JPH0532602A - Naphthylmethylamine derivative and renin inhibitor containing the same - Google Patents

Abstract

PURPOSE:To obtain a new naphthylmethylamine derivative, having renin inhibitory activity and effective in treating hypertension or its pharmaceutically permissible salt. CONSTITUTION:A naphthylmethylamine derivative expressed by formula I (R<1> is morpholinyl and di- or trihydroxyalkylamino expressed by formula II, III, IV or V; R<2> is H, 1-7C alkyl or 4-imidazolinemethyl; R<3> is formula VI or VII) or its pharmaceutically permissible salt, e.g. (2S,3R,4S)-2-[(2R)-2-[1-(4- morpholinylcarbonyl)methyl-N-(1-naphthylmethyl) amino]carbonylmethyl-4- methylpentionyl]amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane. The compound expressed by formula I is obtained by condensing a compound expressed by formula VIII (R<4> is formula II, etc.) with a compound expressed by formula IX or X using a suitable condensing agent and then carrying out deprotecting reaction.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel naphthylmethylamine derivative having a renin inhibitory action and a renin inhibitor containing the same.

[0002]

BACKGROUND ART Renin is a proteolytic enzyme secreted from renal juxtaglomerular cells. Angiotensin I is an angiotensinogen in the renin-angiotensin system.
Convert to.

Further, angiotensin I is converted into angiotensin II by an angiotensin converting enzyme, and exhibits a strong pressor action. Therefore, renin inhibitors are effective in treating hypertension.

Conventionally, as a renin inhibitor, JP-A-59 has been used.
Tripeptides, such as JP-A-155345,
A tetrapeptide such as 9-110661 and a decapeptide such as JP-A-59-231055 have been found. However, since these peptide derivatives are easily hydrolyzed by the action of renin itself and other peptidases in plasma, the duration of the hypotensive action becomes extremely short and the clinical application is limited. (US Pat. No. 4,269,
827 specification). Further, when the molecular weight of the compound used as a drug exceeds 500, it is generally known that the rate of biliary excretion increases and the body absorption rate decreases, but conventional peptide derivatives also have a large molecular weight, It was thought that the actual drug effect would be halved for some reason.

[0005]

DISCLOSURE OF THE INVENTION The present inventors proceeded research with the intention of eliminating peptide bonds that are easily metabolized in the living body and lowering the molecular weight, and found that a compound containing a naphthylmethylamine derivative was renin. They have found that they are very useful as inhibitors and completed the present invention. Therefore, an object of the present invention is to provide a novel renin inhibitor.

[0006]

Means for Solving the Problems The present invention which achieves the above object is represented by the following chemical formula 8

[Chemical 8] (In the formula, R ¹ is chemical formula 9, chemical formula 10, chemical formula 11, or chemical formula 12 shown below.

[Chemical 9]

[Chemical 10]

[Chemical 11]

[Chemical 12] A morpholinyl group and a di- or trihydroxyalkylamino group represented by, R ² is hydrogen, an alkyl group having 1 to 7 carbon atoms which may have a branched or cyclic structure, or a 4-imidazolylmethyl group. , R ³ are the following chemical formulas 13 and 14

[Chemical 13]

[Chemical 14] Is. ) Are naphthylmethylamine derivatives and salts thereof. In addition, the present invention is a renin inhibitor containing the compound represented by the chemical formula 8 or a salt thereof.

The naphthylmethylamine derivative of the present invention is
Chemical formula 15 shown below

[Chemical 15] (In the formula, R ⁴ is chemical formula 16, chemical formula 17, chemical formula 18, or chemical formula 19

[Chemical 16]

[Chemical 17]

[Chemical 18]

[Chemical 19] (Wherein R ⁵ represents an alkyl group having 1 to 6 carbon atoms (which may be the same and may be closed), and R ² has the same meaning as described above (provided that it is a 4-imidazolylmethyl group. , Having a suitable carbamate protecting group)) as a starting material and a suitable condensing agent (for example, dicyclohexylcarbodiimide in combination with 1-hydroxy-benzotriazole, preferably diphenylphosphoryl azide). 20 or 21

[Chemical 20]

[Chemical 21] It can be obtained by carrying out a deprotecting group reaction after condensation with.

The compound used as a starting material in this reaction is a compound shown below.

[Chemical formula 22] And one of chemical formula 23 to chemical formula 26

[Chemical formula 23]

[Chemical formula 24]

[Chemical 25]

[Chemical formula 26] (Wherein R ⁵ has the same meaning as described above) with a suitable strong base (for example, sodium hydride), and then a deprotecting group reaction by hydrogenation is carried out.

[Chemical 27] (Wherein R ⁴ has the same meaning as described above) and the following chemical formula 28

[Chemical 28] (In the formula, R ⁶ is a lower alkyl group or an aryl group, R ² has the same meaning as described above), and can be obtained after a condensation reaction with a succinic acid derivative and a reaction for deprotecting the ester moiety. The above-mentioned succinic acid derivative is preferably subjected to a condensation reaction with an amine derivative after forming a highly reactive mixed acid anhydride using an acid chloride. In addition, both of the above two deprotection group reactions are carried out with a suitable catalyst (preferably 10
% Palladium-carbon) in the presence of ethanol.

The naphthylmethylamine derivative of the present invention is
It is used as a renin inhibitor and a therapeutic agent for hypertension. The dose varies depending on the symptoms, but in general, the daily dose for adults is 1 to 500 m.
g, preferably 5 to 100 mg, and may be administered in 1 to 3 divided doses as needed depending on the symptoms. The administration method can be any form suitable for administration, and oral administration is particularly preferable, but intravenous injection is also possible.

The naphthylmethylamine derivative of the present invention is used as an active ingredient or one of the active ingredients, either alone or mixed with a pharmaceutical carrier or excipient by a conventional method, and then tablets, dragees, powder capsules, granules, suspensions. It can be applied in various forms formulated into agents, emulsions, injections and the like. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate and the like.

The naphthylmethylamine derivative of the present invention exhibits the same renin inhibitory activity even in the form of a pharmaceutically acceptable salt (eg sodium salt, potassium salt).

Next, the present invention will be described more specifically by showing Examples and Test Examples, but the present invention is not limited to these.

[0013]

【Example】

Example 1 (1) 1.47 ml of 1-naphthalenemethylamine and 2.80 ml of triethylamine under an argon atmosphere.
Was dissolved in 20 ml of chloroform, 2.56 g of carbobenzoxy chloride was added dropwise under ice cooling, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature overnight. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in ethyl acetate. This organic layer was treated with 1N hydrochloric acid aqueous solution, water,
The extract was washed with saturated saline and dried over anhydrous sodium sulfate.
After filtering the desiccant, the filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and benzyloxycarbonyl- (was extracted from the ethyl acetate-n-hexane (1: 4 v / v) elution fraction. 1.78 g of 1-naphthylmethyl) amine was obtained.

Then, under an argon atmosphere, 0.95 ml of morpholine and 1.68 ml of triethylamine were dissolved in 10 ml of chloroform, chloroacetyl chloride was added dropwise under ice cooling, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature overnight.

After adding water to the reaction solution and extracting with chloroform, the organic layer was washed with a 1N hydrochloric acid aqueous solution, water and saturated saline, and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was distilled off under reduced pressure to obtain 1.05 g of 4-morpholinylcarbonylmethyl chloride.

Next, under an argon atmosphere, 0.73 g of sodium hydride was added to N, N-dimethylformamide 5
1.7 ml of benzyloxycarbonyl- (1-naphthylmethyl) amine obtained by the above reaction was suspended in ml and cooled with ice.
A solution of 8 g of N, N-dimethylformamide in 5 ml was added, and the mixture was stirred at 0 ° C for 30 minutes. To this, 1.05 g of 4-morpholinylcarbonylmethyl chloride obtained in the previous reaction
5 ml of N, N-dimethylformamide of
The mixture was stirred under ice cooling for 30 minutes and at room temperature overnight. 1M aqueous sodium hydrogensulfate solution was added to the reaction solution and extracted with ethyl acetate.
The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtering the desiccant, the filtrate was distilled off under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and 1- (4-) was obtained from the fraction eluted with ethyl acetate-n-hexane (1: 1 v / v). Morpholinylcarbonyl) methyl-N- (1
1.96 g of -naphthylmethyl) benzyloxyamide was obtained. Then 1.0 g of this compound was added to 10 ml of ethanol.
In 0.1%, 10% palladium-carbon (0.1 g) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to give 1- (4-morpholinylcarbonyl).
Methyl-N- (1-naphthylmethyl) amine 550 mg
was gotten.

(2) Next, 2.52 ml of isocaproic acid was dissolved in 50 ml of tetrahydrofuran under an argon atmosphere and cooled to -78 ° C., and then triethylamine 3.
Add 36 ml and pivaloyl chloride 2.58 ml, -78
The mixture was stirred at 0 ° C for 10 minutes and at 0 ° C for 30 minutes.

On the other hand, in an argon atmosphere, (4
S) -4-Isopropyl-2-oxazolidinone 2.5
Dissolve 8 g in tetrahydrofuran 50 ml, -78 ° C
After cooling in, 12.5 ml of a 1.6 M solution of n-butyllithium was added dropwise and stirred for 30 minutes. This reaction solution was added to the above reaction solution while maintaining -78 ° C, and the mixture was stirred at 0 ° C for 30 minutes. 10m saturated ammonium chloride solution in the reaction solution
1 was added and the solvent was distilled off under reduced pressure. The obtained residue was extracted with ethyl acetate, 1N aqueous sodium hydroxide solution, water, 1M
Washed with aqueous sodium hydrogensulfate solution, water, saturated saline solution,
It was dried over anhydrous sodium sulfate. After filtering the drying agent, the filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-n-hexane (1: 4 v / v) was (4S) -3. 4.18 g of-(4-methylpenthionyl) -4- (2-propyl) oxazolidin-2-one was obtained.

Next, 4.18 g of this compound was dissolved in 50 ml of tetrahydrofuran under an argon atmosphere, and a solution of bistrimethylsilylamide sodium salt 1.0M in 27.
58 ml was added dropwise to -78 ° C., and after stirring for 30 minutes,
4.20 ml of bromoacetic acid t-butyl ester was added dropwise,
The mixture was stirred for 1 hour while maintaining -78 ° C. 10 ml of saturated ammonium chloride aqueous solution was added to the reaction solution, and the solvent was distilled off under reduced pressure. The obtained residue was extracted with ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution, water and a saturated saline solution, and dried over anhydrous sodium sulfate. After filtering the desiccant, the filtrate was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to obtain ethyl acetate-n.
-(4S) -3 from the elution fraction of hexane (1: 9 v / v)
There was obtained 5.16 g of-((2R) -2-((t-butoxycarbonyl) methyl) -4-methylpenthionyl) -4- (2-propyl) oxazolidin-2-one.

Then, 3.27 g of benzyl alcohol was dissolved in 50 ml of tetrahydrofuran under an argon atmosphere,
Under ice cooling, a 1.6M solution of n-butyllithium was added to 14.20.
ml was added dropwise. After stirring for 30 minutes, the compound 5.
A solution of 16 g of tetrahydrofuran in 20 ml was added dropwise to 1
Stir for hours. Saturated ammonium chloride solution 1 in the reaction solution
0 ml was added and the solvent was distilled off under reduced pressure. The obtained residue was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the desiccant, the filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and ethyl acetate-n-hexane (1: 9 v
/ V) From the eluted fraction, 4.68 g of (2R) -2-((t-butoxycarbonyl) methyl) -4-methylpentanoic acid benzyl ester was obtained.

Next, 576.6 mg of this compound was dissolved in 10 ml of dichloromethane under an argon atmosphere, 7.0 ml of trifluoroacetic acid was added under ice cooling, and the mixture was stirred at 0 ° C. for 30 minutes.
Stir at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and (2R)-
475.5 mg of 2-carboxymethyl-4-methylpentanoic acid benzyl ester was obtained.

(3) Next, the compound 47 obtained in (2)
Dissolve 5.7 mg in 5 ml of tetrahydrofuran under an argon atmosphere, and add triethylamine 3 at -15 ° C.
08 μl and 271 μl pivaloyl chloride were added, and the mixture was stirred for 15 minutes, and then 1- (4-morpholinylcarbonyl) methyl-N- (1-naphthylmethyl) amine 5 synthesized in (1) was used.
A solution of 01.1 mg of tetrahydrofuran in 5 ml was added,
The mixture was stirred at -15 ° C for 30 minutes and at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the obtained residue was extracted with ethyl acetate, washed with a 1N aqueous hydrochloric acid solution, water, a saturated aqueous sodium hydrogencarbonate solution, water and a saturated saline solution, and dried over anhydrous sodium sulfate. After filtering the desiccant, the filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and extracted with ethyl acetate-n-hexane (4: 1 v / v) (2
R) -2- (1- (4-morpholinylcarbonyl) methyl-N- (1-naphthylmethyl) amino) carbonylmethyl-4-methylpentanoic acid benzyl ester 550.
0 mg was obtained.

Next, 370.0 mg of this compound was dissolved in 10 ml of ethanol, and 10% palladium-carbon 0.2
g was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After the reaction solution was filtered, the filtrate was distilled off under reduced pressure to give (2R) -2- (1
-(4-morpholinylcarbonyl) methyl-N- (1-
260.0 mg of naphthylmethyl) amino) carbonylmethyl-4-methylpentanoic acid was obtained.

(4) Compound 180.0 obtained in (3)
mg of N, N-dimethylformamide in 3 ml of solution was added to Journal of Organic Chemistry (JO
rg. Chem. ), 53, 6109 (1988) and synthesized (2S, 3R, 4S) -2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane 99.8 mg N, N-dimethylformamide 2 m.
1 solution was added, and diphenylphosphoryl azide 1 was added under ice cooling.
A solution of 35.4 mg of N, N-dimethylformamide in 1 ml and 69 μl of triethylamine were added dropwise, and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature overnight. After distilling off the solvent under reduced pressure, the obtained residue was extracted with ethyl acetate and washed with a 1N hydrochloric acid aqueous solution, water, a saturated sodium hydrogencarbonate aqueous solution, water and a saturated saline solution,
It was dried over anhydrous sodium sulfate. After filtering the desiccant, the filtrate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, and chloroform-methanol (2
00: 1 v / v) Elution fraction (2S, 3R, 4S)-
2-((2R) -2- (1- (4-morpholinylcarbonyl) methyl-N- (1naphthylmethyl) amino) carbonylmethyl-4-methylpenthionyl) amino-1
55.2 mg of -cyclohexyl-3,4-dihydroxy-6-methylheptane was obtained.

The spectroscopic data of this support the structure of Formula 29 shown below.

[Chemical 29] ¹ H NMR (CDCl ₃ ) δ: 0.6 to 2.1 (m, 31H) 2.3 to 5.3 (m, 20H) 6.2 to 6.4 (m, 1H) 7.2 to 8 .2 (m, 7H) (Test Example) Inhibitory effect on human plasma renin activity Plasma renin activity (Plasma renin acti)
vity; PRA) is an angiotensin I (AngI) -producing ability per unit time in an enzymatic reaction of endogenous renin and angiotensinogen (renin substrate) in plasma, and is represented by <ngAngI / ml / hr>. To be done.
200 μl of human plasma and 1 of phenylmethylsulfonyl fluoride as an angiotensin I converting enzyme inhibitor
10 μl of 0 mg / ml ethanol solution, 20 μl of 0.6 M citrate buffer (pH 4.8) for pH adjustment, and 10 μl of a dimethyl sulfoxide solution of the compound of the present invention (Example 1) or 10 μl of dimethyl sulfoxide as a control were mixed. After 1 hour incubation at 4 ° C and 37 ° C, ice-cooling and 5.0m of pepstatin A
The reaction is stopped by adding 10 μl of a g / ml methanol solution. The amount of angiotensin I produced is measured by the radioimmunoassay method and converted per 1 ml of plasma, and the renin activity is calculated from the following formula 1.

[Equation 1] The renin activity inhibitory action of the compound of the present invention was determined by the following formula 2.

[Equation 2] The 50% inhibitory activity molar concentration (IC ₅₀ ) was determined from the inhibitory activity determined by Equation 2, and the results are shown in Table 1.

[Table 1] From the results in Table 1, it was confirmed that the compound according to the present invention has an excellent activity of inhibiting renin activity. (Acute toxicity) An acute toxicity test by oral administration was carried out using ICR male mice (5 weeks old). The LD ₅₀ of the compound of the present invention (Example 1) was 2000 mg / kg or more, and high safety was confirmed.

[0026]

INDUSTRIAL APPLICABILITY As described above, the novel naphthylmethylamine derivative according to the present invention has an excellent renin-inhibiting action and is therefore effective in treating hypertension.

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[Procedure amendment]

[Submission date] May 18, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 1

[Correction method] Change

[Correction content]

[Chemical 1] (In the formula, R ¹ is chemical formula 2, chemical formula 3, chemical formula 4 or chemical formula 5 shown below.

[Chemical 2]

[Chemical 3]

[Chemical 4]

[Chemical 5] A morpholinyl group and a di- or trihydroxyalkylamino group represented by, R ² is hydrogen, and has 1 to 7 carbon atoms.
Is an alkyl group which may have a branched or cyclic structure or a 4-imidazolylmethyl group, and R ³ is represented by the following Chemical formula 6 or Chemical formula 7

[Chemical 6]

[Chemical 7] Is. ) The naphthylmethylamine derivative shown by these, or its pharmaceutically acceptable salt.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/535 AED 7252-4C C07D 233/64 106 7252-4C 295/18 Z 6701-4C 317 / 32 7729-4C C12N 9/99 7823-4B

Claims (2)

[Claims] 1. The following chemical formula 1 (In the formula, R ¹ is the following chemical formula 2, chemical formula 3, chemical formula 4, or chemical formula 5 below. [Chemical 3] [Chemical 4] [Chemical 5] A morpholinyl group and a di- or trihydroxyalkylamino group represented by, R ² is hydrogen, and has 1 to 7 carbon atoms.
Is an alkyl group which may have a branched or cyclic structure or a 4-imidazolylmethyl group, and R ³ is represented by the following Chemical formula 6 or Chemical formula 7 [Chemical 7] Is. ) The naphthylmethylamine derivative shown by these, or its pharmaceutically acceptable salt. 2. A renin inhibitor containing at least one of the naphthylmethylamine derivative according to claim 1 or a salt thereof.