JPH0254342B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates broadly to caprolactam derivatives useful as angiotensin converting enzyme inhibitors and antihypertensive agents. The compounds of the present invention can be represented by the following general formula: [In the formula, R and R ⁴ are the same or different and represent a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group, or an amino group, and R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group ( However, the substituent is an amino group or a phthalimide group), a phenyl lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R ³ represents a hydrogen atom, a lower alkyl group, or an amino lower alkyl group. , an indolyl lower alkyl group, or a phthalimide lower alkyl group, and R ⁵ represents a hydrogen atom]; and a pharmaceutically acceptable salt thereof. Preferred compounds of the general formula are R and R ⁴ being the same or different hydroxy groups, lower alkoxy groups, and phenyl lower alkoxy groups, R ² being a hydrogen atom, lower alkyl group, phenyl group, and R ⁵ being a hydrogen atom. , R ¹ is an alkyl group having 1 to 8 carbon atoms, a substituted lower alkyl group (the alkyl group has 1 to 5 carbon atoms, and the substituent is an amino group or a phthalimide group) or a phenyl lower alkyl group , R ³ is a hydrogen atom, a lower alkyl group, an amino lower alkyl group, an indolyl lower alkyl group, or a phthalimide lower alkyl group. A more preferred compound represented by the general formula is one in which R ³ is a hydrogen atom, a lower alkyl group, an amino lower alkyl group, an indolyl lower alkyl group, and R ¹ has 1 to 8 carbon atoms. an alkyl group, a substituted lower alkyl group (the alkyl group has 1 to 5 carbon atoms and the substituent is an amino group or a phthalimide group)] or a phenyl lower alkyl group, R ⁵ is a hydrogen atom, and R ² is a hydrogen atom, a lower alkyl group, or a phenyl group, and R and R ⁴ are each independently a hydroxy group, a lower alkoxy group, or a phenyl lower alkoxy group. Among the compounds represented by the general formula, the most preferred ones are, where R ³ is a hydrogen atom or a lower alkyl group, R ¹ is an alkyl group having 1 to 8 carbon atoms, a substituted lower alkyl group (the alkyl group is having 1 to 5 carbon atoms, the substituent is an amino group, a phthalimide group, or a phenyl lower alkyl group, R ⁵ is a hydrogen atom, R ² is a hydrogen atom, a lower alkyl group, or a phenyl group, R and R ⁴ are each a hydroxy group, a lower alkoxy group, or a benzyloxy group. The above preferred, more preferred, and most preferred compounds also include pharmaceutically acceptable salts thereof. General formula The products and preferred subgroups of compounds may be prepared by one or more of the following formula methods: R, R ¹ , R ² , R ³ , R ⁴ unless otherwise noted. and R ⁵ are the same as those described in the general formula. R ⁷ = OH, OR ⁹ R ⁹ = lower alkyl, aryl or aralkyl R ⁸ = benzyloxycarbonyl, t-butoxycarbonyl, or other suitable protecting group known in peptide chemistry, X = iodo or bromolysine [or Blicke et al. J. Am. Chem.
Soc.76, 2317 (1954) and subsequently by the method of Tull et al. J.Org.Chem.29, ²⁴²⁵ (1964)]
N-protected derivatives by known methods.
Groups suitable as the protecting group R ⁸ include a phthalimide group, a t-butoxycarbonyl group, and a benzyloxycarbonyl group. R ⁷ is OH or an alkoxy group as required by the method below and R ⁴ is as defined above. The intermediate can be prepared in an aqueous solution with a keto acid or ester, preferably near neutrality, or in a suitable organic solvent such as methanol or acetonitrile in the presence of sodium cyanoborohydride or further if the protecting group does not interfere with the hydrogen. Reductive coupling with suitable catalysts is obtained. This intermediate (R ⁴ =OH and R ⁷ =OR ⁹ ) is heated with a base such as triethylamine in an organic solvent such as acetonitrile to give perhydroazepinone V. The protecting group R ⁸ is removed by a suitable known method and the resulting compound is reductively coupled to a keto acid, ester, etc. to obtain the compound.
Substituents at R and R ⁴ can be varied as necessary by standard methods. The intermediate can be further alkylated with haloesters such as: Additionally, intermediates where ^R4 is OH and ^R7 is OH can be cyclized using dicyclohexylcarbodiimide and N-hydroxysuccinimide in a suitable solvent such as DMF or methylene chloride. Other known peptide coupling methods can also be used if necessary. XII-A=p-toluenesulfonic acid ester -A=Br Also, hydroxy amino acid [Gandry, Can.J.
Res., 26B, 387 (1948)] to the N-protected hydroxy acid XI by established techniques, and then activated, such as by converting the terminal hydroxy group to the tosyl ester XII or bromide by known methods. Reaction with amino acid XI gives an intermediate which can be converted to in the manner described above. Substituted caprolactams (R ² ≠H) are conveniently prepared by Beckman ring expansion of the corresponding 2-substituted cyclohexanone oximes using standard reaction conditions. These caprolactams are then halogenated, e.g. Blacke et al. and Tull
et al., Wineman et al., J. Am. Chem.
Soc. 80, 6233 (1958) and Francis et al., J.Am.
3-amino derivatives can be obtained by the substitution reaction described in Chem. Soc. 80, 6238 (1958). The aminolactam is then obtained by alkylating the exocyclic nitrogen using or by the method described above. is obtained by alkylation in a solvent such as DMF or THF in the presence of a strong base such as sodium hydride. Halokaprolactam (Blicke and above)
Tull) can also be alkylated with a reagent in the presence of a strong base such as sodium hydride in a suitable solvent such as DMF or THF to give an alkylated halolactam. After treatment with azide ions, the above intermediate is obtained by catalytic hydrogenation. Halokaprolactam as amino acid derivative XI
can be reacted with to obtain an intermediate, which can be converted into by the method described above. The starting materials required in the above method are known in the literature or can be prepared from known materials by known methods. In products of the general formula, the carbon atoms and groups to which R ¹ , R ² and R ³ are bonded The ring carbon atom to which is bonded may be an asymmetric carbon atom. The compounds therefore exist in the form of diastereoisomers or enantiomers or mixtures thereof. The synthetic methods described above can use racemic enantiomers or diastereomers as starting materials and intermediates. When diastereomeric products are obtained by synthetic methods, they can be separated by chromatographic or fractional crystallization methods. If a racemic product is obtained, it can be resolved by crystallization of an optically active acid or base salt or by other known methods. The above-mentioned asymmetric carbon atom can have two configurations (S or R), both of which are within the scope of the present invention, but ^R2 , which is exemplified as a specific compound of the present invention, is bonded. S is generally preferred except for carbon configuration. The compounds of this invention form salts with various inorganic and organic acids and bases, which are also within the scope of this invention. These salts include ammonium salts,
Alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, dicyclohexylamine, N-
Examples include salts with organic bases such as methyl-D-glutamine, and amino acid salts such as arginine, lysine, and the like. Salts with organic and inorganic acids can also be formed. Examples include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid, camphorsulfonic acid, and the like. Also, while non-toxic physiologically acceptable salts are particularly useful, other salts are also useful, eg, in isolation or purification of the product. These salts can be prepared in a conventional manner, for example by reacting the free acid or free base form of the product with one or more equivalents of a suitable base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water. , and then removed by freeze-drying in vacuo or by exchanging the cations of the salt present for other cations on a suitable ion exchange resin. Compounds of the invention inhibit angiotensin converting enzyme and thus prevent the conversion of decapeptated angiotensin to angiotensin.
Angiotensin is a powerful pressor substance. Therefore, inhibiting its biosynthesis can have a blood pressure lowering effect, especially in animals and humans where angiotensin is associated with hypertension. Furthermore, the converting enzyme degrades the vasodilator bradykinin. Therefore, inhibitors of angiotensin converting enzyme can lower blood pressure by potentiating bradykinin. Although the relative importance of these and other possible mechanisms remains to be determined, inhibitors of angiotensin converting enzyme are effective hyperemic reagents in a variety of animal models and clinically used in patients with eg renovascular hypertension. , is effective in many human patients with malignant hypertension and essential hypertension. For example, DWCushman et al.
See Biochemistry 16, 5484 (977). Evaluation of convertase inhibitors is performed by in vitro enzyme inhibition assays. For example, a useful method is Y. Piquilloud, A. Reinharz and M.
Roth et al. Biochem. Biophys. Acta, 206, 136
(1970), and in this method the hydrolysis of carbobenzyloxyphenylalanylhistidinylleucine is measured. Also, in vivo
(vivo) evaluations can also be performed, for example, JR
Proc.Soc.Exp.Biol of Weeks and JAJones et al.
Med, 104, 646 (1960) in normotensive rats subjected to angiotensin according to the technique of S. Koletsky et al., Proc. Soc. Exp. Bial.
Med., 125, 96 (1967). Thus, the compounds of the invention are useful in the treatment of hypertension. They are also used in the management of acute and chronic congestive heart failure, in the treatment of secondary hyperaldosteronism, scleroderma, primary and secondary pulmonary hypertension, renal failure, and renovascular hypertension, and in the treatment of vascular disorders such as migraine. It is also useful for management. These compounds of the invention,
Applications to and similar disorders will be obvious to those skilled in the art. In the management of hypertension and the above-mentioned clinical conditions, the compounds of the present invention may be administered orally in tablets, capsules or elixirs, as suppositories for rectal administration, and in compositions such as sterile solutions or suspensions for parenteral or intramuscular administration. used. The compounds of this invention can be administered in dosages that will provide optimal pharmaceutical efficacy to patients in need of such treatment. The dosage typically used varies from patient to patient depending on the severity of the disease, the patient's weight, the special diet the patient has followed, concurrent drug administration, and other factors recognized by those skilled in the art. The dosage range is about 1 to 200 mg per day to the patient, which can be administered at once or in several divided doses. Preferably, the dosage range is about 2.5-100 mg per patient per day. It is often advantageous to administer the compounds of the invention in combination with other antihypertensive agents and/or diuretics. Compounds that can be used in combination with the compounds of the present invention include, for example, amiloride, atenolol, bendroflumesiazide, chlorthalidone, chlorthiazide, clonidine, criptenamine acetate and cryptenamine tannate, deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, Hydrochlorthiazide, hydroflumethiazide, metolazone, metoprolol tartate, methiclothiazide, methyldopa, methyldopa hydrochloride, minoxidil, (S)-1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-3- {[4-(2
-thienyl)-1H-imidazol-2-yl]phenoxy}-2-propanol, polythiazide, pivaloyloxyethyl ester of methyldopa, indacrinone and its enantiomers in various proportions, rifetipine, verapamil, diltiazam, flumethiazide, bendolo flumeshiazide, atenolol, (+)-4-{3-{[2
-(1-hydroxycyclohexyl)ethyl]-4
-Oxo-2-thiazolidinyl}propyl}benzoic acid, bmentanide, prazosin, propranol, indiabok, recinamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, quinesazone,
These include triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxyline procaine, and mixtures and combinations thereof. Typically, the individual daily doses will be about 1/5 or more of the maximum recommended amount of each taken alone.
Examples of these combinations include clinically 1 of the present invention.
One of the antihypertensive agents effective in the range of 2.5 to 100 mg/day can be effectively combined in amounts of 0.5 to 100 mg/day with the following indicated daily doses of the compound: Hydrochlorothiazide (10 ~100mg), timolol (5~60mg), methyldopa (65~200mg),
Pivaloyloxyethyl ester of methyldopa (30-1000 mg), indacrinone and its enantiomers in various proportions (25-150 mg) and (+)-4-
{3-{-[2-(1-hydroxycyclohexyl)
Ethyl]-4-oxo-2-thiazolidinyl}propyl}-benzoic acid (10-100 mg). Additionally, hydrochlorothiazide (10-100mg)
+ timolol (5-60 mg) + convertase inhibitor of the present invention (0.5-100 mg) or hydrochlorothiazide (10-100 mg) + amiloride (5-20 mg) + convertase inhibitor of the present invention (0.5-100 mg) A combination of three types of mixed drugs is also effective in controlling hypertension in hypertensive patients. Of course, these dosage ranges will be adjusted based on the range required for daily divided administration, and doses will depend on the nature and severity of the disease, patient weight, special diet, and other factors. It varies depending on the situation. Typically, these combinations can be formulated into pharmaceutical compositions as described below. about 0.5 to 100 mg of a compound of the general formula or a mixture of compounds or a physiologically acceptable salt thereof in a physiologically acceptable medium, carrier, excipient,
It is formulated into a unit dosage form with binders, preservatives, stabilizers, flavorings, etc. according to conventional pharmaceutical methods. The amount of active substance in these compositions or preparations may be such as to provide a suitable dosage within the above range. Additions to tablets, capsules etc. include: binders such as gum tragacanth, acacia, cornstarch or gelatin, excipients such as microcrystalline cellulose, cornstarch, pre-gelatinized starch, arginine. These include disintegrants such as acids, lubricants such as magnesium stearate, sweeteners such as lactose or saccharin, flavoring agents such as peppermint, wintergreen or cherry oil. When the dosage unit form is a capsule, it can contain, in addition to the above materials, a liquid carrier such as a fatty oil. Various other materials may also be present to modify the coating or physical form of the dosage form. For example, tablets may be coated with cilantro, sugar, or both. A syrup or elixir may contain the active compounds sutucarose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a cherry or orange flavor. Sterile compositions for injection are prepared by adding the active substance to water for injection, natural vegetable oils such as sesame oil, etc. according to conventional pharmaceutical methods.
It can be blended by being dissolved or suspended in a medium such as coconut oil, peanut oil, cottonseed oil, or a synthetic fatty medium such as ethyl oleate. The examples given below are illustrative of the invention and constitute particularly preferred embodiments. Preferred diastereomers of these examples are isolated by column chromatography or fractional crystallization. Example 1 1-Carboxymethyl-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one 10.45 g of N〓-Boc-N〓-Cbz-L- lysine
Dissolve in 125ml methanol and 17ml water. The solution was neutralized with 27.5 ml of 0.5 M cesium carbonate solution,
The resulting solution is concentrated to a syrup at aspirator pressure and 35°C. 100ml syrup
of dimethylformamide and concentrate. Repeat this once again. The residue is dissolved in 75 ml dimethylformamide and 2.7 ml methyl iodide.
The reaction is stirred overnight at room temperature and then the dimethylformamide is removed under vacuum (oil pump).
Add 250 ml of water to the residue and extract into 150 ml of ethyl acetate. 100% ethyl acetate extract
Wash twice with ml of water and then remove the organic phase.
Dry over _MgSO4 . The dried solution is filtered and concentrated in vacuo to give N-Boc-N-Cbz-L-lysine methyl ester. 11.5 g of N〓-Boc-N〓-Cbz-L-lysine methyl ester and 3.3 g of glyoxylic acid hydrate 80
Prepare a ml methanol solution. Add 2 g of 10% palladium activated carbon catalyst and bring the initial pressure to room temperature.
Hydrogenation is carried out for 3 hours at 40 Psi gauge (approximately 2.8 Kg/cm ² gauge). The reaction solution is filtered to remove the catalyst, and the catalyst is washed with methanol. The liquid and washing solution are combined and concentrated in vacuo to N-Boc-N-carboxymethyl-L-lysine methyl ester. 8.0g of N〓-Boc-N〓-carboxymethyl-L
- Lysine methyl ester and 4.7 ml of triethylamine are added to 2.8 ml of acetonitrile and the mixture is refluxed for 3 days. The reaction is cooled and concentrated on a rotary evaporator at aspirator pressure to a yellow glass. glassy material
Dissolve in 175 ml of CH ₂ Cl ₂ and wash three times with 55 ml portions of 20% citric acid, then twice with 55 ml portions of IN NaHCO ₃ . NaHCO ₃ wash solution combined 40%
Adjust the pH of the citric acid solution to 3. The acidified solution is extracted with 6 portions of 60 ml of CH ₂ Cl ₂ . The organic extracts are dried over _MgSO4 , filtered and concentrated at aspirator pressure to yield 3-(S)-t-butoxycarbonylamino-1-carboxymethyl perhydroazepin-2-one. tlc (silica, 20 ethyl acetate: 5 pyridine: 1 acetic acid: 1 water) Rf = 0.8 2.1 g of 3-(S)-t-butoxycarbonylamino-1-carboxymethyl perhydroazepin-2-one was added to 70 c.c. Dissolve in ice-cooled 4NHCl ethyl acetate solution and stir at 0°C for 1 hour. Remove the cooling bath and sparge the mixture with nitrogen for 20 minutes. The precipitate was filtered and washed with ether to give 3-(S)-
Amino-1-carboxymethyl perhydroazepin-2-one hydrochloride is obtained as a white solid. The liquid and washing liquid are combined and filtered to obtain additional product. 4.45g of 2-oxo-4-phenylbutyric acid in 25ml
of water and adjust the pH to 7 with 50% NaOH.
Add 1.14 g of 3-(S)-amino-1-carboxymethyl perhydroazepin-2-one hydrochloride and adjust the pH to 7 again with 50% NaOH. The resulting solution was diluted with water to a total volume of 60 ml and then 0.943 g
of sodium cyanoborohydride. 50ml Dowex after 2 days at room temperature
50 (H ⁺ ) is added and the mixture is stirred for 1 hour. The mixture is extracted with ether and then the Dowex 50 and the aqueous portion are added to the top of a 100 ml column of Dowex 50 (H ⁺ ). Elution is first carried out with water until the eluate becomes neutral, and then with a 2% aqueous solution of pyridine until no more product is eluted (ninhydrin detection). The product containing the eluted fractions is concentrated under aspirator pressure and the residue is redissolved in 50 ml water and refrigerated to dryness. 1-carboxymethyl-3
-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one is isolated as a white extractable solid. Mass spectrum: M+348; 330 (M- _H2O ); 303
(M-CO ₂ H) NMR: (D ₂ O, TSS), δ1.4-2.5 (m, 8H); δ2.6
−3.1 (m, 2H); δ3.3−4.0 (m, 3H); δ4.1
-4.3 (m, 3H); δ7.4 (S, 5H). Example 2 1-Carboxymethyl-3-(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one 280 mg of 1-carboxymethyl-3-(S)-
Aminoperhydro-2-azepinone hydrochloride 50
ml of water and adjust the pH to 6.8 with benzyltrimethylammonium hydroxide solution. The reaction solution is lyophilized and the residue is dissolved in 10 ml of absolute ethanol. Add 1.3 g of ethyl 2-oxo-phenyl butyrate and 7.5 g of powdered 4A molecular sieve. 357 mg of sodium cyanoborohydride was added to the stirred mixture over a period of 4 hours.
Add in equal portions and then stir the reaction solution at room temperature for 1 minute.
Stir overnight. Filter the reaction solution and wash the filter cake with ethanol. The combined filtrate and washings are concentrated in vacuo and the residue is dissolved in 40 ml of water. 10ml
of Dowex 50 (H ⁺ ) and 25 ml of ether are added and the mixture is stirred for 1 hour. The ether layer is removed and the aqueous portion is extracted again with ether. Remove the ether and add 20ml of the aqueous slurry to Dowex 50
(H ⁺ ) column. Elution is first carried out with water until the eluate is neutral and then with a 2% aqueous pyridine solution until no more product is eluted.
The product containing eluted fractions is concentrated in vacuo and the residue is dissolved in water and lyophilized. 396 mg of 1-carboxymethyl-3-(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one is isolated as a white solid. NMR: (D ₂ O, TSS) δ1.2−1.5 (t, 3H); δ1.5
-2.6 (m, 7H); δ2.5-3.2 (m, 2H); δ3.3
-3.7 (m, 3H); δ3.8-4.6 (m, 6H); δ7.4
(S, 5H). Mass spectrum: M+376; 331 ( _MC2H5O ) _;
317 (M-CH ₂ CO ₂ H); 303 (M-
_{CO2C2H5 ) .} Similarly, 3-(S)-amino-1-carboxymethyl perhydroazepin-2-one was converted into ethyl 4
-(3-indolyl)-2-oxobutyrate to react with 1-carboxymethyl-3-(S)-[(1
-ethoxycarbonyl-3-(3-indolyl)
Propyl)amino]perhydroazepin-2-one is obtained. By subjecting this material to standard alkaline hydrolysis (as in Example 3)
1-Carboxymethyl-3-(S)-[(1-carboxy-3-(3-indolyl)propyl)amino]
Perhydroazepin-2-one is obtained. or,
1-Ethoxycarbonylmethyl-3-(S)-1- by esterification in HCl-ethanol
(1-ethoxycarbonyl-3-(3-indolyl)propyl)amino]perhydroazepine-2
-On is obtained. Example 3 1-(1-carboxyethyl-3-(S)-[(1
-carboxy-3-phenylpropyl)amino]-perhydroazepin-2-one 7.6 g N〓-Boc-N〓-Cbz-L-lysine 2.04
Dissolve g of methyl pyruvate in 75 ml of methanol solution. Add 2 g of 10% palladium on activated carbon and hydrogenate at room temperature for 3 hours at an ^initial pressure of 40 psi gauge. Filter the solution, concentrate the liquid using a spirator pressure, and add N〓−Boc−
N-(1-methoxycarbonylethyl)-L-lysine is obtained. 4.76 g of this ester and 1.64 g of N-hydroxysuccinimide are dissolved in 250 ml of dimethylformamide, the solution is cooled to 0 DEG C. and a solution of 3.24 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide is added. The reaction solution was heated at 4°C for 2
Store for days. The molten metal is removed in vacuo (oil pump) and the residue is taken out in chloroform. The mixture is filtered and the liquid is concentrated. The residue was dissolved in 1:1 ethyl acetate-hexane and chromatographed on silica gel using 7:3 hexane:ethyl acetate as the developing solvent. The fractions containing the desired product were combined and concentrated under aspirator pressure to yield 1.75 g of 3-(S)-t-butoxycarbonyl-amino-1-(1-methoxycarbonylethyl).
Perhydroazepin-2-one is obtained. tlc (silica, 7:3 hexane:ethyl acetate) Rf=
0.5NMR (CDCl ₃ , TMS) δ1.2−2.4 (m, 18H);
δ3.2−3.6 (broad, 2H); δ3.7 (S, 3H); δ4.1
−4.6 (broad, 1H); δ4.5−5.4 (2q, 1H); δ5.8
−6.1 (Broad, 1H). Mass spectrum: M+314 (weak); 258 (M-
_C4H8 ); 241 ( _{M - C4H9O} ). 2.5 g of 3-(S)-t-butoxycarbonyl-
Amino-1-(1-methylcarbonylethyl)perhydroazepin-2-one is dissolved in 10 ml of methanol and 10 ml of water and 0.5 ml of 50% NaOH solution is added. The mixture is stored at room temperature for 2 hours and after storage concentrated to a syrup using aspirator pressure. Dissolve the syrup in water and allow the solution to cool in an ice bath. After adjusting the pH to 2 by adding 6N hydrochloric acid, the solution is extracted several times with ethyl acetate. Combine the extract liquid
Dry over MgSO ₄ and concentrate the filtrate under aspirator pressure to obtain 3-(S)-t-butoxycarbonylamino-1-(1-carboxyethyl)perhydroazepin-2-one as a mixture of diastereomers. Isolated as an oil (2.04 g). These isomers were incubated at 50 °C on an XAD ₂ resin column.
Contains 6% acetonitrile in
Separate using 0.1NNH ₄ OH as a developing solvent.
The ammonium salt of the desired isomer is isolated as the first to elute (UV and refractive index detection). 610 mg of the desired isomer are treated with 20 ml of 4N hydrogen chloride in ethyl acetate at 0° C. for 1 hour. After warming the mixture to room temperature and purging with nitrogen for 20 minutes, the solution is concentrated to dryness. The residue is dissolved in water and concentrated again to obtain 3-(S)-amino-1-(1-carboxyethyl)perhydroazepin-2-one hydrochloride. 422 mg of 3-(S)-amino-1-(1-carboxyethyl)perhydroazepin-2-one hydrochloride is dissolved in water and the pH is adjusted to 6.8 with 2M tetrabutylammonium hydroxide. The solution is lyophilized and the residue is dissolved in 10 ml absolute ethanol. Add 1.98 g of ethylmer oxo-4-phenyl butyrate and 7 g of powdered 4A molecular sieves.
A solution of 357 mg of sodium cyanoborohydride in 3 ml of absolute ethanol is added at a rate of 0.5 ml/hour.
After the addition is complete, the reaction is stirred overnight at room temperature. The reaction solution is filtered, the filter cake is washed with ethanol, and the solution and washings are combined and concentrated under aspirator pressure. The residue is dissolved in water and 20 ml of ether and 20 ml of Dowex 50 (H ⁺ ) are added. Stir the mixture for 1 hour and remove the ether layer. The aqueous suspension is extracted twice more with ether and the aqueous portion is then added to a 100 ml column of Dowex 50 (H ⁺ ). Elute with water until the eluate becomes neutral, then elute with a 2% aqueous pyridine solution,
Collect 600ml of eluate. The eluate is concentrated in vacuo, the residue is dissolved in water and lyophilized. 1-(1
-carboxyethyl)-3-(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]
Perhydroazepin-2-one is isolated as a powder (652 mg). NMR: (D ₂ O, TSS) δ1.2−1.5 (t+d, 6H);
δ1.5−2.6 (m, 8H); δ2.6−3.1 (m, 3H);
δ3.2−3.6 (broad, 2H); δ3.9−4.5 (q+
m, 4H); δ7.3 (S, 5H). Mass spectrum: (as monotrimethylsilyl derivative) M+ = 462; 447 (M- _CH3 ); 389,
373. 110 mg of this ethyl ester is dissolved in 1 ml of 1N sodium hydroxide, and the solution is heated at 45° C. overnight. The reaction solution was chromatographed on a Dowex 50 (H ⁺ ) column, first eluted with water, then 2
Elution is performed with % pyridine aqueous solution. 1- in vacuum
The fraction containing (1-carboxyethyl)-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one is concentrated and then freeze-dried. Mass spectrum: (as bistrimethylsilyl derivative): M+, 506; 491 (M+ _-CH3 );
391 (M ⁺ _−CO2TMS ). Example 4 1-Carboxymethyl-3-(S)-[(1-carboxyethyl)amino]perhydroazepine-
2-one 196 mg benzyl pyruvate and 128 mg 3-one
(S)-Aminoperhydroazepin-2-one (Adamson, J. Chem. Soc., 1943, 39) is dissolved in 5 ml of tetrahydrofuran. 0.5 g of anhydrous soluble magnesium acid is added and then a solution of 63 mg of sodium cyanoborohydride in 5 ml of tetrahydrofuran is added dropwise over a period of 25 minutes. After the addition is complete,
The reaction was stirred for an additional hour. Filter the reaction mixture in vacuo. The residue is dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and the filtrate is concentrated in vacuo to give 237 mg of a clear oil. This crude product in ethyl acetate:
Chromatograph on silica gel, eluting with acetonitrile (95:5). 3-(S)-[(1-
The fraction containing benzyloxycarbonylethyl)amino]perhydroazepin-2-one is concentrated. tlc: (silica, ethyl acetate:acetonitrile,
95:5) Rf=0.23 NMR ( _CDCl3 , TMS): δ1.2−2.3 (m, 10H);
δ2.8−3.7 (q+m, 5H); δ5.2 (S, 2H);
δ6.8 (Broad, 1H); δ7.3 (S, 5H). 320 mg of 3-(S)-[(1-benzyloxycarbonylethyl)amino]perhydro-2-azepinone was dissolved in 10 ml of tetrahydrofuran,
0.80ml of 1.37M potassium t-amyloxide
- Add amyl alcohol solution. After 1-2 minutes
A solution of 310 mg of benzyl iodoacetate in 2 ml of tetrahydrofuran is added all at once. 65 at room temperature
After a period of time, the reaction solution is poured into water. After extraction with ether, the organic phase is washed with water and then with brine.
The ether solution is concentrated in vacuo to obtain 440 mg of crude product. The crude product is chromatographed on silica gel eluting with ethyl acetate:acetonitrile (95:5). The fractions containing 1-benzyloxycarbonylmethyl-3-(S)-[(1-benzyloxycarbonylethyl)amino]perhydroazepin-2-one are combined and concentrated to a colorless oil. NMR: (CDCl ₃ , TMS) δ1.2−2.2 (m+d,
9H); δ3.2 (broad, 2H); δ3.5−4.0
(m, 2H); δ4.1−5.0 (m, 2H); δ5.1−5.2
(2S, 4H); δ6.2 (broad, 1H); δ7.3
(S, 10H). Dissolve this diester in aqueous ethanol and
Hydrogenation is carried out over % palladium-activated carbon at an initial pressure of 40 psi gauge (approximately 2.8 Kg/cm ² gauge).
The reaction solution is filtered and the solution is concentrated in vacuo to give 1-carboxymethyl-3-(S)-[(1-carboxyethyl)amino]perhydroazepin-2-one. Example 5 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one 1.5 g of 3,3-dichloroperhydroazepin-2-one [WCFrancis et al., J.Am.Chem.Soc.,
80, 6238 (1958)] in 5 ml of dimethylformamide and the solution was purged with nitrogen. 6.05ml
Add 1.37M potassium t-amyl oxide in t-amyl alcohol and stir for 5 minutes. 2.25
g of ethyl 2-iodopropionate are added and the mixture is then stirred for 4 days at room temperature. Concentrate the reaction in vacuo, add toluene and concentrate again. adding a second toluene portion and filtering;
Concentrate the liquid under vacuum. The residue is chromatographed on silica gel using hexane:ethyl acetate (7:3). Collect the fractions containing the product,
786 g of 3,3-dichloro-1-(1-ethoxycarbonylethyl)perhydroazepin-2-one are isolated. tlc: silica, hexane: ethyl acetate (7:3)
Rf=0.5 NMR: (CDCl ₃ , TMS) δ1.1−2.3(m+t+d,
10H); δ2.5−2.8(m, 2H); δ3.4−3.7(m,
2H); δ4.2 (q, 2H); δ5.05 (q, 1H). Saturate 20ml of methanol with ammonia and 78/
Add mg of the above dichloro compound and 8 ml of water. Transfer 50mg of this solution onto 10% palladium-activated carbon.
Hydrogenation is performed at an initial pressure of 40 psi gauge (approximately 2.8 Kg/cm ² gauge). Filter the mixture and concentrate the liquid in vacuo. Triturate the residue with 50 ml of chloroform, filter and concentrate. The residue is chromatographed on silica gel, eluting with hexane:ethyl acetate (7:3). 3-chloro-1
Fractions containing -(1-ethoxycarbonylethyl)perhydroazepin-2-one as a mixture of diastereomers are collected and concentrated. Mass spectrum: M+247; 212 (M+-Cl); 202
₍ M+ _-C2H5O ). 5.4 g of this monochloroester and 1.63 g of sodium azide are dissolved in a mixture of 5 ml ethanol and 9 ml water. The mixture is refluxed overnight, cooled and concentrated in vacuo. Extract the residue into chloroform, filter, dry the liquor over magnesium sulfate, filter, and concentrate the liquor. The residue is chromatographed on silica gel, eluting with hexane:ethyl acetate (9:1). 3-Azide-1-
The fractions containing (1-ethoxycarbonylethyl)perhydroazepin-2-one are combined and concentrated. Infrared spectrum: νN=N, 2100cm ^-1 ; νC=O,
Ester 1740cm ^-1 ; νC=O, amide 1650
cm ^-1 . The azide is hydrogenated over 10% palladium on activated carbon in aqueous ethanol. After filtration and concentration of the liquid in vacuo, 3-amino-1-(1-carboxyethyl)perhydroazepin-2-one is isolated. This amino ester was hydrolyzed with 1N sodium hydroxide and converted to Dowex 50 (H ⁺ ) using first water and then 2% pyridine aqueous solution as the developing solvent.
3-amino-1-
(1-carboxyethyl)perhydroazepine-
Isolate 2-one. This amino acid was prepared in the same manner as in Example 3 to obtain 1-(1
-carboxyethyl)-3-[(1-carboxy-
3-phenylpropyl)amino]perhydroazepin-2-one. Example 6 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)aminoperhydroazepin-2-one 2.66 g of chromium trichloride hexahydrate in an oxygen-free system A solution of chromous chloride is prepared by adding 5 ml of 5% hydrochloric acid solution to 654 mg of zinc powder. After stirring for 1 hour, excess zinc is removed under nitrogen atmosphere. 3,3-dichloro-1-(1-ethoxycarbonylethyl)perhydroazepine-2-
Add 5 ml of an oxygen-free acetone solution of 100% chloride (made by the method of Example 5) to the above solution. After 30 minutes, the acetone is removed in vacuo, 15 ml of water are added and the aqueous mixture is extracted three times with 20 ml portions of dichloromethane. The organic extract is concentrated in vacuo and the residue is chromatographed on silica gel, eluting with hexane/ethyl acetate (7:3). 3-chloro-
The fractions containing 1-(1-ethoxycarbonylethyl)perhydroazepin-2-one are combined. tlc: (silica, hexane:ethyl acetate, 7:3)
Rf=0.58 This monochloroester is converted to 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one in the same manner as in Example 5. Example 7 1-Carboxymethyl-3-(S)-[(1-carboxy-2-phenylethyl)amino]perhydroazepin-2-one 500 mg of 3-(S)-amino-1-carboxymethyl perhydroazepine Prepare a 5 ml aqueous solution of -2-one. Adjust the pH to 6 with 1N sodium hydroxide solution and add 15 ml of water. This amine is 2.24
g of sodium phenylpyruvate-hydrate and
400 mg of sodium cyanoborohydride and Example 1
The reaction is carried out in the same manner as in . 370 mg of the crude product was purified on an LH-20 column to give 240 mg of 1-carboxymethyl-3-(S)-[(1-carboxy-
2-Phenylethyl)amino]perhydroazepin-2-one is isolated. Mass spectrum (bistrimethylsilyl derivative): M+478; 463 (M+ _-CH3 ); [M+ _CO2Si
(CH ₃ ) ₃ ] NMR (D ₂ O + NaOD): δ1.2−2.0 (m, 6H); δ2.7
−3.0 (d, 2H); δ3.0−4.3 (m, 6H); δ7.3
(s, 5H). Example 8 1-Carboxymethyl-3-(S)-[(1-ethoxycarbonyl-4-phenylbutyl)amino]perhydroazepin-2-one 1.08 g of 3-(S)-amino-1-carboxymethylper Hydroazepine-2-one hydrochloride 5.3g
of ethyl 2-oxo-5-phenylpentanoate, 0.49 g of triethylamine and 630 mg of sodium cyanoborohydride are reacted as in Example 2. The crude product is purified by chromatography on LH20 to isolate the desired ester. NMR (CDCl ₃ + TMS): δ1.3 (t, 3H); δ1.4−
2.4 (m, 10H); δ2.7 (broad t, 2H);
δ2.9−3.9 (m, 5H); δ3.9−4.5 (m, 4H);
δ7.3(s, 5H). Mass spectrum: M+390; 372 (M+ _-H2O );
361 (M+ _-C2H5 ); ₃₄₅ ( _M + _OC2H5 ). Example 9 1-Carboxymethyl-3-(S)-[(1-carboxy-4-phenylbutyl)amino]perhydroazepin-2-one 100 mg of 1-carboxymethyl-3-(S)-
[(1-Ethoxycarbonyl-4-phenylbutyl)amino]perhydroazepin-2-one is hydrolyzed with sodium hydroxide in the same manner as in Example 2. The reaction product is purified on a Dowex 50 to isolate the diacid. NMR (D ₂ O): δ1.4−2.4 (m, 10H); δ2.8 (t,
2H); δ3.2−4.0 (m, 4H); δ4.0−4.8 (m,
3H); δ7.4 (s, 5H). Mass spectrum: M+362; 344 (M+ _-H2O );
317 (M+ _-CO2H ). Example 10 1-Carboxymethyl-3-(S)-[(1-ethoxycarbonyl-4-methylpentyl)amino]perhydroazepin-2-one 815 mg of 3-(S)-amino-1-carboxymethylper 5 ml of hydroazepine-2-one hydrochloride
Dissolve in water, adjust the pH to 6 with 1N sodium hydroxide, and freeze-dry. This salt is reacted as in Example 2 with 3.0 g of ethyl 2-oxo-5-methylhexanoate and 660 mg of sodium cyanoborohydride. The crude product was purified by chromatography on LH-20 to yield 476 mg of pure 1-carboxymethyl-3-(S)-[(1-ethoxycarbonyl)-4-methylpentyl)amino]perhydroazepine-2- Isolate on. NMR ( _D2O , dioxane, δ3.6 internal standard): δ0.7 (d, 6H); δ1.1 (t, 3H); δ1.3−2.2
(m, 11H); δ3.0−3.4 (broad, 2H);
δ3.5−4.3 (m, 6H). Mass spectrum: (monotrimethylsilyl derivative) M+, 414; 399 (M+ _-CH3 ); 341 (M+-
CO ₂ C ₂ H ₅ ) Example 11 1-Carboxymethyl-3-(S)-[(1-carboxy-4-methylpentyl)amino]perhydroazepin-2-one 210 mg of 1-carboxymethyl-3- (S)-
[(1-Ethoxycarbonyl-4-methylphenyl)amino]perhydroazepin-2-one is hydrolyzed with sodium hydroxide in the same manner as in Example 3. Dowex 50 hydrolyzed ester
The diacid is isolated by purification on (H ⁺ ). NMR: CD ₂ O, dioxane δ0.7 (d, 6H); δ0.9−2.3 (m, 11H); δ2.9
−4.4 (m, 6H). Mass spectrum: M+, 314; 296 (M+-
_H2O ); 269 (M+ _-CO2H ). Example 12 3-[t-butoxycarbonylamino]-1-
(1-Carboxyethyl)perhydroazepin-2-one 7.6 g N-t-butoxycarbonyl-N-benzyloxycarbonyl-L-lysine and 1.81 ml
A 75 ml methanol solution of methyl pyruvate is hydrogenated over 10% palladium-carbon in a conventional manner. After filtration and concentration, N-t-butoxycarbonyl-N-(1-methoxycarbonyl-1-ethyl)lysine is isolated. 4.76 g of this lysine derivative, 1.64 g of N-hydroxysuccinimide and 3.24 g of dicyclohexylcarbodiimide are dissolved in 250 ml of DMF. This reaction solution is stored at 0°C for 2 days. Concentrate the reaction in vacuo and dissolve the residue in ethyl acetate. The product is filtered and purified by silica gel chromatography. Purified 3-(S)-t-butoxycarbonylamino-1-(1-methoxycarbonylethyl)perhydroazepin-2-one is isolated. Add 2.59g of this ester to 10ml methanol and 0.5g of this ester.
Hydrolyze in 10 ml _H2O containing 50% NaOH. After 2 hours at room temperature, the reaction is concentrated in vacuo, water is added, cooled to 0° C., acidified to PH2 and extracted with ethyl acetate. The extract is dried and overconcentrated to obtain the acid. This acid was maintained at 50 °C into crushed XAD−
2 resin column, 6% CH ₃ CN: 94%
Separate the diastereomers by elution with 0.1M NH ₄ OH. The diastereomer (isomer A) that first elutes from the column is isolated as an ammonium salt.
This compound is added to 3-(S)-t-butoxycarbonylamino-1-(1-carboxyethyl)perhydroazepin-2-one by carefully acidifying the aqueous solution. This acid is recrystallized from ether-petroleum ether. Melting point 125-126°.
[α] 25°Na = -33.6° (C = 1.8, EtOH). Elemental analysis calculated value (as C ₁₃ H ₂₄ NO ₅ ): C55.98; H8.05; N9.32 Actual value: C55.87; H8.09; N9.37 Second eluting diastereomer (isomer) Body B) 1-(4-carboxy-1-ethyl)-3-
Isolate (S)-t-butoxycarbonylaminoperhydroazepin-2-one. NMR (D ₂ O, TSS) δ1.3−1.5 (s+d, 12H);
δ1.6−2.2 (m, 6H); δ3.3−3.7 (m, 2H);
δ4.4 (m, 1H); δ4.9 (q, partially obscured by _H2O , 1H). Example 13 1-ethoxycarbonylethyl-3-(S)-
[(1-Carboxy-3-phenylpropyl)amino]perhydroazepin-2-one 3-(S)-t-butoxycarbonylamino-1-(1-carboxyethyl) made in Example 12
Perhydroazepin-2-one (isomer A) 2g
was treated with thionyl chloride in absolute ethyl alcohol to give 2.07 g of 3-(S)-amino-1-(1-
ethoxycarbonyl) perhydroazepine-2-
Obtain on hydrochloride. This material was carefully neutralized with ethanolic sodium ethoxide and then condensed with benzyl 2-keto-4-phenylbutyrate as in Example 1. The ketoester was prepared by treating the ketoacid with thionyl chloride in benzyl alcohol and purified via sodium bisulfite addition product. The diastereoisomeric mixture (10.6 g) obtained from this reductive amination was chromatographed on silica gel to yield the respective isomers: isomer A (first elution from the column) and isomer B ( second elution). Each of these was hydrogenated in ethanol over 10% Pd/C at atmospheric pressure to produce 299 mg of 1-ethoxycarbonylethyl-3-(S)-[(1-carboxy-3-phenyl-1-propyl)amino]per Hydroazepin-2-one (isomer A) and 762
mg of 1-ethoxycarbonylethyl)-3-(S)
-[(1-carboxy-3-phenyl-1-propyl)amino]perhydroazepin-2-one (isomer B) was obtained. The first isomer spontaneously transformed from an oil to an amorphous solid (melting point 104-110°C).
The NMR spectrum (CDCl ₃ ) has an aromatic proton singlet at 7.19ppm and an ethyl quadruplet at 4.13ppm.
and the methyl doublet (1.27 ppm) superimposed on the ethyl triplet (1.21 ppm). Second
The NMR spectrum of the isomer of (CDCl ₃ ) is
Aromatic proton singlet at 7.26ppm, ethyl quartet at 4.19ppm, methyl doublet at 1.37ppm and
An ethyl triplet was shown at 1.23 ppm. Example 14 1-carboxymethyl-3-(S)-[(1-carboxy-5-phthalimidyl-1-pentyl)
Amino]perhydroazepin-2-one From the acid of Example 1 S.Wang, J.Org.Chem., 42,
2.86 g of 3- made by the method of 1286 (1977)
(S)-amino-1-benzyloxycarbonylmethyl perhydroazepine-2-one hydroxide 13.4
g of benzyl 2-oxo-5-phthalimidyl hexanoate and 1.73 g of sodium cyanoborohydride are reacted analogously to Example 39. Concentrate the reaction solution in vacuo and dissolve the residue in water.
Adjust the pH to 1 with 6NHCl. After 5 minutes _with 10% _Na2CO3
Adjust the pH to 9.5 and extract with ethyl acetate. The extract is dried and concentrated to obtain the crude diester. Chromatography is performed on silica gel using ethyl acetate-hexane (3:2) as the developing solvent. 2
Isolate the diastereomer eluting at 2.27
g diester is obtained. Add 2.6g of this diester to 15ml dioxane and 5ml
10% palladium dissolved in _H2O and 0.1 ml acetic acid.
Hydrogenation is carried out by a conventional method using activated carbon as a catalyst. Overconcentrate the reaction solution. The residue is chromatographed on LH-20 resin to isolate 1.35 g of diacid. tlc silica gel, _CHCl3 : _CH3OH −8:2Rf=
0.25. Mass spectrum: M+445, m/e400 (M+-
_CO2H ). Example 15 1-carboxymethyl-3-(S)-[(5-amino-1-carboxy-1-pentyl)amino]
Perhydroazepin-2-one The first phthalimide acid described in Example 14 550
mg is dissolved in 5 ml of CH ₃ OH containing 0.159 ml of N-methylhydrazine. The solution is refluxed for 2 hours and then stored at room temperature overnight. The solution is concentrated in vacuo and the residue is dissolved in _H2O . pH to 1 with HCl
and heated on a water bath for 1 hour, then the solution was
Store overnight at °C. Filter and concentrate the liquid. The crude product is purified on LH-20 eluting with methanol. Mass spectrum (tetra-trimethylsilyl derivative): M+603, m/e588 (M+ _-CH3 ); 573 (M+
−2CH ₃ ); 471 [M+−2CH ₃ −CO ₂ Si
( _CH3 ) ₃ ]. Similarly, the second phthalimidodiacid explained in Example 14 was converted into 1-carboxyethyl-3-(S)-
[(5-amino-1-carboxy-1-pentyl)
[amino]perhydroazepin-2-one. Example 16 1-[(1-benzyloxycarbonyl-5-phthalimidyl)pentyl]-3-[1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one 302 mg of 1-[(1- Benzyloxycarbonyl-5-phthalimidyl)pentyl]-3-(S)-
(t-Butyloxycarbonylamino)perhydroazepin-2-one (prepared in Example 19) was treated with a solution of 4MHCl in ethyl acetate,
The solvent was removed in vacuo and taken up in 20ml ethanol, 471mg of 2-keto-4-phenylbutyric acid, 112mg
of sodium methylate in 10 ml of ethanol and 2 g of molecular seeds are added and stirred for 1 hour. then 140 mg of NaBH ₃ CN over 10 hours
Add 15 ml of ethanol solution. go through the troubles,
Then 20 ml of water, 20 ml of ether are added and stirred for 1 hour with 15 ml of Dowex 50 (H ⁺ ) ion exchange resin. The water-resin layer is separated, washed with ether and loaded onto the top of a column containing 60 ml of Dowex 50 (H ⁺ ). Wash the column with water and
Elution is then carried out with a 4% aqueous pyridine solution and methanol. The solvent is removed from the eluted product and the residue is further chromatographically purified on a LH-20 packed column in methanol. The solvent is distilled off from an appropriate fraction to obtain the desired product as a mixture of isomers. The pmr spectrum is consistent with the structure, and the mass spectrum of the silylated material shows m/e = m/e of the monosilylated product.
Shows the molecular ion in 711. Similarly, the above 3-aminoperhydroazepin-2-one was converted into ethyl-4-(3-indolyl)-2
1-[(1-benzyloxycarbonyl-5-phthalimidyl)pentyl]-3 by treatment in the presence of -oxo-butyrate and NaBH ₃ CN
-[(1-ethoxycarbonyl-3-(3-indolyl)propyl)amino]perhydroazepine-
Get 2-on. Example 17 1-[(1-carboxy-5-phthalimidyl)
pentyl]-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazepine-
2-one 604 mg of benzyl ester obtained in Example 16
Add 0.15g of 10% palladium to 20ml of methanol solution.
Perform hydrogenation on carbon for 20 hours. The solvent is removed by filtration to obtain the desired diacid. The pmr is consistent with the structure and confirms the disappearance of the benzyl ester. The mass spectrum of the silylated material shows a molecular ion at m/e = 693 for the disilylated product and m/e 765 for the trisilylated product. Similarly, 1-[(1-benzyloxycarbonyl-5-phthalimidyl)pentyl]-3-
[(1-ethoxycarbonyl-3-(3-indolyl)propyl)amino]perhydroazepine-2
-1-[(1-carboxy-5-phthalimidyl)pentyl]-3-[(1-carboxy-3-(3
-indolyl)propyl)amino]perhydroazepin-2-one is obtained. Example 18 1-[(1-carboxy-5-amino)pentyl]-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one 489 g of the phthalimide of Example 17 in 10 ml methanol and 15 ml of water solution is treated with 260 ml of hydrazihydrate at 70° C. for 3 hours under nitrogen atmosphere. After cooling, volatile components were distilled off, dissolved in 2 ml of methanol, and phthalhydrazide was separated. Chromatography is performed on LH-20 in methanol and the solvent is distilled off from appropriate fractions in vacuo to obtain the product. The pmr spectrum is consistent with the structure, and the mass spectrum of the silylated material shows a trisilylated product peak at m/e = 635 and a tetrasilylated product peak at m/e = 707. Similarly, 1-[(1-carboxy-5-phthalimidyl)pentyl]-3-[1-carboxy-
3-(3-indolyl)propyl)amino]perhydroazepin-2-one was treated with hydrazine hydrate to give 1-[(1-carboxy-5-amino)pentyl]-3-[(1-carboxy- 3-(3-indolyl)propyl)amino]perhydroazepin-2-one was obtained. Example 19 1-[(1-benzyloxycarbonyl-5-phthalimidyl)pentyl]-3-(S)-(t-butoxycarbonylamino)perhydroazepin-2-one 80.6 g of 2-benzyloxycarbonyl-1 ，
3-dithiane to 98.3 g of N-4-bromobutyl-
Phthalimide in 130 ml DMF under nitrogen atmosphere
15.2 g of 50% sodium hydride emulsion
The reaction is allowed to cool in an ice bath while adding 380 ml of benzene emulsion (prewashed with petroleum ether) over a period of 65 minutes. Stir overnight at room temperature;
Water and benzene are added, separation is carried out, and after washing with water, the organic layer is concentrated to dryness in vacuo. This dithiane was diluted with N-bromosuccinimide in acetone and then 5%
After cleavage and concentration in sodium bicarbonate solution 1:
Extract into methylene chloride:hexane of 1. The ketoester is chromatographed on silica in ethyl acetate:hexane 1:1. 5.0g of this ketoester was converted into 674mg of α-t-Boc.
- added by the method described above in the presence of 5.4 g of powdered 4A molecular sieves in L-lysine and absolute ethanol under a nitrogen atmosphere over a period of 6 hours.
Condensation was carried out using 600 mg of sodium cyanoborohydride. The crude product is purified by chromatography on LH-20 in methanol. Conversion to caprolactam is effected by treatment with 1 equivalent of N-hydroxysuccinimide and a slight excess of dicyclohexylcarbodiimide in methylene chloride at 0°C. This reaction takes several days. After filtration and concentration to dryness, the crude product is purified by chromatography on silica gel using 7:3 hexane:ethyl acetate as the developing solvent. The pmr of the product is consistent with its structure and the mass spectrum has a molecular ion at m/e=577. Example 20 1-[(1-carboxy-2-(3-indolyl)
ethyl]-3-(S)-[(1-carboxy-3-
Phenylpropyl)amino]perhydroazepin-2-one Methyl 3-[3-indolyl]-2-oxopropionate (1.09 g) and α-t-Boc-L-lysine (0.246 g) were powdered 4A Dissolve in ethanol solvent containing molecular sieves (1.87 g).
A solution of cyanoborohydride (0.189 g) in ethanol is added over 6 hours at room temperature. After the reaction is complete, the solvent is removed and the residue is partitioned between ether and water. Isolate the aqueous layer and adjust the PH to 3.6.
The crude product is extracted into ethyl acetate and purified by LH-20 chromatography. The ring-closing reaction to 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2-(3-indolyl)ethyl]perhydroazepin-2-one is carried out in the same manner as in Example 3. Saponification of the methyl ester and subsequent treatment with formic acid removes the t-butoxycarbonyl protecting group to give 3-(S)-amino-1-[1
-carboxy-2-(3-indolyl)ethyl]
Perhydroazepin-2-one is obtained. 2-oxo-phenylbutyric acid and other caprolactams are condensed in the presence of sodium cyanoborohydride to give 1
-[1-carboxy-2-(3-indolyl)ethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepine-2
- Get on. The silylated mass spectrum is
The parent ion is shown at 693 m/e [3TMS+477 MWt], and the disappearance of CH ₃ =678 m/e is observed. Example 21 1-[1-carboxy-2-(4-hydroxyphenyl)ethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one methyl 3-(p-Hydroxyphenyl)-2-oxopropionate and α-t-Boc-L-lysine are condensed analogously to Example 19 in the presence of sodium cyanoborohydride. Subsequently, 3-(S)-amino-1-[1-carboxy-2-(4-hydroxyphenyl)ethyl]per Hydroazepine-2-
Get on. This caprolactam and 2-oxo-4-phenylbutyric acid were condensed in the presence of sodium cyanoborohydride, and 1-[1-carboxy-2
-(4-hydroxyphenyl)ethyl]-3-(S)
-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one is obtained. Example 22 1-[1-carboxy-2-phenylethyl]-
3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one methyl 2-oxo-3-phenylpropionate and α-t-Boc-L-lysine Condensation is carried out analogously to Example 19 in the presence of sodium cyanoborohydride. Subsequently, 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2
The ring-closing reaction to form -phenylethyl]perhydroazepin-2-one is carried out in the same manner as in Example 3. After saponification of the methyl ester, the t-butoxycarbonyl group is removed to obtain 3-(S)-amino-1-[1-carboxy-2-phenylethyl]perhydroazepin-2-one. This caprolactam and 2
-Oxo-4-phenylbutyric acid is condensed in the presence of sodium cyanoborohydride to 1-[1-carboxy-2-phenylethyl]-3-(S)-[(1-
Carboxy-3-phenylpropyl)amino]perhydroazepin-2-one is obtained. Example 23 1-(1-ethoxycarbonylethyl)-3-
(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepine-2
-one 1-(1-carboxyethyl)-3-(S)-[(1
-Ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one (2.94 g), a diastereoisomer mixture prepared analogously to Example 13 from isomer A of Example 12, and 40
A solution of ml of ethanol is cooled to 0°C and saturated with hydrogen chloride. After standing overnight at room temperature, the solution was concentrated under vacuum. It was dissolved in water, adjusted to pH 7, extracted with ether and concentrated to obtain 2.87 g of colorless oil. TLC on silica gel showed the presence of two diastereomers. If necessary, these isomers can be separated chromatographically on silica gel, eluting with hexane-ethyl acetate. Example 24 1-(1-benzyloxycarbonylethyl)-
3-(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one 3-(S)-t-butoxycarbonylamino-1-( prepared in Example 12) 1-carboxyethyl)
perhydroazepin-2-one (isomer A)
1-(1-benzyloxycarbonylmethyl) by the method of Wang et al. J.Org.Chem., 42, 1286 (1977)
-3-(S)-t-butoxycarbonylaminoperhydroazepin-2-one. NMR: (CCl ₄ , TMS) δ1.3 (d, 3H); δ1.38
(S, 9H); δ1.7 (m, 6H); δ3.2 (broad, 2H); δ4.2 (m, 1H); δ5.1 (q+s,
3H); δ5.8 (d, 1H); δ7.2 (S, 5H). [α] ²⁵ _D = −23.8 (C = 2.0, EtOH). 3-(S)-Amino-1-(1-benzyloxycarbonylethyl) by removing the t-butoxycarbonyl group in 4MHCl ethyl acetate solution
Perhydroazepin-2-one is obtained. NMR: (D ₂ O, dioxane = 3.67) δ1.2−2.1 (d
+m, 9H); δ3.3. (Broad, 2H); δ4.2
(m, 1H); δ4.6−5.0 (q+s, 3H); δ7.2
(s, 5H). [α] ²⁵ _D = -26.3 (C = 2.2, EtOH) A solution is prepared by dissolving 850 mg of this aminolactam, 2.14 g of ethyl 2-oxo-4-phenylbutyrate, and 267 mg of sodium acetate in 8 ml of ethanol. A solution of 490 mg of sodium cyanoborohydride in 3 ml of ethanol is added over 3.5 hours and stirring is continued overnight. Filter and concentrate the reaction and partition the residue between ethyl acetate and 5% sodium bicarbonate. The organic phase is washed with brine, dried and concentrated.
Crude product on silica gel 3:2 hexane:
1-(1-benzyloxycarbonylethyl)-3-(S)-(1-ethoxycarbonyl-3-phenylpropyl)aminoperhydroazepine by chromatographic purification eluting with ethyl acetate. Two isomers of -2-one are obtained. Isomer A (first elution): [α] ²⁵ _D = -26.6 (C = 2.0,
EtOH). NMR (CCl ₄ , TMS): δ1.0−2.0 (t+d+m,
14H); δ2.5−3.4 (m, 7H); δ4.1 (q,
2H); δ5.0−5.2 (s+m, 3H); δ7.1 (S,
5H); δ7.3 (s, 5H). Isomer B (second elution, main isomer): [α] ²⁵ _D = -40.2 (C = 2.0, EtOH). NMR (CCl ₄ , TMS): δ1.0−2.1 (t+d+m,
14H); δ2.1−3.0(m, 4H); δ3.1−3.7(m,
3H); δ4.1 (q, 2H); δ5.0−5.2 (q+s,
3H); δ7.1 (s, 5H); δ7.25 (3, 5H). Example 25 1-(1-carboxyethyl)-3-[(3-phenyl-1-carboxamido-1-propyl)amino]perhydroazepin-2-one, ammonium salt 260 mg of 1-(1-carboxyethyl) -3-
A 5 ml ethanol solution of [(1-carbuethoxy-3-phenyl-1-propyl)amino]perhydroazepin-2-one was placed in a pressure-resistant reactor, cooled in an ice bath, and saturated with ammonia gas at atmospheric pressure. The reaction vessel was closed and held at room temperature for 72 hours, at which point the reaction was found to be complete as judged by thin layer chromatography. The solvent was evaporated and the product was lyophilized from water. Yield 200mg. Tlc: (silica plate, butanol: acetic acid: water: ethyl acetate = 1:1:1:1) single spot,
Rf = 0.47. Example 26 1-(1-carboxamidoethyl)-3-[(3-
Phenyl-1-carboxy-1-propyl)amino]perhydroazepin-2-one, ammonium salt This compound was prepared from the corresponding ethyl ester analogously to the previous example. Tlc: (silica plate, butanol-acetic acid-water-ethyl acetate 1:1:1:1) single spot,
Rf=0.60. Example 27 1-carboxymethyl-3-[(1-carboxy-3-phenyl-1-propyl)amino]-7
-Methylperhydroazepine-2-one Francis, J.Am.Chem.Soc., 80, 6238 (1958)
of 31.5 g in 100 ml of benzene according to the method of
Reaction of PCl ₅ with 6.35 g of 2-methylcyclohexanone oxime gives 3,3-dichloro-7-methylperhydroazepin-2-one (melting point
132.5-134℃). 0.86g of 35ml THF solution of 6.73g of this lactam
Add to 25 ml THF suspension of NaH over 20 minutes. 8.70g of iodoacetic acid after hydrogen generation
- Add a 20 ml THF solution of butyl over 30 minutes. After confirming the completion of the reaction by TLC, 50 ml of water was added, the organic phase was separated and saturated (NH ₄ ) ₂ SO ₄
Wash with solution. The combined aqueous phases are backwashed with ether and all organic phases are combined and dried over Na ₂ SO ₄ . The solution was dried in vacuo and diluted with 1-t-butoxycarbonylmethyl-3,3
-dichloro-7-methylperhydroazepine-2
- Get on. NMR (CDCl ₃ , TMS): δ1.35 (d, 3H); δ1.45
(s, 9H); δ1.7−2.2 (m, 4H); δ2.6−2.9
(m, 2H); δ3.8−4.4 (m, 3H). 1.55 g of this lactam in 10 ml dioxane and 200 g
A solution of 5 ml H ₂ O containing mg MgO is hydrogenated using 10% palladium on activated carbon as catalyst. Filter the reaction, concentrate in vacuo and partition the residue between water and ether. After drying, concentrate the ether. The ether phase is dried and concentrated to yield 1-t-butoxycarbonylmethyl-3-chloro-7-methylperhydroazepin-2-one as an oil. Analytical samples are prepared by silica gel chromatography. Calculated value _{( C13H22ClNO3} ): C56.62; H8.04; N5.08 Actual value: C56.75; H8.18; _N4.89 . A solution of 7.0 g of this monochlorolactam and 3.1 g of sodium azide in 70 ml of DMF is heated at 100° C. for 20 hours. The reaction is concentrated in vacuo and the residue is partitioned between water and ether. The ether phase is dried and concentrated to obtain the crude product. Crude product on silica gel 7:
Chromatography of 3 with hexane:ethyl acetate yields pure 3-azido-1-t-butoxycarbonylmethyl-7-methylperhydroazepin-2-one. Ir: γN ₃ , 2120 cm ^-1 ; γco, 1750 cm ^-1 , 1680 cm ^-1 . Hydrogenation of 5.1 g of this azide is carried out in 75 ml EtOH using 10% palladium on activated carbon. The filtered reaction solution is concentrated in vacuo to obtain a pure crystalline product as a mixture of diastereomers. The crude product was fractionally crystallized from ether-ethyl acetate to obtain pure main diastereomer 3-amino-1-t.
-Butoxycarbonylmethyl-7-methylperhydroazepin-2-one is obtained (melting point 117.5~
118°). Chromatography of the residue from the mother liquor gives the minor diastereomers. 512 mg of pure 3-amino-1-t-butoxycarbonylmethyl-7-methylperhydroazepin-2-one, the main diastereomer, and 618 mg of ethyl-2-oxo-4-phenylbutyrate.
A solution of 120 mg of acetic acid in 20 ml of ethanol is hydrogenated using 10% palladium on activated carbon as a catalyst. The filtered reaction solution is concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel chromatography using 1:1 ethyl acetate:hexane.
Two herastereomeric racemates of -t-butoxycarbonylmethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one are isolated. Racemic A (first elution fraction) Elemental analysis value: Calculated value (C ₂₅ H ₃₈ N ₂ O ₅ ): C67.24; H8.58;
N6.27 Actual value: C67.30; H8.71; N6.03. Mass spectrum: M+ = 446; m/e: 389 (M
+ _-C4H9 );373( _{M + -C2H5CO2} ); ₃₁₇
(Base, 373−C ₄ H ₈ ). Racemic body B (second elution fraction) Elemental analysis value: Calculated value (C ₂₅ H ₃₈ N ₂ O ₅ ): C67.24; H8.58;
N6.27 Actual value: C66.82; H8.55; N6.10 Mass spectrum is the same as above. 380 mg of racemate B are dissolved in 2 ml of trifluoroacetic acid and the solution is stored at room temperature for 2 hours. The reaction is concentrated in vacuo, treated with water and reconcentrated. 1-
Carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one is isolated as the trifluoroacetate salt (mp 142-145°). Mass spectrum: M+390, m/e: 373 (M+
-OH); 362 (M+-C ₂ H ₄ ); 331 (M+-
_CH2CO2H ); 317 ( _{M + -CO2C2H5} ) _. The above procedure is repeated for racemate A to obtain the isomeric monoester. 200 mg of isomer B monoester trifluoroacetate are dissolved in 2.5 ml of 1N NaOH and the solution is stored at room temperature for 18 hours. The reaction solution was applied to a column of Dowex 50 (H ⁺ ), first eluted with H ₂ O, and then 50
Perform elution with % pyridine. Appropriate fractions were combined and concentrated to give 1-carboxy-methyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-
Methyl perhydroazepin-2-one (racemic B) is isolated (melting point 215-217° decomposed). Mass spectrum: M ⁺ 362; m/e: 344 (M ⁺ -
_H2O ), 318 (M- _CO2 ); 317 (M- _CO2H ). This monoester is treated as described above to isolate the diacid (racemate A). Mass spectrum: M ⁺ 362; m/e: 344 (M ⁺ -
H ₂ O); 318 (M ⁺ −CO ₂ ); 317 (M ⁺ −
_CO2H ). Similarly, the monoester was treated with a minor diastereomer, 3-amino-1-t-butoxycarbonylmethyl-7-methylperhydroazepin-2-one, as described above to obtain a diastereomeric racemate. A second set of diacids is isolated. 1-Carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-7
Each isomer of -methylperhydroazepin-2-one can be converted to the corresponding diethyl ester by the method described in Example 22. Example 28 1-(1-carboxyethyl)-3-(S)-[(1
-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one 1-(1-ethoxycarbonylethyl)-3-
A mixture of diastereomers of (S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one (Example 23) was prepared on silica gel in hexane:ethyl acetate (7:3). Separate by chromatography using Two isomers of this diester are isolated. Isomer A (first elution fraction) NMR (CCl ₄ , TMS): δ1.25 (m, 9H); δ1.4-
2.2 (m, 8H); δ2.7 (m, 2H); δ3.2 (m,
4H); δ3.5 (s, 1H); δ4.2 (2xq, 4H);
δ5.2 (q, 1H); δ7.2 (s, 5H). Isomer B NMR (CCl ₄ , TMS): δ1.15 (t, 9H); δ1.4-
2.2 (m, 8H); δ2.7 (m, 2H); δ3.1−3.7
(m, 4H); δ3.8 (s, 1H); δ4.1 (q,
4H); δ5.1 (q, 1H); δ7.2 (s, 5H). Each of the isomeric esters is hydrolyzed in dilute sodium hydroxide. The hydrolyzate is chromatographed on an acidic ion exchange resin using a 5% aqueous pyridine solution. Concentrate appropriate fractions to obtain each 1-
An isomer of (1-carboxyethyl)-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one is obtained. Isomer A [α] ²⁵ _Na = 37.0 (C = 2.56, 0.1NNaOH) NMR (D ₂ O + NaOH, dioxane = δ3.8):
δ1.33 (d, 3H, J=7hz); δ1.4−2.3 (m,
8H); δ2.6−3.0 (m, 2H); δ3.0−3.6 (m,
4H); Ca δ 4.8 (obscured by H ₂ O); δ 7.4 (s, 5H). Isomer B [α] ²⁵ _oa = -56.7° (C = 2.82,
0.1NNaOH). NMR (D ₂ O + NaOD, dioxane = 3.8):
δ1.3 (d, 3H, J=7h ₃ ); δ1.4−2.3 (m,
8H); 2.5-2.9 (m, 2H); δ3.1-3.8 (m,
4H); ca δ 0.48 (obscured by H ₂ O): δ 7.3 (s, 5H). Example 29 1-(1-carboxy-1-methylethyl)-3
-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one 2-S-amino-6-hydroxyhexanoic acid [Berlinguet and Gandry, J. Biol. Chem., 198 ，
765 (1952)] and the N-t-butoxycarbonyl derivative is prepared using the method of Otuska et al. [Journal of the Chemical Society of Japan, 39, 1171 (1966)]. This protected derivative is converted to O-p-toluenesulfonic acid benzyl ester [D.
Theodoropoulos et al., Biochemistry 6, 3927
(1967)]. This diester was mixed with excess ethyl-2-
Heat in toluene with aminoisobutyrate. The crude reaction product is purified by chromatography on silica gel to isolate N-t-butoxycarbonyl-N-(2-ethoxycarbonyl-2-propyl)lysine benzyl ester. The benzyl ester is removed using standard hydrogenolysis conditions and the resulting acid is cyclized using dicyclohexylcarbodiimide and N-hydroxysuccinimide as in Example 3. After purifying the lactam, it is reacted with ethyl 2-oxo-4-phenylbutyrate and hydrogen analogously to Example 1. The resulting diester is purified by chromatography to isolate the diastereomers. Each of the diastereomeric diesters is hydrolyzed with 1M NaOH and the diacids are purified by ion exchange chromatography. Example 30 1-(1-carboxyethyl)-3-(S)-(1
-Ethoxycarbonyl-3-phenylpropyl)aminoperhydroazepin-2-one The diastereomer described in Example 24 was catalytically dibenzylated in palladium on carbon in aqueous dioxane to give each 1-(1- A diastereomer of (carboxyethyl)-3-(S)-(1-ethoxycarbonyl-3-phenylpropyl)aminoperhydroazepin-2-one was obtained. Isomer A: [α] ²⁵ _D = -22.3° (C = 2.2, EtOH); melting point 132-134 NMR (CDCl ₃ , TMS): δ1.1-1.5 (d = t,
6H); 1.5-2.3 (m, 8H); 2.5-3.0 (m,
2H); 3.35 (m, 4H); 4.2 (q, 2H); 5.1
(q, 1H); 6.65 (s, 2H); 7.2 (s, 5H). Elemental analysis ( _C21H30N2O5 ): Calculated value: C64.59; H7.74; N7.18 _Actual value _: C64.20; H7.74; _N6.70 . Isomer B: [α] ²⁵ _D = -39.9 (C = 3.1EtOH): Melting point
110−113 (EtOAc). NMR (CDCl ₃ , TMS): δ1.2−1.5 (d=t,
6H); 1.5-2.3 (m, 8H); 2.6-2.9 (m,
2H); 3.2−3.7 (m, 4H); 4.2 (q, 2H);
5.1 (q, 1H); 7.2 (s, 7H). Elemental analysis ( _C21H30N2O5 ): Calculated value: C64.59; H7.74; N7.18 _Actual value _: C64.18; _H7.74 ; N6.93. Example 31 Diester of formula obtained from 3-(S)-amino-1-(1-ethoxycarbonylethyl)perhydroazepin-2-one 3-(S)-amino-1-(1-ethoxycarbonylethyl ) Perhydroazepin-2-one (prepared from isomer A as described in Examples 12 and 13) was carried out in place of the following α-ketoesters (Table) and ethyl 2-oxo-4-phenylbutyrate. Reductive condensation was carried out using palladium-activated carbon according to the method of Example 27. The corresponding diesters listed in the table are obtained by treatment and purification as in this example. Moreover, sodium cyanoborohydride can also be used in the same manner as in Example 24 in the reductive condensation. Example 32 Diacid of the formula obtained from 3-(S)-amino-1-(1-carboxyethyl)perhydroazepin-2-one A process comprising the purification process of Example 3 for the diesters listed in the table The product of the formula described in the table ^is obtained by saponification using
R ⁵ , R ⁶ =H, R ³ =CH ₃ , R ⁴ =OH) are obtained. Alternatively, 3-(S)-amino-1-(1-carboxyethyl)perhydroazepin-2-one can be reductively condensed with the α-keto acids listed in the table according to the method of Example 1 to produce the above formula. get something Example 33 Monoester of the formula obtained from 3-(S)-amino-1-(1-carboxyethyl)perhydroazepin-2-one Example 3
is reductively condensed with 3-(S)-amino-1-(1-carboxyethyl)perhydroazepin-2-one (isomer A) in the same manner as above to produce a product of the formula listed in the table (however, R ² , R ⁵ , R ⁶ = H and R ³ = CH ₃ ,
R ⁴ =OH) is obtained. Example 34 Monoester of formula obtained from 3-amino-1-carboxymethyl-7-methylperhydroazepin-2-one Main component diastereomer 3-amino-
1-t-Butoxycarbonylmethyl-7-methylperhydroazepin-2-one (Example 27) was treated with the α-ketoesters listed in the table by the palladium catalytic reduction method (Example 27) or the sodium cyanoborohydride method (Example 27). Reductive condensation was performed using one of the methods described in 24). After purifying the product by chromatography and removing the t-butyl ester (Example 27), a compound of the formula listed in the table (R ² =
CH ₃ ; R ³ , R ⁵ , R ⁶ =H and R ⁴ =OH) are obtained. Example 35 Diacid of the formula obtained from 3-amino-1-carboxymethyl-7-methylperhydroazepin-2-one The monoester made in Example 34 also included the purification method described in Example 3. Products of the formulas listed in the table by saponification using the method (where R ³ , R ⁵ , R ⁶ =H; R ² =CH ₃ ; R, R ⁴ =OH)
get. In addition, the t-butyl ester of the main diastereomer of 3-amino-1-t-butoxycarbonylmethyl-7-methylperhydroazepin-2-one is cleaved with trifluoroacetic acid to obtain 3-amino-1
-Carboxymethyl-7-methylperhydroazepin-2-one can also be obtained. This compound is reductively condensed with the α-keto acids listed in the table according to the method of Example 1 to give the product of the above formula. Example 36 Monoester of the formula obtained from 3-amino-1-carboxymethyl-7-methylperhydroazepin-2-one. -carboxymethyl-
Reductive condensation with 7-methylperhydroazepin-2-one (Example 35) to give the product of the table formula ( ^R3 , ^R5 = H, ^R2 = _CH3 , ^R4 = OH) . Table α-Ketoester a Benzyl 2-oxo-4-phenylbutyrate b Ethyl 4-p-chlorophenyl-2-oxobutyrate c Ethyl 4-(3-indolyl)-2-oxobutyrate d Ethyl 2-oxo- 4-(2-thienyl)
Butyrate e Ethyl 2-oxo-4-(2-naphthyl)
butyrate f ethyl 4-p-hydroxyphenyl-2
-Oxobutyrate g Ethyl Phenoxypyruvate h Ethyl 2-oxo-5-phenylpentanoate i Ethyl 4-p-methoxyphenyl-2-
Oxobutyrate j Ethyl 5-methyl-2-oxohexanoate k Benzyl 2-oxo-6-phthalimidohexanoate

[Table] After γ hydrazine decomposition
Table α-keto acid 2-oxo-4-(2-naphthyl)butyric acid cc 4-p-hydroxyphenyl-2-oxobutyric acid dd enoxypyruvate ee 2-oxo-5-phenylpentanoic acid ff 4-p-methoxyphenyl- 2-oxobutyric acid gg 5-methyl-2-oxohexanoic acid hh 2-oxo-6-phthalimidohexanoic acid Example 37 3-(S)-amino-1-(1-carboxyethyl)perhydroazepin-2-one A monoester of the formula 3-(S)-amino-(1-(1-zenzyloxycarbonylethyl)perhydroazepin-2-one (Example 24) or 3-(S)-amino-1-
(1-Ethoxycarbonylethyl)perhydroazepin-2-one (Example 13) is reacted with some of the keto acids in the table using the method of Example 2 to produce products of the formula listed in the table (where R ² ,
R ⁵ =H; R ³ =CH ₃ , R=OH) is obtained. Monoester of the formula R ¹ R ⁴ ii p-chlorophenethyl benzyloxyjj 2-naphthylethyl benzyloxykk 3-methylbutyl benzyloxyll 4-aminobutyl γ benzyloxymm phenethyl ethoxynn phenethyl benzyloxy Example after decomposition of γhydrazine 38 Monoester of formula obtained from 3-amino-1-carboxymethyl-7-methylperhydroazepin-2-one Main component of 3-amino-1-t-butoxymethyl-7-methylperhydroazepin-2-one The isomer was reacted with benzyl alcohol and thionyl chloride to form 3-amino-1-benzyloxymethyl-
7-Methylperhydroazepin-2-one hydrochloride is obtained, which after treatment with a base gives the free amino ester. This amino ester was reacted in the same manner as in Example 37 to produce products of the formulas listed in the table (R ³ , R ⁵ ,
R ⁶ =H; R ² =CH ₃ ; R=OH). Also, by using ethanol in place of benzyl alcohol, the corresponding ethyl esters listed in the above table are obtained. Example 39 1-(1-benzyloxycarbonylethyl)-
3-(S)-(1-carboxy-3-phenylpropyl)aminoperhydroazepin-2-one A solution of 490 mg of sodium cyanoborohydride in 3 ml of ethanol was added to 2.43 g of t-butyl-2-oxo-4-phenyl fluoride. enylbutyrate, 850 mg of 1-(1-benzyloxycarbonylethyl)-3-(S)-aminoperhydroazepin-2-one hydrochloride (isomer A of Example 24) and 267 mg of sodium acetate.
Add in 10ml ethanol over 2.5 hours.
Stir the reaction overnight at room temperature and overconcentrate. Partition the residue between ethyl acetate and 5% sodium bicarbonate. After drying, the organic phase was concentrated and the residue was chromatographed on silica gel using hexane:ethyl acetate (7:3) to give 1-(1-benzyloxycarbonylethyl)-3-(S)-(1 A purified diastereomer of -t-butoxycarbonyl-3-phenylpropyl)aminoperhydroazepin-2-one is obtained. Isomer A (first elution): [α] ²⁵ _Na = -24.6° (C =
2,
EtOH) Isomer B (second elution): [α] ²⁵ _Na = -31.1° (C =
2,
EtOH). Each of these isomers was treated with HCl-EtOAc to give 1-(1-benzyloxycarbonylethyl)-3-(S)-(1-carboxy-3-phenylpropyl)aminoperhydroazepin-2-one. Obtain the hydrochloride. Isomer A: [α] ²⁵ _Na = -5.14° (C = 2, EtOH). Isomer B: [α] ²⁵ _Na = -15.7° (C = 2, EtOH). NMR (DMSO-d ₆ ): δ1.2-2.1 (m+d, J=
7hz); δ2.4-2.9 (m, partially obscured by DMSO); δ3.0-4.0 (m);
δ4.9 (q, J=7hz); δ5.1 (s); δ7.0 (broad); δ7.2 (s); δ7.35 (s). Example 40 1-Carboxymethyl-3-(1-carboxy-3-phenylpropyl)amino-7-phenylpervidloazepin-2-one 25 g of phosphorous pentachloride in 220 ml of CH ₂ Cl ₂ kept at 0 °C 22 g of 7-phenylcaprolactam and 18.9 g of pyridine in 220 ml of CH ₂ Cl ₂ are added to the solution.
After dropping 45.1 g of phenyltrimethylammonium tribromide, the reaction solution was brought to room temperature. After 3 hours, the reaction solution was poured into ice water and extracted with CH ₂ Cl ₂ . 5 organic phase
Wash with % sodium bisulfite. After drying and concentration,
The crude residue is purified by chromatography on silica gel, eluting with ethyl acetate:hexane (2:3). Concentration of the appropriate fractions yields 16.3 g of 3-bromo-7-phenylperhydroazepin-2-one as a mixture of diastereomers. 15.5 g of this lactam and 14.7 g of iodoacetic acid
- A solution of the butyl ester in 150 ml of tetrahydrofuran is added dropwise to a slurry of 1.45 g of sodium hydrogen in 20 ml of tetrahydrofuran. After 3 hours at room temperature, the reaction is quenched by adding 15 ml of saturated NH ₄ Cl solution.
The reaction is overconcentrated and the residue is partitioned between CHCl ₃ and H ₂ O. The crude product is obtained after drying and concentrating the CHCl ₃ solution. Chromatographed on silica gel using hexane:ethyl acetate (4:1).
Bromo-1-t-butoxycarbonylmethyl-7
- Two isomers of phenylperhydroazepin-2-one are obtained: isomer A (minor component, first elution) and isomer B (major component, second elution). of 20 g of isomer B and 7.69 g of lithium azide.
Heat 100ml dimethylformamide solution at 80°C overnight. After concentration, the residue is partitioned between water and ethyl acetate. The organic phase is dried and concentrated to obtain 3-azido-1-t-butoxycarbonylmethyl-7-phenylperhydroazepin-2-one. This can be recrystallized from ethyl acetate-hexane. NMR (CDCl ₃ , TMS): δ1.45 (s, 9H); δ1.6−
27. (m, 6H); δ3.3 (d, 1H, J=17hz);
δ4.0 (d, 1H, J=17hz); δ4.4 (broad m, 1H); δ4.8 (broad d, 1H); δ7.25
(s, 5H). 2g of 75ml ethanol solution of 8.95g of this azide
Hydrogenated over 10% pd-C at 45° C. for 5 hours. The solution was then filtered and concentrated to yield 8.3 g of 3-amino-1-t-butoxycarbonylmethyl-7-phenylperhydroazepin-2-one. NMR (CDCl ₃ , TMS): δ1.4 (s, 9H); δ1.725
(m+s, 8H); δ3.4 (d, 1H, J=
17hz); δ3.95 (d, 1H, J=17hz); δ4.0
(broad m, 1H); δ4.95 (broad d,
1H); δ7.3 (s, 5H). 3.8g of this amino, 3.7g ethyl 2-oxo-4
- phenylbutyrate and 0.68 ml acetic acid dissolved in 50 ml ethanol were hydrogenated and the isomers were separated as in Example 27, 1-t-butoxycarbonylmethyl-3-(1-ethoxycarnyl-3 -phenylpropyl)amino-7-phenylperhydroazepin-2-one is obtained. Isomer A (first elution)
and isomer B (second elution fraction). Each of the above isomers was treated with trifluoroacetic acid to obtain 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropyl)amino-7-
Each isomer of phenylperhydroazepin-2-one is obtained as the trifluoroacetate salt. Isomer A: NMR (CDCl ₃ , TMS): δ1.3(t);
δ1.5-2.6 (m); δ2.6-3.1 (m); δ3.6-3.9
(m); δ4.2 (q); δ4.0−4.8 (m); δ7.2
(s); δ8.9 (Broad, S). Isomer B: NMR (DMSO-d ₆ , TMS); δ1.27
(t); δ1.6-3.1 (m); δ3.7-4.5 (m+
q); δ4.7 (broad); δ5.1 (broad);
δ7.2(s); δ7.3(s). Each of the above isomers was treated with dilute sodium hydroxide and then purified by chromatography on an acidic ion exchange resin to obtain the corresponding 1-carboxymethyl-
The isomer of 3-(1-carboxy-3-phenipropyl)amino-7-phenylperhydroazepin-2-one is obtained. Isomer A: NMR (D ₂ O + NaOD, dioxane =
δ3.80): δ1.6−2.3 (broad m); δ2.55−
2.9 (m); δ3.25 (t); δ3.5-3.8 (m); δ4.6
−5.1 (broad, obscured by _H2O ); δ7.3(s); δ7.35(s). Isomer B: NMRCD ₂ O + NaOD, dioxane =
δ3.80): δ1.5−2.3 (broad m); δ2.5−2.9
(m); δ3.25 (t); δ3.6 (broad s); δ3.7
−4.2(m); δ4.5−5.2 (m, obscured by _H2O ); δ7.25(s); δ7.35(s). Similarly, a minor diastereomer of 3-bromo-1-t-butoxycarbonylmethyl-7-phenylperhydroazepin-2-one was treated as described above to form a second diastereomeric racemate. A set of diacids is isolated. Example 41 The R ² -substituted product of formula 7-phenylperhydroazepine- by treatment with PCl ₅ or PBr ₅ in benzene or in the manner described in the introduction to Example 40.
Perhydroazepine-2- substituted in the 7-position instead of the 2-one by a group listed in the table
The corresponding 7-substituted 3-bromo-perhydroazepin-2-ones could be obtained by using . Further according to the process described in Example 40, the formula (R=OC ₂ H ₅ , R ₁ =CH ₂ CH ₂ φ, R ₃ =R ₅ =
It was possible to obtain esters of H, R ₄ =OH and R ₂ = groups listed in the table. Furthermore, by performing the same treatment as in Example 40, R
= OH, R ₁ = CH ₂ CH ₂ φ, R ₃ = R ₅ = H, R ₄ = OH
and R ₂ = the group given in the table, the corresponding diacids could be obtained. The stereochemical results in these cases were parallel to those described in the cited examples. Table 7 - Substituted perhydroazepin-2-ones R ₂ = -C ₂ H ₅ -n-C ₄ H ₉ -cyclohexyl-benzyl-(1-piperidino)methyl-p-tolyl-n-anisyl-p-chlorophenyl- (2-pyridyl) (All these compounds are described in the chemical literature) Example 42 R ₂ -aminoalkyl substitution product of formula 2-aminoethyl or 4-aminoethyl in the 7-position
Perhydroazepin-2-ones substituted with aminobutyl groups, all of which are described in the chemical literature, can be converted to the corresponding phthalimide derivatives at their primary amine function by known methods. Example of the resulting compound
40, the formula [where R=OC ₂ H ₅ , R ₁ =CH ₂ CH ₂ φ, R ₃ =R ₅ =H, R ₄
=O-t-butyl, and R ₂ represents the following formula (n=2 or 4)] is obtained. Careful hydrazinolysis removes the phthalimide protecting group to give the corresponding diester, which is treated with trifluoroacetic acid as in Example 40 to give the formula [R=OC ₂ H ₅ , R ₁ =CH ₂ CH ₂ φ, R ₃ =
R ₅ = H, R ₄ = OH and R ₂ = (CH ₂ )uNH ₂ (u=2
or 4)] monoester can be obtained. The corresponding formula [R=R ₄ =OH, R ₁ =CH ₂ CH ₂ φ, R ₃ =R ₅ =H
and R ₂ =(CH ₂ )n-NH ₂ (n=2 or 4)]. The stereochemical results in these cases are similar to those in the cited examples. Example 43 A typical tablet is 1-(1(S)-carboxyethyl)-3-(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepine-2- (25 mg), pre-gelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).
Similarly, for example, 1-(1(S)-carboxyethyl-3-(S)-[(1(S)-carboxy-5-amino-1-pentyl)amino]perhydroazepin-2-one (20 mg ) with the above composition instead of 1-(1(S)-carboxyethyl)-3-(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one. Example 44 Compressed tablets containing 50 mg of active ingredient: mg 1(S)-carboxyethyl-3-(S) per tablet. )−[(1
(S)-Ethoxycarbonyl-3-phenylpropyl)amino]-perhydroazepin-2-one 50 Dibasic calcium phosphate 245 Ethylcellulose (as a 5% ethanol solution)
5 Unmixed granules 255 Additions: Corn starch 14 Magnesium stearate 1 270 Prescription: Mix the above active ingredients and calcium phosphate to form No. 60 mesh powder. Granulate in alcohol with Ethocel and pass the wet granules through a No. 10 screen. granules
Dry at 110㎓ (approximately 43℃) for 12 to 18 hours.
Dry and crush this to make No. 20 mesh.
Additive ingredients are introduced and compressed into tablets weighing 270 mg each. Example 45 Dry-filled capsules containing 5 mg of active ingredient: mg per capsule 1-carboxymethyl-3-(S)-[(1(S)-
Ethoxy-carbonyl-3-phenylpropyl]amino-7(S)-phenylperhydroazepin-2-one 5 Lactose 273 Magnesium stearate 2 mixed powder 280 The above active ingredients, lactose and magnesium stearate are mixed and No. Grind into 60 mesh powder.
Each No. 2 capsule is filled with 280 mg and encapsulated. The above formulation examples can be used in the present invention to produce compressed tablets and capsules of other novel compounds described above. The above examples are Examples 12 and 19 shown for reference.
and 43 to 45, which are illustrative of the novel compounds of the present invention and illustrate methods of making certain compounds as well as particular dosage forms suitable for administering the novel compounds, the present invention is not limited to Examples. It is not intended to be limited by the particular compounds described, the particular reaction conditions described for the preparation of these compounds, or the particular ingredients included in the pharmaceutical formulation, but is intended to include variations and modifications thereof.

Claims (1)

[Claims] 1. A compound represented by the following general formula or a pharmaceutically acceptable salt thereof: [In the formula, R and R ⁴ are the same or different and represent a hydroxy group, a lower alkoxy group, a phenyl lower alkoxy group, or an amino group, and R ¹ is a hydrogen atom, a lower alkyl group, a substituted lower alkyl group ( However, the substituent is an amino group or a phthalimide group), a phenyl lower alkyl group, R ² represents a hydrogen atom, a lower alkyl group, or a phenyl group, and R ³ represents a hydrogen atom, a lower alkyl group, or an amino lower alkyl group. , an indolyl lower alkyl group, or a phthalimide lower alkyl group, and R ⁵ represents a hydrogen atom]. 2. The compound according to claim 1, which is one of the following compound groups: 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazepine-2 -one; 1-(1(S)-carboxyethyl-3(S)-
[(1(S)-carboxy-3-phenylpropyl)
1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1-( S)-carboxyethyl-3(S)-
[(1-(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-benzyloxycarbonylethyl-3-
[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1(S)-benzyloxycarbonylethyl-3
(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1-ethoxycarbonylethyl)-3-
[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepin-2-one; 1-(1(S)-ethoxycarbonylethyl)-3
(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazepine-2
-one; 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1( S)-carboxy-3-phenylpropyl)amino]-7
-Methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]-7
(R)-Methylperhydroazepin-2-one; 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpyropyl)amino]-7
-Methylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-methylperhydroazepin-2-one; 1-Carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(R)-methylperhydroazepine-2-
1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-7-phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1( S)-carboxy-3-phenylpropyl)amino]-7
-Phenylperhydroazepin-2-one; 1-carboxymethyl-3(S)-[(1(S)-carboxy-3-phenylpropyl)amino]-7
(S)-Phenylperhydroazepin-2-one; 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-7
-Phenylperhydroazepine-2-one; 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7-phenylperhydroazepine-2- and 1-carboxymethyl-3(S)-[(1(S)-ethoxycarbonyl-3-phenylpropyl)amino]-7(S)-phenylperhydroazepine-2
-On.