JPS635384B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to novel pharmaceutically useful acetylene derivatives of amines. [Means for solving the problem] The compounds of the present invention are represented by general formula 1. (However, A in the formula is methylene, ethylene or ethylidene). Pharmaceutically acceptable salts and individual optical isomers of compounds of general formula 1 are included within the scope of this invention. In the above formula 1, methylene is used to mean -CH ₂ -, ethylene is used to mean -CH 2 CH 2 -, and ethylidene is used to mean -CH ₂ CH ₂ -.

It is used to mean [formula]. It is clear from the above general formula 1 that the compound of the present invention is an acetylene derivative of amine. Examples of pharmaceutically acceptable salts of the compounds of the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, methanesulfonic acid, salicylic acid,
Non-toxic acid addition salts formed with organic acids such as maleic acid, malonic acid, tartaric acid, citric acid, ascorbic acid, and alkali metals such as sodium, potassium, lithium, alkaline earth metals such as calcium and magnesium, Part A non-toxic compounds formed with inorganic or organic bases such as bases of group light metals such as aluminium, primary, secondary or tertiary organic amines such as cyclohexylamine, ethylamine, pyridine, methylaminoethanol, ethanolamine and piperazine; Contains sex salts. Salts are formed by conventional means. Compounds in which A is methylene or ethylidene are preferred, and compounds in which A is methylene are more preferred. Examples of the compounds of the present invention are as follows. (Note) Hereinafter, "hex" is a translation of (hex) and not "hex". 1,4-hex-2-en-5-ynediamine, 1,5-hept-3-en-6-ynediamine, 2,5-hept-3-en-6-ynediamine, [Compounds of the present invention] Field of Application] (a) The compounds of general formula 1 are irreversible inhibitors of carboxyl group-degrading enzymes involved in polyamine formation, and are useful as pharmacological reagents. Polyamines, especially putrescine, spermidine and spermine, are present in plant and animal tissues and also in certain microorganisms. Although the exact physiological role of polyamines has not been clearly described, there is evidence to suggest that polyamines are involved in cell division and growth (H.G.
Williams-Assiyuman et al. (HG
Williams-Ashman et al), The ltarian J.
Biochem.25, 5-32 (1976), A. Raina and J.
Janne), Med.Biol.53, 121-147 (1975) and DHRussell,
Life Science 13, 1635-1647 (1973). Polyamines are used, for example, in E. coli, Enterobacter, Klebsiella, Staphylococcus aureus, C. cadaveris, Salmonella typhosa and flies. Haemophilus parainfluenza (Haemophilus)
It is an essential growth factor for certain types of microorganisms, such as A. parainfluenza, or is involved in the growth process. Polyamines are implicated in both normal growth and neoplastic growth spurts as there is increased synthesis and accumulation following stimuli that cause cell proliferation. Polyamine levels are also known to be high in fetal tissue, leukemic cells and other rapidly growing tissues. Ornithine, S-adenosylmethionine,
It is known that there is a correlation between the activity of arginine and lysine carboxyl group degrading enzymes and polyamine formation. The biosynthesis of putrescine, spermidine and spermine are interrelated. Putrescine decarboxylates ornithine (decarboxylation) catalyzed by ornithine carboxylase.
It is a product. Putrescine production can also occur by decarboxylation of arginine to produce agmatine, which is hydrolyzed to produce putrescine and urea. Arginine is also involved in ornithine formation through the action of the enzyme arginase. Activation of methionine by S-adenosylmethionine synthetase forms S-adenosylmethionine, which is decarboxylated and
The propylamine moiety of the activated methionine can then be transferred to putrescine to form spermidine, which in turn forms spermine. Putrescine therefore acts as a precursor to spermidine and spermine,
Furthermore, increased synthesis of putrescine has been shown to be the first sign that tissues are undergoing a modified growth process, indicating that it has a significant regulatory effect on the polyamine biosynthetic pathway. . Cadavarine, a decarboxylation product of lysine, has been shown to stimulate the activity of S-adenosyl-methionine carboxylase and is essential for the growth process of many microorganisms, such as H. parainfluenza. It is known that (b) Compounds of formula 1 in which A is methylene or ethylidene are also useful in inhibiting certain rapid growth processes. For example, the compounds are useful in inhibiting spermatogenesis and embryogenesis and thus find use as male fertility inhibitors and abortifacients. The compounds are also useful in inhibiting neoplastic growth such as solid tumors, leukemias, and lymphomas.
When administering a compound of general formula 1 in which A is methylene or ethylene, trans(±)-2-phenylcycloproponamine (trans(±)-2-phenylcycloproponamine) is simultaneously administered by known procedures.
-cycloproponamine) or N-benzyl-N
- It may be desirable to administer a monoamine oxidase inhibitor such as methyl-2-propynylamine. The usefulness of the compound of general formula 1 as an irreversible inhibitor of ornithine or S-adenosylmethionine carboxyl group degrading enzyme can be determined as follows. An aqueous solution of the appropriate compound is given orally or parenterally to male rats or mice. Animals were killed 1 to 48 hours after compound administration, the ventral lobe of the prostate was removed and homogenized, and ornithine and S-adenosylmethionine carboxylase activity was determined by EAPegg and HGWilliams. Ashman),
Biochem.J.108, 533-539 (1968) and J.Janne and H.G.
Biophys.Res.Comm.42 222-228 (1971). (c) Compounds in which A is methylene or ethylene in general formula 1 have the following structure: (wherein 2 is 2 or 3) is a metabolic precursor of a compound. The compound of formula 2 is known as an irreversible inhibitor of γ-aminobutyric acid transaminase, and upon administration of γ-aminobutyric acid (GABA)
This results in high brain levels of (d) The fact that compounds in which A is methylene or ethylene in general formula 1 can be metabolically converted to compounds of formula 2 has been demonstrated by Simler et al., which is currently used to prove antiepileptic activity.
DBA determined by the general method described by Biochem.Pharmacol.22, 1701 (1973)
This may be exemplified by the protective effect of this compound against audiogenic seizures in this strain of mice. (e) The compound of general formula 1 is useful as a chemical intermediate substance for the production of a novel cephalosporin derivative of general formula 3 below. Cephalosporin compounds of Formula 3 are useful as antibiotics. In the above general formula 3, A has the same meaning as defined in general formula 1, M is hydrogen or a negative charge, and Y is hydrogen or acetoxy. Compounds of general formula 3 and their pharmaceutically acceptable salts and individual optical isomers are novel compounds useful as antibiotics and include many well-known cephalosporin derivatives such as cephalexin, cephalothin, or cephaloglycine. It can be administered in a similar manner.
Compounds of general formula 3 and their pharmaceutically acceptable salts and isomers can be administered orally or parenterally and topically to warm-blooded animals, ie birds and mammals, such as cats, alone or in pharmaceutical formulations. dog,
It can be administered to cattle, sheep, horses and humans. For oral administration, the compounds may be administered in the form of tablets, capsules, or pills, or in the form of eluquidyl or suspensions. For parenteral administration, the compounds will best be used in the form of a sterile aqueous solution that may contain other solutes, such as sufficient saline or glucose to make the solution isotonic.
For topical administration, compounds of general formula 3 and their salts and isomers are incorporated into creams or ointments. Examples of microorganisms against which the compounds of general formula 3 and their pharmaceutically acceptable salts and individual optical isomers have activity are Staphylococcus aureus, Salmonella schotmuehleri),
Klebsiella pneumonia
pneumoniae), Diplococcus pneumoniae and Streptococcus pyogenes.
pyogenes). Examples of pharmaceutically acceptable non-toxic inorganic acid addition salts of compounds of general formula 3 include mineral acid addition salts such as hydrochloric acid, hydrobromide, sulfate, sulfamate, phosphate and organic acid addition salts. Salts such as maleates, acetates, citrates, oxalates,
These are succinate, benbrozoate, tartrate, fumarate, malate and ascorbate.
Salts can be made by conventional means. An example of a compound of general formula 3 is (in this specification, pent is translated as (pent), but is translated as (but), and oct is translated as (oct).) 7-[[2-[4-(1- Acetylene-4-aminobut-2-enylaminomethyl)phenyl]
acetyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid. Methods of Administration As pharmacologically useful agents, compounds of general formula 1 can be administered to the patient being treated in a variety of ways to achieve the desired effect. The pharmacologically useful compounds of this invention may be used alone or in combination with others. The pharmacologically useful compounds of the invention may also be administered in the form of pharmaceutical formulations. The compounds may be administered orally, parenterally, eg, intravenously, intraperitoneally or subcutaneously, or topically. The amount of compound administered will vary over a wide range and can be any effective amount. Depending on the patient being treated, the condition to be treated, and the method of administration, the effective amount of the compound will vary from about 0.1 mg per kilogram of patient body weight per dosage unit to 500 mg per kilogram of patient body weight per dosage unit. About 10 mg to about 100 mg will be preferred.
For example, a typical unit dosage form is a tablet containing 10 to 300 mg of the compound of Formula 1, which can be administered to the patient being treated one to four times per day to achieve the desired effect. As used herein, the term patient is used to mean warm-blooded mammals such as cats, dogs, rats, mice, guinea pigs, horses, cows, sheep, and humans. The solid dosage unit form can be conventional. The solid form can be a septum, which can be of the conventional gelatin type, containing the novel compound of the invention and a carrier such as a lubricant and an inert filler such as lactose, sucrose and cornstarch. In another embodiment, the novel compound comprises a conventional tablet base such as lactose, sucrose or cornstarch, a binder such as acacia, cornstarch or gelatin, a disintegrant such as cornstarch, potato starch or alginic acid and a stearic acid or magnesium stearate. It is made into tablets in combination with a lubricant. For parenteral administration, the compounds may be prepared as a solution or suspension of the compounds in a physiologically acceptable diluent, such as water or oil, with or without the addition of surfactants and other pharmaceutically acceptable excipients. It can be administered in an injectable dosage form with a pharmaceutical carrier which can be a sterile liquid. Examples of oils that can be used in these formulations are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil and mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions, ethanol and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions. The compounds can be formulated in a manner that allows sustained release of the active ingredient.
It can be administered in the form of an injection) or an insert formulation. The active ingredient is compressed into pellets or small cylinders and inserted subcutaneously or intramuscularly as a depot injection or implant. Implants can be made of inert materials such as biodegradable polymers or synthetic silicones such as Silastic, a silicone rubber manufactured by Dow Corning. [Production method] The compound in which A is methylene or ethylidene in general formula 1 is prepared by adding one equivalent of a suitably protected propargyl compound, optionally in the presence of a divalent metal cation such as zinc iodide or magnesium bromide. Treatment of the amine with a strong base produces a protected propargylamine, a carbanion intermediate, which can be converted into 2
- alkylated with propenal or butenal and acylated with an alkanoyl halide such as acetyl chloride or propionyl chloride, or an aroyl halide such as benzoyl chloride, or an acid halide such as a lower alkyl haloformate or tertiary butoxycarbonyl azide; Subsequent hydrolysis of 1-amino-1-trimethylsilylacetylenebut-3-en-2-ol to the amide or carbamate, which is dissolved in sodium or potassium bicarbonate, sodium or potassium carbonate, sodium hydroxide or hydroxide Treatment with a base such as potassium gives 4-aminohex-1-en-5-yn-3-
The carboxamide of ol is obtained, and this is dissolved in a solvent such as an ether such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, a hydrocarbon such as benzene or toluene, and a hydrocarbon such as sodium hydride, potassium tert-butoxide, lithium alkylamide such as lithium diisopropyl or Trichloromethylimidate ester is obtained by treatment with trichloroacetonitrile for about 30 minutes to 3 hours at about -30° to 0°C in the presence of a catalytic amount of a base such as alkyl lithium, which Trichloromethylacetamide is obtained by heating in a non-polar solvent such as xylene, toluene, nitrobenzene or chlorobenzene at ~140°C for about 1 to 10 hours, which is then dissolved in an aqueous acid solution such as hydrochloric acid or an aqueous base solution such as sodium hydroxide or potassium hydroxide. It is produced by hydrolysis using The alkylation or acylation reactions mentioned above may be carried out in neutral solvents such as benzene, toluene, ether, tetrahydrofuran, dimethylsulfoxide or hexamethylphosphortriamide. The reaction temperature can vary from -125° to 25°C for about 30 minutes to 24 hours. Hydrolysis of 1-amino-1-trimethylsilylacetylenebut-3-en-2-ol to give the amide is followed by treatment with hydrazine, phenylhydrazine or hydroxylamine or with mineral acids such as hydrochloric acid. With an organic base such as trimethylamine or pyridine in a lower alcoholic solvent such as methanol or ethanol, approximately
This is achieved by processing at 80-110°C for 30 minutes to 2 hours. The appropriately protected propargylamine used in the above reaction is represented by the following general formula 5. In the formula R ₈ is straight-chain or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl and tert-butyl or triethylmethyl. Compounds of formula 5 are prepared by adding protecting groups on the acetylene and nitrogen functional groups of propargylamine. Protection of the nitrogen functionality of propargylamine is carried out by forming a Schiff base with a non-enolized carbonyl-containing compound selected from benzaldehyde, 2,2-dimethylpropanal and 2,2-diethylbutanal in a known manner. . The acetylene function can be protected by reacting the above-mentioned Schiff base with a straight-chain or branched trialkylsilyl chloride in which the alkyl moiety has 1 to 4 carbon atoms, such as trimethylsilyl chloride or triethylsilyl chloride. This is accomplished by forming an alkylsilyl derivative. Suitable strong bases used in the above reaction to form the carbanion are alkyllithiums such as butyllithium, or phenyllithiums, lithium dialkylamides such as lithium diisopropylamide, lithium amide, tertiary potassium butyrate or sodium amide. It extracts protons from the carbon atom adjacent to the acetylene moiety. In the general formula 1, the compound in which A is ethylene is 1-hydroxypent-2-enal with the formula
HCCM′ (where M′ is sodium, lithium or
MgX′, where X′ is chlorine or bromine)
or a complex of lithium acetylide/ethylenediamine in a solvent such as liquid ammonia, dimethyl sulfoxide, ethers such as tetrahydrofuran, dioxane, diethyl ether or dimethoxyethane at about -30° to 25°C for about 1 to 3 minutes. It is produced by time treatment to obtain hept-3-en-5-yn-1,5-diol. Liquid ammonia is the preferred solvent when sodium or lithium acetylide is used. Ether solvents are also preferred when lithium acetylide is used. Ether solvents are preferred when magnesium halides are used with preferred reaction temperatures of about 0-25°C. When lithium acetylide-ethylenediamine complex is used, the preferred solvent is dimethyl sulfoxide using a temperature of 25 DEG C. and a time of about 1 to 12 hours. The diol derivative is treated with phthalamide, triphenylphosphine and diethyldiazodicarboxylate in an ether such as tetrahydrofuran, diethyl ether or dioxane for about 1 to 12 hours at about 25° to 50°C to give the corresponding diphthalamide derivative. , which is treated with hydrazine hydrate in a lower alcoholic solvent such as methanol or ethanol for about 1 to 6 hours at about 25° to 50°C;
It is then treated with an acid such as 6N HCl at 100°C for 1 to 10 hours. Reference example (use as intermediate) 7-[[2-[4-(1-acetylene-5-aminopent-2-enylaminomethyl)phenyl]
-acetyl]amino]-3-acetyloxymethyl-8-oxo-5-thio-1-azabicyclo-[4,2,0]oct-2-ene-2-carboxylic acid 1 g of 3- in 50 ml of ethanol Acetyloxymethyl-7-[[2-[4-chloromethyl)phenyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4,2,0]-octo-2
1 g of 1,5-hept-3-ene-6 with the terminal amino group protected as phthalimide for the -ene-2-carboxylic acid and acetylene functions.
The mixture of -indiaminos was stirred for 24 hours at 25°C and then the solvent was removed leaving a residue which was treated with hydrazine and chromatographed on silica gel using benzene-acetone as eluent 7-
[[2-[4-1-acetylene-5-aminopent-2-enylacetyl]amino]-3-acetyloxymethyl-8-oxo-5-thia-1-asabicyclo-[4,2,0]octo- 2-en-2-
Carboxylic acid was obtained. Pharmaceutical formulations of the compound of general formula 1 are illustrated below. The composition of hard gelatin capsules is exemplified as follows. (a) 1,4-hex-2-ene-5-indiamine 20mg (b) Talc 5mg (c) Lactose 90mg For the prescription, pass the dry powders of (a) and (b) through a fine mesh sieve. It is made by thoroughly mixing. The powder is then packed into hard gelatin capsules with a net fill of 115 mg per capsule. Illustrating a composition for an injection suspension is the following 1 ml ampoule for intramuscular injection. Weight percent (a) 2,5-hept-3-ene-6-indiamine 1.0 (b) Polyvinylpyrrolidone 0.5 (c) Lecithin 0.25 (d) Water for injection made to 100 Mix, homogenize and fill into 1 ml ampoules, seal and heat at 121°C for 20 minutes.
Autoclave. Each ampoule contains 10 mg of new compound (a) per ml. The following examples further illustrate compounds of the invention. Example 1 1,4-hex-2-en-5-indiamine dihydrochloride 21.5 g in 500 ml of tetrahydrofuran
(0.1M) of 3-trimethylsilylprop-2-ynyl-1-iminobenzyl at -70℃
ml of a 1.5M solution of n-butyllithium.
After 5 minutes at -70°C, a solution of zinc iodide made from 8.0 g zinc and 25.4 g iodine in 100 ml tetrahydrofuran is added. The resulting solution was kept at -70°C for 20 minutes, then
5.6g (0.1M, 6.65ml) of 2-propenal -
Added dropwise at 70°C. The solution is held at -70°C for 30 minutes and then 7.8g (0.1M, 70ml) of acetyl chloride is added. Allow the solution to warm to room temperature, dilute with ether, wash well with aqueous sodium bicarbonate solution, then with aqueous sodium chloride solution,
Dry over magnesium sulfate and evaporate to leave an oil, which is taken up in 200 ml of isopropyl alcohol and treated with 10 g (0.093 M) of phenylhydrazine. The mixture is heated at reflux for 20 minutes and then the solvent is evaporated. The residue is dissolved in chloroform and applied to a column of silicon dioxide packed with chloroform. Elute with chloroform and then 5% methanol/chloroform to obtain 1-
Trimethylsilylacetylene-1-aminobuto-
The acetamide of 3-en-2-ol was obtained, which was dissolved in 30 ml of ethanol and dissolved in 30 ml of water.
treated with 2.5 g of potassium hydroxide at room temperature,
Thereafter, methanol is filtered off. The aqueous residue is saturated with sodium chloride and well extracted with methylene chloride. The organic layer was dried over magnesium sulfate and concentrated to leave a residue, which was recrystallized from chloroform/petroleum ether to give 4-aminohexane.
Acetamide of 1-en-5-yn-3-ol (melting point 94°C) was obtained, and 994 mg (6.5 mM) of this was
ml of tetrahydrofuran and add to 24 mg of a 50% suspension of sodium hydroxide (0.5 mM).
After 5 minutes at approximately 25°C, the solution was dropped from a syringe to give 935 mg in 30 ml of tetrahydrofuran pre-chilled to -23°C (dry ice/carbon tetrachloride).
(6.5mM) in trichloroacetonitrile. The resulting solution was stirred for 1.5 hours at −23°C and then evaporated at about 25°C to leave an oil, which was
Dissolve in 30 ml of xylene and heat under reflux for 3 hours, then stand overnight at about 25°C. The resulting precipitate is collected, recrystallized from chloroform and combined with 40 ml of 6N HCl and 100 ml of methanol. The solution is heated under reflux for 12 hours and then concentrated. The resulting residue was thoroughly washed with chloroform, treated with charcoal, filtered, and evaporated to leave a residue, which was recrystallized from ethanol to give 1,4-hex-2-ene-5-indiamine dihydrochloride, melting point 175°C. (Disassembly)
get. Example 2 1,5-hept-3-en-6-ynediamine To a solution of sodium acetylide made from 2.3 g (0.1 M) sodium in 500 ml ammonia is added 35 g (35 mmol) of 5-hydroxypento- 2
- Enal is added. After one hour ammonium chloride is added and the ammonia is allowed to evaporate. The residue was taken up in ether, filtered and concentrated leaving a residue which was taken up in 200 ml of tetrahydrofuran for 48 hours at 25°C.
18.3g (70mM) triphenylphosphine,
Stir with 12.1g (70mM) of diethyl azodicarboxylate and 10.2 (70mM) of phthalimide. The precipitate that forms is filtered off, recrystallized with methanol and then dissolved in 30 ml of ethanol. The ethanol solution was treated with hydrazine hydrate (1.74 g) at reflux overnight, then the solvent was evaporated and the residue
% potassium hydroxide to the base, extracted with dichloromethane, evaporated and distilled to give 1,5-hept-
3-en-6-ynediamine is obtained. When 2-propenal was replaced with an appropriate amount of 2-butenal in the procedure of Example 1, 2,5-
Hept-3-en-6-indiamine dihydrochloride is obtained. Irreversible inhibition of ODC trans-1,4-hex-2-ene-5 by the method described in JACS100, pp. 2551-2553 (1978).
- Rat liver ornithine decarboxylase inactivation rate constant (Kinact) of indiamine is 2.3×
It was 10 ^-3 . Thus, the compounds of the present invention
It has ODC activity, thus supporting its usefulness for anti-tumor and fertility-promoting drug end uses.

Claims (1)

[Claims] 1 formula and pharmaceutically acceptable salts thereof, and their individual optical isomers (wherein A
is methylene, ethylene or ethylidene). 2. The compound according to claim 1, which is 1,4-hex-2-en-5-indiamine or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, which is 2,5-hept-3-en-6-indiamine or a pharmaceutically acceptable salt thereof. 4 formula and pharmaceutically acceptable salts thereof, and their individual optical isomers (wherein A
is methylene or ethylidene), in which one equivalent of a suitably protected propargylamine derivative is mixed with a suitable strong base, optionally in the presence or absence of a divalent metal cation. The resulting protected propargylamine carbanion intermediate is alkylated with 2-propenal or 2-butenal, and the alkylated derivative is treated with a suitable halide, lower alkyl haloformate, or tert-butoxycarbonyl azide. and then hydrolysis to give the amide or carbamate, which is treated with a suitable base to give the carboxamide, which is heated in a suitable solvent in the presence of a catalytic amount of base at about -30 to 0°C. was treated with trichloroacetonitrile for about 30 minutes to 3 hours to obtain trichloromethylimidate ester, which was dissolved in a nonpolar solvent for about 3 hours.
Trichloromethylacetamide is obtained by heating at 110°C to 140°C for about 1 to 10 hours, and this is hydrolyzed with an aqueous acid or base; however, in this case, the above alkylation and acylation reactions are performed in a neutral solvent. A method comprising carrying out the process at a temperature of about -125°C to 25°C for about 30 minutes to 24 hours.