Neutral metalloendopeptidase inhibitors in the treatment of hypertension

Claim 2

The use of a neutral metalloendopeptidase (NMEP) inhibitor for the preparation of pharmaceutical compositions useful in the treatment of hypertension wherein the NMEP inhibitor may be used alone or in combination or association with an atrial peptide or an angiotensin converting enzyme (ACE) inhibitor.

Claim 3

A pharmaceutical composition according to claim 1 comprising an antihypertensive amount of an NMEP inhibitor.

Claim 4

A pharmaceutical composition according to claim 1 comprising an antihypertensive amount of a combination of an NMEP inhibitor and an atrial peptide.

Claim 5

A pharmaceutical composition according to claim 1 comprising an antihypertensive amount of a combination of an NMEP inhibitor and an ACE inhibitor.

Claim 6

A composition according to claims 1 or 4 wherein the ACE inhibitor is chosen from ACE inhibitors having the formula (a) wherein R a is hydroxy, NH2 or lower alkoxy; R I a and R 4 a each is hydrogen, lower alkyl, phenyl or phenyllower alkyl; R 2 a is hydrogen, lower alkyl, phenyl, . substituted phenyl wherein the phenyl substituent is halo, lower alkyl or lower alkoxy, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkylthiomethyl, phenyl-lower alkylthiomethyl, lower alkanoyl-amidomethyl, R 6 a -S-, or. R 7 a ; R 3 a is hydrogen, hydroxy or lower alkyl; R 5 a is lower alkyl, phenyl or phenyl-lower alkyl; R 6 a is lower alkyl, phenyl, substituted phenyl (wherein the phenyl substituent is halo, lower alkyl or lower alkoxy), hydroxy-lower alkyl or amino (carboxy)-lower alkyl; R 7 a is M a is O or S; m a is 1 to 3; n a and p a each is 0 to 2; (b) having the formula R 1 b is alkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl; R 2 b is cycloalkyl, 3-cyclohexenyl or 2-alkyl-3-cyclohexenyl; R 3 b is alkyl, cycloalkyl or phenyl; R 4 b is H or alkyl; One of R 5 b and R 6 b is H and the other is alkyl-X b -, phenyl-X b- alkoxy, phenoxy, phenyl, cycloalkyl, alkyl or phenylalkyl; or R 5 b and R6b together form -X b CH 2 CH 2 X b -, X b is S, SO or SO 2 ; R 7 b is H or CH(R 2 b )OCOR 3 b ; n b is O or 1; 'aryl' is phenyl optionally substituted by halo, alkyl, alkoxy, alkylthio, OH, alkanoyl, N0 2 , amino, dialkylamino and/or CF 3 ; alkyl has 1-10C, cycloalkyl 3-7C, alkoxy 1-8C and alkanoyl 2-9C; (c) having the formula R 1 c and R 2 c are H, 1-7C alkyl, 1-7C haloalkyl, (CH 2 ) m c -D c , 1-7C aminoalkyl or a group of formula: D c is cycloalkyl, furyl, thienyl or pyridinyl; A c is (CH 2 ) n -CHR 21 c , NR 22 c- CHR 23 c or O-CHR 23 c ; n c is 0 or 1; q c is 0-7; R 21 c is H, 1-7C alkyl, 1-7C haloalkyl, benzyl or phenethyl; R 22 c is H or 1-7C alkyl; R 23 c is H, 1-7C alkyl, 1-7C haloalkyl or (CH 2 ) r c D 1 c ; D 1 c is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3-indolyl, 4-imidazolyl, NH 2 , SH, 1-7C alkylthio, guanidino or CONH 2 ; X c is a group of formula (II) c -(V) c , or NR 4 C -CHR 5 c -COOR 6 C ; where R 9 c and R 8 c are H and R 7 c is as defined below; R 9 c and R 7 c are H and R 8 c is as defined below; R 7 c and R 8 c are H and R 9 c is as defined below; R 9 c and R 8 c are H and -CHR 7 c - is replaced by -CR 10 c R 10 c ; R 9 c is H and R 7 c + R 8 c form a double bond; R 9 c is H and R 7 c + R 8 c complete a fused benzene ring; or R 9 c is H and R 9 c + R7 c complete a fused benzene ring; E' c and E" c are H or E' c .+ E" c complete a fused benzene ring; R 7 c is H, 1-7C alkyl, halogen, keto, OH, 2-8C alkanoyl-amino, N 3 , NH 2 , NR 19 c R 20 c , (CH 2 ) m c- D c , O-CONR 15 c R 15 c , 1-7C alkoxy, 1-7C alkylthio, or a group of formula (VI) c , (VII) c or (VIII) c : B' c is a bond or it is 0 or S;R 8 c is keto, halogen, O-CONR 15 c R 15 c , 1-7C alkoxy, 1-7C alkylthio, or a group (VII) c or (VIII) c in which B' c is O or S; R 9 c is keto or a group (VII) c in which B' c is a bond; R 10 c is halogen or Y c R 16 c ; R 11 c , R ' ll C , R 12 c and R' 12 c are H or 1-7C alkyl, or R 11 c is a group of formula (IX) c and the other 3 are H; R 13 c is H, 1-4C alkyl, 1-4C alkoxy, 1-4C alkylthio, Cl, Br, F, CF 3 , OH, Ph, PhO, PhS or PhC H 2 ; R 14 c is H, 1-4C alkyl, 1-4C alkoxy, 1-4C alkylthio, Cl, Br, F, CF 3 or OH; m c is 0-3; p C is 1-3 but it is 2 or 3 only when R 13 c or R 14 c is H, Me, MeO, Cl or F; R 15 c is H or 1-4C alkyl; Y c is O or S; R 16 c is 1-4C alkyl or group (VII) c in which B' c is a bond; or the two R 16 c groups complete a 5-or 6-membered ring in which the C atoms may each bear 1 or 2 alkyls having 1-4C; R 4 c is H, 1-7C alkyl, cycloalkyl or (CH 2 ) r c Ph; R 5 c is H , 1-7C alkyl or (CH 2 ) r c -D 1 c ; r c is 1-4; R 3 c and R 6 c are H, 1-7C alkyl, PhCH 2 , PhCH or CHR 17 c -O-COR 18 c ; R 17 c is H , 1-7C alkyl or Ph; R 18 c is H, 1-7C alkyl, 1-7C alkoxy or Ph; or R 17 c + R 18 c form (CH 2 ) 2 , (CH 2 ) 3 , -CH=CH or o-phenylene; R 19 c is 1-7C alkyl, benzyl or phenethyl; and R 20 c is H or chosen as for R 19 c ; (d) having the formula wherein R d and R 6d are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy (dimethylaminoethoxy), acylamino lower alkoxy (acetylaminoethoxy), acyloxy lower alkoxy (pivaloyloxymethoxy), aryloxy, such as phenoxy, arloweralkoxy, such as benzyloxy, substituted aryloxy or substituted arloweralkoxy wherein the substituent is methyl, halo or methoxy, amino, loweralkylamino, diloweralkylamino, hydroxyamino, arloweralkylamino such as benzylamino; . R ld is hydrogen, alkyl of from 1 to 20 carbon atoms which include branched and cyclic and unsaturated (such as allyl) alkyl groups, substituted loweralkyl wherein the substituent can be halo, hydroxy, lower alkoxy, aryloxy such as phenoxy, amino, diloweralkylamino, acylamino, such acetamido and benzamido, arylamino, guanidino, imidazolyl, indolyl, mercapto, loweralkylthio, arylthio such as phenylthio, carboxy or carboxamido, carboloweralkoxy, aryl such as phenyl or naphthyl, substituted aryl such as phenyl wherein the substituent is lower alkyl, lower alkoxy or halo, arloweralkyl, arloweralkenyl, heteroarlower alkyl or heteroarlower alkenyl such as benzyl, styryl or indolyl ethyl, substituted arloweralkyl, substituted arloweralkenyl, substituted heteroarlower alkyl, or substituted heteroarlower alkenyl, wherein the substituent(s) is halo, dihalo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, acylamino (acetylamino or benzoylamino) diloweralkylamino, loweralkylamino, carboxyl, haloloweralkyl, cyano or sulfonamido; arloweralkyl or heteroarloweralkyl substituted on the alkyl portion by amino or acylamino (acetylamino or benzoylamino); R 2d and R 7d are the same or different and are hydrogen or lower alkyl; R 3d is hydrogen, lower alkyl, phenyl lower alkyl, aminomethyl phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl (such as benzoylamino lower alkyl, acetylamino lower alkyl), amino lower alkyl, dimethylamino lower alkyl, halo lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl, lower alkyl thio lower alkyl; R 4d is hydrogen or lower alkyl; R 5d is hydrogen, lower alkyl, phenyl, phenyl lower alkyl, hydroxy phenyl lower alkyl, hydroxy lower alkyl, amino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, mercapto lower alkyl or lower alkylthio lower alkyl; R 4d and R 5d may be connected together to form an alkylene bridge of from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon atoms and one sulfur atom, an alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge as above substituted with hydroxy, loweralkoxy, lower alkyl or dilower alkyl; and the pharmaceutically acceptable salts thereof; (e) having the formula R 4 e is a substituted proline of the formula R 6 e is halogen, keto, azido, a 1- or 2-naphthyl of the formula a 1- or 2-naphthyloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 7 e is keto, halogen, a 1- or 2-naphthloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 8 e is keto or R 9 e is halogen or -Y e- R l3 e . m e is zero, one, two, or three. R 10 e is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl. R 11 e is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, bromo, fluoro, trifluoromethyl, or hydroxy. n e is one, two or three provided that n is more than one only if R 10 e or R 11 e is hydrogen, methyl, methoxy, chloro, or fluoro. R 12 e is hydrogen or lower alkyl of 1 to 4 carbons. Y e is oxygen or sulfur. R 13 e is lower alkyl of 1 to 4 carbons. or the R 13 e qroup join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons, or a di(lower alkyl of 1 to 4 carbons) substituent. R e and R 5 e are independently selected from hydroxy; lower alkoxy, di(lower alkyl)-amino-lower alkoxy, such as dimethylaminoethoxy, lower alkyl-carbonyl-amino-lower alkoxy, such as acetylaminoethoxy, lower alkyl-carbonvloxy-lower alkoxy, such as pivalovloxymethoxy. wherein m e , n e and R 10 e are as defined above, amino, lower alkyl-amino, di(lower alkyl)-amino, hydroxyamino, benzylamino, or phenethylamino. R 1 e is hydroqen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) q e -cycloakyl, -(CH2)qe-carboxy, -( CH2 )q e- S-lower alkyl, -(CH 2 ) q e -guanidinyl, -(CH 2 ) q e -NH 2 -(CH 2 ) q e -N(lower alkyl)2 Lower alkoxy, or wherein m e , n e , R 10 e and R 11 e are as defined above, R 14 e is lower alkyl, cycloalkyl, or and q e is an inteaer from 1 to 4. R 2 e is hydrogen or lower alkyl. R 3 e is hydrogen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) q e -NH 2 , -(CH 2 ) q e -N-(lower alkyl) 2 , -(CH 2 )q e -quanidinyl, -(CH 2 ) q e -SH, -(CH 2 ) q e -S-lower alkyl, lower alkyl, or wherein R 10 e , n e and q e are as defined above; (f) having the formula X f is an amino or imino acid of the formula R 7 f is hydrogen, lower alkyl, halogen, keto, hydroxy, lower alkyl, azido, amino, a 1- or 2-naphthyl of the formula a 1- or.2-naphthyloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 8 f is keto, halogen, -0-lower alkyl, a 1- or 2-naphthyloxy of the formula -S-lower alkyl, or a 1- or 2-naphthylthio of the formula R 9 2 is keto or R 10 f is halogen or -Y f -R 16 f R 11 f, R' 11 f , R 12 f and R' 12 f are independently selected from hydrogen and lower alkyl or R' ll f , R 12 f and R' 12 f are hydrogen and R 11 f is R 13 f is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, chloro, bromo, fluoro, trifluoromethyl, hydroxy, phenyl, phenoxy, phenylthio, or phenylmethyl. R 14 f is hydrogen, lower alkyl of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to. 4 carbons, chloro, bromo, fluoro, trifluoromethyl, or hydroxy. m f is zero, one, two, three, or four. p f is one, two or three provided that p f is more than one only if R 13 f or R 14 f is hydrogen, methyl, methoxy, chloro, or fluoro. R 15 f is hydrogen or lower alkyl of 1 to 4 carbons. Y f is oxygen or sulfur. R 16 f is lower alkyl of 1 to 4 carbons. or the R 16 f groups join to complete an unsubstituted 5- or 6-membered ring or said ring in which one or more of the carbons has a lower alkyl of 1 to 4 carbons or a di(lower alkyl of 1 to 4 carbons) substituent. R 4 f is hydrogen, lower alkyl, R 5 f is hydrogen, lower alkyl, r f is an integer from 1 to 4. R 19 f is lower alkyl, benzyl, or phenethyl. R 20 f is hydrogen, lower alkyl, benzyl or .phenethyl. R f is hydrogen, lower alkyl, cycloalkyl, -(CH 2 ) 2 -NH 2 , -(CH 2 ) 3 -NH 2 , -(CH 2 ) 4 -NH 2 , -(CH 2 ) 2 -OH, -(CH 2 ) 3 -OH, -(CH 2 ) 4 -OH, -( CH2 ) 2 - SH , -( CH2 ) 3 -SH, or -(CH2)4-SH. R 1 f is hydrogen, lower alkyl, halo substituted lower alkyl, provided that R 1 f is hydrogen only if R f is other than hydrogen. R 2 f is R 3 f is hydrogen, lower alkyl, halo substituted Lower alkyl , cycloalkyl wherein m f , R 14 f , p f and r f are as defined above. R 6 f is hydrogen, lower alkyl, benzyl, benzhydryl, R 17 f is hydroqen, lower alkyl, cycloalkyl, or phenyl. R 18 f is hydrogen, lower alkyl, lower alkoxy, or phenyl or R 17 f and R 18 f taken together are -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH= CH -, or R 21 f and R 22 f are independently selected from hydroqen and lower alkyl. R 23 f is lower alkyl. R 24 f is hydroqen, lower alkyl. (q) havinq the formula either (A) R q and R 9 q are OH, 1-6C alkoxy, 2-6C alkenyloxy, di-(1-6C alkyl)amino-(1-6C) alkoxy, 1-6C hydroxyalkoxy, acylamino-(1-6C)alkoxy, acyloxy-(1-6C)alkoxy, aryloxy, aryloxy-(1-6C)alkoxy, NH 2 , mono- or di-(1-6C alkyl)amino, hydroxyamino or aryl-(1-6C)alkylamino; R 1 g -R 5 g , R 7 g and R 8 g are 1 - 20C alkyl, 2-20C alkenyl, 2-20C alkynyl, aryl, aryl-(l-6C) alkyl having 7-12C or heterocyclyl-(1-6C)alkyl having 7-12C; R 6 g is cycloalkyl, polycycloalkyl, partly saturated cycloalkyl or polycycloalkyl, cycloalkyl-(1-6C)alkyl having 3-20C, 6-10C aryl, aryl-(1-6C)alkyl, aryl-(2-6C)alkenyl or aryl-(2-6C) alkynyl; or R 2 g and R 3 g together with the C and N atoms to which they are attached or R 3 g and R 5 g together with the N and C atoms to which they are attached form an N-heterocycle containing 3-5C or 2-4C and a S atom; all alkyl, alkenyl and alkynyl are optionally substituted by OH, 1-6C alkoxy, thio(sic), 1-6C .alkylthio, NH 2 , mono- or di(1-6C alkyl)amino, halogen or N0 2 ; all 'cycloalkyl' groups (including poly and partially unsaturated) are optionally substituted by halogen, 1-6C hydroxyalkyl, 1-6C alkoxy, amino-(1-6C alkyl)amino, di-(1-6C alkyl)amino, SH, 1-6C alkylthio, N0 2 or CF 3 ; and aryl groups are optionally substituted by OH, 1-6C alkoxy, NH 2 , mono- or di-( 1 -6C alkyl) amino, SH, 1-6C alkylthio, 1-6C hydroxyalkyl, 1-6C aminoalkyl, 1-6C thioalkyl, N0 2 , halogen, CF 3 , OCH 2 0, ureido or guanidino; or (B) R g and R 9 g are H or 1-6C alkoxy; R 1 g and R 2 g are H,. 1-6C alkyl, aryl-(1-6C) alkyl having 7-12C or heterocyclyl-(1-6C) alkyl having 6-12C; R 3 g -R 5 g , R 7 9 and R 8 9 are H or 1-6C alkyl; R 6 9 is cycloalkyl, polycycloalkyl, partly saturated cycloalkyl or polycycloalkyl, cycloalkyl-(1-6C) alkyl having 3-20C, aryl or aryl-(1-6C) alkyl; and aryl has 6-10C and is optionally substituted by 1-6C alkyl, 2-6C alkenyl, 2-6C alkynyl, O H , 1-6C alkoxy, NH 2 , mono- or di-(1-6C alkyl) amino, SH, 1-6C alkylthio, 1-6C hydroxyalkyl, 1-6C aminoalkyl, 1-6C thioalkyl, N0 2 , halogen, CF 3 , OCH 2 0, ureido or guanidino; (h) having the formula wherein: R h is lower alkyl, benzyl, benzylthio, benzyloxy, phenylthio or phenoxy; R 1 h is hydroxy or lower alkoxy; R 2 h is hydrogen, lower alkyl or amino lower alkyl; and the pharmaceutcally acceptable salts thereof; (i) having the formula or a pharmaceutically acceptable salt thereof, wherein R i and R 6i are the same or different and are hydroxy, lower alkoxy, lower alkenyloxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryllower alkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy; R 1i is hydrogen, alkyl of from 1 to 10 carbon atoms, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, substituted arylthio, carboxy, carbamoyl, lower alkoxy carbonyl, aryl, substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy, aralkylthio group is substituted with a group selected from halo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano, or sulfamoyl; R 2i and R 7i are the same or different and are hydrogen or lower alkyl; R 31 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkyl thio lower alkyl; R 4i and R 5i are the same or different and are hydrogen, lower alkyl or Z 1 , or Rand R 51 taken together form a group represented by Q i , U i , V i , Y i , D i or E i , wherein; Z i is wherein X 1i and X 2i independent of each other are 0, S or CH 2 , R 8i and R 9i independent of each other are lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl having 3 to 8 carbon atoms, hydroxy lower alkyl or -(CH 2 ) n Ar i , wherein n i is 0, 1, 2 or 3 and Ar i is unsubstituted or substituted phenyl, furyl, thienyl or pyridyl, wherein said substituted phenyl, furyl, thienyl or pyridyl groups are substituted with at least one group that is independently selected from C 1 to C 4 alkyl, lower alkoxy, lower alkylthio, halo, CF 3 and hydroxy, or R 8i and R 9i taken together form a bridge W i , wherein W i is a single bond or a methylene bridge or a substituted methylene bridge when at least one of X 1i and X 21 is methylene, or W 1 is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms, said substituted methylene bridge or said substituted alkylene bridge having one or two substituents selected from lower alkyl, aryl and aryl lower alkyl groups, and p i is 0, 1 or 2; with the proviso that at least one of R 4 and R 5 is z i , with the proviso that if R 4 is z i and p i is 0 then X 11 and X 2i must both be methylene, and with the proviso that if X 1i and X 2i are both methylene then R 8i and R 9i must form an alkylene bridge W i ; Q i is wherein R 8i , R 9i , X 11 and X 2i are as defined above, p i is 0, 1 or 2, q i is 0, 1 or 2, with the proviso that the sum of p i and q i must be 1, 2 or 3, with the proviso that if p i is 0 then X 1i and X 2i must be methylene, and with the proviso that if X 1 and X 2i are methylene then R 8i and R 9i taken together form a bridge W i , wherein W i is as defined above; V i is wherein R 8i , R 9i , X 1i and X 2i are as defined above, p i is 0, 1 or 2 and q i is 0, 1 or 2, with the proviso that the sum of p i and q i is 1, 2 or 3, with the proviso that if X 1i and X 21 are CH 2 then R 8i and R 9i taken together form a bridge W i , wherein W i is as defined above; U i is wherein W i is as defined above (except that W i may also be a methylene bridge when X 1i and X 2i are oxygen or sulfur), X 1i and X 2i are as defined above, p i is 0, 1 or i is 0, 1 or 2, with the proviso that the sum of p i and q i is 1 or 2, and with the proviso that if p i is 0, X 11 must be CH 2 ; Y i is wherein G i is oxygen, sulfur or CH 2 , a i is 2, 3 or 4 and b i is 1, 2, 3, 4 or 5, with the proviso that the sum of a i and b i is 5, 6 or 7 or G i is CH 2 , a i is 0, 1, 2 or 3, b i is 0, 1, 2 or 3 with the proviso that the sum of a i and b i is 1, 2 or 3, with the proviso that the sum of a i and b i may be 1, 2 or 3 only if R 1i is lower alkyl substituted with aralkylthio or aralkyloxy; D i is wherein F i is 0 or S, j i is 0, 1 or 2 and k i is 0, 1 or 2, with the proviso that the sum of j i and k i must be 1, 2 or 3, and m i is 1, 2 or 3 and t i is 1, 2 or 3, with the proviso that the sum of m i and t i must be 2, 3 or 4; E i is wherein L i is 0 or S, u i is 0, 1 or 2 and v i is 0, 1 or 2, with the proviso that the sum of u i and v i must be 1 or 2, and h i is 1 or 2 and s i is 1 or 2, with the proviso that the sum of h i and s i must be 2 or 3. (j) having the formula wherein R 3 is hydrogen or lower alkyl; R 1 j is hydrogen, 0 lower alkyl, or benzyl; R 2 j is hydrogen or R 3 j -C-wherein R 3 j is lower alkyl, heteroaryl containing 4 to 9 carbon atoms and one or two nitrogen, oxygen or sulfur atoms; phenyl, substituted phenyl having 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, lower alkyl or alkoxy; and n j is 0 or 1; wherein lower alkyl and lower alkoxy include straight or branched groups containing 1 to 4 carbon atoms, and pharmaceutically acceptable salts of the compounds when R j is hydrogen and when R 3 j is heteroaryl containing 1 or 2 nitrogen atoms, are disclosed; (k) having the formula wherein R 4 k is hydrogen or lower alkyl; R 5 k is hydrogen, lower alkyl or benzyl; R 6 k is hydrogen or lower alkyl; A r k is phenyl or phenyl substituted with 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, lower alkyl, lower alkoxy, hydroxy or amino; and m is 0 to 3; wherein lower alkyl and lower alkoxy contain 1 to - 4 straight or branched carbon atoms; and the pharmaceutically acceptable salts thereof; (L) having the formula where wherein: R L and R 2L are independently hydrogen; loweralkyl; aralkyl; or aryl; R 1L is hydrogen; branched or straight chain C 1-12 alkyl and alkenyl; C 3 -C 9 cycloalkyl and benzofused alkyl; substituted loweralkyl where the substituents are halo, hydroxy loweralkoxy, aryloxy, amino, mono- or diloweralkylamino, acylamino, arylamino, guanidino, mercapto, loweralkylthio, arylthio, carboxy, carboxamido, or loweralkoxycarbonyl; aryl; substituted aryl where the substituents are loweralkyl, loweralkoxy, or halo; arloweralkyl; arloweralkenyl; heteroarloweralkyl; .heteroarloweralkenyl; substituted arloweralkyl, substituted arloweralkenyl, substituted heteroarloweralkyl, or substituted heteroarloweralkenyl where the aryl and heteroaryl substituents are halo, dihalo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralklyl, acylamino, mono- or diloweralkylamino, carboxyl, haloloweralkyl, nitro, cyano, or sulfonamido, and where the loweralkyl portion of arloweralkyl may be substituted by amino, acylamino, or hydroxyl; or where X L and Y L taken together are -CH 2 -CH 2 -; R 4L is hydrogen, l oweralkyl; aryl; substituted aryl; R SL is hydrogen; loweralkyl; aryl or substituted aryl; n L is 1 to 3; w L is absent; -CH 2 : or -C-; Z L is -(CH 2 ) m L, where m L is 0 to 2, provided that m L may not-be O and W L may not be absent at the same time; and R 6L is hydrogen; loweralkyl; halo; or OR 4L ; R 2L is. where r L and s L are independently 0 to 3; B L is absent; -O-; - S -; or -NR 8 L; where R 8L is hydrogen; loweralky; alkanoyl; or aroyl; and R 7 L is where R 9L is l oweralkyl; aralkyl; aryl; heteroaryl; or heteroarloweralkyl and these groups substituted by hydroxy, lower alkoxy or halo; carboxyl; carbox amido; nitromethenyl. R 10L is hydrogen; loweralkyl; aryl; or amidino; R 11L hydrogen; l oweralkyl; cyano; amidino; aryl; aroyl; loweralkanoyl; or SO 2 R 13L ; R 12 is hydrogen; loweralkyl; halo; aralkyl; amino; cyano; mono- or diloweralkylamino; or OR 4L ; R 13L is hydrogen; l oweralkyl; or aryl; R 15L is hydrogen; lower alkyl; aralkyl; or aryl. constitute a basic heterocycle of 5 or 6 atoms or benzofused analogs thereof and optionally containing 1-3 N atoms, an oxygen, a sulfur, an S=O, or an SO 2 group optionally substituted by amino, lower alkyl amino, diloweralkyl amino, lower alkoxy, or aralkyl groups; R 3L is C 3-8 cycloalkyl and benzofused C 3-8 cycloalkyl; perhydrobenzofused C 3-8 cycloalkyl; aryl; substituted aryl; heteroaryl; substituted heteroaryl; R 14 is hydrogen or loweralkyl; and, a pharmaceutically acceptable salt thereof; (m) having the formula wherein R 1 m , R 2 m , R 3 m , R 4 m , R 5 m and R 6 m are hydrogen, alkyl, alkenyl, alkynyl, phenyl-alkyl, and cycloalkyl, and may be the same or different, n m is an integer from 0 to 4 inclusive, M m is alkenyl, alkynyl, cycloalkyl, cycloalkyl- alkyl, polycycloalkyl, polycycloalkyl-alkyl, aryl, aralkyl, heteroaryl,- heteroaryl-alkyl, hetero-cycloalkyl, hetero-cycloalkyl-alkyl, fused aryl-cycloalkyl, fused aryl-cycloalkyl-- alkyl, fused heteroaryl-cycloalkyl, fused heteroaryl-cycloalkyl-alkyl, alkoxyalkyl, alkylthioalkyl, alkylamino-alkyl, or dialkylaminoalkyl, Y m is hydroxy, alkoxy, amino, or substituted amino, aminoalkanoyl, aryloxy, aminoalkoxy, or hydroxyalkoxy, and R 7 m is hydrogen, alkanoyl, carboxyalkanoyl, hydroxyalkanoyl, aminoalkanoyl, cyano, amidino, carbalkoxy, z m S or wherein Z m is hydrogen, alkyl, hydroxyalkyl, or the radical wherein R 1 m , R 2 m , R 3 m , R 4 m , R 5 m , R 6 m n m , Mm and Y m are as described above; and where Y m is hydroxy, their non-toxic, pharmaceutically acceptable alkali metal, alkaline earth metal, and amine salts; or (n) havinq the formula wherein R" is hydrogen, lower alkyl or aralkyl; R 1 n is hydrogen, lower alkyl, or benzyl; R 2 n is hydrogen or lower alkyl, and Ar is phenyl or phenyl substituted with 1 or 2 substituents selected from the group consisting of fluorine, chlorine, bromine, lower alkyl, lower alkoxy, hydroxy or amino; X and Y are independently hydrogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, hydroxy, or X and Y together are methylenedioxy; m is 0 to 3; and the pharmaceutically acceptable acid salts thereof; (o) having the formula hydroqen atoms at ring positions 1 and 5 are cis to each other and the 3-carboxy group has the endo orientation: R 1 ° is H, allyl, vinyl or the side chain of an optionally protected naturally occurring a-amino acid; R 2 ° is H, 1-6C alkyl, 2-6C alkenyl or aryl(1-4C alkyl); X° is H or OH and Z° is H, or Y° and Z° together oxyqen; X° is 1-6C alkyl, 2-6C alkenyl, 5-9C cycloalkyl, 6-12C aryl (optionally substituted by one to three 1-4C alkyl or alkoxy, OH, halo, nitro, amino (optionally substituted by one or two 1-4C alkyl), or methylenedioxy) or indol-3-yl); (p) havinq the formula n p is 0 or 1; A p is a benzene or cyclohexane ring: R 1 p and R 2 P are each 1-6C alkyl, 2-6C alkenyl, 5-7C cycloalkyl, 5-7C cycloalkenyl, 7-12C cycloalkylalkyl, optionally partially hydrogenated 6-10C aryl, 7-14C aralkyl or 5-7 membered monocyclic or 8-10 membered bicyclic heterocyclyl containing 1 or 2 S or O and/or 1-4N atoms; all R 1 p and R 2 p qroups are optionally substituted. R 3 P is H, 1-6C alkvl, 2-6C alkenyl or 7-14C aralkyl; (q) having the formula wherein: the ring A q is saturated and n q =0 or 1, or the ring A q is a benzene ring and n q =1, R 1 q represents a lower alkyl qroup having from 1 to 4 carbon atoms which can carry an amino qroup, R 2 q represents a hydrogen atom or a alkyl group havinq from 1 to 4 carbon atoms, R 3 q represents a straight or branched alkyl qroup, a mono- or dicycloalkylalkyl or phenylalkyl group having no more than a total of 9 carbon atoms, or a substituted alkyl qroup of the formula: with R 4 Q =H, a lower alkyl (C 1 to C 4 ) or a cycloalkyl (C 3 to C 6 qroup, R 5 q =H, a lower alkyl (C 1 to C 4 ) a cycloalkyl (C 3 to C 6 ) or an alkoxycarbonyl group, Y q = S or >N-Q q where Q q =H, or an acetyi or benzyloxycarbonyl group, and p q =1 or 2, and q q =0 or 1, and the pharmaceutically acceptable salts thereof ; (r) having the formula wherein B r represents a methylene (-CH 2 -), ethylene (-CH 2 -CH 2 -) or vinylene (-CH=CH-) group, R 1r represents a hydrogen atom or an alkyl, aralkyl, amino- alkyl, monoalkylamino-alkyl, dialkylamino-alkyl, acylamino-alkyl, phthalimido-alkyl, alkoxycarbonylamino- alkyl, aryloxycarbonyl-amino-alkyl, aralkoxycarbonyl- amino-alkyl, alkylaminocarbonylamino-alkyl, arylaminocarbonylamino-alkyl, aralkylaminocaxbonylamino- alkyl, alkylsulphonylamino-alkyl or arylsulphonylamino- alkyl group, R 2r represents a carboxyl, alkoxycarbonyl or aralkoxycarbonyl group or a group of the formula R 3r represents a carboxyl, alkoxycarbonyl or aralkoxycarbonyl group, R 4r and R 5r each represent a hydrogen atom or R 4r and R 5r together represent an oxo group, R 6r and R 7r each represent a hydroqen atom or an alkyl or aralkyl group or R 6r and R 7r together with the nitrogen atom to which they are attached represent a saturated 5 membered or 6-membered heteromonocyclic ring which may contain a further nitrogen atom or an oxygen or sulphur atom, and n r stands for zero, 1 or 2, and pharmaceutically acceptable salts thereof; (s) having the formula wherein R A S and R B S are radicals of the formula respectively in which R 0 S is carboxy or a functionally modified carboxy; R 1 s is hydrogen, lower alkyl, amino(lower) alkyl, aryl, aryl (lower) alkyl, cycloalkyl or cycloalkyl (lower) alkyl; R 2 s is hydrogen or lower alkyl: R 3 s and R 4 s , each independently, represent hydrogen, lower alkyl, lower alkoxy, lower alkanoyloxy, hydroxy, halogen, trifluoromethyl, or R 3 s and R 4 s taken together represent lower alkylenedioxy; R 5 s is hydrogen or lower alkyl, and X S represents oxo, two hydrogens, or one hydroxy together with one hydrogen; and wherein the carbocyclic ring may also be hexahydro or 6, 7, 8, 9-tetrahydro, and salts and complexes thereof; (t) having the formula wherein Ph t is unsubstitued 1,2-phenylene, or 1,2-phenylene substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylenedioxy, hydroxy, halogeno and trifluoromethyl; R o t is hydrogen or HPh t ; each of R l t , R 2 t and R 3 t is hydroqen or lower alkyl; and n t is an inteqer from 1 to 10; the amides, mono- or di-lower alkylamides, lower alkyl esters, (amino, mono- or di- lower alkylamino, carboxy or lower carbalkoxy)-lower alkyl esters, or pharmaceutically acceptable salts thereof.

Claim 7

A composition according to any one of claims 1,4 or 6 wherein the ACE inhibitor is chosen from spirapril, enalapril, ramipril, perindopril, indolapril, lysinopril, CI-925, pentopril, cilazapril, captopril, zofenopril or pivalopril.

Claim 8

A composition according to claim 1 or 3 wherein the atrial peptide is chosen from a human AP 21, a human AP 28, a human AP 23, a human AP. 24, a human AP 25, a human AP 26, a human AP 33, and the corresponding atrial peptides wherein the methionine at position 12 is replaced by isoleucine.

Claim 9

A kit according to claim 1 comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat hypertension in mammals which comprises in one container a pharmaceutical composition comprising a NMEP inhibitor and in a second container, a pharmaceutical composition comprising an atrial peptide as defined in claims 3 or 7.

Claim 10

A kit according to claim 1 comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat hypertension in mammals which comprises in one container a pharmaceutical composition comprising a NMEP inhibitor and in a second container, a pharmaceutical composition comprising an ACE inhibitor as defined in claims 4, 5 or 6.

Claim 11

A composition according to any one of claims 1-9 wherein the NMEP inhibitor is chosen from N-[N-[L-l-(2,2-dimethyl-l-oxopropoxy)methoxy]-carbonyl]-2-phenylethyl]-L-phenylalanyl]-0-alanine; N-(N-[(L-1-carboxy-2-phenylethyl)]-L-phenylalanyl]-β alanine; N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-β-alanine; N-[1-oxo-3-phenyl-2-(phosphonomethyl)propyl]-β-alanine ethyl ester: N-[N-[1-(S)-carboxyl-3-phenylpropyl]-(S)-phenylalanyll-(R)-isoserine; N-[N-[l-(S)-[2-(phenoxy)ethoxycarbonyl]-3-phenylpropyl]-(S)-phenylalanyl]-(S)-isoserine; and N-[2-(S-acetylthiomethyl)-3-phenylpropionyl]-(S)-methionine amide.

Claim 12

ll. A composition according to any one of claims 1-10 wherein the NMEP inhibitor is administered at a dosage level of 1 to 100 mg/kg mammalian weight per day.

Claim 13

A composition according to any one of claims 1, 3, 7, 8 or 10 wherein the NMEP inhibitor is administered at a dosage level of 1 to 100 mg/kg mammalian weight per day and the atrial peptide is administered at a dosage level of 0.001 to 0.1 mg/kg mammalian weight per day.

Claim 14

A composition according to any one of claims 1, 4, 5, 6, 9 or 10 wherein the NMEP inhibitor is administered at a dosage level of 1 to 100 mg/kg mammalian weight per day and the ACE inhibitor is administered at a dosage level of 0.1 to 30 mg/kg mammalian weight per day.

Claim 15

A process for the preparation of a pharmaceutical composition of claim 1 which comprises mixing a NMEP inhibitor, alone or in combination with an atrial peptide or an ACE inhibitor, with a pharmaceutically acceptable carrier.

Claim 16

A process of claim 14 wherein the NMEP inhibitor is as defined in claim 10, the atrial peptide is as defined in claim 7 and the ACE inhibitor is as defined in claims 5 or 6.

Claim 17

A composition according to claims 1, 3-9, 12 or 13 wherein the NMEP inhibitor is a. compound having the formula wherein R 1 is Y-C 6 H 4 -, Y-C 6 H 4 S-, Y-C 6 H 4 O-, a-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, H 2 N(CH 2m -, diphenylmethyl, R 2 is alkyl, alkys-S(O )0-2 (CH 2 ) q -, R 5 (CH 2 ) k S(O) 0-2 (CH 2 ) q -, alkyl-O(CH 2 ) q -, R 5 (CH 2 ) k -O(CH 2 ) q -, R 5 (CH 2 ) q -, H 2 N(CH 2 ) q -, cycloalkyl(CH 2 ) k -, R 13 CONH(CH 2 )q-, R 13 NHCO(CH 2 )q- or R 6 OCO(CH 2 )q -; R 3 is R 4 and R 13 are independently hydrogen, alkyl or Y 1 -C 6 H 4 -; R 5 is Y 2 -C 6 H 4 -, Y 2 -C 6 H 4 S-, Y 2 -C 6 H 4 O-, a-naphthyl, B-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, indolyl or provided that when R 5 is Y 2 -C 6 H 4 S- or Y 2 -C 6 H 4 O-, k is 2 or 3; R 6 , R 7 and R 8 are independently H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, or R 7 and R 8 together with the nitrogen to which they are attached complete a 5-7 membered ring, wherein one of the 4-6 ring members comprising R 7 and R 8 may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom; and wherein the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; R 9 is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl or carbamoylalkyl; n is 0-2; m and k are independently 0-3; q is 1-4; X and X 1 are independently a bond, -O-, -S-, or -CH 2 -; Q is hydrogen or R 10 CO-; R 10 is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, Y 3 -C 6 H 4 -alkyl, alkoxy, Y 3 -C 6 H 4 -, naphthyl, furyl, thienyl or pyridyl; Y, Y 1 , Y 2 and Y 3 independently represent one or more substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, CN, -CH 2 NH 2 , -CO 2 H, -C0 2 alkyl, -CONH 2 and phenyl; and the pharmaceutically acceptable acid addition salts thereof.

Claim 18

A compound having the structural formula wherein R lw is phenyl substituted by one or more substituents independently selected from alkyl, alkoxy, cycloalkyl, cyano and aminomethyl, Y W -C 6 H 4 S-, Y W -C 6 H 4 O-, a-naphthyl, β-naphthyl, furyl, benzofuryl, benzothienyl, H 2 N(CH 2 ) m w -, diphenylmethyl, R 2w is alkyl, alkyl-S(O) 0-2 (CH 2 ) q w -, R 5w (CH 2 ) k w S(O) 0-2 (CH 2 ) q w -, alkyl-O(CH 2 )q w -, R 5w (CH 2 ) k w -O(CH 2 ) q w -, R 5w (CH 2 ) q w -, H 2 N(CH 2 )q w -, cycloalkyl(CH 2 ) k w -, R 13w CONH(CH 2 ) q w -, R 13w NHCO(CH 2 ) q w - or R 6w OCO(CH 2 ) q w -; R 3w is -O R 7w , -NR 7w R 8w , R 4w and R 13w are independently hydrogen, alkyl or Y 1w - C 6 H 4 - ; R 5w is Y 2w -C 6 H 4 -, Y 2w -C 6 H 4 S-, Y 2w -C 6 H 4 O-, α-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, indolyl or provided that when R 5w is Y 2w -C 6 H 4 S- or Y 2w -C 6 H 4 O-, k w is 2 or 3; R 6w , R 7w and R 8w are independently H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, or R 7w and R 8w together with the nitrogen to which they are attached complete a 5-7 membered ring, wherein one of the 4-6 ring members comprising R 7w and R 8w may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; R 9w is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, or carbamoylalkyl; n w is 0-2; m w and k w are independently 0-3; q w is 1-4; X w and X lw are independently a bond, -O-, -S-, or -CH 2 -: Q w is hydrogen or R 10w CO-; R 10w is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, Y 3w -C 6 H 4 -alkyl, alkoxy, Y 3w -C 6 H 4 -, naphthyl, furyl, thienyl or pyridyl; Y w , Y 1w , Y 2w and Y 3w independently represent one or more substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, CN, -CH 2 NH 2 , -C0 2 H, -CO 2 alkyl, -CONH 2 and phenyl; and the pharmaceutically acceptable addition salts thereof.

Claim 19

A compound having the structural formula wherein R lw is phenyl substituted by one or more substituents independently selected from alkyl, alkoxy, cycloalkyl, cyano and aminomethyl, Y W -C 6 H 4 S-, Y W -C 6 H 4 O-, a-naphthyl, β-naphthyl, furyl, benzofuryl, benzothienyl, H 2 N(CH 2 ) m w -, diphenylmethyl, R 2w is alkyl, alkyl-S(O) 0-2 (CH 2 ) q w -, R 5w (CH 2 ) k w S(O) 0-2 (CH 2 ) q w -, alkyl-O(CH 2 )q w -, R 5w (CH 2 ) k w -O(CH 2 ) q w -, R 5w (CH 2 ) q w -, H 2 N(CH 2 )q w -, cycloalkyl(CH 2 ) k w -, R 13w CONH(CH 2 ) q w -, R 13w NHCO(CH 2 ) q w - or R 6w OCO(CH 2 ) q w -; R 3w is -O R 7w , -NR 7w R 8w , R 4w and R 13w are independently hydrogen, alkyl or Y 1w - C 6 H 4 - ; R 5w is Y 2w -C 6 H 4 -, Y 2w -C 6 H 4 S-, Y 2w -C 6 H 4 O-, α-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, indolyl or provided that when R 5w is Y 2w -C 6 H 4 S- or Y 2w -C 6 H 4 O-, k w is 2 or 3; R 6w , R 7w and R 8w are independently H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, or R 7w and R 8w together with the nitrogen to which they are attached complete a 5-7 membered ring, wherein one of the 4-6 ring members comprising R 7w and R 8w may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; R 9w is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, or carbamoylalkyl; n w is 0-2; m w and k w are independently 0-3; q w is 1-4; X w and X lw are independently a bond, -O-, -S-, or -CH 2 -: Q w is hydrogen or R 10w CO-; R 10w is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, Y 3w -C 6 H 4 -alkyl, alkoxy, Y 3w -C 6 H 4 -, naphthyl, furyl, thienyl or pyridyl; Y w , Y 1w , Y 2w and Y 3w independently represent one or more substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, CN, -CH 2 NH 2 , -C0 2 H, -CO 2 alkyl, -CONH 2 and phenyl; and the pharmaceutically acceptable addition salts thereof.

Claim 20

A compound having the structural formula wherein R law is Y w -C 6 H 4 -, Y w -C 6 H 4 S-, Y w -C 6 H 4 O-, α-naphthylr β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, H 2 N(CH 2 ) m w -, diphenylmethyl, R 2aw is R 5aw (CH 2 ) k w S(O) 0-2 (CH 2 ) q w -, R 5aw (CH 2 ) k w -O(CH 2 ) q w -, R 5aw (CH 2 ) q w -, or cycloalkyl-(CH 2 ) k w , and when R 3w is -NR 7w R 8w , R 2aw may also be indolyl-(CH 2 ) q w -, R 13w CONH(CH 2 ) q w -, R 13w NHCO(CH 2 ) q w - or R 6w OCO(CH 2 ) q w -; R 3w is -OR 7w , -NR 7w R 8w , R 4w and R 13w are independently hydrogen, alkyl or Y 1w- C 6 H 4 -; R 5aw is Y 2w -C 6 H 4 - provided Y 2w is not H or OH, y2w- C 6 H 4 S-, Y 2w -C 6 H 4 O-, a-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl or provided that when R 5aw is Y 2w -C 6 H 4 S- or Y 2w C 6 H 4 O-, k w is 2 or 3; R 6w , R 7w and R 8w are independently H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, or R 7w and R 8w together with the nitrogen to which they are attached complete a 5-7 membered ring, wherein one of the 4-6 ring members comprising R 7w and R 8w may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and whereim the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; R 9w is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, or carbamoylalkyl; n w is 0-2; m w and k w are independently 0-3; q w is 1-4; X w and X lw are independently a bond, -0-, -S-, or -CH 2 -; Q w is hydrogen or R 10w CO-; R 10w is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, Y 3w -C 6 H 4 -alkyl, alkoxy, Y 3w -C 6 H 4 -, naphthyl, furyl, thienyl or pyridyl; Y w , Y 1w , Y 2w and Y 3w independently represent one or more substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, CN, -CH 2 NH 2 , -C0 2 H, -CO2alkyl, -CONH 2 and phenyl; and the pharmaceutically acceptable addition salts thereof.

Claim 21

A compound having the structural formula wherein R law is Y w -C 6 H 4 -, Y w -C 6 H 4 S-, Y w -C 6 H 4 O-, α-naphthylr β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, H 2 N(CH 2 ) m w -, diphenylmethyl, R 2aw is R 5aw (CH 2 ) k w S(O) 0-2 (CH 2 ) q w -, R 5aw (CH 2 ) k w -O(CH 2 ) q w -, R 5aw (CH 2 ) q w -, or cycloalkyl-(CH 2 ) k w , and when R 3w is -NR 7w R 8w , R 2aw may also be indolyl-(CH 2 ) q w -, R 13w CONH(CH 2 ) q w -, R 13w NHCO(CH 2 ) q w - or R 6w OCO(CH 2 ) q w -; R 3w is -OR 7w , -NR 7w R 8w , R 4w and R 13w are independently hydrogen, alkyl or Y 1w- C 6 H 4 -; R 5aw is Y 2w -C 6 H 4 - provided Y 2w is not H or OH, y2w- C 6 H 4 S-, Y 2w -C 6 H 4 O-, a-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl or provided that when R 5aw is Y 2w -C 6 H 4 S- or Y 2w C 6 H 4 O-, k w is 2 or 3; R 6w , R 7w and R 8w are independently H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, or R 7w and R 8w together with the nitrogen to which they are attached complete a 5-7 membered ring, wherein one of the 4-6 ring members comprising R 7w and R 8w may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and whereim the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; R 9w is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, or carbamoylalkyl; n w is 0-2; m w and k w are independently 0-3; q w is 1-4; X w and X lw are independently a bond, -0-, -S-, or -CH 2 -; Q w is hydrogen or R 10w CO-; R 10w is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, Y 3w -C 6 H 4 -alkyl, alkoxy, Y 3w -C 6 H 4 -, naphthyl, furyl, thienyl or pyridyl; Y w , Y 1w , Y 2w and Y 3w independently represent one or more substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, CN, -CH 2 NH 2 , -C0 2 H, -CO2alkyl, -CONH 2 and phenyl; and the pharmaceutically acceptable addition salts thereof.

Claim 22

A compound represented by the structural formula wherein R law is Y w -C 6 H 4 -, Y w -C 6 H 4 S-, Y w -C 6 H 4 O-, α-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, H 2 N(CH 2 ) m w- , diphenylmethyl, R 2w is alkyl, alkyl-S(O) 0-2 (CH 2 ) q w -, R 5w (CH 2 ) k w S(O) 0-2 (CH 2 ) q w -, alkyl-O(CH 2 ) q w -, R 5w (CH 2 ) k w- O(CH 2 ) q w -, R 5w (CH 2 ) q w -, H 2 N(CH 2 ) q w -, cycloalkyl(CH 2 ) k w -, R 13w CONH(CH 2 ) q w -, R 13w NHCO(CH 2 ) q w - or R 6w OCO(CH 2 ) q w -; R 3 aw is R 4w and R 13w are independently hydrogen, alkyl or Y lw- C 6 H 4 -; R 5w is Y 2w -C 6 H 4 -, Y 2w -C 6 H 4 S-, Y 2w -C 6 H 4 O-, a-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, indolyl or provided that when R 5w is Y 2w -C 6 H 4 S- or Y 2w -C 6 H 4 O-, k w is 2 or 3; R 6w , R 7w and R 8w are independently H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, or R 7w and R 8w together with the nitrogen to which they are attached complete a 5-7 membered ring, wherein one of the 4-6 ring members comprising R 7w and R 8w may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; R 9w is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, or carbamoylalkyl; n w is 0-2; m w and k W are independently 0-3; q w is 1-4; X w and X lw are independently a bond, -O-, -S-, or -CH 2 -; Q W is hydrogen or R 10w CO-; R 10 w is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, Y 3w -C 6 H 4 -alkyl, alkoxy, Y 3w -C 6 H 4 -, naphthyl, furyl, thienyl or pyridyl; R llw is hydroxyalkyl or substituted phenylalkyl wherein the phenyl group is substituted by one or more groups selected from alkyl, alkoxy, cycloalkyl and cyano; R 12w is H or selected from the same group as R llw ; or R 11w and R 12w together with the nitrogen to which they are attached complete a 5-7 membered ring wherein one of the 4-6 ring members comprising R llw and R 12w may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; Y w , y lw , Y 2w and Y 3w independently represent one or more substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, CN, -CH 2 NH 2 , -C0 2 H, -CO 2 alkyl, -CONH 2 and phenyl; and the pharmaceutically acceptable addition salts thereof.

Claim 23

A compound represented by the structural formula wherein R law is Y w -C 6 H 4 -, Y w -C 6 H 4 S-, Y w -C 6 H 4 O-, α-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, H 2 N(CH 2 ) m w- , diphenylmethyl, R 2w is alkyl, alkyl-S(O) 0-2 (CH 2 ) q w -, R 5w (CH 2 ) k w S(O) 0-2 (CH 2 ) q w -, alkyl-O(CH 2 ) q w -, R 5w (CH 2 ) k w- O(CH 2 ) q w -, R 5w (CH 2 ) q w -, H 2 N(CH 2 ) q w -, cycloalkyl(CH 2 ) k w -, R 13w CONH(CH 2 ) q w -, R 13w NHCO(CH 2 ) q w - or R 6w OCO(CH 2 ) q w -; R 3 aw is R 4w and R 13w are independently hydrogen, alkyl or Y lw- C 6 H 4 -; R 5w is Y 2w -C 6 H 4 -, Y 2w -C 6 H 4 S-, Y 2w -C 6 H 4 O-, a-naphthyl, β-naphthyl, furyl, thienyl, benzofuryl, benzothienyl, indolyl or provided that when R 5w is Y 2w -C 6 H 4 S- or Y 2w -C 6 H 4 O-, k w is 2 or 3; R 6w , R 7w and R 8w are independently H, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or arylalkyl, or R 7w and R 8w together with the nitrogen to which they are attached complete a 5-7 membered ring, wherein one of the 4-6 ring members comprising R 7w and R 8w may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; R 9w is hydrogen, alkyl, carboxyalkyl, mercaptoalkyl, alkylthioalkyl, aminoalkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, guanidinoalkyl, imidazolylalkyl, indolylalkyl, or carbamoylalkyl; n w is 0-2; m w and k W are independently 0-3; q w is 1-4; X w and X lw are independently a bond, -O-, -S-, or -CH 2 -; Q W is hydrogen or R 10w CO-; R 10 w is alkyl, hydroxyalkyl, alkoxyalkyl, dialkylaminoalkyl, Y 3w -C 6 H 4 -alkyl, alkoxy, Y 3w -C 6 H 4 -, naphthyl, furyl, thienyl or pyridyl; R llw is hydroxyalkyl or substituted phenylalkyl wherein the phenyl group is substituted by one or more groups selected from alkyl, alkoxy, cycloalkyl and cyano; R 12w is H or selected from the same group as R llw ; or R 11w and R 12w together with the nitrogen to which they are attached complete a 5-7 membered ring wherein one of the 4-6 ring members comprising R llw and R 12w may be a nitrogen atom, an alkyl-substituted nitrogen atom or an oxygen atom, and wherein the ring may be substituted on the ring carbon atoms with substituents chosen from alkyl and hydroxy groups; Y w , y lw , Y 2w and Y 3w independently represent one or more substituents selected from H, alkyl, cycloalkyl, alkoxy, OH, F, Cl, Br, CN, -CH 2 NH 2 , -C0 2 H, -CO 2 alkyl, -CONH 2 and phenyl; and the pharmaceutically acceptable addition salts thereof.

Claim 24

Process for the preparation of a compound of formula I as defined in claim 17, wherein the compound is prepared by an appropriate process selected from the following processes A and B, and wherein Q w , R lw , R 2w , R 3w and n w are as defined in claim 17, including suitable protection: Process A: condensation of a 3-thiopropionic acid of formula IV, or a reactive derivative thereof, with an amine of formula V Process B: for compounds of formula I wherein R 3w is -NR 7w R 8w , condensation of a (3-thiopropionyl)amino acid of formula VI, or a reactive derivative thereof, with an amine of formula VII wherein both Process A and Process B are followed by isolating the preferred isomer if desired and removal of the protecting groups, if necessary, to yield the desired product, and if desired, preparing a salt thereof.

Claim 25

Process for the preparation of a compound of formula II as defined in claim 18, wherein the compound is prepared by an appropriate process selected from the following processes A and B, and wherein Q w , Rlaw, R 2aw , R 3w and. n w are as defined in claim 18 including suitable protection: Process A: condensation of a 3-thiopropionic acid of formula IV, or a reactive derivative thereof, with an amine of formula V Process B: for compounds of formula I wherein R 3w is -NR 7w R 8w , condensation of a (3-thiopropionyl-)amino acid of formula VI, or a reactive derivative thereof, with an amine of formula VII wherein both Process A and Process B are followed by isolating the preferred isomer if desired and removal of the protecting groups, if necessary, to yield the desired product, and if desired, preparing a salt thereof.

Claim 26

Process for the preparation of a compound of formula III as defined in claim 19 wherein the compound is prepared by an appropriate process selected from the following processes A and B , and wherein Q w , R law , R 2w , r 3aw and n w are as d.efined in claims 19 including suitable protection: Process A: condensation of a 3-thiopropionic acid of formula IV, or a reactive derivative thereof, with an amine of formula V Process B: for compounds of formula I wherein R 3w is -NR 7w R 8w , condensation of a (3-thiopropionyl)amino acid of formula VI, or a reactive derivative thereof, with an amine of formula VII wherein both Process A and Process B are followed by isolating the preferred isomer if desired and removal of the protecting groups, if necessary, to yield the desired product, and if desired, preparing a salt thereof.