`
`USO057671 15A
`
`United States Patent
`
`[191
`
`[11] Patent Number:
`
`5,767,115
`
`Rosenblum et al.
`
`[45] Date of Patent:
`
`Jun. 16, 1998
`
`[54] HYDROXY-SUBSTITUTED AZFTIDINONE
`COMPOUNDS USEFUL AS
`HYPOCHOLESTERDLEMIC AGENTS
`
`Georg et al. Tet. Letters, 26. 33 (1985). pp. 3903-3906.
`Han et al. T31‘. Letters, 45 (1985). pp. 5493-5496.
`
`Primary Examine.»-—Mar|: L. Berch
`Attorney, Agent, or F.:'rm—-—Anita W. Magatli
`
`[57]
`
`ABSTRACT
`
`Hydroxy—substituted azetidinone hypocholesterolemjc
`agents of the formula
`
`[75]
`
`Inventors: Stuart B. Rosenblnm. West Orange;
`Sundeep Dugar. Bridgewater; Duane
`A. Burnett. Fanwood: John W. Clader.
`Cranford; Brill) A. McKi.ttriclI..
`Bloomfield. all of NJ.
`
`[73] Assignee: Schering-Plough Corporation.
`Kcnilwoflh. NJ.
`
`[21] Appl. No.:617,751
`
`[22] Filed:
`
`Mar. 18,1996
`
`Related US. Applicnfion Data
`
`[63] Continuation-in-part of PC1"f[JS94flU099, Sep. 14, 1994.
`continuation-in-part of Ser. No. 251593, Jun. 9. 199%, Pat.
`No. 5,631,365. which is a oonfinuation-in-pan of Ser. No.
`102,440, Sep. 21. 1993, abandoned.
`
`Int. C1.6
`[51]
`C071) 205/08; AGIK 311395
`
`[52] U.S. C1.
`.................... 514f21I3: 5401200
`[58] Field of Search
`540.3200; 5141210
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`M1983 Willard etal.
`H1991 Yang et al.
`331992 Yoshida.
`591994 Yoshida ............... ..
`
`
`
`4,375,475
`4,983 .59?
`5,099,034
`5,350,368
`
`FOREIGN PATENT DOCUMENTS
`
`199630 10!1 986
`264231
`431 938
`337549 103989
`93102048
`231993
`W094i] 7038
`8:11 994
`
`O'I‘I-[ER PUBLICATIONS
`
`Ram ct 3.1. Indian J. Chem, Sect .3, 29B. 12 (1990). pp.
`1134-1137.
`Hoekrnan et 31. J. Agric. Food Chem, 30 (1982). pp.
`9Q0—924.
`Durst er a]. Can. J. Chem, 50 (1972). pp. 3196-3201.
`Otto el al. Liebigs Am. Chem, (1983). pp. 1152-1161.
`Panfll. et al. Heremcycles, 24. 6 (1986). pp. 160&l61';'.
`Schnitzea'—Polol»:off. et 3]. Comp. Biochem. Physiaé, 99A
`U991)» 131;). 6155-670.
`Witzum. Cfrculation. 80. 5 (1989). pp. 1]D1—l1l4.
`lllingworlh. Drugs, 36(Supp. 3} (1988). pp. 63-71.
`Allain. el al. Clln. Chem, 20. (1974). pp. 470-475.
`I-[oI:ie. et al. Atherosclerosis, 38 (1991). pp. 183-192.
`Baxter. er al. J. Biological CJ‘:em., 267. 17 (1992). pp.
`11705-1 1708.
`Current Drugs: Ant£—Arhera5clemn'r: Ager:ts—Summ3ry
`Factfile. May. 1992.
`
`‘F2
`‘F
`ar'~x..—r«:|v).—Y.—rt|:1.—2.
`R]
`
`0
`
`R3 IQ
`
`M3
`
`an-2
`
`or a pharmaceutically acceptable salt thereof. wherein:
`
`AI‘ and Ar’ are aryl or R‘-substituted aryl;
`
`AB is aryl or R5—subs1:ituted aryl;
`
`X. Y and Z are —CH,—. —CH[1ower alkyl)— or
`—C(di.lower aJ.kyl)——;
`
`R and R‘ are -012‘. —0(C0)R‘°. —o(co)oR9 or
`—0(C0)NR"’R7:
`
`R’ and R3 are H or lower alkyl;
`
`qis0cn'l;1‘is C-or l:m. n andpare0—4;providedthatal
`least one oh] and: is 1. and the sum ofn1.n. p. q and I‘ is
`1-6; and provided that when p is 0 and: is 1. the sum of m.
`q and n is 1-5;
`
`R‘ is selected from lower alkyl. R’. —CF,. -—CN. —NO
`and halogen R’
`is selected from —0R6. ——O(C0)Rfi2.
`——O(C0)0R°. —o(cH,),,,0R°. —o(Co)NR°R7.
`—
`7.
`—NR‘(CO)R".
`—NR‘(CO)OR9.
`—NR (CO)l*iR7R .
`—NR°so,R°.
`—c0oR°.
`—CONR°R'.
`-C0R5. —s0,NR5R”.
`5(0),, R9.
`—0(CH2).-m—C00R‘.
`—0(CH;)..roC0NRgR’~
`—(lower a1kylene)COOR° and _4:H=cH—c0oR5;
`
`R‘. R7 and R3 are H. lower alkyl. aryl or aryl-substituted Ic
`
`R9 is lower alkyl. aryl or aryl-substituted lower alkyl:
`
`are disclosed. as well as a method of lowering serurn
`cholesterol by adrninistering said Compounds. alone or in
`combination with a cholesterol biosynthesis i.|:Lh.1'bitor. phar-
`maceutical composilions containing Ll1e1n;and a process for
`preparing them.
`
`9 Claims, No Drawings
`
`Iof22
`
`PENN EX. 2206
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`5,767.} 15
`
`1
`HYDROXY-SUBSTITUTED AZETIDINONE
`COMPOUNDS USEFUL AS
`HYPOCHOLESTEROLEMIC AGENTS
`
`The present application is the United States national
`application corresponding to International Application No.
`PCT'fUS94.I' 10099. filed Scp. 14. 1994 and designating the
`United States. which PCF application is in turn a
`continuation—in—part of U.S. application Ser. No. 082257593.
`filed Jun. 9. 1994. U.S. Pat. No. 5.631.365. which is a
`continuation-in-part of U.S. application Ser. No. OBIIOQ.
`440. filed Sep. 21. 1993. abandoned.
`BACKGROUND OF THE INVENTION
`
`The present invention relates to hydroxy-substituted are-
`tidinones useful as hypocholesterolernic agents in the treat-
`ment prevention of atherosclerosis. and to the oombination
`of a hydroxy-substituted azetidinone of this invention and in
`cholesterol bioxynthesis inhibitor for the treatment and
`prevention of atherosclerosis. The invention also relates to a
`process for preparing hydroaty-substinlteid azetidinones.
`Adtemsclerotic coronary heart disease (CHD) represents
`the major cause for death and cardiovascular morbidity in
`the western world. Risk factors fcr atherosclerotic coronary
`heart disease include hypertension. diabetes mellitus. fa.ltIil}'
`history. male gender. cigar smoke and serum cholesterol. A
`total cholesterol level in excess of 225-250 mgldl is asso-
`ciated wilit significant elevation of risk of CHD.
`Cholesteryl esters are a major component of atheroscle-
`Iotic lesions and the major storage form of cholesterol in
`arterial wall cells. Formation of cholesteryl esters is also a
`key step in the intestinal absorption of dietary cholesterol.
`Thus. inhibition of cholcstcryl ester formation and reduction
`of serum cholesterol is likely to inhibit the progression of
`atherosclerotic lesion formation. decrease the accumulation
`of cholesteryl esters in the arterial wall. and block the
`intestinal absorption of dietary cholesterol.
`A few azetidinones have been reported as being useful
`lowering cholesterol andlor in inhibiting the formation of
`cholesterol-containing lesions in mammalian arterial walls.
`U.S. Pat. No. 4.983.597 discloses N-sulfonyl-2-azetidinones
`as anticholesterolemic agents and Ram. er al.. in Indian J.
`Chem, Sect. B. 2915. 12 (1990). p. 1134-7. disclose ethyl
`4-(2—oxoazetid.i.n—4—yl)phenoxy—a1lranoates as hypolipidemic
`agents. European Patent Publication 264.231 discloses
`1—substituted-4-phenyl-3-(2-oxo-allryliclene)-2-azetidinones
`as blood platelet aggregation inhibitors. European Patent
`199.630 and European Patent Application 337.549 disclose
`elastase inhibitory substituted azetidinones said to be useful
`treating inflammatory conditions resulting i.n tissue destruc-
`tion which are associated with various disease states. e.g.
`atherosclerosis.
`
`W093!l02048. published Feb. 4. 1993. discloses substi-
`t:uted [5-lactarns useful as hypocholcsterolcmic agents.
`The regulation of whole-body cholesterol homeostasis in
`humans and animals involves the regulation of dietary
`cholesterol and modulation of cholesterol biosynthesis. bile
`acid biosynlhesis and the catabolism of the cholesterol-
`conraining plasma lipoproteinis. The liver is the major organ
`responsible for cholesterol biosynthesis and catabolism and
`for this reason. it is a prime determinant of plasma choles-
`terol levels. The liver is the site of synthesis and secretion of
`very low density lipoproteins (VLDL) which are subse-
`quently metabolized to low density Lipoproteins (LDL) in
`the circulation. LDL are the predominant cholesterol-
`carrying lipoproteins in die plasma and an increase in their
`concentration is correlated wim increased atherosclerosis.
`
`S
`
`2
`When intestinal cholesterol absorption is reduced. by
`whatever means. less cholesterol is delivered to the liver.
`The consequence of this action is decreased hepatic lipo-
`protein {VLDL). production and an increase in the hepatic
`clearance of plasma cholesterol. mostly as LDL. Thus. the
`net effect of inhibiting intestinal cholesterol absorption is a
`decrease in plasma cholesterol levels.
`The inhibition of cholesterol biosynthesis by 3-hydroxy-
`3-me-thylglutaryl coenzyme A (HMG Com reductase
`(ECl.l.l.34) inhibitors has been shown to be an effective
`way to reduce plasma cholestaol (Witzum. C‘i.-cuiatiorr, 80.
`5 (1989). p. 1101-1114) and reduce atherosclerosis. Com-
`bination therapy of an HMG CoA reductase inhibitor and a
`bile acid sequesnant has been demonstrated to be more
`etfective in human ltyperlipidernic patients than either agent
`in rnonotherapy (lllingworth. Drugs. 36 (Suppl. 3) (1988). p.
`63-?‘ 1).
`
`SUMMARY OF THE INVENTION
`
`Novel hypocholesterolemic compounds of the present
`invention are represented by the formula I
`
`R
`
`R1
`
`I
`
`.an1—X.-{<|2).,—Y.—(tt2).—
`R‘
`R3
`
`an
`
`N
`
`“M2
`
`o
`
`35
`
`-10
`
`45
`
`55
`
`or a pharmaceutically acceptable salt thereof. wherein:
`Ar‘ and Ar2 are independently selected from the group
`consisting of aryl and R‘-substituted aryl;
`Ar’ is aryl or R5—substituted aryl;
`X. Y and Z are independently selected from the group
`consisting of —CH2—. —CH(lower alkyl)— and
`-—C(dilower alkyl)—-;
`R and R2 are indipendently selected from the group
`consisting of —OR . —o(Co)R°. —O(C0)OR9 and
`—0(C0)NR°R’;
`R‘ and ‘R3 are independently selected from the group
`consisting of hydrogen. lower alkyl and aryl;
`qis Oct 1;: is 0 or 1; tit. 11 andp areindependently 0.1.
`2. 3 or 4; provided that at least one of q and r is l. and the
`sum ofru. n. p. q and r is 1. 2. 3. 4. S or 6; and provided that
`whenp is D and ris 1. the sum ofm. q and n isl. 2. 3. 4 orfi;
`R‘ is 1-5 substiulents independently selected from the
`group consisting of lower alkyl. —OR6. ——0(CO)R$.
`—0{Co)on9. —o(CH,) Mon”. —O(C0)NR5R .
`--NR"R7. -Nn°(C0)R’. —NR°(Co)on9. —Nn‘(co)
`NR7Rs. _NR°so,R9. ——C00R5. -—CoNR‘127. —CoR°.
`—so,Nn‘R’.
`s(o).,_%n‘-°. —0(CII2)1_,0—CO0R°.
`—O(CH2),_,DC0NR‘5R . —(lower allrylene)COOR'5.
`——CH£~—CO0R°. —CF3. —CN. —N02 and halogen:
`R5 is 1-5 substituents independently selected from the
`group consisting of —0R°. —0(CO)R‘. —0(CO)OR9.
`-—-0(CH,),_5OR .-0(co)NR°n7. —Nn"n7. —Nn‘(Co)
`R’. —Nn‘(Co)oR°. —Nn"(C0)NR*R°. ——NR°so2R9.
`—C0oR°. —CoNR“R’. ——COR°. —so,NR‘R’. 5(0)..-
`2R9. —0(CH,),_,0—-CO0R5. —O(CH,]H,,CONR6R-’.
`—(lower alkylene)COOR6 and —CH=Ci-1—CO0R°;
`R6. R1 and R3 are independently selected from the group
`consisting of hydrogen.
`lower alltyl. aryl and aryl-
`substitnted lower alkyl; and
`R9 is lower alkyl. aryl or aryl-substituted lower alkyl.
`R‘ is preferably 13 independently selected snbstituents.
`and R’ is preferably 1-3 independently selected substitu-
`ents. Preferred are compounds of formula I wherein Ar‘ is
`phenyl or R“—substitnted phenyl. especially (4-R“)-
`
`2of22
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`
`5,767,] 15
`
`3
`
`substituted phenyl. Ar’ is preferably phenyl or
`R"-substituted phenyl. especially (4-R‘)-substituted phenyl.
`AI’ is preferably R’-substituted phenyl. especially (4-R5}
`substituted phenyl. When Ar‘ is (4-R‘)-substituted phenyl.
`R‘ is preferably a halogen. When Ar2 and A13 are R‘— and
`R’-substituted phony]. respectively. R‘ is preferably halogen
`or —OR° and R5 is preferably —0R°. wherein R6 is Iowa‘
`alkyl or hydrogen. Especially preferred are compounds
`wherein each of Ar‘ and Ar’ is 4-fluorophenyl and Ar’ is
`4-hydroxyphenyl or 4-methoxypltenyl.
`X. Y and Z. are each preferably —«CH2—.R1 and R3 are
`each preferably hydrogen. R and R2 are preferably —0R°
`wherein R6 is hydrogen. or a group readily rnetabolizable to
`a hydroxyl
`(such as ———O(C0)R5. ——O(CO)OR9 and
`~—0(CO)NR°R7. defined above].
`The sum ofrn. n. p. q and r is preferably 2. 3 or 4. more
`preferably 3. Preferred are compounds wherein tn. :1 and r
`are each zero. q is 1 and p is 2. Also preferred are compounds
`wherein p. q and n are each zero. r is 1 and in is 2 or3. More
`preferred are compounds wherein rn. 11 and r are each zero.
`q is 1. p is 2. 2 is —CH, and n is —oR“0R... especially
`when R‘ is hydrogen. Also more preferred are compounds
`wherein p. q and n are each zero. r is 1. mis 2. X is—CH,—
`and R3 is —0R‘. especially when R5 is hydrogen.
`Another group of preferred compounds is that wherein
`Ar‘ is phenyl or R“-substituted phenyl. AI2 is phenyl or
`R‘-substituted phenyl and A13 is R —substin:1tedphenyl. Also
`preferred are cornpounds wherein A11 is phenyl or
`R"—substituted phenyl. Ar: is phenyl or R‘-substituted
`phenyl. Ar‘ is R —substituted phenyl. and the sum of tn. n. p.
`q and r is 2. 3 or 4. more especially 3. More preferred are
`compounds wherein Ar‘ is phenyl or R"—substituted phenyl.
`A1-2 is phenyl or R“-substituted phenyl A13 is R’-substituted
`phenyl. and wherein m. n and r are each zero. I] is 1 and p
`is 2. or wherein p. q and n are each zero. r is l and m is 2
`or 3.
`'I'his invention also relates to a method of lowering the
`serum cholesterol
`level
`in a mammal
`in need of such
`
`treatment comprising administering an effective amount of a
`compound of formula I. That is. the use of a compound of
`the present invention as an hypocholesterolemic agent is
`also claimed.
`In still another aspect. the present invention relates to a
`pharmaceutical composition comprising a serum
`cholesterol-lowering eflective amount of a compound of
`fonnnla I in a pharmaceutically acceptable carrier.
`'I'he present invention also relates to a method of reducing
`plasma cholesterol levels. and to a method of treating or
`txeventing atherosclerosis. comprising administering to a
`mammal in need of such treatment an effective amount of a
`
`combination of a hydroxy-substituted azetidinone choles-
`terol absorption inhibitor of formula I and a cholesterol
`hiosynthesis inhibitor. ‘That is. the present invention relates
`to the use of a hydroxy-substituted azctidinoue cholesterol
`absorption inhibitor of formula I for combined use witlt a
`cholesterol biosynthesis inhibitor (and. similarly. use of a
`cholesterol biosynthesis inhibitor for combined use with a
`hydroxy-substituted azetidinone cholesterol absorption
`inhibitor of formula I) to treat or prevent athr:-osclerosis or
`to reduce plasma cltolesterol levels.
`In yet another aspect. the invention relates to a pharma-
`ceutical composition comprising an efioctive amount of a
`hydroxy-substituted azetidinone cholesterol absorption
`inhibitor of formula I. a cholesterol biosynthesis inhibitor.
`and a pharrnaceutically acceptable carrier. in a final aspect.
`the invention relates to a kit comprising in one container an
`elfective amount of a hyd.roxy—substituted azetidinone cho-
`
`4
`lesteroi absorption inhibitor of formula I in a phzu-rnaceuti—
`Cally acceptable carrier. and in a separate container. an
`effective amount of a cholesterol biosynthesis inhibitor in a
`pharmaoeutically acceptable carrier.
`
`5
`
`In yet another aspect. the invention relates to a process for
`preparing certain compounds of formula I comprising the
`steps:
`
`10
`
`(a) treating with a strong base a lactone of the fonntlla
`
`A
`
`15
`
`25
`
`35
`
`K.-
`
`A..io/
`
`0
`
`0
`
`wherein R‘ and R3’ are R and R2.respectively. or are suitably
`protected hydroxy groups; Arm is Ar’. a suitably protected
`hydroxy substituted aryl or a suitably protected amino-
`substituted aryl; and the remaining variables are as defined
`above. provided that in lactone of formula B when n and r
`are each zero. p is 14:
`
`(b) reacting the product of step (a) with an imine of the
`forrnula
`
`Ar”
`
`If
`‘mm
`
`45
`
`wherein Arm is Ar’. a suitably protected hydro:ty-
`substituted any] or a suitably protected amino-substituted
`aryl; and Ar” is At’. a suitably protected hydroJty—
`substituted aryl or a suitably protected amino-substituted
`ml:
`
`c} quenching the reaction with an acid:
`
`d) optionally removing the protecting groups from R‘. R2’.
`Ar”. Ar” and Ar”. when present; and
`e) optionally functionalizing hydroxy or amino substitu-
`ents at R. R2. Ar‘. Ar’ and Ar’.
`
`Using the lactones shown above. compounds of formula
`IA and B are obtained as follows:
`
`60
`
`2’
`
`Ar”
`
`.;:.>< .,3=oȣ..+
`
`(cl:R'R').
`X.-
`Ar'°/
`
`65
`
`it
`
`3of22
`
`PENN EX. 2206
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`CFAD V. UPENN
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`
`
`
`5.767.115
`
`5
`-continued
`
`(I31!
`1':
`ar1—x..—t<lT1.—Y.—p—
`R1
`R3
`
`La
`
`rue
`
`N
`
`“A14
`
`wherein the variables are as defined above; and
`
`R3
`
`R’
`lei’f
`Y/ ‘*2,
`RI\i\
`M,/X“ o
`B
`
`0
`
`E_,Ar~"°
`+ ‘M
`
`r
`1”‘
`Ar*—X..—t|3—Y.—(<|3)«—
`R‘
`R3
`
`AI’
`
`N
`
`na
`
`0/
`
`“Ari
`
`wherein the variables are as defined above.
`
`DETAILED DESCRIPTION
`
`As used herein. the term “lower alkyl“ means straighl or
`branched alkyl chains of 1 to 6 carbon atoms.
`“Aryl" means phenyl. naphthyl. indenyl. tetra.hydronaph-
`thyl or indanyl.
`“Halogeno" refers to fluorine. chlorine. bromine or iodine
`fll0l'I1S.
`
`35
`
`The above statement. wherein R‘. R7 and R‘ are said to
`be independently selected from a group of substituents.
`means that R‘. R7 and R3 are independently selected. but
`also that where an R6. R7 or R‘ variable occurs more than
`once in a molecule. those occurrences are independently
`selected (e.g.. if R is ——-{}R‘5 wherein R6 is hydrogen. R‘ can
`be -011‘ wherein R‘ is lower alltyl).
`Compounds of the invention have at least one asymmetric
`carbon atom and therefore all
`isomers. including enanti-
`omers and diastereomers are contemplated as being part of
`this invention. The invention includes (1 and I isomers in
`both pure form and in admixture including raoclnic mix-
`tures. Isomets can be prepared using conventional
`
`45
`
`6
`techniques. either by reacting chiral starting materials or by
`separating isomers of a compound of fonnula I. Isorners may
`also include geometric isomers. e.g. when a double bond is
`present. All such geometric isomers are contemplated for
`this invention.
`
`Those skilled in the art will appreciate that for some
`compounds of formula I. one isomer will show greater
`phannacological activity than another isomer.
`Compounds of the invention with an amino group can
`form phamtaoeutically acceptable salts with organic and
`inorganic acids. Examples of suitable acids for salt forma-
`tion are hydrodtloric. sulfuric. phosphoric. acetic. citric.
`oxalic. malonic. salicylic. malic. fumaric. succinic. ascorbic.
`rnaleic. methanesulfonic and other mineral and carboxylic
`acids well known to those in the art. The salt is prepared by
`contacting the free base form with a suificient amount of the
`desired acid to produce a. salt. The tree base form may be
`regenerated by treating the salt with a suitable dilute aque-
`ous base solution such as dilute aqueous sodium bicarbon-
`ate. The free base form difiers from its respective salt form
`somewhat in certain physical properties. such as solubility in
`polar solvents. but the salt
`is otherwise equivalent to its
`respective free base form for purposes of the invention.
`Certain compounds of the invention are acidic (e.g.. those
`compounds which possess a carboxyl group). These com-
`pounds form phannaoeutically acceptable salts with inor-
`ganic and organic bases. Examples of such salts are the
`sodium. potassium. calcium. aluminum. gold and silver
`salts. Also included are salts formed with pharmaceutically
`acceptable amines such as ammonia. alkyl amines.
`hydroxyalkylamines. N-methylglucamine and the like.
`Cholesterol biosynthesis inhibitors for use in the combi-
`nation of the present invention include HMG CoA reductase
`inhibitors such as
`lovastatin. pravastatin.
`fluvastatin.
`simvastatin. and Cl-98]: HMG CoA synthetase inhibitors.
`for example L-659.699 ((E.E}-l J—[3'R—(hydroxy-n1elhyl)-4'-
`oxo-2'—R-oxetanyl}-3.5.7R-trirnethyl-2.4-undecadienoic
`acid); squalene synthesis inhibitors. for example squalestatin
`l; and squalene epoxidase inhibitors. for example. NB-598
`((E)-N-ethyi-N-(6.6-diIneI.hyl—2-hepten-4~ynyl)—3-[(3.35
`bithiophen-5-y1)rn ethoxy]benzene-methanamine
`hydrodiloride) and other cholesterol biosynthesis inhibitors
`such as DMP-565. Preferred HMG CoA reductase inhibitors
`are lovastatin. pravastatin and simvestatin.
`Compounds of formula I can be prepared by lmown
`methods. for example those described below and in W093!
`02048.
`Method A:
`
`as
`11'
`I
`I
`N“ M“'—X.—(C)a—'I'..—(Clr—Zp
`_
`I
`I
`R1
`to
`
`“arm
`
`I]
`
`i2
`
`‘F
`
`III
`
`T
`
`‘L
`
`£71\0RW
`‘F’
`
`A1-l—X.,.—(!'£3).—Y.—(I'i‘}—Z.,_‘
`
`mi
`
`ar1—x...—(p),—v..—(|C).—
`
`Ari
`
`Ia
`
`0
`
`N"ar=
`
`Ib
`
`0
`
`N“.-.r=
`
`4 of 22
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`5.767.115
`
`'7
`Compounds of fon-hula Ia and lb. wherein Ar‘. Arz. A13. X.
`Y. Z. R‘. R2. R3. m. n. p. q and r are as defined above. can
`be [prepared by treauncnt of an ester of formula 111. wherein
`R‘
`is lower alkyl such as ethyl or a chiral moiety such as
`menthyl or l0-(diisopropylsulfonarn.ido)isobornyl. and the
`remaining variables are as defined above. with a strong base
`such as lithium diisopropylarnide (LDA) in a suitable sol-
`vent such as tetrrahydrolithium (THF) at -78° C. A solubi-
`lizing agent such as hexamethylphosphoric triarnide
`(HMPA) may optionally be added as a cosolvent. An irnine
`of formula ll. wherein Arm and Arm are as defined above.
`is added. the reaction mixuire is either warmed to room
`temperature or maintained at a suitable low temperature
`such as —':‘'8° C. for the appropriate time. followed by
`quenching with a suitable acid such as IN HCl. The product
`is isolated using conventional purification techniques. When
`a protecting group as defined in Table 1 (below) is present
`on one or more of the optionally protected groups. an
`additional step comprising removal of the protecting group
`by conventional techniques is needed. However. for com-
`pounds of formula Ia. lb. or any oompound of formula I
`wherein a protected hydxoxy group Ar”. Ar”. Ar”. R‘ or
`R2‘ is an alkoxy or benzyloxy group. such a protecting group
`need not be removed to obtain a compound of formula I.
`When a chiral ester of formula II] is used. the resulting
`compound of formula In or [b is not Iacernic.
`Imines of formula II (Ar‘°—CH=N—Ar=°) can be pre-
`pared from aldchydes of the formula Ar’°—CHO and
`amines of the formula A.r*—CI-I0 and by procedures well
`known in the art. Aldehydes of formula Ar"—CHO and
`amines of formula Ar2°—NI-I, are commercially available or
`can be prepared via known procedures.
`Method A’:
`
`5
`
`8
`about 5 to about 60 minutes. preferably about 30 minutes.
`l—50% of solubilizing cosolvents may optionally be added.
`preferably about 10% HMPA.
`(b) Add an irnine of formula ll. wherein Ar” andAr’° are
`as defined above. to the product of step (a) over a period of
`5 to 60 minutes. preferably 30 minutes. maintaining the
`reaction mixture at about 0° C. to about -85” C‘.. preferably
`about -78” (3.. for l to 12 hours. preferably about 3 hours.
`or warming the reaction mixture over that time period at a
`rate of about 10° C. per hour to about 70° C. per hour.
`preferably about 30° C. per hour. to a temperature of about
`20° C.
`(c) Quench the reaction with a suitable acid such as HCI
`(JN).
`(cl) The protecting groups on R‘. R2’. Ar”. Ar” andAr3°.
`when present. are removed. if desired. by methods well
`known in the art. for example silyl protecting groups are
`removed by treatment with fluoride.
`e) Compounds of formula I wherein any of R and R2.
`when present. are OR‘ wherein R6 is hydrogen. can be
`converted by well known methods to other compounds of
`formula I wherein R and R2 are functionalized. i.e.. are
`independently selected from the group consisting of OR“.
`—0(CO)R6. —-o{c0}on° and —o(c0)NR°R7. wherein
`R‘. R7 and R” are as defined above and R6“ is lower alkyl.
`aryl. or aryi-lower alkyl. For example. treatment of the
`alcohol with an alkyl halide in the presence of a suitable base
`such as Nail will afiord a.lltoxy—subst:ituted compounds (i.e..
`R or R’ is OR‘. wherein R‘ is lower alkyl): treatment of the
`alcohol with an acylating agent such as aCcI:)'i(!l'li0l'lde will
`result in compounds wherein R or R: is —~—0C(O)R°: treat-
`ment of the alcohol with phosgene followed alcohol of the
`formula I-IOR° affords compounds substituted with a —{)C
`
`2'
`
`R3
`
`E +
`‘~20
`11
`
`0
`
`Y»
`I
`(u|:Im1).,
`kin/X"
`
`IV
`
`R
`
`OH
`
`~‘-*~-€'.=~~*'-~C.~=*~-.
`R1
`R3
`
`N
`
`R
`
`on
`I
`
`.A23 Ar‘--X.--(C),-Y.--(|.‘—
`R‘
`+
`R3
`
`Ar’
`
`N
`
`1:;
`
`0
`
`\Ar3
`
`Id
`
`0
`
`‘-5,:
`
`Compounds of formula Ic and Id. wherein the variables are
`as defined above. can be prepared by a process comprising
`the following steps:
`(a) Treat a lactone of formula IV. wherein the variables are
`as defined above. with a strong base such as an alkyllithiuln
`(e.g.. n-butyl-lithium). a metal hydride [e.g.. sodium
`hydride). a metal alkoxide (e.g.. sodium methoxide). ametal
`halide (e.g.. TiCL,). metal exchange of the lithium enolate
`with a metal halide (e.g.. zinc chloride). metal exchange of
`the lithium enolate with a metal
`all-tyl
`(e.g..
`9—borabicyclononyl
`triflate). or. preferably. a metalarnide
`(e.g.. LDA). in a suitable anhydrous organic solvent such as
`dry THF. ether or benzene. in a dry. inert atmosphere. e.g..
`under nitrogen. The reaction is carried out at about 0° C. to
`about -85” C.. preferably about —'ir'8° C.. over a period of
`
`55
`
`I50
`
`65
`
`osgene
`(0)OR° group; and treatment of the alcohol with
`followed by an amine of the fcrtnllla HNR‘R afioros
`compounds wherein R or R2 is —0C(0 NR°R7. Com-
`pounds of formula I wherein any Ar‘.
`or Ar’ has a
`hydroxy or amino group can be sirnilarly functionalized to
`obtain other compounds of formula 1. i.e.. wherein R‘ and
`R’ are indepcndgntly —or<°“. —o(co)R°". --otoogont
`—0(CH2)é_,0R .——o(co)NR°R’. —Nn"R’. -1412 (co)
`R’. — {CO)0R°. —N'R‘5(C0)NR7R‘ or —NR°S02R9.
`The product of step c. d or e is isolated using conventional
`purification techniques such as extraction. crystallization or.
`preferably. silica gel 60 chromatography. When a chiral
`lactone is used, the resulting compound of formula. Ic or Id
`is not racemic.
`Using the procedtlre described in steps (a)—(e}. lactones of
`formula We can be used to prepare compounds of formula
`
`5of22
`
`PENN EX. 2206
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`9
`
`10
`
`5.767.115
`
`lg and lhprovidedthat when n and r are each zero.p is 1-4:
`
`or ketone ofVI. wherein Arm. X. Y. R‘. R’. R’. m. n and q
`
`R:
`
`R’
`
`M
`it m
`‘me
`
`n
`
`A,m/
`
`‘(of
`Y"/
`“it
`
`9'
`
`‘z.
`
`0 Na
`
`I
`ii
`°“
`Ar*—x...—c—‘r.—rC).-29.,
`R1
`R:
`
`ii
`i"
`M3 A:1—X..—c|:—Y.—(f).-
`+
`R1
`R3
`
`I
`N
`
`Ar’
`
`N
`
`Is
`
`0/
`
`‘ma
`
`:1.
`
`0
`
`“ma
`
`Lactones of formulae IV and We are known in the an or
`can be prepared by methods well known in the art. See. fm'
`example. US. Pat. No. 4.375.475 and J. Agric. Food C'hem.,
`30(5) (1982) p. 920-4.
`Method B:
`
`35
`
`are as defined above. As in the case of Med1odA. protecting
`groups at A;-‘°_ A;-’°_ A.-3°_ R’ and R’ are removed as
`necessary.
`
`|
`0/
`
`This process provides several of the possible diastere-
`“so
`omers which can be separated by a combination of
`I {L crystallization. silica gel chromatography and HPLC. using
`“Eh”
`I
`o
`30 techniques well known in the art. The remaining d1'astere-
`*'l°_x"'-(‘f)¢""'~
`omers can be obtained by inversion reactions such as the
`R‘
`Mitsunobu reaction sequence outlined below. wherein par-
`“
`lial structures of formula If are shown:
`
`R3
`
`V
`
`R
`
`OH
`
`m=—x_—cn|:),—v,—c |"-
`
`R3
`
`+
`
`R‘
`I:
`
`i) ppm, Hcogn. DEAD
`ii}!-lC1.I"Me0H.
`
`3
`
`i"
`‘i
`Ar‘-—X..—($),—Y.—(|3
`R1
`R3
`If
`0/
`
`Ar’
`
`‘A9
`
`NI
`
`45
`
`9" H
`5
`
`0
`
`H
`5
`N\
`
`“'3
`
`A9
`
`Azetidinones of formula V. wherein Ar” and At” are as
`
`defined above. can be reacted to form compounds of formula 50 In the above known Process. DEAD is djdhYlaZ0d_iml.b0xy_
`1e and If i.e.. compounds of formula 1 wherein r is 1. R2 is
`.
`.
`.
`.
`hydroxy and P is mm) by treatmcm of azetidmonc V with
`late and PPh3 ls t1'1pheny1phosp]u.ne.'Ihe reactants are stirred
`a strong base such as lithium iosotxoptylcyclohexylatnide in
`3‘ m(_'m temperature overnight 3'14 the resultant famine
`in suitable solvent such as THF in the presence or absent of
`€533!
`15 C0iW¢1‘T*‘‘«'d 10 the ‘3°"1"35P°'1‘1-1'18 h3’d1'0X3' 905390‘-"1'31
`HMPA at ——'!'8° C.. followed by the addition of an aldehyde
`with the desired steroochernistry.
`
`6 of 22
`
`PENN EX. 2206
`CFAD V. UPENN
`lPR2015-01836
`
`
`
`Method C:
`
`11
`
`5.767.115
`
`12
`
`% A
`
`r°°(1‘{0
`'['iCh, TMEJA
`
`NH
`
`o «<
`0
`
`R‘
`R1‘
`I
`I
`ar'°—x..-(C).—Y,.—(CJ.—z,’\n/
`I
`I
`R1
`R!
`U
`
`,_
`
`+
`
`VI]
`
`P'[a1kyl}3 + djalkylazodiearboxylate
`:-can
`
`Compounds of formula Ia as defined above can be prepared
`by reacting a chiral auxiliary such as the compound of
`formula VIII with an activated carboxylic acid derivative of
`formula V1]. for example an acid chloride (%CI). a mixed
`anhydride formed with pl-ienyl phosphorodichlolidate
`(L=0P(0)(C'1)0Ph). an N—rnethyl—pyridinium ester formed
`from the reaction of an acid with N-rnethyl~2—
`chloropyridiniurn iodide (L=2—oxy—N-rnethylpyridinium
`iodide). and a 2-thiopyridyl ester formed from the reaction
`of an acid chloride and 2-miopyridine. wherein the remain-
`ing variables are as defined above; enolizing the resultant
`product. for example with TiCL, and teI:rarnethyleIhylenedi-
`arnine (TMEDA); condensing with an aldehyde. APOCHO;
`hydrolyzing to the corresponding acid. then reacting the
`compound of formula. Di with an amine. AP°NH2', and
`cyclizing the resultant compound of fonnula X. with. for
`example a triallrylphosphine and a dialk_vlazod.icarbo)ylate.
`As in the case of Method A. protecting groups at Ar”. Ar”.
`Ar”. R‘ and R7 are removed as necessary. This procedure is
`described in detail in W093fl0204-8.
`Method D:
`
`Aim
`
`Er
`‘N40
`:1
`
`+V1IeIa+Ib
`
`35
`
`45
`
`50
`
`S5
`
`Compounds of formula Ia. as defined above can also be
`prepared treatment of an ilnine of formula ll. wherein AP‘)
`and Ar” are as defined above. with an activated carboxylic
`acid duivative of formula VI] as defined above in the
`
`presence of a tertiary amine base such as trielhylamine.
`triburylarnine or cliethylisopropylarnine in an inert solvent
`such as CH,Cl2. Again. as in the case of Method A.
`protecting groups at Arm. A120. Arm. R‘ and R2’ are removed
`
`65
`
`as necessary. Use of other bases. e.g.. pyridine. favors
`formation of compounds of formula Ib.
`Method E:
`
`0 $0
`N
`
`R‘
`R1‘
`I
`|
`\n’\ z,.—(c),—v,.—(c), —x...—Arm
`0
`|
`F
`R3
`R1
`
`XII
`
`11.
`Tick, TMEDA
`
`°
`
`0
`
`7‘
`N
`
`3
`
`at’
`R‘
`I
`l
`;#.—c$1.—Y.—ttf>.—x.—»~r'°
`R:
`R1
`
`XZIJI
`
`Ar”
`
`HN\m-33
`N1N(5i(CH3):)
`inn--—-on
`
`In the first step. compound X1] is dissolved in a suitable
`solvent. e.g.. anhydrous CHZCIZ. and treated with a Lewis
`acid. e.g..TiC.l.4 at about -60° C. to 0° C.. preferably at about
`-25” C.. under a dry. inert atmosphere. e.g.. argon. Atertiaq
`amine base such as TMEDA is added and the mixture stirred
`at about —6D° C. to 0° C.. preferably at about -25” C. to —l5°
`C.. for a period of about
`I
`11. An imine of formula
`Ar3°CH=NAr3° is added neat or optionally as a solution in
`a suitable solvent. e.g. anhydrous CH,Cl,. over a period of
`about 5 min. and the reaction is stirred vigorously at about
`-60” C. to 0° C.. preferably at about —2S° C. to -15” C.. for
`about 3 to 6 11. preferably about 4 h or until the reaction is
`
`7of22
`
`PENN EX. 2206
`
`CFAD V. UPENN
`lPR20l5-01836
`
`
`
`13
`complete by TLC. An acid. eg. acetic acid. is added to
`reaction at the reaction temperature and the mixture is
`allowed to warm to room temperature slowly with stirring
`for about 1-3 hours. preferably about 2 hours. The com-
`pound of formula Xllis isolated by extraction with a suitable
`solvent. e.g. CH2('.‘l,. then purified by crystallization or silica
`gel chromatography.
`In the second step. the product is treated with a strong
`non-nucleophilic base. such as sodium or lithium bistrim-
`etltylsilylamide at about —78° C. to 100° C. After reaction.
`the mixture is poured into aqueous tartaric acid and the
`product isolated from the organic layer. As in the case of
`Method A. protecting groups at Ar”. Ar”. Ar”. R‘ and R2"
`are removed as necessary. This process. including the prepa-
`ration of the starting material of formula XII.
`is also
`described in greater detail in W093/02048.
`Method F:
`
`5.767.115
`
`Method G:
`
`14
`
`5
`
`'5'
`T‘
`_ ._ _
`l_
`(‘Pr Z’
`N t?‘ Y"
`R‘
`R’
`
`AIS
`
`halogenatittg
`a
`tit
`
`0/
`
`N
`
`“A1-2
`
`X\I"II
`
`‘
`
`5
`
`r
`t"
`Ar‘-(-|C)q-Ya-("'J).--Z1»
`R1
`R3
`
`I
`
`1‘N
`
`or’
`
`‘your
`
`0
`
`15
`
`XVIII
`
`far”
`II
`"ms
`
`R,
`I
`Brxc
`.“‘"“$*‘
`R1
`R3
`
`11
`
`xtv
`
`0
`
`Br
`
`~e>
`
`‘-
`
`R1‘
`I
`‘\$—Y.—(p).—2,
`R1
`R5
`
`0
`
`I
`
`IN
`
`M
`
`‘MW
`
`xv
`
`R2
`
`DMSO
`0%
`C—Y,.—(C),—
`-k3N_0
`‘Wm .'..
`,'..
`
`0
`
`XVI
`
`A:Wx..MgBt-ot-
`1|]
`'
`XVI——-VX.“
`
`35
`
`Ar”
`
`N
`
`“mm
`
`R’
`rt-Bu4NOHor
`'
`n.nuu~Iocrotct=a
`xvtnj——>ar=—(r|:t.—Y.—rt|:t.—z,
`R‘
`II’
`
`OH
`I
`
`0
`
`N
`
`‘*.».:=
`
`Compounds of fortnula Ii having a hydroxy substituent on
`the side chain adjacent to the Ar group (i.e.. compounds of
`formula I wherein m is 0) can be prepared by heating a.
`compound of formula XVII. prepared by Method D. above.
`wherein the variables are as defined above. for about 1-6
`hours at about 60° C. to 100° C. with a halogenating agent
`such as N-bromosuccinimide (NBS) in a suitable solvent
`such as CC]. in the presence of an initiating agent such as
`benzoyl peroxide. The resultant compound of formula
`XVIII. whaein Hal is Cl. Br or I and the remaining variables
`are as defined above. is then heatedin a suitable solvent such
`as CH,Cb with a tetl'aa.lk)tl~al'nIn0l1ll]IEl salt such as tetra
`n—butyl—ammonittm hydroxide (n-Bu4NOH) to obtain the
`compound of formula Ia. Alternatively. compound XVIJI
`can be heated in a suitable solvent such as Cl-I,Cl;._ with tetra
`n-butylanunonium lrifiuoroacetate (n-Bu_,NOC(O)CF3) fol-
`lowed by treatment with a mild base such as ethanol
`saturated with NI-I3 to obtain (:0n:tpound 11',
`Method H:
`
`o
`II
`
`45
`
`R1‘
`I
`
`ct—c—Y..r(p),—z,
`R,
`
`xix
`
`0
`
`Ar”
`
`[
`
`I
`N
`
`Hum
`
`Arm——X...D.let.'Pc|“
`
`9
`
`N
`
`\
`
`A1-3°
`
`]:-I’
`
`N
`
`\
`
`mm
`
`oH
`
`R2‘
`I
`Am —x,..—c —Y,.—(c),—z,
`3
`
`lR
`
`xx
`
`0
`
`‘F’
`3”‘
`X}; ArI.0_x__$_Y“_(c}_27
`H
`R3
`|
`
`0