United States Patent (19)
`Aristoff
`
`11
`45)
`
`4,306,075
`Dec. 15, 1981
`
`54
`75)
`(73)
`
`21
`22
`
`63
`
`(51)
`52)
`
`58
`
`COMPOSITION AND PROCESS
`Inventor: Paul A. Aristoff, Portage, Mich.
`Assignee: The Upjohn Company, Kalamazoo,
`Mich.
`Appl. No.: 219,210
`Filed:
`Dec. 22, 1980
`
`Related U.S. Application Data
`Continuation-in-part of Ser. No. 135,055, Mar. 28,
`1980, abandoned.
`Int. Cl. ............................................ CO7C 177/00
`U.S. C. ...................................... 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
`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 48154B/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 specification 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. Specifically the novel chemical analogs of
`CBA2 are those substituted by fluoro (C-5), alkyl (C-9),
`interphenylene (C-5), and methano (C-6a,9). Further
`provided are benzindene analogs of CBA2 and 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)-
`PGF1compounds. Also provided are a variety of novel
`chemical intermediates, e.g., substituted bicyclo3.3.-
`Oloctane intermediates, and chemical process utilizing
`such intermediates which are useful in the preparation
`of the novel CBA2 analogs.
`
`13 Claims, No Drawings
`
`Liquidia - Exhibit 1014 - Page 1
`
`

`

`5
`
`O
`
`COMPOSITION AND PROCESS
`This application is a continuation-in-part of Ser. No.
`135,055, filed Mar. 28, 1980, now abandoned.
`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
`15
`ter.
`The present invention is specifically concerned with
`novel analogs of prostacyclin or PGI2. Specifically, the
`present invention is concerned with analogs of carbacy
`clin modified at the C-5 or C-9 position, e.g., C-5 inter
`phenylene analogs of carbacyclin, 5-fluoro analogs of 20
`carbacyclin, 96-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
`25
`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
`30
`are unsaturated. For convenience, prostacyclin is often
`referred to simply as "PGI2'. Carbacyclin, 6a-carba
`PGI2, 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 PGI2 is
`PGI1 or 5,6-dihydro-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-CBA2 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., PGF2a 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 identification, see Johnson, et al., Pros
`50
`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.
`55
`Accordingly, all of the novel prostacyclin derivatives
`herein will be named as 9-deoxy-PGF1-type com
`pounds, PGI2 derivatives, or preferably as CBA1 or
`CBA2 derivatives.
`In the formulas herein, broken line attachments to a
`ring indicate substituents in the "alpha' (a) configura
`tion, i.e., below the plane of said ring. Heavy solid line
`attachments to a ring indicate substituents in the "beta"
`(6) configuration, 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 configuration or
`attached in a mixture of alpha and beta configurations.
`Alternatively wavy lines will represent either an E or Z
`
`4,306,075
`2
`geometric isomeric configuration or the mixture
`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 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 PGI2 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 (3) 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 of the intermediate which is useful in prepar
`ing the above stereoisoner 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 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.
`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 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),
`
`35
`
`Liquidia - Exhibit 1014 - Page 2
`
`

`

`O
`
`15
`
`20
`
`4,306,075
`3.
`4.
`wherein R18 is hydrogen, hydroxy, hydroxymethyl,
`and Hayashi, M., Chem. Lett. 1437–1440 (1979); and Li,
`Tsung-tee, "A Facile Synthesis of 9(O)-Methano-prosta
`--OR 10 or -CH2OR 10, wherein R10 is an acid-hydro
`lyzable protective group; wherein
`cyclin', Abstract No. 378, (Organic Chemistry), and P.
`A. Aristoff, "Synthesis of 6a-Carbaprostacyclin I2',
`(1) R20, R21, R22, R23, and R24 are all hydrogen with
`R22 being either a-hydrogen or 9-hydrogen,
`Abstract No. 236 (Organic Chemistry) both at Abstract 5
`(2) R20 is hydrogen, R21 and R22 taken together form
`of Papers (Part II) Second Congress of the North
`a second valence bond between C-9 and C-6a, and
`American Continent, San Francisco, California (Las
`R23 and R24 taken together form a second valence
`Vegas, Nevada), USA, 24-29 August 1980.
`bond between C-8 and C-9 or are both hydrogen,
`7-Oxo and 7-hydroxy-CBA2 compounds are appar
`ently disclosed in U.S. Pat. No. 4,192,891. 19-Hydroxy
`O
`(3) R22, R23, and R24 are all hydrogen, with R22 being
`CBA2 compounds are disclosed in U.S. Ser. No. 54,811,
`either a-hydrogen or 3-hydrogen, and
`filed 5 July 1979. CBA2 aromatic esters are disclosed in
`(a) R20 and R21 taken together are oxo, or
`U.S. Pat. No. 4, 180,657. 11-Deoxy-A10- or All-CBA2
`(b) R20 is hydrogen and R2 is hydroxy, being a
`compounds are described in Japanese Kokai No.
`hydroxy or 6-hydroxy;
`77/24,865, published 24 Feb. 1979.
`wherein R27 is the same as R7 except that -(CH2
`SUMMARY OF THE INVENTION
`)2-CH(OH)-CH3 is -(CH2)-CH(OR1)-CH3;
`wherein R32 is hydrogen or R31, wherein R3 is a
`The present specification particular by provides:
`hydroxyl hydrogen replacing group;
`(a) a carbacyclin intermediate of formula IV, V, VI,
`wherein R33 is -CHO or -CH2OR32, wherein R32 is
`VII, VIII, or IX; and
`as defined above;
`(b) a carbacyclin analog of formula X or XI;
`wherein R47 is as defined above or is
`whereing is 0, 1, 2, or 3;
`(1) (C1-C4)alkyl, or
`wherein n is one or 2;
`(2) -CH2OH:
`wherein L1 is o-R3:6-R4, a-R4:f3-R3, or a mixture of
`wherein X1 is
`25
`O-R3:6-R4 and a-R4:6-R3, wherein R3 and R4 are hy
`(1) -COOR1, wherein R is
`drogen, methyl, or fluoro, being the same or different,
`(a) hydrogen,
`with the proviso that one of R3 and R4 is fluoro only
`(b) (C1-C12)alkyl,
`when the other is hydrogen or fluoro;
`(c) (C3-C10)cycloalkyl,
`wherein M1 is a-OH:f3-Rs or a-R5:6-OH, wherein R5
`(d) (C7-C12)aralkyl,
`is hydrogen or methyl;
`(e) phenyl, optionally substituted with one, 2 or 3
`wherein M6 is ol-OR10:f3-R5 or a-R5:f3-OR10, wherein
`chloro or (C1-C3)alkyl,
`R5 is hydrogen or methyl and R10 is an acid hydrolyz
`(f) phenyl substituted in the para position by
`able protective group;
`(i) -NH-CO-R25,
`wherein R7 is
`(ii) -CO-R26,
`(1) -CH2-CH3, wherein m is an integer from
`(iii) --O-CO-R54, or
`one to 5, inclusive,
`(iv) -CH-N-NH-CO-NH2 wherein R25 is
`(2) phenoxy optionally substituted by one, two or
`methyl, phenyl, acetamidophenyl, ben
`three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl,
`zamidophenyl, or -NH2; R26 is methyl,
`or (C1-C3)alkoxy, with the proviso that not more
`phenyl, -NH2, or methoxy; and R54 is phenyl
`than two substituents are other than alkyl, with the
`or acetamidophenyl; inclusive, or
`proviso that R7 is phenoxy or substituted phenoxy,
`(g) a pharmacologically acceptable cation;
`only when R3 and R4 are hydrogen or methyl,
`(2) -CH2OH,
`being the same or different,
`(3) -COL4, wherein L4 is
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl
`(a) amino of the formula -NR51R52, wherein R51
`optionally substituted on the aromatic ring by one,
`and R52 are
`two or three chloro, fluoro, trifluoromethyl,
`(i) hydrogen,
`(C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso
`(ii) (C1-C12)alkyl,
`that not more than two substituents are other than
`(iii) (C3-C10)cycloalkyl,
`alkyl,
`(iv) (C7-C12)aralkyl,
`(4) cis-CH=CH-CH2-CH3,
`(v) phenyl, optionally substituted with one, 2 or
`(5) -(CH2)2-CH(OH)-CH3, or
`3 chloro, (C1-C3)alkyl, hydroxy, carboxy,
`(6) -(CH2)3-CH=C(CH3)2;
`(C2-C5)alkoxycarbonyl, or nitro,
`wherein -C(L1)-R7 taken together is
`(vi) (C2-C5)carboxyalkyl,
`(1) (CA-C7)cycloalkyl optionally substituted by one
`(vii) (C2-C5)carbamoylalkyl,
`55
`to 3 (C1-C5) alkyl;
`(viii) (C2-C5)cyanoalkyl,
`(2) 2-(2-furyl)ethyl,
`(ix) (C3-C6)acetylalkyl,
`(3) 2-(3-thienyl)ethoxy, or
`(x) (C7-C11)benzoalkyl, optionally substituted by
`(4) 3-thienyloxymethyl;
`one, 2 or 3 chloro, (C1-C3)alkyl, hydroxy,
`wherein R8 is hydroxy, hydroxymethyl, or hydrogen;
`(C1-C3)alkoxy, carboxy, (C2-Cs)alkoxycarbo
`wherein R15 is hydrogen or fluoro;
`nyl, or nitro,
`wherein R16 is hydrogen or R16 and R17 taken to
`(xi) pyridyl, optionally substituted by one, 2 or 3
`gether are -CH2- or R16 and R47 taken together form
`chloro, (C1-C3)alkyl, or (C1-C3)alkoxy,
`(xii) (C6-C9)pyridylalkyl optionally substituted
`a second valence bond between C-6a and C-9 or are
`by one, 2 or 3 chloro, (C1-C3)alkyl, hydroxy,
`-CH2-;
`or (C1-C3)alkyl,
`wherein R17 is as defined above or is
`(1) hydrogen, or
`(xiii) (C1-C4)hydroxyalkyl,
`(2) (C1-C4)alkyl;
`(xiv) (C1-C4)dihydroxyalkyl,
`
`30
`
`35
`
`45
`
`50
`
`60
`
`65
`
`Liquidia - Exhibit 1014 - Page 3
`
`

`

`15
`
`10
`
`4,306,075
`6
`5 :
`For those compounds whereing is zero, one, 2 or 3,
`(xv) (C1-C4)trihydroxyalkyl,
`the carbacyclin analogs so described are further charac
`with the further proviso that not more than one of R51
`terized as 2,3,4-trinor-, 3,4-dinor-, or 4-nor, since in this
`ind R52 is other than hydrogen or alkyl,
`(b) cycloamino selected from the group consisting
`event the X-terminated side chain contains (not includ
`ing the phenylene) 2, 3, or 4 carbon atoms, respectively,
`of pyrolidino, piperidino, morpholino, pipera
`in place of the five carbon atoms contained in PGI2.
`zino, hexamethyleneimino, pyrrolino, or 3,4-
`The missing carbon atom or atoms are considered to be
`didehydropiperidinyl optionally substituted by
`at the C-4 to C-2 positions such that the phenylene is
`one or 2 (C1-C12)alkyl of one to 12 carbon
`connected to the C-5 and C-1 to C-3 positions. Accord
`atoms, inclusive,
`.
`.
`. .
`-
`- -
`ingly these compounds are named as 1,5-2,5-, 3,5-, and
`(c) carbonylamino of the formula -NR53CORs1,
`4,5-inter-phenylene CBA compounds when g is zero,
`wherein R23 is hydrogen or (C1-C4)alkyl and
`one, 2, or 3, respectively.
`R51 is other than hydrogen, but otherwise as
`Those CBA analogs wherein Z1 is -CH2-(CH2
`defined above,
`)f-CF2- are characterized as “2,2-difluoro-" com
`(d) sulfonylamino of the formula --NR53SO2R51,
`pounds. For those compounds wherein f is zero, 2, or 3,
`wherein R21 and R23 are as defined in (c),
`the carbacyclin analogs so described are further charac
`(4) -CH2NL2L3, wherein L2 and L3 are hydrogen or
`terized as 2-nor, 2a-homo, or 2a,2b-dihomo, since in this
`(C1-C4)alkyl, being the same or different, or the
`event the X-terminated side chain contains 4, 6, or 7
`pharmacologically acceptable acid addition salts
`carbon atoms, respectively, in place of the five carbon
`thereof when X1 is -CH2NL2L3,
`atoms contained in CBA2. The missing carbon atom is
`20
`wherein Y1 is trans-CH=CH-, cis-CH=CH-,
`considered to be at the C-2 position such that the C-1
`-CH2CH2-, or -C=C-;
`carbon atoms is connected to the C-3 position. The
`wherein Z1 is
`additional carbon atom or atoms are considered as
`hydrogen
`(1) -CH2-(CH2)A-C(R2)2, wherein R2 is
`though they were inserted between the C-2 and C-3
`or fluoro and f is zero, one, 2, or 3;
`positions. Accordingly these additional carbon atoms
`25.
`(2) trans-CH2-CH=CH-,
`are referred to as C-2a and C-2b, counting from the C-2
`(3) -(Ph)-(CH2)-, wherein (Ph) is 1,2-, 1,3-, or
`to the C-3 position.
`1,4-phenylene and g is zero, one, 2, or 3;
`Those CBA analogs wherein Z1 is trans-CH
`wherein Z4 is -CH2- or -(CH2)A-CF2, wherein f
`2-CH=CH- are described as "trans-2,3-didehydro
`is as defined above;
`CBA' compounds.
`30
`.
`.
`.
`:
`with the overall proviso that
`Those novel compounds where n is 2 are further
`(1) R15, R16, and R17 are all hydrogen only when Z1
`characterized as 7a-homo-CBA compounds by virtue of
`is -(Ph)-(CH2)g-, and
`the cyclohexyl ring replacing the heterocyclic ring of
`hydro
`(2) Z1 is -(Ph)-(CH2) - only when R15 is
`prostacyclin.
`Further, the novel compounds are named as 93-alkyl
`gen.
`.
`35
`With regard to the divalent substituents described
`CBA compounds when R17 is alkyl.
`above (e.g., L1 and M1), these divalent radicals are de
`When R16 and R17 taken together are -CH2-(-
`fined as a-Rig-Ri, wherein Ri represents the substituent
`methylene), the novel, compounds so described are
`of the divalent moiety in the alpha configuration with
`"6ag,96-methano-CBA" compounds by virtue of the
`respect to the plane of the C-8 to C-12 cyclopentane
`methylene bridge between C-6a and C-9.
`ring and Ri represents the substituent of the divalent
`When R1s is fluoro, "5-fluoro-CBA' compounds are
`moiety in the beta configuration with respect to the
`described.
`plane of the ring. Accordingly, when M1 is defined as
`The formula XI CBA analogs wherein R20, R21, R22,
`a-OH:f3-Rs, the hydroxy of the M1 moiety is in the
`R23, and R24 are all hydrogen with R22 being (3-hydro
`alpha configuration, i.e., as in PGI2 above, and the R5
`gen are characterized as "9-deoxy-2,9a-methano-3-oxa
`45
`substituent is in the beta configuration.
`4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1' CO
`pounds. Corresponding compounds wherein R22 is a
`The carbon atom content of various hydrocarbon
`containing moieties is indicated by a prefix designating
`hydrogen are characterized as "9-deoxy-2',96-methano
`3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1'
`the minimum and maximum number of carbon atoms in
`the moiety, i.e., the prefix (C-C) indicates a moiety of 50
`compounds. CBA analogs wherein R20, R23, and R24
`the integer "i" to the integer "j" carbon atoms, inclu
`are all hydrogen and R21 and R22 taken together form a
`sive. Thus (C1-C3)alkyl refers to alkyl of one to 3 car
`valence bond between C-9 and C-6a are characterized
`bon atoms, inclusive, or methyl, ethyl, propyl, and iso
`as "9-deoxo-2',9-metheno-3-oxo-3,4,5-trinor-3,7-(1,3'-
`inter-phenylene)-PGF1' compounds. CBA analogs
`propyl.
`Certain novel prostacyclin analogs herein, i.e., for
`wherein R20 is hydrogen and R21 and R22 taken together
`55
`mula X compounds, are all named as CBA or CBA2
`form a second valence bond between C-9 and C-6a and
`compounds, respectively, by virtue of the substitution
`R23 and R24 taken together form a second valence bond
`of methylene for oxa in the heterocyclic ring of prosta
`between C-7 and C-8 are characterized as "9-deoxo
`cyclin and the substitution. CBA2 compounds are those
`2,9-metheno-3-oxa-3,4,5-trinor-3,7-(1,3'-inter
`phenylene)-7,8-didehydro-PGE1' compounds. The for
`exhibiting the olefinic double bond at C-5,6, while
`mula XI CBA analogs wherein R22, R23, and R24 are all
`CBA compounds are those saturated at C-5,6. Formula
`hydrogen and R20 and R21 taken together are oxo are
`XI compounds are named as PGE1 or PGF1 derivatives
`characterized as "6a-oxo-9-deoxy-2,9a-methano-3-oxa
`as hereinafter described.
`4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF1' or "6a
`Novel compounds wherein. Z1 is (Ph)-(CH2) are
`oxo-9-deoxy-2',99-methano-3-oxa-4,5,6-trinor-3,7-
`designated inter-o-, inter-m-, or inter-p-phenylene de
`65
`(1',3'-inter-phenylene)-PGF1' depending on whether
`pending on whether the attachment between C-5 and
`R22 is a-hydrogen or 9-hydrogen, respectively. For
`the -(CH2)g-
`moiety is ortho, meta, or para, respec
`tively.
`mula XI CBA analogs wherein R20, R22, R23, and R24
`
`Liquidia - Exhibit 1014 - Page 4
`
`

`

`O
`
`4,306,075
`8
`7
`compounds are named as "18-(substituted phenyl)-
`are all hydrogen and R21 is a-hydroxy are characterized
`"6ao-hydroxy-9-deoxy-2',9o-methano-3-oxa-4,5,6-
`as
`19,20-dinor' compounds.
`trinor-3,7-(1',3'-inter-phenylene)-PGF1'
`or "6aa
`When R7 is phenylpropyl, the compounds so de
`hydroxy-9-deoxy-2,943-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
`When R7 is substituted phenylpropyl the corresponding
`on whether R22 is a-hydrogen or 3-hydrogen, respec
`compounds are named as "19-(substituted phenyl)-20
`tively. Finally, formula XI TXA analogs wherein R.20,
`nor' compounds.
`R22, R23, and R24 are all hydrogen and R21 is S-hydroxy
`When R7 is phenoxy and neither R3 nor R4 is methyl,
`are characterized as "6ag-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
`PGF1' or "6ag-hydroxy-9-deoxy-2',9a-methano-3-oxa
`tuted phenoxy, the corresponding compounds are
`4,5,6-trinor-3,7-(1,3'-inter-phenylene)-PGF1'
`COs
`named as "16-(substituted phenoxy)-17, 18,19,20
`pounds depending on whether R22 is ol-hydrogen or
`tetranor' compounds. When one and only one of R3 and
`g-hydrogen, respectively. When Z4 is -(CH2)A-CF2
`R4 is methyl or both R3 and R4 are methyl, then the
`and f is zero, the formula XI CBA analogs are addition
`15
`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 compounds are 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 R5 is methyl, the carbacyclin analogs are all
`20
`When R7 is cis-CH=CH-CH2CH3, the com
`named as "15-methyl-CBA' compounds. Further, ex
`pounds so described are named as "cis-17, 18-didehy
`cept for compounds wherein Y1 is cis-CH=CH-,
`dro' compounds.
`compounds wherein the M1 moiety contains an hy
`When R7 is -(CH2)2-CH(OH)-CH3, the com
`droxyl in the beta configuration are additionally named
`pounds so described are named as "19-hydroxy' com
`as "15-epi-CBA' compounds.
`25
`pounds.
`For the compounds wherein Y1 is cis-CH=CH-,
`When R7 is -(CH2)3-CH=C(CH3)2, the com
`then compounds wherein the M1 moiety contains an
`pounds so described are named as "20-isopropylidene'
`hydroxyl in the alpha configuration are named as "15
`compounds.
`epi-CBA' compounds. For a description of this conven
`When -COL1)-R7 is optionally substituted cycloal
`tion of nomenclature for identifying C-15 epimers, see
`30
`kyl, 2-(2-furyl)ethyl, 2-(3-thienyl)ethyl, or 3-thienylox
`U.S. Pat. No. 4,016,184, issued 5 Apr. 1977, particularly
`ymethyl, the compounds so described are respectively
`columns 24-27 thereof.
`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-
`-(CH2)2-, cis-CH=CH-, or -C=C- as the Y1
`thienyl)-18,19,20-trinor compounds, or 16-(3-thienyl
`moiety, are accordingly referred to as "13, 14-dihydro',
`)oxy-17, 18,19,20-tetranor compounds.
`"cis-13', or "13, 14-didehydro' compounds, respec
`When at least one of R3 and R4 is not hydrogen then
`tively.
`(except for the 16-phenoxy or 16-phenyl compounds
`When R7 is straight chained -CH2-CH3,
`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 R4 is methyl), "16, 16
`scribed are named as "19,20-dinor”, “20-nor', '20
`dimethyl' (R3 and R4 are both methyl), "16-fluoro' (R3
`methyl' or "20-ethyl' compounds when m is one, 2, 4
`or R4 is fluoro), “16, 16-difluoro' (R3 and R4 are both
`or 5, respectively. When R7 is branched chain -CH
`fluoro) compounds. For those compounds wherein R3
`2-CH3, then the compounds so described are “17-,
`and R4 are different, the prostaglandin analogs so repre
`18-, 19-, or 20-alkyl' 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
`45
`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-methylpentyl).
`When X1 is -CH2OH, the compounds so described
`When R7 is phenyl and neither R3 and R4 is methyl,
`are named as "2-decarboxy-2-hydroxymethyl' com
`the compounds so described are named as "16-phenyl
`50
`pounds,
`17, 18,19,20-tetranor” compounds. When R7 is substi
`When X1 is -CH2NL2L3, the compounds so de
`tuted phenyl, the corresponding compounds are named
`scribed are named as "2-decarboxy-2-aminomethyl' or
`as "16-(substituted phenyl)-17, 18,19,20-tetranor” com
`“2-(substituted amino)methyl' compounds.
`pounds. When one and only one of R3 and R4 is methyl
`When X1 is -COL4, the novel compounds herein are
`or both R3 and R4 are methyl, then the corresponding
`named as CBA-type amides. Further, when X1 is
`compounds wherein R7 is as defined in this paragraph
`-COOR1, 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., X1 is -COOR1, R1 is p-substituted
`60
`phenyl) include p-acetamidophenyl ester, p-ben
`When R7 is benzyl, the compounds so described are
`Zamidophenyl ester, p-(p-acetamidobenzamido)phenyl
`named as "17-phenyl-18,19,20-trinor”
`compounds.
`ester, p-(p-benzamidobenzamido)phenyl ester, p
`When R7 is substituted benzyl, the corresponding com
`aminocarbonylaminophenyl ester, p-acetylphenyl ester,
`pounds are named as "17-(substituted phenyl)-18,19,20
`p-benzylphenyl ester, p-amidocarbonylphenyl ester,
`trinor' compounds.
`p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl
`When R7 is phenylethyl, the compounds so described
`are named as "18-phenyl-19,20-dinor' compounds.
`ester, p-(p-acetamidobenzoyloxy)phenyl ester, and p
`When R7 is substituted phenylethyl, the corresponding
`hydroxybenzaldehyde semicarbazone ester.
`
`35
`
`55
`
`65
`
`Liquidia - Exhibit 1014 - Page 5
`
`

`

`10
`
`15
`
`20
`
`4,306,075
`9
`10
`boxybenzoylethylamide, o-hydroxybenzoylethylamide,
`Examples of novel amides herein (i.e., X 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-NR51R52 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-
`decylamide, n-undecylamide, and n-dodecylamide, and
`trimethoxybenzoylpropylamide, p-hydroxymethylben
`zoylpropylamide, p-methylbenzoylpropylamide, m
`isomeric forms thereof. Further examples are dime
`thylamide, diethylamide, di-n-propylamide, di-n-butyla
`methylbenzoylpropylamide,
`p-ethylbenzoylpropyla
`mide, methylethylamide, methylpropylamide, methyl
`mide, t-butylbenzoylpropylamide, p-carboxybenzoyl
`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,
`r
`cyclopentylamide, 2,3-dimethylcyclopentylamide, 2,2-
`chlorobenzoylbutylamide, 2,4-dichlorobenzoylbutyla
`dimethylcyclopentylamide, 2-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-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-Ncyclohexylamide.
`benzoylbutyl-amide, t-butylbenzoylbutylamide, p-car
`boxybenzoylbutylamide, m-methoxycarbonylbenzoyl
`Amides within the scope of aralkylamino are benzyla
`mide, 2-phenylethylamide, and N-methyl-N benzyl
`butylamide, o-carboxybenzoylbutylamide, o-hydrox
`amide. Amides within the scope inf substituted phenyla
`ybenzoylmethylamide. Amides within the scope of
`25
`mide are p-chloroanilide, m-chloroanilide, 2,4-
`pyridylamino are a-pyridylamide, 6-pyridylamide, and
`dichloroanilide, 2,4,6-trichloroanilide, m-nitroanilide,
`y-pyridylamide. Amides within the scope of substituted
`p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide,
`pyridylamino are 4-methyl-a-pyridylamide, 4-methyl
`3,4,5-trimethoxyanilide, p-hydroxymethylanilide, p
`A-pyridylamide, 4-chloro-a-pyridylamide, and 4
`methylanilide, m-methyl anilide, p-ethylanilide, t
`chloro-3-pyridylamide. Amides within the scope of
`30
`butylanilide, p-carboxyanilide, p-methoxycarbonyl ani
`pyridylalkylamino are a-pyridylmethylamide, g
`lide, p-carboxyanilide and o-hydroxyanilide. Amides
`pyridylmethylamide,
`ty-pyridylmethylamide, O
`within the scope of carboxyalkylamino are carboxye
`pyridylethylamide, 6-pyridylethylamide, y-pyridyle
`thylamide, carboxypropylamide and carboxymethyla
`thylamide, a-pyridylpropylamide, 6-pyridylpropyla
`mide, carboxybutylamide. Amides within the scope of
`mide, y-pyridylpropylamide, a-pyridylbutylamide, g
`35
`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-methyl-6-pyridyl
`noalkylamino are cyanomethylamide, cyanoethyla
`methylamide,
`4-chloro-a-pyridylmethylamide, 4
`mide, cyanopropylamide, and cyanobutylamide. Am
`chloro-g-pyridylmethylamide,
`4-methyl-a-pyridyl
`40
`ides within the scope of acetylalkylamino are acetylme
`propylamide,
`4-methyl-6-pyridylpropylamide, 4
`thylamide, acetylethylamide, acetylpropylamide, and
`chloro-o-pyridylpropylamide,
`4-chloro-3-pyridyl
`acetylbutylamide. Amides within the scope of ben
`propylamide, 4-methyl-a-pyridylbutylamide, 4-methyl
`Zoylalkylamino are benzoylmethylamide, benzoyle
`(3-pyridylbutylamide,
`4-chloro-a-pyridylbutylamide,
`thylamide, benzoylpropylamide, and benzoylbutyla
`4-chloro-g-pyridylbutylamide, 4-chloro-y-pyridylbu
`45
`mide. Amides within the scope of substituted ben
`tyl-amide. Amides within the scope of hydroxyalk
`Zoylalkylamino are p-chlorobenzoylmethylamide, m
`ylamino are hydroxymethylamide, 3-hydroxyethyla
`chlorobenzoylmethylamide,
`2,4-dichlorobenzoylme
`mide, 6-hydroxypropylamide, y-hydroxypropylamide,
`thylamide,
`2,4,6-trichlorobenzoylmethylamide, m
`1-(hydroxymethyl)ethyl-amide,
`1-(hydroxymethyl)-
`nitrobenzoylmethylamide, p-nitrobenzoylmethylamide,
`propylamide, (2-hydroxymethyl)propylamide, and a,c-
`50
`p-methoxybenzoylmethylamide, 2,4-dimethoxy ben
`dimethyl-hydroxyethylamide. Amides within the scope
`zoylmethylamide,
`3,4,5-trimethoxybenzoylmethyla
`of dihydroxyalkylamino are dihydroxymethyla