United States Patent [19]
`
`_ Aristoff
`
`[11] Patent Number:
`[45] Date of Patent:
`
`4,668,814
`May 26, 1987
`
`[54] INTERPHENYLENE CARBACYCLIN
`DERIVATIVES
`[75] Inventor: Paul A. Aristoff, Portage, Mich.
`[73] Assignee: The Upjohn Company, Kalamazoo,
`Mich.
`[21] Appl. No.: 690,803
`[22] Filed:
`Jan. 11, 1985
`
`[51] Int. Cl.4 .......................................... .. C07C 177/00
`[52] U.S. Cl. .................................... .. 560/51; 544/155;
`544/380; 546/203; 546/204; 546/283; 546/284;
`546/285; 548/540; 549/66; 549/78; 549/79;
`549/305; 549/465; 549/496; 549/499; 549/501;
`549/502; 549/65; 560/45; 560/56; 562/444;
`562/466; 562/499; 562/453; 564/80; 564/88;
`564/89; 564/90; 564/92; 564/93; 564/95;
`564/97; 564/98; 564/99; 564/152; 564/158;
`564/171; 564/174; 564/374; 564/384; 564/427;
`564/453; 564/454; 568/633; 568/808; 568/817
`[58] Field of Search ........................... .. 560/ 51, 45, 56;
`562/444, 466, 499, 453; 542/429; 544/155, 380;
`564/80, 88, 89, 90, 92, 93, 95, 97, 98, 99, 171,
`174, 152, 158, 374, 384, 427, 453
`References Cited
`U.S. PATENT DOCUMENTS
`
`[56]
`
`4,180,657 12/1979 Sih ..................................... .. 542/426
`4,192,891 3/1980 Haslanger
`...... .. 424/305
`4,225,508 9/1980 Sih ......... ..
`260/346.22
`4,238,414 12/1980 Morton
`...... .. 564/453
`4,306,075 12/1981 Aristoff
`.... .. 560/56
`
`4,306,076 12/1981 Nelson . . . . .
`. . . . .. 560/56
`4,349,689 9/1982 Aristoff ............................. .. 560/117
`
`FOREIGN PATENT DOCUMENTS
`
`0024943 11/ 1981 European Pat. Off. .
`0087237 8/1983 European Pat. Off. .
`2900352 7/1979 Fed. Rep. of Germany .
`4063059 5/1979 Japan .
`4063060 5/ 1979 Japan .
`4024865 5/ 1979 Japan .
`2012265 7/1979 United Kingdom .
`2013661 8/1979 United Kingdom .
`2017699 10/1979 United Kingdom .
`2070596 9/ 1981 United Kingdom .
`
`OTHER PUBLICATIONS
`Aristoff, P. A., et al., Advances in Prostaglandin,
`Thromboxane, and Leukotriene Research, 11, 1983, pp.
`267-274, “Synthesis and Structure-Activity Relation
`ship of Novel Stable Prostacyclin Analogs”.
`Aristoff, P. A. and Harrison, A. W., Tetrahedron Let
`ters, 23 (No. 20), 1982; pp. 2067-2070, “Synthesis of
`Benzindene Prostaglandins: A Novel Potent Class of
`Stable Prostacyclin Analogs”.
`Aristoff, P. A., J. Org. Chem, 46 (No. 9), 1981, pp.
`
`1954-1957, “Practical Synthesis of 6a-Carbaprostaglan
`din Iv".
`Barco, A., et al., J. Org. Chem., 45 (No. 32), 1980, pp.
`4776-4778, “A New Elegant Route to a Key Intermedi
`ate for the Synthesis of 9(O)-Methanoprostacyclin".
`Konishi, Y., et al., Chem. Lett., 1979, pp. 1437-1440, “A
`Synthesis of 9(O)—Methanoprostaoyclin“.
`Kojima, K. and Sakai, K., Tetrahedron Letters, 39,
`1978, pp. 3743-3746, “Total Synthesis of 9(O)-Me
`thanoprostacyclin and Its Isomers".
`Morton, D. R., Jr. and Brokaw, F. C., J. Org. Chem., 44
`(No. 16), 1979, pp. 2880-2887, “Total Synthesis of 6a—
`Carbaprostaglandin 12 and Related Isomers”.
`Nicolaou, K. C., et al., J.C.S. Chem. Comm, 1978, pp.
`1067-1068, “Total Synthesis of Carboprostacyclin, A
`Stable and Biologically Active Analogue of Prostacy
`clin (PGIZY‘.
`Shibasaki, M., et al., Chem. Lett., 1979, pp. 1299-1300,
`“A Stereo and Regiospeci?c Route to the Synthetic
`Intermediate for the Synthesis of 9(O)-Methanoprosta
`cyclin".
`Shibasaki, M., et al., Tetrahedron Letters, 5, 1979, pp.
`433-436, “New Synthetic Routes to 9(O)-Methano
`prostacyclin, A Highly Stable and Biologically Potent
`Analog of Prostacyclin".
`Skuballa, V. W. and Vorgruggen, H., Agnew. Chem,
`93, (No. 12), 1981, pp. 1080-1081, “Ein Neuer Weg Zu
`6a-Carbacyclinen-Synthese Eines Stabilen, Biologisch
`potenten Prostacyclin-Analogons".
`Sugie, A., et al., Tetrahedron Letters, 28, 1979, pp.
`2607-2610, “Stereocontrolled Approaches to 9(O)-Me
`thanoprostacyclin”.
`Yamazaki, M., et al., Chem. Lett., 1981, pp. 1245-1248,
`“1,2-Carbonyl Transposition of cis-Bicyclo[3.3.0]oc
`tan-2-one to its 3-One Skeleton: Appl. to Syntheses of
`dI-Hirsutic Acid and d1-9(O)—Methanoprostacyclin”.
`
`Primary Examiner-Paul J. Killos
`Attorney, Agent, or Firm-I__.. Ruth I-Iattan
`[57]
`ABSTRACT
`A compound of the formula
`
`and intermediates useful in preparing same.
`
`11 Claims, No Drawings
`
`1
`
`UT Ex. 2015
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`1
`
`4,668,814
`
`INTERPHENYLENE CARBACYCLIN
`DERIVATIVES
`
`FIELD OF THE INVENTION
`The present invention relates to novel pharmaceuti
`cally useful compounds which are carbacyclin analogs
`having a tricyclic nucleus.
`
`20
`
`25
`
`30
`
`PRIOR ART
`Related interphenylene carbacyclins are described
`and claimed in U.S. Pat. No. 4,306,075, U.S. Pat. No
`4,306,076, and EP No. 87237 (Derwent No. 754477).
`Compounds having a S-membered oxa ring are de
`scribed in European Pat. No. 24-943 (Derwent No.
`19801D).
`Carbacyclin and closely related compounds are
`known in the art. See Japanese Kokai Nos. 63,059 and
`63,060, also abstracted respectively as Derwent Farm
`doc CPI Numbers 48l54B/26 and 48155B/26. See also
`British published speci?cations No. 2,012,265 and Ger
`man Offenlungsschrift No. 2,900,352, abstracted as Der
`went Farmdoc CPI Number 54825B/ 30. See also Brit
`ish published applications Nos. 2,017,699 and 2,013,661
`and U.S. Pat. No. 4,238,414.
`The synthesis of carbacyclin and related compounds
`is also reported in the chemical literature, as follows:
`Morton, D. R., et al, J. Org. Chem., 44:2880-2887
`(1979); Shibasaki, M., et a1, Tetrahedron Lett., 433-436
`(1979); Kojima, K., et al, Tetrahedron Lett., 3743-3746
`(1978); Nicolaou, K. C., et al, J. Chem. Soc., Chemical
`Communications, 1067-1068 (1978); Sugie, A., et a1,
`Tetrahedron Lett., 2607-2610 (1979); Shibasaki, M.,
`Chem. Lett., 1299-1300 (1979), and Hayashi, M., Chem.
`Lett., 1437-40 (1979); Aristoff, P. A., J. Org. Chem. 46,
`1954-1957 (1981); Yamazaki, M., et al, Chem. Lett.,
`1245-1248 (1981); and Barco, A., et al, J. Org. Chem.
`45, 4776-4778 (1980); and Skuballa, W., et al, Angew.
`Chem. 93, 1080-1081 (1981). The utility and synthesis of 40
`compounds closely related to those claimed herein is
`described in Aristoff, P. A., and Harrison, A. W., Tetra
`hedron Lett. 23, 2067-2070 (1982) and in Advances in
`Prostaglandin, Thromboxane, and Leukotriene Re
`search, Vol. 11, 267 (1983).
`7-Oxo and 7-hydroxy-CBA2 compounds are appar
`ently disclosed in U.S. Pat. No. 4,192,891. 19-Hydroxy
`CBA; compounds are disclosed in U.S. Pat. No.
`4,225,508. CBA; aromatic esters are disclosed in U.S.
`Pat. No. 4,180,657. ll-Deoxy-Alo- or AH-CBAZ com
`pounds are described in Japanese Kokai No. 77/24,865,
`published Feb. 24, 1979.
`
`45
`
`50
`
`55
`
`—OCR54.
`
`(iv) —CI~l=N-NHCONH3 wherein R5 is
`methyl,
`phenyl, acetamidophenyl, ben
`zamidophenyl, or --NH3; Ryj is methyl,
`phenyl, ——NI'I2, or methoxy; R54 is phenyl or
`acetamidophenyl; inclusive; or
`(g) a pharmocologically acceptable cation;
`
`(3) —-COL4, wherein L4 is
`(a) amino of the formula —NR51R53 wherein R5]
`and R52 are
`(i) hydrogen,
`(ii) (Cl-C12) alkyl,
`(iii) (C3-C10) cycloalkyl,
`
`(v) phenyl, optionally substituted with one 2 or 3
`chloro, (C1-C3) alkyl, hydroxy, carboxy,
`(C2-C5) alkoxycarbonyl, or nitro,
`(vi) (C2-C5) cyanoalkyl,
`(vii) (C2-C5) carboxyalkyl,
`(viii) (C2-C5) carbamoylalkyl,
`(ix) (C3-C6) acetylalkyl,
`(x) (C7-C11) benzoalkyl, optionally substituted
`by one, 2 or 3 chloro, (C1-C3) alkyl, hydroxy,
`(C1-C3) alkoxy, carboxy, (C2-C5) alkoxy car
`bonyl, or nitro,
`(xi) pyridyl, optionally substituted by one, 2 or 3
`chloro, (C1-C3) alkyl, or (C1-C3) alkoxy,
`(xii) (C6-C9) pyridylalkyl optionally substituted
`by one, 2 or 3 chloro, (C1-C3)a1kyl, hydroxy,
`or (C1-C3) alkoxy,
`I
`(xiii) (C1-C4) hydroxyalkyl,
`(xiv) (C1-C4) dihydroxyalkyl,
`(xv) (C1-C4) trihydroxyalkyl, with the proviso
`that not more than one of R51 and R52 is other
`than hydrogen or alkyl;
`(b) cycloamino selected from the group consisting
`of pyrrolidino, piperidino, morpholino, pipera
`zino, hexamethylenimino, pyrrolino, or 3,4
`didehydropiperidinyl optionally substituted by
`one or 2 (Cl-C12) alkyl of one to 12 carbon
`atoms, inclusive;
`(0) carbonylamino of the formula -—NR53COR51
`wherein R53 is hydrogen or (C1-C4) alkyl and
`R51 is other than hydrogen, but otherwise de
`?ned as above;
`(d) sulfonylamino of the formula —NR53SO1R51,
`wherein R51 and R53 are de?ned in (c);
`(4) --CH2NL2L3 wherein L2 and L3 are hydrogen or
`(C1-C4) alkyl, being the same or different, or the
`pharmacologically acceptable acid addition salts
`thereof when X] is —CH2NL2L3;
`(5) —CN;
`
`SUMMARY OF THE INVENTION
`The present invention provides compounds of For
`mula I wherein:
`X1 is
`(1) —COOR1, wherein R1 is
`(a) hydrogen;
`0)) (Cl-C12) alkyl;
`(c) (C3—C1o) Cycloalkyl;
`(d) (C1-C12) aralkyl;
`(e) phenyl, optionally substituted with one, 2 or 3
`chloro or (C1-C3) alkyl;
`(t) phenyl substituted in the para position by
`(i) —NHCOR25,
`(ii) —COR26,
`(iii)
`
`wherein L20 is a—OH,B-—H; a—-H,B--OH; H,H;
`a-CH3,B--H; a-CHzOILB-H; :0; Or ZCHZ;
`wherein L60 is hydrogen or L20 and L60 taken to
`gether form a double bond between positions 10 and
`l 1;
`wherein Y1 is -CH2CH2--, —SCH2—, —CEC—,
`trans-—CH=CH—, or cis-CH=CH—;
`wherein
`
`65
`
`2
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`
`

`
`4,668,814
`
`4
`
`3
`
`--Y1—C—C—
`II
`II
`M] L]
`
`taken together is
`
`it
`
`=-CH=NNHC--NH—;
`
`5
`
`10
`
`wherein M1 is a—H:,B—-H; :0; a-—-OH:B—R5; or
`a—R5:B—OI-l; wherein R5 is hydrogen or methyl;
`wherein L1 is
`(l) a—R3:B-R4, a—R4:,8——R3, or mixtures thereof 15
`wherein R3 and R4 are hydrogen, methyl, or fluoro,
`being the same or different, with the proviso that
`one of R3 and R4 is fluoro only when the other is
`hydrogen or ?uoro;
`(2) or when M] is a—H:B—-H, L1 is a—OH:B—R3, 2O
`a--R3:B—OH; or a mixture of a--OH:B——R3 and
`a—R3:,B-OH wherein R3 is hydrogen, methyl,
`vinyl, or ethynyl;
`wherein R7 is
`(l) —C,,,H1,1,CH3, wherein m is an integer from one 25
`to 8, inclusive;
`(2) phenoxy optionally substituted by one, 2 or 3
`chloro, ?uoro, trifluoromethyl, (C1-C3) alkyl, or
`(C1-C3) alkoxy, with the proviso that not more
`than two substituents are other than alkyl with the 30
`proviso that R7 is phenoxy or substituted phenoxy,
`only when R3 and R4 are hydrogen or methyl,
`being the same or different;
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl
`optionally substituted on the aromatic ring by one, 35
`2 or 3 chloro, ?uoro, tri?uoromethyl, (C1-C3)
`alkyl, or (C1-C3) alkoxy, with the proviso that not
`more than two substituents are other than alkyl;
`(4) CiS——CH=CH—CH2CH3;
`(5) -—(CH2)2—CH(0H)—CH3;
`(6) —(CH2)3—CH=C(CH3)2;
`(7) -—CpH2pCH:CH2 wherein p is an integer from 2
`to 6, inclusive;
`wherein
`
`40
`
`45
`
`—C—R
`u
`7
`L1
`
`taken together is
`(1) (C4-C7) cycloalkyl optionally substituted by one
`to 3 (Cr-C5) alkyl, or (C1—C5)alkenyl;
`(2) 2~(2-furyl) ethyl;
`(3) 2-(3-thienyl) ethoxy;
`(4) 3-thienyloxymethyl; or
`(5)
`
`CH3
`
`==CHCH2CE CCH3;
`
`50
`
`55
`
`6O
`
`and the individual optical enantiomers thereof with
`the proviso that each compound is other than one
`formed when the substituents X1, Z4, L20, Y1, M1, L1, 65
`and R7 have the following meanings:
`X1 is as de?ned above;
`
`M1 is a--OH:,8—R5, or a—R5:B—OH wherein R5 is
`hydrogen or methyl;
`L1 is a—R3:B—-R4, a—R4:B——R3, or a mixture
`thereof wherein R3 and R4 are hydrogen, methyl,
`or ?uoro, being the same or different, with the
`proviso that one of R3 and R4 is fluoro only when
`the other is hydrogen or fluoro; and
`R7 is as de?ned above except R7 is other than
`—(CH2)2—CH:CH3 and R7 is other than
`—C(L1)R7 taken together is as defined above ex
`cept ——C(L1)R7 is other than (C4—C7)cycloalkyl
`optionally substituted with (C1-C5)alkenyl.
`The present invention also provides a new procedure
`for preparing compounds of Formula 1(a) wherein
`X] is
`(l) —COOR1, wherein R1 is
`(a) hydrogen;
`(b) (Cl-C12) alkyl;
`(0) (C3-C1Q) cycloalkyl;
`(d) (C7—C12) aralkyl;
`(e) phenyl, optionally substituted with one, 2 or 3
`chloro or (C1-C3) alkyl;
`(f) phenyl substituted in the para position by
`(i) —NHCOR25,
`(ii) —'COR26,
`(iii)
`
`or
`
`(iv) —-CH:N-—NHCONHZ wherein R25 is
`methyl,
`phenyl,
`acetamidophenyl, ben
`zamidophenyl, or —-NH;; R26 is methyl,
`phenyl, -—NH2, or methoxy; R54 is phenyl or
`acetamidophenyl; inclusive; or
`(g) a pharmacologically acceptable cation;
`(2) —CH2OH;
`(3) —COL4, wherein L4 is
`(a) amino of the formula —NR51R51 wherein R51
`and R52
`(i) hydrogen,
`(ii) (Ci-C12) alkyl,
`(iii) (C3—Cio) cycloalkyl,
`(iv) (C7-Cr2) aralkyl,
`(v) phenyl, optionally substituted with one 2 or 3
`chloro, (C1-C3) alkyl, hydroxy, carboxy,
`(C2-C5) alkoxycarbonyl, or nitro,
`(vi) (C2-C5) cyanoalkyl,
`(vii) (C2-C5) carboxyalkyl,
`(viii) (C2-C5) carbamoylalkyl,
`(ix) (C3-C6) acetylalkyl,
`(x) (C7-C11) benzoalkyl, optionally substituted
`by one, 2 or 3 chloro, (C1-C3) alkyl, hydroxy,
`(C1-C3) alkoxy, carboxy, (C2-C5) alkoxy car
`bonyl, or nitro,
`(xi) pyridyl, optionally substituted by one, 2 or 3
`chloro, (C1—C3) alkyl, or (C1-C3) alkoxy,
`(xii) (C6-C9) pyridylalkyl optionally substituted
`by one, 2 or 3 chloro, (C1-C3) alkyl, hydroxy,
`or (C1-C3) alkoxy,
`(xiii) (C1-C4) hydroxyalkyl,
`(xiv) (C1-C4) dihydroxyalkyl,
`
`3
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`IPR2016-00006
`
`

`
`4,668,814
`6
`(4) cis—Cl-I:CI-l-CHgCI-I3;
`(5) ——(CH2)2——CH(OH)—CH3;
`(6) —(CH2)3—CH=C(CH3)2;
`(7) C,,H3,,CH:CH3 where p is an integer from 2 to 6,
`inclusive;
`wherein
`
`5
`
`5
`(xv) (C1-C4) trihydroxyalkyl,
`with the proviso that not more than one of R5|
`and R53 is other than hydrogen or alkyl;
`(b) cycloamino selected from the group consisting
`of pyrrol'idino, piperidino, morpholino, pipera
`zino, hexamethylenimino, pyrrolino, or 3,4
`didehydropiperidinyl optionally substituted by
`one or 2 (Ci-C13) alkyl of one to 12 carbon
`atoms, inclusive;
`(c) carbonylamino of the formula —NR53COR5|
`wherein R53 is hydrogen or (C1-C4) alkyl and
`R51 is other than hydrogen, but otherwise de
`?ned as above;
`(d) sulfonylamino of the formula —NR53SO3R51,
`wherein R51 and R53 are de?ned in (c);
`(4) —CH3NL1L3 wherein L3 and L3 are hydrogen
`or (C1-C4) alkyl, being the same or different, or
`the pharmacologically acceptable acid addition
`salts thereof when X] is —CH2NL2L3;
`(5) —CN;
`
`wherein L30 is a—-OH,B—H; a—H,,B—OI-I; H,H;
`a—CH3,B—H; a-CHgOH?-H; :0; 0r :ICHg;
`wherein L60 is hydrogen or L20 and L60 taken to
`gether form a double bond between positions 10 and
`11;
`
`wherein
`
`taken together is
`
`0
`
`20
`
`25
`
`30
`
`35
`
`40
`
`taken together is
`(l) (C4-C7) cycloalkyl optionally substituted by one
`to 3 (C1-C5) alkyl, or (C|—C5)alkyl;
`(2) 2-(2-furyl) ethyl;
`(3) 2-(3-thienyl) ethoxy;
`(4) 3-thienyloxymethyl; or
`(5)
`
`CH3
`
`-CHCH3CECCH3;
`
`and the individual optical enantiomers thereof.
`In the event it is not readily apparent the difference
`between the compounds of Formula I and those of
`Formula I(a) lies in the fact that certain compounds of
`Formula I are excluded by the proviso beginning on
`page 4, line 35. The compounds excluded by the proviso
`in Formula I are described and claimed in US. Pat. No.
`4,306,075 and copending US. application Ser. No.
`351,069 ?led Feb. 22, I982. The novel process described
`herein is applicable to the prior claimed compounds and
`the novel compounds described and claimed herein
`Also, the present invention provides novel intermedi
`ates of Formulas I(b), I(c), I(d) and II as set forth in the
`Formula Chart. In Formulas I(b) and I(c) the group Q
`is cis-CI-I2CH:CI-I2, —CHZCOOH, or
`
`wherein M1 is a——H:B—-H; :O; a—OH:B—R5; or
`a—R5:B-OH; wherein R5 is hydrogen or methyl;
`wherein L1 is
`(l) a—R3:B-—-R4, a—R4:B—R3, or mixtures thereof
`wherein R3 and R4 are hydrogen, methyl, or ?uoro,
`being the same or different, with the proviso that
`one of R3 and R4 is ?uoro only when the other is
`hydrogen or ?uoro;
`(2) or when M] is a—-H:B—H, L1 is a—OI-I:B—R3,
`a’R3:B—OH; or a mixture of a—-OH:B—R3 and
`a—-R3:B—-OH wherein R3 is hydrogen, methyl,
`vinyl, or ethynyl;
`wherein R7 is
`(l) —-C,,,HZ,,,CH3, wherein m is an integer from one
`to 8, inclusive;
`(2) phenoxy optionally substituted by one, 2 or 3
`chloro, fluoro, tri?uoromethyl, (C1-C3) alkyl, or
`(C1-C3)alkoxy, with the proviso that not more than
`two substituents are other than alkyl with the pro
`viso that R7 is phenoxy or substituted phenoxy,
`only when R3 and R4 are hydrogen or methyl,
`being the same or different;
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl
`optionally substituted on the aromatic ring by one,
`2 or 3 chloro, ?uoro, trifluoromethyl, (C1-C3)
`alkyl, or (Cr-C3) alkoxy, with the proviso that not
`more than two substituents are other than alkyl;
`
`45
`
`50
`
`wherein alkyl has from 1 to 4 carbon atoms; L is the
`same as L] in Formula I only any hydrous group is
`protected with an Rx group as de?ned below; Y; is
`—SCH2— or —CH2CH2——, M2 iS a-I'LB-ORX, a
`ORx,B-I-I or I-I,H wherein Rx is a protecting group as
`de?ned below, and R7 has the meaning de?ned in For-'
`mula 1(a). In Formula I(d) Q; is
`
`55
`
`as de?ned above or C01 alkyl wherein alkyl has from 1
`to 4 carbon atoms. The intermediates of Formulas I(a),
`I(b), I(c), I(d) and II are useful in the. preparation of the
`compounds of Formuls I and 1(a).
`The compounds of Formula I and I(a) have useful
`pharmacological properties as de?ned below.
`
`65
`
`DETAILED DESCRIPTION OF INVENTION
`In the compounds of the present invention, and as
`used herein, (”') denotes the (it-con?guration, ( ) denotes
`the B-con?guration, (~) denotes a- and/or B-con?gu
`ration or the E and/or Z isomer.
`
`4
`
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`IPR2016-00006
`
`

`
`4,668,814
`7
`With regard to the divalent groups described above,
`i.e., L30, M1 and L1 said divalent groups are de?ned in
`terms of an a-substituent and a B-substituent which
`means that the a-substituent of the divalent group is in
`the alpha con?guration with respect to the plane of the
`C-8 to C13 cyclopentane ring and the ,B-substituent is in
`the beta con?guration with respect to said cyclopentane
`ring.
`The carbon atom content of various hydrocarbon
`containing groups is indicated by a pre?x designating
`the minimum and maximum number of carbon atoms in
`the moiety. For example, in de?ning the moiety L4 in
`the ——COL4 substituent group the de?nition (C1-C13)al
`kyl means that L4 can be an alkyl group having from
`one to 12 carbon atoms. Additionally, any moiety so
`de?ned includes straight chain or branched chain
`groups. Thus (C|—C12)alkyl as set forth above includes
`straight or branched chain alkyl groups having from 1
`to 12 carbon atoms and as additional illustration, when
`20
`L4 represents, for example, (C3-C5)carboxyalkyl, the
`alkyl moiety thereof contains from 1 to 4 carbon atoms
`and is a straight chain or a branched chain alkyl group.
`Similarly a C3-C5 alkenyl group as may be present on
`the cycloalkyl group represented by —C(I_.1)R7 con
`tains from 3 to 5 carbon atoms and one double bond in
`the chain.
`In Formula I when the hydrogen at position 9 is beta
`the compounds are named as 9-deoxy-2’,9a-methano-3
`oxa-4,5,6-trinor-3,7-(l’,3’-interphenylene)PGF1 com
`pounds, and when it is alpha the compounds are named
`as 9-deoxy-2',9,8-methano-3-oxa-4,5,6-trinor-3,7-(1‘,3’
`interphenylene)PGF1 compounds.
`When Z4 is —CF2— the compounds of Formula I are
`also characterized as 2,2-difluoro and when Z4 is
`——CH2CF3— the compounds are characterized as 2a
`homo-2,2-difluoro.
`When R5 is methyl, the carbacyclin analogs are all
`named as “15-methyl-” compounds. Further, except for
`compounds wherein Y1 is cis-CH:CH_, gompgund;
`wherein the M1 moiety contains an hydroxyl in the beta
`con?guration are additionally named as “15-epi-” com
`pounds.
`For the compounds wherein Y; is cis-CH:CH-—,
`then compounds wherein the M1 moiety contains an
`hydroxyl in the alpha con?guration are named as “15
`epi-CBA” compounds. For a description of this conven
`tion of nomenclature for identifying C-l5 epimers, see
`US. Pat. No. 4,016,184, issued Apr. 5, 1977, particularly
`columns 24-27 thereof.
`The compounds of the present invention which con
`tain —(CH2)2——, cis-CH:CH—, trans —CH:CH—
`or ——CEC— as the Y] moiety, are accordingly referred
`to as “13,14-dihydro”, “cis-l3”, “trans-l3”, or —-l3,14
`55
`didehydro” compounds, respectively. Compounds
`wherein Y] is —SCH2— are named as “13-thio” com
`pounds.
`_
`Compounds wherein Ml is H,H are named as “15
`deoxy” compounds. Compounds wherein M1 is :0 are
`named as “IS-0x0” compounds.
`Compounds wherein
`
`are are named as 13,14,l5,16,17,18,19,20-octanor-l2-[N
`R7-carbamoyl)hydrazono-methyl].
`When R7 is
`
`the compounds so described are named as 17(S),20
`dimethyl compounds.
`When —C(L1)—R7 iS
`
`the compounds are named as “l6-(R,S)methyl-l8,l9
`tetradehydro” compounds.
`When —C(L1)R7 is -—CI~IZCH_—_CHZ the compounds
`so described are named as “19,20-didehydro”.
`When at least one of R3 and R4 is not hydrogen then
`there are described the “l6-methyl” (one and only one
`of R3 and R4is methyl), “16,16-dimethyl” (R3 and R4 are
`both methyl), “16-?uoro” (one and only one of R3 and
`R4 is fluoro), “16,16-difluoro” (R3 and R4 are both
`?uoro) compounds. For those compounds wherein R3
`and R4 are different, the carbacyclin analogs so repre
`sented contain as asymmetric carbon atom at 014.
`Accordingly, two epimeric con?gurations are possible:
`“(16S)” and “(16R)”. Further, there is described by this
`invention the C-16 epimeric mixture: “(16RS)”.
`When X1 is -—CH2OH, the compounds so described
`are named as “2-decarboxy-2-hydroxymethyl” com
`pounds.
`When X; is —CI-I2NL2L3, the compounds so de
`scribed are named as "2=decarboxy-2=aminomethyl” or
`“2-(substituted amino)methyl” compounds.
`When X1 is —COL4, the novel compounds herein are
`named as amides. Further, ‘when X1 is --C0OR1 and
`R1 is other than hydrogen the novel compounds herein
`are named as esters and salts.
`When X1 is CN the novel compounds herein are
`named as 2-decarboxy-2-cyano compounds.
`Examples of phenyl esters substituted in the para
`position (i.e., X1 is -—COOR1, R1 is p-substituted
`phenyl) include p-acetamidophenyl ester, p-ben
`zamidophenyl ester, p-(p-acetamidobenzamido)phenyl
`ester, p-(p-benzamidobenzamido)phenyl ester, p
`amidocarbonylaminophenyl ester, p-acetylphenyl ester,
`p-benzoylphenyl ester, p-aminocarbonylphenyl ester,
`p-methoxycarbonylphenyl ester, p-benzoyloxyphenyl
`ester, p(p-acetamidobenzoyloxy)phenyl ester, and p
`hydroxybenzaldehyde semicarbazone ester.
`Examples of novel amides herein (i.e., X1 is —COL4)
`include the following:
`(1) Amides within the scope of alkylamino groups of
`the formula NR9R1Q are methylamide, ethylamide, n
`propylamide, isopropylamide, n-butylamide, n-pentyla
`mide, tert-butylamide, neopentylamide, n-hexylamide,
`n-heptylamide, n-octylamide, n-nonylamide, n-decyla
`mide, n-undecylamide, and n-dodecylamide, and iso
`meric forms thereof. Further examples are dimethyla
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`mide, diethylamide, di-n-propylamide, diisopropyla
`zoylpropylamide, m-methylbenzoylpropylamide, p
`ethylbenzoylpropylamide, t-butylbenzoylpropylamide,
`mide, di-n-butylamide, methylethylamide, di-tert
`p-carboxybenzoylpropylamide,
`m-methoxycarbonyl
`butylamide, methylpropylamide, methylbutylamide,
`benzoylpropylamide, o-carboxybenzoylpropylamide,
`ethylpropylamide, ethylbutylamide, and propylbutyla
`o-hydroxybenzoylpropylamide,
`p-chlorobenzoyl
`mide. Amides within the scope of cycloalkylamino are
`cyclopropylamide, cyclobutylamide, cyclopentyla
`butylamide,
`m-chlorobenzoylbutylamide,
`2,4
`dichlorobenzoylbutylamide,
`2,4,6-trichlorobenz0yl
`mide, 2.3-dimethylcyclopentylamide, 2,2-dimethylcy
`butylamide, m-nitrobenzoylmethylamide, p-nitroben
`clopentylamide,
`Z-methylcyclopentylamide,
`3-tert
`butylcyclopentylamide, cyclohexylamide, 4-tertbutyl
`zoylbutylamide, p-methoxybenzoylbutylamide, 2,4
`dimethoxybenzoylbutylamide,
`2,4,5-trimethoxyben
`cyclohexylamide, 3-isopr0pylcyclohexylamide, 2,2
`zoylbutylamide, p-hydroxymethylbenzoylbutylamide,
`dimethylcyclohexylamide, cycloheptylamide, cyclooc
`p-methylbenzoylbutyamide, m-methylbenzoylbutyla
`tylamide, cyclononylamide, cyclodecylamide, N-meth
`yl-N-cyclobutylamide, N-methy-N-cyclopentylamide,
`mide, p-ethylbenzoylbutyalmide, m-methylbenzoyl
`N-methyl-N-cyclohexylamide,
`N-ethyl-N-cyclopen
`butylamide, p-ethylbenzoylbutylamide, t-butylbenzoyl
`butylamide, p-carboxybenzoylbutylamide, m-methox
`tylamide, and N-ethyl-N-cycl0hexylamide. Amides
`ycarbonylbenzoylbutylamide, o-carboxybenzoylbutyla
`within the scope of aralkylamino are benzylamide, 2
`phenylethylamide, and N-methyl-N benzyl-amide. Am
`mide, o-hydroxybenzoylmethylamide. Amides within
`the scope of pyridylamino are a-pyridylamide, B
`ides within the scope of substituted phenylamide are
`p-chloroanilide, m-chloroanilide, 2,4-dichloroanilide,
`pyridylamide, and 'y-pyridylamide. Amides within the
`2,4,6-trichloroanilide, m-nitroanilide, p-nitroanilide,
`scope of substituted pyridylamino are 4-methyl-a
`p-methoxyanilide, 3,4-dimethoxyanilide, 3,4,5-trime
`pyridylamide, 4-methyl-B-pyridylamide, 4-chloro-a
`thoxyanilide, p-hydroxymethylanilide, p-methylanilide,
`pyridylamide, and 4-chloro-B-pyridylamide. Amides
`m-methyl anilide, p-ethylanilide, t-butylanilide, p-car~
`within the scope of pyridylalkylamino are a-pyridylme
`thylamide, B-pyridylmethylamide, 'y-pyridylmethyla
`boxyanilide, p-methoxycarbonyl anilide, p-carboxyani
`mide, a-pyridylethylamide, B-pyridylethylamide, 'y
`lide and o-hydroxyanilide. Amides within the scope of
`pyridylethylamide, a-pyridylpropylamide, B-pyridyl
`carboxyalkylamino are carboxyethylamide, cal-boxy
`propylamide, -y-pyridylpropylamide, a-pyridylbutyla
`propylamide and carboxymethylamide, carboxybutyla
`mide, ,B-pyridylbutylamide, and 'y-pyridylbutylamide.
`mide. Amides within the scope of carbamoylalkylamino
`Amides within the scope of substituted pyridylalk
`are carbamoylmethylamide, carbamoylethylamide, car
`ylamido are 4-methyl-a-pyridylmethylamide, 4-methyl
`bamoylpropylamide, and carbamoylbutylamide. Am
`B-pyridylmethylamide,
`4-chloro-a-pyridylmethyla
`ides within the scope of cyanoalkylamino are cyanome
`thylamide, cyanoethylamide, cyanopropylamide, and
`mide, 4- chloro-B-pyridylmethyl-amide, 4-methyl-a
`pyridylpropylamide, 4-methyl-B-pyridylpropylamide,
`cyanobutylamide. Amides within the scope of acety
`4-chloro-a-pyridylpropylamide,
`4-chloro-B-pyridyl
`lalkylamino are acetylmethylamide, acetylethylamide,
`propylamide, 4-methyl-oL-pyridylbutylamide, 4-methyl
`acetylpropylamide, and acetylbutylamide. Amides
`B-pyridylbutylamide,
`4-chloro-a-pyridylbutylamide,
`within the scope of benzoylalkylamino are benzoylme
`4-chloro-B-pyridylbutylamide,
`4-chloro-y-pyridyl
`thylamide, benzoylethylamide, benzoylpropylamide,
`butylamide. Amides within the scope of hydroxyalk
`and benzoylbutylamide. Amides within the scope of
`ylamino are hydroxymethylamide, B-hydroxyethyla
`substituted benzoylalkylamino are p-chlorobenzoylme
`mide, B-hydroxypropylamide, 'y-hydroxypropylamide,
`thylamide,
`m-chlorobenzoylmethylamide,
`2,4
`l-(hydroxymethyl)ethyl-amide,
`l-(hydroxymethyD
`dichlorobenzoylmethylamide, 2,4,6-trichlorobenzoyl
`methylamide, m-nitrobenzoylmethylamide, p-nitroben
`propylamide,
`(2-hydroxymethyl)propylamide, and
`zoylmethylamide, p-methoxybenzoylmethylamide, 2,4
`a,a,-dimethyl-hydroxyethylamide. Amides within the
`dimethoxy benzoylmethylamide, 3,4,5-trimethoxyben
`scope of dihydroxyalkylamino are dihydroxymethyla
`zylmethylamide,
`p-hydroxymethylbenzoylmethyla‘
`mide, B,'y-dihydroxypropylamide, l-(hydroxymethyDZ
`hydroxymethylamide, B,'y-dihydroxybutylamide, [3,8
`mide, p-methylbenzoylmethylamide, m-methylbenzoyl
`methylamide, p-ethylbenzoylmethylamide, t-butylben
`dihydroxybutyl-amide, 7,8-dihydroxybutylamide, and
`l,1-bis(hydroxymethyl)ethylamide. Amides within the
`zoylmethylamide, p-carboxybenzoylmethylamide, m
`methoxycarbonylbenzoylmethylamide, o-carboxyben
`scope of trihydroxyalkylamino are tris(hydroxy
`methyD-methylamide and 1,3-dihydroxy-2-hydroxyme
`zoylmethylamide, o-hydroxybenzoylmethy]amide, p
`thylpropylamide.
`chlorobenzoylethylamide, m-chlorobenzoylethylamide,
`2,4-dichlor0benzoylethylamide,
`2,4,6-trichloroben
`(2) Amides within the scope of cycloamino groups
`zoylethylamide, m-nitrobenzoylethylamide, p-nitroben
`described above are pyrrolidylamide, piperidylamide,
`morpholinylamide,
`hexamethyleneiminylamide,
`zoylethylamide,
`p-methoxybenzoylethylamide,
`p
`methoxybenzoylethylamide,
`2,4-dimethoxybenzoyle
`piperazinylamide, pyrrolinylamide, and 3,4-didehy
`thylamide,
`3,4,Strimethoxybenzoylethylamide,
`p
`dropiperidinylamide each of which may be optionally
`hydroxymethylbenzoylethylamide, p-methylbenzoyle
`substituted with one or 2 straight or branched alkyl
`thylamide, m-methylbenzoylethylamide, p-ethylben
`chains having from 1 to 12 carbon atoms.
`zoylethylamide, t-butylbenzoylethylamide, p-carbox
`(3) Amides within the scope of carbonylamino of the
`ybenzoylethylamide,
`m-methoxycarbonylbenzoyle
`formula -—NR53COR51 are methylcarbonylamide,
`thylamide, o-carboxybenzoylethylamide, o-hydrox
`ethylcarbonylamide, phenylcarbonylamide, and benzyl
`carbonylamide.
`ybenzoylethylamide, o-chlorobenzoylpropylamide, m
`chlorobenzoylpropylamide,
`2,4-dichlorobenzoyl
`(4) Amides within the scope of sulfonylamino of the
`propylamide, 2,4,6-trichlorobenzoylpropylamide, m
`formula —NR53SO2R51 are methylsulfonylamide,
`ethylsufonylamide, phenylsulfonylamide, p-tolylsul
`nitrobenzoylpropylamide, p-nitrobenzoylpropylamide,
`p-methoxybenzoylpropylamide, 2,4-dimethoxybenzoyl
`fonylamide, benzylsulfonylamide.
`propylamide,
`3,4,5-trimethoxybenzoylpropylamide,
`Examples of alkyl of one to 12 carbon atoms, inclu
`p-hydroxymethylbenzoylpropylamide,
`p-methylben
`sive, are methyl, ethyl, propyl, isopropyl, isobutyl, tert
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`butyl, isopentyl, neopentyl, butyl, pentyl, hexyl, heptyl,
`per day are preferred, the exact dose depending on the
`octyl, nonyl, decyl, undecyl, dodecyl, isomeric forms
`age, weight, and condition of the patient or animal, and
`on the frequency and route of administration.
`thereof.
`The addition of these compounds to whole blood
`Examples of (C3—~C1()) cycloalkyl which includes
`provides in vitro applications such as storage of whole
`alkyl-substituted cycloalkyl, are cyclopropyl, Z-methyl
`cyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcy
`blood to be used in heart-lung machines. Additionally
`clopropyl, Z-butylcyclopropyl, cyclobutyl, Z-methylcy
`whole blood containing these compounds can be circu
`clobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl,
`lated through organs, e.g., heart and kidneys, which
`cyclopentyl, 2,2-dimethylcyclopentyl, Z-pentylcyclo
`have been removed from a donor prior to transplant.
`pentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert
`They are also useful in preparing platelet rich concen
`butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethyl
`trates for use in treating thrombocytopenia, chemother
`cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and
`apy, and radiation the therapy. In vitro applications
`cyclodecyl.
`utilize a dose of 0.00l-l.0 pg per ml of whole blood.
`The compounds of the present invention are useful in
`Examples of (C7—C1g) aralkyl are benzyl, 2
`phenylethyl, l-phenylethyl, Z-phenylpropyl, 4-phenyl
`the treatment of peripheral vascular diseases, in the
`butyl, 3-phenylbutyl, Z-(I-naphthylethyl), and l-(2
`same manner as described in U.S. Pat. No. 4,103,026.
`naphthylmethyl).
`Examples of phenyl substituted by one to 3 chloro or
`alkyl of one to 4 carbon atoms, inclsive, are p
`chlorophenyl, m-chlorophenyl, 2,4-dichlorophenyl,
`2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl, p-ethyl
`phenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4
`chloro-2methylphenyl, and 2,4-dichloro-3-methylphe
`nyl.
`The compounds of Formulas I and 1(a) produce cer
`tain prostacyclin-like pharmacological responses. Ac
`cordingly, the novel formula I compounds are useful as
`agents in the study, prevention, control, and treatment
`of diseases, and other undesirable physiological condi- '
`tions, in mammals, particularly humans, valuable do
`30
`mestic animals, pets, zoological specimens, and labora
`tory animals (e.g., mice, rats, rabbits and monkeys). In
`particular, these compounds are useful as anti-ulcer
`agents and anti-asthma agents, and as antithrombotic
`agents as indicated below.
`(a) Platelet Aggregation Inhibition
`The compounds of Formulas I and 1(a) are useful
`whenever it is desired to inhibit platelet aggregation,