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GB1598662A - 10,12-diazoprostaglandins - Google Patents

10,12-diazoprostaglandins Download PDF

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Publication number
GB1598662A
GB1598662A GB52955/76A GB5295576A GB1598662A GB 1598662 A GB1598662 A GB 1598662A GB 52955/76 A GB52955/76 A GB 52955/76A GB 5295576 A GB5295576 A GB 5295576A GB 1598662 A GB1598662 A GB 1598662A
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United Kingdom
Prior art keywords
compound according
alkyl
compound
hydrogen
phenyl
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GB52955/76A
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Beecham Group PLC
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Beecham Group PLC
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Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Priority to GB52955/76A priority Critical patent/GB1598662A/en
Priority to IL53559A priority patent/IL53559A0/en
Priority to NZ185909A priority patent/NZ185909A/en
Priority to ZA00777335A priority patent/ZA777335B/en
Priority to DK551777A priority patent/DK551777A/en
Priority to DE19772755771 priority patent/DE2755771A1/en
Priority to AT0893777A priority patent/AT368498B/en
Priority to AU31613/77A priority patent/AU514523B2/en
Priority to GB2675580A priority patent/GB1598665A/en
Priority to GB2671780A priority patent/GB1598664A/en
Priority to FI773812A priority patent/FI773812A7/en
Priority to NO774348A priority patent/NO774348L/en
Priority to ES465176A priority patent/ES465176A1/en
Priority to FR7738009A priority patent/FR2374309A1/en
Priority to CH1554577A priority patent/CH639076A5/en
Priority to BE183545A priority patent/BE861956A/en
Priority to NL7713971A priority patent/NL7713971A/en
Priority to SE7714373A priority patent/SE7714373L/en
Priority to PH20569A priority patent/PH14398A/en
Priority to JP15279377A priority patent/JPS5382779A/en
Priority to US05/915,165 priority patent/US4152445A/en
Priority to US05/915,164 priority patent/US4147796A/en
Publication of GB1598662A publication Critical patent/GB1598662A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
    • C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
    • C07C273/1827—X being H
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings 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
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom

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

Description

(54) 10,12-DIAZAPROSTAGLANDINS (71) We, BEECHAM GROUP LIMITED, a British Company, of Beecham House, Great West Road, Brentford, Middlesex, 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 and to pharmaceutical compositions containing them.
Offenlegungsschrift No. 2,323,193 discloses that pyrazolidine derivatives of the formula (I)':
wherein A is CH=CH or C#C; R is H, an alkali metal, an amine salt, or an # 12C hydrocarbon or chlorohydrocarbon residue; m is 0 or 1; n is 0-6; and Y and Z are 0 or H, except that Y and Z are not both 0; have similar biological properties to the prostaglandins or are antagonists of prostaglandins.
French Patent Application No. 2,258,376 discloses that lO-aza prostaglandins of formula (II)":
wherein R=H or lower alkyl; R' and R"=CH3 or C2H5; R =H or lower alkyl; Y=-CH2CH2-, or -CH=CH-; Z=-CO or -CH(~OH)-; are useful in the treatement of blood pressure and gastro-intestinal disordes, and in the preparation for confinement.
Belgian Patent No. 835989 discloses that compounds of the formula (III)":
wherein X is CO, protected CO, CROH in which R is hydrogen or C1-4 alkyl and in which the OH moiety be protected; Y is CH2CH2 or CH=CH; Z is CO or CH2; n is 1 to 8; m is 1, 2 or 3; R1 is hydrogen, CH2OH, 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,, alkyl, or taken together with R3 and the carbon atom to which it is attached represents a carbonyl group; R3 is hydrogen, hydroxy or protected hydroxy; R4 is hydrogen or C1-9 alkyl; and salts thereof; have useful pharmacological activity.
A novel class of compounds also having useful pharmacological activity has now been discovered, which compounds are structurally distinct from the prior art referred to above.
Accordingly the present invention provides a compound of the formula (I):
wherein: X is 0 or S; n is 1 to 8; R, is hydrogen, or CO2R, represents an ester group in which the R, moiety contains from 1-12 carbon atoms; R2 is hydrogen, C,, alkyl, or phenyl; R3 is hydroxy or protected hydroxy; R4 is hydrogen, C1-9 alkyl, C3-8 cycloalkyl-C1-8 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, hydroxy, C1-6 alkoxy, phenyl-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; R5 is C1-6 alkyl, C1-6 akyl substituted by a halogen atom or a nitro, hydroxy, C1-6 alkoxy, CO2A, (CO2A)2, or CN group, C5-8 cycloalkyl, phenyl, phenyl-C1-6 alkyl, phenyl-C3-6 cycloalkyl, any of which phenyl moieties may be substituted by one or more halogen atoms or trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups; or a group CO2A; in R5 when present A is hydrogen or CO2A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
A group of compounds within formula (I) include those wherein: X is 0 or S; n is 4 to 8; R, is hydrogen, or CO2R, represents an ester group in which the R, moiety contains from 1 to 12 carbon atoms; R, is hydrogen, C14 alkyl, or phenyl; R, is hydroxy or protected hydroxy; 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; R5 is C1-6 alkyl, phenyl, phenyl-C1-6 alkyl, or group CO2A wherein A is hydrogen or CO2A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
Particularly suitable compounds within formula (I) include those where X is 0.
Suitably n is 5, 6 or 7, preferably 6.
R1 is hydrogen or CO2R1 represents an ester group in which the R1 moiety contains from 1 to 12 carbon atoms. Example of R1 include hydrogen, methyl, ethyl, nand iso- propyl, n-, sec- and tert-butyl, phenyl, benzyl, and tolyl, while normally hydrogen or C18 alkyl groups are preferred.
Suitable examples of R2 include hydrogen, methyl, ethyl and phenyl. More suitably R2 is hydrogen, methyl or ethyl, preferably methyl.
Suitable protected hydroxyl groups 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 group. Preferably R3 is hydroxyl.
Suitable groups R, when R4 is an alkyl group include C49 alkyl groups. Such C49 alkyl groups may be straight chain alkyl groups, such 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 CH2R7, CH(CH3)R7 or C(CH3)R7, wherein R7 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 R, include groups CH(CH3)R4 and C(CH3)2R; wherein R: is straight chain butyl, pentyl and hexyl.
Other suitable examples of R, when This an alkyl group include a C14 alkyl group.
When R4 is or contains a C38cycloalkyl moiety, the moiety may be cyclopropyl. The moiety may also be a C5-8 cycloalkyl moiety such as a cyclohexyl moiety. Examples of suitable C1-6 alkyl moieties when R4 is a C3-8 cycloalkyl-C1-6 alkyl group include methyl, ethyl, propyl, butyl and amyl.
When R4 is an aryl group as previously defined, suitable groups R4 include phenyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1- or 2-naphthyl, (1- or 2-naphthyl)-methyl, 2-(1- or 2-naphthyl)-ethyl, 3-(1- or 2-naphthyl)-propyl and 4-(1or 2-naphthyl)-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or different carbon atoms). 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 listed hereinbefore. 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. Other examples of such groups include hydroxy and benzyloxy. Preferably the aryl moieties when substituted by such groups or atoms will be mono or di-substituted.
Also, R2 and R4 taken with the carbon atom to which they are joined can represent a C58 cycloalkyl group, such as the cyclohexyl group.
Suitable examples of R, include methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl; phenyl; benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, and such phenylalkyl groups branched in their alkyl moieties by one or two methyl groups (at the same or different carbon atoms). More suitably R5 is C16 alkyl such as methyl and ethyl.
R5 may also be a phenyl-C3-6 cycloalkyl group, in which case suitable examples of R5 include phenyl-cyclopropyl.
When R5 is or includes a phenyl moiety, it can optionally be substituted as described above for R4 aryl groups.
When R5 is C58 cycloalkyl, it is suitably cyclohexyl.
When R5 is, or contains, a group CO2A, suitable examples of A include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, phenyl, benzyl and tolyl, while normally for A hydrogen or C16 alkyl are preferred.
R, may also be a C16 alkyl group substituted by a halogen atom or a nitro, hydroxy, C16 alkoxy (such as methoxy), CO2A, (CO2A)2, or CN group. In such cases often R5 will be a methyl group substituted by one of these groups or atoms.
The compounds of the formula (I) may form conventional salts. Such salts include those with alkali and alkaline earth metals, suitably sodium and potassium, and ammonium and substituted ammonium salts.
From the aforesaid it will be seen that one particularly suitable group of compounds within formula (I) is of formula (II):
wherein: X and R1 are as defined in formula (I); n1 is 5, 6 or 7; R12 is hydrogen, methyl, ethyl or phenyl; R4 is hydrogen or C1-9 alkyl; R5 is C1-6 alkyl, phenyl, phenyl-C1-6 alkyl, or a group CO1A wherein A is hydrogen or CO2A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; and salts thereof.
In formula (II) n' is preferably 6. Also suitably X is 0.
R12 is more suitably hydrogen, methyl or ethyl, preferably methyl.
While R14 may be hydrogen or a C11 alkyl group, it is normally a C4-9 alkyl group. In such cases suitable and preferred straight chain and branched groups R'4 include those previously described as suitable and preferred for the group R, when R, is a C49 alkyl group. Such preferred groups R'4 include straight chain pentyl, hexyl and heptyl, and of those normally the most useful is straight chain he1xyl.
Other preferred groups R14 include CH(CH3)R'7 and C(CH3)2R'7 wherein R', is straight chain butyl, pentyl or hexyl.
Suitably R5 is C1-6 alkyl such as methyl and ethyl.
A second group of compounds within formula (I) of particular interest are those of formula (III):
wherein: X and R1 are as defined in formula (I); n; R2 are as defined in formula (II); and R4 is group of formula (IV):
wherein T is a bond, or a C18 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 CF3, methyl, ethyl, nor iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups; and salts thereof In formula (III) n is preferably 6. Also suitably X is 0.
R2 is more suitably hydrogen, methyl or ethyl, preferably methyl.
In formula (IV) often T will be a group HCH2)q wherein q is O to 4. Also, suitably W and Y are hydrogen.
Suitably R5 is C1-6 alkyl such as methyl and ethyl.
Another group of compounds within formula (I) of particular interest is of formula (V):
wherein: X and R1 are as defined in formula (I); n', R'2 and R's are as defined in formula (II); and R34 is a group of formula (VI):
wherein T, W, Y and Z are as defined in formula (IV); and salts thereof.
In formula (V) n' is preferably 6. Also suitably X is 0.
R'2 is more suitably hydrogen, methyl or ethyl, preferably methyl.
In formula (VI) often T will be a group (CH2)q wherein q is O to 4. Also suitably W and Y are hydrogen.
Suitably R's is C16 alkyl such as methyl and ethyl.
A further group of compounds within formula (I) of interest are of formula (VII):
wherein: X and R1 are as defined in formula (I); n', R'2 and R's are as defined in formula (II); and R44 is a group of formula (VIII):
wherein T is as defined in formula (IV) and r is O to 3; and salts thereof.
In formula (VII) n' is preferably 6. Also suitably X is 0.
R'2 is more suitably hydrogen, methyl, or ethyl, preferably methyl.
In formula (VIII) often T will be a group CH2)q wherein q is O to 4. Also suitably r is 1.
Suitably R's is C18 alkyl such as methyl and ethyl.
One compound of the invention that is particularly preferred for its useful activity is 1-(3 '-hydroxy-3'-methylnonyl)-3-methyl-5-(6 "-carboxyhexyl)hydantoin.
The present invention further provides a process for the preparation of the compounds of the formula (I), which process comprises the cyclisation of a compound of formula (IX):
wherein n, R1, R2, R@, IR, Rs and X are as hereinbefore defined; and CO2R' is an ester group in which the R11 moiety contains from 1--12 carbon atoms and thereafter if desired converting Rt, R, or R, in the thus formed compound into other variables R1, R, or R,.
Our copending cognate British Patent Application No. 8,026,717 and 8,026,718 Serial No. 1,598,664 entitled 'Ureidoazelates' describes the preparation of compounds of the formula (IX).
In a preferred process of this invention, the compound of formula (I) is prepared by reaching a compound of formula (X):
wherein n R1, R2, IR, and It, are as hereinbefore defined with RsNCX, during which reaction a compound of formula (IX) is prepared in situ. This preferred process is suitably carried out under reflux in an inert solvent such as benzene. It should be stated that when in this reaction R, is a sterically hindered group then this reaction may proceed only as far as the uncyclised compound of formula (IX), in which case the necessary cyclisation of the compound (IX) can be achieved with a strong base, such as sodium hydride or sodium ethoxide, in a dry organic solvent. Sodium ethoxide in benzene, or potassium t-butoxide in toluene, benzene or hexamethylphosphoramide are suitable reagents.
Compounds of the formula (I) may also be prepared by conventional substitution reactions of a compound of formula (XI):
wherein X, n, R1, R,, R, and R,are as hereinbefore defined with RsX wherein X is a displaceable group such as a halide or other good leaving group. In such reactions it may be necessary to first convert the compound of the formula (XI) to an alkali metal salt of the 10-hydrogen.
The skilled man will realise that in some cases this substitution reaction will also substitute a R1 hydrogen. Thus if a compound is desired wherein R1 is hydrogen in such cases it will be preferred to esterify the R, hydrogen before the substitution reaction, and then de-esterify after the substitution reaction, to give the desired R1 hydrogen compound.
Our copending cognate British Patent Application No. 8017676 and 8017677 Serial No. 1,598,663 entitled "10,12 iazaprostaglandins" describes the preparation of compounds of the formula (X) and (XI).
The conversion of a compound of the formula (I) to another compound of the formula (I) wherein R1, R, and/or R, are altered, when desired or necessary, may be achieved in conventional manner.
For example, if desired the group R1 in the compound may be varied by con ventional esterification and/or de-esterification reactions. Similarly, protected R hydroxy moieties may be deprotected in conventional manner. For example when R, 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). Also when a compound of the formula (I) contains as acidic hydrogen atom(s), salts thereof may be prepared in conventional manner for example by reacting the compound of the formula (I) with the required base.
It will of course be realised that the compounds of the formula (I) 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.
Compounds of the formula (I) have useful pharmacological activity. For example, compounds of the formula (I) have anti-gastric acid secretion activity, anti-ulcer activity, cardiovascular activity e.g. anti-hypertensive activity, platelet aggregation inhibition activity, affect the respiratory tract e.g. bronchodilator activity, anti-fertility activity, smooth muscle activity and/or anti-arrythmic activity.
In general it may be said that the compounds of the formula (I) have a range of pharmacological activities similar to those shown by the natural prostaglandins but that their activity profiles tend to be rather more selective so that each compounds tends to have a major activity readily ascertained by routine pharmacological tests.
The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.
In order to utilise the selectivity of activity found with compounds of the formula (I), normally a given compound will be used in the treatment of the disorder corresponding to the compound's major activity (that is, the disorder for which the compound has the lowest active dose) and will accordingly be formulated into the corresponding pharmaceutical composition, and administered in a manner conventional for treatment of that disorder.
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 microfineowderfor 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 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 non-human animals which comprises the administration to the animal of an effective amount of a compound of the formula (I).
Normally however the compounds will be used in the therapy of human disorders.
The following Examples illustrate the preparation of compounds of the formula (I) and their pharmacological properties.
EXAMPLE 1.
Compound 1.
Dimethyl 2-[N-3 '-hydroxy-3 '-methyldecyl] aminoazelate (9.6 g) was refluxed with methyl iso-cyanate (1.365 g) for 3 hours in dry benzene (80 mls). The benzene was evaporated in vacuo to give a pale yellow gum (10.2 g). This was chromatographed of kieselgel (packing ratio 30:1), using chloroform as eluant to give 1-(3 '- hydroxy-3 '-methyldecyl)-3-methyl-5-(6"-methoxyearbonylheXyl)hydantoin as a clear oil (6 g).
The compounds shown in Table 1 were prepared in a similar manner.
TABLE 1
Compound Number R, R, IR, R3 n 2 C2M5 CH3 n-C6H13 QM5 6 3 C2M5 CH3 n-C6H,3 CH3 6 4 CH3 (CM2) CH3 6 5 CH3 CH3 (CH2)2Ph CH3 6 6 CH3 CH3 n-C6H,3 CH3 6 7 CH3 CH3 CH(CH3)(CH2)3CH3 CH3 6 8 CH3 CH3 Ph CH3 6 9 CM3 CH3 n-C6H,3 Ph 6 10 CH3 CH3 (CH2)2 X CF3 CH3 6 11 CH3 CH3 CH3 CH3 6 12 CH3 CH3 - n-C6H,3 34 CH3 CH3 n-C6Hl3 Pha 6 35 C2H5 CH3 n-C6H,3 CH3 7 36 C2M5 CH3 n C6H,3 H,, CH3 5 37 CH3 CH3 n-C6H,3 CH3 1 EXAMPLE 2.
Compound 13.
Dimethyl 2-[ 1 -(3'-hydroxy-3'-methylnonyl)-3-t-butylureido)iazelate (10 g) was refluxed with potassium t-butoxide (2.5 g) in dry toluene (150 ml) for 3 hours. The toluene was evaporated in vacuo and the resulting gum was partitioned between diethyl ether and very dilute hydrochloric acid. The ether solution was washed with brine then dried (MgSO4) and evaporated in vacuo to give a yellow gum (8.4 g). The gum was chromatographed on kieselgel (250 g) using chloroform as eluant to give 1-(3'-hydroxy-3'-methylnonyl)-3-t-butyl-5-(6"-methoxycarbonylhexyl)hydantoin (5.2) as a clear gum.
EXAMPLE 3.
Compound 14.
Dimethyl 2-[N-3'-benzyloxynonyl]aminoazelate (20 g) was refluxed with methyl iso-cyanate (2.46 g) in dry benzene (200 ml) for 3 hours. The benzene was evaporated in vacuo to give a deep yellow oil which was chromatographed on kieselgel (30:1 packing ratio), using chloroform as eluant, to give 1-(3'-benzyloxy- nonyl)-3-methyl-5-(6"-methoxycarbonylhexyl)hydantoin (9 g) as a colourless gum.
EXAMPLE 4.
Compound 15.
I - (3' - Hydroxy - 3' - methylnonyl) - 3 - ethyl - 5 - (6" - ethoxycarbonylhexyl)hydantoin (1.1 g) was refluxed overnight with 10% aqueous potassium carbonate solution (7.5 ml) and ethanol (30 ml). The solution was cooled and acidified with concentrated hydrochloric acid. The product was extracted into diethyl ether (3 x 100 ml). The ether solution was extracted with 5% sodium bicarbonate solution.
The resulting aqueous phase was back-washed with ether then was acidified with dilute hydrochloric acid. The product was extracted into ether and the ether solution was washed with brine, dried (M > SO4) and evaporated in vacuo to give 1 3 '-hydroxy-3 '-methytnonyl)-3-ethyl4-(6"-carboxyhexyl)hydantoin as a colourless gum (770 mg).
The compounds shown in Table 2 were prepared in a similar manner.
TABLE 2
Compound Compound Number R, R, R, n 16 CH3 n-C7Hls CH3 6 17 CH3 C2M5 CH3 6 18 C CH3 6 19 CH3 (CH2)2Ph CH3 6 20 CH3 n-C6 H13 CH3 6 21 CH3 CH(CH3)(CH2)3CH3 CH3 6 22 CH3 Ph CH3 6 23 H n-C6H.3 CH3 6 24 CH3 n-C6HI3 CtCH3)3 6 25 CH3 n-C6Hl3 Ph 6 (CH2)2- CH, 6 26 CM3 (CH2)2 CF3 CM3 6 27 CH3 CH3 CH3 6 28 CH, n-C, H,, V 6 38 CH, n-C,H,, Ph 39 CH3 n4C6Hl3 TABLE 2 (Continued)
Compound Number R, R4 R, n 40 CH3 n-C6H13 CH3 5 41 CH3 n-C6 H13 CH3 1 47 CH3 n-C6H13 CH2OCH3 6 48 | CH3 | n-C6H13 | CH2CO2H | 6 EXAMPLE 5.
Compound 29.
Dimethyl 2-[N-3'-hydroxy-3'-methylnonyl]aminoazelate (10 g) was refluxed with methyl iso-thiocyanate (1.89 g) in dry toluene (100 ml) for 3 hours. The toluene was evaporated in vacuo to give a yellow oil (11.1 g). The oil was chromatographed on kieselgel (330 g) using chloroform as eluant to give 1-(3'-hydroxy-3'-methyl- nonyl)-3-methyl-5-(6"-methoxycarbonylhexyl)-2-thiohydanto in (9.49 g) as a pale yellow oil.
The compounds shown in Table 3 were prepared in similar manner: TABLE 3
Compound No. R, R2 R4 R, 30 C2H5 CH3 n-C6 H13 CH3 31 | CH3 | CH3 | CH3 | CH3 EXAMPLE 6.
Compound 33.
1-(3'-Benzyloxynonyl)-3-methyl-5-(6"-methoxycarbonylhexyl)hydantoin (5 g) was hydrogenolysed over 10% palladium/charcoal, in dry 1,2-dimethoxyethane (50 mls), at room temperature and atmospheric pressure. The reaction mixture was then filtered through kieselguhr and the 1 ,2-dimethoxyethane was- evaporated in vacuo to give a colourless oil (3.8 g). The oil was chromatographed on silica gel (110 g) using chloroform as eluant to give 1-/3 '-hydroxynonyl)-3-methyl-5-l "-methoxy- carbonylhexyl)hydantoin as a colourless oil (2.48 g).
EXAMPLE 7.
Compound 42.
1-(3'-Hydroxy-3'-methylnonyl)-5-(6"-methoxycarbonylhexyl)hydantoin (5 g) in dry dimethylformamide (10 ml) was added to a stirred suspension of sodium hydride (376 mg; 80% oil dispersion) in dry dimethylformamide (20 ml), under nitrogen, at room temperature. The mixture was stirred overnight. Chloromethyl methyl ether (1.01 g) in dry dimethylformamide (10 ml) was added dropwise and the mixture was stirred for 24 hours at room temperature. The product was partitioned between very dilute hydrochloric acid and diethyl ether. The ether solution was washed with 5% aqueous sodium hydroxide solution, and with brine until the wash: ings were neutral, then was dried and evaporated in vacuo to give a yellow oil (4.1 g). The oil was chromatographed on silica gel (30:1) using chloroform, 1% methanoUchloroform and 2% methanoUchloroform as eluants to give 1-63'-hydroxy- 3 '-methyhtonyl)-3-methoxymethyl4-(6"-methoxycarhonylltexyl)-hydantoin (2.5 g) as a pale yellow gum.
The compounds prepared in Table 7 were prepared in a similar manner.
TABLE 7
Compound Number R5 X R, 43 BrCH2CO2CH3 CH2CO2CH5 44 BrCH2CN CH2CN 45* BrCH(CO2CH3)2 CH(CO2CH3)2 49 BrCH2Ph CH2Ph * The alkali extraction procedure was eliminated.
EXAMPLE 8.
Compound 48.
A 1% solution of sodium hydroxide in dry methanol (I equivalent) was added to a solution of 1-(3'-hydroxy-3'-methylnonyl)-3-methyl-5-(6"-carboxyhexyl)- hydantoin in dry methanol at room temperature. The methanol was evaporated in vacuo at 30 C and the product was triturated with 40/60 petroleum ether. The product was collected and dried over sodium hydroxide in a vacuum desiccator then was ground to a fine, pale yellow powder.
In similar manner was prepared the corresponding lithium salt.
Analytical Data Compound 1.
I.R. (cm-1) : 3450, [OH]; 1760, 1700,
1730, [-CO2CM3], NM R, (T) : 7.15, (s), (OH]: 7.05, (s), [-N-CH3]; 6.95 to 6.35, (m), [-N-CH2-); 6.35, (s), [-CO2CH3]; 6.0, (broad t), [-N-CH].
Analysis C23H42N2O5 requires C, 64.76: H, 9.92; N, 6.57%. found C, 64.44; H, 9.92; N, 6.71%.
Mass Spec . C23H42N2O5 requires . 426.3093 found 426.3065 Compound 2.
I.R. (cm-1) : 3500, [OH]; 1700, 1760,
1730, [-CH2Et] NMR (T) : 7.2, (s) [OH]; 6.2 to 6.8, (m), [CH3CH2N-; -N-CH2)] (CCl4) 5.9, (m) [-N-CH; CO2CH2CH3] Compound 3.
I.R. (cm-1) : 3500, [OH]; 1710, 1760
1730, [-CO2Et] NMR (r) : 7.2, (s), [OH]; 7.0, (s), [-N-CH3]; 6.2 to 7, (m), [-N-CH2]; 5.9, (m) [-N-CH; -CO2CH2CH3] Compound 4.
I.R. (cm-') 3500, [OH]: 1700, 1760
1720, [-CO2-CH3].
NMR (T) : 7.05, (s), [-N-CH3; OH]; 6.2 to 6.9, (m), [-N-CH2]; 6.35,(s), [-CO2CH3] 6.0, (t), [-N-CH] Analysis . C20H34N2O5 requires : C, 62.80; H, 8.96; N, 7.32% found : C, 62.61 ; H, 8.95; N, 7.19% Mass Spec . C20H34N2O5 requires : 382.2468 found : 382.2466 Compound 5.
I.R. (cm-1) : 3500, [OH]; 1700, 1760,
1730, [-CO2CH3).
NMR (#) : 7.75, (t), [-CH2CO2CH3]; 7.3 (m), [-CH2Ph]; 7.1, (s), [-OH]; 7.05, (s), [-N-CH3]; 6.5 to 7.0, (m), [-N-CH2]; 6.5, (s), [-CO2CH3]; 6.05, (broad t), [-N-CH].
Mass Spec . C24H34N2O4[m*-H2O] requires : 414.2518 found : 414.2523 Compound 6.
I.R. (cm-1) 3500, [OH]; 1700, 1760,
1730, [-CO2CH3].
NMR(T) : 7.3,(s), [OH]; 7.05, (s), [-N-CM3]; 6.3 to 7, (m), [-N-CH2]; 6.35, (s), [-CO2CH3]; 6.0, (m), [-N-CH].
Analysis . C22H40N2O5 requires C, 64.05; H, 9.77;N 6.79% found . C, 64.14; H, 9.68; N, 6.62% Mass Spec : C22H38N2O4[m*-H2O] requires . 394.2832 found 394.2848 Compound 7.
I.R. (cm-1) : 3500 [OH]; 1710, 1760,
1730, [-CO2CH3].
NMR (T) 7.75, (m), [-CH2CO2CH3]; 7.2, (s), [OH]; 7.05, (s), [-N-CH3]; 6.4 to 6.9 (m), [-N- CH2]; 6.35, (s), [-CO2CH3]; 6.05, (m), [-N-CH].
Mass Spec : C22H38N2O4 [m*-H2O] requires 394.2831 found . 394.2794 Compound 8.
I R. (cm-1) 3500, [OH]; 1700, 1760,
1730, [-CO2CH3].
Compound 9.
I.R. (cm-') 3500 cm-1, [@ [OH]; 1710, 1770,
1730, [-CO2CH3].
NMR (#) . 7.75 (t), [-CH2CO2CH3]; 7.45, (s), (OR]; 6.2 to 7.0, (m), [-N-CH2]; 6.37, (s), [CO2CH3]; 5.95, (m), [-N-CR]; 2.65, (s), [C6H5].
Mass Spec : C27H42N2Os requires : 474.3094 found : 474.3083 Compound 10.
I.R. (cm-1) : 3500, [OH]; 1710, 1760,
1730, [-CO2CH3].
NMR(#) : 7.8, (t), [-CH2CO2CH3]; 7.3, (m), [-CH2-Ar]; 7.1(s), [-N-CH3]; 6.5 to 7, (m), [-N-CH2]; 6.45, (s), [-CO2CH3]; 6.1 (m), [-N-CH]; 2.65, (broad s), [-Ar].
Mass Spec : C25H33N2O4F3[m*-H2O] requires : 482.2392 found : 482.2415 Compound 11.
I.R. (cm-1) : 3500, [OH]; 1710, 1760.
1730, [-CO2CH3].
NMR (T) : 7.75(t), [-CH2-CO2CH3]; 7.15, (s), [OR]; 7.1, (s), [-N-CH3].
6.2 to 7, (m), [-N-CH2]; 6.4, (s), [-CO2CH3]; 6.05, (m), [N-CH].
Mass Spec C17H30N2O5 requires . 342.2154 found 342.2144 Mass Spec C,7H28N204 [m*-H2O] requires 324.2049 found : 324.2050 Compound 12.
I.R. (cm-1) 3500, [OH]; 1700, 1760,
1740, [-CO2CH3].
NMR (T) : 7.75, (t), [-CH2CO2CH3]; 7.1, (s), [OR]; 6.2 to 7, (m), [-N-CH2]; 6.4, (s), [-CO2CH3]; 6.1, (m), [-N-CH].
Mass Spec . C27H48N2O5 requires 480.3564 found : 480.3536 Compound 13.
I.R. (cm-1) . 3500, [OH]; 1700, 1750,
1735, [-CO2CH3].
NMR(#) . 7.2, (s), [OH]; 6.3 to 7, (m), [-N-CH2-]; 6.3, (s), [-CO2CH3]; 6.2, (m), [-N-CH].
Analysis : C25H45N2O5 requires : C, 66.05; H, 10.20; N, 6.16% found C, 65.89; H, 10.30; N, 6.13% Mass Spec C25H46N2O5 requires 454.3406 found : 454.3451 Mass Spec : C25H44N2O4 [m*-H2O] requires : 436.3301 found : 436.3317 Compound 14.
I.R. (cm-1) . 1710, 1760,
1730, [CO2CH3].
NMR (#) : 7.1, (d), [-N-CH3]; 6.3 to 7, (m), [-N-CH2]; 6.35, (s), [-CO2CH3]; 6.2, (m), [-N-CH]; 5.5, (s, with shoulder), [-OCH2Ph]; 2.75, (s), [-OCH2Ph].
Analysis :. C28H44N2Os requires : C, 68.82; H, 9.08; N, 5.73% found : C, 68.62; H, 9.21;N, 5.66% Mass Spec C28H44N2O5 requires : 488.3250 found : 488.3287 Compound 15.
I.R. (cm-1) : 3700 to 2500, [-CO2H; OH]; 1760, 1710, 1700
NNR (#) : 7.0 to 5.9, (m), [(-N-CH2)x2; -N-CH]; 4.4 (broad s), [-CO2H; OR].
Mass Spec . C22H40N2O5 requires : 412.2937 found 412.2917 Compound 16.
I.R. (cm-1) : 3700 to 2400, [-CO2H; OH]; 1760, 1720, 1700,
NMR (T) . 7.05, (s), [-N-CH3]; 6.95 to 6.35, (m), [-N-CH2]; 6, (broad s), [-N-CH]; 3.15, (broad s), [CO2H; OR].
Analysis : C22H40N2O5 requires : C, 64.05; H, 9.77; N, 6.79% found : C, 64.36; H, 9.99; N, 6.99% Mass Spec : C22H38N2O4 [m*-H2O] requires : 394.2831 found : 394.2848 Compound 17.
I.R. (cm-1) . 3700 to 2500, [CO2H; OH]: 1760, 1700 (broad),
NMR(T) : 7.05,(s), [-N-CH3]; (CD3)2CO 6.9 to 6.1, (m), [-N-CH2]; 5.9 to 5.7, (s + t), [-N-CH; CO2H; OR].
Mass Spec : C17H30N2O5 requires 342.2155 found 324.2174 Compound 18.
I.R. (cm-1) : 3700 to 2400, [CO2H; OH] 1760, 1700 (broad)
NMR (#) . 7.1, (s), [N-CH3]; 6.6, (m), [-N-CH2]; 6.05, (broad s), [CO2H; OH]; 5.85, (t), [-N-CH]; Analysis C,9H32N2Os requires : C,61.93; H, 8.75; N, 7.60% found : C, 61.99; H, 8.97; N, 7.64% Mass Spec : C,9H32N2Os requires . 368.2311 found : 386.2313 Compound 19.
I.R. (cm-1) . 3700 to 2400, [CO2H; OH]; 1760 to 1700,
NMR (#) : 7.3, (m), [-CH2Ph]; 7.05, (s), [-N-CH3]; 6.8 to 6.1(m), [-N-CH2]; 6.15, (s), [-CO2H; OR]; 5.8, (t), [-N-CH].
Analysis C23H34N2Os requires : C, 66.01; H, 8.19; N, 6.69% found : C, 65.82; H, 8.38; N, 6.37% Mass Spec : C23H32N2O4 [m*-H2O] requires : 400.2362 found : 400.2323 Compound 20.
I.R. (cm-1) . 3700 to 2400, [CO2H; OH]; 1760, 1720, 1700,
NMR (#) : 7.1, (s), [-N-CH3]; 6.8 to 6.1, (m), [-N-CH2]; 6.1, (s), [CO2H; OH]; 5.85, (t), [-N-CH].
Mass Spec . C21H36N2O4 [m*-H2O] requires . 380.2675 found : 380.2672 Compound 21.
I.R. (cm-1) 3700 to 2500, [CO2H; OH]; 1760, 1740 to 1690,
NMR (#) . 7.1, (s), [-N-CH3]; (CD3)2CO 6.9 to 6.1, (m), [-N-CH2]; 5.9, (t), [-N-CH]; 5 to 3, (broad hump), [CO2H; OR].
Analysis . C21H38N2O5 requires : C, 63.29; H, 9.61; N, 7.03% found : C, 62.94; H, 9.79; N, 6.65% Mass Spec C21H36N2O4 [m*-H20] requires . 380.2675 found 380.2641 Compound 22.
I.R. (cm-1) . 3700 to 2500, [CO2H, OH]; 1760, 1700 (broad)
NMR (#) : 7.25, (d), [-N-CH3]; 6.9 to 6.1, (m), [-N-CH2]; 5.6, (broad s), [-CO2H, OR]; 2.65, (m), [Ph].
Analysis . C21H30N2O5 requires C, 64.60; H, 7.74; N, 7.17% found : C, 64.83; H, 7.96; N, 6.91% Mass Spec : C2,H28N204 [m*-H2O] requires : 372.2049 found 372.2037 Compound 23.
I.R. (cm-1) : 3700 to 2500, [CO2H; OH]; 1760, 1710 (broad),
NMR(T) : 7.1,(s), [-N-CH3]; 6.8 to 6.1, (m), [-N-CH2]; 5.9, (t), [-N-CH]; 4.5, (broad), [CO2H; OH].
Analysis : C20H36N2O5 requires : C, 62.47; H, 9.44; N, 7.29% found : C, 62.40; H, 9.59; N, 7.04% Mass Spec : C20H36N2O5 requires : 384.2624 found : 384.2640 Compound 24.
I.R. (cm-1) : 3700 to 2400, [CO2H; OH]; 1760, 1700 (broad)
NMR (T) . 6.7, (s), [CO2H; OH]; 7 to 6.3, (m), [-N-CH2]; 6.1, (t), [-N-CH].
Analysis . C24H44N2O5 requires : C, 65.42; H, 10.07; N, 6.36% found : C,65.21;H, 10.29; N, 6.08% Mass Spec : C24H44N2O5 requires : 440.3250 found : 440.3280 Compound 25.
I.R. (cm-1) 3200 to 2600, [CO2H; OH]; 1770, 1700 (broad),
NMT (T) 7 to 6.1, (m), [-N-CH2]; 5.95, (broad), [CO2H; OH]; 5.6, (t), [-N-CH]; 2.6, (d), [Ph].
Mass Spec : C26H38N2O4 [m*-H2O] requires : 442.2832 found : 442.2841 Compound 26.
I.R. (cm-1) . 3200 to 2400, [CO2H; OH]; 1770, 1730 to 1680,
NMR (T) . 7.8, (t), [-CH2-CO2H]; D6DMSO 7.4, (m), [-CH2-Ar]; 7.15, (s), [-N-CH3]; 7 to 6, (m), [-N-CH2]; 5.8, (m), [-N-CH].
Analysis C24H33N2OsF3 requires C, 59.25; H, 6.83; N, 5.76% found C, 59.29; H, 7.13; N, 5.82% Mass Spec . C24H31N2O4F3 [m*-H2O] requires 468.2236 found : 468.2245 Compound 27.
I.R. (cm-1) . 3200 to 2400, [CO2H; OH]; 1760, 1730 to 1690,
NMR (#) : 7.75, (t), [-CH2-CO2H]; (D6DMSO) 7.1, (s). [-N-CH3]; 7 to 6, (m), [-N-CH2]; 5.8, (t), [-N-CH].
Analysis : C16H28N2O5 requires C, 58.52; H, 8.59; N, 8.53% found : C, 58.59; H, 8.71; N, 8.70% Mass Spec : C16H28N2O5 requires : 328.1998 found : 328.1995 Compound 28.
I.R. (cm-1) : 3200 to 2400, [CO2H; OH]; 1760 to 1680,
NMR (T) : 7 to 6.2, (m), [-N-CH2]; (CD3)2CO 6.1, (broad s), [CO2H; OH]; 6.0, (m), 5.5, (m),
Analysis . C25H46N2O5 requires : C, 66.92; H, 9.94; N, 6.00% found : C, 66.57; H, 10.06; N, 6.25% Mass Spec : C26H46N2O5 requires : 466.3406 found : 466.3403 Compound 29.
I.R. (cm-1) 3510, [OH]; 1750 to 1720,
NMR (T) : 7.75, (m), [OH; CH2-CO2CH3]; 6.8, (s), [-N-CH3]; 7 to 6.2, (m), [-N-CH2]; 6.35, (s), [-CO2CH3]; 5.9, (m), [-N-CH].
Analysis : C22H40N2O4S requires C, 61.64; H, 9.41; N, 6.53; S, 7.48% found C, 61.71; H, 9.51; N, 6.54; S, 7.34% Mass Spec C22H38N2O3S [m*-H3O] requires . 410.2603 found . 410.2610 Compound 30.
I.R. (cm-1) : 3500, [OH]; 1740,
NMR (T) : 7.7, (s), [OH]; 6.8, (s), [-N-CH3]; 6.9 to 6.2, (m), [-N-CH2]; 5.9, (m), [-N-CH; -CO2CH2CH3].
Analysis C23H42N2O4S requires : C, 62.41; H, 9.56; N, 6.33; S, 7.24% found C, 62.54; H, 9.85; N, 6.05; S, 7.35% Mass Spec : C23H42N204S requires : 442.2865 found : 442.2866 Compound 31.
I.R. (cm-1) : 3500, [OH]; 1740, 1720,
NMR (#) . 7.45, (s), [OH]; 6.8, (s), [-N-CH3]; 6.9 to 6.2, (m), [-N-CH2]; 6.4, (s), [-CO2CH3]; 5.9, (m), [-N-CH].
Mass Spec : C17H30N2O4S requires : 358.1926 found : 358.1956 Compound 33.
I.R. (cm-1) : 3500, [OH]; 1760, 1710, [
NMR (#) : 7.05, (s), [-N-CH3]; 6.7 to 6.2, (m), [-N-CH2]; 6.35, (s), [-CO2CH3]; 6.0, (s), [-N-CH].
Analysis : C21H38N2O5 requires C, 63.29; H, 9.61; N, 7.03% found . C, 63.61; H, 9.83; N, 7.34% Mass Spec . C2,H38N2OS requires : 398.2780 found : 398.2769 Compound 34.
I.R. (cm-1) ' 3550, [OH]; 1770, 1730 (broad)
NMR (#) : 7.75,(t), [CH2CO2CH3]; 7.35, (m), [Ph-CR]; 7.35, (s), [OR]; 7.0 to 6.2, (m), [-N-CH2]; 6.4, (s), [-CO2CH3]; 6.1, (m), [-N-CH] x 2; 2.7, (s), [Ph].
Mass Spec C30H44N2O4 (m*-H2O) requires . 496.3301 found 496.3303 Compound 35.
I.R. (cm-1) : 3550, [OH]; 1770, 1710
1730, [-CO2C2H5].
NMR (T) . 7.7(t), [CH2CO2C2H5]; 7.5, (s), [OR]; 7.0, (s), [-N-CH3]; 7.0 to 7.2, (m), [-N-CH2]; 6.05 (t), [-N-CH];
Mass Spec . C24H42N2O4 (*-H2O) requires : 422.3144 found : 422.3156 Compound 36.
I.R. (cm-1) 3500, [OH]; 1760, 1710
1720, [-CO2C2H5].
NMR (T) : 7.75, (t), [CH2CO2C2H5]; 7.5, (s), [OR]; 7.05, (s), [-N-CH3]; 6.9 to 6.2, (m), [-N-CH2]; 6.05, (m), [-N-CH]; 5.9, (q), [-CO2CH2CH3].
Mass Spec C22H38N2O4 (m*-H2O) requires : 394.2832 found : 394.2826 Compound 37.
I.R. (cm-1) : 3500, [OH]; 1770, 1710,
1740, [-CO2CH3].
NMR (#) : 7.75, (s), [OH]; 7.1, (m), [CH2CO2CH3]; 6.9 to 6.3 approx, (m), [-N-CH2]; 6.95, (s), [-N-CH3]; 6.25, (s), [-CO2CH3]; 5.7, (t), [-N-CH].
Mass Spec : C17H28N2O4 (m*-H2O) requires : 324.2048 found 324.2056 Compound 38.
I.R. (cm-1) 3700 to 2500, [-CO2H; OH]; 1760, 1720 (broad),
NMR (#) : 7.7, (m), [CH2CO2H]; 7.3 (m), (Ph-CH]; 7.0 to 6.1, (m), [-N-CH2]; 5.9, (t), [-N-CH] x 2; 5.7, (broad s), [CO2H; OH]; 2.75, (s), [Ph].
Mass Spec : C29H42N2O4 (m*-H2O) requires : 482.3145 found : 482.3184 Analysis : C29H44N2O5 requires : C, 69.57; H, 8.86; N, 5.60%. found : C, 69.83; H, 9.05; N, 5.32%.
Compound 39.
I.R. (cm-1) . 3800 to 2500, [-CO2H; OH]; 1770, 1720 (broad),
NMR (#) : 7.7, (t), [CH2CO2H]; 7.1, (s), [-N-CH3]; 7.0 to 6.1, (m), [-N-CH2]; 6.2, (broad s), [-CO2H; OH]; 5.8, (t), [-N-CH].
Mass Spec . C22H38N2O4 (m*-H2O) requires 394.2831 found : 394.2823 Analysis . C22H4ON2o5 requires C, 64.05; H, 9.77; N, 6.79%. found C, 63.98; H, 9.97; N, 6.57%.
Compound 40.
I.R. (cm-1) . 3700 to 2500, [-CO2H; OH]; 1760, 1710 (broad),
NMR (#) . 7.8, (t), [CH2CO2H]; 7.2, (s), [-N-CH3]; 6.9 to 6.1, (m), [-N-CH2]; 5.95, (t), [-N-CH]; 4.6 to 3.3, (broad hump), [-CO2H; OH].
Mass Spec : C20H34N2O4 (m*-H2O) requires : 366.2518 found : 366.2513 Compound 42.
Mass Spec: C16H26N2O4 (m*-H2O) requires: 310.1892 found: 310.1891 Compound 42.
I.R. ( m-): 3500, [OH]; 1770, 1720 (broad),
NMR (#) 7.8, (t), [-CH2CO2CH3]; 7.3, (s), [OH]; 7 to 6, (m), [-N-CH2]; 6.6, (s), [-OCH3]; 6.3, (s), [-CO2CH3]; 5.9, (t), [-N-CH]; 5.2, (s), [CH2OCH3].
Mass Spec : C23H40N2Os (m*-H2O) requires : 424.2937 found : 424.2942.
Compound 43.
I.R. (cm-1) : 3550, [OH]; 1760 to 1710, (broad),
NMR (T) @ 7.75, (t), [CH2CO2CH3]; 7.4, (s), [OR]; 7 to 6.4, (m), [-N-CH2]; 6.4, (s), [CO2CH3]; 6.25, (s), [CO2CH3]; 5.9, (s + m), [-N-CH2CO2CH3; -N-CH].
Mass Spec : C24H40N2O6 (m*-H2O) requires : 452.2886 found : 452.2892 Compound 44.
I.R. (cm-') @ 3500, [OH]; 1765, 1720 (broad),
NMR (T) 7.7, (t), [-CH2CO2CH3]; 7.3, (s), [OH]; 7.0 to 6.3, (m), [-N-CH2]; 6.35, (s), [CO2CH3]; 5.85, (m), [-N-CH]; 5.65, (s), [-CH2CN].
Mass Spec : C23H37N3O4 (m*-H2O) requires : 419.2784 found : 419.2771 Analysis : C23H39N3Os requires C, 63.13; H, 8.98; N, 9.60%. found : C, 63.21; H, 9.13; N, 9.31%.
Compound 45.
I.R. (cm-'): 3500, [OH]; 1730, (very broad),
NMR (T): 7.75, (t), [CH2CO2CH3]; 7.6, (s), [OH]; 7 to 6.4 approx, (m), [-N-CH2]; 6.4, (s), [-CO2CH3];
Mass Spec . C26H42N2O8 (m*-H2O) requires : 510.2941 found : 510.2937 Compound 46.
I.R. (cm-'): 3200 to 2600, [-CO2H; OH]; 1770, 1700 (broad),
NMR (#): 7.7, (t), [-CH2CO2H]; 7 to 6.1 approx, (m), [-N-CH2]; 6.65, (s), [-OCH3]; 5.95, (m), [-N-CH]; 5.15, (s), [-N-CH2OCH3]; 4.3, (broad s), [CO2H; OR].
Mass Spec : C2,H34N204 (m*-H2O-MeOH) requires : 378.2519 found : 378.2507 Compound 47.
I.R.(cm-1) : 3600 to 2400, [CO2H; OH]; 1760 to 1690,
Compound 48.
Analysis : C2,H37N2OsNa requires : C,59.98; H, 8.87; N, 6.66; Na, 5.47%. found : C, 60.15; H, 9.19; N, 6.71; Na, 5.52%.
Compound 49.
I.R. (cm-1) : 3500, [OH]; 1760, 1710,
1730, [CO2CH3).
NMR (y) : 7.8, (t), [-Cl?2CO2CH3]; 7.2, (hump), [-OR]; 7 to 6.2 approx. (m), [-N-Cl?2-]; 6.4, (s), [-CO2CH3]; 6.05, (t), [-N-CR]; 5.45, (s), [CH2Ph]; 2.7, (broad s), [CH2Ph].
PHARMACOLOGICAL DATA Bronchodilation activity 1. The compounds were examined for their ability to inhibit 5-hydroxytryptamine or histamine induced bronchoconstriction in the anaesthetised, artificially respired guinea pig (Konzett-Rossler preparation). The compounds were administered intravenously. The results are shown in Table A.
2. The compounds were also examined for their ability to protect conscious guinea pigs against broncoconstriction induced by an histamine aerosol (Herxheimer test). In these experiments the compounds were administered by aerosol or by oral administration. The results are shown in Table B. The results are the mean of several experiments.
TABLE A
Compound ID50 against 5-hydroxytryptamine-induced Number constriction g/kg, i.v.
1 4.5 2 6.8 3 0.4 4 220 6 1.5 7 3.3 15 5.8 16 8.5 18 > 220 20 0.6 21 3.2 22 60 23 6.0 26 30 30 4.2 Similar results were obtained against histamine-induced bronchoconstriction; for example, compound 20 also had an ID50 of 0.6 g/kg, i.v., against histamineinduced constriction.
TABLE B
Compound Aerosol route Oral route Number Activity; llg/ml Activity; mg/kg 1 A ; 10 2 A ; 10 3 A ; 1.0 A ; 0.25 15 A ; 10 16 A ; 10 20 A ; 0.25 A ; 0.25 A active Anti-ulcer activity Method Anti-ulcer activity was assessed by the inhibition of indomethacin induced gastric damage in the rat according to the method of Eleghe (1974) Israeli J. Med.
Sci. 10. 1451. Rats were starved overnight given 15 mg/kg indomethacin subcutaneously and sacrificed 4 hours later. Stomachs were reflated with n. saline, cut along the greater curvature pinned out and scored for gastric damage by the following system: Score 1-3 - according to degree of erytherma and slight haemorrhage.
* Score 4-6 - according to degree of mucosal erosion.
Score 7-9 - according to depth of gastric damage.
Groups of 7 rats were used for each treatment and the test compound or vehicle were administered 30 minutes prior to giving the indomethacin. Dose of test compound was 100 mg/kg orally and control groups receiving vehicle only were set up simultaneously. Mean values for each treatment were obtained using the above scoring system and the Mann Witney test applied for significance of difference between the values obtained with the treatments.
The results are shown in Table C.
TABLEC
Vehicle Control Test Compound Number Mean Score t S.E. of Mean Mean Score + S.E. of Mean 16 4.86 + 0.77 0.43 + 0.30 (P < 0.01) 21 2.29 + 0.87 0.00 + 0.00 (P < 0.05) 24 3.86 + 0.74 1.14 + 0.74 (P < 0.05) 29 5.8(r- + 0.83 0.14 + 0.14 (P < 0.05) 30 2.00 + 0.79 0.00 + 0.00 Compared with vehicle only treatment, the compounds reduced the mean ulcer score and therefore have significant anti-ulcer activity.
Anti-secretory activity.
The compounds were examined for their ability to inhibit pentagastrinstimulated gastric acid secretion in the anaesthetised, perfused rat stomoch, preparation (Ghosh and Schild preparation). The compounds were administered intra-venously.
Compouind 16 inhibited gastric acid secretion over the dose range 5-10 mg/kg, i.v.
Anti-platelet aggregation activity.
The compounds were examined for their ability to inhibit platelet aggregation induced in vitro by collagen in human platelet rich plasma.
Compounds 17 and 16 inhibited aggregation by 100% and 34%, respectively, at a concentration of 100 yM. The IC,, for Compound 17 against collagen-induced aggregation was 7 pom.
Anti-arrythmic activity.
The compounds were examined for anti-arrythmic activity by determining their ability to prevent heart fibrillation in mice exposed to chloroform.
Compound 16, when given intraperitoneally at 100 mg/kg, prevented fibrillation induced by chloroform in a group of 3 mice.
Toxicity The compounds do not appear to be acutely toxic. For example, Compound 16 was not toxic in mice at doses up to 300 mg/kg, orally, or at doses up to 100 mg/kg, intraperitoneally, whereas Compound 20 was not toxic at doses up to 900 mg/kg, orally, in mice.

Claims (61)

  1. WHAT WE CLAIM IS:1. A compound of the formula (I):
    wherein: X is 0 or S; n is 1 to 8; R1 is hydrogen, or CO2R1 represents an ester group in which the R, moiety contains from 1 to 12 carbon atoms; R, is hydrogen, C14 alkyl, or phenyl; R, is hydroxy or protected hydroxy; R4 is hydrogen, C1-9 alkyl, C3-8 cycloalkyl, C3-8 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, C16 alkyl, hydroxy, C16 alkoxy, phenyl-C1-6 alkoxy or nitro groups; or R, and R, taken with the carbon atom to which they are joined represent a C5-8 cycloalkyl group; R, is C16 alkyl, C16 alkyl substituted by a halogen atom or by a nitro, hydroxy, C1-6 alkoxy, CO2A, (CO2A)2, or CN group, C5-8 cycloalkyl, phenyl, phenyl-C1-6alkyl, phenyl-C3-6 cycloalkyl, any of which phenyl moieties may be substituted by one or more halogen atoms or trifluoromethyl, C16 alkyl, C1-6 alkoxy or nitro groups; or a group CO2A; in R, when present A is hydrogen or CO2A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; or a salt thereof.
  2. 2. A compound according to claim 1, wherein R5 is C5-8 cycloalkyl or phenyl C3-6 cycloalkyl, which phenyl moiety may be substituted by one halogen atom or by one trifluoromethyl, C16 alkyl, C1-6 alkoxy or nitro group.
  3. 3. A compound according to claim 1, wherein R, is C16 alkyl substituted by one halogen atom or by one nitro, hydroxy, C1-6 alkoxy, CO2A, (CO2A)2 or CN group.
  4. 4. A compound according to claim 3, wherein R, is a methyl group substituted by one halogen atom or by one nitro, hydroxy, C16 alkoxy, CO2A, (CO2A)2 or CN group.
  5. 5. A compound according to claim 4, wherein R, is cyanomethyl.
  6. 6. A compound according to any one of the claims 2 to 5, wherein X is O.
  7. 7. A compound according to any one of the claims 2 to 6, wherein n is 5, 6 or 7.
  8. 8. A compound according to any one of the claims 2 to 7, wherein R1 is hydrogen or C16 alkyl.
  9. 9. A compound according to any one of the claims 2 to 8, wherein R, is hydrogen or methyl.
  10. 10. A compound according to any one of the claims 2 to 9, wherein R, is hydroxy.
  11. 11. A compound according to any one of the claims 2 to 10, wherein R, is C1-9 alkyl.
  12. 12. A compound according to claim 1, wherein: X is 0 or S; n is 4 to 8; R, is hydrogen, or CO2IR, represents an ester group in which the R, moiety contains from 1 to 12 carbon atoms; R2 is hydrogen, C1-4 alkyl, or phenyl; R3 is hydroxy or protected hydroxy; R, is hydrogen, C19 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 atom, or trifluoromethyl, C1-6 alkyl, C1-6 alkoxy or nitro groups; R, is C1-6 alkyl, phenyl, phenyl-C1-6 alkyl, or a group CO2A wherein A is hydrogen or CO2A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; or a salt thereof.
  13. 13. A compound according to claim 12, wherein n is 5, 6 or 7.
  14. 14. A compound according to claim 12 or 13, wherein R3 is hydroxy.
  15. 15. A compound according to claim 12, 13 or 14, wherein R4 is C1-6 alkyl.
  16. 16. A compound according to any one of the claims 12 to 15, wherein R5 is C1-6 alkyl.
  17. 17. A compound according to claim 12, of the formula (II):
    wherein: X and R1 are as defined in claim 12; n'is5,6or7; R'2 is hydrogen, methyl, ethyl or phenyl; R4 is hydrogen or C1-9 alkyl; R5 is C1-6 alkyl, phenyl, phenyl-C1-6 -alkyl, or a group CO2A wherein A is hydrogen or CO2A represents an ester group in which the A moiety contains from 1 to 12 carbon atoms; or a salt thereof.
  18. 18. A compound according to claim 17, wherein R15 is C16 alkyl.
  19. 19. A compound according to claim 18, wherein R5 is methyl.
  20. 20. A compound according to claim 18 or 19, wherein X is 0.
  21. 21. A compound according to claim 18, 19 or 20, wherein n' is 6.
  22. 22. A compound according to any one of the claims 18 to 21, wherein R1 is hydrogen or C16 alkyl.
  23. 23. A compound according to any one of the claims 18 to 22, wherein R'2 is hydrogen.
  24. 24. A compound according to any one of the claims 18 to 22, wherein R is methvl.
  25. 25. A compound according to claims 18 to 24, wherein R14 is C46 alkyl.
  26. 26. A sodium salt of a compound according to any one of the claims 18 to 25, when R1 is H.
  27. 27. A compound according to claim 25, wherein R'4 is n-pentyl, n-hexyl or nheptyl.
  28. 28. A compound according to claim 17, wherein R5 is methyl, X is 0, n' is 6, R1 is hydrogen or C1-6 alkyl, R2 is methyl, R4 is n-pentyl, n-hexyl or n-heptyl.
  29. 29. A compound according to claim 28, wherein R4 is n-hexyl.
  30. 30. 1-(3'-Hydroxy-3'-methylnonyl)-3-methyl-5-(6"-carboxy hexyl)hydantoin.
  31. 31. The sodium salt of the compound of claim 30.
  32. 32. A compound according to claim 25, wherein R'4 is a group CH(CH3)R'7, wherein R'7 is n-butyl, n-pentyl or n-hexyl.
  33. 33. A compound according to claim 17, wherein R5 is methyl X is 0, n' is 6, R1 is hydrogen or C1-6 alkyl, R2 is methyl, R4 is CH(CH3)R7, wherein R7 is nbutyl, n-pentyl or n-hexyl.
  34. 34. 1-(3'-Hydroxy-3',4'-dimethyl-octyl)-3-methyl-5-(6"-carboxy hexyl)hydantoin.
  35. 35. A compound according to claim 12, of the formula (VII):
    wherein X and R1 are as defined in claim 12; n', R2 and R5 are as defined in claim 17; R44 is a group of formula (VIII):
    wherein T is a bond, or a C16 alkylene group which may be straight chain or branched by one or two methyl groups at the same or different carbon atoms; and r is 0 to 3.
  36. 36. A compound according to claim 35, wherein R's is C16 alkyl.
  37. 37. A compound according to claim 36, wherein R's is methyl.
  38. 38. A compound according to claim 36 or 37, wherein X is 0.
  39. 39. A compound according to claim 36, 37 or 38, wherein n' is 6.
  40. 40. A compound according to any one of the claims 36 to 39, wherein R1 is hydrogen or C16 alkyl.
  41. 41. A compound according to any one of the claims 36 to 40, wherein R'2 is hydrogen.
  42. 42. A compound according to any one of the claims 36 to 40, wherein R'2 is methyl.
  43. 43. A compound according to any one of the claims 36 to 42, wherein r is 1.
  44. 44. A compound according to claim 35, wherein R's is methyl, X is 0, n' is 6, R1 is hydrogen or C1~6, R'2 is methyl and r is 1.
  45. 45. A compound according to claim 44, wherein R44 is cyclohexyl.
  46. 46. A process for the preparation of a compound according to claim 1, which process comprises the cyclisation of a compound of formula:
    wherein R2, R3, R4, R5, n and X are as defined in claim 1 and R1 is a group such that CO2R1 is an ester group containing up to 12 carbon atoms; and thereafter if desired converting R1, R3 or R5 in the thus formed compound into other variables R1, R3 or R5.
  47. 47. A process for the preparation of a compound according to claim 1 which process comprises the reaction of a compound of the formula (X):
    wherein R,, R,, R,, and n are as defined in claim I and R11 is as defined in claim 46 with a compound RsNCX wherein R, and X are as defined in claim 1; and thereafter if desired or necessary converting R1, R3 or R5 in the thus formed compound into other variables R1, R3 or R5.
  48. 48. A process for the preparation of a compound according to claim 1, which process comprises reacting a compound of formula (XI):
    wherein the variable groups are as defined in claim 1 with R,X wherein X is a displaceable group; and thereafter if desired converting R1, R, or R, in the thus formed compound into other variables R1, R, or R,, wherein R, is as defined in claim 1.
  49. 49. A process according to claim 46, 47 or 48, for the preparation of a compound according to any one of the claims 12 to 45.
  50. 50. A pharmaceutical composition comprising a compound according to any one of the claims 1 to 11 and a pharmaceutically acceptable carrier.
  51. 51. A pharmaceutical composition comprising a compound according to any one of the claims 12 to 45 and a pharmaceutically acceptable carrier.
  52. 52. A process for the preparation of a composition according to claim 50, which process comprises bringing together the compound and the carrier.
  53. 53. A process for the preparation of a composition according to claim 51, which process comprises bringing together the compound and the carrier.
  54. 54. A method of treatment and/or prophylaxis of disorders in non-human animals which comprises the administration to the animal of an effective amount of a compound according to any one of the claims 1 to 11.
  55. 55. A method according to claim 54, using a compound according to any one of the claims 12 to 45.
  56. 56. A process according to claim 46, 47 or 48, substantially as hereinbefore described with reference to any one of the Examples.
  57. 57. A process according to claim 52, substantially as hereinbefore described with reference to Compounds numbered 1,2, 3, 15, 16 and 17 of Examples 1 and 4.
  58. 58. A compound according to claim 1, substantially as hereinbefore described with reference to any one of the Examples.
  59. 59. A compound according to claim 12, substantially as hereinbefore described with reference to any one of the Compounds numbered 1, 2, 3, 15, 16 and 17 of Examples 1 and 4.
  60. 60. A compound according to any one of the claims 1 to 11 and 58, whenever prepared by a process according to any one of the claims 46, 47, 48 and 56.
  61. 61. A compound according to any one of the claims 12 to 45 and 59, whenever prepared by a process according to claim 49 or 57.
GB52955/76A 1976-12-18 1976-12-18 10,12-diazoprostaglandins Expired GB1598662A (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
GB52955/76A GB1598662A (en) 1976-12-18 1976-12-18 10,12-diazoprostaglandins
IL53559A IL53559A0 (en) 1976-12-18 1977-12-07 Novel prostaglandin analogues their preparation and pharmaceutical compositions containing them
NZ185909A NZ185909A (en) 1976-12-18 1977-12-08 1,5-dusubstituted hydantois (or 2-thiohydantoins)and pharmaxeutical compositions
ZA00777335A ZA777335B (en) 1976-12-18 1977-12-08 Pharmaceutical compounds
DK551777A DK551777A (en) 1976-12-18 1977-12-09 PROCESS FOR PRODUCTION OF PROSTAGLAND INDUSTRY PROCEDURE FOR PRODUCTION OF PROSTAGLAND INDUSTRY
DE19772755771 DE2755771A1 (en) 1976-12-18 1977-12-14 DERIVATIVES OF 4-OXO-IMIDAZOLINE, THE PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
AT0893777A AT368498B (en) 1976-12-18 1977-12-14 METHOD FOR PRODUCING NEW CONNECTIONS AND THEIR SALTS
AU31613/77A AU514523B2 (en) 1976-12-18 1977-12-15 Hydantoin and thio-hydantoin derivatives
GB2675580A GB1598665A (en) 1976-12-18 1977-12-15 Ureidoazelates
GB2671780A GB1598664A (en) 1976-12-18 1977-12-15 Ureidoazelates
FI773812A FI773812A7 (en) 1976-12-18 1977-12-16 PHARMACEUTICAL ASSOCIATIONS
NO774348A NO774348L (en) 1976-12-18 1977-12-16 PROCEDURE FOR PREPARING COMPOUNDS OF PHARMACOLOGICAL ACTIVITY
ES465176A ES465176A1 (en) 1976-12-18 1977-12-16 Novel compound having pharmacological activity* method for their production* intermediate compound useful for their production and medical compositions containing same
FR7738009A FR2374309A1 (en) 1976-12-18 1977-12-16 DIAZOLE CYCLE COMPOUND FOR USE AS A MEDICINAL PRODUCT
CH1554577A CH639076A5 (en) 1976-12-18 1977-12-16 Process for the preparation of 4-oxoimidazolidine compounds
BE183545A BE861956A (en) 1976-12-18 1977-12-16 DIAZOLE CYCLE COMPOUND FOR USE AS A MEDICINAL PRODUCT
NL7713971A NL7713971A (en) 1976-12-18 1977-12-16 PROCESS FOR PREPARING NEW HYDANTEIN DERIVATIVES, AND DOSED PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS.
SE7714373A SE7714373L (en) 1976-12-18 1977-12-16 NEW ASSOCIATIONS WITH PHARMACOLOGICAL ACTIVITY
PH20569A PH14398A (en) 1976-12-18 1977-12-19 Pharmaceutical compounds,compositions containing same and method of use
JP15279377A JPS5382779A (en) 1976-12-18 1977-12-19 Novel compound having pharmacological activity* method for their production* intermediate compound useful for their production and medical compositions containing same
US05/915,165 US4152445A (en) 1976-12-18 1978-06-14 1-(3-Hydroxyalk-1-yl)-5-(carboxyalkyl)hydantoin derivatives
US05/915,164 US4147796A (en) 1976-12-18 1978-06-14 1-(3-Hydroxyalk-1-yl)-5-(carboxyalkyl)hydantoin derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB52955/76A GB1598662A (en) 1976-12-18 1976-12-18 10,12-diazoprostaglandins

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK543178A (en) * 1977-12-01 1979-06-02 Wellcome Found THIODYDANTOIN DERIVATIVES
EP0008186A1 (en) * 1978-08-08 1980-02-20 Beecham Group Plc Cyclic diamides, a process for their preparation and their pharmaceutical compositions
JPS5573611A (en) * 1978-11-23 1980-06-03 Wellcome Found Medical drug containing hydantoin derivative

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