Unite States Patent [19]
`Aristoff
`
`1111
`[45]
`
`4,306,075
`Dec. 15, 1981
`
`[54] COMPOSITION AND PROCESS
`[75] Inventor: Paul A. Aristoff, Portage, Mich.
`[73] Assigneez The Upjohn Company’ Kalamazoo’
`Mich.
`[21] Appl- NO-r 219,210
`[22] Filed:
`Dec. 22, 1980
`
`[63]
`
`Related US. Application Data
`Continuation-impart of Ser. No. 135,055, Mar. 28,
`1980’ abandoned‘
`[51] Int. Cl.3 .......................................... .. C07C 177/00
`[52] US. Cl. .................................... .. 560/56; 568/734;
`568/807; 260/239 BF; 568/808; 260/32645;
`260/465 F; 260/465 D; 260/326.5 C; 544/154;
`544/171; 544/176; 544/336; 544/386; 546/203;
`546/205; 546/285; 546/314; 546/309; 546/337;
`548/250; 560/28; 562/466; 562/451; 562/452;
`562/455; 564/80; 564/172; 564/ 174; 564/88;
`564/90; 564/95; 564/158; 568/632; 568/633;
`568/634
`[58] Field of Search .................. .. 560/56, 28; 562/466,
`562/451, 452, 455; 260/239 BF, 326.4 V, 465 F,
`465 D, 326.5 C; 544/154, 171, 176, 336, 386;
`546/203, 205, 285, 314, 309, 337; 548/280;
`564/80, 172, 174, 88, 90, 95, 158; 568/632, 633,
`634, 734, 807, 808
`
`[56]
`
`References Cited
`FOREIGN PATENT DOCUMENTS
`2017699 10/1979 United Kingdom ................ .. 810/56
`OTHER PUBLICATIONS
`Derwent Abstract 48l54B/26 J 54063059 05/21/79.
`Primary Examiner—-PauL J. Killos
`Attorney, Agent, or Firm—L. Ruth Hattan; Robert A.
`Armitage
`ABSTRACT
`[57]
`The present speci?cation provides novel analogs of
`carbacyclin (CBA2), 6a-carba-prostacyclin (6a-carba
`PGI2), which have pronounced prostacyclin-like phar
`macological activity, e.g., as platelet antiaggregatory
`agents. Speci?cally the novel chemical analogs of
`CBAz are those substituted by ?uoro (0-5), alkyl (0-9),
`interphenylene (C-5), and methano (C-6a,9). Further
`provided are benzindene analogs of CBAZ and substi
`tuted forms thereof, i.e., 9-deoxy-2’,9-methano (or 2’,9
`metheno)-3-oxa-4,5,6-trinor-3,7-(l',3'-interphenylene)
`PGFlcompounds. Also provided are a variety of novel
`chemical intermediates, e-g-, substituted bicycl0[3-3-
`0]octane intermediates, and chemical process utilizing
`such intermediates which are useful in the preparation
`of the novel CBAZ analogs.
`
`13 Claims, N0 Drawings
`
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`

`

`1
`
`COMPOSITION AND PROCESS
`
`4,306,075
`
`This application is a continuation-in-part of Ser. No.
`135,055, ?led Mar. 28, 1980, now abandoned.
`
`5
`
`25
`
`30
`
`35
`
`BACKGROUND OF THE INVENTION
`The present invention relates to novel compositions
`of matter and novel processes for preparing these com
`positions of matter. Moreover, there are provided novel
`methods by which certain of these novel compositions
`of matter are employed for pharmacologically useful
`purposes. Further there are provided novel chemical
`intermediates for preparing these compositions‘ of mat
`ter.
`The present invention is speci?cally concerned with
`novel analogs of prostacyclin or PGIZ. Speci?cally, the
`present invention is concerned with analogs of carbacy
`clin modi?ed at the OS or G9 position, e.g., C-S inter
`phenylene analogs of carbacyclin, 5-?uoro analogs of 20
`carbacyclin, 9B-alkyl analogs of carbacyclin, C-6a,9
`tricyclic (cyclopropyl) analogs of carbacyclin, and
`combinations thereof as well as novel benzidene analogs
`thereof.
`Prostacyclin is an endogenously produced compound
`in mammalian species, being structurally and biosyn
`thetically related to the prostaglandins (PG’s). In partic
`ular, prostacyclin exhibits the structure and carbon
`atom numbering of formula I when the C-5,6 positions
`are unsaturated. For convenience, prostacyclin is often
`referred to simply as “PGlz”. Carbacyclin, 6a-carba
`PGIZ, exhibits the structure and carbon atom number
`ing indicated in formula II when the C-5,6 positions are
`unsaturated. Likewise, for convenience, carbacyclin is
`referred to simply as “CBA2”.
`A stable partially saturated derivative of P61; is
`PGIl or 5,6-diliydro-PGI2 when the C-5,6 positions are
`saturated, depicted with carbon atom numbering in
`formula II when the C-5,6 positions are saturated. The
`40
`corresponding 5,6-dihydro-CBAZ is CBA1, depicted in
`formula II.
`As is apparent from inspection of formulas I and II,
`prostacyclin and carbacyclin may be trivially named as
`derivatives of PGF-type compounds, e.g., PGFga of 45
`formula III. Accordingly, prostacyclin is trivially
`named 9-deoxy-6,9a-epoxy-(5Z)-5,6-didehydro-PGF1
`and carbacyclin is named 9-deoxy-6,9a-methano-(5E)
`5,6-didehydro-PGF1. For description of prostacyclin
`and its structural identi?cation, see Johnson, et al., Pros
`taglandins 12:915 (1976).
`For convenience, the novel prostacyclin or carbacy
`clin analogs will be referred to by the trivial, art-recog
`nized system of nomenclature described by N. A. Nel
`son, J. Med. Chem. 17:911 (1974) for prostaglandins.
`Accordingly, all of the novel prostacyclin derivatives
`herein will be named as 9-deoxy-PGF1-type com
`pounds, PGIZ derivatives, or preferably as CBA1 or
`CBAZ derivatives.
`In the formulas herein, broken line attachments to a
`ring indicate substituents in the “alpha” ((1) con?gura
`tion, i.e., below the plane of said ring. Heavy solid line
`attachments to a ring indicate substituents in the “beta”
`([3) con?guration, i.e., above the plane of said ring. The
`use of wavy lines (~) herein will represent attachment
`65
`of substituents in the alpha or beta con?guration or
`attached in a mixture of alpha and beta con?gurations.
`Alternatively wavy lines will represent either an E or Z
`
`2
`geometric isomeric con?guration or the mixture
`thereof.
`A side chain hydroxy at C-l5 in the formulas herein
`is in the S or R con?guration as determined by the
`Cahn-Ingold-Prelog sequence rules, J. Chem. Ed. 41:16
`(1964). See also Nature 212:38 (1966') for discussion of
`the stereochemistry of the prostaglandins which discus
`sion applies to the novel prostacyclin or carbacyclin
`analogs herein. Molecules of prostacyclin and carbacy
`clin each have several centers of asymmetry and there
`fore can exist in optically inactive form or in either of
`two enantiomeric (optically active) forms, i.e., the dex
`trorotatory and laveorotatory forms. As drawn, the
`formula for PGI; corresponds to that endogenously
`produced in the mammalian species. In particular, refer
`to the stereochemical con?guration at C-8 ((1), C-9 ((1),
`C-ll (a) and 012 (B) of endogenously produced pros
`tacyclin. The mirror image of the above formula for
`prostacyclin represents the other enantiomer. The race
`mic form of prostacyclin contains equal numbers of
`both enantiomeric molecules.
`For convenience, reference to prostacyclin and car
`bacyclin will refer to the optically active form thereof.
`Thus, with reference to prostacyclin, reference is made
`to the form thereof with the same absolute con?gura
`tion as that obtained from the mammalian species.
`The term “prostacyclin-type” product, as used
`herein, refers to any cyclopentane derivative herein
`which is ‘useful for at least one of the same pharmaco
`logical purposes for which prostacyclin is employed. A
`formula as drawn herein which depicts a prostacyclin
`type product or an intermediate useful in the prepara
`tion thereof, represents that particular stereoisomer of
`the prostacyclin-type product which is of the same
`relative stereochemical con?guration as prostacyclin
`obtained from mammalian tissues or the particular ste
`reoisomer of the intermediate which is useful in prepar
`ing the above stereoisomer of the prostacyclin type
`product.
`.
`The term “prostacyclin analog” or “carbacyclin ana
`log” represents that stereoisomer of a prostacyclin-type
`product which is of the same relative stereochemical
`con?guration as prostacyclin obtained from mammalian
`tissues or a mixture comprising stereoisomer and the
`enantiomers thereof. In particular, where a formula is
`used to depict a prostacyclin type product herein, the
`term “prostacyclin analog” or “carbacyclin analog”
`refers to the compound of that formula or a mixture
`comprising that compound and the enantiomer thereof.
`
`50
`
`55
`
`60
`
`PRIOR ART
`Carbacyclin and closely related compounds are
`known in the art. See Japanese Kokia 63,059 and 63,060,
`also abstracted respectively as Derwent Farmdoc CPI
`Numbers 48l54B/26 and 48l55B/26. See also British
`published speci?cations 2,012,265 and German Offen
`lungsschrift 2,900,352, abstracted as Derwent Farrndoc
`CPI Number 54825B/30. See also British published
`application Nos. 2,017,699, 2,014,143 and 2,013,661.
`The synthesis of carbacyclin and related compounds
`is also reported in the chemical literature, as follows:
`Morton, D. R., et al., J. Organic Chemistry, 44:2880
`(1979); Shibasaki, M., et al. Tetrahedron Letters,
`433-436 (1979); Kojima, K., et al., Tetrahedron Letters,
`3743-3746 (1978); Nicolaou, K. C., et al., J. Chem. Soc.,
`Chemical Communications, 1067-1068 (1978); Sugie,
`A., et al., Tetrahedron Letters 2607-2610 (1979);
`Shibasaki, M., Chemistry Letters, 1299-1300 (1979),
`
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`

`3
`and Hayashi, M., Chem. Lett. 1437-1440 (1979); and Li,
`Tsung-tee, “A Facile Synthesis of 9(O)-Methano-prosta
`cyclin”, Abstract No. 378, (Organic Chemistry), and P.
`A. Aristoff, “Synthesis of 6a-Car'baprostacyclin 12”,
`Abstract No. 236 (Organic Chemistry) both at Abstract
`of Papers (Part ‘11) Second Congress of the North
`American Continent, San Francisco, California (Las
`Vegas, Nevada), USA, 24-29 August 1980.
`7-Oxo and 7-hydroxy-CBA2 compounds are appar
`ently disclosed in US. Pat. No, 4,192,891. l9-Hydroxy
`CBA; compounds are disclosed in US. Ser. No. 54,811,
`?led 5 July 1979. CBAZ aromatic esters are disclosed in
`US. Pat. No. 4,180,657. ll-Deoxy-Alo- or AH-CBAZ
`compounds are described in Japanese Kokai No.
`77/24,865, published 24 Feb. 1979.
`
`4,306,075
`4
`wherein R18 is hydrogen, hydroxy, hydroxymethyl,
`--—OR]() or —CHZOR](), wherein R10 is an acid-hydro
`lyzable protective group; wherein
`(1) R20, R31, R22, R23, and R24 are all hydrogen with
`R22 being either a-hydrogen or B-hydrogen,
`(2) R20 is hydrogen, R21 and R22 taken together form
`a second valence bond between C-9 and C-6a, and
`R23 and R24 taken together form a second valence
`bond between C-8 and G9 or are both hydrogen,
`or
`(3) R22, R23, and R24 are all hydrogen, with R22 being
`either a-hydrogen or ,B-hydrogen, and
`(a) R20 and R21 taken together are 0x0, or
`(b) R20 is hydrogen and R21 is hydroxy, being a
`hydroxy or B-hydroxy;
`wherein R27 is the same as R7 except that -—(CH2
`
`20
`
`25
`
`30
`
`wherein R32 is hydrogen or R31, wherein R31 is a
`hydroxyl hydrogen replacing group;
`wherein R33 is —CHO or ——CH2OR3z, wherein R32 is
`as de?ned above;
`wherein R47 is as de?ned above or is
`(l) (C1—C4)alkyl, or
`(2) —CH2OH;
`wherein X1 is
`(1) —~COOR1, wherein R1 is
`(a) hydrogen,
`
`(c) (C3—C10)Cycloalkyl,
`
`(e) phenyl, optionally substituted with one, 2 or 3
`chloro or (C1—C3)alky1,
`(f) phenyl substituted in the para position by
`
`35
`
`(ii) —CO—R26,
`
`SUMMARY OF THE INVENTION
`The present speci?cation particular by provides:
`(a) a carbacyclin intermediate of formula IV, V, VI,
`VII, VIII, or IX; and
`(b) a carbacyclin analog of formula X or XI;
`wherein g is 0, 1, 2, or 3;
`wherein n is one or 2;
`wherein L1 is a-R3z?-R4, a-R4:,8-R3, or a mixture of
`a-R3z?-R4 and a-R4:B-R3, wherein R3 and R4 are hy
`drogen, methyl, or ?uoro, being the same or different,
`with the proviso that one of R3 and R4 isfluoro only
`when the other is hydrogen or fluoro;
`wherein M1 is a-OH:B-R5 or a-R5:B-OH, wherein R5
`is hydrogen or methyl;
`wherein M6 is oL-OR10:B-R5 or a—R5:,B-OR10, wherein
`R5 is hydrogen or methyl and R10 is an acid hydrolyz
`able protective group;
`wherein R7 is
`(1) —CmH2m——CH3, wherein m is an integer from
`one to 5, inclusive,
`(2) phenoxy optionally substituted by one, two or
`threechloro, fluoro, trifluoromethyl, (C1—C3)alkyl,
`or (C1—C3)alkoxy, with the proviso that not more
`than two substituents are other than alkyl, with the
`proviso that R7 is phenoxy or substituted phenoxy,
`only when R3 and R4 are hydrogen or methyl,
`being the same or different,
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl
`optionally substituted on the aromatic ring by one,
`two or three chloro, ?uoro, tri?uoromethyl,
`(C1—C3)alkyl, or (C1—C3)alkoxy, with the proviso
`that not more than two substituents are other than
`alkyl,
`
`(iv) —CH:N—NH—CO—NH2 wherein R25 is
`methyl,
`phenyl, acetamidophenyl, ben
`zamidophenyl, or —NH;; R26 is methyl,
`phenyl, -—_NH2, or methoxy; and R54 is phenyl
`or acetamidophenyl; inclusive, or
`(g) a pharmacologically acceptable cation;
`(2) —CH1OH,
`(3) —COL4, wherein L4 is
`(a) amino of the formula —-NR51R52, wherein R5]
`and R52 are
`(i) hydrogen,
`(ii) (C1—Ci2)alky1,
`(iii) (C3-C10)cyc1oalkyl,
`(iv) (C7—C12)aralkyl,
`(v) phenyl, optionally substituted with one, 2 or
`3 chloro, (C1—C3)alkyl, hydroxy, carboxy,
`(C2-C5)alkoxycarbonyl, or nitro,
`(vi) (C2—C5)carboxyalkyl,
`(vii) (C2—C5)carbamoylalkyl,
`(viii) (C2—C5)cyanoalkyl,
`
`(x) (C7—C11)benzoalky1, optionally substituted by
`one, 2 or 3 chloro, (C1-C3)alkyl, hydroxy,
`(C1—C3)alkoxy, carboxy, (C2-C5)alkoxycarbo
`nyl, or nitro,
`.
`(xi) pyridyl, optionally substituted by one, 2 or 3
`chloro, (C1—C3)alkyl, or (C1—C3)alkoxy,
`(xii) (C6—C9)pyridylalkyl optionally substituted
`by one, 2 or 3 chloro, (C1—C3)a1kyl, hydroxy,
`or (C1-C3)alkyl,
`(xiii) (C1—C4)hydroxyalkyl,
`(xiv) (C1—C4)dihydroxyalkyl,
`
`45
`
`50
`
`55
`
`60
`
`65
`
`wherein —C(L1)-R7 taken together is
`(l) (C4—C7)cyc1oalkyl optionally substituted by one
`to 3 (C1-C5) alkyl;
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thienyloxymethyl;
`wherein R3 is hydroxy, hydroxymethyl, or hydrogen;
`wherein R15 is hydrogen or ?uoro;
`wherein R16 is hydrogen or R16 and R17 taken to
`gether are —CH2— or R16 and R47 taken together form
`a second valence bond between C-6a and C-9 or are
`—CH2—;
`wherein R17 is as de?ned above or is
`(1) hydrogen, or
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1019, p. 3 of 54
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`

`

`5 ,
`(xv) (C1-C4)trihydroxyalkyl,‘
`vith the further proviso that not more‘ than one of R51
`ind R52 is other than hydrogen‘or alkyl,
`(b) ‘cycloamino Selected from the group consisting ,
`of pyrolidino, lpiperidino; morpholino, pipera
`zino, h‘e'xa'methylene‘imino, pyrrolino, ‘or 3,4
`didehydropiperidinyl optionally substituted by
`one or 2 (C14C12)alkyl*of-'one' to v12 carbon
`
`atoms, inclusive, ‘»
`
`‘
`
`-»
`
`~
`
`.
`
`.
`
`(c) carbonylamino of the formula —NR53COR51,
`wherein R23 is hydrogen or (C1—C4)alkyl and
`R51 is other than hydrogen, but otherwise as
`
`de?ned above,
`
`‘
`
`'
`
`'
`
`(d) sulfonylamino of the formula ——NR53SO2R51,
`' wherein R21 and R13 are as de?ned in.(c),
`(4) —CH2NL2L3, wherein L2 and L3 are hydrogen or >
`(C1—C4)a1kyl, being the same or different, or-the
`pharmacologically acceptable acid addition salts
`thereof when X] is —CH2NL2L3, .
`>
`
`20
`
`wherein Z1 is
`(l) —CH2——(CH2)f—C(R2)2, wherein R2 is
`or ?uoro and f is zero, one, 2, or'3;
`I
`(2) trans—CH2—CH:CH—,
`(3) —(Ph)-(CH2)g—, wherein (Ph) is l,2-, 1,3-,-or
`1,4-phenylene and g is zero, one, 2, or 3;
`-
`
`hydrogen
`
`is as de?ned above;
`with the overall proviso that
`(1) R15, R16, and R17are all hydrogen only when Z1
`is —(Ph)-'-‘(CH2)g—‘, and
`.
`(2) Z1 is —-(Ph)—(Cl-I2)g+ only when R15 is
`
`hydro
`
`25 -
`
`30
`
`4,306,075
`6
`For‘those compounds wherein g is zero, one, 2 or 3,
`the carbacyclin analogs so described are further charac
`terized as 2,3,4-trinor-, 3,4-dinor-, or 4-nor, since in this
`event the Xi-terminated side chain contains (not includ
`ing the phenylene) 2, 3, or 4 carbon atoms, respectively,
`in place of the ?ve carbon atoms contained in F612.
`The missing carbon atom or atoms are considered to be
`at the O4‘ to C-2‘positions such that the phenylene is
`connected to the C-5 and C-1 to 03 positions. Accord
`ingly these compounds are named as 1,5- 2,5-, 3,5-, and
`4,5-inter-phenylene CBA compounds when g is zero,
`one, 2, or 3, respectively.
`Those CBA analogs wherein Z1 is —CH2——(CH2.
`)f—CF1—- ‘are characterized as “2,2-di?uoro‘” com- >
`pounds. For those compounds wherein fis zero, 2, or 3,
`the carbacyclin analogs so described are further charac
`terized as 2-nor, 2a-homo, or 2a,2b-dihomo, since in this
`event the X1-terminated side chain contains 4, 6, or 7
`carbon atoms, respectively, in place of the ?ve carbon
`atoms contained in CBAZ. The missing carbon atom is
`considered to beat the 02 position such that the C-1
`carbon atoms‘ is connected to the C-3 position. The
`additional carbon atom or atoms are considered as
`though they were inserted between the C-2 and 03
`positions. Accordingly these additional carbon atoms
`are referred to as C-2a and C-2b, counting from the C-2
`to the C-3 position.
`I
`Those CBA analogs wherein Z1 is trans—CH
`2—CH:CH— are described as “trans-2,3-didehydro
`CBA” compounds.
`t
`Those novel compounds where n is 2 are further
`characterized as 7a-horno-CBA compounds by virtue of .
`the-cyclohexyl ring replacing the heterocyclic ring of
`
`35
`
`With regard to the divalent substituents described
`above (e.g., L1 and M1),‘these divalent radicals are de
`fined as a-Riz?-Rj, wherein R; represents the substituent
`of the ‘divalent moiety in the alpha con?guration with
`“ respect to the plane of the C-8 to C-12 cyclopentane
`ring and‘ R] represents the substituent of the divalent
`moiety in the beta con?guration with respect to the‘
`plane of 'the ring. Accordingly, when M] is de?ned as‘
`a-OI-I:B-R5, the hydroxy of the M1 moiety is in the
`alpha con?guration, i.e., as in PGIZ above, and the R5
`substituent is in the betacon?guration.
`The carbon atom content of various hydrocarbon- '
`containing moieties is indicated by a pre?x designating
`the minimum and maximum number of carbon atoms in
`the moiety, i.e., the pre?x (Ci-Cj) indicates a moiety of
`the integer “i” to the integer “j” carbon atoms, inclu~
`sive. Thus (C1—C3)alkyl refers to alkyl of one to 3 car
`bon atoms, inclusive, or methyl, ethyl, propyl, and iso
`propyl.
`‘Certain novel prostacyclin analogs herein, i.e., for
`55
`mula X compounds, are all-named as CBA'1 or CBA;
`compounds, respectively, by virtue of the substitution
`of methylene for oxa in the heterocyclic ring‘of prosta
`cyclin and the substitution. CBA; compounds are those
`exhibiting the ole?nic double bond at C-5,6, while
`CBA] compounds are those saturated at C-5,6.'Formula
`XI compounds are named'as PGE1 or PGF] derivatives
`as hereinafter described.
`‘
`F
`-
`Novel compounds wherein - Z1 is (Ph)'(CH2)g are
`designated inter-0;, inter-m5 or inter-p-phenylene de
`65
`pending on whether the attachment between C-5 andv
`moiety is ortho, meta, or 'para,'respec
`
`50
`
`60
`
`prostacyclin.
`
`.
`
`>
`
`Further, the novel compounds are named as 9B-alkyl
`CBA compounds when R17 is alkyl.
`When R16 and R17 taken together are —CH2—(
`methylene), the novel . compounds so described are
`“6aB,9B-methano-CBA” compounds by virtue of the
`methylene bridge between C-6a and C-9.
`When R15 is fluoro, “S-fluoro-CBA” compounds are
`described.
`-
`The formula XI CBA analogs wherein R20, R21, R22,
`R23,‘ and R24 are all hydrogen with R22 being ,B-hydro
`gen are characterized as "9-deoxy-2‘,9a-methano-3-oxa- ‘
`4,5,6~trinor-3,7-(l',3’-inter-phenylene)-PGF1”
`com
`pounds. Corresponding compounds wherein R22 is a
`hydrogen are characterized as “9-deoxy-2',9B-methano
`3-oxa-4,5,6-trinor-3,7-(l',3’—inter-phenylene)-PGF1”
`compounds. CBA analogs wherein R20, R23, and R24
`are all hydrogen and R21 and R22 taken together form a
`valence bond between C-9 and C-6a are characterized
`as "9-deoxo-2',9—metheno-3-oxo-3,4,5-trinor-3,7-(1',3'
`inter-phenylene)-PGF1” compounds. CBA analogs
`wherein Rzotis hydrogen and R21 and R22 taken together
`form a second valence bond between C-9 and C-6a and
`R23 and R24 taken together form a second valence bond
`between‘ C-7 and G8 are characterized as “9-deoxo:
`2',9-metheno-3-oxa-3,4,5-trinor-3,7-(l',3’-inter
`phenylene)-7,8-didehydro-PGE1” compounds. The for
`mula XI CBA analogs wherein R22, R23, and R24 are all
`hydrogen and R20 and R21 taken together are oxo are
`characterized as "6a-oxo-9-deoxy-2’,9a-methano-3-oxa
`4,5,6-trinor-3,7-(1’,3’-inter-phenylene)-PGF1” or “6a
`oxo-9-deoxy-2',9B-methano-3-oxa-4,5,6-trinor-3,7
`(1’,3’-inter-phenylene)-PGF1” depending on whether
`R22 is a-hydrogen or B-hydrogen, respectively. For
`mula XI CBA‘ analogs wherein R20, R22, R23, and R24
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1019, p. 4 of 54
`
`

`

`20
`
`25
`
`7
`are all hydrogen and R21 is a-hydroxy are characterized
`as
`“6aa-hydroxy-9-deoxy-2’,9a-methano-3-oxa-4,5,6
`trinor-3,7-(l ’,3'-inter-phenylene)-PGF 1 ”
`or
`“62101
`hydroxy-9-deoxy-2’,9B-methano-3-oxa-4,5,6-trinor-3,7
`(l’,3’-inter-phenylene)-PGF1” compounds depending
`on whether R22 is a-hydrogen or B-hydrogen, respec
`tively. Finally, formula XI TXA analogs wherein R20,
`R22, R23, and R24 are all hydrogen and R21 is ,B-hydroxy
`are characterized as "6aB-hydroxy-9-deoxy-2’,9B
`methano-3-oxa-4,5,6-trinor-3,7-(1',3’-inter-phenylene)
`PGF1” or “6aB-hydroxy-9-deoxy-2’,9a-methano-3-oxa
`4,5,6-trinor-3,7-( l ‘,3'-inter-phenylene)-PGF1”
`com
`pounds depending on whether R22 is a-hydrogen or
`,B-hydrogen, respectively. When Z4 is -—(CH2)f-—CF2
`and f is zero, the formula XI CBA analogs are addition
`ally characterized as “2,2-di?uoro” compounds. When f
`is one, 2, or 3, such compounds are additionally charac
`terized as “Za-homo”, “2a,2b-dihomo” or “2a,2b,2c
`trihomo” compounds.
`When R5 is methyl, the carbacyclin analogs are all
`named as “IS-methyl-CBA” compounds. Further, ex
`cept for compounds wherein Y1 is cis—CH:CI-I—,
`compounds wherein the M1 moiety contains an hy
`droxyl in the beta con?guration are additionally named
`as “l5-epi-CBA” compounds.
`For the compounds wherein Y1 is cis—-CH:CH—-,
`then compounds wherein the M1 moiety contains an
`hydroxyl in the alpha con?guration are named as “15
`epi-CBA” compounds. For a description of this conven
`tion of nomenclature for identifying C-15 epimers, see
`U.S. Pat. No. 4,016,184, issued 5 Apr. 1977, particularly
`columns 24-27 thereof.
`The novel carbacyclin analogs herein which contain
`—(CH2)2—, cis—CH:CH—, or —-CEC-— as the Y;
`moiety, are accordingly referred to as “13,14-dihydro”,
`“cis-l3”, or “13,14-didehydro” compounds, respec
`tively.
`When R7 is straight chained -—C,,,H2m-CH3,
`wherein m is as de?ned above, the compounds so de
`scribed are named as “19,20-dinor”, “20-nor”, “20
`methyl” or “20-ethyl” compounds when m is one, 2, 4
`or 5, respectively. When R7 is branched chain —CmH
`2,,,—CH3, then the compounds so described are “17-,
`18-, 19-, or 20-alkyl” or “17,17-, 17,18-, -17,l9-, 17,20-,
`18,18-, 18,19-, 18,20-, 19,19-, or 19,20-dialkyl” com
`45
`pounds when m is 4 or 5 and the unbranched portion of
`the chain is at least n-butyl, e.g., “17,20-dimethyl” com
`pounds are described when m is 5 (l-methylpentyl).
`When R7 is phenyl and neither R3 and R4 is methyl,
`the compounds so described are named as “l6-phenyl
`17,18,19,20-tetranor” compounds. When R7 is substi
`tuted phenyl, the corresponding compounds are named
`as “l6-(substituted phenyl)-l7,18,19,20-tetranor” com
`pounds. When o'ne and only one of R3 and R4 is methyl
`or both R3 and R4 are methyl, then the corresponding
`compounds wherein R7 is as de?ned in this paragraph
`are named as “l6-phenyl or l6-(substituted phenyl)
`l8,l9,20-trinor” compounds or “l6-methyl-l6-phenyl
`or l6-(substituted phenyl)-18,19,20-trinor” compounds
`respectively.
`When R7 is benzyl, the compounds so described are
`named as “l7-phenyl-l8,19,20-trinor”
`compounds.
`When R7 is substituted benzyl, the corresponding com
`pounds are named as “l7-(substituted phenyl)-l8,19,20
`trinor” compounds.
`When R7 is phenylethyl, the compounds so described
`are named as “l8-phenyl-l9,20-dinor” compounds.
`When R7 is substituted phenylethyl, the corresponding
`
`65
`
`4,306,075
`
`0
`
`8
`compounds are named as “IS-(substituted phenyl)
`l9,20-dinor” compounds.
`When R7 is phenylpropyl, the compounds so de
`scribed are .named as “l9-phenyl-20-nor" compounds.
`When R7 is substituted phenylpropyl the corresponding
`compounds are named as “l9-(substituted phenyl)-20
`nor” compounds.
`When R7 is phenoxy and neither R3 nor R4 is methyl,
`the compounds so described are named as “l6-phenoxy
`l7,l8,l9,20-tetranor” compounds. When R7 is substi
`tuted phenoxy, the corresponding compounds are
`named as
`“l6-(substituted
`phenoxy)-l7,l8,l9,20
`tetranor” compounds. When one and only one of R3 and
`R4 is methyl or both R3 and R4 are methyl, then the
`corresponding compounds wherein R7 is as de?ned in
`this paragraph are named as “l6-phenoxy or l6-(sub
`stituted phenoxy)-18,19,20-trinor” compounds or “16
`methyl-l6-phenoxy-
`or
`l6-(substituted
`phenox
`y) l 8, 19,20-trinor” compounds, respectively.
`When R7 is cis—CH:CI-I—CH2CH3, the com
`pounds so described are named as “cis-17,l8-didehy
`dro” compounds.
`When R7 is —(CH2)2-—CH(OH)—CH3, the com
`pounds so described are named as “19-hydroxy” com
`pounds.
`When R7 is ——(CH2)3—CH:C(CH3)2, the com
`pounds so described are named as “20-isopropylidene”
`compounds.
`When ——C(L1)-R7 is optionally substituted cycloal
`kyl, 2-(2-furyl)ethyl, 2-(3-thienyl)ethyl, or 3-thienylox
`ymethyl, the compounds so described are respectively
`15-cycloalkyl-16,l7,18,19,20-pentanor compounds, 17
`(2-furyl)-18,19,20-trinor-CBA
`compounds,
`17-(3
`thienyl)-l8,l9,20-trinor compounds, or 16-(3-thienyl
`)oxy-17,18,19,20-tetranor compounds.
`When at least one of R3 and R4 is not hydrogen then
`(except for the l6-phenoxy or l6-phenyl compounds
`discussed above) there are described the “l6-methyl”
`(one and only one of R3 and R4 is methyl), “16,16
`dimethyl” (R3 and R4are both methyl), “l6-fluoro” (R3
`or R4 is ?uoro), “16,16-di?uoro” (R3 and R4 are both
`fluoro) compounds. For those compounds wherein R3
`and R4 are different, the prostaglandin analogs so repre
`sented contain an asymmetric carbon atom at C-l6.
`Accordingly, two epimeric con?gurations are possible:
`“(16S)” and “(16R)”. Further, there is described by this
`invention the C-l6 epimeric mixture: “(16RS)”.
`When X1 is —CH2OH, the compounds so described
`are named as "2-decarboxy-Z-hydroxymethyl” com
`pounds.
`When X] is —CH2NL2L3, the compounds so de
`scribed are named as "Z-decarboxy-2-aminomethyl” or
`“Z-(substituted amino)methyl” compounds.
`When X1 is —-COL4, the novel compounds herein are
`named as CBA-type amides. Further, when X1 is
`—COOR1, the novel compounds herein are named as
`CBA-type esters and CBA-type salts.
`Examples of phenyl esters substituted in the para
`position (i.e., X1 is --COOR1, R1 is p-substituted
`phenyl)‘ include p-acetamidophenyl ester, p-ben
`zamidophenyl ester, p-(p-acetamidobenzarnido)phenyl
`ester, p-(p-benzamidobenzamido)phenyl ester, p
`aminocarbonylaminophenyl ester, p-acetylphenyl ester,
`p-benzylphenyl ester, p-amidocarbonylphenyl ester,
`p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl
`ester, p-(p-acetamidobenzoyloxy)phenyl ester, and p
`hydroxybenzaldehyde semicarbazone ester.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1019, p. 5 of 54
`
`

`

`25
`
`4,306,075
`9
`10
`boxybenzoylethylamide, o-hydroxybenzoylethylamide,
`Examples of novel amides herein (i.e., X1 is ——COL4)
`include the following:
`p-chlorobenzoylpropylamide,
`m-chlorobenzoyl
`propylamide, 2,4-dichlorobenzoylpropylamide, 2,4,6
`(1) Amides within the scope of alkylamino groups of
`trichlorobenzoylpropylamide, m-nitrobenzoylpropyla
`the formula-NR51R5Z are methylamide, ethylamide,
`n-propylamide, n-butylamide, n-pentylamide, n-hexyla
`mide, p-nitrobenzoylpropylamide, p-methoxybenzoyl
`mide, n-heptylamide, n-octylamide, n-nonylamide, n
`propylamide, 2,4-dimethoxybenzoylpropylamide, 3,4,5
`trimethoxybenzoylpropylamide, p-hydroxymethylben
`decylamide, n-undecylamide, and n-dodecylamide, and
`isomeric forms thereof. Further examples are dime
`zoylpropylamide, p-methylbenzoylpropylamide, m
`thylamide, diethylamide, dim-propylamide, di-n-butyla
`methylbenzoylpropylamide,
`p-ethylbenzoylpropyla
`mide, methylethylamide, methylpropylamide, methyl
`mide, t-butylbenzoylpropylamide, p-carboxybenzoyl
`butylamide, ethylpropylamide, ethylbutylamide, and
`propylamide, m-methoxycarbonylbenzoylpropylamide,
`o~carboxybenzoylpropylamide,
`o-hydroxybenzoyl
`propylbutylamide. Amides within the scope of cy
`cloalkylamino are cyclopropylamide, cyclobutylamide,
`propylamide,
`p-chlorobenzoylbutylamide,
`m
`cyclopentylamide, 2,3-dimethylcyclopentylamide, 2,2
`chlorobenzoylbutylamide, 2,4-dichlorobenzoylbutyla
`dimethylcyclopentylamide, Z-methylcyclopentylamide,
`mide, 2,4,6-trichlorobenzoylbutylamide, m-nitroben
`3-tert-butylcyclopentyl amide, cyclohexylamide, 4-tert
`zoylmethylamide,
`p-nitrobenzoylbutylamide,
`p
`butylcyclohexylamide,
`3-isopropylcyclohexylamide,
`methoxybenzoylbutylamine, 2,4-dimethoxybenz0ylbu
`2,2-dimethylcyclohexylamide, cycloheptylamide, cy
`tyl-amide,
`3,4,5-trimeth0xybenzoylbutylamide,
`p
`clooctylamide, cyclononylamide, cyclodecylamide,
`hydroxymethylbenzoylbutyl-amide, p-methylbenzoyl
`N-methyl-N-cyclobutylamide, N-methyl-N-cyclopen
`butyamide, m-methylbenzoylbutylamide, p-ethyl-ben
`tylamide, N-methyl-N-cyclohexylamide, N-ethyl-N
`zoylbutylamide, m-methylbenzoylbutylamide, p-ethyl
`cyclopentylamide, and N-ethyl-Ncyclohexylamide.
`benzoylbutyl-amide, t-butylbenzoylbutylamide, p-car
`boxybenzoylbutylamide, m-methoxycarbonylbenzoyl
`Amides within the scope of aralkylamino are benzyla
`mide, Z-phenylethylamide, and N-methyl-N benzyl
`butylamide, o-carboxybenzoylbutylamide, o-hydrox
`amide. Amides within the scope nf substituted phenyla
`ybenzoylmethylamide. Amides within the scope of
`mide are
`p-chloroanilide,
`m-chloroanilide,
`2,4
`pyridylamino are a-pyridylamide, ,B-pyridylamide, and
`dichloroanilide, 2,4,6-trichlor0anilide, m-nitroanilide,
`y-pyridylamide. Amides within the scope of substituted
`p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide,
`pyridylamino are 4-methyl-a-pyridylamide, 4-methy1
`3,4,5-trimethoxyanilide, p-hydroxymethylanilide, p
`B-pyridylamide, 4-chloro-a-pyridylamide, and 4
`methylanilide, m-methyl anilide, p-ethylanilide, t
`chloro-B-pyridylamide. Amides within the scope of
`butylanilide, p-carboxyanilide, p-methoxycarbonyl ani
`pyridylalkylamino are a-pyridylmethylarnide, B
`lide, p-carboxyanilide and o-hydroxyanilide. Amides
`pyridylmethylamide,
`'y-pyridylmethylamide,
`a
`pyridylethylamide, ,B-pyridylethylamide, y-pyridyle
`within the scope of carboxyalkylamino are carboxye
`thylamide, carboxypropylamide and carboxymethyla
`thylamide, a-pyridylpropylamide, B-pyridylpropyla
`mide, 'y-pyridylpropylamide, a-pyridylbutylamide, B
`mide, carboxybutylamide. Amides within the scope of
`35
`carbamoylakylamino are carbamoylmethylamide, car
`pyridylbutylamide, and 'y-pyridylbutylamide. Amides
`bamoylethylamide, carbamoylpropylamide, and car
`within the scope of substituted pyridylalkylamido are
`4-methyl-a-pyridylmethylamide, 4-rnethyl-B-pyridyl
`bamoylbutylamide. Amides within the scope of cya
`noalkylamino are cyanomethylamide, cyanoethyla
`methylamide,
`4-chloro-a-pyridylmethylamide, -4
`chloro-B-pyridylmethylamide,
`4-methyl-a-pyridyl
`mide, cyanopropylamide, and cyanobutylamide. Am
`ides withn the scope of acetylalkylamino are acetylme
`propylamide,
`4-methyl-,B-pyridylpropylamide,
`4
`thylamide, acetylethylamide, acetylpropylamide, and
`chloro-a-pyridylpropylamide,
`4-chlor0-B-pyridyl
`propylamide, 4-methyl-a-pyridylbutylamide, 4-methyl
`acetylbutylamide. Amides within the scope of ben
`B-pyridylbutylamide,
`4-chloro-a-pyridylbutylamide,
`zoylalkylamino are benzoylmethylamide, benzoyle
`thylamide, benzoylpropylamide, and benzoylbutyla
`4-ch1oro-B-pyridylbutylamide, 4-chloro-y-pyridylbu
`mide. Amides within the scope of substituted ben
`tyl-amide. Amides within the scope of hydroxyalk
`zoylalkylamino are p-chlorobenzoylmethylamide, m
`ylamino are hydroxymethylamide, B-hydroxyethyla
`chlorobenzoylmethylamide,
`2,4-dichlorobenz0ylme
`mide, B-hydroxypropylamide, 'y-hydroxypropylamide,
`l-(hydroxymethyl)ethyl-amide,
`l-(hydroxymethyD
`thylamide,
`2,4,6-trichlorobenzoylmethylamide, m
`nitrobenzoylmethylamide, p-nitrobenzoylmethylamide,
`propylamide, (2-hydr0xymethyl)propylamide, and a,a
`p-methoxybenzoylmethylamide, 2,4-dimethoxy ben
`dimethyl-hydroxyethylamide. Amides within the scope
`zoylmethylamide,
`3,4,5-trimethoxybenzoylmethyla
`of dihydroxyalkylamino are dihydroxymethylamide,
`mide, p-hydroxyrnethylbenzoylmethylamide, p-methyl
`,8,y-dihydroxypropylamide,
`l-(hydroxymethyDZ
`benzoylmethylamide, m-methylbenzo