NO774348L - PROCEDURE FOR PREPARING COMPOUNDS OF PHARMACOLOGICAL ACTIVITY - Google Patents

Description

Process for making compounds

with pharmacological activity

The invention relates to new compounds that have pharmacological activity, a method for their preparation, intermediate products that are usable in the method and pharmaceutical preparations containing them.

BRD official publication No. 2323193 discloses that pyrazplidine derivatives of formula (I) ':

where A is CH=CH or C=C; R is H, an alkali metal, an amine salt, or a 12 C hydrocarbon or chlorohydrocarbon residue; m is 0 or .1; n is 0-6; p is 0-6; and Y and Z are 0 or with the exception that Y and Z are not both 0; have similar biological properties to the prostaglandins or, are antagonists to prostaglandins.

French Patent Application No. 2258376 discloses that 10-aza-prostaglandins of formula (II)":

where R=Or lower alkyl; R' and R"=CH3 or C2H5' R°=H"or a lower alkyl; Y=-CH2CH2-, or -CH=CH-; Z=-C0 or. -CH(~OH)-; are useful in the treatment of blood pressure and gastro-intestinal disorders, and in preparation for childbirth.

Belgian Patent Document No. 835989 discloses that . compounds of formula (III) " :

where:

X is CO, protected CO, CROH where R is hydrogen or ■ 4~alkyl and where the OH portion may be protected; Y is CH 2 CH 2 or CH=CH; Z is CO or CH 2 ; n is 1-8; m is 1, 2 or 3; R 1 is hydrogen; CH2OH, CH2OH where the OH portion is protected, C02W where W is hydrogen or C02W represents an ester group where the ester portion contains 1 - 12 carbon atoms, or CONH2; R2 is hydrogen, C^_^-alkyl, or forms, together with R^ and the carbon atom to which it is attached, a carbonyl group; R 1 is hydrogen, hydroxyl or protected, hydroxyl; R. is hydrogen or C, n-4 x-y alkyl; . and salts thereof; have useful pharmacological activity-.-A new class of compounds which also have useful pharmacological activity has now been discovered, namely compounds which are structurally different from the prior art compounds referred to above.

Accordingly, the invention provides a compound of formula (I):

where : X is 0 or S;

n is 1 8;

R is hydrogen, or C02R-^ represents an ester group where the R^ portion contains 1-12 carbon atoms;

R 2 is hydrogen, C 1-4 -alkyl or phenyl;

R 1 is hydroxyl or protected hydroxyl;

R4> is hydrogen, C1_g-alkyl, C3-8-cycloalkyl, C3_g-cycloalkyl-C1-6-alkyl, phenyl , phenyl-C1-6-alkyl, naphthyl, naphthyl-C1-6-alkyl, where each of the phenyl or naphthyl moieties can be substituted with one or more halogen, trifluoromethyl, C1-6~alkyl-, hydroxy-, C1-6~-<alkyl->, phenyl-C1-6-alkyloxy or nitro groups; or

R-2 and, together with the carbon atom to which it is attached, may represent a C 1 -g cycloalkyl group;

R 5 is hydrogen, C 1-6 -alkyl, 4-alkyl substituted with a nitro-, hydroxy-, C 1-6 -alkoxy-, CO 2 A-, (CO 2 A) 2 -, CN-, or halogen group, C 5-6 cycloalkyl, phenyl, phenyl-C ^ ^-alkyl, phenyl-C^^-g-cycloalkyl 1, where each of the phenyl parts may be substituted with one or more halogen, trifluoromethyl-, C^_^-alkyl-, ^-alkoxy or nitro groups; or a group C02A; in R,-, A, when present, is hydrogen or CC^A represents an ester group where the A moiety contains 1-12 carbon atoms; and salts thereof.

A group of compounds of formula (I) includes those wherein :■

X is 0 or S;

n is 4-8;

R^ is hydrogen or C02R-^ represents an ester group where ■ the R^ part contains 1-12 carbon atoms; ' '~

R 2 is hydrogen, N-alkyl or phenyl;

R 1 is hydroxyl or protected hydroxyl;

R2 is hydrogen, C1-6-alkyl, C1-6-cycloalkyl, C1-6-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, naphthyl, naphthyl-C1-6-alkyl, where each phenyl or naphthyl moiety may be substituted with one or more halogen, trifluoromethyl, 3-alkyl, C 1-6 -alkyl or nitro groups;

R,, is hydrogen, C^_^-alkyl, phenyl, phenyl-C^_g-alkyl, or eh group C02A where A is hydrogen or C02A represents an ester group where the A part contains 1 -. 12 carbon atoms; and salts thereof.

Particularly suitable compounds of formula (I) include those where X is 0.

Suitably, n is equal to 5, 6 or 7, preferably 6.

R^ is hydrogen or CO 2 R^ represents an ester group where the R^ part contains 1-12 carbon atoms. Examples of R^ include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec.- and tert.-butyl, phenyl, benzyl, toluyl etc., while normally hydrogen or ^-alkyl groups are preferred.

Suitable examples of R 2 include hydrogen, methyl, ethyl and phenyl. More suitably R 2 is hydrogen, methyl or ethyl, preferably methyl.

Suitable protected hydroxyl groups R^ readily include.

hydrolysable groups, for example acylated hydroxy groups where the acyl part contains 1-4 carbon atoms, for example the acetoxy group; and hydroxy groups preferably with easily removable inert groups, for example the benzyl group or similar groups. Preferably, R. is hydroxyl.

Suitable groups R₂ include, when R₂ is an alkyl group, γ-alkyl groups. Such C4_g-alkyl groups can be straight-chain alkyl groups, for example n-butyl, n-pentyl, n-hexyl and n-heptyl, or can be alkyl groups which are branched with one or two methyl groups (at the same or at different carbon atoms).. Thus, for example, R4 can be a group CH2R7, CH(CH3)R7, or C(CH3)^Ry/ where Ry is a straight-chain alkyl group so that the carbon content of the resulting group R^' is 4 - 9.

In general, preferred groups include R₂, when R₂ is an alkyl group, straight chain pentyl, hexyl and heptyl. Of these, straight-chain hexyl is often the most applicable. Other preferred groups R 1 include groups CH(CH 3 )R 7 and C(CH 3 ) 2 R 7 where R y is straight chain butyl, pentyl and hexyl.

Other suitable examples of R₂, when R₂ is an alkyl group, include lower alkyl groups, ie when R₂ is a₂-alkyl group.

When R 1 is or contains a C 3-8 cycloalkyl moiety, the moiety may be cyclopropyl. The part can also be a C 1-6 cycloalkyl part, for example a cyclohexyl part. Examples of suitable C 1-6 alkyl moieties when R 1 is a C 3-6 cycloalkyl-C 6 alkyl group include methyl, ethyl, propyl, butyl and amyl.

When R 1 is an aryl group as previously defined, suitable groups R 2 include phenyl, phenylmethyl, phenyl-ethyl, phenyl-n-propyl, phenyl-n-butyl, naphthyl, naphthyl-methyl, naphthyl-ethyl, naphthyl- n-propyl and naphthyl-n-butyl, and such groups as branched in the alkyl part with one or two methyl groups (on the same or on different carbon atoms). These groups may be substituted in the phenyl or naphthy1 part with normally one, two or three groups selected from. the substituent groups indicated previously. Examples of suitable substituent groups include fluorine, chlorine and bromine atoms and CF-j, methyl, ethyl, n- and iso-propyl, methoxy and ethoxy, n- and iso-propoxy and nitro groups. Other examples of such groups include hydroxyl and benzyloxy. The aryl parts will preferably, when substituted with such groups, be mono- or di-substituted.

Furthermore, R 2 and R 4 , together with the carbon atom to which they are attached, can represent a C 1-6 cycloalkyl group, for example the cyclohexyl group.

Suitable examples of R 1 - include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl; phenyl; phenylmethyl, phenylethyl, phenyl-n-propyl, phenyl-n-butyl, and such phenylalkyl groups which are branched in their alkyl parts with one or two methyl groups (on the same or on different carbon atoms). More suitable is R 1 C 1-6 alkyl, for example methyl and ethyl.

R 8 can also be a phenyl-C 8 -c<y>chloroalkyl<y>l<g>ru<p>pe, in which case suitable examples of R 1 include phenylcyclopropyl.

When R 1 is or includes a phenyl moiety, it may optionally be substituted as described above for R 2 aryl groups.

'When R^ is C 1-6 cycloalkyl, the appropriate cyclohexyl..

When R1 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, toluyl and the like, while normally for A hydrogen or C1-6-alkyl is preferred.

R 1 can also be a C 1 -alkyl group which is substituted by a nitro, hydroxy, C 1 -6 alkoxy (for example methoxy), CO 2 A, (CO 2 A) 2 , CN or halogen group. In such cases, R,- will often be a methylene group substituted with one of these groups.

The compounds of formula (I) can form conventional salts. Such salts include those with alkali and alkaline earth metals, preferably sodium and potassium, and ammonium and substituted ammonium salts.

From what has been said above, it will be seen that one particularly suitable group of compounds within formula (I) has formula (II):

where:

X and R^ are as defined for formula (I);

n<1> is 5, 6 or 7;

R' 2 is hydrogen, methyl, ethyl or phenyl;

R' is hydrogen or C 1 -alkyl;

R is hydrogen, C 1-6 alkyl, f eny 1,. phenyl-C^_^-alky 1,

or a group CC^A where A is hydrogen or CC^A represents an ester group where the A part contains 1-12 carbon atoms;

and salts thereof.

In formula (II), n' is preferably 6. X is also suitably 0.

R' 2 is more suitably hydrogen, methyl or ethyl, preferably methyl.

Although R can be hydrogen or a 1-6 alkyl group, it is normally a C 4-6 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 4 when R 4 is a C 4-8 alkyl group. Such preferred groups R'^ include straight chain pentyl, hexyl and heptyl, and of these normally the most useful is straight chain hexyl. Other preferred groups R'4 include CH(CH3)R'7 and C^CH^)^.^ where R'? is straight chain butyl, pentyl or hexyl.

R 1 - is C 1-6 alkyl, for example methyl and ethyl.

Another group of compounds within formula (I) of particular interest are those of formula (III):

where:

X and R^ are as defined, for formula (I);

n' is 5, 6 or 7;

R 2' is hydrogen, methyl, ethyl or phenyl;

R 4 is a group of formula (IV):

where Ter is a bond, or a γ-alkylene group which may be straight-chain or branched with one or two methyl groups on the same or on different carbon atoms; and W, Y and Z are higher hydrogen or fluorine, chlorine or bromine atoms, or CF^-/

methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy or nitro groups;

R is hydrogen, C 1-6 alkyl, phenyl, phenyl-C 1-6 alkyl, or a group CC-A where A is hydrogen or CO 2 A represents an ester group in which the A portion contains 1-12 carbon atoms; and salts thereof.

In formula (III), n.' preferably 6. X is preferably also 0. R'2 is more suitable hydrogen, methyl or ethyl, preferably methyl.

In formula (IV) T will often be a group -(CH-) - where q

Zq

is 0 - 4. Furthermore, W and Y are often hydrogen.

R', is preferably C 1 -alkyl, for example methyl and ethyl. Another group of compounds within formula (I) of particular interest are those of formula (V):

where : X.and R-^ are as defined for formula. (I) ;

n' is 5, 6 or 7; R' is hydrogen, methyl, ethyl or phenyl;

R<3>^ is a group of formula (VI):

where T, W, Y and Z are as defined for formula (IV);

Rer hydrogen, C^_g-alkyl, phenyl, fehyl-rC^_^-alky 1, or a group CC^A where A is hydrogen or CC^A represents a. ester group where the A part contains 1-12 carbon atoms;. and salts thereof.

In formula (V), n' is preferably 6. Furthermore, X is preferably 0 •

R' 2 is more suitably hydrogen, methyl or ethyl, preferably methyl.

In formula (VI) T will often be a group -(CH„) - where z q q is o - 4. Furthermore, W and Y are often hydrogen.

R'' is suitably C 1-6 alkyl, for example methyl and ethyl.

A further group of compounds of formula (I) of interest have formula (VII):

where:

X and R are as defined for formula (I); n' is 5, 6' or 7; R' 2 is hydrogen, methyl, ethyl or phenyl; 4 R^ is a group of formula (VIII):

where T is as defined for formula (iv), and

r is 0 - 3;

R',_ is hydrogen, C 1-6 alkyl, phenyl, phenyl-C 1-6 alkyl, or

a group CC^A where A is hydrogen or CC^A represents an ester group where the A portion contains 1-12 carbon atoms; and salts thereof.

In formula (VII), n' is preferably 6. Furthermore, X is preferably 0.

R' 2 is more suitably hydrogen, methyl or ethyl, preferably methyl.

In formula (VIII) T will often be a group -(CH~) ,q„- where

q is 0 - 4. Also, r is often 1.

Suitable γ-alkyl, for example methyl and ethyl.

One compound according to the invention which is particularly preferred because of its useful activity is 1-(3'-hydroxy-'3'-methyl-n-nonyl)-3-methyl-5-(6"-carboxy-n- hexyl)hydantoin.

The invention further provides a process for the preparation of compounds of formula (I), comprising cyclization of a compound of formula (IX):

where the variable groups are as defined above; and then,

if desired or necessary, conversion of and/or R^

and/or R,, in the connection thus formed to other' variables Rl'R3 °g V

When R1 and R1 are hydrogen in the compound of formula (IX), the cyclization can preferably be carried out in aqueous conditions at acidic pH, for example in 25% aqueous acid. Such connections of

H—

formula. (IX) can be prepared by reacting a salt M CNX, where M<+>is a metal ion and X is 0 or S as defined, with a compound of formula (X):.

where n, R₂, R₂, R₂ and R₂ are as defined. The metal salt thus obtained can be converted into the acid (IX) with mineral acid. Suitably, M+ is a sodium or potassium ion, preferably a potassium ion.

If R^ is something other than hydrogen and R,_. is. hydrogen, the compound of formula (IX) is conveniently formed in situ during the conversion of a compound of formula (X) to a corresponding compound of formula (I) (wherein R^ is hydrogen) by reaction with M+CNX, a preferred method in according to the invention. This conversion can conveniently be carried out using a hydrochloride salt of the compound of. formula (X) and reacting this salt with M<+>CNXi aqueous solution under reflux or in aqueous dichloromethane with a phase transfer catalyst.

If both R 1 and R 2 are other than hydrogen in the compound of formula (IX), then the compound of formula (IX) is conveniently prepared in situ during the reaction of a compound of formula (X) with R 1 -NCX (where R 2 H), another preferred method according to the invention. This second preferred method is preferably carried out under reflux cooling in an inert solvent, for example benzene and the like. It should be stated that when R,, in this reaction is a sterically hindered group, then. can this reaction proceed only as far as the uncyclized compound of formula (IX); in which case the necessary cyclization of compound (IX) can be carried out with a strong base, for example sodium hydride or sodium hydroxide, in a dry organic solvent. Sodium ethoxide in benzene, or potassium t-butoxide in toluene, benzene or hexamethylphosphoramide are suitable reagents.

The conversion of a compound of formula (I) into a

another compound of formula (I) where R 1 , R 1 and/or R 1 - is substituted, if desired or necessary, can be carried out in a conventional manner.

For example, if desired, the group R₂ in the compound can be varied by conventional esterification and/or deesterification. Likewise, protected R 1 -hydroxy moieties can be deprotected in a conventional manner. For example, when R 1 is a benzyloxy group, the benzyl group can be easily formed by hydrogenolysis. Thus, it can be seen that "protected hydroxy" compounds according to formula (I) are useful intermediates in the preparation of the corresponding "free hydroxy" compounds of formula (I). Moreover, when a compound of formula (I) contains as acidic groups hydrogen atom(s), salts thereof can be prepared in a conventional manner, for example by reaction of the compound

of formula (I) with the required base. For salts of compounds where R 1 is hydrogen, the base should be a strong base, for example sodium in an alcohol, for example ethanol, or the like.

If R,, is hydrogen, compounds of formula (I) can be converted into corresponding compounds but with different -R^ values by conventional substitution reactions with R^X where X is a displaceable group, for example a halide or another group which can easily disappear. In such reactions it may be necessary first to convert the compound' of formula (I)

to an alkali metal salt of the R^ hydrogen.

Those skilled in the art will recognize that in some cases substitution of an R 1 hydrogen will also substitute an R 2 hydrogen. Thus, if a compound is desired where R^ is hydrogen and Rj. eir substituted, in such cases it will be preferred to esterify the R^ hydrogen before the substitution reaction

and then deesterify after the substitution reaction, so that one obtains. the desired R^-hydrogen compound.

It is assumed that the compounds of formula (IX) are new, and thus they form an important part of this compound as intermediate products.

The compounds of formula (X) can be prepared by the method described in Belgian patent document no.

835989 or by analogous methods.

It will of course be understood that the compounds of formula

(I) has asymmetric centers and thus is able to exist

,in a variety of stereoisomeric forms. The invention extends to each of these stereoisomeric forms and to mixtures thereof. The different stereoisomeric forms can be separated from each other by usual methods.

Compounds of formula (I) have useful pharmacological activity. For example, compounds of formula (I) have anti-gastric secretion activity, e.g. anti-ulcer activity, cardiovascular activity e.g. anti-hypertensive activity ■, platelet aggregation inhibitory activity, they affect the respiratory tract, e.g. have bronchodilator activity and has anti-fertility, smooth muscle and anti-arrhythmic activity.

In general, it can be said that compounds within formula (I)

have a number of pharmacological activities similar to those displayed by the natural prostaglandins, but that these activities tend to be a good deal more selective.

The invention therefore also provides a pharmaceutical preparation comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

It is clear that the composition of the pharmaceutical preparation will depend on the nature of the activity displayed by it. the chosen compound of formula (I), and by other factors,

for example, a preference in a particular area of therapy for a particular mode of administration.

The preparations can be in the form of tablets, capsules, powders, granules, throat lozenges or liquid mixtures, for example oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration may be in unit dose form and may contain conventional excipients, for example bulking agents, fillers, tableting lubricants, crumbling agents, as well as acceptable wetting agents and the like. The tablets can be coated according to known methods in normal pharmaceutical practice. Oral liquid preparations can, for example, be in the form of aqueous or oil suspensions, solutions, emulsions, syrups or elixirs, or they can be presented in the form of a dry product for reconstitution with water or another suitable drug carrier before use. Such liquid preparations may contain conventional additives, for example suspending agents, emulsifying agents, non-aqueous drug carriers (which may include edible oils), preservatives and, if desired, conventional flavoring or coloring agents, and the like.

For parenteral administration, liquid unit dosage forms are prepared using the compound of formula (I)

and a sterile drug carrier. The compound can, depending on the carrier and the concentration used, either be suspended or dissolved in the carrier. When preparing solutions, the compound can be dissolved for injection and filter-sterilised before filling into a suitable glass container or ampoule and sealing. Such auxiliary substances as a local anaesthetic, preservatives and buffering agents can advantageously be dissolved in the drug carrier. Parenteral suspensions are prepared in essentially the same way

manner with the exception that the compound is suspended in the drug carrier instead of being dissolved, and that sterilization cannot be carried out by filtration. The compound may be sterilized by exposure to ethylene oxide prior to suspension in the sterile drug carrier. A surfactant or wetting agent is advantageously included in the preparation to facilitate uniform distribution of the compound.

When applicable, the preparations according to the invention can be presented as an aerosol for oral administration or as a microfine powder for insufflation.

As usual practice, the preparations will usually be accompanied by written or printed instructions for use in the relevant medical treatment.

It will of course be understood that the exact dosage

which is used in the treatment of the disorders described above will depend on the relevant compound of formula(s) used, and also on other factors, for example the severity of the disorder to be treated.

The invention also provides a method for treatment and/or prophylaxis of disorders in humans or animals, comprising administering to the sufferer an effective amount of a compound of formula (I).

Normally, however, the compounds will be used in the therapy of human disorders.

The following examples illustrate the preparation of compounds of formula (i) and their pharmacological properties.

EXAMPLE 1 Compound 1

9.6 g of dimethyl-2-[N-3'-hydroxy-3'-methyl-n-decyl]amino azelate was refluxed with 1.365 g of methyl isocyanate for 3 hours in 80 ml of dry benzene. The benzene remained. evaporated in vacuo to give 10.2 g of a pale yellow gum. This was chromatographed on silica gel (pack ratio 30:1), using chloroform as eluent, so that 1-(3'-hydroxy-3'-methyl-n-decyl)-3-methyl-5-(6" -methoxycarbonyl-n-hexyl)hydantoin in the form of a clear oil (6 g).

The compounds shown in Table 1 were prepared in a similar manner.

EXAMPLE 2 Compound 13 20 g of dimethyl 2-[N-(3'-hydroxy-3'-methyl)-n-nonyl]araino azelate was refluxed with 5.12 g of t-butyl isocyanate in 200 ml. dry benzene for 3 hours. The benzene was evaporated in vacuo to give 20 g of a pale yellow gum. The gum was chromatographed on 600 g of silica gel using chloroform as eluent to give dimethyl-2-[N-(3'-hydroxy-3'-hydroxy-3'-methyl-n-nony1)-N-(N ('-t-butylformamido)]amino azelate (11.6 g) as a clear gum.

EXAMPLE 3 Compound 14

10 g of dimethyl-2-[N-(3'-hydroxy-3'-methyl-n-nonyl)-N-(N'-t-butylformamido)]aminoazelate was refluxed with 2.5 g of potassium t-butoxide in 150 dry toluene for 3 hours. The toluene was evaporated in vacuo and the resulting gum partitioned between ether and very dilute hydrochloric acid. The ether solution was washed with brine, dried (MgSO 4 ) and evaporated in vacuo to give 8-.4 g of a yellow gum. The gum was chromatographed on 250 g of silica gel using chloroform as eluent to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-t-butyl-5-(6"-methoxycarbonyl- n-hexyl)hydantoin (5.2 g) in the form of a clear gum.EXAMPLE 4 Compound 15 20 g of dimethyl 2-[N-3'-benzyloxyrnnonyl]aminoazelate was refluxed with 2.46 g of methyl isocyanate in 200 ml of dry benzene for 3 hours The benzene was evaporated in vacuo to give a deep yellow oil which was chromatographed on silica gel (30:1 packing ratio), using chloroform as eluent, to give 1-(3'-benzyloxy -n-nonyl)3-methyl-5-(6"-methoxy-carbonyl-n-hexyl)hydantoin (9 g) in the form of a colorless gum. EXAMPLE 5 Compound 16

1.1 g of 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-ethyl-5-(6"-ethoxycarbonyl-n-hexyl)hydantoin was refluxed overnight with 7.5 ml of a 10% aqueous potassium carbonate solution. and 30 mL of ethanol. The solution was cooled and acidified with concentrated hydrochloric acid. The product was extracted into ether (3 x 100 mL). The ether solution was extracted with 5% sodium bicarbonate solution. The resulting aqueous phase was backwashed with ether and then acidified with dilute hydrochloric acid. The product was extracted into ether, and the ether solution was washed with brine, dried (MgSO4)

and evaporated in vacuo so that 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-ethyl-5-(6 n-carboxy-"n-hexyl)hydantoin was obtained in the form of a colored loose gum (770 mg).

The compounds shown in Table 2 were prepared in a similar manner.

EXAMPLE 6 Compound 30 10 g of dimethyl-2-[N-3'-hydroxy-3'-methyl-n-nonyl]amino azelate was refluxed with 1.89 g of methyl rhizothiocyanate in 100 ml of dry toluene for 3 hours. The toluene was evaporated in vacuo to give 11.1 g of a yellow oil. The oil was chromatographed on 330 g of silica gel using chloroform as eluent to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-methoxycarbonyl-n-hexyl )-2-thiohydantoin (9.49 g) as a pale yellow oil.

The compounds shown in Table 3 were prepared

in a similar manner.

EXAMPLE 8 Compound 34 5 g of 1-(3'-benzyloxy-n-nonyl)-3-methyl-5-(6"-methoxy-carbonyl-n-hexyl)hydantoin was hydrogenolyzed over 10% palladium/charcoal in 50 ml of dry dimethoxyethane at room temperature and atmospheric pressure. The reaction mixture was then filtered through silica gel, and the dimethoxymethane was evaporated in vacuo to give 3.8 g of a colorless oil. The oil was chromatographed on 110 g of silica gel using chloroform as eluent. gave 1-(3'-hydroxy-n-nonyl)-3-methyl-5-(6"-methoxy-carbonyl-n-hexyl)hydantoin as a colorless oil (2.48 g). EXAMPLE 9 Compound 43

Dry hydrogen chloride gas was introduced into an ice-cold solution of 40 g of dimethyl-2-[N-(3'-hydroxy-3'-methyl)-n-nonyl]amirio-. azelate in 1 liter of dry ether. The ether was evaporated in vacuo and the resulting hydrochloride was stirred with 300 ml of water. A solution of potassium cyanate (8.2 g; 1.01 eq.) in 20 mL of water was added and the resulting suspension was stirred at room temperature for 1.5 h and then at reflux for 1.5 h. The mixture was allowed to cool and the product was extracted into dichloromethane. The dichloromethane solution was washed with salt water until the wash water

was neutral and was then dried and evaporated to give 38 g of a yellow gum. A sample was purified by column chromatography. (silica gel, 30:1) using chloroform, and chloroform/methanol mixtures as eluents to give 1-(3'-hydroxy-3'-methyl-n-nonyl)-5-(6"-methoxycarbonyl-n- hexyl)hydantoin in the form of a pale yellow gum.

EXAMPLE 10 Compound 44

5 g of 1-(3'-hydroxy-3'-methyl-n-nonyl)-5-(6"-methoxycarbonyl-n-hexyl)hydantoin in 10 ml of dry dimethylformamide was added to a stirred suspension of sodium hydride (376 mg; 80% oil dispersion) in 20 mL of dry dimethylformamide under nitrogen at room temperature. The mixture was stirred overnight. 1.01 g of chloromethylmethyl ether in 10 mL of dry dimethylformamide was added dropwise, and the mixture was stirred for 24 hours at room temperature. The product was partitioned between very dilute hydrochloric acid and ether. The ether solution was washed with 5% aqueous sodium hydroxide solution and with brine until the wash water was neutral, then dried and evaporated in vacuo to give 4.1 g of a yellow oil. The oil was chromatographed on silica gel ( 30:1) using chloroform, 1% methanol/chloroform and 2% methanol/chloroform as eluents so that

1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methoxymethyl-5-(6"-methoxycarbonyl-n-hexyl)hydahtoin (2.5 g) was obtained in the form of a pale yellow rubber.

The compounds listed in Table 7 were prepared in a similar manner. EXAMPLE. 11 Connection 50 '.'•"_

A 1% solution of sodium hydroxide in dry methanol (1 eq.) was added to a solution of 1-(3'-hydroxy-3'-methyl-n-nonyl)-3-methyl-5-(6"-carboxy- n-hexyl)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 and then ground to a fine, pale yellow powder.

In a similar manner, the corresponding lithium salt was prepared.

Analysis data

Connection 1

I.R. (cm"<1>) : 3450, [OH] ; 1760, 1700, [-N-C-N-C-].;

II II

0 0

1730, |>C02CH3 J ,

NMR., (T) : 7.15 , (s) , [OH] ;

7.05, (s), [-N-CH 3 ];

6.95 to 6.35, (m) , [-N-CH 2 ~] ;

6.35, (s), [-CO 2 CH 3 ];

6.0, (broad t), [-N-CH].

Analysis : C^H^N^ requires : C, 64.76; H,.9.92;N, 6.57% —. found : C, 64.44; H, 9.92; N, 6.71%

Mass spec.<C>23<H>42<N>2°5

requires : 426 .3093 '

found : 426.3065

Connection 2

I.R. (cm<-1>) : 3500, [OH]; 1700, 1760, [-N-C-N-C-]; ii ii

0 0

1730, [-C02Et]

NMR (T) 7.2, (s) [OH] ; 6.2 to 6.8, (m) , [CH,CH„N-; V (CCl 4' ) -N■ -CH 2 ]; 5.9, (m) [-Ni-CH;C02CH2CH3]

Connection 3 I.R. (cm"1) : 3500, [OH]; 1710, 1760 [-N-C-N-C-];

II II

0 0

1730, [-C02Et]

NMR (T) : 7.2, (s), [OH]; 7.0, (s), [-N-CH-j];

6, 2 to 7 , (m) , [-N-CH 2 ] ;

5.9, (m) [-N-CH; -C02CH2CH3]

Connection 4

I.R. (cm<-1>) 3500, [OH]; 1700, 1760,,[-N-C-N-C-]

II II

,00

1720, [-CO2-CH3].

NMR (T ) .: 7.05, (s), [-N-CH 2 ;. OH] ;

6.2 to 6.9, (m) , [-N-CH 2 ;

6.35, (s), [-C02CH3]

6.0, (t)., [ -N-CH]

Analysis .<:><C>20<H>34<N>2<0>5

requires : C, 62.80; H, 8.96; N, 7.32% found : C, 62.61;.H, 8 , 95; N, 7.19%

Mass spec.<:><C>2o<H>34<N>2°5

requires 382.2468 found : 382.2466

Connection 5

I.R. (cm<-1>) : 3500, [OH] ; 1700, 1760., [-N-C-N-C-]; ii ii 0 0 1730, [-CO 2 CH 3 ]NMR (T) : 7.75, (t) , [-CH 2 CO 2 CH 3 ] ; 7.3, (m), [-CH 2 Ph]; 7.1, (s), 1-OH]; 7.05, (s), [-N-CH 3 ]; 6.5 to 7.0, (m), [-N-CH 2 ]; 6.5, (-s) , [-CO 2 CH 3 ] ;

6.05, (broad t) , [-N-CH]

Mass spec.<:><C>24<H>34<N>2<0>4<[>m<*->H2°], requires : 414.2518

found : 414.25 23

Connection 6

I.R. (cm"<1>) 3500, [OH]; 1700, 1760, [-N-C-N-C-]; ■i ii 0 0 1730, [-C02CH3] .

NMR K) : 7 .3 , (s.) , [OH] ;

7.05, (s), [-N-CH 3 ];

6.3 to 7, (m), [-N-CH2];

6.35, (s), [-CO 2 C<H> 3 ];

6.0, (m), [-N-CH].

Analysis<:><C>22<H>4Q<N>2<0>5

requires C, 64.05; H, 9.77; N, 6.79% found : C, 64.14; H, .9 .68 ; N , 6.62%

Connection 7 Connection 8

Connection 9

NMR' ( <X ) : 7.8, (t) , [-CH 2 CO 2 CH 3 ] ;

7.3, (m), I-CH2-Ar];

7.1, (s), [-N-CH 3 ];

6.5 to 7, (m), [-N-CH 2 3 ;

6.45, (s), [-CO 2 CH 3 ];

6.1, (ra), [-N-OH];

2.65, (broad s), ]-Ar].

Mass spec. :<C>25<H>33<N>2<0>4<F>3<[m*->H20]

requires : 482.2392

found : 482.2415

Connection 11

I.R. (cm ) : 3500., [OH] ; 1710, 1760, [-N-C-N-C-] ;

II II

0 0 1730, [-CO 2 CH 3 ].

NMR (T) : 7.75, (t), [-CH 2 -CO 2 CH 3 ];

7.15, (s) , [OH] ;

7.1, (s) , [-N-CH 3 ]:;

6.2 to 7, (m), [-N-CH 2 J;

6.4, (s), [-CO 2 CH 3 ];

6.05, (m), [-N-CH].

Mass spec. ci7<H>3o<N>2°5

requires : 342.2154

found : 342.2144 Mass spec<k.><:><C>17<H>28<N>2°4<tm*->H20l

requires : 324.2049

found : 324.2050

Connection 12

I.R. (cm"1) : 3500, [OH]; 1700, 1760, [-N-C-N-C-];

ii ii 0 0

1740, [-CO 2 CH 3 ].

NMR (T) : 7.75, (t), [-CH2CO2CH3];*

7.1, (s), [OH];

6.2 to 7, (m), [-N-CH 2 ];

6.4, (s), [-CO 2 CH 3 ];

6.1, (m), [-N-CH]..

Mass spec. : C2 7H48N2°5

require : 480.,3564

found : 480.3536

Connection 13 I.R. (cm<_1>) 3400, [OH] ; 1740, [-COCH3];

1630, [-N-C-N-].

II

0

Analysis :<C>26<H>50<N>2<0>6

requires : C, 64.16; H, 10^36; N, 5.76%

found : C, 64.22; H, 10.69; N, 5.43%

Mass Spec .<:><C>25<H>44<N>2°4[m*-H20-CH3OH] .

. requires 436.3301 found :• 436.3293

Connection 14

I.R. (cm<-1>) : 3500, [OH];

1700, 1750, [-N-C-N-C-];.

ii ii

0 o

1735 , [-C02CH3] ..

NMR (T ) : 7.2, (s) ,.[OH] ;

6.3 to 7, (m), [-N-CH2~]; 6 .3 , (s) , [-CO 2 CH 3 ] ;

6.2, (m) , [-N-CH] .

Analysis<:><C>25<H>46<N>2<0>5

requires : C, 66.05; H, 10.20; N, 6.16%

found: C, 65.89; H, 10.30; N, 6.13%

Mass spec.<C>25H46<N>2°5

requires : 454.3406

found : 454.3451 Mass spec<k.><:><C>25<H>44<N>2°4fm^-H20^

requires : 436.3301

found : 436.3317

Connection 15

I.R. (cm<-1>) : 1710, 1760, [-N-C-N-C-];

II II

0 0

1730, [CO 2 CH 3 ].

NMR (T) : 7.1, (d), [-N-CH 3 ];

6.3 to 7, (m), [-N-CH];

6.35, (s), [-CO 2 CH 3 ];

6.2, (m), [-N-CH];

5.5, (s, with shoulder), [-0CH_2Ph] ; 2 .75 , (s)., [-0CH 2 Ph] .

Analysis .:. C^H^O,.

requires : C, 68.82; H, 9.08; N, 5.73%

found : C, 68.62; H, 9.21; N, 5.66%

Mass spec.<:><C>28<H>44<N>2°5

requires :' 488.3250

found 488.3287

Connection 16 I.R. (cm<-1>) : 3700 - 2500,.[-CO 2 H; OH];

1760, 1710, 1700 [-N-C-N-C-; CO-H]

ride ii

0.0

NMR: (T) : .7.0 - 5.9, (m) , [ (-N-CHJX 2 ; -N-CH] );

4.4 (broad s), [-CO 2 H; OH].

Mass spec. : C2 2H40N2°5

requires : 412.2937

found : 412.2917

Connection 17

I.R. (cm_1) : 3700-2400, [-CO 2 H; OH];

1760, 1720, 1700, [-N-C-N-C-; C09H] ..

ii ii

0 0

NMR (T1) : 7.05, (s), [-N-CH 3 ];

6.95 - 6.35, (m) , [-N-CH 2 ; 6 , (broad s) , [-N-CH] ;

3.15, (broad s), [CO 2 H; OH].

Analysis<:>C22^ 205

requires : C, 64.05; H, 9.77; N, 6.79%

found C , 64 .36 ; H, 9.99; N.'6.99%

Mass spec. : C22H38<N>2°4<[m>'<*>~<H>20l

requires : 394.2831

found : 394.2848

Connection 18 I.R. (cm<-1>) : 3700 - 2500, [CO 2 H; OH];

1760, 1700. (broad), [-N-C-N-C-; CO„H] .

ii ii 0 0

NMR (T) : 7., 05 , (s) , [-N-CH 3 ] ;

(<CD>3)2<CO>,6.9-6.1, (m) , [-N-CEL,];

5.9 - 5.7, (s t ), [ -N-CH; CO 2 H; OH] .

Mass spec..<:>ci7H3oN2°5 '

requires : 342.2155

found : 342.2174

Connection 19

I.R. (cm<-1>) : 3700 - 2400, [CO 2 H; OH]

1760, 1700 (broad) [-N-C-N-C-; CO-H].

ii ii ■ ^

0 0

NMR (t) : 7.1, (s) , [N-CH_3]<;>

6.6, (m), [-N-CH 2 ];

6.05, (broad s), [CO 2 H; OH] ; 5 .85, (t) , [-N-CH] ;

Analysis : C-^H^N^

requires : C, 61.93; H, 8.75; N, 7.60%

found.: C, 61.99; H, 8.97; N, 7.64%

Mass spec.<:><c>i9<H>32<N>2°5 requires : 368.2311

found : 368.2313

Connection 20

I.R. (cm-1):3700-2400, [CO 2 H; OH]; 1760 - 1700, [-N-C-N-C-; CO-H]. ■i ii ^ .00

NMR (X) : 7.3, (m), [-CH 2 Ph];

7.05, (s), [-N-CH 3 ]; 6.8-6.1, (m), [-N-CH 2 ];

6.15, (s), [-CO 2 H; OH]; 5.8, (t), [-N-CH].

Analysis<:>C^H^N^

requires : C, 66.01; H, 8.19; N, 6.69%

found : C, 65.82; H, 8.38; N, 6.37%

Mass spec. :<C>23H32N2°4[m<*->H2°]

requires : 400.2362

found : 400,232.3

Connection 21 I.R. (cm<-1>) : 3700 - 2400, [CO 2 H; OH];

1760, 1720, 1700, [-N-C-N-C-; CO^H].

ii ,ii 0 0

NMR (X) : 7.1, (s) , [-N-CH 2 ];

6.8 - 6 ,1, (m) , [-N-GH_2];

6.1, (s) , [CO 2 H; OH] ; 5.85, (t), [-N-CH].

Mass spec. : C21H36<N>2°4<fm*>~<H>20^ requires : 380.2675

found : 380.26 72;

Connection 22 I.R. (cm<-1>) 3700 - 2500, [CO 2 H; OH];

1760, 1740 - 1690, [-N-C-N-C-; CO„H].

■i ii 0 0

NM(R CD3(t)2) CO<:>67,,91, -(6s),1, , [-(mN-)C, H3[-]N;-CH^;

5.9, (t), [-N-CH];

5-3, (broad hump), [C02H; OH].

Analysis<:><C>21<H>38<N>2<0>5

requires : C, 63.29; H, 9.61; .N, 7.03% found : C, 62.94; H, 9.79; N, 6.65%

Mass spec. :<c>2i<H>36<N>2°4<[m>"<if_>H2°l

requires : 380.2675

found : 380.2641

Connection 23

I.R. (cm<-1>) : 3700 - 2500, [CO 2 H, OH];

1760, 1700 (broad), [-N-C-N-C-; C0„H].

ii ii ^ 0 0

NMR (t) : 7.25, (d), [-N-CH 3 ];

6.9 - -6.1, (m) , [-N-CH 2 ] ;

5.6, (broad s), [-CO 2 H, OH];

2.65, (m), [Ph]...

Analysis<:><C>21<H>3o<N>2<0>5

requires : C, 64.60; H, 7.74; N, 7.17% found : C, 64.83; H, 7.96; N, 6.91%

Mass spec<k.><:><c>2i<H>28<N>2°4<[>m<*_>H2°l

requires : 372 .2049

found : 372.2037

Connection 24I.R. (cm"<1>) : 3700 - 2500, [CO 2 H; OH];

1760, 1710 (broad), [-N-C-N-C-; C0,H].

0 0

NMR (X) : 7.1, (s), .[-N-CH 3 1 ;

6.8-6.1, (m), [-N-CH 2 ];

5.9, (t) , [-N-CH] ;

4.5, (broad), [CO 2 H; OH] .

Analysis<:><C>20<H>36<N>2<0>5

requires : C, 62.47; H, 9.44; N, 7.29% found : C, 62.40; H, 9.59; N , 7.04%

Mass spec.<:>C^H^N^

requires : 384.2624

found : 384.2640

Connection 25

I.R. (cm<-1>) : 3700 - 2400, [CO 2 H; OH]; . 1760, 1700 (broad) [-N-C-N-C-; CO^H]. ■i ii . 0 0 NMR fC) : 6.7, (s), [CO 2 H; OH] ; 7 - 6.3, (m), [-N-CH 2 ];

6.1, (t) , [-.N-CH] .

Analysis:<:><Q>24<H>44<N>2<0>5

requires : C, 65.42; H, 10.07; N, 6.36% found : C, 65.21; H, 10.29; N, 6.08%

Mass spec.<:><C>24H44<N>2°5

requires : 440.3250

found : 440.3280

Connection 26

I.R. (cm<-1>) 3200 - 2600, [CO 2 H; OH]; 1770, 1700 (broad), [-N-C-N-C-; CO-H] II II ^ 0 0 NMR (T) : 7 - 6.1, (m), [-N-CH^]; 5.95, (broad), [CO 2 H; OH]; 5,6, (t) , [-N-CH] ; 2.6, (d), [Ph].

Mass spec.<:>C26H38N2°4 [m*-H2°]

requires : 442.2832

found : 442.2841

■ Connection 27

I.R. (cm<_1>) : 3200-2400, [CO 2 H; OH]; 1770, 1730 - 1680, [-N-C-N-C-;.CO H]. ii ii ^ 0 0 NMR (T) 7.8, (t) , [-CH-COH]; D6DMS07.4, (m), [-O^-Ar]; 7.15, (s), [-N-CH 3 ]; 7 - 6, (m), [-N-CH 2 ];

5.8, (m), [-N-CH].

Analysis<:><C>24<H>33<N>2<0>5<F>3

require : C , 59 , 25 ; H, 6.83; N , 5 , 76% found : C, 59.29; H, 7.13; N, 5.82%

Mass spec. : c24H3iN204F3 fm*-H20]

requires : 468.2236

found : 468.2245

Connection 28

I.R. (cm"1) ,: 3200 - 2400, [C02H; OH] ; 1760, 1730 - 1690, [-N-C-N-C-; C0„H]. ii ii 0 0 NMR OD . :. 7.75, (t) , [-CH„-C0„H]; • <D6DMS°) 7.1, (s), [-N-cl3l; 7 - 6, (m), [-N-CH2J;

5.8, (t), [-N-CH].

Analysis<:><C>16<H>28<N>2<0>5

requires : C, 58.52; H, 8.59; N, 8.53% found : C, 58.59; H, 8.71; N, 8.70%

Mass spec.<:><c>i6<H>28<N>2°5

requires : 328,1998

found : 328,1995

Connection 2 9

I.R. (cm~l) : 3200-2400, [CO 2 H; OH];

1760 - 1680, [-N-C-N-C-; C0„H].

ii ii ^ 0 0

NMR (?) : 7 - 6.2, (m) , [-N-CH 2 ;

(C<D>3)2<CO>61^ (broad g) ^ [Co2H; OH]; 6.0, (m) , [-N-CH-C-];

II

0

5 .5 , (m) , [-C-N-CH] .

0 C=0

Analysis : C^H^N^

require : C, 6.6,92; H, 9.94; N, 6.00%

found : C, 66.5 7; H, 10.06; N, 6.25%

Mass spec. : C26H46N2°5

requires : 466.3406

found : 466.3403

Connection. 30

I.R. (cm<-1>) : 3510, [OH]; 1750 - 1720, [-N-C-N-C-; C09CH ]. ii ti ^ A

SO

NMR (T) 7.75, (m) , [OH; CH 2 -CO 2 CH 3 ];

6.8, (s),.[-N-CH^];

7-6.2, (m), [-N-CH 2 ];

6.35, (s), [-CO 2 CH 3 ];

5.9, (ra), [-N-CH].

Analysis<:><C>22<H>40<N>2<0>4<S->

.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. :<C>22<H>3<gN>2<0>3<S><[>ra}<<->H20]requires : 410.2603.

found : 410.2610

Connection 31

I.R. (cm<-1>) : 3500, [OH]; 1740, [-N-C-N-C-; CO^Et].

i n .

SO

NMR (T) : 7.7, (s) , [OH] ;

6.8, (s), [-N-CH3]; 6.9 - 6.2, (ra) , [-N-CH2].;

5.9, (ra), [-N-CH; -C02CH2CH3].

Analysis<:><C>23<H>42<N>2<0>4<S>

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.<C>23<H>42<N>2<0>4<S>

requires : 442.2865

found : 442.2866

Connection 32

I.R. (cm"<1>) : 3500, [OH] ; 1740, 17.20, [-N-C-N-C-; CO-CH ]. ■i ti

SO

NMR (T) : 7.45, (s), [OH];

6.8, (s) , I-Nt-CH 3 J ;

6.9-6.2, (m), [-N-CH 2 ];

6.4, (s), [-CO 2 CH 3 ];

5.9, (m), [-N-CH].

Mass spec. ■:. C17H3QN2O4S

required : 358,1926 found : 3.58,1956

Connection 34

I.R. (cfti"<1>) 3500, [OH] ; 1760, 1710,.1730, ii ii 0 0

[-C0 2 CH 3 J

NMR (T) : 7.05, (s) /'-[-N-CH];

6.7 to 6.2, (m), 1-N-CH 2 ];

6.35, (s), [-CO 2 CH 3 ];

6.0, (s), I-N-CH].

Analysis: C21H3gN2O5

requires : C, 63.29; H, '9.61; N, 7.03% found : C, 63.61; H, 9.83; N,. 7.34%

Mass spec.<:><C>2l<H>38<N>2°5

required : 398.2 780 found : 398.2769

Connection 35

I.R. (cm"<1>) : 3550, [OH]; 1770, 1730 (broad) [-N-C-N-C-; -C0,CH^]■i ii / j 0 0

NMR (t) : 7.75, (t), [CH 2 CO 2 CH 3 ];

7.35 , (m) , [Ph - CHj ;

7.35, (s) , [OH] ;

7.0-6.2, (m) , [-N-CH2| ;

'6.4, (s) , [-CO 2 CH 3 ] ;

6.1, (m), [-N-CH] x 2;

2.7, (s) , [Ph] .

Mass spec. : C^H^N^ (<m*->H20)

requires 496.3301

found : 496.3,303

Connection 36

I.R. (cm-1) : 3550, [OH]; 1770, 1710 [-N-C-N-C-];

M ii

0 0

1730, [-C0.2C2H5]

NMR (t) : 7.7 (t.) , [CT^CO^H ] ;

7.5, (s), [OH]; 7.0, (s), [-N-CH 3 ]; .7.0-7.2, (m), [-N-CH21;

6.05 (t), [-N-CH];

5.85, (q) ,■ [-C-O-bEUCH ]

ii z j

0

Mass spec.<:><C>24<H>42<N>2°4 (m*_H20)

requires : 422.3144

found : 422.3156

Connection 3 7

I.R. (cm<-1>) : 3500, [OH]; 1760, 1710, [-N-C-N-C-]; ■i ii 0 0 1720, [-CQ2C2H5]. NMR (T) : 7.75, (t) , [ CH 2 CO' 2 C 2 H 5 ] ; 7.5, (s) , [OH] ; 7.05, (s), [-N-CH 3 ]; 6.9 - 6.2, (m) , [-N-CH 2 ]; 6 .05 , (m) #in [-N-CH] ;

5.9, (q), [-C02CH2CH3]:

Mass spec.<:><C>22<H>38<N>2°4 (m*-H2°)

required : 394.2832 found : 394.2826

Connection 38

I.R. (cm<-1>). : 3500, [OH]; 1770, 1710, [-N-C-N-C-]; ii M 0 0 1740, [-CO 2 CH 3 j. NMR (T) 7.75 , (s) , [OH] ; 7.1, (m), [CH 2 CO 2 CH 3 ]; approx 6.9 to 6.3, (m), [-N-CH 2 ]; 6.95, (s) , j-N-CH3]; 6 .25 , (s) , [-CO 2 CH 3 '] ;

5.7, (t), [-N-CH].

Mass spec.<:><c>i7<H>28<N>2°4 (<m*>_<H>20^

requires : 324.2048

found : 324.2056

Connection 39

I.R. (cnf<1>) : 3700-2500, [-CO 2 H; OH] ;

1760, 1720 (broad), [-N-C-N-C-; C0„H].

ii ii

0 0

NMR (T) : 7.7, (m), [CH 2 CO 2 H];

7.3, (m), (Ph-CH);

7.0-6.1, • (m) , [-N-CH 2 ] ;

5.9, (t), [-N-CH] x 2;

5.7, (broad s), [CO 2 H; OH];

2.75, (s), [Ph].

Mass spec. : C^H^N^ (m<*>"-H20)

requires : 482.3145

found : 482.3184

Analysis<:>C^H^N^

requires : C, 69.57; H, 8.86; N, 5.60% found : C , 69 .83 ;• H, 9 .05 ; N , 5 .32%.

Connection 40I.R. (cm<-1>) : 3800 - 2500,.[-CO 2 H; OH];.

1770, 1720 (broad), [-N-C-N-C-; C0„H].

ii ii ^ 0 0

NMR (T) : 7.7, (t), [CH 2 CO 2 H];

7.1, (s), [-N-CH3]; 7.0 - 6.1, (m), [-N-CH 2 ];

6.2, (broad), [-C02H;. OH] ;

5.8, (t), [-N-CH].

Mass spec.<:><C>22H38<N>2°4 (m*-H2°)

requires : 394.2831

found : 394.2823

Analysis<:>C2 2H40N2°5 requires C, 64.05; H, 9.77; N, 6.79% found C, 63.98; H, 9.97; N, 6.57%.

Connection 41

I.R. (cm<_1>) : 3700 2500, [-CO 2 H; OH];

1760, 1710 (broad), [-N-C-N-C-; -CO H].

o o NMR ft) : 7.8,. (t) , [CH_2CO2H];

7.2, (s), f-N-CH3];

6.9 - 6.1, (m), f-N-CH 2 ];

5.95, (t), [-N-CH];

4.6 to 3.3,. (broad hump), [-C02H; OH].

Mass spec.<:><C>20<H>34<N>2°4 (m*f"~H20^

requires : 366.2518

found : 366.2513

Connection 42

Mass spec-. : C^ H^^ N^ O^ (m -H2O)

requires. :. 310.1892 found : 310.1891

Connection 43

I<.>R.(cm-<1>) : 3500, [OH]; 3300, [NH]; 1770, 1710, [-N-C-N-C-]; ii ii 0 0 1730, [-CO 2 CH 3 ]. NMR (r) : 7.85, (m), [-CH 2 CO 2 CH 3 ]; 7.5 - 6.5 , (m) ,• [-N-CH 2 ] ; 6 .4, (s) , [-CO 2 CH 3 ] ;

5.95, (broad s), [-N-CH]..

Mass spec.<:><C>21<H>36<N>2°4 (m*_H2°)

required : 380.2675 found : 380.265 9

Connection 44.

I.R. (cm-1) : 3500, [OH]; 1770, 1720 (broad), [-N-C-N-C-; C0„CH-.]. ii ii 0 0 NMR (T-) : 7.8, (t) , [-CH 2 CO 2 CH 3 ] ; 7.3, (s), [OH]; 7 - 6, (m), [-N-CH 2 ];

6.6, (s), (-OHCH 3 );

6.3, (s), [-CO 2 CH 3 ];

5.9, (t), [-N-CH];

5.2, (s), [CH 2 OCH 3 J.

Mass spec.<:>C23H40N2°5 (m^~H20^

requires : 424.2937

found : 424.2942

Connection 45

I.R. (cm<-1>) 3550, [OH]; 1760 - 1710, (broad), [-N-C-N-C-;

■i ii 0 0

-C02CH3]..

NMR (T) : 7.75, (t), [CH 2 CO 2 CH 3 ];

7.4, (s), [OH];

7 - 6.4, (m), [-N-CH 2 ]; .6.4, (s), [CO 2 CH 3 ];

6.25 , (s) , [CO 2 CH 3 ] ; 5.9, (s + m) , [-N-CH 2 CO 2 CH 3 ;. -N-CH] .

Mass sp<e>k.<:><C>24<H>4QN206(m^-^O)

requires : 452.2886

found : 452.2892

Connection 46

I.R. (cm-1) : 3500, [OH] ; 1765, 1720 (broad), [-N-C-N-C-; CO CH ]. 0 0 NMR (T) : 7.7, (t), [-CH 2 CO 2 CH 3 ]; 7.3, (s), [OH]; 7.0 - 6.3, (m), [-N-CH 2 ]; 6.35, (s) , [CO 2 CH 3 1 ; 5 .85 , (m) , [-N-CH] ;

5 .65 , (s) , [-CH 2 CN] .

Mass spec. :<C>23<H>37<N>3<0>4 (<m>^<->H20)

requires : 419.2784

found : 419.2771

Analysis : C23H39N305'

requires : C, 63.13; H, 8.98; N, 9.60%

found : C, 63.21; H, 9.13; N, 9.31%

Connection 47 I.R. (cm<-1>) 3500, [OH]; 1730, (very broad), [-N-C-N-C-; CO^CH^].

0 0

NMR (f) : 7.75, (t) , [CH_2CO2CH3];

7.6, (s), [OH]; approx 7 - 6.4, (m), [-N-CH^];

6.4, (s), [-CO 2 CH 3 ];

6 , 2., (p.) , 5.9, (m), [-N-CH]; 4.9, (s),

Mass spec.<C>26<H>42<N>2°8 (<m*>-<H>2°)

requires : 510.2941

found : 510.2937

Connection 48

I.R. (cm<_1>) : 3200 2600, [-CO 2 H; OH] ;

1770,.1700 (broad), [-N-C-N-C-; CO H].

ii ii

0 0

NMR (T) : 7.7, (t), [-CH 2 CO 2 H];

approximately 7-6.1, (m) , [-N-CH_2] ;

6.65, (s), [-OHCH 3 ];

5.95, (m), [-N-CH]; 5 .15 , (s) , [-N-CH 2 OCH 3 ]';

4.3, (broad s), [CO 2 H; OH].

Mass spec. : C21H34N2°4 (m*-H20_Me0H)

requires : 378.2519

■found : 378.2507

Connection 49

I.R. (cm<-1>) : 3600-2400, [CO 2 H; OH];

1760 - 1690, [-N-C-N-C-; C0»H].

ii ii ^ ■ 0 0

Connection 50

Analysis : C^H^N^jNa requires : C, 5 9.98; H, 8.87; N, 6.66; Na, 5.47% found : C, 60.15; H, 9.19; N,.6.71; Nah, 5.52%

Connection 51

-1 11 I.R. (cm ). : 3500, [OH] ; 1760, 1710, [-N-C-N-C-] ;

ii ii 0 0

1730, [CO 2 CH 3 ].

NMR (T) : 7.8, (t) , [-CH 2 CO 2 CH 3 ];

7.2, (hump), [-0H]; approximately 7 - 6.2, (m) , [-N-CH_2-] ;

6.4, (s), [-CO 2 CH 3 ];

6.05, (t) , [-N-CH] ;

5.45, (s), [CH 2 Ph];

2.7, (broad s), [CH2Ph].

PHARMACOLOGICAL DATA

Bronchiodilatation activity

1. The compounds were tested for their ability to inhibit 5-hydroxytryptamine- or histamine-induced bronchoconstriction in the anesthetized artificially respirated 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 bronchoconstriction induced by a histamine aerosol (Herxheimer test). In these experiments, the compounds were administered by aerosol or orally. The results are shown in Table B. The results are the average of several experiments. Similar results were obtained against histamine-induced bronchoconstriction. For example, compound 21 also had an ID^0 of 0.6^ug/kg, i.v., against histamine-induced constriction.

Anti-ulcer activity

Method

Anti-ulcer activity was determined by inhibition of indomethacin-induced gastric injury in the rat according to the method of Eleghe (1974) Israeli J. Med. Sei.10. 1451. Rats were fasted overnight and given 15 mg/kg indomethacin subcutaneously, and sacrificed 4 hours later. The stomachs were inflated again with n. saline, cut open along the greater curvature, set up with splines and graded regarding gastric damage according to the following system: N

Grade 1 - 3 - according to degree of erythema and light bleeding.

Grade 4 - 6 - according to the degree of mucosal erosion. Grade 7 - 9 - according to the depth of gastric damage.

Groups of 7 rats were used for each treatment, and the test compound or drug vehicle was administered 30 minutes before indomethacin was given. Dose of test compound was 100 mg/kg orally, and control groups that only received the drug carrier were set up at the same time. Mean values for h<y>er treatment were obtained using the above-mentioned grading system, and the Mann-Witney test was used for significance of difference between the values obtained with the treatments.

The results are shown in Table C.

Compared to treatment with only drug carrier, the compounds reduced the mean ulcer grade and therefore have significant anti-ulcer activity.

Anti-secretory activity

The compounds were examined with regard to their ability to

to inhibit pentagastrin-stimulated gastric acid secretion in the gastric sac preparation from the anaesthetized, perfused rat (Ghosh and Schild preparation). The compounds were administered intravenously.

Compound 17 inhibited gastric acid secretion over the dose range 5-10 mg/kg, i.v.

Anti-platelet aggregation activity

The compounds were examined with regard to their ability to

to inhibit platelet aggregation induced in vitro by collagen in platelet-rich human plasma.

Compounds 18 and 17 inhibited aggregation by 100% and 34%, respectively, at a concentration of 100 µM. the IC50~ value. for compound 18 against collagen-induced aggregation was 7 µM.

Anti-arrhythmic activity

The compounds were tested for anti-arrhythmic activity by determining their ability to prevent cardiac fibrillation in mice exposed to chloroform.

Compound 17, 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 17 was not toxic in mice at doses up to 300 mg/kg, orally, or at doses up to 100 mg/kg, intra-peritoneally, while compound 21 was not toxic at doses up to 900 mg/kg, orally , in mice.

Claims (31)

1. Method of making a compound of formula (I) where: X is 0 or S; n is 1-8; R is hydrogen, or CO-^R-^ represents an ester group where the R^ part contains 1-12 carbon atoms;- R 2 is hydrogen, C 1-3 alkyl or phenyl; R 1 is hydroxyl or protected hydroxyl; R4 is hydrogen, C1-g-alkyl, C3-g-cycloalkyl, cycloalkyl-C-1-g-alkyl, phenyl, phenyl-C1-g-alkyl, naphthyl, naphthyl-C1-g-alkyl, each of phenyl- or naphthyl- the moieties may be substituted with one or more halogen, trifluoromethyl, C 1 -C 6 alkyl, hydroxy, C 1 -C 6 , phenyl -C 6 -alkyl or nitro groups; or R 2 and R 1 together with the carbon atom to which they are attached, can represent a C 1 -g cycloalkyl group; R 5 is hydrogen, C 1 -6 - alkyl, C 1 -6 -alkyl substituted with a nitro-, hydroxy-, C 1-6 - alkoxy-,. C02A-, (C02 A)2 -, CN- or halogen group, C5_g-cycloalkyl-, phenyl-, phenyl-C-6-g-alkyl-, phenyl-C36 -cycloalkyl, each of the phenyl parts can be substituted with one or more halogen, trifluoromethyl, C 1 -C 1 -alkyl, alkyl, or nitro groups; or a group CC^ A; if A is present in R 1 , it is hydrogen, or CO 2 A represents an ester group where the A moiety contains 1-12 carbon atoms; or a salt thereof; character-d by cyclization of a compound of formula (IX): where the variable groups are as defined above; and then, if desired or necessary, conversion of and/or R^ and/or Rr in the thus formed connection to other variables R^, R^ and R_. 2. Method as stated in claim 1, - characterized in that a compound of formula (IX) (where R^ is different from hydrogen and R, - is hydrogen) is formed in situ during the reaction of a compound of formula (X):. with a salt M <+> CNX, where M <+> is a metal ion. 3. Method as stated in claim 1, characterized in that a compound of formula (IX) (where R^ and R,, is different from hydrogen) is formed in situ during the reaction of a compound of formula (X) with a compound R^-NCX where R is not hydrogen. 4. Method as stated in claim 1, 2 or 3, characterized in that X is 0. 5...Process as stated in any of claims 1 to 4, characterized in that n is 5, 6 or 7. 6. Method as set forth in any one of claims 1 to 5, characterized in that -R is hydrogen or C^_^-alkyl. 7. Method as set forth in any of claims 1 to 6, characterized in that R2 is hydrogen or methyl. 8. Method as indicated in any of claims 1 to 7, characterized in that R 1 is hydroxyl. 9. Method as set forth in any of the claims .1 to 8, characterized in that R 1 is C 1-6 alkyl. 10. Method as set forth in any one of claims 1 to 9, characterized in that R 1 is C 1-6 alkyl. 11. Method as stated in any one of claims 1 to 10, characterized in that R,, is. G^_^-alkyl substituted with a nitro-, hydroxy-, C-1-6-6-alkyloxy-, CO 2 A-, (CO 2 A) 2 -, CN- or halogen group. 12. Method as set forth in claim 11, characterized in that R,_ is a methylene group substituted with a nitro-, hydroxy-, C1_g- alkoxy-, CO2A-, (C02A)2-, CN-. or halogen group. 13. Method 'as specified in claim 3, characterized in that X is 0 or S; n is 4-8; R^ is hydrogen, or CO-^ R^ represents an ester group where the R^ portion contains 1-12 carbon atoms; R 2 is hydrogen, C 1-3 alkyl or phenyl; R 1 is hydroxyl or protected hydroxyl; in . I ■ R4 is hydrogen, C1_g-alkyl, C5_g-cycloalkyl, C5_g-cycloalkyl-C-^_g-alkyl , phenyl, phenyl-C^_g-alkyl, naphthyl , naphthyl-C^ _^ -alkyl, where The phenyl or naftyl shares may be substituted with one or more halogen, trifluorethyl, c-^ _g-alkyl-,^^^^ ie or nitrogroups; R 5 is hydrogen, C 2 -alkyl , phenyl , phenyl-C 2 -alkyl, or a group C 2 A where A is hydrogen or C 2 A represents an ester group where the A part contains 1-12 carbon atoms; or a salt thereof. 14. Method as stated in claim 13, characterized in that n is 5, 6 or 7. 15. Process as stated in claim 13 or 14, characterized in that is hydroxy. 16. Method as set forth in claim 13, 14 or 15, characterized in that R 1 is erc 2 -y-alkyl. ■ 17. Method as set forth in any one of claims 13 to 16, characterized in that R 1 is 1 -alkyl. 18. Process as stated in claim 1, 2 or 3 for the production of a compound of formula (II): where X and R^ are as defined in claim 1; n'' is 5, 6 or 7; R 12 is hydrogen, methyl, ethyl or phenyl; R'4 is hydrogen or C1-6 alkyl; R'5 is hydrogen, C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, or a group CO2 A where A is hydrogen or CO2A represents .an ester group where the A portion contains 1-12 carbon atoms; or a salt thereof. 19.. Method as stated in claim 18, characterized in that X is 0. 20. Method as stated in claim 18 or 19, characterized in that R 1 is hydrogen or C 1-6 alkyl. 21. Method as stated in claim 18, 19 or 20, characterized in that R'2 is hydrogen. 22. Method as set forth in any one of claims 18 to 21, characterized in that R'^ is methyl. 23. Method as set forth in any one of claims 18' to 22, characterized in that R' 4 . is.c4 -g-alkyl. 24. Method as stated in claim 23, characterized in that R'4 is n-pentyl, or n-hexyl or n-heptyl. 25. Method as stated in claim'24, characterized in that R'4 is n-hexyl. 26. Method as stated in claim 23, characterized in that R'4 is a group CH(CH3)R'7, where R'7 is n-butyl, n-pentyl or n-hexyl. 27. Method as set forth in any one of claims 18 to 26, characterized in that R'5 is C1-6-alkyl. 28. Method as stated in claim 27, characterized in that R 1 j- is methyl. 29. A process as set forth in any one of the preceding claims, including the step of converting a compound of formula (I) wherein R^ is hydrogen into a sodium salt.• 30. Procedure as stated in claim. 1, 2 or.3, adapted for the preparation of the compound 1-(3'.-Hydroxy-3'-methyl-n-nonyl).-3-methyl-5-(6"-carboxy-n-hexyl)hydantoin. 31. Method as stated in claim 30, characterized in that the compound thus formed is converted to its sodium salt.