GB2122203A - Benzo-fused bicyclononanes - Google Patents

Benzo-fused bicyclononanes Download PDF

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GB2122203A
GB2122203A GB08319032A GB8319032A GB2122203A GB 2122203 A GB2122203 A GB 2122203A GB 08319032 A GB08319032 A GB 08319032A GB 8319032 A GB8319032 A GB 8319032A GB 2122203 A GB2122203 A GB 2122203A
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ethyl acetate
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alkyl
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Paul Adrian Aristoff
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
    • C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compounds of the formulae <IMAGE> wherein Y1-CM6-CR3R4R7 is a blocked alkyl-terminated prostaglandin side- group or derivative thereof, the 6,9 and 7,8 bonds are single or double, R is H, OH or O, R18 is H or optionally blocked OH or CH2OH, Z4 is CH2 or (CH2)fCF2, f being 0-3, and X1 is optionally esterified or salified carboxyl, CH2OH aminomethyl or aminocarbonyl.

Description

1 GB 2 122 203 A -1
SPECIFICATION Benzo-fused bicyclononanes
This invention relates to compounds which can be used as intermediates in the preparation of the benzo-fused carbacyclin analogues described and claimed in another divisional of British Patent Application No. 8102901 (Serial No. 2070596), filed on the same date as this divisional, with the 5 Agents Reference GJE 70/2149/01.
For convenience, the prostacyclin and carbacyclin analogues described herein will be referred to by the trivial, art-recognized system of nomenclature described by N.A. Nelson, J. Med. Chem. 17:911 (1974) for prostaglandins. Accordingly, all of the novel prostacyclin derivatives herein will be named as 9-deoxy-PGF,-type compounds. PG12 derivatives, or preferably as CBA, or CBA2 derivatives.
In the formulas herein, broken line attachments to a ring indicate substituents in the "alpha" (a) configuration, i.e., below the plane of said ring. Heavy solid line attachments to a ring indicate substituents in the "beta" (A) configuration, i.e., above the plane of said ring. The use of wavy lines herein will represent attachment of substituents in the alpha or beta configuration or attached in a mixture of alpha and beta configurations. Alternatively wavy lines will represent either an E or Z geometric isomeric configuration or the mixture thereof.
A side chain hydroxy at C-1 5 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 (11966) for discussion of the stereochernistry of the prostaglandins which discussion applies to the novel prostacyclin or carbacyclin analogs herein. Molecules of prostacyclin and carbacyclin each have several 20 centers of asymmetry and therefore can exist in optically inactive form or in either of two enantiomeric (optically active) forms, i.e., the dextrorotatory and laveorotatory forms. As drawn, the formula for PG12 corresponds to that endogenously produced in the mammalian species. In particular, refer to the stereochernical configuration at C-8 (a), C-9 (a), C-1 1 (a) and C-1 2 (A) of endogenously produced prostacyclin. The mirror image of the above formula for prostacyclin represents the other enantiomer. 25 The racemic form of prostacyclin contains equal numbers of both enantiomeric molecules.
For convenience, reference to prostacyclin and carbacyclin will refer to the optically active form thereof. Thus, with reference to prostacyclin, reference is made to the form thereof with the same absolute configuration as that obtained from the mammalian species.
The term "prostacyclin-type" product, as used herein, refers to any cyclopentane derivative herein 30 which is useful for at least one of the same pharmacological purposes for which prostacyclin is employed. A formula as drawn herein which depicts a prostacyclin-type product or an intermediate useful in the preparation thereof, represents that particular stereolsomer of the prostacyclin-type product which is of the same relative stereochemical configuration as prostacyclin obtained from mammalian tissues or the particular stereolsomer of the intermediate which is useful in preparing the 35 above stereoisomer of the prostacyclin type product.
The term "prostacyclin analog" or "carbacyclin analog" represents that stereoisomer of a prostacyclin-type product which is of the same relative stereochernical 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 40 analog" or "carbacyclin analog" refers to the compound of that formula or a mixture comprising that compound and the enantiomer thereof.
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 4815413/26 and 4815513/26.
See also British published specifications 2,012,265 and German Offenl u ngssch rift 2,900,352, 45 abstracted as Derwent Farmdoc CPI Number 5482513/30. See also British published applications 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., 50 et al., J. Chem. Soc., Chemical Communications, 1067-1068 (1978); Sugie, A., et al., Tetrahedron Letters 2607-2610 0 979); Shibasaki, M., Chemistry Letters, 1299-1300 (1979), and Hayashi, M., Chem. Lett. 1437-40 (1979); and Li, Tsung-tee, "A Facile Synthesis of 9(0)-Methano-prostacyclin", Abstract No. 318, (Organic Chemistry), and P. A. Aristoff, "Synthesis of 6a-Carbaprostacyclin 12", 56 Abstract No. 236 (Organic Chemistry) both at Abstract of Papers (Part 11) Second Congress of the North 55 American Continent, San Francisco, California (Las Vegas, Nevada), USA, 24-29 August 1980.
7-Oxo and 7-hydroxy-CBA2 compounds are apparently disclosed in United States Patent 4,192,891. 19-Hydroxy-CBA2 compounds are disclosed in United States Serial No. 054,811, filed 5 July 1979. CBA2 aromatic esters are disclosed in United States Patent 4, 180,657. 11 -Deoxy-A10- or All-CBA2 compounds are described in Japanese Kokai 77/24,865, published 24 February 1979. 60 The present specification particularly provides:
(a) a carbacyclin intermediate of formula IV, V, VI, VII, Vill, or IX; and (b) a carbacyclin analog of formula X or XI; 2 GB 2 122 203 A 2 wherein g is 0, 1, 2, or 3; wherein n is one or 2; wherein L, is a-R:P-R - or a mixture of a-R:P-R and a-R:P-R wherein R and R are 3 41 a-RJ-R31 3 4 4 31 3 4 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 orfluoro; wherein M, is a-OH:P-R, or a- R5:P-OH, wherein R. is hydrogen or methyl; wherein WS a-0Rjo:P-R5 or a-RJ- OR,,, wherein R, is hydrogen or methyl and R,, is an acid hydrolyzable protective group; wherein R7'S (1) -C,,,H2m-CH3, wherein m is an integer from one to 5, inclusive (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (Cl-C3)alkyl, or (Cl-C3)alkoxy, with the proviso that not more than two substituents are other than alky], with the proviso that R, is phenoxy or substituted phenoxy, only when R, and R, are hydrogen or methyl, being the same or different, (3) phenyl, benzyi, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, 15 two or three chloro, fluoro, trif luoromethyl, (Cl-C3)alkyl, or (Cl-C, )alkoxy, with the proviso that not more than two substituents are other than alky], (4) cis CH=CH-CHi---CH3, (5) -(CH,)i--CH(OH)-CH,, or (6) -(CH2)--CH=C(CH3)2; wherein -C(L1)-R, taken together is (1) (C4--C,)cycloalkyl optionally substituted by one to 3 (Cl-C,) alkyl; (2) 2-(2-furyi)ethyi, (3) 2-(3-thienyi)ethoxy, or (4) 3-thienyloxymethyl; wherein R. is hydroxy, hydroxymethyl, or hydrogen; wherein R,. is hydrogen or fluoro; wherein R,. is hydrogen or R,. and R17 taken together are -CH2or R16 and R47 taken together form a second valence bond between C-6a and C-9 or are -CH2_; 30 wherein R17 is as defined above or is (1) hydrogen, or (2) (Cl-CJalkyl; wherein R,. is hydrogen, hydroxy, hydroxymethy], -OR,, or -CH20R10, wherein R,. is an acidhydrolyzable protective group; 35 wherein (1) R20, R21, R22, R2., and R24 are all hydrogen with R22 being either a- hydrogen or P-hydrogen, (2) R2. is hydrogen, R21 and R22 taken together form a second valence bond between C-9 and C- 6a, and R23 and R24 taken together form a second valence bond between C-8 and C-9 or are both hydrogen, or (3) R22, R23, and R24 are all hydrogen, with R22 being either a-hydrogen or P-hydrogen, and 40 (a) R2. and R21 taken together are oxo, or (b) R2. is hydrogen and R21 is hydroxy, being a-hydroxy or P-hydroxy; wherein R27 is the same as R7 except that -(CH2)2-CH(OH)-CH3 is -(CH2)CH(OR,,)-CH3; wherein R32 is hydrogen or R31. wherein R31 is a hydroxyl hydrogen replacing group; wherein R33 is-CHO or-CH20R32, wherein R32 is as defined above; wherein R47 is as defined above or is (1) (Cl-C4) alkyl, or (2) -CH20H; wherein Xl is (1) -COOR1, wherein Ri is (a) hydrogen, (b) (Cl-C12)alkyl, (c) (C3-Cjcycloalkyl, (d) (C7CJaralkyl, (e) phenyl, optionally substituted with one, 2 or 3 chloro or (Cl- C3)alkyl, (f) phenyl substituted in the para position by (i) -NI-I-CO-R2., (ii) -CO-R261 (iii) -O-CO-R.4, or 0v) -CH=N-NH-CO-NH2 wherein R25 is methyl, phenyl, acetamidophenyl, benzamidopheny], or -NH2; R 26'S methyl, phenyl, -NH2, or methoxy; and R,, is phenyl or acetamidophenyl; or (g) a pharmacologically acceptable cation:
(2) -CH20H, 3 GB 2 122 203 A 3 (3) -COL4, wherein L4'S (a) amino of the formula -NR,^,, wherein R,, and R,, are (i) hydrogen, 00 (Cl-C,,)alkyl, ("') (C3-Cjcycloalkyl, Ov) W,-CJaralkyl, (v) phenyl, optionally substituted with one, 2 or 3 chloro, (Cl-C3)alkyl, hydroxy, carboxy, (C2-C,)alkoxycarbonyl, or nitro, NO (C--C,)carboxyalkyl, (V") (C2-C,,)carbamoylalkyl, 10 (viii) (C2_Cdcyanoalkyl, Ox) (C--Qacetylalkyl, (x) (Cl--C,,)benzoalkyi, optionally substituted by one, 2 or 3 chloro, (Cl-C3)alkyl, hydroxy, (Cl-C3)alkoxy, carboxy, (CI-C,)alkoxycarbonyl, or nitro, 15- (xi) pyridyl, optionally substituted by one, 2 or 3 chloro, (C,- C3)alkyl, or (Cl-C3)alkoxy, 15 (xii) (C6-C,)pyridylalkyl optionally substituted by one, 2 or 3 chloro, (C,-C3)alkyl, hydroxy, or (Cl-C,)alkyl, (xiii) (Cl-C,)hydroxyalkyl, NO (Cl-C4)dihydroxyalkyl, (XV) (Cl-C4)trihydroxyalkyl, with the further proviso that not more than one of IR,, and R52 is other than hydrogen or alkyl, (b) cycloamino selected from the group consisting of pyrolidino, piperidino, morpholino, piperazine, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinyl optionally substituted by one or 2 (Cl-C12)alkyl of one to 12 carbon atoms, (c) carbonylamino of the formula -NRUCOR.1, wherein R23 is hydrogen or (Cl-C4)alkyl and R,, is 25 other than hydrogen, but otherwise as defined above, (d) sulfonylamino of the formula -NR53SO,R 511 wherein IR,, and R2, are as defined in (c), (4) -CH2NL2L,,wherein L2 and L3 are hydrogen or (Cl-C4) -alkyl, being the same or different, or the pharmacologically acceptable acid addition salts thereof when X, is - CH2NL2L3.
wherein Y1 is trans-CH=CH-, cis-CH=CH-, -CH2CH--, -C=-C-; wherein Z1 is (1) -CH,-(CH2)f-C(R2)2, wherein R, is hydrogen or fluoro and f is zero, one, 2 or 3, (2) trans-CH27-CH=CH-, (3) -(Ph)-(CH,),--, wherein (Ph) is 1,2-, 1,3-, or 1,4-phenylene and g is zero, one, 2 or 3; wherein Z4 is -CH,- or -(CH2V-CF21 wherein f is as defined above; with the overall proviso that (1) R15, IR,., and R17 are all hydrogen only when Z1 is -(Ph)-(CH2),--, and (2) Z1 is -(Ph)-(CH2)6- only when R15 is hydrogen.
With regard to the divalent substituents described above (e.g., L, and M, ), these divalent radicals are defined as a-Rl:P-Rj, wherein R, represents the substituent of the divalent moiety in the alpha 40 configuration with respect to the plane of the C-8 to CA 2 cyclopentane ring and Rj represents the substituent of the divalent moiety in the beta configuration with respect to the plane of the ring.
Accordingly, when M, is defined as a-OH:P-R,, the hydroxy of the M, moiety is in the alpha configuration, i.e., as in P92 above, and the R. substituent is in the beta configuration.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix 45 designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C,-C,) indicates a moiety of the integer 1---to the integer "j" carbon atoms, inclusive. Thus (Cl-C,) alkyl refers to alkyl of one to 3 carbon atoms, inclusive, or methyl, ethyl, propyl, and isopropyl.
Certain novel prostacyclin analogs herein, i.e., formula X compounds, are all named as CBA, or CBA2 compounds, respectively, by virtue of the substitution of methylene for oxa in the heterocyclic ring 50 of prostacyclin and the substitution. CBA2 Compounds are those exhibiting the olefinic double bond at C-5, 6, while CBA, compounds are those saturated at C-5, 6. Formula XI compounds are named as PGE, or PGF, derivatives as hereinafter described.
Novel compopunds wherein Z, is (Ph)-(CH2)g are designated inter-o-, interm-, or inter-p- phenylene depending on whether the attachement between C-5,6. Formula XI compounds are named as 55 meta, or para, respectively.
For those compounds wherein g is zero, one, 2 or 3, the carbacyclin analogs so described are further characterized as 2,3,4-trinor-, 3,4-dinor-, or 4-nor, since in this event the Xi-terminated side chain contains (not including the phenylene) 2, 3, or 4 carbon atoms, respectively, in place of the five carbon atoms contained in PGl2. The missing carbon atom or atoms are considered to be at the C-4 to 60 C-2 positions such that the phenylene is connected to the C-5 and C-1 to C-3 positions. Accordingly 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 -CH2-(CH2)f-CF2- are characterized as "2, 2-difluoro-" compounds. For those compounds wherein f is zero, 2, or 3, the carbacyclin analogs so described are 65 4 GB 2 122 203 A 4 further characterized as 2-nor, 2a-homo, or 2,a,2b-dihomo, since in this event the X,-terminated side chain contains 4, 6, or 7 carbon atoms, respectively, in place of the five carbon atoms contained in C13AT The missing carbon atom is considered to be at the C-2 position such that the C-1 carbon atom is connected to the C-3 position. The additional carbon atom or atoms are considered as though they were inserted between the C-2 and C-3 positions. Accordingly these additional carbon atoms are referred to as C-2a and C-2b, counting from the C-2 to the C-3 position.
Those CBA analogs wherein Z1 is trans-CH2-CH=CH- are described as -trans2,3-didehydroC13A- compounds.
Those novel compounds where n is 2 are further characterized as 7a-homoCBA compounds by virtue of the cyclohexyl ring replacing the heterocyclic ring of prostacyclin.
Further, the novel compounds are named as 9p-alkyl-CI3A compounds when R17 is alky].
When R,6 and R17 taken together are -CHAmethylene, the novel compounds so described are "6ap,9p-methano-CBA" compounds by virtue of the methylene bridge between C-6a and C-9.
When R,. is fluoro, "5-fluoro-CBA" compounds are described.
The formula Xl CBA analogs wherein R2W R21, R221 R23, and R24 are all hydrogen with R22 being P- 15 hydrogen are characterized as "9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor3, 7-(1',3'-inter-phenylene)PGFlcompounds. Corresponding compounds wherein R 22 is a-hydrogen are characterized as 'Sdeoxy-2',9p-methano-3-oxa-4,5,6trinor-3,7-(1',3'-inter-phenylene)-PGF," compounds. CBA analogs wherein R201 R23, and R24 are all hydrogen and %, and R22 taken together form a valence bond between C-9 and C-6a are characterized as "9-deoxo-2',9-metheno-3-oxo-3,4,5- trinor-3,7-(1',3-interphenylene)-PGFlcompounds. CBA analogs wherein R20 is hydrogen and R21 and R22 taken together form a second valence bond between C-9 and C-6a and R 2. and R24 taken together form a second valence bond between C-7 and C-8 are characterized as "9-deoxo-2',9metheno-3-oxa-3,4,5-trinor-3,7(1',3'-interphenylene)-7,8-didehydro-PGE, 11 compounds. The formula Xl CBA analogs wherein R22, R23, and R24 are all hydrogen and R2. and R21 taken together are oxo are characterized as "6a-oxo-9-deoxy-2',9a- 25 methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene-PGF ill or "6a-oxo9-deoxy-2',9p-methano-3- oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF ill depending on whether R22 is a-hydrogen or P hydrogen, respectively. Formula X] CBA analogs wherein FI 2W R22.1123.ind f124 are all hydrogen and R21 'S a-hydroxy are characterized as "6aa-hydroxy-9-deoxy-2',9a-methano-3-oxa-4, 5,6-trinor-3,7-(1',3inter-phenylene)-PGF," or "6aa-hydroxy-9-deoxy-2,9p-methano-3-oxa-4,5,6trinor-3,7-(1',3-inter- phenylene)-PGF 111 compounds depending on whether R22 is a-hydrogen or P- hydrogen, respectively.
Finally,, formula Xl TXA analogs wherein R20, R22, R23, and R24 are all hydrogen and R21 is P-hydroxy are characterized as "6ap-hydroxy-9-deoxy-2',9p-methano-3-oxa-4,5,6-trinor-3, 7-(1',3'-inter-pheny iene)- PGFl or"6ap-hydroxy-9-deoxy-2,9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3interphenyi ene)-PGF compounds depending on whether R22 is a-hydrogen or P-hydrogen, respectively. When Z, is -(CH2)f-CF2 and f is zero, the formula Xl CBA analogs are additionally characterized as "2,2-difluoro" compounds. When f is one, 2, or 3, such compounds are additionally characterized as "2a- homo", "2a,2b-dihomo" or "2a,2b,2c-trihomo" compounds.
When R5'S methyl, the carbacyclin analogs are all named as 'I 5-methylCI3A- compounds.
Further, except for compounds wherein Y1 is cis-CH=CH-, compounds wherein the M1 moiety contains 40 an hydroxyl in the beta configuration are additionally named as 'I 5-epi- CBA" compounds.
For the compounds wherein Y1 is cis-CH=CH-, then compounds wherein the M1 moiety contai ' ns an hydroxyl in the alpha configuration are named as---1 5-epi-CBA" compounds. For a description of this convention of nomenclature for identifying C-1 5 epimers, see U.S. Patent 4,016,184, issued 5 April 1977, particularly columns 24-27 thereof.
The novel carbacyclin analogs herein which contain -(CH2)i---, cis-CH=CH-, or -C=-C- as the Y1 moiety, are accordingly referred to as '13, 14-dihydro", "cis-1 Y', or---1 3,14-didehydro" compounds, respectively.
When R7 is straight chained -C H2,,i-CH,, wherein m is as defined above, the compounds so described are named as "19,20-dinor",---20-nor", "20-methyi" or "20- ethyi" compounds when m is 50 one, 2, 4 or 5, respectively. When R7 is branched chain -CnH2m-CH3, then the compounds so described are '17-, 18-,19-, or 20-alkyl" or '17,17-, 17,18-,-17,19-, 17, 20-, 18,18-, 18,19-, 18,20-, 19,19-, or 19,20-dialkyl- compounds when m is 4 or 5 and the unbranched portion of the chain is at least n-buty], e.g., 17,20-dimethyi" compounds are described when m is 5 (1 -methyl pentyl).
When R7 is phenyl and neither R 3 nor R4 is methyl, the compounds so described are named as '16- 55 phenyl-1 7,18,1 9,20-tetra nor" compounds. When R7 is substituted phenyl, the corresponding compounds are named as 'I 6-(substituted phenyi)-1 7,18,1 9,20-tetra nor- compounds. When one and only one of R3 and R4 is methyl or both R3 and R4 are methyl, then the corresponding compounds wherein R7 is as defined in this paragraph are named as " 1 6-phenyl or 1 6-(substituted phenyl) 18,1 9,20-trinor" compounds or" 1 6-methyl- 1 6-pheny]- or 1 6- (substituted phenyl)- 18,1 9,20-trinor" 60 compounds respectively.
When R7 is benzy], the compounds so described are named as 'I 7-phenyM 8, 19,20-trino' compounds. When R7 is substituted benzyi, the corresponding compounds are named as ', 17 (substituted phenyl)-1 8,1 9,20-trinor" compounds.
When R7 is phenylethyl, the compounds so described are named as 'I 8phenyM 9,20-dinor" 65 GB 2 122 203 A, 5 compounds. When R7 is substituted phenylethyl, the corresponding compounds are named as---18 (substituted phenyl)-1 9,20-dinor- compounds.
When R7 is phenylpropyl, the compounds so described are named as 'I 9phenyl-20-nor" compounds. When R7 is substituted phenyipropyl the corresponding compounds are named as---1 g (substituted phenyl)-20-nor" compounds.
When R7 is phenoxy and neither R3 nor R4 is methyl, the compounds so described are named as ---1 6-phenoxy-l 7,18,19,20-tetranor" compounds. When R7 is substituted phenoxy, the corresponding compounds are named as 'I 6-(substituted phenoxy)-1 7,18,1 9,20-tetra nor- 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---1 6-phenoxy or 16-(substituted phenoxy)- 10 18,19,20-trinor" compounds or---1 6-methyl-1 6-phenoxy- or 16- (substituted phenoxy)l 8,19,20-trinor compounds, respectively.
When R7 is cis-CH=CH-CH2CH, the compounds so described are named as "cis1 7,18 didehydro" compounds.
When R7 is -(CH2)2-CH(OH)-CH,, the compounds so described are named as 'I 9-hydroxy- 15 compounds.
When R7 is -(CH2)j--CH=C(CHI)2, the compounds so described are named as '20 isopropylidene- compounds.
When -C(W-R7 is optionally substituted cycloalkyl, 2-(2furyl)-ethyl, 2 -Qth ienyi) ethyl, or 3 thienyloxymethyl, the compounds so described are respectively 15- cycloalky]-1 6,17,18,19,20- 20 pentanor compounds, 17-(2-furyi)-1 8,19,20-trinor-CBA compounds, 17-(3- thienyi)-1 8,19,20-trinor compounds, or 16-(3-thienyi)oxy-1 7,18,1 9,20-tetranor compounds.
When at least one of R. and R4 is not hydrogen then (except for the 16phenoxy or 1 6-phenyl compounds discussed above) there are described the---1 6-methyl- (one and only one of R. and R4'S methyl),---1 6,16-dimethyi" (R. and R4 are both methyl),---1 6-fluoro" (R. or R4 isfluoro), 'I 6,16-difluoro- 25 (R3 and R4 are both fluoro) compounds. For those compounds wherein R3 and R4 are different, the prostaglandin analogs so represented contain an asymmetric carbon atom at CA 6. Accordingly, two epimeric configurations are possible: "(1 6S)" and "(1 6R)". Further, there is described by this invention the CA 6 epimeric mixture: -(1 6RS)".
When X1 is -CH20H, the compounds so described are named as "2-decarboxy-2hydroxymethyi" 30 compounds.
When X1 is -CH2NL2L,, the compounds so described are named as "2decarboxy-2 aminomethyi" or "2-(substituted amino)methyi" compounds.
When X1 is -COL4, the novel compounds herein are named as CBA-type amides. Further, when X, is-COOR1, the novel compounds herein are named as CBA-type esters and CBA-type salts. 35 Examples of phenyl esters substituted in the para position (i.e., X, is - COOR, R, is p-substituted phenyl) include p-acetamidophenyl ester, p-benzamidophenyl ester, p-(pacetamidobenza mido) phenyl ester, p-(p-benzamidobenzamido)phenyl ester, p-amidocarbonylaminophenyl ester, p-acetylphenyl ester, p-benzylphenyl ester, p-amidocarbonylphenyl ester, p- methoxycarbonylphenyl ester, p benzoyloxyphenyl ester, p-(p-aceta m idobenzoyloxy) phenyl ester, and phydroxybenzaidehyde 40 semicarbazone ester.
Examples of novel amides herein (i.e., X, is -COL,)Include the following:
(1) Amides within the scope of alkylamino groups of the formula-NR,1R,2 are methylamide, ethylamide, n-propylamide, n-butylamide, n-pentylamide, n-hexylamide, n- heptylamide, n-octylamide, n-nonylamide, n-decylamide, n-undecylamide, and n-dodecylamide, and isomeric forms thereof. Further 45 examples are dimethylamide, diethylamide, di-n-propylamide, di-nbutylamide, methylethylamide, methyl propyla mide, methyl butyla mide, ethyl propyla m ide, ethyl butyla mide, and propylbutylamide.
Amides within the scope of cycloalkylamino are cyclopropylamide, cyclobutylamide, cyclopentylamide, 2,3-dimethylcyclopentylamide, 2,3-dimethylcyclopentylamide, 2- methylcyclopentylamide, 3-tert butylcyclopentyl amide, cyclohexylamide, 4-tert-butylcyclohexylamide, 3isopropylcyclohexylamide, 50 2,2-di methyl cyclohexyl am ide, cycloheptylamide, cyclooctylamide, cyclononylamide, cyclodecylamide, N-methyl-N-cyclobutylamide, N-methyl-N-eyclopentylamide, N-methy]-Ncyclohexylamide, Wethyl-N cyclopentylamide, and N-ethyi-N-cyclohexylamide. Amides within the scope of aralkylamino are benzylamide, 2-phenylethylamide, and N-methy]-N benzyi-amide. Amides within the scope of substituted phenylamide are p-chloroanilide, m-chloroanilide, 2,4dichloroanilide, 2,4,6-trichloroanilide, 55 m-nitroanilide, p-nitroanilide, p-methoxyanilide, 3,4-dimethoxyanilide, 3, 4,5-trimethoxyanilide, p hydroxymethylanilide, p-methylanilide, m-methyl anilide, p-ethylanilide, p-carboxyanilide, p methoxycarbonyl anilide, p-carboxyanalide and o-hydroxyanilide. Amides within the scope of carboxyalkylamino are carboxyethylamide, carboxypropylamide and carboxymethylamide, arboxybutylamide. Amides within the scope of carbamoylalkylamino are carbamoyimethylamide, 60 carbamoylethylamide, carbamoylpropylamide, and carbamoylbutylamide. Amides within the scope of cyanoalkylamino are cyanomethylamide, cyanoethylamide, cyanopropylamide, and cyanobutylamide.
Amides within the scope of acetylalkylamino are acetyimethylamide, acetylethylamide, acetylpropylamide, and acetylbutylamide. Amides within the scope of benzoylalkylamino are benzoyimethylamide, benzoylethylamide, benzoylpropylamide, and benzoylbutylamide. Amides within 65 6 GB 2 122 203 A the scope of substituted benzoylalkylamino are p-chlorobenzoyimethylamide, mchlorobenzoyimethylamide, 2,4-dich lorobenzoyl methyl am ide, 2,4,6- trichlorobenzoyimethylamide, mnitrobenzoyimethylamide, p- nitrobenzoyimethylamide, p-m ethoxybenzoyl methyl am ide, 2,4-dimethoxy benzoyimethylamide, 3,4,5-trimethoxybenzoyimethylamide, p- hydroxymethyibenzoyimethylamide, pmethyl benzoyl methyla mide, m- metthyibenzoyimethylamide, p-ethyibenzoylmethylamide, pcarboxybenzoyimethylamide, m-methoxycarbonyibenzoyimethylamide, o- carboxybenzoyimethylamide, o-hydroxybenzoyimethylamide, p- chlorobenzoylethylamide, m-chlorobenzoylethylamide, 2, 4dichlorobenzoylethylamide, 2,4,6-trichlorobenzoylethylamide, m- nitrobenzoylethylamide, pnitrobenzoylethylamide, p- methoxybenzoylethylamide, p-methoxybenzoylethylamide, 2,4- d imethoxybenzoyl ethyl am ide, 3,4-5-trim ethoxybenzoylethyla mid e, p- hydroxymethyl- benzoylethylamide, p-methyibenzoylethylamide, m-m ethyl benzoylethyla m ide, p ethyibenzoylethylamide, p-carboxybenzoylethylamide, mmethoxycarbonyibenzoylethylamide, o carboxybenzoylethylamide, o-hydroxybenzoylethylamide, p- chlorobenzoylpropylamide, m chlorobenzoylpropylamide, 2,4-dichlorobenzoylpropylamide, 2,4,6trichiorobenzoylpropylamide, m nitrobenzoylpropylamide, p-nitrobenzoylpropylamide, p- methoxybenzoylpropylamide, 2,4 dimethoxybenzoylpropylamide, 3,4,5-trimethoxybenzoylpropylamide, phydroxymethyl benzoylpropylamide, p-methyibenzoylpropylamide, mmethylbenzoylpropylamide, p ethyibenzoylpropylamide, p-carboxybenzoylpropylamide, m- methoxycarbonyibenzoylpropylamide, o carboxybenzoylpropylamide, o-hydroxybenzoylpropylamide, pchlorobenzoyibutylamide, m-chloro benzoylbutylamide, 2,4-dichlorobenzoylbutylamide, 2,4,6-trich lorobenzoyl butyla mid e, m-nitrobenzoyl- 20 methylamide, p-nitrobenzoyibutylamide, p-methoxybenzoylbutylamide, 2,4- dimethoxybenzoyibuty] amide, 3,4,5-trimethoxybenzoyibutylamide, p-hydroxymethyibenzoyibutyi- amide, p-rnethylbenzoyl butyamide, m-methyibenzoyibutylamide, p-ethyi-benzoyibutylamide, m- methyibenzoyibutylamide, p ethyibenzoyibutyi-amide, p-carboxybenzoyibutylamide, mmethoxycarbonyibenzoyibutylamide, o- ca rboxybenzoylbutyla m ide, o-hydroxybenzoyl methyla m ide. Am ides with in the scope of pyridylamino are a-pyridylamide, P-pyridylamide, and -p-pyridylamide. Amides within the scope of the substituted pyridylamino are 4-methyi-apyridylamide, 4-methyi-p-pyridylamide, 4- chloro-a-pyridylamide, and 4 chloro-p-pyridylamide. Amides within the scope of pyridylalkylamino are a- pyridyl methyl am ide, P pyridyimethylamide, y-pyridyl methyl am ide, a-pyridylethylamide, P- pyridylethylamide, - pyridylethylamide, a-pyridylpropylamide, P-pyridylpropylamide, Y- pyridylpropylamide, a pyridyibutylamide, P-pyridylbutylamide, and y-pyridyibutylamide. Amides within the scope of substituted pyridylalkylamido are 4-methyi-a-pyridyimethylamide, 4-methyi- p-pyridyimethylamide, 4-chloro-a-pyridyimethylamide, 4-chloro-p-pyridyimethylamide, 4-methyi-apyridylpropylamide, 4 methyl-P-pyridylpropylamide, 4-chloro-a-pyridylpropylamide, 4-chloro-p- pyridylpropylamide, 4-methyl a-pyridyibutylamide, 4-methyi-p-pyridyibutylamide, 4-chloro-apyridyibutylamide, 4-chloro-p pyridylbutylamide, 4-chloro-y-pyridyibutyi-amide. Amides within the scope of hydroxyalkylamino are hydroxym ethyl am ide, P-hydroxyethylamide, P-hydroxypropylamide, P- hydroxypropyjamide, 1 - (hydroxym ethyl) ethyl-a mide, 1 -(hydroxym ethyl) propyla m ide, (2- hydroxymethyl)propylamide, and a,a dimethyi-hydroxyethylamide. Amides within the scope ofdihydroxyalkylamino are ' dihydroxymethylamide, P,,p-dihydroxypropylamide, 1 -(hydroxymethyi)2- hydroxymethylamide, P,y dihydroxybutylamide, P,S-dihydroxybutyl-amide, p,S-dihydroxybutylamide, and 1, 1 - bis(hydroxym ethyl) ethyl am ide. Amides within the scope of trihydroxyalkylamino are tris(hydroxy methyl) methyl amid e and 1,3-dihydroxy-2-hydroxymethylpropylamide.
(2) Amides within the scope of cycloamino groups described above are pyrrolidylamide, piperidylamide, morpholinylamide, hexamethyleneiminylamide, pipe razinyla mide, pyrrolinylamide, and 45 3,4-didehydropiperidinylamide.
(3) Amides within the scope of carbonylamino of the formula -NR53COR.1 are methylcarbonylamide, ethylcarbonylamide, phenylcarbonylamide, and benzylcarbonylamide.
(4) Amides within the scope of suifonylamino of the formula -NR,3SO2R5, are methyisuifonylamide, ethyisufonylamide, phenyisuifonylamide, ptolyisuifonylamide, benzyisuifonylamide.
Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyi, heptyl, octyl, nonyl, decyl, undecyl, dodecy], isomeric forms thereof.
Examples of (C3--Cjcycloalkyl which includes alkyl-substituted cycloalkyl, are cyclopropyl, 2- methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2- butyicyclopropy], cyclobutyl, 2methylcyclobutyl, 3-propylcyclobuty], 2,3,4triethylcyclobutyi, cyclopentyl, 2,2-dimethylcyclopentyl, 2 pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl, 4-tert- butylcyclohexy], 3-isopropylcyclohexyl, 2,2-di methyl cycl ohexyi, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.
Examples of (C7-C12)aralkyl are benzyi, 2-phenylethyl, 1 -phenylethyl, 2phenylpropyl, 4 phenyibuty], 3-phenylbutyl, 2-(1 -na phthyl ethyl), and 1 -(2-naphthyl methyl).
Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, are p-chloropheny], m-chlorophenyl, 2,4-dichloropheny], 2,4,6-trichlorophenyi, p-tolyl, m-tolyl, o-tolyl, p ethylphenyl, p-tert-butylphenyl, 2,5-di methyl p he nyi, 4-chloro-2methyl phenyl, and 2,4-dichloro-3 methylphenyl.
Examples of (C4-C7)cycloalkyl optionally substituted by (Cl-C,_alkyl are cyclobutyl, 1 - 0 0 7 GB 2 122 203 A propylcyclobutyl, 1 -butylcyclobutyl, 1 -pentylcyclobutyl, 2- methylcyclobutyl, 2-propylcyclobutyl, 3ethyl cyclobutyL 3- propylcyclobutyl, 2,3,4-triethyleyclobutyi, cyclopentyl, 2,2-di methyl cyclopentyl, 3ethylcyclopentyl, 3-propylcyclopentyl, 3-butylcyclopentyl, 3-tert-butylcyclopentyl, 1 -methyl-3propylcyclopentyl, 2-methyl-3- propylcyclopentyl, 2-methy]-4-propyleyclopentyi, cyclohexyl, 3- ethylcyclohexyl, 3-isopropylcyclohexyl, 4-methylcyclohexyl, 4ethylcyclohexyl, 4-propylcyclohexy], 4 butylcyclohexyl, 4tertbutyleyclohexyi, 2,6-dimethylcyclohexyi, 2,2-dimethylcyclohexy], 2,6dimethyi-4propylcyclohexyl, and cycloheptyl.
Examples of substituted phenoxy, phenyimethyi, phenylethy], or phenylpropyl of the R7 moiety are (o-, m-, or p-)tolyl, (o-, m-, or p)ethylphenyi, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m, or p+ propylphenyi,2-propyi-(m-orp-)toiyi,4isopropyi-2,6-xyiyi,3-propyi-4ethylph enyi,(2,3,4-,2,3,5-, 10 2,3,6-, or 2,4,5-)tri methyl phenyl, (o-, m-, or p-Muorophenyl, 2-fluoro- (m- or p-)tolyl, 4-fluoro-2,5-xylyi, (2,4-, 2,5-, 2,6, 3,4-, or 3,5- )difluorophenyi, (o-, m-, or p-)chlorophenyl, 2-chloro-p-tolyl, (3-, 4-, 5-, or 6-)chloro-o-toly], 4-ch lo ro-2 -propyl phenyl, 2-isopropy]-4- chlorophenyi, 4-chloro-3,5-xyiyi, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5- )dichloropheny], 4-chloro-3-fluorophenyi (3- or 4-)chloro-2-fluorophenyi, (o-, m-, orp-(trifiuoromethylphenyi,(o-,m-,orp-)methoxyphenyi,(o-,m-,orp)ethoxypheny i,(4-or5-)chloro- 15 2-methoxyphenyl, 2,4-dichloro-(4- or 6-)methylpheny], (o-, m-, or p- )tolyloxy, (o-, m-, or p+ ethylphenyloxy, 4-ethyi-o-tolyloxy, 5-ethyi-m-tolyloxy, (o-, m-, or p- )propylphenoxy, 2-prooyi-(m- or p+ tolyloxy, 4-isopropyf-2,6-xylyloxy, 3-propy]-4-ethylphenyloxy, (2,3,4-, 2, 3,5-, 2,3,6-, or 2,4,5+ trimethylphenoxy, (o-, m-, or p-)fluorophenoxy, 2-fluoro-(m- or p)tolyloxy, 4-fluoro-2,5-xylyfoxy, (2,4-, 2,5-,2,6-,3,4-,or3,5-)difiuorophenoxy,(o-,m-,orp-)-chiorophenoxy,2-chlorop-t olyloxy,(3,4,'5,org-) 20 chloro-o-tolyloxy, 4-chloro-2-propylphenoxy, 2-isopropyi-4-chlorophenoxy, 4-chloro-3,5-xylyloxy, (2,3-, 2,4-,2,5-, 2,6-, 3,4-, or 3,5-)dichlorophenyloxy, 4-chloro-3- fluorophenoxy, (3- or 4-)chloro-2 fluorophenoxy, (o-, m-, or p-)trifiuoromethylphenoxy, (o-, m-, or p- )methoxyphenoxy, (o-, m-, or p-) ethoxyphenoxy, (4- or 5-)chloro-2-methoxyphenoxy, 2,4-dichloro-(5- or 6- )methylphenoxy, (o-, m- or p-)tolyimethyi, (o-, m-, or p-)ethylphenyl methyl, 4-ethyl-o-tolyl methyl, 5-ethyl-m-tolyl m ethyl, (o-, m-, 25 or p-)propyl phenyl methyl, 2- propy]-(m- or p-)tolyimethyi, 4-isopropy]-2,6-xylyl methyl, 3-propyl4ethyl phenyl methyl, (2,3,4-, 2,3,5-, 2,3,6-, or 2,4,5+tri methylphenyl m ethyl, (0-, m-, or.p-) fl uorophenyl m ethyl, 2-fluoro-(m- or p)tolyimethyi, 441 uoro-2,5-xylyl methyl, (2,4-, 2,5-, 2,6-, 3,4-, or 3,5)difluorophenyi, (o-, m-, or p-)chlorophenyl methyl, 2-ch loro-p-to lyl m ethyl, (3, 4, 5, or 6-)chloro-o- tolyimethyi, 4-chloro-2-propyiphenyl methyl, 2-isopropyi-4-chlorophenyl methyl, 4-chloro-3,5xylyimethyi, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-, or 3,5-) dich lorop henyl methyl, 4-chloro-3-fluorophenyl methyl, Q- or 4-)chioro- 2-fi uorophenyl methyl, (o-, m- or p-)trifi uoromethylphenyl methyl, (o-, m- or p+ m ethoxyphe nyl methyl, (o-, m- or p-)ethoxyphenyl methyl, and (4- or 5-)chloro-2-methoxyphenyl methyl.
The novel CBA analogs disclosed herein produce certain prostacyclin-like pharmacological responses.
Accordingly, the novel formula X and XI CBA analogs are used as agents in the study, prevention, control, and treatment of diseases, and other undesirable physiological conditions, in mammals, particularly humans, valuable domestic animals, pets, zoological specimens, and laboratory animals (e.g., mice, rats, rabbits and monkeys). In particular, these compounds have useful application as antithrombotic agents, anti-ulcer agents, and anti-asthma agents, as indicated below.
(a) Platelet Aggregation Inhibition These novel CBA analogs disclosed herein are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, or to remove or prevent the formation of thrombi in mammals, including man. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of 45 vascular grafts following surgery, to treat peripheral vascular diseases, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to lipernia, and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipiclimia. Other in vivo applications include geriatric patients to prevent cerebral ischemic attacks and long term prophylaxis following myocardial infarcts and strokes. For these purposes, these compounds are administered systemically, e.g., intravenously, subcutaneously, intramuscularly, and in the form of sterile implants for prolonged action. For rapid response, especially in emergency situations, the intravenous route of administration is preferred. Doses of from 0.01 to 10 mg per kg of body weight per day are used, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.
The preferred dosage form for these compounds is oral, although other nonparenteral routes (e.g., buccal, rectal, sublingual) are likewise employed in preference to parenteral routes. Oral dosage forms are conventionally formulated (tablets, capsules) and administered 2-4 times daily. Doses in the range of about 0.05 to 100 mg per kg of body weight per day are effective.
The addition of these compounds to whole blood provides in vitro applications such as storage of 60 whole blood to be used in heart-lung machines. Additionally whole blood containing these compounds can be circulated through organs, e.g., heart and kidneys, which have been removed from a donor prior to transplant. They are also useful in preparing platelet rich concentrates for use in treating thrombocytopenia, chemotherapy, and radiation therapy. In vitro applications utilize a dose of 8 GB 2 122 203 A 8 0.001-1.0,ug per ml of whole blood. For treatment of peripheral vascular diseases, see U.S. Patent 4,103,026.
(b) Gastric Secretion Reduction These novel CBA analogs disclosed herein are also useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control gastric secretion, thereby to reduce or avoid 5 gastrointestinal ulcer formation, and accelerate the healing of such ulcers already present in the gastrointestinal tract. For this purpose, these compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range of from 0. 1 to 20 y-g per kg of body weight per minute, or in a total daily dose by injection or infusion in the range of from 0.01 to 10 mg per kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or 10 animal, and on the frequency and route of aministration.
Preferably, however, these novel compounds are administered orally or by other non-parenteral routes. As employed orally, one to 6 administrations daily in a dosage range of from 1.0 to 100 mg per kg of body weight per day is employed. Once healing of the ulcers has been accomplished the maintenance dosage required to prevent recurrence is adjusted downward so long as the patient or 15 animals remains asymptomatic.
M NOSAC-Induced Lesion Inhibition These novel CBA analogs disclosed herein are also useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti- inflammatory prostaglandin synthetase inhibitors, and are useful for that purpose by concomitant administration of the prostaglandin derivative and the anti-inflammatory prostaglandin synthetase inhibitor. See Partridge et al., U.S. Patent No. 3,781,429, for a disclosure that the ulcerogenic effect induced by certain non steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins. Accordingly these novel CBA analogs herein are useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in Partridge, et al. as non steroidal, anti-inflammatory agents. These are also known to be prostaglandin synthetase inhibitors.
The anti-inflammatory synthetase inhibitor, for example, indomethacin, aspirin, or phenylbutazone is administered in any of the ways known in the art to alleviate an inflammatory conditions, for example, in any dosage regimen and by any of the known routes of systemic administration.
(d) Bronchodilation (Anti-asthma) These novel analogs disclosed herein are also useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediator-induced bronchoconstriction, such as SRS-A, and histamine which are released from cells activated by an antigen-antibody complex. Thus, these compounds control spasm and facilitate breathing in conditions 5 such as bronchial bronchitis, bronchiectasis, pneumonia and emphysema. For these purposes, these compounds are administered in a variety of dosage forms, e.g., orally in the form of tablets, capsules or liquids; rectally in the form of suppositories, parenterally, subcutaneously or intramuscularly, with intravenous administration being preferred in emergency situations; by inhalation in the form of aerosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of from 40 0.01 to 5 mg per kg of body weight are used 1 to 4 times a day, the exact dose depending on the age, weight, and condition of the patient and on the frequency and route of administration. For the above use these CBA analogs can be combined advantageously with other anti- asthmatic agents, such as sympathornimetics (isoproterenol, phenylephrine, ephedrine); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ACTH and prednisolone).
These compounds are effectively administered to human asthma patients by oral inhalation or by aerosol inhalation. For administration by the oral inhalation route with conventional nebulizers or by oxygen aerosolization it is convenient to provide the instant active ingredient in dilute solution, preferably at concentrations of about one part of medicament to from 100 to 200 parts by weight of total solution. Entirely conventional additives may be employed to stabilize these solutions or to provide 50 isotonic media, for example, sodium chloride, sodium citrate, citric acid or sodium bisulfite can be employed. For administration as a self-propelled dosage unit for administering the active ingredient in aerosol form suitable for inhalation therapy the composition can comprise the active ingredient suspended in an inert propellant (such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane) together with a co-solvent, such as ethanol, flavoring materials and 55 stabilizers. Suitable means to employ the aerosol inhalation therapy technique are described fully in United States Patent 3,868,69 1, for example.
When X1 is -COOR1. the novel CBA analogs so described are used for the purposes described above in the free acid form, in ester form, or in pharmacologically acceptable salt form. When the ester form is used, the ester is any of those within the above definition of R, However, it is preferred that the 60 ester be alkyl of one to 12 carbon atoms, inclusive. Of the alkyl esters, methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system; and straight-chain octyl, nonyl, decyl, undecyl, and dodecyl are especially preferred for prolonged activity.
Pharmacologically acceptable salts of the novel prostaglandin analogs of this invention for the purposes described above are those with pharmacologically acceptable metal cations, ammonia, amine 65 9 GB 2 122 203 A 9 cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminium, zinc, and iron are within the scope of this invention.
Pharmacologically acceptable amine cations are those derived from primary, secondary, and tertiary amines. Examples of suitable amines are methylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine, triisopropyla mine, N-methylhexylamine, decylamine, dodecyclamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, a phenylethyl a mine, A-phenylethyla mine, ethylenediamine, diethylenetriamine, adamantylamine, and the like aliphatic, cycloaliphatic, araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperldine, rnorpholine, pyrrolidine, piperazine, and lower-alkyl derivatives thereto, e.g., 1 -m ethyl pipe ridine, 4- ethylmorpholine, 1 -isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and as well as amines containing water solubilizing or hydrophilic groups, e.g., mono, di-, and triethanola mine, ethyldiethanolamine, N-butylethanolamine, 2-amino-1 -butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1 15 propanol, tris-(hydroxymethyl) aminomethane, N-phenylethanola mine, N-(p- tert-amylphenyl) diethanolamine, galactamine, N-methylglyca mine, N-methylglucosa mine, ephedrine, phenylephrine, epinephrine and procaine. Further useful amine salts are of the basic amino acids, e.g. lysine and arginine.
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzy1trimethylammonium and phenyltriethylammonium.
When X1 is -CH2NL2L., the novel CBA analogs so described are used for the purposes described in either free base or pharmacologically acceptable acid addition salt form.
The acid addition salts of the 2-deca rboxy-2-a m I no m ethyl- or 2(substituted aminomethyl)-CBA analogs provided by this invention are the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, cyclohexanesulfa mates, methanesulfonates, ethanesulfonates, benzenesulfonates and toluenesulfonates, prepared by reacting the CBA analog with the stoichiometric amount of the acid corresponding to the pharmacologically acceptable acid addition salt.
To obtain the optimum combination of biological response specificity, potency, and duration of acitivity, certain compounds within the scope of this invention are preferred.
It is preferred that in Xi-terminated side chain for inter-p-phenyleneCBA compounds, g be zero, for inter-m-phenylene-CBA compounds g be zero or one (especially zero), and for inter-o-phenylene CBA compounds g be zero, one, or 2 (especially one). Inter-o- and inter-m-phenylene-CBA compounds, especially inter-m-phenylene-CBA compounds are preferred. Moreover when Z, is -CH--(CH,)F-C(R,),,f is preferably one and R, is preferably hydrogen. When R,'S (Cl-Cd-alkyl, 35 R17 is preferably methyl. Further, when the C- 1 2 side chain contains -CmH2rn-CH3, it is preferred that rn be 3, 4, or 5, most preferably 3. When m is 5, more straight chain isomeric forms are preferred, especially methyl-substituted butyl. Further, it is preferred that, when R7 is aromatic, R7 be phenoxy,. phenyl, or benzyl, including substituted forms thereof. For those compounds wherein R7 is substituted phenoxy or phenylalkyl, it is preferred there be only one or 2 substituents selected from the group consisting of chloro, fluoro, or trifluoromethyl. Further, for those compounds wherein R7 is aromatic, it is preferred that R. and R4 both be hydrogen. Most especially preferred to biological potency are formula X CBA2 analogs exhibiting the same C5 isomeric configuration as CBA2 itself. 45 Especially preferred are those compounds which satisfy two or more of the above preferences. 45 Further, the above preferences are expressly intended to describe the preferred compounds within the scope of any generic formula of novel CBA analogs disclosed herein. Those protective groups within the scope R10 are any group which replaces a hydroxy hydrogen and is neither attacked by nor is reactive to the reagents used in the transformations used herein as a hydroxy is and which is subsequently replaceable by acid hydrolysis with hydrogen in the preparation of 50 the prostaglandin-type compounds. Several such protective groups are known in the art, e.g., tetra hyd ropyra nyl and substituted tetra hyd ropyra nyl. See for reference E.J. Corey, Proceedings of the Robert A. Welch Foundation Conferences on Chemical Research, XIII Organic Synthesis, pgs. 51-79 (1969). Those blocking groups which have been found useful include:
(a) tetra hydropyra nyl; (b) tetrahydrofuranyl; (c) a group of the formula -C(ORjj)(R12)-CH(RJ(Rj,), wherein Rj, is alkyl of one to 18 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 12 carbon atoms, phenyl or phenyl substituted with one to 3 alkyl of one to 4 carbon atoms, wherein R12 and Rj, are alkyl of one to 4 carbon atoms, phenyl, phenyl substituted with one, 2 or 3 alkyl of one to 4 carbon atoms, or when R12 and R,3 are 60 taken together -(CH2),,- or when R12 and R13 are taken together -(CH2)6-- O-(CH2)cl wherein a is 3, 4, or 5 and b is one, 2, or 3, and c is one, 2, or 3, with the proviso that b plus c is 2, 3 or 4, with the further proviso that R12 and R,3 may be the same or different, and wherein RU is hydrogen or phenyl; and (d) silyl groups according to R2 as qualified hereinafter.
GB 2 122 203 A 10 When the protective group R10 is tetra hyd ropyra nyl, the tetrahydropyranyl ether derivative of any hydroxy moieties of the CBAtype intermediates herein is obtained by reaction of the hydroxycontaining compound with 2,3-dihydropyran in an inert solvent, e.g. , dichloromethane, in the presence of an acid condensing agent such as ptoluenesulfonic acid or pyridine hydrochloride. The dihydropyran is used in large stoichiometric excess, preferably 4 to 100 times the stoichiometric amount. The reaction is normally complete in less than an hour at 20-501C.
When the protective group is tetra hyd rofu ra nyl, 2,3-dihydrofuran is used, as described in the preceding paragraph, in place of the 2,3dihydropyran.
When the protective group is of the formula -C(OR11)(R12)-CH(RJ(R14). wherein R,1, R12, R13, and R14 are as defined above, a vinyl ether or an unsaturated cyclic or heterocyclic compound, e.g., 1 - 10 cyclohexen-1 -yI methyl ether or 5,6-dihydro-4-methoxy-2H-pyran, is employed. See C.B. Reese et aL, J. American Chemical Society 89, 3366 (1967). The reaction conditions for such vinyl ethers and unsaturated compounds are similar to those for dihydropyran above.
R2. is a silyl protective group of the formula -Si(G 16 In some cases, such silylations are general, in that they silylate all hydroxyls of a molecule, while in other cases they are selective, in that while one 15 or more hydroxyls are silylated, at least one other hydroxyl remains unaffected. For any of these silylations, silyl groups within the scope of -Si(Gl)3 include trimethylsilyl, dimethylphenylsilyl, triphenylsilyl, t-butyldimethylsilyl and methylphenylbenzylsilyl. With regard to G1, examples of alkyl are methyl, ethyl, propyl, isobutyl, butyl, sec-butyl, tert-butyl and pentyl. Examples of aralkyl are benzyl, phenethyl, a-phenylethyl, 3-phenylpropyl, a-naphthy[methyl, and 2 (a-n a phthyl) ethyl. Examples of phenyl substituted with halo or alkyl are p-chlorophenyl, m-fluorophenyl, o-tolyl, 2,4-dichlorophenyl, p tert-butylphenyl, 4-chloro-2-methylphenyl, and 2,4-d ich I oro-3-m ethyl phenyl.
These silyl groups are known in the art. See for example, Pierce "Silylation of Organic Compounds," Pierce Chemical Company, Rockford, 111. (11968). When silylated products of the charts below are intended to be subjected to chromatographic purification, then the use of silyl groups known to be unstable to chromatography (e.g. trimethylsilyl) is to be avoided. Further, when silyl groups are to be introduced selectively, silylating agents which are readily available and known to be useful in selective silylations are employed. For example, t-butyldimethylsilyl groups are employed when selective introduction is required. Further, when silyl groups are to be selectively hydrolyzed in the presence of protective groups according to R10 or acyl protective groups, then the use of silyl groups 30 which are readily available and known to be easily hydrolyzable with tetra-n-butylammonium fluoride are employed. A particularly useful silyl group for this purpose is t- butyldimethylsilyl, while other silyl groups (e.g. trimethylsilyl) are not employed when selective introduction and/or hydrolysis is required.
The protective groups as defined by R10 are otherwise removed by mild acidic hydrolysis. For example, by reaction with (1) hydrochloric acid in methanol; (2) a mixture of acetic acid, water, and tetra hydrofu ran, or (3) aqueous citric acid or aqueous phosphoric acid in tetrahydrofuran, at temperatures below 550C., hydrolysis of the blocking group is achieved.
R31 is a hydroxy-hydrogen protective group, as indicated above. As such, R31 may be an acyl protective group according to R., an acid hydrolyzable protective group according to R10, a silyl 40 protective group according to R2.1 or an arylmethyl hydroxy hydrogen replacing group according to R34.
Acyl protective groups according to R9 include:
(a) benzoyl; (b) benzoyl substituted with one to 5 alkyl of one to 4 carbon atoms, phenylalkyl of 7 to 12 carbon atoms, or nitro, with the proviso that not more than two substituents are other than alkyl, and that the total number of carbon atoms in the substituents does not exceed 10 carbon atoms, with the further 45 proviso that the substituents are the same or different; (c) benzoyl substituted with alkoxycarbonyl of 2 to 5 carbon atoms; (d) naphthoyl; (e) naphthoyl substituted with one to 9 alkyl of one to 4 carbon atoms, phenylalkyl of 7 to 10 carbon atoms, or nitro, with the proviso that not more than two substituents one either of the fused 50 aromatic rings are other than alkyl and that the total number of carbon atoms in the substituents on either of the fused aromatic rings does not exceed 10 carbon atoms, with the further proviso that the various substituents are the same or different; or (f) alkanoyl of 2 to 12 carbon atoms.
In preparing these acyl derivatives of a hydroxy-containing compound herein, methods generally 55 known in the art are employed. Thus, for example, an aromatic acid of the formula R90H, wherein R9 is as defined above (e.g., benzoic acid), is reacted with the hydroxy- containing compound in the presence of a dehydrating agent, e.g. p-toluensulfonyl chloride or dicyclohexylcarbodiimide; or alternatively an anhydride of the aromatic acid of the formula (Rg)OH, e.g., benzoic anhydride, is used.
Preferably, however, the process described in the above paragraph proceeds by use of the 60 appropriate acyl halide, e.g., R.Hal, wherein Hal is chloro, bromo or iodo. For example, benzoyl chloride is reacted with the hydroxyl-containing compound in the presence of a hydrogen chloride scavenger, e.g. a tertiary amine such as pyridine or triethylamine. The reaction is carried out under a variety of conditions, using procedures generally known in the art. Generally mild conditions are employed:
0-601C., contacting the reactants in a liquid medium (e.g., excess pyridine or in inert solvent such as 65 11 GB 2 122 203 A.11 benzene, toluene, or chloroform). The acylating agent is used either in stoichiometric amount or in substantial stoichiometric excess.
As examples of R, the following compounds are available as acids (ROH), (R,),0, or acyl chlorides (R.CO: benzoy]; substituted benzoyi, e.g., (2-, 3-, or 4- )rnethylbenzoyl, (2-, 3-, or 5- 4-)ethylbenzoyl, (2-, 3-, or 4-)isopropylbenzoyl, (2-, 3-, or 4-)tert- butyibenzoyi, 2,4-dimethy[benzoy], 3,5- 5 dimethyibenzoyi, 2-isopropyitoiuyi, 2,4,6-trimethyibenzoyi, pentamethyibenzoyi, pheny1(2-, 3-, or 4-)toluyi, (2-, 3-, or 4-)phenethylbenzoyl, (2-, 3-, or 4-)nitrobenzoy], (2,4,2,5-, or 2,3-)dinitrobenzoyi, 2,21 dimethyi-2-nitr.obenzoyi, 4,5-dimethyi-2-nitrobenzoyl, 2-nitro-6- phenylethyibenzoyi, 3-nitro-2 phenethylbenzoyi, 2-nitro-6-phenethyibenzoyl, 3-nitro-2-phenethyi-benzoyi; mono esterified phthaloyl, isophthaloyl, or terephthaloyl; 1 - or 2-naphthoy]; substituted naphthoyl, e.g., (2, 3-, 4-, 5-, 6-, or 6-isopropyl-4-methyl-1 -naphthoyl, 8-benzyi-1 -naphthoyi, (3-, 4-, 5-, or 8+nitro-11 -naphthoy], 4,5 dinitro-1 -naphthoyl, (3-, 4-, 6-, 7-, or 8+methyl-11 -naphthoyi, 4-ethyl- 2-naphthoyl, and (5- or 8-)nitro 2-naphthoyl and acetyl.
There may be employed, therefore, benzoyl chloride, 4-nitrobenzoyl chloride, 3,5-dinitrobenzoyl 15 chloride, or the like, i.e. R.Cl compounds corresponding to the above R, groups. If the acyl chloride is not available, it is prepared from the corresponding acid and phosphorus pentachloride as is known in the art. It is preferred that the R.0H, (R1)20, or IR,Cl reactant does not have bulky hindering substituents, e.g. tert-butyl on both of the ring carbon atoms adjacent to the carbonyl attaching site.
The acyl protective groups, according to F1, are removed by deacylation. Alkali metal carbonate or 20 hydroxide are employed effectively at ambient temperature for this purpose. For example, potassium carbonate or hydroxide in aqueous methanol at about 251C is advantageously employed.
R34 is defined as any aryimethyl group which replaces the hydroxy hydrogen of the intermediates in the preparation of the various CBA analogs herein which is subsequently replaceable by hydrogen in the processes herein for preparation of these respective prostacyclin analogs, being stable withrespect 25 to the various reactions to which R34-containing compounds are subjected and being introduced and subsequently removed by hydrogenoiysis under conditions which yield substantially quantitative yields of desired products.
Examples of aryimethyl hydroxy-hydrogen replacing groups are (a) benzyl; (b) benzyi substituted by one to 5 alkyl of one to 4 carbon atoms, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, with the further proviso that the various substituents are the same or different; (c) benzhydry]; (d) benzhydryl substituted by one to 10 alkyl of one to 4 carbon atoms, chloro, bromo, iodo, fluoro, 35 nitro, phenylalkyl of 7 to 12 carbon atoms, with the further proviso that the various substituents are the same or different on each of the aromatic rings; (e) trityl; (f) trityl substituted by one to 15 alkyl of one to 4 carbon atoms, chloro, bromo, iodo, fluoro, nitro, phenylalkyl of 7 to 12 carbon atoms, with the further proviso that the various substituents are the same 40 or different on each of the aromatic rings.
The introduction of such ether linkages to the hydroxy-containing compounds herein, particularly the benzyl or substituted benzyl ether proceeds by methods known in the art, for example by reaction of the hydroxy-containing compound with the benzyl or substituted benzyl halide (chloride, bromide, or iodide) corresponding to the desired ether. This reaction proceeds in the presence of an appropriate 45 condensing agent (e.g., silver oxide). The mixture is stirred and heated to 50-801C. Reaction times of 4 to 20 hours are ordinarily sufficient.
The Charts herein describe the methods whereby the novel intermediates and end products of the present specification are prepared by the novel processes herein. With respect to these charts, g, n, L1,
M11 Me, R7, Re, 1310, 131, R16, R17, R18, R20, R211 R22, R23, and R24, R28, R311 X1, Y1, Z,, and Z4 are as defined 50 above. R37 is the same as R47, but other than -CH20H. R3. is -OR31, hydrogen, or -CH2013311 wherein R., is defined as above. R27 is the same as R7 except that -(CH2)2-CH(OH)CH, is -(CH)2-CH(ORJ-CH3. R37 is the same as R17, but other than hydrogen. Ac is acetyl, Z2 is the same as Zi but not -(Ph)-(CH2(G-'Z3 is the same as Z1, but not trans-CHI-- CH=CH-.
With respect to Chart A, a method is provided whereby the known formula XXI bicyclic lactone is 55 transformed to the carbacyclin intermediate of formula XXV useful in the preparation of formula X CBA compounds wherein R17 is alkyl or R16 and R17 taken together are methano or a second valence bond between C-6a and C-9. With respect to Chart A, the formula XX1 compound is transformed to the formula XX1 1 compound by treatment with the anion of climethyl methylphosphonate. Methods for such a reaction are known in the art. See Dauben, W.G., et al., JACS, 97:4973 (1975), describing a 60 reaction of this type.
The formula XXII lactol is transformed to the formula XXIII cliketone by oxidation methods known in the art. For example, Collins reagent or Jones reagent is employed in this oxidative transformation.
The formula XXIII diketone is cyclized to the formula XXIV compound by an intramolecular Horner- Emmons reaction. The chemical methodology for analogous transformations is known in the art. See 65 12 GB 2 122 203 A 12 Piers, E., et aL, Tetrahedron Letters, 3279 (1979) and Clark, R. D., et al., Synthetic Communications 5:1 (1975).
The formula XXIV compound is transformed to the novel formula M compound wherein R16S hydrogen and R37 is alkyl by treatment with lithium dialkyl cuprate. The lithium dialkyl cuprate is prepared by conventional means, e.g., reaction of anhydrous copper iodide in diethyl ether with an alkyllithium in diethyl ether, and thereafter reacted with the formula XXIV compounds, e.g., in diethyl ether.
The formula XXIV compound is transferred to the novel formula M compound wherein IR,. and R37 taken together are methylene (-CH,--) by one of two methods. By the first method, the formula XXV compound is prepared by treatment of the formula XXIV compound with the anion of trimethyloxosulfonium iodide. See for reference E. J. Corey et al., JACS 87:1353 (1965). By this method, the anion is conveniently generated by treatment of trimethyloxosuifonium iodide in sodium hydride.
By a second method, the formula XXIV compound is converted to the formula M compound wherein R,6 and F1.7 taken together are methylene by first converting the formula XXIV compound to the 15 corresponding formula XXVI hydroxymethyl compound by photochemical addition of methanol (e.g., see G. L. Bundy, Tetr. Lett. 1957, 1975), thereafter treating the resulting hydroxymethyl compound with an excess (e.g., two equivalents) of p-toluenesulfonyl chloride in a tertiary amine base to yield the corresponding formula XXVI I tosylate, and finally treating the resulting formula XXVI I tosylate with base (e.g., potassium t-butoxide) to yield the formula M cyclopropyl compound.
With respect to Chart B, a method is provided whereby the formula X= compound prepared in accordance with methods of Chart A is transformed to the novel C13A, analogs of formula XXXVI.
The formula XXXI compound is transformed to the formula MM compound by methods known in the art for preparing carbacyclin. See for example, British published applications referred to above.
Alternatively, the formula XXXI compound is reacted with formula XXXII compound and thereby 25 successively transformed to the formula Mill, formula M1V and formula MV compounds.
The reaction of the formula Mi compound employing the formula M11 compound is accomplished by methods known in the art. See Moersch, G. W_ J. Organic Chemistry, 36:1149 (197 1) and MuIzer, 1, et al., Tetrahedron Letters, 2949 (1978). The formula XXXII reactants are known in the art or are prepared by methods known in the art. See Example 4 describing one such method of 30 preparation of a formula XXXII compound.
The formula XXXill compound is then transformed to the formula XXXIV compound by decarboxylative dehydration. Procedures for this reaction are known in the art. See Eschenmoser, A., et al., Heiv. Chim. Acta. 58:1450 (1975), Hara, S., et al., Tetrahedron Letters, 1545 (1975) and MuIzer, J., et al., Tetrahedron Letters, 2953 (1978) and 1909 (1979).
Finally, the formula XM compound is prepared from formula X=V compound by selective desilylation. Such procedures are known in the art and typically employ the use of tetra-n-butyl ammonium fluoride and tetrahydrofuran. See Corey, E. 1, et al., JACS 94:6190 (1972).
The formula MV compound is transformed to various acids, esters, amides, and amines of a formula MM by methods known in the art. Particularly useful in this regard are methods described in 40 the aforementioned British published specifications describing the preparation of carbacyclin analogs.
The preparation of formula MXVI compounds from the formula MXV compounds proceeds by, for example, oxidation to the corresponding carboxylic acid, followed by hydrolysis of any protective groups at the C-1 1 or C-1 5 position of the molecule. Such carboxylic acids are then esterified by conventional means or amidized by conventional means. Such amides may, for example, then be reduced to corresponding amines (X, is -CH21\1L21-3 by reduction by lithium aluminum hydride. See U.S.
Patent 4,073,808. In a preparation of the primary alcohols according to formula XXXVI from the formula MXV compound, hydrolysis of any protective groups at C-1 1 or C-1 5 yields such products directly. Hydrolysis is accomplished by procedures described above, e.g., mild acidic conditions at elevated temperatures.
Chart C provides a method whereby the known formula XLI compounds are transformed to the formula XLIV aldehydes employed in Chart D in the preparation of inter- phenylene-C13A2 compounds therein.
With respect to Chart C, the formula XLII compound is prepared from the formula XLI compounds by reduction. Conventional methods known in the art for the transformation of carboxylic acids to corresponding primary alcohols are employed. For example, one extremely useful conventional means for this reduction is employing lithium aluminum hydride as a reducing agent.
The formula XLIII compound is then prepared from the formula XL11 compound by monosilylation.
Particularly, formula XLIII compounds are prepared wherein R2, represents a relatively stable silyl group, most preferably being t-butyidimethyisilyl or phenyidimethyisiiyi. Other silyl groups, particularly trimethyl-silyl (TIVIS) are not preferred for use in connection with the methods of Chart C.
The formula XL111 monosily] derivatives are prepared from the formula XLII compound by reacting the formula XL11 compounds with about an equal molar amount of the silylating agent. For example when R2. is t-butyidimethyisilyi, a single equivalent of t- butyidimethyisilyl chloride is employed in the transformation. Accordingly, there are prepared both monosilyl derivatives of the formula XLII 13 GB 2 122 203 A 13 compound as well as the bis-silyl derivatives corresponding to formula XLII. From this mixture of products, the formula XLIII compound is recovered by conventional means, e.g., column chromatography. Otherwise, the silylation proceeds under conditions conventionally employed for silylating hydroxyl groups. Refer to the discussion hereinabove.
The formula XLIV compound is then prepared from the formula XLIII compound by oxidation of 5 the formula XLIII alcohol to the corresponding aldehyde. Conventional oxidizing agents are employed, e.g., manganese dioxide.
Chart D provides a method whereby the known formula LI ketones are transformed to the formula LX inter-phenylene CBA2 analogs disclosed herein.
In accordance with Chart D the formula Lil compound is prepared from the formula LI compound 1Q by reduction of the formula LI ketone to the corresponding secondary alcohol. This reduction proceeds by conventional means, employing readily available reducing agents. Accordingly, sodium, potassium, or lithium borohydride is conventionally employed in this reduction.
Thereafter, the formula LII alcohol is transformed to the corresponding mesylate (methanesulfonate). Conventional methods for the transformation of alcohols to corresponding 15 mesylates are employed. Thus, the formula LlI alcohol is reacted with methane-sulfonyl chloride in the presence of a tertiary amine (e.g. tri-ethylamine) in the preparation of the formula Ull compound.
Other sulfonyl derivatives corresponding to the formula Lil alcohol may be employed in place of the formula Ull compound in the transformations of Chart D. These other sulfonyl derivatives are preferably those derived from readily available sulfonylating reagents, i. e., the corresponding sulfonyl 20 chlorides. One especially important alternative to the formula Lill compound is the tosylate (toluenesulfonate) corresponding to the formula Lil compound.
The formula Lill compound, or an alternate sulfonate corresponding thereto, is transformed-to the formula LIV compound by treatment with sodium lithium or potassium thlophenoxide. The thiophenoxide is conveniently prepared just prior to the transformation by mixing approximately equal 25 molar amounts of thiophenol and base, e.g., potassium t-butoxide.
This formula LIV compound is then oxidized to the corresponding formula LV compound by oxidation with a readily available oxidizing agent such as mchloroperbenzoic acid.
The formula LV compound is then condensed with-the formula XLIV compound prepared according to Chart C by first treatment of the formula LV compound with a strong base, e.g., n butyllithium, to generate the anion corresponding to the formula LV compound, treatment of the corresponding anion with the alclehyde of formula XLIV and finally treating the resulting adduct with acetic anhydride to yield the formula LVI acetyl compound.
The formula LVI compound is then transformed to the formula LVII compound by reaction with a -30 sodium amalgam. Methods by which the formula LVII olefin is formed from the formula LV compound 35 are analogous to known methods described by Kocienski, P. J., et al., "Scope and Stereochernistry of an Olefin Synthesis from A-Hydroxysu lp hones." JCS Perkin 1, 829-834 (1978).
The formula LVII compound is then transformed to the formula LVIII compound by selective hydrolysis of the silyl group according to R2,. Conventional means for this hydrolysis are employed, e.g., tetra-n-butyl ammonium fluoride. Refer to the discussion above for a description of this hydrolysis. 40
The formula LVIII C-5 diastereomers thusly prepared are conveniently purified into (5-E) and (5-Z) isomeric forms. This transformation proceeds by conventional means, e.g., column chromatography.
Thereafter either the (50 or (54 isomer of formula LVIII is transformed to the formula LIX carboxylic acid or ester by conventional oxidation, followed by optional esterification. One especially convenient means of oxidation is employing the Jones reagent, although other oxidizing agents are 45 employed. Esterification then proceeds by methods hereinafter described.
Finally, the formula LX products are prepared from the formula LIX compound by first hydrolyzing the protective groups under acidic conditions, e.g. mixtures of water, tetrahydrofuran, and acetic acid.
Thereafter, the formula LIX acids and esters are transformed to various other C-1 derivatives by methods hereinafter described.
One especially convenient means of preparing the formula LX compound as a free carboxylic acid (X1 is -COOH), is by purification of the corresponding methyl ester, followed by saponification under basic conditions (e.g., the treatment with potassium carbonate or sodium or potassium hydroxide).
Chart E provides a method whereby the known formula LXI compound is transformed into formula LXIII intermediate useful in the preparation of the novel CBA2 analogs.
so The procedures for the transformation of the formula LX1 compound to the formula LXIII compound are analogous to those describing the transformation in Charts A, B and D of the formula XXI compound to the formula XXW and LX compounds (i.e., corresponding to the transformation of formula LX1 compound to the formula LX1 I compound is the transformation in Chart A of the formula XXI compound to the formula XXV compound and corresponding to the transformation of the formula LX11 60 compound to the formula LX111 compound is the transformation in Chart D of the formula Ll compound to the formula LX compound.). For convenience, the protective groups R31 and R3. may be the same or different, although preferably such protective groups are different, whereby the hydrolysis of a protective group according to R31 is accomplished in the presence of a protective group according to R38 14 GB 2 122 203 A 14 Chart F then provides a method whereby the formula LXXI compound prepared according to Chart E is transformed to the formula LXXII carbacyclin analog in accordance with the present invention. With respect to Chart F, the formula LXXI compound is transformed to the formula LXXII compound by selective hydrolysis of the protective group according to R.,j. Thereafter, the formula LXXII compound is transformed to formula LXXIII compound by methods known in the art, e.g., oxidation of the formula 5 LXXII primary alcohol to the corresponding aldehyde, Wittig oxylacylating the aldehyde, and reduction of the resulting ketone to the secondary or tertiary alcohol corresponding to M1. For an example of the various transformations employed according to Chart F, see Chart A (part VO of U.S. Patent 4,107,427, issued 15 August 1978.
Chart G provides a method whereby the novel formula LXXXI intermediate, prepared according to 10 Chart A, is transformed to the formula LXXXVIII and LXXXIX isomers of the novel C-6-a- and/or C-9substituted CBA2 analogs.
With respect to Chart G, the formula LXXXIII compound is prepared from the formula LXXXI ketone by a Wittig (o-carboxyalkylation employing a formula LXXXII triphenylphosphonium compound.
The Wittig reaction is undertaken under conventional reaction conditions for preparing prostaglandin- 15 type substances. The formula LXXXIII compound is then optionally hydrolyzed to yield the formula X carboxylic acid products or employed in the further transformations of Chart G in ester form.
The formula LXXXIII compound thusly prepared is thereafter preferably separated directly into C-5 isomers of formulas LXXXVIII and LXXXIX (e.g., by chromatographic means followed by hydrolysis of any protective groups at C-1 1 or C-1 5 position of the molecule), or is alternatively transformed to the 20 formula LXXXIV ester by conventional esterification techniques, e.g., ethereal diazomethane treatment or treatment with methyl iodide. The formula LXXXIV ester is then reduced to the corresponding primary alcohol by reduction with a suitable reducing agent, e.g., lithium aluminum hydride, by methods known in the art for preparing prostaglandin-type primary alcohols from corresponding prostaglandin esters.
The formula LXXXV compound represents an especially convenient intermediate for the facile 25 separation of the C-5 diastereomers. Accordingly, the formula LXXXV compound may be separated by conventional means of separation of diastereomeric mixtures, e.g., column chromatography, whereby the formula LXXXVI and formula LXXXVII compounds are prepared in isomerically pure form. These primary alcohols are then conveniently transformed to the formula LXXXVIII and LXXXIX products by methods described above. Refer to the transformations of the formula XXXV compound to the formula 30 XXXVI compound in Chart B. Chart H provides a method wherein the formula XCVII 5-fluoro-CBA2 compounds are prepared from the formula XCIII CBA2 intermediates known in the art. See, for example, British Published Application 2,014,143, especially the discussion relative to step (b) of Chart A therein. This formula XCI sulfoximine is transformed to the formula XCII fluorinated sulfoximine by first generating an anion of the 35 formula XCII compound, e.g., by treatment with n-butyllithium in hexane, and treating the resulting anion with a fluorine source. Particularly preferred as a source of fluorine is perchloryl fluoride (FCIO,).
The formula XCII compound thusly prepared and the known formula XCIII compound described above are then employed in the preparation of the formula XCIV compound by known methods. Refer again to step M of Chart A of British Published Application 2,014,143.
The formula XCIV compound thusly prepared is then transformed to the formula XCV primary alcohol by hydrolysis under mild acidic conditions (e.g., mixtures of acetic acid, water, and tetrahydrofuran) as is known in the art. Thereafter, the formula XCV primary alcohol is oxidized to the corresponding formula XCVI carboxylic acid employing conventional means. For example, treatment with oxygen and an aqueous suspension of platinum oxide hydrogenated at ambient temperature and 45 pressure yields the formula LXXVI carboxylic acid. Thereafter, the formula XCVI compound is transformed into the various formula XCVII products by derivatization or transformation of the carboxyl group of the formula XCVI compound.
The C-5 isomers of the formula XCIV to formula XCVII compounds are conveniently separated at any step during the process of Chart H, but are most conveniently and preferably separated from the 50 formula XCIV diastereomeric mixture. Conventional means, e.g., column chromatography, are employed in the separation.
Chart I provides an optional method whereby the known formula Cl compound is transformed to the formula C111 products herein. With respect to Chart 1, the formula XCII is prepared from the formula XCI compound by the procedure described in Chart H for the preparation of the formula XCVII compound from the formula XCIII compound. This formula C11 CBA2 intermediate is then transformed to the formula CIII compound by the procedures described in Chart F for the transformation of the formula LXXI to the formula LXXIII compound.
Chart J provides the pruferred methods for preparing the formula X CBA analogs wherein Z, is trans-CH2-CH = CH-. With respect to Chart J, R, therein is other than hydrogen or a cation, preferably being lower alkyl. The formula CXIV is prepared from the formula CXI compound by first preparing the a-phenylselenyl derivative thereof, dehydrophenylselenizing, whereby the formula CXIII a,p-unsaturated ester is prepared. This ester is then transformed to the formula CXIV free acid (X, is -COOH) by saponification and this free acid is transformed to the various other formula CXIV compounds as indicated in Chart H (refer to the transformation of the formula XCVI compound to the 65 GB 2 122 203 A 15 formula XCV11 compound).
Chart K provides the preferred method whereby the formula V1 CBA intermediates wherein Z1 is trans-CH2-CH = CH- are prepared. With respect to Chart K, the formula CXX1 compound is transformed to the formula CXXIII compound by methods analogous to those described in Chart J for 5 the preparation of the formula CXIV compound from the formula CM compound.
For a detailed description of the methodology employed in Charts J-K, refer to the discussion in British Patent 2,014,143, and references cited therein.
Charts L-0 provide methods whereby C13A2 intermediates and analogs are employed in the synthesis of corresponding C13A, intermediates and analogs.
Chart L provides the preferred method for preparing the formula V1 I C13A, intermediates wherein 1.0 Z1 is trans-CH2-CH = CH-. With respect to Chart L the formula CXXX1 compound, prepared as the formula CXX11 compound of Chart K, is reduced to the formula CXXXii compound by conventional methods. For a discussion of such methods, and general methodologies for transforming C13A2 intermediates and analogs to corresponding C13A, intermediates and analogs, refer to British Published Application 2,017,699. For example, catalytic hydrogenation with conventional catalysts under 15 atmospheric pressure is employed.
Thereafter, this formula CXXXII compound is successively transformed to the formula CX=11 ap unsaturated ester and the formula CX=V C13A, intermediate by methods described in Charts J-K (i.e., the transformation of the formula CM1 compound to the corresponding formula CXIV compounds and the transformation of the formula CXX11 compound to the formula CXXIII compound).
Otherwise, the formula VII C13A, intermediates are prepared according to the method of Chart M, wherein the formula CXL1 compound, prepared above, is reduced to the formula CXL11 intermediates by techniques described in Chart L and reference cited therein.
Chart N describes the preparation of the various C13A, analogs from the formula CLI compounds prepared in Charts L and M. Procedures employed in Chart N are those described in Chart F above.
Finally, Chart 0 provides an alternative method for the preparation of the formula CILX11 C13A, analogs directly from formula CLX1 C13A2 analogs. This transformation of Chart 0 proceeds by direct reduction of the formula CLX1 compound by methods described in Chart M and references cited therein.
Chart 0 is an especially convenient method for the preparation of CBA, analogs wherein Y, is -CH2CH2_.
The formula M CBA analogs are prepared according to the methods described in Charts P-U.
With respect to Chart P, the formula CI---XX1 compound is known in the art or prepared by methods known in the art. See United States Patent 4,181,789. This compound is conveniently transformed to the corresponding formula CLXXII methylene and formula CI---XX1H hydroxymethyl compounds by methods known in the art. Such procedures are particularly and especially described in United States 35 Patent 4,012,467 and 4,060,534.
The formula CI---XXIII compound thusly prepared is thereafter converted to the formula CIL=V mesylate by methods known in the art, e.g., reaction with methanesulfonyl chloride in a tertiary amine base. Alternatively, other sulfonated derivatives corresponding to the formula CLXXIV compound are prepared such as those described in connection with formula Lill in Chart D.
Thereafter, the formula CLXXIV mesylate (or other sulfonate) is selectively hydrolyzed to yield the formula CI---XXV phenol derivatives. Selective hydrolysis of R2. silyl ether groups in the presence of protected R,. or M. hydroxyl groups is accomplished by methods hereinabove described, i.e., the use of tetra-n-butyl ammonium floride by methods known in the art and hereinabove described. The formula CI---XXV phenol derivative is then cyclized to yield the formula CI--- XXV1 compounds. Cyclization proceeds 45 most conveniently by treatment of the formula XVI compound with base at elevated temperatures. For example, n-butyllithium, sodium hydride, or potassium hydride are conveniently employed at reflux temperatures in organic solvent such as tetrahydrofuran or glyme.
The cyclized formula CI---XXV1 compound is then transformed to the formula CLXXVII compound by w-carboxyalkylation. Methods known in the art are employed, e.g., methods for preparing 3,7-inter- 50 phenylene-PGFa compounds and corresponding phenolic intermediates. For example, the preparation of the formula CI---XXVII compound proceeds by reaction of the formula CI- --XXVI compound with sodium hydride and the alkyl bromoalkanoate corresponding to the -Z,--COOR, group to be introduced into the molecule. Thereafter, the formula CI---XXVIII compound is prepared by deprotection, i.e., hydrolysis under mild acidic conditions of the protective groups, followed by transformation to various other C-1 55 derivatives by methods hereinafter described.
Chart Q provides a method whereby further formula Xl CBA analogs in accordance with the present invention are prepared. In particular formula Xl compounds wherein at least one of R20, R21, R231 or R24 is not hydrogen are prepared. In accordance with Chart Q, the formula CILX= compound, referred to above in the discussion pertaining to Chart P, is oxidized to the corresponding formula 60 CI---XXXII aldehyde by methods known in the art. For example, Collins reagent is employed in this oxidation. When conversion of one C-9 stereoisomer of formula CI---XXXIII to the other is described, refer to the procedure in Chart R.
Thereafter the formula CI---XXXII aldehyde is hydrolyzed to the corresponding formula CI---XXX111 phenol derivative by methods described above for the preparation of the formula CI---XXV compound 65 16 GB 2 122 203 A 16 from the formula CM1V compound of Chart P.
Thereafter, cyclization of the formula CLXXXIII to the corresponding formula CLXXXIV compound is accomplished by heating at reflux in an organic solvent the phenoxide anion of the formula CLXXXIII compound. See for reference Casiraghi, G., et aL, J.C.S. Perkin 1, 2027 (1979). The C-9 isomers of the formula C1-MIV compound are conveniently separated by conventional techniques, e.g., column chromatography. Thereafter, the formula CLXXXIV compound is transformed to the formula CLXXXV compound by methods described in Chart P for the preparation of the formula C1-XXVII compound from the formula CLXXVI compound. This alcohol is then oxidized to the corresponding formula CLMM ketone (e.g., by methods described above for the preparation of the formula CI-MI1 compound from the formula CI-MI compound) or dehydrated to yield the formula C1-XXXVIII compound. Such dehydrations proceed by methods known in the art and include first preparing the mesylate corresponding to the formula CI-MV compound following by treatment with base.
Thereafter, the formula CLMM or CLXXXVIII compound is transformed, respectively, to the formula C1-MVII or CI-MIX compound by methods hereinafter described.
Finally, the formula CI-MIX compound thusly prepared is dehydrogenated to yield the formula CXC compound by conventional means, e.g., catalytic dehydrogenation (palladium-on-carbon catalyst) or treatment with DIDQ (2,3-di ch loro-5,6dicya no- 1,4-benzoqui none).
Chart R provides a method whereby the C-9 epimeric forms of compoundsprepared according to Chart P are prepared. With respect to Chart R, the formula CM aldehyde, prepared as the formula CLXXXII compound of Chart Q is isomerized by treatment under basic conditions (i.e., the use of an 20 organic base such as 1,8-diazobicyclo[5.4.Olundec-7-ene in an organic solvent (e.g., methylene chloride)). Thereafter this gp-aldehyde is reduced to the corresponding formula CXCIII alcohol by treatment with a suitable reducing agent, such as a borohydride reducing agent. (e.g., sodium, lithium, or potassium borohydride). Thereafter, the formula CXCIII alcohol thusly prepared is transformed to the corresponding 9PCI3A analogs by methods described in Chart P, e.g., the transformation of the formula 25 CM111 to the formula C1-XXVIII compound.
Optionally, the various formula XI CBA analogs prepared according to Charts P, Q, and R are prepared by the procedure of Chart S. The procedure of Chart S employs the formula CCI starting material described in chart P which is thereafter converted to the formula CCII compound prepared in accordance with methods described for the preparation of the formula CLXXVIII compound from the 30 formula CM1 compound of Chart P, the formula CLMMI, formula MMIX, formula CXC compounds from the formula CLXXXI compound of Chart Q and the formula CXCIV compounds from the formula CXCI compound of Chart R. The formula CCII compound thusly prepared is then transformed to the formula CCIII compounds by methods hereinabove described, e.g. the transformation of the formula M1 compound to the formula Mill compound of Chart F.
Chart T provides a preferred method whereby the 9-deoxo-2',9-metheno-3oxa-4,5,6-trinor-3,7- (1,3-inter-phenylene)-PGE, compounds of formula CCXII 1 are prepared. In accordance with Chart T the formula CM compound, prepared as the formula CLXXXIII compound of Chart Q, is treated with a methyl Grignard reagent, methyl magnesium bromide and heated at reflux in an organic solvent (e.g.
glyme).
1 The formula CCM11 thusly prepared is then transformed to the formula CCXill product by the method described in Chart P for the preparation of the formula C1-XXVIII product from the formula CI-MI phenol intermediate.
Chart U provides a convenient method whereby formula XI compounds wherein Y1 is trans CH=Cl-1-, the formula CM1 compound of Chart U, are transformed to corresponding formula CM11 45 aldehyde intermediates. This transformation is accomplished by ozonolysis by methods otherwise known in the art.
The formula CM11 intermediate is then conveniently transformed to various formula XI products (the Formula CM111 compound of Chart U) by methods described above, i.e. reaction of the formula CM11 compound with the appropriate Wittig reagent followed by reduction and hydrolysis. Accordingly by the procedure described in Chart U the C-1 2 side chains of the various formula CM1 compounds is conveniently modified by the formula CM11 aldehyde intermediates. As discussed above, the processes herein described lead variously to carboxylic acids (X, is -COOR, and R1 is hydrogen) or to esters or primary alcohols (X, is -CH20H).
When the alkyl ester has been obtained and an acid is desired, saponification procedures, as - 55 known in the art for PGF-type compounds are employed.
When an acid has been prepared and an alky], cycloalkyl, or aralkyl ester is desired, esterification is advantageously accomplished by interaction of the acid with appropriate diazohydrocarbon. For example, when diazomethane is used, the methyl ester is produced. Similar use of djazoethane, diazobutane, and 1 -diazo-2-ethylhexane, and diazodecane, for example, gives the ethyl, buty], and 2- 60 ethylhexyl and decyl esters, respectively. Similarly, diazocyclohexane and phenyidiazomethane yield cyclohexyl and benzyl esters, respectively.
Esterification with diazohydrocarbons is carried out by mixing a solution of the diazohydrocarbon in a suitable inert solvent, preferably diethyl ether, with the acid reactant, advantageously in the same or a different inert diluent. After the esterification reaction is complete the solvent is removed by 9 17 GB 2 122 203 A 17 evaporation, and the ester purified if desired by conventional methods, preferably by chromatography. It is preferred that contact of the acid reactants with the diazohydrocarbon be no longer than necessary to effect the desired esterification, preferably about one to about 10 min, to avoid undesired molecular changes. Diazohydrocarbons are known in the art or can be prepared by methods known in the art. See, for example, Organic Reactions, John Wiley and Sons Inc., New York, N.Y., Vol. 8, pp. 389-394 (1954). 5 An alternative method for alky], cycloalkyl or aralkyl esterification of the carboxy moiety of the acid compounds comprises transformation of the free acid to the corresponding substituted ammonium salt, followed by interaction of that salt with an alkyl iodide. Examples of suitable iodides are methyl iodide, ethyl iodide, butyl iodide, isobutyl iodide, tert-butyl iodide, cyclopropyl iodide cyclopentyl iodide, benzyi iodide, phenethyl iodide, and the like.
Various methods are available for preparing phenyl or substituted phenyl esters within the scope of the invention from corresponding aromatic alcohols and the free acid, differing as to yield and purity of product.
With regard to the preparation of the phenyl, particularly p-substituted phenyl esters disclosed herein (i.e., X1 is -COOR, and R, is p-substituted phenyl), such compounds are prepared by the method 15 described in U.S. Patent No. 3,890,372. Accordingly, by the preferred method described therein, the p substituted phenyl ester is prepared first by forming a mixed anhydride, particularly following the procedures described below for preparing such anhydrides as the first step in the preparation of amido and cycloamido derivatives.
This anhydride is then reacted with a solution of the phenol corresponding to the p-substituted 20 phenyl ester to be prepared. This reaction proceeds preferably in the presence of a tertiary amine, such as pyridine. When the conversion is complete, the p-substituted phenyl ester has been recovered by conventional techniques.
A preferred method for substituted phenyl esters is that disclosed in U.S. Patent No. 3,890,372 in which a mixed anhydride is reacted with an appropriate phenol or naphthol. The anhydride is formed 25 from the acid with isobutylchloroformate in the presence of a tertiary amine.
Phenacyl-type esters are prepared from the acid using a phenacyl bromide, for example p phenylphenacyl bromide, in the presence of a tertiary amine. See, for example, U.S. Patent No.
3,984,454, German Offenlegungsschrift 2,535,693, and Derwent Farmdoe No. 16828X.
Carboxyamides (X, is -COL4) are prepared by one of several amidation methods known in the prior art. See, for example, U.S. Patent No. 3,981,868, issued 21 September 1976 for a description of the preparation of the present amido and cycloamido derivatives of prostaglandin-type free acids and U.S. Patent No. 3,954,741 describing the preparation of carbonylamido and sulfonylamido derivatives of prostaglandin-type free acids.
The preferred method by which the present amido and cycloamido derivatives of the acids are 35 prepared is, first, by transformation of such free acids to corresponding mixed acid anhydrides. By this procedure, the prostaglandin-type free acid is first neutralized with an equivalent of an amine base, and thereafter reacted with a slight stoichlometric excess of a chloroformate corresponding to the mixed anhydride to be prepared.
The amine- base preferred for neutralization is triethylamine, although other amines (e.g., pyridine, 40 methyidiethyla mine) are likewise employed. Further, a convenient, readily available chloroformate for use in the mixed anhydride production is isobutyl chloroformate.
The mixed anhydride formation proceeds by conventional methods and accordingly the free acid is mixed with both the tertiary amine base and the chloroformate in a suitable solvent (e.g., aqueous tetra hydrofu ran), allowing the reaction to proceed at -1 O'C to 201C.
Thereafter, the. mixed anhydride is converted to the corresponding amido or cycloamido derivatives by reaction with the amine corresponding to the amide to be prepared. In the case where the simple amide (-NH2) is to be prepared, the transformation proceeds by the addition of ammonia. Accordingly, the corresponding amine (or ammonia) is mixed with the mixed anhydride at or about -10 to + 1 OOC, until the reaction is shown to be complete.
Thereafter, the novel amido or cycloamido derivative is recovered from the reaction mixture by conventional techniques.
The carbonylamido and sulfonylamido derivative of the presently disclosed PG-type compounds are likewise prepared by known methods. See, for example, U.S. Patent No. 3,954,741 for description of the methods by which such derivatives are prepared. By this known method the acid is reacted with a 55 carboxyacyl or sulfonyl isocyanate, corresponding to the carbonylamido or sulfonylamido derivative to be prepared.
By another, more preferred method the sulfonylamido derivatives of the present compounds are prepared by first generating the PG-type mixed anhydride, employing the method described above for the preparation of the amido and cycloamido derivatives. Thereafter, the sodium salt of the corresponding sulfonamide is reacted with the mixed anhydride and hexamethylphosphoramide. The pure PG-type sulfonylamido derivative is then obtained from the resulting reaction mixture by conventional techniques.
The sodium salt of the sulfonamide corresponding to the sulfonylamido derivative to be prepared is generated by reacting the sulfonamide with alcoholic sodium methoxide. Thus, by a preferred method 65 18 GB 2 122 203 A 18 methanolic sodium methoxide is reacted with an equal molar amount of the sulfonamide. The sulfonamide salt is then reacted, as described above, with the mixed anhydride, using about four equivalents of the sodium salt per equivalent of anhydride. Reaction temperatures at or about OOC are employed.
The compounds of this invention prepared by the processes of this invention, in free acid form, are transformed to pharmacologically acceptable salts by neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed hereinabove. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the 10 inorganic salts, it is usually suitable to dissolve an acid of this invention in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is 15 desired.
To produce an amine salt, an acid of this invention is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually 20 obtained in solid form by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.
Salts wherein the cation is quaternary ammonium are produced by mixing an acid of this invention with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.
The present invention is more completely understood by the operation of the following examples:
EXAMPLE 1 3-oxo-7a-tetrahydropyran-2-yioxy-6p[(3'S)-3'-tetrahydropyran-2yioxy-trans-1 1-octenyllbicyclo[3.3.01-oct-1 -ene (Formula XXIV: R,, is tetrahydropyranyloxy; Y, is trans-CH=CH-, M, is atetrahydropyranyloxy:P-H, L, is a-H:P-H, R27 is n-butyl; and n is the integer one).
Refer to Chart A.
A. To a stirred solution of 19 mi (170 mmoles) dimethyl methyl phosphonate and 600 mi of dry tetrahydrofuran at -781C under an argon atmosphere is added dropwise over 5 min 110 mi (172 mmoles) of 1.56 M n-butyllithium in hexane. The resulting solution is stirred for 30 min at -7811C, treated with 25.4 g of 3a,5a-dihydroxy-2p-(3a-hydroxy-trans-l-octenyi)-1acyclopentaneacetic acid, 35 lactone, bis(tetra hydropyranyl) ether, in 100 mi of dry tetrahydrofuran dropwise over one hr, and stirred for one hr at -78 'C and four hr at room temperature. The reaction is then quenched by addition of 10 m] glacial acetic acid, diluted with 700 mi of brine, and extracted with diethyl ether (3 x 700 mi). The combined ethereal layers are washed with 200 mi bicarb and 500 m] brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 37 g of formula XXII compound as oily 40 white solid: 3-dimethylphosphonomethy]-3-hydroxy-2-oxa-7a-tetrahydropyran2-yioxy-6p[(3'S)-3'- tetra hydropyra n-2-yloxy-trans- 1 '-octenyll -bicyclo [3.3.01 octane. Crystallization of the crude product from hexane and ether yields 22.1 g of purified formula XXII product. Silica gel TLC Rf is 0.22 in ethyl acetate. The melting range is 89-93 OC. NMR absorptions are observed at 3. 72 (doublet, J = 11 Hz) and 3.83 (doublet, J = 11 Hz)S. Characteristic infrared absorptions are 3340, 1250, 1185, 1130, 1075, 45 and 1030 cm-1.
B. To a solution of 10.0 g of the product of Art A in 75 mi acetone stirring under a nitrogen atmosphere at -1 OOC is added over 30 min 9.0 mi of Jones reagent. The resulting suspension is stirred for 30 min at -1 OIC and then quenched with 4 m] 2-propanol. The solvents are decanted away from the green residue and most of the acetone removed at reduced pressure. The acetone concentrate is 50 then taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure yields 8.2 g of formula XXIII product: 2 -deca rboxy-6-desbuty]-6-di methyl phosphonomethyl-6-keto-PG E,, 11,15 bis(tetrahydropyranyl ether). Chromatography of formula XXIII product on 600 g silica gel eluting with 20% acetone in methylene chloride yields 4.95 g of pure formula XXIII product. Silica gel TLC Rf (in 20% acetone in methylene chloride) is 0.22. Characteristic NMR absorptions are observed at 3.14 (doublet, J = 231-14 and 3.80 (doublet, J = 11 Hz), 5.4-5.8(m)S. Characteristic infrared absorptions are observed at 1745,1715,1260,120o, 1185,1130,1030,970,870 cm-1.
C. A suspension of 5.37 g of the product of Example 1, Part B, 1.33 g anhydrous potassium carbonate, and 5.37 g 1 8-Crown-6 ether in 200 mi toluene is heated at 751C for six hr under a nitrogen 60 atmosphere, cooled to O1C, and washed with 200 mi brine, 200 mi of 3:1 water:brine, and 200 m] brine, and dried over anhydrous sodium sulfate. Most of the solvents are removed under reduced pressure and the residue is filtered through 50 g silica gel eluting with 250 mi ethyl acetate to give 3.9 g of formula XXIV product: 3-oxo-7(i-tetrahydropyranyi-2-yioxy-6p[(3'S)-3tetrahydropyran-2-yi- 19 GB 2 122 203 A 19 trans-l'-octenyllbicyclo[3.3.Oloct-1 -ene. The crude product is chromatographed on 300 g silica gel eluting with 60:40 hexane:ethyl acetate to give 2.39 g of pure title product. Silica gel TILC Rf is 0.22 in 60:40 hexane:ethyl acetate. NMR absorptions are observed at 5.18-5.86 (m) and 5.94 (broad singlet)S. Infrared absorptions are observed at 1710 and 1632 cm-1.
Following the procedure of Example 1, but employing the various 3a,5ahydroxy-2-substituted- 5 1 a-cyclopentaneacetic acid 8-lactones of formula XXI, there are prepared each of the various corresponding formula XXIV product wherein n is one.
Further, following the procedure of Example 1, but employing each of the varous 3a,5a dihydroxy-2-substituted-1 a-cyclopentanecpropionic acid 8-lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein n is 2.
Further, following the procedure of Example 1, but employing each of the various 5a-hydroxy-2substituted-1 a-cyclopentanealkanoic acid iactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein R,. is hydrogen. Finally, following the procedure of Example 1, but employing each of the various 3a-hydroxymethyi-5a-hydroxy2-substituted-1 a- cyciopentanealkanoic acid lactones of formula XXI, there are prepared each of the various formula XXIV 15 compounds wherein R,. is -CH20Rj..
EXAMPLE 2 3-oxo-8a-tetrahydropyran-2-yioxy-7p[(3'S)-3'-tetrahydropyran-2yioxy-trans-l 'octenyllbicyclo[4.3.01 non- 1 -ene (Formula XXIV: R,., Y1, M6, R7 are defined in Example 1 and n is the integer 2). Refer to Chart A.
A. A solution of 2.05 mi (18.9 mmoles) of dimethyl methylphosphonate and 100 mi of dry tetrahydrofuran is stirred at -78'C under a nitrogen atmosphere and treated dropwise with 11.8 ml 0 8.9 mmoles) of 1.6 molar n-butyllithiurn in hexane. After stirring for 30 min at -781C, the resulting mixture is treated dropwise over 25 min with 4.25 g of 3a,5a-dihydroxy-2p- (3a-hydroxy-trans-1- 25 octenyl) 1 a-cyclopentane propionic acid, 6-lactone, 11,11 5- bis(tetrahydropyranyl ether), in 30 ml of dry tetrahydrofuran. The resulting mixture is then stirred for one hr at 781)C. The solution is then allowed to stir at ambient temperature for 2 hr and is quenched by addition of 1.2 ml of acetic acid. The mixture is then added to 250 ml of brine and 200 ml of diethyl ether. The aqueous and organic layers are then separated and the aqueous layer extracted twice with diethyl ether. The ethereal extracts are then 30 washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield 5.6 g of crude formula XXII compound, as an oil: 3-(dimethylphosphonomethyl)-3-hydroxy-2- oxa-8ce-tetrahydropyran-2-yi-oxy-7p[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1 Ioctenyll-bicyclo[4.3.0]nonane.
Chromatography on silica gel eluting with 4:1 ethyl acetate:acetone yields 4.1 g of purified formula XXII product. Characteristic NIVIR absorption is observed at 5.15-5.65 (multiplet)8. Silica gel TLC Rf is 0.34 35 in 4:1 ethyl acetate:acetone. Characteristic infrared absorptions are observed at 3350, 1235, and 1030 cm-1.
* B. A suspension of 3.42 g of chromium trioxide and 80 ml of methylene chloride is treated with 5.8 ml of pyridine, stirred at ambient temperature under a nitrogen atmosphere for 30 min, and combined with 3 scoops of dry diatomaceous earth. The resulting mixture is then treated with 3.25 g of 40 the reaction product of Part A and 8 ml of dry dichloromethane, stirred for 30 min at ambient temperature under nitrogen, filtered through 30 g of silica gel (eluting with 200 ml of ethylacetate and acetone, 2:1) and concentrated under reduced pressue. Chromatographing the residue (3.73 g) on 120 g of silica gel, eluting with ethyl acetate and acetone (4:1) yields 2.07 g of formula XXIII product: 2 decarboxy-5-despropyl-6-dimethylphosphonomethyl-5-keto-PGE,, 11,15bis(tetrahydropyranyl ether). 45 Characteristic infrared absorptions are observed at 1740 and 1715 cm-1.
Characteristic NIVIR absorptions are observed at 3.1 (doublet, J = 23Hz) and 3.8 (doublet, J = 11 Hz)8.
C. A suspension of 12 mg of 50% sodium hydride in mineral oil and 3 ml of diglyme is stirred at OIC under an argon atmosphere. The suspensions is then treated with 150 mg of the product of Part B -50 in 3 ml of diglyme. After 1 hr, the cooling bath is removed and the resulting solution is stirred at ambient temperature under argon. After a total of 20 hr from addition of the formula XXIII reactant, the resulting solution is then added to 30 ml of water and extracted with 90 ml of diethyl ether. The ethereal extract is washed with brine (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to a brown oil (1110 mg) and chromatographed on 10 g of silica gel eluting with hexane and 55 ethyl acetate (1:1). There is accordingly prepared 15 mg of formula XXIV compound: 3-oxo-8a tetrahydropyran-2-yloxy-7-[3'S)-3'-tetra hyd ropyra n-2-yl oxy-trans- 1 '- ocetnyll bicyclo [4.3.01 non- 1 - ene. NMR absorptions are observed at 4.7 (broad singlet and 5.3-6.0 (multiplet)8. IR absorption is observed at 1670 cm-1.
Alternatively, the formula XXIV compound above is prepared as follows:
A solution of 150 mg of the product of Part B and 5 ml of dry tetrahydrofuran at OOC under an argon atmosphere is treated dropwise with 0.5 ml of 0.52 M potassium hydride and 18-crown-6 ether (Aldrich Chemical Co. Catalog Handbook of Fine Chemicals 1979-1980, Milwaukee, Wisconsin, P. 133; Pedersenf, J.C., JACS 92:386 0 970)) in tetrahydrofuran (prepared from 800 mg potassium GB 2 122 203 A 20 hydride and 1.0 g 1 8-crown-6 ether in 8.7 ml of dry tetrahydrofuran). After stirring for one hr at OOC under argon, the mixture is added to 30 ml of water, extracted with 90 mg of diethyl ether and the ethereal extract is washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 9 g of silica gel eluting with ethyl acetate and hexane. Formula XXIV 5 product (40 mg) is thereby obtained. Silica gel TLC Rf is 0.30 in ethyl acetate and hexane (1:1).
EXAMPLE 3 lp-Methyl-3-oxo-7a-tetrahydropyran-2-yl-oxy-6p-[(3'S)-3'tetrahydropyran-2-y loxy-trans-l'octenyll-bicyclo-[3.3.0]octane (Formula XXV: Rj, Y1, M6, n, L, R7 are as defined in Example 1, R16S hydrogen and R37 is methyl).
Refer to Chart A.
I A suspension of 2.70 g of anhydrous ccpper iodide is stirred in 100 ml of anhydrous diethyl ether at -200C under an argon atmosphere and is treated dropwise with 20.0 ml of 1.4 M ethereal methyllithium. The resulting solution is then stirred for 15 min at -201C and treated over 2.5 hr at -200C with a solution of 2.00 g of the title product of Example 1 in 100 ml of anhydrous diethyl ether.
15. Stirring is continued for an additional 1.5 hr at -201C and the resulting mixture is added to 200 ml of 1 M aqueous ammonium chloride. The aqueous and organic layers are then separated and the aqueous layer extracted with diethylether (400 ml). The combined organic extracts are then washed with 200 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield 2.4 g of title product as a pale green oil. Chromatography on 25 g of silica gel eluting with hexane in ethyl acetate (3:1) yields 2.0 g of title product as a colorless oil. Characteristic NIVIR absorptions (CDC13 are 20 observed at 1. 18, 3.20-4.43, 4.70, and 5.2-5.9,5. Characteristic infrared absorptions are observed at 1745,1665,1200,1130,1110,1075,1035,1020, 980, and 870 cm-1. Silica gel Rf is 0.26 in ethyl acetate and hexane 0:3). - By procedures known in the art, each of the various novel formula XXV intermediates is transformed to a 9p-methyl-CBA, or CBA, compound by methods examplified hereinafter or known 25 from British Published Specifications 2,013,661,2,014,143, and 2,017,699.
EXAMPLE 4 5-Carboxypentanol, t-butyldimethylsilyl ether A solution of 4 g of sodium hydroxide in 100 ml of methanol and water (4:1) is treated with 10 ml of caprolactone and stirred at ambient temperature under a nitrogen atmosphere. After 20 hr, solvent is 30 evaporated following addition of toluene, yielding 15 g of solid, crude 5-carboxypentanol.
The above solid is suspended in 300 ml of dimethy1formamide under a nitrogen atmosphere, cooled to 01C, treated with 35 g of imidazole, stirred for 15 min at OIC and 15 min at ambient temperature, cooled to OIC and treated with 39 g of t-buty1dimethyl silylchloride. The resulting solution is then allowed to warm to ambient temperature under a nitrogen atmosphere. After 26 hr, the resulting 35 solution is treated with 8 g of sodium hydroxide in 40 ml of water and 40 ml of methanol, with stirring maintained under a nitrogen atmosphere. After 13 hr, the suspension is acidified to pH 4 with 500 ml of 1 N aqueous hydrogen chloride, then saturated with sodium chloride and extracted with ethyl acetate.
The ethyl acetate extracts are then washed with 1 N aqueous sodium hydroxide. The basic extracts are then acidified to pH 4 with concentrated hydrochloric acid, saturated with brine, and extracted with 40 ethyl acetate. The ethyl acetate extracts are then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 22.6 g of a yellow liquid, 5- carboxypentanol, t butyldimethylsilyl ether. Chromatography on 800 g of silica gel eluting with ethyl acetate and hexane (1:9 to 1:1) yields 14.8 g of 5-carboxypentanol, t-butyldimethylsilyl ether. NIVIR absorptions are observed at 0.05 (singlet) and 0.90 (singlet)(5. Infrared absorptions are observed at 3000 (broad) and 45 1700 cm-1.
Following the procedure of Example 4, but employing each of the various lactones corresponding to the w-carboxyalkanol compounds of formula XXXII there are prepared each of the varous formula XXXI I products.
EXAMPLE 5
2-Decarboxy-2-(t-butyidimethyisilyloxy)methyi-5-carboxy-6-hydroxy-9pmethyi-C BA,, 11, 15 bis(tetrahydropyraffiether (Formula XXXIII: R2. is t-butyidimethyisiiyi, Z2 is (CH2),-, n is 1, and R,,, F118, R371 M6, L, and R4 are as defined in Example 3).
Refer to Chart B. A solution of 0.58 m] of dry diisopropylamine and 20 m[ of dry tetrahydrofuran at OOC under an 55 argon atmosphere is treated with 2.6 mi of 1.56 M n-butyllithium in hexane, stirred for 5 to 10 min at OOC, treated with 0.50 g of the title product of Example 4 in 5 mi of tetra hyd rofu ran, stirred for 15 min at OOC and 1 hr at ambient temperature, cooled to O1C, treated with 0.91 g of the title product of Example 3 in 5 mi of tetra hydrofura n, and allowed to slowly warm to ambient temperature under an argon atmosphere. Thereafter, 130 mi of water and 20 m] of brine are added and the mixture extracted 60 with diethyl ether. The ethereal extracts are then washed with 4 mi of 1 N aqueous hydrochloric acid and 150 mi of brine and dried over sodium sulfate, and concentrated under reduced pressure to yield 21 GB 2 122 203 A 21 title product.
Following the procedure of Example 5, but employing each of, the various formula X= compounds described following Example 1, there are prepared each of the varous formula X=11 compounds wherein R2. is t-butyidimethyisilyl and Z2 is -(CH2,-.
EXAMPLE 6
2-Decarboxy-2-(t-butyidimethyisilyloxy)methyi-9p-methyi-CBA2,11,15-bls(tetr ahydropyranylether) (Formula XXXIV: R2e. Z2, n, R,., Y1, Me, L, and R7 are as defined for Examples 1 and 5).
The reaction product of Example 5 (1.37 g) and 16 mi of methylene chloride is treated with 2.9 mi of dimethylformamide dineopentyl acetal, stirred for 3 hr at ambient temperature under nitrogen, added to 160 mi of ice water and 40 mi of brine, and extracted with diethyl ether. The ethereal extracts are 10 then washed with 150 mi of sodium bicarbonate and 150 mi'of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield crude title product. Chromatography on 100 g of silica gel eiuting with 10% ethyl acetate in hexane yields pure title product.
Following the procedure of Example 6, but employing each of the various formula X=11 compounds described following Example 5, there are prepared each of the various corresponding 15 formula XX products wherein R2. is t-butyidimethyisilyl and Z2 is -(CH2)j- .
EXAMPLE 7
2-Decarboxy-2-hydroxmethyl-9p-methyl-CBA2'11,1 5bis(tetrahydropyranyl)ether (Formula XXXV: Z21 n, Rle, R37, R181 Y11 Me, L1, and R7 are as defined in Examples 1 and 5).
Refer to chart B. A solution of 0.71 g of the title product of Example 6and 16 ml of dry tetrahydrofuran at OOC under a nitrogen atmosphere is treated with 3.2 ml of 0.75 molar tetra-n- butylammoniumfluoride and tetra hydrofura n. After allowing the reaction mixture to slowly warm to ambient temperature overnight with stirring, 150 ml of brine is added and the resulting mixture extracted with ethyl acetate. The ethyl acetate extracts are then washed with 0.5 N aqueous potassium bisulfate, 100 ml of sodium bicarbonate, and 100 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield crude title product. Filtering through 25 g of silica gel with 200 ml of ethyl acetate and hexane yields 0.61 g of further purified product. Chromatography on silica gel eluting with 35% ethyl acetate in hexane yields pure title product.
Following the procedure of Example 7, but employing each of the varous formula XXXIV 30 compounds described in and following Example 6, there are prepared each of the various formula XXXV compounds wherein Z2 is -(CH2)3--' Following the procedure of Examples 5, 6, and 7, and employing the various starting materials described in and following these examples and each of the varous formula XXXII compounds described in and following Example 4, there are prepared each of the various formula XXXV compounds. 35 25.
EXAMPLE 8 2-Decarboxy-2-hydroxymethyl-9p-methyl-CBA, (Formula XXXVI: X, is -CH,OH, Z, is -(CH,),f-, Re is hydroxy, Y, is trans-CH=CH-, M, is aOH:A-H, L, is a-H:P-H and R,, is n-butyl). Refer to Chart B. 40 The title product of Example 7 (0.25 g) is combined with 9 ml of acetic acid, water and _tetrahydrofuran (6:3:1) and heated to 37-401C for two hr. Thereafter the resulting mixture is cooled and extracted with diethyl ether. The ethereal extracts are then washed with brine, dried over sodium sulfate and concentrated to yield crude title product. Chromatography on silica gel yields pure title product. 45 Following the procedure of Example 7, but employing each of the various formula XXXV primary 45 alcohols described in bnd following Example 7 there are prepared each of the various corresponding formula XXXVI products wherein X, is -CH20H.
EXAMPLE 9 o-(t-Butyidimethylsilyloxyethyl)benzaidehyde (Formula XLIV: R 28 is t-butyldimethylsilyloxy and g is one). 50 Refer to Chart C. A. To a mixture of 7.6 g of lithium aluminum hydride and 400 ml of dry tetrahydrofuran under a nitrogen atmosphere is added dropwise with stirring 18 g of homophthalic acid (Aldrich Chemical Company) in 250 ml of dry tetrahydrofuran. Dropwise addition rate is adjusted such that mild reflux is maintained during the course of the exothermic reaction. The resulting mixture is then heated at reflux 55 for 5 hr, cooled to OIC, and 7.6 g of water in 50 ml of tetrahydrofuran is added dropwise with stirring. 55 Thereafter 27 ml of 10% aqueous sodium hydroxide is added and the resulting mixture is stirred at ambient temperature for 20 min, filtered, and the filter solids washed with 150 ml of tetra hydrofu ran. The filtrate and tetrahydrofuran wash are then concentrated under reduced pressure to yield 14.0 g of crude fornula XXXII diol, 2-(o-hydroxym ethyl phenyl) eth a nol. Chromatography on 1.2 kg of silica gel, 60 deactivated by addition of 240 ml of ethyl acetate, eluting with ethyl acetate, yields 13.5 g of formula 60 XLII product. Melting range is 41.5-430C.
22 GB 2 122 203 A 22 B. To a solution of 13.5 g of the reaction product of Part A in 50 mi of dry tetrahydrofuran under a nitrogen atmosphere is added with stirring 9. 05 g of imidazole. The resulting solution is then cooled to WC and 13.9 9 of t-butyidimethyisily] chloride is added. The resulting mixture is then maintained for 20 min and thereafter allowed to warm to ambient temperature. After 1 hr, the resulting mixture is then shaken with 500 mi of hexane and diethylether (2:1) and 250 m[ of water and brine OA). The organic layer is then washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield a crude mixture of mono- and bis-silyl ethers corresponding to the starting material of Part A. This mixture of products is then chromatographed on 2 kg of silica gel, deactivated with 400 mi of ethyl acetate and eluted with 25: ethyl acetate and Skellysolve B to yield 6.82 g of formula XLIII product, o-(t-butyidimethyisilyloxyethyi)phenyimethanol. NMR absorptions are observed at 10 7.20-7.52,4.57,3.91 (t, J G.1), 2.93 (t, J 6.1),0.82, and -0.088. Silica gel TLC Rf is 0.54 in 25% ethyl acetate and hexane.
C. A mixture of 5.0 g of the reaction product of Part R, 100 m] of trichloromethane, and 25 9 of activated manganese dioxide (MnO,) is stirred at ambient temperature for 4 hr. Chloroform (100 m]) is then added and the resulting mixture filtered through diatomaceous earth. After washing filter solids 15 with 200 m] of trichloromethane, the resulting filtrate and wash is then concentrated under reduced pressure to yield a residue containing title product. Chromatography on 400 9 of silica gel, deactivated with 80 mi of ethyl acetate and elution with 25% ethyl acetate and hexane yields 2.93 g of pure title product. Silica gel TLC Rf is 0.74 in 25% ethyl acetate and hexane. NMR absorptions are observed at 10.34, 7.25-8.00, 3.89 (t, J 6.0),3.27 (t, J 6.0), 0.83 and -0.096. The mass spectrum exhibits a 20 peak at 265 (M + 1) and other peaks of decreasing intensity at m/e 75, 207, 73, 133, 223, 208, 77, 177, 76 and 105.
Following the procedure described in Chart C, but employing each of the various formula XXX1 acids, there is prepared each of the various corresponding formula XXXIV aldehydes wherein R2,'S t_ butyidimethyisiiyi.
EXAMPLE 10 m-(t-butyidimethylsilyloxymethyl)benzaldehyde (Formula XLIV: g is zero and R2. is t-butyldimethylsilyl).
Refer to Chart C.
A. To a solution of 10.0 g of m-(hydroxymethyl)phenyl methanol in 40 ml of dry tetrahydrofuran under a nitrogen atmosphere is added with stirring 7.35 g imidazole. The resulting solution is then 30 cooled to OOC and 11.3 g of t-butyidimethylsilyl is added. The resulting mixture is then stirred with cooling for 15 min and thereafter allowed to warm to ambient temperature. After 90 min, the resulting mixture is then shaken in 400 ml of hexane and diethyl ether (2:1) and 200 ml of water and brine (1:1).
The organic layer is then washed successively with water and brine (1:1, 300 ml) and brine (150 ml), dried over magnesium sulfate and concentrated under reduced pressure to yield a mixture of mono- and 35 bis-t-butyldimethylsilyloxy ether corresponding to the formula XXXII compound. This mixture of products is then chromatographed on 1.4 kg of silica gel, deactivated by addition of 280 ml of ethyl acetate and eluted with 25-40% ethyl acetate in hexane to yield 7.65 g of pure formula XLIII product, m-(t-butyidimethylsilyloxymethyl)pheny[methanol. Silica gel TLC Rf is 0. 46 in 25% ethyl acetate and hexane. NIVIR absorptions are observed at 7.25, 4.72, 4.60, 2.23, 0.92, and 0.09,5. The mass spectrum 40 exhibits a peak at 251 (MI-1) and other peaks of decreasing intensity at m/e 235, 121, 195, 237, 105,133, 75, 89,236, and 119.
B. A mixture of 5.0 g of the reaction product of Part A and 100 ml of trichloromethane and 25 g of activated magnanese dioxide (MnO. is stirred at ambient temperature for 4 hr. Chloroform (100 ml) is then added and the resulting mixture filtered through diatomaceous earth. The filter solids are washed with 200 ml of trichloromethane and the filtrate and trichloromethane wash are then concentrated under reduced pressure to yield 5.2 g of crude title product. Chromatography on 400 g of silica gel, deactivated with 80 ml of ethyl acetate and elution with ethyl acetate and hexane (1:3) yields 3.65 g of pure title product. Silica gel TLC Rf is 0.46 in 10% ethyl acetate and hexane NIVIR absorptions are observed at 10.00, 7.26-7.86, 4.81, 0.95, and 0.116.
EXAMPLE 11 3-Phenyisuifony]-7a-tetrahydropyran-2-yioxy-6p-[(3'S)-3'tetrahydropyran-2-y ioxy-trans-l'-octenyl]bicyclo-[3.3.01octane (Formula LV: n is the integer one, R,. is tetra hydropyranyloxy, Y, is transCH=Cl1-, M. is a-tetrahydropyranyloxy:p-hydrogen, L, is a-hydrogen:- Phydrogen, R16 and R17 are both hydrogen, and R27 is n-butyl).
Refer to Chart D.
A. Sodium borohydride (0.38 9) is added with stirring to a solution of 2. 90 g of 3-oxo-7a- tetrahyd ropyra n-2-yIoxy-6P-[(3S)-3 '-tetra hyd ropyra n-2-yloxy-tra ns- 1 '-octenyll-bicyclo [3.3.0] octane in ml of 95% aqueous ethanol. The resulting mixture is then stirred at ambient temperature for 20 min.
Thereafter the resulting mixture is shaken in 100 ml of brine and 200 mi of ethyl acetate. The organic 60 layer is then immediately washed in brine dried over magnesium sulfate, and concentrated under reduced pressure to yield 2.94 g of formula LII alcohol: (3RS)-3-hydroxy7a-tetrahydropyran-2-yloxy6-[(3,S)-3'-tetrahydropyran-2-yloxy-trans-l'-octenyllbicyclo[3.3.01octane. Infrared absorptions are 23 GB 2 122 203 A 23 observed at 3600 and 3450 cm-1 and no carbonyl absorption. Silica gel TLC Rf is 0.63 and 0.67 in ethyl acetate and hexane (1:1).
B. To a solution of 2.9 g of the reaction product of Part A in 25 ml of dry dichloromethane and 1.4 ml (1.02 g) of triethylamine at OIC is added with stirring 0.57 ml (0.848 g) of methanesuffonyl chloride over 5 min. The resulting mixture is then stirred an additional 20 min and shaken with 160 ml of diethyl and 80 ml of cold (01C) dilute aqueous hydrochloric acid. The organic layer is then washed successively in brine, dilute aqueous potassium bicarbonate, and brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 3.5 g of crude formula Llll compound: (3RS)-3-hydroxy7 a-hyd roxy-7 a-tetra hyd ropyra n2-yloxy-6A-[(3'S)-3 '-tetra hydropyra n-2-yloxy-trans- 1 octenyll bicyclo [3.3.01 octane, 3-methylsu Ifonate.
C. Thiophenol (1. 13 ml, 1.21 g) is added to a mixture of 1. 12 g of potassium t-butoxide in. 15 ml of dry dimethylsulfoxide (DMSO) under a nitrogen atmosphere. To the solution of potassium thiophenoxide thus prepared is added 3.5 g of the reaction product of Part B in 8 ml of dimethylsulfoxide. The resulting mixture is then stirred at ambient temperature for 16 hr, whereupon additional potassium t-butoxide is added so as to transform the solution to a distinct yellow color. The resulting mixture is then stirred an additional 4 hr at ambient temperature, diluted with 100 ml of diethyl ether and 100 ml of hexane, washed with 5% aqueous potassium hydroxide (200 ml) and brine (200 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield 5 g of a residue of crude formula LIV compound: 3-phenylthio-7-a-tetrahydropyran-2-yloxy-6p- [(3'S)-3'tetrahydropyran-2-yloxy-trans-l'- oxtenyllbicyclo[3.3.0]octane. Chromatography on 300 g of silica gel, deactivated with 40 ml of diethyl 20 ether and 40 ml of trichloromethane and eluted with 5% diethyl ether in trichloromethane yields 3.1 g of pure product. Silica gel TLC Rf is 0.75 in 10% ethyl acetate in dichloromethane.
D. To a solution of 3.1 g of the reaction product of Part C and 50 ml of dichloromethane at OIC is added with stirring over 10 min 2.43 g of 85% m-chloroperbenzoic acid. The resulting mixture is then stirred at OIC for 30 min, diluted with 150 ml of dry ethyl ether, washed with ice cold dilute aqueous 25 potassium hydroxide and brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield 3.4 g of crude title product. Chromatography on 350 g of silica gel, deactivated with mi of ethyl acetate and elution with 500 ml of 30-50% ethyl acetate in hexane yields 2.90 g of pure title product as a mixture of C-6 isomers. Silica gel TLC Rf's are 0. 41, 0.45 and 0.48 in 30% ethyl acetate in hexane (stereoisomers). NMR absorptions are observed at 7.52-8. 02, 5.30-5.67, 4.70, 30 and 3.30-4.138.
Following the procedure of Example 11, each of the fromula Ll compounds is transformed to the corresponding formula LV 3-phenylsulfonyl compound.
EXAMPLE 12 (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 (Formula LX: X, is-COOH, g is one, n is one, R,, and R17 35 are hydrogen, R. is hydroxy, Y1 is trans-CH=CH-, M, is a-OH:P-H, L, is a- H:P-H, and R7 is n-butyi), its methyl ester and the corresponding (54 isomers thereof.
Refer to Chart C.
A. To a solution of 1.26 g of the title product of Example 11 in 15 mi of dry tetrahydrofuran at - -781C under a nitrogen atmosphere is added dropwise with stirring 1.48 mi of 1.6 M n-buty[rithium in 40 hexane over 1 min. After 10 min 0.66 g of title product of Example 4 in 5 m] of dry tetrahydrofuran is added. After 45 min 0.26 m] of distilled acetic anhydride is added. Stirring is then continued at -780C for 3 hr and at ambient temperature for an additional 2 hr. The resulting mixture is then shaken with m] of diethyl ether and 80 m] of saturated aqueous ammonium chloride. The organic layer is then washed with 15 m] of brine, dried over magnesium sulfate, and concentrated under reduced pressure to 45 yield 2.21 g of formula LV1 product as a mixture of isomers: 3-[a-acetoxy-o-(tbutyidi methyl si lyloxyethyi)-a-tolyll-3-ph e nyisu Ifonyl-7 a-(tetra hydropyran-2-yi)oxy- 6p-[(3'S)-3'(tetra hyd ropyra n-2-y1)oxy-tra ns- 1 '-octenyll bicyclo[3.3. 01-octane. R28, g, R17, n, F1,, Y, M6, L, and R27 are defined in Examples 9 and 11. Silica gel TLC Rf range is 0.30-0.53 (8 spots) (stereoisomers) in 25% ethyl acetate and hexane.
B. The mixture of isomeric products of Part A (2.21 g) and 40 mi of methanol and 20 mi of ethyl acetate is stirred at -201C with chips of 5.6% sodium amalgam for 60 min. After decanting liquid, excess amalgam and solids are rinsed by decantation employing 200 m] of diethyl ether. The organic solutions are then combined, washed with brine, dried, and concentrated under reduced pressure to yield 1.8 9 of crude 2-deca rboxy-2-(t-butyidi m ethylsi lyloxymethyi)-2, 5-i nter-o-phenylene-3,4-di nor- 55 CBA2,11,1 5-bis(tetrahydropyranyl ether). Chromatography on 250 g of silica gel, deeactivated with mi of diethyl ether and eluted with 30% diethyl ether in hexane yields 1. 06 g of pure product. Silica gel TLC Rfs are 0.49, 0.56, and 0.62 (stereoisomers) in 30% diethyl ether and hexane. NMR absorptions are observed at 7.20, 6.54, 5.22-5.80, 4.72, 3.38-4.16 and 2. 74-3.008.
C. A solution of 1.06 g of the reaction product of Part B in 10 ml of dry tetrahydrofuran is treated 60 with 3.2 ml of 0.75 N tetra-n-butylammonium fluoride in tetrahydrofuran at ambient temperature for min. The resulting mixture is then diluted with 125 ml of diethyl ether. The resulting solution is then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield a residue of isomeric formula LVIII products: (5E)- and (5Z)-2-decarboxy-2- hydroxymethyl-2,5-inter-o24 GB 2 122 203 A phenylene-3,4-dinor-CBA2, 11,1 5-bis-(tetrahydropyranyl ether). Chromatography on 100 g of silica gel, deactivated with 20 ml of ethyl acetate and eluted with 25-50% ethyl acetate in hexane yields 0.40 g of (5Z) isomer and 0.51 g of (5E) isomer. For the (5Z) isomer silica gel TLC Rf's are 0.31 and 0.35 (stereolsomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.20, 6.51, 5.10-5.72,4.69, 3.32-4.16, and 2.76-3.006. For the (5E) isomer silica gel TLC Rf's are 0.20 and 5 0.24 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.19, 6.50, 5.10-5.64,4.70,3.32-4.10, and 2.88-2.10,5., D. To a solution of 400 mg of the (5Z) reaction product of Part C in 20 ml of dry acetone at -500C is added with stirring 1.0 ml of Jones reagent (prepared as follows: 26. 72 g of chromium trioxide in 23 ml of concentrated sulfuric acid diluted with water to a volume of 100 ml). The resulting mixture is then 10 allowed to warm to -201C over a 20 min period and stirred at -20'C for 30 min. Excess Jones reagent is then destroyed by addition of 0.5 ml of isopropanol. After 5 min the reaction mixture is then shaken in ml of ethyl acetate and 80 ml of brine containing 0.5 ml of concentrated hydrochloric acid. The organic layer is then washed twice in 50 ml of water containing a trace (10 drops) of concentrated hydrochloric acid, twice in 50 ml of water and in brine. The organic layer is then dried over magnesium 15 sulfate and concentrated under reduced pressure to yield 360 mg of crude (5Z)-2,5-inter-o-phenylene 3,4-dinor-CBA2,11,15-bis(tetrahydropyranyI ether), a formula LIX compound. Crude formula LIX compound is then taken up in 30 ml of diethyl ether and extracted in the mixture of 15 ml of water and ml of methanol containing a trace amount (10 drops) of 45% aqueous potassium hydroxide. The extraction is repeated 6 times, until the acid is completely extracted from the ethereal solution. The 20 aqueous extracts are then acidified to pH2 and extracted with ethyl acetate. The organic extract is then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield a residue of pure title product. Silica gel TLC is a streak to about Rf 0. 50 in ethyl acetate and hexane (1:1).
Purified acid is then converted to the corresponding ethyl ester by treatment with excess ethereal diazomethane for 10 min. Following esterification, the resulting reaction mixture is treated with ethyl acetate and washed with dilute aqueous potassium hydroxide and brine. After drying and concentrating to a residue, chromatography on 20 g of silica gel deactivated with 4 ml of ethyl acetate and elution with 10% ethyl acetate in trichloromethane yields 210 mg of (5Z)-2,5inter-o-phenylene-3,4-dinor- I CBA21 methyl ester, 111,1 5-bis(tetrahydropyranyl ether). Silica gel TLC Rf s are 0.52, 0.56, and 0.60 (stereoisomers) in 25% ethyl acetate and hexane. NIVIR absorptions are observed at 7.20, 6.45, 30 5.34-5.78,4.70,3.68, and 3.30-4.283.
E. A mixture of 200 mg of methyl ester of Part D, 5 ml of acetic acid, 2. 5 ml of water, and 1 ml of tetrahydrofuran is heated to 401C and stirred for 4 hr. The resulting mixture is then diluted with 100 ml of ethyl acetate and washed with a mixture of 6 g of 85% aqueous potassium hydroxide in 20 ml of water and 30 g of ice, washed with brine (40 ml), dried over magnesium sulfate, and concentrated 35 under reduced pressure to yield 180 mg of crude (5Z)-2,5-inter-o- phenylene-3,4-dinor-CBA2I methyl ester. Chromatography on 20 g of silica gel deactivated with 4 ml of ethyl acetate and elution with 100 ml of 50% ethyl acetate in trichloromethane and 100 ml of 50% acetone in trichloromethane yields 105 mg of pure product. Silica gel TLC Rf is 0.57 in 40% acetone and trichloromethane and 0.52 in ethyl acetate. NIVIR absorptions are observed at 7.20, 6.43, 5.45-5.59, 3.65,3. 40-4.20, and 3.188. The 40 mass spectrum of the bis TIVIS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 74, 147, 43,129,41,45,167, 59, and an W-C.1-111 peak at 485.2513.
F. To a solution of 105 mg of the reaction product of Part E in 5 ml of methanol and 2.5 ml of water under a nitrogen atmosphere is added 0.33 g of potassium carbonate. The resulting mixture is stirred at ambient temperature for 20 hr whereupon a small quantity (5 drops) of 45% aqueous 4 potassium hydroxide is added. The resulting mixture is stirred for an additional 4 hr at ambient temperature. Thereupon the mixture is shaken with 100 ml of ethyl acetate and excess cold dilute aqueous hydrochloric acid. The organic layer is then washed with brine, dried, and concentrated under reduced pressure to yield 100 mg of pure (5Z)-2,5-inter-o-phenylene-3,4- dinor-CBA2. Silica gel TLC Rf is 0.56 in the A-IX solvent system (the organic phase of an equilibrated mixture of ethyl acetate, acetic 50 acid, cyclohexane, and water, 9:2:9:10). The mass spectrum of the tris TIVIS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 129, 167, 74, 55, 69, 57, 147, and 45 and an M'-CH3 peak at 599.3418.
G. Following the procedure of Part D, 510 mg of the (5E) reaction product of Part C is transformed to31O mgof (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2,11,15- bis(tetrahydropyranyI ether). Silica gel 55 TLC Rf is 0.41 in 25% ethyl acetate and hexane containing 1 % acetic acid, and 220 mg of (5E)-2,5 I inter-o-phenylene-3,4-dinor-CBA2I 11,1 5-bis(tetrahydropyranyl ether)methyl ester. Silica gel TLC R f s are 0.48, 0.5 1, and 0.56 (stereoisomers) in 25% ethyf acetate and hexane. NMR absorptions are observed at 7.20, 6.43, 5.26-5.64, 4.70, 3.65, and 3.30-4.108.
H. Following the procedure of Part E, the reaction product of Part G (210 mg) is transformed to 60 mg of (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2. methyl ester. Silica gel TLC Rf is 0.57 in 40% acetone and trichloromethane and 0.46 in ethyl acetate. NIVIR absorptions are observed at 7.22, 6.44, 5.32-5.47, 3.68, 3.50-4.08, and 3.108. The mass spectrum of the bis TIVIS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 129, 227, 167, 55, 57, 173, 74, 466 and an MI-CH, peak at 541.3198.
GB 2 122 203 A.25 1. Following the procedure of Part F, the reaction product of Part H (110 mg) is transformed to 102 mg of (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2. Silica gel TLC Rf is 0.50 in the A-IX solvent system. The mass spectrum of the tris TMS derivative exhibits peaks of decreasing intensity at m/e 73, 75, 167, 129, 524,453,285,147,434,213, and an M-CH, peak at 599.3424.
EXAMPLE 13 (5 E)- 1,5-inter-m-phenylene-2,3,4-tri no r-CBA 21 Its methyl ester, and the corresponding (U) isomers.
Refer to Chart D.
A. Following the procedure of Example 12, Part A, a solution of 1.26 9 of the title product of Example 6 and 0.62 g of the title product of Example 5 are transformed to 2.3 g of formula W1 compound. Silica gel TLC Rf range is 0.37-0.56 (7 spots) (stereoisomers) in 25% ethyl acetate in hexane.
B. Following the procedure of Example 12, Part B, the reaction product of Part A (2.3 g) is transformed to 1.0 g of isomeric formula LVII compounds: (5E)- and (5Z)-2- decarboxy-2-(t-butyidi methylsi lyloxym ethyl)- 1, 5-inter-m-phenyl ene-2,3,4-tri nor-CBA2. 11,1 5-bis(tetrahydropyranyl ether).
Silica gel TLC R;s are 0.47, 0.54 and 0.58 (stereoisomers) in 30% diethyl ether and hexane.
C. Following the procedure of Example 12, Part C, 1.0 g of the isomerically mixed reaction product of Part B is transformed to 0.51 g of (5Z)-2-decarboxy-2-hyd roxym ethyl- 1,5-inter-m-phenylene-2,3,4 trinor-CBA2.1 1,1 5-bis(tetrahydropyranyl ether) and 0.40 g of (5E)-2decarboxy-2-hydroxymethyi-1,5- --- inter-m-phenylene-2,3,4-trinor-CBA2,1 1,15-bis(tetrahydropyranyl ether). For the (54-isomer, silica gel TLC R;s are 0.31 and 0.35 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are 20 observed at 7.18, 6.36, 5.19-5.65, 4.63, 4.58, 3.31-4.08, and 2.928. For the (5E)-isomer, silica gel TLC Rf's are 0.23 and 0.27 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.19, 6.37, 5.29-5.72, 4.67,4.60, 3.30-4.17, and 2.788.
D. Following the procedure of Example 12, Part D, 510 mg of the (U) reaction product of Part C is transformed to 310 mg of (5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2,11, 1 5-bis(tetrahydropyranyl 25 ether) and 240 mg of (5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2. methyl ester, 11,1 5-bis(tetra hydropyranyl ether). For the acid, silica gel TLC streak to about Rf 0.54 in 50% ethyl acetate and hexane. For the methyl ester, silica gel TLC R;s are 0.58, 0.63, and 0.68 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.28-8.00, 6.40, 5.13- 5.73, 4.71, 3.89, and 3.28-4.088.
E. Following the procedure of Example 12, Part E, 240 mg of the methyl ester product of Part D is transformed to 140 mg of (5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2. methyl ester. Silica gel TLC Rf is 0.49 in ethyl acetate. NMR absorptions are observed at 7.28-7.93, 6.40, 5.34-5.48, 3.88, and 3.328. The mass spectrum of the bis TMS derivative exhibits peaks of decreasing intensity at m/e 83, 85, 73,47, 213, 75, 129, 48, 87, 77, and an M±CH. peak at 527.2996.
F. To a solution of 140 mg of the reaction product of Part E in 6 mi of methanol under a nitrogen atmosphere is added a solution of 0.20 g of 85% potassium hydroxide in 20 mi of water. The resulting mixture is then stirred at ambient temperature for 7 hr, shaken with 200 mi of ethyl acetate and excess cold dilute aqueous hydrochloric acid. The organic layer is then washed with brine, dried over magnesium sulfate, concentrated under reduced pressure to yield 110 g of pure (54-1,5-inter-m- 40 phenylene-2,3,4-trinor-CBA2. Silica gel TLC Rf is 0.60 in the A-]X solvent system. The mass spectrum of the tris TMS derivative exhibits peaks of decreasing intensity at m/e 73, 271, 394, 129, 420, 510, 75, 147, 32, 74, and an M-CH3 peak at 585.3234.
G. Following the procedure of Example 12, Part D, 400 mg of the (5E) reaction product of Part C is transformed to 260 mgof (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2,11, 15-bis(tetrahydropyranyl 45 ether) and 190 mg of (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA,, methyl ester, 11,1 5-bis(tetra hydropyranyl ether). For the acid silica gel TLC streak to about Rf 0.36 in 50% ethyl acetate and hexane.
1 For the methyl ester, silica gel TLC R f s are 0.50, 0.53, and 0.57 (stereoisomers) in 25% ethyl acetate and hexane. NMR absorptions are observed at 7.38-7.95, 6.42, 5.13-5.75, 4. 68, 3.89, and 3.30-4.098.
H. Following the procedure of Example 12, Part E, 190 mg of the reaction product of Part G is transformed to 81 mg of (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2, methyl ester. Silica gel TLC R, is 0.51 in ethyl acetate. NMR absorptions are observed at 7.30-7.93, 6.43, 5.45-5.59, 3.89, 3.50-4.14, and 3.098. The mass spectrum of the bis TMS derivative exhibits peaks of decreasing intensity at m/e 73, 213,129, 75, 83, 452,173, 85, 262, 362, and an W-CH, peak at 527.2996. 55 1. Following the procedure of Example 13, Part F, 81 mg of the reaction product of Part H is transformed to 65 mg of (5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA,. Silica gel TLC Rf is 0.60 in the A-IX solvent system. The mass spectrum of the tris TMS derivative exhibits peaks of decreasing intensity at m/e 73, 271, 394, 75, 510, 129, 420, 147,173, 395, and an W- CH, peak at 585.3227.
Following the procedure of Examples 12-13, but employing each of the various formula LV compounds described in and following Example 11 in each of the various formula XLIV described in and following Examples 9 and 10, there are prepared each of the various formula L compounds in free acid or methyl ester form.
26 GB 2 122 203 A 26 EXAMPLE 14 9fi-methyi-CBA2, methyl ester, 11,1 5-bis(tetrahydropyranyl ether) (Formula 1-XXXIV: R.i, is hydrogen, R37 is methyl, Z2 is -(CH 2) - and R,., Y1, M6, L,, and R7 are as defined in Example 3) and the corresponding (5E) and (5Z) free acids (Formula 1-XXXIII). 5 Refer to Chart G.
A. A suspension of 57% sodium hydride in mineral oil (1.90 g) is washed with hexane and treated with 130 mi of dry dimethyl sulfoxide (DMSO). The resulting suspension is heated at 65CIC for 1 hr under a nitrogen atmosphere and the resulting solution cooled to 150C and treated dropwise over 15 min with 10.0 g of 4-carboxybutyitriphenylphosphonium bromide. The resulting orange solution is stirred for 15 min at 1 OIC and then treated dropwise over 15 min with a solution of 2.12 g of the title 10 product of Example 3 in 20 mi of dry DMSO. The resulting solution is then stirred at ambient temperature under a nitrogen atmosphere for 60 hr, treated with 15 m[ of water, stirred for 30 min at ambient temperature, added to 200 mi of ice water and 100 m] of brine, acidified with 1 N aqueous hydrochloric acid, and extracted with 900 m] of diethyl ether. The ethereal extracts are then washed with 1 1 of water and 200 mi of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 4.8 g of a yellow oil, the formula 1-XXXIII carboxylic acid.
B. The formula 1-XXXIII product and 42 mi of diisopropylethylamine in 120 mi of acetonitrile at 1 OIC under a nitrogen atmosphere is treated with 15 mi of methyl iodide and allowed to warm slowly to ambient temperature. The resulting suspension is then stirred for 16 hr, treated with 3.0 mi of methyl iodide, stirred for an additional 2 hr, added to 500 mi of brine,and extracted with 1 1 of ethyl acetate. 20 The organic extracts are then washed with 250 mi of 0.5 N potassium bisulfate, 250 m] of saturated aqueous sodium bicarbonate, 250 mi of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a solid residue. The residue is then chromatographed on 500 g silica gel, eluting with 8% acetone in hexane to yield 2.25 9 of title formula LXXW product. NMR absorptions (CDO,) are observed at 0.9, 1.05, 1.08, 3.66, 3.02-4.35, 4.70, and 4.956. Infrared absorptions are observed at 1730,1670,1645,1200,1165, 1135, 1080,1035, 1020, 980, and 870 cm-1. Silica gel TLC Rf is 0.46 in ethyl acetate and hexane (11:3) and 0.26 in ethyl acetate and hexane (1:6).
C. Alternatively the isomeric formula 1-XXXHI reaction products of Part A are separated into the (5E) and (54 title free acid products by chromatography on acid washed silica gel eluting with 10-30% ethyl acetate in hexane.
Following the procedure of Example 9, but employing each of the various formula 1-XXX1 ketones in place of the Example 3 product, there are prepared each of the various formula LXXXIV methyl esters wherein Z2 is (CH,)j-.
Further following the procedure of Example 14, but employing a formula LXXXII to-carboxytri- phenylphosphonium compound wherein Z. is other than -(CH.J-, each of the various formula LXXXI 35 ketones is transformed to corresponding formula LXXXIV ester wherein Z2 is other than -(CH2)3--.
EXAMPLE 15 (5Z)-2-Decarboxy-2-hydroxymethyl-9p-methyl-CBA,, 11, 1 5bis(tetrahydropyranyl ether) (Formula LXXXVI: R,6, R371 Z2, R18, M6, 1-1, and R7 are as defined in Example 14 and its (5E) isomer (formula LXXXVII). Refer to Chart G.
A suspension of 0. 16 g of lithium aluminum hydride in 45 ml of dry tetrahydrofuran at OOC under a nitrogen atmosphere is treated dropwise with 1.98 g of the title product of Example 14 in 15 ml of dry tetrahydrofuran. The resulting suspension is stirred for 1 hr at OIC and thereafter for 1 hr at ambient temperature. The resulting mixture is then cooled to OIC, quenched by addition of 0.16 ml of water, 0.16 ml of 15% aqueous sodium hydroxide. After stirring for 1 hr at ambient temperature, treatment with magnesium sulfate and filtration with diatomaceous earth, rinsing with diethyl ether, yields a mixture which is concentrated under reduced pressure. The resulting product, 0.25 g, is chromatographed on 180 g of silica gel, eluting with 30% ethyl acetate in hexane to yield 1.03 g of formula LXXXVII product and 1.06 g of formula LXXXVI product. For the formula LXXXVI product NIVIR 50 absorptions (CDO) are observed at 0.90, 1.09, 3.2-4.4, 4.72, 5.0-5.96. Infrared absorptions are observed at 3470, 1760,1200,1135, 1120,1075, 1035,1020, and 980 cm-1. Silica gel TLC Rf is 0.29 in ethyl acetate and hexane (35:65). For the formula LXXXVII product NMR absorptions (CDC13) are observed at 0.90, 1.05, 3.2-4.4, 4.6-4.95, 5.05-5.976. Infrared absorptions are observed at 3470,1670,1200,1125,1110,1080,1035,1020, and 985 cm-1. Silica gel TLC Rf is 0.36 in ethyl 55 acetate and hexane (35:65).
Following the procedure of Example 15, but employing each of the various formula LXXXIV esters described following Example 14, there are prepared each of the respective formula LXXXVI and formula LXXXVII primary alcohols.
27 GB 2 122 203 A 27 EXAMPLE 16 (5Z)-9p-methy]-CBA2, methyl ester (Formula LXXXVIII: X, is -CO0CH, R, is hydroxy, M, is a-OH:P-H, and R16, R17, L, R71 Y1, and Z2 are as defined in Example 15).
Refer to Chart G.
A. A solution of the formula LXXW title product of Example 15 in 38 mi of acetone at -200C 5 under a nitrogen atmosphere is treated over 5 min with 1.9 mi of Jones reagent (prepared by dissolving 133.6 g of chromium trioxide in 115 mi concentrated sulfuric acid and diluting with water to a volume of 500 mi), stirred for 2 hr at -201C, quenched by addition of 2.3 mi of isopropanol, stirred for 40 min at -201C, diluted with 200 mi of brine, extracted with 400 mi of ethyl acetate, washed with 600 mi of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 1.01 g carboxylic 10 acid corresponding to the formula 1-XXW primary alcohol as a pale green oil.
B. A solution of the product of Part A in 11 mi of acetonitrile at 1 50C under a nitrogen atmosphere is treated with 4.1 mi of dilsopropylethyla mine and 1.5 mi of methyl iodide. The resulting suspension is then stirred at ambient temperature for 17 hr, treated with 0.3 mi of methyl iodide, stirred for 2 hr at ambient temperature, diluted with 50 mi of brine, extracted with 100 mi of ethyl acetate, washed with 15 mi of 0.5 M potassium bisulfate, 50 mi of aqueous sodium bicarbonate and 50 mi of brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to yield 1.02 g of the methyl ester corresponding to the carboxylic acid product of Part A.
C. A solution of the product of Part B in 56 mi of a mixture of tetrahydrofuran, water, and acetic' acid 0:2M is heated to 451C under a nitrogen atmosphere for 3 hr, cooled, diluted with 200 mi of 20 brine, and extracted with 400 m] of diethyl acetate. The organic extracts are then washed with 600 mi of saturated aqueous sodium bicarbonate and 400 mi of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.9 9 of crude title product as a yellow oil.
Chromatographing on 100 9 of silica gel, eluting with hexane and ethyl acetate Q:7) yields 0.39 9 of pure title product as a colorless oil. NMR absorptions (CDCI,) are observed at 0.89, 1.08, 3.5-4.35, 25 3.66, 5.0-5.78. infrared absorptions are observed at 3360, 1740, 1670, 1455, 1435, 1370, 1240, 1225, 1195, 1170, 1075, 1020, and 970 cm-1. Silica gel TLC Rf is 0.22 in ethyl acetate and hexane (73).
Following the procedure of Example 16, but employing each of the various formula 1-XXW compounds described following Example 15, there are prepared each of the various formula 1-XXXVIII 30 9p-methy]-CI3A2 compounds wherein X, is -COOR1.
EXAMPLE 17 (5E)-9p-methyi-CBA2, methyl ester (Formula 1-XXMX: R R X Z R R M L and R are a defined in Example 16).
RefertoChartG.
A. Following the procedure of Example 16, Part A, 0.60 g of the formula LXXXVII product of Example 15 is transformed to the carboxylic acid corresponding to the formula 1-XXXVII primary alcohol, yielding 0.66 g of a green oil.
B. Following the procedure of Example 16, Part B, the product of Part A above (0.66 g) is transformed to the methyl ester corresponding to the carboxylic acid product of Part A, yielding 0.58 g 40 of a yellow oil.
C. Following the procedure of Example 16, Part C, the product of Part B above (0.58 g) is transformed to 0.25 g of title product as a coloriess oil. NMR absorptions (CDCI,) are observed at 0.90, 1.05, 3.30, 3.66, 3.75-4.25, 5.0-5.78. Infrared absorptions are observed at 3360, 1740, 1670, 1455,1435, 1250, 1225, 1195,1170, 1075, 1020, and 970 cm-1. Silica gel TLC Rf is 0.22 in ethyl 45 acetate and hexane (3:7).
Following the procedure of Example 17, but employing each of the various formula 1-XXXVII compounds described following Example 15, there are prepared each of the various formula LXXXIX products wherein X, is -COOCH3.
161 171 11 21 81 11 11 lt 7 EXAMPLE 18 (5Z)-9p-methyl-CBA 2 A solution of 0.28 g of the title product of Example 16 in 8 ml of methanol is stirred at ambient temperature under a nitrogen atmosphere and treated with 1 ml of 8 M aqueous sodium hydroxide. The resulting yellow solution is then stirred for 5 hr at ambient temperature under a nitrogen atmosphere, diluted with 90 ml of ice and brine, acidified to pl-12 with 1 N hydrochloric acid, extracted with 360 ml of 55 ethyl acetate, washed with 120 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.25 g of crude title product. Chromatography on 30 g of silica gel, eluting with the A-IX solvent system (the organic phase of an equillibrated mixture of ethyl acetate, acetic acid, cyclohexane, and water, 9:2:5:10), yields 0.235 g of pure title product as a colorless oil.
NIVIR absorptions (CDC13) are observed at 0.89, 1.08, 3.5-4.35, 5.0-5.7, 6.058. Infrared absorptions 60 are observed at 3340, 2660, 1710,1240, 1205, 1175, 1130,1075, 1055, 1020, and 970 cm-1.
Silica gel TLC Rf is 0.25 in the A-IX solvent system.
28 GB 2 122 203 A 28 Following the procedure of Example 18 each of the various methyl esters prepared following Example 16 is transformed to the corresponding carboxylic acid.
EXAMPLE 19 (5E)-9p-methyl-CBA,.
Following the procedure of Example 18, 0.25 g of the title product of Example 17 is transformed 5 to 0.21 g of title product as a colorless oil. NIVIR absorptions (CDCI,) are observed at 0.90, 1.06, 3.5-4.3, 5.0-5.7, and 5.938. Infrared absorptions are observed at 3340, 2660, 1710, 1300, 1240, 1175,1130, 1075,1055, 1020, and 970 cm-1. Silica gel TLC Rf is 0.27 in the A-IX solvent system.
Each of the various carboxylic acids corresponding to LXXXVIII and LXXXIX wherein X, is -COOH- can be prepared from the corresponding formula LXXXIII reaction products by acid hydrolysis of the tetra hydropyra nyl ether protecting groups of C-1 1 and C-1 5. [The (5Z) LXXXIII reaction products from Example 14, Part C go to formula LXXXVIII products; and the (5E) LXXXIII reaction products from Example 14, Part C go to formula LXXXIX products].
Following the procedure of Example 19, but employing each of the various formula LXXXIX methyl esters described following Example 17, there are prepared each of the various corresponding carboxylic acids.
EXAMPLE 20 2p-(t-butyldimethylsilyloxymethyl)-5p-methyl-7-oxo-3crtetrahydropyran-2-yl-o xy-bicyclo[3.3.0]octane (Formula LXII: n is the integer one, R, is t-butyidimethylsilyi, and R,, is tetra hydropyra nyloxy).
RefertoChartE.
A. A solution of 40.6 g of 3a-benzoyloxy-5a-hydroxy-2p-hydroxymethyl-1 acyclopentaneacetic acid, to-lactone in 250 ml of dimethy1formamide, stirring at OIC under a nitrogen atmosphere, is treated with 25 g of imidazole in 28 g of t-butyldimethylsilyl chloride. The resulting solution is then stirred for 67 hr at ambient temperature, added to 500 ml of water, extracted with three 500 ml portions of diethyl ether, washed with 500 ml of 10% aqueous potassium bisulfate, 500 ml of aqueous sodium bicarbonate and 500 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 59.9 g of 3a-benzoyloxy-5a-hydroxy-2p-(t- butyidimethylsilyloxymethyl)-1 a-cyclopentaneacetic acid, oj lactone as a white solid. NIVIR absorptions (CDCI,) are observed at 0.06,0.91, 2.1-3.12, 3.74, 4.94-5.54, 7.24-7.67, and 7.9-8.28. Infrared absorptions are observed at 1780, 1720,1600, 1585,1490,1270,1255,1180,1115,1100,1070,1050,830, 790, and 710 cm-1. Silica gel TLC Rf 30 is 0.20 in ethyl acetate and hexane (1:4).
B. A solution of 59.1 g of the reaction product of Part A and 500 ml of absolute methanol, stirring at ambient temperature under a nitrogen atmosphere, is treated with 35 ml of a 25% solution of sodium methoxide and methanol. The resulting reaction mixture is then stirred for 90 min at ambient temperature and quenched by addition of 9.5 ml of glacial acetic acid. Methanol is removed under 35 reduced pressure and the resulting residue diluted with 500 ml of saturated aqueous sodium bicarbonate. The resulting mixture is then extracted with two 500 ml portions of ethyl acetate washed with 300 ml of saturated aqueous sodium bicarbonate in 200 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 58 g of an oily solid, crude 3a,5a-dihydroxy-2A-(t-butyI dim ethylsilyloxymethyl)- 1 a-cyclopentaneacetic acid, 6o lactone. This crude product is then chromatographed in 800 g of silica gel, eluting with 20-75% ethyl acetate in hexane to yield pure title product as a white crystal solid. Melting range if 60.51C to 621C. NIVIR absorptions (CDCI,) are observed at 0.06,0.90,1.7-3.0,3.67, 3.9-4.4, and 4.7-5.13.8. Silica gel TLC Rf is 0.3 in 50% ethyl acetate in hexane.
C. A solution of 37.3 g of reaction product of Part B in 400 ml of methylene chloride, stirring at 45 OIC under a nitrogen atmosphere, is treated with 18 ml of dihydropyran and 0.14 g of pyridine hydrochloride. The resulting solution is stirred at ambient temperature for 13 hr, treated with an additional 3 ml of dihydropyran and 30 mg of pyridine hydrochloride, stirred for an additional 4 hr, washed with two 400 ml portions of saturated aqueous sodium bicarbonate and 400 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 49 g of a pale yellow 50 oil, crude 5a-hydroxy-3a-tetrahydropyran-2-yloxy-2p-(tbutyidimethylsilyloxymethyl)-1 a-cyclo pentaneacetic acid, o) lactone. Chromatography on 800 g of silica gel, eluting with 0-75% ethyl acetate in hexane yields 37 g of pure product as a colorless oil. NMR absorptions (CDC13) are observed at 0.05, 0.90, 1.62, 2.0-3.0, 3.6, 3.2-4.4,4.67, and 4.8-5.2.8. Infrared absorptions are observed at 1780,1255,1175,1160,1116,1080,1035,1020,1005, 975,835, and 775 GM-5. Silica gel TLC Rf 55 is 0.25 in hexane and ethyl acetate (2:1).
D. A solution of 28 ml of dimethyl methylphosphonate in 800 ml of dry tetrahydrofuran at -700C under a nitrogen atmosphere is treated with 160 ml of 1.56 M n- butyllithium in hexane, stirred for 30 min at -700C. The resulting mixture, maintained at -700C, is then treated dropwise over 30 min with 41.7 g of reaction product of Part C in 200 ml of tetrahydrofuran. The resulting solution is then stirred at 60 -701C for 1 hr, allowed to warm, stirred for an additional 2.5 hr at ambient temperature, quenched by addition of 14 ml of glacial acetic acid, added to 1 1 of brine, extracted with three 700 ml portions of diethyl ether, washed with 500 ml of brine dried over anhydrous sodium sulfate, and concentrated z 29 GB 2 122 203 A..29 under reduced pressure to yield 63 g of a yellow oil, crude 6p-(t- butyidimethylsilyloxymethyl)-3- di methylphosphonomethyl-3-hyd roxy-2-oxa-7 a-tetra hyd ropyra nyloxybicyclo[3.3.01 octane.
Chromatography on 800 g of silica gel eluting with 50-75% ethyl acetate in hexane yields 44.2 g of pure title product as a colorless oil. NIVIR absorptions (CDC13) are observed at 0.05, 0.89, 1.23-3.02, 2.2-4.37, 4.70, and 4.993. Infrared absorptions are observed at 3380, 1255, 2235, 1120, 1050, 5 1035, 835, and 775 cm-1. Silica gel TLC Rf is 0.25 in ethyl acetate.
E. A suspension of 29.2 g of chromium trioxide in 700 ml of methylene chloride, stirring at ambient temperature under a nitrogen atmosphere, is treated rapidly with 50 ml of pyridine, treated with dry diatomaceous earth, stirred for 5 min, and then treated with 23. 8 g of title product of Part D in 60 ml of methylene chloride. The resulting suspension is then stirred for 45 min at ambient temperature 10 under a nitrogen atmosphere and filtered through 300 g of silica gel, eluting with 2 1 of ethyl acetate in acetone (2:1). Concentration under reduced pressure yields 24 g of a brown yellow oil, crude 3p-(t butyldimethylsilyloxymethyl)-2a-(2'-dimethylphosphonomethyl-2'-oxoethyl)4a-t etrahydro- pyra nyloxy-penta none. High pressure liquid chromatography of 12 g of the crude product on silica gel eluting with 20% acetone in methylene chloride yields 4.54 g of pure product as a colorless oil. NIVIR 15 absorptions (CDCI,) are observed at 0.05, 0.88, 2.8-4.5, 3.77, and 4.868. Infrared absorptions are observed at 1745,1715, 1255, 1130,1115, 1060, 1025, 835, 810, and 775 cm- 1. Silica gel TLC Rf is 0.27 in 20% acetone in methylene chloride and 0.3 in ethyl acetate.
F. A degassed suspension of 0.52 g reaction product of Part E, 0.15 g anhydrous potassium carbonate, and 0.59 g 1 8-crown-6 ether in 20 ml toluene are stirred at 75'C for 6 hr under a nitrogen 20 atmosphere and thereafter cooled to OOC. The resulting solution is then washed successively with 20 ml brine, a solution of 15 ml water and 5 ml brine, and 20 ml brine, dried over anhydrous sodium sulfate, and concentrated t6 yield a brown residue crude 6A-t- butyldimethylsilyloxymethyl-7a-tetrahydropyran-2-yl-oxybicyclo[3.3.0]oct-1 -en-2-one, filtering through 7 g of silica gel and eluting with hexane and ethyl acetate (70 ml, 1:1) yields 0.31 g of product as an oil. High pressure liquid chromatography (10 ml fractions, 3.8 ml/minute flow rate) on silica gel, eluting with hexane and ethyl acetate (3:1) yields 0.20 g of pure product as a colorless oil. NMR absorption (CDCI 3) of the trimethylsilyl derivative are observed at 0.06, 0.90, 1.20-3.20, 3.20-4. 85, and 5.85-6.08. Infrared absorptions are observed at 171011630,1250,1130, 1115, 1075, 1030, 965, 870, 835, 810, 775 cm-1. Silica gel TLC.Rf is 0.34 in hexane and ethyl acetate (2:1).
G. A suspension of 0.35 g of anhydrous copper iodide in 12 ml of anhydrous diethyl ether at -200C under an argon atmosphere is treated dropwise with 2.0 ml of 1.4 M methyllithium. The resulting solution is then stirred at -201C for 15 min, treated at -201C dropwise over 1.5 hr with a solution of 0.22 g of the reaction product of Part F in 12 ml of anhydrous diethyl ether. The resulting suspension is then stirred at -200C for 2 hr, added to 50 ml of 1 M aqueous ammonium chloride, -extracted with 150 ml of diethyl ether, washed with 50 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.23 g of crude title product as a pale yellow oil. Chromatography on 30 g of silica gel, eluting with ethyl acetate and hexane (1 -4) yields 0.22 g of pure title product as a colorless oil. NIVIR absorptions (CDCI,) are observed at 0.05, 0.90, 1.16, 1.3-2.9, 3.3-4.4, and 4.638. Infrared absorptions are observed at 1745, 1255, 1135, 1110,1095, 40 1075,1035, 1020, 835, and 775 cm-1. Silica gel TLC Rf is 0.32 in ethyl acetate and hexane (1:4).
EXAMPLE 21 N-methyl-(l-fluoro-5tetrahydropyranyloxypentyl)phenylsulfoximine (Formula XCll: Z2 is (CH2)32_ and R1. is tetra hyd ro pyra nyl.
RefertoChartH.
Diisopropylamine (0.59 g) is dissolved in 21 ml of tetrahydrofuran and the resulting mixture cooled to -78C with stirring under an argon atmosphere. Thereafter triphenylmethane is added, for use as an indicator, and a solution of n-butyllithium and hexane is added dropwise until the resulting mixture attains a pink color. After stirring for an additional 75 min, the resulting mixture is treated with 1.50 g of N-methyl-(5-tetrahydropyranyloxypentyl)-phenylsulfoximine dissolved in 6 ml of dry tetra hydrofuran. The resulting mixture is then stirred for an additional 30 min at -781C. Thereafter excess perchloryl fluoride (FC1 0) is bubbled through the solution for 4- 5 min, during which time a stream of argon is also bubbled through the mixture for safety reasons. The resulting mixture is then stirred at additional 90 min at -781C and then the reaction is quenched by addition of 5% aqueous sodium bicarbonate. After equilibration of the reaction mixture to ambient temperature, the mixture is 55 diluted with additional 5% aqueous sodium bicarbonate and extracted with methyle ' ne chloride. The organic extracts are then washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to yield 1.64 g of a yellow oil. Chromatography on silica gel columns in a series, -eluting with ethyl acetate and hexane (1:1) yields 0.18 g of the formula XCII title product as a mixture of diastereomers. Silica gel TLC Rf in ethyl acetate and hexane (1:1) are 0.54 (less polar isomer) 60 and 0.45 (more polar isomer). NIVIR absorptions (CDCI,) for the less polar isomer are 1.2-2.15, 3.65, 3.68, 3.1--4.1, 4.4-4.8, 5.5, and 7.4-8.16. NMR absorptions (CDCI,) for the more polar isomer are 1.15-2.20, 3.63, 3.1-4.1, 4.45-4.65, 5.27, and 7.4-8.18.
Following the procedure of Example 2 1, but employing each of the various formula XCI GB 2 122 203 A 30 phenyisulfoxamines, there are prepared each of the various corresponding formula XCH fluorinated phenyisuifoxamines.
EXAMPLE 22
5-Fluoro-2-decarboxy-2-hydroxymethyl-CBA2,1,11,15-tris(tetrahydropyranyI ether). (Formula XCIV:
R16 and R17 are both hydrogen, RIO is tetra hyd ropyra nyl, Z2 is -(CH,)-, n is the integer one, R 18 is 5 tetra hydropyranyloxy, Yj is trans-CH=CH-, M6 is a-tetrahydropyranyloxy:A- hydroxy, R, and R, of the L, moiety are both hydrogen, and R, is n-butyl).
Refer to Chart H.
Diisopropyla mine (164 mg) and triphenyl methane (1.5 mg) are dissolved in 4 ml of dry tetrahydrofuran and the resulting solution is cooled to -781C under a nitrogen atmosphere. A solution 10 of n-butyllithium and hexane is added until a faint pink color is attained. This solution is then stirred an additional 80 min. Thereafter, 0.488 g of the title product of Example 21 in 4 ml of dry tetrahydrofuran is added dropwise. Thereafter 608 mg of 7-oxo-3a-tetrahydropyran-2-yloxy- 2p-[(3'S)-3-tetrahydropyran-2-yloxy-trans-l'-octenyl] bicyclo[3.3.0]octane (Formula XCIII: R 16, R17, n, Rj,, Y1, M6, L1, and R7 are as defined for the title product) in 4 ml of tetrahydrofuran is added to the reaction mixture. After 4 15 min, the resulting mixture is quenched by addition of saturated aqueous ammonium chloride and ethyl acetate is thereafter added to the reaction mixture, which is maintained at -780C. The resulting mixture is then allowed to warm until solids separate. Thereupon additional ethyl acetate is added, the reaction extracted with brine. The ethyl acetate layer is then dried over sodium sulfate and concentrated under reduced pressure.
An aluminum amalgam is then prepared by reacting 0.31 g of 20 mesh aluminum with 2.5 mi of aqueous mercuric chloride followed by washing with ethyl acetate and diethyl ether. The residue from the ethyl acetate layer (described in the preceding paragraph) is dissolved in 5 ml of tetrahydrofuran and the solution cooled to OOC. This cooled solution is then treated with aluminum amalgam, 2 ml of water, and 1 ml of glacial acetic acid. The resulting mixture is then stirred for 2 hr at OOC and 16 hr at 200C. 25 The reaction is then diluted with ethyl acetate and filtered with diatomaceous earth. The ethyl acetate layer is then washed with 5% aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 0.96 g as an oily residue. Chromatographing over 100 g of silica gel and eluting with 500 mi of 15% ethyl acetate in mixed hexanes, 500 ml of 25% ethyl acetate in mixed hexanes, 300 ml of 50% ethyl acetate in mixed hexanes, and 800 ml of 30 50% acetone in methylene chloride, taking 20 ml fractions, yields a less polar isomer in fractions 22-26 (80 mg) and a more polar isomer in fractions 30-36 (74 mg). These isomers represent the C-5 diastereomers of the formula XCIV product. For the less polar isomer, NMR absorptions (CDCI,) are observed at 0.65-2.65, 3.15-4.15, 4.35-4.75, and 5.25-5.756. For the more polar isomer, NMR absorptions (CDC[,) are observed at 0.6-2.65, 3.10-4.16, 4.40-4.7, and 5.2-5.76. Silica gel 35 TLC Rf for the less polar isomer is 0.66 and for the more polar isomer is 0.57 in ethyl acetate and mixed hexanes (3:7).
Following the procedure of Example 22, but employing each of the various formula XCI [I ketones, there are obtained each of the various formula XCIV intermediates wherein Z2 is -(CH2)3-.
Further following the procedure of Example 22, but substituting each of the various fluorinated 40 phenylsulfoximines described following Example 2 1, there are prepared from the various formula XCIll ketones each of the various formula XCIV products wherein Z2 is other than -(CH2)3- EXAMPLE 23 5-Fluoro-2-decarboxy-2-hydroxymethyi-CBA, (more polar isomer) (Formula XCV: R,, R171 Z2, n, R, M, L, and R7 are as defined in Example 17).
Refer to Chart H.
The title product of Example 22 (74 mg) is dissolved in 2 mi of a mixture of tetra hyd rofu ran, water, and glacial acetic acid (2:2:1) and the resulting mixture stirred under a nitrogen atmosphere. The reaction mixture is maintained at ambient temperature for 17 hr, thereafter at 401C for 7 hr, and finally at 230C for an additional 24 hr. The resulting mixture is then diluted with ethyl acetate, washed with 5% aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 52 mg of crude title product. Chromatography over silica gel, eluting with acetone and methylene chloride (60:40) yields 19 mg of pure title product. NMR absorptions (CDC'3) are observed at 0.6-2. 60, 2.60-3.30, 3.30-4.15, 5.1-5.9,5. "C-NMR absorptions (CDCI,) are observed at 135.8, 133.0, 117.5 (d 55 J=18Hz), 77.4, 73.3, 62.6, 57.6, 46.4, 41.1, 38.0, 37.2, 36.2 (d J=5Hz), 31.9, 31.8, 31.2, 29.5 (d J=29Hz), 25.2, 22.5, 14.00. Silica gel TLC Rf is 0.280 in acetone and methylene chloride (1.1).
EXAMPLE 24
5-Fluoro-2-decarboxy-2-hydroxymethyi-CBA 2 (less polar isomer) Following the procedure of Example 23, 85 mg of less polar title product of Example 22 are 60 transformed to 25 mg of pure title product. NMR absorptions (CDC'3) are observed at 0.5-2.5, 3.1-4.75, and 5.05-5.8(5. 13 C-NMR absorptions (CDC'3) are observed at 137.0, 132.6, 77.0, 73.6, 31 GB 2 122 203 A 31 62.3, 57.4,45.5,41.6,36.9, 36.5,34.4 (d J=3.1H4, 32.5 (d J=5.4H4, 31.8, 31.7,29.2 (d J=28.9H4, 25.4, 22.6, 22.4, and 14.08. Silica gel TLC Rf is 0.33 in acetone and methylene chloride.
Following the procedure of Examples 23 and 24, but employing the various diastereomeric products described following Example 22, there are prepared each of the various diastereomers. corresponding to formula XCV.
EXAMPLE 25 5-fluoro-CI3A2 (more polar isomer) (Formula LXXVI: Z, n, R, Y1, M,, L, and R7 are as defined in Example 23).
Refer to Chart H.
The platinum oxide catalyst is prepared by suspending 46 mg of 85% platinum oxide in 9 ml of 10 water and hydrogenating the resulting mixture at ambient temperature and pressure for 34 min. To this suspension is added 58 mg of sodium bicarbonate and 18 mg of the title product of Example 23 dissolved in 2 ml of acetone. The resulting mixture is then warmed to 601C and oxygen bubbled therethrough for 80 min. The reaction mixture is then filtered through diatomaceous earth and the filter cake washed in water. The filtrate is then acidified to pH 4 with 5% aqueous sodium hydrogen sulfate and extracted with ethyl acetate. The organic extracts are then dried over magnesium sulfate and con centrated under reduced pressure to yield 21 mg of pure title product. NMR absorptions (CDCI,) are observed at 0.6-2.8, 3.0-4.2, and 4.65-5.88. 13 C-NMR absorptions (CDCI,) are observed at 176.9, 135.5, 133.2, 118.5 (d J=1 7.5Hz), 77.7, 73.5, 57.3, 46.5, 41.0, 38.2, 37.0, 36.2 (d J=4.8Hz), 32.3, 3 1.1 (d J=1 3.5Hz), 28.5 (d J=28.3Hz), 25.2,22.6, 21.0, and 114.03. Silica gel TLC Rf is 0.39 in 20 the A-IX solvent system.
EXAMPLE 26
5-Fluoro-CBA2 (less polar isomer).
Following the procedure of Example 25, 24 mg of the title product of Example 24 yields 23 mg of pure title product. NMR absorptions (CDCI) are observed at 0.6-2.9, 3.3-4. 2, 5.0-6.05 13C-NMR 25 absorptions (CDCI,) are observed at 176.8,135.4,132.9,118.3 (d J=1 8. 211z), 77.6, 73.4, 57.2,46.3,41.2 37.8, 36.8,34.6 (d J=2.7Hz), 32.8,32.4,31.7, 28.7 (d J=28.4Hz), 25.2,22.6, 2 1.1, and 14.08. TLC Rf is 0.50 in the A-IX solvent system.
The reaction products of Example 25-26 are obtained as diastereomeric mixtures of (5E) and (54 geometric isomers. These geometric isomers are characterized herein as "less polar" and "more 30 polar" isomers based on TLC motilities. The isomers of these 5-fluoro- CBA2 compounds correspond to the (5E) and (5Z) geometric isomers of CBA2 itself. On the basis of relative biological activities, the more polar 5-fluoro-CBA2 isomer yields more potent pharmacological effects and on this basis could be assig ned the (54 structure based on pharmacological considerations alone. However, the 13 C-NMR data suggests the more polar isomer corresponds to the (5E) structure of the 5- fluoro-CBA2 compound.
Following the procedure of Examples 25-26, there are prepared each of the varioius formula XCVI 5-fluoro-CBA2 diastereomers from the starting materials described following Example 24. Further following the procedures known in the art, each of the various 5-
fluoro-CBA2 compounds described in and following Examples 24-25 is transformed to the corresponding formula XCVII 5 fluoro-CBA2 analogs.
EXAMPLE 27 (U)-9-methyl-CBA2 adamantylamine salt The title product of Example 18 (54 mg), (5Z)-9p-methyl-CBA2 in 6 ml of diethyl ether is combined with 23 mg of adamantylamine. After 10 min the precipitate forms which is thereafter stirred for 12 hr, decanted, and concentrated under reduced pressure to yield 68 mg of a solid, pure title product. Melting 45 range is 110-1 141C.
EXAMPLE 28 (5Z)-9p-methyi-CBA2, calcium salt hydrate.
The title product of Example 18 (0.95 g), 9p-methyi-(5Z)-CBA,, calcium oxide (0.064 g), freshly boiled water (9.2 mi), and distilled tetrahydrofuran (6 mi), are combined by heating to 5WC under a 50 nitrogen atmosphere with stirring for 20 min. The resulting mixture is then filtered, washed with tetrahydrofuran, and concentrated under reduced pressure to yield a residue. The residue is then dissolved in tetrahydrofuran (10 mi) and concentrated 8 times to yield a cream-colored foam. This foam is then dissolved in 6 mi of tetrahydrofuran which is dripped into anhydrous diethyl ether (95 mi). The resulting suspension is then stirred for 15 min at ambient temperature under a nitrogen atmosphere and 55 filtered. The filter cake is then washed with anhydrous diethyl ether and dried for 20 hr under reduced pressure at ambient temperature to yield 0.686 g of title product. Melting range is 101 -1 081C. Following atmospheric equillibration melting range is 80-11 71C. Infrared absorptions are observed at 3330, 1670,1555,1455,1345,1310,1270,1075,1020,970 cm-1 32 GB 2 122 203 A 32 EXAMPLE 29 8a-hydroxy-7p-(3a-hydroxy-trans-octenyl)-tricyclo[4.3.llnonan4-one, 8,3-bis(tetrahydropyranyl ether) (Formula XXV: R181 Y11 M6, Ll, R27, and n are as defined in Example 1, R1. and R 37 taken together are CHj--). Refer to Chart A.
A. The formula XXIV title product of Example 1 (4.0 g) and benzophenone (2 g) in one liter of methanol is photolyzed (3500 A lamp) for 3 hr while argon is bubbled through the solution. The methanol is then removed by concentration under reduced pressure and the residue chromatographed on 600 g of silica gel eluting with a mixture ranging from ethyl acetate in hexane (1:3) to 100% ethyl acetate. Compound XXVI, lp-hydroxymethyl-7a-hydroxy-6p-(6'a-hydroxy-trans- l'octenyl)bicyclo[3.3.0]octan-3-one, 7,31-bis(tetrahydropyranyl ether) is obtained as a white solid (3.45 g). Crystallization from-13thyl acetate in hexane yields a white solid with melting range 65-701C. NIVIR absorptions (CDCU are observed at 0.89, 1.17-2.90, 2.92-4.40, 4.69, and 5. 24-5.773. Infrared absorptions are observed at 3420,1730,1200, 1125,1110,1070,1040, 1020, and 970 cm-1. Silica gel TLC Rf is 0.29 in hexane and ethyl acetate (1:4).
B. A solution of 0.6 g of the reaction product of Part A and 0.49 g of ptoluenesulfonyl chloride in ml of pyridine is cooled to O"C under argon for 70 hr, added to 100 ml of ice, diluted with 300 ml of water, and extracted with diethyl ether (800 ml). The ethereal extracts are then washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and chromatographed eluting with 50% to 80% hexane in ethyl acetate to yield 0.49 g of formula XXVII compound, 3-oxo-7a-tetrahydropyran- 20 2-yloxy-6p-[(3's)-3'-tetrahydropyran-2-yloxy-trans-l'-octenyll-1 A-(ptoluenesulfonyl) oxymethylbicyclo[3.3.0]octane, as a colorless oil. NIVIR absorptions (CDC[,) are observed at 0.88, 1.06-2.9, 2.45, 3.17-4.35, 4.52-4.83, 9.2-5.8, 7.37, and 7.813. Infrared absorptions are observed at 1740,1600,1360,1200,1190,1175,1130,1110,1075,1035,1020,970, and 820 cm-1. Silica gel TLC Rf is 0.45 or 0.26 in ethyl acetate and hexane (11 or 1:2).
C. A degassed solution of 0.49 g of the reaction product of Part B and 1 ml of t-butanol in 50 ml of dry tetrahydrofuran at OIC under an argon atmosphere is treated with 0.8 mi of 1.7 M potassium t butoxide in tetrahydrofuran. After 5 min the reaction is allowed to warm and the resulting brown solution stirred for 3 hr at ambient temperature. Thereafter 90 ml of brine is added and the mixture is extracted with 270 ml of ethyl acetate. The ethyl acetate extracts are then washed with 100 ml of 30 saturated aqueous sodium bicarbonate, 100 ml f brine, dried over anhydrous magnesium sulfate, con centrated under reduced pressure, yielding 0.37 g of a brown oil, and chromatographed on 40 g of silica gel eluting with hexane and ethyl acetate (2:1) to yield 0.32 g of pure formula XXV title product as a colorless oil.
D. Alternatively, a suspension of 207 mg of 57% sodium hydride in mineral oil and 1.08 g of trimethyloxosulfonium iodide is treated dropwise under a nitrogen atmosphere with 6 ml of dimethylsulfoxide. The resulting grey slurry is then stirred at ambient temperature for 20 min, treated with 2.03 g of the title product of Example 1 in 4 mi of dry dimethylsulfoxide and stirred for 2 hr at ambient temperature. Thereafter stirring is continued for 1- hr at 501C, the reaction mixture is cooled and diluted with 200 ml of water and thereafter extracted with three 100 ml portions of diethyl ether. 40 The combined ethereal extracts are then washed with 200 ml of water, washed with 100 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, yielding a brown oil, and chromatographed on 250 g of silica gel eluting with ethyl acetate and hexane (1:2) to yield 453 mg of pure title product.
E. For title product prepared according to Part C or Part D above, NIVIR absorptions (CDC13) are 45 observed at 0.25-2.75, 3.15-4.39, 4.68, and 5.2-5.88. Infrared absorptions are observed at 1725, 1665,1135,1080,1040,1020,980cm-1.
The mass spectrum exhibits a molecular ion at 446 and silica gel TLC Rf is 0.30 in ethyl acetate and hexane.
EXAMPLE 30 (54 and (5E)-6ap,9p-methano-CBA2 (Formula X: X, is -COOH, Z, is -(CH2) --, R,, is hydrogen, R,, and R17 taken together are methano, n is one, R. is hydroxy, Y1 is trans-CH=CH-, M, is a-OH:P-H, L, is a-H..P-H, R7 is n- butyl, and the C-5, C-6 positions are unsaturated). Refer to Chart G. 55 A. A suspension of 452 mg of 57% sodium hydride in mineral oil and 30 mi of dimethyisuifoxide is 55 heated to 650C for 1 hr under a nitrogen atmosphere, cooled to 1 70C and therafter treated over 15 min with 2.39 g of 4-carboxybuthyltriphenylphosphonium bromide. The resulting red solution is then stirred for 15 min at 1 7-200C, treated with a solution of 716 mg of the title product of Example 29, 6 m[ of dry dimethyisuifoxide, stirred for 43 hr at 40c1C, cooled to O1C, treated with 3.5 mi of water, stirred for 60 30 min at O1C, added to 75 m] of water and brine (2:1), acidified with one N aqueous hydrochloric acid, 60 and extracted with 225 mI of diethyl ether. The ethereal extracts are then washed with 375 mi of water and 75 m[ of brine, dried over magnesium sulfate, concentrated under reduced pressure, and chromatographed on 150 g of acid-washed silica gel eluting with 10-25% ethyl acetate in hexane to yield 290 mg of (5Z)-6ap,9p-methano-CBA,, 11,1 5-bit(tetrahydropyranyl ether), 70 mg of (5E)-6ap,9p- 33 GB 2 122 203 A- 33 methano-CBA2,11,1 5-bis(tetrahydropyranyl ether), and 400 mg of a mixture of (5E) and (5Z) formula LXXXIII isomers. Rechromatographing the isomeric mixture on 150 g of acid-washed silica gel yields an additional 50 mg of (5E) isomer and 180 mg of (5Z) isomer.
For the (5Z) isomer NIVIR absorptions (CDCI,) are observed at 0.5-2.85, 3. 22-4.4, 4.70, 4.9-5.75, and 10.16. Infrared absorptions are observed at 3600-3000 (abroad band), 1740,1710,1240, 1210,1135, 1080,1035, 1020, 980, and 870 cm-1. Silica gel TLC Rf is 0.27 in hexane, ethyl acetate, and acetic acid (65:34:1). For the (5E) isomer NIVIR absorptions are observed at 0.40-2. 70, 3.2-4.4, 4.70, 5.0-5.8, and 8.828. Infrared absorptions are observed at 3600-3000, 1740, 1710, 1460, 1445, 1200, 1135,1075, 1035, 1020, and 980 cm-1. Silica gel TLC Rf is 0.32 is 0.32 in hexane, ethyl acetate, and acetic acid (65:34:1).
B. A solution of 446 mg of-the (5Z) reaction product of Part A in 44 ml of acetic acid, water, and tetrahydrofuran (6:3:2) is heated at 450C under a nitrogen atmosphere for 3 hr, cooled, added to 200 ml of brine, extracted with 160 ml of ethyl acetate in hexane (3:2), washed with 500 ml of brine, extracted with 120 ml of ethyl acetate and hexane (3:2) dried over sodium sulfate, concentrated under reduced pressure, yielding 0.38 g of a yellow oil and chromatographed on 60 g of acid washed silica gel 15 eluting with 70% ethyl acetate in hexane to yield 170 mg of pure (5Z) title product as a colorless oil.
NIVIR absorptions are observed at 0.5-2.90, 0.89, 4.05, 4.85-5.8, and 6. 138. Infrared absorptions are observed at 3360,2260, 1710,1245, 1240,1075, 1025, and 970 cm-1. The mass spectrum for the tris-trimethylsilyl derivative exhibits a high resolution peak at 578. 3653. Silica gel TLC R, is 0.30 in the A-IX solvent system (the organic phase of an equilibrated mixture of ethyl acetate, acetic acid, 20 cyclohexane, and water; 9:2:5:10).
C. Following the procedure of Part B above 90 mg of the (5E) reaction product of Part A is con verted to 46 mg of (5E) title product as a colorless oil. NMR absorptions are observed at 4.40-2.8, 0.89, 4.06, and 5.0-5.85,5. Infrared absorptions are observed at 3340, 2630, 1710, 1070, 970 cm-1 The mass spectrum exhibits a high resolution peak at 578.3664. Silica gel TLC R, is 0.32 in the A-IX 25 solvent system.
Following the procedure of Examples 27-29, each of the various formula X products is prepared wherein R,6 and R17 are methano from the corresponding formula LXXXI reactants of Chart G.
Accordingly, the above examples provide methods for preparing each of the various formula X CBA analogs of the present invention.
EXAMPLE 31 9deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',31-interphenylene)-PGF,a (Formula Xl:X, is COOH, R20, R21, 112, and R24 are all hydrogen, Z4 is -CH2-, R22 is P-hydrogen, F1, Y, M,, L, and R7 are as defined in Example 8) and its corresponding methyl ester (X, is -CO0CH). 35 Refer to Chart P. A. A solution of methyl phenyl-N-methyl sulfoximine (3.39 g) in dry tetrahydrofuran (60 mi), is alternately degassed and flushed with nitrogen, cooled to -781C and treated dropwise over 7 min with 2.8 M methyl magnesium chloride (7.16 ml). The resulting solution is stirred at -781C for 30 min, then at OOC for 15 min. The reaction is cooled to -780C and treated with a solution of 3-oxa-1,2,4,5,6 pentanor-3,7-inter-m-phenylene-PGE,, 3-(t-butyldimethylsilyl ether), 1 1j 5-bis(tetrahydropyranyl 40 ether) (6.05 g), a formula CLXXI compound, in dry tetrahydrofuran (35 ml). The resulting mixture is stirred for 1.75 hr while the temperature permitted to go from -780C to OOC and then stirred for one hr at OOC. The reaction mixture is then diluted with brine 0 70 ml) and extracted with diethyl ether. The ethereal extracts are then washed successively with brine (1170 ml), 0.5 M aqueous potassium bisulfate (170 ml), saturated aqueous sodium bicarbonate (170 ml) and brine (170 ml), dried over magnesium 45 sulfate, filtered and concentrated to a yellow oil (8.0 g), 9-[(N-methyl)- phenylsulfoximinomethyll-3-oxa1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF,, 3-(t-butyldimethylsilyl ether), 11,15 bis(tetrahydropyranyl ether). A degassed solution of 9-[(Nmethyl)phenylsulfoximinomethyll-3-oxa1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PqF,, 3-(t-buty[dimethylsilyl ether), 11,15 bis(tetrahydropyranyl ether) (8.0 g) in tetrahydrofuran (150 ml) is cooled to OOCI treated with 50% 50 acetic acid/water (45 ml) then immediately with aluminum amalgam under nitrogen. (The aluminum amalgam is prepared by washing 20 mesh aluminum, 8.00 g, with diethyl ether, 170 ml, methanol, 340 ml, mercuric chloride, 8.03 g, in water, 275 mi, methanol, 170 ml, and diethyl ether, 170 ml).
The resulting black suspension is stirred for 1.75 hr during which the reaction temperature is per mitted to go from 00 to 150C (slowly) then cooled to 00, treated with ethyl acetate (210 ml) and stirred 55 for an additional 30 min at OOC. The suspension is filtered through diatomaceous earth and the filter cake washed with ethyl acetate. The combined filtrate is then washed with brine (300 ml), 0.5 M aqueous potassium bisulfate (300 ml), saturated aqueous sodium bicarbonate (300 ml) and brine (300 ml), dried, filtered, and concentrated to a yellow oil, crude formula CLXXII compound (6.03 g), 9-deoxy 9-m ethyl ene-3 -oxa- 1,2,3,4,5,6-penta nor-3,7-i nte r-m-p henyle ne-P G F 1, 3 -(t-b utyld i m ethylsi lyl ether), 60 11,1 5-bis(tetrahydropyranyl ether). The crude product is combined with that from a repeat preparation to yield 10.1 g of formula CLXXII product which is chromatographed on silica gel eluting with 5% ethyl acetate in Skellysolve B (SSB, isomeric hexanes) to yield 6.93 g of 9- deoxy-9-methylene-3-oxa 1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF,, 3-(t-butyldimethylsilyl ether), 11,15- 34 GB 2 122 203 A 34 bis(tetrahydropyranyl ether). NIVIR absorptions are observed at 4.52-5.12 and 6.53-7.30b. Infrared absorptions are observed at 1600 and 1655 cm-1. Silica gel TLC Rf is 0.39 in 10% ethyl acetate in hexane.
B. A degassed solution of 9-deoxy-9-methylene-3-oxa-1,2,4,5,6-pentanor-3, 7-inter-m- phenylene-PGF,, 3-(t-butyidimethyisilyl ether), 11,1 5bis(tetrahydropyranyl ether), the reaction product 5 of Part A, (1.33 g) in dry tetrahydrofuran (70 mi) is cooled to OIC and treated under nitrogen with 0.5 M 9-borabicyclo[3.3.1 Inonane (14 m]), dropwise over 5 min. The colorless solution is stirred for 4.5 hr at OIC and treated with 30% hydrogen peroxide (6 m]) followed by 3 N potassium hydroxide (6 mi). The resulting suspension is stirred for an additional 30 min at OIC and for 75 min while warming to room temperature. The reaction mixture is transferred to a separatory funnel, diluted with brine (300 mi) and 10 ethyl acetate (300 mi). The layers are separated, and the aqueous layer extracted with ethyl acetate (600 mW The organic extracts are washed with brine (6 mi), dried, filtered, and concentrated to formula CM111 product, a colorless oil (3.3 g), g-deoxy-9a-(hydroxymethyi)-3-oxa- 1,2,4,5,6-pentanor-3,7inter-m-phenylene-PGF,, 3-(t-butyidimethyisilyl ether), 11,1 5bis(tetrahydropyranyl ether). The crude formula CM111; product is chromatographed on silica gel (300 g) in 35% ethyl acetate in hexane to yield 1.26 g of 9-deoxy-9a-(hydroxymethyi)-3-oxa-1,2,4,5,6-pentanor-3,7inter-m-phenylene-PG F,, 3 (t-butyidimethyisilyl ether), 11,1 5-bis(tetrahydropyranyl ether) as a coloriess oil. MMR absorptions are observed at 4.73, 5.12-5.70, 6.52-7.236. Infrared absorptions are observed at 3480 and 1670 cm-1. Silica gel TILC R, is 0.21 in 35% ethyl acetate in hexane.
C. A degassed solution of 9-deoxy-9a-hydroxymethyi-3-oxa-1,2,4,5,6pentanor-3,7-inter-m- phenylene-PGFl, 3-(t-butyidimethyisilyl ether), 11,1 5- bis(tetrahydropyranyl ether) (2.01 g), reaction product of Part B, in dry methylene chloride (45 mi) is cooled to -51C under nitrogen and treated with triethylamine (0.72 mi), then with methanesulfonyl chloride (0.76 mi). The resulting solution is stirred at -51C for 5 min then for 75 min while warming to ambient temperature. The reaction solution is poured over ice, and the resulting mixture swirled for a few minutes then transferred to a separatory funnel and 25 partitioned between diethyl ether and brine. The layers are separated, and the aqueous layer extracted with ether (400 mi). The organic layer is washed with brine (200 mi) and saturated aqueous sodium bicarbonate (400 mO, dried, filtered, and concentrated to a formula CILMIV product, a colorless oil (2.69 g), 9-deoxy-ga-mesyloxymethy]-3-oxa-1,2,4,5,6-pentanor-3,7-inter-mphenylene-PGF,, 3-(t butyidimethyisily] ether), 11,1 5-bis(tetrahydropyranyl ether). This product (2.69 g) is chromatographed 30 on silica gel (185 g) eluting with 25% ethyl acetate in Skellysolve B to yield 1.99 g of 9-deoxy-9a mesyloxymethy]-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF,), 11, 1 5-bis(tetrahydropyranyl ether), NMR absorptions are observed at 2.95, 4.70, 5.20-5.70, and 6.52-7. 22.5. Silica gel TILC Rf is 0.30 in 35% ethyl acetate in hexane.
D. A degassed solution of 9-deoxy-9a-mesyloxymethy]-3-oxa-1,2,4,5,6pentanor-3,7-inter-m- 35 phenylene-PGF,, 3-(t-butyidimethyisilyl ether), 11,1 5- bis(tetrahydropyranyl ether) (0.971 g), the reaction product of Part C, in dry tetrahydrofuran (35 mi) is cooled to OIC and treated under nitrogen with 0.75 M tetrabutylammonium fluoride (2.6 mi). The resulting amber solution is stirred for 2.5 hr at 0-51C and is partitioned between ethyl acetate (150 m]) and brine (150 mi). The layers are separated, and the aqueous layer extracted with ethyl acetate (300 mi). The organic layer is then washed with 0.5 40 M aqueous ammonium chloride (150 m]), saturated aqueous sodium bicarbonate (300 m]) and brine (150 m]), dried, filtered and concentrated to give 0.82 g of formula C1- XW product, g-deoxy-ga mesyloxymethy]-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF,, 11,1 5-bis(tetrahydropyranyl ether. Infrared absorptions are observed at 3330 cm-1. Silica gel TLC Rf is 0.37 in 50% ethyl acetate in hexane.
E. A degassed solution of 9-deoxy-9a-mesyloxymethyi-3-oxa-1,2,4,5,6pentanor-3,7-inter-m- phenylene-PGF, 11,1 5-bis(tetrahydropyranyl ether) (0.82 g), reaction product of Part D, is cooled to -40'C under argon and treated with 57% sodium hydride (0.67 g). The resulting suspension is then stirred for 40 min at -401C then 15 min at O'C. The suspension is stirred for an additional 20 min while warming to room temperature and then stirred for 2.5 hr at reflux. The reaction is then cooled to 50 1 O'C, diluted with ice cold brine (200 mi) and extracted with ethyl acetate (450 mi). The ethyl acetate extracts are then washed with brine (300 m]), dried, filtered and concentrated to give 0.72 g of the formula CILMI crude product. The crude product is chromatographed in silica gel (175 g) in 25% ethyl acetate in Skellysolve B to yield 0.49 g of g-deoxy-2,9a-methano-3-oxa-1, 2,4,5,6-pentanor-3,7(1',3'-inter-phenylene-PGF,, 11,1 5-bis(tetrahydropyranyl ether). NMR absorptions are observed at 55 4.77, 5.32-6.03, and 6.52-7.228. Infrared absorptions are observed at 3340 and 1670 cm-1. Silica gel TLC Rf is 0.56 in 35% ethyl acetate in hexane.
F. A degassed solution of g-deoxy-2',9(x-methano-3-oxa-1,2,4,5,6-pentanor3,7-(1',3'-inter-m- phenylene-PGFl, 11,1 5-bis(tetrahydropyranyl ether), (0.47 g), reaction product of Part E, in dry glyme (15 mi) is cooled to OOC and treated under nitrogen with methyl bromoacetate (0.26 mi) followed by 60 57% sodium hydride suspension (0.136 g). Following vigorous effervescence, a white precipitate is formed. The resulting suspension is stirred for 2.5 hr at 0-51C, diluted with ice cold brine (200 mi) and extracted with ethyl acetate (450 m]). The ethyl acetate extracts are washed with brine (300 mi), dried over magnesium sulfate, filtered and concentrated to a pale yellow oil (0. 62 g), formula CLXXVII corn pound, 9-deoxy-2,9(y-methano-3-oxa-4,5,6-trinor-3,7-(1',3- interphenylene)PGF,, methyl ester, 65 GB 2 122 203 A 35 11,1 5-bis(tetrahydropyranyl ether). Infrared absorptions are observed at 1765 and 1740 em-'.
G. A solution of 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'inter-phenylene)-PGF, methyl ester, 11,1 5-bi s (tetra hyd ropyra nyl ether) (0.62 g), reaction product of Part F, in acetic acid (15 mi), water (7.5 mi) and tetrahydrofuran (5 mi) is reacted at 451C under nitrogen for 2.7 hr, cooled 5 and diluted with ice cold brine (200 ml). The resulting suspension is extracted with ethyl acetate (400 mi), and the organic extracts washed with brine (400 mi), saturated aqueous sodium bicarbonate (600 mi) and brine (200 mi). The ethyl acetate extracts are then dried over magnesium sulfate, filtered and concentrated to give 0.44 9 of pale yellow oil.
This crude product is chromatographed on silica gel (60 g) in 50% ethyl acetate in Skellysolve B to yield 0.37 g of product which was crystallized to yield 0.216 g of title product, 9-deoxy-2',9a-methano3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF,, methyl ester. Melting range is 82-841C. NIVIR absorptions are observed at 3.77, 4.62, 5.42-5.63, and 6.53-7.258. Infrared absorptions are observed at 3520, 3400, and 1735 em-'. Silica gel TLC Rf is 0.30 in 35% acetone in methylene chloride.
15. H. A solution of 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'inter-phenylene)-PGF,, 15 methyl ester (0.15 g), reaction product of Part G, in 5% potassium hydroxide in 9:1 methanol-water (5.5 mi) is stirred at OIC under nitrogen. The solution is turbid initially and a precipitate forms within 5 min. The reaction is then stirred for one hr at O1C, diluted with ice cold brine (90 mi), acidified with 1 N hydrochloric acid, and extracted with ethyl acetate (180 m]). The ethyl acetate extract is then washed with brine (270 mi), dried over magnesium sulfate, and concentrated under reduced pressure to yield a 20 waxy, semi-solid (0. 131 g), which is crystallized to yield 0. 105 g of title product, 9-deoxy-2,9a methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF,, Melting range is 131-1331C. NMR absorptions are observed at 4.68, 5.48-5.72, 6.68-7.22. Infrared absorptions are observed at 3460, 3280,1735,1720, and 1700 em-'.
1. The dosage at which the title compounds should be administered to achieve their effect, chiefly 25 anti-platelet aggregation or blood pressure lowering, will vary according to the potency of the particular compound under study. When given orally, the compounds will show a desired effect in man at a dose from about 0.05 to about 50 mg/kg orally, preferably from about 0. 1 to about 5 mg/kg. The compounds 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGF,, methyl ester, given to a rat orally at a dose of 1 mg/kg lowered blood pressure 44 mmHg. After 52 min the blod pressure was 30 still lower 14 mm. Intravenous dosages for the desired effect are from about 1 to about 500 ng/kg/min in man, preferably from about 10 to about 100 ng/kg/min.
EXAMPLE 32
9-Deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',31-inter-phenylene)-1 6, 16-difluoro-PGF, (Formula Xl: X1 is -COOH, L, is a-fluoro:p-fluoro, R201 R20, R21, R23, and R24 are all hydrogen, Z4 is-CH--, R22'S 35 A-hydrogen, F1, Y1, M,, and R7 are as defined in Example 8) and its corresponding methyl ester (X, is -COOCH,).
Refer to Chart P.
A. Diethyl ether (55 mi) tri-n-butylphosphine (2.28 g) and cuprous iodide (2.13 g) are combined with stirring with the resulting mixture being alternately degassed and flushed with nitrogen at 251C for 40 1 hr. The resulting solution is then cooled to -781C and is hereafter referred to as solution 32-1. Thereafter 60 m] of anhydrous diethyl ether and 6.47 g of rn-bromo-phenol, t- butyidimethyisilyl ether are combined and the resulting solution alternately degassed and flushed with nitrogen and cooled to -78'C. After cooling, the resulting mixture is treated with 44.16 mi of a 1.02 M solution of tbutyilithiurn in n-pentane. This reaction mixture is then stirred at -781C for 1 hr and hereinafter referred 45 to as solution 32-11. Solution 32-11 is then transferred with stirring over 15 min to solution 32-1 under a nitrogen atmosphere. The resulting solution changed in color from clear to yellow to an orange-brown to tan. The resulting mixture is then stirred at -781C. for 30 min and labelled solution 32-111. Thereafter 4cr-hydroxy-3p-(4',4'-difi uoro-3a-hyd roxy-tra ns- 1 '-octe nyi) -2- methylene-cycl ope nta none, 4,3' bis(tetrahydropyran-2-yl ether), 4 9, Example 25 of United States Patent 4,181,798, and 38 mi of 50 anhydrous dry ethyl ether are combined with stirring and the resulting mixture alternately degassed and flushed with nitrogen and thereafter cooled to -781C. The resulting solution is referred to herein as solution 32-1V. Solution 32-IV is then added to solution 32-111 with vigorous stirring over 25 min at -78C under a nitrogen atmosphere. The reaction mixture is then stirred at -781C for 30 min and thereafter transferred to 100 mi of 8% glacial acetic acid in diethyl ether (-40IC) with vigorous stirring 55 under a nitrogen atmosphere. The resulting mixture is then diluted with brine and extracted with diethyl ether. The ethereal extracts are then washed with aqueous sodium bicarbonate in brine, dried over sodium sulfate, concentrated under reduced pressure, and chromatographed on silica gel eluting with 20% ethyl acetate in Skellysolve B to yield 5.56 g of pure formula C1-XX1 compound: 1 6,16-difluoro-3 oxa-1,2,43,5,6-pentanor-3,7-inter-m-phenylene-PGE,, 3-(t- butyidimethyisilyl ether), 11, 15- 60 bis(tetrahydropyran-2-yi ether). NMR absorptions (CDCI,) are observed at 0. 18, 3.1-5.0, 5.67, 6.52-6.88, and 6.88-7.26. Infrared absorptions are observed at 1745, 1600, 1585, 1490, 1275, 1260, 1200, 1155, 1125, 1075, 1035, 1025, 975, 840, and 780 em-'. Silica gel TLC Rf is 0.36 and 0.41 in 25% ethyl acetate in Skellysolve B. Silica gel TLC Rf is 0.5 in 5% acetone in methylene chloride.
36 GB 2 122 203 A -36 B. Following the procedure of Example 3 1, Part A, 3.47 g of the reaction product of Part A of this example is converted to 2.98 g of formula C1-XXII product as a colorless oil, 9-deoxy-9-methylene-3 oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-1 6,16-difluoro-PGF,, 3-(t- butylsHyl ether), 11,15 bis(tetrahydropyranyl ether). NMR absorptions are observed at 0.17, 0.97, 1.0-3.2, 3.2-4.4, 4.4-5.0, 53-6.0, and 6.4-7.38. Infrared absorptions are observed at 1655, 1605, 1585,1485, 1275,1260,1200,1144,1125,1080,1025,970,870, and 780 cm-1. Silica gel TLC Rf is 0.31 and at 0.36 in 10% ethyl acetate in hexane.
C. Following the procedure of Example 3 1, Part B, 2.83 g of the reaction product of Part B of this example is converted to 2.5 g of formula C1-XXIII product as a colorless oil, 9-deoxy-9(V (hydroxymethyi)-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-1 6,16difluoro-PGF,, 3At butyldimethylsilyl ether), 11,1 5-bis(tetrahydropyranyl ether). NIVIR absorptions (CIDC1,) are observed at 0.18, 0.98, 1.15-3.0, 3.0-4.5, 4.5-5.0, 53-5.9, and 6.4-7.36. Infrared absorptions are observed at 3460,1670,1600,1585,1485,1275,1260,1160,1135,1125,1075,1025, 975,840' and 780 cm. Silica gel TLC Rf is 0.28 in 35% ethyl acetate in hexane.
D. Following the procedure of Example 3 1, Part C, the reaction product of Part C of this example 15 (2.29 g) is converted to 1.83 g of formula CLXXIV product as a colorless oil, 9-deoxy-9a mesyloxymethyi-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-1 6,16difluoro-PGF,, 3-(t butyidimethyisilyl ether), 11,1 5-bis(tetrahydropyranyl ether). NIVIR absorptions are observed at 0.18, 0.98, 1.15-2.85, 2.95, 311-4.5, 4.5-5.0, 5.2-5.9, and 6.5-7.48. Infrared absorptions are observed at2930,2860,1605,1590,1490,1465,1440,1360,1275,1200,1175,1120, 1025' 20 975, and 840 cm-1. Silica gel TLd Rf is 0.28 in 30% ethyl acetate and hexane.
E. Following the procedure of Example 3 1, Part D, 1.7 g of the reaction product of Part D of this example is converted to 1.6 g of formula C1-XXV product as a yellow oil, 9-deoxy-ga-mesyloxymethyi 3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-1 6,16-difluoro-PGF,, 11,1 5-bis(tetrahydropyranyl ether). Silica gel TLC Rf is 0.34 in ethyl acetate and hexane (1:1).
F. Following the procedure of Example 3 1, Part E, 1.52 g of the reaction product of Part D of this example is converted to 0.83 g of formula C1-XW product as a white foam, 9-deoxy-2',9a-methano3 oxa-1,2,4,5,6-pentanor-3,7-(1',3'-inter-phenylene)-1 6,1 6-difluoro-PGFl, 11,1 5-bis(tetrahydropyranyl ether). NMR absorptions are observed at 0.95, 1.05-2.95, 15-5.0, 53-6.0, and 6.5-7.2b.
Infrared absorptions are observed at3350, 2930,1670,1615, 1590,1465, 1280, 1200,1120,1070, 30 and 975 cm-1. The mass spectrum exhibits peaks at 534, 451, 446, 402, and 348. Silica gel TLC Rf is 0.26 in ethyl acetate and hexane 0:3) and 0.40 in acetone and methylene chloride (1:19).
G. Following the procedure of Example 3 1. Part F. 0.80 g of the reaction product of Part F of this example is converted to 1.06 g of formulaCLXXVII product as a coloriess oil, g-deoxy-2',9cr-methano 3-oxa-4,5,6-trinor-3,7-(1'3'-inter-phenylene)-16,16-difluoro-PGF,, methyl ester, 11,15 bis(tetrahydropyranyl ether). Silica gel TLC Rf is 0.44 in 5% acetone and methylene chloride.
H. Following the procedure of Example 3 1, Part G, 1.0 g of the reaction product of Part G of this example is converted to 0.62 9 of crystalline methyl ester title product, a Formula C1-XWII white solid.
Recrystallization from hexane in diethyl ether yields a material with melting range 93-951C. NMR absorptions are observed at 0.95, 1.10-2.90, 2.90-4.8, 5.4-5.8, and 6.4-7. 3. Infrared absorptions are observed at 3560,3400, 1765, 1750, 1735, 1720, 1675, 1605, 1585, 1270,1215, 1205, 1120, 1105, 1080, 1010, 970, and 770 cm-1. The mass spectrum for the bis-trimethylsilyl derivative exhibits a high resolution peak at 582.2997. Silica gel TLC Rf is 0.35 in hexane and ethyl acetate (1 M.
Following the procedure of Example 3 1, Part H, the reaction product of Part H of this example (0.25 g) is converted to the carboxylic acid title product (158 mg) as a crystalline solid. Melting range is 128-1301C. NMR absorptions (COCD,) are observed at 0.9, 13-3.0, 3.0-4.6,4. 68,4.8-5.5, 6.5-6.9, 5.5-5.9, and 6.6-7.38. Infrared absorptions are observed at 3570, 3480, 3370, 3220,2800,1740,1720,1605,1585,1235,1210,1125,1105,1080, 1000, and 970 cm- 1.
The mass spectrum for the tris-trimethylsilyl derivative exhibits a high resolution peak at 640.3232.
Silica gel TLC Rf is 0. 18 in the A-IX solvent system.
Following the procedure of Examples 31 and 32, there are prepared each of the various formula CLXXVIII products in free acid or ester form from corrsponding formula C1- XX1 reactants.
Formula C1-XWII compounds wherein Y1 is unsaturated (trans- or cis-CH=CH) are transformed to corresponding formula C1-XWII compounds wherein Y is saturated (-CH2CH, -) by hydrogenation, 55 as exemplified below:
1Q EXAMPLE 33
9-Deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-1 3, 14-dihydro-PGF, (Formula Xl:X1 is COOH, Y1 is -CH2CH,--, R2,, R21, R2., and R24 are all hydrogen, Z, is -CH 2 -, R22 IS P-hydrogen, IR, M,, L, and R7 are as defined in Example 8) and its corresponding methyl ester W, is 60 -COOCH3)' A. A solution of the methyl ester title product of Example 31 (0.341 g) in ethyl acetate (35 mi) is treated at ambient temperature with 5% palladium-on-charcoal and hydrogenated at atmospheric pressure. The resulting suspension is then stirred for 70 minutes with a hydrogen uptake of 20 mi 37 GB 2 122 203 A 37 (atmospheric pressure). The resulting suspension is then filtered through diatomaceous earth and the filter cake washed with ethyl acetate. The combined filtrate is then corrcentrated under reduced pressure to yield a colorless oil which is chromatographed on silica gel eluting with ethyl acetate in Skellysolve B to yield 0.306 g of title product (methyl ester), a colorless oil. NMR absorptions (CDCI,) are observed at 0.91 0. 1.07-1.23, 3.3-4.03, 3.77, 4.62, 6.52, and 7.278. Infrared absorptions are observed at 3350,2930,2855,1760,1740,1605,1585,1467,1435,1275,1205,1120, 1080, 1025, and 775 cm-1. Silica gel TLC Rf is 0.54 in ethyl acetate.
B. Following the procedure of Example 3 1, Part H, the title product of Part A of this example (0.177 g) is converted to 0.23 g of title product (free acid) as a solid. Recrystallization from ethyl acetate in hexane yields 0.096 g with melting range 121-123'C. The mass spectrum forthe tris-trimethylsilyl 10 derivatives exhibits a high resolution peak at 606.3553 and other peaks at 591-535, 516,427, 426, 275, 274,173, and 157. Silica gel TLC Rf is 0.27 in A-IX.
EXAMPLE 34
9-Deoxy-21,9p-methano-3-oxo-4,5,6-trinor-3,7-(1',31-inter-phenylene)-PGF, (Formula Xl: X, is COOH, R20, R21, R22, and R24 are al] hydrogen, Z4 is -CH--, R22'S a-hydrogen, R, , Y1, M 21 L,, and R7 are as 15 defined in Example 8) and its corresponding methyl ester (X, is -COOCH3).
Refer to Charts Q and R.
A. A solution of 0.82 g of the reaction product of Example 3 1, Part B, in 16 mi of methylene chloride is stirred at ambient temperature under nitrogen atmosphere and treated with diatomaceous earth followed by 26 m] of Collins reagent prepared from 2.5 mi of pyridine and 1.55 g of chromium trioxide in 20 m] of methylene chloride). The resulting suspension is then stirred for 35 min at ambient temperature under a nitrogen atmosphere and filtered through 30 g of silica gel, eluting with 150 m[ of ethyl acetate.
Concentration under reduced pressure yields 0.90 g of a pale yellow oil. Chromatographing on 85 g of silica _gel eluting Wth 20% ethyl acetate in Skellysolve B yields 0.644 g of pure formula C1-XXXII aldehyde as a _colorless oil, 9-deoxo-9a-formyi-3-oxa-1,2,4,5,6-pentanor-3,7-inter-mphenyiene-PGE,, 3-(t-butyidimethyisilyl ether), 11,1 5-bis(tetrahydropyranyl ether). NMR absorptions are observed at 0.18, 0.88, 0.98, 1.13-3.08, 3.23-4.35, 4.73, 5.25-5.75, 6.57-7.37, and 9. 888. Infrared absorptions are observed at 2730,1720,1600,1585,1485, 1275,1260,1075,1035, 1030,1020, 975, and 840 em' Silica gel TLC Rf is 0.47 in ethyl acetate and hexane 0:3).
B. A degassed solution of 1.5 g of the reaction product of Part A and 0. 36 mi of 1,13 diazobicyclo[5.4.Olundec-7-ene in 150 mi of methylene chloride is stirred for 40 hr at ambient temperature under a nitrogen atmosphere, washed with 100 mi of ice cold 0. 15 M aqueous potassium bisulfate, 100 mi of saturated aqueous sodium carbonate, and 100 mi of brine, dried over anhydrous -- - sodium sulfate and concentrated under reduced pressure to yield 1.5 g of formula CXCII product as a yellow oil, 9-deoxy-9p-formyl-3-oxa-1,2,4,5,6-pentanor-3,7-inter- phenylene-PGFl, 3-(t butyidimethyisiiyl,ether), 11,1 5-bis(tetrahydropyranyl ether).NMR absorptions (CDC'3) are observed at 0.18, 0.89, 0.98, 1.1-3.2, 3.2-4.4, 4.68, 5.2-5.8, 6.58-7.4, and 9.228. Infrared absorptions are observed at 1725,1600,1585,1485,1440,1275,1260,1200,1160,1130,1075,1035, 1020' 975, 870, and 840 cml. Silica gel TLC Rf is 0.24 in ethyl acetate and hexane (13).
C. A solution of 1.5 g of the reaction product of Part B in 40 mi of methanol is treated with stirring 40 at 200C under a nitrogen atmosphere over several minutes with 400 mg of sodium borohydride, stirred for 20 min at 201C. The resulting mixture is then added to a cold solution of 200 mi of brine and 32 mi of 0.1 M aqueous potassium sulfate, extracted with 600 mi of ethyl acetate, washed with 200 m] of saturated aqueous sodium bicarbonate in 200 mi of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and chromatographed on 200 g of silica gel eluting with 35% 45 ethyl acetate in hexane to yield 1.37 g of formula CLCIII product as a colorless oil, 9-deoxy-9p hydroxymethyi-3-oxa-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGF,, 3-(tbutyidimethyisilyl ether), 11,1 5-(tetrahydropyranyl ether). NMR absorptions (CDCI,) are observed at 0. 17, 0.88, 0.99, 1.1-3.0, 3.0-4.35, 4.7, 5.25-5.85, and 6.5-7.48. Infrared absorptions are observed at 3460, 1665, 1605, 1685, 1490, 1275, 1260, 1200, 1160, 1160, 1135, 1115, 1075, 1120, 1005, 975, 50 840, and 780 cm-1. Silica gel TLC Rf is 0.20 in 35% ethyl acetate in hexane.
D. A degassed solution of 1.32 9 of the reaction product of Part B in 0. 47 mi of triethyl amine and m] of methylene chloride at 200C under a nitrogen atmosphere is treated with 0.5 mi of methanesulfonyl chloride, stirred for 5 min at O1C, warmed to 2WIC over 90 min, added to 50 g of ice, diluted with 150 mi of brine, extracted with 450 mi of diethyl ether, washed with 150 mi of brine 55 and 300 mi of saturated aqueous sodium bicarbonate, dried over anhydrous magnesium suffate, concentrated under reduced pressure to yield an oil, and filtered through 70 g of silica gel eluting with 30% ethyl acetate in hexane to yield 1.47 g of mesylate corresponding to the starting material, i.e., the 9p analog of formula MXIV. Silica gel TLC R, is 0.23 in 30% ethyl acetate in hexane.
E. A degassed solution of 1.47 g of the reaction product of Part D and 50 m] of dry tetrahydrofuran 60 at OIC under a nitrogen atmosphere is treated with 3.9 m] of 0.45 M tetra- n-butylammonium fluoride.
The resulting solution is then stirred at 01 C for 4 hr, treated with another 0.5 mi of tetra-n butylammonium fluoride, stirred for 30 min at O1C, diluted with 150 mi of brine, extracted with 450 mi of ethyl acetate, washed successively with 150 mi of 0.5 M aqueous ammonium chloride, 300 mi of 38 GB 2 122 203 A 38 saturated aqueous sodium bicarbonate, and 150 ml of brine, dried over anhydrus sodium sulfate and concentrated under reduced pressure to yield 1.3 g of a yellow oil, the phenol corresponding to the starting material, i.e., the 9A isomer of the formula CLXXV compound. Silica gel TLC Rf is 0.11 in 35% ethyl acetate in hexane.
F. A degassed solution of 1.3 g of the reaction product of Part E in 75 ml of dry glyme at -401C 5 under a nitrogen atmosphere is treated with 90 mg of 57% sodium hydride dispersion in mineral oil, stirred at -40 to -300C for 40 min, stirred at OIC for 15 min, stirred at ambient temperature for 15 min, heated and refluxed for 5 hr, cooled to ambient temperature, added to 200 ml of ice cold glyme, extracted with 450 ml of ethyl acetate, washed with 300 ml of brine, dried over anhydrous on 175 g of silica gel eluting with 25% ethyl acetate in hexane to yield 0.61 g of the 9A isomer corresponding to the formula 10 CLXXVI compound as a viscous oil. NIVIR absorptions are observed at 0.90, 1.07-3.1, 3.1-4.4, 4.75, 5.33-6.16, and 6.5-7.26. Infrared absorptions are observed at 3340, 1665, 1610, 1585, 1500, 1465, 1135, 1110, 1075,1020, and 980 cm-1. Silica gel TLC Rf is 0.26 in 25% ethylacetate in hexane and 0.23 in 5% acetone in methylene chloride. - G. A solution of 0.50 g of the reaction product of Part F in 28 ml of methyl bromoacetate in 16 ml 15 of dry glyme at OIC under an argon atmosphere is treated with 0.14 g of a 57% mineral oil dispersion of sodium hydride. The resulting suspension is then stirred for 2.5 hr at OOC, quenched with 200 ml of cold brine, extracted with 460 ml of ethyl acetate, washed with 300 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.68 g of an oil, the 9A isomer corresponding to the formula CLXXVII compound.
H. A solution of the reaction product of Part G (0.68 g) in 5 ml of tetrahydrofuran, 7.5 ml of water, and 15 ml of acetic acid is heated for 2.5 hr at 451C, cooled, diluted with 200 ml of brine, extracted with 400 ml of ethyl acetate, washed with 400 ml of brine, washed with 200 ml of saturated aqueous sodium bicarbonate, and 200 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield an oil, chroamtographed on 75 g of silica gel eluting with 30% hexane in ethyl 2 15 acetate to 100% ethyl acetate to yield 0.32 g of title methyl ester as a white foam. Crystallization from hot diethyl ether in hexane yields 0.23 g of pure ester product as a white solid. Melting range is 85-870C. NIVIR absorptions (CDC13) are observed at 0.90,1.07-2.9, 2.9-4.5, 4.61, 5.4-5.8, and 6.38-7.346. Infrared absorptions are observed at 3520, 3420, 1735, 1720, 1605,1580, 1300, 1240,1210,1110,1085,1050,1010, 970,760,720, and 710 cm-1. The mass spectrum of the bis- 30 trimethylsilyl derivative exhibits a high resolution peak at 546.3182. Silica gel TLC Rf is 0.14 in 30% ethyl acetate in hexane.
1. Following the procedure of Example 31, Part H, the title product of Part H (158 mg) is transformed to the title free acid (129 mg) as a white solid. Melting range is 1 50-1541C. NIVIR absorptions are observed at 0.90, 1.07-3.5, 3.85-4.35, 4.70, 5.09-5.9, and 6.5-7.36. Infrared 35 absorptions are observed at 3380, 2640, 2560,1730,1605, 1580,1260,1230, 1115,1050,1025, 970, and 770 cm-1.
* Following the procedure of Example 34, each of the various formula XI compounds are prepared wherein R22 is a-hydrogen. Further following the procedure of Example 33, the various 9p-methano isomers of Example 34 and corresponding formula XI compounds wherein Y, is cis- or trans-CH=CHare hydrogenated to corresponding 13,14-dihydro-PGF, compounds.
EXAMPLE 35 9-Deoxo-2',9-metheno-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGE, (Formula M: X, is COOH, R20, R21, R23, and R24 are all hydrogen, Z4 is -CH--, R21 and R,, taken together form a valence bond, R, Y1, MI, L,, and R7 are as defined in Example 8) and its corresponding methyl ester (X, is -COOCH,).
Refer to Chart T.
A. A degassed solution of the reaction product of Example 34, Part A, (1. 68 g) in dry tetrahydrofuran (50 m]) is cooled to OIC and treated under a nitrogen atmosphere with 0.75 M tetrabutylammonium fluoride (4.37 mi). The resulting solution is then stirred at OIC for 2 hr, diluted with brine (300 mO, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 2.3 g of an oil. The oil is chromatographed on silica gel (160 g) in 25% ethyl acetate in Skellysolve B yielding 1.21 g of formula CCXI compound, 9 deoxy-9(t-formyi-1,2,4,5,6-pentanor-3,7-inter-m-phenylene-PGFI, 11,1 5bis(tetrahydropyranyl ether). NIVIR absorptions (CDCI,) are observed at 0.88, 1.13-3.15, 3.27-4. 47, 4.71, 6.10, 6.53-7.41, 9.27(5. Infrared absorptions are observed at 3345, 2930, 2860, 2720, 1735, 1715, 1605, 55 1595,1585, 1485, 1450,1370,1350,1255, 1235, and 970 cm-1. Silica gel TLC R, is 0. 12 in 25% ethyl acetate and hexane and 0.39 in 50% ethyl acetate in hexane.
B. A degassed solution of 0.28 g of the reaction product of Part A in 33 mi of glyme is cooled to -40'C under argon and treated with 2.95 N methyimagnesium chloride in tetrahydrofuran (0.2 mi).
The reaction mixture is stirred at -401C for 15 min, stirred at WC for 15 min, permitted to warm to 60 ambient temperature, stirred at reflux for 115 hr under an argon atmosphere, cooled, diluted with ice cold brine (150 mi), extracted with ethyl acetate (300 mi), washed with brine (300 m]), dried over magnesium sulfate, filtered, concentrated under reduced pressure to yield 0.31 g of an oil, and chromatographed on silica gel eluting with 25% ethyl acetate in Skellysolve B to yield 0.16 g of the A 39 G8 2 122 20 - 3.A 39 formula CCXII compound, 9-deoxy-2',9-metheno-3-oxa-1,2,4,5,6-pentanor-3,7- (1',3-inter-phenylenePGE, 11,1 5-bis(tetrahydropyranyl ether). The mass spectrum of the trimethylsilyl derivative exhibits a molecular peak at 568 and other peaks at 466, 382, 364, 314, 297,267, 255, 243, 230, 2 ' 70,153, and 85. Silica gel TLC Rf is 0.25 in 25% ethyl acetate in hexane and 0.58 in 50% ethyl acetate in hexane.
C. A degassed solution of the reaction product of Part C (0. 16 g) in dry glyme (5 mi) is cooled at -51C and treated with methylbromo acetate (0.04 m]) under a nitrogen atmosphere. The resulting solution is then treated with 50% sodium hydride dispersion in mineral oil (0. 16 g). Precipitate forms in min in the resulting. suspension is stirred for 1.5 hr at 01C, diluted with brine (100 mi), extracted with ethyl acetate (240 mO, washed with brine (100 mO, dried over magnesium sulfate, filtered, concentrated to yield a brown residue which solidifies on refrigeration, and chromatographed on 25 9 of 10 silica gel eluting with 20% ethyl acetate in Skellysolve B to yield 0.136 9 of the bis(tetrahydropyranyl ether) of a formula CCXIII compound: 9-deoxy-2',9-metheno-3-oxa-4,5,6trinor-3,7-(1,3-inter- phenylene)-PGE, methyl ester, 11,1 5-bis(tetrahydropyranyl ether). Melting range is 81-831C. The mass spectrum exhibits peaks at 366, 384, 364, 279, 247, 230,215, 149, and 85. Silica gel TLC Rf is 0.45 in 5% acetone in methylene chloride.
D. Asoluton of the reaction product of Part C (0. 12 9) in tetrahydrofuran (1 mi), water (2 mi) and acetic acid (4 mi) is heated at 451C under a nitrogen atmosphere for 2.25 hr, cooled, and partitioned between brine (100 mi) in ethyl acetate (90 mi). The layers are separated and the aqueous layers extracted with ethyl acetate (160 mi). The organic layers are then washed successively with brine (100 mi), water (100 mi), water (100 mi), saturated aqueous sodium bicarbonate (300 mi) and brine (200 mi), dried 20 over magnesium sulfate, filtered, concentrated to yield 0.97 g of a solid, and chromatographed on 30 g of silica gel, eluting with 85% ethyl acetate in hexane to yield 0.083 g of white crystalline formula CCXIII title " product in methyl ester form. Recrystallization from diethyl ether in hexane yields 0.056 g of pure methyl ester title product. Melting range is 96-981C. NIVIR absorptions (CDCI,) are observed at 0.94, 3.86, 3.92-4.28, 4.72, 5.58-5.86, and 6.62-7.188. Infrared absorptions are observed at 25 3420,1765,1665,1600,1575,1465,1440,1275,1215,1190,1105,1085,970, and 770 cm-1.
The mass spectrum forthe trimethylsilyl derivative exhibits a molecular [on at 554 and other peaks at 454, 383, 365, 364, 230, 229, 225. Silica gel TLC Rf is 0.41 in ethyl acetate.
E. Following the procedure of Example 3 1, Part H, the reaction product of Part D (0. 19 g) is converted to 76 mg of crystalline title product in free acid form. Melting range is 150-1521C. NMR 30 absorptions (C13C1) are observed at 0.91, 1.2-3.48, 3.88-4.15, 4.70, 5.62- 4.66, and 6.63-7.11.
The mass spectrum for the trimethyisilyl derivative exhibits a high resolution peak at 602.3251 and other peaks at 512, 422, 287, 225, 174, and 173. Silica gel TLC Rf is 0. 23 in the A-IX solvent system.
EXAMPLE 36
9-Deoxy-2',9a-methano-3-oxa-4,5,6,13,14,15,1 6,17,18,19,20-undecanor-3,7(l',3'-inter- phenylene)-l 2-formyl-PGF,, methyl ester (formula CCXXI I: X, is -COOCH31 Z4 is -CH2-, R20, R2,, and R23 are hydrogen, R22 is A-hydrogen, and Rj, is tetra hydropyra n-2-yl- oxy).
Refer to Chart U.
Ozone is bubbled through a solution of 0.72 g of the reaction product of Example 31, Part F, in 50 ml of absolute methanol at -781C for 5 min. Thereafter oxygen is bubbled through the resulting 40 solution for 5 min and the solution is treated with 16 ml of dimethyl sulfide. After standing at 16 hr for 01C under a nitrogen atmosphere and 2-1/2 hr at ambient temperature, the solution is diluted with ml of ethyl acetate, washed successively with 100 ml of brine, 100 ml of saturated aqueous sodium bicarbonate and 100 ml of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 175 g of silica gel eluting with 35% ethyl acetate in hexane 45 to yield 367 mg of title product as a colorless oil. NIVIR absorptions (CDCI,) are observed at 1.0-3.0, 3.1-4.5, 3.63, 6.45-7.34, and 9.77.8. The mass spectrum exhibits peaks at 388 and 304. Silica gel TLC Rf is 0. 19 and 0.22 in 25% and 30% ethyl acetate in hexane.
EXAMPLE 37
9-Deoxy-21,9a-methano-20-methy]-3-oxa4,5,6-trinor-3,7-(1',3'-interphenyien e)-PGFj (Formula Xl: 50 X11 Z4, R8, R20, R21, R22, R23, R241 Yll M, and L, are as defined in Example 31 and R7 is n-pentyl) its methyl ester (Z1 is -COOCH3),'tS 15-epimer (M, is a-H:P-OH), and 15-epimer methyl ester (M, is ce-H:P-OH and Z1 is -COOCH3)' Refer to Chart U.
A. A suspension of 56 mg of a 57% sodium hydride dispersion in mineral oil and 4 mi of 55 tetrahydrofuran at 01C under a nitrogen atmosphere is treated with a solution of 286 mg of dimethyl-2 octylphosphonate in 4 mi of tetrahydrofuran, stirred for 5 min at 01C, stirred for 1 hr at ambient temperature, cooled to O'C, treated with a solution of 0.39 g of title product of Example 36 and 4 mi of tetra hyd rofu ran, stirred for 2-1/2 hr at ambient temperature, cooled in O'C, added to a solution of 40 mi of ethyl acetate containing several drops of acetic acid), extracted with 120 m[ of ethyl acetate, washed 60 with 30 mi of saturated aqueous sodium bicarbonate, washed with 30 mi of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield an oil, and chroarntographed on 60 g of silica gel eluting with 25% ethyl acetate in hexane to yield 0.42 g of a colorless oil, 9,1 5-dideoxy-1 5- GB 2 122 203 A 40 keto-21,9a-methano-20-methyl-4,5,6-trinor-3,7-(1',31-inter-phenyiene)-PGF, , methyl ester, 11 - tetrahydropyranyl ether. NMR absorptions are observed at 0.89, 1.05-3.0, 3.5-4.37, 4.62, and 5.97-7.306. The mass spectrum exhibits peaks at 414, 396, 323, 311, and 301. Silica gel TLC Rf is 0.26 in 25% ethyl acetate in hexane.
B. A degassed solution of 42 mg of sodium borohydride and 4 m] of absolute methanol at -301C 5 under a nitrogen atmosphere is treated dropwise with a solution of 391 mg of the title reaction product of Part A in 0.3 mi of methylene chloride and 3 m[ of methanol, stirred for 2A/2 hr at -301C, quenched by careful addition of 0.2 mi of glacial acetic acid, diluted with 70 mi of brine, extracted with 210 m] of ethyl acetate, washed with 70 mi of saturated aqueous sodium bicarbonate, washed with 70 m[ of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to yield 0.42 g of a 10 colorless oil, and chromatographed on 60 g of silica gel eluting with 40% ethyl acetate in hexane to yield 0.36 g of an epimeric mixture of CA 5 alcohols. Silica gel TLC Rf is 0.20 in 40% ethyl acetate in hexane.
C. A solution of the reaction products of Part B above in 3 m] of tetrahydrofuran, 4.5 m[ of water, and 9 mi of acetic acid is heated to 450C under a nitrogen atmosphere for 2.5 hrs, cooled, diluted washed with 100 mi of brine, extracted with 200 m] of ethyl acetate, washed with 100 mi of brine, washed with 300 mi of saturated aqueous sodium bicarbonate and 100 mi of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to a yellow oil, and chromatographed on 60 g of silica gel eluting with 20% ethyl acetate in methylene chloride to yield 96 g of 9-deoxy 21,9a-methano-20-methyi-3-oxa-4,5,6-trinor-3,7-(1,3-inter-phenylene)-1 5epi-PGF,, methyl ester as a 20 colorless oil and 159 mg of 9-deoxy-21,9a-methano-20-methyi-3-oxa-4,5,6- trinor-3,7-(1,3-inter phenylene)-PGFl, methyl ester as a white solid. Recrystallization of the 15a-hydroxy compound from hot hexane in diethyl ester yields 140 mg as a white solid. Melting range is 79-821C. For the title product methyl ester, NMR absorptions are observed at 0.92, 1.08-3.0, 3. 38-4.5, 4.64, 5.33-5.70, and 6.5-7.4. The mass spectrum of the trimethylsilyl derivative exhibits a high resolution peak at 25 560.3375. Silca gel TLC Rf is 0.19 in 20% ethyl acetate in methylene chloride and 0.31 in 20% hexane in ethyl acetate. For the 15-epi compound, NMR absorptions (CDCI,) are observed at 0.89, 1.07-3.0, 33-4.33, 4.63, 5.5-5.8, and 6.55-7.378. Infrared absorptions are observed at 3360,1765, 1750, 1735,1605, 1585,1470,1440,1205,1120,1080, 970, and 770 em-'. The mass spectrum for the trimethylsilyl derivative exhibits a high resolution peak at 560.3385. Silica gel TLC Rf is 0.35 in 20% 30 acetone and methylene chloride and 0.45 in 20% hexane and ethyl acetate.
D. Following the procedure of Example 3 1, Part H, the 1 5a-hydroxy title product of Part C (94 mg) is transformed to 9-deoxy-2',9a-methano-20-methyl-3-oxa-4,5,6-trinor-3,7(1,3-inter-phenylene) - PGFl, title free acid, as a white solid, 81 mg. Melting range is 144- 1461C. NIVIR absorptions (CD3COW3) are observed atO.8, 1.05-2.9, 3.2-4.5,4.65, 5.3?-5.56, and 6.6- 7.28. The mass spectrum of the trimethylsilyl derivative exhibits a high resolution peak at 618.3576. Silica gel TILC Rf is 0. 14 in the A-IX solvent system.
E. Further following the procedure of Example 3 1, Part H, the 1 5-epi title product of Part C (93 mg) is converted to 9-deoxy-21,9a-methano-20-methyi-3-oxa-4,5,6- trinor-3,7-(1,3-interphenylene)-1 5-epi-PGF,, a white solid, 72 mg. Melting range is 105-1080C. NNR absorptions 40 (CD3 OCD3) are observed at 0.90,1.05-2.9,3.2-4.3,4.71, 5.0-5.84, and 6.5- 7.343. Silica gel TLC Rf is 0.19 in the A-IX solvent system.
Following the procedures of Examples 36 and 37, there are substituted CA 2 side chains according to the procedure of Chart U for each of the various formula XI compounds.
Thus, according to procedures described above, there are prepared (5E)-9p-methy]-CBA, compounds, (5Z)-9p-methyi-CBA, compounds, (5E)-5-fluoro-9p-methyi-CBA, compounds, (5Z)-5-fluoro-9p-methy]-CBA, compounds, (5E)-5-fluoro-CBA2 compounds, (5Z)-5-fluoro-CBA2 compounds, (5E)-9p-methyi-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5Z)-9p-methyl-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5E)-9p-methyi-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds, (5E)-9p-methyi-1,5-inter-o-phenylene-3,4,5-trinor-CBA, compounds, (5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, (5E)-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds, (5Z)-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds, 2,2-difluoro-(5E)-9p-methyi-CBA2 compounds, 2,2-difluoro-(5Z)9p-methyl-CBA2 compounds, 2,2,5-trifluoro-(5E)-9p-methy]-CBA2 compounds, 2,2,5-trifluoro-(5Z)-9p-methyl-CBA2 compounds, 2,2,5-trifluoro-(5E)-CBA2 compounds, 41 - -- -:
GB 2 122 203A 41 2,2,5-tr'ifluoro;(5Z)-CBA2 compounds, 1,2-difluoro-(5E)-9p-methyi-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, 2,2-difluoro-(5Z)-9p-methyi-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, 2,2A ifl uoro-(5 E)-9p-m ethyl- 1,5A nter-o-phenylene-2,3,4-tri nor-CBA2 compounds, 2,2-difl uoro-(5E)-9p-m ethyl- 1, 5-inter-o-ph enylene-3,4,5-trinor-CBA2 compounds, 2,2-difluoro-(5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, 2,2-difluoro-(5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, 2,2-difluoro-(5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, 2,2-difluoro-(5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, trans-2,3-didehydro-(5E)-9p-methyi-CBA2 compounds, trans-2,3-didehydro-(5Z)-9p-methyl-CBA2 compounds, trans-2,3-didehydro-(5)-5-fluoro-gp-methyi-CBA2 compounds, trans-2,3-didehydro-(5Z)-fluoro-9p-methyi-CBA2 compounds, trans-2,3-didehydro-(5E)-5-fiuoro-CBA2 compounds, trans-2,3-didehydro-(5Z)-5-fluoro-CBA2 compounds, trans-2,3-didehydro-(5E)-9p-methyi-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, trans-2,3-didehydro-(5Z)-9p-methyi-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, trans-2,3-didehydro-(5E)9p-methyl-1,5-inter-o-phenylene-2,3,4-trinor-CBA2 compounds, trans-2,3-didehydro-(5E)-9p-methyi-1,5-inter-o-phenylene-3,4,5-trinor-CBA, compounds, trans-2,3-didehydro-(5E)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, trans-2,3-didehydro-(5Z)-2,5-inter-o-phenylene-3,4-dinor-CBA2 compounds, trans-2,3-didehydro-(5E)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, trans-2,3-didehydro-(5Z)-1,5-inter-m-phenylene-2,3,4-trinor-CBA2 compounds, 9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-PGFj compounds, 9-deoxy-2',9p-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-inter-phenylene)-PGFj compounds, 25 9-deoxo-2',9-metheno-3-oxa-4,5,6-trinor-3,7-(1',31-inter-phenyiene)-7,8dide hydro-PGEj compounds, 9-deoxo-2',9-metheno-3-oxa-4,5,6-trinor-3,7-(11,3'-inter-phenylene)-PGEj compounds, 6a-oxo-9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(11,3'-interphenylene)-P GFj compounds, 6a-oxo-9-deoxy-2,9p-methano-3-oxa-4,5,6-trinor-3,7-(1',31-interphenylene)-P GFj compounds, 30 6aa-hydroxy-9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenyl ene)-PGF, compounds, 6aa-hydroxy-9-deoxy-2',9p-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenyl ene)-PGFj compounds, 6ap-hydroxy-9-deoxy-2',9a-methano-3-oxa-4,5,6-trinor-3,7-(1',3-interphenyle ne)-PGF,, and 35 6ap-hydroxy-9-deoxy-2',9p-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenyl ene)-PGFj compounds, in free acid or methyl ester form which exhibit the following side chain substituents:
15-cyclohexyi-l 6,17,18,19,20-pentanor-; 17-(2-furyi- 'I 8,19,20-trinor-; 1 6-(3-thienyi)oxy- 17,18,1 9,20-tetranor-; 17-(3-triethyi)-1 8,19,20trinor-; 15-methyl-; 16-methyl-; 15,16-dimethyl-; 16,1 6-di methyl-; 17, 20-dimethyi-; 1 6-fluoro-; 15-methylA 6-fluoro-; 16,16-difluoro-; 15methylA 6,16-difluoro-; 17-plienyi-l 8,19,20-trinor-; 17-(mtrifluoromethylphenyl)-1 8,19,20-trinor-; 17-(m-chlorophenyi)-1 8,19,20trinor-; 17-(p-fluorophenyi)-1 8,19,20-trinor-; 15-methylA 7-phenylA 8,19, 20-trinor-; 16-methylA 7-phenyM 8,19,20-trinor-; 16,16-dimethy]-1 7phenylA 8,19,20-trinor-; 1 6-fluoro-l 7-phenylA 8,19,20-trinor-; 16,1 6-difluoro-l 7-phenylA 8,19,20-trinor-; 1 6-pheny]-1 7,18,19,20-tetranor-; 15-methylA 6-phenylA 7,1 8,19,20-tetranor-; 16-(m-trifi u orom ethyl phenyl)- 17,18,1 9,20-tetranor-; 42 GB 2 122 203 A 42 1 6-(m-chlorophenyl)-1 7,18,19,20-tetranor-; 16-(p-fluorophenyi)-1 7,18,19,20-tetranor-; 16-phenyl- 'I 8,19,20-trinor-; 1 5-methyl- 1 6-pheny]- 18,1 9,20-trinor-; 16-methylA 6-phenyi-l 8,19,20-trinor-; 15,1 6-dimethyi-l 6-pheny]-1 8,19,20-trinor-; 1 6phenoxy-1 7,18,1 9,20-tetranor-; 1 5-methylA 6-phenoxy-l 7,18,1 9,20-tetra nor-; 16-(m-trifluoromethylphenoxy)-1 7,18,19,20-tetranor-; 1 6-(m-chlorophenoxy)-1 7,18,1 9,20-tetranor-; 1 6-(p-fluorophenoxy)-1 7,18,19,20-tetranor-; 1 6-phenoxy- 18,1 9,20-trinor-; 15-methylA 6-phenoxy-l 8,19,20-trinor-; 1 6-methy]-1 6-phenoxy-l 8,1 9,20-trinor-; 15,16-dimethy]-1 6-phenoxy-l 8,1 9,20-trinor-; 13,14-didehydro-; 15-cyclohexylA 6,17,18,19,20-pentanor-1 3,14didehydro-; 17-(2-furyi)-1 8,1 9,20-trinor-1 3,14-didehydro-; 16-(3-thienyi)oxy-1 7,18,19,20-tetranor-1 3,14-didehydro-; 1 7-(3-thienyl)- 18,1 9,20-trinor13,1 4-didehydro-; 1 5-methy]-1 3,14-didehydro-; 16-methy]-1 3,14-didehydro-; 15,1 6-dim ethyl- 13,1 4-didehyd ro-; 16,1 6-dim ethyl 13,1 4-didehyd ro-; 17,20-dimethyl-l 3,14-didehydro-; 16-fluoro-l 3,14-didehydro-; 15-methylA 6-fluoro-l 3,14-didehydro-; 16,1 6-difiuoro-1 3,14-didehydro-; 15-methy]-1 6,16-difluoro-1 3,14-didehydro-; 17-phenylA 8,19,20-trinor-1 3,14-didehydro-; 1 7Arn-trifl uoromethyi phenyl)- 1 8,19,20-trinor-1 3,14-didehydro-; 17-(m-chlorophenyi)-1 8,19,20-trinor-1 3,14-didehydro-; 17-(p-fluorophenyi)-1 8,19,20-trinor-1 3,14-didehydro-; 1 5-methy]- 1 7-phenyi- 18,1 9,20-trinor- 13,1 4-didehydro-; 1 6-methyl- 1 7-phenyi- 18,1 9,20-trinor- 13,1 4-didehydro-; 35 16,1 6-dimethyi-l 7-phenyM 8,19,20-trinor-1 3,1 4-dide hydro-; 16-fluoro-l 7-phenylA 8,19,20-trinor-1 3,14-didehydro-; 16,16-difluoro-1 7-phenyM 8,19,20-trinor-1 3,14-didehydro-; 16-pheny]-1 7,18,19,20-tetranor-1 3,14-didehydro-; 1 5-methylA 6-phenylA 7,18,19,20-tetranor-1 3,14-didehydro-; 40 16-(m-trifluoromethylphenyi)-1 7,18,19,20-tetranor-1 3,14-didehydro-; 1 6-(m-chlorophenyl)-1 7,18,19,20-tetranor-1 3,14-didehydro-; 1 6-(p-fluorophenyi)-1 7,18,19,20-tetranor-1 3,14-didehydro-; 16-pheny]-1 8,19,20-trinor-1 3,1 4-dide hydro-; 1 5-methylA 6-phenylA 8,19,20-trinor-1 3,14-didehydro-; 45 16-methy]-1 6-pheny]-1 8,19,20-trinor-1 3,14-didehydro-; 1 5,16-dimethy]-1 6-phenylA 8,19,20-trinor-1 3,14-didehydro-; 1 6-phenoxy-l 7,18,19,20-tetranor-1 3,14-didehydro-; 1 5-methylA 6-phenoxy-l 7,1 8,19,20-tetranor-1 3,14-didehydro-; 16-(m-trifluoromethylphenoxy)-1 7,18,19,20-tetranor-1 3,14-didehydro-; 50 1 6-(m-chlorophenoxy)-1 7,18,19,20-tetranor-1 3,14-didehydro-; 16-(p-fluorophenoxy)-1 7,18,19,20-tetranor-1 3,14-didehydro-, 16-phenoxy-1 8,1 9,20-trinor-1 3,14-didehydro-; 1 5-methy]-1 6-phenoxy-l 8,19,20-trinor-1 3,14-didehydro-; 16-methy]-1 6-phenoxy-l 8,19,20-trinor-1 3,14-didehydro-; 55 15,1 6-dimethyi-l 6-phenoxy-l 8,19,20-trinor-1 3,14-didehydro-; 13,14-dihydro-; 1 5-cyclohexylA 6,1 7,18,19,20-pentanor-1 3,14-dihydro-; 17-(2-furyi)-1 8,19,20-trinor-1 3,14-dihydro-; 1 6-(3-thienyl)oxy-1 7,1 8,19,20-tetranor-1 3,14-dihydro-; 60 1 7-(3-thienyl)-1 8,19,20-trinor-1 3,14-dihydro-; 15-methylA 3,14-dihydro-; 16-methyl-l 3,14-dihydro-; 15,16-dimethyl-l 3,14-dihydro-; 16,16-dimethyl-l 3,14-dihydro-; 65 43 GB 2 122 203 A.43 3 17,20-dimethyl- 'I 3,14-dihydro-; 16-fluoro-l 3,14-dihydro-; 15-methyl-1 6-fluoro-l 3,14-dihydro-; 16,1 6-difluoro-l 3,14-dihydro-; 15-methyl-1 6,1 6-difiuoro-1 3,14-dihydro-; 17-phenyl-1 8,1 9,20-trinor-1 3,14-dihydro-; 1 7-(m-trifl uoromethyl phenyl)- 1 8,19,20-trinor-1 3,14-dihydro-; 17-(m-chlorophenyi)-1 8,19,20-trinor-1 3,14-dihydro-; 17(p-fluorophenyl)-1 8,19,20-trinor-1 3,14-dihydro-; 15-methylA 7-phenylA 8,19,20-trinor-1 3,14-clihydro-; 1 6-methylA 7-phenyl-1 8,19,20-trinor-1 3,14-clihydro-; 16,1 6-climethyl-1 7-phenyl-1 8,19,20-trinor-1 3,14-dihydro-; 1 6-fluoro-l 7-phenylA 8,19,20-trinorA 3,14-dihydro-; 16,1 6-difluoro-l 7-phenyl-1 8,19,20-trinor-1 3,14-dihydro-; 1 6-phenylA 7,18,19,20-tetranor-1 3,14-dihydro-; 1 5-methy]-1 6-phenyl-1 7,18,19,20-tetranor-1 3,14-dihydro-; 16-(m-trifluoromethylphenyi)-1 7,18,19,20-tetranor-1 3,14-dihydro-; 1 6-(m-chlorophenyl)- 17,18,1 9,20-tetranor- 1 3,14-clihydro-; 1 6-(p-fluorophenyl)- 17,18,1 9,20-tetranor- 13,1 4-dihydro-; 16-pheny]-1 8,19,20-trinor-1 3,14-clihydro-; 1 5-methyl-1 6-pheny]-1 8,19,20-trinor-1 3,14-dihydro-; 16-methyl-1 6-pheny]-1 8,19,20-trinor-1 3,14-dlhydro-; 15,16-dimethyl-l 6-pheny]-1 8,19,20-trinor-1 3,14-dihydro-; 16-phenoxy-1 7,1 8,19,20-tetranor-1 3,14-dihydro-; 1 5-methyl-1 6-phenoxy-l 7,18,19,20-tetranor-1 3,14-dihydro-; 16-(m-trifluoromethylphenoxy)-1 7,18,19,20-tetranor-1 3,14-dihydro-; 16-(m-chlorophenoxy)-1 7,18,19,20-tetranor-1 3,14-dihydro-; 16-(p-fluorophenoxy)-1 7,18,19,20-tetranor-1 3,14-dihydro-; 16-phenoxy-1 8,19,20-trinor-1 3,14-dihydro-; 1 5-methyl-1 6-phenoxy-l 8,19,20-trinor-1 3,14-dihydro-; 16-methyl-1 6-phenoxy-l 8,19,20-trinor-1 3,14-dihydro-1 1 5,16-dimethy]-1 6-phenoxy-l 8,19,20-trinor-1 3,14-dihydro-; 13-cis-; 1 5-cyclohexylA 6,1 7,18,19,20-pentanor-1 3-cis-; 1 7-(2-fu ryi)- 18,1 9,20-trinor- 1 3-cis-; 1 6-(3-thienyi)oxy- 17,18,1 9,20-tetranor- 1 3-cis-; 17-(3-thienyi)-1 8,19,20-trinor-1 3-cis-; 1 5-methyl-1 3-cis-; 1 6-methyl- 1 3-cis-; 1 5,16-dimethyl-l 3-cis-; 16,16-dimethyl-l 3-cis-; 17,20-dimethyl-l 3-cis-; 1 6-fluoro-l 3-cis-; 1 5-methVI-1 6-fluoro-l 3-cis-; 16,1 6-difluoro-l 3-cis-; 15-methyM 6,1 6-difluoro-l 3-cis-; 1 7-phenylA 8,19,20-trinor-1 3-cis-; 1 7-(m-trifluoromethylphenyi)-1 8,19,20-trinor-1 3-cis-; 1 7-(m-chlorophenyi)-1 8,19,20-trinor-1 3-cis-; 1 7-(p-fluorophenyl)-1 8,19,20-trinor-1 3-cis-; 1 5-methy]-1 7-phenylA 8,19,20-trinor-1 3-cis; 16-methyl-1 7-phenylA 8,19,20-trinor-1 3-cis-; 1 6,16-dimethy]-1 7-phenylA 8,19,20-trinor-1 3-cis-; 1 6-fluoro-l 7-phenyM 8,19,20-trinor-1 3-cis-; 16,16-difluoro-1 7-pheny]-1 8,19,20-trinor-1 3-cis-; 1 6-phenyl-1 7,18,19,20-tetranor-1 3-cis-; 15-methylA 6-pheny]-1 7,18,19,20-tetranor-1 3-cis-; 1 6-(m-trifl u oro methyl phenyl)- 1 7,18,19,20-tetranor-1 3-cis-; 16-(m-chlorophenyi)-1 7,18,19,20-tetranor-1 3-cis-; 16-(p-fluorophenyi)-1 7,18,19,20-tetranor-1 3-cis-; 1 6-phenyl-1 8,1 9,20-trinor-1 3-cis-; 15-methylA 6-phenylA 8,19,20-trinor-1 3-cis-; 1 6-methyl-1 6-pheny1A 8,19,20-trinor-1 3-cis-; 1 5,16-dimethyl-1 6-pheny]-1 8,19,20-trinor-1 3-cis-; 16-phenoxy-1 7,18,19,20-tetranor-1 3-cis-; 44 GB 2 122 203 A 44 15-methy]-1 6-phenoxy-1 7,18,19,20-tetranor-1 3-cis-; 16-(mtrifluoromethylphenoxy)-1 7,18,1 9,20-tetranor-1 3-cis-; 16-(mchlorophenoxy)-1 7,18,19,20-tetranor-1 3-cis-; 16-(p-fluorophenoxy)-1 7, 18,19,20-tetranor-1 3-cis-; 16-phenoxy-1 8,19,20-trinor-1 3-cis-; 15methyl-l 6-phenoxy-1 8,1 9,20-trinor-1 3-cis-; 16-methyl-1 6-phenoxy-l 8, 1 9,20-trinor-1 3-cis-; and 15,16-dimethy]-1 6-phenoxy-1 8,19,20-trinor-1 3-cis, A pharmaceutical composition according to the present invention comprises a compound of the 10 invention in association with a physiologically acceptable excipient.
FORMULAS 0 c, a Rir X CH2) n R,,-7 9 E3 0 1 11 Y1-C-C-117 1 R, E3 0 6 R16 -6a (CH2) n i R,,7 % 9 7-a- 11 H M6 L., 1 CH2OR:3p Ris R., -X, )z R.,6--(CH2)n X 1 CH.mOR:3.2 1 Ris CH(R15)-Z1-Xl R,, (C 1j, 2) n R1.7_ CH2OR32 R., I V v VI VII GB 2 122 203 A 45 FORMULAS (continued) xl-Z4-0 7 - \1 R2o:p,__R23 R22 R2,, R33 1 Ris H0-2 Y1-C-C-PI27 Q- A A R1,3' M6 IL,.
R16 4 (CH2) n R1.7 Y1-C-C-R7 11 H 1 M, L, Re R.
VIII IX X 4 X1-4-0 31 61 R2o R21 ^6a 7 R23 1 - R24 R22-r 1 9 a 0 12 Y1-C-C-R7 11 11 11 M, L, xi 46 GB 2 122 203 A 46 CHART A n Y1-C-C-R27 m a R., a 1 M6 L, 0 11 HO v /1/ P (OCH3 2 0 CH2) n Y1-C-C-R2.7 1 M6 L, Ris 0 0 0 \Y 11 11 (C142)n-C-CMI-P(OC'312 Y1-C-C-R27 1 Ris 0 1 o M M xxII Mil 9 a M6 L (Cli-2) n Y.'-c-c-R27 11 11 1 M6 L, R, rs To MI xxIv 47 GB 2 122 203 A 47 CHART A (continued) From XXIV 0 R, r, -5A(CH2) n 1 R37 YiC-C-R27 11 A RiE 1 3 M6 11 0 HO f n H2L 7 Yi-C-C-R27 Ri,s MG L, v 0 TsO ('(CH2) n 1 H2C - Y, -C C-Rp.7 0 11 R16. M6 L, M MI xXVII 48 GB 2 122 203 A 48 CHARTB 0 To xxxvi R,6 CH2)n R3,7 .,Y1-C-C-R27 1 Ks L., R1E3 0 0 LiOC-U-Z2-CH2OR2s 1 Li M/ HO CH-Z2-CH2OR2s R16 P2a) n R3.7 Y1-C C-R27 0 a 1 M6 L, Ris \V To Miv MI MI I Mill 49 GB 2 122 203 A.49 CHART B1continued) From. MI From M.1 I I W Z2-CH2OR26 R, 6 n R3.7 Y1-C-C-R2.7 R., 3 0 0 1 M6 L, W Z2-CH20H R16 R3.7 (P2) n YiC-C-R27 1 Ris 11 11 Ks L 1 Z2-xl R 1,5 R37 k \ ( 1 CH2)n Y1-C-C-R7 -Q--, 11 a R a MI L.& Miv Mv xxxvi GB 2 122 203 A 50 CHARTC p(CH2)9-COOH COOH ', (CH2)9-CH20H CHpOH (CH2)g-CH20Rps CH210H 1 \V (CH2)g-CH2-OR28 CHO XLI XLII XLIII XLIV 51 GB 2 122 203 A 51 CHART D 0 R, CH2) n -R17 -Y 1 C-C-R27 11 H M6 L, Ris OH Ri rs n R1.7_ y,-c-C-R27 11 11 1 M ' 'Ll 6 R, a 0 11 O-S-CH3 11 0 R,6 (CH2) n -< 11 R17 Yi-c-C-R27 1 M6 L., R, rs TO LIV LI LII LIN 52 GB 2 122 203 A 52 CHART D (continued) From LIII 1 S-C Rirs CH2)n R1.7 - Ris M6 L, S02 r-).--c LIV R i rs -n.(C H 2) n R17 f 0Ac (CM2)9-CH2OR2e O-SO2 CH --a R,6 --(,CH2) n R1.7 Y, -C----C-R27 1 ille 11 R M6 l., M/ (CH.2)g-CH2OR2,s R16 (CH2)n R17. -Q---Y, -C-C-R27 11 5 1 M6 11 Ris To LVIII - U Y, -C-C-R27 a A 1. M's 11 Ris LVI LVII x 53 GB 2 122 203 A.53_ CHART D (continued) From LVII 1 CH2) g-c.20H R, 6 --"< (CH2) n R17- Yi-C-C-R27 0 R Ris M6 Ll.
R16 1 CH2) n R1.7" t- (CH2) 9-COOR, i -C-C-R2.7 - Ris 11 9 M6 L, 1 (CH2) 9-Xl R, 6 - \. / CH2)n R17 yl-C-C-R7 -Q--- N a 1 M 1. L.% Re IVIII LIX LX 54 GB 2 122 203 A 54 CHARTE 0 0) (CH2) n 1 1 CH2OR3, 1 R36 0 R, 6 n R.i.7 CH2OR31 R3e Z1-xl R16- CH2) n R17 - Q--- CH20R31 1 R3E3 IXI LX11 LX1H GB 2 122 203 A 55 CHARTF Z.1 -X, R,6.-{(CH2)n Ri.7 CH 2 0 R 3 1 R3s Z1-xl R16 CH2)n R1.7 -Q-"CH20H 1 R3e Z1-xl R16 CH2) n R17 Y-C-C-%g7 1 11 11 Re M,L, LXXI UXII UXIII 56 GB 2 122 203 A 56 CHARTG R16 CHp -A(I) n R37 Y1-C-C-R27 11 a M6 11 Rie 1 G [Pn+ Br (D 0P=CH-Z2COOH - 1 C) 2-COOH R16 1 CH2)n LUXI 1Mil R27 00- \ LUXIII Y1-C-C-R27 g' A 1 M6 L, Ris Z2-COOCH3 R16 CH2)n LUXIV R37 Y1-C-C-R27 11 U 1 M 6 L., R., r, To M/ LXXXVIII and LUXIV To UM 57 GB 2 122 203 A_57 CHART G (continued) From LUXIV \ / Z,2-CH20H R, o (CH2) n R3.7 Y1-C-C-Rz7 1 Rio HON2c-Z2 H R16 -<Y /C - H2)n R37 t 0. a M6 L, LUM Y, -C-C-R27 11 - a R, o K5 L, \V X,-Z2 H R16 1 CH2) n R1.7 X -Q--- Y1-C-C-R.7 11 A 1 M, L, R e UMVIII UM H Z2-CH20H R. 16- ((CH2) n 1 LXXXVII ..IY, -C-C-R27 11 0 1 M6 L, Rio H Z2-xl, R16 -< CH2)n R37 LMIX Y1-C-C-R7 0 h 1 M 1 L., Re 58 GB 2 122 203 A 58 CHARTH 0 0 -S-CH2-CH2-Z2TCH2OR1o H3CH N/ 0 xci CH(F)-CH2-Z2-CH2OR1o xcii H3M 0 R, 6 -""<"(CH2) n . X 1 - Y, C-C-Rzz 11 9 1 M6 ' L, -xl / F Z2-CH2OR1o 1-11 R16 C H 2) n R17 xciv r..Y1-C-C-R27 11 11 Ris M6 L, - "I, 1\4 R., a F Z.2-CH20H 1-1 R, 6 -- (CH2)n 1 R1.7 xCV -Q----Y, -C-C-R 9 A 1 M 1 L., R B To XM MIT 59 GB 2 122 203 A 59 CHART H (continued) From XCV F Z.2-COOH R16. (CH2)n R17 Yl.-C-C-R-;.
Re M, L, F Z2-Xl R,6 CH2) n R1-7 Y, C-C-R7 0 a M, L, 1 R13 xCv I XWII GB 2 122 203 A 60 CHART 1 0 R,6 n R17 CHp.OR31 1 R35 \V F ( Z2-x., R,6 C112) n C H2OR31 1 R3e F Z2-xl R,6 (CH2)n R17 Y.I-C-CA, 11 0 1 M, L, Ra cl cii 1 ciii 61 GB 2 122 203 A '61 CHARTJ Ris CH2-CH2CH2-COORi Ri.r, CH2)n R17 Y, C-C-R7 0 a 1 M, L.& RE PhSe 5 R, 5. CH2-CH2-CH-COOR, R16,CHP) n R17 -h Y1-C-C-R7 a a 1 M,.. L, Ra H COOR, R15 CH2 R16 - ((,CH2)n' R17 - H Y1-C-C-R7 0 a 1 M,L., Re R15 CH2 R16 - (CHp) n R17 Yi-C-C-R7 -Q--- 11 h 1 M, 11 RE3 CM CM cxIII MY 62 GB 2 122 203 A 62 CHART K R15 CH2-CH2-CH2-COOR, R1.6 CH2) n R1.7 CH20R31 1 R3E3 R15 PhS CH2-CH2-CH-COOR, R16 CH2 ) n R1.7 -CH2ORil R3E3 H -- c=c Z1 R,5 c 2 R,6 - ((CH2) n R1.7 ----CH2OR3, 1 R3E3 Uxi Uxii Uxiii 63 GB 2 122 203 A 63 CHARTL PhSe Ris 5 R., 6 1 CH2) n Ri.7 CH2OR31 R38 1 R16 1 Cl] 2) n i PhSe CH(Rl)-CH2CH2.-CH-COOR, Ri.7 CH2OR31 1 R3E3 1 H -1 C=C _,C0OR, CH (R 15) - CH.2 -' '- H R16 CH21n R,7-- CH20R31 R3 C=C CH(Ris)-CH2' H R,6 -<'-(CH2)n R 1.7 >.'-CH2OR31 1 R35 CUM MMI cxxxiii cxxxiv 1 64 GB 2 122 203 A 64 CHART M Ris 3-Xl R, r, CH2) n R1.7 CH2OR31 R36 CH(R15)-Z3-Xl Rl 6 CH2)n R,7 CHpOR31 I R3e CHART N C(R15)-Z1-Xl R 1,s -'A(CH2) n W17 CH2OR31 1 R3E3 CH(R15)-Z1-Xl R16 n R17 Y, -C-C-R7 11 - C R 1 M, L, a ULI cxLlI CLI CLII GB 2 122 203 A 65 CHARTO Ris (' zlxl R, r, - (CH2) n R1.7 1 Y1-C-C-R.7 0 1 M, L, I Re CH (R15)-ZIrX, R16 -(,CH2) n Ri-7 Y1-C-C-R-7 1 - RB C1M CLUI A a m, 11 66 GB 2 122 203 A 66 CHARTP OR2e Y1-c-, C-R2..7 Rie A 11 M6. L, CH2 OR2e Yi-C-C-R2.-7 Ria 0 11 M6 L, M/ C?.20H OR,29 Y1-C Ris 91 M6 L, M/ To CLUIV C1M CUM C1M I I 67 GB 2 122 203 A 67 CHART P (continued) From C1XXIII CH20502CH3 OR2e Y1-C C-R27 Rio It. a Me, L, CH2.0502CH3 1 Yi-C-CA2..7 Rio 11 11 M6 11 W 0-4- X, Yi -C-C-R7 Ria 11 11 M, L, CLUIV CLUT > CLUVIII NO Rio Y1-C-C-R27 9 4 M9 Li \Y 0-4-COOR, Yi-C-C-R27 Ri a M6 L, CUM CLUVII 68 GB 2 122 203.A 68 CHARTQ CH20H OR2E; Y1-C-C-R27 Ri a 11 R M6 L, - NO Rio ?,-C-C-R27 11. 11 M6 Li.
R10OC-L4-0 H Y-C-C-R27 Rio 11 11 M6 1, i z T6CUMI CLUXI CLUXIV CUM CHO To CUMVIII CHO OR2.,3 Yi-C C-R27 Ri a N I MG L i Y1-C-C-R2.7 Me L,.
H CLUXII CLUXIII A 69 GB 2 122 263 A 69 CHART Q (continued) From CUM Ri02C-4-0 CLUM R.is V,-C-C-R27 11 11 M6 L, O-Z4-X, 0 RE3 Y1-C-C-R7 11 it M, L, R10OC-L,-0 R18 Yi -C-C-R27 M6 Ll CUMVII CLUXVIII 0-7-4-Xl Y1-C-C-117 Rs 11 11 M, L, O-Z.-X, V Yi-C-C-Ri M, L, CUMIX M GB 2 122 203 A 70 CHARTR CHO C, YI-C,7R27 Rio 11 11 M6- L., - OR.2a CHO OR2E3 Y1-C-C-R27 Ria 11 it.
M6 L, CH20H OR.2a Y1-C-C-R27 Ris 11 M6 xl, xl-Z4-0 v 1 11 Re Y-C-C-R-7 11 11 M, Li.
cxCI.
UCII cxcIII CEIV 71 GB 2 M 203 A 71 CHARTS 0 CHP.OR31 OR29 xl-z4-o R 2 R2., R22 PR 2.3 R2,, - li 0 Re H24R31 % N Xl-Z4-0 W-2 R21 R22, R:j3 R2.4 R Y1-C-C-R7 11 11 M, L, cci cci I cciii 72 GB 2 122 203 A 72 CHARTT CHO OH Yi-C-C-R27 Ris 11 11 M6 - L, HO Rie Yi-C-C-R27' 11 11 M6 Li-- Xl-Z4-0 1.
j V_ Re Y.I-C-C-R7 it - 11 M., L i CUI Mil CUM 73 G13 2 122 203 A 73 CHART U xlZ4-0 R20 R2, R2 R23 R2t, H Ris H c=c C-C-R7 9 9 M6 L, X1-Z4-0 R2o R2,1 R2 R23 R.2 4 Ris HO X1-Z4-0 R2o R2, R2 R23 R24 Y1-C-C-R7 Re. 0 0 Mi Ll CUM CUM ccxxiii 74 GB 2 122 203 A 74

Claims (4)

  1. CLAIMS 1. A compound of the formula
    X 1_ Z 4_ 0 R 20 1 H R 33 A 9 R 18 wherein R,, is H, OH, CH20H, OR,, or CH20Rl0 and R10 is an acid- hydrolysable blocking group; 5 R20 is H, a-OH, A-OH or =O; R33 is CHO or CH20R32 and R32 is hydrogen or a replaceable blocking group; Z4 is -CH,- or -(CH,)f-CF2- and f is zero, one, 2 or 3; and X, is COORl, CH20H, CH2NL2L3 or COL4; in which R, is hydrogen, a pharmacologically acceptable cation, Cl-12 alkyl, C3-10 cycloalkyl, C7-12 aralkyl, phenyl optionally substituted up to 3 times by chlorine atoms or C 1-4 alkyi radicals, or phenyl 10 substituted in the para-position by -NHCOR25. -COR2W benzoyloxy, acetobenzoyloxy or -CH=N-NH-CONH2 in which R25 is methyl, phenyl, acetamidophenyl, benzamidophenyl or -NH2 and R2,'S methyl, methoxy, phenyl or -NH2. L2 and L3 are indpendently selected from hydrogen and Cl- 4 alkyl; and L4 is -NR2.,R2 -NIFt,,COR127. -NR29SO211'27 or a cycloamino selected from pyrrolidino, 15 piperidino, morpholino, piperazino, hexamethyleneimino, pyrrolino and 3,4- didehydropiperidinyl optionally substituted by one or 2 Cl-12 alkyl radicals, in which R27 is hydrogen, C,-12 alkyl, C3-10 cycloalkyl, C7-12 aralkyl, phenyl optionally substituted by up to 3 substituents selected from chlorine, Cl-3 alkyl, hydroxy, carboxy, (C1-4 alkoxy)carbonyl and nitro, carboxy(C1- 4 alkyl), carbarnoyl(C1-4 alkyl), cyano(C1-4 alkyl), acetyl(C1-4 alkyl), benzo(Cl4 alkyl) optionally substituted by up to 3 substituents 20 selected from chlorine, Cl-3 alkyl, hydroxy, Cl-3 alkoxy, carboxy, (C1-4 alkoxy)carbonyl and nitro, pyridyl optionally substituted by up to 3 substituents selected from chlorine, Cl- , alkyl and Cl-, alkoxy, pyridyl(C,-4 alkyl) optionally substituted by up to 3 substituents selected from chlorine, Cl-3 alkyl and hydroxy, or mono-, di- or tri-hydroxy(C1-4 alkyl), R2, is R27 other than hydrogen, R2. is hydrogen or Cl-U alkyl, and R2. is hydrogen or Cl4 alkyi.
  2. 2. A compound of the formula X,- Z 47- 0 \ 1 R 33 1 1 R 18 wherein R,., R331 Z4 and X, are as defined in claim 1.
    GB 2 122 203 A 75
  3. 3. A compound of the formula wherein R,., R331 Z4 and X, are as defined in claim 1.
  4. 4. A compound of the formula X 0 R 33 R A HO -R- % 1 - Y 1_ C -CR 3 R 4_ R 7 Q 11 1 A R 18 M6 wherein R,. is as defined in claim 1; either R3 and R4 are independently selected from hydrogen, methyl and fluorine, provided that CR.R4 is not CFMe, and R7'S C2-, alkyl, cis-CH=CH-CH:27-CH3' -(CH2)-CHOR,C-CH 3 and JR, . is an acid-hydrolysable blocking group, -(CH2)d--CH=CH(CH3)2 or optionally ring-substituted phenoxy, phenyl, benzyi, phenylethyl or phenyl propyl in which there are no more than 3 ring su bstituents (no 10 more than 2 of which are alkyl) indepdently selected from chlorine, fluorine, trifluoromethyl, C1-3 alkyl and C1-3 alkoxy, provided that neither R3 nor R4 is fluorine when R7 is optionally substituted phenoxy; or CR.R47-R7 is 2-(2-furyl)ethy], 2-(3-thienyi)ethoxy, 3-thienyloxymethy], or C4-7 cycloalkyl optionally carrying up to 3 Cl-, alkyl substituents; M. is a-0Rjo:P-R5 or ct-Rr,.P-ORIO in which R,, is hydrogen or methyl and R,o is as defined above.15 Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1984. Published by the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.
GB08319032A 1980-03-28 1983-07-14 Benzo-fused bicyclononanes Expired GB2122203B (en)

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Publication number Priority date Publication date Assignee Title
CA1241324A (en) * 1984-03-08 1988-08-30 Paul A. Aristoff Interphenylene carbacyclin derivatives
CA2056039A1 (en) * 1991-01-22 1992-07-23 Philip L. Fuchs Carbacyclin analogs

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