DE2855931A1 - SUBSTITUTED 1,4-CYCLOHEXADIENCARBONESE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS - Google Patents

Description

AO-

our no. 22 241 P / S

Merrell Toraude et Compagnie Strasbourg, France

Substituted l ^ -Cyclohexadiencarbonsäurederivate, process for their preparation and pharmaceuticals

The present invention relates to the subject matter defined in the claims.

The substituted! ^ - Cyclohexadiencarbonsäuren and their Derivatives have valuable pharmacological properties.

Various previous studies have shown that gamma-aminobutyric acid is a major transmitter of the central nervous system Cvgl. Physiological Reviews, Volume 54, pp. 418-5 ^ 0 (197 ¹ I) J and that a disturbance of the interplay between excitation and inhibition leads to disease states such as Huntington's chorea (The Lancet, November 9, 1974, p. 1122- 1132), parkinsonism, schizophrenia, epilepsy, depression, hyperkinesis and manic depression. . can lead Cvgl. Biochem. Pharmacol., Vol. 23 »pp. 2637-2649 (1974) 3. Various compounds are known to increase brain levels of gamma-aminobutyric acid, such as n-dipropyl acetate Cvgl. Biochem. Pharm., Volume 22, p. 1701 (1973) 3 by competitive inhibition of gamma-aminobutyric acid transaminase, which leads to a reversible effect that lasts only about 2 hours. It is also known that 4-aminotetroleic acid Cvgl. J. Neurochem., Vol. 19, p. 1849 (1972) 3 is a competitive, reversible inhibitor of gamma-aminobutyric acid transaminase.

In the US-PS _- ^ n 2,959,356 and 3,960,927 are disclosed acetylene or olefin derivatives of amino acids that are irreversible inhibitors of gamma-aminobutyric acid transaminase.

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The natural substance Gabaculin CS-Amino-l ^ -cyclohexadiene-l-carboxylic acid is known to be a selective irreversible inhibitor of gamma-aminobutyric acid transaniinase in vitro and in vivo Cf. Tetrahedron Letters 1976, p. 537 "Biochem. Biophys. Res. Comm., Vol. 76, p. 1276 (1977); J · Am. Chem. Soc, Volume 98, P. 6762, (1976); PEBS. Lett., Vol. 76, p. 207, (1977); and Neuroscience Lett., Vol. 4, p. 51 (1977) 3 »where Gabaeulin acts as a substrate for the transaminase. As a result, gabaculin avoids the depletion of primordial aminobutyric acid, which has been linked to diseases of the central nervous system such as parkinsonism and epilepsy.

It has now been found that the compounds according to the invention Irreversible inhibitors of gamma-aminobutyric acid transaminase are and are more effective than gabaculin and certain other known irreversible inhibitors of gamm-aminobutyric acid transamimase have what the compounds according to the invention for the treatment of the aforementioned disease states makes particularly suitable.

The compounds of the invention are those of the general formula I.

COR ₂ j

NHR

wherein R. is a hydrogen atom, an alkylcarbonyl group in which the alkyl radical ^{comprises 1 to 1} l carbon atoms and is straight or branched, an alkoxycarbonyl group in which the alkoxy radical comprises 1 to M carbon atoms and is straight or branched, or the radical 0

-C-CHNH ₀ I ²

^R 3 denotes in which R, a hydrogen atom, a straight or twisted chain C ₁ -C 4 -alkyl group, the benzyl or p- hydroxybeneyl group ;

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and R ₂ denotes the hydroxy, a straight or branched chain ^ - to Cg -alkoxy group, a group -NRj ₄ R ₅₁ in which R ^ and R ₅ each represent a hydrogen atom or a straight or branched chain C ₁ - to Ch-alkyl group, or the rest

-NH-CH-COOH I.

0 _e

represents in which Rg is a hydrogen atom, a straight or branched chain C ₁ - to C ^ -alkyl group, the benzyl or p-hydroxybenzyl group. The pharmaceutically usable salts of the compounds of the general formula I also fall under the invention.

Typical examples of straight chain lower alkyl groups with 1 to 4 carbon atoms are the methyl, ethyl, n-propyl and n-butyl groups; and for branched chain lower alkyl groups with 1 to 4 carbon atoms the isopropyl, isobutyl and tert-butyl groups.

Typical examples of straight-chain alkoxy groups with 1 to 4 carbon atoms are the methoxy, xthoxy, n-propoxy and n-butoxy group, and for branched-chain alkoxy groups having 1 to 4 carbon atoms, the isopropoxy, isbutoxy and tert-butoxy groups.

Typical examples of straight and branched chain alkoxy groups with 1 to 8 carbon atoms are methoxy, ethoxy, n-propoxy, isoprop'xy, n-butoxy, tert-butoxy,

Neopentoxy, pentoxy, octyloxy, heptyloxy and hexyloxy groups.

Typical examples of pharmaceutically acceptable salts of the invention Compounds are the non-toxic acid addition salts, which with inorganic acids, such as hydrogen chloride, Hydrobromic, sulfuric and phosphoric acid and organic acids are formed, such as trifluoroacetic acid, Methanesulfonic acid, salicylic acid, maleic acid, malonic acid, tartaric acid, Citric acid and ascorbic acid, as well as the non-toxic salts, which are formed with inorganic and organic bases will,

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such as those of alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium and magnesium, light metals of group HT A such as aluminum, organic Amines, such as primary, secondary or tertiary amines, for example cyclohexylamine, ethylamine, pyridine, methylaminoethanol, Ethanolamine and piperidine .. The salts of the compounds according to the invention are prepared by conventional methods. Examples of compounds according to the invention are as follows:

3-amino-l, 4-cyclohexadiene-carboxylic acid,

Methyl or ethyl S-amino-l ^ -cyclohexadiene carboxylate, N-methyl-3-amino-1,4-cyclohexadiene-carboxamide, Nrethyl-3-amino-1,4-cyclohexadiene-carboxamide,.

N-propyl-3 * -amino-l, ¹ l -cyclohexadiene-carboxamide, N, N-di-n-butyl-3-amino-l, 4-cyclohexadiene-carboxamide, methyl-3- (tert-butoxycarbonylamino ) -l, 4-cyclohexadiene-carboxylate, 3-amino-l, 4-cyclohexadiene-carboxamide,

N- (3-Amino-1,4-cyclohexadienyl) carbonylalanine, 3-acetamido-1,4-cyclohexadiene-carboxylic acid and 3-Alanylamino-1,4-cyclohexadiene-carboxylic acid.

Preferred compounds according to the invention are those in which R ^ is a hydrogen atom or an alkylcarbonyl group. Another preferred embodiment of the invention are compounds in which Rp denotes the hydroxy or a straight branched-chain alkoxy group. The most preferred compounds according to the invention are those in which R _{1 is} a hydrogen atom and Rp is the hydroxyl group, as well as their salts.

The compounds according to the invention have the most varied pharmacological usefulness. So they can be used as sedatives. The compounds of general formula I and their Pharmaceutically acceptable salts are used as inhibitors of gamma-aminobutyric acid transaminase useful, which leads to an increase in the brain level of gamma-aminobutyric acid, whereby these compounds for the treatment of puncture disorders of the central nervous system become useful in involuntary

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Movements persist, such as those seen in Huntington's disease Chorea, - Parkinsonism, tai extrapyramidal effects of Medicines such as neuroleptics, seizures that occur in epilepsy, alcohol and barbiturate withdrawal, psychoses, which occur in schizophrenia, depression and manic depression and hyperkinesis, .. ■ The invention "Compounds are also used as hypothermic agents, myorelaxants, cholinergic agents, antibacterial agents, anti-seizure agents, Analgesics, anorexigenic drugs, anti-obesity drugs, tranquillizers, Sedatives and central nervous system stimulants are valuable.

The sedative properties of the compounds of the invention can be determined by measuring the spontaneous motor activity of rodents according to the method of P. Dews, Brit. J. Pharmacol., Volume 8, p. Ηβ (1953) after administration of the compound to be tested by the intravenous, intraperitoneal or oral route to mice or rats.

The ability of the compounds of general formula I to inhibit gamma-aminobutyric acid transaminase can be determined by measurements the gamma-aminobutyric acid transaminase activity can be determined in vitro or in vivo. For example, can measured gamma-aminobutyric acid levels in the brains of mice and rats after treatment with the compound to be tested will. The effectiveness of the inhibition of gamma-aminobutyric acid transaminase of the compounds of formula I can also be used by the protective effect of the treatment of audiogenic seizures can be detected in mice of the strain DBA, using the method described by Simler et al., Biochem. Pharmacol., Vol. 22, pp. 17OI (1973) described method measures j which is currently used as evidence of an anti-epileptic effect.

The capabilities of the compounds of general formula I, a Relieving reserpirrcosis can be demonstrated by the classical test of B. Rubin et al., J. Pharmacol., Volume 120, p. 125 (1957) currently used to determine antidepressant effectiveness. As mentioned above

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has been demonstrated that the compounds of the invention Which one offer certain advantages over gabaculin is a known inhibitor of gamma-aminobutyric acid transamihase, insofar as the compounds according to the invention are more effective inhibitors of the enzyme. The compounds of the invention also contain unconjugated double bonds and, as a result, it is would be expected to be less likely to complex with macromolecules such as DNA or RNA. You are particular effective in reducing gamma-aminobutyric acid transaminase activity and the increase in gamma-aminobutyric acid levels in the brain.

The compounds according to the invention can be administered to the patient to be treated in various ways in order to achieve the desired effect. The compounds can be administered alone or in the form of a pharmaceutical preparation orally, parenterally, such as, for example, intravenously, intraperitoneally, subcutaneously or topically. The amount to be administered will vary widely and it can be any effective amount. Depending on the patient to be treated, the condition to be treated and the route of administration, the effective amount of the compound to be administered varies from about 0.1 to 150 mg / kg of patient body weight per dosage unit; preferably it is about 10 to about 100 mg / kg of body weight of the patient per dosage unit. For example, a typical dosage unit form is a tablet containing 10 to 200 mg of a compound of the formula I, which can be administered to the patient 1 to k times daily.

In the present, the term "patient" is understood to mean a warm-blooded animal, such as mammals such as cats, dogs, rats, mice, Guinea pigs, horses, cattle and sheep.

The solid unit dosage forms can be of conventional nature be. Thus the solid form can be a capsule, for example an ordinary gelatin capsule containing one according to the invention Compound and on a carrier such as a lubricant and inert fillers such as lactose, sucrose and corn starch,

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In another embodiment, the compound according to the invention with conventional tablet bases such as lactose, sucrose or corn starch, in combination with binders such as acacia gum, corn starch or gelatin, tablet _{disintegrants} such as corn starch, potato starch or alginic acid, and a lubricant such as stearic acid or Magnesium stearate, in tablets.

For parenteral administration of the compounds, they can be used as injectable dosages of a solution or suspension of the compound in a physiologically acceptable excipient, with a pharmaceutical carrier which is sterile Liquid such as water and oil, with or without the addition of a surfactant or others pharmaceutically acceptable auxiliaries. Examples of oils, which can be used in these preparations are those of petroleum, or those of animal, vegetable or synthetic origin, such as peanut oil, soybean oil and mineral oil. For injectable solutions in particular, preferred liquid carriers are usually water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol.

The compounds can be in the form of a depot injection or a Implant are administered, which can be formulated so that they allow a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and subcutaneously or intramuscularly as depot injections or Implants are implanted. Inert materials such as polymers that are degradable in the organism or synthetic materials can be used for implants Use silicones.

Examples of pharmaceutical preparations containing a compound according to the invention are given below.

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- V! - 2855931 Per tablet a) 3-Amino-l, ^ - cyclohexadiene-carboxylic acid 20.0 mg b) wheat starch 95.0 mg c) lactose 3I>, 5 mg d) magnesium stearate 1.5 mg

Part of the wheat starch is used to make a granulated starch paste, which together with the rest of the Wheat starch and the lactose are granulated, sieved and mixed with the active ingredient (a) and the magnesium stearate. The mixture is compressed into tablets weighing 150 mg each.

An example of a composition for parenteral injection is the following, with quantities given on a weight-to-volume basis:

lot

a) 3-AmInO-I ₉ ^ -cyclohexadienecarboxylic acid 50.0 mg

b) sodium chloride q.s.

c) water for injection ad 20.0 ml

The composition is prepared by adding the active ingredient (a) and a sufficient amount of sodium chloride in water Injection dissolves to make the solution isotonic. The composition can be contained in a single ampoule of 50 mg of the active ingredient for multiple dosing or in 20 ampoules for single doses.

An exemplary composition for hard gelatin capsules is as follows:

lot

a) 3-Amino-l, ^ - cyclohexadienecarboxylic acid 100.0 mg

b) Talc 35.0 mg

The composition is prepared by forcing the dry powders of (a) and (b) through a fine mesh screen and they mixed well together. The powder is then placed in hard gelatin capsules (No. 0) with a net filling weight of 135 mg per capsule.

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The process for the preparation of the compounds of the general formula I in which R _{1 is} a hydrogen atom and Rp is the hydroxyl group is shown by the schematic diagram below:

COR

: oR

COR

NHCO ₂ CH ₂ Ar

NHCO ₂ CH ₂ Ar

COOH

NHC0 ₂ t - Bu. (8th) -

Formula. J, R ₁ = H ^ R ₂ = OH

In the above schematic representation R is a straight- or branched-chain C ₁ - to Cg-alkoxy, benzyloxy, p-methoxybenzyloxy or 2, ¹ l ~ Dimethoxyben2yloxygruppe; Ar is the phenyl or p-methoxyphehyl group; HA means a mineral acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid; and t.-Bu. means the tertiary butyl group. Examples of straight or branched C ₁ - to Cg -alkoxy groups which R can represent are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxyunä n -Hexylc doll.

The M-phenylsulfinyl-Z-cyclohexenecarboxylic acid ester, the compound (1), is treated with silver anate in the presence of solid iodine in a solvent such as methylene chloride, chloroform, Carbon tetrachloride, tetrahydrofuran or diethyl ether about -10 to 25 ° C about 3 to 24 hours with formation of the 2-iodo-3-isocyano-4-phenylsulfinylcarboxylic acid ester, the compound (2)> reacted which with benzyl alcohol or p-methoxybenzyl alcohol with stirring for about 6 to 18 hours, optionally

in the presence of a catalyst such as diisobutyltin dilaurate or benzyloxylithium or p-methoxybenzyloxylithium, the compound (3) * is added. The carbamate / is with one equivalent of a hindered base, such as triethylamine, diazabicyclooctane, diazabicyclonones or diazabicycloundecene, in a solvent such as acetone, ether, tetrahydrofuran, methylene chloride, chloroform or dioxane ^ at about 25 ° C for about 1 to 4 hours formation of dehydroiodierten derivative of compound (4) treated, which latter ¹ at about 60 to l40 ° C for about 0.5 to 24 hours in a solvent such as a chlorinated hydrocarbon, such as carbon tetrachloride>. or. "an aromatic hydrocarbon, such as xylene or toluene, is heated to form the 1,4-diene derivative, the compound (5). The diene derivative is mixed with excess acid, such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid, the latter being preferred treated in excess anisole or 1,3-dimethoxybenzene to obtain the acid addition salt (6).

If the substituent R in the acid addition salt is other than the tert-butoxy, benzyloxy, p-methoxybenzyloxy or 2,4-dimethoxybenzyloxy group, the acid addition salt or the 3-amino-1,5-cyclbhexadiene carboxylic acid ester salt is the compound (6 ), with 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile '". ■■ -.""".··' ^: * - · '^; \ '. ^: · - "'.'"""'.'. / '- ·, .. or tert- Btitylazidoformiat in the presence of a base, such as an alkylamine such as triethylamine, sodium hydroxide or potassium hydroxide in a solvent such an ether such as diethyl ether, tetrahydrofuran or dioxane, dimethylformamide, a chlorinated hydrocarbon such as methylene chloride or chloroform, at about

with the formation of benzyl or p-methoxybenzyl carbamate,

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25 ° C reacted for about 1 to 24 hours, after which an alkaline hydrolysis and then an acid hydrolysis and, if the free base is desired, a treatment with a base is carried out according to known methods. An alkaline hydrolysis can for example durch.Behandlung with sodium hydroxide or potassium hydroxide for about 1 to 3 hours at about 25 ° C, or with trimethylsilyl iodide in carbon tetrachloride or chloroform at about 25 to 50 ⁰ C for about 4 reaches to 40 hours, wherein the Carbamatsäure, Compound (8) is obtained. The acid hydrolysis of the carbamate acid can be achieved, for example, by treating a lower alcohol with hydrochloric acid, hydrobromic acid or trifluoroacetic acid as a solvent for about 1 to 20 hours at a temperature up to the reflux temperature. , Benzyloxy, p-methoxybenzyloxy or 2,4-dimethoxybenzyloxy group, this derivative can be treated with trifluoroacetic acid in the presence of anisole "and then applied directly to an ion exchange resin, the ^" amino-ljJl-cyclohexadienecarboxylic acid derivative of the formula I being obtained .

For the preparation of the ^ -phenylsulfinyl-2-cyclohexenecarboxylic acid ester, i.e. of the compounds (1), the corresponding esters of 2-trimethylsilyloxy-3-cyclohexenecarboxylic acid are prepared by one trimethylsilyloxybutadiene with a corresponding acrylate according to the in Bull. Soc. Chim. Pr. 1972, p. 1658 reacted, after which the ether is split, for example by treatment with 2 M hydrogen chloride in methanol for example 1 to 10 minutes at about 25 ° C or by treatment with a dilute base such as 0.5 / ft sodium hydroxide in aqueous Methanol (1: 1) for 5 to 10 minutes at about 25 ° C. The thus obtained hydroxy ester is then with benzenesulfenyl chloride in Treated in the presence of a base such as triethylamine in methylene chloride to give the 4-phenylsulfinyl derivative. Other hindered amine bases such as diazabicyclooctane, diazabicyclonones, or diazabicycloundecene can also be used as well as other suitable solvents such as chloroform, ether, tetrahydrofuran and benzene. The response time can range from about 5 minutes to 1 hour while the temperature is about 0-25 ° C.

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The hydroxy ester can, however, also be converted into the corresponding sodium alkoxide by treatment with sodium hydride in ether or tetrahydrofuran, after which it is reacted with benzenesulfenyl chloride, as described above. The compound ^€ * OCE general formula I wherein R ₂ is a straight- or branched-chain C ^ - to CQ-alkoxy group, can be prepared from the corresponding derivatives in which R ₂ is the hydroxyl group by reaction with an alcohol of the formula R ₇ OH at about 25 ° C for 12 to 36 hours, where R _{7 is} a straight or branched C ^ - to Co-alkyl group, such as methyl, ethyl, n-propyl, isopropyl, η-butyl -, tert-butyl, n-pentyl, neopentyl or n-hexyl group, and wherein the alcohol is saturated with gaseous hydrogen chloride.

The compounds of the ■ general formula I in which R denotes the group -NRjjR ^, in which R ₁ , and R, - each _{denote a hydrogen atom or a C 1} - to Cn-alkyl group, are prepared by a functional derivative of the corresponding compound in which R _{0 is} the hydroxyl group, for example the acid halide, such as the acid chloride, or an acid anhydride, and R _{1 has} the meaning, with an excess of an amine of the general formula HNR ^ R ₅ , wherein R ₁ J and R _{5 have} the meanings given above, each free amino group being suitably protected. The reaction is carried out in a solvent such as methylene chloride, chloroform, dimethylformamide, or in ethers such as tetrahydrofuran and dioxane, or in benzene at about 25 ° C. for about 1 to k hours. Suitable amines are ammonia or a compound which is a possible source of ammonia, such as, for example, hexamethylenetetramine; primary amines, for example methylamine, ethylamine or n-propylamine; and secondary amines such as dimethylamine, diethylamine or di-n-butylamine. After the reaction, the amino protective groups are treated with an acid, such as. B. trifluoroacetic acid or hydrobromic acid in dioxane removed.

The compounds of general formula I in which R _{9 is} the group -NH-CH-COOH, in which Rg is a hydrogen atom, a degree or

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branched-chain C ₁ - to C ^ -alkyl group, which is benzyl or p-hydroxybenzyl group, are obtained by reacting an acid anhydride of the corresponding derivative in which Rp is the hydroxy group, and R. is as defined in connection with formula I. has (with the proviso that each free amino group is protected with a suitable protecting group, such as the benzyloxycarbonyl or tert-butoxycarbonyl group) with a compound of the formula NH-CH-COORn _s where Rg is the aforementioned

Has meaning, and Rg is a lower alkyl group, such as the methyl or ethyl group, in an ether solvent such as tetrahydrofuran or dioxane, in the presence of a base such as triethylamine, at about 0 to 50 ⁰ C for about 1 to 2 * »Hours obtained, after which an acid hydrolysis, for example with trifluoroacetic acid or hydrogen bromide in dioxane, and a basic hydrolysis using, for example, sodium hydroxide or sodium borate at a temperature of about 0 to 25 ° C for about 0.5 to 6 hours is carried out.

The compounds of the general formula I in which R ₁ denotes an alkylcarbonyl group, in which the alkyl radical comprises 1 to 4 carbon atoms and is straight or branched chain, and Rp denotes the hydroxyl or an alkoxy group having 1 to 8 carbon atoms, are prepared by reacting the corresponding derivative in which R _{1 is} a hydrogen atom, with an acid halide of the general formula 0

Il

Rg-C-halo

where halo is a halogen atom, such as the chlorine or bromine atom, and Rg is a straight or branched chain C ₁ - to C ^ - alkyl group, such as methyl, ethyl, n-propyl, isopropyl, η-butyl or tert-butyl group, mean ^ or with a corresponding acid anhydride in water in the presence of a base, such as sodium hydroxide or sodium borate, or in dichloromethane in the presence of a

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Amine base, such as, for example, triethylamine, at a temperature of about 0 to 25 ° C. for about 0.5 to 2k hours.

The compounds of general formula I in which R _{1 is} an alkoxy carbonyl group in which the alkoxy radical is straight or branched and has 1 to 4 carbon atoms, are prepared by treating the corresponding derivative in which R is a lower alkoxy group, such as is the methoxy or ethoxy group, and R. is a hydrogen atom, with an alkyl haloformate of the general formula 0

Il

halo-C0R ₁₀

wherein R _{10 is} a straight or branched chain C ₁ - to C ^ -alkyl group; such as, for example, the methyl, ethyl, n-propyl, isopropyl, η-butyl or tert-butyl group; is, and halo is a halogen atom, such as the chlorine or bromine atom, in water in the presence of a base, such as sodium hydroxide or sodium borate, or in dichloromethane in the presence of an amine base, such as triethylamine, at a temperature of about 0 to 25 ° C for about 0.5 to 6 hours, after which a basic hydrolysis is carried out using, for example, sodium hydroxide or sodium borate at a temperature of about 0 to 25 ° C for about 0.5 to 6 hours.

The compounds of the general formula I in which R ₁ is group 0

-C-CHNH ₂

3 β

where R is a hydrogen atom, a straight or branched chain C ₁ - to Cjj-alkyl group, the benzyl or p-hydroxybenzyl group, are prepared by treating the corresponding derivative in which R _{2 is} a lower alkoxy group, such as egäie'M 'ethoxy or ethoxy group, and R _{1 is} a hydrogen st off atom, with an acid of the general formula HOOC-CH-CH ₂

or an anhydride thereof, wherein the amino group with a suitable protecting group, such as the benzyloxycarbonyl or tert-butoxycarbonyl group, and R, the aforesaid Has meaning in an ether

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such as tetrahydrofuran or dioxane, or a chlorinated hydrocarbon such as methylene chloride or chloroform, and, if the free acid is used, in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, at a temperature of about 0 to 35 ⁰ C for about 1 to 22 hours, after which a basic hydrolysis using, for example, sodium hydroxide or sodium borate and an acidic hydrolysis using, for example, trifluoroacetic acid or HBr / dioxane at a temperature of about 0 to 25 ° C. is carried out for about 0.5 to 6 hours. The following examples serve to explain the invention in more detail.

example 1 3-Amino-l, ^ - cyclohexadienecarboxylic acid

A solution of 2 g (10 mmol) of methyl 2-trimethylsilyloxy-2-cyclohexenecarboxylate in 10 ml of methanol was treated with 1N hydrochloric acid for 1 hour at 25 ° C. and then under reduced pressure concentrated and extracted with ether. The organic solution was dried over magnesium sulfate and concentrated. The residue obtained was dissolved in 20 ml of dichloromethane and treated with 1.0 g (10 mmol) Triethylamine and then treated with 1.44 g (10 mmol) of phenylsulfinyl chloride. After one hour at 25 ° C, the solution was with Washed with water, dried and concentrated, 4-phenylsulfinyl-2-cyclohexenecarboxylic acid methyl ester was obtained.

2.6 g (10 mmol) of this methyl ester in 20 ml of dichloromethane were ^{mixed with 2 g (13 mmol) of silver cyanate at 0} ° C. and then with 2.5 g (10 mmol) of iodine in small portions. The mixture was ^{stirred at 0} ° C. for 1 hour and at 25 ° C. for 4 hours and then filtered through Celite. The solution was concentrated, after which 1.4 g (10 mmol) of p-methoxybenzyl alcohol was added. The mixture was stirred for about 16 hours at 25 ° C, after which 50 ml of acetone and then 1.1 g (10 mmol) of diazabicyclooctane were added. After 2 hours at 25 ° C the solvent was evaporated and the residue was taken up in ether and in water. The organic phase was dried and evaporated, leaving a residue which was taken up in toluene and refluxed

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ORIGINAL INSPECTED

temperature was heated for 4 hours, after which the solvent was removed under reduced pressure; the residue was Chromatographed over silica gel, wherein 3 ~ (p-Methoxybenzyloxycarbonylamino) -1, 4-cyclohexadienecarboxylic acid diethyl ester was obtained.

A solution of 640 mg (2 mmol) of this methyl ester in 5 ml of anisole was ^{treated with 5 ml of trifluoroacetic acid at 0} ° C. and the solvents were removed in vacuo to give an oily residue which was treated with ether; this formed a precipitate which was collected and consisted of methyl 3-amino-1,4-cyclohexadienecarboxylate trifluoroacetate. A solution of 500 mg (2.3 mmol) of the amine trifluoro acetate in 2 ml of dimethylformamide was treated with 300 mg (2.3 mmol) of tert-butyl azidoformate for about 16 hours at about 25 ° C., after which the solvent was removed under reduced pressure. The residue was taken up in ether and washed with water. The ether solution was dried and evaporated to give 3-tert-butoxycarbonylamino-lj ^ -cyclohexadiene carboxylate, 400 mg of which was taken up in 2 ml of methanol containing 200 mg of sodium hydroxide in 1.5 ml of water and at 25 ° C 2 Hours of stirring, after which it was acidified with 1 N HCl. The resulting precipitate was collected (200 mg) and dissolved in 4 ml of methanol. The solution was treated with 2 ml of 2N HCl at 25 ^° C. for 24 hours and then diluted with acetone, 3 ~ amino-1,4-cyclohexadiene carboxylic acid being obtained.

Example 2 Ethyl 3-amino-1,4-cyclohexadiene carboxylate hydrochloride

3-Amino-1,4-cyclohexadienecarboxylic acid hydrochloride (200 mg) was dissolved in ethanol containing anhydrous hydrogen chloride and the resulting solution was ^{stirred at 0} ° C. overnight. Evaporation of the solvent led to the ethyl 3-amino-1,4-cyclohexadiene carboxylate hydrochloride.

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ORIGINAL INSPECTED

Example 3 N-propyl-3-amino-l, ^f-t cyclohexadiencarboxamid "hydrochloride

A solution of 240 mg (1 mmol) of 3-tert-butoxycarbonylamino-1,4-cyclohexadienecarboxylic acid in 5 ml of dichloromethane was treated with 202 mg (2 mmol) of triethylamine and Sk mg (1 mmol) of methyl chloroformate. After 30 minutes at 25 ° C., the solution was treated with 60 mg (1 mmol) of n-propylamine for 1 hour at 25 ° C., after which the solution was diluted with dichloromethane, washed with water, dried and evaporated. The residue was stirred in 7 ml of methanol and 3.5 ml of a 5 # aqueous hydrochloric acid for 18 hours. Evaporation gave N-propyl-3-amino-1,4-cyclohexadiene carboxamide hydrochloride.

example k N- (3-Amino-1,4-cyclohexadienyl) carbonylalanine hydrochloride

A solution of 240 mg (1 mmol) of 3-tert-butoxycarbonylamino-1,4-cyclohexadienecarboxylic acid and 5 ml of dichloromethane was treated with 202 mg (2 mmol) of triethylamine and 94 mg (1 mmol) of methyl chloroformate. After 30 minutes at 25 ° C, the solution was treated with 103 mg (1 mmol) of alanine methyl ester and kept at 25 ° C for 1 hour, after which the solution was washed with water, dried and concentrated. The residue was treated with 3 ml of methanol and 120 mg of sodium hydroxide in 2 ml of water for 3 hours at 25 ° C. and then acidified and extracted with dichloromethane. The organic phase was dried and concentrated. The residue was treated with 7 ml of methanol containing 5 % hydrogen chloride for 18 hours at 25 ° C. Evaporation gave N- (3-amino-1,4-cyclohexadienyl) carbonylalanine hydrochloride.

Example 5 3-Acetamido-1- _> 4-cyclohexadienecarboxylic acid

A solution of 190 mg (1 mmol) of methyl 3-amino-1,4-cyclohexadiene carboxylate hydrochloride in 5 ml of dichloromethane was with 78 mg

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ORIGINAL INSPECTED

(1 mmol) acetyl chloride and 202 mg (2 mmol) triethylamine for 1 hour treated at 25 ° C, after which the solution was washed with water, dried and was narrowed. The residue was at 25 ° C. with 3 liters of methanol and 100 ml of sodium hydroxide in 200 ml of water 3 Treated hours, solidified and extracted with dichloromethane. The organic phase was dried and evaporated, whereby 3-acetamido-1,4-cyelohexadienecarboxylic acid was obtained.

Example 6 3-Alanylamino-l, ty-cyclohexadienecarboxylic acid hydrochloride

A solution of 188 mg (1 mmol) of tert-butoxycarbonylalanine in 5 ml of dichloromethane was treated with 101 mg (1 mmol) of triethylamine and 9Ί mg (1 mmol) of methyl chloroformate, and then to a solution of 190 mg (1 mmol) of methyl 3-amino-l, ⁱ l-cyclohexadiene carboxylate hydrochloride and 101 mg (1 mmol) of triethylamine in 5 ml of dichloromethane. After 1 hour at 25 ° C., the solution was washed with water, dried and evaporated. The residue was treated with 3 ml of methanol, 100 mg of sodium hydroxide and 2 ml of water at 25 ° C. for 3 hours, acidified and extracted with chloromethane. The organic phase was dried and concentrated. The residue was treated with 7 ml of methanol containing 3 »5 ml of 5% HCl for 18 hours at 25 ° C. and then concentrated to give 3-alanylamino-l, J-cyclohexadiene-carboxylic acid hydrochloride.

Example 7 N-propyl ^ -acetamido-ljty-cyclohexadiene-carboxanide

A solution of 180 mg (1 mmol) of 3-acetamido-l, ^ - cyclohexadienecarboxylic acid in 5 ml, dichloromethane was treated with 202 mg (2 mmol) triethylamine and 9 ^ 4 mg (1 mmol) methyl chloroformate. To For 30 minutes at 25 ° C, the solution was treated with 60 mg (1 mmol) of n-propylamine for 1 hour at 25 ° C, after which the solution was treated with dichloromethane was diluted, washed with water, dried and evaporated; this was N-propyl - ^ - acetamido-lj ^ -cyclohexadiencarboxamid obtain.

909829/061 3

ORIGINAL INSPECTED

-28- 28559 ^ ·

Example 8

N-propyl-3- (2-anixnopropionamido) -1, 4-cyclohexadiene carboxamide trifluoroacetate

A solution of 310 mg (1 mmol) of 3- (2-tert-ButoxycarbonylaminopropionylamidüJ-ljJt-cyclohexadiencarbonsäure in 5 ml of dichloromethane was treated with 202 mg (2 mmol) of triethylamine and 9 mg of ¹ I (1 mmol) of methyl chloroformate treated. After 30 minutes at 25 ° C., the solution was treated with 60 mg (1 mmol) of n-propylamine for 1 hour at 25 ° C., after which the solution was diluted with dichloromethane and washed with water. The organic phase was dried and concentrated to give a residue. which was treated with 2 ml of trifluoroacetic acid for 1 hour at 25 C and then diluted with anhydrous ether. The precipitated trifluoroacetate was filtered off, whereby N-propyl-3- (2-aminopropionamido) -l, ⁱ l-cyclohexadiene carboxamide trifluoroacetate was obtained.

Example 9 N- (2-propionic acid) -3-acetamido-l _a 4-cyclohexadiencarboxamid

A solution of 180 mg (1 mmol) of 3-acetamido-l, ^1-i cyciohexadiencarbonsäure in 5 ml of dichloromethane was treated with 202 mg (2 mmol) of triethylamine and 9h mg (1 mmol) of methyl chloroformate. After 35 minutes at 25 ° C, the solution was treated with 103 mg (1 mmol) of alanine methyl ester and kept at 25 ° C for 1 hour, after which the solution was washed with water, dried and concentrated. The residue obtained was treated in 3 ml of methanol and 120 mg of sodium hydroxide in 2 ml of water for 3 hours at 25 ° C., acidified and extracted with dichloromethane. The organic phase was dried and concentrated, whereby N- (2-propionic acid) -3-acetamido-lj ^ -cyclohexadiene carboxamide was obtained.

909829/0613

ORIGINAL INSPECTED

Example 10

N- (propionic acid) -3- (2-aminopropionamido) -1, 4-cyclohexadienecarboxamide trifluoroacetate

A solution of 310 mg (1 mmol) of 3- (2-tert-butoxycarbonylaminopropionylainido) -1, ^ - cyclohexadiene carboxylic acid in 5 mg dichloromethane was with 202 mg (2 mmol) triethylamine and 94 mg (1 mmol) Treated methyl chloroformate. After 30 minutes at 25 ° C., the solution was treated with 103 mg (1 mmol) of alanine methyl ester and 1 Maintained at 25 ° C. for an hour, after which the solution was washed with water, dried and concentrated. The residue obtained was kept with 3 ml of methanol and 120 mg of sodium hydroxide in 2 ml of water at 25 ° C. for 3 hours, acidified and extracted with dichloromethane. The organic phase was dried and concentrated, whereby a residue was obtained which was mixed with 2 ml of trifluoroacetic acid 1 Treated hour at 25 ° C and then diluted with anhydrous ether. The precipitated trifluoroacetate was filtered off, wherein N- (2-propionic acid) -3- (2-aminopropionamido) -1,4-cyclohexadiene carboxamide trifluoroacetate was obtained.

The present invention also includes the individual optical isomers of the general formula I. These can be derived from the racemate be prepared by using (+) or (-) binaphthylphosphoric acid. Tetrahedron Letters, Volume 48, pp. 4617-4620 (1971) and U.S. Patent 3,843,030}. Other release agents such as (+) camphor-10-sulfonic acid can also be used.

For: Merrell Toraoidfe et Compagnie Strasbourg ^ Hrarikr ^ i

M. Gehbäuör I ¹ ^

Lawyer

as an officially appointed representative

of the lawyer Dr.jur.H.J.Wolff

909829/0613 '

ORIGINAL INSPECTED

Claims (8)

Claims 1. 3 ~ amino-1,4-cyclohexadiene-carboxylic acid derivatives of the general formula COR NHR; wherein R represents a hydrogen atom, an alkylcarbonyl group in which the alkyl radical comprises 1 to 4 carbon atoms and is straight or branched chain, an alkoxycarbonyl group in which the alkoxy radical comprises 1 to 4 carbon atoms and is straight or branched chain, the group -C-CHNH ₂ wherein R, a hydrogen atom, a straight or branched chain C.- to C ^ -alkyl group, the benzyl or p-hydroxybenzyl group; and R_ is the hydroxyl group, a straight or branched chain C.- to Cg -alkoxy group, the group-NRi.R ₁ -, in which R ₁ . and R, - each represent a hydrogen atom or a straight or branched chain C.- to C ^ -alkyl group, or the group '-NH-CH-COOH
I.
R ₆ mean, in which Rg is a hydrogen atom, a degree or branched chain C.- to C ^ -alkyl group, the benzyl or is p-hydroxybenzyl group; as well as the pharmaceutically acceptable salts and the individual optical isomers thereof. 09829/0613 ORIGINAL INSPECTED 2. Compound according to claim 1, characterized in that FL denotes a hydrogen atom or an alkylcarbonyl group. 3. Compounds according to claim 1, characterized in - that ti
Rp denotes the hydroxyl group or a straight or branched chain alkoxy group. 4. 3-Amino-l, ⁱ J-cyclohexadiene-carboxylic acid, a compound according to claim 1, and its pharmaceutically acceptable salts. 5. 3-Amino-l, ^J -cyclohexadiene-carboxylic acid trifluoroacetate, a compound according to claim 4. 6. Process for the preparation of compounds according to claim 1, characterized in that one (A) for the preparation of those compounds in which R _{1 is} a hydrogen atom and R "is the hydroxyl group, en
a 'carbamate ester of the general formula COR NHCO ₂ CH ₂ Ar where R is a straight-chain or branched C.- to Cg-alkoxy group, the benzyloxy, p-methoxybenzyloxy or 2, ^ - dimethoxybenzyloxy group, and Ar is the phenyl or p-methoxyphenyl group, in excess anisole or 1,3 -Dimethoxybenzol treated with excess acid and, if R is other than trimethylsilyloxy, tert-butoxy, benzyloxy, p-methoxybenzyloxy or 2, ⁱ i-dimethoxybenzyloxy has, the thus formed 3 ~ amino-l, ⁱ J-cyclohexadiene-carbonsäureesterderivat with tert-butoxycarbonylimino-2-phenylacetonitrile or tert-butylazidoformate in the presence of a base in a suitable solvent at about 25 ° C for about 1 to 2k hours and then alkaline and then 909829/061 3 28S5931 acid hydrolysis, and, if the free base is desired, treated with a base, or, when R is the trimethylsilyloxy, tert-butoxy, benzyloxy, p-methylbenzyloxy or 2, ^J-1 Dimethoxybenzyloxygruppe, the 3 -Benzyloxycarbonylamino-1,5-cyclohexadiene-carboxylic acid ester treated with trifluoroacetic acid in anisole and then the product obtained is applied to an acidic ion exchange resin; "* (B) for the preparation of the compounds in which R _{2 is} a gray- or branched-chain C ₁ - to Cg -alkoxy group, the corresponding derivative in which R _? is the hydroxyl group, with an alcohol of the general formula R ₇ OH, wherein R _{7 is} a straight or branched C ₁ -C 6 alkoxy group, which reacts with hydrogen chloride gas at about 25 ° C for about 12 to 36 hours. (c) for the preparation of the compounds in which R_ is the group -NRi ₄ R-, an acid halide or anhydride of the corresponding derivative in which R _{2 is} the hydroxyl group and R _{1 has} the meaning given in claim 1, where each free amino group is suitably protected with an excess of an amine of the formula HNR ₁₄ R ^, wherein Rj, and R ₁ - have the meanings given in claim 1, in a suitable solvent at about 25 ° C for about 1 to k hours treated; (D) for the preparation of the compounds in which R _{2 is} the group -NH-CH-COOH, an acid anhydride of the corresponding ^R 6
related. Derivative in which R _{2 is} the hydroxy group and R _{1 has} the meaning given in claim 1, each free amino group being suitably protected, 8Q9829 / 0613 with a compound of the general formula NH _n -CH-COOR ₀
2, 8 ^R 6
wherein Rg has the meaning given in claim 1 and Rq is a lower alkyl group, reacted in a suitable solvent at about 0 to 50 C for about 1 to 2k hours and then hydrolyzed under acidic and basic conditions; (e) for the preparation of the compounds in which R _{1 is} an alkylcarbonyl group with a straight or branched-chain C ₁ - to C _{1. -alkyl radical and R n is} the hydroxyl group, the corresponding derivative in which R. is a hydrogen atom with an acid halide of the general formula 0 Il R_-C-halo where halo is a halogen atom and R "is a straight or branched-chain C ₁ - to C ₁ , -alkyl group, or a corresponding acid anhydride in water or in dichloromethane in the presence of a base at about 0 to 25 ° C for about 0.5 to 2k Converts hours; (F) for the preparation of the compounds in which R _{1 is} an alkoxy carbonyl group, in which the alkoxy radical is straight or branched chain and has 1 to k carbon atoms, the corresponding derivative in which R is a hydrogen atom and R _{2 is} a mean lower alkoxy group, with an alkyl haloformate of the general formula Il halo-C-0R ₁₀ , in which halo is a halogen atom, and R _{10 is} a straight or branched chain C ₁ - to C ₁ ^ -alkyl group, in water or in dichloromethane in the presence of a base at about 0 to 25 ° C about 0, Converts 5 to 6 hours; 909829/0613 (g) for the preparation of the compounds in which R _{1 is} the group O -C-CH-NH ,, I ^{2 R} 3 is, in which R, which has the meaning given in claim 1, the corresponding derivative in which R. is a hydrogen atom, and R _? denote a straight or branched C ₁ -to Cp-alkoxy group, with an acid of the general formula HOOC-CH-NH ₀ I ^{2 R} 3
or an anhydride thereof in which the amino group is suitably protected, and R-. has the aforementioned meaning, treated in a suitable solvent and, if the free acid is used, in the presence of a dehydrating agent at about 0 to 35 ° C for about 1 to 12 hours and then carrying out an acidic and basic hydrolysis; and (h) for the preparation of a pharmaceutically acceptable salt, the compound thus obtained with a suitable pharmaceutically converts usable acid or base. 7. Process for the preparation of compounds according to claim 1, characterized in that one (A) for the preparation of compounds in which R ^ is a hydrogen atom and R _{2 is} the hydroxyl group, a ¹ <-Phenylsulfinyl-2-cyclohexenecarboxylic acid ester of the general formula COR wherein R is a straight or branched C- to Cg-alkoxy group, the benzyloxy, p-methoxybenzyloxy or 2, ¹ I-dimethoxybenzyloxy group, 909829/0613 with silver cyanate in the presence of solid iodine in a suitable solvent at about -20 to 25 C for about 3 to 24 hours, the 2-iodo-3-isocyano-4-phenylsulfinylcyclohexanecarboxylic acid ester thus formed with benzyl alcohol or p-methoxybenzyl alcohol, optionally in the presence of a suitable catalyst, to the corresponding 3-benzyl- or 3-p-methoxybenzyl carbamate, treated this with one equivalent of a sterically hindered base in a suitable solvent for about 1 to 4 hours at about 25 ° C., the dehydroiodinated derivative thus formed at about 60 to 140 ° C heated for about 0.5 to 24 hours in a suitable solvent, the 1,4-diene derivative is obtained, this treated with excess acid in excess anisole or excess 1,3-dimethoxybenzene, and if R has a meaning other than trimethylsilyloxy -> has tert-butoxy, benzyloxy, p-methoxybenzyloxy or 2,4-dimethoxybenzyloxy, the 3-amino-1,4-cyclohexadienecarboxylic acid thus obtained terderivat with tert-butyl azidoformate in the presence of a base in a suitable solvent at about 25 ° C for about 1 to 24 hours, and then carrying out an alkaline and acidic hydrolysis, and, if the free base is desired, treated with a base, or if R is a trimethylsilyloxy- _s tert-butoxy, benzyloxy- _s p-methoxybenzyloxy or 2,4-dimethoxybenzyloxy group, treating the carbamate ester with trifluoroacetic acid and then with an acidic ion exchange resin; (b) for the preparation of compounds in which R "is a straight or branched C ^ - to Cg -alkoxy group be the corresponding derivative ₃ in which Rp is the hydroxyl group, with an alcohol of the general formula R ₇ OH, in which R ₇ a straight- or branched-chain C ₁ - to C-Alkylgpuppe means which is saturated with hydrogen chloride gas _s is reacted at about 25 ° C from about 12 to 3β hours | ■ O or tert-butoxycarbonylimino-2-phenylacetonitrile 909829/0813 • τ (c) for the preparation of the compounds in which R- is the group -NFUR, -, an acid halide or anhydride of the corresponding derivative in which Rp is the hydroxyl group and R _{1 has} the meaning given in claim 1, with the proviso, that each free amino group is suitably protected with an excess of an amine of the general formula HNR ^ R ₅ , wherein R ^ and R _{5 have} the meanings given in claim 1, in a suitable solvent at about 25 C for about 1 to 4 hours treated; (d) for the preparation of the compounds in which R _? is the group -NH-CH-COOH, ^R 6 '
an acid anhydride of the corresponding derivative in which R "is the hydroxy group and R. is as defined in claim 1, with the proviso that each free amino group is suitably protected, with a compound of the general formula NH ₀ -CH-COORn
2, 8 ^R 6
wherein R / - has the meaning given in claim 1 and Rg is a lower alkyl group, reacting to 2 hours ¹ I in a suitable solvent at about 0 to 50 ⁰ C for about 1 and subsequently carrying out an acidic or basic hydrolysis; (e) for the preparation of the compounds in which R ^ is an alkylcarbonyl group, in which the alkyl radical is straight or branched-chain and comprises 1 to H carbon atoms, while R _{2 is} the hydroxyl group, the corresponding derivative in which R _{1 is} a hydrogen atom, with an acid halide of the general formula Il Rg-C-halo 909829/0613 wherein halo is a halogen atom ^ and R _{q is} a straight or branched chain C ₁ - to. C ₁ ^ alkyl group, or a corresponding acid anhydride is reacted in water in the presence of a base at about 0 to 25 ° C for about 0.5 to 24 hours; (f) for the preparation of the compounds in which R _{1 is} an alkoxycarbonyl group, the alkoxy radical being straight or branched chain and comprising 1 to 4 carbon atoms, the corresponding derivative in which R _{1 is} a hydrogen atom and Rp is a lower alkoxy group, with an alkyl haloformate of the general formula Il
halo-C-0R ₁₀ in which halo is a halogen atom and R _{10 is} a straight or branched chain C.- to C ^ -alkyl group, treated in water or in dichloromethane in the presence of a base at about β to 25 ° C. for about 0.5 to 6 hours; (g) for the preparation of the compounds in which R _{1 represents} the group Il -C-CH-NH ₀ I ^{2 R} 3
means in which R, which has the meaning given in claim 1, the corresponding derivative in which R _{1 is} a hydrogen atom and R _{2 is} a straight or branched C ₁ -C 6 alkoxy group, with an acid of the general formula HOOC-CH -NH ₂ »3 or an anhydride thereof in which the amino group is suitably protected, and R, the aforesaid Has meaning in a suitable solvent and, if the free acid is used, in Treated in the presence of a dehydrating agent at about 0 to 35 ° C for about 1 to 12 hours and then acidic and base hydrolyzed; and 909829/0613 (h) for the preparation of a pharmaceutically acceptable salt, the compound thus obtained with a suitable pharmaceutically converts usable acid or base. 8. A pharmaceutical composition, characterized by a content of a compound according to claim 1 as an active ingredient and a conventional pharmaceutically acceptable carrier. 909829/0613