-v^:
`l*
`
`2836305
`
`nimmt den Rllckstand in Wasser auf, filtriert und kristailisiert
`aus Methanol um; Ausbeute 53 %, F0 1160C# Summenforniel
`Elementaranalyse %
`
`*
`
`{
`
`c
`
`55,50
`55,32
`
`H
`
`5,37
`533
`
`1
`
`11,98
`h36Q
`
`bero r
`gef o'
`
`Beispiel 6
`
`3=-p=n-=Pentylaniinophenyl='5='hydroxymethyl=2=ox0zolidinon (Cods^Nra
`770 328)
`.
`-
`
`1 0 Stufe g B-Benzyloxymethyl^S-p-nitrophenyl^<=0X020lidinors
`
`Man erhSli: diese Verbindung mlt der gleichen Arbeitsweise wle in
`Beispiel 1, v/obei man vors dem geeigneten Propandiol ausgeht^
`Ausbaute 78 %t Fo 1250C? Summsnformel C^H-^N^Og
`Elementaranalyse:
`
`bero '{%)
`gef. (%)
`
`C
`
`62,19
`61,814
`
`H
`
`}i,9l
`t,8T
`
`N
`
`8,53
`8,57
`
`2o Stufe s 3-=p'=Aminophenyl=5=hydroxymetliyl='2'"Oxazolidinon=hydro-=
`chlorid (Code-Nr. 770 21])
`
`In einem Autoklaven erhitzt man eine Suspension von 25 g (0P076
`Mol) der in der vorausgegangenen Stufe hergestellten Verbindungj,
`2 b 5 g Palladium auf 10 % Kohle und 12,5 ml Kthanol/6# 5 n Chlor-
`
`9 0 9 B 0 9 / 1 0 1 S
`
`0439
`
`MYLAN - EXHIBIT 1004 Part 2 of 10
`
`

`

`- 20^-
`
`ie
`
`2836305
`
`wasserstoffsciure in 600 ml absolutem Alkohol unter einem Druck
`von 3 kg Wasserstoff 2 Stunden lang auf 50OC» Dann filtriert
`man, verdampft das Lasungsmittel und kristallisiert den RUckstand
`aus Methanol urn; Ausbeute 64 %, F. 200OCf Summenformel ^]o^13^"^2^3"
`Elementaranalyse:
`
`ber. (%)
`gef. («
`
`c
`h9,09
`48,63
`
`li
`5,36
`5,2?
`
`N
`11,23
`1 1 » 2 5
`
`3. Stufe: 3-p-n-PentyiaminopHenyl-5-hydroxymethyl-2-oxazolidinon
`(Code-Nr» 770 328)
`Eine Suspension von 6,1 g (0,025 Mol) der in der vorausgegangenen
`Stufe hergestellten Verbindung, 4,5 g (0,03 Mol) n-Pentyl-
`bromid, 10 g Kaliumcarbonat und 0,1 g Natriumjodid in 100 ml
`Butanol erhitzt man 12 Stunden lang unter RUckflufi. Dann fil­
`triert man, verdampft das Lbsungsmittel und kristallisiert in
`einem Kther/lsopropylalkohol-Gemisch; Ausbeute 10 JS, F. 1240C(,
`Summenformel Gj 5^22^2^3*
`Elementaranalyse:
`
`ber.
`(%)
`gef. W
`
`611,72
`6hM
`
`7,97
`7,97
`
`10,0?
`10,02
`
`Beispiel 7
`
`3-p-(m-Nitrophenoxyinethyl)phenyl-*5-hydroxymethyl-2-oxazolidinon
`(Code-Nr. 771 263)
`
`Stufe: 3-p-Formylphenyl-5-hydroxymethyl~2-oxazolidinon
`(Code-Nr. _770_054)
`
`9 0 9 8 0 9 / 1 0 1 6
`
`0440
`
`

`

`-Xr
`4 0
`
`2836305
`
`Eine Mischung von 65,4 g 3-p-Formylanilino-1,2-propandiol, 43,6 g
`DiSthylcarbonat und 16 ml Natriummethylat (10 %ige Losung in
`Methanol) in 830 ml Dioxan erhitzt man unter RUckfluB (wobei
`man den gebildeten Alkohol abdestilliert)« Dann filtriert man, dampft
`das Filirat ein, nimtnt den RUckstand in Chloroform auf und wascht
`mit einer verdUnnten Chlorwasserstoffsaurelosung. Dann trocknet
`man, verdampft das Losungsmittel und chromatographiert den RtJck-
`stand an einer Siliciumdioxidkolonne, was zu dem gewUnschten
`Produkt fUhrt; Ausbeute 23
`F. 1230Fr Summenformel C^H^NO^,
`Molekulargewicht 221,21.
`Elementaranalyse:
`
`.
`
`ber.($)
`gef. (%)
`
`C
`59,72
`59,^9
`
`H
`5,01
`^ ,66
`
`IT
`6,33
`6,20 •
`
`2. Stufe: 3-p-Formylphenyl-tert«-butylcarbonyloxymethyl-2-oxa-
`zolidinon (Code-Nr. 771 213)
`Zu einer LSsung von 15,5 g der in der vorausgegangenen Stufe
`hergestellten Verbindung in 180 ml Pyridin gibt man langsam
`12,2 ml tert.-Buttersdurechlorid zu. Nach 1 Stunde bei Umge-
`bungstemperatur verdiinnt man mit Wasser, Fxltriert den gebildeten
`Niederschlag, trocknet ihn und kristallisiert ihn aus Xthanol urn;
`Ausbeute 90 %, F. 1340C, Summenformel C^H^NOg, Molekulargewicht
`305,32.
`Elementaranalyse:
`
`b e r . [ (%)
`gef.
`(JS)
`
`C
`
`62,9b
`62, Gh
`
`H
`
`6,27
`6,57
`
`U
`
`^,59
`
`9 0 9 8 0 9 / 1 0 1 6
`
`0441
`
`

`

`—jjor —
`3/?
`
`2 8 3 6 3 0 5
`
`3. Stufe: 3-p-Hydroxyniethylphenyl-5-tert.-butylcarbonyloxymeihyl-
`2»oxazolidinon (Code-Nr» 771 214)
`
`Zu einer Suspension von 11,3 g der in der voraosgegangenen Stufe
`hergestellten Verbindung in 200 ml Methanol gibt man langsam
`0,7 g Natriumborhydrid zu. Nach 10 Minuten dampft roan das Lbsungs—
`raittel ein, nimmt den RUckstand in ftthylacetqt
`auf, wascht mit
`Wasser, trocknet, verdarapft das LBsongsmittel und kristallisiert
`den RUckstand aus einem Xther/lsopropanol-Gemisch urn; Ausbeute
`80 '%t F. 102OC, Summenformel ^21^5'
`largewieht 307,34.
`Elementaranalyse:
`
`ber; (%)
`gef.
`
`62 >52
`62,58
`
`H
`
`6,89
`7,01
`
`IT
`
`^56
`K32
`
`4. Stufe: 3-p-(m-Nitrophenoxymethyl)phenyl-5-hydroxymethyl-
`2-oxazolidinon (Code-Nr. 771 263}
`
`Zu einer LSsung von 11,7 g der in der voraosgegangenen Stufe
`erhaltenen Verbindung in 150 ml Methylenchlorid gibt man bei
`0oC 10,6 ml TriSthylamin und 6 ml Mesylchlorid zu. Dann verdUnnt
`man nach 3-stUndigem Konta.kt bei Umgebungstemperatur mit Wasser,
`dekantiert und dampft die organische Phase ein* Man gibt den
`dabei erhaltenen RUckstand (gelBst in 100 ml Dimethylformamid)
`zu einer Ldsung von 3,7 g m-Nitrophenol und 1,25 g 50 ^igem
`Natriumhydrid in 50 ml Dimethylformamid und erhitzt die Mischung
`3 Stunden lang auf 60OC* Dann gieBt man die Mischung in Wasser,
`extrahiert mit Athylacetat, trocknet, verdampft das Losungsmittel
`und behandelt den RUckstand mit einer LSsung von 0,6 g Kaliumhydroxid
`
`9 0 9 8 0 9 / 1 0 1 6
`
`0442
`
`

`

`-
`
`5%
`
`2 8 3 6 3 0 5
`
`in 120 ml Methanol. Nach 1 Stunde unter Rllclcf luB gieBt ®an
`die Mischung in Wasser, filtriert den gebildeten Niederschlog
`ab und kristallisiert'aus Methanol und dann aus AtHanoi un;
`Ausbeute 44 %, F0 1420C(t Summenformel C^H^NgO^jr Molekularge-
`wicht 344f310
`Elementaranalyses
`
`ber<,' ($)
`gefi (^)
`
`Beispiel 8
`
`C
`
`59,30
`59,^
`
`H
`if} 68
`^,38
`
`N
`8,
`7,99
`
`3-p-C(2-1,3-=Dithiolanyl)methoxy]phenyl-'5-hydroxymethyl«=2-ojtazoli='
`dinon (Code»=Nro 780 080)
`
`« 69 a est i
`
`1 <, Stufe; 3-p-(2,2=Diathoxy)athoxyphenyl-5--hydroj<ymethyl='2«=oxa'=
`zolidinon (Code-Mro 771 049)
`
`Zu einer Losung von 21 g 3-=-p~Hydroxyphenyl -=• 5--hydrojjyraethyl«2"
`oxazolidinon in 200 ml Dimethylformamid gibt man 4,8 g 50 /^xges
`Natriumhydrid und dann 30 ml Brojiiacetoldehyddiathylacelbal zuo
`Man erhitzt die Mischung 13 Stursden lang auf 50°C, gieBt sie
`danach in Eiswasser, extrahiert mit Xthylacetat, waseh^ mit
`Wasser, dampft das LSsungsmittel ein und chromatographiert den
`Ruckstand an einer Siliciumdioxidkolonneo Nach dem Eloieren
`mit einem CHClg/CH^OH (99/1 )-Gemisch erhalt man 17 g des ge«
`v/Unschten Produkts; Fo 90OC, Summenformel
`^0^e^u^ar9e"=
`v/icht 325,35o
`Elementaranalyse:
`
`9 0 9 3 0 9 / 1 0 1 S
`
`0443
`
`

`

`2 8 3 6 3 0 5
`
`35
`C
`
`59,06
`
`58,82
`
`H
`
`7,13
`
`7,15
`
`N
`
`^31
`
`h ,22
`
`ber» - (JJ)
`
`gef. (%)
`
`2. Stufes 3-p-[(2-l,3-Dithiolanyl)methoxy3phenyl-5-hydroxyffl8thyl-
`2-oxazolidinon (Code-Nr. 780 080)
`
`Man laBt eine Losung von 2,9 g der in der vorousgegangenen Stufe
`hergestellten Verbindung, 1,2 ml 1,2-Sthandithiol und 1 ml Bor-
`trifluoridatherat in 35 ml Methylenchlorid 45 Minuten lang bei
`Umgebungsiemperatur stehen. Dann verdUnnt man mit Xther und fil-
`triert den gebildeten Niederschlag ab; Ausbeute 60 %t F. 160OC,
`Summenforme1
`^NO^Sg, Molekulargewicht 327,42.
`Elementaranalyse:
`
`ber. (%)
`gef. (%)
`
`c
`
`51,35
`51,51
`
`11
`
`5,23
`5,28
`
`w
`H,28
`1^,00
`
`Nach dem gleichen Verfahren, Jedoch ausgehend von entsprechenden
`Reagentien, erh'dlt man die Verbindungen mit den Code-Nummern
`780 077 und 780 112, die in der nachfolgenden Tabelle I angegeben
`sind.
`
`Tabelle I
`
`JP>-KJ
`R / W - Y
`
`- CH-
`
`OH
`
`;
`
`( i )
`
`9 0 9 8 0 9 / 1 0 1 S
`
`0444
`
`

`

`1 i
`8,57;
`8,75
`14,814
`fc.g '8,16
`3,71
`^,223 '11,35
`00
`5,27
`5,TS>
`11,75
`6,76
`7,97 10,02
`5,33
`>1,06
`5,70
`10,09
`10,37
`5,214
`6,56
`l'.,c6
`5,18
`7,00
`b, 814
`6,1414
`^,53
`7,214
`6,89
`6,57
`5,57
`3,83
`6,67
`6,25
`
`5,30
`14,85
`5,32
`5,20
`5,141
`
`66,148
`8,614
`66,148
`8,614
`8, lit, 59,22
`5^,07
`3,70
`11,29 58,08
`58,61
`11,86 bl,02
`10,07 6M7
`55,32
`Va98
`10,00 55,^
`59,06
`10,68
`61,27
`it.78
`-61*, 93
`5,05
`66,ll+
`l;,8l}
`66,0lt
`^,81
`614,66
`5,05
`63,91
`5,32
`68,22
`l+,68
`50,7^
`5,36
`63,75
`5,32
`62,87
`5,62
`
`15,28
`
`^,97
`^97
`14,68
`It,25
`M7
`5,70
`6,83
`7,97
`5,37
`'5,75
`5,38
`6,53
`6,91
`6,62
`. 7,27
`6,91
`6,51
`5,73
`3,86
`• 6,51
`6,07
`
`66,66
`66,66
`59.30
`53,98
`58,06
`58.86
`61,00
`614,72
`55,50
`55,71
`59,53
`61,1+2
`• 6h,96
`66 M
`' 65,96
`6U,96
`. 63.86
`68,21
`50,58
`63,86
`62 f61f
`
`•
`
`N
`
`H
`
`C
`
`N
`
`H
`
`C
`
`($)
`
`gef.
`
`{%)
`Elementaranalyse
`
`ber.
`
`78
`72
`55
`70
`71
`53
`60
`10
`55
`75
`39
`58
`51
`81
`30
`h8
`76
`10
`20
`68
`62
`
`%
`
`138
`135
`•135
`136 ,
`110
`102
`110
`• 12l4
`116
`i6h
`131
`137
`102
`119
`130
`108
`13I4
`1I40
`
`88 •
`120
`186
`
`32^,32
`32^,32
`
`•
`
`376.27
`2^5 ..23
`265f26 '
`236,25
`27873ii
`281j32
`. 280-27
`262.26
`293,31
`277,31
`289r32
`291,3^
`277931
`263,28
`299,31
`261,19
`263,28
`2219.26
`
`' (0C)
`
`wicht
`large- ' punkt
`
`Tobelle I
`
`770222
`770318
`77023l» '
`760557
`770231
`770230
`770155
`770328
`770501
`770126
`770131
`77015^
`770196,
`770^66
`770lt67
`770788 •
`770388
`770696
`770152
`770ii23
`770365
`
`CD
`
`Q
`
`CO
`o
`CXI
`CO
`a
`no
`
`m o
`H
`o
`m
`"D
`CO
`2:
`r-
`z
`Q
`33
`O
`
`NO,i l'17Hl6Br ^
`..•'j 312a12N20l*
`D13H15S05
`p12Kl6N203
`j ::15H22N203
`|b13Hi5KOUs
`;bl3Hi6N2G5
`!c13Wk
`|C15H19N05
`15H19NOl4.
`
`^
`
`fisWii
`p8Hi6N20^
`1i7nl6N206
`
`CM
`
`It-O-CHg-^—^
`lt~0—CH-— "
`fc-OCHg —
`0
`^0-CH^
`
`.
`
`icl6H21N^
`C15VT(\ •
`^ll4H17NOl4-
`i C17H17^
`C11H10F3N03
`Cll4H17NOl4
`C13H15N^
`
`.
`
`I4-0 CH2-<
`'1, €>~-o^CHs-
`I4 CP3
`3 7
`i|-C0C„H„n
`U—C0-Et
`
`•
`
`3-0 CH2 CN
`3"0CH2 CO CH3
`3-wCcC^
`4-ivn-i; jrt-
`l»-s CHg CO CH3
`rs-OH ^
`If-O-CH — f-CH
`If O(CH2)2- CIV
`14 0 CH2-C0-<
`14 0-(CH2)3- CH=CH2C
`l4-0-CH2-<Q
`14 O-CH2-^C| •
`' I4 0-CH2-^>-':.
`
`Summenforme1 Moleku-Schmelz- Ausbeute
`
`R
`
`Code~Nr.
`
`0445
`
`

`

`<J1
`
`."M-.II -""T- l.'""';<t"
`
`IB-nil... n
`
`4^..U
`
`13®
`4,®?
`6,^
`5,48
`4,52
`4,52
`9,46
`9,63
`9,44
`8,23
`7,49
`7»4l
`3,88
`3,75
`3,84
`3,68
`7,79
`
`59,51" 4,79 !
`61,15
`7,06
`59.67
`6,88
`56,87
`6,Ok
`62,26
`5,12
`59,01
`4,93
`611,28
`5,30
`6k,o8
`5,59
`6k,05
`5,kk
`63,5^
`^,58
`5M7
`3,76
`53,97
`3,80
`.57,33 Ml
`55,^3
`4,12-
`55,70
`It, 19
`55.66
`4,13
`6^,33
`5,69
`
`13,95
`4,74
`8,69
`5,53
`4,84
`4,59
`9,33
`9,33
`9,33
`8,18
`7,40
`7,40
`3,98
`3;8o
`3,80
`3,80
`7,86
`
`5,02
`7,17
`6,68
`5?97
`5,23
`4,95
`5,37
`5,37
`5,37
`4,42
`3,99"
`3,99.
`4,30
`4,11
`4,11
`4,11
`5,66
`
`.
`
`•
`
`•
`
`| 32"- J 59,79
`60,99 '
`59?6l
`56.91
` 62,28
`59 ? 00
`63,99
`63,99
`63,99
`63,15
`53.90
`53,90
`58,0^
`,55^5
`55,^5
`55,^5
`6k ,03
`
`73
`40'
`32
`48
`70
`46
`42
`33
`49
`22
`75
`50
`25
`36
`Uo
`50
`
`I 30iV30-'-"j-148
`295,39
`113
`322.35
`121 '
`253,25
`110
`289f2&
`162
`305.34
`153
`300?30
`144
`300,30
`162
`300,30
`138
`3^2,32
`93
`378,76
`114
`378.76
`132
`351.75
`110
`368,21
`135
`365,21
`135
`368,21
`i4o
`356,37
`212
`
`•
`
`c^H21TO35
`016^22^2%
`G12H15ira5
`C15H15KO5
`^15^15^4^
`pe^s's0!!
`hate's0*
`Cl6H^6^20k
`
`Wv
`
`"U-O-OH^
`
`1H>(C%)- O
`k-OCB^-OClL
`k QCH2-roi)
`
`0 z***\
`
`£
`
`V.'.
`
`It-OCHg——
`k-OCH^
`
`i-CliSgO^
` k-OCEg—Cn'H^C1^206
`:^OCH2—C1TH15CIP»O^
`C!17H-S5G;i2^0Ii
`lt-0 CHg—^p^-C) C^K^Cl^O^
`C^H^CijKO^
`^-OCHg—©—®
`
`• ^ocs2H®^r
`
`'
`
`CH-n ^ 19^20^2^5
`
`7706^5
`770180
`750601
`76090H
`770369
`770673
`770299
`770221
`770290
`770789'
`77079C
`1770672
`'770572
`7701*16
`77035it
`770268
`770569
`
`O
`3
`0
`£ '
`1,
`fu-
`V
`
`. ^ ^
`e '
`> i;
`
`v'
`
`-t
`. tv.i
`••o,
`
`m
`.H
`o
`•V,
`CD
`o
`03
`to
`a
`CD
`
`X
`
`H
`
`C
`
`N
`
`($)
`Elementaronalyse
`
` H
`
`. C
`ber.
`
`.
`
`(0C)
`punkt
`So hme IZHAU S teu t Q.
`
`{%)
`
`SummenformelMolekular-
`
`gewicht
`
`i
`
`H
`
`Code-Nr.
`
`To belie I - 1. Fortsetrung
`
`0446
`
`

`

`Ol
`o
`co
`CO
`10,11+ 60,66 5,85 9,98 co
`CO
`
`8,15
`5,91
`
`14,35 67,76
`56,93
`
`h I
`
`If, 07
`Mo
`
`7,89
`5,80
`
`67,68
`56,9^
`
`60,86 5,81+
`
`l+,li0
`
`6,1+7
`
`'1,65 67,^9
`
`6,36
`
`67,76
`
`M5
`
`7,50
`
`!I,59 66,85
`
`7,59
`
`66,06
`
`IK 071
`
`)+,78 65/20 8,16
`
`7,90
`
`65,50
`
`1
`
`OKX
`
`y
`
`5,01 6M^ 7,62 Mi
`
`7,58
`
`61+, 1+9
`
`b,39 67,81 7,71 MS
`
`7,89
`
`67,69
`
`it,53
`
`^,59 66,89 7,85
`
`7,59
`
`66,86
`
`UjO 65,53 8,12 k,6b
`
`7,90
`
`65,50
`
`5,01 614,2^ 7,00 ^,85
`
`7,59
`
`6^119
`
`•
`
`i+,3fl 7,95
`
`8,1 <4 59,Mi
`
`14,68
`
`59,30
`
`k,22 65,29 5,76 3,9^
`
`65,16 5,^7
`
`80
`62
`
`55
`
`32
`
`i+s
`
`02
`
`15
`
`73
`
`35
`
`22
`
`53
`
`1+!+
`
`62
`
`9^
`
`99
`
`06
`
`92
`
`II
`
`{%)
`
`H
`
`C
`
`21
`
`K
`
`C
`
`ber. (%)
`
`Elementaranalyse
`
`UJ
`
`Ausbeute
`
`gewicht -
`^lolekular- Schmelz-
`
`punkt
`
`Sutnmenformel
`
`R
`
`Tabelle 1-2. Fortsetzung
`
`Orv
`cT0-
`
`CK
`/^VXQ -
`
`0
`
`Et
`
`Etv.
`
`.-f-CII2 - 0 -
`
`0 -
`
`0
`
`CH2)2 - 0 -
`/
`
`0 -
`
`NOg'
`
`Q- o - CH2 -
`
`ci
`
`78 0259-
`
`77 090^
`
`78 0076
`
`77 1197
`
`77 12l>9
`
`77 09^9
`
`77 15^5
`
`77 121+6
`
`77 1082
`
`77 1263
`
`77 1181
`
`Code-Nr.
`
`0]
`o
`
`CO
`o
`CO
`03
`a
`CO
`
`-a •<
`O
`O
`
`» 1 »l HI
`
`111
`15^
`
`3.19,39
`295,28
`
`276,28
`
`128
`
`301,33
`
`Cll+ Hl6 N20^
`
`' C17 H19 N0^
`
`136
`
`81+
`
`100
`
`100
`
`ll+2
`
`123
`
`(0")
`
`305,36
`
`C.j !!23 NO^
`
`.
`
`293.35
`
`279,33
`
`319,39
`
`305,36
`
`293,35
`
`279,33
`
`3^,31
`
`331,79
`
`Cl6 ^ N0H
`
`C15 H21
`
`C18 H25 N0^
`
`C17 H23 ^
`
`C16 H23
`
`C15 H21 NOi+
`
`C17 Hl6 N2 06
`
`cl0 H15 CI KO3
`
`NO^ _
`
`Ctl: HI7
`
`QAQ - ...C18
`0 -
`
`0
`
`ZZL
`
`78,0030
`77 0962
`
`MI*.
`
`0447
`
`

`

`cn
`CO
`CD
`CO
`. oo
`
`6,72
`
`3,90
`
`53,47
`
`7,40
`
`3,99
`
`53,90
`
`11,30 58,03 3,85 11,37
`
`4,09
`
`58,53
`
`Mo 7,43
`
`56,16
`
`7,73
`
`4,17
`
`56,35
`
`7,70
`
`6,04
`
`64,78
`
`7,56
`
`5,93
`
`64.85 .
`
`7,94
`
`5,72
`
`60,71
`
`7,52
`
`5,41
`
`61,28
`
`3,45
`
`3,56
`
`3,29 . 47,85
`
`3,79
`
`48,02
`
`78
`
`85
`
`02
`
`32
`
`47
`
`8,71
`
`6.00
`
`64,71
`
`8,91
`
`5,77
`
`64,95
`
`V
`>2
`Osl
`I
`
`4,43
`
`7,02
`
`62,29
`
`4,56
`
`6,89
`
`62,52
`
`4,87
`
`7,21
`
`H,56 62,46
`
`6,89
`
`62,52
`
`it,1*5
`
`6,81+
`
`4,56 62,58
`
`6,89
`
`62,52
`
`^38
`
`5,52
`
`5^,13
`
`n,50
`
`5,50
`
`5^,00
`
`U}0C'
`
`5,28
`
`51,51
`
`11,28
`
`5,23
`
`51,35
`
`K
`
`H
`
`C
`
`N
`
`H
`
`C
`
`gef.• . [i)
`
`(Jj)
`
`ber.
`
`ElementaranaJ.yse
`
`%
`
`76
`
`88
`
`72
`
`65
`
`54
`
`55
`
`60
`
`178
`
`176
`
`110
`
`208
`
`202
`
`145
`
`132
`
`378,76
`
`369,32
`
`370,39
`
`372,37
`
`425,21
`
`314,33
`
`.
`
`160
`
`307,34
`
`130
`
`112
`
`307,34
`
`307,3^
`
`0- C17 Ki5CiN2 06
`
`cl8 ni5 N3 06
`
`CL_
`
`o—
`
`f( V =y
`
`02tt
`F-O
`
`CN NO2.
`'/ ^
`
`77 1199
`
`77 1125
`
`77 0955
`
`-
`
`EtCONH
`
`78 0443
`
`gewichi
`Molekular- Schmelz- Ausbeute
`
`punkt
`
`Sujnmenforrael.
`
`R
`
`To belle 1-3. Fortsetzung
`
`362,31
`
`C1Y 11.5 FN, 0fi
`
`C20 n22 N!> 05
`
`C19 H20 N2 06
`
`c17 H16 1 N04
`
`c17 "18 K2 04
`
`C16H21 N05
`
`C16 ? 21 K05
`
`C16 H21 N05
`
`118
`
`311,35
`
`Cll* H17 N05 3
`
`]60
`
`0C
`
`327,^2
`
`S2
`
`Cll;
`
`CJHgOCONH -^y^O-
`. p
`P^o-
`
`I
`
`NHg
`
`0
`
`•o -
`
`0 -
`
`0^>
`
`er\0.
`C^o-
`
`c-
`
`78 0182
`
`77 1321
`
`*'<*
`
`77 1240
`
`cn
`o 77 1301
`
`<x>
`a
`a>
`CO
`o 77 0900
`73 0112
`
`78 003^
`
`CO
`
`"O -<
`O
`O
`
`73 0080
`
`Code-Nr.
`
`0448
`
`

`

`cn
`o
`CO
`CO
`I CO
`CO
`KJ
`
`I
`
`h,66 |
`
`5,72
`
`72,92
`
`5,80
`
`73,20
`
`Ti
`
`215
`
`295,32
`
`i _'.JI
`
`. ii-L'.'j
`
`. jzi'.'-vrir
`
`©~CS"C%^ W03
`
`lrtr
`
`78 056l(
`
`I
`
`\
`tx>
`L/st
`
`9,7c I
`
`61,75 6,25
`
`9,65
`
`6,25
`
`62,05
`
`1J502
`
`52,98 5,35
`
`1{,10
`
`5,61
`
`52,76
`
`MS
`
`59,Olj 1|,96
`
`h,95 b,59
`
`59,00
`
`^ >72
`
`5,22
`
`k,8h 61,90
`
`5,23
`
`62,28
`
`35
`
`58
`
`23
`
`H
`
`H
`
`C
`
`N
`
`H
`
`c
`
`(#)
`
`gef.
`
`(ft)
`
`ber'.
`
`Elementaranalyse
`
`
`
`%•
`
`Ausbeut?-
`
`68
`
`Iks.
`
`•
`
`lliU
`
`131
`
`0C
`
`290,31
`
`3in9Mf
`
`305, S1!
`
`209,20
`
`C15 ^16 "a0"!
`
`0,5 H,9 n S2
`o15 H15 MO,, S
`
`. C15 H15 "05
`
`gewicht
`Molekular- Schmelz-
`
`punkt
`
`Summenformel
`
`R
`
`'Code-Nr.
`
`Tabelle I - 4« Fortseizung
`
`0—•
`
`0—
`
`cro-
`
`cw
`
`_OAA^
`
`s--
`
`78 0562
`
`78 0077
`
`77 IO67
`
`77 0979
`
`a>
`o
`
`CO
`
`00
`to
`O
`CO
`
`0449
`
`

`

`2 8 3 6 3 0 5
`
`3 0
`
`Die Verbindungen der Formel (l) wurden an Versuchstieren unter-
`sucht und es zeigte sich, daB sie Aktivitaten aof dem psycho-
`tropen Gebiet ols potentielle Antidepressionsmittel aufwiesen.
`Dies© Aktivitaten wurden durcH die nachfolgend beschriebenen
`Tests nachgewiesen:
`
`Test A
`Potenzierung von generellem Zittern bei der Maus, hervorgerufen
`durch eine intraperitoneale Injektion (200 mg/kg) von dl-5-
`Hydroxyt ryptop ha n nach dem von C. Gouret und G« Raynaud in
`"J. Pharmacol.'(Paris)", 1974, 5, 231, beschriebenen Versuch.
`
`Test B
`Antagonismus gegenUber Ptosis, die 1 Stunde nach der intraveniJsen
`Injektion (2 mg/kg) von Resorpin bei dex Maus beobachtet wurde,
`nach dem von C. Gouret und J. Thomas in "J* Phaimacol. (Paris)"/
`1973, 4, 401, beschriebenen Versuch.
`
`Test C
`Verminderung der Dichte der Hinterhaupt-Pontogenicul-Punkte
`(P.G.O*), hervorgerufen duxch eine intravenose Injektion (0,5 mg/«
`kg) von Resorpin bei der Katze nach dem von von A. Coston und
`C. Gouret in "J. Pharmacol. (Paris)", 1976, 7, 409, beschriebenen
`Versuch.
`
`Die Ergebnisse dieser drei Tests sowie diejenigen einer notorisch
`bekannten Vergleichssubstanz, dem Toloxaione, sind in der nach-
`folgenden Tabelle II zusamniengefaBt.
`
`9 0 9 8 0 9 / 1 0 1 6
`
`0450
`
`

`

`^ IfO -
`
`2 8 3 6 3 0 5
`
`Tabelle II
`
`getestete Verbin-
`dungen
`
`Tes-fc A
`DE 50 (mg/kg/p.o.)
`
`Test B
`DE 50 (mg/kg/p.o.)
`
`Test, C
`DS 50 (mg/kg/i.p.)
`
`a)erfindunpsqemaB
`
`770 365
`770 1*23
`770 152
`770 696
`770 388
`770 788
`770 *167
`770 k66
`770 196
`770 15^
`770 131
`770 126
`760 90U
`750 601
`770 180
`770 501
`770 328
`770 155
`770 230
`770 231
`760 557
`770 23^
`770 318
`770 222
`770 569
`770 268
`770 35^
`770 U16
`770 572
`770 672
`770 790
`770 789
`770 298
`
`i
`f
`
`1
`
`5
`15
`
`3
`9
`T6
`20
`5,5
`16,5
`8,5
`31
`U5
`
`35
`16
`lU
`110
`9
`
`5,2
`6
`
`30
`3
`8,5
`
`29
`35
`20
`15
`9
`6,25
`2,8
`9*6
`20
`50
`2,5
`8
`50
`70
`35
`22
`25
`50
`
`ilO
`7,3
`1,5
`25
`2,8
`5
`7
`25
`6,2
`6,3
`25
`50
`3
`55
`
`25
`25
`25
`20
`12,5
`12,5
`1 > 2
`6 > 2
`
`1 ? •
`50
`3
`11
`50
`8
`t5
`25
`35
`22,5
`6,25
`50
`3,3
`0,7
`16
`1, 2
`2,5
`8,5
`30
`10
`3 , 1 2
`19
`25
`2
`12,5
`
`9 0 9 8 0 9 / 1 0 1 6
`
`0451
`
`

`

`Tabelle II - Fortsetzung
`
`--
`
`2836305
`
`getestete Verbin-
`dungen
`
`Test A
`DS 50 (mg/kg/p.o.)
`
`Test B
`DE 50 (mg/kg/p.o.)
`
`Test C
`DE 50 (mg/kg/i.p.)
`
`15
`
`8
`
`a) erfindungsqemaB
`770 221
`770 299
`770 673
`770 81*5
`771 181
`771 263
`771 082
`771 246
`771 21*5
`770 9h9
`771 2U9
`771 197
`780 030
`780 076
`770 98H
`780 259
`770 962
`780 080
`7 8 0 1 1 2
`770 900
`780 03^
`771 301
`771 240
`771 321
`780 182
`780 443
`. 770 955
`771 125
`771 199
`780 562
`770 979
`771 067
`780 077
`"b) Verqleich
`
`"
`
`11,8
`20
`16
`6,25
`6,25
`4
`1,3
`17
`1,5
`10
`22 j 5
`25
`3
`2,3
`10
`1,25
`26
`50
`5
`50
`4,4
`1*9
`35
`25
`4o
`3,7
`13
`3 , 1 2
`1 , 1
`0,8
`i4
`7,5
`25
`
`3,12
`12,5'
`35
`125,5
`6,,25
`3,1
`0,7
`23
`2
`16
`50
`16
`53
`7
`25
`3,2
`50
`50
`5,2
`25
`6,2
`3
`50
`20
`25
`12,5
`7
`1,56
`0,8
`
`35
`12,5
`44
`
`T0L0XAT0NE
`
`§ > 0 9 8 0 9 / 1 0 1 6 50
`
`28
`
`0452
`
`

`

`2836 3 0 5
`
`- j f f -
`k t
`
`Wie aus den vorstehend angegebenen Ergebnissen und denjenigen,
`die in der nachfolgenden Tabelle III angegeben sind, hervorgeht,
`ist der Abstand zwischen den letalen Dosen und den pharmakologisch
`aktiven Dosen ausreichend groBf ura die thejapeutische Verwendung
`der erfindungsgernHfien Verbindungen zu erlaifben.
`
`Tabelle III
`
`getestete Verbindunri
`gen
`
`akute Toxizitat bei der Maus
`verabreichte Dosis
`(mg/kg/p.o.)
`
`Mortal!tat(^)
`
`DL 50
`(mg/kg/p.o.)
`
`a) erfindunpsRemafi
`
`770 131
`770 222
`770 23h
`760 652
`760 557
`771 082
`771 2U5
`771 301
`770 955
`b) Verqleich
`
`*
`
`-
`
`T0L0XAT0NE
`
`1000
`1000
`1000
`1000
`
`2000
`
`0
`0
`0
`0
`
`17
`
`} 2000
`
`1»
`
`1850
`
`9 0 9 8 0 9 / 1 0 1 S
`
`0453
`
`

`

`2836305
`
`- X ' -£3
`
`Wie aus den in den vorstehenden Tabellen angegebenen Ergebnissen
`hervorgeht, haben die erfindungsgemaBen Verbindungen der Formel
`(l) eine Aktivitat (Wirksamkeit), die derjenigen der Vergleichs-
`verbindung Uberlegen oder zumindest gleich ist. Sie sind indi-
`ziert bei endogenen und exogenen depressiven Zustanden und sie
`kiJnnen auf oralem Wege in Form von Tabletten, Dragees, Kapseln,
`in einer mittleren Dosis von 500 rag aktivem Prinzip pro Tag
`verabreicht werden. Sie kSnnen auch in Form von injizierbaren
`LSsungen in einer Menge von 5 bis 50 mg aktivem Prinzip pro Tag
`verabreicht werden, wobei das verwendete LKsimgsmitiel aus bi-
`ntlren oder ternSren Mischungen besteht, die beispielsWeise
`Wasser, Polypropylenglykol oder Poly<3thylenglykol (Sorte 300
`bis 400) oder irgendein anderes physiologisch vertragliches LS-
`sungsmittel enthalten; die relativen Mengenverhaltnisse der
`verschiedenen Lbsungsmittel werden in AbhBngigkeit von der ver-
`abreichten Dosis eingestellt*
`
`Die Erfindung wurde zwar vorstehend unter Bezugnahme auf bevor-
`zugte AusfUhrungsformen nUher erlautert, es ist Jedoch fUr den
`Fachmann selbstverstUndlich, dafi sie darauf keineswegs beschrankt
`ist, sondern dafi diese in vielfacher Hinsicht abgeBndert und
`modifiziert werden kiJnnen, ohne daB dadurch der Rahmen der vor-
`liegenden Erfindung verlassen wird.
`
`Die oben angegebenen Synthese-Zwischenprodukte der Formeln (X)r
`(xi), (xiri), (xv), (xvix), (XVIII), (xxi), (xxn), (XXIII).
`(XXIV), (XXV) und (XXVl) stellen neue Verbindungen dar und bilden
`einen weiteren Gegenstand der Erfindung.
`
`9 0 9 8 0 9 / 1 0 1 8
`
`0454
`
`

`

`UK Patent Application GB
`
`(19)
`
`(12)
`
`2 140 687 A
`
`(11)
`
`(43) Application published 5 Dec 1984
`
`(21) Application No 8334189
`
`(22) Date of filing 22 Dec 1983
`
`(30) Priority data
`
`(31) 493760
`
`(32) 11 May 1983
`
`(33) US
`
`(71) Applicant
`Alza Corporation, (USA—California).
`950 Page Mill Road, Palo Alto. California 94304,
`United States of America
`
`(72) Inventors
`Patrick S. L. Wong,
`Brian Barclay,
`
`Joseph C. Deters,
`Felix Theeuwes
`
`(74) Agent and/or address for service
`F. J. Cleveland & Company. 40—43 Chancery Lane,
`London, WC2A 1JQ
`
`(51) [NT CL3
`A61K9/00 A61M 31/00
`
`(52) Domestic classification
`A5B 829 832 835 M Q
`
`(56) Documents cited
`GB A 2116842
`GB
`1551898
`GB
`1511614
`GB
`1385521
`
`(58) Field of search
`A5B
`
`EP A2 0040899
`EP A1 0010876
`4327725
`US
`4111202
`US
`
`(54) Osmotic drug delivery system
`
`(57) An osmotic system is disclosed comprising a wall
`12, 23 formed in at least a part of a semipermeable
`material that surrounds a compartment 14. The
`compartment contains a first osmotic composition 15,
`16, 17 comprising a beneficial agent 15, and a second
`and different osmotic composition 18, 19. A
`passageway 13 in the wall connects the first
`composition with the exterior of the system.
`
`17
`16
`15
`
`13
`
`FIG. 2
`
`'-itiTiSf
`
`14
`II
`
`18
`
`19
`
`12
`
`FIG. 5
`20
`
`/\i
`
`f
`
`10
`
`i
`
`i
`
`•—' ? ' 9 3
`
`19
`18
`
`16
`15
`17
`
`2K
`22
`
`o
`CD
`N>
`
`O
`(J>
`00
`>
`
`This print takes account of replacement documents submitted after the date of filing to enable the application to comply with the formal requirements
`'of the Patents Rules 1982.
`
`0455
`
`

`

`z i i O t i H l
`
`13
`
`FIG. 2
`
`17
`16
`15
`
`/
`
`19
`
`• *
`
`. •% j
`
`- /
`
`J
`
`14
`II
`
`12
`
`18
`
`13
`
`FIG. 4
`10
`14
`
`II
`
`/ - /
`
`19
`
`18
`
`12
`
`13. v
`
`20
`
`FIG. 7
`II
`
`FIG. I
`
`>h
`
`13
`
`^l0
`
`\
`
`^•11
`
`12
`
`13
`
`FIG. 3
`
`16
`
`t
`
`cr/
`12
`
`19
`
`18
`
`FIG. 5
`20
`
`16
`15
`17
`
`i
`
`i
`
`/
`/
`
`/
`
`/I3
`
`II
`
`10
`
`/
`
`5^14
`a r >//-23
`
`19
`18
`
`XJL
`
`/
`rr7
`J
`21
`22
`
`15
`
`14
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`
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`1
`
`GB 2 140 687 A
`
`1
`
`SPECIFICATION
`Osmotic Device With Dual Thermodynamic Activity
`
`This invention pertains to both a novel and unique delivery system. More particularly, the
`invention relates to an osmotic device comprising a wall formed in at least a part of a semi-permeable
`5 material that surrounds a compartment comprising: (1) a first osmotic composition comprising a
`beneficial agent, and preferably an osmagent and/or an osmopolyer, said composition in contacting
`arrangement with (2) a second osmotic composition comprising an osmagent and an osmopolymer. A
`passageway through the wall connects the exterior of the osmotic device with the first osmotic
`composition containing the beneficial agent for delivering the first composition from the osmotic
`10 device. The osmotic device is useful for delivering beneficial agents that because of their solubilities are 10
`difficult to deliver in a known amount at a controlled rate from an osmotic dispensing system.
`
`5
`
`35
`
`Background of the Invention
`Since the beginning of antiquity, both pharmacy and medicine have sought a delivery system for
`administering a beneficial drug. The first written reference to a dosage form is in the Eber Papyrus,
`15 written about 1 552 B.C. The Eber Papyrus mentions dosage forms such as anal suppositories, vaginal
`pessaries, ointments, oral pill formulations, and other dosage preparations. About 2500 years passed
`without any advance in dosage form development, when the Arab physician Rhazes, 865—925 A.D.,
`invented the coated pill. About a century later the Persian Avicenna, 980—1037 A.D., coated pills with
`gold or silver for increasing patient acceptability and for enhancing the effectiveness of the drug. Also
`20 around this time, the first tablet was described in Arabian manuscrips written by al-Zahrawi, 936—
`1009 A.D. The manuscrips described a tablet formed from the hollow impressions in two facing tablet
`molds. Pharmacy and medicine waited about 800 years for the next innovation in dosage forms, when
`in 1883 Mothes invented the capsule for administering drug. The next quantum leap in dosage forms
`came in 1972 with the invention of the osmotic delivery device by inventors Theeuwes and Higuchi as
`25 disclosed in United States Pat. Nos. 3,845,770 and 3,916,899. The osmotic devices disclosed in those
`patents comprise a semi-permeable wall that surrounds a compartment containing a useful agent. The
`wall is permeable to the passage of an external fluid, and it is substantially impermeable to the passage
`of useful agent. There is a passageway through the wall for delivering the useful agent from the
`osmotic device. These devices release useful agent by fluid being imbibed through the semi-permeable
`30 wall into the compartment at a rate determined by the permeability of the semi-permeable wall and the
`osmotic pressure gradient across the semi-permeable wall to produce an aqueous solution containing
`useful agent that is dispensed through the passageway from the device. These devices are
`extraordinarily effective for delivering a useful agent that is soluble in the fluid and exhibits an osmotic
`pressure gradient across the semi-permeable wall against the external fluid.
`A pioneer advancement in osmotic delivery devices was presented to the dispensing arts by
`inventor Felix Theeuwes In United States Patent No. 4,111,202. In this patent, the delivery kinetics of
`the osmotic device is enhanced for delivering useful agents that are insoluble to very soluble in the
`fluid, by manufacturing the osmotic device with a useful agent compartment and an osmagent
`compartment separated by a film. The film is movable from a rested to an expanded state. The osmotic
`40 device delivers agent by fluid being imbibed through the semi-permeable wall into the osmagent
`compartment producing a solution that causes the compartment to increase in volume and act as a
`driving force that is applied against the film. This force urges the film to expand against the useful
`agent compartment and correspondingly diminish the volume of the useful agent compartment,
`whereby useful agent is dispensed through the passageway from the osmotic device. While this device
`45 operates successfully for its intended use, and while it can deliver numerous useful agents of varying
`solubilities, its use can be limited because of the manufacturing steps and costs needed for fabricating
`and placing the movable film in the compartment of the osmotic device.
`In United States Patent No. 4,327,725 patentees Richard Cortese and Felix Theeuwes provided
`an osmotic dispensing device for delivering beneficial agents, that because of their solubilities in
`50 aqueous and biological fluids, are difficult to deliver in meaningful amounts at controlled rates over
`time. The osmotic devices of this patent comprise a semi-permeable wall surrounding a compartment
`containing a beneficial agent that is insoluble to very soluble in aqueous and biological fluids, and an
`expandable hydrogel. In operation the hydrogel expands in the presence of external fluid that enters the
`device thereby causing the beneficial agent to be dispensed through the passageway from the device.
`55 This device operates successfully for its intended use, and it delivers many difficult to deliver beneficial
`agents for their intended purpose. Now it has been observed, its use can be limited because the
`hydrogel lacks a present ability to imbibe sufficient fluid for the maximum self-expansion needed for
`.
`urging the beneficial agent from the device.
`ft will be appreciated by those versed in the dispensing art, that if an osmotic device can be
`60 provided that exhibits a high level of osmotic activity for delivering a beneficial agent by generating in
`situ an expanding force sufficient for delivering the maximum amount of agent at a controlled rate from
`an osmotic device, such an osmotic device would have a positive value and represent an advancement
`in the dispensing art. Likewise, it will be immediately appreciated by those versed in the dispensing art
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`0463
`
`

`

`that if an osmotic device is made available possessing dual thermodynamic osmotic activity for
`delivering increased amounts of a beneficial agent, said osmotic device would find practical application
`in the fields of pharmacy and medicine.
`
`GB 2 140 687 A
`
`2
`
`2
`
`5
`
`Object of the Invention
`Accordingly, in view of the above presentation, it is an immediate object of this invention to
`provide an osmotic system that represents a further improvement and advancement in the dispensing
`art.
`
`10
`
`15
`
`20
`
`Another object of the invention is to provide an osmotic system manufactured in the form of an
`osmotic device for delivering in vivo a beneficial drug that is difficult to deliver and now can be
`delivered by the osmotic device provided by this invention in therapeutically effective amounts over
`time.
`Another object of the invention is to provide an osmotic system possessing dual osmotic activity,
`which system comprises a compartment containing a first osmotic composition comprising a drug, and
`preferably an osmagent and/or an osmopolymer, and a second osmotic composition comprising an
`osmagent and an osmopolymer, with the compositions acting in concert for delivering the drug from
`the osmotic device.
`Yet another object of the invention is to provide an osmotic device having means for high loading
`of a water-insoluble or a slightly water-soluble drug and means for delivering the drug in either
`instance at a controlled rate and continuously over time.
`Yet another object of the invention is to provide an osmotic device that can deliver a pH
`dependent beneficial agent by providing a neutral medium for delivering the beneficial agent in a finely
`dispersed form for increasing its surface area and for maximizing