JPH0325424B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to novel halomethyl derivatives of lactams of amino acids.

[Structure of the present invention] The compound of the present invention is represented by the following general formula.

In the formula, Y is _F2CH- or _ClCH2- , and n is an integer 3.

Representative examples of pharmaceutically acceptable salts of compounds of the invention include: inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids;
Non-toxic acid addition salts prepared with e.g. methanesulfonic acid, salicylic acid, maleic acid, malonic acid, tartaric acid, citric acid, cyclamic acid and ascorbic acid; and inorganic or organic bases such as alkali metal,
bases of light metals of group A such as aluminum, organic amines such as primary, secondary or tertiary amines such as cyclohexylamine,
Non-toxic salts made with ethylamine, pyridine, methylaminoethanol, ethanolamine and piperazine. This salt is produced by conventional methods.

Preferred compounds of the invention are those where Y is _F2CH- .

[Effects of the present invention] The compound of the general formula is an inhibitor of the decarboxylase enzyme involved in polyamine production, and therefore the compound is useful as a pharmacological agent. Polyamines, especially putrescine, spermidine and spermine, are present in plant and animal tissues and 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 [HG Welliams
Ashman et al., The Italian Journal of Biochemistry 25, 5-32 (1976), A. Raina and J.
janne) Medical Biochemistry 53 , 121
~147 (1975) and DHRussell, Life Sciences 13 , 1635
~1647 (1973)]. Polyamines are commonly used by certain microorganisms, such as E. coli, Enterobacter, Klebsiella, and Staphylococcus aureus.
aureus), C. cadaveris,
Salmonella, typhosa and Haemophilus parainfluenza
parainfluenza) or are associated with their growth stages. Polyamines are associated with both normal growth and rapid neoplastic growth, with an increase in the synthesis and accumulation of polyamines following stimuli that cause cell proliferation. It is also known that polyamine levels are higher in patients with fetal, peritoneal, and rapidly growing tissues. It is known that there is a relationship between the activity of ornithine, S-adenosylmethionine, arginine and lysine decarboxylase enzymes and polyamine production.

The biosynthesis of putrescine, spermidine and spermine are interrelated. Putrescine is a carboxyl group degradation product of ornithine catalyzed by ornithine decarboxylase.
Putrescine production can also occur by decomposing the carboxyl group of arginine to produce agmatine, which is then hydrolyzed to give putrescine and urea. Arginine is also involved in ornithine production through the action of the enzyme arginase. S-
Activation of methionine by adenosylmethionine synthase produces S-adenosylmethionine, which is decomposed by its carboxyl group, and then the propylamine moiety of the activated methionine is converted to putrescine to produce spermidine or polyamine. portion is converted to spermidine to produce spermine. Therefore, putrescine acts as a precursor to spermidine and spermine, and furthermore, increased putrescine synthesis has been shown to be the first sign that tissues are undergoing regenerative growth processes, with a significant impact on polyamine biosynthetic processes. This shows that it has a significant adjustment effect. Cadaverine, a carboxyl group decomposition product of lysine, is S
- It has been shown to stimulate the activity of adenosylmethionine decarboxylase and is known to be essential for the growth process of many microorganisms, such as H. parainfluenza.

Compounds of the general formula are inhibitors of ornithine decarboxylase.

Compounds of the general formula are useful as anti-infective agents and are effective against microorganisms such as Escherichia coli, Enterobacter,
for the growth of Klebsiella, Staphylococcus aureus, C. cadaveris, viruses such as H. parainfluenza, picornaviruses such as encephalomyocarditis, Herpes simplex, variola virus and arboviruses such as Semliki Forest virus. It is effective in controlling bacteria and viruses that rely on polyamines. Compounds of the general formula are also useful in inhibiting certain rapid growth processes. For example, the compounds have been used in the inhibition of spermatogenesis and embryonic development, and have therefore found use as male fertility inhibitors and abortifacients.
The compounds are also useful in suppressing the immune response and therefore they are also utilized as immunosuppressants, and they are also utilized in the suppression of neoplastic growth, such as solid tumors, leukemias and lymphomas.

This compound is also useful as an inhibitor of scalp cell growth as evidenced by prostate enlargement and the development of dandruff, and as an inhibitor of abnormal skin cell growth as evidenced by psoriasis symptoms. The utility of compounds of the general formula as irreversible inhibitors of ornithine or S-adenosylmethionine decarboxylase enzymes in vivo is demonstrated below. An aqueous solution of a compound of the appropriate formula is administered orally or parenterally to male mice or mice. Animals were sacrificed 1 to 48 hours after compound administration, and the ventral lobe of the prostate was removed.
Homogenized, E.A. Pegg and H.G. Williams Biochemical Journal 180 , 533-539
(1968) and G. J. and G. Williams Atsushiman, Biochemical and Biophysical Research Communication 42 , 222-228 (1971). or S-
The activity of adenosylmethionine decarboxylase enzyme was measured.

[Production method] For the production method of the amino acid which is the starting material for the production of the compound of the present invention, see JP-A-54-19913.
Lactams, compounds with the general formula, have the structure [where n and Y have the meanings defined in the formula, and R ₁₉ is a straight chain or branched alkoxy group having 1 to 8 carbon atoms, typically methoxy,
ethoxy, isopropoxy, butoxy or hexyloxy; and more preferably when Y is _ClCH2- , the structure [where n and R ₁₉ have the meanings defined in the formula] from the corresponding α-hydroxymethyl substituted amino acid esters, the amino acid esters are dissolved in a solvent such as a lower alcohol such as methanol, ethanol, isopropyl alcohol, n
- in butanol, water, dimethylformamide, dimethylsulfoxide, hexamethylphosphortriamide or mixtures of these solvents for 1/2 hour to
a suitable base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxy, optionally under a nitrogen atmosphere, at a temperature of about 0°C to 120°C for 24 hours. treatment with potassium tert-butoxide, sodium amide or an organic amine such as a trialkylamine, such as triethylamine, and then when Y is _ClCH2- in a solvent such as formamide, dimethylformamide or dimethylacetamide from 12 to
It is prepared by treatment with a chlorinating agent such as thionyl chloride, phosphorous oxychloride or phosphorus pentachloride at about 40° to 120° C. for 36 hours.

Compounds of the general formula are prepared by methods generally known in the art from the corresponding amino acid, e.g., in a suitable alcohol saturated with HCl gas, such as methanol, ethanol, isopropyl alcohol, n-butanol or n- -obtained by treatment with heptanol.

Compounds of the general formula are prepared by treating one equivalent of ornithine or lysine with two equivalents of benzoyl chloride and then with two equivalents of a base, e.g. sodium hydroxide, by the general method described in Synthesis 1973 , 792. A bisamide is prepared by treating it with an acid anhydride, such as acetic anhydride, for about 1/2 hour at about 90°C and then with aqueous formaldehyde and pyridine for about 8 to 24 hours at about 25°C. treatment and then treatment with water to give the oxodioxane, which is treated with a catalytic amount of sodium methoxide in methanol, then neutralized and heated to about 120°C.
by treatment with an acid, such as hydrochloric acid, for about 2 to 24 hours.

Each optical isomer of the amino acid corresponding to the lactam of the compound of general formula can be obtained from the lactam using (+) or (-) binaphthyl phosphate as described in the tetrahedron letters of R. Viterbo et al.48 ,
4617 (1971). Other resolving reagents can also be used, such as (+) acid-10-sulfonic acid. Similarly, the individual optical isomers of a compound of the formula where Z is β-methylthioethyl, R is hydrogen and R ₁ is hydroxy can be obtained from the free amino acid (+) or (-) binaphthyl phosphate or Other reagents such as (+) Shonou-10
-obtained using sulfonic acid.

Examples Example 1 3-Amino-3-difluoromethyl-2-piperidone Methyl-2-difluoromethyl-2,5-diamino-pentanoate-dihydrochloride (2.7 g) in dry methanol (30 ml). To the solution was added 2 equivalents of sodium methylate in methanol (0.46 g sodium in 20 ml methanol) under nitrogen. The reaction mixture was stirred at room temperature for 3 hours, then the solvent was evaporated under reduced pressure. Extraction of the residue with ether yielded crude 3-amino-3-difluoromethyl-2-piperidone, which was
Purified by crystallization from CHCl ₃ /pentane (mp 149°C) or by distillation (bp 135°C/0.05 mmHg).

Example 2 (-) and (+) 3-amino-3-difluoromethyl-2-piperidone hydrochloride A solution of (-) binaphthyl phosphate (BNPA) (1.27 g) in hot ethanol (50 ml) was added to hot ethanol. A solution of (±) 3-amino-3-difluoromethyl-2-piperidone (0.546 mg) in (5 ml) was added. On cooling, the crystals separated. The reaction mixture was then left at 4°C overnight. When the precipitate was filtered and washed with ethanol and diethyl ether, 0.54 g of (-)binaphthyl phosphate ([α] _D
= -409°C = 0.3, MeOH melting point: 300°C) was obtained. Recrystallization of the mother liquor yielded 0.15 g of (-)binaphthyl phosphate. 1.1 when the filtrate is concentrated
g of sticky material was obtained, which was treated with 3M HCl for 3 hours at room temperature. The (-)BNPA was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized in ethanol to give (+)3-amino-3-difluoromethyl-2-piperidone-hydrochloride (160 mg) ([α] _D = +18°6, C = 1, MEOH)
(melting point 238°C) was obtained. When treated under the same conditions, (-)BNPA salt (436 mg) gave (-)3-amino-3-difluoromethyl-2-piperidone-hydrochloride (137 mg), which was recrystallized in ethanol. (67 mg) ([α] _D = -19°, c = 1.02,
MeOH; melting point = 240°C decomposition).

(Reference example) (-) and (+) 2-difluoromethyl-2,
5-diaminopentanoic acid hydrochloride (-)3-difluoromethyl-3-amino-2
-Piperidone hydrochloride (60mg) heated at reflux in 6M HCl (4ml) for 12 hours. After concentrating under reduced pressure, the residue was dissolved in water and the pH of the solution was adjusted to
Adjusted to 4.5 using a solution of NEt ₃ . The solution was then concentrated under reduced pressure and the residue was extracted multiple times with chloroform and then recrystallized from H ₂ O/EtoH.
(+) 2-difluoromethyl-2,5-diaminopentanoic acid hydrochloride (54 mg) ([α] _D = +6, c =
0.48; MeOH; melting point ≧240°C) was obtained. By the same treatment, (+)3-difluoromethyl-3-
Amino-2-piperidone hydrochloride (96mg) is (-)
This gave 2-difluoromethyl-2,5-diaminopentanoic acid hydrochloride (56 mg). ([α] _D = −10°,
c=0.7, MeOH, melting point ≧244°) (Reference example) 3-hydroxymethyl-3-amino-2-piperidone 2-hydroxymethyl-2,5-diaminopentanoic acid hydrochloride (5 g or 2.5 × 10 ^-2 mol )of
Suspended in 75 ml of anhydrous methanol and the solution saturated with dry hydrogen chloride. The homogeneous solution was then heated under reflux for 48 hours. The reaction mixture was uniformly saturated with dry hydrogen chloride. The solution was evaporated under reduced pressure and the hygroscopic residue (6.2 g) was dried under high vacuum, which was purified by nuclear magnetic resonance with the dihydrochloride salt of 2-hydroxymethyl-2,5-diaminopentanoic acid methyl ester. It was identified that there is. The ester (6.2 g) was dissolved in 100 ml of absolute methanol and 175 ml of a methanol solution of sodium methylate (1.15 g of Na or 5 x 10 ^-2 mol) was added. The reaction mixture was stirred at room temperature for 20 hours under nitrogen. Evaporation of the solvent under reduced pressure and extraction of the residue multiple times with hot chloroform yielded analytically pure 3-hydroxymethyl-3-amino-
2-piperidone (2.9 g) (yield 81%) was obtained. Melting point 145℃.

Example 3 3-Amino-3-chloromethyl-2-piperidone hydrochloride A solution containing 3-hydroxymethyl-3-amino-2-piperidone (7 g or 0.049 mol) in anhydrous dimethylformamide (50 ml) was
One equivalent of thionyl chloride (3.6ml) was added. The reaction mixture was stirred at 80°C under nitrogen. After 24 hours, a further equivalent of thionyl chloride (3.6ml) was added and stirring continued for 2 hours. The solvent was then stripped under reduced pressure. The semi-solid residue was triturated with chloroform (2 x 30 ml) to give 2.1 g.
Crystalline, analytically pure 3-amino-3-chloromethyl-2-piperidone hydrochloride was obtained. Melting point 230℃.

Claims (1)

[Claims] 1 formula Compounds of the formula [wherein Y is _F2CH- or _ClCH2- ], and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, wherein Y is _F2CH- . 3 formulas [In the formula, Y is F ₂ CH- or ClCH ₂ -] In the method for producing a compound which is a lactam of an amino acid or a pharmaceutically acceptable salt thereof, when Y is F ₂ CH-, 2-difluoro Treating the lower alkyl ester of methyl-2,5-diaminopentanoic acid with a base in a suitable solvent for about 1/2 to 24 hours at 0°C to 12°C, optionally under a nitrogen atmosphere. When Y is ClCH ₂ -, the lower alkyl ester of 2-hydroxymethyl-2,5-diaminopentanoic acid is prepared in a suitable solvent at 0°C to 120°C for about 1/2 to 24 hours. , optionally under a nitrogen atmosphere, with a base, resulting in 3-biloxymethyl-
3-Amino-2-piperidone in a suitable solvent at approx.
A method comprising treatment with a chlorinating agent at about 40°C to 120°C for 12 to 36 hours.