United States Patent
`Aristoff
`
`119)
`
`4,306,075
`(11)
`
`[45] Dec, 15, 1981
`
`[54] COMPOSITION AND PROCESS
`
`Inventor:
`75]
`(73] Assignee:
`
`Paul A. Aristoffi, Portage, Mich.
`The Upjohn Company, Kalamazoo,
`Mich.
`
`[21] Appl. No.: 219,210
`(22] Filed:
`Dec. 22, 1980
`
`Related U.S. Application Data
` Continnation-in-part of Ser. No. 135,055, Mar. 28,
`1980, abandoned.
`
`[63]
`
`Tint, C03 cecscssessscsscscssccsesessssscosscsenneee co7c 177/00
`SU]
`BON Mi cereAeror 560/56; 568/734;
`568/807; 260/239 BF; 568/808; 260/326.45;
`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 ....c:.cccccce00.- 560/56, 28; 562/466,
`562/451, 452, 455; 260/239 BF, 326.4 V, 465 F,
`465 D, 326.5 C; $44/154, 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 48154B/26 J 54063059 05/21/79.
`
`Primary Examiner—PauL. J. Killos
`Aitorney, Ageni, or Firm—L. Ruth Hattan; Robert A.
`Armitage
`ABSTRACT
`[57]
`The present specification provides novel analogs of
`carbacyclin (CBA»), 6a-carba-prostacyclin (6a-carba-
`PGI), which have pronounced prostacyclin-like phar-
`macological activity, e.g., as platelet antiaggregatory
`agents. Specifically the novel chemical analogs of
`CBAgare those substituted by fluoro (C-5), alkyl (C-9),
`interphenylene (C-5), and methano (C-6a,9), Further
`provided are benzindene analogs of CBAand substi-
`tuted forms thereof, i.e., 9-deoxy-2',9-methano (or 2’,9-
`metheno)-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-
`PGF)compounds. Also provided are a variety of novel
`chemical
`intermediates, ¢.g., substituted bicyclo[3.3.-
`OJoctane intermediates, and chemical process utilizing
`such intermediates which are useful in the preparation
`of the novel CBA?analogs.
`
`13 Claims, No Drawings
`
`Liquidia - Exhibit 1014 - Page 1
`
`Liquidia - Exhibit 1014 - Page 1
`
`

`

`1
`
`4,306,075
`
`COMPOSITION AND PROCESS
`
`This application ts a continuation-in-part of Ser. No.
`135,055, filed Mar. 28, 1980, now abandoned,
`
`BACKGROUNDOF 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.
`
`10
`
`15
`
`2
`configuration or
`
`the mixture
`
`geometric isomeric
`thereof.
`A side chain hydroxy at C-15 in the formulas herein
`is in the S or R configuration 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 whichdiscus-
`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 orin 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 configuration at C-8 (a), C-9 (a),
`C-11 (a) and C-12 (8) 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 configura-
`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 configuration as prostacyclin
`obtained from mammalian tissues or the particular ste-
`reoisomer ofthe intermediate whichis 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
`configuration as prostacyclin obtained from mammalian
`tissues Of 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.
`PRIOR ART
`
`The present invention is specifically concerned with
`novel analogs of prostacyclin or PGI. Specifically, the
`present invention is concerned with analogsof carbacy-
`clin modified at the C-5 or C-9 position, e.g., C-5 inter-
`phenylene analogs of carbacyclin, 5-fluoro analogs of 2°
`carbacyclin, 9@-alkyl analogs of carbacyclin, C-6a,9
`tricyclic (cyclopropyl) analogs of carbacyclin, and
`combinations thereofas 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 “PGI;". Carbacyclin, 6a-carba-
`PGI, exhibits the structure and carbon atom number-
`ing indicated in formula IT when the C-5,6 positions are
`unsaturated, Likewise, for convenience, carbacyclin is
`referred to simply as “CBA 2”.
`A stable partially saturated derivative of PGI+ is
`PGI) or 5,6-dihydro-PGIy when the C-5,6 positions are
`saturated, depicted with carbon atom numbering in
`formula I] when the C-5,6 positions are saturated. The
`corresponding 5,6-dihydro-CBA3 is CBA), depicted in
`formula II.
`As is apparent from inspection of formulas I andII,
`prostacyclin and carbacyclin may betrivially named as
`derivatives of PGF-type compounds, e.g., PGFia of
`formula III. Accordingly, prostacyclin is
`trivially
`named
`9-deoxy-6,9a-epoxy-(5Z)-5,6-didehydro-PGF,
`and carbacyclin is named 9-deoxy-6,9a-methano-(5E)-
`5,6-didehydro-PGF|. For description of prostacyclin
`andits structuralidentification, see Johnson,et al., Pros-
`taglandins 12:915 (1976),
`For convenience, the novel prostacyclin or carbacy-
`clin analogs will be referred to by thetrivial, 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-PGF)-type com-
`pounds, PGI) derivatives, or preferably as CBA, or
`CBA}derivatives.
`Tn the formulas herein, broken line attachments to a
`ring indicate substituents in the “alpha" (a) configura-
`tion, i.e., below the planeof said ring. Heavy solid line
`aliachmentsto a ring indicate substituents in the “beta”
`(8) configuration,i.., above the planeofsaid ring. The
`use of wavy lines (~) herein will represent attachment
`of substituents in the alpha or beta configuration or
`attached in a mixture of alpha and beta configurations,
`Alternatively wavy lines will represent cither an E or Z
`
`40
`
`45
`
`50
`
`60
`
`Carbacyclin and closely related compounds are
`knownin the art. See Japanese Kokia 63,059 and 63,060,
`also abstracted respectively as Derwent Farmdoc CPI
`Numbers 48154B/26 and 48155B/26. See also British
`published specifications 2,012,265 and German Offen-
`lungsschrift 2,900,352, abstracted as Derwent Farmdoc
`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),
`
`Liquidia - Exhibit 1014 - Page 2
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`Liquidia - Exhibit 1014 - Page 2
`
`

`

`3
`and Hayashi, M., Chem. Lell. 1437-1440 (1979); and Li,
`Tsung-tee, “A Facile Synthesis of 9(0)-Methano-prosta-
`cyclin", Abstract No. 378, (Organic Chemistry), and P.
`A. Aristoff, “Synthesis of 6a-Carbaprostacyclin 12",
`Abstract No. 236 (Organic Chemistry) both at Abstract
`of Papers (Part
`Il) Second Congress of the North
`American Continent, San Francisco, California (Las
`Vegas, Nevada), USA, 24-29 August 1980.
`7-Oxo and 7-hydroxy-CBAz compounds are appar-
`ently disclosed in U.S. Pat. No. 4,192,891. 19-Hydroxy-
`CBA; compoundsare disclosed in U.S. Ser. No. 54,811,
`filed 5 July 1979. CBA» aromatic esters are disclosed in
`U.S. Pat. No. 4,180,657. 11-Deoxy-Alor Al!-CBAa
`compounds are described in Japanese Kokai No.
`77/24,865, published 24 Feb. 1979.
`SUMMARY OF THE INVENTION
`
`The present specification particular by provides:
`(a) a carbacyclin intermediate of formula IV, V, VI,
`VII, VIII, or LX; 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 Ly is a-R3:8-R4, a-R4:8-R3, or a mixture of
`a-Ry:8-Ry and a-Ra:8-Ra, wherein Ra and Rg are hy-
`drogen, methyl, or fluoro, being the same or different,
`with the proviso that one of Ra and R4 is fluoro only
`whenthe other is hydrogen or fluoro;
`wherein M; is a-OH:8-Rs or a-Rs;8-OH, wherein Rs
`is hydrogen or methyl;
`wherein Mg is a-OR jo:8-Rs or a-R5:8-OR jo, wherein
`Rs is hydrogen or methyl and Rio is an acid hydrolyz-
`able protective group;
`wherein R7 is
`(1) —C,,H2,,—CH3, wherein m is an integer from
`one to 5, inclusive,
`(2) phenoxy optionally substituted by one, two or
`three chloro,fluoro, trifluoromethyl, (C)-Ca)alkyl,
`or (C\-Ca)alkoxy, with the proviso that not more
`than two substituents are other than alkyl, with the
`proviso that R7is phenoxy or substituted phenoxy,
`only when R3 and Rg are hydrogen or methyl,
`being the same or different,
`(3) phenyl, benzyl, phenylethyl, or phenylpropy!
`optionally substituted on the aromatic ring by one,
`two or
`three chloro,
`fluoro,
`trifluoromethyl,
`(Ci-Ca)alkyl, or (C)}-C3)alkoxy, with the proviso
`that not more than two substituents are other than
`alkyl,
`(4) cis-CH=CH—CH—CH;,
`(5) —(CH3)2,—CH(OH)—CH3,or
`(6) —(CH2)3—CH—C(CH3)2;
`wherein —C(Lj)-R7 taken together is
`(1) (C4-Cy7)cycloalky! optionally substituted by one
`to 3 (C)-Cs) alkyl;
`(2) 2-(2-furylethyl,
`(3) 2-(3-thienyljethoxy, or
`(4) 3-thienyloxymethyl;
`wherein Rg is hydroxy, hydroxymethyl, or hydrogen;
`wherein Ry5 is hydrogen or fluoro;
`wherein Ryg is hydrogen or Ryg and Rj7 taken to-
`gether are —CHz— or Rjg and Rg7 taken together form
`a second valence bond between C-6a and C-9 or are
`—CH2—,;
`wherein Ry7 is as defined aboveoris
`(1) hydrogen, or
`(2) (Cy-Ca)alkyl;
`
`0
`
`15
`
`20
`
`25
`
`30
`
`40
`
`4s
`
`30
`
`65
`
`4,306,075
`
`4
`wherein Rig is hydrogen, hydroxy, hydroxymethyl,
`—OR 9 or —CH2OR jo, wherein Ryo is an acid-hydro-
`lyzable protective group; wherein
`(1) Rap, Ray. Raz, R23, and R24are all hydrogen with
`R22 being either a-hydrogen or 8-hydrogen,
`(2) Rao is hydrogen, R2] and R22 taken together form
`a second valence bond between C-9 and C-éa, and
`R23 and Raq taken together form a second valence
`bond between C-§ and C-9 or are both hydrogen,
`or
`
`is a
`
`(3) Raz, Ra3, and Ragareall hydrogen, with R22 being
`either a-hydrogen or 8-hydrogen, and
`(a) Rag and Ra; taken together are oxo, or
`(b) Rao is hydrogen and Ra; is hydroxy, being a-
`hydroxy or B-hydroxy;
`wherein R37 is the same as Ry except that —(CHp.
`)o>—CH(OH)—CH3is —(CH2)—CH(OR1))—CHs;
`wherein Raz is hydrogen or R3;, wherein R3,
`hydroxy] hydrogen replacing group;
`wherein R33 is —CHO or —CH2OR9, wherein Razis
`as defined above;
`wherein R47 is as defined above oris
`(1) (C)-Ca)alkyl, or
`(2) —CH20H;
`wherein Xj] is
`(1) —COOR), wherein Rj is
`(a) hydrogen,
`(b) (Ci-C)a)alkyl,
`(c) (Ca~Cip)cycloalkyl,
`(d) (C7-Ci2)aralkyl,
`(e) phenyl, optionally substituted with one, 2 or 3
`chloro or (C)-C3)alkyl,
`(f) phenyl substituted in the para position by
`(i) —NH—CO—R3;,
`(ii) —CO—R2,,
`(ii) —O—CO—Rsa, or
`(iv) —CH=N—NH—CO—NRH)?wherein Rasis
`methyl,
`phenyl,
`acetamidophenyl,
`ben-
`zamidophenyl, or —NHz; R26 is methyl,
`phenyl, —NH)g, or methoxy; and Rsqis phenyl
`or acetamidophenyl; inclusive, or
`(g) a pharmacologically acceptable cation;
`(2) —CH30H,
`(3) —COL4, wherein Ly is
`(a) amino of the formula —NR5|Rs52, wherein Rs)
`and Rsz are
`(i) hydrogen,
`(ii) (Cy-C)a)alkyl,
`(iii) (C3-Cyp)cycloalkyl,
`(iv) (C7-Ci2)aralkyl,
`(v) phenyl, optionally substituted with one, 2 or
`3 chloro,
`(C)-C3)alkyl, hydroxy, carboxy,
`(C2-Cs)alkoxycarbonyl, or nitro,
`(vi) (Ca-Cs)carboxyalkyl,
`(vii) (C2-Cs)carbamoylalkyl,
`(viil) (C2-Cs)cyanoalkyl,
`(ix) (C3-Ce)acetylalkyl,
`(x) (C7-C1,)benzoalkyl, optionally substituted by
`one, 2 or 3 chloro, (C;-C3)alkyl, hydroxy,
`(C\-Ca)alkoxy, carboxy, (C2-Cs)alkoxycarbo-
`nyl, or nitro,
`(xi) pyridyl, optionally substituted by one, 2 or 3
`chloro, (Cj-C3)alkyl, or (C\-C3)alkoxy,
`(xil) (Cg-Cy)pyridylalkyl optionally substituted
`by one, 2 or 3 chloro, (C)—C3)alkyl, hydroxy,
`or (C\-Ca)alkyl,
`(xiii) (Cj-C4)hydroxyalkyl,
`(xiv) (C)-Ca)dihydroxyalky},
`
`Liquidia - Exhibit 1014 - Page 3
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`Liquidia - Exhibit 1014 - Page 3
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`

`

`4,306,075
`
`5
`(xv) (Cy-Ca)trihydroxyalkyl,
`vith the further proviso that not more than one of Rs)
`ind Rs2 is other than hydrogenoralkyl,
`(b) cycloamino selected from the group consisting
`of pyrolidino, piperidino, morpholino, pipera-
`zino, hexamethyleneimino, pyrrolino, or 3,4-
`didehydropiperidinyl optionally substituted by
`one or 2 (Cy-Cy2)alkyl-of one to 12 carbon
`atoms, inclusive,'
`\
`({c) carbonylamino of the formula —NRs53COR4),
`wherein Raj is hydrogen or (C)-Ca)alkyl and
`Rs,
`is other than hydrogen, but otherwise as
`defined above,
`(d) sulfonylamino of the formula —NR53S02R5),
`wherein R3j and R23 are as defined in (c),
`(4) —CH)NL32L3, wherein Lz and L3 are hydrogen or
`(Cj-Ca4)alkyl, being the same or different, or the
`pharmacologically acceptable acid addition salts
`thereof when Xj is —CH2NL13,
`wherein Yj
`is trans—CH—CH—, cis—CH—CH—,
`—CH2CH2—, or —C=C—;
`|
`wherein Z) is
`(1) —CH2—(CH2)-—C(R2)2, wherein Ris hydrogen
`or fluoro and f is zero, one, 2, or 3;
`(2) trans—CH,;—CH—CH—,
`(3) —(Ph)—(CH2)g—, wherein (Ph)is 1,2-, 1,3-, or
`1,4-phenylene and g is zero, one, 2, or 3;
`wherein Z4 is —CH2— or —(CH2)-—CF2, wherein f
`is as defined above;
`with the overall proviso that
`(1) Rus, Rig, and Ry7 are all hydrogen only when 2)
`is —(Ph)—(CH2),—, and
`:
`(2) Z) is —(Ph)—(CHz),— only when Rs is hydro-
`gen.
`With regard to the divalent substituents described
`above (e.g., Ly and My), these divalent radicals are de-
`fined as a-Rj:8-Rj, wherein R;represents the substituent
`of the divalent moiety in the alpha configuration with
`tespect to the plane of the C-8 to C-12 cyclopentane
`ring andRj represents the substituent of the divalent
`moiety in the beta configuration with respect to the
`plane of the ring. Accordingly, when Mj is defined as
`a-OH:8-Rs, the hydroxy of the M; moiety is in the
`alpha configuration, i.e., as in PGIz above, and the Rs
`substituent is in the beta configuration.
`The carbon atom content of various hydrocarbon-
`containing moieties is indicated by a prefix designating
`the minimum and maximum numberof carbon atoms in
`the moiety,i.e., the prefix (C;-C;)) indicates a moiety of
`the integer “i” to the integer “j” carbon atoms, inclu-
`sive. Thus (C)-C3)alky! refers to alkyl of one to 3 car-
`bon atoms, inclusive, or methyl, ethyl, propyl, and iso-
`propyl.
`‘Certain novel prostacyclin analogs herein, 1.e., for-
`mula X compounds, are all named as CBA) or CBA2
`compounds, respectively, by virtue of the substitution
`of methylene for oxa in the heterocyclic ring of prosta-
`cyclin and the substitution. CBA2 compoundsare those
`exhibiting the olefinic double bond at C-5,6, while
`CBA) compoundsare those saturated at C-5,6. Formula
`XI compounds are named as PGE; or PGF)derivatives
`as hereinafter described.
`Novel compounds wherein Z; is (Ph)-(CHa), are
`designated inter-o-, inter-m-, or inter-p-phenylene de-
`pending on whether the attachment between C-5 and
`the —(CH2);— moiety is ortho, meta, or para, respec-
`tively.
`
`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 X)-terminated side chain contains (not includ-
`ing the phenylene)2, 3, or 4 carbon atoms, respectively,
`in place of the five carbon atoms contained in PGI.
`The missing carbon atom or atomsare considered to be
`at the C-4 to C-2 positions such that the phenyleneis
`connected to the C-5 and C-1 to C-3 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 Z; is —CH3—(CHp-
`)p—CF2— are characterized as “2,2-difluoro-” 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 Xj-terminated side chain contains 4, 6, or 7
`carbon atoms, respectively, in place of the five carbon
`atoms contained in CBA2. The missing carbon atom is
`considered to be at the C-2 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 C-3
`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.
`trans—CH-
`is
`Those CBA analogs wherein 2)
`7—CH—CH— are described as “trans-2,3-didehydro-
`CBA" compounds,
`Those novel compounds where n is 2 are further
`characterized as 7a-homo-CBA compounds byvirtue of
`the cyclohexyl ring replacing the heterocyclic ring of
`prostacyclin.
`Further, the novel compoundsare named as 98-alkyl-
`CBA compounds when Rj7 isalkyl.
`When Rig and Ri7 taken together are —CH,—(-
`methylene),
`the novel compounds so described are
`“6a,8,98-methano-CBA" compounds by virtue of the
`methylene bridge between C-6a and C-9.
`When Rjs is fluoro, “5-fluoro-CBA" compoundsare
`described.
`The formula XI CBA analogs wherein Rao, R21, R22,
`R23, and Rag 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-(1',3'-inter-phenylene)-PGF\"
`com-
`pounds. Corresponding compounds wherein R32 is a-
`hydrogenare characterized as “9-deoxy-2',98-methano-
`3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF |"
`compounds. CBA analogs wherein Rao, Rz3, and R24
`are all hydrogen and Ra; 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)-PGF,”
`compounds. CBA analogs
`wherein Rayis hydrogen and Ra; 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 C-8 are characterized as “9-deoxo-
`2',9-metheno-3-oxa-3,4,5-trinor-3,7-(1',3'-inter-
`phenylene)-7,8-didehydro-PGE)” compounds. The for-
`mula XI CBA analogs wherein R22, R23, and R2,are all
`hydrogen and Rp and Raj 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)-PGF,;" or “‘6a-
`oxo-9-deoxy-2',98-methano-3-oxa-4,5,6-trinor-3,7-
`(1’,3'-inter-phenylene)-PGF," depending on whether
`Rog is a-hydrogen or B-hydrogen, respectively. For-
`mula XI CBA analogs wherein Rag, R22, Raz, and Rag
`
`0
`
`25-
`
`30
`
`35
`
`40
`
`45
`
`30
`
`55
`
`60
`
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`

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`4,306,075
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`0
`
`20
`
`are all hydrogen and R32) is a-hydroxy are characterized
`compounds are named as “18-(substituted pheny))-
`as
`“6sa-hydroxy-9-deoxy-2',9a-methano-3-oxa-4,5,6-
`19,20-dinor” compounds.
`trinor-3,7-(1',3'-inter-phenylene)-PGF\"
`or
` ‘“6aa-
`the compounds so de-
`When R7is phenylpropyl,
`hydroxy-9-deoxy-2',98-methano-3-oxa-4,5,6-trinor-3,7-
`scribed are named as “19-phenyl-20-nor” compounds.
`(1’,3’-inter-phenylene)-PGF;" compounds depending
`WhenR7is substituted phenylpropy! the corresponding
`on whether R23 is a-hydrogen or 8-hydrogen, respec-
`compounds are named as “19-(substituted phenyl)-20-
`tively, Finally, formula XI TXA analogs wherein R20,
`nor" compounds.
`Raz, Ra3, and Raaare all hydrogen and Ra) is 8-hydroxy
`When R7is phenoxy and neither Ra nor Rg is methyl,
`are
`characterized
`as
`‘Ga§-hydroxy-9-deoxy-2',96-
`the compounds so described are named as “16-phenoxy-
`methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-
`17,18,19,20-tetranor” compounds, When R7 is substi-
`PGF" or “6a8-hydroxy-9-deoxy-2',9a-methano-3-oxa-
`tuted phenoxy,
`the corresponding compounds are
`4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF;"
`com-
`named
`as
`“‘l6-(substituted
`phenoxy)-17,18,19,20-
`pounds depending on whether R22 is a-hydrogen or
`tetranor” compounds. When one and only one of Ry and
`B-hydrogen, respectively. When Z4 is —(CH2)-p—CF2
`Rg is methyl or both R3 and R4 are methyl, then the
`and f is zero, the formula X] CBA analogs are addition-
`corresponding compounds wherein R7 is as defined in
`ally characterized as “2,2-difluoro” compounds. When f
`this paragraph are named as ‘“16-phenoxy or 16-(sub-
`is one, 2, or 3, such compoundsare additionally charac-
`stituted phenoxy)-18,19,20-trinor” compounds or “16-
`terized as ‘‘2a-homo", “2a,2b-dihomo”™ or “2a,2b,2c-
`methyl-16-phenoxy-
`or
`16-(substituted
`phenox-
`trihomo” compounds.
`y)18,19,20-trinor” compounds, respectively.
`When Rs is methyl, the carbacyclin analogs are all
`the com-
`When Ry is cis—CH—CH—CH2CH3;,
`named as “15-methyl-CBA” compounds, Further, ex-
`pounds so described are named as “cis-17,18-didehy-
`cept for compounds wherein Y; is cis—CH—CH—,
`dro” compounds.
`compounds wherein the M; moiety contains an hy-
`the com-
`When Ry is —(CH2)2—CH(OH)—CHg,
`droxyl in the beta configuration are additionally named
`pounds so described are named as “19-hydroxy” com-
`as ‘“15-epi-CBA" compounds.
`pounds.
`For the compounds wherein Y) is cis—CH—CH—,
`the com-
`When R7 is —(CHz);—CH—C(CH3)2,
`then compounds wherein the M;) moiety contains an
`pounds so described are named as “20-isopropylidene”
`hydroxyl in the alpha configuration are named as “15-
`compounds.
`epi-CBA" compounds. Fora description of this conven-
`When —C(L})-R? is optionally substituted cycloal-
`tion of nomenclature for identifying C-15 epimers, see
`kyl, 2-(2-furylethyl, 2-(3-thienyl)ethyl, or 3-thienylox-
`U.S. Pat. No. 4,016,184, issued 5 Apr. 1977, particularly
`columns 24-27 thereof.
`ymethyl, the compounds so described are respectively
`15-cycloalkyl-16,17,18,19,20-pentanor compounds, 17-
`The novel carbacyclin analogs herein which contain
`
`(2-furyl)-18,19,20-trinor-CBA compounds,—17-(3-
`—(CHz)2—, cis—CH=CH—, or —C=C— as the Yj
`thienyl)-18,19,20-trinor compounds, or 16-(3-thienyl-
`moiety, are accordingly referred to as “13,14-dihydro”,
`Joxy-17,18,19,20-tetranor compounds.
`“cis-13", or ““13,14-didehydro” compounds,
`respec-
`Whenat least one of Ry and Ry is not hydrogen then
`tively.
`(except for the 16-phenoxy or 16-phenyl compounds
`chained —C,,H2,—CH3,
`straight
`is
`When Ry7
`discussed above) there are described the “16-methyl”
`wherein m is as defined above, the compounds so de-
`(one and only one of R3 and Ry is methyl), “16,16-
`scribed are named as “19,20-dinor”’, “20-nor",
`“*20-
`dimethyl” (R3 and R4are both methyl), “16-fluoro” (R3
`methyl” or “20-ethyl” compounds when m is one, 2, 4
`or Ry is fluoro), “16,16-difluoro” (R3 and Rq are both
`or 5, respectively. When R7 is branched chain —C,,H-
`fluore) compounds. For those compounds wherein R3
`2m—CHs3, then the compounds so described are “‘17-,
`and Rgare different, the prostaglandin analogs so repre-
`18-, 19-, or 20-alky]” or “17,17-, 17,18-, -17,19-, 17,20-,
`sented contain an asymmetric carbon atom at C-16.
`18,18-, 18,19-, 18,20-, 19,19-, or 19,20-dialkyl” com-
`Accordingly, two epimeric configurations are possible:
`pounds when m is 4 or 5 and the unbranched portion of
`“(16S)" and “(16R)”. Further, there is described by this
`the chain is at least n-butyl, e.g., ““17,20-dimethyl” com-
`invention the C-16 epimeric mixture: “(16RS)".
`pounds are described when m is 5 (1-methylpenty)).
`When X; is —CH2OH, the compounds so described
`When R7is pheny! and neither R3 and Ry is methyl,
`are named as “2-decarboxy-2-hydroxymethyl” com-
`the compounds so described are named as “16-phenyl-
`pounds,
`17,18,19,20-tetranor™ compounds. When Rz is substi-
`the compounds so de-
`is —CH2NL3L3,
`When X;
`tuted phenyl, the corresponding compounds are named
`scribed are named as “2-decarboxy-2-aminomethyl” or
`as “]6-(substituted phenyl)-17,18,19,20-tetranor” com-
`“2-(substituted amino)methyl” compounds.
`pounds. When one and only one of Ry and Ry is methyl
`When Xj is —COL«g, the novel compounds herein are
`or both R3 and Rg are methyl, then the corresponding
`named as CBA-type amides. Further, when Xj
`is
`compounds wherein R7is as defined in this paragraph
`—COOR),, the novel compounds herein are named as
`are named as “16-phenyl or 16-(substituted phenyl)-
`CBA-type esters and CBA-type salts.
`18,19,20-trinor” compounds or “16-methyl-16-phenyl-
`Examples of phenyl esters substituted in the para
`or 16-(substituted phenyl)-18,19,20-trinor” compounds
`respectively,
`position (i.e, X,
`is —COOR), Ry,
`is p-substituted
`phenyl)
`include
`p-acetamidophenyl
`ester,
`p-ben-
`When Ry is benzyl, the compounds so described are
`named as “17-phenyl-18,19,20-irinor”
`compounds.
`zamidopheny! ester, p-(p-acetamidobenzamido)phenyl
`ester,
`p-(p-benzamidobenzamido)pheny!
`ester,
`p-
`When R7is substituted benzyl, the corresponding com-
`pounds are named as “17-(substituted phenyl)-18,19,20-
`aminocarbonylaminopheny] ester, p-acetylpheny! ester,
`trinor” compounds.
`p-benzylphenyl ester, p-amidocarbonylphenyl ester,
`p-methoxycarbonylphenyl ester, p-benzoyloxypheny!
`When Rz7is phenylethyl, the compoundsso described
`are named as
`‘18-phenyl-19,20-dinor” compounds.
`ester, p-(p-acetamidobenzoyloxy)phenyl ester, and p-
`hydroaybenzaldehyde semicarbazone ester.
`When R7 is substituted phenylethyl, the corresponding
`
`25
`
`40
`
`65
`
`Liquidia - Exhibit 1014 - Page 5
`
`Liquidia - Exhibit 1014 - Page 5
`
`

`

`4,306,075
`
`iA
`
`9
`10
`Examples of novel amides herein (i.e., X; is —COL4)
`boxybenzoylethylamide, o-hydroxybenzoylethylamide,
`include the following:
`p-chlorobenzoylpropylamide,
`m-chlorobenzoyl-
`(1) Amides within the scope of alkylamino groups of
`propylamide, 2,4-dichlorobenzoylpropylamide, 2,4,6-
`the formula-NRs|R52 are methylamide, ethylamide,
`trichlorobenzoylpropylamide, m-nitrobenzoylpropyla-
`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-
`decylamide, n-undecylamide, and n-dodecylamide, and
`trimethoxybenzoylpropylamide; p-hydroxymethylben-
`isomeric forms thereof. Further examples are dime-
`zoylpropylamide,
`p-methylbenzoylpropylamide, m-
`thylamide, diethylamide, di-n-propylamide, di-n-butyla-
`methylbenzoylpropylamide,—_p-ethylbenzoylpropyla-
`0
`mide, methylethylamide, methylpropylamide, methyl-
`mide,
`t-butylbenzoylpropylamide, p-carboxybenzayl-
`butylamide, ethylpropylamide, ethylbutylamide, and
`propylamide, m-methoxycarbonylbenzoylpropylamide,
`propylbutylamide. Amides within the scope of cy-
`o-carboxybenzoylpropylamide,
`o-hydroxybenzoyl-
`cloalkylamino are cyclopropylamide, cyclobutylamide,
`propylamide,
`p-chlorobenzoylbutylamide,
`m-
`cyclopentylamide, 2,3-dimethyleyclopentylamide, 2,2-
`chlorobenzoylbutylamide, 2,4-dichlorobenzoylbutyla-
`dimethylcyclopentylamide, 2-methyleyclopentylamide,
`mide, 2,4,6-trichlorobenzoylbutylamide, m-nitroben-
`3-tert-butyleyclopenty] amide, cyclohexylamide, 4-tert-
`zoylmethylamide,
`p-nitrobenzoylbutylamide,
`p-
`butylcyclohexylamide,—3-isopropyleyclohexylamide,
`methoxybenzoylbutylamine, 2,4-dimethoxybenzoylbu-
`2,2-dimethylcyclohexylamide, cycloheptylamide,
`cy-
`tyl-amide, —3,4,5-trimethoxybenzoylbutylamide,
`—_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-Neyclohexylamide.
`benzoylbutyl-amide,
`t-butylbenzoylbutylamide, p-car-
`Amides within the scope of aralkylamino are benzyla-
`boxybenzoylbutylamide, m-methoxycarbonylbenzoyl-
`mide, 2-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, 8-pyridylamide, and
`dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide,
`y-pyridylamide, Amides within the scope ofsubstituted
`p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide,
`pyridylamino are 4-methyl-a-pyridylamide, 4-methyl-
`3,4,5-trimethoxyanilide,
`p-hydroxymethylanilide,
`p-
`&-pytidylamide,
`4-chloro-a-pyridylamide,
`and
`4-
`methylanilide, m-methyl
`anilide, p-ethylanilide,
`t-
`chloro-8-pyridylamide. Amides within the scope of
`butylanilide, p-carboxyanilide, p-methoxycarbonyl ani-
`pyridylalkylamino
`are
`a-pyridylmethylamide, B-
`lide, p-carboxyanilide and o-hydroxyanilide. Amides
`pyridylmethylamide,
`y-pytidylmethylamide,
`a-
`Within the scope of carboxyalkylamino are carboxye-
`pyridylethylamide, §-pyridylethylamide,
`-y-pyridyle-
`thylamide, carboxypropylamide and carboxymethyla-
`thylamide, a-pyridylpropylamide, $-pyridylpropyla-
`mide, carboxybutylamide. Amides within the scope of
`mide, y-pyridylpropylamide, a-pyridylbutylamide, 6-
`carbamoylakylamino are carbamoylmethylamide, car-
`pyridylbutylamide, and y-pyridylbutylamide. Amides
`bamoylethylamide, carbamoylpropylamide, and car-
`within the scope of substituted pyridylalkylamido are
`bamoylbutylamide, Amides within the scope of cya-
`4-methyl-a-pyridylmethylamide,
`4-methy]-8-pyridyl-
`noalkylamino are cyanomethylamide,
`cyanoethyla-
`methylamide,
`4-chloro-c-pyridylmethylamide,
`4-
`mide, cyanopropylamide, and cyanobutylamide. Am-
`chloro-8-pyridylmethylamide,
`4-methyl-a-pyridyl-
`ides withn the scope of acetylalkylamino are acetylme-
`propylamide,
`4-methyl-8-pyridylpropylamide,
` 4-
`thylamide, acetylethylamide, acetylpropylamide, and
`chloro-a-pyridylpropylamide,
`4-chloro-8-pyridyl-
`acetylbutylamide. Amides within the scope of ben-
`propylamide, 4-methyl-a-pyridylbutylamide, 4-methyl-
`zoylalkylamino are benzoylmethylamide, benzoyle-
`B-pyridylbutylamide,
` 4-chloro-a-pyridylbutylamide,
`thylamide, benzoylpropylamide, and benzoylbutyla-
`4-chloro-8-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, 8-hydroxyethyla-
`chlorobenzoylmethylamide, —2,4-dichlorobenzoylme-
`mide, 8-hydroxypropylamide, y-hydroxypropylamide,
`thylamide,
`2,4,6-trichlorobenzoylmethylamide,
`—m-
`1-(hydroxymethylethyl-amide,
`1-(hydroxymethyl)-
`nitrobenzoylmethylamide, p-nitrobenzoylmethylamide,
`propylamide, (?-hydroxymethyl)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-hydroxymethylbenzoylmethylamide, p-methy]-
`8,y-dihydroxypropylamide,
`1-(hydroxymethy])2-
`benzoylmethylamide, m-methylbenzoylmethylamide,
`hydroxymethylamide, £,y-dihydroxybutylamide, 8,8-
`p-ethylbenzoylmethylamide,—t-butylbenzoylmethyla-
`dihydroxybutyl-amide, y,6-dihydroxybutylamide, and
`mide, p-carboxybenzoylmethylamide, m-methoxycar-
`1,1-bis(hydroxymethylethylamide. Amides within the
`bonylbenzoylmethylamide, o-carboxybenzoylmethyla-
`scope of
`trihydroxyalkylamino
`are
`tris(hydroxy-
`mide,
`o-hydroxybenzoylmethylamide,
`p-chloroben-
`methyl)methylamide and