JPH0585539B2 - - Google Patents

Description

[Detailed description of the invention]

[0001] New bicyclic β-lactam antibiotics, such as thienamycin and its semi-synthetic derivatives, have recently attracted attention. Here, these compounds will be referred to as "thienamycin group compounds." Although these compounds have high antibacterial activity in vivo, they are often metabolized within the mammalian body.

[0002] The main site where the above-mentioned metabolism occurs is the kidney, and in fact enzymes that hydrolyze β-lactams and inactivate thienamycin group compounds have been purified from kidney extracts. From the standpoint of cytological localization, substrate specificity, and sensitivity to enzyme inhibitors, this enzyme may be the well-known kidney dipeptidase (EC 3.4.13.11) (also called dehydropeptidase) itself. At least very similar. Note that β-lactamase activity is expressed only for thienamycin group compounds, and this type of metabolism is not observed in penicillin and cephalosporin, which are typical examples of β-lactam antibiotics.

[0003] The chemical substance that selectively inhibits the metabolism of dipeptidase according to the present invention, that is, the "dipeptidase inhibitor" is a Z-2-acylamino-3-monosubstituted propenoate and has the structure of the following formula. .

[0004]

[Case 2] ■■■ Turtle shell [0057] ■■■

[In the formula, A is a carbon atom 2 of which one or more hydrogens are substituted with an aryl group.
~9 alkylene groups; R ³ is an amino group whose terminal hydrogen is an amino group (which may be derivatized as an acylamino, ureido, amidino, guanidino, alkylamino or alkyl-substituted ammonium), an α-amino acid; from 1 to carbon atoms, which may be substituted with derivative groups, carboxyl groups, alkoxy groups, alkylthio groups, alkylsulfonyl groups or tetrahydrofuryl groups, and which may be substituted with one or more halogen atoms nine linear alkyl groups; R ¹ is hydrogen or a pharmaceutically acceptable cation] Some of the compounds having the above structural formula have an optically asymmetric structure. Upon optical resolution of the racemate, inhibitory activity was present in the dextrorotatory isomer with the S-coordination.

[0006] The compounds having the structural formula of the present invention include the following specific compounds.

[0007] Z-2-(2-spirocyclopentanecarboxamide)-2-butenoic acid; Z-2-(2-phenylcyclopropanecarboxyamide)-2-butenoic acid.

[0008] In the definition of ^R3 , alkyl-substituted ammonium is a hydrocarbon group having 1 to 7 carbon atoms on the positively charged ammonium nitrogen atom (these may be the same or different). It is a combination of three. The α-amino acid derivative group refers to O, N or S of known α-amino acids.
It means a residue such as cysteinyl ( _-SCH2CH ( _NH2 )COOH) or sarcosyl (-N( _CH3 ) _CH2COOH ) in which the hydrogen bonded to is substituted.

[0009] The above-mentioned compound has a Z configuration (J.Am.Chem.
Soc., 90 , 509, 1968).
Determined by NMR spectrum based on the method described in Tetrahedron Lett., p. 891, 1976.

[0010] The compound of the above structural formula has hitherto had R ¹
Although described as a free acid where H is H, it is well known that it can equally be used as a pharmaceutically acceptable derivative such as a salt of an alkali or alkaline earth metal, ammonium or amine. . Sodium, potassium, calcium or tetramethylammonium salts are suitable.

As mentioned above, the compounds of the invention are inhibitors of dipeptidases (EC3.4.13.11) and are used in conjunction with antimicrobial substances that can be degraded in the kidney. The most important group of antibiotics for use with the Z-2-acylamino-3-monosubstituted propenoate of the present invention is the "thienamycin group compounds".
It is. For details on such antibiotic groups, see Japanese Patent Publication No. 61-60816, column 4, line 44 to column 9, line 38.
listed on the line. Further, the specific method of sharing is described in detail in Column 18, Line 4 to Column 19, Line 5 of the same publication. Furthermore, the method for testing the performance of dipeptidase inhibitors to be used in combination with antibacterial substances is shown in Column 17, Line 7 to Column 18, Line 3 of the same publication. The inhibitor binding constant Ki (unit: μM) is desirably 100 or less.

[0012] Novel inhibitor compounds of the present invention ()
can be synthesized by directly condensing an appropriate 2-keto acid or ester () with an amide ().

【0013】

[Chemical 3] R ³ CH ₂ COCO ₂ R ()+R ² CONH ₂
() → In the above formula, R ² is a monovalent compound obtained by bonding -CH= adjacent to the 2-position amide group of the compound of the present invention and a divalent substituent A at two positions to form a ring. is a substituent, R ³ is as defined above,
R is hydrogen or alkyl. Standard reaction conditions are as follows.

[0014] By mixing the acid and amide at a molar ratio of about 1 to 4:1 in an inert solvent such as toluene or methyl isovalerate, and refluxing for 3 to 48 hours (preferably 5 to 24 hours), Remove water by azeotroping. Cooling of this solution usually yields the product as crystals, but it can also be obtained by base extraction of the product. The obtained crude product can be recrystallized by a conventional method.

[0015] When condensing from a ketoester, it is necessary to use a small amount of p-toluenesulfonic acid as a catalyst. This catalyst may also be useful in the condensation of keto acids.

Another route for synthesizing the novel inhibitor compounds of the present invention involves reacting α-amino acid t-butyl ester () with an acid chloride ().

[0017]

[Chemical 4] R ³ CH ₂ CH(NH ₂ )COOC(CH ₃ ) ₃
()+R ² COCl () This reaction proceeds in the presence of a base such as triethylamine in a solvent such as methylene chloride. The N-acylated product () obtained is oxidized with t-butyl hypochlorite followed by addition of sodium methylate. As a result, the 2-methoxy compound (2) and/or its eliminated product, the α,β-unsaturated ester (2), are obtained. Further treatment of this with anhydrous hydrochloric acid or (or a mixture thereof) is converted to the desired α,β-unsaturated acid ().

[0018]

[C5] ■■■ Turtle shell [0058] ■■■ ■■■ Turtle shell [0059] ■■■ ■■■ Turtle shell [0060] ■■■

[0019] The terminal hydrogen of R ³ is amino, quaternary nitrogen,
Many of the thio derivatives, alkoxy- or guanidino-substituted compounds can be easily synthesized from bromine-terminated intermediates. Ureido and the like can be derived from the amino end group by reacting potassium cyanide.

【0020】

[Examples] Hereinafter, specific embodiments of the present invention will be illustrated by examples.

Example 1 Z-2-[β-(2-phenylcyclopropyl)carboxyamide]-2-butenoic acid Based on the general synthesis method described above, the title compound was synthesized and recycled from nitromethane. crystallized (melting point 196
~197.5℃). The yield was 40%. Compared to the calculated value for C ₁₄ H ₁₅ NO ₃ , the actual value of elemental analysis is ±
The results agreed within 0.4%.

[0022] Inhibitor binding constant for this compound
Ki (unit: μM) was 5.

Claims (7)

[Claims] [Claim 1] Formula: [Chemical 1] ■■■ Tortoise shell [0056] ■■■ [In the formula, A is 2 to 9 carbon atoms of which one or more hydrogens are substituted with an aryl group R ³ is an alkylene group whose terminal hydrogen is an amino group (which may be derivatized as an acylamino, ureido, amidino, guanidino, alkylamino or alkyl-substituted ammonium);
carbon, which may be substituted with an α-amino acid derivative group, a carboxyl group, an alkoxy group, an alkylthio group, an alkylsulfonyl group or a tetrahydrofuryl group, and which may be substituted with one or more halogen atoms; A straight-chain alkyl group having 1 to 9 atoms; R ¹ is hydrogen or a pharmaceutically acceptable cation. 2. The compound according to claim 1, wherein the linear alkyl group has its terminal hydrogen substituted with an α-amino acid derivative group. 3. The compound according to claim 2, wherein the α-amino acid derivative group is a cysteinyl group. 4. The compound according to claim 1, wherein the straight chain alkyl group is unsubstituted. 5. The compound according to claim 4, wherein the linear alkyl group is a methyl group. 6. A compound according to claim 1, wherein the pharmaceutically acceptable cation is sodium, potassium, calcium or magnesium. 7. A compound according to claim 1, wherein R ¹ is hydrogen.