GB1572184A - 12-azaprostaglandins - Google Patents

12-azaprostaglandins Download PDF

Info

Publication number
GB1572184A
GB1572184A GB43990/75A GB4399075A GB1572184A GB 1572184 A GB1572184 A GB 1572184A GB 43990/75 A GB43990/75 A GB 43990/75A GB 4399075 A GB4399075 A GB 4399075A GB 1572184 A GB1572184 A GB 1572184A
Authority
GB
United Kingdom
Prior art keywords
alkyl
group
formula
compound according
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB43990/75A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
Original Assignee
Beecham Group PLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Priority to GB43990/75A priority Critical patent/GB1572184A/en
Priority to NZ182264A priority patent/NZ182264A/en
Priority to IL50644A priority patent/IL50644A/en
Priority to IL59758A priority patent/IL59758A/en
Priority to AU18686/76A priority patent/AU506934B2/en
Priority to US05/732,726 priority patent/US4138407A/en
Priority to ZA766180A priority patent/ZA766180B/en
Priority to NO763567A priority patent/NO763567L/no
Priority to GB2157279A priority patent/GB1572185A/en
Priority to FI763000A priority patent/FI763000A/fi
Priority to FR7631527A priority patent/FR2328464A1/en
Priority to PH19027A priority patent/PH14168A/en
Priority to DK479176A priority patent/DK479176A/en
Priority to AT788776A priority patent/AT359658B/en
Priority to IE99/81A priority patent/IE44181B1/en
Priority to HU76BE1277A priority patent/HU179416B/en
Priority to BE171762A priority patent/BE847595A/en
Priority to CA263,940A priority patent/CA1085856A/en
Priority to ES452649A priority patent/ES452649A1/en
Priority to DE19762647969 priority patent/DE2647969A1/en
Priority to IE2330/76A priority patent/IE44180B1/en
Priority to NL7611761A priority patent/NL7611761A/en
Priority to SE7611773A priority patent/SE417090B/en
Priority to JP51127729A priority patent/JPS5257168A/en
Priority to US05/903,143 priority patent/US4177283A/en
Priority to DK427478A priority patent/DK427478A/en
Priority to NO783766A priority patent/NO783766L/en
Priority to US05/962,057 priority patent/US4341789A/en
Priority to US05/962,875 priority patent/US4201864A/en
Priority to FI790589A priority patent/FI790589A/en
Priority to CA345,592A priority patent/CA1091688A/en
Priority to IL59758A priority patent/IL59758A0/en
Publication of GB1572184A publication Critical patent/GB1572184A/en
Priority to PH24708A priority patent/PH16143A/en
Expired legal-status Critical Current

Links

Classifications

    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • 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
    • C07D207/38—2-Pyrrolones

Description

(54) 12-AZAPROSTAGLANDINS (71) We, BEECHAM GROUP LIMITED, a British Company, of Beecham House, Great West Road, Brentford, Mfddlesex, 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 sDecifically the invention relates to 12-azaprostaglandins.
Natural prostaglandins and analogues thereof are known to possess a wide variety pharmacological activities.
British Patent Specification No. 1 428 431 discloses that pyrazolidine derivatives of the formula (I)':
wherein A is CH=CH or CrC; R is H, or alkyl or cycloalkyl each of up to 12 carbon atoms; m is 0 or 1; n is e16; p is e16; and Y and Z are 0 or H2 with the proviso that where one is 0 the other H2, and alkali metal and amine salts thereof when R is H; have similar biological properties to the prostaglandins or are antagonists of prostaglandins.
A paper by Bollinger and Muchowski (Tet. Letters, 1975, 2931) describes the preparation of 11-deoxy-8-azaprostaglandin E1, but states only that one epimer thereof was more active in several biological assays than the other epimer.
U.K. Patent Application No. 51733/74 Specification No. 1,524,818 discloses that compounds of the formula (I)":
wherein: X is CO, protected CO, CROH in which R is hydrogen or C14 alkyl and in which the OH moiety may be protected; Y is CH2CH2 or CB=CH; Z is CO or CH2; n is 1 to 8; m is 1, 2 or 3; Rl is hydrogen, CH20H, CH2OH in which the OH moiety is protected, CO2W wherein W is hydrogen or CO2W represents an ester group in which the ester moiety contains from 1 to 12 carbon atoms, or CONH2; R2 is hydrogen, C,s alkyl, or taken together with R, and the carbon atom to which it is attached represents a carbonyl group; R is hydrogen, hydroxy or protected hydroxy; R, is hydrogen or C1-9 alkyl; and salts thereof; have useful pharmacological activity.
A novel class of compounds having useful pharmacological activity has now been discovered, which compounds are structurally distinct from the prior art referred to above.
The present invention provides a compound of the formula (I):
wherein: mis 1 or 2; n is 4 to 8; X is CO, protected CO, or CROH wherein R is hydrogen or C14 alkyl and wherein the OH group may be protected; R1 is hydrogen or CO2R1 represents an ester group in which the R1 radical contains from 1 to 12 carbon atoms; R3 is hydroxy, or protected hydroxy; R2 and R4 are separately hydrogen, C19 alkyl, Cs cycloalkyl, C,8 cycloalkyl C1-8 alkyl, phenyl, phenyl-C1-6 alkyl, naphthyl, naphthyl-C1-6 alkyl, any of which phenyl or naphthyl groups may be substituted by one or more halogen atoms, or trifluoromethyl, C,, alkyl, C16 alkoxy or nitro groups; or R2 and R4 taken with the carbon atom to which they are joined represent a C3 cycloalkyl group; and salts thereof; except that when one of R2 and R4 is hydrogen or C1 alkyl then the other of R2 and Rr cannot be hydrogen or C19 alkyl.
Suitably m is 1 and n is 5, 6 or 7, preferably 6.
Suitable protected hydroxyl groups CROH and R3 include readily hydrolysable groups such as acylated hydroxy groups in which the acyl radical contains 1 to 4 carbon atoms, for example the acetoxy group; and hydroxy groups ethereified by readily removable inert groups such as the benzyl group. Preferably R3 is hydroxy, and the hydroxy group in CROH is unprotected.
X may be a protected CO group. Suitable examples of such protected CO groups X include groups formed by conventional carbonyl addition and condensation reactions such as acetals, thioacetals, hemithioacetals, oximes, semicarbazones and hydrazones and the like. 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(CH1)OH and C(C2H6)OH.
Preferably X is CO, CHOH or C(CH,)OH, most preferably CO.
R1 is hydrogen or CO2Rl represents an ester group in which the R1 radical contains from 1 to 12 carbon atoms. Examples of R1 include hydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl and toluyl, while normally hydrogen or C14 alkyl groups are preferred.
Suitable groups R, when R4 is an alkyl group include C49 alkyl groups. Such C2 alkyl groups may be straight chain alkyl groups, such as n-butyl, n-pentyl, n-hexyl and n-heptyl, 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 CH2R6, CH(CH1)R or C(CH3) R5, wherein R, is a straight chain alkyl group such that the carbon content of the resultant group R4 is 4 to 9.
In general preferred groups R, when R4 is an alkyl group include straight chain pentyl, hexyl and heptyl groups. Of these, straight chain hexyl is often the most useful.
Other preferred groups R4 include groups CH(CH,)R5 and C(CH,),R wherein R, is straight chain butyl, pentyl and hexyl.
When R4 is or contains a C s cycloalkyl radical, the radical is suitably a cyclo- hexyl radical. Examples of suitable C1 alkyl radicals when R4 is a C58 cycloalkyl C1-6 alkyl groups include methyl, ethyl, propyl, butyl and amyl.
Examples of suitable groups R, when R4 is an aryl group as previously defined include phenyl, phenylbenzyl, phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthyl, naphthylmethyl, 2-( naphthyl)ethyl, 3 - (naphthyl ) propyl, and 4- (naphthyl ) butyl, and such groups branched in the alkyl radical by one or two methyl groups (at the same or different carbon atoms). These groups may be substituted in the phenyl or naphthyl group by normally one, two or three atoms or groups selected from these substituent atoms or listed herein before. Examples of suitable substituents include fluorine, chlorine and bromine atoms and CF3, methyl, ethyl, n- and iso-propyl, methoxy, ethoxy, nand iso-propoxy and nitro groups. Preferably the aryl groups when substituted by such groups will be mono- or di- substituted.
Particularly suitable values for R2 are hydrogen, C14 alkyl and phenyl, for example hydrogen, methyl, ethyl and phenyl. Of these groups preferred groups include methyl and ethyl.
Otherwise R2 can suitably represent groups such as those described above as suitable and preferred groups for R4.
Also, R2 and R4 taken with the carbon atom to which they are joined can represent a C, cycloalkyl group, such as the cyclohexyl group.
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 group of compounds within the compounds of the formula (I) as defined are those wherein X is CO, or CROH wherein R is hydrogen or C1~, alkyl and wherein the OH group may be protected; R, is hydrogen, C14 alkyl or phenyl; and R4 is hydrogen, C1 0 alkyl, phenyl, phenyl-C, alkyl, naphthyl, naphthyl-C14 alkyl, any of which phenyl or naphthyl groups may be substituted by one or more halogen atoms, or trifluoromethyl, C1-6 alkyl, C1-4 alkoxy or nitro groups; except that when R2 is hydrogen or Cl~, alkyl, Rt must be other than hydrogen or C1, alkyl; and salts thereof.
One particularly suitable sub-group of compounds within such compounds of the formula (I) include those of the formula (II): wherein:
m is as defined in formula (I); p is 6 or 8; X' is CO, CHOH or C(CH1)OH; R'l is hydrogen or Cl 4 alkyl; R1 is hydrogen, methyl or ethyl; and R14 is a group of formula (III):
wherein U is a bond, or a Ct- alkylene group which may be straight chain or branched by one or two methyl groups at the same or different carbon atoms; and W, Y and Z are each hydrogen or fluorine, chlorine or bromine atoms, or CF,, methyl, ethyl, nor iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups; and salts thereof.
Often U will be a group (CH)t wherein q is O to 4.
In formula (II) m is most suitably 1, p is most suitably 6, X' is most suitably CO, and R'.-, is most suitably methyl or ethyl. Also, W is most suitably hydrogen.
A second interesting sub-group of compounds within such compounds of formula (I) include those of formula (IV):
wherein m, p, X', R1 and R'2 are as defined in formula (II), and R24 is a group of formula (V):
wherein U, W, Y and Z are as defined in formula (III); and salts thereof.
Often U will be a group (CH2)q wherein q is O to 4.
In formula (IV) m is most suitably 1, p is most suitably 6, X1 is most suitably CO and R12 is most suitably methyl or ethyl.
A third sub-group of compounds within such compounds of formula (I) of particular interests are those of formula (VI):
wherein m, p, Xr and R11 are as defined in formula (II), and R34 is a group of formula (III), a group of formula (V) or a C alkyl group; and salts thereof.
The most suitable values for m and p in formula (VI) are 1 and 6 respectively, and X1 is most suitably CO.
When R34 pizza C4-9 alkyl group, suitable and preferred straight chain and branched groups R3, include those previously described as suitable and preferred for the group R4 when R4 is C4g alkyl group. Such preferred groups Rs4 include straight chain pentyl, hexyl and heptyl, and of these normally the most useful is straight chain hexyl. Other preferred groups R14 include CH(CH3)R1s and C(CH3)2R1s wherein R12 is straight chain butyl, pentyl or hexyl.
A fourth sub-group of compounds that is within formula (I) is of formula (VII):
wherein: p, m, X1, R1, and R12 are as defined in formula (II); and R84 is a group of formula (VIII):
wherein U is as defined in formula (III) and r is O to 3; and salts thereof.
Often U will be a group (CH2)wherein q is O to 6.
In formula (VII) we prefer that p is 6. Most suitably X1 is CO, R12 is methyl or ethyl, and m is 1.
A fifth sub-group of compounds within formula (I) of interest is of formula (IX):
wherein: p, m, X1 and R'1 are as defined in formula (II); Rb2 and Rb4 are separately C6-9 alkyl, or groups of formula (II), (V) or (VIII) as defined or Rb2 and Rb4 taken together with the carbon atom to which they are joined represent C28 cycloalkyl; and salts thereof.
In formula (IX) we prefer that p is 6. Most suitably X1 is CO and m is 1.
Compounds of the formula (II), (IV), (VI), (VII), or (IX) as defined, but wherein X1 is a protected CO group, are also of particular utility.
The compounds of the formula (I) have asymmetric centres, and thus are capable of existing in a number of stero-isomeric 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.
The invention also provides a process for the preparation of the compounds of the formula (I), which process comprises decarboxylating a compound of the formula (X):
wherein m, n, R1, R2, R2 and R1 are as defined in formula (I), to yield a compound of the formula (I) wherein X is CO; and thereafter if desired protecting X, or converting X in the thus formed compound to CROH by reduction when R is hydrogen or by reaction with a C,, alkyl Grignard reagent or C14 alkyl metallic complex when R is C1, alkyl, and then optionally protecting the CROH hydroxy group.
The decarboxylation reaction may be brought about under basic, acid or neutral conditions in conventional manner. For example when m= 1 the reaction is conveniently effected by leaving the chosen compound of the formula (X) in any inert solvent, for example overnight After the reaction R1 may be varied by conventional de-estenfication and/or esterification reactions. Similarly protected CROH and R3 hydroxy groups may be deprotected by conventional methods. For example, when R2 its! 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 theformula (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 R1 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.
It is frequently convenient however to generate the desired compound of the formula (I) directly from an ester of the formula (XI), and often this will in fact be the preferred route:
where R,; contains from 1 to 12 carbon atoms. In such a case R6 is preferably a benzyl group or a lower alkyl group such as ethyl. Thus, treatment of a compound of the formula (XI) with, for example, lithium iodide dihydrate and collidine in anhydrous solvents brings about simultaneous de-esterification and decarboxylation. In cases where m= 1, the compound of formula (XI) can be de-esterified and decarboxylated by leaving the compound standing in an inert solvent, e.g. overnight, or by heating the compound alone or in a high boiling solvent such as toluene or xylene.
It will be appreciated that compounds of the formulae (X) and (XI) are useful intermediates and as such form a useful aspect of this invention.
The compounds of formula (XI) may be prepared by the ring closure of the corresponding diester of formula (XII):
wherein m, n, R1, R2, Ra, and R4 are as defined in formula (I), R6 is as defined in formula (XI), and R7 is a group such that CO2R, is an ester group.
In the process of the invention the group CO2R1 in the intermediates of formula (X), (XI) and (XII) will normally represent an ester group, and if acids of the formula (I) (wherein R1 is hydrogen) are required they will be obtained by de esterification of the corresponding compound of the formula (I) wherein CO2Rl is an ester group. Usually the ester group CO2R7 in formula (XII) will be the same ester group as CO2R1, and for the sake of convenience the ester group CO2R8 will also normally be the same ester group as CO2R1. The ester groups CO2R1/R6/R7 are suitably C1 alkyl esters such as methyl and ethyl esters.
Generally, the ring closure takes place in a dry organic solvent using a strong base such as sodium hydride or sodium ethoxide (or other OR6 or ORr group) to bring about the initial proton abstraction from the a-methylene group.
It has been found that sodium ethoxide in benzene, or potassium toutoxide in toluene, benzene or hexamethylphosphoramide give good results.
The preparation of the compounds of formula (XII) is fully described in our copending U.K. Patent Application No. 21573/79 (Serial No. 1572 iso).
Compounds within the formula (I) have useful pharmacological activity. For example compounds within the formula (I) have anti-gastric secretion activity, cardiovascular activity e.g. anti-hypertensive activity, platelet aggregation inhibition activity, effect the respiratory tract e.g. bronchodilator activity, and have antifertility 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.
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; for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; filler for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
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, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminiumstearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or coloring agents. The compounds of the formula (I) may also if desired be incorporated in a food-stuff, for example in the form of a biscuit.
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 anestheic, 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 for aerosol or oral administration, or as a micofine 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 has been found that a number of the compounds of the formula (I) are potent inhibitors of gastric secretion, and thus have commercial utility as anti-ulcer agents.
In treatment of this nature, the composition containing the formula (I) will preferably be formulated in a manner to allow oral administration. Normally .01 mg/kg to 500 mg/kg per day, most suitably .1 to 100 mg/kg per day, of the compound of the formula (I) in composition form will be administered in such treatment.
Also a number of compounds of the formula (I) have particularly useful activity on the respiratory tract, and thus find utility as for example bronchodilators. Normally compositions containing such compounds of the formula (I) will be formulated for aerosol or oral administration, or as a microfine powder for insufflation, and the treatment will comprise the administration of from .001 mg/kg to 100 mg/kg per day of the compound in composition form.
Further, a number of compounds of the formula (I) are particularly potent inhibitors of platelet aggregation, and thus compositions containing such compound are useful inter alia for administration to humans and animals to prevent clot forma tion for example after surgery to nrevent postoperative thrombosis; in geriatric patients to prevents transient cerebral ischemic attacks; and long-term prophylaxis following myocardial infarcts and strokes - and in general in the treatment or prophylaxis of any disorder caused by an over pronounced tendency of blood platelets to aggregate. Such compositions also have applications in the storage of whole blood in blood banks, and whole blood to be used in heart-lung machines, or to be circulated through organs, e.g. heart and kidneys, which have been removed from a cadaver and prior to transplant.
It will of course be realised that the precise dosage used in the treatment 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 domestic animals which comprises the administration to the sufferer of an effective amount of a compound of the formula (I).
The following Examples illustrate the preparation of compounds of the formula (I) and their pharmacological properties.
EXAMPLE 1.
2-(6'-Ethoxyvarbonyl-heXyl)-1-(3"-hydroxy-3"-methyl-5"-phenyl-pentyl)- pyrrolidin-3,5-dione Potassium tert-butoxide (2.18 g) was added in small portions over one hour to a warm solution of diethyl 2 - [N - (3' - hydroxy - 3' - methyl - 5' - phenyl - pentyl) N - ethoxycarbonylacetyl - amino]azelate (11.9 g) in dry toluene (100 ml). The mixture was gently refluxed for 2 hours.
The solvent was evaporated bl vacuo and the residue taken up in water. The solution was extracted twice with diethyl ether and the aqueous Iayer was acidified with dilute hydrochloric acid and extracted with diethyl ether. This ethereal solution was washed with brine and dried over magnesium sulphate to give a solution of 4ethoxycarbonyl - 2 - (6' - ethoxycarbonyl - hexyl) - 1 - (3" - hydroxy - 3" - methyl5" - phenyl - pentyl) - pyrrolidin - 3,5 - dione. The product decarboxylated on standing in diethyl ether solution overnight. The solvent was evaporated in vacuo to give 2 - (6' - ethoxycarbonyl - hexyl) - 1 - (3" - hydroxy - 3" - methyl - 5" - phenyl pentyl) - pyrrolidin - 35 - dione as a yellow oil (4.7 g).
I.R. spectrum - broad OH absorption at 3430 cm-1.
carbonyl absorptions at 1760 cm'-l, 1720 cm-1 and 1680 cm-1.
The compounds shown in Table 1 were similarly prepared.
TABLE 1
I.R. spectrum OH absorption carbonyl absorptions Compound R2 R4 Cm~l cm 29 CH3 C6Hs 3400 1675, 1720, 1760 30 CH3 CH2C6H5 C,H. 3400 1675, 1720, 1760 31 CH3 (CH2)3C6H5 3400 1675, 1720, 1760 32 CH3 CH2CH(CH3)C6H 3450 1680, 1720, 1760 33 CH3 ( C H2)2wF 3450 1680, 1725, 1765 SOCH, 34 CH3 (CH2)34 3400 1680, 1720, 1760 35 C6H, n-C, H,, 3400 1675, 1725, 1760 36 D 3450 1680, 1725, 1760 EXAMPLE 2.
2-(6'-Ethoxycarbonyl-hexyl)3-hydroxy-1-(3"-hydroxy-3"-methyl-6"-phenyl hexyl) -pyrroiidin-5-one Sodium borohydride (290 mg) was added portionwise to a solution of 2 - (6'ethoxycarbonyl - hexyl) - I - (3" - hydroxy - 3" - methyl - 6" - phenyl - hexyl)pyrrolidin - 3,5 - dione (2.5 g) in dry ethanol (50 ml). The mixture was stirred at room temperature for 2 hours.
The solvent was evaporated in vacuo and the residue was taken up in diethyl ether. The ethereal solution was washed with very dilute hydrochloric acid and with water, dried over magnesium sulphate, and evaporated in vacuo to give a colourless oil. The product was purified by column chromatography to give 2 - (6' - ethoxycarbonyl - hexyl) - 3 - hydroxy - 1 - (3" - hydroxy - 3" - methyl - 6" - phenyl irexyl) - pyrrolidin - 5 - one as a colourless oil (1.5 g, 60% yield).
I.R. spectrum -- broad OH absorption at 3400 caul.
carbonyl absorptions at 1725 cm~l and 1665 cm~l.
The compounds shown in Table 2 were similarly prepared.
TABLE 2
I.R. spectrum OH absorption carbonyl absorptions Compound R2 R4 cm~l cm~l 37 CH3 C6H5 3400 1670, 1720 38 CH3 CH2C6Hs 3400 1670, 1720 39 CH3 (CH2)2c6Hs 3400 1670, 1720 40 -CH3 (CH2)2t3F 3430 1670, 1725 OCH3 41 CH3 (CH2)34 3400 1665, 1725 PHARMACALOGICAL DATA Anti-secretory activity The anti-secretory activity of the compounds was determined by their inhibition of pentagastrin-stimulated gastric acid secretion in the perfused rat stomch preparation (Ghosh and Schild preparation).
2 - (6' - Ethoxycarbonyl - hexyl) - 1 - (3" - hydroxy - 3" - methyl - 6" - phenylhexyl) - pyrrolidin - 3,5 - dione inhibited acid secretion with an approximate ID=9.6
2 - (6' - Ethoxycarbonyl - hexyl) - 3 - hydroxy - 1 - (3" - hydroxy - 3'i methyl - 5" - phenyl - pentyl) - pyrrolidin - 5 - one completely inhibited pregnancy in hamsters when dosed at 25 mg/kg, subcutaneously, on days 6, 7 and 8 after mating.
Toxicity No apparent side effects were observed after administration of 2 - (6' - ethoxycarbonyl - hexyl) - 1 - (3" - hydroxy - 3" - methyl - 6" - phenyl - hexyl) - pyrrolidin3,5 - dione at 100 mg/kg subcutaneously in the hamster and intraduodenally in the rat.
WHAT WE CLAIM IS: 1. A compound of the formula (I):
wherein mis 1 or 2; n is 4 to 8; X is CO, protected CO, or CROH wherein R is hydrogen or C14 alkyl and wherein the OH group may be protected; R1 is hydrogen or CO2R1 represents an ester group in which the R1 radical contains from 1 to 12 carbon atoms; R, is hydroxy, or protected hydroxy; R2 and R, are separately hydrogen, C,, alkyl, C,~, cycloalkyl, C 8 cycloalkyl- C1-6 alkyl, phenyl, phenyl-C1-6 alkyl, naphthyl, naphthyl-C1-6 alkyl, any of which phenyl or naphthyl group may be substituted by one or more halogen atoms, or trifluoromethyl, C1, alkyl, C1-6 alkoxy or nitro groups; or R2 and R4 taken with the carbon atom to which they are joined represent a C5-8 cycloalkyl group; or a salt thereof; except that when one of R, and R1 is hydrogen or C1-4 alkyl then the other of R2 and R, cannot be hydrogen or C1-9 alkyl.
2. A compound according to Claim 1, wherein X is CO, or CROH wherein R is hydrogen or C1-4 alkyl and wherein the OH group may be protected; R2 is hydrogen, C,, alkyl or phenyl; and R, is hydrogen, C, alkyl, phenyl, phenyl-C14 alkyl, naphthyl, naphthyl-Cl, alkyl, any of which phenyl or naphthyl group may be substituted by one or more halogen atoms, or trifluoromethyl, C1, alkyl, C1-6 alkoxy or nitro groups; except that when R2 is hydrogen or C1 alkyl, R4 must be other than hydrogen or C1-9 alkyl or a salt thereof.
3. A compound according to Claim 1 or 2, wherein n is 6.
4. A compound according to Claim 1, 2 or 3, wherein X is CO, protected CO, CHOH or C(CH,)OH.
5. A compound according to any one of the Claims 1 to 4, wherein R1 is hydrogen or a C14 alkyl group.
6. A compound according to any one of the Claims 1 to 5, wherein R2 is hydrogen, C14 alkyl or phenyl.
7. A compound according to any one of the Claims 1 to 6, wherein R3 is hydroxy.
8. A compound according to any one of the Claims 1 and 3 to 7, wherein R4 is phenyl or a phenyl-C1-6 alkyl group either of which phenyl group may be substituted by a halogen atom, or a trifluoromethyl, C1, alkyl, C,-, alkoxy or nitro group.
9. A compound according to Claim 1, of the formula (II):
wnerem: m is as defined in Claim 1; pis6or8; X1 is CO, CHOH or C(CH,)OH; R11 is hydrogen or C14 alkyl; R12 is hydrogen, methyl or ethyl; and R14 is a group of formula (III):
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (32)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    2 - (6' - Ethoxycarbonyl - hexyl) - 3 - hydroxy - 1 - (3" - hydroxy - 3'i methyl - 5" - phenyl - pentyl) - pyrrolidin - 5 - one completely inhibited pregnancy in hamsters when dosed at 25 mg/kg, subcutaneously, on days 6, 7 and 8 after mating.
    Toxicity No apparent side effects were observed after administration of 2 - (6' - ethoxycarbonyl - hexyl) - 1 - (3" - hydroxy - 3" - methyl - 6" - phenyl - hexyl) - pyrrolidin3,5 - dione at 100 mg/kg subcutaneously in the hamster and intraduodenally in the rat.
    WHAT WE CLAIM IS: 1. A compound of the formula (I):
    wherein mis 1 or 2; n is 4 to 8; X is CO, protected CO, or CROH wherein R is hydrogen or C14 alkyl and wherein the OH group may be protected; R1 is hydrogen or CO2R1 represents an ester group in which the R1 radical contains from 1 to 12 carbon atoms; R, is hydroxy, or protected hydroxy; R2 and R, are separately hydrogen, C,, alkyl, C,~, cycloalkyl, C 8 cycloalkyl- C1-6 alkyl, phenyl, phenyl-C1-6 alkyl, naphthyl, naphthyl-C1-6 alkyl, any of which phenyl or naphthyl group may be substituted by one or more halogen atoms, or trifluoromethyl, C1, alkyl, C1-6 alkoxy or nitro groups; or R2 and R4 taken with the carbon atom to which they are joined represent a C5-8 cycloalkyl group; or a salt thereof; except that when one of R, and R1 is hydrogen or C1-4 alkyl then the other of R2 and R, cannot be hydrogen or C1-9 alkyl.
  2. 2. A compound according to Claim 1, wherein X is CO, or CROH wherein R is hydrogen or C1-4 alkyl and wherein the OH group may be protected; R2 is hydrogen, C,, alkyl or phenyl; and R, is hydrogen, C, alkyl, phenyl, phenyl-C14 alkyl, naphthyl, naphthyl-Cl, alkyl, any of which phenyl or naphthyl group may be substituted by one or more halogen atoms, or trifluoromethyl, C1, alkyl, C1-6 alkoxy or nitro groups; except that when R2 is hydrogen or C1 alkyl, R4 must be other than hydrogen or C1-9 alkyl or a salt thereof.
  3. 3. A compound according to Claim 1 or 2, wherein n is 6.
  4. 4. A compound according to Claim 1, 2 or 3, wherein X is CO, protected CO, CHOH or C(CH,)OH.
  5. 5. A compound according to any one of the Claims 1 to 4, wherein R1 is hydrogen or a C14 alkyl group.
  6. 6. A compound according to any one of the Claims 1 to 5, wherein R2 is hydrogen, C14 alkyl or phenyl.
  7. 7. A compound according to any one of the Claims 1 to 6, wherein R3 is hydroxy.
  8. 8. A compound according to any one of the Claims 1 and 3 to 7, wherein R4 is phenyl or a phenyl-C1-6 alkyl group either of which phenyl group may be substituted by a halogen atom, or a trifluoromethyl, C1, alkyl, C,-, alkoxy or nitro group.
  9. 9. A compound according to Claim 1, of the formula (II):
    wnerem: m is as defined in Claim 1; pis6or8; X1 is CO, CHOH or C(CH,)OH; R11 is hydrogen or C14 alkyl; R12 is hydrogen, methyl or ethyl; and R14 is a group of formula (III):
    wherein U is a bond, or a Cl-s alkylene group which maybe straight chain or branched by one or two methyl groups at the same or different carbon atoms; and W, Y and Z are each hydrogen or fluorine, chlorine or bromine atoms or CF3, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups; -or a salt thereof.
  10. 10. A compound according to Claim 9, wherein m is 1.
  11. 11. A compound according to Claim 9 or 10, wherein p is 6.
  12. 12. A compound according to Claim 9, 10 or 11, wherein Xl is CO.
  13. 13. A compound according to any one of the Claims 9 to 12, wherein R12 is methyl.
  14. 14. A compound according to any one of the Claims 9 to 13, wherein W and Y are hydrogen.
  15. 15. A compound according to any one of the Claims 9 to 14, wherein U is a group (CH,)-wherein q is 0 to 4.
  16. 16. A compound according to Claim 1, of the formula (IV):
    wherein m, p, X1, R13 and R1, are as defined in Claim 9; and R24 is a group of formula (V):
    wherein U, W, Y and Z are as defined in Claim 9; or a salt thereof.
  17. 17. A compound according to Claim 16, wherein U is a group ,(CH2)"and qisOto4.
  18. 18. A compound according to Claim 1, of the formula (VI):
    wherein m, p, X' and R1l are as defined in Claim 9, and R34 is a group of formula (III) as defined in Claim 9, a group of formula (V) as defined in Claim 16, or a C49 alkyl group; or a salt thereof.
  19. 19. A compound according to Claim 1, of the formula (VII):
    wherein: p, m, X1, R1l and R12 are as defined in Claim 9; and R & 4 is a group of formula (VIII):
    wherein U is as defined in Claim 9 and r is 0 to 3; or a salt thereof.
  20. 20. A compound according to Claim 19, wherein U is a group (CH2)q wherein q is 0 to 6.
  21. 21. A compound according to Claim 1, of the formula (IX):
    wherein: p, m, X1 and R1l are as defined in Claim 9; Rb1 and Rbs are separately C,, alkyl, or groups of formula (III), (V) or (VIII) as defined in Claims 9, 16 and 19 respectively; or Rb2 and Rb taken together with the carbon atom to which they are joined represent C,-s cycloalkyl; or a salt thereof.
  22. 22. A compound according to any one of the Claims 9 to 21, wherein X1 is defined as a protected carbonyl group.
  23. 23. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically acceptable carrier.
  24. 24. A method of treatment or prophylaxis of disorders in domestic animals, which method comprises the administration of an effective amount of a compound according to Claim 1.
  25. 25. A process for the preparation of a compound according to Claim 1, which process comprises decarboxylating a compound of the formula (X):
    wherein m, n, R1, R2, R2 and R4 are as defined in formula (I) to yield a compound of the formula (I) wherein X is CO; and thereafter if desired protecting X, or converting X in the thus formed compound to CROH by reduction when R is hydrogen or by reaction with a C,-4 alkyl Grignard reagent or C, alkyl metallic compIex when R is C,-4 alkyl, and then optionally protecting the CROH hydroxy group.
  26. 26. A process according to Claim 25, wherein the compound of formula (X) is generated in situ from the corresponding ester.
  27. 27. A compound according to Claim 1, substantially as hereinbefore described.
  28. 28. A process according to Claim 25 or 26, substantially as hereinbefore described in any one of the Examples.
  29. 29. A compound according to Claim 1, whenever prepared by a process according to Claim 25, 26 or 28.
  30. 30. A compound of the formula (X):
    wherein the variable groups are as defined in any one of the claims 1 to 8.
  31. 31. A compound of the formula (XI):
    n K contains from 1 to 12 carbon atoms, and the other variable groups are as dofined in any one of the claims 1 to 8.
  32. 32. A compound according to claim 31, substantially as hereinbefore described with reference to Example 1.
GB43990/75A 1975-10-25 1975-10-25 12-azaprostaglandins Expired GB1572184A (en)

Priority Applications (33)

Application Number Priority Date Filing Date Title
GB43990/75A GB1572184A (en) 1975-10-25 1975-10-25 12-azaprostaglandins
NZ182264A NZ182264A (en) 1975-10-25 1976-10-07 2-carboxyalkyl-1-hydroxyalkyl-pyrrolidin-3,5-dione or-piperidin-3,6-dione derivatives prarmaceutical compostions
IL50644A IL50644A (en) 1975-10-25 1976-10-08 12-aza-11-oxo-15-hydroxyprostanoic acid analogues,their preparation and pharmaceutical compositions containing them
IL59758A IL59758A (en) 1975-10-25 1976-10-08 Alpha-amino-alpha,omega-bis-carboxy-alkane derivatives
AU18686/76A AU506934B2 (en) 1975-10-25 1976-10-14 Aromatic prostaglandin analogues
US05/732,726 US4138407A (en) 1975-10-25 1976-10-15 2,4 Pyrrolidinediones
ZA766180A ZA766180B (en) 1975-10-25 1976-10-15 Aromatic prostaglandin analogues
NO763567A NO763567L (en) 1975-10-25 1976-10-19
GB2157279A GB1572185A (en) 1975-10-25 1976-10-20 Intermediates for the preparation of 12-azaprostaglandins
FI763000A FI763000A (en) 1975-10-25 1976-10-20
FR7631527A FR2328464A1 (en) 1975-10-25 1976-10-20 AROMATIC CYCLIC AMIDES
PH19027A PH14168A (en) 1975-10-25 1976-10-21 2,4-pyrrolidinediones
CA263,940A CA1085856A (en) 1975-10-25 1976-10-22 Pyrrolidine and piperidine prostaglandin analogues
AT788776A AT359658B (en) 1975-10-25 1976-10-22 METHOD FOR PRODUCING NEW CYCLIC AMIDES
IE99/81A IE44181B1 (en) 1975-10-25 1976-10-22 Intermediates for the preparation of 12-azaprostaglandins
HU76BE1277A HU179416B (en) 1975-10-25 1976-10-22 Process for preparing compounds with a nitrogen containing heterocycle
BE171762A BE847595A (en) 1975-10-25 1976-10-22 AROMATIC CYCLIC AMIDES,
DK479176A DK479176A (en) 1975-10-25 1976-10-22 PROCEDURE FOR THE PREPARATION OF AROMATIC CYCLIC AMIDES
ES452649A ES452649A1 (en) 1975-10-25 1976-10-22 2,4 Pyrrolidinediones
DE19762647969 DE2647969A1 (en) 1975-10-25 1976-10-22 CYCLIC AMIDES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PREPARATIONS CONTAINING THESE COMPOUNDS
IE2330/76A IE44180B1 (en) 1975-10-25 1976-10-22 12-azaprostaglandins
NL7611761A NL7611761A (en) 1975-10-25 1976-10-22 PROCEDURE FOR PREPARING NEW SUBSTITUTED CYCLICAL AMIDES AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS.
SE7611773A SE417090B (en) 1975-10-25 1976-10-22 PROCEDURE TO MAKE PHARMACOLOGICALLY ACTIVE HETEROCYCLIC PROSTAGLANDIN ANALOGS
JP51127729A JPS5257168A (en) 1975-10-25 1976-10-23 Production of novel cyclic amide compound * intermediate compound utilized in making the same and pharmaceutical composition containing the same
US05/903,143 US4177283A (en) 1975-10-25 1978-05-05 Aromatic prostaglandin analogues
DK427478A DK427478A (en) 1975-10-25 1978-09-26 AMINOS-SUBSTITUTED ESTERS FOR USE AS INTERMEDIATE PRODUCTS AND METHODS OF PREPARATION
NO783766A NO783766L (en) 1975-10-25 1978-11-09 INTERMEDIATES FOR USE IN THE MANUFACTURE OF AROMATIC PROSTAGLANDIN ANALOGS.
US05/962,057 US4341789A (en) 1975-10-25 1978-11-20 Cycloaliphatic prostaglandin analogues
US05/962,875 US4201864A (en) 1975-10-25 1978-11-22 Oxy-alkylamino acids and esters
FI790589A FI790589A (en) 1975-10-25 1979-02-21 MELLAN PRODUCTS FOR FRAMSTAELLNING AV PHARMACOLOGICAL ACTIVE AROMATIC CYCLIC AMIDER OCH FOERFARANDE FOER FRAMSTAELLNING AV MELLANPRODUKTEN
CA345,592A CA1091688A (en) 1975-10-25 1980-02-13 Pyrrolidine and piperidine prostaglandin analogues
IL59758A IL59758A0 (en) 1975-10-25 1980-04-03 -amino- , -bis-carobxy-alkane derivatives
PH24708A PH16143A (en) 1975-10-25 1980-10-10 Aromatic prostaglandin analogues

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB43990/75A GB1572184A (en) 1975-10-25 1975-10-25 12-azaprostaglandins

Publications (1)

Publication Number Publication Date
GB1572184A true GB1572184A (en) 1980-07-23

Family

ID=10431275

Family Applications (1)

Application Number Title Priority Date Filing Date
GB43990/75A Expired GB1572184A (en) 1975-10-25 1975-10-25 12-azaprostaglandins

Country Status (3)

Country Link
BE (1) BE847595A (en)
GB (1) GB1572184A (en)
ZA (1) ZA766180B (en)

Also Published As

Publication number Publication date
BE847595A (en) 1977-04-22
ZA766180B (en) 1977-09-28

Similar Documents

Publication Publication Date Title
CH647222A5 (en) 9-DESOXY-9A-METHYLENE ISOSTERES OF PGI-2 AND METHOD FOR THE PRODUCTION THEREOF.
US4375479A (en) Indanyl derivatives and use
US4021448A (en) 2-Substituted-indole-1-lower-alkanecarboxamides
US4138407A (en) 2,4 Pyrrolidinediones
SU873883A3 (en) Method of preparing hexahydro-gamma-carbolins or their salts
NO753935L (en)
EP0009608B1 (en) N-phenethylacetamide compounds, processes for their preparation and therapeutic compositions containing them
US4136190A (en) 4,4-dimethyl-3,5-pyrrolidinediones
GB1572184A (en) 12-azaprostaglandins
JPS6064955A (en) 1-(4'-alkylsulfonylphenyl)-2-amino-1,3- propandiol-n-substituted derivative
US4435420A (en) Anti-inflammatory agents and antiasthmatic agents
US4156730A (en) Pharmaceutically active compounds, preparation thereof, intermediates useful in such preparation and compositions containing the compounds
US4262008A (en) 2,4-Disubstituted 5-oxo-5H-hexahydrofuro[3,2b]pyrroles
US4201864A (en) Oxy-alkylamino acids and esters
US4177283A (en) Aromatic prostaglandin analogues
US4119726A (en) Cyclic exo amides
US4187312A (en) 3-Hydroxy-4,4-dimethyl-5-pyrrolidone derivatives
US4001425A (en) Methods of treating hypertension and pharmaceutical compositions comprising 1-tertiary-alkyl-3-(substituted furyl)ureas as antihypertensive agents
DE2755727A1 (en) DERIVATIVES OF 1,2,4-TRIAZOLIDINE-2,5-Dione, METHOD FOR THEIR PREPARATION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
CA1091688A (en) Pyrrolidine and piperidine prostaglandin analogues
US4454136A (en) Substituted benzopyranotriazoles and antiallergic use
US4547516A (en) Antisecretory agents derived from meldrum's acid
US4528372A (en) N-Phthalidyl-5-fluorouracils
US4034045A (en) 2,4-Disubstituted-4b,5,6,7,8,8a,9,10-octahydro-9-oxo-phenanthrenes
US4007207A (en) Alkyl substituted-4-oxo-cyclopenta benzopyrans

Legal Events

Date Code Title Description
PS Patent sealed
PCNP Patent ceased through non-payment of renewal fee