United States Patent
`Aristoff
`
`[19]
`
`4,306,075
`ll 1]
`[45] Dec. 15, 1981
`
`
`
`154] COMPOSITION AND PROCESS
`
`[75]
`
`Inventor:
`
`[73] Assignee:
`
`Paul A. Arlstoff, Portage, Mich.
`The Upjohn Company. Kalamazoo.
`Mich.
`
`[211 Appl. 316.: 219,210
`
`[221 Filed:
`
`066.112.1930
`
`[63]
`
`51]
`52]
`
`[53]
`
`Related 11.5. Application Data
`Continuation-impart of 5121'. No. 135.055, Mar. 28,
`1980, abandoned.
`
`Int. (21.3 ............................................ 0076: 177/00
`11.3. CI. ...................................... 560/56; 563/734;
`563/307; 260/239 BF; 563/303; 260/326.45;
`260/465 F; 260/465 13; 260/3265 (2; 544/154;
`544/171; 544/176; 544/336; 544/336; 546/205;
`546/205; 546/235; 546/314; 546/309; 546/337;
`543/250; 560/23; 562/466; 562/451; 562/452;
`562/455; 564/30; 564/172; 564/174; 564/33;
`564/90; 564/95; 564/153; 563/632; 563/633;
`563/634
`316111 of Search .................... 560/56, 23; 562/466,
`562/451. 452. 455; 260/239 BF, 326.4 v. 465 F.
`465 1:1. 326.5 C; 544/154, 171. 176, 336, 336;
`546/203. 205, 235. 314. 309. 337; 543/230;
`564/30, 172. 174, 33. 90, 95. 153,- 563/632. 633,
`634. 724, 307, 306
`
`[56]
`
`References Cited
`FOREIGN PATENT DOCUMENTS
`
`1017699 lD/I‘J'IQ United Kingdom ..........,_..... SIG/56
`OTHER PUBLICATIONS
`
`Derwem Abstract 481543/26 .1 54063059 05/21/19.
`
`Primary Examinerh—PatlL I. Killos
`Attorney. Agent. or Firm—L. Ruth Hanan; Robert A;
`Armitage
`ABSTRACT
`[57}
`The present specification provides novel analogs of
`carbacyclin (CBAz). fia-carha-pmslacyclht
`(fin-catha-
`PGIZ). which have pronounced prostacyciimlike phar—
`macological activity. eg“ as platelet antiaggregutory
`agents. Specifically the novel chemical analogs of
`CBA; are those substituted by fluoro (C-S). alkyi (C-9),
`interphenylene (GS), and methanol (063.9). Further
`provided are benzindene analogs of (SBA; and substi-
`tuted forms thereof, i.e., 9-deoxy-2',9-methano (or 23,9-
`metheno}3-oxa—4,§.6-trinor-3,T-(l',3'-interphenvlene}-
`PGF 1compounds. Also provided are a variety of novel
`chemical
`intermediates, e.g.. substituted bicyclo[3.3.-
`D]oct1me intermediates, and chemical process utilizing
`such intemediates which are useful in the preparation
`of the novel CBA: analogs.
`
`13 Claims, Nu Drawings
`
`Liquidia - Exhibit 1014 - Page 1
`
`Liquidia - Exhibit 1014 - Page 1
`
`

`

`1
`
`4. 306,0?5
`
`2
`configuration or
`
`COMPOSITION AND PROCESS
`
`This application is a continuation-in-part of Ser. No.
`135.055, filed Mar. 28, 1930, now abandoned.
`
`5
`
`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.
`
`ID
`
`15
`
`The present invention is specifically concerned with
`novel analogs of prostacyclin or POI}. Specifically. the
`present invention is concerned with analogs of carbacy-
`clin modified at the OS or 0-9 position. e.g.. C-S inter-
`phenylene analogs of carbacyclin. S-fluoro analogs of
`carbacyclin. Qfi-alkyl analogs of carbacyclin. 063,9
`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 05.6 positions
`are unsaturated. For convenience. prostacyclin is often
`referred to simply as “P611". Carbacyclin.
`tic-carbu-
`PGIz, exhibits the structure and carbon atom number-
`ing indicated in formula II when the 0-5.6 positions are
`unsaturated. Likewise, for convenience. carbacyclin is
`referred to simply as "C'BAz".
`A stable partially saturated derivative of PG]: is
`PGII or 5.6-dihydro-PGI; when the C-5.6 positions are
`saturated. depicted with carbon atom numbering in
`formula II when the (3-5.6 positions are saturated. The
`corresponding 5,6-dihydro-CBA1 is CBA}, depicted in
`formula 11.
`As is apparent from inspection of formulas I and II.
`prostacyclin and carbacyclin may be trivially named as
`derivatives of POP-type compounds, eg. PGon of
`formula III. Accordingly, prostacyclin is
`trivially
`named
`9-deoxy~fi.9a-cpoxy-(SZ)-S.6-didehydro-PG'F1
`and carbacyclin is named 9.deoxy-6,9a-methano-{5E)—
`5.6-didehydro-PGFI. For description of prostacyclin
`and its structural identification. see Johnson, et 3].. Pros-
`laglandins [2:915 (1975).
`For convenience. the novel prostacyclin or carbacy-
`clin analogs will he referred to by the trivial. art~recog-
`nized system of nomenclature described by N. A. Nel-
`son. 1. Med. Chem. 17:91! (1974) for prostaglandins.
`Accordingly, all of the novel prostacyclin derivatives
`herein will be named as 9-deoxy-PGF1-type com-
`pounds. PGI; derivatives. or preferably as CBAI or
`CBA; derivatives.
`In the formulas herein. broken line attachments to a
`ring indicate substituents in the “alpha" (ct) configura-
`tion. i.e.. below the plane of said ring. Heavy solid line
`attachments to a ring indicate substituents in the “beta"
`(.8) configuration. i.e.. above the plane of said ring. The
`use of wavy lines l ~) 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 either an E or Z
`
`20
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`155
`
`the mixture
`
`geometric isomeric
`thereof.
`A side chain hydroxy at C-lS in the formulas herein
`is in the 5 or R configuration as determined by the
`Cahn-lngoId-Prelog sequence rules. J. Chem. Ed. 41:16
`{1964). See also Nature 212:33 {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 enentiomeric (optically active) forms. i.e.. the dex-
`trorotatory and laveorotatory forms. As drawn.
`the
`formula for P613 corresponds to that endogenously
`produced in the mammalian species. In particular. refer
`to the stereochemical configuration at (2-8 (at), 09 (a).
`C-11 (at) and C-12 [13) of endogenously produced pros-
`tacyclin. The mirror image of the above formula for
`prestacyclin represents the other enantiomer. The race-
`mic form of prostacyclin contains equal numbers of
`both enantiomeric molecules.
`For convenience. reference to prostaoyclin 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 prostacyclimtype 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 slereoisomer of the prostacyclin type
`product.
`The term “prostacyclin analog" or “carbacyclin ana—
`log" represents that stereoisorner of a prostacyclin-type
`product which is of the same relative stereochemical
`configuration as prostacyclin obtained from mammalian
`tissues or a mixture comprising storooisorner 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
`
`Carbucyclin and closely related compounds are
`known in the art. See Japanese Koltia 63.059 and 63,060.
`also abstracted respectively as Derwent Farmdoc CPI
`Numbers 481543/26 and 481553126. See also British
`published specifications 2,012,265 and German Offen-
`lungsschrift 2.900.352. abstracted as Derwent Farmdoc
`CPI Number 543253/30. 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.. .1. Organic Chemistry, 44:2880
`(1979); Shibaaaki, M., et
`a]. Tetrahedron Letters.
`433-436 (1979); Kojima. K., et 3].. Tetrahedron Letters.
`3743-3746 {1978); Nicolaou. K. C... et al., .1. Chem. Soc..
`Chemical Communications. 1067—1068 {1978); Bugle.
`A.. et al.. Tetrahedron Letters 2607-2610 (1919):
`Shibasaki. M.. Chemistry Letters. 1299—1300 {1979).
`
`Liquidia - Exhibit 1014 - Page 2
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`Liquidia - Exhibit 1014 - Page 2
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`

`

`4, 306.07 5
`
`3
`and Hayashi. M.. Chem. Lell. HST—144509219); and Li.
`Tsung-tce. “A Facile Synthesis of 9{O)-Methano-prosta-
`cyclin", Abstract No. 373. {Organic Chemistry}. and P.
`A. Aristoff, “Synthesis of oa—Carbaprostacyclin 1;".
`Abstract No. 236 (Organic Chemistry) both at Abstract
`of Papers (Part
`[1) Second Congress of the North
`American Continent, San Francisco. California (Las
`Vegas, Nevada}, USA. 24-29 August 1930.
`T-Oxo and 7-hydroxy-CBA2 compounds are appar-
`ently disclosed in U.S. Pat. No. 4,192,391. 19-Hydroxy-
`CBA: compounds are disclosed in US. Ser. No. 54,31 I,
`filed 5 July 19?9. CBA: aromatic esters are disolosed in
`U.S. Pat. No. 4.130.657.
`ll-Deoxy-Am- or AN-CBAz
`compounds are described in Japanese Kokai No.
`77/24.365_. published 24 Feb. 1979.
`SUMMARY OF THE INVENTION
`
`The present specification particular by provides:
`(a) a carbucyciin intermediate of formula IV. V. VI.
`VII. VIII. or DC; and
`(b) a oarbacyclin analog of formula X or XI;
`wherein g is O. l. 2, or 3;
`wherein n is one or 2:
`wherein Ll is ot-R3:,6-R4, ct-R4:B-R3. or a mixture of
`a-Ryfl-Ra and fl-R4:fl-RJ. wherein R3 and R4 are hy-
`drogen, methyl. or fluoro. being the same or different,
`with the proviso that one of R3 and R4 isfluoro only
`when the other is hydrogen or l'luoro;
`wherein M1 is a-OH:fl-Rs or a-R513-0H. wherein R5
`is hydrogen or methyl;
`wherein M5 is a-ORwrfl—Rs or u-R5:B-0Rm, wherein
`R5 is hydrogen or methyl and Rmis an acid hydrolyz-
`able protective group;
`wherein R1 is
`(l) —C,,.H;r,.—CH3. wherein n1 is an integer from
`one to 5, inclusive.
`(2) phenoxy optionally substituted by one. two or
`three chloro, fluoro, trifluoromethyl. (C|—C3}alkyl,
`or (Cl—C3)alkoxy. with the proviso that not more
`than two substituents are other than slkyl, with the
`proviso that R? 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,
`tvvo or
`three chloro,
`iluoro,
`trifluoromethyl,
`(Cl—Cs'htlkyl. or (C1-Cg)alkoxy. with the proviso
`that not more than two substituents are other than
`nlkyl.
`(4) ds—CH2cnncnz—CH3.
`(5) ——(CH;)3—-—CH(OH)-CH3. or
`(5} —(CH2)3—CH=C(CH3J1;
`wherein —C{L1)-R1 taken together is
`(l) (Q—Cflcycloalkyl optionally substituted by one
`to 3 (C1-C5) alkyl;
`(2} 2-(2~furyl)ethyl.
`(3) 2-(3-thienyl)ethoxy. or
`(4) 3-thienyloxymethyl:
`wherein R315 hydroxy. hydroxymethyl. or hydrogen;
`wherein R15 is hydrogen or fluoro;
`wherein R]:1 is hydrogen or R15 and R17 taken to-
`gather are “CHz— or Rm and R4;- taken together form
`a second valence bond between 063 and C—9 or are
`—CH2~;
`wherein Rn is as defined above or is
`(l) hydrogen, or
`(2) {C:~C4)alkyl:
`
`is a
`
`4
`wherein Rn; is hydrogen, hydroxy. hydroxymethyl.
`~OR10 or —CH20Rm, wherein Rm is en acid-hydro-
`]yzable protective group: wherein
`(1) R10, R11, R12, R23. and R24 are all hydrogen with
`R23 being either a-hydrogen or B-hydrogen.
`(2) Rm is hydrogen. R21 and R2; taken together form
`a second valence bond between C-9 and 06:1. and
`R23 and R14 taken together form a second valence
`bond between (2-8 and (2-9 or are both hydrogen,
`or
`(3) R21. R23, and R34 are all hydrogen, with R22 being
`either tit-hydrogen or fl-hydrogen. and
`(a) Ran and R3] taken together are onto. or
`(13) R10 is hydrogen and Ru is hydroity, being a-
`hydroxy or ,G-hydroxy;
`wherein R27 is the same as R: except that —(CH1.
`)2—CH{OH)—~CH3 is —(CH2)—CH(0RI o—cuy;
`wherein R3; is hydrogen or R3]. wherein R3:
`hydroxyl hydrogen replacing group;
`wherein R3; is —CHO or —CH20R31. wherein Razis
`as defined above;
`wherein R4? is as defined above or is
`{1) (Ci—C4)alkyl. or
`(2) —CH:0H;
`wherein X] is
`(l) —COOR:. wherein RI is
`(a) hydrogen.
`(b) (Cl-Clzlalkyl,
`(c) (C3—Cm)cycloalkyl.
`(d) (Ci-Cidmlkyl.
`(e) phenyl. Optionally substituted with one, 2 or 3
`chloro or (C1-C3)alky1.
`(f) phenyl substituted in the para position by
`(i) ——NH—CO—R25.
`(ii) —-C0—R15,
`(iii) —O-—CD—R54. or
`(iv) —CH=N—NH—CO—NH2 wherein R25 is
`methyl,
`phenyl.
`acetamidophenyl,
`ben-
`zamidophenyl, or —NH2; R25 is methyl.
`phony]. -—NH2. or methoxy; and R54 is phenyl
`or acetamidophenyl; inclusive. or
`(g) a phannacologicslly acceptable cation;
`(2) —CH20H.
`(3) —COL¢, wherein L4 is
`(a) amino of the formula —NR51R51, wherein R5]
`and R52 are
`(i) hydrogen.
`(ii) (Ci-Ctzlalkyl,
`(iii) (C3~C t0)cycloalkyl,
`(iv) (Ci-Cizlaralkyl.
`(v) phenyl. optionally substituted with one. 2 or
`3 chloro.
`(Cl—Csmky], hydroxy. carboxy.
`(C2-C5)alkoxycarbonyl, or nitro.
`(vi) (C2-C5)carboxyalkyl,
`(vii) (Cg—Cskarbamoylalkyl.
`(viii) (C2-C5)cyanoalltyl,
`(Ix) (C3-C5)acetylalltyl.
`(x) (Ci-Cl abenzoalkyl. optionally substituted by
`one. 2 or 3 chloro. (Cl-C3)alkyl, hydroxy.
`{Cl-C3)alkosy, carboxy. (C2-C5)alkoxycerbo-
`nyl, or nitro,
`(xi) pyridyl, optionally substituted by one. 1 or 3
`chloro. (C1—C3)alkyl. or (C 1—C3)alkoxy.
`(xii) (Cs-C9)pyridylalky] optionally substituted
`by one. 2 or 3 chloro, (C|~C3)alkyl. hydroxy.
`or {CI‘C3)alkyl.
`(xiii) (Cl—C4)hydrosyelkyl.
`(xiv) (C1-Cd)dihydroxyalkyl.
`
`5
`
`to
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4-D
`
`43
`
`50
`
`55
`
`60
`
`65
`
`Liquidia - Exhibit 1014 - Page 3
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`Liquidia - Exhibit 1014 - Page 3
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`

`

`4. 306,075
`
`5
`(xv) (Cl—Ciltrihydroxyalkyl.
`vith the further proviso that not more than one of R5:
`-.nd R52 is other than hydrogen or alkyl,
`(b) 'cycloamino selected from the group consisting
`of pyrolidin‘o. piperidino.‘ morpholino, pipera—
`zinc, hexamethyleneimino, pyrrolino. or 3,4-
`didehydropiperidinyl optionally substituted by
`one or 2 (Cr-C1 milky] of one to 12 carbon
`atoms. inclusive. '
`-
`(c) carbonylamino of the formula —NR53C0R51,
`wherein Rn is hydrogen or (C1—C4Jalkyl and
`R51 is other than hydrogen. but otherwise as
`defined above,
`-
`(d) sulfonylamino of the formula —NR53502R5|.
`wherein R2: and R23 are as defined in (c).
`(4) w—CH1NL1L.3, wherein L2 and L3 are hydrogen or
`{Cl—Ctlalkyl. being the same or different. or the
`phannacologically acceptable acid addition salts
`thereof when X] is —CH2NL1L3.
`wherein Y1 is trms—CH2CH—. cis—CH:CH—-.
`—CH2CH2—. or —CEC-—;-
`'
`wherein Z] is
`(1) —CH1——(CH2)f—C(Rl}2, wherein R2 is hydrogen
`or t'luoro and f is zero. one. 2, or 3.
`(2} trans—Cliz—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;
`wherein 24 is —CH1— or —(CH2)f—CF3, wherein f
`is as defined above;
`with the overall proviso that
`(1] R15. R15. and Rn are all hydrogen only when 2]
`is —(Ph)-—(CH2)g—, and
`.
`(2} Z; is —(Ph)—(CH1)s-— only when R15 is hydrm
`gen.
`With regard to the divalent substituents described
`above (e.g., L1 and M1}. these divalent radicals are de-
`fined as a-Rnfi-Rj, wherein R; represents the substituctlt
`of the divalent moiety in the alpha configuration with
`respect to the plane of the (3-8 to (2-12 cyclopentaue
`ring and R; represents the substituent of the divalent
`moiety in the beta configuration with reapect to the
`plane of'the ring. Accordingly, when M] is defined as
`rt-DH:fl-R5, the hydroxy of the M1 moiety is in the
`alpha configuration. i.e.. as in PGI; above. and the R5
`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 number of carbon atoms in
`the moiety, i.e., the prefix (Cr-Cf) indicates a moiety of
`the integer "i“ to the integer "j" carbon atoms. inclu-
`sive. Thus (Cl-Cghlkyl refers to alhyl of one to 3 car-
`bon atoms, inclusive, or methyl, ethyl. propyl. and iso-
`propyl.
`Certain novel prostacyclin analogs herein. i.e.. for-
`mula X compounds. are all-named as CBA] or CBA;
`compounds, respectively, by virtue of the substitution
`of methylene for can in the heterccyclic ring of prosta-
`cyclin and the substitution. CBA: compounds are those
`exhibiting the olefinic double bond at 05.6, while
`CB'A; compounds are those saturated at C-S.6. Formula
`XI compounds are named as PGEI or PGF] derivatives
`as hereinafter described.
`Novel compounds wherein Z; is (PhHC‘Hflg are
`designated inter-o-.
`inter-m'-. or inter—p-phenylene de-
`pending on whether the attachment between 05 and
`the —(CH2}g-— 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 Xl-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 PGIg.
`The missing carbon atom or atoms are considered to be
`at the (2-4 to C-Z'positions such that the phenylene is
`connected to the C-5 and {3-1 to (2-3 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—{CH1.
`)f—CFr— are characterized as “2.2~dilluoro-“ com-
`pounds. For those compounds wherein f is zero. 2. or 3.
`the carbacyclin analogs so described are further charac-
`terized as 2-nor. Za-horno, or 23,2b-dihomo, since in this
`event the Xrterminated side chain contains 4. 6. or 7
`carbon atoms, respectively. in place of the five carbon
`atoms contained in CBAz. The nursing 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 (3-3
`positions. Accordingly these additional carbon atoms
`are referred to as 023 and C-Zb. counting from the 02
`to the C-3 position.
`trans—CH-
`is
`Those CBA analogs wherein Z]
`2—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 by virtue of
`the-cyclohexyl ring replacing the heterocyclic ring of
`prostacyclin.
`Further. the novel compounds are named as 9B-alltyl-
`CBA compounds when Rn is alkyl.
`When R15 and R11 taken together are —CH1—(-
`methylene),
`the novel compounds so described are
`"tioB,9.8-methano-CBA“ compounds by virtue of the
`methylene bridge between C-fia and 09.
`When R15 is fluoro. “S-iluoro-CBA" compounds are
`described.
`The formula XI CBA analogs wherein R29. R21. R21.
`R13. and R24 are all hydrogen with R32 being iii-hydro-
`gen are characterizedas “9-dooxy-2'. o-methano-fi-oxa-
`4.5.6-tiinor-3J-(l ‘.3’-inter—phenylene}-PGFI "
`com-
`pounds. Corresponding compounds wherein R2; is a-
`hydrogen are characterized as "9-deoxy-2’.9.G-methano-
`3-oxa-4.5.6~trinor-3,7-(l’,3'-inter-phenylene)—PGFI"
`compounds. CBA analogs wherein R10. R23. and R};
`are all hydrogen and R11 and R22 taken together form a
`valence bond between 09 and 0611 are characterized
`as
`“9-deoito-2',9-metheno-3-oao-3.4,5-trinor—3.7«(l’,3‘~
`inter-phenylene)-PGF1" compounds CBA analogs
`wherein Rzuis hydrogen and R2] and R22 taken together
`form a second valence bond between C-9 and (2-63. and
`R23 and R14 taken together form a second valence bond
`between C-‘l and 08 are characterized as “9-deoxo-
`2‘,9-metheno-3—oxa—3.4,S-trinor-3.7-( l '.3’-inter-
`phenylene)-’l,8-didehydro-PGEI“ compounds. The for-
`mula x1 CBA analogs wherein R3, R23, and R24 are all
`hydrogen and R29 and R21 taken together are onto are
`characterized as "fin-oxo-Q-deoxy-Z’.9u-rnethano-3-oxa-
`4,S.6-trinor-3.7-(1',3’-inter-phenylene)—PGF 1" or “6a—
`oxo-Q-deoxy-2',QB-methano-3-oxa-4,S.6-trinor«3,7-
`(1’,3'-inter-phenylene)—PGF1" depending on whether
`R22 is o-hydrogen or B-hydrogen, reapectively. For-
`mula X] CBA analogs wherein R20, R12, R13, and R24
`
`10
`
`15
`
`15-
`
`30
`
`35
`
`45
`
`50
`
`55
`
`tit]
`
`65
`
`Liquidia - Exhibit 1014 - Page 4
`
`Liquidia - Exhibit 1014 - Page 4
`
`

`

`4,306,075
`
`'3'
`are all hydrogen and R21 is a-hydroxy are characterized
`as
`"6an-hydroxy—9-deoxy-2'.9o-methano—3-oxa—4.S.6-
`trinor—3.7-( l ',3'-inter-phenylene}-PGF1“
`or
`“6nd-
`hydroxy-SI-deoxy-Z'.9B-methano-3-oxa-4.5.6-trinor-3.'r'-
`{ i ’,3'-inter-pheny1ene)-PGFl “ compounds depending
`on whether R22 is n-hydrogen or B-hydrogen, reSpcc-
`tively. Finally. formula XI TXA analogs wherein R29,
`R12. R13. and R24 are all hydrogen and R21 is .B-liydrony
`are
`characterized
`as
`"éaB-hydroxy-Q-deoxy-Z'Sfi-
`methane-3-oxa—4.5,6-trinor—3,7-{l'.3"inter-phenylene)-
`PGF] " or “bafi-hydrosy-9-dcoxy-Z'fict-methfil‘lo-J-DM-
`4.5,6-trinor-3J-(l '.3'-inte r-phenylene)-PGF1 "
`com-
`pounds depending on whether R22 is c-hydrogen or
`B-hydrogen, respectively. When 24 is -—(CH2)f—CF2
`and [is zero. the formula XI CBA analogs are addition-
`ally characterized as “2.2-difluoro" compounds. When f
`is one. 2. or 3, such compounds are additionally charac-
`terized as “la-homo". "ZaZb-dihomo“ or “2a.2b.2c-
`trihomo" compounds.
`When R5 is methyl. the carbacyclin analogs are all
`named as "lfi-methyl-CBA" compounds. Further, ex-
`cept for compounds wherein Y; is cis—CH=CH—.
`compounds wherein the M1 moiety contains an by-
`droxyl in the beta configuration are additionally named
`as “lS-epi-CBA" compounds.
`For the compounds wherein YI is cis—CI-I=CH—.
`then compounds wherein the M1 moiety contains an
`hydroxyl in the alpha configuration are named as “15-
`epi-CB " compounds. For a description of this conven-
`tion of nomenclature for identifying C—lS epimers. see
`US. Pat. No. 4.016.184. issued 5 Apr. 1977. particularly
`columns 24-2? thereof.
`The novel carbacyclin analogs herein which contain
`—(Cl-i1)z—, cis—CH=CH—. or ~C=_=C'«- as the Y1
`moiety, are accordingly referred to as "13.14-dihydro”.
`“cis-l3". or “13.14-didehydro“ compounds,
`respec-
`tively.
`chained —CmH;m—CH3.
`straight
`When R7 is
`wherein m is as defined above. the compounds so de-
`scribed are named as "19.20-dinor", “ID-nor". "2D-
`methy “ or “ZCLethyl” compounds when m is one, 2. 4
`or 5. respectively. When R7 is branched chain —C.,.H-
`h—CH}, then the compounds so described are "17-.
`13-, 19-. or ZO-alkyl" or “I7.17-. IT,lS-. -1'.r'.l9-. 1730-,
`13,13-, 13.19-, 1310-. 19.19-, or 19.20-diality ” com-
`pounds when m is 4 or 5 and the unbranched portion of
`the chain is at least n-btltyl, 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 “lb-phenyl-
`17,18,I9.20—tetranor" compounds. When R7 is substi-
`tuted phenyl. the corresponding compounds are named
`as "lo-(substituted phenyl)-lT.IE.l9,20-tetranor" com-
`pounds. 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 defined in this paragraph
`are named as “IE-phony] or lb-(substituted phenyl)-
`18,19,20-trinor“ compounds or “lb-ruethyi-lb-phenyl-
`or Its-(substituted phenyIJ-l8.19.20-trinor” compounds
`reapectively.
`When Rat is benzyl, the compounds so described are
`named as “IT-phenyl-IS.19.20-triuor"
`compounds.
`When R1 is substituted benzyl, the corresponding com-
`pounds are named as "ll-(substituted phenyl)-l 8.19.20-
`trinor“ compounds.
`When R7 is phenylethyl. the compounds so described
`are named as
`"lB-phenyi-l9.20-dinor” compounds.
`When R1 is substituted phenylethyl. the corresponding
`
`compounds are named as “IE-(substituted phenyl)‘
`19.20-dinor“ compounds.
`the compounds so de-
`When R7 is phenylpropyi.
`scribed are named as “19-pl1enyl—2iJ-nor" compounds.
`When R1 is substituted phenylpropyl the corresponding
`compounds are named as “19-(substituted phenyI)-20—
`nor" compounds.
`When R-r is phenorty and neither R3 nor R4 is methyl.
`the compounds so described are named as "lb-phenony-
`17.18.19.20-tetranor“ compounds. When R7 is substi-
`tuted phenoxy,
`the corresponding compounds are
`named
`as
`“lb-(substituted
`phenoxy)—l7,18.l9,20-
`tetranor“ compounds. When one and only one of R3 and
`R4 is methyl or both R; and R4 are methyl, then the
`corresponding compounds wherein R7 is as defined in
`this paragraph are named as “IS-phenoxy or lfi-{sub-
`stituted phenoxy}18,19,20-trinor" corupounds or “16-
`rnethyl-lfi-phenoxy-
`or
`IE-(substituted
`phenox-
`y)lS.19.20-trinor“ compounds, respectively.
`the com-
`When R7 is cis—CHiH—CIhCHJ,
`pounds so described are named as “cis-ITJS-didehy-
`dro" compounds.
`the com-
`When R7 is —{CH2)z—CH(0H)—CH3,
`pounds 90 described are named as "lSl-hydroxy" com-
`pounds.
`the com-
`When R1 is —(CHz)3—CH=C(CH;)2.
`pounds so described are named as "20-iaopropylidene"
`compounds.
`When —C(Li)-R-.r is optionally substituted cycloal-
`kyI, 2-(2-furyl)ethyl, 2-{3-thienyl)ethyl, or 3-thienylox—
`yrnethyl, the compounds so described are respectively
`15-cycloalltyI-16. 17.18.19.20-pentanor compounds, 17-
`(2-furyIJ-18,19.20-trinor-CBA
`compounds,
`iii-(3-
`thienyl)-18,19,20-trinor compounds. or
`lb-(B-thienyl-
`)oxy—l?.lB,19.2D-tetranor compounds.
`When at least one of R3 and R4 is not hydrogen then
`(except for the lfi-phencxy or IG—phenyl compounds
`discussed above) there are described the "lfimethyl"
`(one and only one of R3 and R4 is methyl). "16.16-
`dimethyl” (R3 and Rsare both methyl). “lfi-fluoro“ (R3
`or R4 is fluoro). “16,16-difluoro" (R3 and R4 are both
`fluoro) compounds. For those compounds wherein R3
`and Raare different. the prostaglandin analogs so repre-
`sented contain an asynnnetric carbon atom at 0-16.
`Accordingly. two epirneric configurations are possible;
`“(165)" and “(16R ". Further. there is described by this
`invention the C-16 epimeric mixture: “(16115)“.
`When X1 is —CH10H. the compounds so described
`are named as “2—decarboxy-Z-hydroxymethyl“ corti-
`pounds
`the compounds so de-
`When X1 is —CH2NL2L3.
`scribed are named as “2-decarboxy-2-aminomethyl" or
`"2-(5'ubstituted amino)methyl" compounds.
`When X1 is —-COL4, the novel compounds herein are
`named as EBA-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 (Le, X1 is +CODR1. R1 is p-substituted
`phenyl)
`include
`p-acetamidophenyl
`ester.
`p-ben-
`zamidophenyl ester. p-(p-acetamidobenmmido)phenyl
`ester,
`p-(p-benzamidobenzamido)pheny1
`ester.
`p-
`aminocarbonylaminophenyl ester. p-acetylphenyl ester.
`p-benzylphenyl ester. p-amidocarbonylphenyl ester.
`p-methoxycarbonylphenyl ester. p-benaoyloxyphenyl
`ester, p-(p-acctamidobenzoyloxy)phenyl ester, and p-
`hydroxybenzaldehyde semicarbazone ester.
`
`IE!
`
`IS
`
`25
`
`30
`
`35
`
`4.5
`
`SD
`
`55
`
`65
`
`Liquidia - Exhibit 1014 - Page 5
`
`Liquidia - Exhibit 1014 - Page 5
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`

`

`4,306,075
`
`9
`Examples of novel amides herein {i.e.. X: is —C0L4J
`include the following:
`(1} Amides within the scope of alkylamino groups of
`Iht‘:
`formula—NRissz are methylamide. ethylamide.
`n-propylamide. n—butyiamide, n-pentylamide. n-hexyla-
`mide. n-heptyiamide, n—octylamide, n-nonylamide. n-
`decylamide, n-undecylamide. and n—dodecyiamide, and
`isomeric forms thereof. Further examples are dime~
`thylamide. diethylamide. di-n-pmpylamide. di-n-butyla-
`mide. methylethyiamide. methyipropyiamide, methyl-
`butylamide, ethylpmpylamide. ethylbutylamide. and
`propylbutylamide. Amides within the scope of cy-
`clonikylamino are cyclcprOpylamide. cyc‘tobutylnmide.
`cyclopentylamide, 2,3-:1imethylcyelopentylamide. 2,2-
`dimethyleyclopentylamide, 2-methyicyclopentylamide.
`3-tert-butyleyclopenty] amide, cyclohexylamide. 4-tert-
`butyleyciohexyiamide.
`3-isopropylcyclohexyiamide,
`2,2«dimethylcyclohexyiamide. cycloheptylamide.
`cy-
`clooctylamide,
`cyclononyiamide,
`eyslodecyiemide.
`N—methyl-N-cyclubutylamide, N—methyi-N-cyclapen-
`tylamide, N-methyl-N-cyclohexylamide. N—ethyl-N—
`cyclopentylamide.
`and N-efltyl-Ncyclohenylamide.
`Amides within the scope of aralkylamina are benzyla-
`mide, 2-phenylethylamide, and N-methyl-N benzyt-
`amide. Amide: within the scope ni' substituted phenyla-
`mide
`are
`p-chioroanilide, m-chioroanilide.
`2,4-
`dichlnmanilide, 2.4.6-trichloroanilide. m-nitroanilide.
`p-nitroanilide. p-methoxyanilide, 3.4—dimethoxynnilide,
`3.4.5-trimethoxyanilide,
`p-hydmxymethylanilide.
`p-
`methylanilide,
`tit-methyl
`aniiide. p-ethytanilide,
`t»
`hutytanilide, p-carbuxyanitide, p-methoxycarbonyl ani-
`lide. p-carboxyaniiide and o-hydrnxyaniiide. Amide-s
`within the Scope of carbaxyalkytamino are carboxye-
`thylamide. cmboxypropylamide and carbdxymetbyia-
`mide. carboxybutyiamide. Amides within the scape of
`carbamoyiakyiamino are carbamoylmethylamide. car-
`bamoylethylamide. carbamaylpropylamide, and car-
`bamoylbutylamide. Amide; within the scope of cya~
`nonlkylamino are cyanomethylamide,
`cyanaethyla-
`mide, cyanopropylamide, and cyanubutylarnide. Am-
`ides withn the scope of acetylalkytamino are acetylme-
`thylamide. acetylemylamide, acetylpmpylamide, and
`acetylbutytamide. Amides within the scope of ben-
`zoylalkylamino are benzoylmethylamide. benzoyle-
`Lbylamide. benzoylpropylamide, and henzoyibutyla—
`mide. Amide-5 within the scope of substituted hen-
`zoyialkylarninu are p-chlombenmylmethylamide. m-
`chlorohenzoylmethylamide.
`2,4—dichiorobenzoylme-
`thylamide1
`2.4.6-tric11]orobenzoyimethyiamide,
`m—
`nitrobenzoylmethyiamide. p-nitmbenzoylmethylamide.
`p-methmybenzoylmethylamide.
`2.4-dimethoxy ben-
`zoylmethylamide.
`3.4.5-trimethoxybenzoytmethyta-
`mide, p-hydmxymethylbenztwlmethylamide. p-methyl-
`benzoylmethyiamide‘ m-methylbenzoylmethylamide.
`p-ethyibenzoylmethylamide.
`t-butylbenzoylmethyttt-
`mide, p~carboxybenzoyimethyiamide. m—methnxycar-
`bonylbenzoylmethytamide. o-carboxybcnzuylmethyla—
`mide,
`o-hydroxybenzoylmethylamide.
`p-chloroben-
`zoyiethylamide. mchlorobenznyiethyiamide,
`2.4—
`dichlorobenzoylethyiamide.
`2.4,fi-trichlumbenzoyle-
`thylamide. m-nitrobenzoyiethyiamide. pnitrobeuzoyle-
`thylamide. p-methoxybcnwylethyiamide,
`p—methox-
`ybenzoylethylamide. 2.4-dimethoxybenzoylethylamidc.
`3.4.5'trimetboxybenz‘oylelhylamide, p—hydroxymethyl-
`benzoylethyiamide.
`p-mcthylbenzoylethylamide, m-
`methylbenzoylethylamidc‘
`p-ethylbenzoylethylamide,
`t~butylbcnzcylethyiemide.
`p-carbmybenzoylethyla«
`mide. m-methoxycarbonbeenzoyiethyiamide.
`o-cnr-
`
`ID
`
`[5
`
`20
`
`25
`
`30
`
`35
`
`45
`
`SD
`
`55
`
`60
`
`65
`
`10
`boxybenzoyiethytamide. o-hydroxybenzoylethylamide,
`p-chlorobenmylpropyiamide,
`m-chlorobenzoyl-
`propylarnide. Lit-diehierobenzoylpmpylamide. 2,4,6-
`tn‘chlumbenzoylpropylamide, m-nitrobenzoylpmpyla-
`mide, p-nitrobenzoylprolaylumide. p-methmybenzoyl-
`propylamide. 2,4-dimethoxybenzoylpropylemide. 3,4,5-
`trimethoxybenzoylpmpylnmide, p-hydroxymethylben-
`zoylpmpyiamide.
`p-methylbenzoylpropylamide. m-
`methylhenzoylpropylamide,
`p-ethylbenzoylpropyla-
`mide.
`t-buty]benzoylpropyinmide. p-carbuxybenzoyl-
`propylamide. m-methoxycarbonylbenzoyipropylamide.
`o-carboxybenzoytpropyiamide,
`o-hydroxybenzoyl-
`propyiamide.
`p-chlorobenzoylbutylamide,
`m—
`chtorobenzoylbutylmide,
`2.4-dichlbrobenzoylbutyla—
`mide, 2.4.6-trichlbrobenzoylbutylamide. m-nitroben-
`zoylmethylamide.
`p-nitrobenzoylbutylamide,
`p-
`methoxybenzoylbutylamine, 2,4—dimemoxybenzoylbu-
`tyl-amide.
`3,4.S-trimethoxybenmylbutylamide,
`p-
`hydroxymethylbenzoylbutyi-amide. p-methylbenzoyl-
`butyamide, m-methylbenzoylbutylamide, p-ethyl-ben-
`mylbutylamide, m-methyibenzoylbuty!amide, p-ethyi-
`benzoyibutyl-amide,
`t-butylbenzoylbutylamide, p-car-
`boxybenzoylbutyiamide, m-methoxycarbunylbenzoyl-
`butylamide. o'carboxybenzoylbutylamide. o-hydrox-
`ybenzoylmethytamjde. Amides within the scope. of
`pyridylarnino are a-pyridylamide. B—pyridylamide. and
`1-pyridylarnide. Amides within the scope of substituted
`pyridyiamino are 4-methyi-a-pyridylamide. damethyl-
`fi-pyridylamide,
`4-chloro»a~pyridylamide.
`and
`4-
`chIoro-fi-pyridylamide. Amides within the scope of
`pyridylalkylamino
`are
`a-pyridylmethylamide, B-
`pyridylmethylamide.
`y-pyridylmethylamide.
`Cl.-
`pyridylethylamide,
`fi-pyridylethylamide, y-pyridy]e~
`thylamide, ct-pyridylpropyiamide. B-pyridylpropyla—
`mide, y-pyridylpmpyiamide. a—pyridylbutylamide, fi-
`pyridylbutyiamide. and 7-pyridylbutylamide. Amides
`within the scape of substituted pyridylnlkylanfido are
`4-methyi-ct-pyridylmethylamide.
`4-methyl-fl-pyridyl-
`methylamide,
`4-|:hlore-ct-pyridylmethylamide.
`4~
`chloro-B-pyridylmethylamide.
`4*methyl-a-py1'l-dyl-
`propylamide,
`4-methyl—B-pyridylpropyiamide