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GB2067994A - Isoxazolyl and Isoxazolinyl Prostaglandins - Google Patents

Isoxazolyl and Isoxazolinyl Prostaglandins Download PDF

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GB2067994A
GB2067994A GB8101607A GB8101607A GB2067994A GB 2067994 A GB2067994 A GB 2067994A GB 8101607 A GB8101607 A GB 8101607A GB 8101607 A GB8101607 A GB 8101607A GB 2067994 A GB2067994 A GB 2067994A
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alpha
cyclopentan
enyl
carboxyhex
isoxazolyl
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • 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
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Prostaglandins having the following general formula (I> <IMAGE> Äwherein R is hydrogen; free, esterified or protected carboxy group; free or protected formyl group or free or protected hydroxymethyl group; one of R1 and R2 is a hydrogen atom and the other is a hydroxy group or a protected hydroxy group or R1 and R2 together form an oxo or protected oxo group; n is zero, 1 or 2; D is -(CH2)d-; -(CH2)d- CF2-, in which d is an integer of 1 to 5, or -CH=CH-(CH2)k- wherein k is zero or an integer of 1 to 4; R3 is: <IMAGE> wherein m is zero or 1, g is zero or an integer of 1 to 6, each of R6 and R7, which may be the same or different, is a hydrogen atom, C1-C4 alkyl group of fluorine atom, provided that when one of R6 and R7 is a fluorine atom the other is a hydrogen atom, a methyl group or a fluorine atom; <IMAGE> wherein R6, R7 and m are as defined above; Z is -O-, -S- or -(CH2)g-, wherein g is as defined above, and G is: (a%) a phenyl group unsubstituted or substituted by one or more substituents selected from C1- C4 alkyl groups, halogen atoms; trihalo-C1-C6-alkyl groups and C1- C4 alkoxy groups; (b%) a cycloaliphatic group unsubstituted or substituted by one or more substituents selected from C1- C4 alkyl groups, halogen atoms, trihalo-C1-C6 alkyl groups and C1- C4 alkoxy groups; or (c%) a saturated heteromonocyclic ring containing at least one oxygen, sulphur or nitrogen heteroatom; the symbol --- represents a single or double bond; when the symbol --- in the cyclopentane ring is a single bond then one of R4 and R5 is hydrogen and the other is hydrogen, hydroxy or a protected hydroxy group; or, when the symbol --- in the cyclopentane ring is a double bond, then R4 and R5 taken together represent hydrogenÜ and the pharmaceutically and veterinarily acceptable salts thereof have prostaglandins-like therapeutic activity and are useful interemediates in forming W<13(14)>-15-oxo and W<14(15)>- 13-oxo prostaglandins.

Description

SPECIFICATION Isoxazolyl and Isoxazolinyl Prostaglandins The present invention relates to new isoxazolyl- and isoxazolinyl-prostaglandins, and to a process for their preparation, and to pharmaceutical and veterinary compositions containing them as well as to a new process for the preparation of #14(15)-13 keto- and #13(14)-15 keto-prostaglandins starting from the new isoxazolyl and isoxazolinyl prostaglandins of the invention. The prostaglandins are a well known class of compounds derived from prostanoic acid, which have been shown to have a variety of valuable pharmacological activities [Bergstrom et al., Pharmacol. Rev. 20, 1, 1968]. The prostaglandins, their derivatives and analogues are extremely potent in inducing various biological responses.A few of these biological responses are, for example, stimulation of smooth muscle; inhibition of gastric secretion; reduction of undesirable gastrointestinal side-effects from systemic administration of prostaglandin synthetase inhibitors, e.g. indomethacin, acetylsalicylic acid and phenylbutazone; induction of labor in pregnant female mammals.
Because of their biological responses, PGE, PGF- and PGI-type prostaglandins are useful for phannaceutical and pharmacological purposes, for example for studying, preventing, controlling and alleviating a wide variety of diseases and undesirable pathological conditions in mammals, including humans.
The present invention provides new optically active or racemic prostaglandins of formula (1 )
wherein R is hydrogen; free, esterified or protected carboxy group; free or protected formyl group of free or protected hydroxymetilyl group; one of R, and R2 is hydrogen and the other is hydroxy or a protected hydroxy group or R2 and R2 together form an oxo (=Q) or protected oxo group; n is zero, 1 or 2; D is -(CH2)d-; -(CH2)d-CF2-, in which d is an integer of 1 to 5 or -CH=CH-(CH2)k wherein k is zero or an integer of 1 to 4; iris iS:
wherein m is zero or 1, g is zero or an integer of 1 to 6, each of R6 and R,, which may be the same or different, is hydrogen, C1-C4 alkyl or fluorine, provided that when one of R6 R7 is fluorine and the other is C1-C4 alkyl, this is methyl: or
where , R, and rn are as defined above;Z isO--S-or -(CH2)-, g being as defined above, and G is: (a') a phenyl group unsubstituted or substituted by one or more substituents selected from C1 C4 alkyl, halogen; trihalo-C1-C6-alkyl and C1-c4 alkoxy; b's a cycloaliphatic group unsubstituted or substituted by one or more substituents selected from C1-C4 alleyl, halogen, trihalo-C1-C6 alkyl and C1-C4 alkoxy; or @') a saturated heteromonocyclic ring containing at least one oxygen, sulphur or nitrogen hetero-atom; the symbol @@@ represents a single or double bond; when the symbol @@@ in the cyclopentane ring is a singk bend, taken one of R4 and R6 is hydrogen and the other is hydrogen, hydroxy or a protected hydroxy group; or, when the symbol @@@ in the cyclopentane ring is a double bond, then R4 and R6 taken together represent hydrogen.
The present. invention includes also the pharmaceutically or veterinarily acceptable salts of the compounds of formula (1) as well as all the possible isomers, the metabolites provided with pharmacological activity and the metabolic precursors of the corn-pounds of formula (1).
Preferred salts are the salts of the compounds of formula (1) where R is a carboxy group with pharmaceutically or veterinarily acceptable bases. These may be inorganic bases, for example alkali metal, e.g. sodium or potassium, or alkaline earth metal, e.g. calcium or magnesium, hydroxides and organic bases, for instance amines, e.g. methylamine, diethylamine, trimethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, decylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, &alpha;;-phenylethylamine, p-phenylethylamine, ethylenediamine, diethylenetriamine, or other similar aliphatic or aromatic amines or heterocyclic amines e.g. piperidine, morpholine, pyrrolidine, piperazine, as well as substituted derivatives like 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, hydrophilic derivatives like mono-, di- and triethanolamine, 2-amino-2-butanol, 2-amino-1-butanol, 2-amino-2-ethyl-1 ,3-propanediol, 2-amino2-methyl-1-propanol, tris-(hydroxymethyl)-aminomethane, N-phenylethanolamine, N-(p-tertamylphenyl)-diethanolamine, ephedrine, procain, - and ss-amino acids like lysine and arginine.
When R is an esterified carboxy group it is, for example, an alkoxycarbonyl group, preferably a C2-C5 alkoxycarbonyl group. When R is a protected carboxy group, it is for example protected through one of the following protecting groups: tert.butyl, benzhydryl, p.-methoxybenzyl, p.nitrobenzyl, trityl and trialkylsilyl, preferably by means of the trialkylsilyl group.
When R is a protected formyl group, it is for example protected by ketal or thioketal residue, preferably in the form of an ethylenedioxide or an ethylenthioketal group.
When R is a protected hydroxymethyl group, the hydroxy group is for example protected in the form of ether or ester readily convertible into hydroxy group under mild conditions, for instance acid hydrolysis. Preferred protecting groups for the hydroxyl function are acetal ethers, in particular tetrahydropyranyl ether, and silyl ethers, in particular trialkyl silyl ether. When R, and R2, taken together with the carbon atom to which they are linked form a protected carbonyl group, this is, for example, a group of formula
in which X and X', independently, are oxygen or sulphur and each of Ra and Rb, whetiterthe same or different, is C1-C6 alkyl or Ra and Rb, taken together, form a straight or branched C2-C6 alkylene chain.
A cycloaliphatic group may be mono-, bi- or tricyclic. A monocyclic, C3-C9 cycloalkyl is preferred, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. If bicyclic, norbornyl is preferred. If tricyclic, adamantyl is preferred.
A saturated heteromonocyclic ring preferably is a pentatonic or heyatomic saturated heteromonocyclic ring containing 0 or S, in particular tetrahydrnfuryl and tetrahydrothienyl.
A trihalo-C1-C0 alkyl group is preferably a trihalomethyl group, in particular trifluoromethyl or trichloromethyl preferably trifluoromethyl.
A -C4 alkyl group is preferably methyl or ethyl. A C1-C4 alkoxy group is prefe; abl metlioxy or ethoxy. A halogen atom is preferably fluorine or chlorine.
In the formulae of the present application, the broken line broken lines (''''') indicate that the substituents are in the &alpha;-configuration, i.e. below the plane of the cyclopentane ring, and the wedged line (@) indicates that the substituents are in the p-configuration, i.e. above the plane of 'the cyclopentane ring. A wavy line (~~) indicates that a subatituent may be both in the a- and in the p-, or, respec-ively, both in the S- and in the R-configuration.
Preferred compounds of the invention are the compounds of formula (I), wherein R is COOR', wherein R' is hydrogen, methyl or ethyl; n is 2; D is -(CH2)4-or cis-CH=CH-(CH2)k- \EJherein k is 2 or 3; R1 is hydroxy and R2 is hydrogen or R1 and R2, taken together, form an an oxo or protected oxo group; R3 is as defined above, but preferably n-C5H11,n-C6H13, -C(CH3)2-n-C4H9,-C(CH3)2 O-n-C4H9,-CH2-C(CH3)2-O-n-C4H9,
R4 is hydroxy and R6 is hydrogen, as well as the pharniaceutically and veterinarily acceptable salts thereof, especially alkali metal salts (of the compounds in which R is a carboxy group).Specific examples of the compounds or the invention are the following: 1. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-methylcyclopentan-1-one.
2. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-allylcyclopentan-1-one.
3. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan- 1-one.
4. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2a-carboxymethylcyclopentan-1-one.
5. (1) 3-j3-[5-(2 '-hexyl)isoxazolylj}-2a-(6-carboxyhexyl)-cyclopentan-1 -one.
6. (#) 3ss-{3-[5-(1'-Fluoropentyl)isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one.
7. (#) 3ss-{3-[5-(2'-Fluoro-2'-hexyl)isoxazolyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
8. (#) 3ss-{3-[5-(2'-Cyclohexylethylisoxazolyl)}-2&alpha;-(6-craboxyhexyl)cyclopentan-1-one.
9. (#) 3ss-{3-[5-(5'-Phenylethylisoxazolyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
10. (#) 3ss-[3-(5-Cyclohexylisoxazolyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
11. (#) 3ss-{3-[5-Phenoxymethylisoxazolyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
12. (+) 3ss-{3-[5-(2'-n-Buoxy-2'-propyl)isoxazolyl]-2&alpha;-(6-carboxyhexyl)cyclopentan- 1-one.
13. (#)-{3-[5-(2'-Methyl-2'-n-butoxy-propylisoxazolyl] }-2 a-(6-carboxyhexyl)cyclopentan- 1-one.
14. (#) 3ss-{3-[5-(2'-[2-tetrahydrofuryl]ethyl)isoxazolyl}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
15. (#) 3ss-[3-5-n-Pentylisoxazolyl)-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1-one.
16. (#) 3ss-(5-n-Hexylisoxazolyl)]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1-one.
17. (#) 3ss-[3-(5-n-Pentylisoxazolyl)-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
18. (#) 3ss-[3-[5-(2'-Hexyl)isoxazolyl)-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
19. (#) 3ss-{3-[5-(1'-Fluoropentyl)isoxazolyl]}-2alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
20. (#) 3ss-{3-[5-(2'-Fluoro-2'-hexyl)isoxazolyl]}-2alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1 one.
21. (#) 3ss-{3-[5-(2'-Cyclohexylethyl)isoxazolyl]}-2alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1- one.
22. (#) 3ss-{3-[5-(2'-Phenylethyl)isoxazolyl]}-2alpha;-(carboxyhex-2(3)-enyl)cyclopentan-1-one.
23. (#) 3ss-{3-[5-Cyclohexylisoxazolyl]}-2alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
24. (#) 3ss-{3-[5-Penoxymethylisoxazolyl]}-2alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
25. (#) 3ss-{3-[5-(2'-N-Butoxy-2'-propyl)isoxazolyl]}-2alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1 one.
26. (+) 3ss-{3-[5-(2'-Methyl-2'-n-butoxypropyl)isoxaozolyl] i-2a-(6-carboxyhex-2(3)- enyl)cyclopentan-1-one.
27. (#) 3ss-{3-[5-(2'-Tetrahydrofuryl]ethyl)isoxazolyl]}-2alpha;-(6-carboxyhex-2(3) enyl)cyclopentan- 1-one.
28. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2alpha;-methylcyclopentan- 1-one.
29. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one 30. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-carboxymethylcyclopentan-1-one.
31. (#) 3ss-{3-[5-(2'-Hexylisoxazol-2(3-inyl]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
32. (#) 3ss-{3-[5-(1'-Fluoropentyl)isoxazol-2(3-inyl]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
33. (#) 3ss-{3-[5-(2'-Fluoro-2'-hexyl)isoxazol-2(3)inyl]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
34. (#) 3ss-{3-[5-(2-Cyclohexylethyl)isoxazol-2(3-inyl]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
35. (#) 3ss-{3-[5-(2'-Phenylethyl)isoxazol)-2(3)-inyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
36. (t) 3ss-[3-(5-Cyclohexylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan- 1-one.
37. (#) 3ss-{3-[5-Phenoxymethylisoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
38. (+) 3ss-{3-[5-(2'-n-Butoxy-2'-propyl)isoxazol-2 (3)-inyl] }- 2&alpha;-(6-carboxyhexyl)-cyclopentan-1- ona.
39. (F) 3ss-{3-5-(2'-Methyl-2'-n-butoxypropyl)isoxazol-2(3)-inyl] }-2a-(6- carboxyhexyl)cyclopentan- 1-one.
40. (#) 3ss-{3-[5-(2'-[2-Tetrahydrofuryl]ethyl)isoxazol-2(3)-inyl]}-2&alpha;-(6- carbóxyhexyl)cyclopentan- 1 -one.
41. (#) 3ss-{3-[5-(2'-Hexyl)isoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
42. (+) 3ss-{3-[5-( 1 '-Fluoropentyl)isoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan 1-one.
43. (#) 3ss-{3-[5-(2'-Fluoro-2'hexyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan- 1-one.
44. (#) 3ss-{3-[55(2'-Cyclohexylethyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan-1 -one.
45. (#) 3ss-{3-[2'-Phenylethyl)isoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1- one.
46. (#) 3ss-{3-[5-Cyclohexylisoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
47. (#) 3ss-{3-[5-Phenoxymethylisoxazol-2(3)-Inyl]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1- one.
48. (#) 3ss-{3-[5-(2'-n-Butoxy-2'-propyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3- enyl)cyclopentan-1 -one.
49. (#) 3ss-{3-[5-(2'-Methyl-2'-n-butoxypropyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan- 1-one.
50. (#) 3ss-{3-[5-(2'-[2-Tetrahydrofuryl]ethylisoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan- 1-one.
51. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2-allylcyclopentan-1-ol.
52. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;)]-2&alpha;-allylcyclopentan-1ss-ol.
53. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;)]-2&alpha;-(6-carboxyhexyl)-cyclopentan-1&alpha;-ol.
54. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;)]-2&alpha;-(6-carboxyhexyl)-cyclopentan-1ss-ol.
55. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;)]-2&alpha;-carboxymethyl-cyclopentan-1&alpha;-ol.
56. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;)]-2&alpha;-carboxymethyl-cyclopentan-1ss-ol.
57. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;)]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1&alpha;-ol.
58. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;)]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1ss-ol.
59. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1 a-ol.
60. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1ss-ol.
61. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhexyl)cyclopentan- 1 a-ol.
62. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan-1ss-ol.
63. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-carboxymethylcyclopentan-1 a-ol.
64. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl]-2&alpha;-carboxymethylcyclopentan-1 ss-ol.
65. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-3(4)-eny)lcyclopentan-1&alpha;-ol.
66. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1ss-ol.
67. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1 a-ol.
68. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl]-2&alpha;-(6- carboxyhex-2(3)-enyl)cyclopentan 1 1,B-ol.
69. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-n-butoxycarbonylmethyl)-cyclopent-3(4)-en-1-one.
70. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;- (6-n-butoxycarbonylmethyl)-cyclopentan- 1-one.
71. (3) 3ss-[3-(5-n-Pentylisoxazolinyl)]-2&alpha;-(6-n-butoxycarbonylhexyl)-cyclopentan-1-one.
The invention is further exemplified by the pharmaceutically and veterinarily acceptable salts each o the above compounds 171, especially of compounds containing a carboxy group.
In the above names of compounds: 2'-hexyl is equivalent to 1 '-methyl-n-pentyl; 1 '-fluoropent;yl to 1 '-fluoro-n-pentyl; 2'-fluoro-2'-hexyl to 1'-fluoro-1'-methyl-n-pentyl; phenoxymethyl to (1 '-phenoxy)methyl; 2'-n-butoxy-2'-propyl to (1', 1'-dimethyl-1'-butoxy)methyl; 2'-methyl-2'-n-butoxypropyl to (2,2'-dimethyl-2'-butoxy)ethyl; hex-#2,3 enyl to hex-2(3)-enyl.
hex-#3,4-enyl to hex-3(4)-enyl; and A23-isoxazolinyl to isoxazol-2(3)-inyl.
The alternative versions are used hereinafter in this description.
The compounds of formula (I) are useful starting materials for the preparation of #14(15)-13 3-oxo- and #13(14)-15-oxo-prostaglandin analogs of formula (
wherein R, R1, R2, R4 R6, D and n are as defined above and A is
wherein R3 is as defined above. The process is described in more detail later in this specification.
The compounds of formula (I) can be prepared by a process comprising reacting an optically active or racemic compound of formula (III)
wherein r is as defined above; one of R', and R'2 is hydorgen and the other is a hydroxy-protecting group (which can be of a known @@@@, usually b@und to the ring through an ethereal oxygen atom) or R'1 and R'2 together form an oxo group or protected oxo group one of R'4 and R'6 is hydrogen and the other is hydrogen or a hydroxy-protecting group (which can be of a known kind, usually bound to the ring through an ethereal oxygen atom), and D and n are as defined above, with a compound of formula (IV) B-R3 (lav) wherein B is CH2=CH- or CHEC-- and R3 is as defined above, thus giving a compound of formula (V)
wherein R',, R'2, R'4, R'5, R, D, n and R3 are as defined above and the symbol - - . is a single or, respectively, a double bond and, if desired, removing the protecting groups and/or, if desired, saponifying a compound of formula (I) when R is an esterified carboxy group and, if desired, salifying a compound of formula (I) where R is a free carboxy group and/or, if desired, converting a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof and/or, if desired, resolving a mixture of isomers of formula (I) into the single isomers.
Protecting groups for the hydroxyl functions are ether or ester residues readily converted to hydroxyl groups under mild conditions, for instance acid hydrolysis. Preferred groups include silyl ethers, for instance, trialkylsilyl ethers like trimethyl-, dimethyl-ter-butyl-, dimethylisopropyl-, or dimethyl-ethylsilyl-ether; and also acetal- and enol-ether residues, for instance, tetrahydropyranyl ether, tetrahydrofuranyl ether, dioxanyl ether, oxathianyl ether,
where Alk is C1-C6-alkyl. oxo-protecting groups are preferably ketal and thioketal residues, e.g.
groups in which X' and X, Ra and Rb are as defined above.
The reaction of a compound with formula (III) with a compound of formula (IV), may be carried out, for example, in an inert organic solvent, preferably anhydrous benzene, at temperature ranging from about 10 C to about 350C, preferably at 250C, for a time ranging from 12 hours to 24 hours.
The reaction is preferably performed in the presence of a catalyst which may be, for instance, a tertiaryamine, in particular triethylamine, and in the presence of a condensing agent such as, for example, phenyl isocyanate or POCK 3.
The optional removal of the protecting groups in a compound of formula (V) may be carried out in a conventional manner. For example, the ether protecting groups may be removed from the hydroxyl functions with mild acid hydrolysis, for instance with mono- or poly-carboxylic acids like acetic, formic, citric, oxalic, or tartaric acid in a solvent like water, acetone tetrahydrofurane, dimethoxyethane or a low molecular weight alcohol, or with a sulfonic acid like p-toluenesulfonic in a low molecular weight alcohol like anhydrous ethanol or methanol, or with a polystyrenesulfonic resin.
For example, a 0.1-0.25 N polycarboxylic acid (iike oxalic or citric) is used with a suitable lowboiling solvent miscible with water and readily removable under vacuum at the end of the reaction.
Silyl ether residues may be selectively removed in the presence of other protecting groups with F- ions in solvents like tetrahydrofurane and dimethylformarnide.
Ester protecting groups may be removed by following typical saponification procedures.
Ketal and thioketal protecting groups are generally removed with mild acid hydrolysis as described above. Thioketals may be selectively removed in the presence of other protecting groups with, for instance, mercuric chloride in aqueous acetone or acetonitrile, or a mixture of them, in the presence of an alkaline earth metal carbonate like that of calcium or magnesium.
The carboxy protecting groups may be removed by mild acid, i.e. HCI or H2SO4 hydrolysis.
The optional conversion of a compound with formula (I) in which R is an esterified carboxy group (i.e., a C1-C5-alkoxycarbonyl) to one in which R is a free carboxyl group may be effected using standard saponification procedures: treatment with an alkali metal or alkaline earth metal hydroxide in water or aqueous alcohol, followed by acidification.
The optional salification of a compound of formula (I) may be performed by usual procedures by treatment with a stoichiometric amount of the desired basis.
Also the optional conversion of a compound of formula (I), or a salt thereof, into another compound of formula (I), or a salt thereof may be carried out by known methods.
Thus, for example, a compound of formula (I) where the symbol represents a single bond may be converted into the corresponding compound of formula (I) where the symbol - - - represents a double bond by oxidation.
The oxidation reaction may be carried out with a suitable oxidizing agent, e.g. CrOMnO KMnO4, y-MnO2, N-bromo succinimide, preferably with y-MnO2 in an inert organic solvent, e.g.
dioxane, benzene or their mixtures, preferably in benzene, at temperature ranging from about 500C to the reflux temperature and with an excess of the oxidizing agent.
Preferably 5 to 15, in particular 10, molar equivalents of the oxidizing agent are used for one molar equivalent of the compound (I).
Furthermore, a compound with formula (I), in which one of R, and R2 is hydrogen and the other is hydroxy may be obtained from a compound with formula (I), in which Rz and R2 taken together, form an oxo group by reduction, for example, with a mixed hydride, preferably with NaBH4 in water, in an aqueous alcoholic solvent or dimethylformamide, or with LiAIH4 in an anhydrous solvent like ethyl ether or tetrahydrofurane, at a temperature ranging from room temperature to the boiling point of the solvent, or with potassium selectidride according to usual procedures.
A compound with formula (I), in which R, and R2, taken together form an oxo group may be obtained from a compound of formula (I), in which one of R, and R2 is hydrogen while the other is hydroxy by selective oxidation with excess activated MnO2 in an inert, preferably chlorinated, solvent like methylene chloride or chloroform at room temperature or, alternatively, with 1.1-1.2 molar equivalents of dichlorodicyanobenzoquinone in an inert solvent like dioxane, benzene or a mixture of these at a temperature ranging from 400C to the boiling point of the solvent.
A compound with formula (I), in which R1 and R2, taken together, form a protected carbonyl group, R is esterified CC}OH, D is an alfrylene-chain, may be converted, if desired, into a compound of formula (I), in which R, and R2, taken together, form a protected carbonyl group, D is an alkenylenechain, R is as defined above, by reduction of the esterified -COOH in the 2&alpha;;-chain to a formyl group and subsequent reaction with a suitable Wittig reagent of general formula (C6H5)3P(CHi2)d dR, wherein d and R are as defined above, The reduction may be carried out by a suitable reducing agent, e.g. DlBAH in an organic solvent, e.g. toluene. The Witting reaction may be carried out in DMSO as solvent and at room temperature.A compound with forinula (I), in which D is an alkylene-chain and R is an esterified -COOH, may be converted, if desired, into a compound of formula (I), in which D is an alkenylene-chain and R is as defined above, by a process comprising: a) saponification by treatment at room temperature with lithium hydroxide in an aqueous methanol, affording, after acidification, e.g. with sulphuric acid, a 2-oxa-bicyclo[3.3.0]oct.an-3-one derivative; b) reduction, e.g. with DIBAH; and c) treatment with a suitable Wittig reagent of general formula (C6H5)3P-(CH2) dR, wherein d and R are as defined above.
When in the obtained compound R is an esterified carboxy group, it may be obtained free by known methods. The optional conversion of a compound with formula (I), wherein R is a hydroxymethyl group or a formyl group, into one in which R is respectively a formyl or a free carboxy group may be effected by using standard oxidation procedures well known in o,-,anic chemistry. Also the optional conversion of a compound with formula (I), wherein R is a carboxy group or a formyl group, into one in which R is respectively a formyl or a hydroxymethyl group may be carried out by following standard reduction procedures well known in organic clemistry.
A compound of formula (I) wherein R, and R2 tkrr, together form a protected carbonyl group, both R4 and R5 are hydrogen and the symbol - - - in the cyclopentane ring represents a single bond may be converted into a compound of formula (I), in which R, and R2 taken together form a carbonyl group, the symbol = in the cyclopentane ring represents a double bond and R4 and R5 taken together represent hydrogen by following known procedures. For example by halogenating the cyclopentane ring in a compound of formula (I) and subsequent dehydrohalogenation of the obtained intermediate.
The halogenation of a compound of formula (I) may be carried out by following standard procedures, as well as the dehydrohalogenation process; for example as halogenating agent may be used pyridinium bromide perbromide and as dehydrohalogenating agent may be used diazobicycloundecene. Also the deprotection of the carbonyl group may be carried out by following well known procedures in organic chemistry, for example as reported above as regards the removal of protecting groups in a compound of formula (V).
The optional resolution of a mixture of isomeric compounds with formula (I) into the individual isomers may be carried out in a conventional manner using standard techniques like. e.g., fractional crystallization from a suitable solvent or chromatography, either thin layer, column or liquid-liquid at low, medium or high pressure. Silica gel or magnesium silicate may be used as support with a solvent like cyclohexane, n-hexane, benzene, methylene chloride, ethyl ether, isopropyl ether, ethyl acetate or methyl acetate as the mobile phase.The compounds with formula (III) in which R'1 and R'2 taken together with the carbon atom to which they are linked form a protected carbonyl group, may be obtained starting from the 3-nitromethylene-2-substituted-cyclopentan-1-one of formula (Illa)
wherein R, R'4, R'5, D and n are as defined above, by conventional ketalization process.
The compounds with formula (III), in which one of R'1 and R'2 is hydrogen and the other is a known protecting group bound to the cyclopentane ring by an ethereal oxygen, are obtained by reduction, for example with mixed hydrides, preferably with NaBH4 as reported above, of a compound of formula (lila), followed by protection of the hydroxyl function by a known protecting group, as reported above.
The compounds with formula (Illa) may be obtained by reacting a compound with formula (VI)
wherein R, R'4, R'5, D and n are as defined above, with nitrometane in the presence of tetramethylguanidine, preferably at roorn temperature and subsequently treating with a dilute mineral acid, e.g. dilute hydrochloric acid.
The compounds of formula (VI) are known compounds: [Alvarez, F. S. et al., Tetrah. lett.: 369 (1973); Burton, T. S. et al., H. Chem. Soc. Perkin: 1,2550 (1976); Caton, H. P. L., Synthetic Cornm.,: 4(5), 303 (1974);Borghi,j.,Tetrah. lett.:3815 (1972)1, or they may be obtained starting from known compounds by methods well known in the art.
Thus, for example a compound with formula (VI) wherein n is zero, D is -(CH2)d, where-d is 1, R is COOCH3 and R'4 and R'6 are both hydrogen, may be converted into another compound of formula (VI) by the process herebelow indicated.
Protection of the carbonyl group, e.g., as ethylendioxyketal, in the compound (Vla) and subsequent reduction of the ester group, e.g. with diisobutylaluminiumhydride, in the compound (Vlb) leads to the aldehyde (Vlc) which may be masked, according to known methods, to give the compound (Vld).
Selective removal of the aldehydic protecting group in the compound (Vld) gives the aldehyde (Vle) having an additional carbon atom in the chain.
Wittig reaction on the aldehydes (Vlc) and (Vle), that is reaction with an an ylide of formula (C6H5) ,P=CH(CH2)ktR where k and Rare as defined above, leads to a compound of formula (Vlf)
that is a compound of formula (VI), wherein n is 2; D is-CH=CH-(CH2)k-, in which k is as defined above; R'4 and R'5 are both hydrogen, and R is as defined above.
As already said the second object of the invention is a new process for the preparation of #14(15)- 1 3-oxo and h13''4L1 5-oxo-prostaglandin of formula (II) starting from compounds with formula (I).
The compounds of formula (I) useful as starting material for this new process are, in particular, the compounds of formula (I) where the symbol @@@ represents a double bond which, as stated above, may also be obtained if desired, by oxidizing the corresponding compounds where the symbol - represents a single bond.
The said new process comprises: reducing a compound of formula (la)
where R, Rr, R2, R3, R4, R5, n and D are as defined above and wherein the free carboxy- and hydroxy or carbonyl groups possibly present are in protected form, to give, according to the used reduction conditions, either a compound of formula (VII)
wherein R, R's, R'2, R3, R'4, R'5, n and Dare as defined above our a compound of formula (VIII)
wherein R, R'1, R'2,R3, R'4, R'5, n and D are as defined above and, if desired, removing the protecting groups in a compound of formula (VII) thus giving a A1314-1 5-oxo prostaglandin of formula (IX)
wherein R, R,, R2, R3, R4, R5, n and Dare as defined above; or converting a compound of formula (VIII) into a compound of formula (X)
wherein R, R', R'2, R3, R'4,F R'5, n and D are as defined above and R8 is C1-C6@ alkyl or phenyl; and reducing a compound of formula (X) to give a compound of formula (XI)
wherein R, R'1, R'2, R3, R'4, R'5, R8, n and D are as defined above, and hydrolyzing a compound of formula (XI) ad, if desired, removing the protecting groups possibl@ present, thus @iving a #14(15)-13- oxo-prostaglandin of formula (XII)
wherein R, R1, R2, R3, R4, R5, n and D are as defined above.
Protecting groups for formyl, hydroxy, carbonyl and carboxy functions may be the sampe reported above for the synthesis of the compounds of formula (I). Also the removal of the formyl, hydroxy, carbonyl and carboxy protecting groups may be carried out as reported above as regards the synthesis of the compounds of formula (I).
The reduction of a compound of formula (la) to give a compound of formula (VII) is preferably carried out by treatment with alkali metal, in particular sodium or potassium, and ammonia in the presence of a proton source such as, for example, a lower aliphatic alcohol like ethyl-, n-propyl-, nbutyl- or tert-butyl-, preferably tert-butyl-, alcohol. The reaction tempernture may vary between about +50C and about -500C.
The reaction proceeds through a non-isolable imino-ketone which readily changes into the compound (VII).
The reduction of a compound of formula (Ia) to give a compound of formula (VIII) may be carried out with hydrogen in the presence of a suitable catalyst e.g. Pd on inert supports or Adam's Pt, preferably, palladium on carbon, in a lower aliphatic alcohol, e.g. methanol, ethanol, propanol and butanol, preferably in methanol, and at temperature ranging from about 50C to about 500 C, preferably at room temperature.The ,B-amino-ketone derivative with formula (will) may be isolated and converted, e.g. by direct acylation, for example by reacting with an acyl halide, preferably chloride, in particular a C1-C6 aliphatic acyl chloride, e.g. acetyl chloride, or benzoyl chloride, in an inert solvent, e.g. pyridine, into the acylamino derivative with formula (X). Many methods for this conversion are known per se.
The reduction of a compound of formula (X) may be performed by known methods e.g. by treatment with mixed hydrides, in particular sodium borohydride in aqueous or aqueous alcoholic solvent or lithium aluminium hydride in an anhydrous inert organic solvent preferably diethylether or tetrahydrofurane.
A mixture of epimeric S and R alcohols of formula (Xl) thus obtained, which, if desired may be resolved into the single isomers by fractionate crystallization or by chromatography.
The hydrolysis of a compound of formula (Xl) to give, after optional removal of the protecting groups, a compound of formula (XII) may be carried out by treatment with dilute mineral acids, e.g.
hydrochloric or sulphuric, preferably sulphuric acid.
In these conditions hydrolysis of the enaminic function and elimination of the hydroxy group occur simultaneously.
Carboxy groups are normally protected as esters and can be re-generated by saponification. The oxo-prostanoic acid derivatives of formulae (IX) and (XII) are known substances [W. Bartmann et al.
"Biologically active 1 1-deoxy prostaglandins in Chemistry Biochemistry s Pharmacological activity of of Prostanoids", S. M. Roberts and F. Scheinmann, Pergamon Press Ltd. Oxford 1979 page 1974]. In particular the 15-oxo derivatives, may also form metabolically by action of 1 5-hydroxy-prostaglandin- dehydrogenase on 15-S-hydroxy prostaglandins.
The #13(14)-15-oxo prostaglandins of formula (IX) and the #14(15)-13-oxo prostaglandins of formula (XII) are useful intermediates in the synthesis of other prostaglandins. Thus, for example, hydrogenation of the 13,14- or, respectively, 14,1 5-double bond in the compound (IX) and (XII), by known methods, leads to the corresponding 13,14- and 14,15-ethylene derivatives, while known halogenation and dehydrohalogenation processes on the 13,14- or 14,15-double bond lead to the corresponding acetylenic compounds.
Prior or subsequent reduction of the 15- or 1 3-oxo group by known methods, gives 15(S,R)- or, respectively, 13(S,R)-hydroxy derivatives.
The isoxazolyl and isoxazolinyl prostaglandinsof the present invention show the same pharmacological activities as the natural prostaglandins. They are in particular very active stimulator, in vitro and in vivo, of the smooth muscle and are also highly active in potentiating the other known smooth stimulators, e.g. various ergot alkaloids including derivatives and analogs thereof. Therefore these new compounds are useful, in place of, or in association with, less than the usual dosage of these known smooth muscle stimulators, for controlling or preventing atonic uterine bleeding after delivery or abortion and during puerperium.In this purpose, the compounds are administered by oral route, after delivery or abortion, at a dose in the range of about 0.1 to about 20 mg per kg of body weight provided, the exact dosage depends on the age, weight and clinical conditions of the patient or animal. The compounds of the invention are also useful both in man and anirnal for reducing and controlling the excessive gastric secretion, thereby they reduce or avoid the gastrointestinal mucose damages and accelerate the healing of the gastrointestinal ulcers.For this purpose the new drugs may be administered for parenteral, e.g. subcutaneously, or oral route at a dose in the range of about 0.01 mg to about 3 mg per kg of body weight in a single or in a total daily dose: the exact dosage depends on the age, weight and clinical conditions of the patient or animal and on the frequency and the route of administration.
The compounds of the invention are also useful for reducing the undesirable gastrointestinal sideeffects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors and may be, therefore, used for this purpose in association with them.
The dosage for these compounds in accord with this treatment will depend upon a variety of factors, including the type, age, weight, sex and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular prostaglandin-type compound to be administered. For example, not every human in need of an anti-inflammatory substance experiences the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree.But it is within the skill of the attending physician or veterinarian to determine that administration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject and to prescribe an effective amount of a compound of the invention to reduce and then substantially to eliminate those undesirable effects.
The isoxazolyl and isoxazolinyl prostaglandins of the invention are also useful in the treatment of asthma. For example, these compounds are useful as bronchodilators or as inhibitors of mediators, 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 such as bronchiai asthma, bronchitis, 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 for of suppositories; parenterally e.g.
subcutaneously or intramuscularly, with intravenous administration being preferred in emergency situation; by inhalation in the form of aereosols or solutions for nebulizers; or by insufflation in the form of powder. Doses in the range of about 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 the isoxazolyl and isoxazolinyl prostaglandins of the invention can be combined advantageously with other anti-asthmatic agents, such as sympathorn imetics (isoproterenol, phenylephrine, ephedrine, etc.); xanthine derivatives (theophylline and aminophylline); and corticosteroids (ATCH and prednisolone).
For their platelet antiaggregatory activity and feeble dilating action of capillary vessels the compounds of the invention are also useful in treating peripheral vascular disease in humans. For these conditions are administered orally or parenterally, e.g. i.v. or i.m., in a daily dose range of 0.2-1 5 mg/kg, i.e. 1-4 times a day, the exact dose depending on the age, weight and condition of the patient and on the frequency and route of administration.
The compounds of the invention are useful in place of oxytocin to induce labor in pregnant female animals, including man, cows, sheep and pigs, at or near term, or in pregnant animals with intrauterine death of the foetus from about 20 weeks to term. For this purpose, the compound is infused intraveneously at a dose of 0.01 to 50 yg per kg of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the foetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 60 hours after the membranes have ruptured and natural labor has not yet started. An alternative route of administration is oral. They are further useful for controlling the reproductive cycle in menstruating female mammals, including humans. By the term menstruating female mammals is meant animals which are mature enough to menstruate, but not so old that regular menstruation has ceased. For that purpose the isoxazolyl and isoxazolinyl prostaglandins are administered orally at a dose level in the range 0.01 mg to about 20 mg per kg of body weight of the female mammal, advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. Intravaginal and intrauterine routes are alternate methods of administration. Additionally, expulsion of an embryo or a foetus is accomplished by similar administration of the compound during the first or second trimester of the normal mammalian gestation period.
The compounds of the invention are further useful in causing cervical dilation in pregnant and non-pregnant female mammals for purposes of gynaecology and obstetrics. In labor induction and in clinical abortion produced by these compounds, cervical dilation is also observed. In cases of infertility, cervical dilation produced by these compounds is useful in assisting sperm movement to the uterus.
Cervical dilation by the isoxazolyl and isoxazolinyl prostaglandin of the invention is also useful in operative gynaecology such as D and C (Cervical Dilation and Uterine Curettage) where mechanical dilation may cause perforation of the uterus, cervical tears, or infections. It is also useful for diagnostic procedures where dilation is necessary for tissue examination. For these purposes, the compound is administered locally or orally. The isoxazolyl or isoxazolinyl prostaglandin of the invention for example, is administered orally or vaginally at doses of about 5 to 50 mg, per treatment of an adult female human, with from one to five treatments per 24 hours period. Alternatively the compound is administered intramuscularly or subcutaneously at doses of about one to 25 mg per treatment.The exact dosages for these purposes depend on the age, weight and condition of the patient or animal.
The new isoxazolyl on isoxazolinyl prostaglandins of the invention are useful for treating proliferating skin diseases of man and domesticated animals, including psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell carcinomas of the skin, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant sun-induced keratosis, non-malignant keratosis, acne, and seborrheic dermatitis in humans and atopic dermatitis and mange in domesticated animals. These compounds alleviate the symptoms of these proliferative skin diseases: psoriasis, for example, being alleviated when a scale-free psoriasis lesion is noticeably decreased in thickness or noticeably but incompletely cleared or completely cleared.For those purposes, such compounds are applied topically as compositions including a suitable pharmaceutical carrier, for example as an ointment lotion, paste, jelly, spray, or aerosol, using topical bases such as petrolatum, lanolin, polyethylene glycols, and alcohols. These compounds, as the active ingredients, constitute from about 0.1% to about 1 5% by weight of the composition, preferably from about 0.5% to about 2%. In addition to topical administration, injection may be employed, as intradermally, intra- or perilesionally, or subcutaneously, using appropriate sterile saline compositions.
In view of their high therapeutic index the compounds of the invention can be safely used in therapy.
As mentioned above, the compounds covered by this invention are useful in human and veterinary therapy, with several administration methods. They may be given orally in tablets, capsules, drops or syrups; rectally in suppositories; parenterally, in solutions or suspensions gives subcutaneously or intramuscularly; intravenously, as preferred in emergencies; by inhalation in aerosols or vaporizer solutions; in sterile grafts for prolonged action; or endovaginally, for instance in vaginal suppositories.
Pharmaceutical and veterinary compositions of the compounds covered by this invention may be prepared conventionally using common carriers and/or diluents. For example, sterile and isotonic aqueous solutions are preferred for intravenous injection or infusion. Sterile aqueous solutions or suspensions in aqueous or non-aqueous medium are used for subcutaneous or intramuscular injections. A sterile compress or a silicone rubber capsule containing or impregnated with the active ingredient may be used for sterile grafts.
Conventional carriers and diluents include water, gelatine, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, talc, stearic acid, calcium and magnesium stearate, glycols, starch, gum arabic, gum adragant, alginic acid, alginates, lecithin, polysorbates, vegetable oils, etc.
The compounds may be administered in a vaporizer using an aqueous suspension or solution of them, preferably in their salt forms, for instance the sodium salt. Or the compounds may be suspended or dissolved in one of the common liquified propellants like dichiorodifluoromethane or dichlorotetrafluoroethane and supplied in a pressurized container, e.g. an aerosol. When the compound is not soluble in the propellant, a co-solvent must be added to the pharmaceutical formulation for instance, ethanol, dipropyleneglycol and/or a sulface active substance.
The following Examples illustrate the present invention. The abbreviations DMSO and DIBAH mean, respectively, dimethylsulphoxide and diisobutylaluminium hydride. Ethyl ether means diethyl ether.
Example 1 A mixture of 2methyI-cyclopent-2-en-1 -one (0.0729 mol), nitromethane (0.371 mol) and tetramethylguanidine (0.0238 mol) was left at room temperature until total disappearance of the starting product (approximately 12 hours).
The whole was then diluted with water (20 ml), addition was made of dilute (1 :1) hydrochloric acid (20 ml) and extraction was performed with ethyl ether (3x25 ml).
The ether extracts were dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. The resulting residue, consisting of (+) 3/3-nitromethyl-20r-methyl-cyclopentan-1-one, was used in the subsequent step without further purification. With the same procedure, the following compounds were similarly obtained:: (#) 3ss-nitromethyl-2&alpha;-(n-butoxy-carbonyl-methyl)-cyclopentan-1-one; I.R. (film) # 1730 cm-1 # 1550 cm-1 N.M.R. # ppm (CDCI3) 0.95 (t, 3 H, J=7) 2.7 (m, 2 H) 4.1 (t, 2H, J=6) 4.35 (dd, 1 H, J=12, J=8) 4.62 (dd, 1 H, J=1 2, J=6); (#) 3ss-nitromethyl-2&alpha;-allylcyclopentan-1-one; I.R. (film # 1735, 1545, 1375 cm; (#) 3ss-nitromethyl-2&alpha;-(6-n-butoxy-carbonylhexyl)-cyclopentan-1-one; (#) 3ss-nitromethyl-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)-cyclopentan-1-one; (#) 3ss-nitromethyl-2&alpha;-(6-n-butoxy-carbonyl-#3,4-hexenyl)-cyclopentan-1-one.
Example 2 A solution of (t) 3ss-nitromethyl-2&alpha;-methylcyclopentan-1-one (0.063 ml), ethylene glycol (0.200 mol) in anhydrous benzene containing p-toluenesulphonic acid (0.0015 mol) was refluxed for 18 hours in an apparatus provided with a water separator. After cooling to room temperature, addition was made of triethylamine (3 ml), the whole was washed with water (2x25 ml) and dried (MgSO4).
After removal of the solvent under vacuum, there was a residue of (+) 3ss-nitromethyl-2&alpha;- methylcyclopentan-1-one ethyleneketal, purifiable by distillation at 0.01 mm Hg.
By proceeding similarly, the following compounds were obtained: (+) 3,B-nitromethyl-2-(n-butoxy-carbonyl-methyl)-cyclopentan- 1 -one-ethyleneketal; I.R. (film u 1730 cm-' # 1550 cm-1 N. M.R. # ppm (CDCI3) 0.95 (t, 3 H, J=7) 3.9 (s 4 H) 4.1 (t, 2H, J=7) 4.4 (dd, 1 H, J=1 2, J=8) 4.6 (dd, 1 H, J=1 2, J=7); (#) 3ss-nitromethyl-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-nitromethyl-2&alpha;-allylcyclopentan-1-one-ethyleneketal; I.R. (film) # 3080, 1640, 1545, 1375 cm-1.
(#) 3ss-nitromethyl-2&alpha;-(6-n-butoxy-carbonyl)-#2,3-hexenyl)-cyclopentan-1-one ethyleneketal; (+) 3ss-nitromethyl-2&alpha;-(6-n-butoxy-carbonyl)-#3,4-hexenyl)-cyclopentan 1-one ethyleneketal.
Example 3 To a solution of (+) 3ss-nitromethyl-2&alpha;-methylcyclopentan-1-one ethyleneketal (2.01 g, 0.01 mol) 1-heptyne (1.92 g, 0.02 mol) in anhydrous benzene (20 ml) containing a few drops of triethylamine, dropwise addition was made of a solution of phenylisocyanate (3.21 g, 0.027 mol) in benzene (10 ml), care being taken to maintain the temperature of the reaction mixture approximately 250C, by external cooling. After completion of the said addition, the reaction mixture was stirred overnight at room temperature, and was then heated for 2 hours at 60 C.After cooling to 0 G, the precipitated solids were separated by filtration and the benzene filtrate was first washed with a dilute solution of ammonium hydroxide (2x25 ml, 5%), then with water (25 ml) and finally dehydrated (MgSO4), Removal of the solvent under vacuum left a residue which was purified by chromatography on silica gel (eluent: ethyl ether/petroleum ether 1:3), obtaining (+) 3ss-[3-(5-n-pentylisoxazolyl]-2&alpha;- methylcyclopentan-1-one ethyleneketal, b.p. 123-124 C at 0.01 mm. Yield 60%.
I.R. (film) # 1600 cm-1.
N.M.R. # ppm (CCI4) 0.06-1.0 (m, 6 H) 3.9(s,4H) 5.8 (s, 1 H).
Example 4 To a solution of (+) 3ss-nitromethyl-2&alpha;-(6-butoxy-carbonylhexyl)-cyclopentan-1-one ethyleneketal (1.48 g, 0.004 mol), 1-heptyne (0.76 g, 0.008 mol) in anhydrous benzene (15 ml) containing a few drops of triethylamine dropwise addition was made of a solution of phenylisocyanate (1.27 g, 0.01 mol) in benzene (7 ml), care being taken to maintain the temperature at 25 C. After stirring for 12 hours at room temperature, the whole was heated at 6006 for 3 hours.
The mixture, cooled to 0 C, was filtered and the benzene filtrate then washed with ammonium hydroxide (2x25 ml, 5%), water (25 ml) and finally dried (MgSO4).
The removal of the solvent under vacuum left a residue consisting of (+) 3p-[3-(5-n- pentylisoxazolyl]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal which was chromatographed on silica gel, eluting with ethyl ether/petroleum ether (1:3). Yield 57%. The product occurred as a dense oil with the following spectrophotometric characteristics: I.R. y 1730 cm-1 # 1600 cm-1.
The following compounds were similarly obtained: (#) 3ss-[3-(5-n-penyl-isoxazolyl)]-2&alpha;-(n-butoxy-carbonyl-methyl)-cyclopentan-1-one ethyleneketal; I.R. (film) # 1740 cm-1 # 1600 cm-1 N.M.R. 6 ppm (CDCl3) 0.7-1.1 (m, 6 H) 3.9 (s, 4 H) 4 (t, 2H, J=7) 5.91(s, I H); (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)-cyclopentan-1-one ethyleneketal; I.R. (film) # 1740 cm-1 # 1600 cm-1; (#) 3ss-[3-(5-n-penyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-#3,4-hexenyl)-cyclopentan-1-one ethyleneketal; I.R. (film) V 1732 cm-1 # 1641 cm-1;; (#) 3ss-{3-[5-(1'-methyl)-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1- one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro,1'-methyl-n-pentyl-isoxazolyl-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1- one ethyleneketal; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-cyclohexyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal;; (#) 3ss-{3[5-(1'-phenoxy)-methyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1',1'-dimethyl,1'butoxy)-methyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-tetrahydrofuryl)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan- 1-one ethyleneketal; (#) 3ss-{3-[5-n-hexyl-isoxazolyl}-2&alpha;-(6-n-butoxycarbonyl-#3,4-hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-n-pentyl-isoxazolyl}-2&alpha;-(6-n-butoxycarbonyl-#3,4-hexenyl)-cyclopentan-1-one ethyleneketal;; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-isoxazolyl)]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro, 1'methyl)-n-pentyl-isoxazolyl}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-isoxazolyl}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl}-2&alpha;-(6-n-butoxycarbonyl-#2,3-hexenyl)-cyclopentan1-one 1-one ethylene ketal; (#) 3ss-{3-[5-cyclohexyl-isoxazolyl}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'phenoxy-methyl-isoxazolyl}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal;; (#) 3ss-{3-[5-(1',1'-dimethyl,1'-butoxy)-methyl-isoxazolyl}-2&alpha;-(6-n-butoxy-carbonyl-#2,3- hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-tetrahydrofuryl)-ethylisoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl)-#2,3-hexenyl)- cyclopentan- 1 -one ethyleneketal.
Example 5 To a solution of (+) 3ss-nitromethyl-2&alpha;-allylcyclopentan-1-one (1.83 g, 0.01 mol), 1-heptyne (1.92 g, 0.02 mol) in anhydrous benzene (20 ml) containing a few drops of triethylamine, dropwise addition was made of a solution of phenylisocyanate (3.21 g, 0.027 mol) in benzene (10 ml) under stirring. After 24 hours at room temperature the whole was heated at 600C for 2 hours, then cooled to 0 C and the precipitated solids were filtered. The benzene filtrate was first washed with 5% aqueous ammonia (2x25 ml), then with water and was finally dried over anhydrous magnesium sulphate.
The residue which was obtained by removing the solvent was absorbed on silica gel and eluted with ethyl ether/petroleum ether (1:4) to give (+) 3fi-[3-(5-n-pentyl-isoxazolyl)]-2-allylcyclopentan-1- one (yield 37%).
I.R. (KBr): v 1745 cm-1 # 1645 cm-1 # 1605 cm-1.
N.M.R. S ppm (CCl4) 0.9 (t, 3 H, J=5) 4.93 (mb, 2 H) 5.8 (mb, 1 H) 5.93 (s, 1 H).
By proceding analogously the following compounds were obtained: (#) 3ss-[3-(5-n-pentyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#3,4-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-hexyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#3,4-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-pentyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (+) 3-(3-[5-( 1 '-methyl) -n-pentyl-isoxazolyU }-2&alpha;-6-carboxy-hex-#2,3-enyl)-cyclopentan- 1-one; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-isoxazolyl]}-2&alpha;-(6-n-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-fluoro),1'-methyl)-n-pentyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1 -one;; (#) 3ss-[3-[5-(2'-cyclohexyl)-ethyl-isoxazolyl]-2&alpha;-(6-carboxyl-hex-#2,3-enyl)-cyclopentan-1-one; (+) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan- 1 one; (#) 3ss-[3-(5-cyclohexyl-isoxazolyl]-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1',1'-dimethyl, 1'-butoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl) cyclopantan- 1 -one; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1 -one; (#) 3ss-{3-[5-(2'-tetrahydrofuryl)-ethyl-isoxazolyl]}-2&alpha;
;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1- one.
Example 6 To a solution of phenylisocyanate (3.21 g, 0.027 mol) in benzene (10 ml) dropwise addition was made under stirring and at 250C of a mixture of (+) 3ss-nitromethyl-2&alpha;-methylcyclopentan-1-one ethyleneketal (2.01 g, 0.01 mol), 1-heptene (1.94 g, 0.02 mol) in benzene (20 ml) containing a few drops of triethylamine. After stirring overnight at room temperature, the reaction mixture was heated at 600C for 2 hours, cooled to 0 C and filtered. The benzene filtrate was washed with 5% aqueous ammonia (2x25 ml), water (25 ml) and then dried (MgSO4).Removal of the solvent under vacuum left a residue consisting of (+) 3ss-(5-n-pentyl-#2,3-isoxazolinyl)-2&alpha;-methylcyclopentan-1 -oneethyleneketal which, after chromatography on silica gel (eluent: ethyl ether/petroleum ether) occurred as a crystalline solid, m.p. 53 OC (Yield 70%).
N.M.R. # ppm (CCl4) 7-1.0 (m, 6 H) 3.8 (s, 4 H) 4.3 (m, 1 H).
By proceeding similarly, the following compounds were obtained: (#) 3ss-(5-n-pentyl-#2,3-isoxazolinyl)-2&alpha;-(n-butoxy-carbonyl-methyl)-cyclopentan-1-one ethyleneketal.
I.R. (film) # 1720 cm-1.
N.R.R. (# ppm (CDCl3) 0.7 - 1.1 (m, 6H) 3.9 (s, 4 H) 4.1 (t,2H,J=7) 4.3-4.8 (m, 1 H); (#) 3ss-(5-n-pentyl-#2,3-isoxazolinyl)-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal.
I.R. (film (# 1735 cm-1.
N.M.R. ppm (CDCl3) 0.75-1 (m, 6 H) 2.45-3.1 (m,2H) 3.93 (s, 4 H) 4.09 (t, 2 H, J=6) 4.25-4.7 (m, 1 H); (#) 3ss-{3-[5-(1'-methyl)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1 -one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl)-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan- 1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro, 1'-methyl)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-6-n-butoxy-carbonyl-hexyl)- cyclopentan-1 -one ethyleneketal;; (+) 3/3-f 3-[5-(2'-phenyl)-ethyl-#2,3-isoxazol inyl] }-2a-(6-n-butoxy-carbonyl-hexyl)-cyclopentan- 1 one ethyleneketal; (#) 3ss-[3-(5-cyclohexyl-#2,3-isoxazolinyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal; (3) 3ss-{3-[5-(1'-phenoxy)-methyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (+) 3ss-1 3-[5-( 1', 1 '-dimethyl, 1 '-butoxy)-methyl-#2,3-isoxazolinyl] }-2a-(6-n-butoxy-carbonyl- hexyl)-cyclopentan-1 -one ethyleneketal; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal;; (#) 3ss-{3-[5-(2'-tetrahydrofuranyl)-ethyl-#2,3-isoxazolinyl]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (3) 3ss-{3-[5-(1'-methyl)-n-pentyl-#2,3-isoxazolinyl]-2&alpha;-6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro,1'-methyl)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3- hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl) cyclopentan-l-one-ethyleneketai; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-[3-(5-cyclohexyl-#2,3-isoxazolinyl)]-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)-cyclopentan-1- one ethyleneketal; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-#2,3-isoxazolinyl)]-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1',1'-dimethyl, 1'-butoxy)-methyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3- hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3- hexenyl)-cyclopentan-1 -one ethyleneketal; (#) 3ss-{3-[5-(2'-tetrahydrofuranyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;;-(6-n-butoxy-carbonyl-#2,3- hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbonyl-#3,4-hexenyl-cyclopentan-1- one ethyleneketal; (#) 3ss-{3-[5-n-hexyl-#2,3-isoxazolinyl]}-2&alpha;-(6-n-butoxy-carbony-#3,4-hexenyl)-cyclopentan-1 one ethyleneketal.
Example 7 By proceeding similarly to Example 6, starting from (+) 3p-nitromethyl-2-allylcyclopentan-l - one, (+) 3ss-(5-n-pentyl-#2,3-isoxazolinyl-2&alpha;-allylcyclopentan-1 -one was obtained, analogously starting from (+) 3ss-nitromethyl-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan- -one the following compounds were obtained:: (#) 3ss-{3-[5-(1'-methy)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan 1-one; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1- one; (#) 3ss-{3-[5-(1'-fluoro,1'-methyl)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1 -one; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan 1-one; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1- one; (#) 3ss-[3-(5-cyclohexyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[6-1'-phenoxy)-methyl-#2,3-isoxazolinyl]}-2alpha;;-(6-carboxy-hex-#2,3-enyl)-cyclopentan- 1-one; (#) 3ss-{3-[5-(1',1'-dimethyl,1'-butoxy)-methyl-#2,3-isoxazolinyl]-2&alpha;-(6-carboxyhex-#2,3-enyl)- cyclopentan-1 -one; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-#2,3-isoxazolinyl]-2&alpha;-(6-carboxyhex-#2,3-enyl)- cyclopentan- 1-one; (#) 3ss-{3-[5-(2'-tetrahydrofuranyl)-ethyl-#2,3-isoxazolinyl]-2&alpha;-(6-carboxyhex-#2,3-enyl)- cyclopentan-1 -one.
Analogously starting from (#) 3ss-nitromethyl-2&alpha;-(6-carboxy-hex-#3,4-ethyl)-cyclopentan-1-one the following compounds were obtained: (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-hexyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl)-cyclopentan-1-one.
Example 8 A solution of (+) 3,B-[3-(5-n-pentyl-A23-isoxazolinyl)]-2-methylcyclopentan-1 -one ethyleneketal (1 g, 0.035 mol) in benzene (20 ml) was refluxed in an apparatus provided with water separator for 12 hours in the presence of y-MnO2 (10 g). The boiling solution was filtered on Gelite, the inorganic salts washed with benzene (5 x 15 ml) and the solvent evaporated under vacuum. There was obtained, with quantitative yield, (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-methylcyclopentan-1-one ethyleneketal.
i.R. (film) V 1600 cm~1.
N.M.R. a ppm (CCI4) 0.6-1.0 (m, 6H) 3.9 (s,4 H) 5.8 (s, 1 H).
By proceeding analogously starting from their A2,3-isoxazolinyl derivatives, the following compounds were obtained: (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(n-butoxy-carbonyl-methyl)-cyclopentan-1-one ethyleneketal; I.R. (film) v 1740 cm1 # 1600 cm-1.
N.M.R. S ppm (CDCI3) 0.7-1.1 (m, 6H) 3.9 (s,4 H) 4 (t, 2 H, J=7) 5.91 (s,H); (3) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyle)-cyclopentan-1-one ethyleneketal; I.R. (film) # 1730 cm-1 # 1600 cm-1; N.M.R. a ppm (CDCl3); (#) 3ss-{3-[5-(1'-methyl)-n-pentyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1- one ethyleneketal; (+) 3/3-{3-[5-( 1 '-fluoro)-n-pentyl-isoxazolyl] }-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan- 1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro, 1'-methyl)-n-pentyl-isoxazolyl]}-2&alpha;;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1- one ethyleneketal; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-[3-(5-cyclohexyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-[3-(5-(1'-phenoxy)-methyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1- one ethyleneketal; (#) 3ss-{3-[5-(1',1'-dimethyl,1'-butoxy)-methyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-isoxazolyl]}-2&alpha; ;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-tetrahydrofuranyl)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-hexyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-methyl)-n-pentyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro, 1'-methyl)-n-penyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal;; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)-cyclopentan- 1-one ethyleneketal; (#) 3ss-[3-(5-cyclohexyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-isoxazolyl)]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1',1'-dimethyl, 1'-butoxy)-methyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3- hexenyl)-cyclopentan-1 -one ethyleneketal; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal;; (#) 3ss-{3-[5-(2'-tetrahydrofuranyl)-ethyl-isoxazolyl]}-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carobnyl-#3,4 -hexenyl)-cyclopentan- 1-one ethyleneketal; (#) 3ss-[3-(5-n-hexyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-#3,4-hexenyl)-cyclopentan-1-one ethyleneketal; (3) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-#2,3-hexenyl)-cyclopentan-1-one ethyleneketal.
Example 9 By proceeding similarly to Example 8, starting from (#) 3ss-[3-(5n-pentyl-#2,3-isoxazolinyl)]-2&alpha;- allylcyclopentan-1-one, (#) 3ss-[3-(5-n-pentylisoxazolinyl)]-2&alpha;-allylcyclopentan-1-one was obtained.
Analogously, starting from the corresponding #2,3-isoxazolinyl derivatives, the following compounds were obtained: (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-hexyl-isoxazolyl)]-2&alpha;-(6-carbonxy-hex-#3,4-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-pentyll-isoxazolyl)]-2&alpha;-(6-carbonxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-1'-methyl)-pentyl-isoxazolyl]}-2&alpha;-(6-carbonxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-1'-fluoro)-pentyl-isoxazolyl]}-2&alpha;-(6-carbonxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-1'-fluoro,1-methyl)-pentyl-isoxazolyl]}-2&alpha;-(6-carbonxy-hex-#2,3-enyl)-cyclopentan 1-one; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl]}-2&alpha;;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-cyclohexyl-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopenan-1-one; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1',1'-dimethyl, 1'-butoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1 -one; (+) 3/3-i 3-[5-(2 ',2'-dimethyl,2 '-butoxy)-ethyl-isoxazolyl]-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan- 1-one; (#) 3ss-{3-[5-(2'-tetrahydrofuryl)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1- one.
Example 10 To a solution of (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(n-butoxy-carbonyl-methyl)-cyclopentan-1- one ethyleneketal (0.3 mol) in dry toluene cooled at -70 C a 1.2 M solution of DIBAH in toluene (0.6 molar equiv.) was added in a period of 30 minutes. The mixture was stirred for an additional period of 30 minutes at -70-75 C and then the excess of the reagent was destroyed by adding 1:1 mixture of MeOH and toluene (15 ml).
The reaction mixture was warmed at room temperature and stirred in the presence of 6 ml of a saturated solution of NaH2PO4 in water. The precipitate was filtered and the clear solution was evaporated to dryness to afford (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(formylmethyl)-cyclopentan-1- one ethyleneketal as a dense oii.
I.R. (CHCl3) # 2730 cm-1 # 1725 cm-1 # 1600 cm-1.
N.M.R. a ppm (CDCI3) 0.9 (t, 3 H, J=6) 3.9 (s, 4 H) 5.9 (s, 1 H) 9.65 (t, 1 H, J=1 .5).
By proceeding analogously, the following compounds were obtained: (+) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(formylmethyl)-cyclopentan- 1-one ethyleneketal: (+) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(formyl-ethyl)-cyclopentan- 1-one ethyleneketal; (I) 3ss-[3-(5-n-hexyl-#2,3-isoxazolinyl)]-2&alpha;-(formyl-ethyl)-cyclopentan- 1 -one ethyleneketal; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(formyl-ethyl)-cyclopentan-1one ethyleneketal; (+) 3ss-[3-(5-n-hexyl-isoxazolyl)]-2&alpha;-(formyl-ethyl)-cyclopentan- 1-one ethyleneketal.
Example 11 Potassium tert-butoxide (0.6 equiv.) was added under stirring to a solution of 3methoxycarbonyl-propyl-triphenyl-phosphonium bromide (0.3 mol equiv.) in DMSO (15 ml). To the red ylide a solution of (+) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(formylmethyl)-cyclopentan-1 -one ethyleneketal was added.
The reaction mixture was stirred for 4 hours at room temperature, diluted with water and extracted with benzene-ethyl ether. The organic extracts were discarded and the alkaline phases were acidified until pH 6.5 with dilute sulphuric acid. After extraction with ethyl ether, the organic extracts were collected, washed with water and dried on MgSO4.
Addition of ethereal solution of diazomethane was followed by evaporation and the crude material was purified by column chromatography on silica gel (ethyl ether:cyclohexane=40:60) affording (3) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(5-methoxy-carbonyl-#2,3-pentenyl)- cyclopentan-1-one ethyleneketal.By proceeding analogously the following compounds were obtained: (#) 3ss-3-(5-n-pentyl-isoxazolyl)-2&alpha;-(6-methoxy-carbonyl)-#3,4-hexenyl)-cyclopentan-1-one ethyleneketal; (+) 3ss-[3-(5-n-h exyl-isoxazolyl)]-2&alpha;-(6-methoxy-carbonyl-#3,4-hexenyl)-cyclopenta n- 1 -one ethyleneketal; (#) 3ss-3-(5-n-pentyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,4-hexenyl)-cyclopentan-1- one ethyleneketal; (#) 3ss-3-(5-n-hexyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#3,4-hexenyl)-cyclopentan-1- one ethyleneketal.
Example 12 8y proceeding analogously to Example 11, by reaction with a solution of 3-methoxycarbonyl- butyl-triphenyl-phosphonium bromide, the following compounds were obtained: (#) 3ss-{3-[5-(1'-methyl)-n-pentyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl)- cyclopentan- 1 -one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro-1'-methyl)-n-pentyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3- hexenyl)-cyclopentan-1 -one ethyleneketal;; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl) cyclopentan- 1 -one ethyleneketal; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl)- cyclopentan-1 -one ethyleneketal; (#) 3ss-{3-[5-(5-cyclohexyl-#2,3-isoxazolinyl)]-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl)-cyclopentan-1- one ethyleneketal; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl)- cyclopentan- 1 -one ethyleneketal; (#) 3ss-{3-[5-(1',1'-dimethyl,1'-butoxy)-methyl-#2,3-isoxazolinyl)]}-2&alpha;-(6-methoxy-carbonyl)-#2,3- hexenyl)-cyclopentan- 1-one ethyleneketal; ; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-#2,3-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3- hexenyl)-cyclopentan-1 -one ethyleneketal; (#) 3ss-{3-[5-(2'-tetrahydrofuranyl)-ethyl-#2,3-isoxazolinyl)]}-2&alpha;-(6-methoxy-carbonyl)-#2,3- hexenyl)-cyclopentan- 1-one ethyleneketal; (#) 3ss-{3-[5-n-pentyl-isoxazolinyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl)-cyclopentan-1-one ethyleneketal.
Example 13 Starting from the A2 3-isoxazolinyl derivatives obtained in the Examples 11 and 12 and by the oxidation process with y-Mn02 according to Example 8, the following compounds were obtained: (#) 3ss-{3-[5-(1'-methyl)-n-pentyl-isoxazolyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl)- cyclopentan- 1 -one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-isoxazolyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-fluoro,1'-methyl)-n-pentyl-isoxazolyl)-2&alpha;-(6-methoxy-carbonyl)-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-isoxazolyl]}-2&alpha;-(6-methoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal;; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl]}-2&alpha;-(6-methoxy-carbonyl-#2,3-hexenyl)-cyclopentan- 1-one ethyleneketal; (#) 3ss-[3-(5-cyclohexyl-isoxazolyl)]-2&alpha;-(6-methoxy-carbonyl-#2,3-hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-isoxazolyl]}-2&alpha;-(6-methoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(1',1'-dimethyl,1'-butoxy)-methyl-isoxazolyl]}-2&alpha;-6-methoxy-carbonyl)-#2,3- hexenyl)-cyclopentan-1-one ethyleneketal; (+) 3/3-f 3-f5-(2',2 '-dimethyl,2 '-butoxy)-ethyl-isoxazolylj J-2a-(6-methoxy-carbonyl-A2,3- hexenyl)-cyclopentan-1-one ethyleneketal;; (#) 3ss-{3-[5-(2'-tetrahydrofuryl)-ethyl-isoxazolyl]}-2&alpha;-(6-methoxy-carbonyl-#2,3-hexenyl)- cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(n-pentyl-isoxazolyl)]}-2&alpha;-(6-methoxy-cabonyl-#3,4-hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-{3-[5-(n-hexyl)-isoxazolyl)]}-2&alpha;-(6-methoxy-carbonyl-#3,4-hexenyl)-cyclopentan-1-one ethyleneketal; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(5-methoxy-carbonyl-#2,3-pentenyl)-cyclopentan-1-one ethyleneketal.
Example 14 (#) 3ss-[3-(5-n-pentyl-isoxazolyl]-2&alpha;-(n-butoxy-carbonyl-methyl)-cyclopentan-1-one (0.6 g) was dissolved in ethanol (15 ml) and tr@ated at 0 C with 0.15 g of NaBH4. The reaction mixture was stirred for 1 hour and after destruction of the reagent excess by adding few drops of 15% aqueous acetic acid, the solvents were evaporated under vacuum and the crude residue was chromatographed on silica gel (ethyl ether as eluent) affording (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(n-butoxycarbonylmethyl)- cyclopentan-1ss-ol and (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(n-butoxycarbonylmethyl)-cyclopentan- 1&alpha;-ol.
By proceeding analogously the following compounds were obtained: (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-allyl-cyclopentan-1&alpha;-ol; I.R. (film u 3370, 1640, 1600 cm-1; N.M.R. # ppm (CCl4) 0.86 (t, 3 H, J=5), 4.73-5.3 (m, 2H), 5.4-5.8 (m, 1H), 5.9 (s, 1 H); (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-allyl-cyclopentan-1ss-ol; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxyhexyl)-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;(6-carboxyhexyl)-cyclopentan-1ss-ol; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;(carboxyhexyl)-cyclopentan-1&alpha;-ol; I.R. (film. # 1680 cm-1, 1600 cm-1.
after NEt3: # 1600 cm-1, 1550 cm-1.
N.M.R. ppm (CDCl3): 5.9 (s, -C'4--H, 1 H) 6-5.5 (sb, -COOH, -OH) 4.5 (m, -C5-h, 1 H) 0.95 (t, -CH3, 3 H); (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(carboxymethyl)-cyclopentan- 1 /3-ol; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl-cyclopentan-1ss;-ol; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl-cyclopentan-1ss;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hexyl)-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hexyl)-cyclopentan-1ss;-ol;; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-methyl)-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-methyl)-cyclopentan-1ss;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hex-3,4-enyl)-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hex-3,4-enyl)-cyclopentan-1ss;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hex-2,3-enyl)-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxy-hex-2,3-enyl)-cyclopentan-1ss;-ol; Example 15 A solution of (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(n-butoxycarbonylmethyl)-cyclopentane-1&alpha;;- of was saponified by treatment at room temperature with lithium hydroxide in aqueous methanol, affording after acidification to pH 3.2 with sulphuric acid dl, 6-exo[3-(5-n-pentyl-isoxazolyl]-2-oxabicyclo[3.3.0]octan-3-one.
I.R. (film) # 1780 cm-1 # 1600 cm-1.
N.M.R. S ppm (CDCl3) 0.9 (t, 3 H, J=6) 5.05 (m, 1 H) 5.85 (s, 1 H).
DIBAH reduction of this compound afforded (+ (3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(1 '-ethanale) cyclopentan-1&alpha;-ol-@-lactol.
I.R. (film): 1600 cm-1, with band from 3000 up to 3500 cm-1.
N.M.R. ppm (CDCl3) 5.9 (s,-C'4-H, 1 H) 5.65 (m,-C5-H, 1 H) 4.9 (m, CH-OH, 1 H) 0.95 (t,-CK3,3 H).
which after reaction with 4-carboxybutylphosphonium bromide in DMSO in the presence of potassium tert-butoxide as mentioned in Example 11 afforded (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxy- A2,3-hexenyl)-cyclopentan- 1 a-ol.
By proceeding analogously the following compounds were obtained: (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl)-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1&alpha;-ol; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolyl)]-2&alpha;-(6-carboxy-hex-#3,4-enyl)-cyclopentan-1&alpha;-ol.
Example 16 A solution of (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxycarbonylhexyl)-cyclopentan-1- one-ethyleneketal (1.2 g) in acetic acid-water (1:1;25 ml) was left for 16 hours at 40 C. The solvents were evaporated to dryness in vacuum and the residue was extracted with ethyl ether, washed with 5% NaHCO3 aqueous solution until neutral.
the organic extract was dried on anhydrous sodium sulphate, filtered and evaporated under vaccum. The removal of the solvent under vacuum left a residue consisting of (#) 3ss-[3-(5-n-pentyl isoxazolyl)j-2a-(6-n-butoxycarbonylhexyl)-cycloperitari- 1 -one which was chromatographed on silica gel, eluting with ethyl ether/petrnleum ether (1.5:3), yield 82%.
The product was a dense oil with the following spectrnphotometric characteristics: I.R. film # 1742 cm-1. 1715 cm-1.
By proceeding analogously the following compounds were obtained: (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(n-butoxycarbonymethyl)-cyclopentan-1-one: I.R. V 1730 cm-1 # 1600 cm-1; N.M.R. a ppm (CDCl3) 0.7-1.1 (m, 6 H) 4.5 (t, 2 H, J=7) 5.9 (s, 1 H); (#) 3ss-[3-(5-n-phenyl-isoxazolyl)]-2&alpha;-(6-n-butoxycarbonyl-#3,4-hexenyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-phenyl-isoxazolyl)]-2&alpha;-(6-n-butoxycarbonyl-#2,3-hexenyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-phenyl-#2,3-isoxazolinyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1-one.
Example 17 A solution of (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonyl-hexyl)-cyclopentan-1- one was saponified by treatment at room temperature with lithium hydroxide in aqueous methanol, affording, after acidification to pH 3.2 with sulphuric acid, (#) 3ss-[3-(5-n-pentyl-isoxazolyl]-2&alpha;-(6-n- carboxy-hexyl)-cyclopentan-1-one.
By proceeding analogously the following compounds were obtained: (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(carboxymethyl)-cyclopentan 1 -one; Elemental analysis: Calculated: C: 64.49%; H: 7.58% N: 5.01% Found:C: 64.32%; H: 7.39%; N: 4.97% I.R.: (CHCl3):# (1740 cm-1:# 1715 cm-1. # 1600 cm-1; N.M.R. a ppm (CDCI3) 9.25 (sb. -COOH, 1 H) 5.95 (s,-C'4-H, 1 H) 0.95 (t, -CH3-, 3 H); (#) 3ss-{3-[5-(1'-methyl)-pentyl-isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-fluoro)-pentyl-isoxazolyl[}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-fluoro, 1'-methyl)pentyl-isoxazolyl]-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethylisoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one;; (#) 3ss-{3-[5-cyclohexyl-isoxazolyl)]-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1',1'-dimethyl, 1'-butoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1- one; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1- one; (#) 3ss-{3-[5-(2'-tetrahydrofuryl)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-6-carboxy-hex-#3,4-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-hexyl-isoxazolyl)]-2&alpha;-6-carboxy-hex-#3,4-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-(1'methyl)-n-pentyl-isoxazolyl)]-2&alpha;;-6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-(1'-fluoro)-n-pentyl-isoxazolyl)]-2&alpha;-6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-(1'-fluoro,1'-methyl)-n-pentyl-isoxazolyl)]-2&alpha;-6-carboxy-hex-#2,3-enyl)- cyclopentan- 1-one; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-isoxazolyl]-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-[3-(5-cyclohexyl-isoxzolyl)]-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1',1'-dimethyl, 1'-butoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1-one; (#) 3ss-{3-{5-(2',2'-dimethyl,2'-butoxy)-ethyl-isoxazolyl]}-2&alpha;;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1 -one; (#) 3ss-{3-[5-(2'-tetrahydrofuryl)-ethyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentna-1- one; (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-[3-[5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(carboxymethyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-methyl)-n-pentyl-#2,3-isoxazolinyl]}]-2&alpha;-(6-carboxy-hexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-fluoro,1'methyl)-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxyhexyl)-cyclopentan- 1-one; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(2'-phentyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-cyclohexyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1',1'-dimethyl,1'-butoxy)-methyl)-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxyhexyl)- cyclopentan-1-one; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl)-#2,3-isoxazolinyl]-2&alpha;-(6-carboxyhexyl)- cyclopentan-1-one; (#) 3ss-{3-[5-(2'-tetrahydrofuranyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1- one; (#) 3ss-{3-[5-(1'methyl)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan- 1-one; (#) 3ss-{3-[5-(1'-fluoro,1'-methyl)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1-one; (#) 3ss-{3-[5-(2'-cyclohexyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan- 1-one; (#) 3ss-{3-[5-(2'-phenyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1- one; (#) 3ss-{3-[5-cyclohexyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan-1-one; (#) 3ss-{3-[5-(1'-phenoxy)-methyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)-cyclopentan- 1-one; (#) 3ss-{3-[5-(1',1'-dimethyl,1'-butoxy)-methyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1-one; (#) 3ss-{3-[5-(2',2'-dimethyl,2'-butoxy)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1-one;; (#) 3ss-{3-[5-(2'-tetrahydrofuranyl)-ethyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex-#2,3-enyl)- cyclopentan-1-one; Example 18 Metallic sodium was added to a stirred mixture of liquid ammonia (75 ml), tetrahydrofuran (25 ml), t-butyl alcohol (0.022 g, 0.003 mol) and (+) 3ss-[3-(5-n-pentyl-isoxazolyl]-2&alpha;-(6-n- butoxycarbonyl-hexyl)-cyclopentan-1-one ethyleneketal (0.45 g, 0.001 mol) until a persistent blue colour was produced. After stirring for a further 15 minutes, the solution was decolourated by adding solid ammonium chloride, while the ammonia was allowed to evaporate in a current of nitrogen. The residue was taken up with ethyl ether (150 ml) and saturated solution of ammonium chloride (40 ml).
The organic phase was separated and the aqueous phase extracted with chloroform (4x30 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum. The residue (0.5 g approx.) was dissolved in toluene (30 ml) and refluxed for 18 hours in the presence of a trace amount of p-toluenesulphonic acid. After evaporation of the solvent, the residue was absorbed on silica gel and eluted with ethyl ether/petroleum ether (1:1) to give (#) 3ss-(3-oxo-n-#1,2-trans-octenyl)-2&alpha;-(7- hydroxy-n-heptyl)-cyclopentan-1-one ethyleneketal (yield 53%), occurring as a dense oil.
I.R. (film) 3470 cm-1 1670 cm-1 1630 cm~1.
By proceeding similarly, starting from the compounds obtained in Examples 5, 8, 9 and 16, the respective derivatives were obtained.
Example 19 Metallic sodium was added to a stirred mixture of liquid ammonia (50 ml), tetrahydrofuran (distilled from aluminium lithium hydride) (15 ml), t-butyl alcohol (1.55 g, 0.021 mol) and (+) 323-[3-(5- n-pentyl-isoxazolyl)J-2a-methylcyclopentan- 1 -one-ethyleneketal (0.56 g, 0.0071 mol) until a persistent blue colour was produced. After stirring for a further 1 5 minutes, the solution was decolourated by adding solid ammonium chloride, while the ammonia was evaporated in a current of inert gas. The residue was taken up with ethyl ether (50 ml) and saturated solution of ammonium chloride (40 ml). The organic phase was separated and the aqueous phase extracted with methylene chloride (3x50 ml).
The extracts were combined, dried (MgSO4) and evaporated under vacuum. The residue was refluxed for 24 hours in a solution of toluene (30 ml) containing a trace amount of p-toluenesulphonic acid. After removal of the solvent under vacuum, the remaining oil was absorbed on silica gel, eluted wit ethyl ether/petroleum ether (1:1) and finally distilled at 0.11 mmçlg to give (+) 3/3-(3-oxo-n-A'w2- trans-octenyl)-2&alpha;-methyl-cyclopentan-1-one-ethyleneketal (yield 65%).
I.R. (film) 1670 cm-1 1626 cm~'.
N.M.R. a ppm (OCI4) 0.6-1.0 (m, 6 H) 3.8 (s, 4 H) 5.9 (d, 1 H, J=6) 6.6 (dd, 1 H, J=8).
Example 20 A solution of (t) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-methyl-cyclopental (yield 65%). -one-ethyleneketal (1 g, 0.0035 mol) in methanol (20 ml) was added to a pre-hydrogenated suspension of platinum oxide (0.2 g) in methanol (15 ml) and stirred under an atmosphere of hydrogen at room pressure until the hydrogen (1 mole) was wholly absorbed.
The catalyst was filtered on Celite, care being taken to wash several times with methyl alcohol (4x 15 ml) and the filtrate was concentrated under vacuum. The residue consisting of 3-oxo-n-#1,2-trans-octenyl)-2&alpha;-methyl-cyclopentan-1 (#) 3ss-(1-amino)- -one-ethyleneketal was used without further purifications.
I.R. (film) 3350 cm-' 1600 cm~1 1510 cm~1.
Example 21 A solution of (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxy-carbonylhexyl)-cyclopentan- 1 one-ethyleneketal (1 g, 0.0022 mol) in methanol (20 ml) was added to a pre-hydiogenated suspension of platinum oxide (0.2 g) in methanol (20 ml) and stirred under an atmosphere of hydrogen at room pressure until the hydrogen (1 mol) was comp@@tely absorbed. The catalyst was filtered on Celite, washed with methanol (3 x25 ml) and the filtrate concentrated under vacuum to obtain (+) 3/3-( 1 - amino-3-oxo-n-#1,2-trans-octenyl)-2&alpha;-(6-n-butoxycarbonylthexyl)cyclopentan-1-one-ethyleneketat as crude residue, which was utilized as such in the subsequent step.
Example 22 A solution of crude (+) 3,B-(1 -amino-3-oxo-n-#1,2-trans-octenyl)-2&alpha;-methyl-cyclopentan-1-one- ethyleneketal (1 g, 0.0035 mol) in pyridine (25 ml) was added to dropwise at 0 C with freshly distilled benzoyl chloride (0.98 g, 0.007 mol), then left at room temperature overnight.
The whole was diluted with water (25 ml), extracted with methylene chloride (2 x25 ml), the organic extract was washed with water (2x25 ml) and dried (MgSO4). After removal of the solvent under vacuum, the residue was crystallized from n-pentane to obtain (+) 3p-(1 -benzoylamino-3-oxo-n- #1,2-trans-octenyl)-2&alpha;-methyl-cyclopentan- 1 -one-ethyleneketal m.p. 59-600C. Yield 76%.
I.R. (film) 1685 cm-1 1630 cm-1 1590 cm-1 1500 cm~1.
N.M.R. Sppm (CDCI3) 0.93 (t, 3 H, J=5) 1.00 (d, 3 H, J=8) 3.9 (s,4 H) 5.66 (s, 1 H) 7.3-8.3 (m, 5 H) 13.63 (s, 1 H).
By proceeding similarly, starting from the compounds obtained in Examples 5, 8, 9 and 16, the respective derivatives were obtained.
Example 23 To a solution of crude (+) 3ss-(1 -amino-3-oxo-n-A1 '2-trans-octenyl)-2a-(6-n-butoxycarbonyl- hexyl)-cyclopentan-1-one-ethyleneketal coming from catalytic reduction (1 g. 0.0022 mol) in pyridine (25 ml) dropwise addition was made at 0 C of freshly distlled benzoyl chloride (0.84 g, 0.006 mol), and stirring was proceeded with for 24 hours at room temperature. The whole was diluted with water (25 rnl), extracted with methylene chloride (3x25 ml), the organic phase was washed with water (2x25 ml) and dried (MGS04).After removal of the solvent under vacuum, the residue was absorbed on silica gel and eluted with ethyl ether/pentane (1:3) to give (3)ss-(1-benzoylamino-3-oxo-n-#1,2- trans-octenyl)-2&alpha;-(6-n-butoxycarbonyl-hexyl)cyclopentna-1-one-ethyleneketal (yield 54%). The product occurred as a colourless oil.
I.R. (film) 1720 cm-' 1685 cm-1 1630 cm-1 1590 cm-' 3200 cm-1 N.M.R. S ppm (CDCI3) 0.66-1.00 (m, 6 H) 3.96(s,4H) 4.06 (t, 2 H, J=6) 5.8 (s, 1 H) 7.3-8.3 (m, 5 H) 11.7(s,1 H).
By proceeding similarly, starting from all the compounds similarly obtained in Example 22, the analogous respective derivatives were obtained.
Example 24 To a solution of (#) 3ss-(1-benzoylamino-3-oxo-n-#1,2-trans-octenyl)-2&alpha;-methyl-cyclopentan-1- one-ethyleneketal (2 g, 0.0035 mol) in methanol (30 ml) addition was made, in small portions, of NaBH4 (0.5 g) at room temperature. After further stirring for 2 hours, the whole was diluted with water (20 ml), extracted with methylene chloride (3x30 ml), the organic extract washed with water (2x 15 ml) and finally dried (MgSO4). After filtration, the organic mixture was concentrated to about half volume 9 (45 ml); 1 N sulphuric acid (20 ml) was added and the reacting mixture stirred overnight.The organic phase was separated, washed with water (2x25 ml) and dried (MgSO4). After removal of the solvent under vacuum, the residue was chromatographed on silica gel. By eluting with ethyl ether/pentane (1:2) there was obtained (#) 3ss-(1-oxo-n-#2,3-trans-octenyl)-2&alpha;-methyl-cyclopentan-1- one-ethyleneketal as a colourless oil.
I.R. (film) 1730 cm-1 1685 cm-1 1660 cm~' 1620 cm-1 N.M.R. S ppm (CDCI3) 0.7-1.1 (m,6H) 3.9 (s, 4 H) 4.06 (5, 2 H, J=7) 6.13(dd,1 H,J=16,J=1.5) 6.90 (dd, 1 H, J=1 6, J=8).
Example 25 To a solution of (#) 3ss-(1-benzoylamino-3-oxo-n-#1,2-trans-octenyl)-2&alpha;-(6-n-butoxycarbonyl- hexyl)-cyclopentan-1-one-ethyleneketal (1.5 g, 0.0013 mol) in methanol (25 ml) addition was made, in small portions, of NaBH4 (0.3 g) at room temperature, care being taken to continue the stirring for a further two hours. The whole was diluted with water (30 ml), extracted with methylene chloride (3x25 ml), washed with water (2x 15 ml) and dried (MgSO4).
The organic filtrate was concentrated under vacuum (to about 25 ml), 1 N sulphuric acid (15 ml) was added and the two-phase mixture was stirred at room temperature for 12 hours. The organic phase was separated, washed with water (20 ml), dried (MgS04) and evaporated under vacuum, leaving an oily residue which was purified by vacuum evaporation, to obtain (+) 3p-(1 -oxo-n-A2,3- trans-octenyl)-2&alpha;-(6-n-butoxycarbonylhexyl)-cyclopentan-1-one-ethyleneketal as a colourless oil.
I.R. (film) V 1730 cm~1.
Example 26 Starting from (#) 3ss-nitromethyl-2&alpha;-(6-methoxycarbonyl-hex-#2,3-enyl)-1&alpha;-benzoyloxy-4&alpha;- dimethyl-tert.butyl-silyloxy-cyclopentane (8.6 g) and by proceeding similarly to Example 3, (+) 3,B-[3- (5-n-pentyl-isoxazolyl)-2&alpha;-(6-methoxycarbonyl-hex-#2,3-enyl)-1&alpha;-benzoyloxy-4&alpha;-dimethyl-tert.butyl- silyloxy-cyclopentane (6.45 g) was obtained.
Example 27 Starting from (+) 3,B-nitromethyl-2-(6-methoxycarbonyl-hex-A2 3-enyl)- a-benzyloxy-4a- dimethyl-tert.butyl-silyloxy-cyclopentane and by proceeding similarly to Example 6, (+) 3,B-[3-(5-n- pentyl-#2,3-isoxazolyl)]-2&alpha;-(6-methoxycarbonyl-hex-#2,3-enyl)-1&alpha;-benzoyloxy-4&alpha;-dimethyl- tert.butyl-silyloxy-cyclopentane was obtained.
Example 28 By proceeding similarly to what is reported in Example 8, starting from (+) 3/3-L3-(5n-pentyl-A2.3- isoxazolinyl]-2&alpha;-(6-methoxycarbonyl-hex-#2,3-enyl)-1&alpha;-benzoyloxy-4&alpha;-dimethyl-tert.butyl-silyloxycyclopentane, (+) 3,B-[3-(5-n-pentyl-isoxazolyl)]-2-(6-methoxycarbonyl-hex-å2 1 a- benzoyloxy-4a-dimethyl-tert.butyl-silyloxy-cyclopentane was obtained.
Example 29 (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-methoxycarbonyl-hex-#2,3-enyl)-1&alpha;-benzoyloxy-4&alpha;- dimethyl-tert.butyl-silyloxy-cyclopentane (0.5 equiv.) was reacted in anhydrous methyl alcohol (30 ml) at room temperature with potassium carbonate (0.01 equiv.) and the mixture was stirred for three hours. The solvent was evaporated under vacuum and the residue, taken up with ethyl acetate, was washed with a solution of disodium phosphate. The solvent was evaporated to dryness and the residue was chromatographed on silica gel column (eluent: ethyl acetate/cyclohexane=75/25) thus giving (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-methoxycarbonyl-hex-#2,3-enyl)-4&alpha;-dimethyl-tert.butyl-silyloxycyclopentane-1&alpha;-ol.
A sample of this compound was heated in acetone in the presence of 0.2 N aqueous oxalic acid and after the usual work up, as reported in Example 34, (#) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6- methoxycarbonyl-hex-#2,3-enyl)-cyclopentane-1&alpha;,4&alpha;-diol was obtained.
Example 30 A solution of (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-methoxycarbonyl-hex-#2,3-enyl)-4&alpha;- dimethyl-tert.butyl-silyloxy-cyclopentan-1 a,4a-diol (0.5 g) in acetone (25 ml), cooled to 10 to -1 30C, was reacted with 2.5 ml of Jones reagent and added dropwise to the stirred mixture. After 20 minutes the reaction was stopped by addition of excess/benzene (80 ml) and the organic phase was washed with 35% aqueous (NH4)2S04 solution until neutral and then evaporated to dryness. The residual 9-oxo compound was dissolved in acetone (20 ml) and the solution was heated at 420C after addition of 0.15 N oxalic acid (1 5 ml) for 14 hours. The excess of acetone was evaporated under vacuum.The aqueous phase was extracted with ethyl acetate arid after chromatographic separation on silica gel (using as eluent cyclohexane/ethyl acetate=65/3 5) (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6- methoxycarbonyl-hex-#2,3-enyl)-cyclopentan-4&alpha;-ol-1 -one was obtained.
Example 31 (+) 3ss-[3-(5-n-pentyl-isoxazolyl)]-2-(1 '-ethanale)-cyclopentan- 1 a-oI-y-Iactol (0.45 g) was dissolved in methyl alcohol (5 ml) and a few drops of ethereal solution of BF3, recently distilled were added. The mixture was taken at 200C for two hours and at 00C for 1 hour. The obtained product was purified by thin layer chromatography and then Et3N (1 ml) was added. The mixture was evaporated to dryness. The residue, dissolved in ethyl ether, was washed with a saturated solution of NaHCO3, dried on anhydrous Na2SO4. The solvent was evaporated to dryness, thus giving (+) 3,-13-(n- pentyl-isoxazolyl)]-2a-( 1 '-ethanale)-cyclopentan- 1 ct-oly-ladtol-methylether, as an oil which was purified by chromatography on silica gel column (eluent: ethyl ether/petroleum ether=3/7) (yield 87.23%); 0.41 g).
I.R. (film): V 1600 cm~1.
N.M.R. (CDCI3): 5.9 a ppm (s, -C'4-H, 1 H) 5.1 # ppm (m, - C5-H, 1 H) 4.75 S ppm (m, CH-0CH3, 1 H) 3.3 a ppm (d, --0-C,'3, 3 H) 0.95 # ppm (t, -CH3, 3 H).
Example 32 To dry liquid ammonia (100 ml), a mixture of (+) 3ss-[3-(n-pentyl-isoxazolyl)]-2&alpha;-(1 '-ethanale)cyclopentan-1 &alpha;-ol-#-lactol-methylether (1.04 g; 0.00372 mol) and tert.butyl alcohol (0.82 g; 0.01016 mol) was added, at -400C and under nitrogen atmosphere. Sodium (about 0.35 g) was added portionwise until the solution was persistently blue coloured. Then the solution was decolourated with ammonium chloride and the ammonia was evaporated at room temperature under nitrogen atmosphere. The residue was taken up with water and acidified cautiously with 30% phosphate buffer to pH 5 at 0 C. The solution was extracted with chloroform and the solvent was evaporated off under vacuum. the residue was taken up with anhydrous benzene and added to with p-toluensulphonic acid (0.1 g).The mixture was refluxed for 24 hours; the toluene was evaporated and the residue chromatographed on silica gel, thus giving (+) 3ss-(3-oxo-n-#1,2-trans-octenyl)-cyclopentan-1 &alpha;-ol-2&alpha;- ethanale-y-lactolmethylether, as an oily product (0.5 g).
I.R. (CHCl3):# 1700 cm-1 v 1680 cm-1 # 1630 cm-1 # 1590 cm-1 V 970cm-1.
N.M.R. (CDCI3) 3.35 b ppm (s, 3 H) 4.7 b ppm (m, 1 H) 5.1 a ppm (m, 1 H) 6.1 # ppm (dd, 1 H, J=16) 6.7 # ppm (dq, 1 H, J=16).
Example 33 By proceeding similarly to wha-i is reported in Example 14 and starting from (+) 3ss-(3-oxo-n-#1,2- trans-octenyl)-cyclopentan-1&alpha;-ol-2&alpha;-ethanale-#-lactol-methylether, (#) 3ss-[3(S,R)-hydroxy-n-#1,2- trans-octenyl)-cyclopentan-1&alpha;-ol-2&alpha;-ethanale-#-lactolmethylether was obtained, which was then chromatographed on silica gel column, thus giving the respective 3S and 3R allyl alcohols.
Example 34 A solution of (+) 3ss-(3S-hydroxy-n-#1,2-trans-octenyl)-cyclopentan-1 a-oI-2a-ethanale-v-Iactol- methylether (0.6 g) in acetone (7 ml) was heated at 400C for 4 hours in the presence of 0.2 N aqueous oxalic acid (5 ml) and of a small amount of hydroquinone. The acetone was evaporated under vacuum and the residue extracted with ethyl ether.The organic extracts were washed until neutral with aqueous saturated ammonium sulphate and evaporated to dryness, affording pure (#) 3ss-(3S-hydroxy- n-#1,2-trans-octenyl)-cyclopentan-1 &alpha;-ol-2&alpha;-ethanale-#-lactol. This compound by reaction with 4carboxy-butylphosphonium bromide in dimethylsulphoxide in the presence of potassium tert.-butoxide as mentioned in Example 11 afforded (+) 3/3-[3S-hydroxy-n-A' 2-trans-octenyl)-2cg-(6-carboxy-hex- #2,3-enyl)-cyclopentan-1&alpha;-ol.
Example 35 ( + ) 3fi-[3-(5-n-pentyi-isox3zolyl)]-2cr-(6-n-butoxycarbonyl methyl)-cyclopentan-1 -one ethylenketal (1 g; 2.63. 10-3 mol) was dissolved in fresh-distilled methylene chloride (13 ml). The solution was cooled to -1 00C under nitrogen and pyridinium bromide perbrornide (1.003 g) was added. The reacting mixture was left at 0CC for 90 min, then at 1 30C for 2.5 hours and then diluted with methylene chloride, washed with NaHCO3 and finally with 1 N thiosulphate.After removal of the solvent, the residue was chromatographed on silica gel (eluent: ethyl ether/petroleum ether=0.5/9.5), thus giving (#) 5(&alpha;,ss)-bromo-3ss-[3-(5-n-pentyl-isoxazolyl)]-2&alpha;-(6-butoxycarbonyl-methyl)- cyclopentan-1-one ethylenketal.
1H II.M.R. (CDCI3): X ppm 4-4.4 (m, 7 H); 5.95 (s, 1 H).
1.6 g of the product as obtained above were dissolved in xylene (3 ml). Diazabicycloundecene (3 ml) was added to the solution and the reacting mixture was heated at 1 400C for 1.5 hours under nitrogen atmosphere, then cooled, diluted with water and extracted with ether. The organic layers were washed and dried on anhydrous magnesium sulphate, thus giving (I-) 3ss-[3-(5-n-pentyl-isoxazolyl)]- 2&alpha;-(6-n-butoxycarbonyl-methyl)-cyclopent-#3,4-en-1-one-ethylenketal, which was chromatographed on silica gel (eluent: ethyl ether/petroleum ether=2/8).
'H N.M.R. (CDCI3): 3.8 4.2 (m, 6 H); 6.1 (s, 1 H); 6.25 (m, 1 H). (ppm l.R. (CHCI3): 1740, 1640, 1600 cm-1.
Starting from the product as obtained and by the proceeding similarly to Example 16, (#) 3ss-[3 (5-n-pentyl-isoxazolyl)]-2&alpha;-(6-n-butoxycarbonyl-methyl)-cyclopent-#3,4-en-1-one was obtained.
Example 36 To an aqueous dispersion of (#) 3ss-[3-(5-n-pentyl-#2,3-isoxazolyl)]-2&alpha;-(6-carboxy-hexyl)- cyclopentan-1&alpha;-ol (2.15 g) in water (40 ml) a stoichiometric amount of NaHCO3 was added, so obtaining the complete solution of the compounds. This solution was then @yophilized, thus obtaining sodium salt of the starting acid.
The salts of the acids described in Examples 5, 7, 9, 14 and 15 were obtained similarly.
Formulation Examples Formulation 1: Tablet (5 mg) Tablets, each weighing 80 mg and containing 5 mg of the, active substance, are manufactured as follows: Composition (for 100,000 Tablets) (#) 3ss-{3-[5-(1'-phenoxy)-methyl-isoxazolyl)]-2&alpha;-(6-carboxylhexyl-#2,3- enyl)-cyclopentan-1 -one 500 g Lactose 5000 g Corn starch 2320 g Talc powder 250 g Magnesium stearate 30 g The lactose and half the corn starch are mi::ed; the mixture is then forced through a sieve of 0.5 mm mesh size. Corn starch (18 g) is suspended in warm water (180 ml). The resulting paste is used to granulate the powder.The granules are dried, comminuted on a sieve of mesh size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets using punches of 5 mm diameter.
Formulation 2: Intramuscular Injection An injectable pharmaceutical composition was manufactured by dissolving 1-5 mg of (#) 3ss [3-(5-n-pentyl-#2,3-isoxazolinyl)]-2&alpha;-(6-carboxyhexyl)-cyclopent-1&alpha;-ol sodium salt in sterile water or sterile normal saline solution (1-2 ml).
Formulation 3: Capsule (5 mg) (#) 3ss-{3-[5-(1'-phenoxy)-methyl-isoxazolyl]}-2&alpha;-(6-carboxy-hex-#2,3- enyl)-cyclopentan-1-one 500 mg Lactose 89.8 mg Corn starch 5.0 mg Magnesium stearate 0.2 mg Totai 100.0 mg Encapsulate in two-piece hard gelatin capsules.
Formulation 4: Aerosol (#) 3ss-{3-[5-(1'-fluoro)-n-pentyl-#2,3-isoxazolinyl]}-2&alpha;-(6-carboxy-hex- A2,3-enyl)-cyclopenta n- 1-one 1 Ethanol 10% Lecithin 0.2% Mixture of dichlorodifluoromethene and dichlorotetrafluoroethane (70:30 mixture) q.s. 100%

Claims (90)

Claims
1. A compound having the general formula (i)
wherein R is hydrogen; free, esterified or protected carboxy group; free or protected formyl group or free or protected hydroxymethyl group; one of R1 and R2 is a hydrogen atom ant the other is a hydroxy group or a protected hydroxy group or R1 and R2 together form an oxo or protected oxo group; n is zero, 1 or 2; D is -(CH2)d-;-(CH2)d-CF2-, in which d is an integer of 1 to 5, or -CH=CH-(CH2)kwherein k is zero or an integer of 1 to 4; R3 is::
wherein m is zero or 1, g is zero or an integer of 1 to 6, each of R6 and R7, which may be the same or different, is a hydrogen atom, C1-C4 alkyl group or fluorine atom, provided that when one of R6 and R7 is a fluorine atom the other is a hydrogen atom, a methyl group or a fluorine atom;
wherein R,, R7 and m are as defined above;Z is -O-, -S- or -(CH2)g-, wherein g is as defined above, and G is: (a') a phenyl group unsubstituted or substituted by one or more substituents selected from C1-C4 alkyl groups, halogen atoms; trihalo-C1-C6-alkyl groups and C1-C4 alkoxy groups; b') a cycloaliphatic group unsubstituted or substituted by one or more substituents selected from C1-C4 alkyl groups, halogen atoms, trihalo-C 1-C6 alkyl groups and C1-C4 alkoxy groups; or c') a saturated heteromonocyclic ring containing at least one oxygen, sulphur or nitrogen heteroatom; the symbol @@@ @@ represents a single or double bond; when the symbol @ @@ in the cyclopentane ring is a single bond, then one of R4 and R5 is hydrogen and the other is hydrogen, hydroxy or a protected hydroxy group; or, when the symbol @@@ in the cyclopantane ring is a double bond, then R4 and R5 taken together represent hydrogen, and the pharmaceutically and veterinarily acceptable salts thereof.
2. A compound having the general formula (I) given in claim 1, wherein R is COOR', R' being a hydrogen atom or a methyl or ethyl group; n is 2; D is (CH2)d wherein d is 4, or cis-CH=CH- (CH2)k-wherein k is 2 or 3; R1 is a hydroxy group and R2 a hydrogen atom or R2 a hydrogen atom or R1 and R2 together, form an oxo group; R3 is as defined above, but preferably n-C5H11, n-C6H13, -C(CH3)2-n-C4H9, -C(CH3)2-O-n-C4H9, -CH2-C(CH3)2-O-n-C4H9,
R4 is a hydroxy group and R5 is a hydrogen atom, and pharmaceutically and veterinarily acceptable salts thereof.
3. A compound according to claim 2 in the form of alkali metal salts.
4. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2-methylcssxclopentan-1-one.
5. (+) 3,B-[3-(5-n-Pentylisoxazolyl)]-2cr-allylcyclopentan-1-one.
6. (t) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan-1 -one.
7. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-carboxymethylcyclopentan- 1 -one.
8. (+) 3ss-[3-(5-(2'-hexyl)-isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan- 1-one.
9. (#) 3ss-{3-[5-(1'-Fluoropentyl)isoxazolyl]}-2&alpha;-(6-carboxyhexyl-cyclopentan-1-one.
10. (#) 3ss-{3-[5-(2'-Fluoro-2'hexyl)isoxazolyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
11. (#) 3ss-{3-[5-(2'-Cyclohexylethylisoxazolyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
12. (#) 3ss-{3-[5-(2'-Phenylethylisoxazolyl)]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one.
13. (#) 3ss-[3-(5-Cyclohexylisoxazolyl)]-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one.
14. (t) 3ss-{3-[5-Phenoxymethylisoxazolyl] }-2-(6-carboxvhexyl)cyclopentan-1 -one.
15. (#) 3ss-{3-[5-(2'-n-Butoxy-2'-propyl)isoxazolyl]}-2&alpha;-(6-carboxyhexyl)-cyclopentan-1-one.
16. (#) 3ss-{3-[5-(2'-methyl-2'-n-butoxy-propylisoxazolyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1- one.
17. (#) 3ss-{3-[5-(2'-[2-tetrahydrofuryl]ethyl)isoxazolyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
18. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1-one.
19. (+) 3ss-[3-(5-n-Hexylisoxazolyl)]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1 -one.
20. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan- 1-one.
21. (#) 3ss-{3-[5-(2'-Hexyl)isoxazolyl]}-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
22. (#) 3ss-{3-[5-(1'-Fluoropentyl)isoxazolyl]}-2&alpha;-(6-carboxy-hex-2(3)-enyl)cyclopentan-1-one.
23. (+) 3ss-{3-[5-(2'-Fluoro-2'-hexy)isoxazoly] j-2a-(6-carboxyhex-2 (3)-enyl)cyclopentan- 1-one.
24. (#) 3ss-{3-[5-(2'-Cyclohexylethyl)isoxazolyl]}-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1- one.
25. (+) 3ss-[3-(5-(2'-Phenylethyl)isoxazolyl] )-2a-(carboxyhex-2 (3)-enyl)cyclopentan- 1-one.
26. (+) 3ss-[3-(5-Cyclohexylisoxazolyl)]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan- 1-one.
27. (#) 3ss-{3-[5-Phenoxymethylisoxazolyl]}-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1-one.
28. (#) 3ss-{3-[5-(2'-n-Butoxy-2'-propyl)isoxazolyl]}-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1- one.
29. (#) 3ss-{3-[5-(2'-Methyl-2'-n-butoxypropyl)isoxazolyl]}-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan-1 -one.
30. (#) 3ss-{3-[5-(2'-[2-Tetrahydrofuryl]ethyl)isoxazolyl]}-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan-1 -one.
31. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-methylcyclopentan-1-one.
32. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan- 1-one.
33. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-carboxymethylcyclopentan- 1 -one.
34. (#) 3ss-{3-[5-(2'-Hexylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
35. (#) 3ss-{3-[5-(1'-Fluoropentyl)isoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
36. (+) 3ss-[3-[5(2'-Fluoro-2'-hexyl)isoxazol-2(3)-inyl] }-2o-(6-carboxyhexyl)cyclopentan- 1-one.
37. (+) 3ss-{3-[5-(2'-Cyclohexylethyl)isoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhexyl)cyclopentan- 1-one.
38. (#) 3ss-{3-[5-(2'-Phenylethyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
39. (+) 3ss-[3-(5-Cyclohexylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan- 1 -one.
40. (#) 3ss-{3-[5-Phenoxymethylisoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1-one.
41. (#) 3ss-{3-[5-(2'-n-Butoxy-2'-propyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhexyl)cyclopentan-1- one.
42. (+) 3,B-{3-5-(2'-Methyl-2'-n-butoxypropyl)isoxazol-2(3)-inyl] }-2&alpha;-(6- carboxyhexyl)cyclopentan- 1 -one.
43. (#) 3ss-{3-[5-(2'-[2-Tetrahydrofuryl]ethyl)isoxazol-2(3)-inyl]}-2&alpha;- (6-carboxyhexyl)cyclopentan- 1 more.
44. (+) 3P-13-[5-(2'-Hexyl)isoxazol-2 (3)-inyl] }-2&alpha;-(6-carboxyhex-2 (3)-enyl)cyclopen La n-1 -one.
45. (#) 3ss-{3-[5-(1'-Fluorophenyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan- 1-one.
46. (#) 3ss-{3-[5-(2'-Fluoro-2'-hexyl)isoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan-1 -one.
47. (#) 3ss-{3-[5-(2'-Cyclohexylethyl)isoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan-1 -one.
48. (#) 3ss-{3-[5-(2'-Phenylethyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1- one.
49. (1) 3ss-[3-(5-Cyclohexylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhex-2 (3)-enyl)cyclopontan- 1-one.
50. (#) 3ss-{3-[5-Phenoxymethylisoxazol-2(3)-inyl]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1- one.
51. (+) 3ss-{3-[5-(2'-n-Butoxy-2'-propyl)isoxazol-2(3)-inyl] }-2-(6-carboxyhex-2 (3) enyl)cyclopentan-1 -one.
52. (#) 3ss-{3-[5-(2'-Methyl-2'-n-butoxyproyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan-1 -one.
53. (#) 3ss-{3-[5-2'-[2-Tetrahydrofuryl]ethyl)isoxazol-2(3)-inyl]}-2&alpha;-(6-carboxyhex-2(3)- enyl)cyclopentan-1 -one.
54. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-allylcyclopentan-1&alpha;-ol.
55. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-al Iylcyclopentan- 1 /3-ol.
56. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan-1&alpha;-ol.
57. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhexyl)cyclopentan-1ss;-ol.
58. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;- carboxymethyl-cyclopentan-1&alpha;-ol.
59. (+) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-carboxymethyl-cyclopentan-1 /3-ol.
60. (+) 3ss-[3-(5-n-Pentylisoxazolyl)-2&alpha;-(6-carboxyhex-3 (4)-enyl)cyciopentan- 1 a-ol.
61. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1ss-ol.
62. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1&alpha;-ol.
63. (#) 3ss-[3-(5-n-Pentylisoxazolyl)]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1ss-ol.
64. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhex)cyclopentan- 1 cz-ol.
65. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhex)cyclopentan- 1 /3-ol.
66. (1) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]- 2a-carboxymethylcyclopentan- 1 -ol.
67. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-carboxymethylcyclopentan-1ss-ol.
68. (+) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1 a-ol.
69. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhex-3(4)-enyl)cyclopentan-1ss-ol.
70. (+) 3p-[3-(5-n-Pentylisoxazol-2 (3)-inyl)]-2-(6-carboxyhex-2 (3)-enyl)cyclopentan- 1 -ol.
71. (#) 3ss-[3-(5-n-Pentylisoxazol-2(3)-inyl)]-2&alpha;-(6-carboxyhex-2(3)-enyl)cyclopentan-1ss-ol.
72. (+) 3ss-[3-(5-n-Pentylisoxazolyl]-2&alpha;-(6-carboxyhexyl)cyclopentan- 1-one.
73. (+) )3ss-[3]-(5-n-Pentylisoxazolyl]-2&alpha;-(6-n-butoxycarbonyl methyl)cyclopentan-1 -one.
74. (+) 3ss-[3-(5-n-Pentylisoxazolyl]-2&alpha;-(6-n-butoxycarbonylmethyl)cyclopent-3(4)-en- 1-one.
75. A pharmaceutically or veterinarily acceptable salt of a salt-forming compound according to any one of claims 4 to 74.
76. A pharmaceutically or veterinarily acceptable salt of a carboxylic acid according to any one of claims 6 to 30, 32 to 53 and 56 to 71.
77. Every compound and salt according to claim 1 specifically hereinbefore mentioned other than those speciFically claimed in claims 4 to 76.
78. A compound or salt according to claim 1 in optically active form.
79. A process for the preparation of a compound claimed in claim 1, the process comprising reacting an optically active or racemic compound of formula (III)
wherein one of R', and R'2 is a hydrogen atom and the other is a hydroxy-protecting group or R' and R'2, together form an oxo or protected oxo group, one of R'4 and R'5 is a hydrogen atom and the other is a hydrogen group or a hydroxy-protecting group, and R, D and n are as defined in claim 1, with a compound of formula (IV) B-R3 wherein B is (i) CH2=CH-- or (ii) CH=-C- and R3 is as defined in claim 1, to give a compound of formula (V)::
wherein R'" R'2, R'4, R'5, R, D, n and R3 are as defined above and the symbol = is respectively (i) a single or (ii) a double bond and, if desired, removing the protecting groups.
80. A process according to claim 79 comprising saponifying a compound of formula (I) where R is an esterified carboxy group.
81. A process according to claim 79 or 80 comprising salifying a compound of formula (I) where R is a carboxy group.
82. A process according to any one of claims 79-81 comprising resolving a racemic mixture of formula (I) into an optically active form.
83. A process according to any one of claims 79-82 carried out in an inert organic solvent at a temperature of from 10 to 350C in the presence of a tertiary gamine catalyst and a condensation agent.
84. A process according to any of claims 79-83 substantially as hereinbefore described with reference to any one of the Examples.
85. A pharmaceutical or veterinary composition containing a compound or salt claimed in any one of claims 1 to 78 and a pharmaceutically or veterinarily acceptable carrier and/or diluent.
86. A composition according to claim 85 substantially as hereinbefore described with reference to any one of the Formulation Examples.
87. A process for the preparation of A1314-1 5-oxo prostaglandins of formula (II)
wherein R, R1, R2, R3, R4, R5, D and n are as defined in claim 1, comprising reducing a compound of formula (la)
where R, R1, R2, R3, R4, R5, n and D are as defined in claim 1, with the proviso that no unprotected carbonyl groups are present, to give a compound of formula (VII)
wherein R, R'1, R'2, R3, R'4, R'5, n and D are as defined in claim 79 and, protecting groups and/or saponifying an esterified carboxy group.
88. A process for the preparation of At4('5)-13-oxo prostaglandins of formula (I!)
wherein R, R1, R2, R3, R4, R5, D and n are as defined in claim 1 which comprises reducing a compound of formula (la) as defined in claim 87 to give a compound of formula (VIII)
wherein R, R'1, R'2, R3, R'4, R'5, n and Dare as defined in claim 79, acylating the compound of formula (VIII) to give a compound of formula (X):
wherein R, R'1, R'2, R3, R'4, R'5, n and D are as defined in claim 78 and Rs is a C1-C6 alkyl or phenyl group; reducing the compound of formula (X) to give a compound of formula (Xl):
wherein R, R',, R'2, R3, R'4, R'5, R8, n and D are as defined above, and hydrolyzing the compound of formula (Xl) and, if desired, removing the protecting groups present.
89. A process for the preparation of compounds of formula (II) from compounds of formula (I), according to claim 87 or 89 substantially as hereinbefore described with reference to any one of the Examples.
90. A compound or salt according to any one of claims 1-78 or a composition according to claim 85 or 86 for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body.
GB8101607A 1980-01-25 1981-01-20 Isoxazolyl and isoxazolinyl prostaglandins Expired GB2067994B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0127930A3 (en) * 1983-03-15 1985-03-06 Glaxo Group Limited Aminocyclopentane esters and their preparation and pharmaceutical formulation
EP0265248A3 (en) * 1986-10-22 1988-10-05 Glaxo Group Limited Cyclopentyl ethers and their preparation and pharmaceutical formulation
AU2007248180B2 (en) * 2006-05-04 2012-09-06 Allergan, Inc. Cyclopentane-derivatives and their use as ocular hypotensive agents

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0127930A3 (en) * 1983-03-15 1985-03-06 Glaxo Group Limited Aminocyclopentane esters and their preparation and pharmaceutical formulation
EP0265248A3 (en) * 1986-10-22 1988-10-05 Glaxo Group Limited Cyclopentyl ethers and their preparation and pharmaceutical formulation
AU2007248180B2 (en) * 2006-05-04 2012-09-06 Allergan, Inc. Cyclopentane-derivatives and their use as ocular hypotensive agents

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