Starting materials in the synthesis of thrombin and kininogenase inhibitors

The invention concerns the compounds of the formulas: ##STR1## and protected forms and salts thereof which serve as starting materials in an improved method of synthesizing serine protease inhibitors. The invention further concerns an improved method for synthesizing serine protease inhibitors which utilizes the compounds.

This invention relates to new competitive inhibitors of trypsin-like serine 
proteases, especially thrombin and kininogenases such as kallikrein, their 
synthesis, pharmaceutical compositions containing the compounds as active 
ingredients, and the use of the compounds as thrombin inhibitors and 
anticoagulants and as antiinflammatory inhibitors, respectively. The 
invention also relates to novel use of compounds as starting materials in 
synthesis of a serine protease inhibitor. Furthermore the invention 
relates to a novel structural fragments in serine protease inhibitors. 
BACKGROUND 
Blood coagulation is the key process involved in both haemostasis (i.e. 
prevention of blood loss from a damaged vessel) and thrombosis (i.e. the 
pathological occlusion of a blood vessel by a blood clot). Coagulation is 
the result of a complex series of enzymatic reactions, where one of the 
final steps is conversion of the proenzyme prothrombin to the active 
enzyme thrombin. 
Thrombin plays a central role in coagulation. It activates platelets, it 
converts fibrinogen into fibrin monomers, which polymerise spontaneously 
into filaments, and it activates factor XIII, which in turn crosslinks the 
polymer to insoluble fibrin. Thrombin further activates factor V and 
factor VIII in a positive feedback reaction. Inhibitors of thrombin are 
therefore expected to be effective anticoagulants by inhibition of 
platelets, fibrin formation and fibrin stabilization. By inhibiting the 
positive feedback mechanism they are expected to excert inhibition early 
in the chain of events leading to coagulation and thrombosis. 
Kininogenases are serine proteases that act on kininogens to produce kinins 
(bradykinin, kallidin, and Met-Lys-bradykinin). Plasma kallikrein, tissue 
kallikrein, and mast cell tryptase represent important kininogenases. 
Kinins (bradykinin, kallidin) are generally involved in inflammation. For 
example, the active inflammation process is associated with increased 
permeability of the blood vessels resulting in extravasation of plasma 
into the tissue. The ensuing plasma exudate contains all the protein 
systems of circulating blood. The plasma-derived kininogens inevitably 
will be interacting with different kallikreins, forming kinins continually 
as long as the active plasma exudation process is ongoing. Plasma 
exudation occurs independent of the mechanisms that are involved in the 
inflammation, whether it is allergy, infection or other factors (Persson 
et al., Editorial, Thorax, 1992, 47:993-1000). Plasma exudation is thus a 
feature of many diseases including asthma, rhinitis, common cold, and 
inflammatory bowel diseases. Particulary in allergy mast cell tryptase 
will be released (Salomonsson et al., Am. Rev. Respir. Dis., 1992, 
146:1535-1542) to contribute to kinin formation and other pathogenic 
events in asthma, rhinitis, and intestinal diseases. 
The kinins are biologically highly active substances with smooth muscle 
effects, sectretory effects, neurogenic effects, and actions that may 
perpetuate inflammatory processes including activation of phospholipase 
A.sub.2 and increasing vascular permeability. The latter action 
potentially induces a vicious circle with kinins providing for the 
generation of more kinins etc. 
Tissue kallikrein cleaves primarily low molecular weight kininogen to 
produce kallidin and plasma kallikrein preferably releases bradykinin from 
high molecular weight kininogen. 
PRIOR ART 
Inhibitors of thrombin based on the amino acid sequence around the cleavage 
site for the fibrinogen A.alpha. chain were first reported by Blomback et 
al. in J. Clin. Lab. Invest. 24, suppl 107, 59, (1969), who suggested the 
sequence Phe-Val-Arg (P9-P2-P1, herein referred to as the P3-P2-P1 
sequence) to be the best inhibitor. 
In U.S. Pat. No. 4,346;078 has S. Bajusz et al. described the thrombin 
inhibitor H-DPhe-Pro-Agm, a dipeptidyl derivative with an aminoalkyl 
guanidine in the P1-position. 
Inhibitors of thrombin based on peptide derivatives with a cyclic 
aminoalkyl guanidine, e.g. 3-aminomethyl-1-amidinopiperidine, in the 
P1-position have been disclosed in EP-A2-0,468,231. 
In EP-A2-0,185,390 has S. Bajusz et. al. disclosed that replacing the 
agmatine with an arginine aldehyde gave a thrombin inhibitor which had 
much higher potency. 
Inhibitors of kallikrein based on the amino acid sequence around the 
cleavage site Arg-Ser have been reported earlier. 
The arginine chloromethyl ketones H-DPro-Phe-Arg-CH.sub.2 Cl and H-D 
Phe-Phe-Arg-CH.sub.2 Cl were reported as plasma kallikrein inhibitors by 
Kettner and Shaw in Biochemistry 1978, 17:4778-4784 and Meth. Enzym. 1981, 
80:826-842. 
Likewise, esters and amides containing the H-DPro-Phe-Arg sequence were 
reported by Fareed et al. in Ann. N.Y. Acad. Sci. 1981, 370:765-784 to be 
plasma kallikrein inhibitors. 
Inhibitors of serine proteases that are based on electrophilic ketones 
instead of aldehydes in the P1-position are described in the following 
patent documents: 
EP-A2-0,195,212 describing peptidyl .alpha.-keto esters and amides, 
EP-A1-0,362,002 describing fluoroalkylamide ketones and EP-A2-0,364,344 
describing .alpha., .beta., .delta.-triketo compounds possessing different 
peptidase inhibiting properties. 
Inhibitors of trypsin-like serine proteases, such as thrombin and 
kallikrein, based on C-terminal boronic acid derivatives of arginine and 
isothiouronium analogues thereof have been revealed in EP-A2-0,293,881. 
WO 92/04371 describing kininogenase inhibitors, e.g. kallikrein inhibitors 
based on derivatives of arginine. 
EP-A1-0,530,167 describing .alpha.-alkoxy ketone derivatives of arginine as 
thrombin inhibitors. 
DISCLOSURE OF THE INVENTION 
An object of the present invention is to provide novel and potent 
trypsine-like serine protease inhibitors, especially anticoagulantia and 
antiinflammatory compounds with competitive inhibitory activity towards 
their enzyme i.e. causing reversible inhibition. More specifically 
anticoagulants for prophylaxis and treatment of thromboembolic diseases 
such as venous thrombosis, pulmonary embolism, arterial thrombosis, in 
particular myocardial infarction and cerebral thrombosis, general 
hypercoagulable states and local hypercoagulable states, e.g. following 
angioplasty and coronary bypass operations, and other situations where 
thrombin is believed to play a role, e.g. Alzheimers disease, as well as 
inhibition of kininogenases for treatment of inflammatory disorders e.g. 
asthma, rhinitis, urticaria, inflammatory bowel disease, and arthritis. A 
further object is to obtain thrombin inhibitors which are orally 
bioavailable and selective in inhibiting thrombin over other serine 
proteases. A further object of the invention is to obtain kininogenase 
inhibitors which can be given orally, rectally, topically e.g. dermally, 
or via the inhalation route. 
Compounds 
According to the invention it has been found that compounds of the general 
Formula I, either as such or in the form of physiologically acceptable 
salts, and including stereoisomers, are potent inhibitors of serine 
proteases, especially thrombin and kininogenases such as kallikrein: 
EQU A.sup.1 --A.sup.2 --NH--(CH.sub.2).sub.n --B Formula I 
wherein: 
A.sup.1 represents a structural fragment of Formula IIa, IIb, IIc, IId or 
IIe; 
##STR2## 
wherein: k is an integer 0, 1, 2, 3 or 4; 
m is an integer 1, 2, 3 or 4; 
q is an integer 0, 1, 2 or 3; 
R.sup.1 represents H, an alkyl group having 1 to 4 carbon atoms, or 
R.sup.11 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is 
possibly substituted in the position which is alpha to the carbonyl group, 
and the alpha substituent is a group R.sup.17 --(CH.sub.2).sub.p -- 
wherein p is 0,1 or 2 and R.sup.17 is methyl, phenyl, OH, COOR.sup.12, 
CONHR.sup.12, where R.sup.12 is H or an alkyl group having 1 to 4 carbon 
atoms, and R.sup.11 is H or an alkyl group having 1 to 6 carbon atoms, or 
R.sup.1 represents Ph(4-COOR.sup.12)--CH.sub.2 --, where R.sup.12 is as 
defined above, or 
R.sup.1 represents R.sup.13 --NH--CO-alkyl-, where the alkyl group has 1 to 
4 carbon atoms and is possibly substituted alpha to the carbonyl with an 
alkyl group having 1 to 4 carbon atoms and where R.sup.13 is H or an alkyl 
group having 1 to 4 carbon atoms or --CH.sub.2 COOR.sup.12, where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.12 OOC--CH.sub.2 --OOC-alkyl-, where the alkyl 
group has 1 to 4 carbon atoms and is possibly substituted alpha to the 
carbonyl with an alkyl group having 1 to 4 carbon atoms and where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.14 SO.sub.2 --, Ph(4-COOR.sup.12)--SO.sub.2 --, 
Ph(3-COOR.sup.12)--SO.sub.2 --, Ph(2-COOR.sup.12)--SO.sub.2 -, where 
R.sup.12 is as defined above and R.sup.14 is an alkyl group having 1-4 
carbon atoms, or 
R.sup.1 represents --CO--R.sup.15, wherein R.sup.15 is an alkyl group 
having 1-4 carbon atoms, or 
R.sup.1 represents --CO--OR.sup.15, where R.sup.15 is as defined above, or 
R.sup.1 represent --CO--(CH.sub.2).sub.p --COOR.sup.12, where R.sup.12 is 
as defined above and p is an interger 0, 1 or 2, or 
R.sup.1 represents --CH.sub.2 PO(OR.sup.16).sub.2, --CH.sub.2 SO.sub.3 H or 
--CH.sub.2 --(5-(1H)-tetrazolyl), where R.sup.16 is, individually at each 
occurrence, H, methyl or ethyl; 
R.sup.2 represents H or an alkyl group having 1 to 4 carbon atoms or 
R.sup.21 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and, 
where R.sup.21 is H or an alkyl group having 1 to 4 carbon atoms; 
R.sup.3 represents an alkyl group having 1-4 carbon atoms, and the alkyl 
group may or may not carry one or more flourine atoms, or 
R.sup.3 represents a cyclopentyl, cyclohexyl- or a phenyl group which may 
or may not be substituted with an alkyl group having 1 to 4 carbon atoms, 
or 
R.sup.3 represents a phenyl group substituted with a OR.sup.31 group, where 
R.sup.31 is H or an alkyl group having 1 to 4 carbon atoms and k is 0, 1, 
or 
R.sup.3 represents a 1-naphthyl or 2-naphthyl group and k is 0, 1, or 
R.sup.3 represent a cis- or trans-decalin group and k is 0, 1, or 
R.sup.3 represents 4-pyridyl, 3-pyrrolidyl or 3-indolyl which may or may 
not be substituted with a OR.sup.31 group, where R.sup.31 is as defined 
above and k is 0, 1, or 
R.sup.3 represents Si(Me).sub.3 or CH(R.sup.32).sub.2, wherein R.sup.32 is 
a cyclohexyl- or a phenyl group; 
R.sup.4 represents H, an alkyl group having 1 to 4 carbon atoms, a 
cyclohexyl- or a phenyl group; 
A.sup.2 represents a structural fragment of Formula IIIa, IIIb or IIIc 
##STR3## 
wherein: p is an interger 0, 1 or 2; 
m is an integer 1, 2, 3 or 4; 
Y represents a methylene group, or 
Y represents an ethylene group and the resulting 5-membered ring may or may 
not carry one or two fluorine atoms, a hydroxy group or an oxo group in 
position 4, or may or may not be unsaturated, or 
Y represents --CH.sub.2 --O--, --CH.sub.2 --S--, --CH.sub.2 --SO--, with 
the heteroatom functionality in position 4, or 
Y represents a n-propylene group and the resulting 6-membered ring may or 
may not carry in position 5 one fluorine atom, a hydroxy group or an oxo 
group, carry two fluorine atoms in one of positions 4 or 5 or be 
unsaturated in position 4 and 5, or carry in position 4 an alkyl group 
with 1 to 4 carbon atoms, or 
Y represents --CH.sub.2 --O--CH.sub.2 --, --CH.sub.2 --S--CH.sub.2 --, 
--CH.sub.2 --SO--CH.sub.2 --, or 
Y represent --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --; 
R.sup.3 is as defined above; 
R.sup.5 represents H or an alkyl group having 1 to 4 carbon atoms, or 
R.sup.5 represents --(CH.sub.2).sub.p --COOR.sup.51, where p is 0, 1 or 2 
and R.sup.51 is H or an alkyl group having 1 to 4 carbon atoms; 
n is an integer 0, 1, 2, 3 or 4; 
B represents a structural fragment of Formula IVa, IVb, IVc or IVd 
##STR4## 
wherein: r is an interger 0 or 1; 
X.sup.1 represent CH.sub.2, NH or is absent; 
X.sup.2 represents CH.sub.2, NH or C.dbd.NH; 
X.sup.3 represents NH, C.dbd.NH, N--C(NH)--NH.sub.2, CH--C(NH)--NH.sub.2, 
CH--NH--C(NH)--NH.sub.2 or CH--CH.sub.2 --C(NH)--NH.sub.2 ; 
X.sup.4 represents CH.sub.2 or NH; 
Preferred combinations of X.sup.1, X.sup.2, X.sup.3, X.sup.4 and r are 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is CH--C(NH)--NH.sub.2 
and r is 0, 1, or, 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is N--C(NH)--NH.sub.2 
and r is 0, 1, or 
X.sup.1 and X.sup.3 are NH, X.sup.2 is C.dbd.NH, X.sup.4 is CH.sub.2 and r 
is 0, 1, or 
X.sup.1 and X.sup.4 are CH.sub.2, X.sup.2 is C.dbd.NH, X.sup.3 is NH and r 
is 0, 1, or 
X.sup.1 is CH.sub.2, X.sup.2 and X.sup.4 are NH, X.sup.3 is C.dbd.NH and r 
is 1, or X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
CH--NH--C(NH)--NH.sub.2 and r is 0, 1, or 
X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
CH--C(NH)--NH.sub.2 and r is 0, or 
X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
N--C(NH)--NH.sub.2 and r is 0; 
Particularly preferred combinations of X.sup.1, X.sup.2, X.sup.3, X.sup.4 
and r are 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is CH--C(NH)--NH.sub.2 
and r is 1; X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
N--C(NH)--NH.sub.2 and r is 0 or 1; 
X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
N--C(NH)--NH.sub.2 and r is 0; 
X.sup.1 and X.sup.3 are NH, X.sup.2 is C.dbd.NH, X.sup.4 is CH.sub.2 and r 
is 1; 
X.sup.5 represents C(NH)--NH.sub.2 or NH--C(NH)--NH.sub.2 ; 
R.sup.6 is H or an alkyl group having 1-4 carbon atoms; 
X.sup.6 represents CH or N; 
Compounds of Formula I having S-configuration on the A.sup.2 amino acid are 
preferred ones, of those compounds also having R-configuration on the 
A.sup.1 amino acid are particularly preferred ones. 
In the present context the term "an alkyl group having 1 to 4 carbon atoms" 
may be straight or branched unless specified otherwise. An alkyl group 
having 1 to 4 carbon atoms may be methyl, ethyl, n-propyl, i-propyl, 
n-butyl, i-butyl, s-butyl and t-butyl. 
In the present context the term "an alkyl group having 1 to 6 carbon atoms" 
may be straigh or branched unless specified otherwise. An alkyl group 
having 1 to 6 carbon atoms may be methyl, ethyl, n-propyl, i-propyl, 
n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, 
neo-pentyl, n-hexyl or i-hexyl. When unsaturation is referred to, a 
carbon-carbon double bond is intended. 
The wavy lines on the carbon atom in the carbonyl group in formulas IIa, 
IIb, IIc, IId, IIe, IIIa, IIIb, IIIc, on the nitrogen atom in formulas 
IIIa, IIIb, IIIc and on the carbon atom in the ring system in formulas 
IVa, IVb, IVc, IVd signfy the bond position of the fragment. 
Abbreviations are listed at the end of this specification. 
According to the invention it has been found that compounds of the general 
Formula Ia, either as such or in the form of physiologically acceptable 
salts, and including stereoisomers, are potent inhibitors of thrombin: 
EQU A.sup.1 --A.sup.2 --NH--(CH.sub.2).sub.n --B Ia 
wherein: 
A.sup.1 represents a structural fragment of Formula IIa, IIb, IIc or IId, 
preferably IIa or IIb; 
wherein: 
k is an integer 0, 1, 2, 3 or 4, preferably 0, 1; 
q is an integer 0, 1, 2 or 3, preferably 1; 
R.sup.1 represents H, an alkyl group having 1 to 4 carbon atoms, R.sup.11 
OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is possibly 
substituted in the position which is alpha to the carbonyl group, and the 
alpha substituent is a group R.sup.17 --(CH.sub.2).sub.p --, wherein p is 
0,1 or 2 and R.sup.17 is methyl, phenyl, OH, COOR.sup.12, CONHR.sup.12, 
where R.sup.12 is H or an alkyl group having 1 to 4 carbon atoms, and 
R.sup.11 is H or an alkyl group having 1 to 6 carbon atoms, or 
R.sup.1 represents Ph(4-COOR.sup.12)--CH.sub.2 --, where R.sup.12 is as 
defined above, or 
R.sup.1 represents R.sup.13 --NH--CO-alkyl-, where the alkyl group has 1 to 
4 carbon atoms and is possibly substituted alpha to the carbonyl with an 
alkyl group having 1 to 4 carbon atoms and where R.sup.13 is H or an alkyl 
group having 1 to 4 carbon atoms or --CH.sub.2 COOR.sup.12 where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.12 OOC--CH.sub.2 --OOC-alkyl-, where the alkyl 
group has 1 to 4 carbon atoms and is possibly substituted alpha to the 
carbonyl with an alkyl group having 1 to 4 carbon atoms and where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.14 SO.sub.2 --, Ph(4-COOR.sup.12)--SO.sub.2 --, 
Ph(3-COOR.sup.12)--SO.sub.2 --, Ph(2-COOR.sup.12)--SO.sub.2 -- where 
R.sup.12 is as defined above and R.sup.14 is an alkylgroup having 1-4 
carbon atoms, or 
R.sup.1 represents --CO--R.sup.15, wherein R.sup.15 is an alkyl group 
having 1-4 carbon atoms, or 
R.sup.1 represents --CO--OR.sup.15, where R.sup.15 is as defined above, or 
R.sup.1 represent --CO--(CH.sub.2).sub.p --COOR.sup.12, where R.sup.12 is 
as defined above and p is an interger 0, 1 or 2, or 
R.sup.1 represents --CH.sub.2 PO(OR.sup.16).sub.2, --CH.sub.2 SO.sub.3 H or 
--CH.sub.2 --(5--(1H)-tetrazolyl), where R.sup.16 is, individually at each 
occurrence, H, methyl or ethyl; 
Preferably R.sup.1 represents R.sup.11 OOC-alkyl-, where the alkyl group 
has 1 to 4 carbon atoms and R.sup.11 is H. 
R.sup.2 represents H or an alkyl group having 1 to 4 carbon atoms, or 
R.sup.21 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and 
R.sup.21 is H or an alkyl group having 1 to 4 carbon atoms; 
R.sup.3 represents an alkyl group having 1-4 carbon atoms, and the alkyl 
group may or may not carry one or more fluorine atoms, or 
R.sup.3 represents a cyclopentyl, cyclohexyl- or a phenyl group which may 
or may not be substituted with an alkyl group having 1 to 4 carbon atoms, 
or 
R.sup.3 represents a 1-naphthyl or 2-naphthyl group and k is 0, 1, or 
R.sup.3 represent a cis- or trans-decalin group and k is 0, 1, or 
R.sup.3 represents Si(Me).sub.3 or CH(R.sup.32).sub.2, wherein R.sup.32 is 
a cyclohexyl- or phenyl group; 
R.sup.4 represents an alkyl group having 1 to 4 carbon atoms, a cyclohexyl 
or a phenyl group, preferably a cyclohexyl or a phenyl group; 
A.sup.2 represents a structural fragment of Formula IIIa, IIIb or IIIc, 
preferably IIIa; 
wherein: 
p is an interger 0, 1 or 2; 
m is an integer 1, 2, 3 or 4, preferably 2, 3; 
Y represents a methylene group, or 
Y represents an ethylene group and the resulting 5-membered ring may or may 
not carry one or two fluorine atoms, a hydroxy group or an oxo group in 
position 4, or may or may not be unsaturated, or 
Y represents --CH.sub.2 --O--, --CH.sub.2 --S--, --CH.sub.2 --SO--, with 
the heteroatom functionality in position 4, or 
Y represents a n-propylene group and the resulting 6-membered ring may or 
may not carry in position 5 one fluorine atom, a hydroxy group or an oxo 
group, carry two fluorine atoms in one of positions 4 or 5 or be 
unsaturated in position 4 and 5, or carry in position 4 an alkyl group 
with 1 to 4 carbon atoms, or 
Y represents --CH.sub.2 --O--CH.sub.2 --, --CH.sub.2 --S--CH.sub.2 --, 
--CH.sub.2 --SO--CH.sub.2 --, or 
Y represent --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --; 
R.sup.3 represents an alkyl group having 1-4 carbon atoms, or 
R.sup.3 represents a Si(Me).sub.3 group; 
R.sup.5 represents H or an alkyl group having 1 to 4 carbon atoms, 
preferably H or a methylgroup, or 
R.sup.5 represents --(CH.sub.2).sub.p --COOR.sup.51, where p is 0, 1 or 2 
and R.sup.51 is H or an alkyl group having 1 to 4 carbon atoms, preferably 
p is 0 and R.sup.51 is H; 
n is an integer 0, 1, 2, 3 or 4, preferably 1, 2, 3; 
B represents a structural fragment of Formula IVa, IVb, IVc or IVd, 
preferably IVa or IVb 
wherein: 
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5 and X.sup.6 are as defined 
above; 
r is an integer 0 or 1; 
R.sup.6 is H or an alkyl group having 1-4 carbon atoms, preferably H; 
preferred combinations of X.sup.1, X.sup.2, X.sup.3, X.sup.4 and r are 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is CH--C(NH)--NH.sub.2 
and r is 0 or 1, or 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is N--C(NH)--NH.sub.2 
and r is 0 or 1, or 
X.sup.1 and X.sup.3 are NH, X.sup.2 is C.dbd.NH, X.sup.4 is CH.sub.2 and r 
is 0 or 1, or 
X.sup.1 and X.sup.4 are CH.sub.2, X.sup.2 is C.dbd.NH, X.sup.3 is NH and r 
is 0 or 1, or 
X.sup.1 is CH.sub.2, X.sup.2 and X.sup.4 are NH, X.sup.3 is C.dbd.NH and r 
is 1, or 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
CH--NH--C(NH)--NH.sub.2 and r=0 or 1, or 
or X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
CH--C(NH)--NH.sub.2 and r is 0, 
or X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
N--C(NH)--NH.sub.2 and r is 0; 
Particularly preferred combinations of X.sup.1, X.sup.2, X.sup.3, X.sup.4 
and r are 
X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
N--C(NH)--NH.sub.2 and r is 0, or 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is CH--C(NH)--NH.sub.2 
and r=1, or 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is N--C(NH)--NH.sub.2 
and r=0 or 1, or 
X.sup.1 and X.sup.3 are NH, X.sup.2 is C.dbd.NH, X.sup.4 is CH.sub.2 r is 
1; 
X.sup.5 represents C(NH)--NH.sub.2 or NH--C(NH)--NH.sub.2, preferably 
C(NH)--NH.sub.2 ; 
X.sup.6 represents CH or N; 
According to a preferred embodiment the invention relates to compounds of 
Formula Ia, 
wherein: 
A.sup.1 represents a structural fragment of Formula IIa, 
wherein: 
k is 0 or 1; 
R.sup.1 represents R.sup.11 OOC-alkyl-, where the alkyl group has 1 to 4 
carbon atoms, particularly methylene, ethylene and R.sup.11 is H; 
R.sup.2 represents H; 
R.sup.3 represents a cyclohexyl group; 
A.sup.2 represents a structural fragment of Formula IIIa, wherein: 
Y represents a methylene group, an ethylene group, or a n-propylene group 
and the resulting 6-membered ring may or may not carry in position 4 an 
alkyl group with 1 to 4 carbon atoms, preferably Y represents methylene, 
ethylene; 
R.sup.5 represents H; 
B represents a structural fragment of formula IVa wherein: 
X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
N--C(NH)--NH.sub.2, r is 0 and n is 1 or 2; 
X.sup.1, and X.sup.3 are NH, X.sup.2 is C.dbd.NH, X.sup.4 is CH.sub.2, r is 
1 and n is 2, or 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is CH--C(NH)--NH.sub.2, 
r is 1 and n is 1, or 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is N--C(NH)--NH.sub.2, r 
is 0 or 1 
and n is 1 or 2, or 
More particularly preferred are compounds wherein B represents a structural 
fragment fo formula IVb wherein: 
X.sup.5 represents C(NH)--NH.sub.2, R.sup.6 is H, and n=1 
Preferred compounds of the invention are: 
HOOC--CH.sub.2 -(R)Cgl-Aze-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cgl-Aze-Pab 
HOOC--CH.sub.2 -(R)Cgl-Pro-Pab 
HOOC--CH.sub.2 -(R)Cgl-Pro-Pab 
(HOOC--CH.sub.2).sub.2 -(R)Cgl-Pro-Pab 
H-(R)Cgl-Pic-Pab 
HOOC--CH.sub.2 -(R,S)CH(COOH)-(R)Cgl-Pic-Pab 
H-(R)Cha-Aze-Pab 
HOOC--CH.sub.2 -(R)Cha-Aze-Pab 
HOOC--CH.sub.2 -(R,S)CH(COOH)-(R)Cha-Aze-Pab 
HOOC--CH.sub.2 -(RorS)CH(COOH)-(R)Cha-Aze-Pab/a 
HOOC--CH.sub.2 -(RorS)CH(COOH)-(R)Cha-Aze-Pab/b 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Aze-Pab 
HOOC--CH.sub.2 --NH--CO--CH.sub.2 -(R)Cha-Aze-Pab 
H-(R)Cha-Pro-Pab 
HOOC--CH.sub.2 -(R)Cha-Pro-Pab 
HOOC--CH.sub.2 -(Me) (R)Cha-Pro-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Pro-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(Me) (R)Cha-Pro-Pab 
HOOC--CH.sub.2 -(RorS)CH(COOH)-(R)Cha-Pro-Pab/a 
HOOC--CH.sub.2 -(RorS)CH(COOH)-(R)Cha-Pro-Pab/b 
HOOC--CH.sub.2 --NH--CO--CH.sub.2 -(R)Cha-Pro-Pab 
EtOOC--CH.sub.2 --CH.sub.2 --CH.sub.2 -(R)Cha-Pro-Pab 
Ph (4-COOH) --SO.sub.2 -(R)Cha-Pro-Pab 
H-(R)Cha-Pic-Pab 
HOOC--CH.sub.2 -(R)Cha-Pic-Pab 
HOOC--CH.sub.2 -(RorS)CH(COOH)-(R)Cha-Pic-Pab/a 
HOOC--CH.sub.2 -(RorS)CH(COOH)-(R)Cha-Pic-Pab/b 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Pic-Pab 
HOOC--CO-(R)Cha-Pic-Pab 
HOOC--CH.sub.2 -C-(R)Cha-Pic-Pab 
Me--OOC--CH.sub.2 --CO-(R)Cha-Pic-Pab 
H.sub.2 N--CO--CH.sub.2 -(R)Cha-Pic-Pab 
Boc-(R)Cha-Pic-Pab 
Ac-(R)Cha-Pic-Pab 
Me-SO.sub.2 -(R)Cha-Pic-Pab 
H-(R)Cha-(R,S)betaPic-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-(R,S) betaPic-Pab 
HOOC--CH.sub.2 -(R)Cha-Val-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Val-Pab 
H-(R)Hoc-Aze-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Hoc-Aze-Pab 
HOOC--CH.sub.2 -(R,S)CH(COOH)-(R)Hoc-Pro-Pab 
HOOC--CH.sub.2 -(R)Hoc-Pic-Pab 
(HOOC--CH.sub.2).sub.2 -(R)Hoc-Pic-Pab 
HOOC--CH.sub.2 -(R)Pro(3-(S)Ph)-Pro-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Pro(3-(S)Ph)-Pro-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Tic-Pro-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cgl-Aze-Pig 
HOOC--CH.sub.2 -(R)Cgl-Pro-Pig 
H-(R)Cha-Aze-Pig 
HOOC--CH.sub.2 -(R)Cgl-Aze-Pac 
H-(R)Cha-Pro-Pac 
H-(R)Cgl-Ile-Pab 
H-(R)Cgl-Aze-Pab 
HOOC-(R,S)CH (Me)-(R)Cha-Pro-Pab 
MeOOC--CH.sub.2 -(R)Cgl-Aze-Pab 
EtOOC--CH.sub.2 -(R)Cgl-Aze-Pab 
.sup.n BuOOC--CH.sub.2 -(R)Cgl-Aze-Pab 
.sup.n HexOOC--CH.sub.2 -(R)Cgl-Aze-Pab 
H-(R)Cgl-Pro-Pac 
HOOC--CH.sub.2 -(R)Cha-Pro-Pac 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cgl-Pro-Pac 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Aze-Pac 
HOOC--CH.sub.2 -(R)Cha-Aze-Pig 
HOOC--CH.sub.2 -(R)Cha-Pro-Pig 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Pro-Pig 
(HOOC--CH.sub.2).sub.2 -(R)Cgl-Pro-Pig 
HOOC--CH.sub.2 --CH.sub.2 (HOOC--CH.sub.2)-(R)Cha-Pro-Pig 
HOOC--CH.sub.2 -(R)Cgl-Aze-(R,S)Itp 
HOOC--CH.sub.2 -(R)Cha-Aze-(R,S)Itp 
H-(R)Cha-Pic-(R,S)Itp 
HOOC--CH.sub.2 -(R)Cha-Pic-(R,S)Itp 
H-(R)Cgl-Pro-(R,S)Hig 
HOOC--CH.sub.2 -(R)Cgl-Pro-(R,S)Hig 
H-(R)Cha-Pro-(R,S)Hig 
H-(R)Cgl-Aze-Rig 
HOOC--CH.sub.2 -(R)Cgl-Aze-Rig 
HOOC--CH.sub.2 -(R)Cha-Pro-Rig 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Aze-Rig 
HOOC--CH.sub.2 -(R)Cha-Pro-(S)Itp 
H-(R)Cha-Pro-(R,S)Nig 
H-(R)Cha-Pro-Mig 
H-(R)Cha-Pro-Dig 
H-(R)Cha-Aze-Dig 
At present the particularly preferred compounds of formula Ia is 
HOOC--CH.sub.2 -(R)Cgl-Aze-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Aze-Pab 
HOOC--CH.sub.2 -(R)Cha-Pro-Pab 
HOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Pro-Pab 
HOOC--CH.sub.2 -(R)Cha-Pic-Pab 
HOOC--CH.sub.2 -(R)Cgl-Pro-Pig 
EtOOC--CH.sub.2 -(R)Cgl-Aze-Pab 
HOOC--CH.sub.2 -(R)Cha-Pro-Pac 
HOOC--CH.sub.2 -(R)Cha-Pro-Pig 
In the above tables of compounds, the letters /a and /b refer to a 
substantially pure stereoisomer at the carbon atom noted "RorS". The 
stereoisomer can be identified for each compound with reference to the 
experimental part herein. "R,S" refers to a mixture of stereoisomers. 
According to the invention it has been found that compounds of the general 
Formula Ib, either as such or in the form of physiologically acceptable 
salts, and including stereoisomers, are potent inhibitors of kininogenases 
: 
EQU A.sup.1 --A.sup.2 --NH--(CH.sub.2).sub.n --B Ib 
wherein: 
A.sup.1 represents a structural fragment of formula IIa, IIb or IIe, 
preferably IIa or IIb; 
wherein: 
k is an integer 0, 1, 2, 3 or 4, preferably 0, 1; 
q is an integer 0, 1, 2, or 3, preferably 1; 
R.sup.1 represents H, an alkyl group having 1 to 4 carbon atoms, or 
R.sup.11 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and is 
possibly substituted in the position which is alpha to the carbonyl group, 
and the alpha substituent is a group R.sup.17 --(CH.sub.2).sub.p --, 
wherein p is 0, 1 or 2 and R.sup.17 is methyl, phenyl, OH, COOR.sup.12, 
CONHR.sup.12, where R.sup.12 is H or an alkyl group having 1 to 4 carbon 
atoms, and R.sup.11 is H or an alkyl group having 1 to 6 carbon atoms, or 
R.sup.1 represents Ph(4-COOR.sup.12)--CH.sub.2 --, where R.sup.12 is H or 
an alkyl group having 1 to 4 carbon atoms, or 
R.sup.1 represents R.sup.13 -NH--CO-alkyl-, where the alkyl group has 1 to 
4 carbon atoms and is possibly substituted alpha to the carbonyl with an 
alkly group having 1 to 4 carbon atoms and where R.sup.13 is H or an alkyl 
group having 1 to 4 carbon atoms or --CH.sub.2 COOR.sup.12 where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.12 OOC--CH.sub.2 --OOC-alkyl-, where the alkyl 
group has 1 to 4 carbon atoms and is possibly substituted alpha to the 
carbonyl with an alkyl group having 1 to 4 carbon atoms and where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.14 SO.sub.2 --, Ph(4-COOR.sup.12)--SO.sub.2 --, 
Ph(3-COOR.sup.12)--SO.sub.2, Ph(2-COOR .sup.2)--SO.sub.2 --, where 
R.sup.12 is as defined above and R.sup.14 is an alkylgroup having 1-4 
carbon atoms, or 
R.sup.1 represents --CO--R .sup.5, wherein R.sup.15 is an alkyl group 
having 1-4 carbon atoms, or 
R.sup.1 represents --CO--OR.sup.15 where R.sup.15 is as defined above, or 
R.sup.1 represent --CO--(CH.sub.2).sub.p --COOR.sup.12, where R.sup.12 is 
as defined above and p is 0, 1 or 2, or 
R.sup.1 represents --CH.sub.2 PO(OR.sup.16).sub.2, --CH.sub.2 SO.sub.3 H or 
--CH.sub.2 --(5-(1H)-tetrazolyl), where R.sup.16 is, individually at each 
occurrence, H, methyl or ethyl; 
R.sup.2 represents H or an alkyl group having 1 to 4 carbon atoms or 
R.sup.21 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and 
R.sup.21 is H or an alkyl group having 1 to 4 carbon atoms; 
R.sup.3 represents an alkyl group having 1-4 carbon atoms, and the alkyl 
group may or may not carry one or more fluorine atoms, or 
R.sup.3 represents a cyclopentyl, cyclohexyl- or a phenyl group which may 
or may not be substituted with an alkyl group having 1 to 4 carbon atoms, 
or 
R.sup.3 represents a phenyl group substituted with a OR.sup.31 group, where 
R.sup.31 is H or an alkyl group having 1 to 4 carbon atoms and k is 0, 1, 
or 
R.sup.3 represents a 1-naphthyl or 1-naphthyl group and k is 0, 1, or 
R.sup.3 represent a cis- or trans-decalin group and k is 0,1, or 
R.sup.3 represents 4-pyridyl, 3-pyrrolidyl or 3-indolyl which may or may 
not be substituted with a OR.sup.31 group, where R.sup.31 is as defined 
above and k is 0, 1, or 
R.sup.3 represents Si(Me).sub.3 or CH(R.sup.32).sub.2, wherein R.sup.32 is 
a cyclohexyl- or phenyl group; 
R.sup.4 represents H, an alkyl group having 1 to carbon atoms, a cyclohexyl 
or a phenyl group, preferably H; 
A.sup.2 represents a structural fragment of formula IIIb or IIIc, 
preferably IIIb 
wherein: 
p is an integer 0, 1 or 2; 
m is an integer 1, 2, 3, or 4, preferably 2, 3; 
R.sup.3 is as defined above; 
n is an integer 0, 1, 2, 3 or 4, preferably 1,2,3; 
B represents a structural fragment of Formula IVa, IVb, IVc or IVd, 
preferably IVa or IVb; 
wherein: 
X.sup.1, X.sup.2, X.sup.3, X.sup.4 are as defined above; 
R.sup.6 is H or an alkyl group having 1-4 carbon atoms, preferably H or a 
methyl group; 
r is an integer 0 or 1; 
preferred combinations of X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is CH--C(NH)--NH.sub.2 
and r is 0 or 1, or 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is N--C(NH)--NH.sub.2 
and r is 0 or 1, or 
X.sup.1 and X.sup.3 are NH, X.sup.2 is C.dbd.NH, X.sup.4 is CH.sub.2 and r 
is 0 or 1, or 
X.sup.1 and X.sup.4 are CH.sub.2, X.sup.2 is C.dbd.NH, X.sup.3 is NH and r 
is 0 or 1, or 
X.sup.1 is CH.sub.2, X.sup.2 and X.sup.4 are NH, X.sup.3 is C.dbd.NH and r 
is 1, or 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
CH--NH--C(NH)--NH.sub.2 and r is 0 or 1, 
or X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
CH--C(NH)--NH.sub.2 and r is 0, or 
X.sup.1 is absent, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is 
N--C(NH)--NH.sub.2 and r is 0; 
particularly preferred combinations of X.sup.1, X.sup.2, X.sup.3 and 
X.sup.4 are 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is CH--C(NH)--NH.sub.2 
and r is 1 or, 
X.sup.1, X.sup.2 and X.sup.4 are CH.sub.2, X.sup.3 is N--C(NH)--NH.sub.2 
and r is 1; 
X.sup.5 represents C(NH)--NH.sub.2 or NH--C(NH)--NH.sub.2, preferably 
C(NH)--NH.sub.2 ; 
X.sup.6 represents CH or N. 
Preferred compound of the invention are: 
H-(R)Pro-Phe-Pab 
HOOC-CH.sub.2 -(R)Pro-Phe-Pab 
H-(R)Phe-Phe-Pab 
HOOC-CO-(R)Phe-Phe-Pab 
HOOC-CH.sub.2 -(R)Phe-Phe-Pab 
H-(R)Cha-Phe-Pab 
HOOC-CH.sub.2 -(R)Cha-Phe-Pab 
H-(R)Phe-Cha-Pab 
HOOC-CH.sub.2 -(R)Phe-Cha-Pab 
H-(R)Cha-Cha-Pab 
HOOC-CH.sub.2 -(R)Cha-Cha-Pab 
Furthermore, it has been found that compounds of the general Formula V, 
either as such or in the form of physiologically acceptable salts, and 
including stereoisomers, are potent inhibitors of serine proteases, 
especially thrombin and kininogenases such as kallikrein after oral or 
parenteral administration: 
EQU A.sup.1 --A.sup.2 --NH--(CH.sub.2).sub.n --B--D Formula V 
wherein: 
A.sup.1 represents a structural fragment of Formula IIa, IIb, IIc, IId or 
IIe; 
##STR5## 
wherein: k is an integer 0, 1, 2, 3 or 4; 
m is an integer 1, 2, 3 or 4; 
q is an integer 0, 1, 2 or 3; 
R.sup.1 represents R.sup.11 OOC-alkyl-, where the alkyl group has 1 to 4 
carbon atoms and is possibly substituted in the position which is alpha to 
the carbonyl group, and the alpha substituent is a group R.sup.17 
--(CH.sub.2).sub.p --, wherein p is 0,1 or 2 and R.sup.17 is COOR.sup.12, 
CONHR.sup.12, where R.sup.12 is H or an alkyl group having 1 to 4 carbon 
atoms or a benzyl group, and R.sup.11 is H or an alkyl group having 1 to 6 
carbon atoms, or a benzyl group, or 
R.sup.1 represents Ph(4-COOR.sup.12)--CH.sub.2 --, where R.sup.12 is as 
defined above, or 
R.sup.1 represents R.sup.13 -NH-CO-alkyl-, where the alkyl group has 1 to 4 
carbon atoms and is possibly substituted alpha to the carbonyl with an 
alkyl group having 1 to 4 carbon atoms and where R.sup.13 is H or an alkyl 
group having 1 to 4 carbon atoms or --CH.sub.2 COOR.sup.12, where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.12 OOC--CH.sub.2 --OOC-alkyl-, where the alkyl 
group has 1 to 4 carbon atoms and is possibly substituted alpha to the 
carbonyl with an alkyl group having 1 to 4 carbon atoms and where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.14 SO.sub.2 --, Ph(4-COOR.sup.12)--SO.sub.2 --, 
Ph(3-COOR.sup.12)--SO.sub.2 --, Ph(2-COOR.sup.12)--SO.sub.2 --, where 
R.sup.12 is as defined above and R.sup.14 is an alkyl group having 1-4 
carbon atoms, or 
R.sup.1 represents --CO--R.sup.15, wherein R.sup.15 is an alkyl group 
having 1-4 carbon atoms, or 
R.sup.1 represents --CO--OR.sup.15, where R.sup.15 is as defined above, or 
R.sup.1 represent --CO--(CH.sub.2).sub.p --COOR.sup.12, where R.sup.12 is 
as defined above and p is an interger 0, 1 or 2, or 
R.sup.2 represents H or an alkyl group having 1 to 4 carbon atoms or 
R.sup.21 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and, 
where R.sup.21 is H, an alkyl group having 1 to 4 carbon atoms or a benzyl 
group; 
R.sup.3 represents an alkyl group having 1-4 carbon atoms, and the alkyl 
group may or may not carry one or more flourine atoms, or 
R.sup.3 represents a cyclopentyl, cyclohexyl- or a phenyl group which may 
or may not be substituted with an alkyl group having 1 to 4 carbon atoms, 
or 
R.sup.3 represents a phenyl group substituted with a OR.sup.31 group, where 
R.sup.31 is H or an alkyl group having 1 to 4 carbon atoms and k is 0, 1, 
or 
R.sup.3 represents a 1-naphthyl or 2-naphthyl group and k is 0, 1, or 
R.sup.3 represent a cis- or trans-decalin group and k is 0, 1, or 
R.sup.3 represents 4-pyridyl, 3-pyrrolidyl or 3-indolyl which may or may 
not be substituted with a OR.sup.31 group, where R.sup.31 is as defined 
above and k is 0, 1, or 
R.sup.3 represents Si(Me).sub.3 or CH(R.sup.32).sub.2, wherein R.sup.32 is 
a cyclohexyl- or a phenyl group; 
R.sup.4 represents H, an alkyl group having 1 to 4 carbon atoms, a 
cyclohexyl- or a phenyl group; 
A.sup.2, B and n are defined as described under Formula I above; 
D is Z or (Z).sub.2 wherein Z represents a benzyloxycarbonyl group. 
The benzyloxycarbonyl group (Z or (Z).sub.2) will bind to the amidino- or 
guanidino nitrogens present in B. 
Preferred and particularly preferred combinations are the same as described 
for Formula I above. 
Furthermore, it has been found that compounds of the general Formula Va, 
either as such or in the form of physiologically acceptable salts, and 
including stereoisomers, are potent inhibitors of thrombin after oral or 
parenteral administration: 
EQU A.sup.1 --A.sup.2 --NH--(CH.sub.2).sub.n --B--D Formula Va 
wherein: 
A.sup.1 represents a structural fragment of Formula IIa, IIb, IIc or IId, 
preferably IIa or IIb; 
wherein: 
k is an integer 0, 1, 2, 3 or 4, preferably 0, 1; 
q is an integer 0, 1, 2 or 3, preferably 1; 
R.sup.1 represents R.sup.11 OOC-alkyl-, where the alkyl group has 1 to 4 
carbon atoms and is possibly substituted in the position which is alpha to 
the carbonyl group, and the alpha substituent is a group R.sup.17 
--(CH.sub.2).sub.p --, wherein p is 0,1 or 2 and R.sup.17 is COOR.sup.12, 
CONHR.sup.12, where R.sup.12 is H, an alkyl group having 1 to 4 carbon 
atoms or a benzyl group, and R.sup.11 is H or an alkyl group having 1 to 6 
carbon atoms, or a benzyl group, or 
R.sup.1 represents Ph(4-COOR.sup.12)--CH.sub.2 --, where R.sup.12 is as 
defined above, or 
R.sup.1 represents R.sup.13 --NH--CO-alkyl-, where the alkyl group has 1 to 
4 carbon atoms and is possibly substituted alpha to the carbonyl with an 
alkyl group having 1 to 4 carbon atoms and where R.sup.13 is H or an alkyl 
group having 
1 to 4 carbon atoms or --CH.sub.2 COOR.sup.12 where R.sup.12 is as defined 
above, or 
R.sup.1 represents R.sup.12 OOC--CH.sub.2 --OOC-alkyl-, where the alkyl 
group has 1 to 4 carbon atoms and is possibly substituted alpha to the 
carbonyl with an alkyl group having 1 to 4 carbon atoms and where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.14 SO.sub.2 -, Ph(4-COOR.sup.12)-SO.sub.2 -, 
Ph(3-COOR.sup.12)-SO.sub.2 -, Ph(2-COOR.sup.12)-SO.sub.2 - where R.sup.12 
is as defined above and R.sup.14 is an alkylgroup having 1-4 carbon atoms, 
or 
R.sup.1 represents -CO-R.sup.15, wherein R.sup.15 is an alkyl group having 
1-4 carbon atoms, or 
R.sup.1 represents -CO-OR.sup.15, where R.sup.15 is as defined above, or 
R.sup.1 represent -CO-(CH.sub.2).sub.p -COOR.sup.12, where R.sup.12 is as 
defined above and p is an interger 0, 1 or 2, or 
Preferably R.sup.1 represents R.sup.11 OOC-alkyl-, where the alkyl group 
has 1 to 4 carbon atoms and R.sup.11 is as defined above. 
R.sup.2 represents H or an alkyl group having 1 to 4 carbon atoms, or 
R.sup.21 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and 
R.sup.21 is H or an alkyl group having 1 to 4 carbon atoms or a benzyl 
group; 
R.sup.3 represents an alkyl group having 1-4 carbon atoms, and the alkyl 
group may or may not carry one or more fluorine atoms, or 
R.sup.3 represents a cyclopentyl, cyclohexyl- or a phenyl group which may 
or may not be substituted with an alkyl group having 1 to 4 carbon atoms, 
or 
R.sup.3 represents a 1- naphthyl or 2-naphthyl group and k is 0, 1, or 
R.sup.3 represent a cis- or trans-decalin group and k is 0, 1, or 
R.sup.3 represents Si(Me).sub.3 or CH(R.sup.32).sub.2, wherein R.sup.32 is 
a cyclohexyl- or phenyl group; 
R.sup.4 represents an alkyl group having 1 to 4 carbon atoms, a cyclohexyl 
or a phenyl group, preferably a cyclohexyl or a phenyl group; 
A.sup.2, B and n are defined as described under Formula Ia above; 
D is Z or (Z).sub.2 ; 
Z represents a benzyloxycarbonyl group. 
Preferred integers, groups or combinations and particularly preferred 
combinations are the same as described for Formula Ia above but R.sup.11 
is H, an alkyl group having 1 to 6 carbon atoms or a benzyl group. 
Preferred compounds having Formula Va are: 
BnOOC--CH.sub.2 -(R)Cgl-Aze-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cgl-Aze-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cgl-Pro-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cgl-Pro-Pab(Z) 
(BnOOC--CH.sub.2).sub.2 -(R)cgl-Pro-Pab(Z) 
BnOOC--CH.sub.2 -(R,S)CH (COOBn)-(R)Cgl-Pic-Pab (Z) 
BnOOC--CH.sub.2 -(R)Cha-Aze-Pab (Z) 
BnOOC--CH.sub.2 -(R,S)CH(COOBn)-(R)Cha-Aze-Pab(Z) 
BnOOC--CH.sub.2 -(RorS)CH(COOBn)-(R)Cha-Aze-Pab(Z)/a 
BnOOC-Ch.sub.2 -(RorS)CH(COOBn)-(p) cha-Azc-Pab(Z)/b 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Aze-Pab (Z) 
BnOC--CH.sub.2 --Ni--CO--CH.sub.2 -(R)Cha-Aze-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pro-Pab(Z) 
BnOOC--CH.sub.2 -(Me) (R)Cha-Pro-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Pro-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(Me)(R)Cha-Pro-Pab(Z) 
BnOOC--CH.sub.2 -(R,S)CH(COOBn)-(R)Cha-Pro-Pab(Z) 
BnOOC--CH.sub.2 --NH--CO--CH.sub.2 -(R)Cha-Pro-Pab (Z) 
Ph (4-COOH)--SO.sub.2 -(R)Cha-Pro-Pab (Z) 
Boc-(R)Cha-Pic-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pic-Pab(Z) 
BnOOC--CH.sub.2 -(R,S)CH(COOBn)-(R)Cha-Pic-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Pic-Pab(Z) 
EtOOC-CO-(R)Cha-Pic-Pab(Z) 
MeOOC--CH.sub.2 --CO-(R)Cha-Pic-Pab (Z) 
H.sub.2 N--CO--CH.sub.2 -(R)Cha-Pic-Pab(Z) 
Ac-(R)Cha-Pic-Pab(Z) 
Me-SO.sub.2 -(R)Cha-Pic-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cha-Val-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cha-(R,S) Val-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Hoc-Aze-Pab (Z) 
BnOOC--CH.sub.2 -(R,S)CH(COOBn)-(R)Hoc-Pro-Pab(Z) 
BnOOC--CH.sub.2 -(R)Hoc-Pic-Pab(Z) 
(BnOOC--CH.sub.2).sub.2 -(R)Hoc-Pic-Pab(Z) 
BnOOC--CH.sub.2 -(R)Pro(3-(S)Ph)-Pro-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R) Pro(3-(S) Ph)-Pro-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R) Tic-Pro-Pab(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cgl-Aze-Pig (Z).sub.2 
BnOOC--CH.sub.2 -(R)Cgl-Pro-Pig(Z)2 
BnOOC--CH.sub.2 -(R)Cgl-Aze-Pac (Z) 
BnOOC-(R,S)CH(Me)-(R)Cha-Pro-Pab(Z) 
MeOOC--CH.sub.2 -(R)Cgl-Aze-Pab(Z) 
EtOOC--CH.sub.2 -(R)Cgl-Aze-Pab(Z) 
.sup.n BuOOC--CH.sub.2 -(R)Cgl-Aze-Pab(Z) 
.sup.n HexOOC--CH.sub.2 -(R)Cgl-Aze-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pro-Pac(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cgi-Prc-Pac(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Aze-Pac(Z) 
BnOOC--CH.sub.2 -(R)Cha-Aze-Pig(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pro-Pig(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Pro-Pig(Z) 
(BnOOC--CH).sub.2 -(R)Cgl-Pro-Pig(Z) 
BnOOC--CH.sub.2 --CH.sub.2 (BnOOC--CH.sub.2)-(R)Cha-Pro-Pig(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pic-(R,S)Itp(Z) 
BnOOC--CH.sub.2 -(R)Cgl-Pro-(R,S)Hig(Z) 
BnOOC--CH.sub.2 -(R)Cgl-Aze-Rig(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pro-Rig(Z) 
BnOOC--CH.sub.2 --CH.sub.2 -(R)Cha-Aze-Rig(Z) 
Particularly preferred compounds are: 
BnOOC--CH.sub.2 -(R)Cgl-Aze-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pro-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pic-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cgl-Pro-Pig(Z).sub.2 
EtOOC--CH.sub.2 -(R)Cgl-Aze-Pab(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pro-Pac(Z) 
BnOOC--CH.sub.2 -(R)Cha-Pro-Pig(Z) 
Furthermore, it has been found that compounds of the general Formula Vb, 
either as such or in the form of physiologically acceptable salts, and 
including stereoisomers, are potent inhibitors of kallikrein after oral or 
parenteral administration: 
EQU A.sup.1 --A.sup.2 --NH --(CH.sub.2).sub.n --B--D Formula Vb 
wherein: 
A.sup.1 represents a structural fragment of formula IIa, IIb or IIe, 
preferably IIa or IIb; 
wherein: 
k is an integer 0, 1, 2, 3 or 4, preferably 0, 1; 
q is an integer 0, 1, 2, or 3, preferably 1; 
R.sup.1 represents R.sup.11 OOC-alkyl-, where the alkyl group has 1 to 4 
carbon atoms and is possibly substituted in the position which is alpha to 
the carbonyl group, and the alpha substituent is a group R.sup.17 
--(CH.sub.2)p-, wherein p is 0, 1 or 2 and R.sup.17 is COOR.sup.12, 
CONHR.sup.12, where R.sup.11 is H or an alkyl group having 1 to 4 carbon 
atoms, and R.sup.11 is H or an alkyl group having 1 to 6 carbon atoms, or 
a benzyl group, or 
R.sup.1 represents Ph(4-COOR.sup.12)--CH.sub.2 -, where R.sup.12 is as 
defined above, or 
R.sup.1 represents R.sup.13 --NH--CO-alkyl-, where the alkyl group has 1 to 
4 carbon atoms and is possibly substituted alpha to the carbonyl with an 
alkyl group having 1 to 4 carbon atoms and where R.sup.13 is H or an alkyl 
group having 1 to 4 carbon atoms or --CH.sub.2 COOR.sup.12 where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.12 OOC--CH.sub.2 --OOC-alkyl-, where the alkyl 
group has 1 to 4 carbon atoms and is possibly substituted alpha to the 
carbonyl with an alkyl group having 1 to 4 carbon atoms and where R.sup.12 
is as defined above, or 
R.sup.1 represents R.sup.14 SO.sub.2 --, Ph(4-COOR.sup.12) --SO.sub.2 --, 
Ph(3-COOR.sup.12)--SO.sub.2, Ph(2-COOR.sup.12)--SO.sub.2 --, where 
R.sup.12 is as defined above 
and R.sup.14 is an alkylgroup having 1-4 carbon atoms, or 
R.sup.1 represents --CO--R.sup.15, wherein R.sup.15 is an alkyl group 
having 1-4 carbon atoms, or 
R.sup.1 represents --CO--OR.sup.15, where R.sup.15 is as defined above, or 
R.sup.1 represent --CO--(CH.sub.2).sub.p -COOR.sup.12, where R.sup.12 is as 
defined above and p is 0, 1 or 2, or 
R.sup.2 represents H or an alkyl group having 1 to 4 carbon atoms or 
R.sup.21 OOC-alkyl-, where the alkyl group has 1 to 4 carbon atoms and 
R.sup.21 is H, an alkyl group having 1 to 4 carbon atoms or a benzyl 
group; 
R.sup.3 represents an alkyl group having 1-4 carbon atoms, and the alkyl 
group may or may not carry one or more fluorine atoms, or 
.sup.3 represents a cyclopentyl, cyclohexyl- or a phenyl group which may or 
may not be substituted with an alkyl group having 1 to 4 carbon atoms, or 
R.sup.3 represents a phenyl group substituted with a OR.sup.31 group, where 
R.sup.31 is H or an alkyl group having 1 to 4 carbon atoms and k is 0, 1, 
or 
R.sup.3 represents a 1-naphthyl or 1-naphthyl group and k is 0, 1, or 
R.sup.3 represent a cis- or trans-decalin group and k is 0,1, or 
R.sup.3 represents 4-pyridyl, 3-pyrrolidyl or 3-indolyl which may or may 
not be substituted with a oR.sup.31 group, where R.sup.31 is as defined 
above and k is 0, 1, or 
R.sup.3 represents Si(Me).sub.3 or CH(R.sup.32).sub.21 wherein R.sup.32 is 
a cyclohexyl- or phenyl group; 
R.sup.4 represents H, an alkyl group having 1 to carbon atoms, a cyclohexyl 
or a phenyl group, preferably H; 
A.sup.2, B and n are defined as described under Formula Ib above; 
D represents Z or (Z).sub.2. 
Preferred integers, groups or combinations and particularly preferred 
combinations are the same as described in Formula Ib above but R.sup.11 is 
H. an alkyl group having 1 to 6 carbon atoms or a benzyl group. 
Preferred compounds having Formula Vb are: 
Boc-(R) Pro-Phe-Pab(Z) 
BnOOC-CH.sub.2 -(R)Pro-Phe-Pab(Z) 
Boc-(R) Phe-Phe-Pab(Z) 
MeOOC--CO-(R)Phe-Phe-Pab(Z) 
BnOOC-CH.sub.2 -(R)Phe-Phe-Pab (Z) 
In a further embodiment the invention relates to novel use of a compound of 
the formula: 
##STR6## 
as a starting material in synthesis of a peptidic serine protease 
inhibitor, and in particular in synthesis of peptidic thrombin inhibitors 
or kininogenases inhibitors. It can be used as such or having the amidino 
group either mono- or diprotected at the nitrogens with a protective group 
such as benzyloxy carbonyl. Protection of the amidino derivatives is 
carried out by methods known in the art for amidino compounds. This 
compound is named "1-amidino-4-aminomethylbenzene " or "H-Pab" herein. The 
compound has been previously disclosed in inter alia Biochem. Pharm. vol 
23, p. 2247-2256. 
The structural fragment of the formula 
##STR7## 
has however not been previously disclosed as a structural element in a 
pharmaceutically active compound, especially a peptic compound. The 
fragment renders a serine protease inhibitor, and in particular a thrombin 
inhibitor or kininogenases inhibitor valuable. 
In a further embodiment the invention relates to novel use of a compound of 
the formula: 
##STR8## 
as a starting material in synthesis of a thrombin inhibitor. The compound 
may have the amidino group either mono- or diprotected at the nitrogens 
with a protective group such as benzyloxy carbonyl. Protection of the 
amidino derivatives is carried out by methods known in the art for amidino 
compounds. This compound is named "1-amidino-4-aminomethyl cyclohexane" or 
"H-Pac" herein. 
The compound has been previously disclosed in DE 2748295. 
The structural fragment of the formula 
##STR9## 
has however not been previously disclosed as a structural element in a 
thrombin inhibitor valuable. 
In a further embodiment the invention relates to a novel compound of the 
formula: 
##STR10## 
and the use of said compound as a starting material in synthesis of a 
serine protease inhibitor, especially a thrombin inhibitor or kininogenase 
inhibitor. The compound may have the amidino group either mono- or 
diprotected at the nitrogens with a protective group such as benzyloxy 
carbonyl. Protection of the amidino derivatives is carried out by methods 
known in the art for amidno compounds. This compound is named "4- 
aminoethyl-1-amidino piperidine" or "H-Rig" herein. 
The structural fragment of the formula 
##STR11## 
has however not been previously disclosed as a structural element in a 
pharmaceutically active compound, especially a peptic compound. The 
fragment renders a serine protease inhibitor, and in particular a thrombin 
inhibitor or kininogenases inhibitor varuable. 
In a further embodiment the invention relates to a novel compound of the 
formula: 
##STR12## 
and the use of said compound as a starting material in synthesis of a 
serine protease inhibitor especially a thrombin inhibitor or kininogenase 
inhibitor. The compound may have the amidino group either mono- or 
diprotected at the nitrogens with a protective group such as benzyloxy 
carbonyl. Protection of the amidino derivatives is carried out by methods 
known in the art for amidino compounds. This compound is named "1,3- 
diaza-2-imino-4-aminoethyl cyclohexane" or "H-Itp" herein. 
The structural fragment of the formula 
##STR13## 
has however not been previously disclosed as a strucural element in a 
pharmaceutically active compound, especially a peptic compound. The 
fragment renders a serine protease inhibitor, and in particular a thrombin 
inhibitor or kiniogenases inhibitor varuable. 
In a further embodiment the invention relates to novel compounds of the 
formula: 
##STR14## 
where n is 1 or 2 
s is 0 ro 1, 
and the use of said compounds as a starting material in synthesis of serine 
protease inhibitors, especially thrombin inhibitors or kininogenases 
inhibitors. The compound may have the amidino group either mono- or 
diprotected at the nitrogens with a protective group such as benzyloxy 
carbonyl. Protection of the amidino derivatives is carried out by methods 
known in the art for amidino compounds. These compounds are named: 
1-amidino-3-aminomethyl pyrrolidine or "H-Nig" when n is 1 and s is 1 
1-amidino-3-aminoethyl pyrrolidine or "H-Hig" when n is 2 and s is 1 
3-aminomethyl-1-amidino azetidine or "H-Mig" when n is 1 and s is 0 
3-aminoethyl-1-amidino azetidine or "H-Dig" when n is 2 and s is 0 
The structural fragment of the formula 
##STR15## 
has however not been previously disclosed as a structural element in a 
pharmaceutically active compound, especially a peptic compound. The 
fragment renders a serine protease inhibitor, and in particular a thrombin 
inhibitor or kininogenases inhibitor valuable. 
A further embodiment of the invention are the novel compounds having the 
amidino group mono- or di-protected at the nitrogens with a benzyloxy 
carbonyl group, examples of such compounds are 
4-aminomethyl-1-(N-benzyloxycarbonylamidino) benzene (H-Pab(Z)), 
4-aminomethyl-1-(N,N'-di(benzyloxycarbonyl)amidino) benzene 
(H-Pab(Z).sub.2), 
4-aminomethyl-1-(N-benzyloxycarbonylamidino) cyclohexane (H-Pac(Z)), 
4-aminomethyl-1-(N,N'-di(benzyloxycarbonyl)amidino) cyclohexane 
(H-Pac(Z).sub.2), 
4-aminoethyl-1-(N-benzyloxy-carbonylamidino piperidine (H-Rig(Z)), 
4-aminoethyl-1-N,N'-di(benzyloxycarbonyl)amidino piperidine 
(H-Rig(Z).sub.2), 
(3RS) -1-(N-benzyloxycarbonylamidino) -3-aminomethyl pyrrolidine 
(H-Nig(Z)), 
(3RS)-1-(N,N'-di(benzyloxycarbonyl)amidino)-3-aminonethyl pyrrolidine 
(H-Nig(Z).sub.2), 
(3RS)-1-(N-benzyloxycarbonylamidino)-3-aminoethyl pyrrolidine (H-Hig(Z)), 
(3RS)-1-(N,N'-di(benzyloxycarbonyl)amidino)-3-aminoethyl pyrrolidine 
(H-Hig(Z).sub.2), 
3-aminomethyl-1-(N-benzyloxycarbonylamidino) azetidine (H-Hig(Z)), 
3-aminomethyl-1-(N,N'-di(benzyloxycarbonyl)amidino) azetidine 
(H-Mig(Z).sub.2), 
3-aminoethyl-1-(N-benzyloxycarbonylamidino) azetidine (H-Dig(Z)), 
3-aminoethyl-1-(N,N'-di(benzyloxycarbonyl)amidino) azetidine 
(H-Dig(Z).sub.2), 
Said compounds are used as starting materials in the preparation of the 
claimed peptide derivatives of formulas I, Ia, Ib, V, Va and Vb. 
Medical and Pharmaceutical Use 
The invention also provides compositions and methods for the treatment, in 
a human or animal organism, of conditions where inhibition of thrombin is 
required and of physiologically disorders especially inflammatory 
diseases. 
The thrombin inhibiting compounds of the invention are expected to be 
useful in particular in animals including man in treatment or prophylaxis 
of thrombosis and hypercoagulability in blood and tissues. They are 
furthermore expected to be useful in situations where there is an 
undesirable excess of the thrombin without signs of hypercoagulability, 
for example as in Alzheimers disease and pancreatitis. Disease states in 
which these compounds have a potential utility, in treatment and/or 
prophylaxis, include venous thrombosis and pulmonary embolism, arterial 
thrombosis, such as in myocardial infarction, unstable angina, 
thrombosis-based stroke and peripheral arterial thrombosis and systemic 
embolism usually from the atrium during arterial fibrillation or fror the 
left ventricule after transmural myocardial infarction. Further, these 
compounds have expected utility in prophylaxis of athercsclerotic diseases 
such as coronarv arterial disease, cerebral arterial disease and 
peripheral arterial disease. Further, these compounds are expected to have 
synergistic antithrombotic effects when combined with any antithrombotic 
agent with a different mechanism of action, such as the antiplatelet agent 
acetylsalicylic acid. Further, these compounds are expected to be useful 
together with thrombolytics in thrombotic diseases, in particular 
myocardial infarction. Further, these compounds have expected utility in 
prophylaxis for re-occlusion after thrombolysis, percutaneous 
trans-luminal angioplasty (PTCA) and coronary bypass operations. Further, 
these compounds have expected utility in prevention of re-thrombosis after 
microsurgery and vascular surgery in general. Further, these compounds 
have expected utility in treatment and prophylaxis of disseminated 
intravascular coagulation caused by bacteria, multiple trauma, 
intoxication or any other mechanism. Further, these compounds are expected 
to be useful in anticoagulant treatment when blood is in contact with 
foreign surfaces in the body such as vascular grafts, vasculars stemts, 
vascular catheters, mechanical and biological prosthetic or any other 
medical device. Further, these compounds have expected utility in 
anticoagulant treatment when blood is in contact with medical devices 
outside the body such as during cardiovascular surgery using or heart-lung 
machine or in haemodialysis. 
A further expected utility of the anticoagulant compounds of the invention 
are in rinsing of catheters and mechanical devises used in patients in 
vivo, and as anticoagulants for preservation of blood, plasma and other 
blood products in vitro. 
The antiinflammatory inhibiting compounds of the invention are expected to 
be useful in particular in animals including man in treatment or 
prophylaxis of inflammatory diseases such as asthma, rhinitis, 
pancreatitis, uticaria, inflammatory bowel diseases, and arthritis. An 
effective amount of kininogenase inhibiting compounds with or without a 
physiologically acceptable carrier or diluent can be used solely or in 
combination with other therapeutic agents. 
The compounds inhibit the activity of kallikreins assessed with chromogenic 
substrates according to known procedures. The anti-inflammatory actions of 
the present compounds can for example be studied by their inhibition of 
allergen-induced exudative inflammatory processes in airway mucosa or gut 
mucosa. 
Pharmaceutical Preparations 
The compounds of the invention will normally be administered orally, 
rectally, dermally, nasally, tracheally, bronchially, parenterally or via 
inhalation route, in the form of pharmaceutical preparations comprising 
the active ingredient either as a free base or a pharmaceutical acceptable 
non-toxic organic or inorganic acid addition salt, e.g. the hydrochloride, 
hydrobromide, sulphate, hydrosulphate, nitrate, lactate, acetate, citrate, 
bensoate, succinate, tartrate, trifluoroacetate and the like in a 
pharmaceutically acceptable dosage form. Depending upon the disorder and 
patient to be treated and the route of administration, the compositions 
may be administered at varying doses. 
The dosage form may be a solid, semisolid or liquid preparation prepared by 
per se known techniques. Usually the active substance will constitute 
between 0.1 and 99% by weight of the preparation, more specifically 
between 0.1 and 50% by weight for preparations intended for parenteral 
administration and between 0.2 and 75% by weight for preparations suitable 
for oral administration. 
Suitable daily doses of the compounds of the invention in therapeutical 
treatment of humans are about 0.001-100 mg/kg body weight at peroral 
administration and 0.001-50 mg/kg body weight at parenteral 
administration. 
Preparation 
A further objective of the invention is the mode of preparation of the 
compounds. The compounds of Formula I and V may be prepared by processes 
comprise coupling of an N-terminally protected dipeptide or aminoacid, 
when a N-terminally amino acid is used a second aminoacid is added 
afterwards using standard methods to a compound 
EQU H.sub.2 N--(CH.sub.2)n--X 
wherein n is an integer 0, 1, 2, 3 or 4, X is B or B-D where B is as 
defined in formula I and D is as defined in formula V as such or having 
the guanidino or amidino nitrogens either mono or diprotected with an amin 
protecting group such as a benzyloxy carbonyl-, tert-butyloxy carbonyl- or 
p-toluenesulphonyl- group or X is a group transferable into B followed by 
removal of the protectary group(s) or deprotection of the N-terminal 
nitrogen followed by alkylation of the N-terminal nitrogen and if desired 
deprotection by known methods and if desired forming a physiologically 
acceptable salt, and in those cases where the reaction results in a 
mixture of stereoisomers, these are optionally separated by standard 
chromatographic or re-crystallisation techniques, and if desired a single 
stereoisomer is isolated. 
In more detail the compounds of Formula I or V may be prepared by either of 
the following methods: 
Method Ia 
Coupling of an N-terminally protected dipeptide, selected from A.sup.1 and 
A.sup.2 in Formulas I or V and prepared by standard peptide coupling, with 
a compound 
##STR16## 
using standard peptide coupling,shown in the formula 
##STR17## 
wherein n is as defined in Formula I W.sup.1 is an N-teminal amino 
protecting group such as tert-butyloxy carbonyl and berzyloxy carbonyl and 
and Q.sup.1 is --C(NH)-NH.sub.2, --C(NW.sup.2) --NH--W.sup.2, 
--C(NH)--NH--W.sup.2, --NH--C(NH)--NH.sub.2, --NH--C(NH)--NH--W.sup.2, 
--N(W.sup.2)--C(NH)--NH--W.sup.2 or --NH--C(NW.sup.2)--NH--W.sup.2, where 
W.sup.2 is an amine protecting group such as tert-butyloxy carbonyl or 
benzyloxy carbonyl, or Q.sup.1 is --CN, --CO--NH.sub.2 or --CS--NH.sub.2, 
where the group is subsequently transferred into a amidino group (e.g 
giving Q.sup.1 =--C(NH)--NH.sub.2) by methods known in the art or Q.sup.1 
is NH.sub.2 or NH-W.sup.2, where w.sup.2 is as defined above, where the 
amino group is subsequently transferred into a guanidino group (giving 
Q.sup.1 =--NH--C(NH)--NH.sub.2), after deprotection of the W.sup.2 -group 
when Q.sup.1 is --NH--W.sup.2 (W.sup.2 in this case must be orthogonal to 
W.sup.1 ), by methods known in the art. 
The final compounds can be made in any of the following ways, depending on 
the nature of the Q.sup.1 --group used: Removal of the protecting group(s) 
(when Q.sup.1 =--C(NH)--NH.sub.2, --C(NW.sup.2)--NH--W.sup.2, 
--C(NH)--NH--W.sup.2, --NH--C(NH)--NH.sub.2, --NH--C(NH)--NH--W.sup.2, 
--N(W.sup.2)--C(NH)--NH--W.sup.2 or --NH--C(NW.sup.2)--NH--W.sup.2), or a 
selective deprotection of the W.sup.1 - group (e.g when Q.sup.1 
=--C(NW.sup.2)--NH--W.sup.2, --C(NH)--NH--W.sup.2, 
--NH--C(NH)--NH--W.sup.2, --N(W.sup.2)--C(NH)--NH--W.sup.2 or 
--NH--C(NW.sup.2)--NH--W.sup.2 (W.sup.2 in this case must be orthogonal to 
W.sup.1) followed by alkylation of the N-terminal nitrogen by methods 
known in the art and if desired deprotection by known methods. 
Method Ib 
Coupling of an N-terminally protected amino acid,selected from A.sup.2 in 
Formulas I or V and prepared by standard methods, with a compound of 
formula 
##STR18## 
using standard peptide coupling, shown in the formula 
##STR19## 
wherein n, W.sup.1, and Q.sup.1 are as defined above followed by 
deprotection of the W.sup.1 -group and coupling with the N-terminal amino 
acid, in a protected form, leading to the protected peptide described in 
Method Ia. The synthesis to the final peptides is then continued according 
to Method Ia. 
Method IIa 
Coupling of an N-terminally protected dipeptide, selected from A.sup.1 and 
A.sup.2 in Formulas I or V and prepared by standard peptide coupling, with 
a compound 
##STR20## 
using standard peptide coupling,shown in the formula 
##STR21## 
wherein n is as defined in Formula I, W.sup.1 is an N-teminal amino 
protecting group such as tertbutyloxy carbonyl and benzyloxy carbonyl and 
and Q.sup.1 is --C(NH)--NH.sub.2, --C(NW.sup.2)--NH--W.sup.2, 
--C(NH)--NH--W.sup.2, --NH--C(NH)--NH.sub.2, --NH--C(NH)--NH--W.sup.2, 
--N(W.sup.2)--C(NH)--NH--W.sup.2 or --NH--C(NW.sup.2)--NH--W.sup.2 , where 
W.sup.2 is an amine protecting group such as tert-butyloxy carbonyl or 
benzyloxy carbonyl, or Q.sup.1 is --CN, --CO--NH.sub.2 or --CS--NH.sub.2, 
where the group is subsequently transferred into a amidino group (e.g 
giving Q.sup.1 =--C(NH)--NH.sub.2) by methods known in the art or Q.sup.1 
is NH.sub.2 or NH--W.sup.2, where W.sup.2 is as defined above, where the 
amino group is subsequently transferred into a guanidino group (giving 
Q.sup.1 =--NH--C(NH)--NH.sub.2), after deprotection of the W.sup.2 -group 
when Q.sup.1 is --NH--W.sup.2 (W.sup.2 in this case must be orthogonal to 
W.sup.1) by methods known in the art. 
The final compounds can be made in any of the following ways, depending on 
the nature of the Q.sup.1 --group used: Removal of the protecting group(s) 
(when Q.sup.1 =--C(NH)--NH.sub.2, --C(NW.sup.2)--NH--W.sup.2, 
--C(NH)--NH--W.sup.2, --NH--C(NH)--NH.sub.2, --NH--C(NH)--NH--W.sup.2 , 
--N(W.sup.2)--C(NH)--NH--W.sup.2 or --NH--C(NW.sup.2)--NH--W.sup.2), or a 
selective deprotection of the W.sup.1 - group (e.g when Q.sup.1 
=--C(NW.sup.2)--NH--W.sup.2, C(NH)--NH--W.sup.2, --NH--C(NH)--NH--W.sup.2, 
--N(W.sup.2)--C(NH)--NH--W.sup.2 or --NH--C(NW.sup.2)--NH--W.sup.2 (W2 in 
this case must be orthogonal to W.sup.1) followed by alkylation of the 
N-terminal nitrogen by methods known in the art and if desired 
deprotection by known methods. 
Method IIb 
Coupling of an N-terminally protected amino acid, selected from A.sup.2 in 
Formulas I or V and prepared by standard methods, with a compound of 
formula 
##STR22## 
using standard peptide coupling, shown in the formula 
##STR23## 
wherein n, W.sup.1 and Q.sup.1 are as defined above followed by 
deprotection of the W.sup.1 -group and coupling with the N-terminal amino 
acid, in a protected form, leading to the protected peptide described in 
Method IIa. The synthesis to the final peptides is then continued 
according to Method IIa. 
Method IIIa 
Coupling of an N-terminally protected dipeptide, selected from A.sup.1 and 
A.sup.2 in Formulas I or V and prepared by standard peptide coupling, with 
a compound 
##STR24## 
using standard peptide coupling,shown in the formula 
##STR25## 
wherein n is as defined in Formula I and r is 0.1 when X.sup.1, x.sup.2 
and X.sup.4 are CH.sub.2 or r is 0 when X.sup.2 and X.sup.4 are CH.sub.2 
and X.sup.1 is abscent, W.sup.1 is an N-teminal amino protecting group 
such as tert-butyloxy carbonyl and benzyloxy carbonyl and and Q.sup.2 is 
--C(NH)--NH.sub.2, --C(NW.sup.2)--NH--W.sup.2, or --C(NH)--NH--W.sup.2 , 
where W.sup.2 is an amine protecting group such as tert-butyloxy carbonyl 
or benzyloxy carbonyl, or Q.sup.2 is equal to W.sup.2 where the amino 
group, after deprotection of the W.sup.2 group (W.sup.2 in this case must 
be orthogonal to W.sup.1),is subsequently transferred into a guanidino 
group using a unprotected, N-protected or N,N'-diprotected guanidation 
reagent by methods known in the art (giving Q2=--C(NH)--NH.sub.21 
--C(NW.sup.2)--NH--W.sup.2 or --C(NH)--NH--W.sup.2). 
The final compounds can be made in any of the following ways, depending on 
the nature of the Q.sup.2 --group used: Removal of the protecting group(s) 
(when Q.sup.2 =--C(NH)--NH.sub.2, --C(NW.sup.2)--NH--W.sup.2 or 
--C(NH)--NH--W.sup.2), or a selective deprotection of the W.sup.1 --group 
(e.g when Q.sup.2 =--C(NW.sup.2)--NH--W.sup.2, --C(NH)--NH--W.sup.2 
,W.sup.2 in this case must be orthogonal to W.sup.1) followed by 
alkylation of the N-terminal nitrogen by methods known in the art and if 
desired deprotection known methods. 
Method IIIb 
Coupling of an N-terminally protected amino acid,selected from A.sup.2 in 
Formulas I or V and prepared by standard methods, with a compound of 
formula 
##STR26## 
using standard peptide coupling, shown in the formula 
##STR27## 
wherein n, r, X.sup.1, X.sup.2 and X.sup.4, W.sup.1, and Q.sup.2 are as 
defined above followed by deprotection of the W.sup.1 -group and coupling 
with the N-terminal amino acid, in a protected form, leading to the 
protected peptide described in Method IIIa. The synthesis to the final 
peptides is then continued according to Method IIIa. 
Method IVa 
Coupling of an N-terminally protected dipeptide, selected from A.sup.1 and 
A.sup.2 in Formulas I or V and prepared by standard peptide coupling, with 
a compound 
##STR28## 
using standard peptide coupling, shown in the formula 
##STR29## 
wherein n is as defined in Formula I, W.sup.1 is an N-terminal amino 
protecting group such as tert-butyloxy carbonyl or benzyloxy carbonyl and 
W.sup.3 is H or an amino protecting group such as aryl sulfonyl, benzyloxy 
carbonyl or tert-butyloxy carbonyl. The final compounds can be made in any 
of the following ways: Removal of the protecting group(s), or a selective 
deprotection of the W.sup.1 -group (W.sup.1 must be orthogonal to W.sup.3) 
followed by alkylation of the N-terminal nitrogen and if desired 
deprotection. 
Method IVb 
Coupling of an N-terminally protected amino acid, selected from A.sup.2 in 
Formulas I or V and prepared by standard methods, with a compound of 
formula 
##STR30## 
using standard peptide coupling, shown in the formula 
##STR31## 
wherein n, W.sup.1, and W.sup.3 are as defined above followed by 
deprotection of the W.sup.1 -group (W1 must be orthogonal to W.sup.3) and 
coupoing with the N-terminal amino acid, in a protected form, leading to 
the protected peptide described in Method IVa. The synthesis to the final 
peptides is then continued according to Method IVa.