`Meese et al.
`
`(10) Patent No.:
`
`(45) Date of Patent:
`
`US 7,384,980 B2
`Jun. 10, 2008
`
`US007384980B2
`
`(54) DERIVATIVES OF
`3,3-DIPHENYLPROPYLAMINES
`
`(75)
`
`Inventors: Claus Meese, Monheim (DE); Bengt
`Sparf, Trangsund (CH)
`
`(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 156 days.
`
`(21) Appl.No.: 11/201,756
`
`(22)
`
`Filed:
`
`Aug. 10, 2005
`
`(65)
`
`Prior Publication Data
`
`US 2006/0270738 A1
`
`Nov. 30, 2006
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 10/766,263, filed on
`Jan. 27, 2004, now Pat. No. 7,230,030, which is a
`continuation of application No. 09/700,094, filed as
`application No. PCT/EP99/03212 on May 11, 1999,
`now Pat. No. 6,713,464.
`
`(30)
`
`Foreign Application Priority Data
`
`May 12, 1998
`
`(EP)
`
`................................ .. 98108608
`
`(51)
`
`Int. Cl.
`(2006.01)
`A01N 37/12
`(2006.01)
`A01N 37/44
`(2006.01)
`A61K 31/22
`(2006.01)
`C07D 69/00
`(52) U.S. Cl. ...................................... .. 514/551; 560/140
`(58) Field of Classification Search ............... .. 514/551;
`560/ 140
`
`See application file for complete search history.
`
`(56)
`
`References Cited
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`DE
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`DE
`EP
`EP
`EP
`EP
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`EP
`EP
`GB
`GB
`GB
`GB
`GB
`GB
`
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`(Continued)
`OTHER PUBLICATIONS
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`
`(Continued)
`
`Primary Examiner—Zachary C Tucker
`(74) Attorney, Agent, or Firm—Kenyon & Kenyon LLP
`
`(57)
`
`ABSTRACT
`
`The invention concerns novel derivatives of 3,3-diphenylpro-
`pylamines, methods for their preparation, pharmaceutical
`compositions containing the novel compounds, and the use of
`the compounds for preparing drugs. More particularly, the
`invention relates to novel prodrugs of antimuscarinic agents
`with superior pharmacokinetic properties compared to exist-
`ing 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.
`
`16 Claims, 1 Drawing Sheet
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0001
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0001
`
`
`
`US 7,384,980 B2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`
`1025041
`GB
`1 169 944
`GB
`1 169 945
`GB
`W0 89/06644
`W0
`W0 93/23025
`W0
`W0 94/11337
`W0
`W0 96/12477
`W0
`W0 98/03067
`W0
`W0 98/43942
`W0
`W0 98/56359
`W0
`W0 99/58478
`W0
`W0 00/12069
`W0
`W0 00/27364
`W0
`W0 01/34139
`W0
`W0 02/11702
`W0
`W0 02/089773
`W0
`W0 03/002059
`W0
`W0 03/007918
`W0
`W0 03/020241
`W0
`W0 03/021271
`W0
`W0 03/026564
`W0
`W0 03/035599
`W0
`W0 03/039464
`W0
`W0 03/063834
`W0
`W0 03/099268
`W0
`W0 03/103637
`W0
`W0 03/106421
`W0
`W0 W0 2004/019892
`
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`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0002
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0002
`
`
`
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`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0003
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0003
`
`
`
`U S. Patent
`
`Jun. 10,2008
`
`US 7,384,980 B2
`
`F4(3.1
`
`
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0004
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0004
`
`
`
`1
`DERIVATIVES OF
`3,3-DIPHENYLPROPYLAMINES
`
`US 7,384,980 B2
`
`2
`
`lower absorption/bioavailability, leading to pre-systemic side
`effects or interactions due to non-absorbed antimuscarinic
`drug. In a method to circumvent this disadvantage, different
`prodrugs of the metabolite have been synthesized and tested
`for their antimuscarinic activity, potential absorption through
`biological membranes and enzymatic cleavage.
`
`BRIEF 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-
`diphenylpropylarnines which will be more useful as prodrugs
`for treatment of urinary incontinence and other spasmogenic
`conditions that are caused by muscarinic 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 pro-
`drugs of antimuscarinic agents with superior pharmacoki-
`netic properties compared to present drugs as oxybutynin and
`tolterodine, methods for preparing thereof, pharmaceutical
`compositions containing them, a method of using said com-
`pounds and compositions for the treatment of urinary incon-
`tinence, gastrointestinal hyperactivity (irritable bowel syn-
`drome) and other smooth muscle contractile conditions.
`According to the present invention, novel 3 ,3 -diphenylpro-
`pylamines are provided, which are represented by the general
`formulae I and VII‘
`
`O — R’
`
`Formula I
`
`X
`
`R — O
`
`A
`
`A
`
`0
`
`0A
`
`A
`
`HO
`
`X
`
`Formula VII’
`
`This application is a continuation of U.S. patent applica-
`tion Ser. No. 10/766,263, filed Jan. 27, 2004, now U.S. Pat.
`No. 7,230,030, which is a continuation of U.S. patent appli-
`cation Ser. No. 09/700,094, filed Jan. 2, 2001, now U.S. Pat.
`No. 6,713,464, which is a 371 ofPCT/EP99/03212, filed May
`1 1, 1999.
`The present invention relates to novel derivatives of 3,3-
`diphenylpropylarnines, methods for their preparation, phar-
`maceutical compositions containing the novel compounds,
`and the use of the compounds for preparing drugs.
`
`BACKGROUND OF THE INVENTION
`
`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 of
`the contractions in the overactive bladder resulting in symp-
`toms such as urinary frequency, urgency and urge inconti-
`nence. For this reason, antimuscarinic drugs have been pro-
`posed for the treatment of bladder overactivity.
`Among the antimuscarinic drugs available on the market,
`oxybutynin is currently regarded as the gold standard for
`pharmacological treatment of urge incontinence and other
`symptoms related to bladder overactivity. The effectiveness
`of oxybutynin has been demonstrated in several clinical stud-
`ies, but the clinical usefulness of oxybutynin is limited due to
`antimuscarinic side effects. Dryness of the mouth is the most
`common experienced side effect which may be severe enough
`to result in poor compliance or discontinuation of Treatment
`(Anders son, K.-E., 1988, Current concepts in the treatment of
`disorders of micturition, Drugs 35, 477-494; Kelleher et al.
`1 994).
`Tolterodine is a new, potent and competitive, muscarinic
`receptor antagonist intended for the treatment ofurinary urge
`incontinence and detrusor hyperactivity. Preclinical pharma-
`cological data show that tolterodine exhibits a 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 oxybutynin exhibits the
`reversed selectivity. Tolterodine is equipotent to oxybutynin
`at urinary bladder muscarinic receptors and the favourable
`tissue selectivity of tolterodine demonstrated in the preclini-
`cal studies has been confirmed in clinical studies. Thus a good
`clinical efficacy has been combined with a very low number
`of incidences of dry 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 (Nil-
`vebrant et al., 1997, Eur. J. Pharmacol. 327 (1997), 195-207).
`Combined pharmacological and pharmacokinetic data indi-
`cate that it is most likely that the metabolite gives a major
`contribution to the clinical effect in most patients.
`WO 94/1 1337 proposes the active metabolite oftolterodine
`as a new drug for urge incontinence. Administration of the
`active metabolite directly to patients has the advantage com-
`pared to tolterodine that only one active principle (com-
`pound) has to be handled by the patient which normally
`should result in a lower variation in efiicacy and side effects
`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 property
`of the new compounds (3,3-diphenylpropylamines) com-
`pared to the parent compounds which normally results in a
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`/K
`
`T
`(CH2)n
`1
`
`o
`
`YO
`
`O
`
`X
`
`60
`
`HO
`
`A
`
`A
`
`65
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0005
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0005
`
`
`
`US 7,384,980 B2
`
`3
`wherein R and R‘ are independently selected from
`a) hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl, substituted or
`unsubstituted benzyl, allyl or carbohydrate; or
`b) formyl, C1-C6 alkylcarbonyl, cycloalkylcarbonyl, substi-
`tuted or unsubstituted arylcarbonyl, preferably benzoyl; or
`c) C1-C6 alkoxycarbonyl, substituted or unsubstituted ary-
`loxycarbonyl, benzoylacyl, benzoylglycyl, a substituted or
`unsubstituted amino acid residue; or
`
`d)
`
`wherein R4 and R5 independently represent hydrogen, C1-C6
`alkyl, substituted or unsubstituted aryl, preferably substituted
`or unsubstituted phenyl, benzyl or phenoxyalkyl wherein the
`alkyl residue has 1 to 4 carbon atoms and wherein R4 and R5
`may form a ring together with the amine nitrogen; or
`6)
`
`Ra
`>—N—so3—
`R7
`
`wherein R6 and R7 independently represent C1-C6 alkyl, sub-
`stituted or unstubstituted aryl, preferably substituted or
`unsubstituted phenyl, benzyl or phenoxyalkyl wherein the
`alkyl residue has 1 to 6 carbon atoms; or
`f) an ester moiety of inorganic acids,
`g) —SiRaRbR6, wherein Ra, R1,, R6 are independently
`selected from C1-C4 alkyl or aryl, preferably phenyl,
`with the proviso that R‘ is not hydrogen, methyl or benzyl if R
`is hydrogen,
`X represents a tertiary amino group of formula la
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`
`45
`
`wherein R8 and R9 represent non-aromatic hydrocarbyl
`groups, which may be the same or different and which
`together contain at least three carbon atoms, and wherein R8
`and R9 may form a ring together with the amine nitrogen,
`Y and Z independently represent a single bond between the
`(CH2)n group and the carbonyl group, O, S or NH,
`A represents hydrogen (IH) or deuterium (2H),
`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
`enantiomers.
`
`The aforementioned compounds can form salts with physi-
`ologically acceptable organic and inorganic acids. Further-
`more,
`the aforementioned compounds comprise the free
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`4
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`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 C1_8-alkyl, especially C1_5 -alkyl,
`or adamantyl, R8 and R9 together comprising at least three,
`preferably at least four carbon atoms.
`According to another embodiment ofthe invention, at least
`one of R8 and R9 comprises a branched carbon chain.
`Presently preferred tertiary amino groups X in formula I
`include the following groups a) to h):
`
`—N
`
`—N
`
`CH(CH3)2
`
`CH(CH3)2
`
`CH3
`
`C(CH3)3
`
`CH3
`
`—N
`
`C(CH3)3CH3CH3
`
`H3C
`
`CH3
`
`—N
`
`H3C
`
`CH3
`
`H3C
`
`CH3
`
`—N
`
`H3C
`
`CH3
`
`CH3
`—N
`
`3)
`
`b)
`
`0)
`
`d)
`
`5)
`
`0
`
`g)
`
`11)
`
`Group a) is particularly preferred.
`The aforementioned tertiary amino groups X are described
`in W0 94/ l 1337 and the compounds according to the present
`invention can be obtained by using the corresponding starting
`compounds.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0006
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0006
`
`
`
`US 7,384,980 B2
`
`5
`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG. 1 shows formulation of the active metabolite from
`
`different prodrugs by human liver S9 (%) in l h. 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 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 —CH2—C6H5 which is optionally substituted by
`one or more substituents on the phenyl ring. Suitable substitu-
`ents are selected from alkyl, alkoxy, halogen, nitro and the
`like. Suitable halogen atoms are fluorine, chlorine and iodine
`atoms. Preferred substituted benzyl groups are 4-methylben-
`zyl, 2-methylbenzyl, 4-methoxybenzyl, 2-methoxybenzyl,
`4-nitrobenzyl, 2-nitrobenzyl, 4-chlorobenzyl and 2-chlo-
`robenzyl.
`In the compounds according to the present invention the
`term “C1-C6 alkylcarbonyl” denotes a group R—C(:O)—
`wherein R is an alkyl group as defined hereinbefore. Preferred
`C1-C6 alkylcarbonyl groups are selected from acetyl, propio-
`nyl,
`isobutyryl, butyryl, valeroyl and pivaloyl. The term
`“cyclo-alkylcarbonyl” 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-(C6H5—), naphthyl-(C1OH7—), anthryl-
`(C 14H9—), etc. Preferred aryl groups according to the present
`invention are phenyl and naphthyl with phenyl being particu-
`larly preferred.
`The term “benzoyl” denotes an acyl group of the formula
`—CO—C6H5, wherein the phenyl ring may have one or more
`substituents.
`
`Preferred sub stituents ofthe aryl group and in particular of
`the phenyl group are selected from alkyl, alkoxy, halogen and
`nitro. As substituted benzoyl groups 4-methylbenzoyl, 2-me-
`thylbenzoyl, 4-methoxybenzoyl, 2-methoxybenzoyl, 4-chlo-
`robenzoyl, 2-chlorobenzoyl, 4-nitrobenzoyl and 2-nitroben-
`zoyl may be mentioned.
`The term “C1-C6 alkoxycarbonyl” refers to a group ROC
`(:O)— wherein R is an alkyl group as defined hereinbefore.
`Preferred C1-C6 alkoxycarbonyl groups are selected from
`CH3C(:O)—, C2H5—OC(:O)—, C3H7C(: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 pre-
`ferred amino acid residues are selected from the group con-
`sisting ofglycyl, 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 polyhy-
`droxy aldehyde or polyhydroxy ketone of the formula
`21114
`C”H O or C,1(H2O),1 and correponding carbohydrate groups
`are, for example, described in Aspinal, The Polysaccharides,
`New York: Academic Press 1982, 1983 . A preferred carbohy-
`drate group in the compounds according to the present inven-
`tion is a glucuronosyl group, in particular a l[3-D-glucurono-
`syi group.
`The term “LG” as used herein denotes a leaving group
`selected from halogenides, carboxylates, imidazolides and
`the like.
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`6
`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 general formulae
`II and II‘
`
`Formula II
`
`Formula II’
`
`Ofi/(CH2)n/k0
`
`wherein R1 represents hydrogen, C1-C6 alkyl or phenyl.
`Particularly preferred phenolic monoesters are listed
`below:
`
`(:)-formic acid 2-(3-diisopropylamino-l-phenylpropyl)-
`4-hydroxymethylphenyl ester,
`(:)-acetic acid 2-(3 -diisopropylamino-l -phenylpropyl)-4-
`hydroxymethylphenyl ester,
`(:)-propionic acid 2-(3 -diisopropylamino-l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(1)-n-butyric acid 2-(3 -diisopropylamino-l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(1)-isobutyric acid 2-(3 -diisopropylamino-l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`R-(+)-isobutyric acid 2-(3 -diisopropylamino-l -phenyl-
`propyl)-4-hydroxymethylphenyl ester,
`(1)-2,2-dimethylpropionic acid 2-(3-diisopropylamino-l-
`phenylpropyl)-4-hydroxymethylphenyl ester,
`(1)-2-acetamidoacetic acid 2-(3 -diisopropylarnino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(1)-cyclopentanecarboxylic acid 2-(3-diisopropylamino-
`l-phenylpropyl)-4 -hydroxymethylphenyl ester,
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2018 - 0007
`
`Patent Owner, UCB Pharma GmbH – Exhibit 2018 - 0007
`
`
`
`US 7,384,980 B2
`
`7
`(1)-cyclohexanecarboxylic acid 2-(3 -diisopropylamino-l -
`phenylpropyl)-4-hydroxymethylphenyl ester,
`(:)-benzoic acid 2-(3 -diisopropylamino- l -phenylpropyl)-
`4-hydroxymethylphenyl ester,
`R- (+)-benzoic acid 2-(3 -diisopropylamino- l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(:)-4 -methylbenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(:)-2 -methylbenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(1)-2-acetoxybenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(1)-l -naphthoic acid 2-(3 -diisopropylamino- l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(:)-2 -naphthoic acid 2-(3 -diisopropylamino- l -phenylpro-
`pyl)-4-hydroxymethylphenyl ester,
`(1)-4-chlorobenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(:)-4 -methoxybenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(:)-2 -methoxybenzoic acid 2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4-hydroxymethylphenyl ester,
`(:)-4 -nitrobenzoic acid 2-(3 -diisopropylamino-l -phenyl-
`propyl)-4-hydroxymethylphenyl ester,
`(:)-2 -nitrobenzoic acid 2-(3 -diisopropylamino-l -phenyl-
`propyl)-4-hydroxymethylphenyl ester,
`(1)-malonic acid bis-[2-(3 -diisopropylamino-l -phenyl-
`propyl) -4 -hydroxymethyl -phenyl] ester,
`(:)-succinic acid bis-[2-(3 -diisopropylamino-l -phenyl-
`propyl) -4 -hydroxymethyl -phenyl] ester,
`(1)-pentanedioic acid bis-[2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4 -hydroxymethyl-phenyl] ester,
`(1)-hexanedioic acid bis-[2-(3 -diisopropylamino- l -phe-
`nylpropyl)-4 -hydroxymethyl-phenyl] ester.
`B