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WO1997011717A1 - Treatment of chronic progressive renal failure - Google Patents

Treatment of chronic progressive renal failure Download PDF

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Publication number
WO1997011717A1
WO1997011717A1 PCT/EP1996/004101 EP9604101W WO9711717A1 WO 1997011717 A1 WO1997011717 A1 WO 1997011717A1 EP 9604101 W EP9604101 W EP 9604101W WO 9711717 A1 WO9711717 A1 WO 9711717A1
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Prior art keywords
renal failure
pharmaceutically acceptable
compound
progression
phenyl
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PCT/EP1996/004101
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French (fr)
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David Saul Cohen
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Novartis Ag
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Priority to AU72116/96A priority Critical patent/AU7211696A/en
Publication of WO1997011717A1 publication Critical patent/WO1997011717A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors

Definitions

  • Chronic progressive renal failure can be caused by different underlying diseases and is characterized by a deterioration of kidney function starting from a mild form followed by moderate and severe forms and progressing to the so-called end stage renal disease (ESRD). These stages can be identified in a conventional way e.g. by determining the creatinine clearance values for which well-defined ranges are assigned to the different stages of renal insufficiency. Patients with ESRD have to undergo drastic therapeutic treatments, including, haemodialysis, continuous ambulatory peritoneal dialysis, and kidney transplantation. Chronic renal failure is a medical condition which affects a significant proportion of the population and its incidence is increasing.
  • ACE angiotensin converting enzyme
  • This invention relates to a method for the treatment of progressive renal failure and prevention of the progression of chronic renal failure in mammals by administration to a mammal in need thereof of a compound of formula I having the S,S-configuration
  • R T represents carbocyclic or heterocyclic monocyclic aryl, or biaryl
  • R 3 represents hydrogen or carboxyl derived acyl
  • R 4 represents lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, or biaryl-lower alkyl
  • COOR 2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester
  • n represents 2-6; or a pharmaceutically acceptable salt thereof.
  • Ri represents phenyl or phenyl substituted by hydroxy, acyloxy or lower alkoxy; or R t represents biphenylyl;
  • R 3 represents hydrogen, lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl;
  • R 4 represents lower alkyl, benzyl or benzyl substituted by hydroxy, halo, lower alkyl, acyloxy, lower alkoxy or trifluoromethyl;
  • COOR 2 represents carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, or pyridylmethoxycarbonyl; or a pharmaceutically acceptable salt thereof.
  • a more particular embodiment of the invention is represented by the compounds of formula II having the S,S-configuration wherein R, represents phenyl or phenyl substituted by hydroxy, acyloxy derived from a carboxylic acid or lower alkoxy; R 3 represents hydrogen, methoxy-lower alkanoyl, or lower alkanoyl; R represents lower alkyl, benzyl or benzyl substituted by hydroxy, halo, lower alkyl, lower alkanoyloxy, lower alkoxy or trifluoromethyl; COOR 2 represents carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl or pyridylmethoxycarbonyl; or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment relates to the compounds of formula II having the S.S-configuration wherein Rt represents 4-hydroxyphenyl, 4-acyloxyphenyl, 4- fluorophenyl or 4-methoxyphenyl; R 3 represents hydrogen, methoxyacetyl or lower alkanoyl; R represents isopropyl; and COOR 2 represents carboxyl or lower alkoxycarbonyl; or a pharmaceutically acceptable salt thereof.
  • Ri represents 4-hydroxyphenyl, 4- methoxyphenyl, 4-(thienylcarbonyloxy)phenyl, 4- (pyridylcarbonyloxy) phenyl, 4- (lower alkoxyacetyloxy)phenyl, 4-lower alkanoyloxyphenyl or 4-(lower alkoxycarbonyloxy)phenyl;
  • R 3 represents lower alkanoyl;
  • R 4 represents isopropyl; and COOR 2 represents lower alkoxycarbonyl.
  • Preferred species relate to the S,S isomers of formula II, (a) wherein R, is 4-hydroxyphenyl, R 2 ethyl, R 3 is acetyl and R is isopropyl; (b) wherein R, is 4- hydroxyphenyl, R 2 hydrogen, R 3 is hydrogen and R 4 is isopropyl; or a pharmaceutically acceptable salt thereof; (c) wherein Ri is 4-(2- methoxyacetyloxy)phenyl, R 2 is ethyl, R 3 is acetyl and R 4 is isopropyl; (d) wherein R T is 4-methoxypheny, R 2 ethyl, R 3 is acetyl and R is isopropyl; and (e) wherein Ri is 4-methoxyphenyl, R 2 and R 3 are hydrogen, and R 4 is isopropyl; or a pharmaceutically acceptable salt thereof.
  • esters are preferably prodrug ester derivatives, such being convertible by solvolysis or under physiological conditions to the free carboxylic acids of formula I.
  • prodrug esters are preferably e.g. lower alkyl esters, cycloalkyl esters, lower alkenyl esters, aryl-lower alkyl esters, ⁇ - (lower alkanoyloxy)-lower alkyl esters such as the pivaloyloxy-methyl ester, and ⁇ -(lower alkoxycarbonyl- or di-lower alkylamino carbonyl-)-lower alkyl esters.
  • Pharmaceutically acceptable salts are salts derived from pharmaceutically acceptable bases for any acidic compounds of the invention, e.g. those wherein COOR 2 represents carboxyl.
  • Such are e.g. alkali metal salts (e.g. sodium, potassium salts), alkaline earth metal salts (e.g. magnesium, calcium salts), amine salts (e.g. tromethamine salts).
  • alkali metal salts e.g. sodium, potassium salts
  • alkaline earth metal salts e.g. magnesium, calcium salts
  • amine salts e.g. tromethamine salts.
  • Aryl represents carbocyclic or heterocyclic aryl, either monocyclic or bicyclic.
  • Monocyclic carbocyclic aryl represents optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituents, such being advantageously lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano, trifluoromethyl, amino, lower alkanoylamino, lower alkyl-(thio, sulfinyl or sulfonyl), lower alkoxycarbonyl, mono- or di-lower alkylcarbamoyl, or mono- or di- lower alkylamino.
  • Bicyclic carbocyclic aryl represents 1- or 2-naphthyl 1- 2-naphthyl preferably substituted by lower alkyl, lower alkoxy or halogen.
  • Monocyclic heterocyclic aryl represents preferably optionally substituted thiazolyl, thienyl, furanyl or pyridyl.
  • Optionally substituted furanyl represents 2- or 3-furanyl, or 2- or 3-furanyl preferably substituted by lower alkyl.
  • Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl, or 2-, 3- or 4- pyridyl preferably substituted by lower alkyl, halogen or cyano.
  • Optionally substituted thienyl represents 2- or 3-thienyl, or 2- or 3-thienyl preferably substituted by lower alkyl.
  • Optionally substituted thiazolyl represents e.g. 4-thiazolyl, or 4-thiazolyl substituted by lower alkyl.
  • Bicyclic heterocyclic aryl represents preferably indolyl or benzothiazolyl optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen, advantageously 3-indolyl or 2-benzothiazolyl.
  • Aryl as in aryl-lower alkyl is preferably phenyl or phenyl substituted by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, trifluoromethyl, cyano, lower alkanoylamino or lower alkoxycarbonyl; also, optionally substituted naphthyl.
  • Aryl-lower alkyl is advantageously benzyl or 1 - 2-phenethyl optionally substituted on phenyl by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen or trifluoromethyl.
  • lower referred to herein in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up and including 4 and advantageously one or two carbon atoms. Such may be straight chain or branched.
  • a lower alkyl group preferably contains 1 -4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.
  • a lower alkoxy group preferably contains 1 -4 carbon atoms and represents for example methoxy, propoxy, isopropoxy or advantageously ethoxy.
  • a lower alkoxycarbonyl group preferably contains 1 to 4 carbon atoms in the alkoxy portion and represents, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.
  • Halogen preferably represents fluoro or chloro, but may also be bromo or iodo.
  • Acyl is derived from a carboxylic acid and represents preferably optionally substituted lower alkanoyl, cycloalkylcarbonyl, carbocyclic aryl-lower alkanoyl, aroyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, advantageously optionally substituted lower alkanoyl, or aroyl.
  • Lower alkanoyl is preferably acetyl, propionyl, butyryl, or pivaloyi.
  • Optionally substituted lower alkanoyl for example represents lower alkanoyl or lower alkanoyl substituted by lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoylthio, lower alkoxy, or by lower alkylthio; also lower alkanoyl substituted by e.g. hydroxy, di-lower alkylamino, lower alkanoylamino, morpholino, piperidino, pyrrolidino or 1 -lower alkylpiperazino.
  • Aroyl is carbocyclic or heterocyclic aroyl, preferably monocyclic carbocyclic or monocyclic heterocyclic aroyl.
  • Monocyclic carbocyclic aroyl is preferably benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl.
  • Monocyclic heterocyclic aroyl is preferably pyridylcarbonyl or thienylcarbonyl.
  • Acyloxy is preferably optionally substituted lower alkanoyloxy, lower alkoxycarbonyloxy, monocyclic carbocylic aroyloxy or monocyclic heterocyclic aroyloxy; also carbocyclic or heterocyclic aryl-lower alkanoyloxy.
  • Optionally substituted lower alkanoyloxy is preferably lower alkanoyloxy, such as acetyloxy, substituted by any group indicated above under optionally substituted alkanoyl.
  • Aryl-lower alkoxycarbonyl is preferably monocyclic carbocyclic-lower alkoxycarbonyl, advantageously benzyloxycarbonyl.
  • Biaryl represents monocarbocyclic aryl substituted by monocyclic carbocyclic or monocyclic heterocyclic aryl, and preferably represents biphenylyl, advantageous 4-biphenylyl optionally substituted on one or both benzene rings by lower alkyl, lower alkoxy, halogen or trifluoromethyl.
  • Biaryl-lower alkyl is preferably 4-biphenylyl-lower alkyl, advantageously 4-biphenylyl-methyl.
  • the above compounds of formula I are effective for the treatment of chronic progressive renal failure, in particular for the prevention and inhibition of the deterioration of kidney function in mammals, including man, resulting from renal dysfunction of various etiologies, by administering to a subject in need thereof a therapeutically effective amount of a compound of the invention over a prolonged period of time.
  • the pertinent renal dysfunctions include glomerular disorders (i.e. glomerulonephropathy such as non-lgA glomerulonephropathy and glomerulonephritis, diabetic nephropathy, nephrosclerosis and the like.
  • Diagnostic signs of chronic renal failure include elevated serum urea, elevated serum creatinine, proteinuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia and urinary proteinaceous casts.
  • the inhibition of the progression of the renal failure can be evaluated by measuring these parameters in mammals by methods well known in the art, e.g. by measuring creatinine clearance.
  • the beneficial renal protective effects for the treatment of chronic progressive renal failure can be evaluated in a remnant kidney model in normotensive, Sprague-Dawley rats.
  • This is a model of chronic renal failure (end- stage renal failure) induced by ligation (and subsequent infarction) of 2-3 branches of the left renal artery and removal of the right kidney resulting in one- sixth of functional renal mass.
  • the pathophysiological consequences of this procedure are severe hypertension, extensive proteinuria, marked reductions in glomerular filtration rate (as indicated by reduced creatinine clearances), natriuresis, kaliuresis and striking renal histological abnormalities (glomerular and tubular, including glomerular and arteriolar lesions, tubular dilation and the presence of proteinaceous casts). Results obtained with drug treated and vehicle (propylene glycol) treated rats are compared.
  • Drug administration is by the subcutaneous route via Alzet osmotic minipumps, starting at one week following surgery and continued for periods up to 13 weeks following renal artery
  • ethyl N-[[[1 -[2-(S)-acetylthio-3-methyl-1 -oxo- butyl]amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosinate (the compound of formula II of the S,S-configuration wherein Ri is 4-methoxyphenyl, R 2 ethyl, R 3 is acetyl and R 4 is isopropyl, also called CGS 30,440) is effective in inhibiting the progression of chronic renal failure in this model at a dose of about 1 and 3 mg/kg/day.
  • CGS 30,440 is the compound of example 1 (hh) in European patent application No. 655,461.
  • CGS 30,440 attenuates the extent of the glomerular and arteriolar lesions, decreases proteinaceous casts and decreases the severity of tubular dilation compared to control aminals.
  • the compounds of the invention are angiotensin converting enzyme (ACE) inhibitors as well as neutral endopeptidase (NEP) inhibitors.
  • ACE angiotensin converting enzyme
  • NEP neutral endopeptidase
  • Benazepril is one of the ACE inhibitors disclosed to be useful for the treatment of progressive renal failure in U.S. patent 5,238,924.
  • CGS 30,440 is substantially superior to benazepril hydrochloride in inhibiting the progression of chronic progressive renal failure in the above rat model.
  • CGS 30,440 is effective in reducing the extent of proteinaceous casts and the severity of tubular dilation.
  • CGS 30,440 demonstrates substantial activity at a dose where benazepril is inactive.
  • a potent neutral endopeptidase (NEP) inhibitor namely CGS 24,592, S-(+)-N-[2-(phosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3- aminopropionic acid, the compound of example 2 of U.S. patent 5,155,100, is inactive in the above rat model at a dose of 10 mg/kg/day.
  • NEP inhibition by itself is shown not to improve renal function in this model of end stage chronic renal failure, no benefit is expected from the NEP inhibitory activity of e.g. CGS 30,440.
  • CGS 30,440 (the S,S- isomer of formula II wherein R, is 4-methoxyphenyl, R 2 is ethyl, R 3 is acetyl and R 4 is isopropyl) is in fact substantially superior in efficacy to the potent ACE inhibitor benazepril for the treatment of progressive chronic renal failure.
  • the invention also relates to the use of a compound of the formula I having the S,S-configuration as defined hereinbefore for the manufacture of a pharmaceutical composition for the treatment of chronic progressive renal failure or for the prevention of the progression of chronic renal failure.
  • the invention also relates to a pharmaceutical composition for the treatment of chronic progressive renal failure or for the prevention of the progression of chronic renal failure comprising a therapeutically effective amount of a compound of the formula I having the S,S-configuration as defined hereinbefore and a carrier.
  • the compounds can be administered orally, transdermally or intravenously, preferably orally, in any well-known suitable dosage form, such as tablets or capsules, which can be prepared according to methods well-known in the art.
  • suitable dosage form such as tablets or capsules, which can be prepared according to methods well-known in the art.
  • the compounds of the invention can be administered preferably in amounts ranging from about 5 to 500 mg/day over a prolonged period of time, the exact dosage depending on the compound and the mode of administration. The duration of administration will also depend on the condition of the subject involved. - 1 1
  • CGS 30,440 demonstrating both angiotensin converting enzyme (ACE) inhibition and neutral endopeptidase (NEP) inhibitory properties was studied in a remnant kidney model in normotensive, Sprague-Dawley rats. This is a model of chronic renal failure induced by ligation (and subsequent infarction) of 2-3 branches of the left renal artery and removal of the right kidney resulting in one- sixth of functional renal mass.
  • the pathophysiological consequences of this procedure are severe hypertension, extensive proteinuria, marked reductions in glomerular filtration rate (as indicated by reduced creatinine clearances), natriuresis, kaliuresis and striking renal histological abnormalities (glomerular and tubular).
  • CGS 30,440 is compared to CGS 24,592, an NEP inhibitor, which elevates endogenous levels of atrial natriuretic peptide (ANP) and to benazepril hydrochloride, an ACE inhibitor.
  • Drug administrations using propylene glycol as the vehicle) are by the subcutaneous route via Alzet osmotic minipumps (ALZA Corp., Palo Alto, CA). Drug is given at one week following surgery and continued for 6 weeks following renal artery ablation.
  • Systolic blood pressure is elevated similar to non-treated rats as are the fractional excretions of Na ⁇ K + and Cl ' . Histologically, similar degrees of glomerular and tubular damage are observed in both the vehicle and CGS 24,592-treated rats.
  • CGS 30,440 when compared to benazepril HCI (both at 6.5 ⁇ mole/kg/day, about 3.0 mg/kg/day), a dose that in normotensive non-ablated animals reduces systolic blood pressures to a similar extent by either drug, demonstrates efficacy superior to benazepril and vehicle-treated group in preserving renal function and maintaining normal renal architecture. Systolic blood pressures are reduced to the greatest extent with CGS 30,440 treatment.
  • CGS 30,440 significantly (p ⁇ 0.05) reduces proteinurea, improves creatinine clearance (GFR), and normalizes electrolyte fractional excretions.
  • CGS 30,440 and benazepril hydrochloride moderately attenuate the extent of glomerular and vascular lesions. However, only CGS 30,440 significantly reduces the extent of proteinaceous casts and the severity of tubular dilation.
  • CGS 30,440 In a followup study assessing the efficacy of CGS 30,440 over benazepril hydrochloride over 6 weeks of treatment at a dose of 2.2 ⁇ mole/kg/day (equivalent to 1.0 mg/kg/day) greatly enhanced efficacy is observed for CGS 30,440.
  • Benazepril hydrochloride is ineffectual at this dose in regard to reducing systolic blood pressure and reducing renal pathophysiology.
  • CGS 30,440 significantly reduces blood pressure and increases creatinine clearance compared to vehicle and benazepril HCI-treated rats. Proteinuria and the fractional excretion of electrolytes are also reduced (p ⁇ 0.05) by CGS 30,440.

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Abstract

This invention relates to a method for the treatment of progressive renal failure and prevention of the progression of chronic renal failure in mammals by administration to a mammal in need thereof of a compound of formula (I) having the S,S-configuration, wherein R1 represents carbocyclic or heterocyclic monocyclic aryl, or biaryl; R3 represents hydrogen or carboxyl derived acyl; R4 represents hydrogen, lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, or biaryl-lower alkyl; COOR2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; n represents 2-6; or a pharmaceutically acceptable salt thereof.

Description

TREATMENT OF CHRONIC PROGRESSIVE RENAL FAILURE
Background of the Invention
Chronic progressive renal failure can be caused by different underlying diseases and is characterized by a deterioration of kidney function starting from a mild form followed by moderate and severe forms and progressing to the so- called end stage renal disease (ESRD). These stages can be identified in a conventional way e.g. by determining the creatinine clearance values for which well-defined ranges are assigned to the different stages of renal insufficiency. Patients with ESRD have to undergo drastic therapeutic treatments, including, haemodialysis, continuous ambulatory peritoneal dialysis, and kidney transplantation. Chronic renal failure is a medical condition which affects a significant proportion of the population and its incidence is increasing.
At present there is no satisfactory treatment for chronic renal failure and there is a great need for a drug which can significantly inhibit the progression of chronic renal failure.
The effect of angiotensin converting enzyme (ACE) inhibitors on the progression of renal failure has been disclosed, e.g. in U.S. patent 5,238,924.
Cyclic amino acid derivatives which are ACE inhibitors and neutral endopeptidase inhibitors are described in U.S. patent 5,432,186 and European patent application No. 655,461 published May 31 , 1995. Although the compounds are indicated to possess e.g. diuretic and natriuretic properties and to be useful for the treatment of "renal insufficiency", there is no indication that the progression of chronic renal failure in mammals is inhibited. Summary of the Invention
It has now been found that the compounds of formula I, below, which are disclosed in European patent application No. 655,461 , are unexpectedly effective for the treatment of progressive renal failure and prevention of the progression of chronic renal failure.
Detailed Description of the Invention
This invention relates to a method for the treatment of progressive renal failure and prevention of the progression of chronic renal failure in mammals by administration to a mammal in need thereof of a compound of formula I having the S,S-configuration
R3S I C*H — C II
Figure imgf000004_0001
(cH2)n
wherein RT represents carbocyclic or heterocyclic monocyclic aryl, or biaryl; R3 represents hydrogen or carboxyl derived acyl; R4 represents lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, or biaryl-lower alkyl; COOR2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; n represents 2-6; or a pharmaceutically acceptable salt thereof.
Said compounds and their preparation are described in U.S. patent 5,432,186 and allowed U.S. application No. 08/263,859, both of which are incorporated herein by reference. The compounds are also described in corresponding European patent application No. 655,461 published May 31 , 1995 which is also incorporated by reference. A particular embodiment of the invention is represented by a method of treatment with the compounds of the formula II having the S,S-configuration
R, O O £H2 — Rι
R,S T CH — C ll NH ,C II NH C TH COOR2
wherein
Ri represents phenyl or phenyl substituted by hydroxy, acyloxy or lower alkoxy; or Rt represents biphenylyl;
R3 represents hydrogen, lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl;
R4 represents lower alkyl, benzyl or benzyl substituted by hydroxy, halo, lower alkyl, acyloxy, lower alkoxy or trifluoromethyl;
COOR2 represents carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, or pyridylmethoxycarbonyl; or a pharmaceutically acceptable salt thereof.
A more particular embodiment of the invention is represented by the compounds of formula II having the S,S-configuration wherein R, represents phenyl or phenyl substituted by hydroxy, acyloxy derived from a carboxylic acid or lower alkoxy; R3 represents hydrogen, methoxy-lower alkanoyl, or lower alkanoyl; R represents lower alkyl, benzyl or benzyl substituted by hydroxy, halo, lower alkyl, lower alkanoyloxy, lower alkoxy or trifluoromethyl; COOR2 represents carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl or pyridylmethoxycarbonyl; or a pharmaceutically acceptable salt thereof.
A preferred embodiment relates to the compounds of formula II having the S.S-configuration wherein Rt represents 4-hydroxyphenyl, 4-acyloxyphenyl, 4- fluorophenyl or 4-methoxyphenyl; R3 represents hydrogen, methoxyacetyl or lower alkanoyl; R represents isopropyl; and COOR2 represents carboxyl or lower alkoxycarbonyl; or a pharmaceutically acceptable salt thereof. Another preferred embodiment relates to the compounds of formula II having the S,S-configuration wherein Ri represents 4-hydroxyphenyl, 4- methoxyphenyl, 4-(thienylcarbonyloxy)phenyl, 4- (pyridylcarbonyloxy) phenyl, 4- (lower alkoxyacetyloxy)phenyl, 4-lower alkanoyloxyphenyl or 4-(lower alkoxycarbonyloxy)phenyl; R3 represents lower alkanoyl; R4 represents isopropyl; and COOR2 represents lower alkoxycarbonyl.
Preferred species relate to the S,S isomers of formula II, (a) wherein R, is 4-hydroxyphenyl, R2 ethyl, R3 is acetyl and R is isopropyl; (b) wherein R, is 4- hydroxyphenyl, R2 hydrogen, R3 is hydrogen and R4 is isopropyl; or a pharmaceutically acceptable salt thereof; (c) wherein Ri is 4-(2- methoxyacetyloxy)phenyl, R2 is ethyl, R3is acetyl and R4 is isopropyl; (d) wherein RT is 4-methoxypheny, R2 ethyl, R3 is acetyl and R is isopropyl; and (e) wherein Ri is 4-methoxyphenyl, R2 and R3are hydrogen, and R4 is isopropyl; or a pharmaceutically acceptable salt thereof.
Pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or under physiological conditions to the free carboxylic acids of formula I.
Pharmaceutically acceptable prodrug esters are preferably e.g. lower alkyl esters, cycloalkyl esters, lower alkenyl esters, aryl-lower alkyl esters, α- (lower alkanoyloxy)-lower alkyl esters such as the pivaloyloxy-methyl ester, and α-(lower alkoxycarbonyl- or di-lower alkylamino carbonyl-)-lower alkyl esters.
Pharmaceutically acceptable salts are salts derived from pharmaceutically acceptable bases for any acidic compounds of the invention, e.g. those wherein COOR2 represents carboxyl. Such are e.g. alkali metal salts (e.g. sodium, potassium salts), alkaline earth metal salts (e.g. magnesium, calcium salts), amine salts (e.g. tromethamine salts). The definitions as such or in combination as used herein, unless denoted otherwise, have the following meanings within the scope of the present invention.
Aryl represents carbocyclic or heterocyclic aryl, either monocyclic or bicyclic.
Monocyclic carbocyclic aryl represents optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituents, such being advantageously lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano, trifluoromethyl, amino, lower alkanoylamino, lower alkyl-(thio, sulfinyl or sulfonyl), lower alkoxycarbonyl, mono- or di-lower alkylcarbamoyl, or mono- or di- lower alkylamino.
Bicyclic carbocyclic aryl represents 1- or 2-naphthyl 1- 2-naphthyl preferably substituted by lower alkyl, lower alkoxy or halogen.
Monocyclic heterocyclic aryl represents preferably optionally substituted thiazolyl, thienyl, furanyl or pyridyl.
Optionally substituted furanyl represents 2- or 3-furanyl, or 2- or 3-furanyl preferably substituted by lower alkyl.
Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl, or 2-, 3- or 4- pyridyl preferably substituted by lower alkyl, halogen or cyano.
Optionally substituted thienyl represents 2- or 3-thienyl, or 2- or 3-thienyl preferably substituted by lower alkyl.
Optionally substituted thiazolyl represents e.g. 4-thiazolyl, or 4-thiazolyl substituted by lower alkyl. Bicyclic heterocyclic aryl represents preferably indolyl or benzothiazolyl optionally substituted by hydroxy, lower alkyl, lower alkoxy or halogen, advantageously 3-indolyl or 2-benzothiazolyl.
Aryl as in aryl-lower alkyl is preferably phenyl or phenyl substituted by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, trifluoromethyl, cyano, lower alkanoylamino or lower alkoxycarbonyl; also, optionally substituted naphthyl.
Aryl-lower alkyl is advantageously benzyl or 1 - 2-phenethyl optionally substituted on phenyl by one or two of lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen or trifluoromethyl.
The term "lower" referred to herein in connection with organic radicals or compounds respectively defines such with up to and including 7, preferably up and including 4 and advantageously one or two carbon atoms. Such may be straight chain or branched.
A lower alkyl group preferably contains 1 -4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.
A lower alkoxy group preferably contains 1 -4 carbon atoms and represents for example methoxy, propoxy, isopropoxy or advantageously ethoxy.
A lower alkoxycarbonyl group preferably contains 1 to 4 carbon atoms in the alkoxy portion and represents, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonyl.
Halogen (halo) preferably represents fluoro or chloro, but may also be bromo or iodo.
Acyl is derived from a carboxylic acid and represents preferably optionally substituted lower alkanoyl, cycloalkylcarbonyl, carbocyclic aryl-lower alkanoyl, aroyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, advantageously optionally substituted lower alkanoyl, or aroyl.
Lower alkanoyl is preferably acetyl, propionyl, butyryl, or pivaloyi.
Optionally substituted lower alkanoyl for example represents lower alkanoyl or lower alkanoyl substituted by lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoylthio, lower alkoxy, or by lower alkylthio; also lower alkanoyl substituted by e.g. hydroxy, di-lower alkylamino, lower alkanoylamino, morpholino, piperidino, pyrrolidino or 1 -lower alkylpiperazino.
Aroyl is carbocyclic or heterocyclic aroyl, preferably monocyclic carbocyclic or monocyclic heterocyclic aroyl.
Monocyclic carbocyclic aroyl is preferably benzoyl or benzoyl substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl.
Monocyclic heterocyclic aroyl is preferably pyridylcarbonyl or thienylcarbonyl.
Acyloxy is preferably optionally substituted lower alkanoyloxy, lower alkoxycarbonyloxy, monocyclic carbocylic aroyloxy or monocyclic heterocyclic aroyloxy; also carbocyclic or heterocyclic aryl-lower alkanoyloxy.
Optionally substituted lower alkanoyloxy is preferably lower alkanoyloxy, such as acetyloxy, substituted by any group indicated above under optionally substituted alkanoyl.
Aryl-lower alkoxycarbonyl is preferably monocyclic carbocyclic-lower alkoxycarbonyl, advantageously benzyloxycarbonyl.
Biaryl represents monocarbocyclic aryl substituted by monocyclic carbocyclic or monocyclic heterocyclic aryl, and preferably represents biphenylyl, advantageous 4-biphenylyl optionally substituted on one or both benzene rings by lower alkyl, lower alkoxy, halogen or trifluoromethyl.
Biaryl-lower alkyl is preferably 4-biphenylyl-lower alkyl, advantageously 4-biphenylyl-methyl.
It has been found that the above compounds of formula I are effective for the treatment of chronic progressive renal failure, in particular for the prevention and inhibition of the deterioration of kidney function in mammals, including man, resulting from renal dysfunction of various etiologies, by administering to a subject in need thereof a therapeutically effective amount of a compound of the invention over a prolonged period of time. The pertinent renal dysfunctions include glomerular disorders (i.e. glomerulonephropathy such as non-lgA glomerulonephropathy and glomerulonephritis, diabetic nephropathy, nephrosclerosis and the like.
Diagnostic signs of chronic renal failure include elevated serum urea, elevated serum creatinine, proteinuria, glomerular and arteriolar lesions, tubular dilation, hyperphosphatemia and urinary proteinaceous casts. The inhibition of the progression of the renal failure can be evaluated by measuring these parameters in mammals by methods well known in the art, e.g. by measuring creatinine clearance.
The above-cited effects are demonstrable in vivo tests, using advantageously mammals, e.g. mice, rats, dogs or monkeys. Said compounds can be applied in vivo either enterally, parenterally, advantageously orally or intravenously, e.g. as a suspension or in aqueous solution. The dosage may range depending on the route of administration, between about 0.01 and 50 mg/kg, advantageously between about 0.1 and 25 mg/kg.
The beneficial renal protective effects for the treatment of chronic progressive renal failure can be evaluated in a remnant kidney model in normotensive, Sprague-Dawley rats. This is a model of chronic renal failure (end- stage renal failure) induced by ligation (and subsequent infarction) of 2-3 branches of the left renal artery and removal of the right kidney resulting in one- sixth of functional renal mass. The pathophysiological consequences of this procedure are severe hypertension, extensive proteinuria, marked reductions in glomerular filtration rate (as indicated by reduced creatinine clearances), natriuresis, kaliuresis and striking renal histological abnormalities (glomerular and tubular, including glomerular and arteriolar lesions, tubular dilation and the presence of proteinaceous casts). Results obtained with drug treated and vehicle (propylene glycol) treated rats are compared. Drug administration is by the subcutaneous route via Alzet osmotic minipumps, starting at one week following surgery and continued for periods up to 13 weeks following renal artery ablation.
Illustrative of the invention, ethyl N-[[[1 -[2-(S)-acetylthio-3-methyl-1 -oxo- butyl]amino]-1-cyclopentyl]carbonyl]-O-methyl-L-tyrosinate (the compound of formula II of the S,S-configuration wherein Ri is 4-methoxyphenyl, R2 ethyl, R3 is acetyl and R4 is isopropyl, also called CGS 30,440) is effective in inhibiting the progression of chronic renal failure in this model at a dose of about 1 and 3 mg/kg/day. CGS 30,440 is the compound of example 1 (hh) in European patent application No. 655,461. CGS 30,440 attenuates the extent of the glomerular and arteriolar lesions, decreases proteinaceous casts and decreases the severity of tubular dilation compared to control aminals. As stated above, the compounds of the invention are angiotensin converting enzyme (ACE) inhibitors as well as neutral endopeptidase (NEP) inhibitors.
Benazepril is one of the ACE inhibitors disclosed to be useful for the treatment of progressive renal failure in U.S. patent 5,238,924.
As demonstrated in the example, CGS 30,440 is substantially superior to benazepril hydrochloride in inhibiting the progression of chronic progressive renal failure in the above rat model. In contrast to benazepril, CGS 30,440 is effective in reducing the extent of proteinaceous casts and the severity of tubular dilation. Furthermore, CGS 30,440 demonstrates substantial activity at a dose where benazepril is inactive. In addition, a potent neutral endopeptidase (NEP) inhibitor, namely CGS 24,592, S-(+)-N-[2-(phosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3- aminopropionic acid, the compound of example 2 of U.S. patent 5,155,100, is inactive in the above rat model at a dose of 10 mg/kg/day.
Since NEP inhibition by itself is shown not to improve renal function in this model of end stage chronic renal failure, no benefit is expected from the NEP inhibitory activity of e.g. CGS 30,440.
It is therefore surprising and unexpected that CGS 30,440 (the S,S- isomer of formula II wherein R, is 4-methoxyphenyl, R2 is ethyl, R3 is acetyl and R4 is isopropyl) is in fact substantially superior in efficacy to the potent ACE inhibitor benazepril for the treatment of progressive chronic renal failure.
The invention also relates to the use of a compound of the formula I having the S,S-configuration as defined hereinbefore for the manufacture of a pharmaceutical composition for the treatment of chronic progressive renal failure or for the prevention of the progression of chronic renal failure.
The invention also relates to a pharmaceutical composition for the treatment of chronic progressive renal failure or for the prevention of the progression of chronic renal failure comprising a therapeutically effective amount of a compound of the formula I having the S,S-configuration as defined hereinbefore and a carrier.
For use in the treatment of chronic progressive renal failure the compounds can be administered orally, transdermally or intravenously, preferably orally, in any well-known suitable dosage form, such as tablets or capsules, which can be prepared according to methods well-known in the art. The compounds of the invention can be administered preferably in amounts ranging from about 5 to 500 mg/day over a prolonged period of time, the exact dosage depending on the compound and the mode of administration. The duration of administration will also depend on the condition of the subject involved. - 1 1
Experimental Part
CGS 30,440, demonstrating both angiotensin converting enzyme (ACE) inhibition and neutral endopeptidase (NEP) inhibitory properties was studied in a remnant kidney model in normotensive, Sprague-Dawley rats. This is a model of chronic renal failure induced by ligation (and subsequent infarction) of 2-3 branches of the left renal artery and removal of the right kidney resulting in one- sixth of functional renal mass. The pathophysiological consequences of this procedure are severe hypertension, extensive proteinuria, marked reductions in glomerular filtration rate (as indicated by reduced creatinine clearances), natriuresis, kaliuresis and striking renal histological abnormalities (glomerular and tubular). CGS 30,440 is compared to CGS 24,592, an NEP inhibitor, which elevates endogenous levels of atrial natriuretic peptide (ANP) and to benazepril hydrochloride, an ACE inhibitor. Drug administrations (using propylene glycol as the vehicle) are by the subcutaneous route via Alzet osmotic minipumps (ALZA Corp., Palo Alto, CA). Drug is given at one week following surgery and continued for 6 weeks following renal artery ablation.
The potent NEP inhibitor, CGS 24,592, given at 10 mg/kg/day for 6 weeks, does not improve GFR nor reduce proteinuria. Systolic blood pressure is elevated similar to non-treated rats as are the fractional excretions of Na\ K+ and Cl'. Histologically, similar degrees of glomerular and tubular damage are observed in both the vehicle and CGS 24,592-treated rats.
CGS 30,440, when compared to benazepril HCI (both at 6.5 μmole/kg/day, about 3.0 mg/kg/day), a dose that in normotensive non-ablated animals reduces systolic blood pressures to a similar extent by either drug, demonstrates efficacy superior to benazepril and vehicle-treated group in preserving renal function and maintaining normal renal architecture. Systolic blood pressures are reduced to the greatest extent with CGS 30,440 treatment. CGS 30,440 significantly (p<0.05) reduces proteinurea, improves creatinine clearance (GFR), and normalizes electrolyte fractional excretions. CGS 30,440 and benazepril hydrochloride moderately attenuate the extent of glomerular and vascular lesions. However, only CGS 30,440 significantly reduces the extent of proteinaceous casts and the severity of tubular dilation.
In a followup study assessing the efficacy of CGS 30,440 over benazepril hydrochloride over 6 weeks of treatment at a dose of 2.2 μmole/kg/day (equivalent to 1.0 mg/kg/day) greatly enhanced efficacy is observed for CGS 30,440. Benazepril hydrochloride is ineffectual at this dose in regard to reducing systolic blood pressure and reducing renal pathophysiology. In contrast, CGS 30,440 significantly reduces blood pressure and increases creatinine clearance compared to vehicle and benazepril HCI-treated rats. Proteinuria and the fractional excretion of electrolytes are also reduced (p<0.05) by CGS 30,440.

Claims

13 -WHAT IS CLAIMED IS:
1. A method for the treatment of chronic progressive renal failure in mammals which comprises administering to a mammal in need thereof a renal failure inhibiting amount of a compound of the formula I having the S,S- configuration
R. o £H2 — R*
R,S f CH — I CI NH T CH — COOR, w
Figure imgf000015_0001
(CH2)n
wherein RT represents carbocyclic or heterocyclic monocyclic aryl, or biaryl; R3 represents hydrogen or carboxyl derived acyl; R4 represents lower alkyl, carbocyclic or heterocyclic aryl-lower alkyl, or biaryl-lower alkyl; COOR2 represents carboxyl or carboxyl derivatized in form of a pharmaceutically acceptable ester; n represents 2-6; or a pharmaceutically acceptable salt thereof; or of said compound in combination with one or more pharmaceutically acceptable carriers.
2. A method according to claim 1 which comprises administering to a mammal in need thereof a renal failure inhibiting amount of a compound of formula II having the S,S-configuration
Figure imgf000015_0002
wherein
Ri represents phenyl or phenyl substituted by hydroxy, acyloxy or lower alkoxy; or R represents biphenylyl;
R3 represents hydrogen, lower alkanoyl, methoxy-lower alkanoyl, benzoyl or pyridylcarbonyl; R represents lower alkyl, benzyl or benzyl substituted by hydroxy, halo, lower alkyl, acyloxy, lower alkoxy or trifluoromethyl;
COOR2 represents carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl, or pyridylmethoxycarbonyl; or a pharmaceutically acceptable salt thereof; or of said compound in combination with one or more pharmaceutically acceptable carriers.
3. A method according to claim 2 which comprises administering to a mammal in need thereof a renal failure inhibiting amount of a compound of formula II having the S.S-configuration wherein Ri represents phenyl or phenyl substituted by hydroxy, acyloxy derived from a carboxylic acid or lower alkoxy; R3 represents hydrogen, methoxy-lower alkanoyl, or lower alkanoyl; R4 represents lower alkyl, benzyl or benzyl substituted by hydroxy, halo, lower alkyl, lower alkanoyloxy, lower alkoxy or trifluoromethyl; COOR2 represents carboxyl, lower alkoxycarbonyl, benzyloxycarbonyl or pyridylmethoxycarbonyl; or a pharmaceutically acceptable salt thereof; or of said compound in combination with one or more pharmaceutically acceptable carriers.
4. A method according to claim 2 which comprises administering to a mammal in need thereof a renal failure inhibiting amount of a pharmaceutical formulation comprising a compound of formula II having the S,S configuration wherein RT represents 4-hydroxyphenyl, 4-acyloxyphenyl, 4-f luorophenyl or 4- methoxyphenyl; R3 represents hydrogen, methoxyacetyl or lower alkanoyl; R4 represents isopropyl; and COOR2 represents carboxyl or lower alkoxycarbonyl; or a pharmaceutically acceptable salt thereof; or of said compound in combination with one or more pharmaceutically acceptable carriers.
5. A method according to claim 2 which comprises administering to a mammal in need thereof a renal failure inhibiting amount of a compound of formula II having the S.S-configuration wherein Ri represents 4-hydroxyphenyl, 4- methoxyphenyl, 4-(thienylcarbonyloxy)phenyl, 4-(pyridylcarbonyloxy)phenyl, 4- (lower alkoxyacetyloxy)phenyl, 4-lower alkanoyloxyphenyl or 4-(lower alkoxycarbonyloxy) phenyl; R3 represents lower alkanoyl; R4 represents isopropyl; and COOR2 represents lower alkoxycarbonyl; or of said compound in combination with one or more pharmaceutically acceptable carriers. O 97/11717 PC17EP96/04101
- 15 -
6. A method according to claim 2 which comprises administering to a mammal in need thereof a renal failure inhibiting amount of a compound selected from compounds of formula II having the S.S-configuration (a) wherein Ri is 4- hydroxyphenyl, R2 ethyl, R3 is acetyl and R is isopropyl; (b) wherein R, is 4- hydroxyphenyl, R2 hydrogen, R3 is hydrogen and R4 is isopropyl; or a pharmaceutically acceptable salt thereof; (c) wherein R< is 4-(2- methoxyacetyloxy)phenyl, R2 is ethyl, R3 is acetyl and R is isopropyl; (d) wherein Ri is 4-methoxyphenyl, R2 ethyl, R3 is acetyl and R4 is isopropyl; and (e) wherein Ri is 4-methoxyphenyl, R2 and R3 are hydrogen, and R4 is isopropyl; or a pharmaceutically acceptable salt thereof; or of said compound in combination with one or more pharmaceutically acceptable carriers.
7. A method according to claim 2 which comprises administering to a mammal in need thereof a renal failure inhibiting amount of the compound of formula II having the S.S-configuration wherein Ri is 4-methoxyphenyl, R2 ethyl, R3 is acetyl and R is isopropyl; in combination with one or more pharmaceutically acceptable carriers.
8. A method according to claim 7 involving the inhibition of a disorder selected from: the deterioration of kidney functions; the progression of glomerulonephritis, glomerulonephropathy, diabetic nephropathy or nephrosclerosis; the formation of glomerular lesions, arteriolar lesions, urinary proteinaceous casts and tubular dilation; and the progression of end stage renal disease.
9. A method according to claim 7 or the treatment of chronic progressive renal failure or for the prevention of the progression of chronic renal failure over a prolonged period of time.
10. Use of a compound according to any one of claims 1 -7 for the manufacture of a pharmaceutical composition for the treatment of chronic progressive renal failure or for the prevention of the progression of chronic renal failure.
11. Use according to claim 10 for the manufacture of a pharmaceutical composition for involving the inhibition of a disorder selected from: the deterioration of kidney functions; the progression of glomerulonephritis, glomerulonephropathy, diabetic nephropathy or nephrosclerosis; the formation of glomerular lesions, arteriolar lesions, urinary proteinaceous casts and tubular dilation; and the progression of end stage renal disease.
12. Use according to claim 10 or 1 1 for the manufacture of a corresponding pharmaceutical composition for the treatment or for the prevention over a prolonged period of time.
13. A pharmaceutical composition for the treatment of chronic progressive renal failure or for the prevention of the progression of chronic renal failure, comprising a therapeutically effective amount of a compound according to any one of claims 1 -7.
14. A pharmaceutical composition according to claim 13 for involving the inhibition of a disorder selected from: the deterioration of kidney functions; the progression of glomerulonephritis, glomerulonephropathy, diabetic nephropathy or nephrosclerosis; the formation of glomerular lesions, arteriolar lesions, urinary proteinaceous casts and tubular dilation; and the progression of end stage renal disease.
15. A pharmaceutical composition according to claim 13 or 14 for the treatment or for the prevention over a prolonged period of time.
PCT/EP1996/004101 1995-09-27 1996-09-19 Treatment of chronic progressive renal failure WO1997011717A1 (en)

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US6919343B2 (en) 2002-02-08 2005-07-19 Merck & Co., Inc. N-biphenyl(substituted methyl) aminocycloalkane-carboxamide derivatives
US7091380B2 (en) 2002-02-08 2006-08-15 Merck & Co., Inc. N-biphenylmethyl aminocycloalkanecarboxamide derivatives

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