Renin inhibitors

• US 5,169,841 A
• Filed: 11/03/1988
• Issued: 12/08/1992
• Est. Priority Date: 11/05/1987
• Status: Expired due to Fees

• Current Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Original Assignee: Hoechst Aktiengesellschaft (Sanofi )
• Inventors: Kleeman, Heinz-Werner, Scholkens, Bernward, Ruppert, Dieter, Urbach, Hansjorg
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Russell, Mark W.
• Application Number:
  US07/266,960
• Time in Patent Office: 1,496 Days
• Field of Search: 549/4, 549/213, 548/405, 548/110, 546/13, 562/7, 558/288, 558/280, 564/8, 514/64, 514/2, 514/63, 544/229
• US Class Current: 514/63
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

The invention relates to compounds of the formula 1 ##STR1## in which A¹ denotes a radical of the formulae ##STR2## A² is absent or represents a radical of the formula ##STR3## R², R³ and R⁴ are as defined in the specification, and X and Y, independently of one another, represent --O-- or --NR¹³ --, and to the salts thereof. Also described is a process for the preparation of the compounds of the formula 1, corresponding pharmaceutical products, and the use thereof as medicines, and intermediates for the preparation of these compounds.

Claims

1. A compound of the formula I ##STR8## in which A¹ is a radical of the formulae II or III, ##STR9## in which R₁ is (C₁ -C₈)-alkylsulfonyl;

(C₁ -C₈)-alkylsulfinyl;

(C₁ -C₁₁)-alkanoyl;

(C₃ -C₉)-cycloalkylcarbonyl;

(C₆ -C₁₀)-aryl-(C₂ -C₁₁)-alkanoyl;

2-pyridyl-(C₁ -C₈)-alkanoyl;

3pyridyl-(C₁ -C₈)-alkanoyl;

4-pyridyl-(C₁ -C₈)-alkanoyl;

pyrrolyl-2-carbonyl;

pyridyl-3-carbonyl;

benzenesulfonyl;

(C₁ -C₁₀)-alkoxycarbonyl;

2-(trimethylsilyl)-ethoxycarbonyl;

2,2,2-trichloroethoxycarbonyl;

1,1-dimethyl-2,2,2-trichloroethoxycarbonyl;

(C₆ -C₁₄)-aryl-(C₁ -C₆)-alkoxycarbonyl,

R² is mono- or bicyclic (C₃ -C₁₈)-cycloalkyl or (C₃ -C₁₈)-cycloalkylmethyl, the cycloalkyl moiety optionally being substituted by (C₁ -C₄)-alkyl;

R³ and R⁴ are hydrogen, or form, together with boron, X and Y, a mono-, bi- or tricyclic mono-, di-, tri- or tetra-(C₁ -C₁₂)-alkylated, saturated or partially unsaturated ring system which as 5-18 ring members and, apart from boron, X, Y and carbon, can also contain an --O-- member, an --NR¹³ -member, or a --CR¹⁴ R¹⁵ -member,

X and Y are --O--,

R⁵ is isopropyl, n-propyl, n-butyl, isobutyl, sec.-butyl, carbamoylmethyl, 2-carbamoylethyl, mercaptomethyl, 2-(methylthio)ethyl, (1-mercapto,1-methyl)-ethyl, hydroxymethyl, 1-hydroxyethyl, cyclohexylmethyl, 4-imidazolylmethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 3-indolylmethyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyl, (benzodioxolane-5-yl)methyl, 2-thienyl, 2-thienylmethyl, 2(2-thienyl)-ethyl, 3-thienyl, 3-thienylmethyl, 2(3-thienyl)ethyl, 4-chlorobenzyl, 2-(methylsulfinyl)ethyl, 2-(methylsulfonyl)ethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl, (1-methyl-4-imidazoyl )methyl, (3-methyl-4-imidazolyl)methyl, phenyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 3-pyrazolylmethyl, 4-pyrimidinylmethyl, 2-indolylmethyl, 2-benzo[b]thienylmethyl, or 3-benzo[b]thienylmethyl,

R⁶ is hydrogen,

R¹² is hydrogen or methyl or forms, together with R¹, a mono- or bicyclic saturated or partially unsaturated ring system which has 5-12 ring members and, apart from carbon, can also contain 1 sulfur atom which can optionally be oxidized to the sulfoxide or sulfone,

R¹³ is hydrogen or (C₁ -C₄)-alkyl,

R¹⁴ and R¹⁵ are, independently of one another, hydrogen, (C₁ -C₈)-alkyl, hydroxymethyl, 2-hydroxyethyl, (3-hydroxysulfonyl, 2-hydroxypropyl)amino, (2-hydroxysulfonylethyl)amino, (2-hydroxysulfonylpropyl)amino, (carboxymethyl)amino, or bis(2-hydroxyethyl)amino,

A² is a radical which is linked N-terminal to A¹ and C-terminal to the amino boronic acid derivative and has the formula VIII, ##STR10## R⁵ and R⁶ being defined as above, as well as the physiologically tolerated salts thereof.

2. A compound of the formula I as claimed in claim 1 in which:

A¹ represents a radical of the formula II or III in which

R¹ denotes (C₁ -C₆)-alkylsulfonyl;

(C₁ -C₆)-alkylsulfinyl;

(C₁ -C₆)-alkoxycarbonyl;

(C₆ -C₁₀)-aryl-(C₁ 1∝

C₆)-alkoxycarbonyl,

R² denotes (C₅ -C₈)-cycloalkyl;

(C₅ -C₁₁ -cycloalkylmethyl;

[(C₁ -C₄)-alkyl-cyclohexyl]methyl;

R³ and R⁴ represent hydrogen, or form, together with boron, X and Y, a 1,3,2-dioxaborolane radical which is optionally substituted by 1 to 4 methyl groups, a [4,5-diisopropyl]-1,3,2-dioxaborolane, a [(N-B)-(2,2'"'"'-imino-diethanolato)-boryl)], a pinandioxyboryl or a 1,3,2-dioxaborinane radical whose carbon atom in position 5 is substituted by R¹⁴ and R¹⁵,

X and Y represent --O--,

R⁵ denotes n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, carbamoylmethyl, 2-carbamoylethyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 2-thienylmethyl, 3-thienylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, imidazol-4-yl-methyl or 2-thiazolylmethyl,

R⁶ represents hydrogen,

R¹² denotes hydrogen,

R¹⁴ and R¹⁵ denote, independently of one another, hydrogen, (C₁ -C₈)-alkyl, hydroxymethyl, 2-hydroxyethyl, (3-hydroxysulfonyl, 2-hydroxypropyl)-amino, (2-hydroxysulfonylethyl)amino, (2-hydroxysulfonylpropyl)amino, (carboxymethyl)amino or bis(2-hydroxyethyl)amino, and

A² represents a radical of the formula VIII, with R⁵ and R⁶ being defined as above, and the physiologically tolerated salts thereof.

3. A method for the treatment of high blood pressure, which comprises administration of an effective amount of a compound of the formula I as claimed in claim 1, or a physiologically tolerated salt thereof.

4. A pharmaceutical composition for the treatment of high blood pressure comprising an effective amount of a compound of the formula I as claimed in claim 1, or a physiologically tolerated salt thereof, and a pharmaceutically acceptable vehicle.