GB1585181A - 12-azaprostanoic acid derivatives - Google Patents

12-azaprostanoic acid derivatives Download PDF

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GB1585181A
GB1585181A GB21304/76A GB2130476A GB1585181A GB 1585181 A GB1585181 A GB 1585181A GB 21304/76 A GB21304/76 A GB 21304/76A GB 2130476 A GB2130476 A GB 2130476A GB 1585181 A GB1585181 A GB 1585181A
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compound
hydrogen
formula
methyl
alkyl
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Beecham Group PLC
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Beecham Group PLC
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Priority to GB21304/76A priority Critical patent/GB1585181A/en
Priority to NZ184084A priority patent/NZ184084A/en
Priority to US05/796,701 priority patent/US4156730A/en
Priority to BE177633A priority patent/BE854704A/en
Priority to DE19772722118 priority patent/DE2722118A1/en
Priority to SE7705857A priority patent/SE417095B/en
Priority to FR7715258A priority patent/FR2351962A1/en
Priority to CA278,738A priority patent/CA1095522A/en
Priority to AU25305/77A priority patent/AU506783B2/en
Priority to IE1035/77A priority patent/IE45436B1/en
Priority to ZA00773021A priority patent/ZA773021B/en
Priority to DK220977A priority patent/DK220977A/en
Priority to NL7705573A priority patent/NL7705573A/en
Priority to JP5972577A priority patent/JPS52142062A/en
Publication of GB1585181A publication Critical patent/GB1585181A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • 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
    • C07D317/10—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 not condensed with other rings
    • C07D317/14—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 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
    • 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
    • C07D317/10—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 not condensed with other rings
    • C07D317/14—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 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

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

Description

(54) 12-AZAPROSTANOIC ACID DERIVATIVES (71) We, BEECHAM GROUP LIMITED, a British Company of Beecham House, Great West Road, Brentford, Middlesex, England, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel compounds having pharmacological activity, to a process for their preparation, to intermediates useful in that process, and to pharmaceutical compositions containing them.
More-specifically the invention relates to 12-azoprostanoic acid derivatives.
Natural prostaglandins and analogues thereof are known to possess a wide variety of pharmacological activities.
British Patent Specification 1428431 discloses that pyrazolidine derivatives of the formula (I)':
wherein A is CH=CH or C=C R is H, or athyl or cycloalkyl each having up to 12 carbon atoms; m isO or 1; n is 06; p is 06; and Y and Z are O or H2 except that Y and Z are not both 0 and alkali metal and amine salt thereof when R is H; have similar biological properties to the prostaglandins or are antagonists of prostaglandins.
Japanese Patent Application No. 51001461 discloses the preparation of a compound of formula (II)':
and states that this compound has laxative activity.
A novel class of compounds having useful pharmacological activity has now been discovered, which compounds are structurally distinct from the known compounds referred to above.
The present invention provides a compound of the formula (I):
wherein: mis 0 or 1; n is 4 to 8; A is hydrogen, and when m is 0 and R5 is methyl it may also be methyl or a group CO2B wherein B is hydrogen or CO2B represents an ester group in which the B moiety contains from 1 to 12 carbon atoms; X is CO, protected CO, CROH in which R is hydrogen or C14 alkyl and in which the OH moiety may be protected; R, is hydrogen, or CO2R, represents an ester group in which the R1 moiety contains 1 to 12 carbon atoms; R4 is hydrogen, C1-9 alkyl, C5-8 cycloalkyl, C5-8 cycloalkyl C1-6 alkyl, phenyl, phenyl-C1-6 alkyl, naphthyl, naphthyl-C1-6 alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, C1-6 alkoxy, or nitro groups; D is a group -CH2-CH(R6)-CH(R7)-C(R2)(R3)-, a group -CH2-CH(R6)-CH(R7)-CH(R8)-C(R2)(R3)-, a group -CH2-CH(R6)-CH(R7)-CH(R81)-C(R2)(R3)or a group -CH2-C(R10)(R3)- wherein R2 is hydrogen, C1-4 alkyl or phenyl; R3 is hydroxy or protected hydroxy; R6, R7, R8, R81 and R10 are hydrogen, C1-4 alkyl or phenyl; and R5 is hydrogen, and when mis 0 it may also be methyl; and salts thereof when R1 is hydrogen.
It is normally preferred that m is 0.
Suitably n is 5, 6 or 7, preferably 6.
A must be hydrogen when m is 1, and also when R5 is hydrogen. When m is 0 and R5 is methyl, A can be hydrogen, methyl or a group CO2B as defined. Suitable examples of B include hydrogen and methyl, ethyl, propyl, butyl, phenyl, benzyl and tolyl, while normally for B hydrogen or C14 alkyl are preferred. While the groups B and R, may be different, it is normally preferred that they are both hydrogen or the same C14 alkyl group.
Suitable protected hydroxyl groups CROH and R3 include readily hydrolysable groups such as acylated hydroxy groups in which the acyl moiety contains 1 to 4 carbon atoms, for example the acetoxy group; and hydroxy groups etherified by readily removable inert groups such as the benzyl. Preferably R3 is hydroxy, and the hydroxy moiety in CROH is unprotected.
Suitable protected CO groups X include groups formed by conventional carbonyl addition and condensation reactions such as acetals, thioacetals, hemithioacetals, oximes, semicarbazones and, hydrazones. Of such groups often the acetal type derivatives will be most useful, for example when X is a group
Examples of suitable groups X include CO, CHOH, C(CH3)OH and C(C2H5)OH. Preferably X is CO, CHOH or C(CH3)OH, most preferably CO.
R1 is hydrogen or CO2R1 represents an ester group in which the R1 moiety contains from I to 12 carbon atoms. Examples of R, include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl and, tolyl, while normally hydrogen or C14 alkyl groups are preferred.
Of the groups possible for R2, we have found that hydrogen, methyl, ethyl and phenyl are the most suitable. Of these groups, preferred groups include methyl and ethyl.
Preferably R3 is hydroxy.
Suitable groups R4 when R4 is an alkyl group include C39 alkyl groups. Such C3s alkyl groups may be straight chain alkyl groups, such as n-propyl, n-butyl, npentyl, n-hexyl, n-heptyl and n-octyl or may be alkyl groups branched by one or two methyl groups (at the same or different carbon atoms). Thus for example, R4 may be a group CH2R11, CH(CH3)R11 or C(CH3)R11, wherein R11 is a straight chain alkyl group such that the carbon content of the resultant group R4 is 3 to 9. The -D-R4 moiety in formula (I) when R4 is an alkyl group will not normally exceed 12 carbons in length.
When R4 is or contains a C58 cycloalkyl moiety, the moiety is suitably a cyclohexyl moiety. Examples of suitable C16 alkyl moieties when R4 is a C56 cycloalkyl-C,~8 alkyl group include methyl, ethyl, propyl, butyl and amyl.
When R4 is an aryl group as previously defined, suitable groups R4 include phenyl, benzyl, phenthyl, 3-phenyl-propyl, 4-phenylbutyl, naphthyl, naphthylmethyl, 2(naphthyl)ethyl, 3-(naphthyl)propyl and 4-(naphthyl)butyl. These groups may be substituted in the phenyl or naphthyl moiety by normally one, two or three groups or atoms selected from those substituent groups or atoms listed herein before. Examples of suitable substituent groups or atoms include fluorine, chlorine and bromine atoms and CF3, methyl, ethyl, n- and iso-propyl, methoxy and ethoxy, n- and iso- propoxy and nitro groups. When m is 1, R5 must be hydrogen. However it may be hydrogen or methyl when m is 0, and often compounds wherein R5 is methyl in this manner have particularly useful pharmacological properties and benficial stability.
R6, R7, R8, R81 and R10 are each independently, C1-4 alkyl or phenyl, Suitable examples of such groups include hydrogen, methyl, ethyl and phenyl; preferred examples of R6, r7, R8, and R81 include hydrogen, methyl and ethyl; preferred examples of R10 include methyl and ethyl.
The compounds of the formula (I) may form conventional acid salts when R1 is hydrogen. Such salts include those with alkali and alkaline earth metals, suitably sodium and potassium, and ammonium and substituted ammonium salts.
A particularly suitable class of compounds within formula (I) are those wherein D is a group -CH2-CH(R6)-CH(R7)-C(R2)(R3)-, a group -CH2-CH(R6)-CH(R7)-CH(R8)-C(R2)(R3)-, or a group -CH2-C(R10)(R3)-, where R2, R3, R6, R7, R8 and R10 are as defined above.
It will of course be realised that the compounds of the formula (I) can have asymmetric centres, and thus are capable of existing in a number of stereoisomeric forms. The invention extends to each of these stereoisomeric forms, and to mixtures thereof. The different stereoisomeric forms may be separated one from the other by the usual methods.
From the aforesaid it may be seen that one particularly suitable sub-group of compounds within the formula (I) are those of the formula (II):
wherein: m is O or 1; p is 5, 6 or 7; X' is CO, protected CO, CHOH or C(C113)OH; R'1 is hydrogen or C14 alkyl; R2, R8 and R, are as defined in formula (I); R'4 is C38 alkyl, or a group of formula (III), (IV) or (V) as defined below:
wherein: q is O to 5; r is O to 3; and W, Y, Z are each independently hydrogen, fluorine, chlorine, bromine, CF3, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups; and salts thereof, when R1' is hydrogen.
In formula (II) it is generally preferred that m is 0. p is most suitably 6.
X' is preferably CO or protected CO, most preferably CO.
R2 is most suitably methyl, ethyl or phenyl, preferably methyl or ethyl.
R6 and. R, are suitably hydrogen, methyl or ethyl.
When R'4 is a C3B alkyl group, suitable and preferred groups R'4 include those previously described as suitable and preferred alkyl groups for R4. Examples of such groups include n-propyl, n-pentyl and n.hexyl, and of these normally the most useful is n-pentyl.
A particularly preferred sub-group of compounds within the formula (I) are those of the formula (VI):
wherein the variables are as defined in formula (II), except for R8 which is as defined in formula (I).
RB is suitably hydrogen, methyl or ethyl.
Suitable and preferred values for the other variables are as described for formula (II) compounds.
A further group of compounds within those of formula (I) are those of formula (VII):
wherein the variables are as defined in formula (II), except for A' which is hydrogen, a group CO2R'1, or methyl.
Preferably A' is hydrogen or methyl.
Suitable and preferred values for the other variables are as described for formula (II) compounds.
Another group of compounds within those of formula (I) are those of formula (VIII):
wherein the variables are as defined in formula (VI) and formula (VII).
Suitable and preferred values for these variables are as previously described for formula (VI) and formula (VII) compounds.
The aforesaid sub-groups (II), (VI), (VII) and (VIII) refer to compounds of the formula (I) wherein the side chain attached to nitrogen has a 4 or 5- hydroxy group (numbering from nitrogen). Important sub-groups within formula (I) also exist when this side chain has a 2- hydroxy group, and these sub-groups include the following: Compounds of the formula (IX):
wherein: m, p, X' and R are as defined in formula (II); R10 is hydrogen, C14 alkyl or phenyl; and R24 iS C59 alkyl, or a group of formula (III), (IV) or (V) as hereinbefore defined; and salts thereof, when R is hydrogen.
In formula (IX), it is generally preferred that m is 0. p is most suitably 6, X' is preferably CO or protected CO, most preferably CO.
R,o is suitably hydrogen, methyl or ethyl, preferably methyl.
When R24 is a C59 alkyl group, it is suitably a straight chain alkyl group such as n-pentyl, n-hexyl, n-heptyl and n-octyl, optionally branched by one or two methyl groups. Examples of such alkyl groups include -CH2R12, CH(CH3)R12 and C(CH3)2R12 wherein R12 is a straight chain alkyl group such that the carbon content of the resultant group R24 is 5 to 9.
Compounds of the formula (X):
wherein: the variables are as defined in formula (IX) except for A' which is hydrogen, a group CO2R'1, or methyl; and salts thereof, when R,' is hydrogen.
Preferably A' is hydrogen or methyl.
Suitable and preferred values for the other variables are as described for formula (IX) compounds.
Important sub-groups within formula (I) also exist when the D-R4 side chain has a 6-hydroxy group (numbering from nitrogen), and these sub-groups include compounds of formula (A):
wherein: m, p, X', R,' are as defined for formula (II).
R11 is hydrogen or C1-4 alkyl; R2, r6, r7, r8 and R81 are as defined in formula (I); and R4' is a C16 alkyl group, or a group of formula (III), (IV) or (V) as hereinbefore defined; and salts thereof when R1' is hydrogen.
In formula (A) it is generally preferred that m is 0. p is most suitably 6.
X' is preferably CO or protected CO, most preferably CO.
R2 is most suitably methyl, ethyl or phenyl, preferably methyl or ethyl.
R6, R7, R8 and R81 are suitably hydrogen, methyl or ethyl, preferably hydrogen.
When R4" is a C1-6 alkyl group, it is suitably n-propyl or n-butyl.
Often in formulae (III) and (IV) at least Y and Z will be hydrogen.
Preferably in formula (V) r is 1.
Other interesting sub-groups when the -D-R4 side chain has a 6-hydroxy group include those compounds of formula (B):
wherein the variable groups are as defined with respect to formula (A), except for A1 which is hydrogen, a group CO2R11, or methyl; and salts.thereof.
Preferably A1 is hydrogen or mthyl.
Suitable and preferred values for the other variables are as described for formula (A) compounds.
The invention also provides a number of processes for preparing the compounds of formula (I): 1. Compounds of formula (I) wherein m is 0, R5 is methyl and A is hydrogen or CO2B The process comprises the methylation of a compound of formula (XI):
wherein n, R1, D and R4 are as defined in formula (I), and A is hydrogen or CO2B to yield a compound of the formula (I) wherein X is CO; and thereafter if desired converting X in the thus formed compound to protected CO by conventional methods, or to CROH by reduction when R is hydrogen or by reaction with a C14 alkyl Grignard reagent or C14 alkyl metallic complex when R is C14 alkyl, and then optionally protecting the CROH hydroxy moiety.
The methylation is conveniently carried out by reacting the chosen compound of the formula (Xi) with a strong base and a source of CH3# ions in an inert solvent.
Suitable strong bases include sodium hydride, suitable sources of CH3# ions include the methyl halides such as methyl iodide, and suitable inert solvents include benzene.
2. Compounds of the formula (I) wherein m is 0, R5 is methyl and A is methyl The process comprises methylating a compound of the formula (I) wherein m is 0, R5 is methyl, A is hydrogen and X is CO; and thereafter if desired carrying out the optional X conversions described in process 1.
The methylation is suitably carried out as for a compound of formula (Xl) in 1., but in a more polar solvent such as dimethylformamide.
3. Compounds of the formula (I) wherein m is 0, R5 is methyl, and A is hydrogen or methyl These compounds may also be prepared by a process which comprises methylating a compound of formula (I) wherein X is CO, m is 0, R5 is hydrogen and A is hydrogen with excess methylating agent under the appropriate conditions, and optionally carrying out the aforesaid X conversions.
Compounds wherein Rs is methyl and A is hydrogen will be formed first further excess of methylating agent will give the corresponding A = methyl compound.
4. Compounds of the formula (I) wherein m is 0, R5 is methyl and A is CO2B The process comprises cyclising a compound of formula (XII):
wherein CO2R13 is an ester group, to give a compound of the formula (I) wherein X is CO, and thereafter if desired carrying out the aforesaid X conversion reactions.
Most suitably R13 is a C14 alkyl group q a benzyl group, and the groups R13, B and R, are the same C14 alkyl group such as the methyl or ethyl groups. Generally, the cyclisation reaction takes place in a dry organic solvent using a strong base such as sodium hydride or sodium ethoxide (or other -OR13 or -OB group) to bring about the initial proton abstraction from the methine group. It has been found that sodium ethoxide in benzene or potassium t-butoxide in toluene, benzene or hexamethylphosphoramide, give good results.
5. Compounds of the formula (I) wherein R5 and A are hydrogen The process comprises decarboxylating a compound of formula (XIII):
and thereafter if desired converting X from CO to other values in the aforesaid manner.
The decarboxylation reaction may be brought about under basic, acid or neutral conditions in conventional manner. For example when m = 0 the reaction is conveniently effected by heating the chosen compound of the formula (XIII) in a suitable solvent such as toluene or xylene.
It is frequently convenient however to generate the desired compound of the formula (I) directly from an ester of the formula (XIV), and often this will in fact be the preferred route:
It has been found that often it is sufficient to bring about de-esterification and subsequent decarboxylation in the chosen compound of the formula (XIV) simply to leave the compound standing in an inert solvent, for example overnight.
Otherwise the desired de-esterification and decarboxylation in the chosen compound of the formula (XIV) can be brought about by treatment with, for example, lithium iodide dihydrate in anhydrous solvent. In cases where m = 0, the compound of the formula (XIV) can also for example be de-esterified and decarboxylated by heating the compound alone or preferably in a high boiling solvent such as toluene or xylene.
After these Processes 1 to 5, R1 may be varied by conventional deesterification and/or esterification reactions. Similarly protected CROH and R3 hydroxy moieties may be deprotected by conventional methods. For example, when R3 is a benzyloxy group, the benzyl group may readily be removed by hydrogenolysis. Thus it may be seen that 'protected hydroxy' compounds of the formula (I) are useful intermediates in the preparation of the corresponding 'free hydroxy' compounds of the formula (I).
The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is protected CO may be carried out under conventional reaction conditions for, for example, carbonyl addition and. condensation reactions.
The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is CHOH may be carried out by conventional methods for reducing a ketone to an alcohol, for example by sodium borohydride reduction.
The conversion of a compound of the formula (I) wherein X is CO to the corresponding compound wherein X is CROH in which R is C14 alkyl may be carried out by conventional Grignard or alkyl metal, (suitably alkyl lithium) reactions.
When R, is hydrogen, salts of compounds of the formula (I) may be prepared in conventional manner, for example, by reacting the chosen compound of the formula (I) with the required base.
Intermediates for Process 1 to 5.
Process I Compounds of formula (XI) wherein A is CO2B may be prepared by the cyclisation of a compound of formula (XV):
Often in this cyclisation reaction a mixture of products will be obtained, and the required compound of the formula (XI) wherein A is CO2B will be separated therefrom by conventional methods.
The reaction is carried out as for the cyclisation described in Process 4.
The compounds of the formula (XV) may be prepared by an exactly analogous method to that used for the preparation of compounds of formula (XII) as described below.
When A is hydrogen in the compound of the formula (XI) then this compound of the formula (XI) may be prepared by the monomethylation of a compound of formula (XVI):
This monomethylation will be carried out by conventional methods such as those described in Process I for the monomethylation of a compound of the formula (XI). After the monomethylation it will often be necessary to separate the desired monomethyl compound of the formula (XI) from byproducts formed in the reaction, and this may be done in conventional manner.
Process 4 The compounds of the formula (XII) may be prepared by the reaction of a compound of formula (XVII):
with a reactive acylating derivative of an acid of formula HO2CCH3)2-CO211 or an ester thereof.
Suitable reactive acylating derivatives of this acid include R13O2C-C(C113)2-CO-Z wherein Z is a readily displaceable group such as Cl, Br, OSO2CH3 or OSO2C8H4CH3 or such derivatives wherein Z is OH in the presence of dicyclohexylcarbodiimide as a condensing agent.
The compounds (XVII) may be prepared by the reaction of an amine (XVIII): H2NDR4 (XVIII) with a compound of formula (XIX):
wherein Q is a group readily displaceable by an electron rich group.
The displacement reaction occurs under conventional reaction conditions, for example, in an alcoholic solvent in the presence of Na2CO3 or pyridine.
The preparation of the required amine of formula (XVIII) will be a routine matter to the skilled chemist. Two suitable preparations are illustrated in the Examples.
Process 5 Compounds of the formula (XIV) may be prepared by the cyclisation of a compound of formula (XX):
in the usual manner.
These compounds (XX) may be prepared in an exactly analogous manner to the preparation described above for compounds of the formula (XII).
The intermediates of formulae (XI) to (XIV) are believed to be novel and as such form important aspects of the present invention.
Compounds within the formula (I) have useful pharmacological activity. For example compounds within the formula (I) have anti-gastric secretion activity, antiulcer activity, cardiovascular activity e.g. antihypertensive activity, platelet aggregation inhibition activity, affect the respirator tract e.g. bronchodilator activity, and have anti-fertility and smooth muscle activity.
In general it may be said that compounds within the formula (I) have a range of pharmacological activities similar to those shown by the natural prostaglandins, but that these activities tend to be rather more selective. They have also proved to be beneficially stable compounds, particularly compounds wherein RB is methyl.
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.
Clearly the formulation of the said pharmaceutical composition will depend on the nature of the activity shown by the chosen compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular mode of administration.
The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and if desired conventional flavouring or colouring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
When appropriate, the compositions of this invention may be presented as an aerosol for oral administration, or as a microfine powder for insufflation.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
It will of course be realised that the precise dosage used in the treatent of any of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.
The invention also provides a method of treatment and/or prophylaxis of disorders in non-human animals which comprises the administration to the sufferer of an effective amount of a compound of the formula (I).
The following Examples 12 to 17 illustrate the preparation of compounds of the formula (I) and their pharmacological properties.
Examples I to 11 illustrate the preparation of intermediates for the compounds of the formula (I).
Example 1.
N, N-D ibenzyl-4-oxovaleramide A solution of levulinic acid (58 g) in dry methylene chloride (300 ml) was added to a solution of dibenzylamine (98.5 g) in dry methylene chloride (300 ml). The mixture was stirred at 0 and a solution of dicyclohexylcarbodiimide (106 g) in dry methylene chloride (300 ml) was added dropwise. Stirring was continued for 3 hours.
The mixture was filtered and the filtrate evaporated in vacuo. The residue was taken up in ether and filtered. The filtrate was washed with dilute hydrochloric acid, sodium bicarbonate solution and then with sodium chloride solution until the washings were neutral. The ether layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give N.N-dibenzyl-4-oxovaleramide as a yellow oil (120 g).
I.R. spectrum -amide carbonyl absorption at 1640 cm-'.
- carbonyl absorption at 1705 cm-'.
N.M.R. spectrum - 10 proton singlet at 2.85 # [(C6#5CH2)2N-] - 4 proton singlet at 5.55 T [(PhC#2)2N-1 -4 proton broad multiplet at 7.4
- 3 proton singlet at 7.9
The compounds shown in Table I were similarly prepared TABLE i
Compound n Carbonyl absorptions cm-1 1 3 1705, 1640 2 4 1705, 1640 Example 2.
N, N,-D ibenzyl-4-( 1 ,3-dioxolano)-valeramide Ethanediol (50 g) and toluene p-sulphonic acid (1 g) were added to a solution of N,N-dibenzyl-4-oxovaleramide (120 g) in dry benzene (600 ml) and the mixture was refluxed under a Dean and Stark head for 3 hours.
The reaction mixture was allowed to cool and was then washed with sodium carbonate solution and with water until the washings were neutral, dried over anhydrous sodium sulphate and evaporated in vacuo to give N,N-dibenzyl-4-(1,3dioxolano)-valeramide as a yellow oil (115 g).
I.R. spectrum - amide carbonyl absorption at 1640 cm-1.
- absence of ketone carbonyl absorption.
N.M.R. spectrum - 10 proton singlet at 2.85 # [(C6#5CH2)2N-] - 4 proton singlet at 5.55 # [(PHC#202N-] - 4 proton singlet at 6.2 t
- 4 proton broad multiplet at 7.8
- 3 proton singlet at 8.8 T
The compounds shown in Table 2 were similarly prepared TABLE 2
Compound n Carbonyl absorption (cm-1) 3 3 1705 4 4 1705 Example 3.
N,N-Dibenzyl-5-aminopentan-2-one ethylene acetal N,N-Dibenzyl-4-(1,3-dioxolane)-valeramide (115 g) in dry tetrahydrofuran (300 ml) was added dropwise to a suspension of lithium aluminium hydride ( 17 g) in dry tetrahydrofuran (500 ml). The mixture was gently refluxed for 2 hours.
The mixture was cooled in an ice-bath and water (300 ml) was added dropwise.
The reaction mixture was stirred at room temperature for 30 minutes and filtered.
The residue was washed several times with ether and the combined organic fractions were washed with water and dried over anhydrous sodium sulphate and evaporated in vacuo to give N,N-dibenzyl-5-aminopentan-2-one ethylene acetal as a yellow oil (90 g).
I.R. spectrum - absence of amide carbonyl absorption.
N.M.R. spectrum - 10 proton singlet at 2.8 # [(C6#5CH2)2N-] - 4 proton singlet at 6.25 T
- 4 proton singlet at 6.5 # [(PhC#2)2N-] - 2 proton broad multiplet at 7.65 # (N-C#2-) - 4 proton broad multiplet at 8.5 T
- 3 proton singlet at 8.85 T
The compounds shown in Table 3 were similarly prepared TABLE 3
Compound n Example 4.
N,N,-Dibenzyl-3-aminopropyl methyl ketone A solution of N,N-dibenzyl-5-amino-pentan-2-one ethylene acetal (90 g) in ethanol (500 ml) containing dilute hydrochloric acid (200 ml) was refluxed for I hour. The solution was allowed to cool and the ethanol was evaporated in vacuo.
The residue was dissolved in water and extracted with ether. The aqueous layer was made alkaline with dilute sodium hydroxide solution and was extracted twice with ether. The combined ethereal extracts were washed with water, dried over anhydrous sodium sulphate and evaporated in vacuo, to give a brown oil. The product was purified by chromatography to give N,N-dibenzyl-3-aminopropyl methyl ketone as a red-brown oil (60 g).
I.R. spectrum -carbonyl absorption at 1700 cm-t N.M.R. spectrum - 10 proton singlet at 2.7 T l(C8H5CH2)2N-] - 4 proton singlet at 6.5 t [(PhC#2)2N-] - 4 proton broad multiplet at 7.6
- 3 proton singlet at 8.0
-2 proton broad multiplet at 8.3
TABLE 4
Compound n Carbonyl absorption (cm-1) 7 4 1700 8 5 1700 Example 5.
4-Methyl-1-(N,N-dibenzylamino)-nonan-4-ol Pentyl magnesium bromide was prepared under nitrogen from magnesium (8 g) and pentyl bromide (50.3 g) in dry tetrahydrofuran (150 ml).
A solution of N,N,-dibenzyl-3-aminopropyl methyl ketone (45 g) in dry tetrahydrofuran (200 ml) was added dropwise to the Grignard reagent. The mixture was stirred and refluxed overnight.
A saturated solution of ammonium chloride was added and the product extracted three times with ether. The organic fractions were combined, washed with sodium chloride solution, dried over anhydrous sodium sulphate and evaporated in vacuo to give 4-methyl-I-(N,N-dibenzylamino)nonan-4-ol as a brown oil (60 g).
I.R. spectrum -broad OH absorption at 3300 cm-l.
-absence of carbonyl absorption.
The compounds shown in Table 5 were similarly prepared.
TABLE 5
OH absorption Compound Grignard Reagent n R4 cm-1 9 C4H9MgBr 4 C4H9 3300 10 PhCH2CH2MgBr 3 CH2CH2Ph 3300 11 C7H7MgBr 5 C3H7 3300 Example 6.
I -Amino-4-methylnonan-4-ol A solution of 4-methyl-1-(N,N-dibenzylamino)-nonan-4-ol (50 g) in ethanol (200 ml) was added to a slurry of 10% Pd/C (6 g) in ethanol. One drop of concentrated hydrochloric acid was then added to the mixture.
The mixture was hydrogenated at 70 and 200 p.s.i. for 3 days. The mixture was filtered through kieselguhr and evaporated. The oily product was fractionally distilled to give l-amino-4-methylnonan-4-ol as a colourless liquid (7 g), b.p.
110-115 /0.5 mm Hg.
I.R. spectrum -broad absorption at 3300 cm-1 due to OH,NH2 N.M.R. spectrum - 3 proton singlet at 7.8 T which disappears on shaking with D2O.
The compounds shown in Table 6 were similarly prepared.
TABLE 6
NH2,OH absorption Compound n R4 cm-l 12 4 C4H9 3300 13 3 CH2CH2 Ph 3300 14 5 C3H7 3300 Example 7.
2-Methyl-2-trimethylsilyloxynonanitrile Trimethylsilyl cyanide (17.4 g) was slowly added to a stirred solution of 2nonanone (24.9 g) and zinc iodide (1.12 g). The reaction mixture was cooled by periodic use of an ice - salt bath during the addition. The mixture was then stirred for 1 hour at room temperature.
I.R spectrum - 1250, 850, 760cm-1 (-Si-CH3) N.M.R. spectrum -9 proton singlet at 9.75 T (-OSi(CH3)3) Example 8.
2-Hydroxy-2 -methylnonylamine 2-Methyl-2-trimethylsilyloxynonanitrile (42.3 g) in dry ether (100 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (13.4 g) in dry ether (350 ml). Reflux occurred and this was maintained by external heating for 1 hour after the final addition. The mixture was cooled to 0 and water (13.5 ml), 15% sodium hydroxide solution (13.5 ml) and water (40 ml) were added dropwise in sequence. The resulting mixture was stirred for half-an-hour at room temperature, then was filtered through Kieselguhr. The resulting solution was dried over sodium sulphate and evaporated in vacuo to give 2-hydroxy-2-methylnonylamine, b.p.
97--99"/0.25 mm Hg.
Example 9.
Dimethyl 2-[N-(4 '-hydroxy4 '-methyl-n-nonyl).amino]azelate A solution of diethyl 2-bromoazelate (13.1 g) in dry ethanol (50 ml) was added dropwise to a refluxing solution of l-amino-4-methylnonan-4-ol (6.9 g) in dry ethanol (75 ml) containing a suspension of anhydrous sodium carbonate (6 g). The mixture was refluxed with stirring for 12 hours.
The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was taken up in ether (150 ml) and the ethereal solution was washed with sodium chloride solution until the washings were neutral, dried over anhydrous sodium sulphate and evaporated in vacuo to give diethyl 2-[N-(4'-hydroxy4'-methyl- n-nonyl)-amino]azelate as a yellow oil (15.8 g).
I.R. spectrum -ester carbonyl absorption at 1720 cm-l.
The compounds shown in Table 7 were similarly prepared.
TABLE 7
Compound n R1 R4 15 4 Me n-C4Hg 16 3 Me CH2CH2Ph 17 3 Me n-C5H11.
18 1 Me n-C7H1, 19 5 Me n-C3H, Example 10.
Diethyl 2 - [N - 04 ' - hydroxy - 4 ' - methyl - n - nonyl) - N - ethoxycarbonyl - acetylaminolazelate A solution of monoethylmalonate (0.6 g) in dry methylene chloride (15 ml) was added to a solution of diethyl 2 - [N - (4' - hydroxy - 4' - methyl - n - nonyl) amino]azelate (2.075 g) in dry methylene chloride (15 ml). The mixture was stirred at room temperature and a solution of dicyclohexylcarbodiimide (1.03 g) in dry methylene chloride (15 ml) was added dropwise. Stirring was continued for 3 hours.
The mixture was filtered and the filtrate evaporated in vacuo. The residue was taken up in ether and filtered. The ethereal solution was washed with dilute hydrochloric acid, sodium bicarbonate solution and then with sodium chloride solution until the washings were neutral. The ether layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give diethyl - 2 - [N - (4' - hydroxy - 4' methyl - n - nonyl) - N - (ethoxycarbonyl - acetyl)amino]azelate as a yellow oil, (2.3 g).
I.R. spectrum -ester carbonyl absorption at 1730 cm-l.
-amide carbonyl absorption at 1650 cm-l.
The compounds shown in Table 8 were similarly prepared. TABLE 8
I.R. SPECTRUM Amide OH carbonyl Compound n R1 R4 (cm-1) (cm-1) 20 4 Me n-C4H9 3400 1640 21 3 Me CH2CH2Ph 3400 1640 22 3 Me n-C8H11. 3400 1650 23 1 Me n-C7H15 3400 1650 24 5 Me n-C3H7 3400 1640 Example 11.
4 - Ethoxycarbonyl - 2 - (6' - ethoxycarbonyl - n - hexyl) - 1 - (4" - hydroxy - 4" methyl - n - nonyl) - pyrrolidin - 3,5 - dione Potassium tert-butoxide (0.54 g) was added in small portions over 30 minutes to a warm solution of diethyl 2 - [N - (4' - hydroxy - 4'methyl - n - nonyl) - N (ethoxycarbonyl - acetyl)aminolazelate (2.3 g) in dry toluene (100 ml). The mixture was gently refluxed for It hours.
The solvent was evaporated in vacuo and the residue was taken up in water.
The solution was extracted twice with ether and the aqueous layer was acidified with dilute hydrochloric acid and extracted with ether. This ethereal solution was washed with sodium chloride solution and dried over anhydrous sodium sulphate to give a solution of 4 - ethoxycarbonyl - 2 - (6' - ethoxycarbonyl - n - hexyl) - I (4" - hydroxy - 4" - methyl - n - nonyl) -pyrrolidin - 3,5 - dione.
The compounds shown in Table 9 were similarly prepared. TABLE 9
Compound n R1 R4 25 4 Me n-C4H9 26 3 Me CH2CH2Ph 27 3 Me n-C5H11 28 1 Me n-C7H15 29 5 Me n-C3H7 Example 12.
2 - (6' - Ethoxycarbonyl - n - hexyl) - 1 - (4" - hydroxy - 4" - methyl - n - nonyl) pyrollidin - 3,5 - dione.
A solution of 4 - ethoxycarbonyl - 2 - (6' - ethoxycarbonyl - n - hexyl) - 1 (4" - hydroxy - 4" - methyl - n - nonyl) - pyrrolidin - 3,5 - dione in ether was allowed to stand over anhydrous sodium sulphate overnight. The solution was filtered and the filtrate evaporated to give an orange oil. The product was purified by chromatography to give 2 - (6' - ethoxycarbonyl - n - hexyl) - I - (4 " - hydroxy 4" - methyl - n - nonyl) - pyrrolidin - 3,5 - dione as a pale yellow oil.
I.R. spectrum - broad OH absorption at 3500 cm-1.
- amide carbonyl absorption at 1685 cm-1.
-ester carbonyl absorption at 1730 cm-'.
- carbonyl absorption at 1770 cm-1.
The compounds shown in Table 10 were similarly prepared.
TABLE 10
I.R. SPECTRUM OH absorption Carbonyl absorptions Compound n R1 R4 (cm-1) (cm-1) 30 4 Me n-C4H9 3400 1760, 1730, 1690 31 3 Me CH2CH2Ph 3400 1760, 1730, 1685 32 3 Me n-C5H11 3400 1770, 1730, 1685 33 1 Me n-C7H159 3400 1760, 1730, 1680 34 5 Me n-C3H7 3400 1760, 1730, 1685 Example 13.
2 - (6' - Methoxycarbonyl - n - hexyl) - 3 - hydroxy - 1 - (4" - hydroxy - 4" methyl - n - nonyl) - pyrolidin - 5 - one sodium borohydride (290 mg) was added in protions to a stirred solution of 2 (6' - methoxycarbonyl - n - hexyl) - 1 - (4" - hydroxy - 4" - methyl - n nonyl) - pyrrolidin - 3,5 - dione (2.5 g) in dry metanol (30 ml). Stirring was continued for 2 hours at room temperature.
The solvent was evaporated in vacuo and the residue was dissolved in ether.
The ethereal solution was washed with very dilute hydrochloric acid and with water, dried over sodium sulphate and evaporated in vacuo to give a yellow gum.
The product was purified by chromatography to give 2 - (6' - methoxy - carbonyl - n - hexyl) - 3 - hydroxy - 1 - (4" - hydroxy - 4" - methyl - n - nonyl) pyrrolidin - 5 - one as a pale yellow gum (900 mg).
I.R. spectrum - broad OH absorption 3400 cm-1.
- carbonyl absorptions 1730, 1660 cm-1.
The compounds shown in Table 11 were similarly prepared.
TABLE 11
I.R. SPeCTRUM OH absorption carbonyl absorptions Compound n R1 R4 (cm-1) (cm-1) 35 4 Me n-C4H9 3400 1730, 1670 36 3 Me CH2CH2Ph 3400 1720, 1660 37 1 Me n-C7H15 3400 1730, 1670 MASS SPECTRUM Compound Molecular ion Base peak 35 - 342 M+ - C4H9 36 433 328 M + - CH2CH2Ph Example 14.
2 - (6' - Carboxy - n - hexyl) - 3 - hydroxy - I - (2" - hydroxy - 2" - methyl - n nanyl) - pyrrolidin - 5 - one A 10% solution of potassium carbonate (6 ml) was added to a solution of 2 (6' - methoxycarbonyl - n - hexyl) - 3 - hydroxy - 1 - (2" - hydroxy - 2" - methyl - n - nonyl) - pyrrolidin - 5 - one (600 mg) in ethanol (20 ml). The mixture was gently refluxed for 24 hours.
The solvent was evaporated in vacuo and the residue was taken up in water.
The aqueous solution was extracted with ether and acidified with dilute hydrochloric acid. The acid solution was extracted with ether and this ethereal solution was washed with water, dried over magnesium sulphate and evaporated in vacuo to give 2 - (6' - carboxy - n - hexyl) - 3 - hydroxy - 1 - (2" - hydroxy 2" - methyl - n - nonyl) - pyrrolidin - 5 - one as a yellow gum (400 mg).
I.R. spectrum - broad OH absorption around 3450 cm~'.
- carbonyl absorptions at 1710, 1670 cm-1.
Mass Spectrum - Base peak 367 M±112O Example 15.
4,4 - Dimethyl - 2 - (6' - ethoxycarbonyl - n - hexyl) - 1 - (4" - hydroxy - 4" - methyl - n - nonyl) - pyrrolidin - 3,5 - dione Sodium hydride (0.87 g, 80% dispersion in mineral oil) was washed with hexane, blown dry under nitrogen and suspended in dry benzene (25 ml). A solution of 2 - (6' - ethoxycarbonyl - n - hexyl) - 1 - (4" - hydroxy - 4" - methyl - n nonyl) - pyrrolidin - 3,5 - dione (3 g) in dry benzene (30 ml) was added and the mixture was stirred at room temperature under nitrogen for 1 hour.
The mixture was heated to 700 and a solution of methyl iodide (10 g) in dry benzene (10 ml) was added dropwise. The mixture was heated at 700 for 2 hours.
The reaction mixture was cooled and glacial acetic acid (1 ml) was added. The mixture was filtered and the filtrate evaporated in vacuo to give a yellow oil. The product was purified by column chromatography to give 4,4 - dimethyl - 2 - (6' ethoxycarbonyl - n - hexnyl) - 1 - (4" - hydroxy - 4" - methyl - n - nonyl) pyrrolidin -3,5 - dione as a yellow oil 1.0 g).
I.R. spectrum -carbonyl absorptions at 1760, 1730 and 1690 cm~'.
-broad OH absorption at 3450 cm-1.
The compounds shown in Table 12 were similarly prepared.
TABLE 12
I.R. SPECTRUM OH absorption Carbonyl absorptions Compound n R1 R4 cm-1 cm-1 38 4 Me n-C4H9 3450 1760, 1730, 1690 39 3 Me CH2CH2Ph 3450 1760, 1730, 1685 40 3 Me n-C5H11 3450 1760, 1730, 1680 41 1 Me n-C7H159 3450 1760, 1730, 1685 Example 16.
1 - (4' - Hydroxy - 4' - methyl - n - nonyl) - 2 - (6" - methoxycarbonyl - n - hexyl) 2,4,4 - trimethyl - pyrrolidin - 3,5 - dione A solution of 1 - (4' - hydroxy - 4' - methyl - n - nonyl) - 2 - (6" - methoxycarbonyl - n - hexyl) - pyrrolidin - 3,5 - dione (4 g) in dry dimethylformamide (25 ml) was slowly added to a suspension of sodium hydride (1,3 g, 80% dispersion in mineral oil) in dry benzene (20 ml) and dry dimethylformamide (20 ml). The mixture was stirred for 2 hours under nitrogen at room temperature.
A solution of methyl iodide (15 g) in dry dimethylformamide (10 ml) was added dropwise and stirri ng was continued for 3 hours.
Glacial acetic acid (1 ml) was added and the solvent was removed in vacuo. The residue was taken up in ehter and the ethereal solution was washed with water, dried over magnesium sulphate and evaporated to give a yellow oil. the product was purified by column chromatography to give I - (4' - hydroxy - 4 ' - methyl - n nonyl) - 2 - (6" - methoxvcarbonyl - n - hexyl) - 2,4,4 - trimethyl -pyrrolidin - 3,5 dione as a yellow oil (1.4 g).
I.R. spectrum carbonyl absorptions at 1750, 1730, 1670 cm-1 broad OH absorption at 3450 cm~'.
Example 17.
2 - 66' -carboxy -n - hexyl) - 4,4 - dimethyl -1 -(5" -hydroxy - 5" - methyl - n nonyl) - pyrrolidin - 3,5 - dione A 10% solution of potassium carbonate (10 ml) was added to a solution of 4,4 dimethyl - 2 - (6' - methoxycarbonyl - n - hexyl) - I - (3" - hydroxy - 3" methyl - n - nonyl) - pyrrolidin - 3,5 - dione (600 mg) in ethanol (40 ml). The mixture was gently refluxed for 24 hours.
The solvent was evaporated in vacuo and the residue was taken up in water..
The aqueous solution was extracted with ether and acidified with dilute hydrochloric acid. The acid solution was extracted with ether and this ethereal solution was washed with water, dried over magnesium sulphate and evaporated in vacuo to give 2 - (6' - carboxy - n - hexyl) - 4,4 - dimethyl - 1 - (5" - hydroxy - 5" methyl - n - nonyl) - pyrrolidin - 3,5 - dione as a yellow gum (400 mg).
I.R. spectrum - carbonyl absorptions at 1760, 1710, 1670 cm-1 - broad OH absorption around 3400 cm~'.
Mass spectrum - Base Pcak 354 M±C4H9 Pharmacological Data Section The compounds were examined for their ability to inhibit 5-hydroxytryptamine induced bronchoconstriction in the anaesthetised, artificially respired guinea pig (Konzett-Rossler preparation - ref: H. Konzett and R. Rossler, 1940, Arch. exp. Path. Pharmak., 195, 71). 2 - (6' - Methoxycarbonyl - n - hexyl) - 1 (5" - hydroxy - 5" - methyl - n - nonyl) - pyrrolidin - 3,5 - dione (Compound 30 of Table 10) inhibited bronchoconstriction with an IC50 of 12 g/kg, intravenously.
The compounds were examined for their ability to inhibit pentagastrinstimulated gastric acid secretion in the anaesthetised, perfused rat stomach preparation (Gosh and Schild preparation - ref: M. N. Ghosh and H. O. Schild, 1958, Brit. J. Pharmacol, 13, 54) 2 - (6' - Ethoxycarbonyl - n - hexyl) - 1 - (4" hydroxy - 4" - methyl - n - nonyl) - pyrrolidin - 3,5 - dione (Compound of Example 12) and 4,4 - dimethyl - 2 - (6' - methoxycarbonyl - n - hexyl) - 1 (4" - hydroxy - 4" - methyl - n - nonyl) - pyrrolidin - 3,5 - dione (Compound 40 of Table 12) were active in this test at 0.5 and 5 mg/kg, i.v., respectively.
The compounds were also examined for their ability to inhibit gastric acid secretion in the pyloric ligated rat model (Shay rat preparation - ref: Shay et al, 1945, Gastroenterology, 5, 43). 2 - (6' - Ethoxycarbonyl - n - hexyl) - 1 - (4" hydroxy - 4" - methyl - n- nonyl) - pyrrolidin - 3,5 - dione (Compound of Example 12); 4,4 - dimethyl - 2 - (6' - methoxycarbonyl - n - hexyl) - 1 - (4" - hydroxy - 4" - methyl - n - nonyl) - pyrrolidin - 3,5 - dione (Compound 40 of Table 12); and I - (4' - hydroxy - 4' - methyl - n - nonyl) - 2 - (6" - methoxycarbonyl - n - hexyl) - 2,4,4 - trimethyl - pyrrolidin - 3,5 - dione (Compound of Example 16) were active in this test at 100, 150 and 100 mg/kg, intraduodenally, respectively.
The compounds were also examined for their ability to inhibit indomethacin induced gastric ulceration in the rat and the Compound of Example 12 was active in this anti-ulcer test at 100 mg/kg, orally. This same compound was also active in inhibiting cold restraint induced ulceration at 150 mg/kg, orally.
Toxicity No toxic effects were observed at the doses given.

Claims (49)

  1. WHAT WE CLAIM IS:1. A compound of the formula (I):
    wherein: m is 0 or 1; n is 4 to 8; A is hydrogen, and when m is 0 and R5 is methyl it may also be methyl or a group CO2B wherein B is hydrogen or CO2B represents an ester group in which the B moiety contains from 1 to 12 carbon atoms; X is CO, protected CO, CROH in which R is hydrogen or C1-4 alkyl and in which the OH moiety may be protected; R1 is hydrogen, or CO2R, represents an ester group in which the R1 moiety contains 1 to 12 carbon atoms; R4 is hydrogen, C1-9 alkyl, C5-8 cycloalkyl, C5-8 cycloalkyl-C1-6 alkyl, phenyl, phenyl-C1-6 alkyl, naphthyl, naphthyl-C1-6 alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, C16 alkoxy, or nitro groups;, D is a group -CH2-CH(R6)-CH(R7)-C(R2)(R3)-, a group -CH2-CH(R6)-CH(R7)-CH(R8)-C(R2)(R3)-, a group -CH2-CH(R6)-CH(R7)-CH(R8)-CH(R81)-C(R2)(R3) or a group -CH2-CH(R10)(R3)- wherein R2 is hydrogen, C1-4 alkyl or phenyl; R3 is hydroxy or protected hydroxy; R8, R7, r8, r81 and R10 are hydrogen C1-4 alkyl or phenyl; and R5 is hydrogen, and when mis 0 it may also be methyl; and salts thereof when R1 is hydrogen.
  2. 2. A compound as claimed in claim 1, wherein D is a group -CH2-CH(R6)-CH(R7)-C(R2)(R3)-, a group -CH2-CH(R6)-CH(R7)-CH(R8)-C(R2)(R3)-, or a group -CH2-CH(R10)(R3)-, Wherein R2, R3, R6, R7, R8 and R10 are as defined in claim 1.
  3. 3. A compound as claimed in claim 2, wherein m is 0.
  4. 4. A compound as claimed in claim 2 or 3, wherein n is 5, 6 or 7.
  5. 5. A compound as claimed in claim 2, 3 or 4, wherein A is hydrogen or methyl.
  6. 6. A compound as claimed in any one of the claims 2 to 5, wherein X is CO, or C(CH3)OH.
  7. 7. A compound as claimed in any one of the claims 2 to 6, wherein R4 is a C39 alkyl group.
  8. 8. A compound as claimed in any one of the claims 2 to 7, wherein r4 is a phenyl or phenyl-C1-6 alkyl group, which phenyl moieties may optionally be substituted by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups.
  9. 9. A compound as claimed in any one of the claims 2 to 8, wherein D is a group -CH2-CH(R6)-CH(R7)-CH(R8)-C(R2)(R3)-, where R2, R3, R4, R7 and R8 are as defined in claim 1.
  10. 10. A compound as claimed in any one of the claims 2 to 9, wherein R2 is hydrogen, methyl, ethyl or phenyl.
  11. 11. A compound as claimed in any one of the claims 2 to 9, wherein R3 is hydroxy.
  12. 12. A compound as claimed in any one of the claims 2 to 11, wherein any group R6, R7, R8 or R8 present is hydrogen.
  13. 13. A compound as claimed in claim 1, of formula (II):
    wherein: m is 0 or 1; p is 5, 6 or 7; X' is CO, protected CO, CHOH or C(CH3)OH; R', is hydrogen or C1-4 alkyl; R2, R6 and R7 are as defined in formula (I); R14 is C38 alkyl, or a group of formula (III), (IV) or (V) as defined below:
    wherein: q is 0 to 5; r is 0 to 3; and W, Y, Z are each independently hydrogen, fluorine, chlorine, bromine, CF3, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups; and salts thereof, when R,' is hydrogen.
  14. 14. A compound as claimed in claim 13, wherein m is 0.
  15. 15. A compound as claimed in claim 13 or 14, wherein p is 6.
  16. 16. A compound as claimed in claim 13, 14 or 15, wherein R2 is methyl or ethyl.
  17. 17. A compound as claimed in claim 13, 14, 15 or 16, wherein R'4 is a C38 alkyl group.
  18. 18. A compound as claimed in any one of the claims 13 to 17, wherein R6 and R7 are hydrogen.
  19. 19. A compound as claimed in claim 1, of the formula (VI):
    wherein m, p, X', R', R2, R6, R7 and R4' are as defined in claim 13, and R9 is hydrogen, C14 alkyl or phenyl.
  20. 20. A compound as claimed in claim 19, wherein m is 0.
  21. 21. A compound as claimed in claim 19 or 20 wherein. p is 6.
  22. 22. A compound as claimed in claim 19, 20 or 21, wherein R2 is methyl or ethyl.
  23. 23. A compound as claimed in any of claims 19, to 22, wherein R14 is a C38 alkyl group.
  24. 24. A compound as claimed in any one of the claims 19 to 23, wherein R6, R7 and R8 are hydrogen.
  25. 25. A compound as claimed in claim 1, of the formula (VII):
    wherein p, X', R,', R2, R6, R7 and R4' are as defined in claim 13, and A' is hydrogen or methyl.
  26. 26. A compound as claimed in claim 25, wherein p is 6.
  27. 27. A compound as claimed in claim 25 or 26, wherein R2 is methyl or ethyl.
  28. 28. A compound as claimed in claim 25, 26 or 27, wherein R'4 is a C3~8 alkyl group.
  29. 29. A compound as claimed in any one of the claims 25 to 28, wherein R6 and R7 are hydrogen.
  30. 30. A compound as claimed in claim 1, of the formula (VIII):
    wherein p, X', R,1, R2, R4, R7, RB and R4' are as defined in claim 19, and A' is hydrogen or methyl.
  31. 31. A compound as claimed in claim 30, wherein p is 6.
  32. 32. A compound as claimed in claim 30 or 31, wherein R2 is methyl or ethyl.
  33. 33. A compound as claimed in claim 30, 31 or 32, wherein R'4 is a C39 alkyl group.
  34. 34. A compound as claimed in any one of the claims 30 to 33, wherein R8, R7 and R8 are hydrogen.
  35. 35. A process for the preparation of a compound as claimed in claim 1, which process comprises either: (a) The methylation of a compound formula (XI):
    wherein n, R1, D and R4 are as defined in claim 1, and A is hydrogen or CO2B to yield a compound of the formula (I) wherein m is 0, X is CO, RB is methyl and A is hydrogen or CO2B; or (b) Methylating a compound of the formula (I) as defined in claim 1 but wherein m is 0, R5 is methyl, A is hydrogen and X is CO to yield a compound of the formula (I) wherein m is 0, R5 is methyl, A is methyl and X is CO; or (c) Cyclising a compound of formula (XIII):
    wherein n, R1, R4, B and D are as defined in claim 1 and CO2R13 is an ester group, to give a compound of the formula (I) wherein m is 0, X is CO, R5 is methyl and A is CO2B; or (d) Decarboxylating a compound of formula (XIII):
    wherein m, n, R1, R4 and D are as defined in claim 1, to give a compound of formula (I) wherein X is CO, and R5 and A are hydrogen; and thereafter if desired converting X in the thus formed compound to protected CO or to CROH by reduction when R is hydrogen or by reaction with a C14 alkyl Grignard reagent or C14 alkyl metallic complex when R is C14 alkyl, and then optionally protecting the CROH hydroxy moiety.
  36. 36. A process as claimed in claim 35, for the preparation of a compound as claimed in claim 2.
  37. 37. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier.
  38. 38. A pharmaceutical composition comprising a compound as defined in any. one of the claims 2 to 34 and a pharmaceutically acceptable carrier.
  39. 39. A compound as claimed in claim 1 substantially as hereinbefore described with reference to any one of the Examples 12 to 17.
  40. 40. A process as claimed in claim 35, substantially as hereinbefore described with reference to any one of the Examples 12 to 17.
  41. 41. A compound as claimed in claim 1, whenever prepared by a process as claimed in any one of the claims 35, 35 or 40.
  42. 42. A method of treatment or prophylaxis of disorders in non-human animals which comprises the administration of an effective amount of a compound as claimed in claim 1.
  43. 43. A method of treatment or prophylaxis of disorders in non-human animals which comprises the adminstration of an effective amount of a compound as claimed in any one of the claims 2 to 34.
  44. 44. A compound of the formula (XI):
    wherein the variable groups are as defined in any one of the claims 1 to 12.
  45. 45. A compound of the formula (XII):
    wherein CO2R,3 is an ester group and the other variable groups are as defined in any one of the claims I to 12.
  46. 46. A compound according to claim 45, substantially as hereinbefore described with reference to Example 10.
  47. 47. A compound of the formula (XIII):
    wherein the variables are as defined in any one of the claims 1 to 12.
  48. 48. A compound of the formula (XIV):
    wherein R,3 is an ester group and the other variables are as defined in any one of the claims I to 12.
  49. 49. A compound according to claim 48, substantially as hereinbefore described with reference to Example 11.
GB21304/76A 1976-05-22 1976-05-22 12-azaprostanoic acid derivatives Expired GB1585181A (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
GB21304/76A GB1585181A (en) 1976-05-22 1976-05-22 12-azaprostanoic acid derivatives
NZ184084A NZ184084A (en) 1976-05-22 1977-05-12 2-carboxyalkyl-pyrrolid-in or piperidin-one or-dione derivatives and pharmaceutical compositions
US05/796,701 US4156730A (en) 1976-05-22 1977-05-13 Pharmaceutically active compounds, preparation thereof, intermediates useful in such preparation and compositions containing the compounds
BE177633A BE854704A (en) 1976-05-22 1977-05-16 NEW CYCLIC AMIDES
DE19772722118 DE2722118A1 (en) 1976-05-22 1977-05-16 CYCLIC AMIDES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS
SE7705857A SE417095B (en) 1976-05-22 1977-05-17 PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE CYCLIC AMIDES WITH SUBSTITUTE GROUPS AT THE N ATOM AND ALFA COLATOM
FR7715258A FR2351962A1 (en) 1976-05-22 1977-05-18 NEW CYCLIC AMIDES
CA278,738A CA1095522A (en) 1976-05-22 1977-05-18 Prostaglandin analogues and their preparation
AU25305/77A AU506783B2 (en) 1976-05-22 1977-05-19 Cyclic amides and pharmaceutical compositions containing them
IE1035/77A IE45436B1 (en) 1976-05-22 1977-05-20 12-azaprostanoic acid derivatives
ZA00773021A ZA773021B (en) 1976-05-22 1977-05-20 Pharmaceutical active compounds
DK220977A DK220977A (en) 1976-05-22 1977-05-20 PROCEDURE FOR MAKING CYCLIC AMIDES
NL7705573A NL7705573A (en) 1976-05-22 1977-05-20 PROCESS FOR PREPARING PHARMACOLOGICALLY ACTIVE SUBSTITUTED CYCLIC AMIDES CONTAINING PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS.
JP5972577A JPS52142062A (en) 1976-05-22 1977-05-23 Novel compound having pharmacological activity* its preparation* intermediate compound for its preparation and medical composition containing novel compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB21304/76A GB1585181A (en) 1976-05-22 1976-05-22 12-azaprostanoic acid derivatives

Publications (1)

Publication Number Publication Date
GB1585181A true GB1585181A (en) 1981-02-25

Family

ID=10160622

Family Applications (1)

Application Number Title Priority Date Filing Date
GB21304/76A Expired GB1585181A (en) 1976-05-22 1976-05-22 12-azaprostanoic acid derivatives

Country Status (3)

Country Link
BE (1) BE854704A (en)
GB (1) GB1585181A (en)
ZA (1) ZA773021B (en)

Also Published As

Publication number Publication date
BE854704A (en) 1977-11-16
ZA773021B (en) 1978-04-26

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