(±)-acetic acid 2-(3-diisopropylamino-l-phenylpropyl)-4-
`.methoxymethylphenyl ester,
`(±)-acetic acid 2-(3-diisopropylamino-l-phenylpropyl)-4-
`ethoxymethylphenyl ester,
`(±)-2-(3-diisopropylamino- 1 -phenylpropyl)-4-
`trimethylsilanyloxymethylphenol,
`(±)-diisopropyl-[3-phenyl-3-(2-trimethylsilanyloxy-5-
`trimnetbylsilanyloxymethylphenyl)-propyl]-amine,
`(±)-[3-(3-diisopropylamino-1 -phenylpropyl)-4-
`trimethylsilanyloxyphenyl]-methanol,
`(±) -diisopropyl-[3-(5 -m etho xyme thyl-2-
`trimehylsilanyloxyphenyl)-3-phenylpropylamine,
`.(±) -di iso prop yl1-[3 -(5 -e tho xy me.t h y-2-
`trimethylsilanyloxyphenyl)-3-phenylpropylamine,
`(±)-[4-(tert.-butyl-dimethylsilanyloxy)-3-(3-
`diisopropylamino -1 -phenylpropyl)-phenyl]- methanol,
`(±)-acetic acid 4-(tert.-butyl-dimethylsilanyloxy)-3-(3-
`diisopropylamino-1-phenylpropyl)-benzyl ester,
`(±)-4-(tert. -butyl-dimethylsilanyloxy)-3-(3-
`diisopropylamino-1-phenylpropyl)-phenol,
`(±)-acetic acid 4-(tert.-butyl-dimethylsilanyloxy)-2-(3-
`diisopropylamino-1-phenylpropyl)-phenyl ester,
`(±)-{3-[2-(tert.-butyl-dimethylsilanyloxy)-5-(tert.-butyl-
`dimethylsilanyloxymethyl)-phenyl]-3-phenylpropyl}-
`diisopropylamine,
`(±)-[4-(tert.-butyl-diphenylsilanyloxy)-3-(3-
`diisopropylamino- 1-phenylpropyl)-p henyl]- methanol,
`(±)-acetic acid 4-(tert. -butyl-diphenylsilanyloxym ethyl)-
`2-(3-diisopropylamino-l-phenylpropyl)-phenyI ester,
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0013
`
`

`
`US 6,713,464 Bl
`
`(±-4-(tert. -but yl-dip hen ylsilIan yloxymethyl)-2-(3 -
`diisopropylamino-l-phenylpropyl)-phenol,
`(±)-{13-[2-(tert.-butyl-diphenylsilanylox*y)-5-(tert.-butyl-
`diphenylsilanyloxymethyl)-phenyl]-2-phenylpropyl} -
`1
`diisopropylamine,
`(±)-acetic acid 4-benzyloxy-3-(3-diisopropylamino-l-
`phenylpropyl)-benzyl ester,
`(±)-benzoic acid 4-benzyloxy-3-(3-d4isopropylamino-l-
`phenylpropyl)-benzyl ester,
`(t)-isobutyric acid 4-benzyloxy-3-(3-diisopropylamino-
`I-phenylpropyl)-benzyl ester,
`(±)-2-(3-diisopropylamino-1-phenylpropyl)-4-(1 1-D-
`glucuronosyloxymethyl)-phenol.
`F) Carbonates and carbamnates represented by the general 15
`formulae VII and VIII
`
`1
`
`Formula VII
`
`Formula VIII
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`k(CH2)r
`
`0 yz
`
`Particularly preferred carbonates and carbarnates are
`listed below:
`(±)-N-ethylcarbamic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(t)-N,N-dimethylcarbamic acid 2-(3-diisopropylamino-
`1-phenylpropyl)-4-hydroxymethylphenyI ester,,
`(±)-N,N-diethylcarbamic acid 2-(3-diisopropylarnino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(±)-N-phenylcarbamic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester,
`(:t)-[2-(3-diisopropylamino-1 -phenylpropyl)-4-
`hydroxyme thyl-phe noxyc arbonylarnino ]acetic acid
`ethyl ester hydrochloride,
`(t)-N-ethylcarbamic acid 3-(3-diisopropylamino-l-
`phenylpropyl)-4-N-ethylcarbamoyloxybenzyI ester,
`(±)-N,N-dimethylcarbamic acid 3-(3-diisopropylamino-
`1-phenylpropyl)-4-N,N-dimethylcarbamoyloxybenzyl
`ester,
`(t)-N,N-diethylcarbamic acid 3-(3-diisopropylamino-1-
`phenylpropyl)-4-N,N-diethylcarbamoyloxybenzyl
`ester,
`(±)-N-phenylcarbamic acid 3-(3-diisopropylamino-1-
`phenylpropyl)-4-N-phenylcarbamoyloxybenzyl ester,
`(±)-f{4-[2-(3-diisopropylamino-l1-phenylpropyl)-4-
`hydroxymethylphenoxycarbonylamino]-butyl}-
`carbamic acid 2-(3-diisopropylamino-l-phenylpropyl)-
`4-hydroxymethylphenyl ester,
`(±)-carbonic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester ethyl
`ester,
`(±)-carbonic acid 27.(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyI ester phenyl
`ester,
`(±)-carbonic acid 2-(3-diisopropylamino-1-
`phenylpropyl)-4-ethoxycarbonyloxymethylphenyl
`ester ethyl ester,
`(±)-carbonic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-phenoxycarbonyloxymethylphenyI
`ester phenyl ester.
`G) 3,3-Diphenylpropylamines selected from
`(i) compounds of the formulae IX and IX'
`
`Formula IX
`
`wherein Y, Z and n are as defined above and wherein R 1
`and R"3 represent a C,-C 6 alkoxycarbonyl group or
`
`2
`
`N-CO-
`
`R'
`
`wherein R 4 and R5 are as defined above.
`
`N
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2010 - 0014
`
`

`
`13
`-continued
`
`US 6,713,464 B1
`
`Formula IX'
`
`HO
`
`Y--
`
`N
`
`N
`
`with an equivalent of an acylating agent selected from
`
`wherein o and p are the same or different and represent
`the number of methylene units -(CH2-)-and may
`range from 0 to 6,
`(ii) (±)-Benzoic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-sulphooxymethyl