Classifications

• • 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
• • 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
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/2242—Atrial natriuretic factor complex: Atriopeptins, atrial natriuretic protein [ANP]; Cardionatrin, Cardiodilatin
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to the treatment and prevention of myointimal proliferation in atherosclerosis, restenosis induced by angioplasty or vascular reconstructive surgery,
• glomerulonephritis glomerulosclerosis or other diseases involving vascular cell proliferation, comprising administration of a natriuretic peptide, a neutral endopeptidase (NEP) inhibitor, a combination of a natriuretic peptide and an NEP inhibitor, or a combination of an NEP inhibitor and an angiotensin converting enzyme (ACE) inhibitor.
• NEP neutral endopeptidase
• ACE angiotensin converting enzyme
• the invention also relates to a pharmaceutical composition for use in treating or preventing myointimal proliferation in
• Atherosclerosis restenosis induced by angioplasty or vascular reconstructive surgery, glomerulonephritis, glomerulosclerosis or other diseases involving vascular cell proliferation comprising a natriuretic peptide, an NEP inhibitor, a combination of a natriuretic peptide and an NEP inhibitor, or a combination of an NEP inhibitor and an ACE inhibitor in a pharmaceutically acceptable carrier.
• SMC smooth muscle cell
• natriuretic peptides represents a series of peptide families responsible for fluid homeostasis and blood pressure control. Three types of natriuretic peptides have been identified to date, including atrial natriuretic peptides (ANP), brain natriuretic peptides (BNP) and C-type natriuretic peptides (CNP).
• ANP atrial natriuretic peptides
• BNP brain natriuretic peptides
• CNP C-type natriuretic peptides
• ANP for example, are a family of vasodilator, diuretic and ant ⁇ hypertensive peptides which maintain salt and water homeostasis as well as to regulate blood pressure. (See, Espiner, et al., Lancet , 1 (1989) 707-710, and Needleman, et al., Ann. Rev. Pharma. Tox., 29
• ANP is rapidly inactivated in the circulation by at least two processes: a receptor mediated clearance as reported in Amer. J. Physiol. , 256 (1989) R469-R475, and an enzymatic inactivation via NEP reported in Biochem. J., 243 (1987) 183-187.
• ANP stimulates smooth muscle cell particulate guanylate cyclase activity, which results in an increase in the intracellular pool of cyclic guanosine monophosphate (cGMP). It has been reported that cGMP elevating agents inhibit the proliferation of SMCs, in vitro and that high
• ANP concentrations of ANP inhibit SMC proliferation in vitro when either platelet derived growth factor (PDGF) or serum are used as mitogens.
• PDGF platelet derived growth factor
• Neutral endopeptidase (EC 3.4.24.11; enkephalinase; atriopeptidase; NEP) is a zinc containing metalloprotease which cleaves a variety of peptide substrates on the amino terminal side of aromatic amino acids. See Biochemistry J., 241 (1987) 237-247. Substrates for this enzyme include, but are not limited to ANP, BNP, CNP, met and leu enkephalin, bradykinin, neurokinin A, and substance P. It has been demonstrated that inhibitors of NEP potentiate the hypotensive, diuretic, natriuretic and plasma ANP responses to pharmacological injection of ANP in experimental animals.
• NEP inhibitors lower blood pressure and exert ANP like effects such as diuresis and increased cGMP excretion in some forms of experimental hypertension.
• the antihypertensive action of NEP inhibitors is mediated through ANP because antibodies to ANP will neutralize the reduction in blood pressure.
• NEP inhibition is associated with little or no elevation of plasma ANP. See, Sybertz, et al., J. Hypertension, 8 (1990) S161-S167.
• ACE inhibitors are a class of drugs known to be effective in treating some types of hypertension by blocking the rise in blood pressure caused by increases in vascular resistance and fluid volume due to the-formation of angiotensin II from angiotensin I.
• the use of ACE inhibitors for treating or preventing restenosis following angioplasty has been claimed, for example in European Patent Application 459,318, but others report that while ACE inhibitors appear to be active against restenosis in rats, studies in primates have not been sucessful.
• the present invention relates to a method of treating or preventing myointimal proliferation in atherosclerosis, restenosis induced by angioplasty or vascular reconstructive surgery,
• glomerulonephritis, glomerulosclerosis or other diseases involving vascular cell proliferation comprising administering an effective amount of a natriuretic peptide or an NEP inhibitor to a mammal in need of such treatment.
• the method also relates to treating or preventing said diseases or conditions by administering a combination of an ACE inhibitor and an NEP inhibitor or a combination of a natriuretic peptide and an NEP inhibitor.
• compositions comprising an amount of a natriuretic peptide or an NEP inhibitor effective to treat or prevent myointimal proliferation in atherosclerosis, restenosis induced by angioplasty or vascular reconstructive surgery, glomerulonephritis, glomerulosclerosis or other diseases involving vascular cell proliferation, in a
• the invention also relates to a pharmaceutical composition comprising a combination of an ACE inhibitor and an NEP inhibitor and a pharmaceutical composition comprising a combination of a natriuretic peptide and an NEP inhibitor in a pharmaceutically acceptable carrier.
• NEP inhibitors suitable for use in this invention include carboxyalkyl dipeptides disclosed in U.S. patent 4,610,816, herein incorporated by reference, having the formula
• R 1 a is alkyl having from 1 to 6 carbon atoms, adamantylmethyl, cycloalkylmethyl having from 4 to 8 carbon atoms or A a -X a m a -C n a H 2n a - ⁇ wherein X a is oxygen or sulfur;
• a a is phenyl which may be substituted with the group Y a (wherein Y a is halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, 2- or 3-furanyl, 2- or 3-thienyl, or phenyl (which may be substituted with halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms or alkyl having from 1 to 6 carbon atoms)), benzyl (the phenyl ring of which may be substituted with the group Y a as defined herein), 1- or 2- naphthyl, 2- or 3-furanyl or 2- or 3-
• R 2 a and R 6 a may be the same or different and each is
• B a -X a m a -C n a H 2n a -0- ⁇ wherein B a is phenyl (which may be substituted with the group Y a as defined herein) or 1 - and 2-naphthyl; and X a , m a and n a are as defined herein provided that, when n a 0, m a is zero ⁇ , -OCH 2 OCO-alkyl having from 3 to 8 carbon atoms, -OCH 2 CO-phenyl ⁇ the phenyl ring of which may be substituted with the group Y a as defined herein ⁇ , 1 -glyceryl,
• R 7 a is hydrogen, alkyl having from 1 to 6 carbon . atoms, or phenyl which may be sustituted with the group Y a as defined herein, and R 8 a is hydrogen or alkyl having from 1 to 6 carbon atoms ⁇ ;
• R 2 a may also be -NR 7 a R 8 a wherein R 7 a and R 8 a are as defined herein;
• R 3 a is alkyl having from 1 to 6 carbon atoms, cycloalkylmethyl having from 4 to 8 carbon atoms, 2- or 3-thienylmethyl, 2- or 3- furanylmethyl, 1- or 2-naphthylmethyl, or benzyl the phenyl ring of which may be substituted with the group Y a as defined herein;
• R 4 a is D a -C n a H 2 n a -O m a - wherein D a is selected from hydrogen, alkyl having from 1 to 4 carbon atoms or phenyl which may be substituted with the group Z a ; ⁇ wherein Z a is halogen, hydroxy, trifluoromethyl, alkoxy having from 1 to 6 carbon atoms, or alkyl having from 1 to 6 carbon atoms ⁇ ; and m a and n a are as defined herein;
• R 4 a may also be -NR 5 a COR 7a ⁇ wherein R 5a and R 7 a are as
• R 5 a is as defined herein and R 9 a is alkyl having from 1 to 6 carbon atoms or phenyl which may be substituted with the group Y a as defined herein ⁇ ;
• R 5 a is hydrogen or alkyl having from 1 to 6 carbon atoms; and p is 1 or 2; or pharmaceutically acceptable addition salts thereof; wherein preferred compounds are N-[N-[(L)-[1-[(2,2-di-methyl-1,3- dioxolan-4-yl)-methoxy]carbonyl]-2-phenylethyl]-L-phenyl-alanyl]- ⁇ - alanine and N-[N-[(L)-1-carboxy-2-phenylethyf]-L-phenyl-alanyl]- ⁇ - alan ⁇ ne;
• R 1b is phenyl substituted by 1 to 3 substituents independently selected from alkyl, alkoxy, cycloalkyl, cyano, and
• R 2b is alkyl, alkyl-S(O) 0-2 (CH 2 ) q b - , R 5b (CH 2 ) k b -S(O) 0-2 (CH 2 ) q b - , alkyl-O(CH 2 ) q b - , R 5b (CH 2 ) k b-O(CH 2 ) q b - , R 5b (CH 2 ) q b - , H 2 N(CH 2 )q b - , cycloalkyl(CH 2 ) k b - , R 13b CONH(CH 2 ) q b - , R 13b NHCO(CH 2 )q b - or R 6b OCO(CH 2 ) q b - ;
• R 3b is -OR 7b , -NR 7b R 8b ,
• R 4b and R 13b are independently hydrogen, alkyl or Y 1b -C 6 H 4 - ;
• R 5b is Y 2b -C 6 H 4 - , Y 2b -C 6 H 4 S- , Y 2b -C 6 H 4 O- , a-naphthyl, b- naphthyl or provided that when R 5b is Y 2b -C 6 H 4 S- or Y 2b -C 6 H 4 O- , k b is 2 or 3;
• R 6b , R 7b and R 8b are independently H, alkyl, hydroxyalkyl,
• R 9b is hydrogen alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl or carbamoylalkyl;
• n b is 0-2;
• m b and k b are independently 0-3;
• q b is 1-4;
• X b and X 1b are independently a bond, -O- , -S- or -CH 2 - ;
• Q b is hydrogen or R 10b CO- ;
• R 10b is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl,
• Y b , Y 1b , Y 2b and Y 3b independently represent 1 to 3 substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, CN, -CH 2 NH 2 , -COOH, -COOalkyl, -CONH 2 and phenyl;
• R 1ab is Y b -C 6 H 4 - , Y b -C 6 H 4 S- , Y b -C 6 H 4 O- , a-naphthyl, b-naphthyl, H 2 N(CH 2 ) m b - or diphenylmethyl;
• R 2ab is R 5ab (CH) k b S(O) 0-2 (CH 2 ) q b - , R 5ab (CH) q b - or
• R 2ab may also be R 13b CONH(CH 2 )q b - , R 13b NHCO(CH 2 ) q b- or R 6b OCO(CH 2 ) q b - ;
• R 3ab is -OR 11b -NR 11b R 12b ,
• R 5ab is Y 2b -C 6 H 4 - provided Y 2b is not H or OH, Y 2b -C 6 H 4 S- , Y 2b -C 6 H 4 O- , a-naphthyl, b-naphthyl or provided that when R 5ab is Y 2b -C 6 H 4 S- , Y 2b -C 6 H 4 O- , k b is 2 or 3;
• R 11b is hydroxyalkyl, substituted phenylalkyl wherein the phenyl group is substituted by 1 or more groups selected from alkyl, alkoxy, cycloalkyl and cyano;
• R 12b is H or selected from the same group as R 11b ;
• alkyl or each alkyl portion has 1-6 carbon atoms and cycloalkyl is C 3 -C 6 ; or pharmaceutically acceptable addition salts thereof;
• Q d is hydrogen or R 7d CO- ;
• R 1d is lower alkyl, cyclolower alkyl, aryl or heteroaryl
• R 2d is hydrogen; lower alkyl; cyclolower alkyl; lower alkyl
• R 3d is -OR 5d or-NR 5d R 6d ;
• R 4d and R 9d are independently -(CH 2 ) q d R 8d , provided that when R 4d and R 9d are both hydrogen, R 2d is biphenyl,
• R 5d and R 6d are independently selected from the group
• R 7d is hydrogen, lower alkyl or aryl
• R 8d is hydrogen, hydroxy, lower alkoxy, mercapto, lower alkylthio, aryl or heteroaryl; n d is 1 or 2;
• p d is 0 or 1
• q d 0, 1 or 2;
• t d is 0 or 1;
• preferred compounds are N-[2(S)-mercapto-methyl-3-(2-methylphenyl)propanoyl]-(S)-isoserine and N-(S)-[3-mercapto-2-(2-methylphenyl)propionyl]-(S)-2-methoxy- ⁇ -alanine;
• R 1e is H, alkyl, arylalkyl, or aryl
• R 2e is H, alkyl, alkenyl or alkynyl, wherein the alkyl portion is
• R 3e and R 4e are independently alkyl or arylalkyl; or R 3e and R 4e together with the carbon to which they are attached form a 5-, 6- or 7-membered ring wherein said ring comprises 0 to 1 heteroatoms selected from the group consisting of sulfur and oxygen, wherein said ring is unsubstituted or is substituted on a carbon atom ring member by an alkyl or aryl group, or wherein said ring is substituted by a fused benzene ring;
• R 5e is H, alkyl, alkoxyalkyl, alkylthioalkyl, aryl, arylalkyl,
• heteroaryl heteroaryl, heteroarylalkyl, arylalkoxyalkyl or arylalkylthioalkyl;
• R 6e is H, hydroxy, alkoxy, alkyl, alkoxyalkyl, alkylthioalkyl,
• R 7e is hydroxy, alkoxy, aryloxy, arylalkoxy, amino, alkylamino or dialkylamino;
• m e is 0 or 1 ;
• n e 0, 1, 2 or 3;
• R 1f is lower alkyl, cyclolower alkyl, aryl or heteroaryl
• R 2f is hydrogen; lower alkyl; cyclolower alkyl; lower alkyl
• R 3f is -OR 5f or-NR 5f R 6f ;
• R 4f and R 9f are independently -(CH 2 )q f R 8f ;
• R 5f and R 6 f are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl and aryl lower alkyl, or R 5f and R 6f together with the nitrogen to shich they are attached form a 5-7 membered ring;
• R 7f is phenyl substituted by 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkoxy, cycloalkyl, halo, cyano and aminomethyl;
• R 8f is hydrogen, hydroxy, lower alkoxy, mercapto, lower alkylthio, aryl or heteroaryl;
• n f is 1 or 2;
• p f is 0 or 1
• q f 0, 1, or 2;
• t f is 0 or 1 ;
• preferred compounds are 1 ,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo3,1-propanediyl]]-bis-(S)-isoserine and 1 ,1'-[dithio-bis-[2(S)-(2-methylbenzyl)-1-oxo-3,1- ⁇ ropanediyl]]-bis-(S)-methionine;
• R g is a group of the formulae
• R 1 g is 1-3 substituents selected from the group consisting of
• R 2 g is H, -COR 11 g or -CH 2 OCOR 11 g ;
• R 3 g is -OR 12 g , -NR 12 gR 13 g or -OCH(R 14 g)CONR 12 gR 13 g ;
• R 4 g, R 5 g, R 6 g, R 7 g, R 8 g, R 9 g and R 10 g are each independently lower alkyl; or aralkyl or cycloalkylalkyl, wherein the aryl or cycloalkyl ring is optionally substituted by 1-3 substituents selected from lower alkyl, OH, halogen, lower alkoxy and NH 2 ; or R 4 g and R 5 g together with the carbon to which they are attached comprise a 5-, 6- or 7-membered ring;
• R 11 g is lower alkyl, aryl or arylmethyl
• R 12 g and R 13 g are each independently hydrogen; lower alkyl, optionally substituted by 1-2 OH or lower alkoxy groups; lower alkoxyalkoxy; halogen; lower haloalkoxy; NH 2 ; alkylamino; dialkylamino; Ar; or Het; or R 12 g and R 13 g together with the nitrogen to which they are attached comprise a 5-, 6- or 7membered ring, wherein said ring may contain ring members selected from the group consisting of -N- , -N (alkyl)- or -O- , and wherein said ring is optionally substituted at a carbon atom ring member by an alkyl or OH substituent;
• Ar g is an aryl group optionally substituted by 1-3 substituents
• Het g is a 5- or 6-membered saturated ring, wherein 1-2 ring
• memebers are oxygen atoms and wherein said ring is optionally substituted by 1-2 lower alkyl groups;
• R 14 g is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl,
• alkylthioalkyl aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl or carbamoylalkyl;
• n g 0, 1, 2, 3 or 4;
• R1 h is H or R 5 h CO-;
• R 2 h is Y h -C 6 H 4 - , Y h -C 6 H 4 S- , Y h -C 6 H 4 O- , Y h -C 6 H 4 CH 2 S- ,
• R 3 h is -OR 6 h , -NR 6 h R 7 h or
• R 4 h is hydrogen, lower alkyl or aryl lower alkyl
• R 5 h is lower alkyl, hydroxylower alkyl, lower alkoxy lower alkyl, (di-lower alkyl) amino lower alkyl, Y 1 h -C 6 H 4 -lower alkyl, lower alkoxy, Y 1 h -C 6 H 4 - , naphthyl, furyl, thienyl or pyridyl;
• R 6 h and R 7 h are independently hydrogen, lower alkyl or
• substituted lower alkyl wherein the substituents are selected from the group consisting of 1 or 2 hydroxy groups, 1 or 2 lower alkoxy groups, lower alkoxy lower alkoxy, halogeno, halogeno lower alkoxy, amino, mono- or di-lower alkyl amino, heterocycloalkyl, lower alkyl heterocycloalkyl, aryl, substituted aryl wherein the substituents on aryl are 1-3 substituents selected from the group consisting of lower alkyl, hydroxy, halogeno, lower alkoxy and amino, and a 5-6 membered saturated ring comprising 1-2 oxygen atoms as ring members wherein the ring carbon atoms are substituted with 0-2 lower alkyl substituents; or R 6 h and R 7 h together with the nitrogen to Which they are attached complete a 5-7 membered ring, wherein 0-1 of the 4-6 ring members comprising R 6 h and R 7 h is a nitrogen atom, an alkyl
• R 8 h is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl or carbamoylalkyl; n h is 0-3;
• X h and X 1 h are independently a bond, -O- , -S- or -CH 2 - ;
• Y h , Y1 h and Y 2 h are independently 1 to 3 substituents selected from the group consisting of hydrogen, lower alkyl, cyclolower alkyl, lower alkoxy, OH, F, Cl, Br, I, -CN, -COOH, -COO-lower alkyl, -CH 2 NH 2 , -CONH 2 and aryl;
• R 1i is H, alkyl, arylalkyl, aryl or aryloxyalkyl;
• R 2i is alkyl, alkenyl, alkynyl, alkoxy or alkylthio, wherein the alkyl portion is substituted with 0-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkoxyalkoxy, alkylthio, aryl, alkoxyalkylthio, arylalkoxy and arylalkylthio;
• R 3i and R 4i are independently alkyl or arylalkyl; or R 3i and R 4i together with the carbon to which they are attached form a 5- , 6- or 7-membered ring wherein said ring comprises 0 to 1 heteroatoms selected from the group consisting of sulfur and oxygen, wherein said ring is unsubstituted or is substituted on a carbon atom ring member by an alkyl or aryl group, or wherein said ring is substituted by a fused benzene ring;
• R 5i is H, alkyl, alkoxyalkyl, alkylthioalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkoxyalkyl or arylalkylthioalkyl;
• R 6i is H, hydroxy, alkoxy, alkyl, arylalkoxy, alkoxyalkyl,
• alkylthioalkyl arylalkoxyalkyl, arylalkylthioalkyl, aryl or heteroaryl;
• R 7i is hydroxy, alkoxy, aryloxy, arylalkoxy, amino, alkylamino or dialkylamino;
• m i is 0 or 1 ;
• n i 0, 1, 2 or 3;
• a k is a 4-, 5- or 6-membered alkylene chain substituted with 1 to 3 substituents selected from the group consisting of hydrogen, hydroxy, alkyl or aryl; a 4-, 5- or 6-membered alkenylene chain, wherein 1 to 3 of the saturated carbon atoms are substituted as defined for the alkylene chain; a 4-, 5- or 6- membered hetero-atom-containing chain comprising 2 to 5 carbon atoms and 1 or 2 hetero atoms selected from the group consisting of oxygen and sulfur, wherein when 2 heteroatoms are present, the heteroatoms are non-adjacent; or an alkylene or hetero-atom-containing chain as defined above wherein said alkylene or hetero-atom-containing chain is substituted with a fused benzene ring;
• Q k is hydrogen or R 5k CO- ;
• R 1k is H, alkyl, arylalkyl or aryl
• R 2k is H, alkyl, alkoxyalkyl, alkylthioalkyl, aryl, arylalkyl,
• heteroaryl heteroarylalkyl, arylalkoxyalkyl, or
• R 3k is H, hydroxy, alkoxy, alkyl, arylalkoxy, alkoxyalkyl,
• alkylthioalkyl, arylalkoxyalkyl, arylalkylthioalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, or R 2k and R 3k form an alkylene chain of 1 to 5 carbon atoms, thereby, together with the carbons to which they are attached, completing a 5-, 6-, or
• R 4k is hydroxy, alkoxy, aryloxy, arylalkoxy, amino, alkylamino or dialkylamino;
• R 5k is alkyl or aryl
• m k is 0 or 1 ;
• n k 0, 1 , 2 or 3;
• a preferred compound is N-[1-(acetylthiomethyl)-cyclopentanecarbonyl]- (S)-methionine ethyl ester;
• Yq is -(CHR 5 q) n q-(CR 3 qR 4 q)- or -(CR 3 qR 4 q) p qXq(CR 3 qR 4 q) q q- , wherein two substituents selected from the group consisting of
• R 3 q, R 4 q and R 5 q together with the carbons to which the substituents are attached, when the substituents are present on adjacent carbon atoms, can form a benzene, cyclopentane or cyclohexane ring;
• Xq is -O- , -S- , -SO- or -SO 2 - ;
• Qq is hydrogen or R 6 qCO- ;
• n q is 1, 2, 3 or 4;
• R 1q is lower alkyl; aryl selected from the group consisting of
• phenyl, naphthyl, substituted phenyl and substituted naphthyl wherein said substituted phenyl and substituted naphthyl groups are substituted with 1-3 substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halo, trifluoromethyl, phenyl, phenoxy, and phenylthio; heteroaryl or substituted heteroaryl, wherein heteroaryl is selected from the group consisting of furanyl, thienyl, pyrrolyl and pyridyl, and wherein said substituted heteroaryl is substituted with 1-3 substituents selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, halo, trifluoromethyl, phenyl, phenoxy, and phenylthio;
• R 2q is hydrogen, lower alkyl, hydroxylower alkyl
• R 3q and R 4q are independently hydrogen, loweralkyl, aryllower alkyl, heteroaryllower alkyl, substituted-aryllower alkyl or substituted-heteroaryliower alkyl, wherein aryl, heteroaryl, substituted aryl and substituted heteroaryl are as defined above;
• R 5q is hydrogen, loweralkyl, aryllower alkyl, heteroaryllower alkyl, hydroxy, lower alkoxy, mercapto, lower alkylthio, substituted- aryllower alkyl or substituted-heteroaryliower alkyl, wherein aryl, heteroaryl, substituted aryl and substituted heteroaryl are as defined above; and
• R 6q is lower alkyl, aryl or heteroaryl, wherein aryl and heteroaryl are as defined above; wherein a preferred compound is 3(S)-[2-(acetylthio-methyl)-3-phenylpropionyl]amino- ⁇ -caprolactam;
• a r completes a 5 or 6 membered carbocyclic ring which may be saturated or monounsaturated;
• R 1r is H or (C 1 -C 4 )alkyl
• R r and R 4r are each independently H, (C 1 -C 6 )alkyl
• Y r is either a direct bond or an alkylene group of from 1 to 6
• R 7r NR 5r SO 2 - or R 8r SONR 5r - with the proviso that Y r is not a direct bond when R 2r is H, aryl or heterocyclyl;
• R 3r is a group of the formula
• R 5r is H, (C 1 -C 6 )alkyl or aryl(C 1 -C 6 )alkyl;
• R 6r is aryl, heterocyclyl or a group of the formula
• R 7r is (C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, heterocyclyl,
• R 8r is (C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, heterocyclyl or
• R 9r is H, OH, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, aryl, aryl(C 2 -C 6 ) heterocyclyl, heterocyclyl(C 1 -C 6 )alkyl, R 12r CONH- , R 12r SO 2 NH- or (R 13r ) 2 N- ;
• R 10r and R 11r are each independently H or alkyl; or R 10r is H and R 11r is amino, (C 1 -C 6 )alkyl, imidazolylmethyl, aryl, aryl(C 1 -
• C 6 )alkyl hydroxy (C 1 -C 6 )alkyl or methylthio(C 1 -C 6 )alkyl; or the two groups R 10r and R 11r are joined together to form, with the carbon atom to which they are attached, a 3 to 6 membered carbocyclic ring or a ring which may optionally be substituted by amino, (C 2 -C 4 )alkanoyl or aroyl; or a pyrrolidine or piperidine ring which is substituted by amino, (C 2 -C 4 )alkyl or aroyl; amino;
• R 12r is (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, aryl, aryl(C 1 -C 6 )alkyl, heterocyclyl or heterocyclyl(C 1 -C 6 )alkyl;
• R 13r is H, (C 1 -C 6 )alkyl, aryl or the two groups R 13r are taken
• R 14r is (R 13r ) 2 NCO- , R 12r OCH 2 - or R 15r OCO- ;
• R 15r is (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl or aryl(C 1 -C 6 )alkyl;
• R 16r is H, halo, 4-hydroxy, 4-(C 1 -C 6 alkoxy), 4-(C 3 -C 7 cycloalkoxy), 4-(C 2 -C 6 alkenyloxy), 4-[(C 1 -C 6 alkoxy)carbonyloxy], 4-[(C 3 -C 7 cycloalkoxy)carbonyloxy] or 3-(C 1 -C 4 alkyl)SO 2 NH-;
• R 20r is H, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 2 -C 6 )alkanoyl or halo; and pharmaceutically acceptable salts thereof and bioprecursors therefor;
• a s completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring;
• B s is (CH 2 ) m s wherein m s is an integer of from 1 to 3;
• each of R s and R 4s is independently H, alkyl, benzyl or an alternative biolabile ester-forming group
• R 1s is H oralkyl
• R 2s and R 3s are each independently H, OH, alkyl or alkoxy; and R 5s is alkyl, alkenyl, alkynyl, arylalkynyl, cycloalkyl, cycloalkenyl, alkoxy, -NR 6s R 7s , -NR 8s COR 9s -NR 8s SO 2 R 9s or a saturated heterocyclic group;
• R 6s and R 7s are each independently H, alkyl, cycloalkyl (optionally substituted by hydroxy or alkoxy), aryl, arylalkyl, alkoxyalkyl or heterocyclyl; or the two groups R 6s and R 7s are taken together with the nitrogen to which they are attached to form a
• R 8s is H or alkyl
• R 9s is alkyl, CF 3 , aryl, aryl, alkyl, arylalkoxy, heterocyclyl, alkoxy or
• R 10s is alkyl, aryl, heterocyclyl, or -NR 6s R 7s wherein R 6s and R 7s are as previously defined;
• R 11s is alkyl, cycloalkyl, aryl or heterocyclyl
• R 12s is H oralkyl
• amino acid derivatives disclosed in European Patent Publication 419,327A1 having the formula
• R 4t is hydrogen, lower alkyl, phenyl or phenyl(lower alkyl); R 2t is selected from the group consisting of hydrogen, lower alkyl, hydroxy(lower alkyl), phenyl, pheny(lower alkyl),
• X t is selected from the group consisting of mercaptomethyl
• Application 343,911 having the formula wherein A u completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring;
• B u is (CH 2 )m u wherein m s is an integer of from 1 to 3;
• each of R u and R 4u is independently H, alkyl, benzyl or an alternative biolabile ester-forming group
• R 1u is H or alkyl
• R 2u and R 3u are each independently H, OH, alkyl or alkoxy, or R 2u and R 3u are linked together and are (CH 2 ) r u wherein r u is an integer from 1 to 4;
• Y u is an optional alkylene group of from 1 to 6 carbon atoms which may be straight or branched-chain;
• R 5u is R 6u CONR 9u -, R 6u SO 2 NR 9 u-, R 6u CO 2 -, R 6u CO-, R 6u SO q U -, R 7u NR 9u SO 2 -, or R 7u OCO-;
• R 6u is a group of the formula
• R 7u is a group of the formula
• R 9u is H, alkyl, aryl, cycloalkyl, heterocyclyl, arylalkyl, or hererocyclylalkyl;
• R 8u is R 9u CONR 9u -, R 9u SO 2 NR 9u -, R 13u R 14u N(CH 2 ) p u -, or R 9u O-, wherein each R 9u is as previously defined;
• R 10u and R 11u are each independently H or alkyl; or R 10u is H and R 11u is alkyl which is substituted by OH, SH, SCH 3 , NH 2 , arylalkyl-OCONH-, NH 2 CO-, CO 2 H, guanidino, aryl or heterocyclyl; or the two groups R 10u and R 11u are joined together to form, with the carbon atom to which they are attached, a 5 or 6 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be substituted by alkyl or fused to a further 5 or 6 membered saturated or unsaturated carbocyclic ring;
• R 10u is H, n u is 0 and R 8u and R 11u are linked to form a 2-(N-COR 9u -4-aminopyrrolidinyl) group;
• R 12u is R 13u R 14u NCO-, R 9u OCH 2 - or heterocyclyl, wherein R 9u is as previously defined;
• R 13u and R 14u are each independently H, alkyl, cycloalkyl, aryl, arylalkyl, alkoxyalkyl, aminoalkyl, heterocyclyl or heterocyclylalkyl; or the two groups R 13u and R 14u are taken together to form, with the nitrogen to which they are attached, a pyrrolidinyl, piperidino,
• n u is 0 or 1 ;
• p u is 0 or an integer of from 1 to 6;
• NEP inhibitors suitable for use in the present invention were taken from the noted patents or applications.
• NEP inhibitors include SQ 28603 (N-[2(mercaptomethyl)-1-oxo-3-phenylpropyl]- ⁇ -alanine), disclosed in South African Patent Application 84/0670; UK 69578 (cis-4-[[[1-[2-carboxy-3(2-methoxyethoxy)propyl]-cyclopentyl]carbonyl]amino]cyclohexanecarboxylic acid) and its active enantiomer(s); thiorphan and its enantiomers; retro-thio ⁇ han; phosphoramidon; SQ 29072 (7-[[2- (mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-heptanoic acid); and MDL 100,173, having the formula
• any pro-drug forms of the abovelisted NEP inhibitors e.g., compounds in which one or more carboxylic acid groups are esterified.
• Another aspect of the invention is the administration of a combination of an ACE inhibitor and an NEP inhibitor. While the use of any ACE inhibitor is contemplated, the following Table I lists ACE inhibitors preferred for use in the combination of this invention:
• Still another aspect of the present invention described above relates to the combination of an NEP inhibitor with a natriuretic peptide.
• a number of ANP have been isolated so far, all having the same core sequence of 17 amino acids within a cysteine disulfide bridge, but having different N-termini lengths.
• These peptides represent N-terminal truncated fragments (21-48 amino acids) of a common preprohormone (151 and 152 amino acids for man and rats, respectively).
• Human, porcine and bovine carboxy-terminal 28-amino acid peptides are identical and differ from similar peptides in rats and mice in that the former contain a methionine group at position 12 while the latter contain isoleucine.
• Various synthetic analogs of naturally occuring ANF's also have been found to have comparable biological activity. Examples of ANFs contemplated for use in this invention are a human AP 21 (atriopeptin I), a human AP 28, a human AP 23
• atriopeptin II or APII a human AP 24, a human AP 25, a human AP 26, a human AP 33, and the corresponding rat sequence of each of the above wherein Met 12 is lle BNP have been found to be divergent among species, while mammalian CNP is highly conserved among species. See Suga et. al., Endocrinology, 130, 1 (1992) p. 229-239.
• NEP inhibitors in treating atherosclerosis, restenosis induced by angioplasty or vascular reconstructive surgery, glomerulonephritis, glomerulosclerosis or other diseases involving vascular cell proliferation in an animal model can be demonstrated by the following procedure.
• the left carotid arteries of male spontaneously hypertensive rats (300-350g) were deendothelialized and injured by the balloon catheter method of
• rats were anesthetized with Metofane (methoxyflurane) and a 2 Fr Fogarty embolectomy catheter was inserted into the left external carotid artery.
• the catheter was advanced 5 cm, inflated and retracted 3 times, turning the catheter 90° each time.
• Animals were autopsied following exsanguination with ketamine (40 mg/kg) plus xylazine (10 mg/kg) i.m. anesthesia at specified timepoints following balloon injury.
• Standard samples of the control right and balloon injured left carotid arteries were taken for DNA and morphometric analyses.
• the carotid artery DNA content was determined in 5 mm samples taken 5 mm from their aortic origin by the method of La Barca, as reported in Anal. Biochem., 102 (1980) 344.
• the DNA results were expressed as the ratio of the left or ballooned carotid to the right control carotid.
• Three samples were taken for histology at 2.5 mm intervals cephalad from the DNA sample from each carotid artery and fixed in 4% paraformaldehyde containing 10% sucrose (wt/vol). Paraffin-embedded sections were stained with the Gomori trichrome-aldehyde fuchsin stain and
• natriuretic peptides can be similarly tested by administering the peptide by continuous intravenous infusion using techniques and apparatus well known in the art.
• the NEP inhibitor may be administered simultaneously with the ACE inhibitor or the natriuretic peptide, or the combination of drugs can be administered sequentially, with either being administered first, using the appropriate method of administration for each compound.
• a variety of pharmaceutical dosage forms are suitable for administration of the drugs. Oral or parenteral administration is preferred, although mechanical delivery systems such as transdermal and intra-catheter dosage forms are also contemplated.
• the typical daily dosage of the NEP inhibitor for this invention when admnistered alone for treatment or prevention of atherosclerosis and restenosis, is about 0.3 mg/kg to about 100 mg/kg of mammalian weight per day administered in single or divided doses; for the natriuretic peptide alone, the typical dosage 0.001 to 0.1 mg natriuretic peptide/kg of mammalian weight per day, in single or divided dosages; for the combination of an NEP inhibitor and a natriuretic peptide, the typical dosage is 0.3 to 100 mg of NEP inhibitor/ kg mammalian weight per day in single or divided dosages plus 0.001 to 0.1 mg natriuretic peptide/kg of mammalian weight per day, in single or divided dosages; and for the combination of an NEP inhibitor and an ACE inhibitor, the typical dosage is 0.3 to 100 mg of NEP inhibitor/kg mammalian weight per day in single or divided dosages plus 0.1 to 30 mg ACE inhibitor/kg of mamm
• the NEP inhibitors of this invention can be administered alone in dosage ranges of about 10 to about 500 mg NEP inhibitor per dose given 1 to 4 times a day; natriuretic peptides can be administered alone in dosage ranges of about 0.01 to about 1 mg natriuretic peptide given 1 to 6 times a day (total daily dosage range of .01 to 6 mg/day); for the combination of an NEP inhibitor and a natriuretic peptide, the dosage ranges are about 10 to about 500 mg NEP inhibitor per dose given 1 to 4 times a day and about 0.01 to about 1 mg natriuretic peptide given 1 to 6 times a day
• the drug or combination of drugs is preferably administered in a pharmaceutically acceptable carrier, e.g. for oral or parenteral administration.
• a pharmaceutically acceptable carrier e.g. for oral or parenteral administration.
• the combinations of drugs may be co-administered in a single composition, or components of the combination therapy may be administered separately. Where the components are administered separately, any convenient combination of dosage forms may be used, e.g. oral NEP inhibitor/parenteral natriuretic peptide, oral NEP
• parenteral ACE inhibitor parenteral NEP inhibitor/parenteral natriuretic peptide
• parenteral NEP inhibitor/parenteral ACE inhibitor parenteral NEP inhibitor/parenteral ACE inhibitor.
• the number of doses of each component given per day may not necessarily be the same. e.g. where one component may have a greater duration of activity, it will therefore need to be administered less frequently.
• Typical oral formulations for compounds used in this invention include tablets, capsules, syrups, elixirs and suspensions.
• Typical injectabJe formulations for compounds used in this invention include solutions and suspensions.
• the typical pharmaceutically acceptable carriers for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, and sorbitol; starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicaicium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; betacyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other non-toxic compatible fillers,
• the present invention includes treatment with a combination of active ingredients, wherein said active ingredients may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. That is, two kits are NOT TO BE CONSIDERED FOR PCT PROCEDURE

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• 1992
  • 1992-09-14 EP EP92115681A patent/EP0533084A1/de active Pending
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  • 1992-09-14 WO PCT/US1992/007524 patent/WO1993005809A1/en not_active Application Discontinuation
  • 1992-09-14 EP EP92920659A patent/EP0605589A1/de not_active Withdrawn
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