CH639076A5 - Process for the preparation of 4-oxoimidazolidine compounds - Google Patents

Description

The invention relates to a process for the preparation of new derivatives of 4-oxo-imidazolidine which are pharmacologically active.

45 In DT-OS 23 23 193 pyrazolidine derivatives of the general formula (I) 'are described

CH_ (A) (CR) CO "R / 2V 'nr 2 n 2

50

(I) '

CH9-CH0CH (CH2) pCH5

(IX)

l2,

0H

in the

A is an ethylene or ethylene residue,

R is a hydrogen atom, an alkali metal or amine salt, a hydrocarbon radical with 12 or more carbon 60 atoms or a chlorinated hydrocarbon,

m has the value 0 or 1,

n and p each represent an integer 0 to 6,

Y and Z represent oxygen or hydrogen atoms, with the proviso that Y and Z do not simultaneously mean a 65 oxygen atom.

These compounds either have biological properties corresponding to the prostaglandins or are prostaglandin antagonists.

3rd

639076

FR-PS 2 258 376 describes 10-aza prostaglandins of the general formula (II) "

0

H

ch2ch2ch2ch2ch2ch2c-or

(ii) "

(I)

r «

y-z-c-ch2ch2ch2ch3

r "

in which R is a hydrogen atom or a lower alkyl radical, R 'and R "represent the methyl or ethyl group, R ° represents a hydrogen atom or a lower alkyl radical, Y represents the ethylene or ethylene group and Z represents the CO group or the CH (- OH) group.These derivatives are valuable for the treatment of blood pressure and for the treatment of gastro-intestinal disorders and in the preparation of deliveries.

In BE-PS 835 989 compounds of the general formula (III) are described ch2 - y - (ch2) n - r1

(ch ")

(III) '

in which X is an optionally protected caibonyl group or the CROH group, where R represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms and where the hydroxyl group can be protected, Y represents the ethylene or ethylene, Z fgr is a CO-- or CH2 group, n is 1 to 8, m is 1, 2 or 3, Rj is a hydrogen atom, a CH2OH group, the hydroxyl group of which can be protected, a group -C02W, in which W is a hydrogen represents atom or a hydrocarbon radical having 1 to 12 carbon atoms,

or the group is -CONH2, R2 represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, where R2 together with R3 and the carbon atom,

to which they are attached, which can form carbonyl groups, R3 represents a hydrogen atom or an optionally protected hydroxyl group and R4 represents a hydrogen atom or an alkyl radical having 1 to 9 carbon atoms, and their salts.

These compounds have valuable pharmacological activity.

A new class of compounds has now been found which also have valuable pharmacological activity and which differ significantly in structure from the known compounds.

The present invention accordingly relates to a process for the preparation of the derivatives of 4-oxo-imidazo-lidin of the general formula (I)

io in the

X is an oxygen or sulfur atom,

m has the value 1 to 8,

CORj denotes an ester group, wherein Rj is an organic radical with 1 to 12 carbon atoms,

15 R2 represents a hydrogen atom, a phenyl group or an alkyl radical with 1 to 4 carbon atoms,

Rs represents a hydroxyl group or a protected hydroxyl group,

R4 represents a hydrogen atom, an alkyl radical having 1 to 9 20 carbon atoms, a cyclohexyl, a phenyl or naphthyl group or a cycloalkylalkyl or phenylalkyl radical containing 3 to 8 carbon atoms in the ring, each in the alkyl radical 1 to 6 Have carbon atoms, where the phenyl groups can be substituted by at least one halogen atom, a trifluoromethyl, hydroxyl or nitro group or an alkyl, alkoxy or phenylalkoxy radical each having 1 to 6 carbon atoms in the alkyl radical, or

R2 and R4 together with the carbon atom to which they are bound can form a cycloalkyl radical having 5 to 8 carbon atoms and

R5 is an alkyl radical having 1 to 6 carbon atoms, which can be substituted by at least one halogen atom, a nitro, hydroxyl or CN group, an alkoxy radical having 1 to 6 carbon atoms or the radical C02A or (C02A) 2, a cycloalkyl radical with 5 to 8 carbon atoms, a phenyl radical, a phenylalkyl radical with 1 to 6 carbon atoms in the alkyl radical, a phenylcycloalkyl radical with 3 to 6 carbon atoms in the cycloalkyl radical, the respective Phe-40 nyl radicals being substituted by at least one halogen atom , a trifluoromethyl or nitro group or an alkyl or alkoxy radical each having 1 to 6 carbon atoms, or the radical is C02A, where A can be a hydrogen atom or an organic radical having 1 to 12 carbon 45 atoms, and their salts .

A group of derivatives which fall under the general formula (I) are those in which X is an oxygen or sulfur atom,

n has the value 4 to 8,

CORj is an ester group in which Rx is an organic radical having 1 to 12 carbon atoms,

R2 represents a hydrogen atom, a phenyl group or an alkyl radical with 1 to 4 carbon atoms,

R3 represents a hydroxyl group or an etherified or esterified hydroxyl group,

R4 represents a hydrogen atom, an alkyl radical having 1 to 9 carbon atoms, a cyclohexyl radical, a phenyl group or a cycloalkyl-alkyl or phenylalkyl radical containing 5 to 8 carbon atoms in the ring, each of which has 1 to 6 carbon atoms in the alkyl-60 radical, where the phenyl groups can be substituted by at least one halogen atom, a trifluoromethyl or nitro group or an alkyl or alkoxy radical each having 1 to 6 carbon atoms, and 65 R5 is a hydrogen atom, an alkyl radical having 1 to 6 carbon atoms, the phenyl group, a phenylalkyl radical with 1 to 6 carbon atoms in the alkyl radical or the group C02A, where A is a hydrogen atom or an orga

639076

4th

is a radical having 1 to 12 carbon atoms, and their salts.

Particularly suitable derivatives of the general formula (I) are those in which X is an oxygen atom.

Conveniently, n has the value 5, 6 or 7, preferably 6.

Rt is an organic residue with 1 to 12 carbon atoms. Examples of Rx are the methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, phenyl, benzyl and the toluyl group, with alkyl radicals having 1 to 6 carbon atoms usually being preferred .

Suitable examples of the radical R2 are the hydrogen atom, the methyl, ethyl and phenyl group. R2 stands even more suitably for a hydrogen atom, the methyl or ethyl group, preferably the methyl group.

Suitable acylated or etherified hydroxyl groups R3 are easily hydrolyzable radicals, such as the acylated hydroxyl groups in which the acyl radical has 1 to 4 carbon atoms, for example the acetoxy group, or those hydroxyl groups which are etherified by easily removable inert radicals, such as the benzyl group. However, R3 is preferably the hydroxyl group.

If the radical R4 is an alkyl radical, it expediently has 4 to 9 carbon atoms. Such alkyl groups having 4 to 6 carbon atoms can be straight-chain alkyl groups, such as the n-butyl, n-pentyl, n-hexyl and the n-heptyl group, or they can be substituted by one or two methyl groups on the same carbon atom or on different carbon atoms represent branched alkyl radicals. Accordingly, R4 can be, for example, a radical -CH2R7, -CH (CH3) R7 or -C (CH3) 2R7, where R7 is a straight-chain alkyl radical, so that the total carbon content of such a radical R4 makes up 4 to 9 carbon atoms.

When R4 is an alkyl group, straight chain pentyl, hexyl and heptyl groups are usually preferred. Of these groups, the straight chain hexyl group is often the most advantageous. Other preferred radicals R4 are the radicals -CH (CH3) R7 and -C (CH3) 2R, where R7 is the straight-chain butyl, pentyl and hexyl group.

When R4 is an alkyl group, examples of other suitable R4 groups are lower alkyl groups having 1 to 4 carbon atoms.

R4 can have the meaning cyclohexyl, means an alkyl radical substituted by a C3-C8 cycloalkyl radical, this cycloalkyl radical can represent the cyclopropyl group. This cycloalkyl radical can also have 5 to 8 carbon atoms, such as the cyclohexyl group. Examples of suitable alkyl radicals having 1 to 6 carbon atoms are, when R4 is a 3 to 8 carbon atoms in the ring having cycloalkyl-alkyl radical having 1 to 6 carbon atoms in the alkyl radical, the methyl, ethyl, propyl, butyl and amyl group.

If the R4 radical is an aryl radical as defined above, suitable R4 radicals are the phenyl, phenylmethyl, phenylethyl, phenyl-n-propyl, phenyl-n-butyl, naphthyl -, Naphthyl-methyl, naphthyl-ethyl, naphthyl-n-propyl and the naphthyl-n-butyl group as well as those radicals in which the alkyl radicals can be branched by one or two methyl groups on the same carbon atom or on different carbon atoms. In the respective phenyl or naphthyl groups, the above-mentioned radicals can usually be substituted by one, two or three radicals of such substituents as those listed above. Examples of such substituents are fluorine, chlorine and bromine atoms as well as nitro, trifluoromethyl, methyl, ethyl, n and isopropyl, methoxy, ethoxy, n and isopropoxy groups. Other examples of such substituents are the hydroxy and the ben-

cyloxy group. Such aryl radicals containing substituents are preferably mono- or disubstituted.

In addition, the radicals R2 and R4 together with the carbon atom to which they are attached can represent a cycloalkyl radical having 5 to 8 carbon atoms, such as the cyclohexyl group.

Examples of suitable radicals R5 are the methyl, ethyl, n and isopropyl, n, sec and tert-butyl, phenyl, phenyl, methyl, phenyl-ethyl, phenyl-n-propyl , Phenyl-n-butyl group and those phenyl-alkyl radicals which can be branched by one or two methyl groups on the same carbon atom or on different carbon atoms in their alkyl moieties. In particular, the R5 radical is an alkyl radical having 1 to 6 carbon atoms, such as the methyl and the ethyl group.

The Rs radical can also be a phenylcycloalkyl radical with 3 to 6 carbon atoms in the cycloalkyl radical, a suitable example of the R5 radical being the phenylcyclopropyl group.

If the radical R5 is the phenyl group or represents a radical substituted by a phenyl group, it can optionally be substituted in such a way as described above for the R4 aryl radicals.

If the radical R5 is a cycloalkyl radical having 5 to 8 carbon atoms, it expediently means the cyclohexyl group.

If the radical R5 is the group C02A or represents a radical with such a group, suitable examples of A are the hydrogen atom, the methyl, ethyl, n- and iso-propyl-, n-, sec- and tert-butyl -, phenyl, benzyl, toluyl group and the like, wherein for A the hydrogen atom or an alkyl radical having 1 to 6 carbon atoms is usually preferred.

The radical R5 can also be an alkyl radical having 1 to 6 carbon atoms, which is substituted by halogen atoms, nitro, hydroxyl or nitrile groups or by alkoxy radicals having 1 to 6 carbon atoms, such as the methoxy group, or by the radicals C02A or (C02A) 2 . In such cases the radical R5 is often the methylene group which is substituted by one of the aforementioned radicals.

The compounds of the general formula (I) can form customary salts if the radical R 1 or also if the radical R 5 is a hydrogen atom. Examples of such salts are alkali metal and alkaline earth metal salts, suitably sodium and potassium salts, and ammonium and substituted ammonium salts.

It can be seen from the above that a particularly suitable group of derivatives of the general formula (I) has the general formula (II)

0

1 ar- ^ J-002e!

e \ - / I .1 <°

x 4

in the

X and Rj have the meanings given in the general formula (I),

n1 has the value 5, 6 or 7,

R \ is a hydrogen atom or the methyl, ethyl or phenyl group,

R 4 represents a hydrogen atom or an alkyl radical having 1 to 9 carbon atoms,

R * 5 is an alkyl radical having 1 to 6 carbon atoms, one

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

639076

Phenyl radical, a phenyl-alkyl radical with 1 to 6 carbon atoms in the alkyl radical or a radical C02A, where A is a hydrogen atom or an organic radical with 1 to 12 carbon atoms and their salts.

In the general formula (II), n1 preferably has the value 6. Conveniently, X also denotes an oxygen atom.

The R ^ radical is more conveniently the methyl or ethyl group, preferably the methyl group.

Although the RJ4 radical may be a hydrogen atom or an alkyl radical with 1 to 9 carbon atoms, it is usually an alkyl radical with 4 to 9 carbon atoms. In the latter case, suitable and preferred straight-chain and branched-chain radicals for R \ are the above-described suitable and preferred radicals for R4 when R4 is an alkyl radical with 4 to 9 carbon atoms. Such preferred R * 4 radicals are straight chain pentyl, hexyl and heptyl groups, of which radicals the straight chain hexyl group is usually the most preferred. Other preferred radicals Rx4 are the radicals -CH (CH3) R1, and -C (CH3) 2R17, in which the radical R1 is the straight-chain butyl, pentyl or hexyl group.

The radical R * 5 is expediently an alkyl radical having 1 to 6 carbon atoms, such as the methyl or the ethyl group.

A second group of derivatives of the general formula (I) of particular interest are derivatives of the general formula (III)

0

,1'

5

oh in the

X and Rx have the meanings given for the general formula (I),

n1 has the value 5, 6 or 7,

R * 2 is a hydrogen atom which is methyl, ethyl or phenyl group,

R24 is a radical of the general formula (IV)

¥

T

in the

T is a bond or an alkylene radical having 1 to 6 carbon atoms, which is straight-chain or branched by one or two methyl groups on the same carbon atom or on different carbon atoms, and

W, Y and Z each represent a hydrogen, fluorine, chlorine or bromine atom, which mean nitro, trifluoromethyl, methyl, ethyl, n or isopropyl, methoxy or ethoxy group and

Rx5 represents an alkyl radical with 1 to 6 carbon atoms, the phenlyl group, a phenylalkyl radical with 1 to 6 carbon atoms in the alkyl radical or a radical C02A, where A is a hydrogen atom or an organic radical with i to 12 carbon atoms, and their salts .

In the general formula (III), n1 preferably has the value 6. The radical X is also expediently an oxygen atom.

Rl2 is in particular a hydrogen atom or the methyl or ethyl group, preferably the methyl group.

In the general formula (IV) the radical T is frequently a radical - (CH2) q-, where q has the value 0 to 4. Conveniently, W and Y are hydrogen atoms.

The R ^ radical is expediently an alkyl radical having 1 to 6 carbon atoms, such as the methyl and ethyl group.

Another group of derivatives of the general formula (I) with particular interest are derivatives of the general formula (VII)

0

l _ / '^ 0E2 ^ nl002El e1 -fl, r1 2 ""

x oh in the

X and Rj have the meanings given in the general formula (I),

n1 has the value 5, 6 or 7,

R * 2 is a hydrogen atom or the methyl, ethyl or phenyl group,

R44 represents a radical of the general formula (VIII) in the

T has the meanings given in the general formula (IV) and r has the value 0 to 3, and

R ^ represents an alkyl radical with 1 to 6 carbon atoms, the phenyl group, a phenylalkyl radical with 1 to 6 carbon atoms in the alkyl radical or a radical COaA, where A is a hydrogen atom or an organic radical with 1 to 12 carbon atoms,

and their salts.

In the general formula (VII), n1 preferably has the value. 6. The radical X expediently denotes an oxygen atom.

The radical R'2 is particularly advantageously a hydrogen atom or the ethyl group, but preferably the methyl group.

In the general formula (VIII) the radical T is often the radical - (CH2) q-, where q has the value 0 to 4. Suitably r also has the value 1.

The radical R * g is expediently an alkyl radical having 1 to 6 carbon atoms, such as the methyl and ethyl group.

A compound of the present invention is particularly preferred due to its advantageous activity. It is the compound 1- (3'-hydroxy-3'-methyl-n-nonyl) -3-methyl-5- (6 "-carboxy-n-hexyl) -hydantoin.

The method according to the invention is defined in claim 1.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

639076

6

The radicals Rx and / or R3 and / or R5 of the compounds obtained according to the invention can also be converted into other variable radicals Rt, R3 and Rä.

In the process according to the invention, in which both radicals Rj and Rg in the case of a compound of the general formula (IX) represent radicals other than hydrogen atoms, the compound of the general formula (IX) is reacted during the reaction of a compound of the general formula (X) with a compound of the general Formula R5NCX, made in situ. This process is conveniently carried out in an inert solvent, such as benzene or the like, under reflux. It is pointed out that if the Rg radical in this reaction is a sterically hindered radical, the reaction can then only proceed to the uncyclized compound of the general formula (IX), the required cyclization of the compound of the general formula (IX ) can be achieved with a strong base, such as sodium hydride or sodium ethoxide, in an anhydrous organic solvent. Suitable reagents are sodium ethoxide in benzene or potassium tert-butoxide in toluene, benzene or hexamethylphosphoramide.

The conversion of a derivative of a subgroup of a compound of the general formula (I) prepared according to the invention into another subgroup can be achieved in a conventional manner.

If appropriate, the radical R 1 in a compound can be varied, for example, by customary esterification and / or saponification processes. In the same way, the protective groups of protected hydroxyl groups as radicals R3 can be split off in the usual way. For example, when the Rs group is the benzyloxy group, the benzyl group can be split off smoothly by hydrogenolysis. It can be seen that derivatives of the general formula (I) with protected hydroxyl groups are valuable intermediates in the preparation of the corresponding derivatives of the general formula (I) with free hydroxyl groups. Even if a derivative of the general formula (I) contains an acidic hydrogen atom or acidic hydrogen atoms, its salt can be prepared in a conventional manner, for example by reacting a derivative of the general formula (I) with a corresponding base.

The intermediates of the general formula (IX) are new.

The starting materials of the general formula (X) for the process according to the invention can be prepared by the process described in BE-PS 835 989 or by analogous processes.

It is clearly evident that the derivatives of the general formula (I) have asymmetric centers and that these derivatives can exist in a number of stereoisomeric forms. The invention also extends to these stereoisomeric forms and to their mixtures. The various stereoisomeric forms can be separated from one another by customary methods.

The derivatives of the general formula (I) have valuable pharmacological activities. For example, they inhibit gastric juice secretion, have anti-ulcer activity and cardiovascular activity, for example an activity against high blood pressure, inhibit platelet aggregation, act on the respiratory tract, i.e. they have bronchodilator activity, and have an anti-fertility effect and a smooth muscle effect, and have an antiarrhythmic activity.

In general it can be said that the derivatives of the general formula (I) correspond in their pharmacological effects to natural prostaglandins, but that their effects are more selective.

Accordingly, the compounds of formula I prepared according to the invention can be used as active ingredients in medicinal products. In addition to the active ingredients, such preparations usually contain pharmacologically acceptable carrier materials, diluents and / or excipients.

Of course, the preparation of such pharmaceutical preparations depends on the type of activity shown by the corresponding derivative of the general formula (I), as well as on other factors, for example the preference of a particular mode of administration for a particular therapy. The medicinal preparations can be in the form of tablets, capsules, powders, granules, lozenges or as liquid preparations, such as oral or sterile parenteral solutions 15 or suspensions.

Tablets and capsules for oral administration can be in single doses and contain conventional pharmacologically acceptable excipients such as binders, fillers, lubricants, disintegrants and compatible humectants. The tablets can be coated in a conventional manner. Liquid oral preparations of the medicinal preparations according to the invention are e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or dry preparations that are reconstituted with water or another diluent before use. The liquid preparations can contain conventional additives, such as suspension aids, emulsifiers, non-aqueous vehicles, which can be edible oils, preservatives and optionally conventional flavoring agents or colorants.

For paranteral administration, the derivatives of the general formula (I) obtained according to the invention are either suspended or dissolved in a sterile diluent, depending on the concentration and diluent. 35 The derivatives obtained according to the invention can be dissolved for injections and sterile filtered before they are filled into a suitable bottle or ampoule and sealed. Advantageously, adjuvants such as local anesthetics, preservatives and / or puffing substances can also be dissolved in the diluent. Parenteral suspensions are prepared in the same way, but the compound obtained according to the invention is suspended in the diluent and is not sterilized by filtration. The compound obtained according to the invention can be sterilized by treating with ethylene oxide before suspending in the sterile diluent. Advantageously, a surface-active compound or a wetting agent is added to the suspension in order to ensure the uniform distribution of the compound. The medicinal products mentioned can also be prepared as an aerosol or as a finely divided powder for insufflation.

As is common practice, medicinal products are accompanied by a written or printed instruction for use.

The dosage of the medicinal preparations naturally depends on the derivative of the general formula (I) used and on the severity of the disease to be treated.

The medicinal products with the compounds of formula I 60 or their salts as active ingredients can be used for the treatment or prophylaxis of diseases in humans or animals.

The derivatives of the general formula (I) of the present invention are usually used in the therapy of human diseases.

The examples illustrate the invention with regard to the preparation of the derivatives of the general formula (I) and their pharmacological properties.

7

639076

Example 1 Compound 1

(CH2) 6C02Me

10th

9.6 g of dimethyl 2- (N-3'-hydroxy-3'-methyl-n-decyl) -amino-azelaia are allowed to reflux for three hours with 1.365 g of methyl isocyanate in 80 ml of anhydrous benzene. After evaporation of the benzene under reduced pressure, 10.2 g of a pale yellow, gummy substance is obtained, which is chromatographed on silica gel with a packing ratio of 30: 1 using chloroform as the eluent. 6 g of l- (3'-hydroxy-3'-methyl-n-decyl) -3-methyl-5- (6 "-methoxycarbonyl-n-hexyl) hydantoin are obtained as a light oil.

The compounds listed in Table I below were prepared in an analogous manner.

TABLE I

15

20th

R,

_tfX / - <CH2> nC02Kl

'I

oh r,

Liaison No.

Ri ra

R4

Rs

2 C2H5 CH3 C6H13 C2H5 6

3 C2H5 CH3 C6H13 CH3 6

4 CH, j ^) CH, 6

5 CH3 CH3 (CH2) 2Ph CH3 6

6 CH3 CH3 C6H13 CH3 6

7 CH3 CH3 CH (CH3) C4H9 CH3 6

8 CH3 CH3 Ph CH3 6

9 CH3 CH3 C6H13 Ph 6

10 ch3 ch3,. fOL ch3

(ch2) 2j <> ICF3

11 ch3 ch3 ch3 ch3

12

ch3

ch3

csh13

6

35

ch3

ch3

c6h13

ph-ZX

6

36

c2h5

ch3

ch3

7

37

c2h5

ch3

c6h13

ch3

5

38

ch3

ch3

CßHn ch3

1

639076

8th

Example 2 Compound 13

MeOgC

(ch3> 3c ~

(CH ^ Wyfe

-NK ^ H

■ ^^ oìr ^ c

6 = 13

Connection 14

(ch3> 3 ^ "

OOHjPh

20 g of 2- (N-3'-benzyloxy-n-nonyl) -amino-azelaic acid di-methyl ester are boiled under reflux with 2.46 g of methyl isocyanate in 200 ml of anhydrous benzene for 3 hours. After evaporating the benzene under reduced pressure, a dark yellow oil is obtained which is chromatographed on silica gel with a packing ratio of 30: 1 using chloroform as the eluent. 9 g of l- (3'-benzyloxy-n-nonyl) -3-methyl-5- (6 "- methoxycarbonyl-n-hexyl) -hydantoin are obtained as a colorless, rubber-like substance.

Example 5

20 g of 2- [N- (3'-hydroxy-3'-methyl) -n-nonyl] -amino-aze-lainic acid dimethyl ester are refluxed with 5.12 g of tert-butyl isocyanate in 200 ml of anhydrous benzene for 3 hours . After evaporation of the benzene under reduced pressure, 20 g of a pale yellow, rubbery substance are obtained, which is chromatographed on 600 g of silica gel using chloroform as the eluent. 11.6 g of 2- [N- (3'-hydroxy-3'-methyl-n-nonyl) -N- (N'-tert-butylformamido)] - amino-azelainic acid dimethyl ester are obtained as clear gummy substance.

Example 3

10th

15

Connection 16

° 2H5

(CH ^ COgMe

. 6H «6 * 15

10 g of 2- [N- (3'-hydroxy-3'-methyl-n-nonyl) -N- (N'-tert.-butylformamido)] - amino-azelainic acid dimethyl ester are mixed with 2.5 g of potassium Let tert-butoxide boil under reflux in 150 ml of anhydrous toluene for 3 hours. After the toluene has been evaporated off under reduced pressure, the rubber-like substance obtained is distributed between ether and very dilute hydrochloric acid. The ethereal solution is washed with brine, then dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 8.4 g of a yellow gummy substance is obtained, which is chromatographed on 250 g of silica gel using chloroform as the eluent. 5.2 g of l- (3'-hydroxy-3'-methyl-n-nonyl) -3-tert-butyl-5- (6 "-methoxycarbonyl-n-hexyl) -hydantoin are obtained as a clear, rubber-like substance .

Example 4 Compound 15

0

. (CH ^ gCOgMe

(ch2) 6co2h

20 1.1 g of l- (3'-hydroxy-3'-methyl-n-nonyl) -3-ethyl-5- (6 "- ethoxycarbonyl-n-hexyl) -hydantoin are mixed with 7.5 ml of 10- percent aqueous potassium carbonate solution and 30 ml of ethanol are refluxed overnight. After cooling, the solution is acidified with concentrated hydrochloric acid 25. This solution is extracted three times with 100 ml of ether each. The ethereal solution is then extracted with 5 percent sodium bicarbonate solution. The aqueous solution obtained The phase is washed back with ether and then acidified with dilute hydrochloric acid, the substance extracted in ether 30 and the ethereal solution are washed with brine, then dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 770 mg of 1- (3'-hydroxy -3'-methyl-n-no-nyl) -3-ethyl-5- (6 "-carboxy-n-hexyl) -hydantoin as a colorless, rubbery substance.

The compounds listed in Table II below were prepared in an analogous manner.

TABLE II

40

45

. (cl2) n002h

R.

- / y

50

55

60

65

Sales

binding

No.

R2

R4

Rs n

17th

ch3

c7h15

ch3

6

18th

ch3

c2h5

ch3

6

19th

0

ch3

6

20th

ch3

(CH2) 2Ph ch3

6

21st

ch3

C6Hl3

o sc

CO

6

22

ch3

ch (ch3) c4h9

ch3

6

23

ch3

Ph ch3

6

24th

H

QH13

ch3

6

25th

ch3

£ -6 ^ 13

c (ch3) 3

6

639 076

TABLE II (continued)

Sales

binding

No.

Ra

R4

Rs n

5

26

ch3

Ph

6

27th

ch3

* ca2> 2

3J_gf3 ch-

6

10th

28

ch3

O

SC

CO

ch3

6

29

ch3

QHl3

n

6

39

ch3

ceh13

ph-Z-A

6

40

ch3

c (jh13

ch3

7

41

ch3

qjhj;)

ch3

5

42

ch3

^ -6 ^ 13

ch3

1

48

ch3

CeHi3

ch2och3

6

49

ch3

^ 6 ^ -13

ch2co2h

6

Example 6 Compound 30

(CHgJgCOgMe c6e13

5 g of l- (3'-benzyloxy-n-nonyl) -3-methyl-5- (6 "-methoxy-15 carbonyl-n-hexyI) -hydantoin are dissolved in 50 ml of anhydrous dimethoxyethane in the presence of 10 percent palla dium charcoal catalyst at room temperature and normal pressure After filtering the reaction mixture by Kieseiguhr and after evaporating the di-20 methoxyethane under reduced pressure, 3.8 g of a colorless oil are obtained, which is added to 110 g of silica gel using chloroform as eluent 2.48 g of l- (3'-hydroxy-n-nonyl) -3-methyl-5- (6 "-methoxycarbonyl-n-hexyl) -hydantoin are obtained as colorless

25 oil.

Example 10 Compound 50

30th

35

CH3N

0

(CH2) 6CO ^ Na ©

at,

10 g of 2- (N-3'-hydroxy-3'-methyl-n-nonyl) -amino-azelainic acid dimethyl ester are refluxed with 1.89 g of methyl isothiocyanate in 100 ml of anhydrous toluene for 3 hours. After evaporating the toluene under reduced pressure, 11.1 g of a yellow oil are obtained, which is chromatographed on 330 g of silica gel using chloroform as the eluent. 9.49 g of l- (3'-hydroxy-3'-methyl-n-nonyl) -3-methyl-5- (6 "- methoxycarbonyl-n-hexyl) -2-thio-hydantoin are obtained as a light yellow oil .

The compounds listed in Table III below were prepared in an analogous manner.

TABLE III

? h3

<cv2f-C6H13

OH

40 At room temperature, a solution of 1- (3'-hydroxy-3'-methyl-n-nonyl) -3-methyl-5- (6 "-carboxy-n-hexyl) -hydantoin in anhydrous methanol. After evaporating off the methanol 45 at 30 ° C. under reduced pressure, the substance obtained is triturated with petroleum ether with a boiling range of 40 to 60 ° C. Then the substance obtained is filtered , dries it over sodium hydroxide in a vacuum desiccator and finally grinds it to a fine pale yellow powder.

The corresponding lithium salt is produced in an analogous manner.

J—

55

r,

4th

I.R. (cm-1):

60

NMR (x):

Connection no.

Ri

Ra

R4

Rs

31

c2h5

ch3

c6h13

ch3

32

ch3

ch3

ch3

ch3

65

Compound 1 3450, [OH]; 1760, 1700, [-N-C-N-C-];

II II

o o

1730, [-C02CH3].

7.15, (s), [OH];

7.05, (s), [-N-ŒJ

6.95 - 6.35, (m), [-N-CH2-];

6.35, (s), [-C02 £ H3];

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

639076

10th

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR (x): (CC14)

LR. (cm-1):

NMR (x):

LR. (cm-1):

NMR (x):

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

I.R. (cm-1):

c23h42n2o5

c 64.76 h 9.92 n 6.57% c 64.44 h 9.92 n 6.71%

C2sH42N205

426.3093 426.3065

Connection 2

NMR (x):

10th

3500, [OH]; 1700, 1760, [-N-C-N-C-]; Mass spectrum:

II II calculated:

O O found:

1730, [-COaEt]. 15

7.2, (s) [OH]; 6.2 - 6.8, (m),

[CH3CH2N-; -N-QH2]; 5.9, (m) [-N-ÇH; C02 £ H2CH3].

Connection 3

i i

3500, [OH]; 1710, 1760, [-N-C-N-C-];

II II

o o

1730, [-C02Et].

i

7.2, (s), [OH]; 7, 0, (s), [-N-CH3];

i

6.2-7, (m), [-N-ÇHJ

i

5.9, (m) [-N-QH; -CO, CH, CH, 1st Connection 4

i i

3500, [OH]; 1700, 1760, [-N-C-N-C-];

II II o o

1720, [-C02-CH3].

i

7.05, (s), [-N-CH3; OH];

6.2 - 6.9, (m), [-N-ÇH,];

6.35, (s), [-C02CH3];

6.0, (t), [-N-CH1.

^ (jH ^ N ^ g

C 62.80 H 8.96 N 7.32% C 62.61 H 8.95 N 7.19%

C20H34N2O5

382.2468

382.2466

Connection 5

LR. (cm-1):

20th

NMR (x):

25th

30th

35

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

40

I.R. (cm-1):

45

NMR (x):

50

Mass spectrum: calculated: 60 found:

3500, [OH]; 1700, 1760, [-N-C-N-C-]; 65 I.R. (cm-1):

II II

o o

1730, [-C02CH3].

7.75, (t), [-CH2C02CH3]; 7.3, (m), [-CH2Ph]; 7.1, (s), [-OH];

i

7.05, (s), [-N-ÇHJ;

i

6.5-7.0, (m), [-N-CHJ; 6.5, (s), [-C02CH3];

i

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

C24H34N204 [m * -H20]

414.2518

414.2523

Connection 6

i i

3500, [OH]; 1700, 1760, [-N-C-N-C-];

II II o o

1730, [-C02CH3].

7.3, (s), [OH];

i

7.05, (s), [-N-CH3];

i

6.3 - 7, (m), [-N-ÇHJ;

6.35, (s), [-C02CH3]; 6.0, (m), [-N-ÇH].

CaH (0N2Os

C 64.05 H 9.77 N 6.79% C 64.14 H 9.68 N 6.62%

WA [m * -H20]

394.2832

394.2848

Connection 7

i i

3500, [OH]; 1710, 1760, [-N-C-N-C-];

II II o o

1730, [-C02CH3].

7.75, (m), [-CH2C02CH3]; 7.2, (s), [OH];

i

7.05, (s), [-N-CH3];

i

6.4-6.9, (m), [-N-ÇH,];

6.35, (s), [-C02CH3];

6.05, (m), [-N-ÇH],

0 ^ 33 ^ 04 [m * -H20]

394.2831

394.2794

Connection 8

i i

3500, [OH]; 1700, 1760, [-N-C-N-C-];

II II o o

1730, [-co-joty.

11

639076

I.R. (cm-1):

NMR (x):

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR (x):

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR Ou):

Mass spectrum:

calculated:

found:

Mass spectrum:

calculated:

found:

Compound 9 3500 cm-1, [OH]; 1710, 1770,

[-N-C-N-C-]; 1730, [-C02CH3].

II II o o

7.75, (t), [-CH2C02CH,]; 7.45, (s), [OH];

i

6.2 - 7.0, (m), [-N-CH2]; 6.37, (s), [-C02CH3];

i

5.95, (m), [-N-ÇH];

2.65, (s), [C6H5],

c27h42n2o5

474.3094 474.3083

Compound 10 3500, [OH]; 1710, 1760, [-N-C-N-C-];

ii ii o o

1730, [-C02CH3].

7.8, (t), [-ÇH2C02CH3];

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

7.1, (s), [-N-ÇH,];

6.5 - 7, (m), [-N-ÇH,];

6.45, (s), [-C02CH3];

i

6.1, (m), [-N-ÇH];

2.65 (broad s), [-Ar].

C25H33N204F5 [m * -H20]

482.2392

482.2415

Connection 11

i i

3500, [OH]; 1710, 1760, [-N-C-N-C-];

II II O o

1730, [-C02CH3].

7.75, (t), [-CH2-CO2CH3];

7.15, (s), [OH];

7.1, (s), [-N-ÇH3];

i

6.2 - 7, (m), [-N-CH,!:

6.4, (s), [-C02ÇH3];

6.05, (m), r-N-CHl.

C17H30N2O5

342.2154

342.2144

C17H23N204 [m * -H20]

324.2049

324.2050

I.R. (cm-1):

NMR (x):

10th

15

Mass spectrum:

calculated:

found:

20th

I.R. (cm-1):

25th

30th

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

35

I.R. (cm-1):

40

NMR (x):

45

so analysis for: calculated: found:

Mass spectrum: 55 calculated: found:

Mass spectrum: calculated: 60 found:

65 I.R. (cm-1):

Compound 12 3500, [OH]; 1700, 1760, [-N-C-N-C-];

II II

o o

1740, [-C02CH3].

7.75, (t), [-CH2C02CH3]; 7.1, (s), [OH];

6.2-7, (m), [-N-ÇHJ; 6.4, (s), [-C02CH3];

6.1, (m), [-N-QH],

c27h48n2o5

480.3564 480.3536

Compound 13 3400, [OH]; 1740, [-C02CH3];

i i

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

II

O

C26H50N2Oe

C 64.16 H 10.36 N 5.76% C 64.22 H 10.69 N 5.43%

C25H44N204 [m * -H20-CH30H]

436.3301

436.3293

Compound 14 3500, [OH];

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

II II o o

1735, [-C02CH3].

7.2, (s), [OH];

i

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

6.3, (s), [-C02QH3];

6.2, (m), [-N-ÇH],

C25H46N205

C 66.05 H 10.20 N 6.16%

C 65.89 H 10.30 N 6.13%

c25h46n2o5

454.3406 454.3451

C25H44N204 [m * -H2Oj

436.3301

436.3317

Connection 15

i i

1710, 1760, [-N-C-N-C-];

II II

o o 1730, [C02CH3].

639076

12

NMR (x):

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR (x):

Mass spectrum:

calculated:

found:

I.R. (cm4):

NMR (x):

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR (x): (CD ^ CO

7.1, (d), [-n-çh3];

i

6.3-7, (m), [-N-QH2];

6.35, (s), [-C02QH3];

6.2, (m), [-n-çh];

5.5, (s, with shoulder), [-OCELPh]; 2.75, (s), [-OCH2Ph].

c28h44n2o5

c 68.82 h 9.08 n 5.73% c 68.62 h 9.21 n 5.66%

488.3250 488.3287

Compound 16 3700 - 2500, [-c02h; Oh];

1760, 1710, 1700 [-n-c-n-c-; c02h].

II II o o

7.0 - 5.9, (m), [(N-CH2) x2; -N-ÇH]; 4.4 (broad s), [-C02H; OH].

C22H40N2O5

412.2937

412.2917

Compound 17 3700-2400, [-C02H; OH]; 1760, 1720,

i i

1700, [-N-C-N-C-; C02H].

II II o o

7.05, (s), [-N-ÇHJ;

6.95 - 6.35, (m), [-N-ÇHJ;

i

6, (broad s), [-N-ÇH];

3.15, (broad s), [C02H; OH]

c22h40n2o5

C 64.05 H 9.77 N 6.79% C 64.36 H 9.99 N 6.99%

C22H38N204 [m * -H20]

394.2831

394.2848

Compound 18, 3700-2500, [C02H; OH];

1760, 1700 (broad) [-N-C-N-C-; C02H].

II II o o

7.05, (s), r-N-CH, l;

i

6.9-6.1, (m), [-N-CH2];

i

5.9-5.7, (s + t), [-N-ÇH; C02H; OH].

Mass spectrum:

calculated:

found:

I.R. (cm-1):

10th

NMR (x):

15

Analysis for: 20 calculated: found:

Mass spectrum: calculated: 25 found:

I.R. (cm-1):

30th

NMR (x):

35

40

Analysis for: calculated: 45 found:

Mass spectrum:

calculated:

found:

50

I.R. (cm-1):

55

NMR (x):

60

65

Mass spectrum:

calculated:

found:

ci, h30n2o5

342.2155

342.2174

Compound 19 3700-2400, [C02H; OH];

i i

1760, 1700 (broad) [-N-C-N-C-; C02H].

II II o o i

7.1, (s), [N-CHg];

6.6, (m), [-N-ÇHJ;

6.05 (broad s), [C02H; OH];

i

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

Ci9H32N2O5

C 61.93 H 8.75 N 7.60% C 61.99 H 8.97 N 7.64%

368.2311 368.2313

Compound 20 3700-2400, [C02H; OH];

i i

1760 -1700, [-N-C-N-C-; C02H].

II II

0 o

7.3, (m), [CH2Ph];

I.

7.05, (s), [-N-®];

1

6.8 - 6.1, (m), [-N-CHj];

6.15, (s), [-C02H; OH];

I.

5.8, (t), [-N-ÇH],

C23H24N205

C 66.01 H 8.19 N 6.69%

C 65.82 H 8.38 N 6.37%

WA [m * -H20]

400.2362

400.2323

Compound 21 3700-2400, [C02H; OH];

i i

1760, 1720, 1700, [-N-C-N-C-; C02H].

II II o o

I.

7.1, (s), r-N-CH, l;

I.

6.8 - 6.1, (m), [-N-CR2ÌI 6.1, (s), [CO 2 H; OH];

I.

5.85, (t), [-N-ÇH].

C21H36N204 [m * -H20]

380.2675

380.2672

13

639076

I.R. (cm-1):

NMR (x): (CD3) 2CO

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

Compound 22 3700 - 2500, [C02H; OH]; 1760,

i i

1740 to 1690, [-N-C-N-C-; C02H].

II II o o i

7.1, (s), [-N-ÇH3];

i

6.9-6.1, (m), [-N-ÇH,];

i

5.9, (t), [-N-ÇH];

5 - 3, wide. Hump [C02H; OH].

c2iH38n2o5

C 63.29 H 9.61 N 7.03% C 62.94 H 9.79 N 6.65%

C21H36N204 [m * -H20]

380.2675

380.2641

I.R. (cm-1):

NMR (x):

10th

Analysis for: calculated: 15 found:

Mass spectrum:

calculated:

found*.

20th

I.R. (cm-1):

I.R. (cm-1):

nmr (x):

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

I.R. (cm-1):

Compound 23, 3700-2500, [C02H, OH];

i i

1760, 1700 (broad) [-N-C-N-C-; C02H].

II II o o i

7.25, (d), r-N-CH, l;

1

6.9 - 6.1, (m), [-N-CH2];

5.6 (broad s), [-C02H, OH];

2.65, (m), [Ph].

C21H30N2O5

€ 64.60 H 7.74 N 7.17% C 64.83 H 7.96 N 6.91%

C21H28N204 [m * -H20]

372.2049

372.2037

25th

NMT (x):

30th

Mass spectrum: 35 calculated: found:

40 I.R. (cmr1):

45

Compound 24 3700 - 2500, [C02H; OH];

i i

1760, 1710 (broad) [-N-C-N-C-; C02H]. so

Il II o nmr (x):

drdmso nmr (x):

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

7.1, (s), [-N-çh3];

6.8 - 6.1, (m), [-N-ÇHJ;

i

5.9, (t), [-N-ÇH];

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

C20H36N2O5

C 62.47 H 9.44 N 7.29% C 62.40 H 9.59 N 7.04%

C2oH36N205

384.2624 384.2640

55 Analysis for: calculated: found:

Mass spectrum: 60 calculated: found:

I.R. (cm-1):

65

Compound 25 3700-2400, [C02H; OH];

i i

1760, 1700 (broad) [-N-C-N-C-; C02H].

II II o o

6.7, (s), [CO 2 H; OH];

i

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

1

6.1, (t), [-N-ÇH].

C24H44N205

C 65.42 H 10.07 N 6.36%

C 65.21 H 10.29 N 6.08%

C24H44N205

440.3250

440.3280

Compound 26 3200-2600, [C02H; OH];

i i

1770, 1700 (broad) [-N-C-N-C-; C02H].

II II o o i

7-6.1, (m), [-N-CH2];

5.95, (broad), [C02H; OH];

i

5.6, (t), [-N-ÇH];

2,6, (d), [Ph],

C26H38N204 [m * -H20]

442.2832

442.2841

Compound 27 3200-2400, [C02H; OH];

i i

1770, 1730-1680, [-N-C-N-C-; C02H].

II II o o

7.8, (t), [-CH2-CO2H]; 7.4, (m), [-CH2-Ar];

7.15, (s), [-N-ÇH3];

i

7-6, (m), [-N-ÇH,];

i

5.8, (m), [-N-ÇH].

C24H33N205F3

C 59.25 H 6.83 N 5.76%

C 59.29 H 7.13 N 5.82%

C24H31N204Fs [m * -H20]

468.2236

468.2245

Compound 28 3200-2400, [C02H; OH];

i i

1760, 1730-1690, [-N-C-N-C-; C02H].

II II o o

639076

14

NMR (x): (D6DMSO)

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR (x): (CD3) 2CO

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

I.R. (cmJ):

NMR (x):

Analysis for:

calculated:

found:

Mass spectrum:

calculated:

found:

7.75, (t), [-CH2-CO2H];

i

7.1, (s), [-N-CH3];

7-6, (m), [-N-ÇHJ; 5.8, (t), [-N-QH].

C16H28N2 ° 5

C 58.52 H 8.59 N 8.53% C 58.59 H 8.71 N 8.70%

c16h28n205

328.1998 328.1995

Compound 29 3200-2400, [C02H; OH];

i i

1760-1680, [-N-C-N-C-; C02H].

II II o o

7 - 6.2, (m), r-N-CH.1: 6.1, (broad s), [CO 2 H; OH];

6.0, (m), [-N-ÇH-C-];

II

O

5.5, (m), [-C-N-ÇH].

ii i o 0 = 0

c2ch4Gn205

C 66.92 H 9.94 N 6.00% C 66.57 H 10.06 N 6.25%

c26h45n205

466.3406 466.3403

Compound 30 3510, [OH]; 1750- 1720,

i i

[-N-C-N-C-; C02CH3],

II II

S o

7.75, (m), [OH, CH2-CO2CH3];

6.8, (s), [-N-CH3];

7-6.2, (m), [-N-CH2];

6.35, (s), [-C02CH3];

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

C22H40N2O4S

C 61.64 H 9.41 N 6.53 S 7.48% C 61.71 H 9.51 N 6.54 S 7.34%

C22H38N203S [m * -H20]

410.2603

410.2610

I.R. (cm-1):

NMR (x):

10th

Analysis for: 15 calculated: found:

Mass spectrum: calculated: 20 found:

I.R. (cm4):

25th

NMR (x):

30th

35

Mass spectrum: calculated: 40 found:

I.R. (cm-1):

45

NMR (x):

50

55

Analysis for: calculated: found:

6o mass spectrum: calculated: found:

65

I.R. (cm-1):

Connection 31

i i

3500, [OH]; 1740, [-N-C-N-C-; C02Et].

II II

S o

7.7, (s), [OH];

i

6.8, (s), [-N-ÇH3];

6.9 - 6.2, (m), f-N-CH,];

i

5.9, (m), [-N-CH; -C02CH2CH3]. C23H42N204S

C 62.41 H 9.56 N 6.33 S 7.24% C 62.54 H 9.85 N 6.05 S 7.35%

QANAS

442.2865

442.2866

Compound 32 3500, [OH]; 1740, 1720,

i i

[-N-C-N-C-; C02CH3].

II II

S o

7.45, (s), [OH];

6.8, (s), [-N-ÇH3];

I.

6.9-6.2, (m), [-N-CTU;

6.4, (s), [-C02CH3];

5.9, (m), [-N-QH],

Cj.7H30N2O4S

358.1926 358.1956

Compound 34 3500, [OH]; 1760, 1710,

i i

[-N-C-N-C-]; 1730, [-C02CH3].

II II o o

I.

7.05, (s), [-N-ÇH3];

I.

6.7 - 6.2, (m), [-N-ÇHJ;

6.35, (s), [-C02QH3];

i

6.0, (s), [-N-ÇH].

C21H38N2Os

C 63.29 H 9.61 N 7.03%

C 63.61 H 9.83 N 7.34%

C2iH3BN2OS

398.2780 398.2769

Compound 35 3550, [OH]; 1770, 1730 (broad) [-N-C-N-C-; -C02CH3],

II II o o

15

639 076

NMR (x):

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR (x):

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR (x):

Mass spectrum:

calculated:

found

7.75, (t), [CH2C02CH3]; 7.35, (m), [Ph-CH]; 7.35, (s), [OH];

7.0-6.2, (m), [-N-CHJ; 6.4, (s), [-C02CH3];

6.1, (m), [-N-QH] x 2; 2.7, (s), [Ph].

C30H44N2O4 (m * -H20)

496.3301

496.3303

Compound 36 3550, [OH]; 1770, 1710, [-N-C-N-C-];

II II

o o

1730, [-cqahj.

7.7 (t), [CH2C02C2H5];

7.5, (s), [OH];

i

7.0, (s), [-N-QÜ;

7.0 - 7.2, (m), [-N-ÇH,];

i

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

5.85, (q), [-C-0-CH2CH3].

II

O

C24H42N204 (m * -H20)

422.3144

422.3156

NMR (x):

10th

Mass spectrum::

calculated:

found:

15

I.R. (cm-1):

20th

NMR (x):

25th

30th

Mass spectrum:

calculated:

found:

35 analysis for: calculated: found:

40 I.R. (cm-1):

Compound 37 3500, [OH]; 1760, 1710, [-N-C-N-C-];

II II

OO 45 NMR (x):

1720, [-C02C2H5].

7.75, (t), [CH2C02C2H5];

7.5, (s), [OH];

7.05, (s), [-N-QHS];

i

6.9 - 6.2, (m), [-N-ÇHJ;

i

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

C22H38N204 (m * -H20)

394.2832

394.2826

50

Mass spectrum: 55 calculated: found:

Analysis for: calculated: 60 found:

7.75, (s), [OH];

7.1, (m), [CH2C02CH3];

6.9 - about 6.3 (m), [-N-ÇHJ;

i

6.95, (s), [-N-ÇH3];

6.25, (s), [-C02CH3];

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

C17H28N204 (m * -H20)

324.2048

324.2056

Compound 39 3700-2500, [-C02H; OH];

i i

1760, 1720 (broad) [-N-C-N-C-; C02H].

II II

o o

7.7, (m), [CH2CO2H]; 7.3, (m), (Ph-CH];

i

7.0 - 6.1, (m), [-N-CHJ;

i

5.9, (t), [-N-ÇH] X 2;

5.7, (broad s), [C02H; OH];

2.75, (s), [Ph],

^ 29 ^ 42N204 (m * -H20)

482.3145

482.3184

c29h44n2o5

C 69.57 H 8.86 N 5.60% C 69.83 H 9.05 N 5.32%

Compound 40 3800-2500, [-C02H; OH];

1770, 1720 (broad) [-N-C-N-C-; C02H].

II II o o

7.7, (t), [CH2C02H];

i

7.1, (s), [-N-ÇH3];

i

7.0-6.1, (m), [-N-ÇHJ;

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

i

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

C22H38N204 (m * -H20)

394.2831

394.2823

C22H40N2O5

C 64.05 H 9.77 N 6.79% C 63.98 H 9.97 N 6.57%

Connection 38

i i

I.R. (cm-1): 3500, [OH]; 1770, 1710, [-N-C-N-C-]; 65

II II

o o

1740, [-C02CH3].

Connection 41 I.R. (cm-1): 3700-2500, [-C02H; OH];

1760, 1710 (broad) [-N-C-N-C-; -C02H].

II II

o o

639 076

NMR (x):

16

Mass spectrum:

calculated:

found:

Mass spectrum:

calculated:

found:

I.R. (cm-1):

NMR (x):

Mass spectrum:

calculated:

found:

I.R. (cm-1):

Analysis for:

calculated:

found:

7.8, (t), [CH2C02H];

i

7.2, (s), [-N-CHj];

i

6.9 - 6.1, (m), [-N-ÇH,];

i

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

4.6 - 3.3, (br. Hump) [-C02H; OH].

C20H34N2O4 (m * -H20)

366.2518 366.2513

Connection 42 C16H26N204 (m * -H20)

310.1892 310.1891

Compound 48 3200-2600, [-C02-H; OH];

i i

1770, 1700 (broad) [-N-C-N-C-; C02H].

II II o o

7.7, (t), [-CH2C02H];

i

7 to about 6.1 (m), [-N-CH2];

6.65, (s), [-OCHs];

i

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

5.15, (s), [-N-CH2OCH3];

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

C21H34N204 (m * -H20-Me0H)

378.2519 378.2507

Compound 49 3600-2400, [C02H; OH];

i i

1760-1690, [-N-C-N-C-; C02H].

II II o o

Compound 50 C21H3, N205Na

C 59.98 H 8.87 N 6.66 Na 5.47%

C 60.15 H 9.19 N 6.71 Na 5.52%

specified. These results are averages of several experiments.

TABLE A

20th

25th

30th

35

Connection of the example

ID50 against a 5-hydroxy-tryptamine-induced constriction Hg / kg, i.v.

1

4.5

2nd

6.8

3rd

0.4

4th

220

6

1.5

7

3.3

16

5.8

17th

8.5

19th

> 220

21st

0.6

22

3.2

23

60

24th

6.0

27th

30th

31

4.2

40

Similar results are obtained compared to bronchoconstriction induced by histamine. For example, compound no. 21, when administered intravenously, has an ID50 value of 0.6 [Ag / kg body weight against a histamine-induced constriction.

TABLE B

, Connection of the

Example

Administration in the form of an aerosol, activity; [ig / ml

Oral administration

Activity; mg / kg

Pharmacological experiments

Effect as a bronchodilator:

1. The compounds of the present invention are examined for their ability to inhibit bronchoconstriction induced by 5-hydroxy-tryptamine or by histamine in anesthetized, artificially ventilated merging pigs (cf. H. Konzett and R. Rossler in Arch. Exp Arth. Pharmak. 195 (1940), page 71). The compounds are administered intravenously. The results obtained are shown in Table A below.

2. The compounds of the present invention are also tested for their ability to protect conscious guinea pigs against bronchoconstriction induced by a histamine aerosol (Herxheimer test). In these experiments, the compounds are administered by aerosol or orally. The results obtained are shown in Table B below

55

1

A

10th

-

2nd

A

10th

-

3rd

A

1.0

A;

0.25

16

A

10th

-

17th

A

10th

-

21st

A

0.25

A;

0.25

active

60

Effect against stomach ulcers

The activity against gastric ulcers is assessed by the inhibition of indomethacin-induced gastric damage in rats according to the method of Eleghe iru «Israeli 65 J. Med. Sei. * 10 (1974), page 1451. The rats are left to starve overnight and then given subcutaneously 15 mg / kg body weight indomethacin and the animals are killed 4 hours later. The stomachs are in n saline

17th

639076

Slurried solution, cut along the stuck large curvature and classified for gastric damage according to the following system:

1-3 points: according to the degree of redness and slight bleeding;

4-6 points: according to the degree of attack on the mucous membrane;

7-9 points: according to the depth of the stomach damage.

Groups of 7 rats are used for each treatment. The compound to be tested or the bare solvent (blind test) is administered 30 minutes before indomethacin administration. The dose for the compound to be tested is 100 mg / kg body weight and is administered orally. The control groups receive only the solvent that is co-administered at the same time. Averages are obtained for each treatment using the aforementioned rating system, and the Mann-Witney test is used for the significance of the difference between the values obtained in the treatments.

The results obtained are shown in Table C below.

TABLE C

Connection of the example

Blind test (solvent only); averaged score ± error range of the averaged score

17th

4.86 ± 0.77

0.43 ± 0.30 (P <0.01)

22

2.29 ± 0.87

0.00 = fc 0.00 (P <0.05)

25th

3.86 ± 0.74

1.14 ± 0.74 (P <0.05)

30th

2.86 ± 0.83

0.14 ± 0.14 (P <0.05)

31

2.00 ± 0.79

0.00 ± 0.00

Compared to the blind test, that is to say treatment with only the solvent, the compounds of the present invention lower the mean score for gastric ulcers and therefore have a significant activity against gastric ulcers.

Effect against gastric juice secretion:

The compounds of the invention are tested for their ability to inhibit pentagastrin-stimulated gastric juice secretion in anesthetized perfused stomachs of io rats (see MN Ghosh and HO Schild in "Brit. J. Pharmak." 13 (1958), page 54) ).

The compounds are administered intravenously.

Compound No. 17 inhibits gastric juice secretion when doses of 5 to 10 mg / 15 kg body weight are administered intravenously.

Effect against platelet aggregation:

The compounds are tested for their ability to inhibit platelet aggregation induced in vitro by collagen in a human plasma rich in blood cells.

Compounds No. 18 and No. 17 inhibit aggregation 100% and 34% at a concentration of 100 [JiMol. The IC60 value for compound no. 18 against collagen-induced aggregation 25 is 7 [mol.

Anti-arrhythmic activity:

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

Compound No. 17 prevents intraperitoneal administration of 100 mg / kg body weight from chloroform-induced cardiac fibrillation in a group of 3 mice.

35 Toxicity:

The compounds of the present invention do not appear to have acute toxicity. For example, Compound No. 17 shows no toxicity in mice up to 300 mg / kg body weight when administered orally or 40 at doses up to 100 mg / kg body weight when administered intraperitoneally. Compound No. 21, for example, shows no toxicity in mice at doses up to 900 mg / kg body weight when administered orally.

v

Claims (5)

639076 2nd PATENT CLAIMS 1. Process for the preparation of new compounds of the general formula CK2) RC ° 2R1 (I) 10th wherein X represents O or S; n = 1 to 8; the group C02Rj represents an ester group in which there is an organic radical containing 1 to 12 C atoms; R2 is hydrogen, C1-4-alkyl or phenyl; R3 is hydroxy, or acylated or etherified hydroxy; R4 is hydrogen, Cj_9-alkyl, cy-clohexyl, C3_! Rcycloalkyl-C1_6-alkyl, phenyl, phenyl-C ^ g - alkyl, where each phenyl group one or more times by halogen, trifluoromethyl, C ^ alkyl, hydroxy , C ^ g-alkoxy, phenyl-Cj-e-alkoxy or nitro, or R2 and R4 together with the carbon atom to which they are attached represent a C5_8-cycloalkyl group, R5 C. _ {; - alkyl, CM-alkyl, C5.8-cycloalkyl, phenyl, phenyl-C 1-6-alkyl or phenyl-C3_6-cycloalkyl, which is substituted by nitro, hydroxyl, C 1-4 alkoxy, C02A, (C02A) 2, CN or halogen, CN, or halogen, where each phenyl group can be substituted one or more times by halogen, trifluoromethyl, C 1-4 alkyl, C 1-6 alkoxy or nitro, or is a group C02A, where in R5, if present, A is hydrogen or C02A represents an ester group in which Part A represents an organic radical which has 1 to 12 carbon atoms and their salts, characterized in that a compound of the general formula (CH_) CO, R. / n 2 1 where R! - R4 and n have the meaning given above, with an isocyanate or isothiocyanate of the formula R5NCX, wherein R5 and X have the meaning given above, and the resulting compound of the formula (CH2! NC02R1 in which the various groups have the meaning given above, cyclized in situ and, if appropriate, converting the compound of the formula I obtained into its salt. 2. The method according to claim 1 for the preparation of a compound of the formula I in which R3 is a free hydroxyl group and its salts, characterized in that a compound of the formula I in which R3 is an acyloxy group is prepared and then the acyl cleaves group and the compound obtained optionally converted into its salt. 3. The method according approached 1 for the preparation of a compound of formula I, wherein R3 is a free hydroxyl group and its salts, characterized in that a compound of formula I, wherein R3 is an etherified hydroxyl group, is prepared and then cleaves the ether group and the resulting compound is optionally converted into its salt. 4. The method according to claim 1, characterized in that a compound of the general formula 0 15 20th (II) wherein X and Rx have the meaning given in claim 1, n ', 5, 6 or 7, R / methyl, ethyl or phenyl, R.J1 hydrogen or C ^ alkyl, R.-1 C ^ alkyl, phenyl , Phenyl-C1_6-alkyl or a group C02A, where 25 A is hydrogen or COaA is an ester group, in which A is an organic radical containing 1 to 12 C atoms, or a salt thereof is prepared. 5. A process for preparing a compound of the formula I in which Rj is hydrogen, characterized in that a compound of the formula I in which Rj - R5, X and n have the meaning given in claim 1 is claimed in claim 1 , produces and then splits off Ri and the compound obtained is optionally converted into its salt. 35 6. The method according to claim 5, characterized in that l- (3'-hydroxy-3'-methyl-n-nonyl) -3-methyl - 5- (6 "-carboxy-n-hexyl) -hydantoin or its sodium salt. (X) 40