Claims
- 1. A prostaglandin analogue of the formula: ##STR187## wherein A represents a group of the formula: ##STR188## wherein R.sup.1 represents a hydrogen atom or a straight- or branched-chain alkyl group of 1 to 4 carbon atoms and the double bond between C.sub.5 and C.sub.6 in the formula (IIg) and (IIi) are Z and E, respectively, B represents a group of the formula: ##STR189## wherein R.sup.2 represents a straight- or branched-chain alkyl group of 1 to 8 carbon atoms, n represents zero or an integer of 1 to 2, and the double bond between C.sub.13 and C.sub.14 in formula (I) is E; or a non-toxic salt thereof when R.sup.1 represents a hydrogen atom, the formula or a cyclodextrin clathrate thereof.
- 2. A prostaglandin analogue according to claim 1, wherein R.sup.1 represents a hydrogen atom or a methyl group.
- 3. A prostaglandin analogue according to claim 1, wherein the alkyl group represented by R.sup.2, in the group of the formula B, represents a straight- or branched-chain alkyl group of 1 to 4 carbon atoms.
- 4. A prostaglandin analogue according to claim 1, wherein n represents zero.
- 5. A prostaglandin analogue according to claim 1, which is one of the formula: ##STR190## wherein .circle.A2 represents a group of the formula: ##STR191## wherein R.sup.1a represents a hydrogen atom or a methyl group, and .circle.B2 represents a group of the formula: ##STR192## wherein R.sup.2a represents a straight- or branched-chain alkyl group of 1 to 4 carbon atoms, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
- 6. A prostaglandin analogue according to claim 5, which is 15-[(1S,3R)-3-butylcyclopentyl]-16, 17, 18, 19, 20-pentantor-6,9 .alpha.-methano-PGI.sub.2 or methyl ester thereof.
- 7. A prostaglandin analogue according to claim 5, which is 15-[(1S,3S)-3-butylcyclopentyl]-16, 17, 18, 19, 20-pentantor-6,9 .alpha.-methano-PGI.sub.2 or methyl ester thereof.
- 8. A pharmaceutical composition which comprises, as active ingredient at least one prostaglandin analogue of the formula (I) depicted in claim 1, wherein the various symbols are as defined in claim 1, or a non-toxic acid addition salt thereof, or a cyclodextrin clathrate thereof, in association with a pharmaceutical carrier or coating.
- 9. A method of combating hypertension or of inhibiting blood platelet aggregation in a patient which comprises administering to the patient an effective amount of a prostaglandin analogue of the formula (I) as depicted in claim 1, wherein the various symbols are as defined in claim 1, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 59-151369 |
Jul 1984 |
JPX |
|
Parent Case Info
This is a division of application Ser. No. 331,011, filed Mar. 30, 1989, now U.S. Pat. No. 4,935,446, which in turn is a continuation of application Ser. No. 757,305, filed Jul. 22, 1985, now abandoned.
The present invention relates to novel isomers of prostaglandin (abbreviated to PG hereafter) analogues having a specific steric configuration. More particularly, the present invention relates to novel isomers of PG analogues which comprise an alkyl-substituted cycloalkyl group in the group in the grouping attached to the 15-position.
PGs are derivatives of prostanoic acid having the following structure: ##STR1## Various types of PGs are known, and their types depend on the structure of the alicyclic ring and the substituents. For example, the alicyclic rings of PGA, PGD, PGE, PGF, PGI.sub.2, 6,9.alpha.-nitrilo-PGI and 6,9.alpha.-methano-PGI.sub.2 have the following structures, respectively: ##STR2##
In the above structural formulae or in the other structural formulae in this specification, according to the generally accepted nomenclature, the broken line indicates that the substituent attached thereto is behind the ring plane, i.e. is of the .alpha.-configuration, the bold line indicates that the substituent attached thereto is in front of the ring plane, i.e. is of the .beta.-configuration, and the wavy line indicates that the substituent attached thereto is of the .alpha.-configuration or the .beta.-configuration.
These compounds are sub-classified according to the positions of the double bonds in the side chains attached to the alicyclic ring at the 8-position and the 12-position. The PG-1 compound has a trans double bond (trans-.DELTA..sup.13) between C.sub.13 -C.sub.14 and the PG-2 compound has a cis double bond between C.sub.5 -C.sub.6 and a trans double bond between C.sub.13 -C.sub.14 (cis-.DELTA..sup.5, trans-.DELTA..sup.13).
Further, when one or more methylene groups are removed from the aliphatic group attached at the 12-position of the alicyclic ring of a prostaglandin, said compound is known as a nor-prostaglandin according to the general rule of the organic nomenclature, and the number of the removed methylene groups is indicated by adding di-, tri- etc. before the prefix "nor".
The PGs generally have pharmacological properties. For example, they exert various effects, including the stimulation of contraction of smooth muscles, a hypotensive effect, a diuretic effect, a bronchial dilation effect, the inhibition of lypolysis, the inhibition of platelet aggregation and the inhibition of gastric acid secretion. Therefore, they are useful in treatments of hypertension, thrombosis, asthma and gastric and intestinal ulcers, in the induction of labor and abortion in pregnant mammals, in the prevention of arteriosclerosis and also as diuretics. They are liposoluble substances present in extremely small quantities in the tissues which secrete PGs in vivo in animals.
The following patents and published applications describe PG analogues which comprise an alkyl-substituted cycloalkyl group in the grouping attached to the 15-position of the PG skeleton:
The cycloalkyl moiety of an alkyl-substituted cycloalkyl group leads to the existance of steric isomers. That is, four optical isomers may occur when two asymmetric carbon atoms (i.e. the carbon atom by which the cycloalkyl group is attached to the PG skeleton, and that bonded to the alkyl substituent) exist, or two geometrical isomers in cis form and trans form may occur when no asymmetric carbon atoms exist (see the following structures, with the proviso that these structures do not limit the present invention).
(i) When asymmetric carbon atoms exist:
(a) when the cycloalkyl group is of the formula: ##STR3##
(b) when the cycloalkyl group is of the formula: ##STR4##
(c) when the cycloalkyl group is of the formula: ##STR5##
(ii) when no asymmetric carbon atoms exist:
(a) when the cycloalkyl group is of the formula: ##STR6##
(b) when the cycloalkyl group is of the formula: ##STR7## wherein R represents an alkyl substituent and *C represents an asymmetric carbon atom.
However, in the specifications of the patents and published applications listed above there is no specific description of the existence of the isomers just described and there is no preparative example which shows that the separation of such isomers has been carried out in practice. Furthermore, the difference in pharamacological activity between each isomer has never been investigated before.
As a result of research and experimentation the isomeric forms depicted above have been synthesised for the first time. Investigation of the pharmacological activity of each of the isomers thus obtained has revealed that there is a great difference in pharmacological activity between the isomeric forms.
Detailed investigations have shown that:
(i) when two asymmetric carbon atoms exist, the isomers having the carbon atom bonded to the PG skeleton in S-configuration (i.e. isomers in (S,R) form and in (S,S) form) generally show stonger PG-like pharmacological activities than those having the carbon atom bonded to the PG skeleton in R-configuration (i.e isomers in (R,R) form and in (R,S) form), and
(ii) when isomers in cis form and trans form exist, the isomer in cis form generally shows stronger PG-like pharmacological activities than that in trans form.
Generally speaking, it is entirely impossible to foresee whether or not a difference in steric configuration will affect the pharmacological activity of a chemical compound, and which isomer has the strongest activity, if the activity is affected. These questions cannot be answered until the pharmacological effect is confirmed following synthesis of the individual isomers. Similar considerations apply to PG analogues which comprise an alkyl-substituted cycloalkyl group in the grouping attached to the 15-position. The fact that the isomers in (S,R) form, in (S,S) form and in cis form, have stronger pharmacological activity than the other isomers, has been discovered following synthesis of the isomers and testing thereof.
Prior to preparation of the isomers it was entirely impossible to foresee that the above fact can be generally applied to PG analogues having any fundamental PG skeleton (defined as the moiety A hereafter).
Furthermore, it is not preferable to formulate pharmaceutical compositions using a mixture of isomers. The component ratio of each isomer in a mixture sometimes changes greatly according to slight differences in reaction conditions (e.g., reaction temperature, reaction time, solvents, conditions for purification) when a mixture of isomers is prepared. However, taking account of the strict quality standards required when preparing materials relating to human health, such as the standards established for the preparation of pharmaceuticals, it is undesirable to change the component ratio of a mixture among each lot. Bearing this in mind the significance of the present invention which permits the preparation of individual isomers can be readily appreciated.
Accordingly, the present invention provides PG analogues of the general formula: ##STR8## (wherein A represents a group of the general formula: ##STR9## (wherein X represents a cis-vinylene group or an ethylene group, Y represents an ethylene group or a trans-vinylene group, R.sup.1 represents a hydrogen atom or a straight- or branched-chain alkyl group of 1 to 4 carbon atoms and the double bond between C.sub.5 and and C.sub.6 in the formulae (IIg) and (IIi) are Z and E, respectively), B represents a group of the general formula: ##STR10## (wherein R.sup.2 represents a straight- or branched-chain alkyl group of 1 to 8 carbon atoms), n represents zero, or an integer of 1 or 2 and the double bond between C.sub.13 and C.sub.14 in the formula (I) is E; with the exclusion of the compound wherein A represents a group of the formula (IIe) in which R.sup.1 represents a hydrogen atom, B represents a group of the formula: ##STR11## and n is zero), and non-toxic salts thereof when R.sup.1 represents a hydrogen atom, and non-toxic acid addition salts thereof when A represents a group of the formula (IIh), and cyclodextrin clathrates thereof.
In the above structural formulae or in the other structural formulae in this specification, ##STR12## mean the same configuration, and indicate that two substituents are attached to the cyclohexyl group in cis configuration to each other, and ##STR13## mean the same configuration, and indicate that two substituents are attached to the cyclohexyl group in trans configurations to each other. The cyclobutyl group is shown in a similar manner.
Compounds of the general formula (I) wherein A represents a group of the formula: (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) and (IIi) can be called PGA, PGD, PGE, PGF, 6-keto-PGE.sub.1, 6-keto-PGF.sub.1.alpha., PGI.sub.2, 6,9.alpha.-nitrilo-PGI and 6,9.alpha.-methano-PGI.sub.2 derivatives, and compounds wherein Y represents a trans-vinylene group can be called trans-.DELTA..sup.2 compounds.
Furthermore, the compounds of the present invention can be named as derivatives of a prostanoic acid. For example, the compound of the formula: ##STR14## can be called (13E)-(11.alpha.,15.alpha.)-6,9-dioxo-11,15-dihydroxy-15-[(1S,3R)-3-propylcyclopentyl]-16,17,18,19,20-pentanorprost-13-enoic acid, and the compound of the general formula: ##STR15## can be called (13E)-(9.alpha.,11.alpha.,15.alpha.)-6,9-nitrilo-11,15-dihydroxy-15-(cis-4-propylcyclohexyl)-16,17,18,19,20-pentanorprost-13-enoic acid methyl ester.
The PG skeleton represented by A in the general formula I is preferably a group of the formula (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), and more preferably a group of the formula (IId), (IIe), (IIh) or (IIi).
In the group of the formula A, as the alkyl group represented by R.sup.1, there may be mentioned methyl, ethyl, propyl, butyl and isomers thereof. R.sup.1 is preferably a hydrogen atom. More preferably R.sup.1 is a hydrogen atom or a methyl group.
In the general formula (I) the alkyl-substituted cycloalkyl group represented by B is preferably a cyclopentyl group of the formula (IIIc) or (IIId) or a cyclohexyl group of the formula (IIIe), (IIIf) or (IIIg), and more preferably a group of the formula (IIId), (IIIf) or (IIIg).
In the group of the formula B, as the alkyl group represented by R.sup.2, there may be mentioned methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof; a straight- or branched-chain alkyl group of 1 to 4 carbon atoms is preferred.
As a preferred group represented by the formula B, there may be mentioned: ##STR16##
In the general formula (I), n is preferably zero, 1 or 2, and more preferably zero.
Accordingly, as a preferred group of compounds of the present invention, there may be mentioned PG analogues of the general formula: ##STR17## (wherein .circle.A.sub.1 represents a group of the general formula IIc, IId, IIe, IIf, IIg, IIh or IIi,
As a more preferred group of compounds of the present invention, there may be mentioned PG analogues of the general formula: ##STR18## (wherein .circle.A.sub.2 represents a group of the general formula IId, IIe, IIh or IIi (wherein X and Y are as hereinbefore defined, and R.sup.1 represents a group R.sup.1a which represents a hydrogen atom or a methyl group), and .circle.B.sub.2 represents a group of the general formula IIId, IIIf or IIIg (wherein R.sup.2 represents a group R.sup.2a which represents a straight- or branched-chain alkyl group of 1 to 4 carbon atoms)), or non-toxic salts thereof, or non-toxic acid addition salts thereof, or cyclodextrin clathrates thereof.
The compounds of the general formula (I) may be prepared by methods known per se. By the expression "methods known per se" as used in this specification is meant methods heretofore used or described in the literature.
Compounds of the general formula (I) may be prepared by synthetic routes starting from compounds of the general formula: ##STR19## (wherein R.sup.3 represents a hydrogen atom or an acyl group, R.sup.4 represents a hydrogen atom or a hydroxy-protecting group which is eliminated under an acidic condition, e.g., a tetrahydropyran-2-yl group, and the other symbols are as hereinbefore defined) or compounds of the general formula: ##STR20## (wherein one of R.sup.5 and R.sup.6 represents an acetyl group and the other represents a hydrogen atom, or R.sup.5 and R.sup.6 together represent an oxo group, and R.sup.7 represents a hydroxy-protecting group which is eliminated under an acidic or alkaline condition, e.g. tetrahydropyran-2-yl, tert-butyldimethylsilyl or benzoyl group, and a dialkyl phosphonate of the general formula: ##STR21## (wherein R.sup.8 represents an alkyl group of 1 to 4 carbon atoms, preferably a methyl or ethyl group, and the other symbols are as hereinbefore defined), by the methods described in the following patent specifications, or obvious modifications thereof:
(1) when A represents a group of the formula (IIa), (IIc) and (IId), as described in Japanese Patent Kokai No. 52-27753 and British Patent Specification No. 1545213;
(2) when A represents a group of the formula (IIb), as described in Japanese Patent Kokai Nos. 58-216155 and 59-5154, and European Patent Publication Nos. 97023 and 99672;
(3) when A represents a group of the formula (IIe), as described in Japanese Patent Kokai No. 54-44639 and British Patent Specification No. 2079268;
(4) when A represents a group of the formula (IIf), as described in Japanese Patent Kokai No. 53-127441 (Derwent Abstract No. 90273A);
(5) when A represents a group of the formula (IIg), as described in Japanese Patent Kokai No. 53-103464 and British Patent Specification No. 1598953;
(6) when A represents a group of the formula (IIh), as described in Japanese Patent Kokai No. 54-125653 and British Patent Specification No. 2016456;
(7) when A represents a group of the formula (IIi), as described in Japanese Patent Kokai Nos. 54-130543, 55-64541 and 59-51276, British Patent Specification No. 2017699, and European Patent Publication No. 105651.
Optical isomers and geometric isomers which occur in the group represented by B, may be resolved and separated to a desired isomer at the stage of a phosphonate of the general formula (VI), and then, by using the obtained isomer, the subsequent reactions for synthesizing PGs may be carried out; or the reactions for synthesizing PGs may be carried out by using a phosphonate containing a mixture of each isomer, and resolution and separation may be conducted at an appropriate step during reactions; or the two methods described above may be appropriately combined.
Methods for the resolution of optical isomers or methods for the separation of geometric isomers are well known per se. For example, they may be carried out by conventional means, e.g., by high pressure liquid, thin layer or column chromatography on silica gel or on magnesium silicate, or by known methods for optical resolution (cf. Tables of resolving agents and optical resolutions, University of Notre Dame press (1972)).
Starting materials of the general formula (IV) may be prepared by the methods described in Japanese Patent Kokai No. 50-137961 and British Patent Specification No. 1482928, or obvious modifications thereof.
Starting materials of the general formula (V) may be prepared by the methods described in Japanese Patent Kokai Nos. 54-130543, 55-64541 and 59-51276, British Patent Specification No. 2017699, and European Patent Publication No. 105651, or obvious modifications thereof.
Dialkyl phosphonates of the general formula (VI) may be prepared by reacting a compound of the general formula:
Carboxylic esters of the general formula (VII) in which n is an integer of 1 may be prepared from the carboxylic ester of the general formula (VII) in which n is zero, by the sequence of reaction steps illustrated in the following Scheme 1. In Scheme 1, LAH means the reduction by using lithium aluminium hydride, and R.sup.10 represents a tosyl or mesyl group and the other symbols are as hereinbefore defined. ##STR23##
Each step may be carried out by methods known per se.
Carboxylic esters of the general formula (VII) in which n is an integer of 2 may be prepared by repetition of the same procedure as illustrated in Scheme 1, by using a carboxylic ester of the general formula (VII) in which n is an integer of 1, i.e., a compound of the general formula (VIIb), as starting material.
Carboxylic esters of the general formula (VIIa) may be prepared by methods known per se, for example, by the sequence of reaction steps illustrated in the following Scheme 2 to 5, wherein R.sup.11 represents an alkyl group of 1 to 4 carbon atoms (preferably methyl group), R.sup.12 represents a hydroxy-protecting group which is eliminated under an acidic condition (preferably, tetrahydropyran-2-yl group), R.sup.2b represents a hydrogen atom or a straight- or branched-alkyl group of 1 to 7 carbon atoms, R.sup.2c represents a straight- or branched-chain alkyl group of 1 to 7 carbon atoms, LDA represents a lithium dialkylamide (for example, lithium diisopropylamide), X represents a halogen atom (for example, bromine or iodine atom), m represents an integer of 1 to 4, p represents an integer of 2 to 4, q represents an integer of 1 to 4, and the other symbols are as hereinbefore defined. ##STR24##
In Schemes 2 to 5, each reaction may be carried out by methods known per se. Compounds used as starting materials in each reaction are known per se, or may be easily prepared from known compounds by methods known per se.
The resolution of dl-compounds or the separation of the mixture of cis-form and trans-form may be carried out at the desired step. In the schemes, the preferred steps at which resolution or separation are effected are shown, but resolution or separation may be carried out at other steps.
In Scheme 2, the process for the preparation of 2S-alkyl-substituted cycloalkanecarboxylic acids is illustrated, and 2R-alkyl-substituted cycloalkanecarboxylic acids may be prepared by the same procedure as described in Scheme 2 by using the corresponding compound of the general formula (VIII) as starting material.
Compounds of the general formula (VIII) in which m represents an integer of 2, 3 or 4, may be prepared by repetition of the same procedure as illustrated in Scheme 1, by using a compound of the general formula (VIII) in which m represents an integer of 1.
In Scheme 3, there is no asymmetric carbon atom in the compound of the general formula (IX) in which q represents an integer of 1. In the case of the compound in which q is an integer of 1, the separation of cis-form from trans-from is preferably carried out on the compound of the general forula (X) or (XI).
According to a feature of the present invention compounds of general formula I may be prepared as follows:
(I) when A represents a group of the formula (IIa), (IIc) or (IId), by the hydrolysis of a compound of the general formula: ##STR25## (wherein R.sup.13 represents a hydroxy-protecting group which is eliminated under acidic conditions, and the other symbols are as hereinbefore defined), or by the hydrolysis of a compound of the general formula: ##STR26## (wherein Z represents ##STR27## or >C.dbd.O, and the other symbols are as hereinbefore defined), or by the hydrolysis of a compound of the general formula: ##STR28## (wherein R.sup.14 represents a hydrogen atom or a hydroxy-protecting group which is eliminated under acidic conditions, and the other symbols are as hereinbefore defined), followed optionally by esterification, by saponification or by the conversion of a PGE compound wherein A represents a group of the formula (IIc) to a PGA compound of general formula (I) wherein A represents a group of the formula (IIa) by methods known per se;
(II) when A represents a group of the formula (IIb), by the hydrolysis of a compound of the general formula: ##STR29## (wherein the various symbols are as hereinbefore defined), followed optionally by esterification;
(III) when A represents a group of the formula (IIe) or (IIf), by the hydrolysis of a compound of the general formula: ##STR30## (wherein the various symbols are as hereinbefore defined), or by the hydrolysis of a compound of the general formula: ##STR31## (wherein R.sup.15 and R.sup.16, which may be the same or different, each represent a hydroxy-protecting group which is eliminated under acidic conditions, or a trimethylsilyl group, with the prviso that at least one of the symbols R.sup.15 and R.sup.16 represents a trimethylsilyl group, and the other symbols are as hereinbefore defined), followed optionally by esterification;
(IV) when A represents a group of the formula (IIg), by the dehydrohalogenation of a compound of the general formula: ##STR32## (wherein X.sub.1 represents a bromine or iodine atom, the absolute configuration of C.sub.5 and C.sub.6 are (5R,6R) or (5S,6S) or a mixture thereof, and the other symbols are as hereinbefore defined), followed optionally by esterification;
(V) when A represents a group of the formula (IIh), by the cyclisation of a compound of the general formula: ##STR33## (wherein the various symbols are as hereinbefore defined), followed optionally by esterification or saponification;
(VI) when A represents a group of the formula (IIi), by the hydrolysis of a compound of the general formula: ##STR34## (wherein R.sup.1b represents a straight- or branched-chain alkyl group of 1 to 4 carbon atoms, and the other symbols are as hereinbefore defined), or by the hydrolysis of a compound of the general formula: ##STR35## (wherein R.sup.17 represents a hydrogen atom or a hydroxy-protecting group which is eliminated under acidic conditions, R.sup.18 represents a hydroxy-protecting group which is eliminated under acidic conditions, and the other symbols are as hereinbefore defined), or by the hydrolysis of a compound of the general formula: ##STR36## (wherein R.sup.19 represents a hydroxy-protecting group which is eliminated under alkaline conditions, and the other symbols are as hereinbefore defined), or by the reduction of a compound of the general formula: ##STR37## (wherein the various symbols are as hereinbefore defined), followed optionally by esterification or saponification.
The hydroxy-protecting group represented by R.sup.13, R.sup.14, R.sup.15, R.sup.16 and R.sup.18 is preferably tetrahydropyran-2-yl. The hydroxy-protecting group represented by R.sup.17 is preferably tetrahydropyran-2-yl or tert-butyldimethylsilyl. The hydroxy-protecting group represented by R.sup.19 is prefererably benzoyl.
Compounds of the general formulae (XII) to (XXIII) are prepared by the synthetic routes hereinbefore referred to, starting from compounds of general formulae IV, V and VI.
The hydrolysis under acidic conditions of the groups OR.sup.13, OR.sup.14 (when R.sup.14 is other than a hydrogen atom), OR.sup.15, OR.sup.16, the trimethylsilyl group, OR.sup.17 (when OR.sup.17 is other than a hydrogen atom), and OR.sup.18, may be carried out by mild hydrolysis with (1) an aqueous solution of an organic acid such as acetic acid, propionic acid, oxalic acid or p-toluenesulphonic acid, or an aqueous solution of an inorganic acid such as hydrochloric acid, sulphuric acid or phosphoric acid, advantageously in the presence of an inert organic solvent miscible with water, e.g. a lower alkanol such as methanol or ethanol, preferably methanol, or an ether such as 1,2-dimethoxyethane, dioxan or tetrahydrofuran, preferably tetrahydrofuran, at a temperature from ambient to 75.degree. C., or (2) an anhydrous solution of an organic acid such as p-toluenesulphonic acid or trifluoroacetic acid in a lower alkanol such as methanol or ethanol at a temperature from 10.degree. C. to 45.degree. C., or (3) an anhydrous solution of p-toluenesulphonic acid-pyridine complex in a lower alkanol such as methanol or ethanol at a temperature from 10.degree. to 60.degree. C. Advantageously the mild hydrolysis under acidic conditions may be carried out with a mixture of dilute hydrochloric acid and methanol, a mixture of acetic acid, water and tetrahydrofuran, a mixture of phosphoric acid, water and tetrahydrofuran, a mixture of p-toluenesulphonic acid and methanol or a mixture of p-toluenesulphonic acid-pyridine complex and methanol.
The hydrolysis under alkaline conditions of the group OR.sup.19 may be carried out by reaction with an aqueous solution of an alkali metal, e.g. sodium or potassium, or an alkaline earth metal, e.g. calcium or barium, hydroxide or carbonate in the presence of a water-miscible solvent, e.g. an ether such as dioxan or tetrahydrofuran or an alkanol containing 1 to 4 carbon atoms, such as methanol or ethanol, at a temperature from -10.degree. C. to 70.degree. C., preferably at ambient temperature.
The dehydrohalogenation of a compound of the general formula (XVIII) may be carried out with a known dehydrohalogenation reagent, for example, (1) when X.sub.1 represents a bromine atom, a bicycloamine such as DBU (i.e. 1,5-diazabicyclo[5.4.0]undecene-5), DBN (i.e. 1,5-diazabicyclo[4.3.0]nonene-5) or DABCO (i.e. 1,4-diazabicyclo[2.2.2]octane), or an alkali metal, e.g. sodium or potassium, alcoholate containing from 1 to 4 carbon atoms, or (2) when X.sub.1 represents an iodine atom, a bicycloamine such as DBN, DBU or DABCO, or an alkali metal, e.g. sodium or potassium, alcoholate containing from 1 to 4 carbon atoms, superoxide, carbonate, hydroxide, benzoate, acetate, trifluoroacetate or bicarbonate, or silver acetate, or tetramethylammonium superoxide. The reaction may be carried out at a temperature from ambient to 110.degree. C., preferably at a temperature from ambient to 80.degree. C., and (1) when the reagent is a bicycloamine, optionally in the presence of an inert organic solvent, preferably in the absence of an inert organic solvent or in the presence of toluene or benzene, or (2) when the reagent is other than a bicycloamine, in the presence of an inert organic solvent, e.g. an alkanol containing from 1 to 4 carbon atoms, such as methanol or ethanol, or N,N-dimethylformamide.
When the reaction is carried out in the presence of a solvent, the reaction mixture may be concentrated under reduced pressure at a low temperature, e.g. at 0.degree. C. to 5.degree. C. after the reaction. The residue thus obtained or the reaction mixture obtained when the reaction is carried out in the absence of a solvent, may be adjusted, (1) when R.sup.1 represents a hydrogen atom, to pH 5 to 7 or, (2) when R.sup.1 represents an alkyl group, to pH 7 to 9 with an aqueous solution of an acid, e.g. dilute hydrochloric acid, and/or phosphate buffer, and extracted with an easily removable organic solvent such as diethyl ether. The extract, when R.sup.1 represents a hydrogen atom, may be dried to give a solution of the desired PGI.sub.2 analogue. The extract, when R.sup.1 represents an alkyl group, may be dried and concentrated under reduced pressure to give the desired PGI.sub.2 analogue. If desired, a product wherein R.sup.1 represents an alkyl group, may be purified by thin layer or column chromatography on silica gel or magnesium silicate pretreated with triethylamine to give the pure PGI.sub.2 analogue.
The cyclisation of a compound of the general formula (XIX) may be carried out in an inert organic solvent, e.g. toluene, benzene or acetonitrile, at a temperature from ambient to 110.degree. C.
The reduction of a compound of the general formula (XXIII) may be carried out by using any suitable reducing reagent such as sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, lithium tri-tert-butoxyaluminium hydride, lithium trimethoxyaluminium hydride, sodium cyanoborohydride, potassium tri-sec-butylborohydride, lithium aluminium hydride-quinine complex (-)-isobornyloxymagnesium iodide in an inert organic solvent, e.g. an alkanol containing from 1 to 4 carbon atoms such as methanol, ethanol or isopropanol, or an ether such as tetrahydrofuran, dioxan or 1,2-dimethoxyethane, or a mixture of two or more such solvents, at a temperature from -78.degree. C. to ambient. Preferably, the reduction is effected using diisobornyloxyaluminiumisopropoxide (described in our Japanese Patent Kokai No. 54-76552), or a diisobutyl(alkyl-substituted or unsubstituted) phenoxyaluminium [described in our Japanese Patent Kokai No. 54-154739 and J. Org. Chem., 44, 1363 (1979)], or a lithium 1,1'-binaphthyl-2,2'-dioxyaluminium hydride [described in J. Amer. Chem. Soc., 101, 5843 (1979)]. The product thus obtained is a mixture of isomers in which the 15-hydroxy group is in .alpha.- or .beta.-configuration and the mixture may be separated by conventional means, for example, by thin layer, column or high-speed liquid chromatography on silica gel to give the desired 15.alpha.-hydroxy isomer.
The conversion of the PGE compound to a PGA compound may be carried out by subjecting the PGEs to dehydration using an aqueous solution of an organic or inorganic acid having a higher concentration than that employed for hydrolysing the OR.sup.13 group of compounds of general formula XII, e.g. 1N hydrochloric acid, if desired in the presence of cupric chloride, or acetic acid, and heating at a temperature of 30.degree. to 60.degree. C. PGA compounds can be also obtained directly from compounds of general formula XIII and XIV, wherein Z represents >C.dbd.O, when such stronger acidic conditions are utilized to hydrolyze the OR.sup.13 groups as the intermediate PGEs will then be dehydrated in situ to PGA compounds.
The esterification of the acids of the general formula (I) may be carried out by methods known per se, for example by reaction with (i) the appropriate diazoalkane in an inert organic solvent, e.g. diethyl ether, at a temperature of from -10.degree. to 25.degree. C. and preferably 0.degree. C., (ii) the appropriate alcohol in the presence of dicycloxhexylcarbodiimide as condensing agent, or (iii) the appropriate alcohol following formation of a mixed anhydride by adding a tertiary amine and pivaloyl halide or an alkylsulphonyl or arylsulphonyl halide (cf. British Patents Nos. 1362956 and 1364125).
The saponification of the esters of the general formual (I) wherein A represents a group of the formula (IId), (IIh) or (IIi), to the corresponding acids, may be carried out by reaction with an aqueous solution of an alkali metal, e.g. sodium or potassium, or an alkaline earth metal, e.g. calcium or barium, hydroxide or carbonate in the presence of a water-miscible solvent, e.g. an ether such as dioxan or tetrahydrofuran or a lower alkanol such as methanol or ethanol at a temperature from -10.degree. to 70.degree. C. preferably at ambient temperature.
The saponification of the esters of the general formula (I) wherein A represents a group of the formula (IIc) to the corresponding acid, may be carried out by using bakers' yeast [cf. C. J. Sih et al, J. Amer. Chem. Soc., 94, 3643-3644 (1972)]
Cyclodextrin clathrates of PG analogues of the general formula (I) may be prepared by using .alpha.-, .beta.- or .gamma.-cyclodextrin, or a mixture thereof by methods described in the specifications of British Patent Nos. 1351238 and 1419221. Conversion into cyclodextrin clathrates serves to increase the stability and the solubility of PG analogues of the general formula (I), and therefore facilitates their use as pharmaceuticals.
The compounds of general formula (I) wherein R.sup.1 represents a hydrogen atom may, if desired, be converted by known methods into salts. Preferably the salts are non-toxic salts and water-soluble. Suitable non-toxic salts include the alkali metal, e.g. sodium or potassium, salts, the alkaline earth metal, e.g. calcium or magnesium, salts and ammonium salts, and pharmaceutically acceptable, (i.e. non-toxic) amine salts. Amines suitable for forming such salts with a carboxylic acid are well known and include organic amine salts, for example, tetraalkylammonium, such as tetramethylammonium, salts, methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts, lysine salts, arginine salts or N-methylglucamine salts.
Salts may be prepared from the compounds of general formula (I) wherein R.sup.1 represents a hydrogen atom, by known methods, for example by reaction of stoichiometric quantities of an acid of general formula (I) and the appropriate base, e.g. an alkali metal hydroxide or carbonate, ammonium hydroxide, ammonia or an organic amine, in a suitable solvent.
The compounds of general formula (I) wherein A represents a group of the formula (IIh) may, if desired, be converted by known methods into acid addition salts, which are preferably non-toxic salts and water-soluble.
Examples of suitable non-toxic acid addition salts are the salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid and nitric acid, and the salts with organic acids such as acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, benzoic acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid, isethionic acid, glucuronic acid and gluconic acid.
Acid addition salts may be prepared from the compounds of general formula (I) wherein A represents a group of the formula (IIh), by known methods, for example by reaction of stoichiometric quantities of a compound of the general formula (I) wherein A represents a group of the formula (IIh) and the appropriate acid in a suitable solvent.
The PG analogues of the general formula (I), non-toxic salts thereof, non-toxic acid-addition salts thereof and cyclodextrin clathrates thereof having a specific steric configuration show stronger pharmacological activity than the corresponding isomers which are not embraced by the present invention. Furthermore, the strong activity extends to all of the pharmacological properties typical of the PGs.
The PG analogues of the general formula (I), non-toxic salts thereof, non-toxic acid addition salts thereof and cyclodextrin clathrates thereof have advantages in hypotensive effect and inhibitory effect on blood platelet aggregation, and, therefore, are particularly useful as hypotensive agents for the treatment of hypertension, and as inhibitory agents of blood platelet aggregation for the treatment of disorders of the peripheral circulation and for the prevention and treatment of thrombosis, cardiostenosis, myocardial infarction and arteriosclerosis.
For example, the results of standard laboratory tests (i) inhibitory effect on adenosine diphosphate (ADP)-induced blood platelet aggregation in platelet-rich plasma of rats (in vitro) and (ii) hypotensive effect by intraveneous administration to the allobarbital-anaesthetized dog (in vivo), of the compounds of the present invention (isomers in the SR-form, SS-form and cis-form) and the compounds for comparison (isomers in the RR-form, RS-form and trans-form), are shown in the following tables. Furthermore, the effects of mixtures of each isomer are also shown in the tables for reference. In the tables, all the activities are indicated relative to the activity of PGE.sub.1, taken as 1.
As will be seen from the tables, in the case of the compounds having an alkyl-substituted cyclopentyl group after the 15-position of the PG skeleton, both 16S-isomers have several times to more than ten times stronger an inhibitory effect on blood platelet aggregation and hypotensive effect than the corresponding 16R-isomer, and in the case of the compounds having an alkyl-substituted cyclohexyl group after the 15-position of the PG skeleton, the isomer in cis-form has several times stronger an inhibitory effect on blood platelet aggregation and hypotensive effect than the isomer in trans-form. Furthermore, the compounds of the present invention are generally more potent as compared with the mixtures of each isomer, and, therefore, are understood to be useful enough as pharmaceuticals.
Further, the compounds of the present invention have very weak toxicity, and, therefore, were confirmed to be sufficiently safe and suitable for medical use.
Preferred compounds of the general formula (I) of the present invention are, for example, as follows:
US Referenced Citations (1)
| Number |
Name |
Date |
Kind |
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4479966 |
Hayashi |
Oct 1984 |
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Non-Patent Literature Citations (1)
| Entry |
| Imaki, Adv. Prost Res. 19, pp. 666-9 (1988). |
Divisions (1)
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Number |
Date |
Country |
| Parent |
331011 |
Mar 1989 |
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Continuations (1)
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Number |
Date |
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| Parent |
757305 |
Jul 1985 |
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Patent Grant
5109021
