JPH0154346B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION In its broadest aspects, the present invention relates to enantholactam derivatives and pharmaceutically acceptable salts thereof useful as angiotensin converting enzyme inhibitors and as antihypertensive agents. The compound of the present invention can be represented by the following formula. In the formula, R and R ⁴ are the same or different and are hydroxy, lower alkoxy, or phenyl lower alkoxy, R ¹ is phenyl alkyl, R ³ is hydrogen or alkyl, and R ² is hydrogen or alkyl. It is. Unless otherwise specified, lower alkyl expressed as a variable includes a straight or branched chain hydrocarbon of 1 to 6 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl, etc.). Lower alkoxy means alkoxy containing 1-6 carbon atoms. Compounds of the invention include their pharmaceutically acceptable salts. Products of formula () and preferred subgroups are produced by one or more methods or subroutes represented by the equations below. R, ^R1 , ^R2 , ^R3
and R ⁴ are the same as in formula () unless otherwise specified. Perhydroazocin-2-one () or Blichk et al., J.Amer.Chem.Soc. 76 , 2317
(1954) from 2-substituted cycloheptanone by the method of PX ₃ (X=Br
or Cl) to convert to (). [Nagasawa et al., J.Med.Chem. 14 , 501 (1971)].
When reacted with sodium or lithium azide in a solvent such as DMF or ethanol [e.g. Brenner et al., Helv.Chim.Acta
41, 181 (1958)] is obtained. This compound can be alkylated with an iodoester () to give () in the presence of a strong base such as sodium hydride in a solvent such as DMF or TMF. Reduction of () with hydrogen and a suitable catalyst such as palladium on carbon provides ().
The intermediate () is then dissolved in a solvent such as ethanol,
Reductive condensation with a keto acid or ester () using a catalyst such as palladium on carbon provides (). Alternatively, sodium cyanoborohydride can be used to perform this reduction. Groups R and R ₄ can be modified by known methods if desired. For example, if R=OEt and _R4 =Ot-Bu, the diester () can be converted to the monoester R=OEt and _R4 =OH by treating it with trifluoroacetic acid. If R=R ₄ =OEt, then () is converted into a dibasic acid R=R ₄ =OH by hydrolysis with a base.
It can be converted to Alternatively, () can be alkylated with () in the presence of a strong base such as sodium hydride,
As mentioned above, it is possible to convert intermediate () to () by reaction with an azide salt. If desired, () can be prepared by alkylating () (alternative conditions of Naganawa, supra) with (N) to yield intermediate (XI). Treatment of (XI) with hydrogen and a catalyst (such as palladium on carbon) gives (). Alternatively, (X=Cl, Br, R ₄ =OH) can be converted to the iodo compound (X=) by known methods, such as sodium iodide in acetone. This iodolactam is mixed with toluene or
When reacted with an amino acid ester in a solvent such as DMF in the presence of a halide scavenger such as Ag ₂ O, (R≠OH, R ₄ ≠OH) is obtained. If desired, XII can be reduced with hydrogen in the presence of a suitable catalyst to give XII, which can be alkylated with a ketoester in the presence of a suitable catalyst and hydrogen to give XII. Alternatively, sodium cyanoborohydride can be used. Alkylation of X to give (R≠OH, R ₄ ≠OH) can be accomplished using an iodoester in the presence of a strong base such as sodium hydride in a solvent such as THF. The starting materials required for the above methods described herein are known in the literature or can be prepared by known methods from known starting materials. In the product of general formula (), R ¹ , R ² and R ³
The carbon atom to which is attached and the carbon atom of the ring to which the moiety [formula] is attached can be asymmetric. The compounds of the invention therefore exist in diastereoisomeric forms or as mixtures thereof. The synthetic methods described above can utilize racemates, enantiomers, or diastereomers as starting materials. When the synthesis produces diastereoisomers or products, the diastereoisomers or products can be separated by chromatography or fractional crystallization. When a racemate forms, it can be resolved by crystallization of a salt with an optically active acid or base or by methods well known in the art. These partial structures of formula () [formula] [formula] and [formula] can have two coordinations (S or R), and both are included within the scope of the present invention. , S-type is generally preferred. Both configurations at the carbon to which R ₂ is attached are included within the scope of this invention. The compounds of this invention form salts with various inorganic and organic acids and bases, which are also included within the scope of this invention. Such salts include ammonium salts, alkali metal salts (sodium and potassium salts), alkaline earth metal salts (calcium and magnesium salts), salts with organic acids, namely dicyclohexylamine salts, N-methyl-D-glucamine,
Contains salts with amino acids (arginine, lysine, etc.). organic and inorganic acids (e.g. HCl, HBr,
It is also possible to prepare salts with H ₂ SO ₄ , methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid, camphorsulfonic acid). Other salts are also useful (e.g. when isolating and purifying the product)
However, non-toxic physiologically acceptable salts are of particular value. The salt is prepared by conventional means, for example by combining 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 resulting salt is not soluble, such as water. It is prepared by reaction in vacuum or in a solvent which is removed by freeze-drying, or by converting the ions of the salt present with others on a suitable ion exchange resin. Compounds of the invention inhibit angiotensin converting enzyme and thus prevent the conversion of decapeptide angiotensin to angiotensin.
Angiotensin is a powerful precursor. Thus, inhibition of its biosynthesis results in a decrease in blood pressure, especially in animals and humans where hypertension is associated with angiotensin. Additionally, the converting enzyme degrades bradykinin, a vasodilator substance. Therefore, inhibitors of angiotensin-converting enzyme also lower blood pressure by activating bradykinin. Although the relative importance of these and other possible mechanisms remains to be established, inhibitors of angiotensin-converting enzyme are effective antihypertensive agents in a variety of animal models and clinically, e.g. It is effective for many people suffering from vascular, malignant, and essential hypertension. for example,
DW
Cushman et al., Biochemistry , 16 , 5484 (1977)
See. Converting enzyme inhibitors are evaluated by an in vitro enzyme inhibition assay. For example, a useful method is the one by Piquilloud, A., and Reinharts (A.) that measures the hydrolysis of carbobenzyloxyphenylalanylhisdinylleucine.
Reinharz) and M. Roth,
This is the method of Biochem Biophys. Acta, 206 , 136 (1970). In-vivo evaluation can be performed, for example, by G.I. R. Weeks (JR Weeks) and J. A. JAJones, Pror.Soc.Exp.
Biol.Med. 125 , 96 (1967) in normal rats treated with angiotensin. The compounds of the invention are therefore useful in the treatment of hypertension. These compounds are useful in the management of acute and chronic congestive heart disorders, in the treatment of secondary hyperaldosteronism, sclerodactyly, primary and secondary pulmonary hypertension, renal failure and renovascular hypertension, and It also has value in the management of vascular diseases such as migraines.
The application of the compounds of the invention to these and similar diseases will be apparent to those skilled in the art. In the treatment of hypertension and the clinical conditions mentioned above, the compounds of the invention may be formulated into tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration. It can be used as a composition such as The compounds of this invention can be administered to patients in need of such treatment in amounts that will provide the best pharmaceutical efficacy. The dosage depends on the nature and extent of the disease,
the weight of the patient, any special diet given to the patient after administration;
Varies from patient to patient depending on co-administered drugs and other factors recognized by those skilled in the art;
Dosage is generally about 1 to 200 mg per patient daily. This medication can be administered once or divided into several doses. Preferably, the dosage range is per patient;
Approximately 2.5 to 100 mg per day. It is often advantageous to administer the compounds of the invention in combination with other antihypertensive agents and/or diuretics. For example, compounds of the invention include amiloride,
atenolol, bendrofmethiazide, chlorothiazide, clonidine, cryptenamine acetate and cryptenamine tannate, deserpidine,
Diazoxide, guanetidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metroprolol tartrate, methyclothiazide, methyldopa, methyldopa hydrochloride, minoxidil, (S)-1-{[2
-(3,4-dimethoxyphenyl)ethyl]amino}-3-{[4-(2-thienyl)-1H-imidazol-2-yl]phenoxy}-2-propanol, polythiazide, pivalrogroxyethyl of methyldopa Esters, indacrinone and its enantiomers in various proportions, nifedipine, verapamil, diltiazam, flumethiazite, bendroflumethiazide, atenolol, (+)-4-{3-
{-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid, bumetanide, prazosin, propranolol, rauwolfia serpentia, rescinnamine, reserpine, spironolactone, timolol, trichlorme Thiazide, benzthiazide, quinetazone,
triclinahuane, triamterene, acetazolyleamide, aminophylline, cyclothiazide,
It is possible to use it in combination with compounds such as meletoxyline procaine and mixtures and formulations thereof. Typically, individual daily dosages of these formulations can range from about 1/5 of the lowest recommended clinical dose when administered at one time to the highest recommended clinical dose. . An example of these combinations is 2.5− per day.
One of the antihypertensive agents of the present invention that is clinically effective in the range of 100 mg can be effectively combined with the indicated daily dosage of the following compounds at levels in the range of 0.5-100 mg per day. It is possible. : Hydrochlorothiazide (10-100mg), Timolol (5-6
mg), methyldopa (65−2000 mg), 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, triple drug combinations of hydrochlorothiazide (10-100 mg), timolol (5-60 mg) and converting enzyme inhibitors of the invention (0.5-100 mg), or hydrochlorothiazide (10-100 mg), amiloride (5-
20 mg) and the converting enzyme inhibitor of the present invention (0.5-100
The triple drug formulation of mg) is an effective formulation for controlling blood pressure in hypertensive patients. Of course, these dosage ranges can be adjusted according to the need for multiple daily administrations, and as mentioned above, this dosage will depend on the nature and extent of the disease, the patient's weight, special diet and other factors. It varies depending on the factors. Typically, these formulations can be formulated into pharmaceutical compositions as discussed below. about 0.5 to 100 mg of a compound of the formula or a mixture of physiologically acceptable salts thereof is mixed with a physiologically acceptable medium, carrier, excipient, binder, preservative, stabilizer, flavoring agent. , in unit dosage form as required by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage within the indicated range will be obtained. The following are examples of supplementary drugs that can be incorporated into tablets, capsules, etc. Binders such as gum tragacanth, gum arabic, corn starch or gelatin; Excipients such as microcrystalline cellulose; Dispersants such as corn starch, pre-gelatinized starch, alginic acid; Lubricants such as magnesium stearate; sugar, lactose , or sweeteners such as saccharin;
Flavoring agents such as sweet potato, sweet potato or cherry oil. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as an oil or fat. Various other materials may be added to modify the physical form of the dosage unit to give it another shape or to coat it. For example, tablets may be coated with syrup, sugar or both. A syrup or elixir may contain the active compound, sugar as a sweetening agent, methyl and propylparabens as preservatives, a dye and cherry or orange flavor. Sterile compositions for injection include dissolving or suspending the active ingredient in a vehicle such as water for injection, natural vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, or synthetic lipid vehicles such as ethyl oleate. It may be prepared according to conventional pharmaceutical methods. If necessary, it is also possible to incorporate a buffer, a preservative, an oxidizing agent, etc. The following examples are intended to illustrate the invention and constitute particularly preferred embodiments. Preferred diastereomers in these examples are isolated by column chromatography or fractional crystallization. Example 1 1-carboxymethyl-3 [(1-carboxy-
3-Phenylpropyl)amino]perhydroazosin-2-one 8.0 g of t-butyl iodoacetate dissolved in 60 ml of tetrahydrofuran with vigorous stirring of a suspension of 0.80 g of sodium hydride in 30 ml of tetrahydrofuran. and 5.86 g of 3,3-dichloroperhydroazocin-2-one [Nagasawa et al., J.Med.Chem . 14,501
(1971)] solution over a period of 20 minutes. After the addition is complete, the reaction is stirred at room temperature for 1.5 hours and then quenched with 5 ml of saturated NH ₄ Cl solution. Filter the reaction solution and concentrate the solution. Add ether to the residue, filter, wash with H ₂ O and brine.
The ether solution was dried and concentrated to yield 9.3 g of 1-
t-Butoxycarbonylmethyl-3,3-dichloroperhydroazocin-2-one is obtained. Prepare samples for analysis by silica gel chromatography. Melting point 75-76.5°. Analysis _{( C13H21Cl2NO3} ) Calcd: C, 50.33; _H , 6.82; _N , 4.52. Actual values: C, 50.28; H, 7.05; N, 4.59. To a solution of 3.10 g of this ester in 20 ml dioxane and 10 ml H ₂ O, 0.5 g MgO and 0.3 g
Add 10% palladium on carbon. This mixture is hydrogenated at room temperature and under 40 psi hydrogen pressure. Filter the reaction solution, concentrate the solution, and add ether to the residue. The ether is washed with water and brine, dried and concentrated to yield 2.75 g of 1-t-butoxycarbonylmethyl-3-chloroperhydroazocin-2-one. Samples are prepared for analysis by column chromatography on silica gel using hexane:ethyl acetate. Melting point 97.5−99°. Analysis _{( C13H22ClNO3 )} . Calculated: C, 56.61; H, 8.04; Cl, 12.85. Actual values: C, 56.79; H, 8.10; Cl, 12.49. Alternatively, 4.12 g of 3-bromoperhydroazocin-2-one [Nagasawa et al., J. Med. Chem. 14, 501 (1971)] as described above.
, 5.0 g of t-butyl iodoacetate and
React with 0.55g of sodium hydride. After treatment, 5.10 g of 3-bromo-1-1-t-butoxycarbonylmethyl perhydroazocin-2-one are obtained. Samples for analysis are prepared by column chromatography on silica gel using hexane-ethyl acetate. Melting point 107.5-109°. Analysis ( _{C13H22BrNO3 )} Calcd: C, 48.75; _H , 6.93; N, 4.37. Actual values: C, 48.78; H, 7.12; N, 4.26. A solution of 15.6 g of monobromolactam in 500 ml of DMF is prepared. 2.43g NaI and 3.9g _NaN3
is added and the stirred solution is then heated to 85-90° for 16 hours. The cooled reaction mixture is concentrated in vacuo and the residue is partitioned between 500 ml ether and 100 ml _H2O . Wash the ether layer with water and brine. The ether solution is decolorized with activated charcoal, dried and filtered. Concentrate the liquid to dryness. Adding 25 ml of petroleum ether to the residue yields 9.6 g of 3-azido-1-t.
-butoxycarbonylmethylperhydroazocin-2-one is precipitated. Analytical samples are prepared by column chromatography on silica gel using hexane-ethyl acetate. Melting point 101-102℃. Analysis _{( C13H22N4O3 ) .} Calculated values: C, 55.30; H, 7.85; N, 19.84. Actual values: C, 55.33; H, 8.07; N, 19.69. Alternatively, azidolactam can be prepared from the monochlorolactam described above by this method. 9.5 g of 3-azido-1-t-butoxycarbonylmethyl perhydroazocin-2-one in 85 ml
Dissolve in ethanol. Hydrogenation is carried out at room temperature under 40 psi hydrogen pressure with 10% palladium on carbon as a catalyst. When the reaction solution is filtered and concentrated, 3-
Amino-1-t-butoxycarbonylmethyl perhydroazocin-2-one is obtained. An analytical sample is obtained by recrystallization from ether-hexane. Melting point 87-88°. Analysis _{( C13H24NO3 )} . Calculated values: C, 60.93; H, 9.43; N, 10.93. Actual values: C, 60.99; H, 9.59; N, 10.71. 4.096 g of this amine and 4.95 g of ethyl 2 in 150 ml of ethanol containing 0.96 g of acetic acid
The -oxo-4-phenyl oxobutyrate solution is hydrogenated at room temperature under 40 psi hydrogen pressure using 0.5 g of 10% palladium on carbon as a solvent. The reaction mixture was filtered and the liquid was concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel using hexane-ethyl acetate as eluent. eluted second from the column, 1
Isolation of the desired racemic diastereomer (isomer B) of -t-butoxycarbonylmethyl-3[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1-perhydroazocin-2-one do. NMR (CDCl ₃ , TMS) δ7.2 (S,
5H), δ3.5−4.5 (m, 6H), δ3.0−3.4 (m, 3H),
δ2.6−2.9(m, 2H), δ1.5−2.3(m), δ1.5(S
),
δ1.3(t), 22H in total. Analysis ( _C25H38N2O5 ) Calcd _: C, 67.24; _H , 8.58; _N , 6.27. Actual values: C, 66.96; H, 8.68; N, 6.06. A trace amount of the racemic diastereomer (isomer A), which is eluted first from the column, is isolated. Analysis ( _C25H38N2O5 ) Calcd _: C, 67.24; _H , 8.58; _N , 6.27. Actual values: C, 66.98; H, 8.69; N, 6.04. This diester (isomer B) is treated with trifluoroacetic acid. Concentrate the reaction mixture in vacuo,
Boil several times with _H2O . 1-Carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-1-perhydroazocin-2-one is obtained as a crystalline trifluoroacetate. Melting point 211-213°. Analysis ( _{C21H30N2O5.CF3CO2H} ) _Calculated values _: C, _54.11 ; H, 6.12 _{; N} , 5.49. Actual values: C, 54.12; H, 6.21; N, 5.82. This salt is passed through a column of Dowex 50 (H ⁺ ) and trifluoroacetic acid is removed by elution with pyridine water. NMR (D ₂ O, NaOD, TSS) δ1.1
(t, 3H), δ1.3−2.2(m, 10H), δ2.4−4.2(m
，
10H), δ7.1(s, 5H). The monomethyl ester trifluoroacetate (isomer B) is treated with 1M NaOH at room temperature. The reaction mixture is passed through a column of Dowex 50 (H ⁺ ), eluting first with water and then with pyridine water. The appropriate fractions are combined and concentrated to yield 1-carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazosin-2-one as a crystalline solid. Melting point 265-268° (decomposed). Analysis ( _{C19H26N2O5.1 / 2H2O} ), calculated: C, _61.44 ; H, 7.26; _N , 7.53. Actual values: C, 61.26; H, 7.38; N, 7.18. Repeating the above sequence for Isomer A diester yields Isomer A2 basic acid. Example 2 1-Carboxymethyl-3-[(1-carboxy-4-phenylbutyl)amino]perhydroazosin-2-one 2.56 g of 3-amino-1-t-butoxycarbonylmethylperhydroazosin-2 −on and 3.30
g of ethyl 5-phenyl-2-oxopentanoate is reacted with hydrogen using palladium on carbon as described in Example 1. The reactions are worked up as described above and the two racemic diastereomeric diesters are isolated after column chromatography on silica gel. Isomer A is eluted first,
Isomer B is eluted second. 900 mg of isomer B are treated with 10 ml of trifluoroacetic acid for 1.5 hours at room temperature. Trifluoroacetic acid is removed in vacuo to obtain the monoethyl ester. Dissolve this ester in 10 ml of 1M NaOH and store the solution overnight at room temperature. The reaction mixture is chromatographed on Dowex 50 (H ⁺ ) as described above to yield the dibasic acid (isomer B). melting point 245
−246.5° (decomposition). Isomer A diester is treated as described above,
The dibasic acid is isolated as a lyophilized white powder. Example 3 1-(1-carboxyethyl)-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazosin-2-one A solution of 250 mg of lithium azide in 6 ml of DMF was prepared and To this is added 412 mg of 3-bromoperhydroazocin-2-one, the reaction is heated under nitrogen at 70-75°C for 23 hours, concentrated in vacuo,
The residue is dissolved in H ₂ O and extracted with ethyl acetate.
The extract is dried and concentrated to a semi-solid residue. This crude product was purified with ethyl acetate:acetonitrile 9:1
Perform chromatography on silica gel using as the eluent. 3-azidoperhydroazocin-2-one is isolated as a white solid (melting point 108-109°). 156 mg of this azide was mixed with 30 mg of this azide in 3 ml of THF.
Add to the HaH suspension then add 400 ml of
Add mg of methyl 2-iodopropionate solution. Heat the reaction mixture under nitrogen at 55-60° for 18 hours. After cooling, the reaction is stopped with _H2O .
Ether is added and the organic layer is washed with 5% NaHCO ₃ , water and brine. Dry the organic layer and concentrate to an oil. The crude product was chromatographed on silica gel, eluting with ethyl acetate, 3
-Azido-1-(1-carbomethoxyethyl)perhydroazocin-2-one is isolated. NMR
(CDCl ₃ ): δ1.4−2.3 (d+m, 2H), δ3.45 (m,
2H), δ3.7 (s, 3H), δ4.1 (t, 1H), δ4.6 (2
×
q, 1H). The ester is saponified with dilute NaOH and the reaction mixture is acidified and extracted with methylene chloride. After drying and concentrating the extract, 3-azido-1-(1
-carboxyethyl)perhydroazocine-2-
Isolate on. This material is fractionally crystallized from acetonitrile as the dicyclohexylamine salt to obtain the desired diastereomer. Alternatively, this diastereomer can be obtained by reverse phase chromatography or from XAD-2 resin at 8%
It can be separated by elution with ammonium phosphate buffer of CH ₃ CN-9% 0.05MPH7. In either case, the desired isomer is eluted first. This acid, Wang J.Org.Chem.42,
1286 (1977) to the methyl ester. This azide was converted to an amine, which was used in Example 1.
1-(1-methoxycarbonylethyl)-3-(1-ethoxycarbonyl-3-phenyl) after chromatography on silica gel. Propyl) aminoperhydroazosine-2
- Isolate on. Isomer A- (eluted first): NMR
(CDCl ₃ , TMS): δ1.1−1.2 (d+t+m), δ2.5
-2.9 (m), δ3.15 (t), δ3.3 (wide s), δ3.
4−
3.8(m+s), δ4.1(q), δ4.6(q), δ7.1(s
). Analysis _{( C23H34N2O5} ) Calcd: C, 66.00; _H , 8.18; _N , 6.69. Actual values: C, 65.93; H, 8.43; N, 6.66. Isomer B- (second eluting). NMR
(CDCl ₃ , TMS: δ1.0−2.2(d+t+m), δ2.5−
2.9 (m), δ3.15 (t), δ3.45 (s), δ3.65 (s
), δ3.4
-3.9 (wide), δ4.1 (q), δ4.4 (q), δ7.1 (
s). Analysis _{( C23H34N2O5} ) Calcd: C, 66.00; _H , 8.18; _N , 6.69. Actual values: C, 65.63; H, 8.08; N, 6.53. Each of these isomers is hydrolyzed with dilute caustic soda. This hydrolyzate was purified by chromatography on an ion exchange resin and after lyophilization,
The corresponding isomer of -(1-carboxyethyl)-3-(1-carboxy-3-phenylpropyl)aminoperhydroazocin-2-one is obtained. Isomer A _Analysis ( _{C20H28N2O5.11} / _2H2O ) Calculated: C, _59.41 ; H, 7.73; _N , 6.92. Actual values: C, 59.33; H, 7.42; N, 6.87. Isomer B Analysis ( _C20H28N2O5.1 / _4H2O ) Calculated: C, _63.05 ; _H , 7.53; _N , 7.35. Actual values: C, 63.13; H, 7.50; N, 7.28. Other diastereomers of 3-azido-1-(carboxyethyl)perhydroazocin-2-one also include 1-(1-carboxyethyl)- as described above.
3-(1-carboxy-3-phenylpropyl)
The second set of diastereomers of aminoperhydroazocin-2-one is changed. Example 4 1-Carboxyethyl-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one 3-azidoperhydroazo using 10% Pd/C in ethanol Syn-2-one (Example 3)
is reduced to 3-aminoperhydroazocin-2-one. NMR (CDCl ₃ , TMS): δ1.67 (wide s, 8H), δ2.25 (wide s, 2H), δ3.35 (m,
2H), δ3.8 (m, 1H), δ (7.0, wide, 1H), 50
1.42g of this amine in ml ethanol, 0.59g
of acetic acid and 3.09 g of ethyl 2-oxo-4-phenylbutyrate are hydrogenated over a 10% Pd/C catalyst. After filtering and concentrating the reaction solution,
The product is purified by chromatography on silica gel to isolate 3-[(1-ethoxycarbonyl-3-phenyl-1-propyl)amino]perhydroazocin-2-one. As described in Example 1, this lactam
Reduction with t-butyl iodoacetate in the presence of NaH. As described in Example 1, 1-t-butoxycarbonylmethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one was prepared after chromatography on silica gel. Isomers A and B are obtained. Using the method of Example 1, these diesters are converted to the corresponding dibasic acids. Example 5 1-Carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]-8-methylperhydroazocin-2-one 17 g 2-methylcycloheptanone in 75 ml concentrated hydrochloric acid Cool the solution and add 13.2 g of sodium azide in portions. The reaction is stirred at 0° C. for 1 hour and then at room temperature for 2 hours. Add 150 ml of ice water to the reaction solution, adjust the pH to 7 with potassium carbonate, and extract with chloroform. This extract was treated with activated charcoal, dried over _MgSO4 , filtered, and concentrated to give a crude
-Methylperhydroazocin-2-one is obtained. Obtain a pure sample by recrystallization from hexane. (Melting point 70-73°) Analysis ( _C8H15NO ) Calculated: C, 68.04; H, 10.71; _N , 9.91. Actual values: C, 67.75; H, 10.74; N, 9.81. A solution of 16.9 ml of PBr ₃ in 70 ml of benzene is cooled to 5° and 9.3 ml of bromine are added dropwise with good stirring.
Once the addition is complete, heat the reaction to 60° for 3 hours. Cool the reaction and add the lower layer to a mixture of H ₂ O and CH ₂ Cl ₂ . After shaking, remove the organic layer and extract the aqueous layer again. Wash the organic portion with _H2O and _NaHSO3 . Dry with Ma ₂ SO ₄ and concentrate in vacuo to give 3-
Bromo-8-methylperhydroazocin-2-one is obtained. The product is purified by chromatography on silica gel. Analysis _{( C8H15BrNO} ). Calculated: C, 43.65; H, 6.41; N, 6.36; Br, 36.31. Actual values: C, 43.84; H, 6.48; N, 6.28; Br, 36.14. Dissolve 14.5 g of bromolactam and 9.7 g of lithium azide in 150 ml of dimethylformamide,
Heat to 80°. Concentrate the reaction in vacuo and partition the residue between _H2O and ethyl acetate. The organic layer is dried and concentrated to give 3-azido-8-methylperhydroazocin-2-one as a gummy solid. Treatment with ether yields the pure product (melting point
111−112°) is obtained. Analysis _{( C8H15N4O} ) Calculated: _C , 52.73; H, 7.74; N, 30.75. Actual values: C, 52.53; H, 7.82; N, 30.28. 5.65 g of azide as described in Example 1
7.9g t-butyl iodoacetate and 0.82g
of sodium hydride to give 1-t-butoxycarbonylmethyl-3-azido-8-methylperhydroazosin-2-one, which is purified by chromatography on silica gel. NMR
(CCl ₄ , TMS), δ1.0−2.2 (m), δ1.3(d), δ1.45
(s), δ3.45 (d, J=16Hz), δ3.95 (d, J=16
Hz), δ4.3−5.1 (m). 6.4 g of this azide was converted into 1-t-butoxycarbonylmethyl-3-
Reduction to amino-8-methylperhydroazocin-2-one. NMR (CDCl ₃ ), δ1.25(d), δ1.4
(s), δ1.3−2.3 (m), δ3.55 (d, J=16Hz),
δ4.2 (d, J = 16Hz), δ3.8−4.8 (m). 2.7 g of this amine was hydrogenated with 3.9 g ethyl 2-oxo-4-phenylbutyrate and 0.5 g acetic acid as described in Example 1, and 1
-t-Butoxycarbonylmethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-8-methylperhydroazocin-2-one is obtained as a mixture of diastereomers. The mixture is separated by chromatography on silica gel to give the two racemic diastereomers. Isomer A (eluted first) NMR (CCl ₄ ,
TMS), δ1.2(d), δ1.3(t), δ1.45(s), δ1.3
−2.2
(m), δ2.4−2.8 (m), δ3.3 (d, J=17Hz),
δ3.2
-3.4 (m), δ.3.7 (t), δ4.1 (d, J=17Hz),
δ4.1
(q), δ7.1(s). Isomer B (eluted second), NMR (CCl ₄ ,
TMS), δ1.15(d) δ1.25(t), δ1.45(s), δ1.1
−2.2
(m), δ2.5−2.9 (m), δ3.25 (d, J=12Hz),
δ3.2−3.65 (m), δ4.0 (d, J=16Hz), δ4.1 (
q),
δ7.1(s). Isomer B is converted to 1-carboxyethyl-3-(1-ethoxycarbonyl-3-phenylpropyl)amino-8-methylperhydroazocin-2-one trifluoroacetate as described in Example 1. . NMR (D ₂ O−DCl, dioxane = 3.63) δ1.1(d),
δ1.2 (t), δ1.4-2.2 (wide), δ2.25 (m),
δ2.7
(m), δ3.5 (wide), δ3.7 (t), δ4−4.5 (q
+
m), δ7.15(s). The above monoester was converted to 1-carboxymethyl-3-(1-carboxy-3-phenylpropyl)amino-8- as described in Example 1.
Convert to methylperhydroazocin-2-one. NMR (D ₂ O + NaOD, dioxane = 3.80),
δ1.3(d), δ1.8 (wide m), δ2.7(m), δ3.2(
wide t), δ3.55 (d, J=16Hz), δ4.1 (d, J=16
Hz), δ3.6−4.2 (m), δ7.35 (s). Example 6 (+)-1-carboxymethyl-3-(S)-
[(1-(S)-Carboxy-3-phenylpropyl)amino]perhydroazosin-2-one 154.5 g of 3-bromoperhydroazosin-2
-one (Example 1), 58.6 g of sodium azide,
215ml ethanol, 215ml _H2O at 85-90°
Heat for 22 hours. Store this solution at 0° for 2 hours,
98.4 g of 3-azidoperhydroazocin-2-one are recovered. After concentration, a further 20.4 g are isolated from the mother liquor. 100.6 g of this azide was prepared as in Example 1 in the presence of 16.5 g of sodium hydride.
Alkylation with 150.8 g of t-butyl iodoacetate. 130.6 g of 1-tert-butoxycarbonylmethyl-3-azidoperhydroazocin-2-one are isolated. This azide was prepared in Example 1.
to 1-t-butoxycarbonylmethyl-3-aminoperhydroazocin-2-one as described in . Dissolve 94.7 g of this amine in 600 ml of acetonitrile, and dissolve 47.5 g of L-
Add a warm solution (60°) of pyroglutamic acid. The solution is stirred at room temperature for 2 hours and then stored at 4° for 18 hours. filtrate and remove the solid matter with acetonitrile (2
56.4 g of 1-t-butoxycarbonylmethyl-3-(R)-aminoperhydroazocin-2-one L-pyroglutamate are isolated. By repeatedly slurrying this salt with acetonitrile, a constant melting point (183-185°) can be achieved.
Refine it to become. (−)-1-t-Butoxycarbonylmethyl-3-(R)-aminoperhydroazocin-2-one is isolated by treatment of the pure salt with aqueous ammonia. [α] ²⁵ _Na =-
43.3° (C=0.71, EtOH). The filtered mother liquor is concentrated and the residue is dissolved in 260 ml of H ₂ O. Add 60 ml of ammonium hydroxide and extract with ethyl acetate. Dry and concentrate the extract
61.1 g of amine are obtained. Dissolve this amine in 600ml of acetonitrile,
2. Add to 30.5 g of D-pyroglutamic acid in hot acetonitrile. After isolation and purification of the salt obtained as described above, 51.6 g of 1-t-butoxycarbonylmethyl-3-(S)-aminoperhydroazocin-2-one D-pyroglutamate (melting point 183- 185°). This salt was converted to (+)-1-t-butoxycarbonylmethyl-3-(S)-aminoperhydroazocine-2- as described above.
Convert on. [α] ²⁵ _Na = 43° (C = 1.55,
EtOH). The amine was hydrogenated with ethyl 2-oxo-4-phenyl-butyrate as described in Example 1 and after chromatography (+)-1-t-butoxycarbonylmethyl-3-
(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one (isomer B) is isolated. t- by 4NHCl
The butoxy ester was removed and (+)-1-carboxymethyl-3-(S)-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazosin-2-one hydrochloride, mp 171- 173゜(disassembly)
get. Analysis ( _{C21H30N2O5.HCl} ) Calculated _values : C, 59.08; _H , 7.26; _N , 6.56. Actual values: C, 58.79; H, 7.48; N, 6.57. [α] ²⁵ _Na ° = 29.4° (C = 1.8, EtOH). This monoester was hydrolyzed as described in Example 1 and after purification (+)-1-carboxymethyl-3-(S)-[(1-carboxy-3-phenylpropyl)amino]per Hydroazosine
Get 2-on. Analysis ( _{C19H26N2O5.1 / 4H2O} ) Calculated: C, _62.21 ; _H , 7.14; N, 7.72. Actual values: C, 62.09; H, 7.23; N, 7.63. [α] ²⁵ _Na = 47.2° (C = 1.7, 1N NaOH) Example 7 (+)-1-benzyloxycarbonylmethyl-3-(1-carboxy-3-phenylpropyl)aminoperhydroxyazosine-2 -one (+)-3-Amino-1-t-butoxycarbonylmethyl perhydroazocin-2-one (Example 6) is treated with HCl in ethyl acetate. After concentration,
The residue is passed through an acidic ion exchange resin and (+)-3-amino-1-carboxymethyl perhydroazocin-2-one is eluted with 5% aqueous pyridine.
[α] ²⁵ _D = 93.9 (C = 1.80, H ₂ O). A solution of 2.36 g of the hydrochloride of this amino acid in 15 ml of benzyl alcohol is cooled to 0° and treated with 2 ml of thionyl chloride. This mixture is left at room temperature for 2 days. After pouring the reaction into ether and stirring for 30 minutes, the ether is decanted from the gummy product. The ether solution is washed with water and the washings are used to dissolve the gummy material. The resulting aqueous solution is made basic and extracted with ethyl acetate. After drying and concentration, (+)-3-amino-1-
Benzyloxycarbonylmethyl perhydroazocin-2-one is isolated. 929 mg of benzyl ester in 10 ml of ethanol,
A solution of t-butyl-2-oxo-4-phenylbutyrate and 0.18 ml of acetic acid is treated with 650 mg of sodium cyanoborohydride in 30 ml of ethanol over 3.5 hours. The reaction is then stirred at room temperature overnight. The reaction mixture is concentrated and the residue is partitioned between ethyl acetate and 5% _NaHCO3 . Concentration of the organic layer yielded the crude product, which was chromatographed on silica gel (3:2 hexane:
Purification by ethyl acetate) gives the isomer of 1-benzyloxycarbonylmethyl-3-(1-t-butoxycarbonyl-3-phenylpropyl)aminoperhydroazocin-2-one. Isomer A (eluted first): [α] ²⁵ _D = −12.5
゜(C=2, EtOH). Isomer B (eluted second): [α] ²⁵ _D = -
4.2° (C=2, EtOH). The t-butyl ester was removed from each isomer by treatment with HCl in ethyl acetate to give 1-benzyloxycarbonylmethyl-3-(1-carboxy-3-phenylpropyl)-aminoperhydroazocine-2. - Get on. Isomer A: [α] ²⁵ _D = -27° (C = 2, EtOH). Isomer B: [α] ²⁵ _D = +17.5° (C = 2, EtOH). Example 8 1-(1-carboxyethyl)-3-(1-ethoxycarbonyl-3-phenylpropyl)aminoperhydroazocin-2-one With hydrogen and palladium on carbon as described in Example 7. , 3-azido-1-(1-carboxyethyl)perhydroazocin-2-one (Example 3)
-(1-carboxyethyl)perhydroazocin-2-one. This amino acid is converted to benzyl ester hydrochloride. 1 mmol of this ester hydrochloride is reacted with 4 mmol of ethyl 2-oxo-4-phenylbutyrate, 1 mmol of sodium acetate and 2-3 mmol of sodium cyanoborohydride in ethanol. Concentrate the reaction mixture and remove the residue.
Partition between _H2O and ethyl acetate. The organic solvent soluble portion was purified by silica gel chromatography to obtain 1-(1-benzyloxycarbonylethyl)-3-(1-carboethoxy-3-phenylpropyl)aminoperhydroazocin-2-one. Isolate the isomer. Each diastereomer was hydrogenated with palladium on carbon in aqueous dioxane and 1-(1-carboxyethyl)-3-(1-carboethoxy-3-
Phenylpropyl) aminoperhydroazocine
The individual diastereomers of 2-one are obtained. Example 9 1-(1-benzyloxycarbonylethyl)-
3-(1-carboxy-3-phenylpropyl)
Aminoperhydroazocin-2-one The diastereomer of this compound was prepared by following the method of Example 7, 3-amino-1-(1-
benzyloxycarbonylethyl) perhydroazocin-2-one (Example 8) and t-butyl 2
-oxo-4-phenylbutyrate. Example 10 R ² and R ³ = H, R ⁴ = OH, R = -O-
Monoester product of benzyl formula 3-amino-1-t-butoxycarbonylmethyl perhydroazocin-2-one (Example 6)
benzyl 2-oxo-4-in place of ethyl 2-oxo-4-phenylbutyrate in the presence of palladium on carbon as described in Example 1.
Reductive condensation with phenylbutyrate. The processing methods described in the examples (including removal of the t-butyl ester) yielded products of formula (R ² =
R ³ =H, R ⁴ =OH, R=-O-benzyl) is obtained. Alternatively, the reductive condensation can be carried out in the presence of sodium cyanoborohydride, as described in Example 7. Purification of diester and t
- After removal of the butyl ester, a compound of the above-mentioned formula is obtained. Example 11 Diethyl ester of the formula in which R ² and R ³ are H The dibasic salt of the formula prepared in Example 9 or 10 (R ² , R ³ =H, R=R ⁴ =OH) was dissolved in ethanol-
Treatment with HCl gives the diester hydrochloride of the corresponding formula (R ² , R ³ =H, R, R ⁴ =ethoxy). Treat these hydrochlorides with potassium carbonate,
Convert to the free base diester by extraction with ethyl acetate. After drying and removing the solvent, the free base is obtained. Example 12 Tablets containing 50 mg of active ingredient are molded. Per tablet, mg 1-carboxymethyl-3-[(1-carboxy-
3-Phenyl-1-propyl)amino]perhydroazosin-2-one...5 Dicalcium phosphate...245 Ethylcellulose (unmixed granules as a 5% solution in ethanol ...5 ...255 Addition: Corn starch... 14 Magnesium stearate ...1 270 Example 13 Dry-filled capsules containing 5 mg of active ingredient. 5 mg lactose per capsule 5 Magnesium stearate 273 Mixed powder 2 280 The active ingredients described above, lactose and magnesium stearate are mixed, Powder is passed through No. 60 mesh. 280 mg each is placed in No. 2 capsules. The above composition can be used to prepare tablets or capsules of other novel compounds of the present invention as described above. The foregoing examples describe the preparation of certain compounds illustrating the novel compounds of the present invention, and specific dosage forms suitable for administering the novel compounds. It is understood that the invention should not be limited to the specific compounds described in the Examples, the specific reactions described in preparing these compounds, or the specific ingredients included in the pharmaceutical compositions. It should be understood that these variations and modifications are included within the scope of the invention.

Claims (1)

[Claims] 1 formula and pharmaceutically acceptable salts thereof [wherein R and R ⁴ are independently hydroxy, lower alkoxy, or phenyl lower alkoxy, R ¹ is phenyl alkyl, and R ³ is hydrogen or and R ² is hydrogen or alkyl]. 2 1-Carboxymethyl-3-[(1-carboxy-3-phenylpropyl)amino]perhydroazosin-2-one, 1-carboxymethyl-3-(S)-[(1(S)-
Carboxy-3-phenylpropyl)amino]perhydroazocin-2-one, 1-benzyloxycarbonylmethyl-3-
[(1-carboxy-3-phenylpropyl)amino]perhydroazocin-2-one, 1-benzyloxycarbonylmethyl-3-
(S)-[(1(S)-carboxy-3-phenylpropyl)amino]perhydroazosin-2-one, 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl) Amino] perhydroazocin-2-one, 1-carboxymethyl-3(S)-[(1-(S)
-ethoxycarbonyl-3-phenylpropyl)
Amino]perhydroazosin-2-one, 1-carboxymethyl-3(S)-[((S)-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazosin-2-one hydrochloride, 1 -Ethoxycarbonylmethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one, 1-ethoxycarbonylmethyl-3(S)-[(1
(S)-Ethoxycarbonyl-3-phenylpropyl)amino]perhydroazocin-2-one, 1-(1-carboxyethyl)-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino] Perhydroazocin-2-one and 1-carboxymethyl-3-[(1-ethoxycarbonyl-3-phenylpropyl)amino]-8
-Methylperhydroazocin-2-one. 3 formulas The compound of is reductively alkylated with the formula and then, if necessary, protecting groups are removed to give the desired product, and if desired, chromatography, fractional crystallization,
or by resolution with a suitable optically active acid or base to isolate the biologically more active isomer and, if desired, to prepare a salt of the desired product by conventional means. consists of things. formula A method for producing a compound. [In the formula, R and R ⁴ are independently hydroxy, lower alkoxy, or phenyl lower alkoxy, R ¹ is phenyl alkyl, R ³ is hydrogen or alkyl, and R ² is hydrogen or alkyl. be〕.