W094/09010 •
`
`• PCT /EP93/02604
`
`- 33 -
`
`Example 28: 40-0-£2-(4' ,5'-dicarboethoxv-1'.2' .3'-triazol-1 '-vl)-ethvlJ-rapamvcin
`
`98 mg of 40-0-(2-azidoethyl)-rapamycin and 32 mg d.iethylacetylene d.icarboxylate
`
`are suspended in 0.5 ml toluene and heated at 65 C for Sh. Tile reaction mixture is then
`
`cooled at room temperature. loaded on 10 g silica gel and eluted with hexane/ethyl acetate
`
`1/1 to afford the title product: MS (FAB) m/z 1175 (20%,M+Na); 1121 (15%, M-MeOH);
`
`1103 (60%, M-(MeOH+H20))
`
`H-NMR (CDC13) d: 0.62 (lH, q, J=12 Hz); 1.40 (3H, t, J=8 Hz); 1.42 (3H, t, J=8 Hz); 3.13
`
`(3H, s); 3.25 (3H, s); 3.33 (3H. s)
`
`MBA (rel. IC50): 2.7
`
`IL-6 dep. prol. (rel. IC50): 12
`
`The previous examples may also be made using as starting material instead of
`
`rapamycin, 9-deoxo-rapamycin, 26-d.ihydro rapamycin, or 9-deoxo-, 26-d.ihyd.ro-rapamycin.
`
`Alternatively, and preferably, as described e.g., in example 20, the rapamycin compounds of
`
`the above examples may be hydrogenated or reduced, using suitable protecting groups where
`
`necessary. The following novel methods for reducing the keto at C9, or hydrogenating the
`
`keto at C26 are provided:
`
`Example 29: Removal of keto at C9
`
`A stream of hydrogen sulfide is passed at room temperature through a stirred
`
`solution of 3.2 g (3.5 mmol) of rapamycin in 50 ml pyridine and 2.5 ml DMF. The solution
`
`turns from colorless to yellow. After two hours, the introduction of hydrogen sulfide is
`
`stopped and stirring is continued for five days, during which time the solution turns
`
`gradually orange. 1LC and HPLC analysis verifies complete consumption of the starting
`
`material and the presence of a single new compound. The solution is purged with nitrogen
`
`for one hour and concentrated under reduced pressure. The residue is taken up in ethyl
`
`acetate, washed with cold lN HCl solution (3x), saturated sodium bicarbonate solution and
`
`saturated brine. The organic layer is dried over anhydrous sodium sulfate and filtered and
`
`concentrated under reduced pressure. The residue is ta.ken up in ether and the precipitated
`
`
`
`

`
`W094/09010 •
`
`• PCT /EP93/02604
`
`- 34 -
`
`sulfur is filtered off. Concentration of the ethereal solution followed by column
`chromatography on silica gel (10:4: 1 CH2Cl2'i-Pr20/Me0H) yields 9-deoxorapamycin as a
`colorless foam. The identity of the product is confirmed by nuclear magnetic resonanc,e
`
`spectroscopy (NMR), mass spectrometry (MS), and/or infrared spectrosopy (IR). 9- ·
`deoxorapamycin is found to exhibit the following characteristic physical data: 1H NMR
`(CDC~) o 1.61 (3H,dJ = 1 Hz, Cl7-CH3), 1.76 (3H,dJ = 1.2 Hz,C29-CH3), 2.42 (lH,d,J =
`14.5 Hz, H-9), 2.74 (lH,d,J = 14.5 Hz, H-9), 3.13 (3H,s,C16-0CH3) 3.5 (3H,s,C27-0CH3),
`3.40 (3H,s,C39-0CH3), 5.40 (lH,dJ = 10 Hz, H-30), 5.57 (1H,dd.J1 = 8.6 Hz, 12 = 15 Hz,
`H-22), 5.96 (lH,d,J = 9 Hz, H-18), 6.09 (lH,d,J = 1.7 Hz, 10-0H), 6.15 (1H,dd,J1 = 10 Hz,
`12 = 15Hz, H-21), 6.37 (1H,dd.J1 = 1.5 Hz, 12 = 5 Hz, H-19), 6.38 (lH,J = 9.5 Hz, H-20).
`13C NMR (CDC13) o 38.5 (C-9). 98.0 (C-10), 170.7 (C-1), 173.0 (C-8), 208.8 (C-32), 216.9
`(C-26).
`
`MS(FAB) m/z 922 8[M+Na+]), 899 (M+), 881 ([M-H2on. 868 ([M-OCH3t}, 850
`([M-(H20+0CH3)n.
`
`
`IR (major peaks)(cm· 1) 987, 1086, 1193, 1453, 1616, 1717, 1739, 3443.
`
`MBA (rel. ICs0):
`MLR (rel. ICso ): 14
`
`IL-6 dep. prol. (rel. ICso ): 9
`
`Example 30: Dihvdrogenation of keto at C26
`
`To a stirred solution of 421 mg (1.6 mmol) of tetramethylammonium
`
`triacetoxyborohydride in 2 ml of acetonitrile is added 2 ml of acetic acid. The resulting
`
`mixture is stirred for 30 minutes at room temperature and cooled to _35·c. At this
`
`temperature a solution of 180 mg (0.2 mmol) of 9-deoxo-rapamycin in 1 ml of acetonitrile is
`
`added and the resulting mixture is allowed to stir for 24 hours. The mixture is quenched
`
`with a saturated sodium potassium tartrate solution and allowed to warm to room
`
`temperature. Stirring is continued until both layers are clear and ethyl acetate is added. The
`
`layers are separated and the aqueous layer is extracted twice with ethyl acetate. The resulting.
`
`organic solution is washed once with a 10% sodium bicarbonate solution and twice with
`
`
`
`

`
`W094/09010 •
`
`• PCT /EP93/02604
`
`- 35 -
`
`saturated brine, then dried over anhydrous sodium sulfate, filtered and concentrated under
`
`reduced pressure. The residue is purified by column chromatography on silica gel (90: 10
`
`AcOEt-hexane). As the starring material in this case was 9-deoxoraparnycin, the final
`
`compound is 9-deoxoraparnycin, 26-dihydrorapamycin is produced as a colorless foam,
`having the following characteristic spectroscopic data: 1H NMR (CDC13) (major isomer) o.9
`(3H,d,J = 6.9 Hz, CHCH3), 0.93 (3H,d,J = 6.9 Hz, CHCH3), LOO (3H,d,J = 6.9 Hz CHCH3),
`1.07 (3H,d,J = 6.9 Hz, CHCH3), 1.17 (3H,d,J = 6.9 Hz, CHCH3 ), 1.61 (3H,d,J = !Hz,
`Cl 7-CH3 ), 1.73 (3H,d,J = 1.2 Hz, C29-CH3), 2.43. (lH,dd,J = 4.1 and 16.0 Hz, H-33), 2.46
`(lH.d,J = 13.8 Hz, H-9), 2.58 (IH,m.H-25), 2.77 (lH,d,J = 13.8 Hz, H-9), 2.82 (lH,dd,J =
`8.3 and 16.0 Hz, H-33), 3.17 (IH,dd,J = 4.1 and 9.2 Hz, H-27), 3.61 (2H,m, H-14 and H28),
`5.19 (IH,ddd,J = 4.1, 4.6 and 8.3 Hz, H-34), 5.49 (lH, broad d,J = 5.0 Hz, H-2), 5.56
`(lH,d,J = 9.1 Hz, H-30), 5.75 (IH,dd,J = 6.9 and 14.7 Hz, H-22), 5.76 (lH,s,10-0H), 5.99
`(lH,broad d,J = 9.2 Hz, H-18), 6.10 (lH,m,H-21), 6.36 (2H,m,H-19 and H-20);
`
`MS (FAB) m/z 924 ([M +Na]), 852 ([M-(H20 + CH30)n.
`MBA (rel. IC50): 47
`MLR (rel. IC50 ): 134
`IL-6 dep. proL (rel. IC50 ): 78
`
`26-dihydrorapamycin is prepared in the same manner. using rapamycin in place of
`
`9-deoxorapamycin. This product has the following characteristic spectroscopic data:
`13C-NMR (CDC13) (major isomer) d = 208.3 (C-32); 194.0 (C-9); 169.3 (C-1); 166.6 (C-8);
`140.9 (C-22); 136.5 (C-29); 136.2 (C-17); 133.5 (C-20); 129.l (C-21); 128.7 (C-18); 126.2
`
`(C-30); 125.3 (C-19); 98.6 (C-10); 84.4 (C-39); 83.9 (C-16; 81.6 (C-27); 75.4 (C-34); 74.3
`(C-28); 73.9 (C-40); 72.9 (C-26); 67.4 (C-14); 59.l (27-0CH3 ); 56.6 (39-0CH3); 55.9
`(16-0CH3); 51.3 (C-2); 46.8 (C-31); 44.3 (C-6); 40.4 (C-33); 40.4 (C-25); 39.5 (C-24); 38.8
`(C-15); 38.0 (C-36); 34.3 (C-23); 34.2 (C-38); 33.5 (C-11); 33.3 (C-37); 33.2 (C-35); 31.5
`(C-42); 31.3 (C-41); 30.9 (C-13); 27.1 (C-12); 27.0 (C-3); 25.2 (C-5); 21.4 (23-CH3); 20.7
`(C-4); 17.3 (ll-CH3 ); 16.l (31-CH3); 15.9 (35-CH3 ); 14.4 (25-CH3); 14.2 (29-CH3 ); 10.3
`(17-CH3).
`
`Sb
`
`/~
`
`
`
`

`
`WO 94/09010 e '· .,~
`
`PCT /EP93/02604
`
`- 36 -
`
`MS (FAB) m/z : 884 (M-OCH3, 35%); 866 (M-[OCH3 + H20], 100%; 848 (M-[OCH3 + 2
`H20], 40%).
`MBA (rel. IC50 ): 1.7
`MLR (rel. IC50 ): 1
`IL-6 dep. prol. (rel. IC50 ): 7.5
`
`37
`
`
`
`

`
`MUI}
`'~ENT CLAIM
`I
`FEL
`'mONSHEET
`(FOP.. ~ jORM PT0-875)
`.
`·~· "\\"11
`APTIR
`AfTIR
`AS PILID
`lot AMINDMINT 2•d AMINDMINT
`iND. '.,;
`'olP.
`IND.
`DIP.
`
`-DI,,
`
`,IND~
`I
`
`..
`
`I
`I
`
`tJ.
`
`.'.
`
`l i
`
`1
`,2,
`3
`,4
`.s
`6
`1·
`
`8
`9
`10
`11
`12
`13
`
`"'
`
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`89
`40
`41
`42
`48
`44
`46
`46
`47
`48
`49
`60
`i .J
`TOTAL
`IND.
`TOTAL 1/i/
`DEP.
`~~..\iU:s l1'1 ·1
`
`( ~"!
`
`'
`
`- ··~,,-
`
`.
`
`1,
`
`..
`
`'
`
`-..J
`I
`
`- J TOTAL
`
`IHO,
`TOTAL
`OIP.
`~t'IfJ-s
`
`dYI 41~13 I
`.
`~-,l
`I
`I
`...
`~...,.
`.
`t I AIMS
`
`"":..;
`
`61
`52
`63
`64
`SS
`56
`57
`58
`59
`80
`61
`62
`83
`64
`85
`ff
`87
`68
`89
`70
`71
`72
`73
`74
`76
`76
`77
`78
`79
`80
`81
`82
`83
`64
`86
`88
`81
`B8
`89
`90
`91
`92
`93
`94
`96
`96
`97
`98
`89
`100
`
`IND.
`
`CllP.
`
`IND.
`
`DIP.
`
`IND.
`
`c
`
`-
`
`.J - J
`
`--
`
`J
`'·
`
`
`
`

`
`. '
`
`"_;r";‘-.?%7 e-‘«:'~_--:
`
`.f..; 43.,
`
`~
`
`v v v:
`
`7 N "
`'KPPUCANT.'S NAME<[PLEA5EPH|NT)
`
`,,-V
`
`_
`
`‘V
`
`'
`
`‘
`
`-
`; w
`
`_
`
`'
`
`-W
`
`‘
`
`, 1;
`
`.
`
`" ‘
`
`’_
`
`-
`
`‘J:
`.’:»zSU3CLASS L.--,.-:;
`:‘ NE'SU.3,Cl-A33 PER,“-OCKL. ,
`-
`‘
`‘
`.
`V
`
`'
`
`.
`‘K5 :3
`
`'
`
`V
`
`lV¢':¢Ll’I‘l‘:"f‘I Acélflnnflhnn Q”: nfi
`
`;
`
`‘
`
`
`
`

`
`'·$EARCHED
`.,
`S~b.
`'
`
`Date
`
`Exmr.
`
`Class
`
`S'tO
`
`SI>/
`
`}iq\
`4'S~ ls'AflRlk lf"i/13
`Jl/ i
`~ ~() J4F ~ J~.f)fc, \.
`'\~~
`
`J4~f>
`
`I
`
`.
`
`•
`
`...
`'SEARCH NOTES
`"
`lAS- ON- l../Nf;
`STA! "" '\
`~~APRtJ.. lf.,;7tf.3 .
`\
`\ · 1qq6
`
`Date
`
`Exmr.
`
`'\ '\
`\ \
`\ ...
`
`.
`
`;
`
`INTERFERENCE SEARCHED
`sub. ·,
`Exmr.
`Class
`Date
`.J!.~~\ )~~CJ . ~ ;J".:8
`6J.lj- \~
`
`;S#v
`.51.q
`
`u
`
`CRIGHT OUTSIDE}
`
`
`
`

`
`5665772
`IRWQftll/111~
`
`EXAMINER
`
`111 ! '
`
`:";'. ·1 ·1
`
`'
`
`1.:1. f~\~ 'j. p
`fifl.~~--
`
`', '"
`
`·t:i I ·ti! fr ) tiN/ l"f.
`l/Ef\ft;; ff['
`
`~vt3:·----
`
`CER1lf!CATE
`JUN 3 0 1998
`OF COBRlCDON
`
`'!OTAL
`SHEETS
`DRWGS. CIAIMS
`
`FlUNG FEE
`INOEP.
`Cl.AIMS RECEM.D
`
`ATIORNEY'S
`DOCl<ETNO.
`
`r)-n~!<YLOn::t) RAi-,(?;~VC!N ;y::~<IV()f tv:.: {':'\ 1
`) MMl.tN(lSl:~·! :Ht \:~,;t~l'I! t t·:
`
`--~ ---·-------:~-- -
`
`PARTS OF APPLICATION
`FILEO SEPARATELY
`NOTICE OF ALLOWANCE MAILED
`
`Assistant Examiner
`~~._;;: ~~
`ROBERT T. BOND
`. PRIMA Y EXAMINER
`~ff Ti UNIT 12n->
`
`Label
`Area
`
`WARNING:
`
`Primary Examiner
`PREPARED FOR ISSUE
`
`
`
`

`
`/
`
`Staple. Issue ~lip Here
`
`IDNO.
`/,,_,.
`ti { v,
`"
`
`DATE
`25 -;:) -'1.c;' -
`f( /J; Jr,,..,
`J
`~ /1/b
`ti/('.,,
`-:Jn
`
`POSmON
`CLASSIFIER
`
`EXAMINER
`TYPIST
`VERIFIER
`CORPS CORR.
`SPEC.HAND
`FILEMAINT.
`DRAFTING
`
`INDEX OFICLAIMS
`
`Date
`
`Claim
`
`~ ~ J.I
`-~ V,C"
`i1
`
`I~ -<ft
`"
`
`~
`
`::::-
`
`I'-
`
`.....
`I
`I
`
`....
`=
`-:..
`
`j
`
`'I.. \'
`,J 10
`.,,. 11
`u. 12
`~ 13
`' 14
`15
`16
`17
`111
`J
`Irr 19
`20
`21
`22
`23
`24
`25
`26
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`. 44
`45
`46
`47
`48
`49
`50
`
`Date
`
`Claim
`ii ~
`ii'. ~
`0
`51
`52
`53
`54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`11
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`84
`es
`86
`87
`88
`89
`90
`91
`92
`93
`94
`95
`96
`97
`98
`99
`100
`
`... - .. .__
`- - ~ SYMBOLS
`.J ..... ,.,::::::;,.. ........... Rtjoclod
`
`-................................. -
`
`- (Tbrouull ... mllmll -
`+ ·-····· .. ···-·-·············" Rnb1Cl!d
`N ................................. Non-led
`1 ............. - ................. 1 -
`A ................................. Appeal
`0 ................................. Objodld
`
`lLEFT INSIDE\
`
`.Foreign prlolltv Cllalmlld
`•38 USC 118 condlllDna met
`I
`~ andAcknoWledged , ;
`HOBERl'S HONOR
`b.-{.~Nl!(I?. C6HF'OR~
`j
`59 ROIJTE. 10
`
`E.AS"I HA~,OVEr\ 1
`
`··1
`
`.
`.
`
`0-/'.\LKYLIHED R~:
`l MMUNflSUl'i-'kES!:i ·
`.
`~
`\
`'
`
`PARTS CF APPUCA110N1
`FILED SEPARATELY
`I
`NOTICE OF ALLOWANCE
`.
`I
`
`/J .f b . ll~!
`
`ISSUEFEE
`
`j
`
`i
`
`Label i
`
`. -11,~:., i : .. ·r: ·,1:-; r. . ·1, :·:' ·t·:.·
`
`'~ c;!•!' ·; !·· j" {;!.'.~:'
`
`j
`Df\ T
`·11J
`
`J
`
`i
`1 l
`1
`~,·*~t1}\l\ 1:,0N/F'C·1 At1
`VER if\: I El>
`'J.
`.. !!_SL§" .. -:--
`
`Area
`
`.;
`
`l
`\ :
`
`'·
`
`1·
`:'
`I i".
`
`+ "'~-
`
`
`
`

`
`•
`
`PCT
`
`REQUEST
`
`•
`
`For receiving Office use only
`
`r
`•
`1
`ln1cmahona App 1ca11on o.
`
`. P~T/EP 93 I 0 2 604
`-
`\ 24. 09. 93 /
`
`24 SEP 1993
`International Filim? Date
`
`The undersigned requests that the present
`international application be processed
`according to the Patent Cooperation Treaty.
`
`Box No. I
`
`TITLE OF INVENTION
`RAPAMYCIN DERIVATIVES
`
`Box No. II
`
`APPLICANT
`
`.UROPEAN ftATENT OFFICE
`PCT INTE~NA TtONAL APPLICATION
`Name of receiving Office.and .. PCT International Application-
`
`Applicant's or agent's file reference
`(if desired) (12 .characters mazimum)
`
`l00-7932
`
`..
`
`Name and address:
`
`(Family namrt:;llowed bv given name; for a legal artity, fell official
`designation..
`address musl include postal code and name of counlry.)
`
`D This person is also inventor.
`
`SANDOZ LTD.
`Lichtstrasse 35
`CH-4002 Bas le
`Switzerland
`
`Telephone No.
`061 324 44 53
`Facsimile No.
`061 322 75 32
`Teleprioi.cr No.
`965 050 55
`
`State (i.e. counlry) of nationality:
`CH
`This person is applicant
`for the ;:>urposes of:
`
`D
`
`all designai.cd
`Stai.cs
`
`CH
`Dall designated St.ates except
`the Unii.cd Stai.cs of Amenca
`
`I State (i.e. c.oun1ry) of residence:
`
`D
`
`tbc United Slates
`of Amcric-.a only
`
`[RJ lhe St.ates indicated in
`1he Supplement.al Box
`
`Box No. III
`
`FURTHER APPLICANTS AND/OR (FURTHER) INVENTORS
`
`l"ame and address:
`
`for a legal oilirv, fell official
`(Famih· ltDme followed bv given ltDme;
`designation.. The address mU.Sl include postal code and name "of counlry.)
`SANDOZ-PATENT-GMBH
`Humboldtstrasse 3
`D-79539 Lorr a ch
`Germany
`
`This person is:
`~ applicant only
`D applicant and inventor
`D inventor only (If llUs check-box
`I St.ale (i.e. coun1ry) of residence:
`DE
`
`Dall dcsign.ai.cd Sr.aics exccpl the Uoii.cd Stai.cs o( America D the United States
`o( America only
`for a legal e1'1ity, JU.II official
`(Famih- n.ame/no/lowcl by given n.ame;
`ne address mu.sl include postal code and n.ame of CCNll.U')'.)
`desig1'a1ion..
`
`Stale (i.e. counJT)·) of nationality:
`DE
`
`This person is applicant
`for the purposes of:
`
`Name and address:
`
`D all dcsigoai.cd
`
`Sui.cs
`
`is marlced, do nol fill in belo-...·.)
`
`·
`
`~ the Stai.cs indicaled io
`the Supplemeor.al Box
`
`This person is:
`
`SANDOZ-ERFINDUNGEN
`VERWALTUNGSGESELLSCHAFT M.B.H.
`Brunner Strasse 59
`A-1230 Vienna
`Austria
`
`State {i.e. cou1111-y,1 of nationality:
`AT
`
`AT
`
`~ applicant only
`D applicant and inventor
`D inventor only (lf:hi.s checlc-bor
`is mar/c.e.d, do llOl Ji II in below.)
`I State (i.e. c.oun1ry) _of residence:
`This person is applicant D all dcsigoai.cd D all dcsigoai.cd Stai.cs except D the United Stales ~ the Stai.cs indicated io
`States
`1bc Uoii.cd St.lites of America
`for the purposes of:
`[19 Further applicants and/or (further) inventors are .indicated on a continuation sheet.
`Form PCT/R0/101 {first sheet) (July 1993)
`
`o( America only
`
`tbc Supplemental Box
`
`See J1ious lo 1he request form
`
`
`
`

`
`• Sheet No.
`
`2
`
`.T/EP 9 3 I O L 6 0 4
`
`Continuation or Box No. HI
`
`FURTHER APPLICANTS AND/OR (FURTHER) INVENTORS
`
`If none of the following sub-boxes is used, I his sheet is not lo be inc laded in the request.
`
`Name and address:
`
`for a legal Olliry, full official
`(Familv Mm1£ollowe.J by givot Mme;
`de.sigMiion..
`e address must include postal code an.ti name of coulllry.)
`
`This person is:
`
`COTTENS, Sylvain
`In den Reben 12
`CH-4108 Witterswil
`Switzerland
`
`is marlced, do not fill in below.)
`
`D applicant only
`0 applicant and inventor
`D inventor only (If this checlc-bo:r
`I State (i.e. coulllry) of residence:
`CH
`D all designated States except
`of America oaJy D the Si.au:.s. indica1ed in
`[Kl tbe United States
`
`State (i.e. coun1ry) of nationality:
`CH
`This person is applicant
`for the purposes of:
`
`D all designated
`
`Si.ates.
`
`the United States. of America
`
`tbe Supplemental Box
`
`Name and address:
`
`for a legal Olliry, full official
`(Family Mmr£ollowe.d bv given name;
`e address "must include postal code an.ti name "of counlry.)
`design.aJion..
`
`SEDRANI, Richard
`Herrengrabenweg 15
`CH-4054 Bas le
`Switzerland
`
`This person is:
`
`D applicant only
`~ applicant and inventor
`D inventor only (If this checlc·box
`
`is marUd, do not fi II in below.).
`
`State (i.e. counlry) of nationality:
`LU
`
`CH
`
`I State (i.e. counlry) of residence:
`This person is applicant D all designated o all designated Slates. except ~ lbe United States D the Si.ates indica1ed in
`
`for the purposes of:
`
`Si.ates.
`
`the United States. of America
`
`of America oaJy
`
`the Supplemental Box
`
`Name and address:
`
`for a legal Ollity, full official
`(Familv MmT-/::/lowed bv given Mme;
`address 'must include postal code an.ti NJme of counlry.)
`de.signa1iofl.
`
`This person is:
`
`D applicant only
`D applicant and inventor
`D inventor only (If this check-box
`
`is marUd, do not fi II in below.)
`
`State (i.e. counlry) of nationaliry:
`
`This. person is. applicant D all designated
`
`for the purpos.es of:
`
`Siaie:s
`
`I State (i.e. coun1ry) of residence:
`D all designated Stau:.s. except
`
`the United Staies or America D the United States or America oaJy D the States. indica1ed in
`
`the Supplemental Box
`
`Name and addreu:
`
`for a legal enJity, fu:.I/ official
`fFamifr nameT/::/lowetf bv given name;
`address "mu.st incb.de postal code and name of country.)
`de.sigmuiofl.
`
`This person is:
`
`D applicant only
`D applicant and inventor
`D inventor only (If this cho:Jc-bor
`is marlced, do not fi II in below.)
`
`State (i.e. counlry) of nationality:
`
`I State (i.e. co11n1ry) of residence:
`This person is. applicant D all designair.d D all designated States. except D the United States D tbe States indicated in
`D Further applicants and/or (further) inventors are indicated on another continuation sheet.
`
`for the purposes of:
`
`Staie:s
`
`tbe United States. of Amenca
`
`of America oaJy
`
`tbe Supplemental Box
`
`Form PCr/R0/101 (continuation sheet) (July 1993)
`
`See Notes to the request form
`
`
`
`

`
`• Sheet No.
`
`Box No. IV AGENT OR COMMON REPRESENTATIVE; OR ADDRESS FOR CORRESPONDENCE
`
`3
`
`.T/EP 9 3 I O 2 6 O 4
`
`The per$on identified below is hereby/has been ~ppointed to ~C:t on behalf
`of the applicant(s) before the competent lntematJonal Authont1es as:
`(Family NUne followed by gi\.'Ql name;
`for a legal en1j1y, !If// official
`Name and address:
`derigntUion. ™. address mu.st incwde posial coJe and name of coul'llT)'.)
`
`D agent
`
`~ common representative
`Telephone No.
`061 324 44 53
`Fzscimile No.
`061 322 75 32
`
`SANDOZ LTD.
`Patents & Trademarks Div.
`Lichtstrasse 35
`CH-4002 Basle
`Teleprinter No.
`Switzerland
`965 050 55
`D Mark this check-box where no agent or common representative is/has been appointed and the space above is used instead to
`
`indicate a special address to which correspondence should be sent.
`
`Box No.V
`
`DESIGNATION OF STATES
`
`The following designations are hereby made under Rule 4.9(a) (mark the applicable dieck-bozes; al least ON: mu.st be mar/ce.d):
`Regional Patent
`(81 EP European Patent: AT Austria. BE Belgium, CH and LI Switzerland and Liechtenstein. DE Germany, DK Denmark,
`ES Spain, FR France, GB United Kingdom, GR Greece, IE Ireland, IT Italy, LU Luxembourg, MC Monaco,
`NL Netherlands, PT Portugal, SE Sweden, and any other State which is a Contracting State of the European Patent
`Convention and of the PCT
`DOA OAPI Patent: Benin, Burkina Faso, Cameroon, Central African Republic. Clad, Congo, C.Ote d'Ivoire, Gabon, Guinea,
`Mali, Mauritania, Niger, Senegal, Togo, and any other State which is a member State of OAPI and a Contracting State
`of the PCT (if otner kind of protection or treatmenl desired, sp«ify on doaetl line) ...................•..................•..
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`SD Sudan
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`............................... .
`
`....................... .
`
`National Patent (if other land of protection or treatmenJ desired, specify on doaed line):
`0 AT Austria
`0 MN Mongolia ............................... .
`0 MW Malawi
`I2SJ AU Australia
`0 BB Barbado.s
`0 NL Netherlands
`0 BG Bulgaria
`[81 NO Nor-..,.ay
`0 BR Brazil
`[81 NZ New Zealand ............................ .
`D BY Belarus
`[8l PL Poland
`D PT Portugal ................................ .
`[8J CA Canada
`D CH and LI s .... itzerland and Liechtenstein
`(2$1 RO Romania
`. . . . . . . . . . . . . . . . . . . . . . . ~ RU Russian Federation
`~ CZ Czech Republic
`0 DE Germany
`0
`0 DK Denmark
`0
`SE Sweden
`0 ES Spain
`(81 SK Slovakia
`t8J Fl
`0 UA Ukraine
`Finland
`. . . . . . . . . . . . . . . . . . . . . . . . . . . .
`0 GB United Kingdom
`(':81 US United States of America
`125'.J HU Hungary ........................... .
`~ JP
`Japan
`D
`KP Democratic People"s Republic of Korea .....
`
`D VN Viet Nam
`
`[8J
`D
`D
`D
`D
`
`KR Republic of Korea .................... .
`KZ Kazakhstan
`LK Sri Lanka
`
`........................ .
`
`LU Luxembourg
`
`MG Madagascar
`
`Check-boxes reserved for designating States (for the purposes of
`a national patent) which have become party to the PCT after
`issuance of this sheet:
`D
`D
`D
`D
`
`In add ltlon to the designations made above. the applicant also makes under Rule 4.9(b) all designations which would be permitted
`und~iliePCTexce~iliedesignatio~~of ___________________________________ _
`The applicant declares that tho.se additional designations are subject to confirmation and that any designation which is not confirmed
`before the expiration of 15 months from the priority date is to be regarded as withdrawn by the applicant at the expiration of that time
`Ii mil. (Confirmation of a designation consists of the filing ofa notiu sp«ifying tho.t designation an.d the paymenJ of the designation and confirmalion
`·
`fees. Confirma.tion must re.ach the receiving Office wir.hln the 15-monlh time limiL)
`
`Form PCT/R0/101 (second sheet) (July 1993)
`
`See Note.s to the request form
`
`
`
`

`
`Supplemental Box
`
`If the Suppbemenlal Box is not used, this sheet ned 11ot he U.cbuld in the request.
`
`Sheet No.
`
`4
`
`tlCT/EP 9 3 J o 2 6 u 4
`
`•
`
`Use I.his box in the following~:
`J. If, in an~ of the Boxes, the space is insufficU!nl to
`furnish all the usformarion:
`
`in particular:
`
`in such ctl.Sll!, write •connnuarion of Box No •••• • {indicale the number
`of the Box] and furnish the information in the .sa.me manner a.s
`required a.cconling to the caplWns of the Box in which the space wa.s
`in.suffu:U!nt;
`
`(i)
`
`if more than three persons are involved as applicants
`and/or invenlors and no •continualion sheet• is
`available:
`
`in such case, wrize •continuation of Bax No. llr and indica1ejor each
`a.ddi1iolt.QI person the sante type -of infonna.1ion as require
`in Bax
`No. III;
`
`(ii)
`
`if, in Bax No. II or in any of the sub-boxes of Bo:r
`No. Ill, the indication "the States indicated in the
`Supplemenlal Bo:r" is ch.t:clc.ed:
`
`(iii)
`
`if, in Bax No. II or in any of the sub-boxes of Bo:r
`No. Ill, the inventor or the inventor/applicanr is not
`inventor for the pu'P'?ses of all design.aled Stales or
`for the purposes of the Unized Stales of America:
`
`(iv)
`
`(v)
`
`if, in addition to the agent(s) indicaled inBo:rNo. IV,
`th.ere are further agents:
`if, in Bo.x No. V. the name of any State (or OAP/) is
`accoti:ied by the indication "patent of addition., "
`"certi cale of addition." or "invenlor's certificate
`ition.," or if, in Bo:r No. V, the name of the
`of a
`United States of America is accompanied by an
`indication "Continuation" or "Continuation-in(cid:173)
`part•:
`
`(vi)
`
`if th.ere are more thaJI three earlier applications
`whose priority is claimed:
`
`2. If the applicanr claims. in respect of any design.a1ed
`Office, tk benefits of provisions of the national law
`concerning non-prejudicial disclosures or excep1ions to
`laclc of novelty:
`
`Continuation of Box No. II
`
`in such case, write •continuation of Box No.11• or •continuation of Bo:r
`No. /Ir or •continualion o(BOJU!S No. II and No. III- (as the case may
`be), indicate the lt.Qmt: of lhe applicanl(s) involved and. ru:xt to (each)
`such name, the Slate or States (and/or, where applicable, European or
`OAP/ patent) for the purposes of which lhe NVned person is applicant;
`
`in such case, write •Continuation of Box No. /J• or •Conlin.uation of Bo:r
`No. llr or •Conlinuation of BOJU!S No. ll and No. /JI" (as the case may
`be), indicate the name of the inventor(s) and. N!Xt to (each) such name,
`the State or States (and/or, where applicable, European or OAP/ patent)
`for the purposes of which the named person is inventor;
`
`in such case, write •continuation of Bo:r No. IV" and indicate for each
`further agent the sante type of information as required in Bo.x No. IV;
`
`in such case, write "Conlinuation of Bax No. V" and the lt.Qme of each
`Stale involved (or OAP/), and after the name of each such State (or
`OAP/), the number of the parent title or parenl application and the dale
`of grant of the parenl tizle or filing of the parenl applicalion;
`
`in such case, write "Conlinuation of Bo:r No. VI" and indicale for each
`additional earlier application the sante type of information as required
`.
`in Bo.x No. VI.
`
`in such case. write •statemenl Concerning Non-Prejudicial Disclosures
`or; Excep1ions to Lacie. of Novelty" and furnish thal statement below.
`
`SANDOZ LTD. is applicant for all designated countries except
`DE (Germany), AT (Austria)and US.
`Continuation of Box No. III
`SANDOZ-PATENT-GMBH is applicant for DE
`SANDOZ-ERFINDUNGEN
`VERWALTUNGSGESELLSCHAFT M.B.H. is applicant for AT (Austria) only
`
`(Germany) only
`
`Form PCT/R0/101 lsupplemental sheet} (July 1993}
`
`See Notes 10 1h.t: requesl form
`
`
`
`

`
`Box No. VI
`
`PRIORITY CLAIM
`
`Sheet No.
`
`5
`Further priority claims are indicated io the Supplement.al Box D
`
`•
`
`The priority of the following earlier application(s) is hereby claimed:
`Country
`(in wliich, or for Which, the
`applicati0tt wcu filed)
`item (1)
`
`Filing Date
`(d.trylmonlhlyear)
`
`Application No.
`
`Office of filing
`- (o,Jy for regio-1 or
`in1er11DtuJNJI applicatio11)
`
`9 October 1.992
`(09/1.0/92)
`
`9221.220.8
`
`GB
`
`item (2)
`
`item (3)
`
`MOT~ th~ folfowing ~cJ:.-bor if the certified copy of. the earlier applicaJion is to be wued by the Office whicli for lht: PllT"(>OSC.S of the prc.settJ ittJenuuion.al
`opplicot1on as lht: rece1111ng Office (a fee may be reqwrui):
`D The receiving Office is hereby requested to prc~rc and transmit to the International
`
`Bureau a cerufied copy of the carrier application(s) identified above as itcm(s) :
`
`Box No. VII EARLIER SEARCH
`
`Fill in where a search (ittJematiOtUJ/, i11JematioNJl·typt: or other) by the /n1erna.tio11D/ Searchi11g Authority_ has alreadv bce11 carried out or rt:quc.st.t:d and the
`Authority is now requested to ba..se ~ i111emation.al search. to the crie11J eassible, on the rc.sr.Jts O{rhat earlier search.. 1tiettJify such search or request t:i1ht:r by
`refere11ee to the relewnl applic01ion (or ~translation thl!reofl or by re}erence to the searcli request:
`Country (or regional Office):
`Date (Jay/molllhlyear):
`
`Number:
`
`Box No. VIII CHECK LIST
`
`This international applica1ion contains
`the following number or sheets:
`5
`1. request
`:
`sheets
`36
`sheelS
`:
`2. description
`4
`3. claims
`sheelS
`:
`1
`4. abstract
`sheets
`:
`-
`5. drawings
`sheets
`:
`46
`
`Total
`
`:
`
`sheets
`
`This international application is accompanied by the itcm(s) marked below:
`
`1. D separate signed
`2 D copy of general
`3 o stalcment explaining
`4 D priori.ty documcnl(s)
`
`power of anomey
`
`power of anorncy
`
`Jack of signature
`
`idt:ntifrt:d in Box /Vo. VI
`as ilt:m(s):
`
`·
`
`·
`
`·
`
`5. D fee calcuialion sheet
`6 D separate indications concerning
`D nucleotide and/or amino acid
`8 D other (s,.,,.ci~·):
`
`·
`
`7.
`
`·
`
`deposited microorganisms
`
`sequence listing (diskette)
`
`r- J.T
`
`Figure No. - - - - - of the drawings (if any) should accompany the abstract when it is published.
`
`Box No. IX
`
`SIGNATIJRE OF APPLICANT OR AGENT
`
`1. Date or actual receipt of the purported
`international application:
`
`3. Conccted date of ac1ual receipt due to later but
`timely received papers or drawings completing
`1he u
`rted international a
`lication:
`
`4. Daie of timely receipt of the required
`corrections under PCT Article 11(2):
`5. International Searching Authority ISA /
`specified by the applicant:
`
`For receiving Office use only - - - - - - - - - - - - - - - - - - - - - - - - .
`2 4 SEP 1993
`2. Drawings:
`
`0 received:
`0 nol received:
`
`6.D Transmittal of search copy delayed
`
`until search fee is paid
`
`Date or receipt or the record copy
`by the lnlernational Bureau:
`
`Form PCT/R0/101 (last sheet) (July 1993)
`
`For International Bureau use on l y - - - - - - - - - - - - - - - - - - - - - -
`
`St:t: Nott:s to the rt:qut:sl form
`
`
`
`

`
`PATENT COOPERATION TREATY
`PCT
`•
`•
`
`INTERNATIONAL SEARCH REPORT
`
`(PCT Article 18 and Rules 43 and 44)
`
`see Notification of Transmittal of International Search Report
`(Form PCT/ISA/220) as well as, where applicable, item S below.
`
`FOR FURTHER
`ACTION
`lnternational filing date( day/month/year)
`24/09/93
`
`(Earliest) Priority Date (day/month/year)
`09/10/92
`
`Applicant's or agent's file reference
`
`100-7932
`International application No.
`PCT I EP 93/ 02604
`Applicant
`
`SANDOZ LTD. et al.
`
`This international search report has been prepared by this International Searching Authority and is transmitted to the applicant
`according to Article 18. A copy is being transmitted to the International Bureau.
`
`4
`sheets.
`This international search report consists of a total of
`[XJ
`It is also accompanied by a copy of ea.ch prior art document cited in this report.
`
`I. [XJ
`
`2. D
`
`3. D
`
`Certain claims were found unsiearchable (see Box l).
`
`Unity of invention is lacking (see Box II).
`
`The international application contains disclosure of a nudeotide and/or wnino acid sequence listing and the
`international search was carried out on the basis of the sequence listing
`
`D filed with the international application.
`D furnished by the applicant separately from the international application,
`D but not ;wcompanied by a statement to the effect that it did not include
`
`matter going beyond the disclosure in the international application as filed.
`
`D Transcri~d by this Authority
`
`4. With regard to the title, D the text is approved as submitted by the applicant.
`00
`the text has been established by this Authority to read as follows:
`0-ALKYLATED RAPAMYCIN DERIVATIVES AND THEIR USE, PARTICULARLY AS IMMUNO(cid:173)
`SUPPRESSANTS
`
`S. With regard to the abstract,
`
`D
`00
`
`the text is approved as submitted by the applicant.
`the text has been established, according to Rule 38.2(b), by this Authority as it appears in
`Box I II. The applicant may, within one month from the date of mailing of this international
`search report. submit comments to this Authority.
`
`6. The figure of the drawings to be published with the abstract is:
`
`Figure No.
`
`D as suggested by the applicant.
`D
`D
`
`because the applicant failed to suggest a figure.
`
`because this figure better characterizes the invention.
`
`D None of the figures.
`
`Form PCT/ISA/210 (first sheet) (July 1992)
`
`
`
`

`
`•,
`\ __
`
`INTERNATION
`
`EARCH REPORT
`
`International application No.
`
`CT I EP 93/ 02604
`
`Box I Observations where certain claims were found unsearchable (Continuation or item 1 or first sheet)
`
`This international search report has not been established in respect of certain claims under Article l 7(2)(a) for the following reasons:
`
`l. D Claims Nos.:
`
`because they relate to subject matter not required to be searched by this Authority, namely:
`
`2. D
`
`3. D
`
`Claims Nos.:
`because they relate to parts of the international application that do not comply with the prescribed requirements to such
`an extent that no meaningful international search can be carried out, specifically:
`Claim 9 refers to the description. Therefore (R.6.2(a),PCT) it has not been
`searched.
`Claims searched completely: 1-8
`
`Claims Nos.:
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`Box II Observations where unity or invention is lacking (Continuation of item 2 of first sheet)
`
`This International Searching Authority found multiple inventions in this international application, as follows:
`
`1. D
`
`2.D
`
`As all required additional search fees were timely paid by the applicant, this international search report covers all
`searchable claims.
`
`As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment
`of any additional fee.
`
`3. D
`
`As only some of the required additional search fees were timely paid by the applicant, this international search report
`covers only those claims for which fees were paid, specifically claims Nos.:
`
`4.o
`
`No required additional search fees were timely paid by the applicant. Consequently, this international search report is
`restricted to the invention first mentioned in the claims; it is covered by claims Nos.:
`
`Remark on Protest
`
`D The additional search fees were accompanied by the applicant's protest.
`D No protest accompanied the payment of additional search fees.
`
`Form PCT/ISA/210 (continuation of first sheet (1)) (July 1992)
`
`
`
`

`
`....-~~~'---·N-~~RNATIONAI;~_R_c_H_RE~P-O~R-T~~~~~~~~~-S-·-·-c._Tl~E-P_9_3_J~02_6_o_4~~~·~~---t
`
`Box Ill TEXT OF THE ABSTRACT (Continuation oritem S of the first sheet)
`
`International application No .
`
`Novel 0-alkylated derivatives of rapamycin of formula (I), especially
`40-0-alkylated derivatives, are found to have pharmaceutical utility,
`particularly as an immunosuppressants.
`
`/-"'
`19
`
`Form PCT/ISA/210 (continuation of first sheet (2)) (July 1992)
`
`