DE2449272A1 - 8,10-DIAZA-9-OXO- (AND-THIOXO) -11,12SECOPROSTAGLANDINE AND METHOD FOR THEIR PRODUCTION - Google Patents

Description

Patent attorneys

Dr. \ h- Warier Abltz
Dr. Dieter F. M ο rf
Dr. Hans "-A. Brauns. Oct. 16, 1974

8 Munich Bö, Pienzenaueratr. 28 ^ 495

MERCK & CO., INC.

126, East Lincoln Avenue, Rahway, New Jersy 07065,

V.St.A.

- (and -thioxo-) - 11,12-secoprostaglandins and methods of making them

The present invention relates to novel 8,10-diaza-9-oxo (and thioxo -) - 11,12-secoprostaglandins. These Connections can be represented by the following structural formula:

VyXl »-.— ώ — W — ν / I Λ J λ— I WXl ^, J λ— X

Herein, R means carboxy or a carboxy salt formed from a pharmaceutically acceptable cation, such as metal cations, which differ from alkali metals, alkaline earth metals and amines such as ammonia, primary and secondary amines and quaternary Ammonium hydroxides, derive, was formed. Particularly preferred Metal cations are those that differ from alkali metals, such as sodium, potassium, lithium and the like.,

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and alkaline earth metals such as calcium, magnesium and the like, as well as other metals such as aluminum, iron and zinc.

Pharmaceutically acceptable cations derived from primary, secondary or tertiary amines or quaternary ammonium hydroxides derive are methylamine, dimethylamine, trimethylamine, ethylamine, N-methylhexylamine, benzylamine, oc-phenethylamine, Ethylenediamine, piperidine, morpholine, pyrrolidine, 1,4-dimethyIpiperazine, ethanolamine, diethanoiamine, Triethanolamine, tris (hydroxymethyl) aminomethane, N-methylglucamine, N-methylglucosamine, ephedrine, procaine, tetramethylammonium hydroxide, Tetraethylammonium hydroxide, benzyltrimethylammonium and the like.

R can also be alkoxy carbonyl (-COOAIk), where Alk is alkyl with Λ to 10 carbon atoms, carbamoyl (-CONH ₂ ), substituted carbamoyl (-CONR ⁶ R?), Where R ⁶ and R? can represent hydrogen, lower alkyl having 1 to 4 carbon atoms or di-lower alkylaminoalkyl having 4 to 7 carbon atoms, or are carbazoyl (-CONEINHp).

A means ethylene (-CH ₂ CH ₂ -), trimethylene (-α-methylethylene (-CH ₂ -CH (CH ₃ ) -), ß-methylethylene "" (-CH (CH ₅ ) CH ₂ -), α, α-dimethylethylene (-CH ₂ -C (CHj) ₂ -), ß, ß-dimethylethylene (-C (CH, ^ CH ₂ -) or oxymethylene (-0-CH ₂ -). (Please note that then when A consists of a bridge of 2 carbon atoms, the term "α" refers to the carbon atom adjacent to R and "ß" refers to the other carbon atom.)

R ¹ means carbamoyl or thiocarbamoyl.

Z means methylene, ethylene, trimethylene, tetramethylene, Vinylene (-CH = CH-) or ethynylene (-CbC-).

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E denotes, independently of one another, hydrogen or methyl.

R * means hydrogen or lower alkanoyl with 1 to 5 Carbon atoms, for example formyl, acetyl, propionyl, Butyryl, isobutyryl, valeryl, pivaloyl and the like.

fi denotes, independently of one another, hydrogen or methyl.

IK means hydrogen, lower alkyl with 1 to 4 carbon atoms, that is either straight-chain or branched (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), vinyl or 2,2,2-trifluoroethyl.

5 2 5

In addition, R ^ and R, if R ^ for lower alkyl and R stand for methyl, be combined with one another (with deduction of hydrogen) that they form a carbocyclic ring form with 6 to 9 ring members.

5?

If Ήτ stands for lower alkyl and R stands for hydrogen, R ^ can also be combined with the ^{carbon atom bearing R and OR- 7 to} form a carbocyclic ring with 5 to 8 ring members.

A preferred embodiment of the present invention refers to 11,12-secoprostaglandins of the following general Formula:

¹ -N- (CH ₂ ) ^ - A «-COOH (CH ₂ ) ₃ -CC (R ⁴ ) ₂ - (CH ₂ ) ₂ -R ⁸

R ² OH

Here, A ¹ denotes ethylene or oxymethylene, R ¹ , R and R

have the meanings given above, and R stands for lower alkyl having 1 to 4 carbon atoms. In addition,

O p p

nen R and R, when R is methyl, together form one form carbocyclic ring with 6 to 9 ring members. Even

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β ρ ρ

can E, when R is hydrogen, with the R bearing Carbon atom to form a carbocyclic ring with 5 to 8 ring members.

It should be noted that the carbon atom which the OR * - Group in the formula I carries, and that which carries the hydroxyl group in the formula II, are asymmetrical. The present invention also includes stereoisomers in which the asymmetric center is exclusively in either one or the other of the two possible configurations R and S is present.

The compounds of formula I are called 8,10-diaza-9-oxo- (and-thioxo -) - 11,12-secoprostaglandins described because their structure is based on the naturally occurring prostaglandins are related.

The prostaglandins represent a biologically outstanding class of naturally occurring, highly functionalized CpQ fatty acids, which are found in a considerable number of different mammalian tissues from three essential fatty acids, namely 8,11,14-eicosatrienoic acid, 5 * 8,11,14 -Eicosatetraenoic acid and 5 »8,11,14,17-eicosapentaenoic acid. Every known prostaglandin is formally derived from the parent compound called "prostanoic acid". The latter is a CpQ fatty acid which is covalently bridged between carbon atoms 8 and 12 in such a way that a vicinally substituted trans-cyclopentane is formed in which the carboxy-bearing side chain is in the "a" position or below the plane of the ring and the other side chain is in the ⁿ ß "position or above the plane of the ring, as shown in formula III.

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13 15

17 19

The six known primary prostaglandins, PGE ^, PGE ^, PGE ,, PGF ^, PGFp and PGF, which are directly through building Metabolism from the above-mentioned essential fatty acids via the action of prostaglandin synthetase as well as the three prostaglandins that result from in vivo dehydration of the PGE compounds, d. H. PGA, «, PGAp and PGA ~ result, subdivide into three groups, namely the PGE, PGF and PGA series due to the three different cyclopentane core substitutions. This is illustrated in the following formulas:

HO '

PGE core

PGF core α

PGA core

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OH

CO ₂ H

OH

It should be noted that the Arabic indices denote the number of carbon-carbon double bonds in the Indicate the compound and that the Greek indices used in the PGF series represent the stereochemistry of the Specify C-9 hydroxyl group.

Although the prostaglandins were independent of Goldblatt (J. Chem. Soc. Chem. Ind. Lond., J> 2, 1056 (1933)) in England and of Euler (Arch. Exp. Path. Pharmark., 175, 78 (1934) )) were found in Sweden in the mid-1930s, little attention was paid to these complex IT natural products by the scientific world until the early 1960s. The early sixties coincide with the advent of modern instruments (e.g. mass spectrometry), which in turn was a necessary prerequisite for the successful isolation and structure elucidation of these compounds by Bergströn and colleagues / cf. Angew.Chem. Int. Ed., 4, 410 (1965) 7

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and references cited there for an evaluation of this work /. In the past decade, very great scientific efforts have been made at the international level to develop both biosynthetic and chemical pathways to prostaglandins and subsequently to study their biological activities. During this period, prostaglandins have been shown to occur extensively at low levels in a myriad of mammalian tissues, where they are both rapidly anabolized and catabolized, and to exhibit a wide range of pharmacological activities, including (a) functional hyperaemia, ( b) inflammatory response, (c) effects on the central nervous system, (d) transport of water and electrolytes, and (e) regulation of cyclic AMP, where they play prominent roles. Further details regarding the prostaglandins can be found in recent reviews of their chemistry / JE Pike, Fortschr. Chem. Org. Naturst., 28 »(1970) and GF Bundy, A. Rep. In Med. Chem., 2» 157 (197227, Biochemie / JW Hinman, A. Rev. Biochem., 41 , 161 (19722 / , physiological significance / EW Horton, physiol. Rev., 4 <}, 122 (196927 and general clinical application ß. W. Hinman, Postgrad. Med. J., 46, 562, (197027 ·

The potential use of natural prostaglandins as medically useful therapeutic agents in various Mammalian disease states are obvious, but are severely affected by three major disadvantages: (a) Prostaglandins are known to be present in various Mammalian tissues are rapidly metabolized in vivo to a variety of metabolites that produce the desired, do not exhibit original biological activities * (b) the natural prostaglandins naturally lack the biological specificity required for a successful therapeutic agent, and (c) albeit limited amounts of Prostaglandins are currently produced by both chemical and biochemical processes, their pro-

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production costs are extremely high, and as a result, they are only very limited available.

The task was therefore to synthesize novel compounds, which are the natural prostaglandins structurally related but have the following unique advantages: (a) ease of synthesis, resulting in low production costs; (b) Specificity of biological activity from either prostaglandin mimicry or prostaglandin antachronism type; (c) increased metabolic stability. The combination this advantage enables the provision of effective, orally and parenterally active, therapeutic agents for the treatment of a variety of human and animal diseases. Applications in the kidney, heart and vascular, Gastrointestinal, respiratory, internal apparatus and reproductive systems and in combating lipoid metabolism, inflammation, Blood clotting, skin diseases and certain cancers are included.

More specifically, prostaglandin antagonists can be used clinically as agents for improving kidney function (e.g., renal vasodilation), agents for treatment and prophylaxis of certain autoimmunity diseases and hypersensitive conditions, as anti-ulcer agents, Fertility control agents, anti-thrombotic agents, anti-asthma agents, anti-fat decomposing agents, anti-tumor agents and agents for the treatment of certain skin diseases act.

Prostaglandin antagonists can be used as anti-inflammatory agents, anti-diarrheal agents, antipyretic agents, agents to prevent early labor and medicines to treat headaches are effective.

The compounds according to the invention are particularly useful for improving kidney function, for loading

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Treating Hypertension, For The Treatment Of Dwarfism And The Prevention Of Thrombus Formation It should be emphasized that not all of these compounds are useful in every way; however, each compound has been subjected to various analyzes and each compound has shown activity in at least one area.

The compounds according to the invention can be administered either locally or systemically, ie intravenously, subcutaneously, intramuscularly, orally, rectally or by aerosolization in the form of sterile implants for a long-term effect. They can be formulated for this purpose in any of numerous pharmaceutical and non-toxic carriers.

The pharmaceutical agents can be sterile, injectable suspensions or solutions or solid, orally administrable, pharmaceutically acceptable tablets or capsules. The agents can also be for sublingual administration or for use in suppository form. It is particularly advantageous to prepare agents in dosage unit forms for the purpose of facilitating and economical administration and uniformity of the dosage. The term "dosage unit form" as used herein relates to physically discrete units which are suitable as uniform dosages for people and animals; each unit contains a predetermined amount of active material, which is calculated in such a way that the desired biological effect results in connection with the required pharmaceutical agents «,

By way of illustration, it should be noted that a sterile, injectable agent can be in the form of an aqueous or oily suspension or solution.

The sterile injectable agent can be an aqueous or oily suspension or solution. Suspensions can be

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according to the known technology using .suitable dispersing and wetting agents and suspending agents are prepared. Solutions are made in a similar fashion the salt form of the compound. For laboratory animals, Freund's incomplete adjuvant or sterile is used Saline solution (9%) preferred as the carrier. For parenteral use in humans, e.g. B. the intramuscular or intravenous use or local perfusion, the diluent can be a sterile, aqueous carrier which contains a preservative such as methyl paraben, propyl paraben, phenol or chlorobutanol. The watery one Carrier can also be sodium chloride, preferably in such an amount that it is isotonic, as well as a suspending agent, for example gum arabic, polyvinylpyrrolidone, methyl cellulose, acetylated monoglyceride (im Commercially available as Myvacet from Distillation Products Industry, a subsidiary of Eastman Kodak Company), monomethylglyceride, dimethylglyceride, or a massive high molecular weight polysorbitan (commercially available under the trade names Tween or Span from Atlas Powder Company, Wilmington, Delaware). Other Substances used in the manufacture of chemotherapeutic agents containing the compound, are for example glutathione, 1,2-propanediol, glycerine and glucose. In addition, the pH of the agent is measured using an aqueous solution such as tris (hydroxymethyl) aminomethane (tris buffer).

Oily pharmaceutical carriers can also be used, because they break the link and allow high dosages. Many find oily carriers for pharmaceutical purposes usually use, for example petroleum, lard, cottonseed oil, peanut oil, sesame oil or the like.

Preferably, the agents, whether they are aqueous or oily, are used in a concentration in the range from 2 to 50 mg / ml

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manufactured. Lower concentrations require excessive amounts of liquid. Concentrations higher than 50 mg / ml are difficult to maintain and are preferably avoided.

Medicinal forms for oral administration to laboratory animals or human patients can also be prepared provided that they are encapsulated for release in the intestine. The remedy experiences an enzymatic Degradation in the acidic environment in the stomach. The same dosage levels can be used as for injectable forms will; however, even higher levels can be used to compensate for biodegradation during transport will. In general, a solid unit dosage form can be prepared containing 0.5 mg to 25 mg of active Contains component.

The doses used are whatever the route of administration is taken, about 0.10 to 20 mg per kg of body weight 1 to 4 times per day. The exact dose depends on the age, weight and condition of the patient and the frequency and route of administration.

The low cost and easy accessibility of the invention Connections require that the connections are particularly promising in veterinary medicine, in which area they are comparable in their usability with their usability in human medicine.

The synthesis of compounds of the type represented by formula I in which R is carboxy, Hl? Water and R 'denote carbamoyl (formula IVa), is carried out by the base-catalyzed hydrolysis of a compound of formula V. The starting material is dissolved in a solvent such as ethanol, which contains a base such as sodium ethoxide, and is added with a slight excess of hydrogen peroxide.

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treated beyond Λ molar equivalent.

NC-N- (CH ₂ ) ₄ -A-C00H

CH ₀ -ZCC (R ^) ₀ -CH ₀ CH ₀ -R ⁵ V

. ² / \ ^{2 22} ΈΓ OH

O ^τ

NH ₂ -CN- (CH ₂ ) ₄ -A-C00H

CH ₀ -ZCC (E ^) ₀ -CH ₀ CH ₀ -E ^{5 IVa}

ρ / \ 2 2 2

E ^ OH

The reaction mixture is then allowed to stand at a temperature of 15 ° C. to 55 ° C. for 1 to 60 hours. The product is isolated by diluting the reaction mixture with water, with a mineral acid such as hydrochloric acid, acidified and the product extracted with an appropriate organic solvent such as methylene chloride. That Product can be isolated by evaporating the solvent. If cleaning is necessary, it can go through Recrystallization (if the product is a solid) or by chromatography can be carried out.

The synthesis of compounds of the type represented by the formula I in which R is carboxy, R ^ is hydrogen and R ^{1 is} thiocarbamayl (formula IVb) takes place by using a compound of the formula V:

NC-N- (CH ₀ ) ^ - A-COOH ι ^ - ** ■ ₄

-CR ₂ OH

CH ₀ -ZC-

² η / \

S.
, C. . (CH ₀ ) ^ - A-COOH

CH ₂ -ZCC (R ⁴ ) ₂ -CH ₂ CH ₂ -R ⁵ IVb

OH

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in the presence of a free radical initiator catalyst treated with an aliphatic thiolic acid with 1 to 5 carbon atoms and then a mild basic one Is subjected to hydrolysis.

The starting compound is first dissolved in thiolacetic acid, and the resulting solution is irradiated for a period of 1 to 12 hours with a lamp which capable of generating ultraviolet light. After the solvent has been removed by evaporation in vacuo, the residue is dissolved in aqueous ammonium hydroxide solution and at a temperature of 15 ° C to 35 ° C 24 to Stirred for 72 hours. After cooling and acidifying with a mineral acid such as hydrochloric acid, separates the product is separated, which is purified by chromatography.

Compounds of the type represented by the formula V. is, by mild hydrolysis of compounds of formula VI using a base such as a Alkali hydroxide, for example sodium hydroxide, in a solvent such as an alcohol, for example Methanol or ethanol, and stirring the mixture for a period of 5 to 40 hours at a temperature from 15 to 35 ° C. The product is isolated by diluting with water with a mineral acid such as Hydrochloric acid, acidified and the product extracted with an appropriate organic solvent such as ethyl acetate and the solvent is evaporated.

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NC-N- (CH ₀ ), - A-COOAIk CH ₂ -ZC-

² j

R ² j0C0CH,

NC-N- _(CH2) ^ - A-COOH

CH ₀ -ZCC (R ⁴ ^ -CH ₀ CH ₀ -R 2 _{/ χ} 2 2 2

R ^ OH

The synthesis of compounds represented by the formula VI re presented can be done by either of two methods. According to the first method, the alkali salt becomes the Formula VII reacted with a compound of the formula VIII (where X is halogen and M is an alkali metal ion):

/ NC-IP- (CH ₂ ) ₄ -A-C00Alk7 # VIIa -t

x-CH ₂ -zcc (r ⁴ ) ₂ -ch ₂ ch ₂ -r5 viii

NC-N- (CH ₂ ) ₄ -A-C00Alk VI

CH ₀ -ZCC (R ⁴ ) 5-CHpCH ₀ -R ⁵

R ^ OCOCH,

The alkali salt (VIIa) is prepared by treating a compound of formula VII

NC-NH- (CH ₂ ) ₄ -A-C00Alk VII

with sodium hydride in a solvent such as a 1: 1 mixture from benzene and dimethylformamide. After the salt has formed, compound VIII at ambient temperature and the mixture is stirred and heated to 50 to 100 ° C for 10 to 24 hours. The product is isolated by adding the reaction mixture

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poured into water, extracted with benzene and the solvent is evaporated. The purification is carried out by chromatography using silica gel.

According to the second method for the synthesis of compounds of the formula VI, an alkali metal salt of the formula IXa with a Compound of formula X implemented. The alkali salt (IXa)

IXa

X- (CH ₂ ) ^ - A-COOAIk X

-N- (CH ₂ ) ₄ -A-COOAlk -ZCC (R ^) ₂

ΈΓ OCOCH,

() ₂₂₂ VI

is made by treating a compound of formula IX with Sodium hydride in a solvent such as a 1: 1 mixture of benzene and dimethylformamide.

NC-NH-CH ₂ -ZCC (R ^) ₂ -CH ₂ CH ₂ -R ⁵ IX

R * OCOCH, 5th

After the salt has formed, the compound X is added at ambient temperature and the reaction mixture is heated to 35 ° to 100 ° C for 1 to 48 hours. The product is made according to that described for the first method Working method isolated.

From a therapeutic standpoint, it is often advantageous to prepare compounds according to the invention (formula I) in which the asymmetric carbon atom, which carries the OR - ^ - group, exclusively in the R-

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/ 6

or S configuration is available. It should be remembered that the corresponding atom in the natural prostaglandins. is in the S configuration. The inversion of this center can, but does not need to, reduce the biological one To produce activity, although there is often a marked increase in biological specificity.

In the series of 8,10-diaza-11,12-secoprostaglandins according to the invention connections that have exclusively R or S configuration at this center can thereby be used be prepared using previously cleaved compounds of the formulas VIII or IX and those described above Process steps are carried out. An example of the use of such a previously cleaved compound IV is given in the section "Manufacture of Intermediates (Examples J and K)".

The directly obtained products of the processes described above can be used to prepare the other products of the formula I can be converted into derivatives.

1. The basic procedures provide compounds where R is carboxy. To obtain carboxy salts, the Acid products are dissolved in a solvent such as ethanol, methanol, glyme and the like., And the solution is mixed with a suitable alkali or alkaline earth hydroxide or alkoxide for the preparation of the metal salt or with an equivalent Amount of ammonia, amine, or quaternary ammonium hydroxide Treated to produce the amine salt. In any case, either the salt separates out of the solution and can be separated by filtration or, if the salt is soluble, it can be recovered by evaporation of the solvent will. Aqueous solutions of the carboxylic acid salts can be prepared by treating an aqueous suspension of the carboxylic acid with an equivalent amount of an alkaline earth hydroxide or oxide, alkali hydroxide, carbonate or bicarbonate, of ammonia, an amine or a quaternary ammonium hydroxide getting produced.

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To obtain carboxy esters (ie compounds in which R is alkoxycarbonyl), the acid products are treated in ether with an ethereal solution of the appropriate diazoalkane. For example, methyl esters are made by reacting the acid products with diazomethane. To obtain products in which R is carbamoyl or substituted carbamoyl, the acid product is first converted into an active Woodward ester. For example, the acid product can be reacted with N-tert-butyl-5-methylisoxazolium perchlorate in acetonitrile in the presence of a base such as triethylamine to produce an active ester in which R

-COC (CH,) = CH-NH-C- (CH ₅ ) ₅ means. Active esters of this type can be mixed with ammonia for the preparation of products of the formula I in which R is carbamoyl, with primary or secondary amines or di-lower-alkylaminoalkylamines for the preparation of products in which R is substituted

6 7 tuted carbamoyl, ie -CONR R ', are implemented.

2. The basic procedure provides products for which B? Means hydrogen. In the case of compounds of the formula IVa and IVb, the reaction with formic acid, acetic anhydride, propionic anhydride, butyric anhydride, isobuternic anhydride, valeric anhydride, pivalic anhydride and the like, without solvents at temperatures of 25 C to 60 C, compounds in which R ^ formyl, acetyl, propionyl , Butyryl, isobutyryl, valeryl or pivaloyl.

1. Reactances of the formula VII are prepared from compounds of the formula XII by a three-stage process. Treating compounds of the formula XII with potassium cyanate in water, then heating the solution for Λ to 5 hours to 50 ° C to 100 ° C, cooling and adjusting the pH to about 5 with mineral acid results in the ureido-

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compound (Formula XIII).

XII

NH ₂ -COHH- (CH ₂ ) ^ - A-COOH

XIII

NC-NH- (CH ₂ ) ^ - A-COOAIk NH ₂ CONH (CH ₂ ) ₄ -C00Alk

VII

XIV

By esterifying the compound XIII with a lower alkanol in an acid under conventional esterification conditions, the corresponding ester (formula XIV) is obtained with p-Toluenesulfonyl chloride is dehydrated in pyridine. In Cases in which the amino acids of the formula XII are not known, they can be selected from the known halogen acids X according to the classic phthalimide synthesis (where X is halogen means) are produced.

X- (CH ₂ ) ^ - A-COOAIk + KN

N- (CH Y-A-COOAIk

XII

2. The reactant villa, which has the following general formula having

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-C- (CR ^) ₂ CH ₂ CH ₂ R ⁵ Villa

H 'OCOCH,

in which X is halogen and R and R ^ are as defined above, is prepared in the following manner. A Grignard reagent R ⁵ CH ₂ CH ₂ (R) ₂ C-MgJ or R ⁵ CH ₂ CH ₂ (R ^) ₂ -MgBr in ether is allowed to _{react with a nitrile X (CH 2} ), CN. The resulting imine is hydrolyzed in aqueous, acidic solution to form ketones of the formula XI:

X (CH ₂ ) ₃ C (= O) C (R ^) ₂ CH ₂ CH ₂ R ⁵ XI

The ketones (XI) are converted into the corresponding alcohols X (CH ₂ ), - CH (OH) -C (R ^) ₂ CH ₂ CH ₂ R with sodium or potassium borohydride in a suitable solvent such as methanol, ethanol or diglyme ⁵ reduced. Acetylation of these alcohols, preferably with acetic anhydride, provides reactants VIII A.

Treating the ketone XI with methyl magnesium iodide (CH, MgJ) in ether gives compounds of the formula X (CH ₂ ) ₃ C (CH ₃ ) (OH) C (R ⁴ ) ₂ CH ₂ CH ₂ R ⁵ , which after acylation with acetic anhydride in pyridine, compounds of the formula VIIIb give:

X- (CH ₂ ) ₃ CC (R ⁴ ) ₂ CH ₂ CH ₂ R ⁵ VIIIb CH, OCOCH,

The reactants VIIIc, which have the following general formula:

Br-CH ₂ CHC-CHC (R ^) ₂ CH ₂ CH ₂ R ⁵ VIIIc

OCOCH,
5

4 5-in which X and R and R "^ have the meanings given above, are produced in the following way. Acetylenic alcohols

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HCsC-CH (OH) C (R ⁴ ) ₂ CH ₂ CH ₂ R ⁵ are treated with acetic anhydride to form the acetylated alcohols HCsC-CH-C (R) pCHp-

OCOCH,

CHpR treated. These compounds are treated with paraformaldehyde and diethylamine to produce the tertiary amines (C ₂ H ₅ ) ₂ N-CH ₂ CsC-CH-C (R ⁴ ) ₂ CH ₂ CH ₂ R ⁵ , which,

OCOCH _x

when treated with cyanogen bromide, they provide reactants VIIIc. The acetylenic alcohols HCsC-CH (OH) -C (R ⁴ ) _o -

5 * -

₂₂ R- ', which are intermediates for the compounds of the formula VIIIc, are prepared by reacting ethynylmagnesium bromide or lithium acetylide with aldehydes of the formula R ⁵ CH ₂ CH ₂ C (R ⁴ ) ₂ CH0.

By using the split R and S forms of the alcohols HC5C-CH (OH) C (R ⁴ ) ₂ CH ₂ CH ₂ R ⁵ in the scheme given above, the corresponding R and S forms of reactant VIIIc can be obtained.

It should be noted here that the use of the R or S enantiomers of the reactant VIIIc, the R and S enentiomers

h c

of compounds of the formula V, in which R. and R

ο have the meanings given above and R is hydrogen and Z is -CSC- (formula Va).

NC-N- _(CH2) 4-A-COOH

CH ₂ -Z ^I -C; -C (R ⁴ ) ₂ CH ₂ CH ₂ R ⁵ Va

H OH

These optically active products Va can be hydrogenated over a platinum catalyst to give the R and S enantiomers of compounds of the formula Va, in which Z denotes ethylene —CH ₂ —CH ₂ -.

The reactant VIIId, of the following general formula: comprising:

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Br-CH ₂ -CH = CH-CH-G (R ^) ₂ CH ₂ CH ₂ R ⁵ VIIId OCOCH _x

in which X ₁ R and R ^ have the meanings given above, is prepared in the following manner. A Grignard reagent R ⁵ CH ₂ CH ₂ C (R ^) ₂ MgBr or R ⁵ CH ₂ CH ₂ C (R ^) ₂ MgJ is allowed to react with crotonaldehyde, so that after hydrolysis the alcohol CH ₃ CH = CH- Gives CH (OH) -C (R ^) ₂ CH ₂ CH ₂ R ⁵ . This alcohol is preferably acetylated with acetic anhydride without a solvent at 30 to 100 ° C. for 2 to 12 hours and gives the intermediate product CH ₃ CH = CH-CH (OCOCH ₅ ) C (R ⁴ ) ₂ CH ₂ CH ₂ R ⁵ . This intermediate product is allowed to react with N-bromosuccinimide in chloroform at 50 to 70 ° C. for 2.5 to 5 hours, so that allylic bromination is effected and the reactant of the formula VIIId results.

3. Reactant IX, where R ^{2 is} H (IXb), is prepared by the following reactions.

NC-NH- (CH ₂ ) ₅ -CH-C (R ^) ₂ CH ₂ CH ₂ R ⁵ IXb OCOCH,

The alcohol of the formula X (CH ₂ ) ^ CH-C (R ^) ₂ CH ₂ CH ₂ R ⁵ prepared in section 2 above is treated with dihydropyran and

Oh

a catalytic amount of acid to form X (CH ₀ ) -, - CH-C (R O ₂ CH ₂ CH ₂ R ^. Treatment of this halogen-OTHP

Combination with the sodium salt of the phthalimide in dimethylformamide provides the corresponding phthalimido compound. The cleavage of this compound with hydrazine in ethanol and the subsequent acid hydrolysis yield the amine NH ₂ - (CH ₂ ) ₅ -CH-C (R ^) ₂ CH ₂ CH ₂ R ⁵ , which after treatment with OH

Potassium cyanate in water gives the corresponding hydroxyurea results, which is acetylated and then with p-toluenesulfonyl chloride

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is dehydrated in pyridine to give reactant IX.

4. The preparation of reactants of Formula X

X- (CH ₂ ) ₄ -A-C00Alk X

has been in the scientific literature and in the patent literature in those cases described in which A is ethylene, Trimethyleη, α-methylethylene, ß-methylethylene, α, α-dimethylethylene or ß, ß-dimethylethylene means. For the production of reactants in which A is oxymethylene, an ester of glycolic acid HOCHoCOOAIk with a strong Base, preferably sodium hydride, in a non-protonic solvent (dimethylformamide, glyme and the like) treated, and the resulting anion is allowed to react with a 1,4-dihalobutane, preferably 1,4-dibromobutane. The glycolic acid ester and the base are approximately equimolar Quantities used; advantageously a 1.5 to 2 molar excess of the dihalobutane is used.

5 · Method of obtaining optical antipodes of some of the compounds according to the invention have been described above. After that, one of the constituents of the molecule will be in front of his Incorporation split into the whole molecule. Other methods can also be used. For example, racemate. Mixtures are separated from the physicochemical Differences between the ingredients using chromatography and / or fractional crystallization Advantage is taken. The racemic products and intermediates of the present invention can be prepared according to any of numerous cleavage methods, which are well described in the chemical literature, into their optically active components be split.

Those compounds which are carboxylic acids can by treatment with an optically active base, such as (+) or (-) a-methylbenzylamine, (+) or (-) a- (1-naphthyl) -ethylamine,

- 22 - '
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Brucine, cinchonine, cinchonidine or quinine, into the diastereoisomers Salts are converted. These diastereoisomeric salts can be separated by fractional crystallization.

The carboxylic acids according to the invention can also be prepared by using an optically active alcohol such as estradiol-3-acetate or (d) - or (l) -menthol, converted into esters and the diastereoisomeric esters by crystallization or by can be split by chromatographic separation.

Bacemic carboxylic acids can also be determined by chromatography cleaved with reverse phase and absorption chromatography using an optically active support and adsorbent will.

Compounds according to the invention which have free hydroxyl groups can contain acid chlorides or anhydrides, which differ from optically active acids, such as (+) - 1ß-camphorsulfonic acid, (+) - a-bromocamphor-7 ^ -sulphonic acid or d- or 1-6,6'-dinitrodiphenic acid, derive, are esterified to esters, which can be cleaved by crystallization.

Another method for producing pure optical isomers involves incubating the racemic mixture with certain microorganisms, such as fungi, according to methods recognized in the technology and the extraction of the product formed by the enzymatic conversion.

The methods described above are especially effective when the method is applied to a compound in which there is an asymmetric center according to the methods already described has previously been split.

The present invention is further described in the following examples.

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Manufacture of intermediates A. Manufacture of i-chloro-4-acetoxynonane

Step 1 ; Production of 1-chloro-4-nonanone

155 » 34 g (1.5 mol) of 4-chlorobutyronitrile were added. Stirring is continued for an additional hour. The reaction mixture is poured into a mixture of 1000 g of finely crushed ice and 750 ml of concentrated hydrochloric acid. The ether layer is quickly separated and discarded. The aqueous layer is heated on a steam bath for 1 hour in order to hydrolyze the intermediate amine and to effect the separation of the xetone as an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the remaining oil is distilled. 69.0 g (26%) of a colorless oil (boiling point 115 Ms 117 ° C / 14 mm; pmr (proton magnetic resonance) (CDCl,) </ 0.90 (3H, t), 3.56 (2H , t, CH ₂ Cl).

Step 2; Production of 1-chloro-4-nonanol

A suspension of 6.62 g (0.175 mol) of sodium borohydride and 1.3 g of sodium hydroxide in 310 ml of ethanol is added dropwise treated in the course of 1 hour with 61.40 g (0.349 mol) of 1-chloro-4-nonanone, while the temperature was 45 to 50.degree is held. Stirring is continued for 1 hour without external cooling .

The reaction mixture is made with concentrated hydrochloric acid acidified to the congo red endpoint, and then becomes

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15 495

the ethanol removed under reduced pressure. The residue is treated with 200 ml of water and the resulting oil extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed in vacuo, and the compound named in the title is obtained as a pale yellow oil residue (yield 58.85 g; ultra-red spectrum (pure substance) 3400 cm " ¹ ).

step 3 ' Manufacture of i-chloro-4-acetoxynonane

A mixture of 111.99 g (0.627 mol) 1-chloro-4-nonanol and 128.0 g (1.254 moles) of acetic anhydride is heated on a steam bath for 1 1/2 hours.

The volatiles are removed under reduced pressure and the remaining oil is distilled. This gives 88.6 g (64%) of a colorless oil (b.p. 13Ο to 133 ⁰ C / 14 mm; pmr (GdCl ₅₎ ^ To, 89 (3H, t), 2.02 (3H, s CH ₅ COO ), 3.53 (2H, t CH ₂ Cl), 4.89 (1H, m). Analysis:

Calculated for: C ₁₁ H ₂₁ ClO ₂ : C, 59.85; H 9.59;

Found: C, 59.87; H 9 _r 67.

B. Manufacturing; of 1-chloro-4-acetoxy-8-methylnonane

Step 1 : Preparation of 1-chloro-8-methyl-4-nonanone

Regarding the Grignard reagent, which consists of a mixture of 200.00 g (1.21 moles) 1-bromo-4-methylpentane and 29.43 g (1.21 moles) magnesium has been prepared in 800 ml of ether, 125.30 g (1.21 mol) of 4-chlorobutyronitrile are added dropwise over 1 hour given. Stirring is continued for an additional hour.

The reaction mixture is finely crushed into a mixture of 800 g Ice and 600 ml concentrated chlorinated water

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chemical acid poured. The ether layer is quickly separated and discarded. The aqueous layer is heated on a steam bath for 1 hour in order to hydrolyze the intermediate imine and to effect the separation of the ketone as an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed in vacuo and the remaining oil is distilled. 23.3 g (10 %) of a colorless oil are obtained (boiling point 121 to 122 ° C./15 mm; pmr (CDCl ₅ ) Zo, 89 (6H, d), 3.57 (2H, t

Analysis:

Calculated for C ₁₀ H ₁ QClO: C, 62.98; H 10.04;

Found: C, 62.86; H 10.20.

Step 2 : making i-chloro-e-methyl - ^ - nonanol

A suspension of 2.3 g (0.061 mol) of sodium borohydride and 0.5 g of sodium hydroxide in 110 ml of ethanol is added dropwise with 23.0 g (0.121 mol) of i-chloro-8-methyl-4-nonanone for 1 hour treated while maintaining the temperature at 45 to 50 ° C. It will be without outside for another hour cooling continued to stir.

The reaction mixture is acidified to the Congo Red end point with concentrated hydrochloric acid, and then the ethanol is removed under reduced pressure. The residue is treated with 70 ml of water and the resulting oil is extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is removed in vacuo, and the compound named in the title is obtained as a pale yellow, oily residue (yield 22.73 S> ultrared spectrum (pure substance) 3400 cm "' ¹ ).

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step 3 ' Manufacture of i-Ghlor-4-acetoxy ^ e-methyliionaii

A mixture of 22.73 g (0.118 mol) 1-chloro-8-methyl-4-nonanol and 24.07 g (0.236 moles) of acetic anhydride is heated on a steam bath for 1 1/2 hours.

The volatiles are removed under reduced pressure and the residual oil is distilled. You get »58 g (58%) of a colorless oil (boiling point 138 to 139 ° C /

1g

15mm; pmr (CDCl ₅ ) / θ, 85 (6H, d), 2.02 (3H, s CH ₅ COO), 3.53

₅
(2H, t CH ₂ Cl), 4.92

C. Preparation of 1-chloro-4-acetoxyundecane Step 1: making 1-chloro-4-undecanone

This connection is made in essentially the same way as as described for i-chloro-4-nonanone (Example 1, Step 1) made using the following reactances:

1-bromoheptane 214.94 g (1.2 mol)

Magnesium 29.18 g (1.2 moles)

Ether 800 ml

4-chlorobutyronitrile 124.27 g (1.2 moles)

The compound named in the title is obtained as a colorless oil (yield 60.4 g (15%); bp I35 to 140 ° C / 15 mm; pmr (CDCl ₃ ) 6 0.93, (3H, t), 3, 57 (2H, t CH ₂ Cl).

Step 2: making 1-chloro-4-undecanol

This connection is made in essentially the same way as as described for i-chloro-4-nonanol (example A, step 2), prepared using the following reactants:

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15 495 Q

Sodium borohydride 5 »55 g (0.14-7 mol)

Sodium hydroxide 1.12 g

Ethanol 265 ml

i-chloro-4-undecanone 60.00 g (0.294 moles).

The compound named in the title is obtained as a yellow, oily residue (yield 60.02 g).

step 3 '' Production of i-chloro-4-acetoxyundecane

This connection is made in essentially the same way as as described for i-chloro-4-acetoxynonane (Example A, Step 3) using the following Reactants made:

1-chloro-4-undecanol 60.02 g (0.29 mol)

Acetic anhydride 59.16 g (0.58 mol)

The compound named in the title is obtained as a colorless oil (yield 44.6 g (62%); boiling point 155 to 158 ° C / 15 mm; pmr (CDCl ₅ ) J 0.88 (3H, t), 2.02 (3H, s CH ₅ COO), 3.53 (2H, t CH ₂ Cl), 4.92 (1H, m).

Analysis:

Calculated for C ₁₅ H ₂₅ ClO ₂ : C, 62.76; H 10.13;

Found: C, 63.03; H 10.40

D. Preparation of i-chloro ^ -acetoxy-S ^ -dimethylnonane

According to the procedure described for 1-chloro-4-acetoxynonane (Example A) is obtained if, instead of amylbromineJLd 1-bromo-4,4-dimethylpentane used, one after the other: 1-chloro-8, e-dimethyl-4-nonanone, 1-chloro-8,8-dimethyl-4-nonanol and i-chloro ^ -acetoxy-SjS-dimethylnonane.

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E. Preparation of 1-chloro-4-aceto: xy-9 <9i9-trifluoronic acid

According to the procedure described for i-chloro-4-acetoxynonane (Example A) is obtained if 1-bromo-5,5 »5-trifluoropentane is used instead of amyl bromide: i-chloro-9,9,9-trifluoro-4-nonanone, 1-chloro-9,9,9-trifluoro-4-nonanol and 1-chloro-4-acetoxy-9,919-trifluorononane.

Έ. Production of 1-chloro-4-acetoxy-8-nonene

According to the procedure described for i-chloro-4-acetoxynonane (Example A) is obtained if instead of amyl bromide 1-bromo-4-pentene used, one after the other: i-chloro-8-nonen-4-one, 1-chloro-8-nonen-4-ol and i-chloro - ^ - acetoxy-enones.

G. Preparation of 1-chloro-4-acetoxy-3,5-dimethylnonane Step 1: Production of 1-chloro-5,5- <3-JPi6thyl-4-nonanone

400 ml of an ethereal solution of 1,1-DimethyIpentylmagnesiumchlorid, which consists of 24.3 g of 0 »0 mol) of magnesium and 134.5 g (1.0 mol) of i-chloro-i ^ -dimethylpentane according to the procedure of Whitmore and Badertscher ßS. At the. Chem. Soc. , JÜ £ i 1559 (1933I /) are added dropwise with stirring over 6 hours to 197 g (1> 4 mol) of 4-chlorobutyryl chloride in 400 ml of ether. The reaction mixture is stirred for a further 12 hours. It is then poured into a Mixture of ice and dilute hydrochloric acid is poured in. The ether layer is separated off, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the residue is distilled in a water jet vacuum through a Vigreaux column. The product is obtained as a colorless oil.

Step 2: Preparation of 1-chloro - ^, ^ - dimethyl-4-nonanol

According to the procedure described for i-chloro-4-nonanol (Example A, step B) is obtained if instead of

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so

and stirring and heating at 50 ° C for 6 hours continued 1-chloro-4-nonahone 1-chloro-5,5-dimethyl-4-nonanone and the R
sets, i-

step ^: Production of i-chloro-4-acetoxy-3 <5-dimethylnonane

According to the procedure described for 1-chloro-4-acetoxynonane (Example A, step 3), if 1-chloro-5,5-dimethyl-4-nonanol is used instead of i-chloro-4-nonanol and heating continued on the steam bath for 4 hours, 1-chloro-4-acetoxy-5 _} 5- ^< iimethylnonane.

H. Preparation of 1-bromo-4-acetoxy-2-nonene

A mixture of 75.5 g (0.4 mole) 4-acetoxy-2-nonene, 80.0 g (0.4-5 moles) of N-bromosuccinimide and 500 ml of carbon tetrachloride is refluxed for 3 hours. The mixture is then cooled and the suspended succinimide through Filter removed. The carbon tetrachloride solution is with diluted sodium bicarbonate solution and water and washed dried over sodium sulfate. The carbon tetrachloride is evaporated off in vacuo and the oily residue is distilled. 62 g (59%) of 1-bromo-4-acetoxy-2-nonene are obtained as a pale yellow oil (boiling point 110 to 112 ° C./0.1 mm).

I. ₁ . Preparation of i-bromo-4-acetoxy-2-nonyne

Step 1: Preparation of 5-acetoxy-1-octyne

100 g (0.794 mol) of i-octyn-3-ol are dissolved in 79 g (1.0 mol) of pyridine, and 81.6 g (0.80 mol) of acetic anhydride are added dropwise with stirring over the course of 1 hour. The temperature rises to 45 ° C. The solution is heated for 1 hour at 55 ° C and then _s cooled and abge ml of ice-cold 200, poured 5% hydrochloric acid. The oily product is taken up in ether, washed with water and brine and dried over sodium sulfate. The ether is evaporated,

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and the oily residue is distilled. 106.4 g are obtained (80%) 3-acetoxy-i-octyne (bp 91 to 92 ° C / 15 mm.

Step 2: Preparation of 1-diethylamino-4-acetoxy-2-nonyne

A mixture of 5818 S (Oi35 mol) 3-acetoxy-i-octyne, 28.5 g (0.39 mole) diethylamine, 13.8 g (0.46 mole) paraformaldehyde and 60 ml of p-dioxane is heated on the steam bath under a reflux condenser for 17 hours. The resulting Solution is cooled and diluted with 250 ml of ether. The solution is extracted with 300 ml of 5% hydrochloric acid. The acidic, aqueous extract is made basic with 10% sodium hydroxide solution. The amine released is taken up in ether, washed with water and brine and dried over sodium sulfate. The ether is evaporated and the oily residue is distilled (yield 73.1 g (89%) of 1-diethylamino-4-acetoxy-2-nonyne; bp 103 bis 109 ° C / 0.3 mm).

Analysis:

Calculated for C ₁₅ H ₂₇ NO ₂ : C, 71.10; H 10.74; N 5.33;

Found: C, 70.73; H 11.03; N 5.55-

Step 3 » Preparation of 1-bromo-4-acetoxy-2-nonyne

A solution of 50.6 g (0.20 mol) of i-diethylamino-4-acetoxy-2-nonyne and 21.2 g (0.20 mol) of cyanogen bromide in 250 ml of ether is left at 25 ° to 27 ° for 18 hours C stand. The ether solution is washed with 5% hydrochloric acid solution, water and brine and dried over sodium sulfate. The ether is evaporated and the oily residue is distilled. After a first run of diethyl cyanamide, 34.1 g (65 %) of 1-bromo-4-acetoxy-2-nonyne are collected (boiling point 97-105 ° C./0.2 mm).

Analysis:

Calculated for C ₁₁ H ₁₇ BrO ₂ : C, 50.59; H 6.56

Found: C, 50.54; H 6.49.

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J. Preparation of 1-bromo-4 (R) -acetoxy-2-nonyne

According to the procedure described in Example 1, if instead of the racemic i-octyn-3-ol (R) -1-octyn-3-ol (/ a7p ⁶ + 6.1 ° / C 3.1, CHCl ₅ /) used, one after the other: 3 (R) -acetoxy-1-octyne, fa / ψ + 70 ° / Q, 3.1, CHCly \ 1-Di-

ethylamino-4 (R) -acetoxy-2-nonyne, / Ο7ίτ + 74 ° / C 3.2, and 1-bromo-4 (R) -acetoxy-2-nonyne, / 07 ^ ° + 75 °

3.2, chci ^ /.

K. Preparation of 1-bromo-4 (S) -acetoxy-2-nonyne

According to the procedure described in Example 1, if instead of the racemic "l-octyn-3-ol (S) -1-octyn-3-ol, I% 7r \ - 6.4 ° / C 3.3, CHCl J used, one after the other: 3 (S) -acetoxy-1-octyne, W ^ - 79 ° B> 3.0, CHC1 ^ 7, 1-diethylamino-4 (S) -acetoxy-2-nonyne, ZÖ7t) - 80 ° / C 3.3, CI ¹ CIa? And 1-bromo-4 (S) -acetoxy-2-nonyne, / ö ^^ - 83 ° / 3.7,

L. Preparation of Methyl 7-bromo-2-methylheptanoate

Step 1 : making 5-acetoxypentyl chloride

102 g (1 mol) of acetic anhydride are added dropwise with stirring to 90 g (0.74 mol) of pentamethylene chlorohydrin. The resulting solution is on the steam bath for 1 hour heated for a long time, and left to stand at room temperature overnight. The reaction mixture is distilled. You get 83.6 g (69%) 5-acetoxypentyl chloride (boiling point 101 to 104 ° C / 20 mm).

Step 2: Preparation of diethyl (5-acetoxypentyl) methylmalonate

4.8 g (0.2 mol) of sodium hydride are used as a 50% suspension washed in petroleum with petroleum ether under nitrogen to remove the petroleum and suspended in 150 ml of dry benzene, and the suspension is cooled in an ice bath.

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34.8 g (0.2 mol) of diethyl methyl malonate dissolved in 150 ml of dried DMP are added dropwise to the suspension given by sodium hydride. The mixture is left to stand at room temperature overnight. Then 0.4 g of potassium iodide and 32v9 g (0.2 mol) of 5-acetoxyphenyl chloride added, and the mixture is left in an oil bath for 24 hours Heated to 125 ° C. The reaction mixture is concentrated in vacuo, diluted with 200 ml of ether and filtered to remove sodium chloride to remove. The filtrate is washed with brine, dried over anhydrous magnesium sulfate and concentrated. 39> 6 g (66%) of an oily product are obtained.

step 3 '' Production of 7-bromo-2-methylheptanoic acid

A mixture of 68 g (0.23 mol) of the crude diethyl (5-acetoxypentyl) methylmalonate and 100 ml of 48% strength aqueous hydrobromic acid is refluxed for 20 hours. The mixture is then concentrated by distillation until the internal temperature has risen to 120.degree. 96 ml of distillate (2 layers) are collected. The remaining liquid is cooled, dissolved in ether, washed with brine and dried over magnesium sulfate, and the solution is concentrated in vacuo. This gives 54 g of crude ^7-B rom-2-methylheptanoic acid as dark, viscose liquid.

Step 4: Preparation of Methyl 7-bromo-2-methylheptanoate

A solution of 54 g (0.24 mol) of the crude 7-bromo-2-methylheptanoic acid and 2 drops of concentrated sulfuric acid in 300 ml of absolute methanol is refluxed for 5 hours cooked. After standing overnight at room temperature the solution is concentrated in vacuo and diluted with water. The mixture becomes saturated by adding Sodium carbonate solution made basic, and the product is absorbed into ether. The ether extract is washed with water and dried over anhydrous magnesium sulfate

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5098 17/1234

and distilled. This gives 11.8 g (16%) of methyl 7-bromo-2-methylheptanoate (bp 67 "to 70 ° C / 0.5 now; pmr _(CDCl3) J 1.13 (3H, d 2-CH ₅ ), 2.4-2 (1H, m CHCOOCH ₅ ), 3.38 (2H, t, CH ₂ Br), 3.65 (3H, s CH ₃ O)

M. Preparation of ethyl 4-bromobutoxyacetate

9 »° 6 (O> 375 mol) sodium hydride are in 1,2-dimethoxyethane suspended. The mixture is stirred and cooled in an ice bath while 39.0 g (0.375 mol) of ethyl glycollate added dropwise over 1 hour. 108 g (0.5 mol) 1,4 ~ dibromobutane are added at once to the resulting, given thick suspension. The mixture is gently warmed to start the strongly exothermic reaction. The mixture is then heated on the steam bath for 3 hours. The mixture is poured into cold water. the heavy oil layer is taken up in ether, washed with three portions of water and dried over sodium sulfate.

By evaporating the ether and distilling the oily residue 21.3 g (24%) of ethyl 4-bromobutoxyacetate are obtained as a colorless oil (bp 99 to 103 ° / 0.2 mm).

N. Preparation of ethyl 7-cyanamidoheptanoate

Step 1 ; Production of ethyl 7-ureidoheptanoate

A solution of 2.9 g (0.02 mol) 7-aminoheptanoic acid in 20 ml A solution of 1.62 g (0.02 mol) of potassium cyanate in 10 ml of water is added to water, and this solution is passed through Addition of 6N hydrochloric acid made weakly acidic. The reaction mixture is heated on the steam bath for 1 hour; during this time a solid separates away. The reaction mixture is cooled and the solid collected and dried. The yield is 3> 1 g> and the melting point is 166 ° C. The solid will not further cleaned. The solid is dissolved in 25 ml of ethanol, Dissolve 100 ml of benzene and 0.2 ml of sulfuric acid for 20 hours

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15 4-95

heated to reflux temperature for a long time. The water formed is caught in a Dean-Stark trap. That The reaction mixture is cooled and poured into 150 ml of water ■ and then extracted with chloroform (2 × 100 ml). The organic Layer is washed with brine, dried over sodium sulfate, and the solvent is removed in vacuo. removed. The resulting solid is crystallized from butyl chloride. 2.4 g (56%) of the melt at 90 to 92 ° C.

Analysis:

Calculated for C ₁₀ H ₂₀ N ₂ O ₅ : C 55.53; H 9.32; N 12.95

Found: C, 55.82; H 9.45; N 12.80

Step 2 : making ethyl 7-cyanamidoheptanoate

A solution of 2.1 g (0.01 mol) of ethyl 7-ureidoheptanoate in 10 ml of pyridine is mixed with 2.0 g (excess) of p-toluenesulfonyl chloride offset. The reaction mixture is stirred at room temperature for 2 hours, poured into 100 ml of water and then extracted with ether (2 × 100 ml). The ether becomes with 5% hydrochloric acid (2 × 25 ml) and brine and then dried over sodium sulfate. The solvent is removed in vacuo. Ethyl 7-cyanamidoheptanoate is obtained as a light yellow oil (yield 1.7 gj 86%).

Analysis:

Calculated for C ₁₀ H ₁₈ N ₂ O ₂ : C, 60.58; H 9.15; N 14.13

Found C, 60.52; H 9.18; N 13.82

0. Production of 4-acetoxynonylcyanamide

Step 1: Preparation of 1-chloro-4- (2-tetrahydropyranyl oxy) -nonane ] -

To a stirred solution of 11.0 g (0.062 mol) 1-chloro-4-hydroxynonane (Example 1, Step 2) and 5.2 g (0.062 mol) of dihydropyran which is cooled in an ice bath

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15 495

Added 5 drops of concentrated hydrochloric acid. A slight exothermic reaction is noted and, after this is over, the reaction mixture is allowed to stand to come to room temperature and then left stand for another 2 hours. At the end of this period several flakes of sodium hydroxide are added and the reaction mixture is distilled in vacuo. The yield of 1-chloro-4- (2-tetrahydropyranyloxy) nonane is 12.5 g (77% boiling point 96 to 102 ° C / 0.1 mm). After the repeated Distilling results in a boiling point of 90 to 92 ° C / 0.1 mm.

Step 2: making N- / ² 4 ~ (2-tetrahydropyranyloxy) -

nonyl7-phthalimide

1.5 g (excess) of sodium hydride (53%) are added three times washed with benzene by decantation, and then 100 ml of dimethylformamide is added. This stirred suspension a solution of 4.3 g (0.03 mol) of phthalimide in 50 ml of dimethylformamide is added at such a rate that that the temperature is kept below 35 ° C. A clear solution is obtained, which is mixed with 7 »8 g (0.03 mol) 1-chloro-4- (2-tetrahydropyranyloxy) -nonane added. The resulting solution is stirred and heated to 95 ° C for 20 hours heated. The reaction mixture is then concentrated in vacuo to half its volume, poured into 200 ml of ice water and extracted with ether (2 × 150 ml). The ether is mixed with 5% sodium hydroxide (2 × 50 ml) and saturated sodium chloride solution (2 × 50 ml) and then washed over sodium sulfate dried. Evaporation of the ether gives 4.5 g (yield 45%) of N- / 4- (2-tetrahydropyranyloxy) -nonyl7-phthalimide, that melts at 59 to 61 C. After crystallizing from cyclohexane, the product melts 62 to 63 ° 0.

- 36 -

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3>

Analysis:

Calculated for C ₂₂ H ₅₁ NO ₄ : C 70.75; H 8.36; N 3.75

Found: C, 71.03; H 8.28; N 3.81

Step 3 s Preparation of 4- (2-tetrahydropyranyloxy) nonylamine

64% aqueous hydrazine (10 ml excess) is added to a solution of 33.0 g (0.88 mol) of N-Z4- (2-tetrahydropyranyloxy) -nonyl7-phthalimide in 300 ml of absolute ethanol, and the reaction mixture is Heated to reflux for 1.5 hours. An additional 5 ml of hydrazine (64 %) is added and refluxing is continued for 1.5 hours. The reaction mixture is cooled to room temperature and the white solid present is removed by filtration. The filtrate is concentrated to 75 ml in vacuo and then poured into 200 ml of water. The solution is made basic with 5% sodium hydroxide and then extracted with ether (3 x 100 ml). The ether layer is washed with saturated sodium chloride solution and then dried over sodium sulfate. The ether is removed in vacuo and the resulting oil distilled. The yield of 4- (2-tetrahydropyranyloxy) nonylamine is 16.0 g (75%; boiling point 100 to 102 ° C./0.1 mm).

Analysis:

Calculated for C ₁₄ H ₂₉ NO ₂ : C, 69.08; H 12.01; N 5.75

Found: C, 68.58; H 12.42; N 5.66

Step 4 : Making 4-Acetoxynonylurea

To a stirred suspension of 4.8 g (0.02 mol) of 4- ° (2-tetrahydropyranyloxy) nonylamine just enough 10% hydrochloric acid is added to 75 ml of water to dissolve to effect. Then 1.62 g (0.02 mol) of potassium cyanate added and the reaction mixture gently heated on the steam bath for 1 hour. During this time separates an oil off. The reaction mixture is cooled and washed with ether

509817/1234

(2 χ 75 ml) extracted. The ether is made over sodium sulfate dried and then concentrated in vacuo. 4-Hydroxynonylurea is obtained as an oily residue. The 4-hydroxynonylurea is taken up in 20 ml of pyridine and 2.0 g (0.02 Moles) acetic anhydride are added. The reaction mixture is then stirred at room temperature for 8 hours Poured into 100 ml of water and extracted with ether (2 × 100 ml). The ether is treated with 5% hydrochloric acid and Washed brine and dried over sodium sulfate. Removal of the solvent in vacuo gives the in the Heading named compound as an oily residue.

Step 5 » Preparation of 4-acetoxynonylcyanamide

To a stirred solution of 2.4 g (0.01 mol) of 4-acetoxynonylurea 2.0 g (excess) of p-toluenesulfonyl chloride are added in one portion to 10 ml of pyridine. The reaction mixture is stirred at room temperature for 6 hours and then poured into 15Ο ml of water. The aqueous mixture is extracted with ether (3 × 75 ml), and the ether is washed with 5% hydrochloric acid and brine and dried over sodium sulfate. The solvent is removed in vacuo. 4 ~ Acetoxynonylcyanamid is obtained as oily residue.

P. Preparation of 1-acetoxy-1- (3-bromo-1-propynyl) cyclohexane

Step 1 : making i-acetoxy-i-ethinylcyclohexane

100 g (0.8 mol) of 1-ethynylcyclohexan-i-ol are added dropwise added with stirring to a mixture of 86.7 g (0.85 mol) of acetic anhydride and 0.25 ml of sulfuric acid. The temperature the reaction mixture is kept at 10 to 12 ° C. by means of an ice bath during the addition. The mixture will then stirred without cooling for 1.5 hours. It is then poured into 300 ml of ice water. The oily product turns into ether added, with water, dilute sodium bicarbonate solution

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and brine ^ washed and dried over sodium sulfate. Distillation gives 107 g (80%) of 1-acetoxy-1-athinylcyclohexane (Bp 95 to 97 ° C / 15 mm).

Step 2 ; Preparation of 1-acetoxy-1- (3-diethylamino- 1-propynyl; cyclohexane

A mixture of 64.00 g (0.385 mol) of 1-acetoxy-i-ethinylcyclohexane, 30.95 g (0.424 mol) diethylamine, 15.00 g (0.00 mol) paraformaldehyde, 1.5 g copper (I) chloride and 60 ml Dioxane are stirred well. An exothermic reaction gradually develops which, in order to prevent splashing, External cooling may be required. After this initial reaction, the mixture is placed on a steam bath Heated for 1.5 hours.

The cooled reaction mixture is treated with ether and the product extracted with ice-cold, 5%, concentrated hydrochloric acid. This cold, aqueous, acidic solution is then made basic with ice-cold, 10% sodium hydroxide. The oily amine is extracted with ether and the combined extracts are washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent is removed in vacuo, and the oily residue is distilled. 72.7 S (75%) are obtained on a light yellow oil (boiling point 113 to 115 ° C / 0.15 mm; pmr (CDCl ₃ ), S 1.07 (6H, t), 2.02 (3H, s CH ₃ COO), 2.60 (4H, q CH ₅ CH ₂ N), 3.52 (2H, s

Step 3 s Preparation of 1-acetoxy-1- (3-bromo-1-propynyl) cyclohexane

31 »8 g (0.3 mol) of cyanogen bromide are added to a solution of 61 g (0.24 mol) of 1-acetoxy-1- (3-diethylamino-1-propynyl) cyclohexane is added and the resulting solution is left for 18 hours stand at 25 to 27 ° C for a long time. The ethereal solution becomes with 5% hydrochloric acid solution, water and saline solution washed and dried over sodium sulfate. The ether becomes

- 39 -

509817/1 234

evaporated and the oily residue distilled. 34.8 g (55%) of 1-acetoxy-1- (3-bromo-1-propynyl) cyclohexane are obtained as a slightly yellowish oil (bp 114 to 120 ° C / 0.2 mm).

Q. Preparation of 1-acetoxy-1- (3-bromo-1-propynyl) cyclo octane

By using the procedures described in Example P, if 1-ethynylcyclooctanol- (i) is used in step 1 instead of i-ethynylcyclohexan-ol- (l) starts, in succession: step 1, 1-acetoxy-i-ethinylcyclooctane; Step 2, 1-acetoxy-1- (3-diethylamino-1-propynyl) cyclooctane; Step 3> 1-Acetoxy-1- (3-bromo-1-propynyl) -cyclooctane.

R. Manufacture of i-chloro - ^ - acetoxy- ^ methylnonane

The Grignard reagent, prepared from 14.2 g (0.1 mol) of iodomethane and 2.4 g (0.1 mol) of magnesium in ethereal solution, is added dropwise to an ethereal solution of 17.6 g (0.1 mol) of 1-chlorine. 4-nonanone (example A, step 1) given. The reaction mixture is gently refluxed for 3 hours, then cooled and carefully poured into 300 ml of ice water. The ether layer is separated off, washed with brine and dried over sodium sulfate. By removing the ether in vacuo, 1-chloro-4-hydroxy-4-methylnonane is obtained as an oil. The tertiary alcohol is dissolved in pyridine and treated with 1 molar equivalent of acetic anhydride at 60 to 80 ⁰ C for 8 to 16 hours. I-chloro-4-acetoxy-4-methylnonane is obtained as a colorless oil.

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example 1

Preparation of 7 - / '1- (4-Hydroxynonyl) -ureidQ7-heptanoic acid

Step A: Preparation of ethyl-7- / N- (4-acetoxynonyl) -cyanamido_7-hep t ano at

0.48 g (0.01 mol) of sodium hydride (57% in petroleum) are washed twice with benzene and then suspended in 50 ml of benzene and 50 ml of dimethylformamide. 1.98 g (0.01 mol) of ethyl 7-cyanamidoheptanoate (Example N, Step 2) are added and the suspension is heated on the steam bath for 15 minutes. The reaction mixture is cooled to room temperature, 2.6 g (0.01 mol) of i-chloro-4-acetoxynonane (Example A, Step 3) are added and then the reaction mixture is heated on the steam bath for 2 hours and then for 18 hours stirred for a long time at room temperature. The reaction mixture is poured into 300 ml of water and extracted with benzene (3 × 100 ml). The benzene is washed with brine and then dried over sodium sulfate. Removal of the solvent gives an oil which is purified by silica gel chromatography. 3% methanol in chloroform is used as the elution solvent. By evaporating the appropriate fraction, ethyl 7-ZN- (4-acetoxynonyl) cyanamido7-heptanoate is obtained. The yield is 3.2 g (83%).

Analysis:

Calculated for C ₂₁ H ₃₈ N ₂ O ₄ : C, 65.96; H 9.96; N 7.32

Found: C, 65.53; H 10.08; N 6.94.

Step B : Preparation of 7 -_ ^ - (4-Hydroxynonyl) -cyanamidq7- heptanoic acid ___

A solution of 3.6 g (0.01 mol) of ethyl 7 -__ N- (4-acetoxynonyl) -cyanamidq7-heptanoate in 40 ml of ethanol, 20 ml of an aqueous solution of 1.4 g (0.0035 mol) of sodium hydroxide are added. The reaction mixture is at room temperature for 20 hours

- 41 5098 17 / 123A

15 495

The stirred long, 100 ml of water are added and the solution is acidified with dilute HCl and extracted with ethyl acetate (3 x 75 ml). The organic layer is washed with brine, dried over sodium sulfate and then evaporated in vacuo to an oil. The oil is taken up in 100 ml of water by carefully adding 10% sodium hydroxide. The basic solution is extracted with ether (2 × 25 ml) and then again acidified with dilute hydrochloric acid. The oil which separates out is taken up in ethyl acetate, and the extract is dried over sodium sulfate and then concentrated in vacuo. The compound given in the title is obtained as an oily residue. The yield is 1.5 g (48%) of 7-./N-(4~Hydroxynonyl)-cyanamidQ7 ⁱ '-heptanoic acid, which exists as the hemihydrate.

Analysis:

Calculated for C ₁₇ H ₅₂ N ₂ O ₅ -1 / 2HgO: C, 63.51; H 10.35; N 8.71

Found: C, 63.48; H 10.25; N 8.35

Step C: Preparation of 7 - ^ - (4-Hydroxynonyl) -ureido7- heptanoic acid

A solution of 0.4 g (excess) sodium hydroxide in 50 Water and 50 ml of ethanol are mixed with 1.5 g (0.005 mol) of 7 ~ Z & - (4-Hydroxynonyl) -cyanamido7-heptanoic acid added. The clear solution that is obtained is mixed with 1.25 ml (excess) Treated 30% hydrogen peroxide. At the end of 2 hours, the reaction mixture is poured into 150 ml of water, with dilute hydrochloric acid acidified and extracted with methylene chloride (3 x 75 ml). The organic layer will washed with brine and then dried over sodium sulfate. Evaporation of the solvent gives a oil that solidifies when left standing. The solid will crystallized from butyl chloride. 7-ΖΪ- (4-Hydroxynonyl) -ureido7-heptanoic acid is obtained. The yield is 1.4 g (85%) of a material which melts at 75 to 76 ° C.

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¹⁵ "2U9272

Anylse:

Calculated for C ₁₇ H ₅₄ N ₂ O ₄ : C, 61.78; H 10.37; N 8.48

Found: C, 62.09; H 10.69; N 8.43

Example 2

Preparation of 7-Z ⁷ I- (4-hydroxy- (E) -2-nonenyl) -ureido7- heptanoic acid.

The synthesis of this compound is carried out as described in Example 1, but with the modification that in step A the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2-nonane (Example H). The product of step A is therefore ethyl-7-ZN- (4-acetoxy- (E) -2-nonenyl) - cyanami do7-hep t ano at.

Analysis:

Calculated for ^C 21 ^H 36 ^N 2 ° 4 ^{: 66} °> ^{28 ° H} 9.54; N 7.36

Found: C, 65.95; H 9.45; N 7.23

The product of step G is 7-ZN- (4-hydroxy- (E) -2-nonenyl) -cyanamido7-heptanoic acid and the product of step C 7-2? - (4-Hydroxy- (E) -2-nonenyl) -ureidq7-heptanoic acid. This Product is in the form of the hydrate.

Analysis:

Calculated for C ₁₇ H ₅₂ N ₂ O ₄ -H ₂ O: C, 58.93; H 9.89; N 8.07

Found: C, 59.04; H 9.84; N 7.96

Example 3

Preparation of 7- / 1- (4-hydroxynonyl) thioureidQ7 ^ heptanoic acid Step A: 7- / i- (4-hydroxynonylthioureidci7-heptanoic acid

A solution of 4.2 g (0.0134 moles; Example 1, Step B) 7-Z & - (4-Hydroxynonyl) -cyanamidp_7-heptanoic acid in 15 ml Thiolacetic acid is placed in a Vicor flask with an ultra-

•. - 43 -

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15 495

2AA9272

violet lamp irradiated for 2.5 hours and then remains over Standing at night. The solvent is removed in vacuo and the remaining oil is dissolved in 150 ml of ammonium hydroxide. This solution is stirred at room temperature for 48 hours, cooled in ice and then acidified with 6N hydrochloric acid. The oil that separates out is extracted with ethyl acetate. The acetate layer is dried over sodium sulfate and then concentrated in vacuo down to an oil that through. Silica gel chromatography is further purified. That Product is removed from the column with a 6% methanol / chloroform mixture eluted. Evaporation of the appropriate fractions gives 7-Z ^ - ^ - (hydroxynonyl) -thioureido7-heptanoic acid as viscosSs oil. The yield is 3> 2 g (69%).

Analysis:
Calculated for found:

C ₁₇ H ₃₄ N ₂ O ₃ S:

C 58.92; N 9.89; N 8.08 C 58.95; H 10.04; N 7.94.

Example 4

Preparation of 7 - ^ - (4-Hydroxy-2-noninyl) -ureido7-heptanoic acid

The synthesis of this compound is as described in Example 1, however carried out with the amendment that in step A the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2-nonyne (example 1, step 3) will. The product of step A is thus ethyl 7- ^ - (4-acetoxy-2-noninyl) -cyanamido_7-heptanoate. In the following 7-ZN- (4-hydroxy-2-noninyl) -cyanamido7-heptanoic acid is obtained in steps (B) and 7- / Ϊ- (4-hydroxy-2-noninyl) -ureido_7-heptanoic acid (C).

Example 5

Preparation of 7 - /? - (3 (R) -Hydroxynonyl (-ureido7heptanoic acid) The synthesis of this compound is carried out as in Example 1

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509817/1234

wrote, but carried out with the modification that in step A the i-chloro-4-acetoxynonane by an equimolar Amount of 1-bromo-4 (R) -acetoxy-2-nonyne (Example J) replaced will. The product of step A is thus ethyl-7-Z ^ - (4 (R) -acetoxy-2-nonynyl) -cyanamido7-heptanoate. In the following 7- / N- (4- (R) -hydroxy-2-noninyl) -cyanamido7-heptanoic acid is obtained in steps (B) and 7- / 1- (4- (R) -Hydroxy-2-nonynyl) -ureido7-heptanoic acid (C). The product of step C is converted over a platinum-on-charcoal catalyst to 7- / 1- (4 (R) -hydroxynonyl) -ureide £ 7-heptanoic acid hydrogenated.

Example 6

Production of Ί-1Λ- (4 (S) -hydroxynonyl) -ureido7-heptanoic acid

The synthesis of this compound is carried out as described in Example 1, but with the modification that in step A the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4 (S) -acetoxy-2-nonyne ( Example K) is replaced . The product of step A is thus ethyl 7 - /% - (4 (S) -acetoxy-2- noninyl) -cyanamido7-heptanoate. In the following steps 7- / | 5- (4- (S) -hydroxy-2-noninyl) -cyanamido7heptanoic acid (B) and 7-ZTI- (4 (S) -hydroxy-noninyl) -ureid _: o7- heptanoic acid (C). The product of step C is hydrogenated over a platinum-on-charcoal catalyst to give 7- £ T- (4 (S) -hydroxynonyl) -ureid27-heptanoic acid.

Example 7

Production of 7 ~ ΖΪ- (4— hydroxynonyl) -ureido7-2-methyl heptanoic acid

Step A; Production of ethyl-7- / Ii- (4-acetoxynonyl) -

cyanamide Q7-2-methylheptanoate

A stirred suspension of 5 »0 g (excess) sodium hydride (57% in petroleum) in a solvent mixture of 75 ml of benzene and 75 ml of dimethylformamide is added over 30 minutes

_ 45 -509817/1234

with 22.6 g (0.1 mol) of 4-acetoxynonylcyanamide (Example 0, Step 5) ϊ which are dissolved in 20 ml of benzene, treated. Stirring is continued for 1 hour. Then 25.3 g (0.1 mol) of ethyl 7-bromo-2-methylheptanoate (Example L, Step 4 ·) added dropwise, and the reaction mixture is heated on the steam bath for 3 »5 hours. The cooled reaction mixture is poured into 400 ml of water and extracted with ethyl acetate (2 × 200 ml). the organic fractions are combined, washed with brine and then dried over sodium sulfate. The solvent is removed in vacuo. Ethyl 7- / N- (4- acetoxynonyl) -cyanamido7-2-methylheptanoate is obtained as a pale yellow Liquid.

Step B : Making 7 ~ ZN- (4-Hydroxynonyl) -cyanamido7-

2-methylheptanoic acid

A solution of 7.6 g (0.02 mol) of ethyl 7- / N- (4-acetoxynonyl) -cyanamido7-2-methylheptanoate in 50 ml of ethanol is treated with a solution of 1.6 g (0.04 mol) of sodium hydroxide in 15 ml of water added, and the reaction mixture is at ambient temperature Stirred for 20 hours. Most of the ethanol is then removed in vacuo and the residue is taken up in 150 ml of water. The solution is extracted once with ether and then acidified with dilute hydrochloric acid. The oil, which separates is extracted with ether and the ether is washed with brine, dried over sodium sulfate and removed in vacuo. 7 - / $ - (4-Hydroxynonyl) -cyanamido7-2-methylheptanoic acid is obtained as yellow oil.

Step C : Making 7-Z ^ - (4-Hydroxynonyl) -ureidq7-

2-methylheptanoic acid -

A solution of 0.4 g (excess) sodium hydroxide in 50 ml Water and 50 ml of ethanol are mixed with 1.5 g (0.005 mol) of 7- / φ-hydroxynonyl) -cyanamido7-2-methylheptanoic acid offset. The clear solution obtained is mixed with 1.25 ml (excess) Treated 30% hydrogen peroxide. After 2 hours it will

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the reaction mixture was poured into 125 ml of water, acidified with hydrochloric acid and extracted with ethyl acetate (3 x 75 ml). The organic phase is washed with brine and then dried over sodium sulfate. Evaporation of the solvent gives 7- / β- { ^L <~ hydroxynonyl) -ureido / -2-methylheptanoic acid as a viscous oil.

Example 8

Preparation of 7-Z ^ - (^ Hydroxynonyl) -ureido7-2,2-dimethyl heptanoic acid

The synthesis of this compound is carried out as described in Example 7, but with the modification that in step A the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of methyl 2,2-dimethyl-7-iodoheptanoate . The product of step A is thus methyl 7- / R- (4- acetoxynonyl) -cyanamido7-2,2-dimethylheptanoate. In the following steps 7- / ft- (4 - Hydroxynonyl) -cyanamido7-2,2-dimethylheptanoic acid (B) and 7-Z ⁷ I - (^ - Etydroxynonyl) -ureido7-2,2-dimethylheptanoic acid (C. ),

Example 9

Production of 7-Z? - (4 ~ hydroxynonyl) -ureido7-3-ynethyl heptanoic acid

The synthesis of this compound is carried out as described in Example 7, but with the modification that in step A the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of methyl J-methyl ^ -iodoheptanoate . The product of step A is thus methyl 7-Z ^ - (4-acetoxynonyl) -cyanamido7-3-methylheptanoate. In the following steps, 7-Zfr- '(4-hydroxynonyl) -cyanamido_7-3-methylheptanoic acid (B) and 7- / Ϊ- (4-hydroxynonyl) -ureido7-2-methylheptanoic acid (C) are obtained.

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495 2U9272

Example 10

Production of 7 - / ^ - (4-hydroxynonyl) -ureido7-3 »3-dimethyl heptanoic acid

The synthesis of this compound is as described in Example 7, but carried out with the amendment that in Step A replaces the ethyl 7-bromo-2-methylheptanoate with an equivalent amount of methyl 3,3-dimethyl-7-dodheptanoate will. The product of step A is thus methyl 7- / li- (4-acetoxynonyl) -cyanamido7-3i3-dimethylheptanoate. In the following steps 7-Z ^ - (^ - hydroxynonyl) -cyanamido7-3i3-dimethylheptanoic acid is obtained (B) and 7-Z'l- (4-hydroxynonyl) -ureido7-3,3-dimethylheptanoic acid (C). "

Example 11

Preparation of 4 - / ^ - (4-Hydroxynonyl) -thioureido7-butoxy acetic acid

The synthesis of this compound is initially carried out as described in Example 7, but with the modification that in step A the ethyl 7-bromo-2-methylheptanoate is replaced by an equimolar amount of ethyl 4-bromobutoxyacetate (Example M). The product of step A is thus ethyl 4- ^ K- (4-acetoxynonyl) -cyanamido-7-butoxyacetate. The product of the hydrolysis (step B) is thus 4- / li- (4-hydroxynonyl) -cyanamido-7-butoxyacetic acid. This product is then treated as described in Example 31, Step A, to ^{produce the heading 4- / 5} I- (4-hydroxynonyl) -thioureido-7-butoxyacetic acid.

Example 12

Preparation of 7- ^ l- (4-Hydroxy-8-methylnonyl) -thioureido7- heptanoic acid

The synthesis of this compound is initially as in Example

509817/1234

1 described ^ however, carried out with the amendment that in step A the i-chloro-4-acetoxynonane by an equimolar Amount of I-chloro - ^ - acetoxy-8-methylnonane (Example B, Step 3) is replaced. The product of step A is thus ethyl 7-Z ^ - (4-acetoxy-8-methylnonyl) -cyanamido-7-heptanoate. The hydrolysis (step B) gives 7-ZR- (4-hydroxy-8-methylnonyl) -cyanamido7-hept acidic. This product is then, as in Example 3> Step A, described, to form the title compound, 7-Z ^ - (4-Hydroxy-8-methylnonyl) -thioureido-7-heptanoic acid treated.

Example 13

Preparation of 7-Z ^ - (4-Hydroxyundecyl) -thioureido7-heptanoic acid

The synthesis of this compound is initially carried out as described in Example 1, but with the modification that in step A the i-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxyundecane (Example G, step 3) is replaced. The product of step A is thus ethyl 7-Zfr- (4-acetoxyundeeyl) -cyanamide £ 7-heptanoate. In the following steps 7- / 5- (4-Hydroxyondecyl) -cyanamido7-heptanoic acid (B) is obtained. This product is then, as described in Example 3 »Step A, treated and gives the compound mentioned in the heading 7- ^ ⁵ I - (4-Hydroxyunde cyl) -thioureidg7-heptanoic acid.

Example 14

Production of 7-zi- (4-hydroxy-8,8-dimethylnonyl) -ureido7- h.eptanoic acid

The synthesis of this compound is as described in Example 1, but carried out with the modification that in step A the 1-chloro-4-acetoxynonane by an equimolar Amount of 1-chloro-4-acetoxy-8,8-dimethylnonane (Example D) is replaced. The product of step A is thus ethyl

- 49 -5098 17 / 123A

7-Z ^ "" (4 ~ acetoxy-8,8-dimethylnonyl) -cyanamidoJ / '- heptanoate.
In the following steps 7- / S- (4 - hydroxy-8,8-dimethylnonyl) -cyanajnidq / -heptanoic acid (B) and 7- / Ϊ- (4— hydroxy-8,8-dimethylnonyl) - ureido7-heptanoic acid (C).

Example 15

Preparation of 7-Z ^ - (^ - Hydroxy-9,9 »9-trifluorononyl) -ureido7- heptanoic acid \

The synthesis of this compound is carried out as described in Example 1, but with the modification that in step A the i-chloro-4-acetoxynonane is replaced by an equimolar amount of ^/ l-chloro-4-acetoxy-9.9 »9, trifluorononane (Example E) is replaced. The product of step A is therefore ethyl 7- £ ß- (4-acetoxy-9.9 j 9-trifluorononyl) -cyanamidjoZ-heptanoate. In the following steps you get 7 - / ^ - ( ^z * ~ hydroxy-9 »9» 9-trifluorononyl) -cyanamido7-heptanoic acid (B) and 7- / ⁵ I- (4-hydroxy-9 »9» 9- trifluorononyl) ureidoT-heptanoic acid (C).

Example 16

Production of 7-Z? - (4-Hydroxy ~ 8-nonenyl) -ureidq7-heptanoic acid

The synthesis of this compound is as in Example 1
described, but carried out with the modification that in step A the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-8-nonane. The product of step A is thus ethyl 7-ZK- (4-acetoxy-8-nonenyl) -cyanamidoj-heptanoate. In the following steps 7-Z ^ ~ (^ - hydro: xy-8-nonenyl) -cyanamide <^ - heptanoic acid (B) and 7- / Ί- (4-hydroxy-8-nonenyl) -ureidg7 ~ heptanoic acid (C).

Example 17

Preparation of 7 - / ^ - ( ^/ l ~ Hydroxy-5) 5-dimethylnonyl) -ureido7- heptanoic acid

The synthesis of this compound is carried out as in Example 1

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wrote, but carried out with the modification that in step A the i-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-5 »5-di-diethylnonane (Example G). The product of step A is thus ethyl 7- / ß- (4-acetoxy-5,5-dimethylnonyl) -cyanamido7-heptanoate. In the following steps you get 7- / R- (H- hydroxy-5,5-dimethylnonyl) -cyanamido7-heptanoic acid (B) and 7- / i- (4 - hydroxy-5,5-aimethylnonyl) -ureido7- heptanoic acid (C).

Example 18

Production of 7- / 3- (4-Hydroxy-4-methylnonyl) -ureido7- heptanoic acid

The synthesis of this compound is carried out as described in Example 1, but with the modification that in step A the I-chloro - ^ - acetoxynonane by an equimolar Henge of i-chloro - ^ - acetoxy - ^ - methylnonane (Example E) is replaced. The product of step A is thus ethyl 7- / li- (4-acetoxy-4-methylnonyl) cyanamido7-heptanoate. In the following steps 7-Z ^ - (4-Hydroxy-4- methylnonyl) -cyanamido7-heptanoic acid (B) and 7- / ⁷ I - (^ - hydroxy-4-meth.ylnonyl) -ureido7-heptanoic acid are obtained (C).

Analysis:

Calculated for C ₁₈ H ₅₆ N ₂ O ₄ : C, 62.77; H 10.53; N 8.15

Found: C, 62.51; H 11.08; N 7.75

Example 19

Preparation of 7- {i-Z3- (1-Hydroxycyclohexyl) -2-propyn-1-yl7-ureidolheptanoic acid

The synthesis of this compound is as described in Example 1, but carried out with the modification that in step A the 1-chloro-4-acetoxynonane by an equimoalre Amount of 1-acetoxy-1- (3-bromo-1-propynyl) cyclohexane (Example P) is replaced. The product of step A is thus

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Ethyl 7- {N- _(i 3- ( ^/ l-acetoxycycloliexyl) -2-propyn-1-yl7-C7a2iamidoj · heptanoate. In the following steps you get 7- ^ N -_ / 3-Bydroxycyclohexyl) -2- propyn- ^/ 1-yl7-cyanamidol-heptanoic acid (B) and 7 - {"1-Z3- (1-hydroxycyclohexyl) -2-propyn-1-yl7-ureidojheptanoic acid (C).

Example 20

Production of 7- £ i-Z3-0-Hydroxycyclohexyl) -propyl7-ureido £ heptanoic acid - _

The hydrogenation of 7- {i- / 3- (1-Hydroxycyclohexyl) -2-propyn-1-yl7-ureidqj-heptanoic acid (Example 19) over a platinum on charcoal catalyst gives 7- £ i-Z3- (1-hydroxycyclohexyl) propylZ-ureidcjb.eptanoic acid as a pale yellow oil.

Example 21

Preparation of 7-fi- / 5- (1-Hydroxycyclooctyl) -2-propyn-1- yl7-ureidoj - heptanoic acid

The synthesis of this compound is carried out as described in Example 1, but with the modification that in step A the i-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-acetoxy-1- (3-bromo-1-propynyl) -cyclooctane (Example Q) is replaced. The ^p roduct of Step A is thus ethyl-7- / B / J> - (1 -acetoxycyclooctyl) -2-propyn-1-j £ / ~ cyanamidoj-heptanoate. In the following steps 7- £ ^ - / 5-0-Hydroxycyclooctyl) -2-propyn-1-yl7-cyanami do_J-heptanoic acid (B) and Ί ~ \ 1- / 3 - (^ -Hydroxycyclooctyl) -2 -propin-1-yl7-ureido ^ -heptanoic acid (C).

Example 22

Preparation of 7- / i-Z5- (1-Hydroxycyclooctyl) -propyl7-ureido | heptanoic acid

The hydrogenation of 7- ^ 1- / 5- (1-Hydroxycyclooctyl) -2-propyne-

1-yl7-ureido i-heptanoic acid (Example 21) over a platino

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on charcoal catalyst gives 7- / 1- / 5- (1-Hydroxycyelο-octyl) -propyX7-ureido ^ -heptanoic acid.

Example 23

Preparation of methyl 7-zi- (4-hydroxynonyl) thioureidq7- heptanoate

A solution of approximately 2.5 (0.06 mol) diazomethane in 100 ml of ether is mixed with a solution of 10.3 g (0.03 mol) of 7- / 1- (4-hydroxynonyl) -thioureido7-heptanoic acid (Example 3) mixed in 50 ml of ether. The resulting solution leaves stand at room temperature for 4 hours. Then acetic acid is added to the excess diazomethane destroy, and the solution is made with dilute sodium bicarbonate solution and brine and then dried over sodium sulfate. By evaporating the volatile Substances under reduced pressure are obtained methyl 7-ΖΪ- (4-hydroxynonyl) thioureido7-heptanoate as a viscous oil.

Example, el 24

Manufacture of decyl 7- / 1- (hydroxynonyl) ureido7-heptanoate

Using the method of Example 23 one obtains by replacing the ethereal solution of the diazomethane with an ethereal solution of 1-diazodecane and instead of the 7- / ϊ- (4 ~ Hydroxynonyl) thioureido_7-heptanoic acid 7 ~ Z? - (4-Hydroxynonyl) -ureidq7-heptanoic acid used, decyl 7- / 1- (4-hydroxynonyl) ureido_7-heptanoate as a viscous oil.

Example 25

Production of N- / X2-dimethylamino) -äthyl7-7-Z ^ - (4-kyclroxy nonyl) -ureido7-heptanamide

A solution of 3 * 3 S (10 mij) 7 - /? - (4-Hydroxynonyl) -ureido7-

- 53 -

50 9 817/123 k

heptanoic acid (Example 1, Step C), 1.74 ml (12.5 mmol) Triethylamine and 18 ml of distilled water in 100 ml of acetonitrile is with 3.0 g (12.5 mmol) of N-tert-butyl-5-methylisoxazolium perchlorate treated. The resulting solution is vacuumed at 20-25 ° G over the course of 4 hours evaporated to give a sticky residue, which was triturated with 150 ml of water for 15 minutes at 0 to 5 ° C will. After decanting the aqueous phase, the oily residue is in a 1: 1 mixture of benzene and Ether (200 ml) dissolved. The organic extract is dried over sodium sulfate and then concentrated in vacuo. Man get the desired "active ester".

A solution of 0.88 g (10 mmol) of 2-dimethylaminoethylamine in 25 ml of acetonitrile is added to a solution of the "active" ester "in acetonitrile (25 ml), and the solution is stirred at 25 ° C. for 17 hours solvent is removed in vacuo, and distributes the residual oil partitioned between 200 ml ether and 200 ml of water. the ethereal layer ^is> with 5% * hydrochloric acid (2 χ 50 mL). the aqueous phase is basified with aqueous sodium carbonate and then with The ether extract is washed with 100 ml of brine, dried over sodium sulfate and evaporated in vacuo viscous oil back.

Example 26 Preparation of 7- / i- (4-hydroxynonyl) -ureido7-heptanamide

Using the method of Example 25, but using an acetonitrile solution of ammonia instead of the acetonitrile solution of 2-dimethylaminoethylamine, 7- / ^; 1- (4-hydroxynonyl) ureido7-heptanamide.

509817/1234

2 A 49 272

Example 1 27

Production of 7- / i- (4 ~ acetoxynonyl) -ureido7-heptanoic acid

A mixture of 9.9 g (0.03 mol) 7- / i- (4 ~ hydroxynonyl) -ureido / -heptanoic acid (Example 1, Step C) and 6.1 g (0.06 mol) of acetic anhydride is added for 18 hours 60 ° C heated. The mixture is cooled and taken up in 80 ml of ethyl ether. The solution comes with an ice cold one Extracted solution of 8 g of sodium hydroxide in 150 ml of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The oil that separates is extracted with ether, washed with water and dried over sodium sulfate. The ether is evaporated and the oily residue by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent cleaned. 7 ~ ΖΪ- (4 ~ acetoxynonyl) -ureidg7-heptanoic acid is thus obtained as yellow oil.

If, instead of the acetic anhydride used in Example 27, an equivalent amount of propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride or pivalic anhydride is used and the reaction is carried out as described in Example 27, one obtains ^ - / Λ - (4 ~ propionyloxynonyl ) -ureido7-heptanoic acid ,! - {Λ- (4-butyryloxynonyl) -ureido_7-heptanoic acid, 7-ZTI "~ (4" -Isobutyryloxynonyl) -ureido7-heptanoic acid, 7- / 1 - (^ - valeryloxynonyl) -ureido7- heptanoic acid or 7-Z? - (4 ~ pi'valoyloxynonyl) -ure heptanoic acid.

Example 28 Approach of capsules

7 ~ Z? - (4-Hydroxynonyl) -ureido-7-heptanoic acid 50 g

Stearic Acid (U.S.P- Triple Press) 125-g Pluronic F-68 7.5 g

Corn starch 125 6

- 55 -5 09 8 17/123 k

The stearic acid and Pluronic are combined in a vessel and melted using a water bath at 60 to 65 ° C. The heating is discontinued and the 7- / 3 - (4-hydroxynonyl) ureido / heptanoic acid is dispersed into the mixture and the corn starch is added with stirring. Stirring is continued until the mixture has cooled to ambient temperature. The mixture is crushed to grain size by sieving and placed in a hard gelatin capsule No. 0, which contains 307.5 mg of total solids and 50 mg of? - / Ά- (ΐ \ - hydroxynonyl) -ureido7-heptanoic acid per capsule.

Example 29

Multiple dose solution approach for intramuscular and intravenous, parenteral use

7-Z? - (4-Hydroxynonyl) -thioreido7 ~

heptanoic acid 1 g

Tris (hydroxymethyl) amino q.s. for setting methane of the solution to one

(analytically pure, Tham) pH value of 7 ^

Sodium Chloride (U.S.P.) q.s. for extraction

an isotonic solution

Methyl paraben 10 mg

Propyl paraben 1 mg

Distilled water (pyrogen-free) q.s. up to 10 ml

^{The 7 - /? - (z} * - hydroxynonyl) -thioureido7-heptanoic acid suspended in about 6 ml of water is treated with tris (hydroxymethyl) aminomethane while stirring until the pH has reached 7.4. The methyl paraben and propyl paraben are added with stirring and sufficient sodium chloride is added to form an isotonic solution. After water has been added to bring the final volume to 10 ml, the solution is sterilized by membrane filtration and placed in an ampoule by an aseptic method. The solution contains that

- 56 -509817 / 123 / »

¹⁵⁴⁹⁵ s> 2U9272

Tham salt of 7-Z ^ - ( ^z * ~ hydroxynonyl) -thioureid _: p7-tieptanoic acid in an amount which is equivalent to 100 mg / ml of the free acid.

Example 30

Manufacture of suppositories

7- / 1- (4-Hydroxy-4-methylnonyl) ureido7-heptanoic acid 200 g

Butylated hydroxyanisole 82 mg

Butylated hydroxytoluene 82 mg ^

Ethylenediamine tetraacetic acid 163 mg

Glycerin, U.S.P. 128 g

Sodium chloride, microfine 52.5 g

Polyethylene glycol 6000 128 g

Polyethylene glycol 4000 1269 g

The polyethylene glycol 4000 and the polyethylene glycol 6000 were placed in a vessel surrounded by a water bath at the temperature necessary to keep the molten contents at 60 to 65 ° C. Butylated hydroxyanisole and butylated hydroxytoluene were added to the melt with stirring. Then the ethylenediaminetetraacetic acid and the microfine sodium chloride were added and distributed in the mixture. Then the J- £ * \ - ( ¹ I-Ry dr oxy- 4-methylnonyl) -ureido7-heptanoic acid was added and distributed in the mixture. Finally the temperature was lowered to 55 to 60 ° C. and the glycerine was added and distributed.

While maintaining the temperature from 55 to 60 ° C and with constant mixing, the melt is placed in plastic suppository hollows of a conventional cold-forming device distributed by suppositories. The suppositories produced in this way had a total content of 1.7778 g. Of which were 200 mg 7- / i- (4-Hydroxy-4-methylnonyl) -ureido7-heptanoic acid.

- 57 -509817/1234

Claims (1)

Claims Λ. Compounds of the general formula in which: R carboxy, a carboxy salt or one derived from carboxy Rest; A ethylene, trimethylene, oc-methylethylene, ß-methylethylene, α, α-dimethylethylene, ß, ß-dimethylethylene or oxymethylene; R carbamoyl or thiocarbamoyl; Z methylene, ethylene, trimethylene, tetramethylene, Vinylene or ethynylene;
ο
R is independently hydrogen or methyl; Ή? Hydrogen or lower alkanoyl; Ii is independently hydrogen or methyl; R ^ hydrogen, straight or branched chain Lower alkyl of 1 to 4 carbon atoms (for example Methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), vinyl or 2,2,2-trifluoroethyl; 5 2 S with the proviso that R and R when R ^ is lower alkyl ρ
and R stands for methyl, can be combined with one another with deduction of hydrogen to form a carbocyclic ring having 6 to 9 members and that 5 5 2 R when R ^ is lower alkyl and R is hydrogen 2 ⁷ I.
stand, with the carbon atom bearing R and OR ^ to form a carbocyclic ring with 5 to 8 members. - 58 -509817/1234 15 495 ^. 2. Connections after. Claim 1, characterized in that E carboxy, a carboxy salt with the formula: wherein Me is a pharmaceutically acceptable cation derived from a metal or an amine, or a radical derived from carboxy of the formula: -COOY, -CONR ⁶ ! ^ Or -CONHNH ₂ , means in which Y stands for alkyl with 1 to 10 carbon atoms, Ί-succinimidoethyl, 1- (pivaloyloxy) -ethyl, 2-acetamidoethyl or di-lower alkylamino-lower alkyl and E and R are each independently hydrogen, lower alkyl with 1 to 4 carbon atoms or di-lower alkylaminoalkyl mean with 4 to 7 carbon atoms. 3- compounds according to claim 2, characterized in that R carboxy or a pharmaceutically acceptable carboxy salt means. 4. Compounds according to claim 3 »characterized in that the formula: - (CH ₂ ) ₂ -R ⁵ R ² OH in which mean: R carbamoyl or thiocarbamoyl;
R is hydrogen or methyl; - 59 -509817/1234 495 ^ί0 2U9272 A ethylene, trimethylene, α-methylethylene, ß-methylethylene, α, α-dimethylethylene, ß, ß-dimethylethylene or oxymethylene; Z methylene, ethylene, trimethylene or tetramethylene; R is hydrogen or methyl; and Έ? Hydrogen, lower alkyl, vinyl or 2,2,2-trifluoroethyl 5- connections according to claim 4, characterized in that that A is ethylene or oxymethylene. 6. Compounds according to claim 5i, characterized in that 2 4
that R and R are hydrogen. 7 connections according to claim 6, characterized in that that Z means ethylene. 8. Compounds according to claim 7i, characterized in that that A means ethylene. 9. Compounds according to claim 8, characterized in that R is carbamoyl. 10. A compound according to claim 9, characterized in that
that R ^ means ethyl and the compound 7-Z * l- (4 ~
Hydroxynonyl) ureido7-heptanoic acid. 11. 7- / ⁷ I - (^ - (R) -Hydroxynonyl) -ureido7-heptanoic acid after
Claim 10, characterized in that the carbon atom which carries the hydroxyl group in the
R configuration is available. 12. 7-Z ^ - (4- (S) -hydroxynonyl) -ureido7-heptanoic acid according to
Claim 10, characterized in that the carbon atom which bears the hydroxyl group is in the S configuration. - 60 509817/1234 13 · Connection according to claim 10, characterized in that the R ^ group is combined with that carbon atom ρ
which carries the R and OH substituents and that the compound is 7- {l- / T-hydroxycyclohexyl) propyl.7-ureidojheptanoic acid. 14. A compound according to claim 9 »characterized in that E ^ means 2,2,2-trifluoroethyl. 15 · Connection according to claim 9 »characterized in that R ^ means isobutyl. 16. A compound according to claim 9 »characterized in that R- ^ means vinyl. 17 · Connection according to claim 8, characterized in that 1
R is thiocarbamoyl. 18. 7 ~ ^Z;: '- (^ ~ hydroxynonyl) -thioureido7-l ^{ai ie} P't isäure characterized according to claim 17 "that R · ⁷ signifies ethyl. 19 · Compound according to claim 17 »characterized in that R ^{y is} isopropyl. 20. A compound according to claim 17 »characterized in that R ^ means η-butyl. 21. A compound according to claim 7 »characterized in that that A means oxymethylene. 22. 4 - ^ - (4-Hydroxynonyl) -ureidc_7-butoxyacetic acid according to. Claim 21, characterized in that R is carbamoyl and R ^ are ethyl. 23. 4- / n- (4-Hydroxynonyl) -thioureido-7-butoxyacetic acid - 61 -509817 / 123A according to claim 21, characterized in that R is thiocarbamoyl and R ^ is ethyl. 24. A compound according to claim 5 »characterized in that 2 4 that R is methyl and R is hydrogen. 25 · 7-ΖΪ - (^ - Hydroxy-4-methylnonyl) -ureido / -heptanoic acid according to claim 24, characterized in that Z is ethylene, R is carbamoyl, A is ethylene and R ^ is ethyl. 26. 7-Z ⁷ I- (4-hydroxynonyl) -ureido7-2,2-dimethylheptanoic acid according to claim 7i, characterized in that A α, α- 1 5 ·· Dimethylethylene, R carbamoyl and R ^ mean ethyl. 27 · 7 ~ Zi- (4-hydroxynonyl) -ureido7-2-methylheptanoic acid Claim 7> characterized in that A α-methyl 1 5 ·· ethylene, R carbamoyl and R ^ mean ethyl. 28 7 ~ ^Z:; i "- ( ^{/ t} ~ hydroxynonyl) -ureidg7-3-methylheptanoic acid according to claim 7» characterized in that A ß-methyl 1 5 ·· ethylene, R carbamoyl and R ^ mean ethyl. 29 · 1 ~ Ü) - (4-Hydroxynonyl) -ureido7-3,3-dimethylheptanoic acid according to claim 7? characterized in that A 1 5 ·· ß, ß-dimethylethylene, R carbamoyl and R ^ mean ethyl. 30. A compound according to claim 5, characterized in that p 4 R is hydrogen and R is methyl. 31. Compounds according to claim 3i, characterized in that that they have the formula R ¹ -N- (CH ₂ ) ^ - A-COOH CH ₂ -ZCC (R ⁴ ) ₂ (CH ₂ ) ₂ R ⁵ H OH - 62 509817/1234 2U9272 in which mean:
Z vinylene or ethynylene;
R carbamoyl or thiocarbamoyl; A ethylene, trimethylene, a-methylethylene, ß-methylethylene, α, α-dimethylethylene, ß, ß-dimethylethylene or oxymethylene;
4th
R is hydrogen or methyl; and Rp is hydrogen or straight-chain or branched lower alkyl having 1 to 4 carbon atoms, vinyl or 2,2,2-trifluoroethyl; and R ^ can be combined with the carbon atoms bearing H and OH to form a carbocyclic ring with 5 to 8 members. 32. Connections according to claim 31 »characterized in that that A means ethylene. 33 · Connections according to claim 32, characterized in that 4th
that R is hydrogen. 34. Compounds according to claim 33, characterized in that that Z means vinylene. 35 · Compounds according to claim 34, characterized in that R is carbamoyl and R ^ is ethyl. 36. Compounds according to claim 34, characterized in that R is thiocarbamoyl and R ^ is ethyl. 37 · Compounds according to claim 33 »characterized in that Z denotes ethynylene. 38. Compounds according to claim 37 »characterized in that R is carbamoyl and R ^ is ethyl. 39 · Connections according to claim 37 »characterized in that that R is thiocarbamoyl and R ^ is ethyl. - 63 5098 17/1234 40. Compounds according to claim 37 »characterized in that /] C _1- that R carbamoyl and R ^ mean ethyl, where the R group is combined with that carbon which carries the H and OH substituents. 41. Compounds according to claim 37 »characterized in that R is carbamoyl and R ^ butyl, where the R group is combined with that carbon which carries the H and OH substituents. 42. Process for preparing compounds of the formula -CN- (CH ₂ ) ^ - A-COOH ( ⁴ ) ( CH ₂ -ZCC (R ⁴ ) ₂ (CH ₂ ) ₂ R OH in which: A ethylene, trimethylene, oc-methylethylene, ß-methylethylene, α, α-dimethylethylene, ß, ß-dimethylethylene or oxymethylene; Z methylene, ethylene, tri- 2 methylene, tetramethylene, vinylene or ethynylene; R ₀ 4 5 and R is independently hydrogen or methyl; and R ^ Hydrogen, lower alkyl, vinyl or 2,2,2-trifluoro 5 2 5 ethyl; with the proviso that R and R-, if R ^y for Lower alkyl and R are methyl, with one another Withdrawal of hydrogen to form a carbocyclic ring with 6 to 9 members can be combined cc ρ and that R ^ when R ^ is lower alkyl and R is hydrogen stand, with that carbon atom which carries R and OH, with the formation of a carbocyclic Rings with 5 to 8 members can be combined, characterized in that a compound of the formula NC-N- ΈΓ- OH - 64 - 509817/1234 2 4 5 in which A, ~ Z, R, R and R ^ have the meanings given above have hydrolyzed in the presence of a basic catalyst. 43 · The method according to claim 42, characterized in that the basic catalyst is alkaline hydrogen peroxide. 44. Process for preparing compounds of the formula: ^ C-N- (CHok-A-COOH OH in which: A ethylene, trimethylene, cc-methylethylene, ß-methylethylene, α, α-dimethylethylene, ß, ß-dimethylethylene or oxymethylene;
Z methylene, ethylene, trimethylene, tetramethylene, vinylene or ethynylene; 4 ■ R and R are independently hydrogen or methyl; and Ή? Hydrogen, straight-chain or branched-chain lower alkyl having 1 to 4 carbon atoms (for example methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), vinyl or 2,2,2 ^ -trifluoroethyl, with 5 2 6 with the proviso that R ^ and R, when R ^ is lower alkyl and R stand for methyl, with each other under deduction » of hydrogen can be combined to form a carbocyclic ring with 6 to 9 members 5 5 2 and that R when R- 'is lower alkyl and R is Are hydrogen, with the carbon atom 2 5 the R and OR ^ carries, forming a carbocyclic Ring with 5 to 8 links can, characterized in that a compound of the formula: - 65 509817/1234 15 4-95 _tgL CCH ₂ ) _Λ -Α-ΟΟΟΗ CH _O -ZCC (R ⁴ ) _O (CH _O ) _O R ^{5 2} «A, 2 2 2 eh, 2 4 5 in which A, Z, R, R and R ^ have the meanings given above have, with a thiolaliphatic acid having 1 to 5 carbon atoms in the presence of a free Reacts radical-generating initiator catalyst and then with a basic hydrolyzing agent treated. 45 · The method according to claim 44, characterized in that that the thiolaliphatic acid and thiolacetic acid the catalyst is UV light. 46. Process for preparing compounds of the formula R ¹ -N- (CH ₂ ) ₄ -A-C00H CH ₀ -ZCC (R ⁴ ) _o (CH ₀ ^ R ⁵ in which mean: R ^ lower alkanoyl with 1 to 5 carbon atoms, R carbamoyl or thiocarbamoyl; Z methylene, ethylene, trimethylene, tetramethylene, vinylene or ithynylene; R is hydrogen or methyl; A ethylene, Trimethylene, cc-methylethylene, ß-methylethylene, α, α-dimethylethylene, ß, ß-dimethylethylene or oxymethylene; 4 5 R is hydrogen or methyl; and R- ^ hydrogen, lower alkyl, Vinyl or 2,2,2-trifluoroethyl with the proviso, 5 2 5 2 that R ^ and R when R ^ is lower alkyl and R is Are methyl, can be united to form a carbocyclic ring with 6 to 9 members and that 5 2 5 2 R ^ and R, when R ^ stand for lower alklyl and R for hydrogen, can be combined to form a carbocyclic ring with 5 to 8 members, characterized in that a compound of the formula - 66 509817/1234 R ¹ -N- (CH ₂ ) ₄ -A-C00H
( ⁴ ) ( ₂ / \ ² ir oh 1 2 4 5
in which R, A, Z, R, R and R ^{y have} the meanings given above, with an acylating agent of the following structure: (R ⁵ -CO) ₂ O,
in which R ^ has the meaning given above, treated. 47 * means containing a compound according to claim 1 in a non-toxic, pharmaceutically-acceptable Carrier. 48. Composition according to claim 47, which is suitable for oral administration in tablet form is suitable. 49. Composition according to claim 47, which is suitable for oral administration in capsule form is suitable. 50. Composition according to claim 47, which is suitable for the parenteral Administration is suitable. 51. Composition according to claim 47, which is suitable for use suitable in suppository form. 509817/1234