(19) United
`
`States
`
`(12) Reissued
`Patent
`al.(10)
`
`Buschmann
`et
`
`(45)
`
`Date
`
`Patent Number:
`
`of
`Reissued
`
`US RE39,593
`Patent:
`USO0RE39593E
`
`EA
`
`pr.
`
`24, 2007
`
`(54) 1-PHENYL-3-DIMETHYLAMINOPROPANE
`COMPOUNDS
`
`WITH A
`PHARMACOLOGICAL
`
`EFFECTS(75)
`
`Inventors:
`Helmut
`
`Buschmann,
`Esplugues
`
`de
`Llobregat
`
`(ES); Wolfgang
`Strassburger, Wuerselen
`
`(DE); Elmar
`
`Friderichs,
`Stolberg
`
`Gruenenthal
`
`GmbH, Aachen
`
`
`(73) Assignee:
`(DE)
`
`(DE)
`
`
`
`(21)
`
`Appl.
`
`No.: 10/462,844
`
`(22)
`Filed:
`
`Jun. 17,
`2003
`
`
`
`
`
`Related U.S. Patent
`
`Documents
`
`
`
`Reissue of: (64) Patent No.: 6,248,737
`
`
`
`
`
`Issued:
`
`Jun.
`
`19, 2001
`
`Appl. No.:
`08/466,911
`Jun.
`6, 1995
`
`Filed:
`
`(30)
`Foreign
`
`Application
`Priority
`
`Data
`
`Jul. 23,
`
`
`1994 (DE) ........................................
`..
`
`44
`26
`
`245
`
`(51)
`Int.
`
`(52)
`
`U.S.
`
`Cl.
`A61K
`31/535
`(2006.01)
`
`Cl.
`
`.................. .. 514/238.2;
`514/114;
`514/452;
`514/456;
`514/488;
`514/534;
`514/546;
`514/653;
`514/654;
`544/86;
`549/362;
`549/348;
`558/190;
`
`RS 1016 - 000001
`
`

`
`US RE39,593
`age
`2
`
`EP
`
`OTHER PUBLICATIONS
`
`A. Antoniadou—Vyza
`et al., “Synthese
`Des Phenylalky-
`lamines Encombrésâ€
`Chimika
`
`Chronika,
`New
`
`Series,
`14,
`
`(1985) pp.
`
`79-88.J.
`S. New
`et
`
`al., “Applications
`of
`Lithium Aluminum
`
`Hydride
`in
`
`the Synthesis of Substituted Ethyl—
`and
`Propy-
`lamines†Synthesis
`
`(May 1983)
`
`pp. 388—389.H.
`H.
`Ong
`
`et al.,
`“Photocyclizations.
`III.
`Synthesis
`of
`
`3 ,6—Dimethyl—8—hydroxy—3
`,4,
`5,
`6—tetrahydro—3—benzazocin—2(1H)mneâ€
`J.
`Org.
`Chem.,
`
`38(5)
`1973
`
`pp. 924-927.Lagidze
`
`et al.,
`Chemical
`
`Abstracts,
`vol.
`
`78, abstract 57901,
`1972.
`
`Tramatoni,
`“Advances
`in
`the Chemistry of Mannich Basesâ€,
`Synthesis, 1973, pp. 703—775.
`J. Am. Chem. Soc., 74
`p.
`
`1316 (1952).
`
`Chem. Abstr.,
`63,
`Olofsson
`et
`
`p. 6912e (1965).
`
`al., “Value
`of
`the Vinyloxycarbonyl Unit
`Hydroxyl Protection: Application
`of
`
`the Synthesis of
`Nalor-
`
`in
`
`phineâ€,
`Tetrahedron
`
`Welch et al.,
`
`Letters,
`No.
`
`18, 1977, pp. 1571—1574.
`
`RS 1016 - 000002
`
`

`
`US RE39,593 E
`
`11-PHENYL-3-DIMETHYLAMINOPROPANE
`
`COMPOUNDS WITH
`
`
`
`HARMACOLOGICAL EFFECTS
`
`AP
`
`Matter
`
`[]
`
` appears in the
`
`enclosed in
`
`heavy brackets
`
`original
`patent
`
`made
`by
`
`but forms
`no
`
`part of
`this
`
`reissue speciï¬-
`cation;
`
`matter printed
`in
`
`italics indicates
`
`the additions
`
`reissue.CROSS REFERENCE
`
`T
`0 RELATED
`
`application
`is
`
`APPLI
`CA
`
`
`
`77 ONThis
`
`a reissue of US.
`Pat.
`
`OF THE
`
`INVENTIONThe
`
`No. 6,248, 737.
`BACKGROUND
`
`present invention
`
`relates
`
`to
`1-phenyl-3-
`
`dimethylaminopropane compounds, to a
`method of prepar-
`
`ing them,
`and
`
`to the
`use
`
`of these substances
`as pharmaceu-
`
`tical active
`ingredients.
`The treatment of chronic and non-chronic pain
`situations
`
`is of great importance
`in
`
`medicine.
`This
`
`large number
`of
`
`publications.
`Thus,
`1-naphthyl-3 -aminopropane-1-ols
`
`narcotic effect are known from EP
`176
`tertiary alcohols with y-amino groups
`are
`
`is reflected
`in
`the
`
`for example,
`
`with
`an analgesic-
`
`049. Secondary and
`
`described
`in
`
`J.
`
`323,
`793
`
`ap
`
`ara-
`
`Pharm. Sci.
`59,
`
`1038 (1970) and in
`J. Prakt.
`Chem.
`
`(1981);
`phenyl-dimethylaminopropanols
`containing
`
`substituted phenyl radical
`are
`
`described
`in
`
`Chem.
`Abstr.
`
`54,
`
`20963c (1960)
`and
`
`in Chem. Abstr.
`
`RS 1016 - 000003
`
`

`
`US RE39,593 E
`
`I,
`in which the
`variable
`
`3mula
`
`X represents OH, which
`is
`
`characterized
`in
`
`that a
`[3-dimethylaminoketone of
`formula
`
`II
`
`0is
`
`reacted with
`an
`
`organometallic
`compound
`
`of formula IIIR4
`
`in which Z
`represents MgCl,
`MgBr,
`
`MgI or
`Li,
`
`to form a
`
`compound of
`formula
`
`I in
`which
`
`X represents OH.
`
`The reaction of a
`[3-dimethylaminoketone with a Grignard
`
`reagent of
`
`formula III,
`
`in
`which
`
`Z represents MgCl,
`MgBr
`
`an organolithium compound of formula III,
`
`or MgI, or
`
`with
`can be carried out in
`an
`
`a liphatic ether,
`for
`
`example
`diethyl
`
`ether and/
`or
`
`tetrahydrofuran,
`at
`
`C. and +60° C.
`
`Organolithium compounds
`
`temperatures
`between —70°
`
`of
`formula
`
`II
`can
`
`were carried
`out
`
`124 521,
`i.e.
`
`4
`
`according
`to
`
`the method disclosed
`in
`
`DD
`
`if [3-aminoketones corresponding to
`the
`
`formula
`
`0
`
`\&
`
`acirc;€˜is
`
`R5—:
`K/ /
`N/
`
`R4
`
`be obtained by the
`replacement
`
`of halogen by lithium,
`
`for
`
`example, by
`reacting
`
`a compound of formula III,
`
`in
`
`which
`Z
`
`represents
`Cl,
`
`Br or
`I,
`
`with
`a
`
`n-hexane.
`[3-dimethylaminoketones
`of
`
`obtained
`from
`
`ketones
`of
`
`solution
`of
`
`n-butyllithium
`in
`
`formula
`II
`
`can be
`
`general
`formula
`
`IV
`
`RS 1016 - 000004
`
`

`
`US RE39,593 E
`
`reaction is
`usually
`
`5The
`
`conducted
`in
`
`the absence of
`solvent
`
`at a
`temperature between
`0° C. and
`20° C.
`
`Replace-
`
`ment
`of
`
`OH by
`C1
`ï¬guration.
`
`is effected while maintaining
`
`the con-
`
`The present invention also relates
`
`
`to a method
`of prepar-
`ing 1-phenyl-3-dimethylarninopropane
`
`compounds of for-
`
`mula l,
`in which X
`represents an OCOR6
`group
`
`where R6
`is
`
`a C1_3-alkyl, which
`is
`
`characterized
`in
`
`that a
`compound of
`formula
`
`1, in
`which X represents OH, is
`reacted with an
`acid
`
`chloride
`Cl—COOR6.
`
`The reaction
`is
`preferably
`conducted in a
`solvent, for
`
`example
`
`dichloromethane,
`toluene
`
`and/or tetrahydrofuran,
`
`at
`a
`
`temperature
`between —10°
`1-phenyl-3-dimethylaminopropane
`C.
`and +30° C.
`compounds of for-
`
`mula I,
`in which R5
`is H and
`R4
`
`or meta-
`
`is a
`meta-phosphate group,
`meta-carbonate group, meta-carbamate
`group
`carboxylate group, can be
`obtained
`
`corresponding
`1-(3-hydroxyphenyl)-3-
`dimethylaminopropane
`
`of formula I in
`compounds
`
`the form
`
`by the
`reaction
`
`of
`the
`
`RS 1016 - 000005
`
`

`
`US RE39,593 E
`
`(+1)
`
`(-1)
`
`|H
`
`
`
`—c1Enantiomers
`
`of (1):
`(—)-
`(2S,3 S)-1-dimethylamino-3
`
`-(3
`
`-methoxyphenyl)-2 -methylpentan-3-ol Hydrochloride(—
`1)
`
`and
`(+)-(2R,3R)-1-dimethylamino-3-(3
`-methoxyphenyl)-2-
`
`methylpentan-3-ol Hydrochloride(+ 1).
`
`The base
`was
`
`released
`from
`
`(1) with
`dichloromethane/
`
`sodium hydroxide
`solution.
`
`romethane was
`distilled
`
`After
`drying
`
`olf under
`Vacuum.
`
`the solution dichlo-
`
`The racemate
`
`was then
`separated
`
`HPLC column.
`
`The
`
`on the
`chiral
`hydrochlorides, which had a
`melting point of
`150—151°
`C.,
`
`8
`
`of
`183—184°
`C.
`were obtained with trimethylchlorosilane/
`water in 2-butanone/diisopropyl ether.
`
`Example 4
`
`were
`prepared
`
`from the
`enantiomers
`
`obtained
`by
`
`reaction
`
`with trimethylchlorosilane/water
`in 2-butanone.
`(-1)
`yield: 42%
`theoretical
`[ot]DRr=—31.8°
`(c=0.99;
`methanol)
`(+1):
`yield: 41%
`theoretical
`[0t]D-Rr+33.0°
`(c=0.96; methanol)
`
`Example 3
`
`C1
`
`C1
`
`20
`
`25
`
`(2RS
`,3
`
`RS)-3
`-(3 -isopropoxyphenyl)-1-dimethylamino
`-2-
`methylpentan-3 -ol Hydrochloride
`(3)
`
`30
`
`25 g
`
`RS 1016 - 000006
`
`

`
`US RE39,593 E
`
`9E
`
`
`
`xample 6
`
`H05‘
`
`H ,.,,,,,l/
`
`H—Cl
`/N\(2RS,3RS)-1-dimethylamino-2-methyl-3-(3
`
`-
`
`trifluoromethylphenyl)-pentan-3-ol
`Hydrochloride(5)
`
`21.2 g of
`crude mixture were
`obtained under the
`
`condi-
`
`tions cited
`for
`
`Example
`1
`
`from 14.3
`g
`1-dimethylamino-2-methylpentan-3-one,
`g (130
`29.3
`mmole) 1-bromo-3-trifluoromethylbenzene
`and
`3.2 g
`(130
`
`(100 mmole)
`
`mmole) magnesium
`tumings.
`
`This mixture was introduced
`
`on to a
`6x40
`
`cm column packed
`with
`
`silica
`gel
`
`and eluted
`
`with 10:1
`diisopropyl
`
`obtained, from
`which
`
`theoretical) with
`a
`
`7.8 g
`of
`
`melting
`point
`
`ether/methanol.
`9.1
`
`g of
`base were
`
`hydrochloride
`(5)
`
`(18.5%
`
`of 189—190°
`C.
`was
`
`obtained with
`trimethylchlorosilane/water
`in 2-butanone.
`
`
`
`Example 7
`
`}
`.11, Ill,
`
`;
`
`._II,, 1,,
`
`10
`1-dimethylamino-2-methylpentan-3-one,
`82.5
`mmole)
`1-bromo-3-fluorobenzene
`and
`9.23 g
`(470 mmole)
`
`g (470
`
`magnesium turnings. This
`mixture
`
`7x50 cm
`column
`
`packed
`with
`
`was introduced on to
`a
`
`silica
`gel
`
`and eluted with 1:1
`
`ethyl
`acetate/methanol.
`
`13.0
`g
`
`of base
`were
`
`obtained,
`from
`
`/N\
`
`H—Cl
`
`(2RS,3RS)-1-dimethylamino-2-methyl-3-(3-m-tolyl)-
`pentan-3-ol Hydrochloride (6)
`75 g
`of crude mixture were obtained as in
`Example
`
`47.3 g (330
`
`which
`11.2
`
`1 from
`
`g of
`hydrochloride
`
`(7)
`(11.5%
`
`theoretical)
`
`RS 1016 - 000007
`
`

`
`US RE39,593 E
`
`11
`
`1-dimethylamino-2-methylpentan-3-one,
`25.0
`mmole)
`1-bromo-3-methylsulphanylbenzene
`and
`
`g (123
`
`3.0 g
`(123
`
`tumings. This
`mixture
`
`was introduced
`
`mmole)
`magnesium
`
`on
`to
`
`a 7x40
`cm
`
`column packed
`with
`
`10:1 ethyl
`acetate/methanol.
`
`silica gel
`and
`
`eluted
`with
`
`8.35
`g
`
`of base were
`
`obtained,
`from
`
`which 7.2
`g
`
`of hydrochloride
`(9)
`
`(19%
`theoretical)
`
`with a
`melting
`
`point of
`159—160°
`C.
`were
`obtained
`
`with trimethylchlorosilane/water
`in 2-butanone.
`
`Example 11
`
`/N\
`
`(2RS,3RS)-3-benzofuran-6-yl-1-dimethylamino-2-
`methylpentan-3 -ol
`Hydrochloride(10)
`
`3.45 g
`(18
`
`according to
`EP
`
`mmole)
`6-bromobenzofurane (prepared
`
`355 827)
`and
`
`6 ml
`1,2-dibromoethane,
`
`dissolved in
`60 ml dry
`ether,
`
`were added drop-wise
`over
`
`1.5
`
`hours to 2.12
`g
`
`(87 mole) magnesium
`turnings
`
`in
`30 ml dry
`
`ether;
`after
`
`the addition the mixture was heated under
`reflux
`
`for 30 minutes.
`
`Thereafter,
`2.5
`
`g (18 mmole)
`1-dimethylamino-2-methylpentan-3-one
`dissolved
`in
`7.5 ml
`
`ether was
`added
`
`an ice bath
`to
`
`drop-wise
`over
`
`1.5 hours whilst
`cooling
`
`in
`
`maintain
`an
`
`intemal
`temperature
`
`of
`5—10°
`
`RS 1016 - 000008
`
`

`
`US RE39,593 E
`
`from which
`3.6
`
`13obtained,
`
`g of
`hydrochloride
`
`(15)
`(32%)
`
`theoretical)
`with
`
`a melting
`point
`
`of 124° C.
`
`were
`obtained
`with trimethylchlorosilane/water
`in 2-butanone.
`
`Example 17(+15)
`
`(-15)
`
`
`
`H—ClEnantiomers
`
`(—)-(2S,3S)-4-dimethylamino-2-(3-methoxyphenyl)-3-
`
`methylbutan-3 -ol
`Hydrochloride (-15)
`
`of (15):
`
`and
`
`base were
`dissolved
`
`14
`
`in 25
`ml
`
`dry toluene and slowly added
`
`(+)-(2R,3R)-4-dimethylamino-2-(3
`-methoxyphenyl)-3-
`
`methylbutan-3 -ol
`Hydrochloride(+15).
`
`drop-wise to
`71 ml (85
`mole)
`
`diisobutylaluminium
`hydride
`
`The base
`was
`
`released
`from
`
`hydrochloride
`(15),
`
`which
`
`was
`complete,
`
`the
`mixture
`
`of a
`1.2 molar solution of
`
`in toluene. When the
`addition
`
`was heated for 8
`hours
`
`under
`
`The
`reaction
`
`in Example 16, with
`dichloromethane/
`
`reflux
`and
`then cooled to room
`temperature.
`
`was prepared
`as
`
`sodium hydroxide
`solution.
`
`dichloromethane by
`distillation,
`
`rated into
`the
`
`enantiomers
`on
`hydrochlorides were
`obtained
`
`After
`drying
`
`the
`racemate
`
`and removal of
`
`mixture was diluted with 25
`ml
`
`toluene.
`9.4
`
`ml ethanol
`
`was then sepa-
`
`20
`
`followed by 9.4
`ml
`
`water were
`added
`
`bath. After stirring
`for
`
`drop-wise
`whilst
`
`one hour
`whilst
`
`bath the
`reaction
`
`mixture
`was
`
`freed from
`
`by ï¬ltration, and
`
`the
`residue
`was
`
`washed
`
`trimethylchlorosilane/water
`in 2-butanone.
`(-1 5):
`yield: 41%
`theoretical
`m.p.: 117—118°
`C.
`[(X]DRT=—38.6°
`(c=1.05; methanol)
`
`a chiral HPLC column. The
`
`from the
`enantiomers
`
`with
`
`25
`
`cooling in an
`ice
`
`cooling in the
`ice
`
`30
`
`aluminium
`salts
`
`three times
`
`RS 1016 - 000009
`
`

`
`US RE39,593 E
`
`1 5Example 20
`HHosâ€
`H .,.,,â€l/
`/(1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-
`
`dimethylpropylphenol Hydrochloride( 1 7)
`
`H:Cl
`
`N
`\
`
`prepared
`under
`
`the conditions cited
`
`Compound (17)
`was
`
`in Example
`18
`
`starting
`from
`
`was
`obtained
`
`as in
`Example
`85% theoretical
`
`m.p.:
`232° C.
`
`methoxy
`
`compound (15)
`which
`
`16.Yield:
`
`
`
`Example 21
`
`(+17)
`
`5"’,
`1,,
`
`H ‘
`Cl
`(-17)
`
`\\\OH
`
`,_.5
`
`1 6
`Example 22
`
`.11, I'll’
`
`/N‘
`H*Cl
`
`(+)-(1R,2R)-3
`-(3 -dimethylamino-1-ethyl-1-fluoro-2-
`methylpropyl)-phenol
`Hydrochloride(+
`
`18
`
`)
`
`HO
`H
`
`.,,,Iâ€
`H ‘
`Cl
`
`1st Step
`
`20
`
`25
`
`N
`\
`
`/
`
`30
`
`/N\
`
`(+)-(1R,2R)-3-(3-benzyloxyphenyl)-1-dimethylamino-2-
`methylpentan-3 -ol (+1 9)
`
`RS 1016 - 000010
`
`

`
`US RE39,593 E
`
`17extracted
`
`twice with
`50
`
`ml dichloromethane. The
`combined
`
`were dried
`and
`
`freed from
`solvent
`
`by distil-
`
`vacuum. The
`crude
`
`mixture obtained (8.04 g)
`
`organic
`phases
`
`lation
`under
`
`was introduced on to
`a
`
`gel
`and
`
`eluted with
`1:1
`
`(+20) (40%
`theoretical)
`
`6x50 cm column
`packed
`
`with silica
`
`ethyl acetate/methanol. 3.04
`g
`
`of
`base
`
`were obtained as a
`light yellow,
`viscous
`
`oil.3rd
`Step:
`(+)-(1R,2R)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-
`methylpropyl)-phenol Hydrochloride(+l 8)
`
`3.0 g (91
`mole) of (+20)
`were dissolved
`in 15 ml
`of dry
`methanol
`
`and added
`to
`
`0.44 g
`palladium on activated carbon
`(10%
`
`Pd) in
`a
`
`hydrogenation
`apparatus.
`
`after stirring
`
`for three
`hours
`
`215 ml
`hydrogen
`
`at room
`tem-
`
`catalyst
`was
`
`removed by
`ï¬ltration, and
`
`the
`
`removed by
`distillation.
`
`2.22 g
`of base were
`
`which 2.0
`g
`
`of hydrochloride
`
`(+18)
`(79%
`
`was
`consumed
`
`perature.
`The
`
`methanol
`was
`
`obtained,
`from
`
`theoretical)
`were
`
`obtained
`with trimethylchlorosilane/water
`
`in 2-butanone.
`m.p.: 174—176°
`C.
`[(X]DRT=+29.5°
`(c=1.08; methanol)
`
`Example 23
`
`gen was
`subsequently
`
`18
`
`passed
`over
`
`the reaction mixture
`
`RS 1016 - 000011
`
`

`
`US RE39,593 E
`
`19vacuum
`
`from a
`water pump. The
`residue
`
`sodium
`hydrogen
`
`carbonate
`solution
`
`alkaline
`reaction
`
`was obtained. After extracting
`
`was treated with
`concentrated
`
`until an
`
`twice
`with
`
`organic
`phases
`
`50 ml
`dichloromethane
`
`were dried
`over
`
`distilled
`olf
`
`was
`then
`
`in
`each
`
`case the
`combined
`
`sodium sulphate. Dichloromethane
`
`under vacuum
`and
`
`the residue (4 g)
`
`was taken
`up
`
`in 2-butanone.
`
`After
`the
`
`addition
`of
`
`trimethylchlorosilane/water,
`3.8
`
`theoretical)
`crystallised
`
`g of
`hydrochloride
`
`(+21)
`(98%
`
`out.m.p.: 194—196°
`C.[ot]DRr=+24.5°
`(c=1.10;
`
`methanol)
`Example 25
`
`HO
`
`.,,,,0/ H ‘
`Cl
`
`N
`
`/\
`
`(-)-(1R,[2S]
`ZR)-3-(3-dimethylamino-1-ethyl-2-
`methylpropyl)-phenol
`hydrochloride(-21)
`Enantiomer
`(-21)
`
`was obtained in 45%
`yield
`
`conditions
`cited
`
`in Example 24 from
`(-1),
`
`under
`the
`
`which
`was
`
`prepared
`in Example 2.
`as
`m.p.: 168—170°
`C.
`[ot]DRr=—27.5°
`(c=0.97; methanol)
`
`Example 26
`
`RS 1016 - 000012
`
`

`
`US RE39,593 E
`
`21ethyl
`
`acetate in
`each case. After
`drying
`
`the combined orgamc
`phases,
`
`the solvent
`was
`
`mixture
`were
`
`obtained,
`which
`
`column packed
`with
`
`removed by
`distillation.
`
`4.8 g
`crude
`
`was introduced on to
`a 6x30
`cm
`
`silica gel
`and
`
`eluted, ï¬rstly with
`
`ethyl acetate,
`
`then with
`9:1
`
`ethyl acetate/methanol and
`
`ï¬nally
`with
`4:1 ethyl
`acetate/methanol.
`
`3.8
`g
`
`of base
`were
`
`obtained,
`from
`
`which 3.1
`g
`
`with a
`melting
`
`of hydrochloride (27)
`
`(33%
`theoretical)
`
`point of
`
`174° C.
`were
`
`obtained
`with trichlorosilane/water
`
`in
`
`2-butanone.3rd
`
`Step:
`(1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3
`-
`
`methoxyphenyl)-propan-1 -ol
`3.0
`Hydrochloride(25)
`
`g crude
`mixture
`
`cited
`in
`
`Example 1,
`
`from
`
`was obtained, under the
`conditions
`
`2.8 g
`(10 mmole) of
`(27)
`in
`
`the
`form
`
`of the
`base,
`
`1.4 g
`(13 mole) bromoethane and
`0.32
`g
`
`(13 mole)
`magnesium
`
`This mixture
`was
`
`tumings,
`using
`
`introduced
`on
`
`packed with
`silica
`
`ether/methanol, 2.1
`g
`
`gel and
`eluted
`
`of base
`were
`
`g of hydrochloride
`
`(25)
`(55%
`
`ether as
`the
`
`solvent.
`
`to a
`3x20
`cm
`
`with 19:1
`
`diisopropyl
`
`column
`
`obtained,
`from
`
`which
`1.9
`
`theoretical)
`with
`
`a melting
`
`point of 230°
`C.
`were
`
`2-butanone/
`ethyl acetate.
`
`obtained
`with trichlorosilane/water in
`
`RS 1016 - 000013
`
`

`
`US RE39,593 E
`
`23R1
`
`is a
`C1_4-alkyl group;
`R2
`represents
`or a C1_4-alkyl group, and
`H
`R3
`is different from R2
`and
`
`represents
`H
`
`or a straight chainC1_4-alkyl
`
`group, and
`R5 represents H, and
`R4
`
`represents
`meta-O—Z,
`where
`
`Z is
`H, C1_3-alkyl,
`PO(OC1_4alkyl)2, CO(OC1_5-
`
`alkyl),
`CONH—C6H4—(C1_3-alkyl)
`or CO—C6H4—R7,
`in
`which R7
`is ortho-OCOC1_3-
`
`alkyl
`or
`
`meta- or
`para-CH2N(R8)2, where R8 is
`
`C1_4-alkyl
`or
`
`4-morpholino,
`or
`R4 represents meta-S-C1_3-alkyl,
`meta-Cl,
`
`meta-F,
`meta-
`
`CR9R16R11,
`ortho-OH, ortho-O—C2_3-alkyl,
`para-F
`or para-
`CR9R16R11,
`where
`
`R9, R16
`and R11 independently represent
`
`para-OH or
`para-O—C1_3-
`
`Ho
`
`F, or
`r
`R5 represents para-Cl,
`para-F,
`
`alkyl, and
`R4
`
`represents
`meta-Cl,
`
`meta-F,
`meta-OH
`meta-O—C1_3-alkyl,
`or
`R4 and
`R5
`
`together
`represent 3,4-OCH=CH—
`or
`3,4-
`OCH=CHO—;
`or
`a salt
`thereof
`
`with a
`physiologically
`
`or
`
`acceptable acid.]
`[2. An isolated l-phenyl-3
`-dimethylaminopropane diaste-
`reoisomer according
`to
`
`claim 1,
`wherein
`
`Xr
`
`epresents OH,
`F,
`
`C1 or
`H;
`R1 represents a C1_4-alkyl group;
`R2 represents
`H
`R3 is
`different
`
`or CH3;
`
`from
`R2
`
`and represents H or
`CH3,
`
`and
`
`R5 represents
`
`RS 1016 - 000014
`
`

`
`US RE39,593 E
`
`25
`
`X R1
`I
`
`\ 1%R5—:
`K/ /
`
`/R
`
`4 Nwherein
`
`X
`
`represents OH,
`F,
`
`Cl, H
`or an OCOR6
`group
`
`R6 is
`a C1_3-alkyl group;
`R1
`is a
`C1_4-alkyl group;
`R2
`represents
`H
`
`or a C1_4-alkyl group and
`R3
`
`or a
`straight chain C1_4-alkyl group,
`or
`
`together
`form
`
`a C4_7
`cycloalkyl
`
`radical,
`and
`
`in which
`
`represents
`H
`
`R2 and
`R3
`
`R5 represents H, and
`R4
`
`represents
`meta-O—Z,
`
`where Z is
`H, C1_3-alkyl,
`PO(OC1_4alkyl)2, CO(OC1_5-
`
`alkyl),
`CONH—C6H4—(C1_3-alkyl)
`or CO—C6H4—R7,
`in
`which R7
`is ortho-OCOC1_3-
`
`alkyl or meta- or para-CH2N(R8)2, where R8 is
`C1_4-alkyl
`or 4-morpholino,
`or R4 represents meta-S—C1_3-alkyl,
`meta-Cl, meta-F,
`meta-CR9R1°R11,
`ortho-OH, ortho-O—C2_3_alkyl,
`para-F
`para-CR9R1°R11,
`where
`R9, R10
`and
`
`or
`
`R11 independently
`
`represent H or
`or
`F,
`R5 represents para-Cl,
`para-F,
`
`alkyl, and
`R4
`
`represents
`meta-Cl,
`
`R3 is dijferent from
`R2
`
`para-OH
`chain Cm-alkyl
`or para-O—C1_3-
`group,
`
`meta-F,
`meta-OH
`
`or
`
`R5 represents
`H,
`
`26
`
`and represents H or
`a
`
`straight
`
`wherein
`0<m<n,
`
`and
`
`and R4
`represents meta&acirc;&euro;&rdquo;0&acirc;&euro;&rdquo;Z,
`
`RS 1016 - 000015
`
`

`
`
`
`US RE39,593 E
`
`2713.
`
`An
`
`isolated I-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`tereoisomer according to
`
`claim
`X
`
`10, wherein
`
`represents
`
`OH,
`
`F,
`
`Cl,
`
`or
`H;R1
`
`is
`a
`
`C1_4-alkyl
`group;
`
`R2 represents CH ;R3
`
`is
`
`H; andR5 represents H, and
`
`
`
`
`R4 represents meta-O&acirc;&euro;&rdquo;C1_3-alkyl,
`
`meta-OH, meta-S&acirc;&euro;&rdquo;
`
`
`
`C1_3-alkyl, meta-F, meta-Cl, meta-
`
`
`
`and
`R4
`represents
`
`meta-Cl, or
`
`
`
`CH3, meta-CFZH, meta-CF3, or para-CF3,
`
`
`
`
`
` orR5 represents para-Cl, or para-F,
`
`meta-F,
`orR4
`
`and
`R5
`
`
`
`14. An
`
`together
`
`represent 3,4-OCH=CH&acirc;&euro;&rdquo;.
`isolated
`I-phenyl-3-dimethylaminopropane
`dias-
`tereoisomer
`
`according to
`
`claim
`
`
`10, wherein X represents
`
`
`
`OH, F,
`
`Cl,
`or
`
`an
`
`OCOR6group in
`
`which
`R6
`
`is
`a C1_3-alkyl
`
`group.
`15.
`
`An isolated I-phenyl-3-dimethylaminopropane
`dias-
`tereoisomer
`
`according to
`
`claim
`
`
`10, wherein R2
`
`R3
`is H
`
`16.
`
`An isolated I-phenyl-3-dimethylaminopropane
`dias-
`tereoisomer
`
`according to
`
`claim
`
`
`10, wherein
`
`
`represent F
`17.
`
`An isolated I-phenyl-3-dimethylaminopropane
`dias-
`tereoisomer
`
`according to
`
`claim
`
`
`10, wherein X represents
`
`OH
`18.
`
`An isolated I-phenyl-3-dimethylaminopropane
`dias-
`
`is
`
`CH3, and
`
`R9,
`R16 and R11
`
`RS 1016 - 000016
`
`

`
`US RE39,593
`
`
`
`E2932. An
`
`
`isolated I-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`
`
`tereoisomer according to
`
`claim
`
`25,
`
`wherein
`X represents
`OH.33.
`
`An
`
`isolated I-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`claim
`
`25,
`
`wherein
`
`X represents F,
`
`tereoisomer according to
`
`
`Cl, Hor
`an
`
`OCOR6
`
`group
`
`in
`
`which
`
`R6
`is
`
`aC
`
`
`1_3-alkyl group.
`34.
`
`at
`least
`
`An
`
`isolated I-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`
`
`tereoisomer having a configuration corresponding to
`
`Ic:R6 Ia
`
`R4<\ //2
`
`Ic
`
`and
`
`
`
`one offormulae Ia
`
`wherein
`
`RS 1016 - 000017
`
`

`
`
`
`US RE39,593 E
`
`3145.
`
`An
`
`isolated 1-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`tereoisomer according to
`
`F,
`Cl
`
`or
`an
`
`OCOR6
`
`group
`
`claim
`
`41,
`
`wherein
`X represents
`OH,
`
`aC
`
`1_3-alkyl
`group.
`46.
`
`in
`
`which
`
`R6
`is
`
`An
`
`isolated 1-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`claim
`
`41,
`
`wherein
`R2
`
`tereoisomer according to
`
`R3
`
`is
`
`CH3, and
`
`is
`
`H.47. An
`
`isolated 1-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`tereoisomer according to
`
`claim
`
`41,
`
`wherein
`
`R9,
`
`R16
`and
`
`R11
`
`represent F48.
`
`An
`
`isolated 1-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`claim
`
`41,
`
`wherein
`X represents
`OH.49.
`
`tereoisomer according to
`
`An
`
`isolated 1-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`claim
`
`41,
`
`wherein
`
`X represents F,
`
`tereoisomer according to
`
`Cl,
`
`Hor
`
`an
`
`OCOR6
`
`group
`in
`
`which
`R6
`
`50. An isolated 1-phenyl-3-dimethylaminopropane
`
`
`dias-
`tereoisomer
`
`
`having a configuration corresponding
`
`
`to for- mula Ic:
`
`is
`a
`
`C1_3-alkyl
`group.
`
`Ic
`
`wherein
`Xrepresents
`
`RS 1016 - 000018
`
`

`
`
`
`US RE39,593
`
`E33R1 is
`
`a C1_4-alkyl
`group;
`
`R2 represents a C1_4-alkyl
`
`
`group, andR3
`
`is
`
`dijferent from
`
`R2
`
`and represents H
`
`are
`
`
`disposed threo
`
`or
`a straight
`
`
`
`chain C1_3-alkyl group, such
`
`that
`
`Xand
`
`the
`dimethy&acirc;&euro;&rdquo;
`
`lamino group
`
`in
`
`relation to each
`
`other,
`
` andR5 represents H, and
`
`
`
`
`R4 represents meta&acirc;&euro;&rdquo;O&acirc;&euro;&rdquo;Z,
`C6H4&acirc;&euro;&rdquo;
`
`(C1_3-alkyl) or CO&acirc;&euro;&rdquo;C6H4&acirc;&euro;&rdquo;R7,
`in
`which
`
`R7 is
`ortho-
`
`
`
`OCOC1_3-alkyl or
`
`meta-
`orpara-CH2N(R6)2,
`
`where R6
`
`is C1_4-alkyl
`
` or 4-morpholino,or R4
`
`represents meta-S&acirc;&euro;&rdquo;C1_3-alkyl,
`
`meta-Cl, meta-F,
`
`
`meta-CR9R16R11, ortho-OH, ortho-O&acirc;&euro;&rdquo;C2_3-alkyl,
`
`RS 1016 - 000019
`
`

`
`3586.
`
`claim
`
`8, whereinX
`
`F,
`
`Cl,
`
`or
`H;R1 represents a
`
`C1_4-alkyl
`
`
`group;R2 represents CH ;R3
`
`Am
`
`
`
`
`
` ethod according to
`
`represents
`
`OH,
`
`
`
`US RE39,593 E
`
`represents
`
`H, andR5 represents H, and
`
`
`
`CH3, meta-CFZH, meta-CF3, or para-CF3,
`
`
`
`
`R4 represents meta-OC1_8-alkyl,
`
`meta-OH, meta-S&acirc;&euro;&rdquo;C1_3-alkyl,
`
`
`meta-F, meta-Cl, meta-
`
`
`
`and
`R4
`represents
`
`meta-Cl, or
`
`
`
`
`
` orR5 represents para-Cl, or para-F,
`
`meta-F,
`orR4
`
`together
`
`represent 3,4-OCH=CH&acirc;&euro;&rdquo;.
`87.
`
`and
`R5
`
`Am
`
`
`
`
`
` ethod according to
`
`claim
`8,
`
`wherein
`R5
`
`is
`H and
`
`claim
`8,
`
`wherein
`R5 is Hand
`
`claim
`8,
`
`wherein
`X represents
`
`which
`R6
`
`is
`a C1_3-alkyl
`
`claim
`8,
`
`wherein
`R2 is C1_4-
`
`C1_3
`alkyl.
`
`Ho
`
`r
`
`and
`is
`
`claim
`8,
`
`wherein
`R9,
`
`R10
`and
`
`R4
`
`is
`meta-OCH8.
`88.
`An
`
`method
`
`according to
`
`R4
`
`is
`meta-OH
`89.
`A
`
`method
`
`according to
`
`
`
`OH,
`
`F,
`Cl
`
`or
`an
`
`OCOR6
`
`group in
`
`group.
`90.
`A
`
`
`
`alkyl, and
`
`method
`
`according to
`
`
`
`
`
`R3 is dijferentfrom R2
`
`9].
`A
`
`method
`
`according to
`
`R&acirc;&euro;
`
`represent F
`
`RS 1016 - 000020
`
`

`
`US RE39,593
`
` EIaIcwherein
`Xrepresents
`
`OH, F,
`
`RS 1016 - 000021
`
`

`
`
`
`US RE39,593 E
`
`I
`
`R5
`10
`
`wherein X represents
`
`H,
`
`5
`
`C1_4-alkyl
`group,
`
`
`R1
`
`is
`a
`
`R2 represents a
`
`is
`
`dijferent from
`
`C1_4-alkyl
`
`group, 15R3
`
`R2
`
`and represents H
`
`or
`a straight
`
`
`
`chain C1_3-alkyl group,and
`
`
`
`R5 represents H,
`
`and
`
`R4 represents meta&acirc;&euro;&rdquo;0&acirc;&euro;&rdquo;Z,
`
`
`
`where Z
`
`40
`
`and
`2
`
`are
`
`both asym-
`
`a(
`
`
`
`
`
`IR, 2R)
`
`the
`
`diastereomer has
`
`is
`
`H, C1_3-alkyl, P0(0C14-alkyl)2,
`
`
`
`
`wherein carbon atoms at positions I
`C0(0C1_5-
`alkyl), C0NH&acirc;&euro;&rdquo;C6H4&acirc;&euro;&rdquo;(C1_3-alkyl)
`
`or C0&acirc;&euro;&rdquo;C6H4&acirc;&euro;&rdquo;
`
`R7, in
`which
`R7
`
`
`
`
`
`metric carbons and
`
`is
`ortho-0C0C1_3-alkyl
`
`or meta- or
`para-CH2N(R8)2,
`
`where R8
`
`or
`(IS,
`
`is
`H,
`
`is
`H,
`
`and
`R4
`
`and
`R4
`
`ZS) configuration,
`
`is
`or a salt
`
`C1_4-alkyl or
`4-morpholino,
`
`thereofwith a physiologically
`
`or R4 represents meta-S&acirc;&euro;&rdquo;C1_3-alkyl,
`
`meta-Cl, meta-F,
`
`acceptable acid.
`20
`meta-CRQRIORH,
`
`
`142. An isolated I-phenyl-3-dimethylaminopropane
`
`ortho-OH, ortho-0&acirc;&euro;&rdquo;C2_3-alkyl,
`dias-
`
`
`tereoisomer according to
`
`para-F or para-CRQRIORH,
`
`
`
`
`where R9, R10 and R11 independently represent H or
`
`F, or
`
`25
`
`claim
`
`
`14], wherein R5
`
`is meta-OCH3.
`
`
`143. An isolated I-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`tereoisomer according to
`
`claim
`
`
`14], wherein R5
`
`R5
`
`
`
`
`represents para-Cl, para-F, para-OH or para-0&acirc;&euro;&rdquo;
`
`C1_3-alkyl, and
`R4
`
`
`
`represents meta-Cl, meta-F, meta-
`OH or meta-0&acirc;&euro;&rdquo;C1_3-alkyl,
`or
`R4
`and
`
`R5
`
`
`together represent 3,4-0CH=CH&acirc;&euro;&rdquo;
`or 3,4-
`0CH=CHO&acirc;&euro;&rdquo;,
`and
`
`30
`
`is meta-OH
`
`
`144. An isolated I-phenyl-3-dimethylaminopropane
`dias-
`
`
`
`tereoisomer according to
`
`claim
`
`14], wherein
`
`R2 represents CH ;
`
`
`R3 is H; and
`R5
`
`
`represents H, and R4 represents meta-0&acirc;&euro;&rdquo;C1_3-alkyl,
`
`meta-OH, meta-S&acirc;&euro;&rdquo;
`
`
`
`
`I-3-alkyl, meta-F, meta-Cl, meta-
`
`
`
`
`CH3, meta-CFZH, meta-CF3, or para-CF3, or
`
`RS 1016 - 000022
`
`

`
`UNITED STATES PATENT
`
`AND TRADEMARK
`OFFICE
`
`CERTIFICATE
`
`
`
`OF CORRECTIONPATENT
`
`
`
`NO. :
`
`RE
`39,593
`
`E
`
`Page
`1
`
`of 1
`
`:1
`
`
`
`0/462844DATED
`
`APPLICATION
`NO.
`
`et
`
`a1.It
`
`:A
`
`pril 24, 2007
`INVENTOR(S)
`
`:H
`
`e1rnutBuschrnann
`
`is certified that error
`appears
`
`in the
`above&acirc;&euro;&rdquo;identified
`patent
`and that
`said
`
`Letters
`Patent
`
`is
`hereby
`
`corrected
`as
`
`
`
`shown below:Cols.
`
`25, 27,
`29,
`
`32, 34,
`35
`
`and 37,
`In
`
`claims
`9,
`
`formula
`la
`
`should
`
`read
`--R5--.
`
`C01. 35, In
`claim
`
`86, line
`4
`
`should read:
`
`--R2 represents
`CH3;--
`
`25, 34,
`66,
`
`77, 95,
`and
`
`106, &acirc;&euro;&oelig;R6&acirc;&euro;
`in
`
`RS 1016 - 000023
`
`

`
`UNITED STATES PATENT
`
`AND TRADEMARK
`OFFICE
`
`CERTIFICATE
`
`
`
`OF CORRECTIONPATENT
`
`
`
`NO. :
`
`RE
`39,593
`
`E
`
`Page
`1
`
`of 1
`
`:1
`
`
`
`0/462844DATED
`
`APPLICATION
`NO.
`
`et
`
`a1.It
`
`:A
`
`pril 24, 2007
`INVENTOR(S)
`
`:H
`
`e1rnutBuschrnann
`
`is certified that error
`appears
`
`in the
`above&acirc;&euro;&rdquo;identified
`patent
`and that
`said
`
`Letters
`Patent
`
`is
`hereby
`
`corrected
`as
`
`
`
`shown below:In
`
`claim 66,
`C01.
`
`33, lines
`7-10
`
`should read:
`--
`
`R5 represents H, and
`R4
`
`represents
`meta-O-Z,
`
`where Z is
`H, C1_3-alkyl,
`PO(OC1_4a]ky1)2, CO(OC1_5-alkyl),
`CONH-C6H4-(C1_3-alkyl)
`or
`CO-C6H4-R7,
`in
`which
`R7
`
`is ortho-OCOC1_3-alkyl
`
`or meta- or
`para-CH2N(R8)2, where R8 is
`C1_4-alkyl or
`
`4-morpholino, --
`
`RS 1016 - 000024
`
`

`
`UNITED STATES PATENT
`
`AND TRADEMARK
`OFFICE
`
`Pagg
`1
`
`0f2
`APPLICATION
`
`CERTIFICATE
`
`
`
`OF CORRECTIONPATENT
`
`
`
`NO. 2 RE39,593
`
`E
`
`:A
`
`NO.
`
`: 10/462844DATED
`pril 24, 2007
`
`INVENTOR(S)
`
`Letters
`Patent
`
`is hereby corrected
`as
`
`shown below:
`
`et
`al.It
`
`:H
`
`e1mutBuschmarm
`
`is certified that error
`appears
`
`in the
`above&acirc;&euro;&rdquo;identified
`patent
`and that
`said
`
`Claim
`42,
`
`col. 30,
`line
`
`52, &acirc;&euro;&oelig;R1 is
`
`a C1_4-alkyl
`group;&acirc;&euro; should read --
`R1
`
`42, col.
`30,
`
`line 54,
`&acirc;&euro;&oelig;R8 is
`
`H;
`and&acirc;&euro;
`should
`read --
`R3
`
`is H;
`and
`
`--.
`
`represents
`a
`
`C1_4-alkyl
`group;
`
`--.
`Claim
`
`Claim 59,
`col.
`
`32, lines 14-15,
`&acirc;&euro;&oelig;(+)-(2R,
`3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-
`
`methylpentan-3-ol
`hydrochloride (+1)&acirc;&euro; should read
`
`-- (dc)-(2RS,
`3RS)-1-dimethylamino-3-(3-
`methoxyphenyl)-2-methylpentan-3-ol
`
`hydrochloride (il) --.
`
`RS 1016 - 000025
`
`

`
`CERTIFICATE
`OF CORRECTION (continued) Page
`
`f 2
`U.S.
`
`2o
`
`Pat. No.
`RE39,593
`
`EClaim 121, Col.
`
`38, lines 23-24,
`&acirc;&euro;&oelig;(+)-(2RS,
`3RS)-l-dimethylamino-3-(3-methoxyphenyl)-2-
`
`methylpentan-3-ol hydrochloride (+l)&acirc;&euro;
`
`
`should read -- (dc)-(2RS,
`3RS)-1-dimethylamino-3-(3-
`methoxyphenyl)-2-methylpentan-3-ol
`hydrochloride
`
`(il)
`--.Claim
`
`147, col.
`40,
`
`lines 31-32,
`&acirc;&euro;&oelig;(&acirc;&euro;&rdquo;)-(1R,2R)-3R-(3-dimethylarnino-1-ethyl-2-methylpropyl)-phenol&acirc;&euro;
`should
`
`RS 1016 - 000026