JPH0545583B2 - - Google Patents

Description

[Detailed description of the invention]

(Field of Industrial Application) The present invention provides novel α-lactam antibiotics useful as pharmaceuticals or intermediates for the production of β-lactam antibiotics.
The present invention relates to (2-oxo-1-azetidinyl)acetic acid derivatives, salts thereof, and methods for producing them. (Structure of the Invention) The compound of the present invention is an α-(2-oxo-1-azetidinyl)acetic acid derivative represented by the following general formula () and a salt thereof. [The symbols in the formula have the following meanings. R ¹ ; amino group or formula

Group represented by [Formula] R ² ;Formula

[Formula] or

Group represented by the formula R ³ ; hydroxyl group, lower alkoxy group, or amino group R ⁴ ; hydrogen atom or lower alkyl group. The same applies hereinafter] In addition, the manufacturing method of the present invention is based on the formula () α-(2-oxo-1-azetidinyl) represented by
Acetic acid or a reactive derivative thereof at the carboxy group, ammonia represented by the general formula () R ¹ -H (), or a histidylproline derivative or a compound in which the N-terminal amino group of the histidylproline derivative is activated. General formula () characterized by reacting α-(2-oxo-1-azetidinyl) represented by
This is a method for producing acetic acid derivatives. In the above general formula, the lower alkyl group represented by R ⁴ is a straight chain or branched group having 1 to 5 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, etc. It is an alkyl group with a shape. In addition, the lower alkoxy group represented by R ³ is a linear or branched alkoxy group having 1 to 5 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group, etc. be. The compounds of the present invention () may have an asymmetric carbon atom, and include compounds that have stereoisomers based on this asymmetric carbon atom. The target compounds of the present invention include separated and mixtures of these isomers. Compound () also forms a salt. Salts with non-toxic acids such as inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, and organic acids such as citric acid, acetic acid, tartaric acid, optionally with sodium,
Examples include salts with bases such as potassium. The object compound () of the present invention can be prepared as it is or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, granules, tablets, capsules, etc.
It can be administered orally or parenterally in the form of injections (intravenously, subcutaneously, intramuscularly), suppositories, and the like. The dosage of the compound () of the present invention varies depending on the type of compound (), age, body weight, symptoms, route of administration, etc., but for example, in the case of injection, approximately
0.001-10mg preferably 0.01-0.1mg (single dose)
and about 0.05 to 500 mg for oral administration, preferably 0.1
~10 mg (single dose). (Problems to be Solved by the Invention) Compounds related to the object compound () of the present invention are also known as "thyrotropin-releasing hormone".
L-pyroglutamyl-L-histidyl-L-prolinamide (H-pGlu-His-
Pro−NH ₂ ) is known. The existence of TRH has been known since the 1960s, but its structure was confirmed in 1970 [Endo-
crinology, 86 , 1143 (1970). TRH is originally a thyrotropin (TSH) in the mammalian pituitary gland.
It was thought to be a hormone that regulates the release of However, subsequent research revealed that this tripeptide
The biological functions of TRH are not limited to the regulation of TSH release, but appear to have broader effects on the central nervous system (CNS), a discovery that opens up a new field of research [Science , 178 ,
417 (1972), Lancet, 2 , 999 (1972)]. Thus, in addition to its TSH-releasing activity, TRH also plays a role in reducing sleep duration induced by barbiturates and alcohol, suppressing hypothermia symptoms stimulated by various drugs, increasing locomotor activity, and decreasing sleep duration induced by barbiturates and alcohol. Prevention of generalized tonicity caused by schizophrenia, enhancement of memory, improvement of symptoms of schizophrenia,
It is known to have effects on the CNS, such as antidepressant effects. Furthermore, TRH has been found to be an ameliorating and therapeutic agent for disorders of consciousness caused by functional or organic disorders in the brain, such as head trauma, brain surgery, cerebrovascular disorders, brain tumors, etc., especially acute or subacute disorders of consciousness. (Unexamined Japanese Patent Publication No. 51-118841)
issue). In terms of clinical treatment, TSH release activity is weaker than that of TRH, or shows almost no activity, and moreover, as mentioned above,
There has been a demand for a TRH derivative that has an effect on the CNS equal to or greater than that of TRH. Various TRH derivatives have been synthesized for such purposes, and their effects on the CNS have also been further expanded. Compounds synthesized for this purpose include, for example, their TSH release activity is weaker than that of TRH, but they have anesthetic antagonism, increase locomotor activity, or dopamine-like effects, leading to sleep drug addiction, consciousness disorders, hyperactive children, and schizophrenia in humans. , TRH derivatives that are said to be useful for improving treatment of depression and Parkinson's disease (Japanese Patent Publication No.
52-116465), hexobarbital has the effect of reducing consciousness disturbance after head trauma, and decreases the duration of sleep. Patients with consciousness disturbance caused by organic or functional disorders in the brain, senility or mental fatigue. TRH derivatives that are said to be useful for patient treatment and the treatment of depression, etc.
No. 59714) is known. (Effects of the Invention) The target compound of the present invention has a chemical structural feature in that it has an α (2-oxo-1-azetidinyl) acetyl group, which has never been employed in TRH derivatives. Since it has a significantly stronger CNS effect than conventionally known TRH derivatives, it can be used as an agent for improving consciousness disorders, such as schizophrenia, depression, sequelae of cerebrovascular accidents, head trauma, senile dementia, epilepsy, or loss of motivation and depression. , is useful as an ameliorating agent for memory decline, etc. The compounds of the present invention also include those useful as intermediates for the production of β-lactam antibiotics. (Specific explanation of the manufacturing method of the present invention) Next, the manufacturing method of the present invention will be explained. The reaction route in the production method of the present invention is illustrated as follows. That is, according to the present invention, the target compound ()
(a-1) React compound () with compound () to produce compound (), and then react this compound () with compound (), or (a-2) React compound () with compound (). () by reacting with compound (-a) and then reacting this compound (-a) with compound (), or (b) by treating compound () with ammonia (-b). can be manufactured. The reaction for producing the compound (-a) employed in (a-1) or (a-2) above is a peptide synthesis reaction, and a method known per se is used. Commonly used methods include a method using dicyclohexycarbodiimide as a condensing agent, an azide method, an acid chloride method, an acid anhydride method, and an active ester method. To carry out these methods, prior to the peptide-forming reaction in each step, functional groups such as amino groups, imino groups, and carboxyl groups of the raw material compound that do not participate in the reaction are protected, and The amino group, imino group or carboxy group involved in the peptide formation reaction is activated if necessary. Examples of protecting groups for amino groups include benzyloxycarboxy group, tert-butoxycarbonyl group, p-methoxybenzyloxycarbonyl group,
Phthaloyl group, trifluoroacetyl group, etc.
In addition, examples of protecting groups for imino groups include tosyl group, benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, benzyl group, 2,
Examples include 4-dinitrophenyl group. As the protecting group for the carboxyl group, ester forms such as methyl ester, ethyl ester, benzyl ester, p-nitrobenzyl ester, and tert-butyl ester are used. The groups involved in the reaction can be activated by using the phosphazo method using phosphorus trichloride, the isocyanate method using phosgene, or the phosphite method when the group is an amino group or an imino group, or the activation of a carboxyl group. In this case, it is carried out in the form of an active ester (such as an ester with 2,4-dinitrophenol or an ester with N-hydroxysuccinimide), an azide, or a carboxylic acid anhydride. Among these, a method using dicyclohexylcarbodiimide as a condensing agent, an active ester method, or an azide method are preferred for the reaction between compounds () and (). Alternatively, a method of directly preparing a peptide using an N-carboxylic anhydride of an amino acid without using a protecting group can also be used. Next, the peptide-forming reaction is carried out in a conventional manner in an inert solvent at room temperature or with heating. Suitable solvents include dimethylformamide (DMF);
Ethyl acetate, dichloromethane (methylene chloride),
Tetrahydrofuran and the like are used. When it is necessary to remove a protecting group from a reaction product, for example, in the case of a benzyl ester, it is necessary to remove the protecting group by catalytic reduction, and when the protecting group is benzyloxycarbonyl or p-methoxybenzyloxycarbonyl, it is necessary to remove it by catalytic reduction or hydrobromic acid. - When the protecting group is a tert-butoxycarbonyl group, it can be easily removed by acid decomposition by treatment with acetic acid. Further, the reaction for producing the compound (-b) employed in the above (b) is a synthesis reaction of an acid amide, and a method known per se can be employed. Commonly used methods include dehydration using excess ammonia and activated alumina as a catalyst, acid halide method, acid anhydride method, and ester ammonolysis method. In particular, the ester ammonolysis method is advantageous in consideration of the ease of obtaining the raw material compound, the yield, and the like. The reaction is carried out by mixing the compound () in an organic solvent such as methanol or ethanol with an excess of liquid ammonia relative to the compound (), preferably with a mixture of water or glycol and ammonia, which is known to accelerate the reaction. This is carried out by cooling or processing at room temperature. In addition, ammonium chloride, sodium methoxide,
Sodium amide, butyl lithium, etc. can also be used. (Example) Hereinafter, the present invention will be further explained with reference to Examples. In addition, the manufacturing method of the raw material compound is shown in a reference example. The abbreviations used in Examples and Reference Examples have the following meanings. NMR Nuclear magnetic resonance spectrum IR Infrared absorption spectrum Mass Mass spectrometry spectrum mp Melting point His Histidine residue Pro Proline residue DMF Dimethylformamide HOBT 1-Hydroxy-1,2,3-benzotriazole DCC Dicyclohexylcarbodiimide reference example Ethyl α-(2-oxo-1-azetidinyl)
Dissolve 1 to 1.44 g of acetate in 28 ml of methanol, and add 10 ml of 1N aqueous sodium hydroxide solution under ice cooling.
dropwise and react at 10-15°C for 1 hour. The reaction solution was ice-cooled, 10 ml of 1N hydrochloric acid was added, methanol was distilled off under reduced pressure, the remaining aqueous solution was saturated with sodium chloride, and extracted three times with 140 ml of ethyl acetate. The ethyl acetate solutions were combined, dried over anhydrous sodium sulfate, and then concentrated to obtain 2 to 950 mg of α-(2-oxo-1-azetidinyl)acetic acid. NMR (CDCl ₃ + CD ₃ OD) δppm: 3.97 (2H, s),
3.45 (2H, t, J = 4Hz), 3.02 (2H, t, J =
4Hz) IR (CHCl ₃ solution) cm ^-1 : 1740 Mass (m/z): 128 (M ⁺ ) Example 1 Dissolve 2.18 g of L-histidyl-L-prolinamide dihydrobromide in 27 ml of DMF and heat at -15 to -10°C.
Cool and add 1.63 ml of triethylamine. After reacting at this temperature for 20 minutes, the precipitate formed is removed to obtain a solution of L-histidyl-L-prolinamide. This is immediately used for the next synthesis reaction. 868mg of compound 2 and 859mg of HOBT in DMF14
ml and methylene chloride (14 ml) and cooled on ice.
Add 1.31 g of DCC and react for 40 minutes. The above DMF solution of L-histidyl-L-prolinamide is added to this reaction mixture, and the mixture is reacted overnight at 0 to 4°C.
The precipitate is removed, the liquid is concentrated to dryness, and the residue is subjected to column chromatography using silica gel. By eluting with chloroform-methanol-concentrated ammonia water (80:20:2), N
610 mg of -oxo-1-azetidinylacetyl)-L-histidyl-L-prolinamide 4 was obtained. NMR (CD ₃ OD) δppm: 7.60 (1H), 6.98 (1H),
4.44 (1H, m), 3.91 (2H, s), 3.74 (1H, m),
2.9-3.1 (4H, m), 1.8-2.2 (4H, m) IR (KBr) cm ^-1 : 3360, 1730, 1665, 1630 Mass (m/z): 362 (M ⁺ ). Example 2 Dissolve 843 mg of compound 1 in 0.8 ml of methanol,
Add 0.4ml of concentrated ammonia water under ice-cooling, and let it cool at room temperature.
Stirred for 18 hours. The reaction mixture was concentrated under reduced pressure;
The residue was subjected to column chromatography (silica gel
30 g, chloroform-methanol (10:1) to obtain 550 mg of crude product. This was crystallized by treatment with a mixture of chloroform (3 ml) and ether (3 ml) to obtain 5 to 360 mg of α-(2-oxo-1-azetidinyl)acetamide as colorless crystals. mp 112-113℃ NMR ( _CDCl3 ) δppm: 3.04 (2H, t, J=4
Hz), 3.42 (2H, t, J=Hz), 3.90 (2H, s),
5.88 (1H, broad), 6.35 (1H, broad)

Claims (1)

[Claims] 1. General formula [The symbols in the formula have the following meanings. R ¹ ; Amino group or group represented by the formula [Formula] R ² ; Group represented by the formula [Formula] or [Formula] R ³ ; Hydroxyl group, lower alkoxy group, or amino group R ⁴ ; Hydrogen atom or lower alkyl α-(2-oxo-1-azetidinyl) represented by
Acetic acid derivative or its salt 2 Formula () α-(2-oxo-1-azetidinyl) represented by
acetic acid or a reactive derivative thereof, and the general formula () R ¹ -H () [Symbols in the formula have the following meanings. R ¹ ; Amino group or group represented by the formula [Formula] R ² ; Group represented by the formula [Formula] or [Formula] R ³ ; Hydroxyl group, lower alkoxy group, or amino group R ⁴ ; Hydrogen atom or lower alkyl group] A general formula () characterized by reacting with ammonia represented by, or a histidylproline derivative or a compound in which the N-terminal amino group of a histidylproline derivative is activated. α(2-oxo-1-azetidinyl) represented by
Method for producing acetic acid derivatives.