Pharmaceutical compounds

Details Pharmaceutical compounds Pharmaceutical compounds

1995-07-03

2001-05-22

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C530S331000

Reexamination Certificate

active

06235717

ABSTRACT:

The present invention relates to compounds which show inhibition of endothelin converting enzyme (ECE), to pharmaceutical compositions containing such compounds and to their use in animal and human medicine.
Endothelins (ETs) are highly homologous 21 amino acid polypeptides and are formed in human and other mammalian cells and tissues from the corresponding big endothelin (BETs) precursors through hydrolysis of a Trp
21
-Val
22
or a Trp
21
-Ile
22
bond by ECE to form the ETs. ETs have potent and sustained smooth muscle contractile actions, in particular ET-1 and ET-2 are the most potent and long-acting of known vasoconstrictor substances.
ETs are known to be associated with a wide variety of pathological states (Doherty A. M. J.Med.Chem 35/9 p1493-1508[1992]) and it has been postulated that there may exist the potential for therapy of such disease states by interference with ET receptors (Doherty A. M. ibid) or by inhibition of ECEs (JP 4-41430, WO 92/13545 and WO 92/12170).
A class of compounds has now been found which are effective ECE inhibitors. Such compounds are useful in treatment of myocardial infarction, angina pectoris, cerebral infarction (stroke), cerebral vasospasm, ischemic cardiac insufficiency, Raynaud's disease and other vasospastic diseases, atherosclerosis, essential hypertension, pulmonary hypertension, asthma, respiratory distress syndrome, acute renal failure, cyclosporin-induced renal failure, endotoxic shock, endotoxin-induced multiple organ failure, acute failure following organ trasplantation, Crohn's disease, ulcerative colitis, gastric ulcer, escleroderma and lupus erythematosus.
The present invention provides peptide compounds of formula (I) or a salt thereof,
wherein:
R
1
is C
5-7
aryl; C
5-7
aryl C
1-7
alkyl; C
5-7
aryl C
1-4
alkoxy; C
5-7
aryloxy-C
1-4
alkyl; carboxy C
1-4
alkyl; C
1-4
alkoxycarbonyl C
1-4
alkyl; C
1-4
alkyl or di-phenyl C
1-4
alkyl, such aryl groups or aryl moieties of aryl-containing groups being optionally substituted with C
1-4
alkyl, halo, nitro, carboxyl or sulphonyl, or R
1
is a group of formula IIa, IIb or IIc:
 where n=0 or 1;
 where n=0 or 1 and where Z is —CONH— or —CH
2
— and R
5
is benzyloxy; 1,2,3,6tetrahydro-2,6-dioxo-4-pyrimidinyl; or 2,5dioxo-4-imidazolidinyl; or
 where R
6
is hydrogen or C
1-4
alkyl;
R
2
is indol-3-yl-methyl; C
5-7
aryl; or C
5-7
aryl C
1-4
alkyl, such aryl groups or aryl-moieties of aryl-containing groups being optionally substituted with hydroxy or halo; benzothienylmethyl; or C
1-4
alkyl;
R
3
is formyl; maleimidomethyl; methoxycarbonylvinyl; dimethoxymethyl; semicarbazonomethyl; C
1-4
alkyl; R
4
dithio; R
4
dithio-C
1-4
alkyl; R
4
dithioacetyl; R
7
C
1-4
alkylamido; R
7
C
1-4
alkylamidomethyl; —COR
8
; —CH(OH)R
9
; —COCOR
10
; or —COC≡CR
11
, in which R
4
is C
1-4
alkyl, C
5-7
aryl or C
1-4
alkyl C
5-7
aryl; R
7
is acetoxy, halo, maleimido or hydroxy; R
8
is
 CHO; C
1-4
alkenyl, C
1-4
alkyhalo or C
1-4
alkylthio; R
9
is CHO, C
1-4
alkenyl or
 such oxiranyl moiety being optionally substituted with C
1-4
alkyl or C
1-4
alkoxycarbonyl; R
10
is C
1-4
alkoxy; C
5-7
aryloxy; C
1-4
alkyl, hydrogen; hydroxy or methoxycarbonyl; and R
11
is hydrogen or Si(CH
3
); such aryl groups or aryl moieties of aryl-containing groups being optionally substituted with nitro or carboxy;
X is benzyl optionally substituted with C
1-4
alkoxy or halo; C
1-4
alkyl; indol-3-yl-methyl; naphthylmethyl; benzyloxybenzyl or cyclo C
1-6
alkylmethyl; and
Y is benzyl optionally substituted with C
1-4
alkyl or C
1-4
alkoxy; indol-3-yl-methyl; naphthylmethyl; benzyloxybenzyl or C
1-4
alkyl.
Preferably R
1
is C
5-7
aryl C
1-4
alkoxy; C
5-7
aryl C
1-4
alkyl; C
5-7
aryloxy C
1-4
alkyl or is a group of Formula IIa or IIb where n=0 or 1 and where Z is —CONH— or —CH
2
and R
5
is benzyloxy; 1,2,3,6tetrahydro-2,6-dioxo-4-pyrimidinyl or 2,5,dioxo-4-imidazolidinyl, or is a group of Formula IIc where R
6
is hydrogen or C
1-4
alkyl.
Preferably R
2
is indol-3yl-methyl; phenyl or benzyl optionally substituted with halo or hydroxy.
Preferably R
3
is formyl; semicarbazonomethyl; —COR
8
; R
7
C
1-4
alkylamido or R
7
C
1-4
alkylamidomethyl; in which R
8
is
CHO; C
1-4
alkenyl, C
1-4
alkylhalo or C
1-4
alkylthio and R
7
is acetoxy, halo, maleimido, or hydroxy.
Preferably X is benzyl optionally substituted with halo; indol-3-yl-methyl; naphthyl-methyl; C
1-4
alkyl; or benzyloxybenzyl.
Preferably Y is naphthylmethyl; indol-3-yl-methyl, benzyloxybenzyl; C
1-4
alkyl; benzyloxyC
1-4
alkyl.
More preferably R
1
is benzyloxy; [5-(hexahydro-2-oxo-1H-thieno(3,4-d]imidazol-4-yl)valeramido]pentyl; 6-[6-[(1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl)formamido]hexanamido]pentyl; 6-[6-(benzyloxy)formamido]hexanamido]pentyl; 12-[(benzyloxy)acetamido]undecanyl; 5-phenylbutyl; phenoxyethyl; 5-(hexahydro-2-oxo-(1H-thieno(3,4-d)imidazol-4-yl)butyl; 3-pyridylmethoxy; benzyl; 2-phenylethyl, 3-phenylethyl; N-[(benzyloxy)carbonyl)]-4-O-tert-butyl-L-aspart-1-yl; N-[(benzyloxy)carbonyl)]-L-aspart-1-yl; 6-[6-[2-(2,5-dioxo-4-imidazolidinyl) acetamido]hexanamido]pentyl; 3-pyridylmethoxy; 6-benzyloxycarbonylaminopentyl.
More preferably, R
2
is indol-3-yl methyl, chlorobenzyl; bromobenzyl; phenyl; benzyl, 4-hydroxybenzyl.
More preferably, R
3
is formyl; 2-oxiranylcarbonyl; semicarbazonomethyl; glyoxyloyl; acryloyl; chloroacetyl; 2-chloroacetyl; 2-acetoxyacetamido; (2-chloro-acetamido)methyl; (2-maleimidoacetamido)-methyl; 3-(malemidoacetamido)-methyl; 1-maleimidomethyl; propynoyl; (3-maleimidopropionamido)methyl.
More preferably, X is indol-3-yl-methyl; bromobenzyl; 1-naphthylmethyl; iodobenzyl; benzyloxybenzyl; [S]-1-methylpropyl; 2-napthylmethyl; benzyl; methyl; 4-chlorobenzyl; 2-methylpropyl; 1-methylethyl.
More preferably, Y is indol-3-yl-methyl; 1′-naphthylmethyl; 2-napthylmethyl; benzyloxybenzyl; 4-ethoxybenzyl; [S]-methylpropyl and, 1-methylethyl.
Particularly preferred compounds of the present invention are those wherein R
1
is 5-(hexahydro-2-oxo-1Hthieno[3,4-d]imidazol-4-yl)butyl or benzyloxy; R
2
is indol-3-yl-methyl or phenyl and R
3
is formyl or oxiranylcarbonyl; X is bromobenzyl, iodobenzyl or indol-3-yl-methyl, and Y is 2-napthylmethyl or indol-3-yl-methyl.
Most preferred embodiments of the present invention include compounds selected from the group comprising:
N-[[5-(hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]-1-p-bromophenylalanyl-L-1-naphthylalanyl-L-N-[1-formyl]2-(1H-indol-3-yl)ethyl]amide; or
N-[[5-(hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]-L-tryptophanyl-L-tryptophanyl-L-N-[1-formyl]2-(1H-indol-3-yl)ethyl]amide; or
N-[(benzyloxy)carbonyl-L-p-bromophenylalanyl-L-1-naphthylalanyl-L-N-[1-[2-oxiranylcarbonyl]]2-phenylethyl]amide,
N-[(benzyloxy)carbonyl-L-p-bromophenylalanyl-L-1-naphthylalanyl-1-L-formyl-1-(1H-indol-3-yl-methyl)-methyl]amide,
N-[(benzyloxy)carbonyl-L-p-bromophenylalanyl-L-2-naphthylalanyl-1-L-formyl-1-(1H-indol-3-yl-methyl)-methyl]amide,
N-[(benzyloxy)carbonyl-L-tryptophanyl-L-1-naphthylalanyl-1-L-formyl-1-(1H-indol-3-yl-methyl)-methyl]amide; or a salt thereof.
N-[(benzyloxy)carbonyl-L-p-iodophenylalanyl-L-1-naphthylalanyl-1-L-formyl-1-(1H-indol-3-yl-methyl)-methyl]amide,
N-[[5-(hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]-L-p-bromophenylalanyl-L-1-naphthylalanyl-L-N-[1-formyl]2-(1H-indol-3-yl)ethyl]amide,
N-[[5-(hexahydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]-L-tryptothanyl-L-tryptophan-L-N-[1-formyl]2-(1H-indol-3-yl)ethyl]amide,
N-(benzyloxy)carbonyl-L-p-bromophenylalanyl-L-1-naphthylalanyl-L-N-[1-[2-oxiranylcarbonyl]2-phenylethyl]amide, and
N-[(benz

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