HUT72896A - Cyclic compounds useful as inhibitors of platelet glycoprotein iib/iiia - Google Patents

Description

The present invention relates to novel cyclic compounds containing carbocyclic ring systems and having antagonistic activity on the platelet glycoprotein IIb / IIIa complex. The present invention relates to pharmaceutical compositions containing the above compounds which inhibit platelet aggregation and are thus useful as thrombolytic agents and / or for the treatment of other thromboembolic disorders.

Platelet activation and consequent aggregation, as well as the selection of various factors, are associated with pathophysiological conditions. Examples include cardiovascular and cerebrovascular thromboembolic disorders such as unstable angina thromboembolic disorders, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. Platelet involvement in these diseases is based on their ability to form aggregates or blood clots, primarily following injury or plaque rupture in the artery wall.

824O3-734O / TEL

Platelets are known to play an essential role in maintaining homeostasis and in developing arterial thrombosis. Platelet activation has been shown to be enhanced in coronary thrombolysis, which delays the onset of flow and obstruction. Clinical studies with aspirin, ticlopidine and the monoclonal antibody to platelet glycoprotein IIb / IIIa have shown that platelets are involved in unstable angina, early myocardial infarction, transient ischemic attack and cerebral palsy.

Platelets are activated by a wide variety of agonists, resulting in altered platelet shape, precipitated particulate components, and platelet aggregation. Platelet aggregation promotes the formation of a blood clot by concentrating activated clotting factors in one place. Various endogenous agonists have been identified, such as adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin and collagen. Because more endogenous agonists are involved in the activation of platelet function and aggregation, an inhibitor acting on all agonists would be a much more effective antiplatelet agent than the currently available one agonist specific antiplatelet agent.

The currently known antiplatelet agents are effective against only one type of agonist. Such is aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A ₂ synthetase inhibitors or receptor antagonists that act against thromboxane A ₂ ; and hirudin, which acts against thrombin. Recently, common pathways have been identified for all known agonists, namely the platelet glycoprotein IIb / IIIa complex (GPIIb / IIIa), a membrane protein that mediates platelet aggregation. A broad description of GPIIb / IIIa can be found in Phillips et al., Cell 65: 359-362 (1991). The development of GPIIb / IIIa antagonists is a promising new option in antiplatelet therapy. Human studies with GPIIb / IIIa-specific monoclonal antibody show that GPIIb / IIIa antagonists have antithrombotic activity.

There is a need for a GPIIb / IIIa-specific antiplatelet agent that inhibits the agonist-induced activation and aggregation of platelets. Such an agent would provide a much more effective antiplatelet therapy than currently available agonist-specific platelet inhibitors.

GPIIb / IIIa does not bind soluble proteins to non-stimulated blood platelets, but in activated blood platelets GPIIb / IIIa binds four soluble adhesion proteins, which are fibrinogen, von Willebrand factor, fibronectin and vitronectin. Binding of fibrinogen and von Willebrand factor to GP11b / 1111a induces platelet aggregation. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence, which is commonly found in GPIIb / IIIa-binding adhesive proteins.

Several RGD-containing peptides and related compounds are known to block fibrinogen binding and inhibit the formation of a blood clot (e.g., Cadroy et al., 1989, J. Clin. Invest. 84: 939-944; and US 4952562). EP 0319506, EP 0422938, EP 0422937, EP 0341915, WO

89/07609, WO 90/02751, WO 91/04247 and EP 0343085).

FIELD OF THE INVENTION The present invention relates to carbocyclic ring systems of stretched structure which serve as templates for cyclizing peptides which exhibit high affinity and selectivity for GPIIb / IIIa.

The present invention thus relates to novel cyclic compounds containing carbocyclic ring systems and useful as antagonists of the platelet glycoprotein IIb / IIIa complex. The present invention relates to pharmaceutical compositions containing such cyclic compounds which inhibit platelet aggregation and are thus useful as thrombolytic agents and / or as agents for the treatment of thromboembolic disorders.

The present invention also relates to combination products, i.e. pharmaceutical compositions, containing the novel cyclic compounds of the invention as a combination partner with an anticoagulant such as warfarin or heparin; antiplatelet agents such as aspirin, piroxicam or ticlopidine; a thrombin inhibitor such as boropeptide, hirudin or agratroban; in the presence of a thrombolytic agent such as a tissue plasminogen activator, anistreplase, urokinase or streptokinase, or a combination thereof, which may be formulated, for example, in the form of a kit containing the combination partners.

The attached figures are intended to provide a better understanding of the invention.

Figure I shows cyclic (D-AbuNMeArg-Gly-Asp-Mamb) (Compound A) and cyclo (D-Val-NMeArgGly-Asp-Mamb) (Compound B) cyclic platelet aggregation inhibitor and thrombolytic shows its effect on pre-formed platelet-rich blood clots at different concentrations. Platelets are incubated with an agonist for 30 minutes to form a blood clot. The cyclic compounds of the invention effectively clot the clot, with Compound A having an IC50 of about 0.0005 mmol / L, in comparison, the linear RGDS peptide is a much less potent thrombolytic, even at significantly higher concentrations.

II. Fig. 4A is the cyclic IIb / IIIa antagonist cyclo (D-AbuNMeArg-Gly-Asp-Mamb) (Compound A) and cyclo (D-Val-NMeArg-GlyAsp-Mamb) (Compound B) and standard thrombolytic tissue plasminogen activator (tPA). ), urokinase (UK) and streptokinase (SK) in thrombolytic activity in previously formed platelet-rich blood clots. Platelets are incubated with an agonist for 30 minutes to form a blood clot. Both Compound A and Compound B show significant thrombolytic activity relative to standard thrombolytic tissue plasminogen activator, urokinase and streptokinase.

In III. Fig. 4A shows the thrombolytic effect of cyclic cyclo (D-Abu-NMeArg-Gly-Asp-Mamb) (Compound A) and standard thrombolytic tissue plasminogen activator (tPA), urokinase (UK) and streptokinase (SK), alone and in combination; in the case of a clot rich in platelets. Platelets are incubated with an agonist for 30 minutes to form a blood clot. Compound A exhibits a significant thrombolytic activity within which it significantly disrupts the blood clot at 1.0 pmol / L. In addition, Compound A in combination with tissue plasminogen activator, urokinase, or streptokinase is significantly better than Compound A alone and substantially

- 6 is better than the sum of the effects obtained by the administration of the two active substances alone.

The IV. Fig. 6A shows the thrombolytic effect of the cyclic IIb / IIIa antagonist cyclo (D-Val-NMeArg-Gly-Asp-Mamb) (Compound B) and standard thrombolytic tissue plasminogen activator (tPA), urokinase (UK) and streptokinase (SK); in combination with a previously formed platelet-rich blood clot. Platelets are incubated with an agonist for 30 minutes to form a blood clot. Compound B exhibits a significant thrombolytic effect, including a significantly better disruption of the blood clot than tissue plasminogen activator, urokinase or streptokinase. In addition, Compound B, when combined with tissue plasminogen activator, urokinase or streptokinase, is significantly better than Compound B alone and substantially better than the sum of the effects of the two active ingredients.

Figure V shows the thrombolytic effect of cyclo- (D-Val-NMeArg-Gly-Asp-Me-Mamb) (Example 68, 1 isomer) (Compound C) alone and with standard thrombolytic tissue plasminogen activator (tPA) urokinase. (UK) and streptokinase (SK) in previously formed platelet-rich blood clots. Platelets are incubated with an agonist for 30 minutes to produce a blood clot. Compound C alone has a significant thrombolytic effect. When combined with tissue plasminogen activator, urokinase or streptokinase, the thrombolytic effect is greater than the sum of the effects achieved with the active substances alone.

VI. Figure 3B shows the thrombolytic effect of cyclo- (D-Val-NMeArg-Gly-Asp-Me-Mamb) (Example 68a, 2 isomers) alone and with standard thrombolytic tissue plasminogen activator (tPA), urokinase (UK). and in combination with streptokinase (SK) in a previously formed platelet-rich blood clot. Platelets are incubated with an agonist for 30 minutes to produce a blood clot. Compound D alone has a significant thrombolytic effect. When combined with a tissue plasminogen activator, urokinase or streptokinase, the thrombolytic effect is greater than the sum of the effects obtained with the active substances alone.

VII. Fig. 6A shows the in vivo thrombolytic and thrombotic inhibitory activity of the cyclic glycoprotein IIb / IIIa antagonist cyclo (D-Abu-NMeArg-Gly-Asp-Mamb) (Compound A) in combination with standard thrombolytic streptokinase (SK). The experiment was performed on an animal model with arterial thrombosis. The figure shows the effect of the initial administration in% of the clot destruction. Compound A alone exhibits good in vivo thrombolytic activity and the compound A / streptokinase combination has enhanced in vivo thrombolytic activity and at the same time allows for a significant reduction in the streptokinase dose. Thus, the study found that the dose of streptokinase required in vivo for 100% digestion could be significantly reduced when Compound A was co-administered with streptokinase.

Figs. 11a-d show the effect of administration of Compound A or saline after streptokinase (SK) or tissue plasminogen activator (tPa) thrombolysis, which results in the time required for re-occlusion and the percentage of re-occlusion. The saline used as a control exhibits 100% re-occlusion whereas virtually no re-occlusion occurs when Compound A is administered.

···· ························· ·

In the novel compounds of formula I of the present invention, R ³¹ is a C 6 -C 14 saturated, partially unsaturated, or aromatic carbocyclic ring system substituted with 0 to 4 R ¹⁰ or R ^10a ,

R ³² is -C (= O) -, -C (= S) -, -S (= O) ₂ -, -S (= O) - or -P (= Z) (ZR ¹³ ) -,

Z is sulfur or oxygen, n and n 'are independently 0-2,

R ¹ and R ²² are independently hydrogen,

C 1-8 alkyl substituted with 0-2 R ¹¹ ,

2- 8 alkenyl substituted with 0-2 R ¹¹ groups,

2- 8 alkynyl substituted with 0-2 R ¹¹ groups,

3- 10 carbon atoms, cycloalkyl having 0-2 ^R11 bowl group is substituted, aryl substituted with 0-2 R ¹² groups, 5-10 membered heterocyclic ring system comprising one to four heteroatoms selected from nitrogen atoms, sulfur atoms and / or atoms may oxy and substituted with 0-2 R ¹² , oxygen, fluorine, chlorine, bromine or iodine, -CF ₃ , -CN, -CO ₂ R ¹³ , -C (= O) R ¹³ , -C (= O) N (R ¹³ ) 2i -CHO, -CH ² OR ¹³ , -O (O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ¹ ', -NR ¹³ C (= O) N (R ¹³ ) 2i -NR ¹⁴ SO ² N (R ¹³ ) 2i -NR ^{of 14} SO2R ^13a, -SO3H, -SO2R ^13a, -SR ^13, -S (= O) ^{R 13a,} -SO 2 N (R ¹³⁾ 2, -N ^(R13) 2i, -NHC (= NH) NHR ^13,

-C (= NH) NHR ¹³ , = NOR ¹³ , -NO ₂ , -C (= O) NHOR ¹³ , -C (= O) NHNR ¹³ R ^13a , or -OCH 2 CO 2 H or 2- (1-morpholino) or an ethoxy group

R ¹ and R ²¹ together form a 3-7 membered carbocyclic ring substituted with 0-2 R ¹² groups, and n '= 2, R ¹ or R ²¹ on the adjacent carbon, together with ^R1 or ^R21 -gyel -gyel forms a direct bond and thus forms a double bond or a triple bond between the carbon atoms,

R ²² and R ²³ together form a 3-7 membered carbocyclic ring substituted with 0-2 R ¹² groups, or n = 2 case, direct or together R ²² R ²³ on the adjacent carbon with R ²² or R ²³ malate forms a bond and thus forms a double bond or a triple bond between the carbon atoms, or

R ²¹ = in the case of hydrogen, R ¹ and R ² together form a 5-8 membered carbocyclic ring substituted with 0-2 R ¹² ,

R ¹¹ is oxygen, fluorine, chlorine, bromine or iodine, CF3, -CN, -CO2R ^13, -C (= O) ^R13, -C (= O) N ^(R13) 2, -CHO , -CH ₂ OR ¹³ , -OC (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ^13, -NR ¹⁴ C (= O) OR ^13a, -NR ¹³ C (= O) N (R ¹³⁾ 2, -NR ¹⁴ SO2N ^(R13) 2, NR ¹⁴ SO2R ^13a, -SO 3 H, -SO ₂ R ^13a, -SR ^13, -S (= O) R ¹³ ', -SO 2 N (R ¹³⁾ 2, -N ^(R13) 2, -NHC (= NH) ^NHR13, -C (= NH) NHR ¹³ , = NOR ¹³ , -NO 2, -C (= O) NHOR ¹³ , -C (= O) NHNR ¹³ R ^13a , -OCH 2 CO 2 H, or 2- (1-morpholino) ethoxy;

- C 10 -C 5 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 2 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl (the alkyl group is substituted with 1-5 substituents where the substituent may be

-NR ¹³ R ^14, -CF _3, -NO ₂ -SO _{2 R} ¹³ · R or -S (= O) R ^13a group is), aryl substituted with 0-2 R ¹² groups, 5-10 membered heterocyclyl, a ring system containing from 1 to 4 heteroatoms selected from nitrogen, sulfur and / or oxygen, substituted with 0-2 R ¹² , R ^{12 being} phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halo, hydroxy, nitro, cyano, (C 1 -C 5) alkyl, (C 3 -C 6) cycloalkyl, (C 3 -C 6) cycloalkylmethyl, (C 7 -C 10) arylalkyl, (C 1 -C 5) alkoxy, -CO 2 R ¹³ , -C (= O) NHOR ^13a , -C (= O) NHN (R ¹³ ) 2, = NOR ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , - C (= O) R ¹³ ,

-OC (= O) OR ^13a , -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -OC (= O) N (R ¹³ ) 2i -NR ¹³ C ( = O) R ¹³ , -NR ¹³ C (= O) OR ^13a , -NR ¹³ C (= O) N (R ¹³ ) ₂ ,

SO2N -NR ¹³ (R ¹³⁾ 2, NR ¹³ SO2R ^13a, -SO 3 H, -SO ₂ R ^13a, -S (= O) R ^13a, -SR ¹³ or -SO 2 N (R ¹³⁾ 2 group of formula 2 C 6 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy,

- (C 1 -C 11) alkylcarbonyloxy, (C 1 -C 4) -alkylcarbonylamino, (C 1 -C 4) -alkylcarbonylamino, -OCH ₂ CO ₂ H, 2- (1-morpholino) ) ethoxy group, a C1-4 alkyl group (the alkyl group is -N ^(R13) _2, -NO2, or substituted with -CF _{3 R} -S (= O) R ¹³ 'group of formula);

R ¹³ is independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 4 -C 12) alkylcycloalkyl, aryl, (C 1 -C 10) alkyl-aryl, or (C 3 -C 10) -alkoxy-alkyl-. group,

R ^13a is C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl or C 3 -C 10 alkoxyalkyl, two R ¹³ groups attached to the same nitrogen atom taken together - (CH ₂ ) ₂ . ₅ - or - _(CH2) O _(CH2) - to form a group of formula,

R ¹⁴ is hydroxy, hydrogen, C 1 -C 4 alkyl or benzyl,

R ²¹ and R ²³ are each independently hydrogen,

C1-C4 alkyl optionally substituted with one to six halogens and benzyl,

R ² is hydrogen or C 1 -C 8 alkyl, R ¹⁰ and R ¹⁰ 'are each independently phenyl, benzyl, phenethyl, phenoxy, benzyloxy when logenic, hydroxy, nitro, cyano, C 1-6 alkyl, 3 -6 carbon atoms · · · · · · · · · · · · · · · · · · · · · · · · · ···

- 12 cycloalkyl, C 3-6 cycloalkylmethyl, C 7-10 arylalkyl, C 1-6 alkoxy, -CO ₂ R ¹³ , -C (= O) NHOR ¹³ ·, -C (= O) N (R ¹³ ) 21 -C (= O) NHN (R ¹³ ) 2, -NO R ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ¹³ ', -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ¹³ ', -NR ¹³ C (= O) N (R ¹³ ) ₂ ,

SO2N -NR ¹³ (R ¹³⁾ 2, -NR ¹³ so2r ¹³ ', -SO 3 H, -SO ₂ R ^13', S (= O) R ¹³ ', -SR ¹³ or -SO 2 N (R ¹³⁾ 2 , C2-6 alkoxyalkyl group, a methylenedioxy group, ethylenedioxy group, a C1-4 haloalkyl group (group C D _{W V,} wherein v is 1-3 and w 1- (2v + 1)), C 1 -C 4 haloalkoxy, C 1 -C 4 alkylcarbonyloxy, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylcarbonyl-. an amino group, -OCH ₂ CO ₂ H, a 2- (1-morpholino) ethoxy group or a C 1-4 alkyl group (the alkyl group is -N (R ¹³ ) ₂ , -CF _3i -NO ₂ or -S). (= O) R ¹³ 'is substituted),

J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) C (R ⁴ ) (R ⁵ ) C (= O) -, wherein

R ³ is hydrogen or C 1-8 alkyl, R ⁴ is hydrogen or C 1-3 alkyl, R ⁵ is hydrogen,

C 1 -C 8 alkyl substituted with 0-2 R ¹¹ groups; ·········································• · · · «· ··

- C 13 -C 8 alkenyl substituted with 0-2 R ¹¹ ,

2- 8 alkynyl substituted with 0-2 R ¹¹ groups,

3- 10 carbon atoms, substituted with 0-2 R ¹¹ groups, aryl substituted with 0-2 R ¹² groups, 5-10 membered heterocyclic ring system containing nitrogen, sulfur and / or oxygen atom as the heteroatom one to four and substituted with 0-2 R ¹² , oxygen, fluoro, chloro, bromo or iodo, -CF ₃ , -CN, -CO ₂ R ¹³ , -C (= O) R ¹³ , -C ( = O) N (R ¹³ ) 2 i -CHO, -CH ² OR ¹³ , -OC (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , -OC (= O) N (R ¹³ ) 2 , -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ¹³ ·, -NR ¹³ C (= O) N (R ¹³ ) _2> -NR ¹⁴ SO ₂ N (R ¹³ ) 2, - NR ¹⁴ SO2R ^13a, -SO 3 H, -SO ₂ R ^13a, -SR ^13, -S (= O) R ^13a, -SO ₂ N (R ¹³⁾ 2, -N ^(R13) 2i, -NHC (= NH) NHR ¹³ , -C (= NH) NHR ¹³ , = NOR ¹³ , -NO 2, -C (= O) NHOR ¹³ , -C (= O) NHNR ¹³ R ^13a , = NOR ¹³ , -B (R ³⁴ ) ( R ³⁵ ) or -OCH ₂ CO ₂ H, 2- (1-morpholino) ethoxy, -SC (= NH) NHR ¹³ , -N ₃ , -Si (CH ₃ ) ₃ , - (1-5). (C 1 -C 6 alkyl) -NHR ¹⁶ - (C 0 -C 6 alkyl) -X or (a) wherein q is independently 0 or 1; and b is; or

- (CH ₂ ) _m S (O) _p (CH ₂ ) ₂ X wherein m is 1 or 2 and p 'is 0 to 2 or 4; ··· • · · · «· * · 4 · ··

- 14 R ³ and R ^{4 taken} together form a group of formula (c) wherein n is 0 or 1,

X is a group of formula (d), or

R ³ and R ⁵ together form - (CH 2) _t - or - (CH ₂ ) S (O) p C (CH ₃ ) 2 - wherein t is 2-4 and p 'is 0-2, or

R ⁴ and R ⁵ together form a group - (CH ₂ ) _U - wherein u is 2-5,

R ¹⁶ is an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group,

K is the D or L isomeric amino acid of formula -N (R ⁶ ) CH (R ⁷ ) C (= O) -, wherein

R ⁶ is hydrogen or C 1-8 alkyl,

R ⁷ is - (C 1 -C 7 alkyl) -X, a group of the formula (e) wherein q is independently 0-2 and the substituent is in the 3- or 4-position of the phenyl ring; wherein q is independently 0-2 and the substituent is in the 3- or 4-position of the cyclohexyl group, and the group of formula (g) and - (CH ₂ ) _m O- (C 1-4 alkyl) - A group of the formula X wherein m is 1 or 2, ·

·· • · • · <<«« ♦ ♦ ♦

And - (CH ₂ ) _m S (O) _p - (C 1 -C 4 alkyl) -X wherein m is 1 or 2 and p 'is 0-2,

X is -N (R ¹³ ) R ¹³ , -C (= NH) (NH 2), -SC (= NH) -NH 2, -NH-C (= NH) (NHCN), - NH-C (= NCN) (NH 2) or -NH-C (= N-OR ¹³ ) (NH 2), or

R ⁶ and R ⁷ together form a group of formula (h) wherein q is independently 1 or 2, n is 0 or 1 and

X is -NH ₂ or a group of formula (d),

L is -Y (CH ₂ ) _V C (= O) -, wherein

Y is -NH, -N- (C 1 -C 3 alkyl), oxygen or sulfur, v is 1 or 2,

M is an amino acid D or L isomeric amino acid of formula (i) wherein q 'is 0-2,

R ¹⁷ is hydrogen or C 1-3 alkyl,

^{13 R8} -CO2R, -SO3R ^13, -SO 2 NHR ^14, -B (R ³⁴⁾ (R ^35), -NHSO2CF _3i -CONHNHSO ₂ CF _3, -PO ^(OR13) 2, -PO ^{(OR13) R13} or a group of formula -SO2NH-heteroaryl (said heteroaryl of 5-10 ring members and 1-4 heteroatoms selected from nitrogen, sulfur and / or oxygen) and -SOzNHCOR ^13, -CONHSO2R ^13a -CH2CONHSO ₂ R ^{13a, 13a} -NHSO2NHCOR, -NHCONHSO2R ^13a , -SO2NHCONHR ^13, or -CO2R ^13b , • 9 · * 4 · • <• <

- 16 R ³⁴ and R ³⁵ is independently -OH, -F, group -N ^(R13) _2, or C1-8 alkoxy, or

R ³⁴ and R ³⁵ together form a C 2-20 cyclic boronic ester which may optionally contain 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, or a C 2-20 divalent cyclic boronic amide optionally containing 1 to 4 heteroatoms nitrogen, sulfur and / or contain an oxygen atom or form a cyclic boramide ester of 2 to 20 carbon atoms optionally containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen,

R ^13b is

a) C 1-8 alkyl;

b) C2-C8 alkenyl,

c) C 2-8 alkynyl,

d) C3-C8 cycloalkyl,

e) C 1-8 alkyl substituted with optionally substituted substituents

i) an aryl radical optionally substituted by 1-2 halogen, phenyl, C1-5 alkyl, C1-5 alkoxy, _-NO2, -S (O) _0-2 - (C 1-5 alkyl), OH, -N (R ¹³ ) 2, -CO 2 R ¹³ , -CON (R ¹³ ) 2, and / or -C _V F _W , wherein v is 1-3 and w is 1- (2v + 1), (ii) C3-C8 cycloalkyl, (iii) (j), - (-) - (-) - - - - - - - - - - - - - - - - - - - - - - - - · It «··

f) aryl optionally substituted with 1 to 2 halogens, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO 2, -S (O) ₀ -2- (C 1 -C 5 alkyl), -OH, - N (R ¹³ ) 2, -CO 2 R ¹³ , -CON (R ¹³ ) 2, and / or -C _V F _W , wherein v is 1 to 3 and w is 1 (2v + 1),

g) C 2 -C 8 alkyl, alkenyl or alkynyl, each with C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, phenoxy, benzyloxy, halo, -NO ₂ , -CN, - CO ₂ R ¹³ , -CON (R ¹³ ) 2, -N (R ³⁶ ) COR ³⁶ , morpholino, 2- (1-morpholino) ethoxy, -N (R ¹³ ) 2, -N * ^(R13) _3, OCOCH3, _CF3, and / or -S (O) _0-2 R ^13a groups are substituted in the formula,

h) -CH (R ³⁶ ) OR ³⁸ ;

i) -CH (R ^3e ) OC (= O) R ³⁷ ;

j) -CH (R ³⁶ ) OC (= O) OR ³⁸ ;

k) -CH (R ³⁶ ) OC (= O) N (R ³⁷ ) ₂ ;

l) -CH (R ³⁶ ) N (R ³⁶ ) C (= O) R ³⁶ ;

m) -CH (R ³⁶ ) CO ₂ R ³⁷ ,

n) -CH (R ³⁶ ) CON (R ¹³ ) ₂ ;

o) -CH (R ³⁶ ) N (R ¹³ ) ₂ ;

q) a group of formula (k),

r) a group of the formula I,

s) a group of the formula m;

t) a group of the formula n;

u) A group of formula (o), ··· «• · to · <<

• ·· ··· * ··· ν · * · • • V 4 · · 44

- 18 R ³⁶ is independently hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, phenyl or benzyl,

R ³⁷ is

a) a hydrogen atom,

b) C 1-8 alkyl or C 3-8 cycloalkyl, which may be substituted with 1-2 substituents, wherein the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, may be substituted with -N ^(R13) 2, -CO2R ^13, -C (O) N ^(R13) 2 and / or C _V M _W group of formula wherein v is 1-3 and w = 1 to (2v + 1)

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, may be substituted by -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W group of formula wherein v is 1-3 and w = 1 to (2v + 1)

R ³⁸ is as defined

- 19 R ³⁹ ··· »* v •« te · · * ··· ·· «V ··· • · · * ··· ·» · * ·

a) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, where the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1 to 3 and w = 1 to (2v + 1)

b) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1 to 3 and w = 1 to (2v + 1), meaning

a) a hydrogen atom,

b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be

i) C 1-6 alkyl, ii) C 1-6 alkoxy, - iii) aryl having 0-2 halogen, phenyl,

C 1 -C 6 data group, C 1 -C 6 alkoxy group, -NO 2. -S (C 1 -C 5 alkyl), -SO (C 1 -C 5 alkyl), -SO ₂ (C 1 -C 5 alkyl), -OH, -N (R ¹³ ) 2, -CO 2 R ¹³ , -C (= O) may be substituted by N (R ¹³ ) 2 and / or C _V F _W where v is 1 to 3 and w is 1 (2v + 1),

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO 2, -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, - It may be substituted by a group of formula N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1 )

R ⁴⁰ is hydrogen, C 1 -C 5 alkyl, or benzyl, provided that at least one of the following conditions is met:

1) R ³² is other than -C (= O) -, or

2) p 'is different from 0, or

3) q 'is different from 0, or

4) q is different from 0-1, or (5) X is -NH-C (= NH) NHCN, -NH-C (= NCN) (NH ₂ ) or -NH-C (= NOR ¹³ ) NH Or ₂

5) R ⁸ is -B (R ³⁴ ) (R ³⁵ ) or -CO ₂ R ^13b .

The present invention relates to pharmaceutically acceptable salts or prodrug forms of the above compounds.

The aforementioned compounds may be used as platelet aggregation inhibitors, thrombolytics and / or thromboembolic agents (where the above restrictions 1-5 do not apply), alone or in combination with one or more additional agents, wherein the additional agent may be an anticoagulant such as warfarin or heparin; antiplatelet agents such as aspirin, piroxicam or ticlopidine; a thrombin inhibitor such as boropeptide, hirudin or argatroban; a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase.

Preference is given to compounds of formula I in which

R ^{31 is} bonded to (C (R ²³ ) R ²² ) n and (C (R ²¹ ) R ¹ ) n · attached to two different atoms of the carbocyclic ring.

Further preferred are compounds of formula I wherein n is 0 and n 'is 0, n is 0 and n' is 1, n is 0 and n 'is 2, n is 1 and n' is 0, n is 1 and n 'is 1, n is 1 and n' is 2, n is 2 and n 'is 0, n is 2 and n' is 1 or n is 2 and n 'is 2.

Further preferred are compounds of formula I wherein

R ⁶ is methyl, ethyl or propyl.

Further preferred are the compounds of formula I or their pharmacologically acceptable salts or prodrugs wherein

R ³¹ is a C 6-14 saturated, partially saturated or aromatic carbocyclic ring substituted with 0-4 R ¹⁰ or R ¹⁰ ',

R ³² is -C (= O) -, -C (= S) - or -S (= O) ₂ -, n and n 'are independently 0-2,

R ¹ and R ²² are independently hydrogen,

C 1-8 alkyl substituted with 0-2 R ¹¹ ,

2- 8 alkenyl substituted with 0-2 R ¹¹ groups,

2- 8 alkynyl substituted with 0-2 R ¹¹ groups,

3- to 8 carbon atoms which is substituted with 0-2 R ¹¹ groups,

C 6 -C 10 bicycloalkyl substituted with 0-2 R ¹¹ , aryl substituted with 0-2 R ¹² , 5-10 membered heterocyclic ring system containing one to four heteroatoms nitrogen, sulfur and / or oxygen, and substituted with 0-2 R ¹² and oxygen, fluorine, chlorine, bromine or iodine, -CF ₃ , -CN, -CO ₂ R ¹³ , -C (= O) R ¹³ , -C ( = O) N (R ¹³ ) 2, -CHO, -CH 2 OR ¹³ , -O C (= O) R ¹³ , -O C (= O) OR ^13a , -OR ¹³ , -OC (= O) N (R ¹³ ). 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ¹³ ·, -NR ¹³ C (= O) N (R ¹³ ) ₂ , • - · · 4 · ···· ·· '9 · 9 9 • ♦ ♦ · »· · · · ·

- 23 ¹⁴ NR SO2N (R ¹³⁾ R 21 ^{14 13} so2r ', -SO 3 H, -SO ₂ · r ^13, -SR ^13, -S (= O) R ^13i, -SO 2 N (R ¹³⁾ -CH 21 _2N ^(R13) 2i, -N (R ¹³⁾ 2,

-NHC (= NH) NHR ¹³ , -C (= NH) NHR ¹³ , or -NO ₂ . obsession

R ¹ and R ²¹ together form a 5-7-membered carbocyclic ring which may be substituted with 0-2 R ¹² groups, and n '= 2, R ¹ or R ²¹ together with R ¹ or R -gyel -gyel ²¹ on the adjacent carbon forms a direct bond so that a double bond or a triple bond is formed between the carbon atoms, or

R ²² and R ²³ together form a 3- to 7-membered carbocyclic ring which

May be substituted with 0-2 R ¹² groups, and n = 2, form a direct bond with R ²² or R ²³ on the adjacent carbon with R ²² or R ²³ malate, and thus between the carbons is a double bond or a triple bond is formed, obsession

R ²¹ = in the case of hydrogen, R ¹ and R ² together form a 5-8 membered carbocyclic ring which may be substituted with 0-2 R ¹² ,

R ¹¹ is oxygen, fluorine, chlorine, bromine or iodine, CF3, -CN, -CO2R ^13, -C (= O) ^R13, -C (= O) N ^(R13) 2, -CHO , -CH ₂ OR ¹³ , -OC (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹⁴ C (= O) OR ^13a , -NR ¹³ C (= O) N (R ¹³ ) 2, -NR ¹⁴ SO ² N (R ¹³ ) ^{2 i} -NR ¹⁴ SO ² R ¹³ ', -SO ³ H, -SO2R ^13a, -SR ^13, -S (= O) R ^13a, -SO 2 N (R ¹³⁾ 2, -CH 2 N (R ¹³⁾ 2 R, -N ^(R13) 2i, -NHC (= NH) ^NHR13, -C (= NH) NHR ¹³ , = NOR ¹³ , -NO 2, or

- 24 R ¹²

C 1-5 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, C 2-6 alkoxyalkyl, C 1-4 alkyl (which is -NR ¹³ R ^14, -CF _3, -NO _{2i -SO2} ^R13, or -S (= O) ^R13 group of formula * is substituted), aryl substituted with 0-2 R ¹² groups, or

A 5 to 10 membered heterocyclic ring system containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen and substituted with 0-2 R ¹² is phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halo, hydroxy, nitro, cyano, (C 1 -C 5) -alkyl, (C 3 -C 6) -cycloalkyl, (C 3 -C 6) -cycloalkylmethyl, (C 7 -C 10) -alkyl, (C 1 -C 5) -alkoxy, -CO 2 R ¹³ , -C (= O) NHOR ^13a , -C (= O) NHN (R ¹³ ) 2, = NOR ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (-O) OR ^13a , -NR ¹³ C (= O) N (R ¹³ ) ₂ , -NR ¹³ SO ₂ N (R ¹³⁾ 2, NR ¹³ SO2R ^13a, -SO 3 H, -SO ₂ R ^13a, -S (= O) R ^13a, -SR ¹³ or -SO 2 N (R ¹³⁾ 2, C 2-6 alkoxyalkyl group, methylenedioxy, ethylenedioxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyloxy, C 1-4 alkylcarbonyl, 1- C 4 alkylcarbonylamino-25, -OCH ₂ CO ₂ H, 2- (1-morpholino) ethoxy, C 1-4 alkyl (the alkyl is -N (R ¹³ ) ₂ , -CF _3i -NO 2 or -S (= O) R ¹³ ')

R ¹³ is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl, or C 3 -C 10 alkoxyalkyl; group,

R ^13a is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 4 -C 12) alkylcycloalkyl, aryl, (C 1 -C 10) alkylaryl, or (C 3 -C 10) alkoxyalkyl, or the same the two R ¹³ groups attached to the nitrogen atom taken together form - (CH ₂ ) ₂ - ₅ or - (CH ₂ ) O (CH ₂ ) -,

R ¹⁴ is hydroxy, hydrogen, C 1 -C 4 alkyl or benzyl,

R ²¹ and R ²³ are each independently hydrogen, C 1-4 alkyl optionally substituted with 1 to 6 halogens, or benzyl,

R ² is hydrogen or C 1-8 alkyl,

R ¹⁰ and R ^10a are each independently phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halo, hydroxy, nitro, cyano, C 1-5 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl-. a group, C 7 -C 10 arylalkyl, C 1 -C 5 alkoxy, -CO 2 R ¹³ , -C (= O) NHOR ¹³ *, -C (= O) NHN (R ¹³ ) ₂ ,

- 26 = NOR ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ¹³ ', -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ³ C (= O) OR ¹³ ', -NR ¹³ C (= O) N (R ¹³⁾ _2, -NR ¹³ SO2N ^(R13) 2, NR ¹³ SO2R ^13a, -SO 3 H, -SO ₂ R ¹³ , -S (= O) R ^13a , -SR ¹³ or -SO ₂ N (R ¹³ ) 2, C 2 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy. C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyloxy, C 1-4 alkylcarbonyl, C 1-4 alkyl-; a carbonylamino group, -OCH 2 CO 2 H, a 2- (1-morpholino) ethoxy group or a C 1 -C 4 alkyl group (the alkyl group is -N (R ¹³ ) 2, -CF ₃ , -NO ₂ or -S ( = O) R ^13a is substituted),

J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) C (R ⁴ ) (R ⁵ ) C (= O) -, wherein

R ³ is hydrogen or methyl,

R ⁴ is hydrogen or C 1-3 alkyl, R ⁵ is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, C 1-6 cycloalkylethyl, phenyl, phenylmethyl, -CH ₂ OH, -CH ₂ SH, -CH ₂ OCH ₃ , -CH ₂ SCH _3i -CH ₂ CH ₂ SCH _3i - (CH ₂ ) _s NH ₂ , - (CH ₂ ) _s NHC (= NH) (NH ₂ ) or - (CH ₂ ) _S NHR ¹⁶ where s is 3-5 or • · ·

- R ³ and R ⁵ together form - (CH ₂ ) _t - (t = 2-4) or - (CH ₂ ) SC (CH ₃ ) ₂ -, or

R ⁴ and R ⁵ together form - (CH ₂ ) _U - wherein u is 2-5,

R ¹⁶ is an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group,

K is the D or L isomeric amino acid of formula -N (R ⁶ ) CH (R ⁷ ) C (= O) -, wherein

^R6 is hydrogen or C1-8 alkyl, ^R7 is - (C1-7 alkyl) -X formula (e) a group wherein q is independently 0-2, and the substituents of the phenyl or 3- A 4-position group of the formula (f) wherein q is independently 0-2 and the substituent is a 3-position or 4-position of the cyclohexyl group;

- (O ₂ ) ™ O - (C 1 -C 4 alkyl) -X wherein m is 1 or 2, or - (CH ₂ ) _m S - (C 1 -C 4 alkyl) -X wherein m is 1 or 2,

X is -NH-C (= NH) (NH ₂ ), -NHR ¹³ , -C (= NH) (NH ₂ ), or -SC (NH) -NH ₂ , or

R® and ^R7 together (h ') form a group of formula whereby * · "

- 28 n is Ο or 1,

X is -ΝΗ ₂ or -NH-C (= NH) (NH ₂ )

L is -Y (CH ₂ ) _V C (= O) -, wherein

Y is -NH, -N (C 1 -C 3 alkyl) -, oxygen or sulfur, v is 1 or 2,

M is the D or L isomeric amino acid of formula (i) wherein q 'is 0-2,

R ¹⁷ is hydrogen or C 1-3 alkyl,

^{R8 13} -CO2R, -SO3R ^13, -SO 2 NHR ^14, -B (R ³⁴⁾ (R ^35), -NHSO2CF _3, -CONHNHSO ₂ CF _{3 R,} -PO ^(OR13) 2, -PO (OR ¹³⁾ R ¹³ -S02NH-heteroaryl group or the formula (5-10 membered heteroaryl and 1-4 heteroatoms selected from nitrogen, sulfur and / or oxygen atom), a group of formula -SO ₂ NH-heteroaryl (said heteroaryl and 5-10 membered 1-4 hetero atoms include nitrogen, sulfur and / or oxygen), and -SO ₂ NHCOR ^13, -CONHSO2R ^13a -CH2CONHSO ₂ R ^{13a, 13a} -NHSO2NHCOR, -NHCONHSO2R ^{13a, 13b} -SO2NHCONHR ¹³ or -CO2R group of the formula

R ³⁴ and R ³⁵ are each independently hydroxy, fluoro, -NR ¹³ R ^14, or C 1 -C 8 alkoxy, or

R ³⁴ and R ³⁵ together form a C 2-20 cyclic boronic ester optionally containing 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, or a C 2-20 hetero divalent cyclic boronamide optionally containing 1 to 4 heteroatoms nitrogen containing a sulfur atom and / or an oxygen atom or forming a cyclic boramide ester of 2 to 20 carbon atoms optionally containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen,

R ^13b is

a) C 1-8 alkyl;

b) C2-C8 alkenyl,

c) C 2-8 alkynyl,

d) C3-C8 cycloalkyl,

e) C 1-8 substituted alkyl, wherein the substituent may be

(i) aryl optionally substituted with 1 to 2 halogens, phenyl, C 1 -C 5 alkyl,

C 1-5 alkoxy, -NO _2, -S (O) _0-2 - (C 1-5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, -CON (R ¹³⁾ 2, and / or substituted with -C _V F _W where v is 1-3 and w is 1- (2v + 1), ii) C3-C8 cycloalkyl, iii) j),

f) aryl optionally substituted with 1 to 2 halogens, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO ₂ , -S (O) ₀ . ₂ - (1 -5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, CON ^(R13) 2, and / or substituted by a group of formula -C _V F _W where v is 1 -3 and w are 1- (2v + 1), «·

R ³⁶ r37

g) C 2 -C 8 alkyl, alkenyl or alkynyl, each with C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, phenoxy, benzyloxy, halo, -NO ₂ , -CN, -CO ₂ R ¹³ , -CON (R ¹³ ) 2, -N (R ³⁶ ) COR ³⁶ , morpholino, 2- (1-morpholino) ethoxy, -N (R ¹³ ) 2, -N ^{+ (R13)} _3, OCOCH _3, -CF _3, and / or -S (O) _0th Substituted with ₂ -R ^13a ,

h) -CH (R ³⁶ ) OR ³⁸ ;

i) -CH (R ³⁶ ) OC (= O) R ³⁷ ;

j) -CH (R ³⁶ ) OC (= O) OR ³⁸ ;

k) -CH (R ³⁶ ) OC (= O) N (R ³⁷ ) ₂ ;

l) -CH (R ³⁶ ) N (R ³⁶ ) C (= O) R ³⁶ ;

m) -CH (R ³⁶ ) CO ₂ R ³⁷ ,

n) -CH (R ³⁶ ) CON (R ¹³ ) ₂ ;

o) -CH (R ³⁶ ) N (R ¹³ ) ₂ ;

q) a group of formula (k),

r) a group of the formula I,

s) a group of the formula m;

t) a group of the formula n;

u) a group of the formula (o) independently of one another hydrogen, C 1-8 -alkyl, C 3-10 -cycloalkyl, phenyl or benzyl;

a) a hydrogen atom, · ·

R ³⁸ • ·· · ········································································· ·

b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO 2, -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, - It may be substituted by a group of formula N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1 )

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1 to 3 and w = 1 to (2v + 1), meaning

a) C 1-8 -alkyl or C 3-8 -cycloalkyl which may be substituted with 1-2 identical or different substituents, wherein the substituent may be

i) C 1-4 alkyl; ii) C 3-8 cycloalkyl;

R ³⁹ • · «···· ··" · ♦ * "• ··· ··· · · · ·· ·· ♦ iii) C 1-5 alkoxy, iv) aryl substituted by 0-2 halogen, phenyl .

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1)

b) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1-3 and w is 1 - (2v + 1), meaning

a) a hydrogen atom,

b) C 1-8 alkyl or C 3-8 cycloalkyl, which may be substituted with 1-2 identical or different substituents, wherein the substituent may be

(i) C 1-6 alkyl, (ii) C 1-6 alkoxy, (iii) aryl having 0-2 halo, phenyl,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N (R ¹³ ) ₂ , ···

- 33 -CO ₂ R ¹³ , -C (= O) N (R ¹³ ) ₂ and / or C _V F _W , wherein v is 1-3 and w is 1- (2v + 1),

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1)

R ⁴⁰ is hydrogen, C 1-5 alkyl or benzyl.

Further preferred are the above compounds having the formula

R ³¹ is as defined

(a) a 6-membered saturated, partially unsaturated or aromatic carbocyclic ring substituted with 0-3 R ¹⁰ or R ^10a ,

b) an 8-11 membered saturated, partially saturated, or aromatic fused bicyclic carbocyclic ring substituted with 0-4 R ¹⁰ or R ^10a , or

c) a 14-membered saturated, partially saturated, or aromatic tricyclic carbocyclic ring substituted with 0-4 R ¹⁰ or R ^10a .

Further preferred are compounds of formula I wherein

Meaning of R ³¹ • · ♦ ♦ ♦ ♦ ♦ * * * · * *

a) a 6-membered, saturated, partially saturated or aro other carbocyclic ring of formula (p *) wherein any bond forming the carbocyclic ring may be a single bond or a double bond and may be substituted with 0-4 R ¹⁰ ,

b) A 10-membered, saturated, partially saturated, or aro bicyclic carbocyclic ring of formula (r ') wherein any bond forming the carbocyclic ring may be a single bond or a double bond and may be substituted with 0-4 R ¹⁰ or R ^10a. .

c) A (saturated, partially saturated, or aromatic bicyclic carbocyclic group of the formula (s ') or (t') wherein any bond forming the carbocyclic group may be a single bond or a double bond and is 0-4 R ¹⁰ or R ^10a. may be substituted with a group.

Further preferred are compounds of formula I wherein

R ³¹ is a group of formula (u), (v), (x) or (y) wherein the dashed line may be a single bond or a double bond substituted with 0-3 R ¹⁰ or R ^10a , n is 0 or 1, n 'is 0-2.

Further preferred are compounds of formula I wherein

R ¹ and R ²² are independently selected from the group consisting of phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, -10 • ·

- C 35 arylalkyl, C 1-5 alkoxy, -CO ² R ¹³ . -C (= O) NHOR ¹³ ', -C (= O) NHN (R ¹³ ) 2, -OR ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ¹³ ', -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ¹³ ', -NR ¹³ C (= O) N (R ¹³ ) 2 .

SO2N -NR ¹³ (R ¹³⁾ 2 R ^13, -NR SO2R ^13a, -SO 3 H, -SO ₂ R ^13a, -S (= O) R ^13a, -SR ¹³ or -SO 2 N (R ¹³⁾ 2, 2-6 C 1-4 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyloxy C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino, -OCH ₂ CO ₂ H, 2- (1-morpholino) ethoxy, or C 1-4 alkyl (the alkyl group is substituted with -N (R ¹³ ) 2, -CFR ³ , -NO 2 or -S (= O) R ^13a ).

Further preferred are the compounds of formula I, and their pharmacologically acceptable salts or prodrugs, wherein

R ³¹ is a group of formula (u), (v), (x), (y ') or (y "), which may be independently substituted with 0-3 R ¹⁰ or R ^10a , n" being 0 or 1, n 'is 0-2,

R ¹ and R ²² are each independently hydrogen, C 1 -C 4 alkyl, phenyl, benzyl, 2-4. «· · *« «* * · ·

- C 36 phenylalkyl or C 1-4 alkoxy,

R ²¹ and R ²³ are each independently hydrogen or

C 1-4 alkyl,

R ² is hydrogen or C 1-8 alkyl,

R ¹³ is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl, or C 3 -C 10 alkoxyalkyl; group,

R ^13a is C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl or C 3 -C 10 alkoxyalkyl, or two R ¹³ groups bound to the same nitrogen atom together - (CH ₂ ) ₂ . ₅ - or - _(CH2) O _(CH2) - form a group of formula

R ¹⁴ is hydroxy, hydrogen, C 1 -C 4 alkyl or benzyl,

R ¹⁰ and R ^10a are each independently hydrogen, C 1-8 alkyl, phenyl, halogen, or C 1-4 alkoxy,

J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) C (R ⁴ ) (R ⁵ ) C (= O) -, wherein

R ³ is hydrogen or methyl,

R ⁴ is hydrogen or C 1-3 alkyl,

R ⁵ is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, C 1-6 cycloalkylethyl, phenyl, phenylmethyl, -CH ₂ OH, -CH _{2 S} H, * 9 9> «« • · · · · · · · ♦ * * · * ·· · * · ··

- 37 -ch ₂ and ₃ , -ch ₂ sch ₃ , -CH ₂ CH ₂ SCH _3i - (CH ₂ ) .NH ₂ , - (CH ₂ ) _s NHC (= NH) (NH ₂ ) or - (CH ₂₎ ) _{S is} NHR ¹⁶ wherein s is 3-5,

R ¹⁶ is an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group, or

R ³ and R ⁵ together form - (CH ₂ ) _t - (t = 2-4) or - (CH ₂ ) _S C (CH ₃ ) ₂ -, or

R ⁴ and R ^{5 are} - (CH ₂ ) _U - wherein u is 2-5,

K is the L-isomeric amino acid of the formula -N (R ⁶ ) CH (R ⁷ ) C (= O) - wherein

R ⁶ is hydrogen or C 1-8 alkyl,

R ^{7 is} (e ') or (e') wherein q is 0 or 1,

- (CH ₂ ) _r X wherein r is 3-6 and (f ') or (r'') - (CH ₂ ) _m S (CH ₂ ) ₂ X where m is 1 or 2,

- (C 3 -C 7 alkyl) -NH- (C 1 -C 6 alkyl), (g),

- (CH ₂ ) _m O- (C 1-4 alkyl) -NH- (C 1-6 alkyl) wherein m is 1 or 2, or - (CH ₂ ) _m S- (C 1-4 alkyl) ) -NH- (C 1 -C 6 -alkyl) where: • t · 4 · · · · · · · · 9

- 38 m is equal to 1 or 2,

X is -NH ₂ , -NH-C (= NH) (NH ₂ ), or

R ⁶ and R ⁷ together form a group of formula (c) wherein n is 0 or 1 and

X is -NH ₂ or -NHC (= NH) (NH ₂ ), L is -Y (CH ₂ ) _V C (= O) -, wherein

Y is -NH, O or S, v is 1 or 2,

M is the D or L isomeric amino acid of formula (i) wherein q 'is 0-2,

^R17 is hydrogen or C1-3 alkyl, ^{R8 13} -CO2R, -SO3R ^13, -SO 2 NHR ^14, -B (R ³⁴⁾ (R ^35), -NHSO2CF _3, -CONHNHSO ₂ CF _3, -PO (OR ¹³ ) 2i -PO (OR ¹³ ) R ¹³ or -SO ₂ NH-heteroaryl (the heteroaryl group having 5-10 members and containing 1-4 heteroatoms nitrogen, sulfur and / or oxygen), SO ₂ NH-heteroaryl (heteroaryl group 5-10) membered and 1-4 heteroatoms selected from N, S and / or O), -SO2NHCOR ^13, -CONHSO2R ¹³ ', -CH ₂ CONHSO ₂ R ^{13a, 13a} -NHSO2NHCOR, -NHCONHSO2R ^13a, -SO2NHCONHR ¹³ or -CO ₂ R ^13b ,

R ^13b is

a) C 1-8 alkyl;

b) C2-C8 alkenyl,

c) C 2-8 alkynyl,

d) C3-C8 cycloalkyl,

e) C 1-8 -alkyl substituted with 4 4 ··· ··· 4 4

- 39 where the substituent may be

i) aryl substituted by 1-2 halogen, phenyl port, C1-5 alkyl, C1-5 alkoxy, -NO2, -S (O) ₀ 2- (C1-5 alkyl), -OH, -N (R ¹³ ) 2, -CO 2 R ¹³ . -CON (R ¹³ ) 2i and / or -C _V F _W may be substituted where v is 1 to 3 and w is 1- (2v + 1), ii) C 3 -C 8 cycloalkyl, iii) (j) a group of the formula

f) aryl optionally substituted with 1 to 2 halogens, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO 2, -S (O) ₀ -2- (C 1 -C 5 alkyl), -OH, - N (R ¹³ ) 2, -CO 2 R ¹³ , -CON (R ¹³ ) 2, and / or -C _V F _W , wherein v is 1-3 and w is 1- (2v + 1),

g) C 2 -C 8 alkyl, alkenyl or alkynyl, each with C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 5 alkoxy, phenoxy, benzyloxy, halo, -NO 2, -CN, -CO ₂ R ¹³ , -CON (R ¹³ ) ₂ , -N (R ³⁶ ) COR ³⁶ , morpholino,

With 2- (1-morpholino) ethoxy, -N (R ¹³ ) 2, -N ⁺ (R ¹³ ) 3, -OCOCH 3, -CF ₃ , and / or -S (O) o. Substituted with ₂ -R ^13a ,

h) -CH (R ³⁶ ) OR ³⁸ ;

i) -CH (R ³⁶ ) OC (= O) R ³⁷ ;

j) -CH (R ^3e ) OC (= O) OR ³⁸ , te * · · · · · · · · 9 ··· · · ·· a ♦ ·

k) -CH (R ³⁶ ) OC (= O) N (R ³⁷ ) ₂ ;

l) -CH (R ³⁶ ) N (R ³⁶ ) C (= O) R ³⁶ ;

m) -CH (R ³⁶ ) CO ₂ R ³⁷ ,

n) -CH (R ³⁶ ) CON (R ¹³ ) ₂ ;

o) -CH (R ³⁶ ) N (R ¹³ ) ₂ ;

q) a group of formula (k),

r) a group of the formula I,

s) a group of the formula m;

t) a group of formula (n),

u) a group of the formula (o),

R ³⁶ is independently hydrogen, (C 1 -C 8) -alkyl, (C 3 -C 10) -cycloalkyl, phenyl or benzyl,

R ³⁷ is

a) a hydrogen atom,

b) C 1-8 -alkyl or C 3-8 -cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N (R ¹³ ) ₂ ,

-CO ₂ R ¹³ , -C (= O) N (R ¹³ ) _2, and / or C _V F _W , wherein v is 1 to 3 and w is 1 to (2v + 1),

- 41 • ·· ··· · ··· ··· * ·· '·

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1-3 and w is 1 - (2v + 1)

R ³⁸ is as defined

a) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, where the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, It may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w is 1 - (2v + 1)

b) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, group may be substituted with -N (R ¹³⁾ 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v * ··· "···· * · · ·· ··· ··

- 42 v has a value of 1 -3 and w has a value of 1 - (2v + 1),

R ³⁹ is represented

a) a hydrogen atom,

b) C 1-8 -alkyl or C 3-8 -cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be

(i) C 1-6 alkyl, (ii) C 1-6 alkoxy, (iii) aryl having 0-2 halo, phenyl,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1)

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1)

R ⁴⁰ is hydrogen, C 1-5 alkyl or benzyl.

Also preferred are the 1 -3-disubstituted phenyl derivatives of the general formula (II) in which the phenyl ring may be substituted with 0-3 R ¹⁰ .

R ¹⁰ is independently hydrogen, C 1-8 alkyl, phenyl, halo, or C 1-4 alkoxy,

R ¹ is hydrogen, C 1-4 alkyl, phenyl, benzyl or C 1-4 phenylalkyl,

R ² is hydrogen or methyl,

R ¹³ is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl, or C 3 -C 10 alkoxy. -alkyl,

R ^13a is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 4 -C 12) alkylcycloalkyl, aryl, (C 1 -C 10 alkyl) -aryl, or (C 3 -C 10) alkoxyalkyl, or two R ¹³ groups bound to the same nitrogen atom together - (CH ₂ ) ₂ . ₅ - or - _(CH2) O _(CH2) - to form a group of formula,

R ¹⁴ is hydroxy, hydrogen, C 1-4 alkyl, or benzyl,

J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) C (R ⁴ ) (R ^S ) C (= O) -, wherein

R ³ is hydrogen or methyl,

R ⁴ is hydrogen or C 1-3 alkyl,

- 44 ^R5 is hydrogen, C1-8 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-methyl, C1-6 cycloalkyl-ethyl group, phenyl group, phenylmethyl group, -CH ₂ OH, -CH ₂ SH, -CH ₂ OCH ₃₁ -CH ₂ SCH ₃ , -CH ₂ CH ₂ SCH ₃ , - (CH ₂ ) _s NH ₂ , - (CH ₂ ) _s NHC (= NH) (NH ₂ ) or - (CH ₂ ) _s NHR ₁₆ wherein s is 3-5,

R ¹⁶ is an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group, or

R ³ and R ⁵ together form -CH ₂ CH ₂ CH ₂ -, or

R ⁴ and R ⁵ together form - (CH ₂ ) _U - wherein u is 2-5,

K is the L-isomeric amino acid of the formula -N (R ⁶ ) CH (R ⁷ ) C (= O) - wherein

R ⁶ is hydrogen or C 1-8 alkyl,

^R7 is (aa) R, group (b) wherein q is 0 or 1;

- (CH ₂ ) _r -X wherein r is 3-6, (c), (ad), - (CH ₂ ) m S (CH ₂ ) ₂ X, where m is 1 or 2,

- (C 3 -C 7 alkyl) -NH- (C 1 -C 6 alkyl), (ae) - (CH ₂ ) _m -O- (C 1 -C 4 alkyl) -NH- (C 1 -C 6 alkyl). C 1 -C 6 alkyl, where m is 1 or 2, and - (CH ₂ ) _m -S- (C 1 -C 4 alkyl) -NH- (C 1 -C 6 alkyl) wherein

- 45 m is equal to 1 or 2,

X is -NH ₂ or -NH-C (= NH) (NH 2) with the proviso that X is different from -NH ₂ when r is 4 or

R ⁶ and R ⁷ together form a group of formula (c) wherein n is 0 or 1,

X is -NH ₂ or -NHC - (= NH) (NH ₂ );

L is -Y (CH ₂ ) _V C (= O) -, wherein

Y is -NH-, oxygen or sulfur, v is 1 or 2,

M is the D or L isomeric amino acid of formula (i) wherein q 'is 0-2,

R ¹⁷ is hydrogen or C 1-3 alkyl,

R ⁸ -CO ² R ¹³ , -SO ³ R ¹³ , -SO ² NHR ¹⁴ , -B (R ³⁴ ) (R ³⁵ ), -NHSO ₂ CF _3i -CONHNHSO ₂ CF ₃ , -PO (OR ¹³ ) 2, -PO (OR ¹³ ). R ¹³ or -SO ₂ NH-heteroaryl (heteroaryl having 5-10 members and containing 1-4 heteroatoms nitrogen, sulfur and / or oxygen), -SO ₂ NH-heteroaryl (heteroaryl having 5-10 members and 1-4 heteroatoms nitrogen) , S and / or O), -SO ₂ NHCOR ^13, -CONHSO2R ¹ ', -CH ₂ CONHSO ₂ R ^13', -NHSO2NHCOR ^13a, -NHCONHSO2R ¹³ ', -SO2NHCONHR ¹³ or -CO ₂ R ^13b group of the formula

R ^13b is

a) C2-C8 alkenyl,

b) C2-C8 alkynyl,

c) substituted C 1 -C 8 alkyl, where the substituent may be

i) aryl optionally substituted with 1 to 2 halogen atoms, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO ₂ , -S (O) ₀ -2- (C 1 -C 5 alkyl), -OH, -N (R ¹³ ) 2, -CO 2 R ¹³ , -CON (R ¹³ ) 2, and / or -C _V F _W , wherein v is 1-3 and w is 1- (2v + 1), ii) C3-C8 cycloalkyl, iii) j),

e) an aryl group having 1 to 2 halogens, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO ₂ , -S (O) ₀ . ₂ - (1 -5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, CON ^(R13) 2, and / or C is substituted by a group of formula _V F _W where v is 1 -3 and w are 1- (2v + 1),

f) C2-C8-alkyl, alkenyl or alkynyl, which may be substituted with 1 to 2 identical or different substituents, wherein the substituent may be C1-C4-alkyl, C3-C8-cycloalkyl, C1-C5-alkoxy, phenoxy , benzyloxy, halogen, -NO ₂ , -CN, -CO ₂ R ¹³ , -CON (R ¹³ ) 2, or -N (R ³⁶ ) COR ³⁶ , morpholino, 2- (1-morpholino). no) -ethoxy, -N (R ¹³ ) 2, -N ⁺ (R ¹³ ) ₃ -OCOCH _3, -CF ₃ or -S (O) ₀ -2 -R ^13a ;

g) -CH (R ^3e ) OR ³⁸ ,

h) -CH (R ^3e ) OC (= O) R ³⁷ ;

i) -CH (R ³⁶ ) OC (= O) OR ³⁸ ,

j) -CH (R ^3e ) OC (= O) N (R ³⁷ ) ₂ ;

k) -CH (R ³⁶ ) CO ₂ R ³⁷ ,

(l) a group of the formula (k) or

m) a group of the formula m;

R ³⁶ is independently hydrogen, (C 1 -C 8) -alkyl, (C 3 -C 10) -cycloalkyl, phenyl or benzyl,

R ³⁷ is

a) a hydrogen atom,

b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, may be substituted by -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W group of formula wherein v is 1-3 and w = 1 to (2v + 1)

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 -alkyl; C 1-6 -alkoxy; _R 38

- 48 ports, -NO 2, -S (C1-5 alkyl), -SO (C1-5 alkyl), _-SO2 (C1-5 alkyl), -OH, -N ^(R13) 2, - CO2R ¹³ , -C (= O) N (R ¹³ ) 2, and / or C _V F _W , wherein v is 1 to 3 and w is 1 to (2v + 1).

a) C 1-8 -alkyl or C 3-8 -cycloalkyl which may be substituted with 1-2 identical or different substituents, wherein the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkyl, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1 to 3 and w = 1 to (2v + 1)

b) aryl substituted by 0-2 halogen, phenyl, C1-6 alkyl, C1-6 alkoxy, -NO _2i -S (C1-5 alkyl), -SO (C1-5 alkyl), _-SO2 (C1-5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W can be substituted by a group wherein v is 1 -3 and • · ·

- 49 w = 1- (2v + 1),

R ³⁹ is represented

a) a hydrogen atom,

b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be

(i) C 1-6 alkyl, (ii) C 1-6 alkoxy, (iii) aryl having 0-2 halo, phenyl,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1 to 3 and w = 1 to (2v + 1)

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1 to 3 and w = 1 to (2v + 1)

R ⁴⁰ is hydrogen, C 1-5 alkyl or benzyl.

Preference is given to compounds of formula II wherein the phenyl ring may be substituted with 0-2 R ¹⁰ or R ^10a ,

- 50 R ¹⁰ or R ¹⁰ 'independently of one another are hydrogen, C 1 -C 8 alkyl, phenyl, halo or C 1 -C 4 alkoxy,

R ¹ is hydrogen,

R ² is hydrogen,

R ¹³ is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl, or C 3 -C 10 alkoxy; alkyl,

R ^13a is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 4 -C 12) alkylcycloalkyl, aryl, (C 1 -C 10 alkyl) -arylpowder, or (C 3 -C 10) alkoxyalkyl, or two R ¹³ groups bonded to the same nitrogen atom together - (CH ₂ ) ₂ . ₅ - or - _(CH2) O _(CH2) - form a group of formula

R ¹⁴ is hydroxy, hydrogen, C 1 -C 4 alkyl or benzyl,

J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) CH (R ⁵ ) C (= O) -, wherein

R ³ is hydrogen and

R ⁵ is hydrogen, -CH ₃ , -CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH _3i -CH ₂ CH ₂ SCH _3, -CH ₂ CH (CH _{3) 2 R} - (CH _{2) 4} NH ₂ or - (3-5C) alkyl group of formula -NHR ^16, or

R ³ is methyl and

^R5 is hydrogen, or

R ³ and R ⁵ together form a group -CH ₂ CH ₂ CH ₂ -, - · ♦ ♦ ♦ ♦ ♦ · · «

- 51 R ¹⁶ represents an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group,

K is the L-isomeric amino acid of the formula -N (CH ₃ ) CH (R ⁷ ) C (= O) - wherein

R ⁷ is - (CH ₂ ) 3 NHC (= NH) (NH ₂ ),

L is -NHCH ₂ C (= O) -, wherein

M is the D isomer or the L isomeric amino acid of formula (i) wherein q 'is 1

R ⁴ is hydrogen or methyl,

R ¹⁷ is hydrogen,

R ⁸ -CO ₂ H, the group -S0 ₃ H or CO ₂ R ^13b formula

R ^13b is

-CH (R ³⁶ ) 0 C (= O) R ³⁷ ,

-CH (R ³⁶ ) OC (= O) OR ³⁸ or a group of formula (I),

R ³⁶ is C 1 -C 4 straight alkyl or hydrogen,

R ³⁷ is

a) a hydrogen atom,

b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 -alkyl, C 1-6 -alkoxy ···· • β ··

- 52 ports -ΝΟ2, -S (1 -5 carbon atoms) alkyl, -SO (C1-5 alkyl), _-SO2 (C1-5 alkyl), -OH, -N ^(R13) 2, - CO ² R ¹³ , -C (= O) N (R ¹³ ) 2 and / or C _V F _W , wherein v is 1 to 3 and w is 1 to 2 (v + 1),

c) an aryl group having 0-2 halogens, a phenyl group,

C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1-3 and w is 1 - (2v + 1)

R ³⁸ is as defined

a) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, where the substituent may be

(i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl,

C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1), • ·

- 53 b) an aryl group having 0-2 halogens, phenyl, C 1-6 alkyl, C 1-6 alkoxy, -NO 2, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), - _SO2 (C1-5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W of formula may be substituted by a group, wherein v is 1-3 and w is 1- (2v + 1),

R ³⁹ is C 1 -C 4 alkyl, benzyl or phenyl.

Further preferred are the compounds of formula II, the pharmacologically acceptable salts thereof having the formula

R ¹ and R ² are each independently hydrogen or methyl,

J is D-Val, D-2-aminobutyric acid, D-Leu, D-Ala, Gly, D-Pro, D-Ser, D-Lys, beta-Ala, Pro, Phe, NMeGly, D-NIe, D- Phg, D-Ile, D-Phe, D-Tyr, Ala, ^Ν ε -p-azidobenzoyl-D-Lys, N ^E benzoyl-benzoyl-D-Lys, D-Lys-NMriptofanil, NT-p-nitrobenzyl benzoyl-D-Lys, NT-p-acetylbenzoyl-D-Lys, NT-dansyl-D-Lys, N ^E -glycyl-D-Lys, N ^e -glycyl-p-benzoyl-benzoyl-D-Lys, Ν ^ε- ρ-phenyl-benzoyl-D-Lys, Ν ^ε- m-benzoyl-benzoyl-D-Lys, Ν- ^ε- o-benzoyl-benzoyl-D-Lys,

K is NMeArg or Arg,

L is Gly, beta-Ala or Ala,

M is Asp, alphaMeAsp, betaMeAsp, NMeAsp, D-Asp, Asp (methylcarbonyloxymethyl ester), Asp (ethylcarbonyloxymethyl ester),

As p- (t -butyl l -carbonyloxymethyl ethyl ester), · · · · · · ····························•

- 54 Asp (cyclohexylcarbonyloxymethyl ester),

Asp (1- (methylcarbonyloxy) ethyl ester),

Asp (1- (ethylcarbonyloxy) ethyl ester),

Asp (1- (t-butylcarbonyloxy) ethyl 1-ester),

Asp- (1- (cyclohexylcarbonyloxy) ethyl ester), Asp- (i-propyloxycarbonyloxymethyl ester), As p- (ci chlorohexylcarbonyloxy) m-ethyl ester), Asp (t-butyloxycarbonyloxymethyl ester),

Asp- (1- (i-propyl-oxy-carbonyl-oxy) -thi-ester),

Asp (1- (cyclic ex-1-oxycarbonyl-oxy) ethyl ester),

Asp (1- (t-butyl 1-oxycarbonyloxy) ethyl 1-ester),

Asp (dimethylaminoethyl 1-ester),

Asp (diethylaminoethyl 1-ester),

Asp - ((1,3-dioxo-5-methyl 1-cyano-chloro-pentene-2-n-4-yl) methyl 1-ester),

Asp - ((5- (t-butyl) -1,3-dioxa-cyclopenten-2-on-4-yl) methyl ester);

Asp - ((1,3-dioxa-5-phenylcyclopenten-2-one-4-yl) methyl 1-ester) or

Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl 1-ester).

Further preferred are the compounds of formula II or their pharmacologically acceptable salts thereof

^R1 and ^R2 are each independently hydrogen or methyl,

J is D-Val, D-2-aminobutyric acid, D-norvaline, D-Leu,

D-Ala, Gly, D-Pro, D-Ser, D-Lys, Beta-Ala, Pro, Phe,

NMeGly, D-NIe, D-Phg, D-lle, D-Phe, D-Tyr, Ala,

K is NMeArg,

- 55 L is Gly,

M is Asp, alphaMeAsp, betaMeAsp, NMeAsp, D-Asp, Asp- (methylcarbonyloxymethyl ester), Asp- (ethylcarbonyloxymethyl ester), Asp- (tb Travel 1-carbonyl). oxymethyl ester), Asp (cyclohexylcarbonyloxymethyl ester), Asp (1- (methylcarbonyloxy) ethyl ester), Asp (1- (ethylcarbonyl) yloxy) ethyl ester), Asp (1- (t-butylcarbonyloxy) ethyl ester), Asp (1- (cyclohexylcarbonyloxy) ethyl ester), Asp- (i-propyloxycarbonyloxymethyl ester), Asp (cyclohexylcarbonyloxymethyl ester), Asp-O-butyloxycarbonyloxymethyl ester),

Asp (1- (i-propyloxycarbonyloxy) ethyl ester),

Asp (1- (cyclohexyloxycarbonyloxy) ethyl ester),

Asp (1- (t-butyloxycarbonyloxy) ethyl ester),

Asp (dimethylamino-ethyl ester),

Asp (di-ethylamino-ethyl-ester),

Asp - ((1,3-dioxa-5-methyl-cyclopenten-2-on-4-yl) methyl ester);

Asp - ((5- (t-butyl) -1,3-dioxa-cyclopenten-2-on-4-yl) methyl ester);

Asp - ((1,3-dioxa-5-phenylcyclopenten-2-one-4-yl) methyl ester) or

Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester).

Particular emphasis is given to the following compounds of the invention and their pharmacologically acceptable salts:

- A compound of formula II wherein

R ¹ and R ² are hydrogen,, <♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦.

- 56 for J with D,

K is NMeArg,

L is Gly and

M is Asp (methylcarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J represents D-Val ,,

K is NMeArg,

L is Gly and

M is Asp (ethylcarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (t-butylcarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (cyclohexylcarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (1- (methylcarbonyloxy) ethyl ester);

- A compound of formula (II) wherein * · V · · · · · · · · · · ·

- 57 R ¹ and R ² are hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (1- (ethylcarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (1- (t-butylcarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (1- (cyclohexylcarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (isopropyloxycarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (cyclohexylcarbonyloxymethyl ester);

·· • V «« · «

* · T · ··· ··

• ·· · ♦ ·

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (t-butyloxycarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (1- (isopropyloxycarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (1- (cyclohexyloxycarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (1- (t-butyloxycarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L stands for Gly and • · · · * * ··· ·· 4 «« · · · · ···

- 59 M is Asp (dimethylaminoethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (diethylaminoethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp - ((1,3-dioxa-5-methylcyclopenten-2-one-4-yl) methyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp - ((5- (t-butyl) -1,3-dioxa-cyclopentene-2-one-4-yl) methyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp - ((1,3-dioxa-5-phenylcyclopenten-2-one-4-yl) methyl ester);

- A compound of formula II wherein

- 60 R ¹ and R ² are hydrogen,

J is D-Val,

K is NMeArg,

L is Gly and

M is Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp-methylcarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (ethylcarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (t-butylcarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

- 61 M is Asp (cyclohexylcarbonyl) methyl ester;

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (1- (methylcarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (1- (ethylcarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (1- (t-butylcarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp- (1- (cyclo-exo-1-carboxyl) oxy) ethyl;

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

- 62 L is Gly and

M is Asp-isopropyloxycarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (cyclohexylcarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (t-butyloxycarbonyloxymethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (1- (isopropyloxycarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (1- (cyclohexyloxycarbonyloxy) ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

- 63 K for NMeArg,

L is Gly and

M is Asp (1- (t-butyloxycarbonyloxyO-ethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (dimethylaminoethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp (diethylaminoethyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp - ((1,3-dioxa-5-methylcyclopenten-2-one-4-yl) methyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen,

J is D-2-aminobutyric acid,

K is NMeArg,

L is Gly and

M is Asp - ((5- (t-butyl) -1,3-dioxa-cyclopenten-2-one-4-yl) methyl ester);

• · ·

- a compound of formula (II) wherein R ¹ and R ² are hydrogen,

J is D-2-aminobutyric acid, K is NMeArg, L is Gly and

M is Asp - ((1,3-dioxa-5-phenylcyclopenten-2-one-4-yl) methyl ester);

- A compound of formula II wherein

R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg; L is Gly and

M is Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester).

The compounds of the present invention have been found to inhibit glycoprotein IIb / IIIa (GPIIb / IIIa). As mentioned above, GPIIb / IIIa mediates the process of platelet activation and aggregation. The compounds of the present invention inhibit platelet activation and aggregation by any known endogenous platelet agonist.

The compounds are thus useful in the treatment or prevention of processes involving platelet activation and aggregation. Examples include arterial or venous cardiovascular or cerebrovascular thromboembolic disorders such as unstable angina, thromboembolic disorders, first or recurrent myocardial infarction, sudden ischemic death, pulmonary atherosclerosis, diabetes. The above state • · • ·

For treating 65 capsules, the patient is administered a pharmacologically effective amount of a compound of the invention. The compounds of the present invention inhibit the binding of fibrinogen to platelets and inhibit platelet aggregation and are therefore useful in the treatment of a thrombus or embolus or in the prevention of thrombus or embolism in a mammal. Thus, the compounds of the present invention may be used as a medicament for blocking fibrinogen by preventing fibrinogen from acting at receptor sites.

The compounds of the invention may be combined with other active ingredients or administered together. Examples of these include coagulation inhibitors such as heparin or warfarin, and antiplatelet agents or platelet inhibitors such as aspirin, piroxicam or ticlopidine. The compounds of the invention may also be combined with thrombin inhibitors such as boropeptides, hirudin or argatroban. The compounds of the present invention may also be combined with thrombolytic or fibrinolytic agents such as plasminogen activators, anistreplase, urokinase or streptokinase. The compounds of the invention may also be combined with a combination of the above active ingredients and / or other therapeutic agents. The effect of such combination products may be synergistic or additive in relation to the effect of the compounds of the invention in the treatment or prevention of, for example, thromboembolic diseases.

The GPIIb / IIIa antagonists of the present invention are the final steps in the normal pathway of platelet aggregation to normal platelet-induced platelet aggregation.

.... .. ..:

........

in his mouth. On the other hand, GPIIb / IIIa antagonists do not affect platelet granular secretion, i.e., the release of various important biomolecules from the alpha particle (PAI-1) or the dense particle (serotonin). The above platelets, selected from platelets, play an important role in arterial cramping (serotonin) and in reducing the efficiency of natural disruptors (PAI-1). The combination of the compounds of the present invention and other agents may interfere with this mechanism and thus provide a particularly effective therapy for various heterogeneous thromboembolic disorders.

The GPIIb / IIIa antagonists of the invention, which exhibit strong affinity for the platelet GPIIb / IIIa receptor (Kd <0.01 pmol / l), are not only effective in preventing thrombosis but also accelerate the dissolution of platelet rich blood clot, and therefore such antiplatelet agents are both acute and chronic. can be better utilized in thromboembolic disorders. Such a strategy can be an effective adjunctive therapy in combination with thrombolytic therapy. Platelet activation after thrombolytic therapy may play a significant role in delaying re-flow and re-occlusion.

The term anticoagulant (or coagulation inhibitor) refers to drugs that inhibit blood coagulation. Examples of such agents are warfarin, heparin and low molecular weight heparin (abbreviated as LMWH), and their pharmacologically acceptable salts or prodrugs. Because of their efficacy, warfarin, heparin or LMWH are preferred anticoagulants. Suitable as warfarin • «

For example, crystalline warfarin or amorphous sodium warfarin. Heparin can be used, for example, as its sodium or sulfate salt.

The term antiplatelet agent (or platelet inhibitor) refers to an agent that inhibits platelet function, thereby inhibiting platelet aggregation, adhesion or granular excretion. Such active substances include various known non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpirone, and the pharmacologically acceptable salts or prodrugs thereof. Among the NSAIDS, aspirin (acetylsalicylic acid or ASA), which is widely known and can be used with good results, and piroxicam, a once-daily anti-platelet agent, are preferred, particularly aspirin. The active ingredient piroxicam is marketed by Pfizer Inc. (New York, USA) as FELDANE. Ticlopidine or pharmacologically acceptable salts or prodrugs thereof may also be used as antiplatelet agents. Ticlopidine is also advantageous due to its gentle properties on the gastrointestinal tract. Thromboxane A ₂ receptor antagonists and thromboxane A ₂ synthetase inhibitors as well as their pharmacologically acceptable salts or prodrugs are also useful as platelet inhibitors.

The term thrombin inhibitor refers to an agent that inhibits the serine protease thrombin. Inhibition of thrombin inhibits various thrombin-mediated processes • · ·

68 such as thrombin mediated platelet activation (i.e., platelet aggregation and / or granular secretion of plasminogen activator inhibitor 1 and / or serotonin) and / or fibrin formation. Examples of such inhibitors include boropeptides, hirudin, and argatroban, and their pharmacologically acceptable salts and prodrugs. Boropeptides such as boric acid derivatives of lysine, ornithine, arginine and homoarginine, such as C-terminal alpha-aminoboronic acid derivatives, and the corresponding isothiuronium analogs are preferably used as thrombin inhibitors. The term hirudin encompasses the corresponding derivatives or analogs of hirudin, also known as hirudin, such as disulfate hirudin.

Preferred boropeptide thrombin inhibitors are disclosed in US 5,187,157 and EP 293881. Other boropeptide thrombin inhibitors are disclosed in WO 92/07869 and EP 471651.

The term thrombolytic (or fibrinolytic) agent (or thrombolytic or fibrinolithium) refers to an agent that disrupts the blood clot (thrombus). Examples of such materials include tissue plasminogen activator, anistreplase, urokinase or streptokinase, and their pharmacologically acceptable salts or prodrugs. The tissue plasminogen activator (tPA) is commercially available from Genentech Inc. (South San Francisco, California, USA). The term anistreplase refers to an anisoylated plasminogen streptokinase activator complex (EP 028489). Anistreplase is marketed by Beecham Group (Middlesex, England) as EMINASE. The urokinase out • ♦

Section 69 encompasses double and single chain urokinase, within which the latter is preferred, also known as prourokinase.

Combination products wherein the cyclic compounds of the present invention are combined or administered with a suitable anticoagulant agent, antiplatelet agent, thrombin inhibitor, and / or thrombolytic agent, have a superior effect over the administration of the compounds alone and thus allow dose reduction of each active agent. A lower dose reduces the risk of side effects and thus increases the safety of treatment.

Clinical examination of crystalline sodium warfarin as an anticoagulant agent alone demonstrates the efficacy of the treatment or the secondary prevention of coronary artery disease. Out of three published, randomized, controlled trials of acute myocardial infarction, oral anticoagulant treatment significantly reduced overall mortality and the incidence of recurrence of infarction in one study. Of the four published, extensive, randomized, and controlled trials of oral anticoagulants, the incidence of re-infarction and premature death were reduced in three cases in the secondary prevention of myocardial infarction. Studies of the effect of warfarin on the reoccurrence of myocardial infarction have also shown a significant reduction in mortality, recurrence of myocardial infarction, and stroke compared to placebo in post-myocardial infarction.

The results of the anti-platelet agent itself, such as acetylsalicylic acid (ASA) alone, have also shown promise in the prevention and treatment of coronary artery disease.

- 70 for treatment. In patients with unstable angina, ASA reduces myocardial infarction and death in two large, randomized, double-blind, placebo-controlled clinical trials. In addition, ASA has been shown to be useful in secondary prevention of myocardial infarction in several cumulative studies, as it reduces the risk of recurrence of myocardial infarction and death. In addition, one of the two studies conducted on the effect of ASA on the primary prevention of coronary artery disease reports a dramatic and another report insignificant effects. In addition to their action on coronary artery disease, antiplatelet agents such as ASA and ticlopidine can be used to prevent stroke in people with cerebrovascular disease. Pooled data from nine randomized trials have shown that ASA alone is effective in reducing the risk of complete stroke in people with a history of ischemic attack. Ticlopidine alone has recently been shown to be effective in this case.

With respect to thrombin inhibitors, such as boropeptides, these compounds have been shown to excellently regulate thrombin-mediated processes. Studies with hirudin, another thrombin inhibitor, have shown that this compound is effective in treating venous and arterial thrombosis.

Thrombolytic agents such as plasminogen activator (tPA), streptokinase or urokinase have also recently been used in the treatment of patients with acute myocardial infarction. These standard thrombolytic agents, when administered alone, promote the formation of plasmin, which destroys platelet-rich fibrin clots.

However, thromboembolic disorders are known to have different pathophysiology. Therapeutic treatment of diseases should therefore take into account the various pathophysiological options and use components that mitigate the various pathophysiological aspects. A combination product comprising an anticoagulant such as warfarin or heparin or a platelet disruptor such as aspirin, piroxicam or ticlopidine or a thrombin inhibitor such as boropeptide, hirudin or argatroban, or a thrombolytic agent such as tissue plasminogen activator, , or a combination thereof with the novel cyclic compounds of the present invention, satisfies this condition. In addition, a lower dose of each active ingredient, sufficient to produce an additive or synergistic effect, significantly reduces the risk of side effects of the active ingredient administered alone at high doses. In addition, the use of a single dosage form preferred according to the invention is generally more convenient for the patient. A further advantage of a single dosage form is that it reduces the risk of confusion for the patient, which often occurs when multiple drugs are administered simultaneously. The combined use of an anticoagulant agent and a compound of the invention, an antiplatelet agent, and a compound of the invention, a thrombin inhibitor, and a compound of the invention, a thrombolytic agent, and a compound of the invention, or combinations thereof.

Metastatic tumor cells are known to express high levels of GPIIb / IIIa. The compounds of the invention are either

72 combination products can also be used to treat and prevent metastatic cancer.

The compounds described may contain centers of asymmetry. Unless otherwise indicated, all chiral, diastereomeric, and racemic forms are included. The disclosed compounds may also contain various geometric isomers of olefins, C = N double bonds, and the like, and include all stable isomers. The compounds of the present invention containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. The optically active forms are prepared in conventional manner, for example by resolution of the racemic forms or by synthesis with optically active starting materials. Two different isomers (cis and trans) may appear on the peptide bond, both may occur, and all stable isomers are within the scope of the invention. Unless otherwise indicated, the compounds of the invention contain the L isomeric amino acid at the J, K, L and M positions. Except as noted above, the structure includes all chiral, diastereomeric, racemic, and all geometric isomeric forms, otherwise the specific stereochemical or isomeric forms are specified. The D and L isomeric forms of a given amino acid are given the usual three-letter abbreviation as follows: D-Leu, D-Leu, L-Leu or L-Leu.

If a variable occurs several times in the molecule (for example, R ¹ -R ⁸ , m, η, ρ, X, or Y), the interpretation of these variables is independent of each occurrence. For example, when a group is substituted with 0-2 R ¹¹ ,

73, the group may optionally carry up to two R ¹¹ groups, and the meaning of each R ¹¹ group is independently selected from the meaning given to R ¹¹ . Another example is the group -N (R ¹³ ) ₂ , wherein the two R ¹³ groups on the nitrogen atom are independently selected from the group given.

If a bond in a group intersects the bond between the two atoms in the ring, then that group can be bonded to any atom in the ring.

The combination of different substituents and / or variables is permissible if the combination results in a stable compound.

By stable compound or stable structure is meant a compound which can withstand isolation up to the desired degree of purity from the reaction mixture and can be formulated as an effective therapeutic agent.

Substituted means that one or more hydrogen atoms of a given atom are replaced by a group selected from the given interpretation provided that the normal valence of the given atom is not exceeded and substitution results in a stable compound. If the substituent is a keto group (i.e. = 0), then the two hydrogen atoms on the atom are replaced.

The term alkyl refers to a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms. The term "haloalkyl" means a branched or unbranched saturated aliphatic hydrocarbon group having the indicated number of carbon atoms and having one or more halogen atoms

- substituted with 74 (by way of example, -C _V F _W where v is 1-3 and w is 1- (2v + 1)), the alkoxy is a defined alkyl bonded through an oxygen bridge, the cycloalkyl is a saturated cyclic group which may be a mono-, bi- or polycyclic ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl, while bicycloalkyl is a saturated bicyclic ring system, such as [3.3.0] [4.3.0] bicyclooctane; ] bicyclononane, [4.4.0] bicyclo decane (decalin) and [2.2.2] bicyclooctane. The alkenyl group contains a straight or branched hydrocarbon chain and one or more unsaturated carbon bonds which may occur at any stable point in the chain, such as ethenyl and propenyl. The alkynyl group contains a straight or branched hydrocarbon chain and one or more triple carbon-carbon bonds which may occur at any stable point in the chain, such as ethynyl or propynyl.

The term boric acid refers to the group -B (R ³⁴ ) (R ³⁵ ) wherein R ³⁴ and R ³⁵ are each independently hydroxy, fluoro, -NR ¹³ R ¹⁴ or C 1-8 alkoxy, or R ³⁴ and R ³⁵ together form a cyclic boronic ester containing from 2 to 20 carbon atoms and optionally from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, forms a divalent cyclic boramide containing from 2 to 20 carbon atoms and optionally from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen atoms contains or forms a cyclic boramide ester group having 2 to 20 carbon atoms and giving 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen;

- Contains 75 motors. Such cyclic boronic ester, boramide or boramide ester may be optionally substituted with 1-5 R ¹¹ groups.

The boronic ester may be a boronic acid protecting group, such as a di-derivative such as pinanediol and pinacol, which form pinanediol boronic ester and pinacol boronic acid. Other examples of diols for boric esters include pefluoro-pinacol, ethylene glycol, diethylene glycol 1,2-ethanediol,

1,3-propanediol, 1,2-propanediol, 1,2-butanediol, 1,4-butanediol, 2,3-butanediol, 2,3-hexanediol, 1,2- hexane diol, catechol, 1,2-diisopropylethane diol, 5,6-dicanediol and 1,2-dicyclohexyl ethanediol.

The halogen atom may be fluorine, chlorine, bromine or iodine. The elien ion is a small, negatively charged ion such as chloride, bromide, hydroxide, acetate or sulfate.

The aryl or aromatic group may be phenyl or naphthyl. The carbocyclic group may be any stable 3-7 membered monocyclic or bicyclic ring, 7-14 membered bicyclic or tricyclic ring, and up to 26 membered polycyclic rings, which may be saturated, partially unsaturated or aromatic. Examples of such a carbocyclic group include cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indonyl, adamantyl and tetrahydronaphthyl (tetralin).

The heterocyclic group or heterocyclic ring system may be any stable 5-7 membered monocyclic or bicyclic ring, or a 7-10 membered bicyclic heterocyclic ring, which may be saturated, partially unsaturated or aromatic, containing carbon atoms and 1-4-heteroatom nitrogen, oxygen.

- Contains 76 atoms and / or sulfur atoms, wherein the nitrogen and sulfur atoms are optionally in oxidized form and wherein the nitrogen atom is optionally in quaternized form. The term includes bicyclic groups in which a heterocyclic ring as defined above is fused to a benzene ring. The heterocyclic ring may be attached via any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on nitrogen. Examples of such heterocyclic rings include benzpyran, thiadiazine, tetrazole, benzofuran, benzothiophene, indoline, quinoline, isoquinoline, benzimidazole, piperidine, 4-piperidone, 2-pyrrolidone, tetrahydrofuran, tetrahydroquinoline, tetrahydroisoquinoline, decahydroquinoline, decahydro 2,3-, 1,2,4- and 1,3,5-triazine), 6H-1,2,5-thiadiazine, 2H, 6H1,5,2-dithiazine, thiophene, tetrahydrothiophene, thiantrene, furan, pyran , isobenzofuran, chromium, xanthene, phenoxanthine, 2H-pyrrole, from red, imidazole, pyrazole, thiazole, isothiazole, oxazole (such as 1,2,4- and 1,3,4oxazole), isoxazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, 3H-indole, indole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, 4aH-carbazole, carbazole, beta-carboline, phenanthridine, acridine, perimidine, phenanthroline, phenazine, fenarsazine, phenothiazine, furazane, phenoxacin, isochroman, chroman, pyrrolidine, pyrroline, imi dazolidine, imidazoline, pyrazolidine, pyrazoline, piperazine, indoline, isoindoline, quinuclidine or morpholine. Also possible are fused ring systems and spiro ring systems containing, for example, the above-mentioned heterocyclic rings.

77 Any group which, when administered to a mammal, is cleaved to form a free hydroxy, amino or sulfhydryl group, is a group attached to an oxygen atom, a nitrogen atom or a sulfur atom which is cleaved from an oxygen atom, nitrogen atom or sulfur atom when administered to a mammal and thus a free hydroxyl group. , a compound containing an amino group or a sulfhydryl group. When the mammal is administered to the mammal, a leaving group for the formation of a free hydroxy, amino or sulfhydryl group is, for example, C 1-6 alkyl substituted with 0-3 R ¹¹ , C 3-6 alkoxyalkyl substituted with 0-3 R ^11. C 1-6 alkylcarbonyl substituted with 0-3 R ¹¹ , C 1-6 alkoxycarbonyl substituted with 0-3 R ¹¹ , substituted C 1-6 alkylaminocarbonyl substituted with 0-3 R ¹¹ , benzoyl substituted with 0-3 R ¹² , phenoxycarbonyl substituted with 0-3 R ¹² , and phenyl substituted with 0-3 R ¹² ; aminocarbonyl group substituted with 0-3 R ¹² groups. Further examples of the cleavage moiety upon administration to a mammal to form a free hydroxyl, amino or sulfhydryl group include hydroxyl protecting groups, amine protecting groups or sulfhydryl protecting groups.

The term amine protecting group means any group used in organic synthesis to protect an amine group. Such amine protecting groups are described in Greene, Protective Groups in Organic Synthesis, by John Wiley and Sons,

78 New York (1981) and The Peptides: Analysis, Synthesis, Biology, Volume 3, Academic Press, New York (1981). Any known amine protecting group may be used. Examples of amine protecting groups include:

1) acyl groups such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl;

2) aromatic carbamate groups such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1 (p-biphenyl) -1-methylethoxycarbonyl and g-fluorenylmethyloxycarbonyl group (Fmoc),

3) aliphatic carbamate groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl,

4) a cyclic alkyl carbamate group such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;

5) alkyl groups such as triphenylmethyl and benzyl;

6) trialkylsilane such as trimethylsilane and

7) thiol groups such as phenylthiocarbonyl and dithiazuccinoyl.

Further examples of amine protecting groups include acyl groups such as azido-benzoyl, p-benzoyl-benzoyl, obenzyl-benzoyl, p-acetyl-benzoyl-powders, dansyl, glycyl-p-benzoyl-benzoyl, phenyl-benzoyl, m-benzoyl-benzoyl and benzoyl-benzoyl.

The term pharmacologically acceptable salt means an acidic or basic salt of a compound of formula (I). Examples of pharmacologically acceptable salts include basic groups such as amines with mineral acid or organic.

79 salts of acids and alkali metal or organic salts of acidic groups such as carboxylic acids.

The term prodrug refers to a covalently bonded carrier which, when administered to a mammal, delivers the compound of formula (I) in vivo. Prodrugs of compounds of formula (I) may be prepared by modifying the functional groups present in the compound such that the modified derivative is cleaved to the parent molecule in a conventional manner or under in vivo conditions. Exemplary prodrugs of the compounds of formula I include those in which the hydroxyl, amine or sulfhydryl group is attached to a group which, when administered to a mammal, cleaves to form a free hydroxyl, amino or sulfhydryl group. Exemplary prodrugs include the acetate, formate and benzoate derivatives of the alcohol and amine functional groups present in the compound of formula (I).

Pharmaceutically acceptable salts of the compounds of the invention may be prepared by reacting the free acid or base form with a stoichiometric amount of the appropriate base or acid in water, organic solvent or mixture thereof, preferably in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetone. . A list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA (USA), 1418 (1985).

The term amino acid refers to an organic compound having a basic amino group and an acidic carboxyl group at the same time. The term encompasses modified and unusual amino acids, such as: Roberts and Vellaccio: The

80 Peptides, 5, 342-429 (1983). Examples of modified or unusual amino acids for use in the present invention include D-amino acids, hydroxylysine, 4-hydroxyproline, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenyl- glycine, beta-phenyl-proline, tert-leucine, 4-aminocyclohexylalanine, N-methyl norleucine, 3,4-dehydroproline, 4-aminopiperidine-4-carboxylic acid, 4-aminocaproic acid, trans 4-aminomethyl-cyclohexanecarboxylic acid, 2-, 3- and 4- (aminomethyl) -benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid and 2-benzyl-5 amino acid.

An amino acid residue is a portion of an amino acid that occurs in a peptide.

The term peptide refers to a linear compound consisting of two or more amino acids linked together by peptide bonds. The term peptide also encompasses compounds consisting of peptide components and non-peptide components, such as pseudopeptides or peptide-like residues or other non-amino acid components. Such a compound consisting of peptide and non-peptide components may be a peptide analog.

The pseudopeptide or peptide-like compound is a compound which mimics the structure of an amino acid residue or a peptide having, for example, a non-amide bond between the peptide-like group and the amino acid residue (pseudopeptide bond) and / or non-amino acid substituents and / or or a modified amino acid residue.

The pseudopeptide residue refers to that part of the pseudopeptide or peptide-like group present in the peptide.

***. ··; · * * ·· ··· ·· * · ..

81 A peptide bond is a covalent amide bond formed by leaving water between the carboxyl group of one amino acid and the amino group of another amino acid.

The pseudopeptide bond represents an isostere of peptide bond that can be used instead of the normal amide bond. Such an amide equivalent bond can be formed between atoms that are not commonly found in peptides or proteins, which mimic the space requirement of the amide bond and which stabilize the molecule against enzymatic degradation.

The compounds of the present invention can be prepared by various methods known in the art of organic synthesis. Some preferred methods are described below.

The following abbreviations are used:

D-Abu = D-2-aminobutyric acid beta-Ala, b-Ala or BetaAla = 3-aminopropionic acid Boc = tert-butoxycarbonyl Boc-iodo-Mamb = tert-butyloxycarbonyl-3-aminomethyl-4-iodo benzoate Boc-Mamb = tert-butyloxycarbonyl-3-aminomethyl-benzo ésav Boc-ON = [2- (tert-butyloxycarbonyl-oxyimino) -2-phenyl- acetonitrile CI ₂ Bzl = dichlorobenzyl CBZ or Cbz = carbobenzyloxy DCC = dicyclohexylcarbodiimide DIEA = diisopropylethylamine di-NMeOrn = N-alphaMe-N-gammaMe-ornithine DMAP = 4-dimethylaminopyridine

··· ··· ··

HBTU = 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl- uró ammonium hexafluorophosphate

You're NMeArg

Arg = alpha-N-methyl-arginine NMeAmf = N-methylaminomethylphenylalanine NMeAsp = alpha-N-methyl aspartic acid

You're NMeGly

MeGly = N-methylglycine N-Me-Mamb = N-methyl-3-aminomethyl-benzoic acid NMM = N-methylmorpholine OcHex = O-cyclohexyl Obzl = O-benzyl TBTU = 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyl- uro nium tetrafluoroborate Tos = tosyl.

The following three-letter abbreviations are used to designate amino acids, but the one-letter amino acid abbreviation is not used in this specification:

Bottom: alanine

Arg: arginine

Asn: Asparagine

Asp: aspartic acid

Cys: cysteine

Gin: Glutamine

Glu: glutamic acid

Gly: glycine

His: histidine

Ile: isoleucine

Leu: leucin ·

- 83 Lys: lysine

Met: methionine Nle: norleucine Phe: phenylalanine Phg: phenylglycine Pro: proline Ser: serine Thr: threonine Trp: tryptophan Tyr: tyrosine Val: valine.

The compounds of the invention may be prepared by standard standard synthetic methods. Preferred methods are those described below.

Peptides are generally lengthened by deprotection of the alpha amino group of the C-terminal residue and linked to the next suitably protected amino acid by forming a peptide bond. The deprotection and coupling is repeated until the desired sequence is obtained. The coupling may be carried out stepwise with the appropriate amino acids or by condensation of fragments (containing two or more amino acids) or by combining the two methods or by solid phase peptide synthesis (Merrifield, J. Am. Chem. Soc., 85, 2149-2154 (1963)).

The compounds of the invention may also be prepared using an automatic peptide synthesizer. Further literature on peptide synthesis can be found in Stewart and Young, Solid Phase Peptide Synthesis, 2nd edition, Pierce Chemical Co., Rockford, IL, USA (1984); Gross, Meienhofer and Udenfriend:

- 84 The Peptides: Analysis, Synthesis, Biology, Volumes 1, 2, 3, 5 and 9, Academic Press, New York (1980-1987); Bodanszky, Peptide Chemistry: A Practical Textbook, Springer-Verlag, New York (1988); Bodanszky et al., The Practice of Peptide Synthesis, Springer-Verlag, New York (1984).

Coupling or cyclization of two amino acid derivatives, one amino acid and one peptide, or two peptide fragments, can be accomplished by conventional coupling methods such as the azide method, the mixed carboxylic acid anhydride method (isobutyl chloroformate method), the carbodiimide method (dicyclohexyl). carbodiimide, diisopropylcarbodiimide or water soluble carbodiimide method), active ester method (p-nitrophenyl ester or N-hydroxysuccinimido ester method), Woodward K-reagent method, carbonyldiimidazole method, phosphorus reagent ( such as BOP-CI) or oxidation-reduction method. Some of the above methods (in particular the carbodiimide method) can be improved using 1-hydroxybenzotriazole. These coupling procedures are carried out in solution (liquid phase) or solid phase.

To prevent the formation of unwanted bonds, the following amino acid functional groups are protected during the coupling reaction. Such protecting groups are described, for example, in Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, New York (1981) and The Peptides: Analysis, Synthesis, Biology, Volume 3, Academic Press, New York (1981).

• · ·

The alpha-carboxyl group of the C-terminal residue is generally protected by an ester which can be cleaved during the formation of the carboxylic acid. Examples of such protecting groups include:

1) alkyl esters such as methyl ester and tert-butyl ester,

2) aryl esters such as benzyl ester and substituted benzyl ester, or

3) esters such as trichloroethyl ester and phenacyl ester which can be cleaved under mild alkaline conditions or under mild reductive conditions.

In the solid phase reaction, the C-terminal amino acid is bound to an insoluble carrier (usually polystyrene). Such an insoluble carrier contains a group which reacts with the carboxyl group to form a stable but easily cleavable bond during peptide formation. Examples include oxime resins (DeGrado and Kaiser, J. Org. Chem. 45, 1295-1300 (1980)), chlorine or bromomethyl resins, hydroxymethyl resins and aminomethyl resins. These resins are generally commercially available and contain the desired C-terminal amino acid.

The alpha-amino group of each amino acid must be protected. Any conventional protecting group may be used. Examples include:

1) acyl protecting groups such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl;

2) aromatic carbamate protecting groups such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1- (p-biphenyl) -1-methylethoxycarbonyl and 9-fluorenylmethyloxy; carbonyl group (Fmoc),

3) aliphatic carbamate protecting groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl,

4) cyclic alkyl carbamate protecting groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;

5) alkyl protecting groups such as triphenylmethyl and benzyl;

6) trialkylsilane such as trimethylsilane, and

7) thiol-protecting groups such as phenylthiocarbonyl and dithiazuccinoyl.

Preferred alpha-amino protecting groups are Boc and Fmoc. Most amino acid derivatives are commercially available in protected form for peptide synthesis.

The alpha-amino protecting group is cleaved before the next amino acid is bound. When a Boc group is used, this can be accomplished with trifluoroacetic acid alone or in dichloromethane or hydrochloric acid in dioxane. The resulting ammonium salt is neutralized prior to coupling or in situ in an alkaline solution such as aqueous buffer or tertiary amine in dichloromethane or dimethylformamide. When the Fmoc group is used, the reagent may be piperidine or substituted piperidine in dimethylformamide or any secondary secondary amine or aqueous alkaline solution. Deprotection is carried out between 0 ° C and room temperature.

Functional residues in the side chain of amino acids are protected by one of the aforementioned groups during peptide formation. One skilled in the art will recognize that the appropriate protecting group for the side chain functional groups is selected depending on the amino acid and peptide protecting groups. When selecting such a protecting group, it is important that it is not cleaved during removal and coupling of the alpha amino acid protecting group.

For example, when a Boc group is used as an alpha-amino protecting group, the following protecting groups may be used: p-toluenesulfonyl (tosyl) and nitro for arginine, benzyloxycarbonyl, substituted benzyloxycarbonyl, or tosyl. lysine, benzyl or alkyl ester such as cyclopentyl ester for glutamic acid and aspartic acid, benzyl ether for serine and threonine, benzyl ether, substituted benzyl ether or 2-bromobenzyloxycarbonyl for tyrosine a p-methylbenzyl group, a p-methoxybenzyl group, an acetamidomethyl group, a benzyl group or a t-butylsulfonyl group for cysteine, while the indole moiety of tryptophan can be left without protecting group or protected formyl group.

When an Fmoc group is used as the alpha-amino protecting group, a tert-butyl-based protecting group is generally used. For example, Boc can be used for lysine, tert-butyl ether for serine, threonine and tyrosine and tert-butyl ester for glutamic acid and aspartic acid.

After the peptide is formed and cyclized, all protecting groups are removed. In the case of liquid phase synthesis, deprotection can be accomplished by any of the methods described above. These methods are known to those skilled in the art.

In the case of solid phase synthesis, the peptide is cleaved from the resin without deprotection of the functional groups that affect the cyclization. Thus, when the peptide is cyclized in solution, free alpha-carboxylate and free alpha-amino groups are prepared during the cleavage without further cleavage of the protecting groups. Alternatively, the peptide may be coupled from the resin by hydrazinolysis followed by the azide method. Alternatively, the peptide may be prepared on an oxime resin and then removed by intramolecular nucleophilic substitution to provide a cyclic peptide (Osapay, Profit and Taylor, Tetrahedron Letters, 43, 6121-6124 (1990)). When using an oxime resin, the Boc group is generally used as a protecting group. In this case, the side chain protecting groups are preferably removed with anhydrous hydrogen fluoride containing dimethyl sulfide, anisole, thioanisole or p-cresol as an additive at 0 ° C. Cleavage of the peptide can also be accomplished with other acidic reagents such as trifluoromethanesulfonic acid / trifluoroacetic acid.

Unusual amino acids useful in the present invention can be prepared by methods known to those skilled in the art (The Peptides: Analysis, Synthesis, Biology, Vol. 5, 342-449, Academic Press, New York (1981)). For example, an N-alkyl amino acid may be prepared by the method described previously (Cheung et al., Can. J. Chem. 55, 906 (1977); Freidinger et al., J. Org. Chem. 48, 77 (1982)).

The compounds of the present invention may be prepared by the methods described below and by the methods described in WO 93/07170. Exemplary compounds, but not specifically described, are described in WO 93/07170.

Representative examples of materials and methods that can be used to prepare the compounds of the present invention are provided below.

Manual solid phase peptide synthesis was performed in a 25 mL polypropylene filter tube (BioRad Inc.). Oxime resin (substitution level = 0.96 mmol / g) was prepared by DeGrado and Kaiser, J. Org. Chem. 45, 1295 (1980). The reagents and solvents were used without further purification. The tert-butyloxycarbonyl (Boc) amino acids and other starting amino acids are commercially available (Bachem Inc., Bachem Biosciences Inc., Philadelphia, PA, USA, Advanced ChemTech, Louisville, KY, USA, Peninsula Laboratories, Belmont, CA, USA, and Sigma, St. Louis, MO, USA). 2 (1H-Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and TBTU are available from Advanced ChemTech. N-methylmorpholine (NMM) is m-cresol, D-2-aminobutyric acid (Abu), trimethylacetyl chloride, diisopropylethylamine (DIEA), 3-cyanobenzoic acid, and [2- ( tert-butyloxycarbonyl-oxyimino) -phenylacetonitrile] (Boc-ON) is available from Aldrich Chemical Company. Dimethylformamide (DMF), ethyl acetate, chloroform (CHCl ₃ ), methanol (MeOH), pyridine and hydrochloric acid (HCl) are available from Baker. Acetonitrile, dichloromethane (DCM), acetic acid (HOAc), trifluoroacetic acid (TFA), ethyl ether, triethylamine, acetone, and magnesium sulfate are available from EM Science. 10% Pd / C catalyst is available from Fluka Chemical Company. Absolute ethanol is available from Quantum Chemical Corporation. Thin layer chromatography (TLC) was performed on a silica gel 60 F ₂₅₄ TLC plate (0.2 mm layer thickness) available from EM Separations. UV light, iodine and / or ninhydrin spray were used to develop TLC tests. The melting point is determined in a Thomas Hoover or Electrothermal 9200 melting point apparatus and is reported without correction. HPLC analysis was performed on a Hewlett Packard 1090, Waters Delta Prep 3000, Rainin or DuPont 8800 system. The NMR spectra were recorded on a 300 MHz Generic Electric QE-300, Varian 300 or Varian 400 spectrometer. Wood atomic bombardment mass spectrometry (FAB-MS) was performed on a VG Zab-E dual focus mass spectrometer using an Xenon FAB ion source or a Finnigan MÁT 8230 instrument.

3- or 4-substituted Boc-aminomethylbenzoic acid derivatives useful as intermediates in the preparation of the compounds of this invention are prepared by conventional methods (Tett. Lett. 4393, (1975); Modern Synthetic Reactions, HO House (1972); or Harting et al., J. Am. Chem. Soc. 50, 3370 (1928). An example of the preparation is shown in Scheme A.

To prepare 3-aminomethylbenzoic acid hydrochloride, 10.0 g (68 mmol) of 3-cyanobenzoic acid are dissolved in 200 ml of ethanol and heated in a water bath at 35-50 ° C. Concentrated hydrochloric acid (6.12 mL, 73 mmol) was added and the solution transferred to a 500 mL nitrogen purged round bottom flask containing 1.05 g of 10% Pd / C catalyst. After stirring for 38 hours under a hydrogen atmosphere, the suspension is filtered through a sintered glass filter and washed thoroughly with water. The ethanol was removed under reduced pressure and a white solid

The aqueous phase containing 91 was diluted to 250 ml with water. It is stirred with 250 ml of ethyl ether and the suspension is transferred to a shaking funnel. Shake well to dissolve the solid. The aqueous phase was washed twice with ether and concentrated under reduced pressure to a volume of 150 ml. Lyophilization gave 8.10 g (64%) of 3-aminomethylbenzoic acid hydrochloride as a beige solid.

1 H-NMR (D ₂ O): δ 4.27 (s, 2H), 7.60 (t, 1H), 7.72 (d, 1H), 8.06 (d, 2H).

Tert-Butyloxycarbonyl-3-aminomethyl-benzoic acid (BocMamb) was prepared by ltoh, Hagiwara and Kamiya, M.P. Became. 4393 (1975). 3-Aminomethyl-benzoic acid hydrochloride (3.0 g, 16.0 mmol) was dissolved in water (60 mL). To this was added a solution of Boc-ON (4.33 g, 17.6 mmol) in acetone (60 mL) followed by triethylamine (5.56 mL, 39.9 mmol). The yellow solution was adjusted to pH 9 (wet pH paper) with additional 1.0 mL (7.2 mmol) of triethylamine. After stirring overnight at room temperature, the acetone is removed under reduced pressure and the aqueous phase is washed three times with ether. The aqueous phase was then adjusted to pH 2 with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were washed three times with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give 2.58 g (64%) of the title compound as a white solid.

Melting point: 123-125 ° C.

- 92 ¹ H NMR (CDCl): δ 1.47 (s, 9H), 4.38 (br s, 2H), 4.95 (br s,

1H), 7.45 (t, H), 7.55 (d, 1H), 8.02 (d, 2H).

Tert-Butyloxycarbonyl-N-methyl-5-aminomethyl-benzoic acid (Boc-NMeMamb) was prepared. Olsen, J. Org. Chem. 35, 1912 (1970), which is depicted in Scheme B.

The aminomethylbenzoic acid analogs can be prepared by conventional methods. R is -CH ₃ , -CH 2 CH ₃ ,

-CH ₂ CH ₂ CH _3, -CH ₂ CH ₂ CH ₂ CH _{3 R-CH (CH3) 2,} -C _{(CH3) 3,} -CH group (CH ₃₎ CH ₂ CH ₃ formula, benzyl, cyclopentyl or the preparation of compounds containing a cyclohexyl group is represented by Scheme C-1, a compound of formula R -CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ or a phenyl group is prepared from Scheme C-2, while R is -CH ₃ or phenyl The preparation of compounds is illustrated in Schemes C-3 and C-4.

3- [N- (tert-Butyloxycarbonyl) amino] ethylbenzoic acid (Boc-MeMamb) is prepared according to Scheme C-4. 3-Acetylbenzoic acid (0.50 g, 3 mmol), hydroxylamine hydrochloride (0.70 g, 10 mmol) and pyridine (0.70 mL, 9 mmol) were refluxed in ethanol (10 mL) for 2 hours. The reaction mixture was evaporated, the residue was stirred with water, filtered and dried. 0.51 g (94.4%) of the oxime is obtained in the form of a white solid.

1 H-NMR (CD 3 OD): δ 7.45-8.30 (m, 4H), 2.30 (s, 3H).

MS (CH 4 -Cl) [M + H-O] = 164.

0.51 g (3 mmol) of oxime in ethanol in the presence of 1.5 g of 10% Pd / C catalyst and 0.25 ml (3 mmol) of concentrated hydrochloric acid in a Parr apparatus 2.1 x 10 ⁵ Pa ·

Hydrogenate at 93 for 5 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was stirred with ether. 0.48 g (85.7%) of the amine hydrochloride is obtained in the form of a white solid.

¹ H-NMR (CD 3 OD): δ 7.6-8.15 (m, 4H), 4.55 (q, 1H), 1.70 (s, 3H).

MS [M + H] = 166.

The amine hydrochloride derivative (0.40 g, 2 mmol) was dissolved in water (15 mL) and a solution of Boc-ON (0.52 g, 2.1 mmol) in acetone (15 mL) followed by triethylamine (0.8 mL, 6 mmol). We are added. The mixture was reacted for 20 hours. The reaction mixture is concentrated, partitioned between ethyl acetate and water, the aqueous phase is adjusted to pH 2 with 10% hydrochloric acid, and the product is extracted with ethyl acetate and recrystallized from ethyl acetate / hexane after usual work-up. This gave 0.30 g (57%) of the title compound as a white solid. Melting point: 116-118 ° C.

¹ H-NMR (CDCl 3): δ 7.35-8.2 (m, 4H), 4.6 (bs, 1.5H), 1.50 (d, 3H), 1.40 (s, 9H) .

MS (NH 5 -Cl) [M + NH <] = 283.

3- (1'-1'-tert-butyloxycarbonyl) amino] benzylbenzoic acid (Boc-PhMamb)

The title compound is prepared according to Scheme C-4 in a manner similar to the preparation of the methyl derivative. A solution of 3-benzoylbenzoic acid (2.00 g, 9 mmol), hydroxylamine hydrochloride (2.00 g, 29 mmol) and pyridine (2.00 mL, 25 mmol) in ethanol was refluxed for 12 hours. After usual work-up, 2.41 g of a white solid are obtained. Product traces • «

- Contains 94 pyridine but can be used in the next step without further purification.

Crude product was 2.00 g (about 8 mmol) in 200 ml ethanol, and 2.00 g of 10 wt% Pd / C and 1.3 ml (16 mmol) concentrated hydrochloric acid was hydrogenated in the presence of 2,1x10 ⁵ Pa pressure for 1 h. The catalyst was filtered off and the reaction mixture was evaporated. The residue was stirred with ether and dried in vacuo. This gave 2.12 g (97%) of the amine hydrochloride as a white solid.

¹ H-NMR (CD 3 OD): δ 7.4-8.15 (m, 10H), 5.75 (s, 1H).

MS (CH ₄ -Cl) [M + H-OH] = 211.

The amine hydrochloride derivative (1.00 g, 4 mmol) was converted to the Boc derivative as described for the methyl derivative. Recrystallization from ethanol / hexane gave 0.60 g (48%) of the title compound as a white solid. Melting point: 190-192 ° C.

1 H-NMR (CD 3 OD): δ 7.2-8.0 (m, 10H), 5.9 (2s, 1H, 2 isomers),

1.40 (s, 9H).

MS (NH 3 -Cl) [M + NH ₄ -C ₄ H ₈ ] = 289.

Tert-butyloxycarbonyl-D-2-amino-butyric acid

The title compound was obtained by ltoh, Hagiwara and Kamiya, in Dept. Became. 4393 (1975) according to Scheme D.

D-2-aminobutyric acid (1.0 g, 9.70 mmol) was dissolved in water (20 mL) and mixed with a solution of Boc-ON (2.62 g, 10.6 mmol) in acetone (20 mL). The resulting white precipitate was dissolved by the addition of triethylamine (3.37 mL, 24.2 mmol) to give a pale yellow solution (pH 9, wet pH paper). The solution overnight • · · ·

After stirring for 95 hours at room temperature, the acetone was removed under reduced pressure. The remaining aqueous phase was extracted three times with ether, adjusted to pH 2 with concentrated hydrochloric acid, and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 2.05 g of tert-butyloxycarbonyl-D-2-aminobutyric acid are thus obtained in the form of an oil (more than quantitative yield, solvent) which can be used without further purification.

1 H-NMR (CDCl 3): δ 0.98 (t, 3H), 1.45 (s, 9H), 1.73 (m, 1H),

1.90 (m, 1H), 4.29 (m, 1H), 5.05 (m, 1H).

Tert-Butyl 1-oxycarbonyl-3-aminophenyl I-acetic acid

The tert-butyloxycarbonyl-3-aminophenylacetic acid used as an intermediate in the preparation of the compounds of this invention is prepared in a conventional manner. As an example, the procedure of Coliman and Groh, J. Am. Chem. Soc. 104, 1391 (1982), shown in Scheme E.

Tert-Butyloxycarbonyl-3-aminophenylacetic acid g (66 mmol) 3-aminophenylacetic acid (Aldrich), 15.8 g (72 mmol) di-tert-butyl dicarbonate and 8.6 g A solution of DIEA (50 g, 66 mmol) in dichloromethane (50 mL) was stirred at room temperature overnight. The reaction mixture was evaporated, partitioned between dichloromethane and water, the aqueous layer was separated, adjusted to pH 3 with 1N hydrochloric acid and extracted with dichloromethane. The extract was washed with water and brine, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from heptane to give 3.7 g (22%) of the title compound as a white solid.

Melting point: 105 ° C.

1 H-NMR (CDCl 3): δ 7.35 (s, 1H), 7.25 (m, 3H), 6.95 (m, 1H),

6.60 (br s, 1H), 3.65 (s, 2H), 1.50 (s, 9H).

4-, 5- and 6-Substituted 3-aminomethylbenzoic acid hydrochloride; and 4-, 5- and 6-substituted tert-butyl 1-oxycarbonyl-3-aminomethylbenzoic acid. originating from

4-, 5- and 6-substituted 3-aminomethylbenzoic acid hydrochloride and 4-, 5-, and 6-substituted tert-butyl 1-oxycarbonyl-3-aminomethyl- are used as starting materials for the preparation of the compounds of the invention. benzoic acid derivatives are prepared in a conventional manner. As an example, Felder et al., Helv. Chim. Acta 48, 259 (1965); de Diesbach: Helv. Chim. Acta, 23, 1232 (1949); Truitt and Creagn, J. Org. Chem., 27, 1066 (1962); Sekiya et al., Chem. Pharm. Bull. 11, 551 (1963); and Scheme F.

4-Chloro-3-amino-methyl-1-benzoic acid hydrochloride

The title compound is described by Felder et al., Helv. Chim. Acta, 48, 259 (1965). To a solution of 15.7 g (100 mmol) of 4-chlorobenzoic acid in 150 ml of concentrated sulfuric acid was added 23.7 g (150 mmol) of N-hydroxymethyl dichloroacetamide in portions. After stirring for 2 hours at room temperature, the reaction mixture was poured onto ice (375 g), stirred for 1 hour, filtered and washed with water. The solid

The bulk of 97 is soluble in 5% w / w sodium bicarbonate solution, filtered and adjusted to pH 1 with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and air-dried overnight. 26.2 g (89%) of 4-chloro-3-dichloroacetylaminomethylbenzoic acid are obtained in the form of a white powder.

A suspension of 26.2 g (88 mmol) of 4-chloro-3-dichloroacetylaminomethylbenzoic acid in 45 ml of acetic acid, 150 ml of concentrated hydrochloric acid and 150 ml of water was refluxed for 3 hours, then filtered hot and allowed to cool to room temperature. . The solid was filtered, washed with ether and then with acetone / ether and air dried overnight. 7.6 g (39%) of the title compound are obtained in the form of white crystals.

Melting point: 278-279 ° C.

¹ H NMR (D _e -DMSO): δ 13.40 (br s, 1H), 8.75 (br s, 3H), 8.20 (s, 1H), 7.95 (dd, 1H); 7.70 (d, 1H),

4.20 (br s, 2H).

Tert-butyloxycarbonyl-4-chloro-3-methyl-benzoic acid

A solution of 6.7 g (30 mmol) of 4-chloro-3-aminomethylbenzoic acid hydrochloride and 9.3 g (92 mmol) of triethylamine in 50 mL of water was treated with 9.2 g (38 mmol) of Boc-ON in 50 mL of tetrahydrofuran. and cooled to 0 ° C. After stirring overnight at room temperature, the volatiles were removed under reduced pressure: The residue was taken up in water, washed with ether, adjusted to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was stirred with ether / hexane to give 7.4 g (87%) of the title compound as a white powder. Melting point: 159 ° C (dec.).

¹ H NMR (D _e -DMSO): δ 13.20 (br s, 1H), 7.90 (s, 1H), 7.80 (dd, 1H), 7.60 (br s, 1H); 7.55 (d,

1 H), 4.20 (br d, 2H), 1.40 (s, 9H).

4- and 6-Substituted tert-Butyl 1-Oxycarbonyl-3-Amino-Methyl-Isoic Acid Stem Coatings

The title compound is prepared in a similar manner to tert-butyloxycarbonyl-4-chloro-3-aminomethylbenzoic acid. The compounds of formula (III) listed in the following table are thus obtained:

_R 1 °. R ¹⁰ Mp (° C) H cl 159 H I 168 H Me 155 H Sample check 171 cl H 150 I H 182 Me H 166 Sample check H 79

2-Aminomethyl-benzoic acid hydrochloride and 2-aminomethyl-phenyl-acetic acid hydrochloride

2-Aminomethylbenzoic acid hydrochloride and 2-aminomethylphenylacetic acid hydrochloride may be used as intermediates in the preparation of the compounds of the present invention.

- 99 produced. As an example, Naito et al., J. Antibiotics, 30, 698 (1977), Young and Sweet, J. Am. Chem. Soc., 80, 800 (1958), and Scheme G.

2-Amino-methyl 1-phenyl-1-acetic acid-D-1 actam

The title compound was prepared by a modified version of the method of Naito et al., J. Antibiotics, 30, 698 (1977). To a suspension of 10.8 g (82 mmol) of 2-indanone and 9.4 g (82 mmol) of azidotrimethylsilane in 115 ml of chloroform and ice-cooled is added 25 ml of concentrated sulfuric acid at a rate such that the temperature is 30-40 ° C. left. After 3 hours, the mixture was poured onto ice and the aqueous phase was basified with concentrated ammonium hydroxide. The chloroform layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by sublimation (145 ° C, <1 mm) followed by recrystallization from benzene. This gave 5.4 g (45%) of the title compound as pale yellow crystals.

Melting point: 149-150 ° C.

1 H-NMR (CDCl ₃ ): δ 7.20 (m, 5H), 4.50 (s, 2H), 3.60 (s, 2H).

2-Aminomethyl-phenyl-1-acetic acid hydrochloride

The title compound was prepared by a modified version of the method of Naito et al., 1977, J. Antibiotics, 30, 698. A mixture of 6.4 g (44 mmol) of 2-aminomethylphenylacetic acid D-lactam and 21 ml of 6N hydrochloric acid was refluxed for 4 hours. The reaction mixture was treated with activated carbon (Norit A), filtered, evaporated to dryness and the residual oil was mixed with acetone. After filtration, 5.5 g (62%) of the title compound are obtained as colorless crystals.

Melting point: 168 DEG C. (dec.).

H NMR (D _e -DMSO): δ 12.65 (br s, 1H), 8.35 (br s, 3H), 7.50 (m, 1H), 7.35 (m, 3H); 4.05 (ABq, 2H), 3.80 (s, 2H).

2-Amino-m-ethyl-lacto-ω-lactam

The title compound was obtained from Danishefsky et al., J. Org. Chem. 40, 796 (1975). A mixture of 45 g (33 mol) of methyl o-toluate, 57 g (32 mol) of N-bromosuccinimide and 0.64 g of dibenzoyl peroxide in 175 ml of carbon tetrachloride was refluxed for 4 hours. The cooled reaction mixture was filtered, evaporated to dryness under reduced pressure, dissolved in methanol (250 mL) and treated with concentrated ammonium hydroxide (75 mL, 1.11 mol). The mixture was refluxed for 5 hours, then concentrated, filtered and the solid washed with water and ether. Recrystallization from water gave 11.0 g (26%) of the title compound as a white solid.

Melting point: 150 ° C.

1 H-NMR (CDCl ₃ ): δ 7.90 (d, 1H), 7.60 (t, 1H), 7.50 (t, 2H),

7.00 (br s, 1H), 4.50 (s, 2H).

2-Aminomethyl-benzoic acid v-hydrochloride

The title compound was prepared in a similar manner to 2-aminomethylphenylacetic acid hydrochloride. From lactam (3.5 g, 26 mmol) 2.4 g (50%) of the title compound were obtained as colorless crystals.

· * ·· · ♦ • · »• ··· ··« ·

- 101 Melting point: 233 DEG C. (dec.).

1 H-NMR (D-DMSO): δ 13.40 (br s, 1H), 8.35 (br s, 3H), 8.05 (d, 1H), 7.60 (m, 3H), 4.35 (br s, 2H).

Preparation of other cyclic peptide intermediates

As an alternative to Mamb for use as the R ³¹ carbocyclic group of cyclic peptides of the invention, aminoalkylnaphthoic acid and aminoalkyl tetrahydronaphthoic acid are mentioned. Representative representatives of aminoalkylnaphthoic acid and aminoalkyltetrahydronaphthoic acid as intermediates in the preparation of the cyclic peptides of the present invention are described below. These compounds are prepared according to Scheme H. Such a procedure is described, for example, by Earnest I, J. Kalvoda, G. Rihs and Mutter M., Tett. Became. Vol. 31, 28, 4011-4014 (1990).

8-Amino-5,6,7,8-tetrahydro-2-naphthoic acid hydrochloride (Compound 8)

In Scheme H, 4-phenylbutyric acid (1) is converted to ethyl ester (2), which is acylated with aluminum chloride and acetyl chloride. The resulting 4-acetylphenylbutyric acid ethyl ester (3) is saponified to give 4-acetylphenylbutyric acid (4). The acetyl group is then oxidized and the resulting 4-carboxyphenylbutyric acid (5) is converted to 1-tetralin-7-carboxylic acid (6) with aluminum chloride by Friedel-Crafts cyclization. The process is carried out in an appropriate yield. At this point, tetralone is divided into two portions and one is converted to the oxime (7) with sodium acetate and hydroxylamine hydrochloride. Hydrogenation of the oxime with the 8-amino-

102 -5,6,7,8-tetrahydro-2-naphthoic acid hydrochloride is obtained in the form of a racemic mixture which can be incorporated as an intermediate into the cyclic peptide.

The part

To a solution of 4-phenylbutyric acid (50.0 g, 0.3 mol) in ethanol (140 ml) was added concentrated sulfuric acid (0.53 ml) and the mixture was refluxed for 5 hours. The cooled solution was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. 56.07 g (0.29 mol, 97%) of ethyl 4-phenylbutyric acid are obtained in the form of a yellow liquid.

1 H-NMR (CDCl ₃ ): δ 7.3-7.1 (m, 5H), 4.1 (q, 2H, J = 7.1Hz), 2.7 (t, 2H, J = 7, 7Hz), 2.3 (t, 2H, J = 7.5Hz),

1.95 (quintet, 2H, J = 7.5Hz), 1.25 (t, 3H, J = 7.1Hz).

Part B.

To a solution of aluminum chloride (153 g, 1.15 mol) in acetyl chloride (38.5 ml, 42.5 g, 0.54 mol) in dichloromethane (1500 ml) was added 4-phenyl (50.0 g, 0.26 mol). a solution of ethyl butyric acid in 500 ml of dichloromethane was added dropwise. After stirring for 15 minutes at room temperature, the reaction mixture was poured into 2000 ml of ice-cold concentrated hydrochloric acid and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. This gave 53.23 g (0.23 mol, 88%) of ethyl 4-acetylphenylbutyric acid as a dark yellow liquid.

- 103 ¹ H NMR (CDCl): δ 7.9 (d, 2H, J = 8.1Hz), 7.25 (d, 2H, J =

8.4Hz), 4.1 (q, 2H, J = 7.1Hz), 2.75 (t, 2H, J = 7.6Hz), 2.6 (s, 3H), 2.35 (t , 2H, J = 7.6Hz), 2.0 (quintet, 2H, J = 7.5Hz), 1.25 (t, 3H, J = 7.1Hz).

Part C

To a solution of 4-acetylphenylbutyric acid ethyl ester (50.0 g, 0.21 mol) in ethanol (1250 ml) was added dropwise a solution of sodium hydroxide (50.0 g) in water (1250 ml). The mixture was stirred at reflux for 4 hours, then concentrated to half volume and adjusted to pH 0 with 1N hydrochloric acid. The precipitate was filtered off and washed with water. 53.76 g (0.26 mol, 99%) of 4-acetyl-1-phenylbutyric acid are obtained in the form of a white solid. Melting point: 50-50 ° C.

¹ H-NMR (CDCl 3): δ 7.9 (d, 2H, J = 8.1Hz), 7.25 (d, 2H, J

9.1 Hz), 2.75 (t, 2H, J = 7.7Hz), 2.6 (s, 3H), 2.4 (t, 2H, J = 7.3Hz), 2.0 (quintet , 2H, J = 7.4Hz).

Part D

To a solution of sodium hypochlorite (330 mL, 17.32 g, 0.234 mol) in 50% sodium hydroxide solution (172 mL) at 55 ° C was added 16.0 g (0.078 mol) of solid 4-acetylphenylbutyric acid in portions. at a rate of 60-70 ° C. After stirring for 20 hours at 55 ° C, the mixture was cooled and quenched by dropwise addition of 330 ml of 25% w / w sodium bisulfite. The mixture was transferred to a beaker and carefully acidified with concentrated hydrochloric acid. The precipitated solid is filtered off, washed with water and dried, then chlorobutane ··· * 4 · · · 4 * ···

104, then mixed with hexane. 15.31 g (0.074 mol, 95%) of 4-carboxyphenylbutyric acid are obtained in the form of a white solid.

Melting point: 190-195 ° C.

¹ H-NMR (DMSO): δ 12.55 (bs, 1H), 8.1 (s, 1H), 7.85 (d, 2H, J = 8.1Hz), 7.3 (d, 2H, J = 8.1Hz), 2.7 (t, 2H, J = 7.5Hz), 2.2 (t, 2H, J = 7.4Hz), 1.8 (quintet, 2H, J = 7.5Hz) ).

Part E

A mixture of 10.40 g (0.05 mol) of 4-carboxyphenylbutyric acid, 33.34 g (0.25 mol) of aluminum chloride and 2.90 g (0.05 mol) of sodium chloride was added for 30 minutes. Stirring is carried out at 0 ° C. The reaction mixture was cooled to 60 ° C, carefully mixed with 250 ml of 1N cold hydrochloric acid and extracted with dichloromethane. The combined organic layers were washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The solid residue was stirred with chlorobutane to give 9.59 g (0.05 mol, 100%) of 1-tetralone-7-carboxylic acid as a brown solid.

Melting point: 210-215 ° C.

1 H-NMR (DMSO): δ 8.4 (s, 1H), 8.1 (d, 2H, J = 8.0Hz), 7.5 (d,

1H, J = 7.9Hz), 3.0 (t, 2H, J = 6.0Hz), 2.65 (t, 2H, J = 6.6Hz), 2.1 (quintet, 2H, J = 6 , 3 Hz).

Part F

1.0 g (0.0053 mol) of 1-tetralone-7-carboxylic acid, 1.93 g (0.024 mol) of sodium acetate and 1.11 g (0.016 mol) of hydroxylamine hydrochloride in 15 ml of methanol / water 1: 1 solution was stirred at reflux for 4 hours. The mixture finally

- 105, cooled and diluted with 50 ml of water. The solid was filtered, washed with water and dried. Trituration with hexane gave 0.78 g (0.0038 mol, 72%) of 1-tetralone oxime-7-carboxylic acid as a white solid, m.p. 205-215 ° C. ¹ H-NMR (DMSO): δ 11.3 (s, 1H), 8.4 (s, 1H), 7.8 (d, 1H,

J = 7.7Hz), 7.3 (d, 1H, J = 7.7Hz), 2.8 (t, 2H, J = 5.9Hz), 2.7 (d, 2H, J = 6.6Hz) ), 1.91,7 (m, 2H).

Part G

To a mixture of 0.75 g (0.0037 mol) of 1-tetralone oxime-7-carboxylic acid in 25 ml of methanol was added 0.54 ml (0.20 g, 0.0056 mol) of concentrated hydrochloric acid and 0.10 g of 5 wt% Pd A / C catalyst was added and hydrogenation was carried out at room temperature for 20 hours at 4.14 x 10 ⁵ Pa under shaking. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by flash chromatography eluting with hexane / ethyl acetate 1: 1. There was thus obtained 8-amino-5,6,7,8-tetrahydro-2-naphthoic acid hydrochloride (0.225 g, 0.001 mol, 27%) as a racemic mixture and a white solid.

Melting point: 289-291 ° C.

1 H-NMR (DMSO): δ 8.55 (bs, 3H), 8.2-8.1 (m, 1H), 7.85-7.8 (m, 1H), 7.35-7. 25 (m, 1H), 4.5 (m, 1H), 2.9-2.8 (m, 2H), 2.1-1.9 (m, 3H), 1.85-1.7 ( m, 1H).

N- (BOC) -8-Aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (Compound 12)

- 106 ··· »·« · «·. ,, -. ··: · '' ·.! ··· · * χ

In Scheme Α Η, the remainder of the tetralone is converted to the methyl ester (9). Gregory G.B. and Johnson, A.L., JOC, 55, 1479 (1990), the tetralone methyl ester (9) is first converted to cyanohydrin with trimethylsilyl cyanide and zinc iodide and then dehydrated with phosphorus oxychloride in pyridine. This gives methyl 8-cyano-5,6-dihydro-2-naphthoate (11). This is divided into two portions and one portion is hydrogenated, protected with N-BOC and saponified. This gives N-BOC8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (12) which can be incorporated into the cyclic peptide.

The part

To a mixture of 7.0 g (0.037 mol) of 1-tetralone-7-carboxylic acid in 13.6 ml (10.8 g, 0.30 mol) of methanol was added 0.07 ml (0.12 g, 0.0012 mol) of hydrochloric acid. and stirred for 5 hours under reflux. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting solid was purified by flash chromatography eluting with hexane / ethyl acetate 75:25. The solid was stirred with hexane to give 3.61 g (0.018 mol, 49%) of 1-tetralone-7-carboxylic acid methyl ester as a yellow solid.

Melting point: 170-172 ° C.

1 H-NMR (CDCl ₃ ): δ 8.7 (s, 1H), 8.15 (d, 1H, J = 8.1 Hz), 7.35 (d,

1H, J = 8.1Hz), 3.95 (s, 3H), 3.05 (d, 2H, J = 6.1Hz), 2.7 (t, 2H, J = 6.4Hz), 2, 15 (quintet, 2H, J = 6.2Hz).

- 107 Part B

3.50 g (0.017 mol) of methyl 1-tetralone-7-carboxylic acid,

A solution of 1.98 g (0.02 mol) of trimethylsilyl cyanide and 0.10 g of zinc iodide in 20 ml of benzene is stirred for 15 hours at room temperature. Pyridine (20 mL) and phosphorus oxychloride (4.0 mL, 6.55 g, 0.0425 mol) were added dropwise. The mixture was stirred at reflux for 1 hour and then concentrated to dryness under reduced pressure. The residue was taken up in chloroform, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. This gave 1.70 g (0.008 mol, 47%) of methyl 8-cyano-5,6-dihydro-2-naphthoate as a yellow solid.

Melting point: 73-75 ° C.

1 H-NMR (CDCl 3): δ 8.0-7.9 (m, 1H), 7.3-7.2 (m, 1H), 6.95 (t,

1H, J = 4.8Hz), 3.95 (s, 3H), 2.9 (t, 2H, J = 8.3Hz), 2.6-2.4 (m, 3H).

Part C

To a mixture of methyl 8-cyano-5,6-dihydro-2-naphthoate (0.80 g, 0.0038 mol) in methanol (25 ml) was added concentrated hydrochloric acid (0.56 ml) and 5% Pd / C (0.40 g), and shake for 20 hours at room temperature under a hydrogen pressure of 3.45 x 10 ⁵ Pa. The mixture was then filtered through celite and washed with methanol. The filtrate was evaporated to dryness under reduced pressure and the residue was stirred with hexane. This gave 0.80 g (0.0037 mol, 97%) of methyl 8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate as a white solid.

Melting point: 172-179 ° C.

- 108 ^1H-NMR (DMSO): δ 8.2-8.0 (m, 4H), 7.9-7.7 (m, 6H), 7.5-7.2 (m, 4H); 3.9-3.8 (m, 7H), 3.3-2.7 (m,

10H), 2.0-1.6 (m, 8H).

Part D

Methyl 8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate (0.78 g, 0.0036 mol) and triethylamine (0.55 ml, 0.40 g, 0.004 mol) in 75% aqueous tetrahydrofuran 0.99 g (0.004 mol) of solid 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile are added in portions. After stirring at room temperature for 3 hours, the mixture was concentrated to half volume and extracted with diethyl ether. The aqueous phase was adjusted to pH 1.0 with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography eluting with 8: 2 hexane: ethyl acetate. 0.54 g (0.0017 mol, 47%) of methyl N-BOC-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate is obtained in the form of a white solid.

Melting point: 72-80 ° C.

¹ H-NMR (DMSO): δ 13.8 (s, 1H), 7.8-7.65 (m, 3H), 7.6-7.5 (m, 3H), 7.25-7, 20 (m, 1H), 7.15-7.05 (m, 1H), 3.9-3.8 (m, 1H), 3.2-2.8 (m, 4H), 1.8-. 1.6 (m, 3H); 1.4 (s, 6H).

Part E

To a solution of 0.50 g (0.0016 mol) of methyl N-BOC-8-aminomethyl-5,6,7,8-tetrahydro-2-naphthoate in 12.5 ml of ethanol, 0.50 g of sodium hydroxide 12.5 of a solution of water in water. The mixture was stirred at reflux for 4 hours, then concentrated to half volume and adjusted to pH 1.0 with 1N hydrochloric acid. The residue was purified by flash chromatography eluting with hexane / ethyl acetate 1: 1 and then ethyl acetate / methanol 9: 1. N-BOC-2-aminomethyl-5,6,7,8-tetrahydro-2-naphthoic acid (0.19 g, 0.00062 mol, 39%) was obtained as a racemic mixture and a white solid.

Melting point: 172-176 ° C.

1 H-NMR (DMSO): δ 7.8 (s, 1H), 7.65 (d, 1H, J = 8.1Hz), 7.15 (d,

1H, J = 8.1 Hz), 7.1-7.0 (m, 1H), 3.2-3.1 (m, 2H), 3.0-2.7 (m, 4H), 1 , 8-1.6 (m, 4H), 1.4 (s, 9H).

N-B0C-8-Amino-1-2-naphthoate and Compound (14)

The remaining naphthoate (11) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) with dioxane to give methyl 8-cyano-2-naphthoate (13) by aromatization of the adjacent ring. The nitrile is then reduced by hydrogenation and the methyl ester is saponified to a carboxylic acid. The acid is protected with an N-BOC group to give N-BOC-8-aminomethyl-2-naphthoic acid (14) which can be incorporated as an intermediate into the cyclic peptide.

The part

1.0 g (0.0047 mol) of methyl 8-cyano-5,6-dihydro-2-naphthoate and 1.07 g (0.0047 mol) of 2,3-dichloro-5,6-dicyano-1, A solution of 4-benzoquinone in 50 ml of dioxane was stirred at 120 ° C for 16 hours. The mixture was then poured into ice water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate. 0.72 g (0.0034 mol, 73%) of methyl 8-cyano-2-naphthoate is obtained in the form of a tan solid.

Melting point: 178-182 ° C.

¹ H-NMR (CDCl 3): δ 8.95 (s, 1H), 8.3-8.2 (m, 1H), 8.15-8.10 (m,

1H), 8.0-7.95 (m, 2H), 7.7-7.6 (m, 1H), 4.05 (s, 1H).

Part B.

To a mixture of methyl 8-cyano-2-naphthoate (1.0 g, 0.0047 mol) in methanol (35 ml) was added concentrated hydrochloric acid (0.69 ml) and 5% Pd / C (0.20 g) for 6 hours at room temperature, Shake under a hydrogen pressure of 45 x 10 ⁵ Pa. The reaction mixture was then filtered through celite and washed with methanol. The filtrate was evaporated to dryness under reduced pressure and the residue was stirred with hexane. 0.76 g (0.0035 mol, 75%) of methyl 8-aminomethyl-2-naphthoate is obtained in the form of an oil.

¹ H-NMR (DMSO): δ 8.75 (s, 1H), 8.5 (bs, 2H), 8.2-8.05 (m, 3H), 7.75-7.70 (m, 2H), 4.6 (s, 2H), 3.95 (m, 3H).

Part C

To a solution of 0.75 g (0.0035 mol) of methyl 8-aminomethyl-2-naphthoate in 50 ml of dry tetrahydrofuran at 0 ° C is added 5.83 ml of 0.5 M lithium hydroxide solution. After stirring for 20 hours at room temperature, an additional aliquot of lithium hydroxide was added and stirred for an additional 20 hours. The solid was filtered and the filtrate was evaporated to dryness under reduced pressure. The solid was stirred with diethyl ether to give 0.67 g (0.0033 mol, 95%) of 8.

There was thus obtained -111minomethyl-2-naphthoic acid as a white solid.

Melting point: 223-225 ° C.

¹ H-NMR (DMSO): δ 8.6 (s, 1H), 8.1-7.9 (m, 1H), 7.8-7.7 (m, 4H), 7.55-7. Δ (m, 1H), 7.45-7.35 (m, 2H),

4.2 (s, 2H).

Part D

To a solution of 0.50 g (0.00025 mol) of 8-aminomethyl-2-naphthoic acid and 0.038 ml (0.028 g, 0.000275 mol) of triethylamine in 5 ml of 50% aqueous tetrahydrofuran was added in portions 0.068 g (0.000275 mol) of a solid. 2- (tert-Butoxycarbonyl-oxyimino) -2-phenyl-acetonitrile was added. After stirring for 5 hours at room temperature, the mixture was concentrated to half volume and extracted with diethyl ether. The aqueous phase was adjusted to pH 1.0 with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. This afforded 0.050 g (0.00017 mol) of N-BOC-8-aminomethyl-2-naphthoic acid as a solid.

Melting point: 190-191 ° C.

¹ H-NMR (DMSO): δ 13.1 (bs, 1H), 8.8 (s, 1H), 8.0 (q, 2H,

J = 7.9Hz), 7.9 (d, 1H, J = 8.1Hz), 7.6 (t, 1H, J = 7.5Hz), 7.65-7.55 (m, 2H), 4.6 (d, 2H, J = 5.5Hz), 1.4 (s, 9H).

Preparation of cyclic peptides

The tert-butyloxycarbonyl-3-aminomethylbenzoic acid (Boc-Mamb) is coupled to an oxime resin DeGrado and Kaiser, J. Org. Chem., 45, 1295 (1980), ♦.

- 12 using one equivalent of 3-aminomethylbenzoic acid (based on the substitution level of the resin), one equivalent of HBTU and three equivalents of NMM. Alternatively, Boc-Mamb (equivalent) can be coupled to the oxime resin with equivalent DCC and DMAP in methylene chloride. The switching time is 15-96 hours. The substitution level is determined by the picric acid assay (Sarin, Kent, Tam and Merrifield: Anal. Biochem. 117, 145-157 (1981)) or by the quantitative ninhydrin assay (Gisin: Anal. Chim. Acta, 58, 248-249 (1972)). a. The unreacted oxime groups are blocked with dimethylformamide (0.5 mol / L trimethylacetyl chloride / 0.5 mol / L diisopropylethylamine) for 2 hours. Boc deprotection was performed with 25% TFA in DCM for 30 minutes. The remaining amino acid or amino acid derivative is coupled with a 2- to 10-fold excess (relative to the first amino acid or amino acid introduced) of the appropriate amino acid or amino acid derivative in the presence of HBTU in about 8 mL of DMF. The resin is then neutralized in situ with three equivalents of NMM (relative to the amount of amino acid) with a coupling time of from 1 hour to several days. The course of the coupling is checked by a qualitative ninhydrin assay or picric acid assay when the amino acid is coupled to a secondary secondary. Depending on the result, the amino acid coupling is repeated as necessary.

After the linear peptide was prepared, the N-terminal Boc group was removed with 25% TFA / DCM for 30 minutes. The resin is then neutralized with DIEA / DCM. The cyclization and cleavage of the peptide was carried out according to the method of Osapay and Taylor, J. Am. Chem. Soc., 112, 6046 (1990).

- 13 resins are suspended in about 10 ml / g DMF, equivalents of acetic acid (relative to the first amino acid) are added and stirred at 50-60 ° C for 60-72 hours. It is then filtered through a sintered glass filter, the DMF filtrate is evaporated and dissolved in acetic acid or acetonitrile / water 1: 1 and finally lyophilized. Alternatively, the material is dissolved in methanol and precipitated with ether. This affords a protected cyclized material. This is treated in the usual manner with anhydrous hydrogen fluoride (Stewart and Young, Solid Phase Peptide Synthesis, 2nd edition, Pierce Chemical Co., 85, 85, 1984) containing 1 ml / g of m-cresol or anisole. The treatment was carried out at 0 ° C for 2060 minutes to remove the side chain protecting groups. The crude product was purified by reverse phase HPLC analysis on a 2.5 cm preparative Vydac C18 column with a linear acetonitrile gradient containing 0.1% TFA. This gives a crude cyclized product. The following N-alpha-Boc protected amino acids can be used in the synthesis:

Boc-Arg (T os),

Boc-N-a-MeArg (Tos);

Boc-Gly

Boc-Asp (OcHex);

Boc-3-aminomethyl-4-iodo-benzoic acid, Boc-D-lle,

Boc-NMeAsp (OcHex), Boc-NMe-Mamb, Boc-D-Phg,

Boc-D-Asp (OBzl), Boc-L-Asp (OcHex), Boc-aMe-Asp (OcHex),

-114 ···· ♦ · · · · · · · · · · ·

BME-Boc-Asp (OcHex);

Boc-L-Ala, Boc-L-Pro, Boc-D-NIe, Boc-D-Leu, Boc-D-Val, Boc-D-2-Aminobutyric acid (Boc-D-Abu), Boc-Phe .

Boc-D-Ser (Bzl), Boc-D-Ala, Boc-3-aminomethylbenzoic acid (Boc-Mamb), Boc-D-Lys (2-CIZ),

Boc-beta-Ala,

Boc-D-Pro, Boc-D-Phe, Boc-D-Tyr (Cl ₂ Bzl), Boc-NMe-Amf (CBZ), Boc-aminotetralinecarboxylic acid, Boc-aminomethylnaphthoic acid,

Boc-4-amino-1-benzoic acid, Boc-NMeGly.

Other examples of the preparation of the compounds of the invention include the process described in WO 93/07170 and the following examples. In the accompanying tables, the compounds represented by the compounds of the invention are given.

3a. example

Cyclo- (Abu-NMeArg-Gly-Asp-Mamb) ♦ · · · * · ···· · · · · · · ·

- 15 (in formula (II), J is Abu, K is NMeArg, L is Gly, M is Asp, R ¹ is hydrogen and R 2 is hydrogen)

The title compound was prepared according to the general procedure for Cyclo- (D-Val-NMeArg-Gly-AspMamb) (Example 4). The Boc-Mamb starting material was bound to the oxime resin by the DCC / DMAP method. TBTU is used as the coupling reagent. The peptide was prepared at a scale of 0.596 mmol to give 182 mg (38.4%) of the protected cyclic peptide. 176 mg of peptide and 0.176 ml of anisole in anhydrous hydrogen fluoride-treated at 0 C for 20 min ^q. The crude product is precipitated with ether, dissolved in aqueous acetonitrile and lyophilized. 116 mg (90.4%) of the title compound are obtained (calculated as the fluoride salt). Purification by reverse phase HPLC on a preparative Vydac C18 column (2.5 cm) with a gradient of 0.45% / min 9-27% acetonitrile / 0.1% TFA followed by lyophilization of the product as the TFA salt. This gave a fluffy white solid (1.92% yield, 0.574% overall yield).

FAB-MS: [M + H] = 561.39.

Example 4

Cyclization and salification of the compound of Example 4

It has been found that the compounds of the invention can be isolated by crystallization from an organic or aqueous solution.

The zwitterionic compound of Example 4 is converted to the mesyl salt (methanesulfonate salt) (Example 4 (methanesulfonate)) to which the zwitterionic compound isopropyl at 25 mg / ml.

It is stirred under reflux in 116 panol and a solution of 1.0 molar equivalent of methanesulfonic acid (based on the water content of the zwitterion) in isopropanol is added slowly. The heating was stopped and the solution was cooled to 5 ° C in an ice bath. After stirring for one hour, it is filtered, the solid is washed three times with cold isopropanol and dried under vacuum to constant weight.

The following salts were prepared from the compound of Example 4 using 1.0 equivalent of the appropriate acid in the above procedure:

Example 4 (Biphenylsulfonate):

zwitterionic compound + 1.0 equivalent of biphenylsulfonic acid;

Example 4 (alpha-naphthalene sulfonate):

zwitterionic compound + 1.0 equivalent alpha-naphthalenesulfonic acid;

Example 4 (beta-naphthalene sulfonate):

zwitterionic compound + 1.0 equivalent of beta-naphthalenesulfonic acid;

Example 4 (Benzenesulfonate):

zwitterionic compound + 1.0 equivalent benzenesulfonic acid;

Example 4 (p-toluene sulfonate):

zwitterionic compound + 1.0 equivalent of p-toluenesulfonic acid.

The following salts of the compound of Example 4 were prepared by crystallization from an aqueous system.

Example 4 (sulfate):

mg of the amorphous compound of Example 4 (the zwitterionic compound is lyophilized from a solution of two molar equivalents of acetic acid in water) is dissolved in 1N sulfuric acid per ml at pH 2.5. After allowing to stand at room temperature, the precipitate was filtered through a sintered glass filter and dried under vacuum to constant weight.

• · ·

-1 174. Example (methanesulfonate (mesyl)):

100 mg of amorphous DMP728 are dissolved in ml of water and 1.2 molar equivalents of methanesulfonic acid (4 M aqueous solution). Allow to stand at room temperature to form large, flat crystals.

Example 4 (Benzenesulfonate):

Dissolve 100 mg of zwitterionic compound per ml in water and 1.2 equivalents of benzenesulfonic acid. After allowing to stand at room temperature, the precipitate was filtered through a sintered glass filter, washed with a little isopropanol and dried under vacuum to constant weight.

Example 4 (p-toluene sulfonate):

Dissolve 100 mg of the zwitterionic compound per ml in water and 1.2 molar equivalents of toluenesulfonic acid. After allowing to stand at room temperature, the precipitate was filtered through a sintered-glass filter and dried in vacuo to constant weight.

Example 17

Cyclo- (D-Met-NMeArg-Gly-Asp-Mamb) (In formula (II), J is D-Met, K is NMeArg, L is Gly, M is Asp, R ¹ is hydrogen and R ² is hydrogen)

The title compound was prepared according to the general procedure for Cyclo (D-Val-NMeArg-Gly-AspMamb) (Example 4). The Boc-Mamb starting material was bound to the resin by the DCC / DAMP method. The peptide was prepared in a scale of 0.179 mmol to give 105 mg (69.7%) of the protected cyclic peptide. 105 mg of the peptide and 0.105 ml of anisole were treated with anhydrous hydrogen fluoride at 0 ° C for 20 minutes · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · «· ·« «

- Through 118. The crude material was precipitated with ether, dissolved in aqueous acetonitrile and lyophilized. 72 mg (92.3%) of the title compound are obtained (calculated as the fluoride salt). Purification was by reverse phase HPLC on a preparative Vydac C18 column (2.5 cm) with a gradient of 0.23% / min 14.4-23.4% acetonitrile / 0.1% TFA. After lyophilization, the TFA salt of the title compound was obtained as a fluffy white solid (13.2% yield, 7.4% overall yield), FAB-MS: [M + H] = 607.3.

Example 401

Cyclo- (D-Abu-NMeArg-Gly-D-Asp-Mamb) (In formula II, J is D-Abu, K is NMeArg, L is Gly, M is D-Asp, R ¹ is hydrogen and R ² is hydrogen)

The title compound was prepared according to the general procedure for Cyclo (D-Val-NMeArg-Gly-AspMamb) (Example 4). The Boc-Mamb starting material was bound to the oxime resin by the DCC / DMAP method. TBTU is used as the coupling reagent. The peptide was prepared at a level of 0.596 mmol to give 273 mg (57.6%) of the protected cyclic peptide. 263 mg of peptide and 0.263 ml of anisole were treated with anhydrous hydrogen fluoride at 0 ° C for 20 minutes. The crude product is precipitated with ether, dissolved in aqueous acetonitrile and lyophilized. This gives 218 mg (more than quantitative yield of the fluoride salt) of the title compound. Purification was by reverse phase HPLC on a preparative Vydac C18 column (2.5 cm) with a gradient of 0.23% / min 10.8 to 19.8% acetonitrile / 0.1% TFA. TFA salt form of the title compound · ♦ ·

- lyophilized on 119 bar. This gave a fluffy white solid (40.4% yield, 21.9% overall yield).

FAB-MS: [M + H] = 561.37.

Example 402

Formula cyclo- (D-Abu-DNMeArg-Gly-Asp-Mamb) (A (II) J = D-Abu, K is DNMeArg, L = Gly, M = Asp, ^R1 is hydrogen and ^R2 is H)

The title compound was prepared according to the general procedure for Cyclo (D-Val-NMeArg-Gly-AspMamb) (Example 4). The Boc-Mamb starting material was bound to the oxime resin by the DCC / DMAP method. TBTU is used as the coupling reagent. The peptide was prepared at a level of 0.596 mmol to give 241 mg (50.8%) of the protected cyclic peptide. 235 mg of the peptide and 0.235 ml of anisole were treated with anhydrous hydrogen fluoride at 0 ° C for 20 minutes. The crude material was precipitated with ether, dissolved in aqueous acetonitrile and lyophilized. This gave 168 mg (98.3%) of the title compound (calculated as the fluoride salt). Purification was by reverse phase HPLC on a preparative Vydac C18 column (2.5 cm) with a gradient of 0.23% / min 12.6-21.6% acetonitrile / 0.1% TFA. The title compound is lyophilized as the TFA salt. This gave a fluffy white solid (2.3% digest, 0.99% overall yield).

FAB-MS [M + H] = 561.36.

Example 403

Cyclo- (D-Ala-p-guanidinyl-Phe-Gly-Asp-Mamb) • · · · * · · · · · · · · · · · · · · · · · · · · · ·

- 120 (In formula (II), J is D-Ala, K is pguanidinyl-Phe, L is Gly, M is Asp, R ¹ is hydrogen and R ² is hydrogen) mg (38.3 pmoles) of cyclo (D -Ala-p-amino-Phe-Gly-AspMamb) TFA salt 14.3 mg (114.9 pmol) formamidine sulfonic acid and 18.7 mg (153.2 pmol) 4-dimethylaminopyridine are dissolved in 5 ml ethanol in a 10 ml round-bottomed flask. The mixture was refluxed for 3 hours, followed by addition of additional 14.3 mg formamidine sulfonic acid and 18.7 mg 4-dimethylaminopyridine. After refluxing for 3 hours, the reaction was approximately 75% complete by reverse phase HPLC. The ethanol was removed under reduced pressure and the residue was purified on a preparative Vydac C18 column (2.5 cm) with a gradient of 0.45% / min 0-18% acetonitrile / 0.1% TFA. The title compound is lyophilized as the TFA salt. This gave a white solid (28% yield, 26.4% overall yield).

FAB-MS: [M + H] = 581.30.

Example 404

Cyclo- (D-Abu- (DiNMe-guanidinyl-Orn) -Gly-Asp-Mamb) (In Formula II, J is D-Abu, K is DiNMe-guanidinyl-Orn, L is Gly, D is Asp, R ¹ is hydrogen and R ² is hydrogen)

10.53 mg (16.3 μπιόΙ) of TFA salt of cyclo (D-Abu-Di-DiNMeOrn-Gly-AspMamb), 6.08 mg (48.99 pmol) of formamidine sulfonic acid and 8.00 mg (65.57 pmol) 4-Dimethylaminopyridine is dissolved in 2.5 ml of ethanol in a 10 ml round-bottomed flask. The mixture was refluxed for 2 hours and then stirred overnight at room temperature. Reflux again for an hour,

121 followed by addition of 6.08 mg of formamidine sulfonic acid and 8.00 mg of 4-dimethylaminopyridine were added and reflux continued for a further 2 hours. Finally, the ethanol was removed under reduced pressure and the residue was purified on a preparative Vydac C18 column (2.5 cm) with a gradient of 0.45% / min 3.6-18% acetonitrile / 0.1% TFA. The title compound is lyophilized as the TFA salt. This gave a white solid (57.2% yield, 53.5% overall yield).

FAB-MS: [M + H] = 575.34.

Example 405

Formula cyclo- (D-Abu-DiNMeLys-Gly-Asp-Mamb) (A (II) J = D-Abu, K is DiNMeLys, L = Gly, M = Asp, ^R1 is hydrogen and ^R2 is hydrogen) and

Cyclo- (D-Abu-NMeLys-Gly-Asp-Mamb) (In formula (II) J = D-Abu, K is NMeLys, L = Gly, M = Asp, ^R1 is hydrogen and ^R2 is hydrogen)

The di-N-methyl amino acid derivatives are described by Olsen, J. Org. Chem. 35, 1912 (1970) or using the NaH / CH _{3 I} method. The mono-NMe-lysine amino acid is formed as a by-product of the corresponding di-NMe-lysine derivative during synthesis. The title compounds are prepared by standard solution-phase peptide synthesis. Total yield of cyclo (D-Abu-DiNMeLys-Gly-AspMamb) 0.31%, FAB-MS: [M + H] = 547.3; total yield of cyclo (D-Abu-NMeLys-Gly-Asp-Mamb) 0.25%, FAB-MS [M + H] = 533.3.

122 100a. example

Cyclo- (D-Abu-NMeArg-Gly-Asp-3-aminomethyl-6-chlorobenzoic acid)

The title compound is prepared by the general solution-phase procedure for cyclo (D-Val-NMeArg-Gly-AspMamb), except that 4,4'-dinitrobenzophenone oxime is used. The cyclic peptide (330 mg, 0.40 mmol) was deprotected with excess hydrogen fluoride in the presence of anisole. Purification was by reverse phase HPLC on a preparative Vydac C18 column (2.5 cm) with a gradient of 1.0% / min to 10-38% acetonitrile / 0.1% TFA. The title compound was obtained as the TFA salt (114 mg, 41%) as a fluffy white solid.

¹ H NMR (D _e -DMSO): δ 9.00 (d, 1H), 8.40 (m, 2H), 7.50 (m,

1H), 7.40 (d, 1H), 7.30 (m, 2H), 7.15 (s, 1H), 7.00 (br s, 4H), 5.15 (dd, 1H), 4 , 65 (q, 1H), 4.50 (dd, 1H), 4.40 (q, 1H), 4.05 (dd, 1H), 3.95 (dd, 1H), 3.65 (dd, 1H), 3.10 (q, 2H), 3.05 (s, 3H), 2.75 (dd, 1H), 2.50 (m, 1H),

1.95 (m, 1H), 1.75 (m, 2H), 1.60 (m, 1H), 1.35 (m, 2H), 0.95 (t, 3H).

FAB-MS: [M + H] = 595.4.

100b. example

Cyclo- (D-Abu-N MeArg-Gly-Asp-3-Aminomethyl-6-iodobenzoic acid)

The title compound is prepared by the general solution-phase procedure for the cyclo (D-Val-NMeArg-Gly-AspMamb) compound, except that 4,4'-dinitrobenzophenone oxime is used. About the cyclic peptide (350 mg, 0.38 • ·

With an excess of hydrogen fluoride in the presence of anisole. Purification was by reverse phase HPLC on a preparative Vydac C18 column (2.5 cm) with a gradient of 1.0% / min to 10-38% acetonitrile / 0.1% TFA. The title compound was isolated as the TFA salt (150 mg, 49%) as a fluffy white solid.

¹ H-NMR (Dc-DMSO): δ 8.90 (d, 1H), 8.40 (m, 2H), 7.70 (d,

1H), 7.50 (m, 1H), 7.30 (m, 1H), 7.05 (s, 1H), 7.00 (d, 1H), 7.00 (br s, 4H), δ , 15 (dd, 1H), 4.65 (q, 1H), 4.45 (dd, 1H), 4.40 (q, 1H), 4.00 (q, 1H), 3.90 (q, 1H), 3.65 (dd, 1H), 3.10 (q, 2H), 3.05 (s, 3H), 2.70 (dd, 1H),

2.50 (m, 1H), 1.95 (m, 1H), 1.75 (m, 2H), 1.60 (m, 1H), 1.40 (m, 2H), 0.95 (t , 3H).

FAB-MS: [M + H] = 687.3.

100c. example

Cl (Cl-D-Abu-NMeArg-Gly-Asp-3-Amino-ethyl-6-methyl-benzoic acid) (In formula (X), J is D-Abu, K is NMeArg, L is Gly, M is Asp, R ¹⁰ stands for Me)

The title compound is prepared by the general solution-phase procedure for cyclo (D-Val-NMeArg-Gly-AspMamb), except that 4,4'-dinitrobenzophenone oxime is used. The cyclic peptide (130 mg, 0.16 mmol) was deprotected with excess hydrogen fluoride in the presence of anisole. Purification was by reverse phase HPLC on a preparative Vydac C18 column (2.5 cm) with a gradient of 1.0% / min to 10-38% acetonitrile / 0.1% TFA. The title • · • · • ·

Compound 124 was isolated as the TFA salt (31 mg, 28%) as a fluffy white solid.

¹ H NMR (D _e -DMSO): δ 8.70 (d, 1H), 8.40 (m, 1H), 8.30 (t,

1H), 7.50 (m, 1H), 7.45 (m, 1H), 7.15 (q, 2H), 7.05 (s, 1H), 7.00 (brs, 4H), δ, 15 (dd, 1H), 4.65 (q, 1H), 4.45 (m, 2H), 4.00 (m, 2H), 3.65 (dd, 1H), 3.10 (q, 2H) ), 3.05 (s, 3H), 2.75 (dd, 1H), 2.50 (m, 1H), 2.30 (s, 3H), 2.00 (m, 1H), 1.75 (m, 2H), 1.60 (m, 1H), 1.35 (m, 2H), 0.95 (t, 3H).

FAB-MS: [M + H] = 575.4.

Preparation of representative prodruq derivatives

1st step

N-Benzyloxycarbonyl-N '-methyl-4-cyano-L-2-amine Novic Acid

A solution of 28.03 g (100 mmol) of Z-GIn in 300 mL of THF was mixed with 100 mL of 1.93 M phosgene (193 mmol) in toluene, excluding moisture. The solution was stirred at room temperature for 2 hours and then concentrated to 200 ml at 30 ° C. Water (200 mL) was added slowly and with stirring, stirred at room temperature for 2 hours, then the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed four times with brine, dried over magnesium sulfate and evaporated. The oily product is dried over potassium hydroxide overnight.

The dry oily product was taken up in 300 mL of dry THF and treated with 49.8 mL (800 mmol) of methyl iodide.

- 125 forfeiture and ice bath. Sodium hydride (10 g, 250 mmol, 60% in oil dispersion) was added slowly and stirred in an ice bath for 1 hour and then at room temperature for 22 hours. The reaction mixture was diluted with ethyl acetate (50 mL), stirred for 10 minutes, and water (100 mL) was added slowly. The solution was adjusted to pH 8-9 with a few drops of 4N hydrochloric acid and the organic solvent was removed at 30 ° C. Dilute with 100 ml water and then 10 ml 0.1N sodium thiosulphate solution and extract twice with ether. The aqueous phase was cooled in an ice bath and slowly adjusted to pH 3 with 4N hydrochloric acid. During acidification, the crystallizing product is filtered off, washed several times with water and dried. 26.0 g (94%) of the title compound are obtained. Melting point: 81-83 ° C.

1 H-NMR (CDCl ₃ ): δ 2.15 (m, 1H), 2.38 (m, 1H), 2.42 (m, 2H),

2.96 and 2.98 (2s, cis and trans _N-CH3), 4.62 (m, 1H), 4.90 (b, 1H), 5.19 (s, 2H), 7.35 ( m, 5H).

Step 2 N ice 5mL dry THF solution of ^the compound methyl 4-cyano-L-2-aminobutyric acid-N-carboxyanhydride, 11.05 g (40 mmol) of Example 1, a bath 15 g (72 phosphorus pentachloride) was added and the mixture was stirred for 2 hours and then evaporated to dryness. The residue was stirred with petroleum ether to give a solid. It is filtered, washed with petroleum ether and dissolved in dry acetonitrile. The insolubles were filtered off and the solution was evaporated. The solid material was cold and cold.

- Wash with 126 volts and dry. 5.86 g (87%) of the title compound are obtained.

Melting point: 90-92 ° C.

¹ H-NMR (CDCl 3): δ 2.18 (m, 1H), 2.39 (m, 1H), 2.60 (m, 2H),

3.02 (s, 3H); 4.28 (m, 1H).

Step 3

^{N-Boc-D-2-aminobutyryl-N-methyl-4-cyano-2-L-L-gluco} aminobutiri ici nt-butyl ester

To a solution of glycine t-butyl ester hydrochloride (3.68 g, 22 mmol) in chloroform (40 mL) was added N-methylmorpholine (4.84 mL), cooled to -40 ° C, and 3.36 g (20 mmol). A solution of the compound of Example 2 in 20 ml of dry acetonitrile was added. The reaction mixture was stirred for 1 hour at -20 ° C and the solvent was evaporated to a volume of about 10 ml.

To a solution of 8.08 g (21 mmol) of N-Boc-D-2-aminobutyric acid dicyclohexylamine salt in 30 ml of chloroform was added 3.91 ml (20.5 mmol) of diphenylphosphine chloride at -10 ° C, and the mixture is stirred at -5 ° C to -10 ° C for 1 hour. Then, 10 ml of the solution prepared above and 2.42 ml of N-methylmorpholine are added. The mixture was stirred at 0 ° C to -5 ° C for 24 hours and then concentrated. Dilute with ethyl acetate and filter off insoluble matters. The filtrate was washed four times with sodium bicarbonate solution and three times with brine, dried over magnesium sulfate and concentrated to a small volume. Meanwhile, the product crystallizes. This was diluted with petroleum ether and then cooled to give a solid

- 127 ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · . 6.2 g (70%) of the title compound are obtained.

Melting point: 90-92 ° C.

FAB-MS (MH ⁺ ): calculated 441.3; found 441.3.

Step 4

^{N-Boc-D-2-aminobutyryl-N-methyl-N} ', N''- (bis-benzyloxy-ylcarbonyl) -L-arginate için Ig I-t-butyl ester

A solution of the compound of Step 3 (4.63 g, 10.5 mmol) in methanol (70 mL) was combined with a solution of concentrated hydrochloric acid (1.2 mL) in methanol (10 mL) and cooled in platinum (IV) oxide (200 mL). The mixture was hydrogenated for 1 hour at 3.8 x 10 ⁵ Pa, and then the catalyst was filtered off and triethylamine (2.09 ml, 15 mmol) was added. The solvent was removed under reduced pressure and the residue was taken up in 20 mL of THF. To this was added N, N'-bis-benzyloxycarbonyl-S-methylisothiourea (3.58 g, 10 mmol) followed by triethylamine (2.09 mL, 15 mmol). The mixture was stirred overnight, whereupon the vessel was vacuum removed several times to remove methanethiol by-product. Ethyl acetate was added and the solution was washed with 1% citric acid, brine, 5% w / w sodium bicarbonate solution and again brine, dried over magnesium sulfate and evaporated. Crystallization from ethyl ether / petroleum ether gave 7.2 g (95%) of product.

FAB-MS (MH ⁺ ): calculated 755.4; found 755.4.

- 128 -

Step 5

^{D-2-amino-butyryl-N-methyl-N _<B> N?} '- compound (bi8z-nitrobenzyloxycarbonyl) -L-arginyl-glycine TFA salt g (11.9 mmol) of Step 4 90 50 ml of a 50% solution of TFA in methylene chloride was stirred at room temperature for 2 hours and then concentrated at 30 ° C. Cold ether was added, and after standing, the precipitated solid was filtered, washed with ether and dried. Yield: 8.4 g (99%). FAB-MS (MH ⁺ ): calculated 599.3; found 599.3.

Step 6

3- (Aminomethyl) benzoic acid hydrochloride

3-Cyanobenzoic acid (5.88 g, 40 mmol) was suspended in THF (50 mL) and the mixture was heated with stirring. After complete dissolution of the solid, isopropanol (50 mL) was added and allowed to cool to room temperature. 4.2 ml of cold concentrated hydrochloric acid and 300 mg platinum (IV) oxide was added, and hydrogenated 3,8 χ 10 ⁵ psi overnight. The reaction mixture was diluted with ether (50 mL), the precipitate was filtered off, washed with ether and dissolved in methanol. The catalyst was filtered off and the solvent removed under reduced pressure. 6.2 g (82%) of the title compound are obtained.

^1H-NMR (DMSO-d _e): δ 4.08 (d, 2H), 7.53 (t, 1H), 7.80 (d, 1H);

7.94 (d, 1H), 8.10 (s, 1H), 8.65 (s, 3H).

Step 7

Fmoc-L-aspartyl (t-butyl) -3- (aminomethyl) benzoic acid • · · · · · · 9 · · · 9 ··· ··· · · 4 · • · · · ·· «·· · ··

- A solution of 129 17.33 g (30 mmol) of FmocAsp (But) OPfp and 6.19 g (33 mmol) of the compound of Step 6 in 50 mL of DMF in an ice bath was treated with 11.5 mL (66 mmol) of diisopropylethyl ethyl acetate. and added for 5 hours at room temperature. 5% citric acid (200 mL) was added and the mixture was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated. The solid was washed with ether / petroleum ether and dried to give 16.3 g (100%) of the title compound.

1 H-NMR (DMSO-dt): δ 1.35 (s, 8H), 2.48 (dd, 1H), 2.70 (dd,

1H), 4.2-4.4 (m, 6H), 7.30 (t, 2H),

7.4-7.5 (m, 4H), 7.7-7.9 (m, 7H), 8.55 (t, 1H), 12.92 (s, 1H).

Step 8

Fmoc-L-aspartyl (t-butyl) -3- (aminomethyl) benzoyl-D-2-aminobutyryl-N * -methyl-N ^w , N ^w '- (bis-benzyloxycarbonyl) L -arginyl-gl icin

A mixture of Step 7 (10.89 g, 20 mmol), pentafluorophenol (4.05 g, 22 mmol) and DCC (4.13 g, 20 mmol) in THF (50 mL) was stirred overnight at room temperature. The dicyclohexylurea was filtered off, washed with THF and the filtrate was evaporated. To this was added a solution of Step 5 (14.25 g, 20 mmol) in DMF (40 mL) followed by diisopropylethylamine (7.32 mL, 42 mmol). After stirring for 4 hours at room temperature, the insoluble matters were filtered off, the filtrate was added to 200 ml of 3% citric acid with stirring and extracted twice with ethyl acetate. The combined extracts were washed with brine,

- dried over 130 of soda ash and evaporated. The residue was stirred with ether / petroleum ether to give 22 g (98%) of product. FAB-MS (MH +): calculated: 1125.5; found 1125.7.

Step 9 Synthesis of [L-aszpartin- (t-butyl) -3- (aminomethyl) benzoyl-D-amino-butyryl-N 2am ^ro N ^m - (bis-benzyl-l-oxy-carbonyl-L -arginilglicil]

A solution of 22.5 g (20 mmol) of the compound of Step 8 and 14.66 g (120 mmol) of 4-dimethylaminopyridine in 100 mL of DMF is stirred overnight at room temperature, and then 6.42 g (20 mmol) of mmol) of TBTU in 200 mL of DMF was added over 3 hours and stirred for an additional 1 hour. It was diluted with ethyl acetate (1000 mL) and washed twice with 1% citric acid, then brine (3x) and evaporated to dryness. The residue was taken up in THF, filtered and the solvent removed under reduced pressure. The solid was washed with ether and dried to give 16 g (90%) of product, FAB-MS (MH ⁺ ): calculated: 885.4; found 885.2.

Step 10

Cyclo [L-aspartyl-3- (aminomethyl) benzoyl-D-2-aminobutiriI N ^w, N ^w '- (bis-benzyloxy-carbonyl) -L-arginyl-glycyl] (16 g, 18 A solution of the compound of Step 9 in 200 ml of 50% TFA / methylene chloride was stirred at room temperature for 1.5 hours and then concentrated. The residue was stirred with ether to give 14.5 g (97%) of product. FAB-MS (MH ⁺ ): calculated 829.4; found 829.1.

- 131 ν «· ν 44 *« «· *» ♦ · »· · ♦ *» 4 · «· ·« 44 • · · · • 4 »4« «· ·

Example 301

Cl-Cl- [L-aspartyl 1- (acetoxymethyl) -3- (amino o -methylbenzoyl-D-2-aminobutyryl-L-arginylglycyl)]

A mixture of Step 10 (1.42 g, 1.7 mmol), bromomethyl acetate (980 mL, 10 mmol) and triethylamine (976 mL, 7 mmol) in DMF (10 mL) was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and the solution was washed three times with brine, dried over magnesium sulfate, concentrated and dried. The residue was taken up in DMF (8 mL) and treated with methanesulfonic acid (130 mL, 2 mmol) followed by 150 mg 10% Pd / C. The mixture is hydrogenated at atmospheric pressure for 2 hours, the catalyst is filtered off and the solution is diluted with water. Purification by ophthalmic HPLC afforded 650 mg of pure product (51).

FAB-MS (MH ⁺ ): calculated 633.3; found 633.2.

Example 308

Ci-O- [L-Aspartyl- (pi-1-oxymethyl) -3- (amino-methyl-benzoyl-D-2-amino-butyryl-L-arginyl-glycyl)]

4.14 g (5 mmol) of the compound of Step 10, 4.3 mL (30 mmol) of chloromethyl pivalate, 2.8 mL (20 mmol) of triethylamine and 4.5 g (30 mmol) of sodium iodide. ml of DMF was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed three times with brine, dried over magnesium sulfate and evaporated. The residue was taken up in 15 mL of ethyl acetate and purified on a silica gel column eluting with ethyl acetate / THF 1: 1. 1.5 g of pure product are obtained, which is dissolved in 10 ml of DMF and at atmospheric pressure

- 132 (130 mg) was hydrogenated on 10% Pd / C in the presence of 100 ml of methanesulfonic acid for 2 hours. The catalyst was filtered off, washed with DMF and the solution diluted with water. Purification by ophthalmic HPLC afforded 1 g (26%) of pure product.

FAB-MS (ΜH *): calculated 675.3; found 675.3.

Example 351

Cyclo [L-aspartyl (isopropyloxycarbonyloxymethyl) -3-aminomethyl) -benzoyl-D-2-aminobutyryl-L-arginylglycyl] 4.14 g (5 mmol) A mixture of Step 10, 4.58 g (30 mmol) of chloromethyl isopropyl carbonate, 2.8 mL (20 mmol) of triethylamine and 4.5 g (30 mmol) of sodium iodide in 10 mL of DMF Stir at room temperature for 18 hours. It was diluted with ethyl acetate (100 mL) and the solution was washed three times with brine, dried over magnesium sulfate and evaporated. The residue was taken up in 10 mL of ethyl acetate / THF 1: 1 and eluted on a silica gel column with ethyl acetate / THF 1: 1. 1.6 g of product are obtained, which is dissolved in 100 ml of DMF and hydrogenated on 150 mg of 10% by weight Pd / C for 2 hours at atmospheric pressure. The catalyst was filtered off, washed with DMF and the solution diluted with water. Purification by ophthalmic HPLC afforded 1 g (25%) of pure product.

FAB-MS (MH ⁺ ): calculated 667.3; found 667.3.

Reference is also made to the following U.S. patents filed on the same date as the present application: Representative No. DM-6535, inventor: Maduskuie and Pesti; representatives file number: DM-6650, inventor:

- 133 Zhang, Ma and DeGrado; DM-6665, inventor: DeGrado, Dorow, Ward and Xue.

The compounds of the present invention have platelet destructive activity as evidenced by standard platelet aggregation assay or platelet fibrinogen binding assay. A compound is considered active in these assays if the IC ₅₀ is less than about 1 mM. Platelet aggregation and fibrinogen binding assays demonstrating the antiplatelet effect of the compounds of the invention are described below.

In the platelet aggregation assay, venous blood is drawn from the arm of a healthy human donor who is drug-free and aspirin-free for at least 2 weeks prior to blood collection. Blood was collected in 10 ml citrated Vacutainer tubes. The blood is centrifuged at 150 g for 15 minutes at room temperature and the platelet-rich plasma (PRP for short) is removed. The remaining blood is centrifuged at 1500 g for 15 minutes at room temperature and the platelet-poor plasma (PPP) is removed. Samples were analyzed on an aggregometer (PAP-4 Platelet Aggregation Profiler) relative to a PPP blank (100% permeability). Add 200 μΙ PRP to each assay tube and set the permeability to 0%. 20 μΙ of different agonists (ADP, collagen, arachidonate, epinephrine, thrombin) were added to the tubes and the aggregation profile (% permeability versus time) was recorded. Results are expressed as% inhibition of agonist-induced platelet aggregation. To determine the IC ₅₀ value, the test compounds are administered at various concentrations before platelet activation.

The platelet fibrinogen binding assay measures the binding of ¹²⁵ l of fibrinogen to the platelet Bennett et al., Proc. Natl. Acad. Sci. USA 80, 2417-2422 (1983). Platelet fractions were separated from human PRP (h-PRP) on a Sepharose column. An aliquot of platelets (5 x 10 ⁸ cells), together with 1 mM calcium chloride, was plated in 96-well plates before activation of human gel-purified platelets (HGPP, abbreviated as "human gel purified platelets"). Activation of human gel-purified platelets is accomplished with ADP, collagen, arachidonate, epinephrine and / or thrombin in the presence of ¹²⁵ L of fibrinogen as ligand. ¹²⁵ L of fibrinogen binds to activated platelets and are separated by centrifugation from free platelets and counted in a gamma counter. To determine the IC ₅₀ value, the test compounds are administered at various concentrations before platelet activation.

The novel cyclic glycoprotein IIb / IIIa compounds of the present invention have a thrombolytic effect, i.e., they are capable of destroying the platelet-rich fibrin clot formed and can thus be used to treat thrombus formation, as demonstrated by the assays presented below. Preferred thrombolysis compounds are cyclic compounds of the present invention having an IC 50 (i.e., a molar concentration required for 50% clot destruction) of up to about 1 mM, preferably up to about 0.1 mM, most preferably up to about 0. , 01 mmol / l, mainly

135 up to about 0.0001 mmol / l, including about 0.0005 mmol / l.

The IC ₅₀ is determined by standard thrombolysis assays. Preferred thrombolytic agents are those compounds of the invention having a Kd of less than 100 nM, preferably less than 10 nM, most preferably 0.1 to 1.0 nM.

For thrombolytic examination, venous blood is drawn from healthy human donors, free of drugs and aspirin, for at least two weeks prior to blood collection, and blood samples are filled into 10 ml citrated Vacutainer tubes. The blood is centrifuged at 1500 g for 15 minutes at room temperature and platelet rich plasma (PRP) is removed. PRP is then added once with 10 ³ M agonist ADP, epinephrine, collagen, arachidonate, serotonin, thrombin, or a mixture thereof, and the PRP is incubated for 30 minutes. The PRP is then centrifuged at 2500 g for 12 minutes at room temperature. The supernatant was discarded and the platelets remaining in the test tube were suspended in platelet-poor plasma (PPP), which serves as a source of plasminogen. The suspension was examined on a Coulter Counter (Coulter Electronics, Inc., Hialeah, FL, USA) to determine the number of platelets at time 0. After determination of the 0-time value, test compounds are added at various concentrations. At different times, samples are taken and platelets are counted in a Coulter Counter. To determine the percentage digestion, the platelet count measured after addition of the test drug is subtracted from the platelet count at time 0 and divided by the number measured at time 0. The result is multiplied by 100 to obtain the percentage of the clot induced by the test compound. IC ₅ o value to determine the test compounds were added at various concentrations and the percentage lysis was determined.

In the platelet granular secretion assay, the role of the claimed platelet GP IIb / IIIa receptor antagonists in modifying the granular secretion of alpha or dense granule or intracellular Ca ²⁺ binding proteins is examined. These compounds have no significant effect on the granular secretion of plasminogen activator inhibitor type 1 (PAI1) from alpha particles, the mobilization of intracellular calcium reserves, or the selection of the vasoconstrictor from serum granule dense granules. Other antiplatelet agents such as aspirin or antithrombin hirudin inhibit granular secretion of antifibrinolithium (PAI-1) or vasoconstrictor (serotonin). By combining the general anti-aggregation effect and the antiplatelet effect, an optimal clinical effect is achieved.

The novel cyclic compounds of the present invention may also be used in combination product, which means that the pharmaceutical composition is in addition to the novel cyclic compound of the invention, an anticoagulant such as warfarin or heparin or a platelet disruptor such as aspirin, piroxicam or ticlopidine, or thrombin inhibitor. Thus, it contains a boropeptide, hirudin or argatroban, or a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or a combination thereof. Such combination products have 137 blue platelet destructive and thrombolytic effects, as evidenced by the studies performed.

The novel cyclic compounds of the present invention and their combination products containing them are described above and further applications are described below.

For the assay of platelet GP IIb / IIIa binding activity, ¹²⁵ L of fibrinogen binding is measured in purified human platelets (h-GPP). Representatives of the compounds of the invention have a high affinity for binding ^{125 I of} fibrinogen to h-GPP (IC ₅₀ = 5-100 nM), which is independent of the use of the agonist. The enzyme-linked immunosorbent assay (ELISA) uses purified GP IIb / IIIa receptors obtained from human platelets. Representatives of the compounds of the invention directly inhibit the binding of fibrinogen to RGD recognition sites with an IC _{50 of} 0.5-10 nM. The efficacy of the claimed compounds in inhibiting the binding of fibrinogen platelets to the GP IIb / IIIa receptor is related to the number of binding sites as evidenced by the fact that the IC ₅₀ decreases with the number of platelets.

Compound A (Example 3) replaces ¹²⁵ L of fibrinogen bound to activated platelets. In this assay, activated platelet-bound fibrinogen is incubated for 20 minutes before compound A administration. This means that Compound A has a high affinity for fibrinogen in the previously formed platelet rich blood clot. This effect explains the destructive action of the compounds of the invention. High-affinity binding (K d = 0.1 nmol / L) detected in the ³ H-labeled compound for activated human platelets, which is carried out by Scatchard analysis. In addition, purified • «· · • · V

- In a 138 GP IIb / llla biotinylated fibrinogen ELISA, Compound A exhibits a competitive inhibitory activity with a Ki value of 0.4 nmol / L according to the Michaelis-Menten assay.

As will be demonstrated later, in the human PRP aggregation assay, Compound A not only inhibits platelet agonist-induced aggregation, it also destroys aggregated platelets upon initiation of aggregation. The aggregation-disrupting effect of Compound A is dependent on concentration and timing of administration relative to platelet activation. The earlier the addition of Compound A after aggregation induction, the greater the destructive effect (Fig. 1a).

We further investigate the efficacy of Compound A in disrupting preformed platelet rich blood clots. Thrombolytic activity of Compound A was also measured (Figs. Ib and II). Compound A and Compound B (Example 4) show a significant destructive effect on preformed platelet-rich blood clot (Figure Ib). In addition, Compound A exhibits a synergistic effect in vitro and in vivo with conventional thrombolytics on the destruction of platelet-rich thrombi (Figure IIIb). The concentration-dependent destructive activity of Compounds A and B is shown in Figure Ib, where the IC 50 is 0.5-1.0 pmol / L. In contrast, the RGDS tetrapeptide is ineffective under the same conditions (Fig. Ib).

In addition, Compound A (0.1-1.0 pmol / L) and streptokinase, urokinase or t-PA have been shown to have a synergistic effect in the digestion of pre-formed platelet-rich blood clot in vitro (Figure III). These results confirm the in vivo destructive properties of the compounds of the present invention. ·························· ···

- 139 tenseness. In addition, administration of the new antagonists is expected to significantly reduce the dose of thrombolytic agent required to break down the blood clot and prevent re-occlusion and / or relapse. Platelet activation is known to play a significant role in delaying re-flow and re-occlusion after thrombolytic therapy. The compounds of the present invention thus provide an effective aid in thrombolytic therapy or angioplasty.

The cyclic glycoprotein IIb / IIIa antagonist compounds of the present invention substitute for ¹² ez fibrinogen bound to activated platelets in the platelet fibrinogen binding assay. The results show that the compounds have high affinity for replacing fibrinogen in a previously formed platelet-rich blood clot. Without being bound by any particular theory, these results may explain the surprising thrombolytic efficacy of the compounds of the invention.

Figure I:

Representative representatives of the cyclic compounds of the invention, namely the compound of Example 3 (cyclo- (DAbu-NMeArg-Gly-Asp-Mamb)), wherein R ¹ and R ² are hydrogen, J is D-2- amino-butyric acid, K is alpha-N-methyl-arginine, L is glycine and M is aspartic acid (also known as Compound A) and the compound of Example 4 (Cyclo- (D-Val-NMeArg-Gly-Asp-Mamb)). ), the formula (II) R ¹ and R ² is hydrogen, J is D-valine, K is a-N-methyl-arginine, L is glycine, and M is aspartic acid) (also known as compound B) hatékony9 9 9 · • «· · ·«

9 9 9 9 9 9 ··· • · · ·

9 9 · · · «9

- 140 were analyzed by human PRP aggregation assay (Fig. 1a). As shown in Fig. I, 0.1 pmol / L potently inhibits aggregation (destruction of aggregation) induced by 10 μηιόΙ / Ι AD 1.5 minutes after initiation of aggregation.

In the human PRP aggregation assay, the compounds of the invention not only inhibit platelet agonist-induced aggregation, but also aggravate platelet aggregation upon initiation of aggregation (Fig. 1a). The destructive action of Compound A is dependent on the concentration and timing of administration after platelet activation. The earlier compound A is added after aggregation starts, the greater the efficiency.

Compounds A and B were tested at different concentrations in the thrombolytic assay (Figure Ib). As shown in Figure Ib, compounds A and B disrupt the previously formed platelet-rich blood clot. Platelets are incubated with an agonist mixture (TEAC mixture) for 30 minutes at a concentration of 0.01 U / ml thrombin, 250 pmol / l epinephrine, 250 gm / l ADP and 10 gg / ml collagen. As a comparator, the arginine-glycine-asparagine linear peptide (RGDS) of the arginine-glycine-asparagus sequence is used as a reference. The results are shown in Figure I. The compounds of the invention (Compounds A and B) are effective in disrupting the previously formed platelet-rich blood clot. The results show that Compounds A and B exhibit an IC50 of about 0.5-1.0 pmol / L, and in comparison, the RGDS linear peptide is less effective at significantly higher concentrations (IC ₅₀ > 1 μΓπόΙ / Ι).

• · 4 ·· ··

- 141 -

II. figure:

Compounds A and B were tested at 0.001 mM in the above thrombolytic assay, where platelets were stimulated with 1 x 10 &lt; ³ &gt; ³ M ADP, reference standard thrombolytic tissue plasminogen activator (tPa, 10 pg / ml), urokinase ( UK, 900 U / ml) and streptokinase (SK, 500 U / ml). The results are shown in Table II. is shown. The compounds of the present invention (Compounds A and B) effectively degrade the previously formed platelet-rich blood clot, where Compound A exhibits significantly better disruption activity than tissue plasminogen activator, urokinase and streptokinase, and Compound B exhibits significantly better disruption activity. such as streptokinase. The results show that the destructive effect of Compound A is at least 70%.

Ill, figure:

In III. 1 pmol / l shows the effect of the compound in the digestion of a previously formed platelet rich blood clot. The thrombin, 0.01 U / ml thrombin, 250 pmol / l epinephrine, 250 pmol / l ADP, and 10 pg / ml collagen were used for 30 minutes to produce a blood clot. Compound A is significantly more potent in disrupting the blood clot than tissue plasminogen activator (tPA, 10 pg / ml), urokinase (UK, 900 U / ml) and streptokinase (SK, 500 U / ml). A synergistic (greater than additive) effect was observed between standard thrombolytic and IIb / IIIa antagonist Compound A. Data shown are mean ± standard deviation, where n = 3 per group.

- 142 • · · · · · ··· ··· ················································· · · · · · · · · · · · · · · · · · · · ·

Figure V:

Compound C was tested at a concentration of 1 pmol / L in the above thrombolytic assay alone and in combination with standard thrombolytic, which may be tissue plasminogen activator (tPA, 10 pg / ml), urokinase (UK, 900 U / ml) and streptokinase (SK, 500 U / ml). . The results show that Compound C, when combined with tissue plasminogen activator, urokinase or streptokinase, exhibits greater activity than additive.

VI. figure:

Compound D was used at a concentration of 1 g / L in the above thrombolytic assay alone and in combination with standard thrombolytic, which may be tissue plasminogen activator (tPA, 10 pg / ml), urokinase (UK, 900 U / ml) and streptokinase (SK, 500 U / ml). . The results show that Compound D, when combined with a tissue plasminogen activator, urokinase or streptokinase, exhibits a greater than additive effect.

VII. figure:

The Vlla. 1 pmol / l shows the effect of the compound in the digestion of a previously formed platelet rich blood clot. The thrombus, 250 μΓηόΙ / Ι epinephrine, 250 μΓηόΙ / Ι adenosine diphosphate, and 10 pg / ml collagen were used for 30 minutes to form a blood clot. Compound A is more effective in digesting the clot than SK (500 U / ml), UK (900 U / ml) or tPA (10 pg / ml). A synergistic effect is observed between standard thrombolytic and IIb / IIIa antagonist Compound A. Data are mean ± standard deviation, n = 3 per group.

• ·

- 143 A VIIb. Figure 3B shows the in vivo thrombolytic activity of Compound A and its interaction with standard thrombolytics. Compound A was administered at a dose of 1 mg / kg i.v. dose in the modified Lucchesi model effectively destroys the thrombus in the femoral artery. In addition, Compound A, when combined with a sub-optimal dose of standard thrombolytics such as 75 KU streptokinase, exhibits a synergistic effect, completely destroys the thrombus, restores flow, and prevents re-occlusion. Data are mean ± standard deviation, n = 3-6 per group.

Vili, figure:

The effect of the compound and saline on anesthetized male or female mongrel dogs was tested at 1.0 mg / kg i.v. doses of thrombolysis with streptokinase (250-300 x 1000 lU / kg) or tPA to prevent re-occlusion of the femoral artery. Compound A 100% inhibits re-occlusion for at least 240 minutes, whereas saline treated animals re-occlude within 42 ± 10 minutes. Compound A 1.0 mg / kg i.v. doses of SK or tPA effectively inhibits re-occlusion after thrombolysis. Data are mean ± standard deviation, n = 6 per group.

To investigate the antiplatelet effect of the cyclic GP IIb / IIIa receptor antagonist and aspirin and / or heparin combinations according to the present invention, 12 male mice (8-15 months, 8-12 kg) of thiamyl sodium bred for this purpose were given 15 mg / kg i.v. dose and 100 ng / kg alpha-chloralose i.v. dose anesthetized. The dogs were exposed to positive respiratory pressure (15 mg / kg (a), 20 breaths / min). We open the

144 femoral arteries and veins to measure arterial blood pressure and heart rate, and to take blood samples and inject intravenously.

Treatment groups:

/. group (salt): saline i.v. by injection;

//. group (aspirin): 10 mg / kg p.o. dose 30 minutes before blood sampling;

III. Group (Compound A): 0.08 mg / kg i.v. injection;

ARC. Group (Aspirin / Compound A): Aspirin 10 mg / kg p.o. After 30 minutes, 0.08 mg / kg i.v. dose of Compound A prior to administration.

Measurements:

(a) assaying blood samples for platelet aggregation ex vivo and counting platelet counts;

(b) measuring the bleeding time in minutes over the total duration;

(c) measuring the plasma level of Compound A in each group by ELISA.

Results:

Combinations of Compound A / Aspirin, Compound A / Heparin and Compound A / warfarin show better antiplatelet effects than Compound A alone. This effect does not significantly affect bleeding time or platelet count.

The compounds of the invention may be administered by any means by which the active ingredient is contacted within the body with the site of action, glycoprotein IIb / IIIa (GP IIb / IIIa). Accordingly, they may be administered in the conventional manner as a single therapeutic agent or as a combined therapeutic agent, as a second antiplatelet agent, a4 • ·

- 145 gonist-specific aspirin, piroxicam, ticlopidine, anticoagulant warfarin or heparin, thrombin inhibitor boropeptide, hirudin or argatroban, thrombolytic agent, tissue plasminogen activator, anistreplase, urokinase or streptokinase, and combinations thereof. The compounds of the invention, or combinations of the compounds of the invention and other therapeutic agents, may be administered alone or generally with a pharmaceutical carrier selected depending on the mode of administration and standard pharmaceutical practice.

The dosage of the novel cyclic compounds of the present invention will depend on various known factors. Examples include the pharmacodynamic characteristics of the patient being treated, the mode of treatment, the age, health and weight of the patient being treated, the nature and extent of the symptoms, the type of supplementary treatment, the frequency of treatment and the effect desired. The daily dose of the active ingredient is usually about 0.01 to 10 mg / kg body weight.

The dosage form suitable for administration contains from about 1 mg to about 100 mg of active ingredient per dosage unit. The amount of active ingredient in such a pharmaceutical composition is generally 0.5 to 95% by weight, based on the total weight of the composition.

The active ingredient may be administered orally in solid dosage forms such as capsules, tablets or powders, and in liquid dosage forms such as elixir, syrup and suspension. It can also be administered parenterally in a sterile liquid dosage form.

Gelatin capsules contain the active ingredient and a powdered carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Such carriers can be used to apply 4 V · 4 4 ·· 4 * VI4 · V 4 · 4 · 4

- 146 pails for making compressed tablets. Tablet and capsule formulations may also be formulated as sustained release formulations for sustained release over several hours. The compressed tablet may be coated with a sugar or film to mask the unpleasant taste and to protect the tablet from environmental influences, or an enteric coating to ensure selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring and flavoring agents.

For parenteral solutions, the carrier will usually comprise water, a suitable oil, saline, aqueous dextrose (glucose), and a suitable sugar solution or glycol, such as propylene glycol or polyethylene glycol. Solutions for parenteral administration preferably contain the active ingredient in the form of a water-soluble salt with a suitable stabilizer and, if desired, a buffer. Other components include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, or combinations thereof, and citric acid and its salts, sodium EDTA, and preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company.

Preferred dosage forms for administration of the compounds of the present invention are as follows:

• · · ···

- 147 Capsules:

A large amount of capsules is prepared by filling 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate into a standard two-piece hard gelatin capsule.

Soft gelatin capsules:

A mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is pumped into a gelatin to form a soft gelatin capsule containing 100 mg of the active ingredient. The capsule is washed and dried.

Tablet:

Large quantities of tablets are prepared in the usual manner, with a unit dose composition of 100 mg of active ingredient, 0.2 mg of colloidal silica, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. The tablet may be coated to improve taste or delay absorption.

A combination product of the invention comprising a novel cyclic IIb / IIIa antagonist compound of the invention and an anticoagulant such as warfarin or heparin or a platelet disruptor such as aspirin, piroxicam or ticlopidine, or a thrombin inhibitor such as boropeptide, hirudin or argatroban, or trom such as tissue plasminogen activator, anistreplane, urokinase, or streptokinase, or combinations thereof, may be formulated in any of the dosage forms described above, and may be administered by any of the methods described above.

• ·· ···

The combination product of the present invention is preferably formulated in a single dosage form (i.e., combined in a capsule, tablet, powder or liquid formulation). If the combination product is not formulated as a unit dosage form, the cyclic glycoprotein IIb / IIIa compound of the present invention and the anticoagulant, antiplatelet agent, thromine inhibitor and / or thrombolytic agent may be administered simultaneously (i.e., together) or in any order, e.g. the compound of the invention is administered followed by administration of an anticoagulant, antiplatelet agent, thrombin inhibitor and / or thrombolytic agent. When the active compounds are not administered simultaneously, the compound of the invention and the anticoagulant, antiplatelet agent, thrombin inhibitor and / or thrombolytic agent may be used for up to about 1 hour, preferably for up to about 30 minutes, especially for up to about 5 minutes. add in minutes. The combination product is preferably administered orally. The term oral agent, oral inhibitor, oral compound and the like refers to an oral compound. The cyclic IIb / IIIa antagonist compound of the present invention and the anticoagulant, antiplatelet agent, thrombin inhibitor and / or thrombolytic agent are preferably administered in the same manner (i.e., both orally) but may be administered in a different manner (e.g., one of the combination product). orally and the other component intravenously). The dosage of the combination product of the present invention will depend on various factors, such as the pharmacodynamic characteristics of the patient being treated, the route of administration, the

- the age, health and weight of 149 patients, the nature and extent of the symptoms, the type of supplementary treatment, the frequency of treatment and the effect desired.

The appropriate dosage of the combination product of the present invention may be readily determined by one of ordinary skill in the art, based upon the general teachings herein. When the cyclic compound of the invention is combined with an anticoagulant agent, a typical daily dose is about 0.01-10 mg of the cyclic compound of the invention and about 1-7.5 mg of the anticoagulant, preferably about 0.1-1 mg of the cyclic compound of the invention and 1-5 mg anticoagulant per patient body weight. In a typical dosage form of this type of combination product, such as a tablet, the amount of the novel compound of the invention is generally about 5-10 mg and the amount of anticoagulant is about 1-5 mg.

When the novel compound of the invention is combined with another antiplatelet agent, a typical daily dose is about 0.01-25 mg of the cyclic compound of the invention and about 50-100 mg of additional antiplatelet agent, preferably about 0.1-1 mg of the present invention. new compound and about 1-3 mg of platelet destructive agent per patient body weight. Typical dosage forms of this type of combination product include, for example, about 5 mg of the novel compound of the invention and about 150 mg of the additional anti-platelet agent or about 25 mg of the cyclic compound of the invention and the additional anti-platelet agent amount of drug is about 50 mg.

When the novel compound of the invention is combined with a thrombolytic agent, the typical daily dose is about 0.1 to 1 mg of the cyclic compound of the invention per 1 kg of body weight, wherein the amount of thrombolytic agent is about 30 mg / kg of the thrombolytic agent used alone. It can be reduced by 70-80% when co-administered with a compound of the invention. This type of combination product is typically in the form of a dose, such as about 10 mg of the novel compound of the invention in the tablet.

When two or more of the above-mentioned therapeutic agents are combined or administered simultaneously with the compound of the invention, the typical daily dose may be reduced relative to the usual dose of the active ingredient alone, taking into account the additive or synergistic effect obtained with the additional agent.

When using a single dosage form, there is the potential for chemical interaction between the combined active ingredients (e.g., a compound of the invention and an anticoagulant such as warfarin or heparin, or a novel compound of the invention and a platelet disruptor such as aspirin, piroxicam). or ticlopidine, or between a novel compound of the invention and a thrombin inhibitor such as boropeptide, hirudin, or argatroban, or a combination of a novel compound of the invention and a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase) . Therefore, the combination product of the invention is preferably formulated in a dosage form that combines the active ingredients in a single dosage form, but minimizes (i.e. reduces) the physical contact between the active ingredients.

• · ·

In the case of an oral formulation, contact may be reduced by coating the active ingredient with an enteric coating. By providing an enteric coating with one of the active ingredients, not only the contact between the combined active ingredients is reduced, but it is also possible to control the release of the component concerned in the gastrointestinal tract so that this component is released in the gut rather than in the gut. Alternatively, for oral administration, one of the active ingredients may be provided with a sustained release coating, which will delay the release of the active ingredient in the gastrointestinal tract while reducing physical contact between the combined active ingredients. Alternatively, the sustained release component is additionally provided with an enteric coating, wherein this component is released only in the intestine. Alternatively, one component of the combination composition of the invention may be coated with a sustained release and / or enteric polymer and the other component coated with another polymer such as low viscosity hydroxypropylmethyl cellulose (HPMC) or other suitable known material. to further isolate the active ingredients. The polymer coating poses an additional barrier to the interaction of the components.

The combination product of the present invention wherein one of the active ingredients is enteric coated may be formulated as a tablet, wherein the enteric coated component and the other active ingredient are mixed and compressed into tablets or enteric coated.

- A component of train 152 is compressed to form a tablet layer and the other active ingredient is compressed to form an additional layer. Optionally, one or more placebo layers, which are located between the active ingredient layers, may be used to further separate the two layers. The composition of the invention may also be formulated in the form of a capsule, whereby one of the active compounds is compressed into tablets or microtablets, granules or granules and coated with an enteric coating. The microtablets, granules or granules thus coated are then filled into capsules, or combined with the granules of the other active ingredient in capsules.

Methods for reducing contact between the components of a combination product of the present invention, administered in a single dosage form or separately, but administered at the same time and in the same manner, are well known to those of ordinary skill in the art.

The present invention may also be provided in the form of a pharmacological kit for use in inhibiting platelet aggregation, treating a blood clot and / or treating thromboembolic disorders, comprising a therapeutically effective amount of a novel cyclic platelet glycoprotein IIb / IIIa compound of the present invention, warfarin or heparin or a platelet disruptor such as aspirin, piroxicam or ticlopidine or a thrombin inhibitor such as boropeptide, hirudin or argatroban or a thrombolytic agent such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or a combination thereof or in sterile containers. Sterilization of the container is accomplished by standard sterilization procedures known to those skilled in the art. The sterile container for the materials may be a separate container or one or more multi-container containers, such as a two-container container marketed as UNIVIAL (Abbott Labs, Chicago, Illinois, USA). The novel compound of the invention, the anticoagulant agent, the antiplatelet agent, the thrombin inhibitor, the thrombolytic agent, and / or combinations thereof may be formulated separately or combined in a single dosage form as described above. The kit may optionally contain one or more different conventional pharmaceutical kit components, such as one or more pharmaceutical carriers or vials for mixing the components known to those skilled in the art. The kit may further comprise instructions, for example in the form of an insert or label, indicating the amount of the components to be administered, the mode of administration and / or the method of mixing the components.

Representative compounds of the invention are set forth in the following tables. The biological activity of the compounds in the tables is given by the IC ₅₀ value determined in the above platelet aggregation assay. The IC ₅ o value is defined as follows:

+++: IC ₅₀ value of less than 1 pmol / l ++: IC ₅₀ value of 1-10 pmol / l +: IC 50 value greater than 10 to 100 pmol / l

When examining a mixture of isomers of a compound, such as the isomer 1 and the isomer 2, the mixture is bi-

The ological efficiency of 154 is given in brackets for each isomer.

155 Table I Compounds of Formula IV (wherein J is -N (R ³ ) -C (R ⁴ ) (R ⁵ ) C (= O) -; Optical Isomeric Form; R ¹⁰ Hydrogen, unless otherwise indicated)

Pld.sz. R ³ R ⁴ R ⁵ FAB-MS / M + H / Optical isomer ^IC 50 1 H H H 533.26 ++ + 2 H H CH3 547.23 (D) +++ 2a H H CH3 (L) 3 H H CH2CH3 561.46 (D) +++ 3a H H CH2CH3 (L) 3c H H CH 2 CH 3 _R 10.i 687.33 (D) +++ 4 H H CH (CH3) 2 575.45 (D) ++ + 4a H H CH (CH3) 2 (L) 5 H H CH2CH (CH3) 2 589.48 (D) ++ + 5a H H CH2CH (CH3) 2 (L) 6 H H CH2CH2CH3 (D) 6a H H CH2CH2CH3 (L) 7 H H CH2CH2CH2CH3 589.26 (D) +++ 7a H H CH2CH2CH2CH3 (L) 8 H H (CH2) 5CH3 (D) 8a H H (CH2) 5CH3 (L)

• · · «·«

- 156 -

Pld.sz. R ³ R ⁴ R ⁵ FAB-MS / M + H / Optical isomer ^IC 50 9 H H (CH2) 7CH3 (D) 9a H H (CH2) 7CH3 (L) 10 H H C (CH3) 3 (D) 10a H H C (CH3) 3 (L) 11 H H phenyl 609.27 (D) ++ + 11a H H phenyl (L) 12 H H phenylmethyl 623.28 (D) +++ 12a H H phenylmethyl (L) 13 H H CH 2 OH (D) 13a H H CH 2 OH (L) 13b H H (CH2) 3NH2 (D) 13c H H (CH2) 3NH2 (L) 13d H H (CH2) 3 NHC (= NH) NH2 (D) 13e H H (CH2) 3 NHC (= NH) NH2 (L) 13f H H (CH2) 4NH2 604 .32 (D) ++ + 13g H H (CH2) 4NH2 (L) 13h H H (CH2) 4NHC (= NH) NH2 (D) 13i H H (CH2) 4NHC (= NH) NH2 (L) 13 j H H (CH2) 5NH2 (D) 13k H H (CH2) 5NH2 (L) 131 H H (CH2) 5 NHC (= NH) NH2 (D) 13m H H (CH2) 5 NHC (= NH) NH2 (L) 13n H H (CH2) 4CH3 (D) 13o H H (CH ₂ ) 4 CH ₃ (L)

157 -

Pld.sz. R ³ R ⁴ R ⁵ FAB-MS / M + H / Optical isomer ^IC 50 13p H H (CH2) 6CH3 (D) 13q H H (CH2) 6CH3 (L) 13r H H CH (CH3) CH2CH3 589.34 (D) ++ + 13s H H CH (CH3) CH2CH3 (L) 14 H H 2 SH (D) 14a H H 2 SH (L) 15 H H CH2OCH3 (D) 15a H H CH2OCH3 (L) 16 H H CH2SCH3 (D) 16a H H CH2SCH3 (L) +++ 17 H H CH2CH2SCH3 (D) 17 H H CH2CH2SCH3 (L) 18 CH3 H H 547.34 +++ 19 H CH ₃ CH ₃ 20 H CH2 CH3 CH2CH3 21 H H cyclopentyl (D) 21a H H cyclopentyl (L) 22 H H cyclohexyl (D) 22a H H cyclohexyl (L) ++ + 23 H H c cyclohexyl1-methyl1 (D) 23c H H cyclohexylmethyl (L) 23a H H CH (CH 3) 2 R ¹⁰ = I 701.37 (D) 23b H H CH (CH ₃ ) 2 R ^10a I (L)

··· * · «Ι _{Μ (} ··

-15823d

23e

- (CH ₂ ) ₄ -nc

23f

23g

23h

- (CH,) ₄

H

I

- (CH 3) ₄ -nc

O NHiH

I I I

C - C j

H I

Η Η O

II I I II

CH

I - (CH 3) ₄ - N - C - c - N - COC - CH,

I

H

23k i CH>

231

H

I

- (CH _a ) ₄ - n—

23m

23n

Η O I II - (CH 3 -N-C

• * ♦ ·· <··· «· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · pit ·

23ο Η Η

- 159 -

23ρ Η Η

Ο

Η Ο θ ^{= 0} I II J ».

- (CHj) ₄ -nc ··· ·

Continuation of Table I

- 160 FAB-MS / M + S / Optical isomer

573.46 (L)

573.35 (D) (D) ^IC 5O +++

Pld.sz. J

- 161 FAB-MS / M + S / Optical isomer

28b

28c

28d

28e

547.28 (D) (L) (L) +++ Continuation of table

Pld.sz.

FAB-MS / M + S /

Optical IC _5Q isomer

28f Η H

639.54 (D) ++ +

28g Η H / = \ y ~ ^0H (L) ··· / · ··· *. · *: *, ·

Further preferred compounds of the invention are those of Table I wherein Asp is replaced by one of the following groups: alpha-MeAsp, beta-MeAsp, NMeAsp, D-Asp,

Asp (methyl-carbonyloxy-methyl ester),

As p- (ethyl I-carbonyloxymethyl ester),

Asp (t-butylcarbonyloxymethyl ester), Asp (cyclohexylcarbonyloxymethyl ester),

Asp (1- (methylcarbonyloxy) ethyl ester),

Asp (1- (ethylcarbonyloxy) ethyl ester),

Asp (1- (t-butylcarbonyloxy) ethyl ester),

Asp- (1- (cyclohexylcarbonyloxy) ethyl ester), Asp- (i-propyloxycarbonyloxymethyl ester), Asp- (cyano-hexexyloxycarbonyloxy) ethyl ester), Asp (t-butyloxycarbonyloxymethyl),

Asp (1- (i-propyloxycarbonyloxy) ethyl ester),

Asp (1- (cyclohexyloxycarbonyloxyO-ethyl ester),

Asp (1- (t-butyl 1-oxycarbonyloxy) ethyl ester),

As p- (dimethyl-ethyl minoethyl ester),

Asp (diethylamino-ethyl ester),

Asp - ((1,3-dioxa-5-methyl-cyclopenten-2-on-4-yl) methyl ester);

Asp - ((5- (t-butyl) -1,3-dioxa-cyclopenten-2-on-4-yl) methyl ester);

Asp - ((1,3-dioxa-5-phenylcyclopenten-2-one-4-yl) methyl ester) or

Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester).

- 163 -

Table 2 Compounds of Formula V (wherein J is -NH-C (R ⁴ ) (R ⁵ ) -C (= O) -, the Optical Isomeric Form of J)

Pld.sz. R ⁴ R ⁵ FAB-MS / M + H / Optical isomer ^IC 50 29 H H 519.26 ++ 30 H CH3 533.26 (D) ++ 31 H CH3 533.25 (L) 32 H CH (CH3) 2 561.22 (D) ++ 32a H CH (CH3) 2 (L) 33 H CH2CH (CH3) 2 575.45 (D) ++ 33a H CH2CH (CH3) 2 (L) 34 H CH2CH3 547.21 (D) ++ 34a H CH2CH3 (L) 35 H CH 2 OH 549.31 (D) ++ 35a H CH 2 OH (L) 36 H phenylmethyl 609.25 (D) + 37 H phenylmethyl 609.26 (L) +

- 164 -

Table 3 Compounds of Formula VI (wherein K is -N (R 6) -CH (R 7) -C (= O) -, the Optical Isomeric Form of K)

by date R ⁶ R ⁷ FAB-MS / M + H / Optical isomer 32 H - (CH 2) 3 NHC (= NH) (NH2); 561.22 (L) 32a H - (CH 2) 3 NHC (= NH) (NH2); (D) 4 CH3 - (CH 2) 3 NHC (-NH) (NH2); 575.45 (L) 4b CH3 - (CH 2) 3 NHC (= NH) (NH2); 575.31 (D) 38 CH3 - (C "2) 4NHC (-NH) (NH2); (L) 38a CH3 - (CH2 / 4NHC (= NH) (NH2); (D) 39 H -ch ₂ - ^^ _ ch ₂ nh ₂ (L) 39a H -CH ₂ - ^ ~~ y -CH ₂ NH ₂ (D) 40 CH3 -CH ₂ - ^ 2 ^ "CH ₂ NH ₂ 595.23 (L) 4Öa CH3 -ch ₂ - ^ ~ ^ -ch ₂ nh ₂ (D) 41 CH3 NH - CHCH 2 Ν H \ = / nh ₂ (L)

- 165 continued the table

41a CH3 NH 1 / nh ₂ (D) 42 CH3 -CH2SCH2CH2NH2 (L) 42a C «3 -CH2SCH2CH2NH2 (D) 43 CH3 -CH2SCH2CH2NHC ("NH" (NH2) (L) 43a CH3 -CH2SCH2CH2NHC (»NH) (NH2) (D) 44 CH3 -CH2CH2SCH2CH2NH2 (L) 4 4a CH3 -CH2CH2SCH2CH2NH2 (D) 45 CH3 CH2CH2SCH2CH2NHC (= NH) (NH 2.) (L) 45a CH3 CH2CH2SCH2CH2NHC (NH) (NH 2.) (D) 46 CH3 NH (L) 4 6a CH3 NH (D) 47 CH3 (L) 4 7a CH3 (D) 48 CH3 - CH ₂ CH ₃ NH 3 (L) 48b CH3 - ch ₂ ch ₂ nh ₂ (D)

• · ·

- 166 continue the table

Pld.sz. R ⁶ R ⁷ FAB-MS / M + H / Optical IC _5Q isomer 48a ch ₃ - ^ch '-OC (L) 48d ch ₃ (D) 49 CH3 (L) 4 9a CH3 ^ch, O ^{cB! 8h} ^ “ ^h (D)

continue the table

Pld.sz. K

FAB-MS / M + H /

o • · ♦ · · · ♦ · · · · · · · · · · · · · · · · · · · · · · · ·

- 167 -

Table 4 Compounds of formula VII

Pld.sz. L FAB-MS / M + H / Optical isomer IC ^ q 4 -NHCH 2 C (-0) - 575.45 +++ 54 -NHCH2CH2C (= 0) - 589.32 ++ 55 -0CH2C (-0) - 56 -OCH2CH2C (= 0) - 57 -SCH2C (-0) - 58 -SCH2CH2C (= 0) -

589.31 (L) +

58c -NHCH (CH 3) C (= O) - 168 -

Table 5 Compounds of Formula VIII (wherein M is -NR (R ¹⁰ ) C (R ⁸ ) (R ⁹ ) C (= O) -)

Pld.sz. R ⁸ R ⁹ R ¹⁰ FAB-MS / M + H / Optics IC ^ Q isomer 4 2 COOH H H 575.45 (L) +++ 63 2 COOH CH3 H 589.29 1 isomer 63a 2 COOH CH3 H 589.27 2 isomer 64 -CH (CH3) COOH H H 589.43 1 isomer 64a -CH (CH3) COOH H H 589.45 2 isomer * 64b 2 COOH CH3 589.42 64c -CH2C00H H H 575.42 (D) ++ 66 -CH2SO3H H H

• · · · · ·································•••

- 169 -

Table 6 Compounds of Formula IX (This Table gives the optical isomeric form of the -CH (R ¹ ) N (R ² ) - moiety)

Pld.sz. R ¹ R ² FAB-MS / M + H / Optical isomer ^IC 50 4 H H 575.45 ++ + 68 CH3 H 589.31 1 isomer +++ 68a CH3 H 589.31 2 isomer +++ 69 CH2CH3 H R 69a CH2CH3 H S 7G CH (CH3) 2 H R 70a CH (CH3) 2 H S 71 CH2CH2CH3 H R 71a CH2CH2CH3 H S 72 CH2CH2CH2CH3 H R 72a CH2CH2CH2CH3 H S 73 C (CH 3) 3 H R 73a C (CH3) 3 H S 74 CH (CH3) CH2CH3 H R 74a CH (CH3) CH2CH3 H S 75 benzyl H R 75a benzyl H S

* · · · • · ·

Pld.sz. R ¹

FAB-MS / M + H / Optical isomer

76 phenyl H 651.33 1 isomer ++ 7 6a phenyl H 651.33 2 isomer ++ 77 cyclopentyl H R 77a cyclopentyl H S 78 cyclohexyl H R 78a cyclohexyl H S 79 H CH3 589.33 80 H CH2CH3 81 H CH2CH2CH3 82 H CH (CH3) 2 83 H CH2CH2CH2CH3 84 H C (CH3) 3 85 H CH (CH3) CH2CH3 86 H benzyl

• «

- 171 - • · · · · · · · · · · · · · · · · ·

Példasz. Structure 87 NMeArg D-Val Gly \ asp ^ο τΊι / ^ ^NH NMeArg / D-Val 1 Gly 88 \ asp ° / .NH

Table 7

FAB-MS / M + H / ^IC 50 575.41 ++ + 1 isomer 575.44 ++ +

isomer

89a

615.34 +++

89b ^ Gly _x

615.35 +++

89c

NMeArg

I

625.32 ++

example Number

- 172 Table 8

Structure

Gly

89d X NMeArg I asp I 1 D-Abu | NH t O a J r L

FAB-MS (M + H / IC)

687.33 +++

533.34 ++

89e _x ^Gly dl-NMeOrn ^A * ^P l

589 +++

575 +++

N-MaArg /

575 +++

D-Val

• · «· ·· ♦

- Table 173 9 Compounds of Formula X (wherein J is D, K is NMeArg, L is Gly, and M is Asp)

example Number _R l ° a R ¹⁰ FAB-MS / M + H / ^IC 50 93 cl H 609 ++ + 94 I H 701.37 +++ 95 Sample check H 623 (+ H2O) 96 Me H 589 +++ 97 H cl 609 ++ + 98 H I 701 99 H Sample check 605 +++ 100 H Me 589 +++

Table J continued (where J is D-Abu, K is NMeArg, L is Gly and M is Asp)

100Ah

100bH

100CH

cl 595.4 ++ + I 687.3 ++ + Me 575.4 +++

3-9. wherein D-Val is substituted with one of the following residues: D-2-aminobutyric acid, D-Leu, D-Ala, Gly, D-Pro, D-Ser, D-Lys, betaAla, Pro, Phe, NMeGly , D-NIe, D-Phg, D-lle, D-Phe, D-Tyr, Alá.

Table 10 Compounds of Formula XI (wherein L is Gly, M is Asp, R ² and R ¹ are hydrogen, K is -N (R ⁶ ) CH (R ⁷ ) C (= O) - · · ··· · • <♦ • ♦ · ·· «

- 174 -

group and J represents D) Példasz . R ⁶ R ⁷ Optical IC _5Q isomer 101 CH3 - (Ch ₂ ) ₂ - / ~ \ h L 102 CH3 - (CH ₂ ) ₂ —ΛΑη D 103 CH3 - (Ch ₂ ) ₃ - L 104 CH3 - (CH ₂ > 3 — ζ ~ \ ΐΗ D 105 CH3 - (CH ₂ ) ₄ - \ h L 106 CH3 - <ch ₂ ) ₄ - D

······················································································································································································Hing

- 175 -

107 CH3 —Ch ₂ o— \ h 108 CH3 —CH ₂ O— \ lH 109 CH3 L -CH ₂ OCH ₂ - \ | H 110 CH3 -CH ₂ QCH ₂ - \ lH 111 CH3 L "CH ₂ O (CH ₂ ) ₂ - 1 H 112 CH3 -CH ₂ O (CH ₂ ) ₂ - \ | H 113 CH3 ~ (CH ₂ ) ₂ O - 1 H 114 CH3 D ~ (CH ₂ ) ₂ O - \ h 115 CH3 - (CH ₂ ) ₂ OCH ₂ - \ h 116 CH3 - (CH ₂ ) ₂ OCH ₂ - \ 1H

* ··· ··· · * »« »··· ··» »·

- 176 -

CH3 L —-CH ₂ S— \ h CH3 D —CH ₂ S CH3 L -CH ₂ SCH ₂ - / NH CH3 ~ * CH ₂ SCH ₂ - / NH CH3 L -CH ₂ S (CH ₂ ) ₂ - / NH CH3 D -CH ₂ S (CH ₂ ) ₂ - / NH CH3 - (CH ₂ ) ₂ S - / NH CH3 D ~ (CH ₂ ) ₂ S - / NH CH3 L - (CH ₂ ) ₂ SCH ₂ - / NH CH3 D - (CH ₂ ) ₂ SCH ₂ - / NH CH3 -CH 2 -S- (CH 2) 3 -NH-CH 3 L CH3 -CH 2 -S- (CH 2) 3 -NH-CH 3 D

- 177 -

129 CH3 -CH2-S- (CH2) 3 -NH- CH2CH3 L 130 CH3 -CH 2 -S- (CH 2) 3 -NH- CH2CH3 D 131 CH3 -CH2-S- (CH2) 3 -NH- CH (CH3) 2 L 132 CH3 -CH 2 -S- (CH ₂ ) 3 -NH-CH (CH 3) 2 D 133 CH3 -CH2-S- (CH2) 3 -NH- CH2CH2-CH3 L 134 CH3 -CH2-S- (CH2) 3NH- CH2CH2-CH3 D 135 CH3 -CH2-S- (CH2) 3 -NH- C (CH3) 3 L 136 CH3 -CH2-S- (CH2) 3 -NH- C (CH3) 3 D 137 CH3 CH2-O- (CH2) 3-NH-CH3 L 138 CH3 CH2-O- (CH2) 3-NH-CH3 D 139 CH3 CH2-O- (CH2) 3-NH CH2CH3 L 140 CH3 CH ₂ -O- (CH ₂ ) 3 -NH-CH ₂ CH 3 D 141 CH3 CH ₂ -O- (CH 2) 3 -NH-CH (CH 3) 2 L 142 CH3 CH2-O- (CH2) 3-NH CH (CH3) 2 D 143 CH3 CH2-O- (CH2) 3-NH CH2CÜ2CH3 L 144 CH3 CH2-O- (CH2) 3-NH CH2CH2CH3 D 145 CH3 CH2-O- (CH2) 3-NH L

C (CH ₃ ) 3

- 178 -

146 CH3 CH2-O- (CH2) 3-NH C (CH3) 3 D 147 CH3 -CH2-S- (CH2) 2-NH-CH3 L 148 CH3 -CH2-S- (CH2) 2-NH-CH3 D 149 CH3 -CH2-S- (CH2) 2-NH CH2CH3 L 150 CH3 -CH 2 -S- (CH 2) 2 -NHCH 2 CH 3 D 151 CH3 -CH2-S- (CH2) 2-NH CH (CH3) 2 L 152 CH3 -CH2-S- (CH2) 2-NH CH (CH3) 2 D 153 CH3 -CH 2 -S- (CH 2) 2 -NH- CH2CH2-CH3 L 154 CH3 -CH 2 -S- (CH 2) 2 -NH- CH2CH2-CH3 D 155 CH3 -CH 2 -S- (CH 2) 2 -NH- C (CH3) 3 L 156 CH3 -CH2-S- (CH2) 2-NHC (CH3) 3 D 157 CH3 CH2-O- (CH2) 2-NH-CH3 L 158 CH3 CH2-O- (CH2) 2-NH-CH3 D 159 CH3 CH2-O- (CH2) 2-NH CH2CH3 L 160 CH3 CH2-O- (CH2) 2-NH CH2CH3 D 161 CH3 CH2-O- (CH2) 2-NH CH (CH3) 2 L 162 CH3 CH2-O- (CH2) 2-NH CH (CH3) 2 D 163 CH3 CH2-O- (CH2) 2-NH L

CH2CH2CH3

- 179 -

164 CH3 CH 2 -O- (CH ₂ ) 2 -NH-CH ₂ CH ₂ CH ₃ D 165 CH3 CH 2 -O- (CH 2) 2 -NH-C (CH ₃ ) 3 L 166 CH3 CH 2 -O- (CH ₂ ) 2 -NH-C (CH ₃ ) 3 D 167 CH3 -CH 2 -S- (CH ₂ ) 4 -NH-CH 3 L 168 CH3 -CH 2 -S- (CH ₂ ) 4 -NH-CH 3 D 169 CH3 -CH 2 -S- (CH ₂ ) 4 -NH- CH ₂ CH ₃ L 170 CH3 -CH 2 -S- (CH ₂ ) 4 -NH- CH ₂ CH ₃ D 171 CH3 -CH 2 -S- (CH ₂ ) 4 -NH-CH (CH 3) 2 L 172 CH3 -CH2-S- (CH2) 4-NH CH (CH3) 2 D 173 CH3 -CH 2 -S- (CH ₂ ) 4 -NH-CH ₂ CH ₂ -CH ₃ L 174 CH3 -CH 2 -S- (CH ₂ ) 4 -NH-CH ₂ CH ₂ -CH ₃ D 175 CH3 -CH 2 -S- (CH ₂ ) 4 -NH-C (CH 3) 3 L 176 CH ₃ -CH ₂ -S- (CH ₂ ) 4 -NH-C (CH 3) 3 D 177 CH3 CH ₂ -O- (CH ₂ ) 4 -NH-CH 3 L 178 CH3 CH ₂ -O- (CH ₂ ) 4 -NH-CH 3 D 179 CH3 CH ₂ -O- (CH ₂ ) 4 -NH- CH ₂ CH 3 L 180 ch ₃ CH ₂ -O- (CH ₂ ) 4 -NH-CH ₂ CH 3 D 181 CH3 CH ₂ -O- (CH ₂ ) 4 -NH- L

CH (CH3) 2

-180-

182 CWhen CH2-O- (CH2) 4-NH CH (CH3) 2 D 183 CH3 CH2-O- (CH2) 4-NH CH2CH2CH3 L 184 CH3 CH2-O- (CH2) 4-NH CH2CH2CH3 D 185 CH3 CH 2 -O- (CH 2) 4 -NH-C (CH ₃ ) 3 L 186 CH3 CH 2 -O- (CH 2) 4 -NH-C (CH ₃ ) 3 D 187 CH3 -CH 2 -S- (CH 2) 5 -NH-CH 3 L 188 CH3 -CH 2 -S- (CH 2) 5 -NH-CH 3 D 189 CH3 -CH 2 -S- (CH 2) 5 -NH-CH 2 CH ₃ L 190 CH3 -CH 2 -S- (CH 2) 5 -NHCH 2 CH ₃ D 191 CH3 -CH2-S- (CH2) 5-NH CH (CH3) 2 L 192 CH3 -CH2-S- (CH2) 5-NH- CH (CH3) 2 D 193 CH3 -CH2-S- (CH2) 5-NH CH2CH2-CH3 L 194 CH3 -CH2-S- (CH2) 5-NH- CH2CH2-CH3 D 195 CH3 -CH2-S- (CH2) 5-NH C (CH3) 3 L 196 CH3 -CH2-S- (CH2) 5-NH- C (CH3) 3 D 197 CH3 CH2-O- (CH2) 5-NH-CH3 L 198 ch ₃ CH2-O- (CH2) 5-NH-CH3 D 199 CH3 CH2-O- (CH2) 5-NH L

CH2CH3 • ·

- 181 -

200 CH3 CH2-O- (CH2) 5-NH- CH2CH3 D 201 CH3 CH2-O- (CH2) 5-NH CH (CH 3) 2 L 202 CH3 CH2-O- (CH2) 5-NH CH (CH3) 2 D 203 CH3 CH2-O- (CH2) 5-NH CH2CH2CH3 L 204 CH3 CH2-O- (CH2) 5-NH- CH2CH2CH3 D 205 CH3 CH 2 -O- (CH 2) 5 -NH-C (CH ₃ ) 3 L 206 CH3 CH 2 -O- (CH 2) 5 -NH-C (CH ₃ ) 3 D

207 CH3 - (CH2) 2-S- (CH2) 3-NH-CH3 L 208 CH3 - (CH2) 2-S- (CH2) 3-NH-CH3 D 209 CH3 - (CH 2) 2 -S (CH 2) 3 -NH-CH ₂ CH ₃ L 210 CH3 - (CH 2) 2 -S- (CH 2) ₃ NH-CH ₂ CH ₃ D 211 CH3 - (CH2) 2-S- (CH2) 3-NH CH (CH3) 2 L 212 CH3 - (CH 2) 2 S (CH2) 3-NHCH (CH3) 2 D 213 CH3 - (CH 2) 2 -S (CH ₂ ) 3 -NH-CH ₂ CH ₂ -CH 3 L 214 CH3 - (CH2) 2-S- (CH2) 3-NHCH2CH2-CH3 D 215 CH3 - (CH2) 2-S- (CH2) 3 NHC (CH3) 3 L 216 CH3 - (CH2) 2-S- (CH2) 3 NHC (CH3) 3 D 217 CH3 - (CH2) 2-0- (CH2) 3-NH-CH3 L

- 182 -

218 CH ₃ - (CH2) 2-0- (CH2) 3-NH-CH3 D 219 CH3 - (CH2) 2-0- (CH2) 3-NH-CH2CH3 L 220 CH3 - (CH2) 2-0- (CH2) 3-NH-CH2CH3 D 221 CH3 - (CH 2) 2 -O- (CH 2) 3 -NH-CH (CH ₃ ) 2 L 222 CH3 - (CH2) 2-0- (CH2) 3-NHCH (CH3) 2 D 223 CH3 - (CH2) 2-0- (CH2) 3-NH CH2CH2CH3 L 224 CH3 - (CH2) 2-0- (CH2) 3-NH CH2CH2CH3 D 225 ch ₃ - (CH 2) 2 -O- (CH ₂ ) 3 -NH-C (CH ₃ ) 3 L 226 CH3 - (CH 2) 2 -O- (CH ₂ ) 3 -NH-C (CH ₃ ) 3 D 227 CH3 - (CH2) 2-S- (CH2) 2-NH-CH3 L 228 CH3 - (CH 2) 2 S (CH2) 2-NH-CH3 D 229 CH3 - (CH 2) 2 -S- (CH 2) 2 NH-CH ₂ CH ₃ L 230 CH3 - (CH 2) 2 -S- (CH 2) 2 -NH-CH ₂ CH ₃ D 231 CH3 - (CH 2) 2 -S- (CH 2) 2 -NH- CH (CH3) 2 L 232 CH3 - (CH2) 2-S- (CH2) 2-NH CH (CH3) 2 D 233 CH3 - (CH2) 2-S- (CH2) 2-NHCH2CH2-CH3 L 234 CH3 - (CH 2) 2 -S- (CH 2) 2 -NHCH 2 CH 2 -CH 3 D 235 CH3 - (CH 2) 2 -S- (CH 2) 2 -NHC (CH ₃ ) ₃ L 236 ch ₃ - (CH2) 2-S- (CH2) 2-NH D

C (CH3) 3

- 183 -

237 CH3 - (CH 2> 2-O- (CH 2) 2 -NH-CH 3) L 238 CH3 - (CH2) 2-0- (CH2) 2-NH-CH3 D 239 CH3 - (CH 2) 2 -O- (CH 2) 2 -NH-CH 2 CH 3 L 240 CH3 - (CH2) 2-0- (CH2) 2-NH-CH2CH3 D 241 ch ₃ - (CH ₂ ) ₂ -O- (CH ₂ ) 2 -NHCH (CH 3) 2 L 242 CH3 - (CH 2) 2 O - (CH 2) 2 -NHCH (CH 3) 2 D 243 CH3 - (CH 2) 2 -O- (CH 2) 2 -NHCH 2 CH 2 CH 3 L 244 ch ₃ - (CH2) 2-0- (CH2) 2-NHCH2CH2CH3 D 245 CH3 - (CH 2) 2 -O- (CH 2) 2 -NH-C (CH ₃ ) 3 L 246 CH3 - (CH 2) 2 -O- (CH 2) 2 -NH-C (CH ₃ ) 3 D 247 CH3 - (CH2) 2-S- (CH2) 4-NH-CH3 L 248 CH3 - (CH2) 2-S- (CH2) 4-NH-CH3 D 249 CH3 - (CH 2) 2 -S- (CH 2 J 4 -NH-CH ₂ CH ₃₎ L 250 CH3 - (CH 2) 2 -S- (CH 2) 4 -NH-CH ₂ CH ₃ D 251 CH3 - (CH2) 2-S- (CH2) 4-NH-CH (CH3) 2 L 252 CH3 - (CH2) 2-S- (CH2) 4-NH-CH (CH3) 2 D 251 CH3 - (CH2) 2-S- (CH2) 4-NH CH2CH2-CH3 L 254 CH3 - (CH2) 2-S- (CH2) 4-NHCH2CH2-CH3 D 255 ch ₃ - (CH2) 2-S- (CH2) 4-NH L

C (CH3) 3

- 184 -

256 CH3 - (CH 2) 2 -S- (CH 2) 4 -NH- C (CH3) 3 D 257 CH3 - (CH2) 3-NH-CH3 L 258 CH3 - (CH2) 3-NH-CH3 D 259 CH3 - (CH 2) 3 -NH-CH 2 CH 3 L 260 CH3 - (CH 2) 3 -NH-CH 2 CH 3 D 261 CH3 - (CH2) 3-NH-CH (CH3) 2 L 262 CH3 - (CH 2) 3 -NH-CH (CH 3) 2 D 263 CH3 - (CH 2) 3 -NH-CH 2 CH 2 CH 3 L 264 CH3 - (CH 2) 3 -NH-CH 2 CH 2 CH 3 D 265 ch ₃ - (CH 2) 3 -NH-C (CH 3) 3 L 266 CH3 - (CH ₂ ) 3 -NH-C (CH 3) 3 D 267 CH3 - (CH 2) 4 -NH-CH 3 L 268 CH3 - (CH2) 4-NH-CH3 D 269 CH3 - (CH2) 4-NH-CH2CH3 L 270 CH3 - (CH 2) 4 -NH-CH 2 CH 3 D 271 CH3 - (CH2) 4 -NH-CH (CH3) 2 L 272 CH3 - (CH 2) 4 -NH-CH (CH 3) 2 D 273 CH3 - (CH 2) 4 -NH-CH 2 CH 2 CH 3 L 274 CH3 - (CH2) 4-NH-CH2CH2CH3 D 275 CH3 - (CH 2) 4 -NH-C (CH ₃ ) 3 L 276 CH3 - (CH 2) 4 -NH-C (CH ₃ ) 3 D 277 CH3 - (CH2) 5-NH-CH3 L 278 CH3 - (CH2) 5-NH-CH3 D 279 CH3 - (CH2) 5-NH-CH2CH3 L 280 CH3 - (CH 2) 5 -NH-CH 2 CH 3 D

• · ·

- 185 -

281 CH3 - (CH2) 5-NH-CH (CH3) 2 L 282 CH3 - (CH2) 5-NH-CH (CH3) 2 D 283 CH3 - (CH 2) 5 -NH-CH 2 CH 2 CH 3 L 284 CH3 - (CH 2) 5 -NH-CH 2 CH 2 CH 3 D 285 CH3 - (CH 2) 5 -NH-C (CH ₃ ) 3 L 286 CH3 - (CH 2) 5 -NH-C (CH ₃ ) 3 D 287 CH3 - (CH 2) 6 -NH-CH 3 L 288 CH3 - (CH 2) 6 -NH-CH 3 D 289 CH3 - (CH 2) 6 -NH-CH 2 CH 3 L 290 CH3 - (CH 2) 6 -NH-CH 2 CH 3 D 291 CH3 - (CH2) 6-NH-CH (CH3) 2 L 292 CH3 - (CH 2) 6 "-NH-CH (CH3) 2 D 293 CH3 - (CH 2) 6 -NH-CH 2 CH 2 CH 3 L 294 CH3 - (CH 2) 6 -NH-CH 2 CH 2 CH 3 D 295 CH3 - (CH 2) 6 -NH-C (CH ₃ ) 3 L 296 CH3 - (CH 2) 6 -NH-C (CH ₃ ) 3 D

• · «« · · ··· ··· · ··· · · · · · · · · · · · · · · · · · · · ·

Further preferred are compounds of Table 10 wherein D-Val is substituted with one of the following groups: D-2-aminobutyric acid, D-Leu, D-Ala, Gly, D-Pro, D-Ser, D -Lys, beta-Ala, Pro, Phe, NMeGly, D-NIe, D-Phg, D-lle, D-Phe, D-Tyr, Al.

Further preferred are compounds of Table 10 wherein Asp is replaced by one of the following groups: alpha-MeAsp, beta-MeAsp, NMeAsp, D-Asp,

Asp (methyl-carbonyloxy-methyl ester),

Asp (ethylcarbonyloxymethyl ester),

Asp (t-butylcarbonyloxymethyl ester), Asp (cyclohexylcarbonyloxymethyl ester), Asp (1- (methylcarbonyloxy) ethyl ester) , Asp (1- (ethylcarbonyloxy) ethyl ester),

Asp (1- (t-butylcarbonyloxy) ethyl ester),

Asp (1- (cyclohexylcarbonyloxy) ethyl ester),

As p- (i-propyl-oxy-carbonyloxy-ethyl ester),

As p- (cyclic ohexylcarbonyl oxy-methyl ester), Asp- (t-butyloxycarbonyloxymethyl ester),

Asp (1- (i-propyloxycarbonyloxy) ethyl ester),

Asp (1- (cyclohexyloxycarbonyloxy) ethyl ester),

Asp (1- (t-butyloxy-carbonyloxy) ethyl ester),

Asp (dimethylaminoethyl ester), Asp (diethylaminoethyl ester), Asp - ((1,3-dioxa-5-methylcyclopentene-2-one-4-yl) methyl ester )

Asp - ((5- (t-butyl) -1,3-dioxa-cyclopenten-2-on-4-yl) methyl ester);

Asp - ((1,3-dioxa-5-phenylcyclopentene-2-one-4-yl) methyl ester) or • ··

Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester).

Table 11 Compounds of Formula XII (wherein J is D-Abu)

Példászám

301 -CH 2 -O-C (= O) -CH 3

302 -CH 2 -O-C (= O) -CH 2 CH 3

303 -CH 2 -O-C (= O) -CH (CH 3) 2

304 -CH 2 -O-C (= O) - (CH 2) 2 -CH 3

305 -CH 2 -O-C (= O) - (CH 2) 3 -CH 3

306 -CH 2 -O-C (= O) -CH 2 -CH (CH 3) 2

307 -CH 2 -O-C (= O) -CH (CH 3) -CH 2 -CH 3

308 -CH 2 -O-C (= O) -C (CH 3) 3

309 -CH 2 -O-C (= O) -cyclopropyl

310 -CH 2 -O-C (= O) -cyclobutyl

311 -CH 2 -O-C (= O) -cyclopentyl

312 -CH 2 -O-C (= O) -cyclohexyl

313 -CH 2 -O-C (= O) -phenyl

314 -CH 2 -O-C (= O) -4-methylphenyl

315 -CH2-OC (= O) -4- _et ylphenyl

FAB-MS / M + H /

633.2

675.3

-188-CH2-O-C (-O) -4-isopropylphenyl

-CH 2 -O-C (R) -4-propylphenyl

-CH 2 -O-C (= O) -4 - t -butylphenyl

-CH 2 -OC ( ^B O) -4-methoxyphenyl

-CH 2 OC ( '0) -4-ethoxyphenyl _-CH2 ~ 0-C (= C) 4-p _r i _ZO Qpii-oxyphenyl

-CH 2 -O-C (-O) -4-propyloxyphenyl

-CH 2 -O-C (= O) -4-tert -oxyphenyl

-CH 2 -O-C (-O) -4-biphenyl

CH (CH3) -O-C ( "O) -CH3

CH (CH3) -O-C (= 0) CH2CH3

-CH (CH 3) -O-C (-O) -CH (CH 3) 2

-CH (CH 3) -O-C (= O) - (CH 2) 2 -CH 3

-CH (CH 3) -OC (-O) - (CH 2) 3 "C ^h 3

CH (CH3) -O-C (= 0) -CH2-CH (CH3) 2

-CH (CH 3) -O-C (= O) -CH (CH 3) -CH 2 -CH 3

CH (CH3) -O-C (= 0) -C (CH3) 3

-CH (CH 3) -O-C (= O) -cyclopropyl

-CH (CH 3) -O-C (-O) -cyclobutyl

-CH (CH 3) -O-C (= O) -cyclopentyl

-CH (CH 3) -O-C (= O) -cyclohexyl

-CH (CH 3) -O-C (-O) -phenyl

-CH (CH 3) -O-C (= O) -4-methylphenyl

-CH (CH 3) -O-C (= O) -4-ethylphenyl

-CH (CH 3) -O-C (= O) -4-isopropylphenyl

-CH (CH 3) -O-C (-O) -4-propylphenyl

- 189 -CH (CH 3) -O-C (= O) -4-t-butylphenyl

-CH (CH 3) -O-C (-O) -4-methoxyphenyl

-CH (CH 3) -O-C (-O) -4 'ethoxyphenyl

-CH (CH 3) -OC (= 0) ~ 4- £ _ZO p _rO pi ^ _ _ox £ _f _e nil

-CH (CH 3) -O-C (- O) -4-propyloxyphenyl

-CH (CH 3) -O-C (O) -4-t-butoxyphenyl

-CH (CH3) OC (-0) _{biphenyl-4-phenylspiro}

-CH 2 -O-C (-O) -O-CH 3

-CH2-0-C (= 0) -O-CH2CH3

-CH2-0-C (= 0) -O-CH (CH3) 2

-CH 2 -OC (= O) -O- (CH 2) 2 ^ch 3

-CH2-O-C (= 0) -0- (CH2) 3-CH3

-CH 2 -O-C (-O) -O-CH 2 -CH (CH 3) 2

-CH2-0-C (= 0) -O-CH (CH3) -CH2-CH3

-CH2-C-C (= 0) -O-C (CH3) 3

-CH 2 -O-C (= O) -Ο-cyclopropyl

-CH2 ^- O-C (= O) -O-cyclobutyl

-CH 2 -O-C (= O) -O-cyclopentyl

-CH 2 -O-C (-0) -O-cyclohexyl

-CH 2 -O-C (= O) -O-f _en ii

-CH 2 -O-C (= O) -O-4-methylphenyl

-CH 2 O 0 -C (= O) -O-4-ethylphenyl

-CH ₂ ~ OC (= 0) ~ 0-4-i _ZO p _rO pii_f _en ii

-CH 2 "C-C (-0) -0-4- p _r piperidinopropyl-phenyl

-CH 2 -O-C (-O) -O-4-t-butylphenyl

667.3 here

- 190 CH2 O-C (-0) O ~ ^{- _} 4-methoxyphenyl

-CH 2 -O-C (-O) -Ο-4-ethoxyphenyl

-CH 2 -O-C (-O) -Ο-4-isopropyloxyphenyl

-CH 2 "O" C (= O) -Ο-4-propyloxy-phenyl

-CH 2 -O-C (= O) -O-4 't-Butoxyphenyl -CH 2 -O-C (= O) -Ο-4-biphenyl

-CH (CH 3) -O-C (-O) -O-CH 3

CH (CH3) -O-C (= 0) -O-CH2CH3

-CH (CH 3) -O-C (= O) -O-CH (CH 3) 2

-CH (CH 3) -O-C (= O) -O- (CH 2) 2 -CH 3

-CH (CH 3) -O-C (= O) -O- (CH 2) 3 -CH 3

-CH (CH 3) -O-C (= O) -O-CH 2 -CH (CH 3) 2

-CH (CH 3) -O-C (-O) -O-CH (CH 3) -CH 2 -CH 3

-CH (CH 3) -O-C (= O) -O-C (CH 3) 3

-CH (CH 3) -O-C (= O) -O-cyclopentyl

-CH (CH 3) -O-C (= O) -O-cyclobutyl

-CH (CH 3) -O-C (= O) -O-cyclopentyl

-CH (CH 3) -O-C (= O) -O-cyclohexyl

-CH (CH 3) -O-C (= O) -O-phenyl

-CH (CH 3) -O-C (= O) -O-4-methylphenyl

-CH (CH 3) -O-C (= O) -O-4-ethylphenyl

-CH (CH 3) -O-C (= O) -O-4-isopropylphenyl

-CH (CH 3) -O-C (= O) -O-4-propylphenyl

-CH (CH3) OC (= 0) -0-4- £, _{-but-methylphenyl}

- 191 -CH (CH3) -O-C (-O) -O-4-methoxyphenyl

-CH (CH 3) -O-C (-O) -Ο-4-ethoxyphenyl

-CH (CH3) OC ( "> 0) -0-4- _ZO £ p _r OPh-oxyphenyl

-CH (CH3) OC (-0) -0-4-p _rop ii_ _ox i-phenyl

-CH (CH 3) -O-C (-O) -O-4-L-butoxyphenyl

-CH (CH 3) -O-C (= O) -O-4-biphenyl

CH ₂ -N (CH ₃ ) 2

CH ₂ -N (CH ₂ -CH ₃ ) 2

CH ₂ CH ₂ -N (CH 3) 2

CH 2 -CH 2 -N (CH 2 CH 3) 2

CH ₂ -CH ₂ -N

CH ₂ -CH ₂ - o

-CH (CH 3) 0 C (= O) C (CH 3) 2 OCH 3 o

She

CH ₂ C (= O) OCH 3

CH ₂ C (-O) O-tBu

Preferred are compounds of Table 10 wherein DAbu is replaced by one of the following groups: D-Val, D-Leu, DAla, Gly, D-Pro, D-norvaline, D-Ser, D-Lys, beta. Ala, Pro, Phe, NMeGly, D-NIe, D-Phg, D-lle, D-Phe, D-Tyr and Ala.

Claims (15)

Claims C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1), • · · · · ··· - 230 b) an aryl group having 0-2 halogen atoms, phenyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -NO ₂ , -S (C 1 -C 5 alkyl), -SO (C 1 -C 5 alkyl), _-SO2 (C1-5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W can be substituted by a group of formula where v is 1-3 and w is 1- (2v + 1), R ³⁹ is C 1 -C 4 alkyl, benzyl or phenyl. C 1-6 alkyl, C 1-6 alkoxy, -NO _2i -S (C1-5 alkyl), -SO (C1-5 alkyl), _-SO2 (C1-5 alkyl), -OH, - It may be substituted by a group of formula N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1 ) R ³⁸ is as defined a) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, where the substituent may be (i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl, C 1-6 alkyl, C 1-6 alkoxy, -NO 2, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), - OH, -N (R ¹³ ) ₂ , CO ₂ R ¹³ , -C (= O) N (R ¹³ ) ₂ and / or C _V F _W , wherein v is 1 to 3 and w is 1- (2v + 1), c) an aryl group having 0-2 halogens, a phenyl group, C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1 to 3 and w = 1 to (2v + 1) R ⁴⁰ is hydrogen, C 1-5 alkyl or benzyl. C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1) c) an aryl group having 0-2 halogens, a phenyl group, C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and F _V be / or C substituted by a group _W, wherein v is 1-3 and w is 1 - (2 v +1) R ³⁹ is represented a) a hydrogen atom, - 226 - b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be (i) C 1-6 alkyl, (ii) C 1-6 alkoxy, (iii) aryl having 0-2 halo, phenyl, C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W groups can be of formula where v is 1 to 3 and w is 1 - (2v + 1) b) an aryl group having 0-2 halogens, a phenyl group, C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, may be substituted with -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W group of formula whereby * · - 225 v is 1 -3 and w is 1 - (2v + 1), R ³⁸ is as defined a) C 1-8 -alkyl or C 3-8 -cycloalkyl which may be substituted with 1-2 identical or different substituents, wherein the substituent may be (i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkyl, (iv) aryl having 0-2 halogens, phenyl, C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N ^(R13) 2, substituted -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W groups can be of formula wherein v is 1-3 and w is 1 - (2v + 1) c) an aryl group having 0-2 halogens, a phenyl group, C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N (R ¹³ ) ₂ , -CO ₂ R ¹³ , -C (= O) N (R ¹³ ) ₂ and / or C _V F _W , wherein v is 1 to 3 and w is 1 (2v + 1), R ⁴⁰ is hydrogen, C 1-5 alkyl or benzyl. - 218 · «« · · · · * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· · C 1-6 -alkyl, C 1-6 -alkoxy, -NO 2, -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, - N (R ¹³ ) ₂ , -CO ₂ R ¹³ , -C (= O) N (R ¹³ ) _2, and / or C _V F _W , wherein v is 1 to 3 and w is 1 to (2v + 1), c) an aryl group having 0-2 halogens, a phenyl group, C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, group may be substituted with -N (R ¹³⁾ 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and - 217 ···· ······················································································································· (w (1) (2v + 1). ) R ³⁹ is represented a) a hydrogen atom, b) C 1-8 -alkyl or C 3-8 -cycloalkyl which may be substituted with 1-2 identical or different substituents, wherein the substituent may be (i) C 1-6 alkyl, (ii) C 1-6 alkoxy, (iii) aryl having 0-2 halo, phenyl, C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N (R ¹³ ) ₂₁ -CO ₂ R ¹³ , -C (= O) N (R ¹³ ) _2, and / or C _V F _W , wherein v is 1 to 3 and w is 1 to (2v + 1), b) an aryl group having 0-2 halogens, a phenyl group, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy 9 · · _R 3S · 9 · · · · · · · - 216 ports, -NO ₂ , -S (C 1 -C 5 alkyl), -SO (C 1 -C 5 alkyl), -SO ₂ (C 1 -C 5 alkyl), -OH, -N (R ¹³ ) 2, -CO 2 R ¹³ , -C (= O) N (R ¹³ ) 2 and / or C _V F _W , wherein v is 1 to 3 and w is 1 to (2v + 1), a) C 1-8 -alkyl or C 3-8 -cycloalkyl which may be substituted with 1-2 identical or different substituents, wherein the substituent may be (i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl, C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N ^(R13) 2, substituted -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W groups can be of formula where v is 1 to 3 and w is 1 - (2v + 1) c) an aryl group having 0-2 halogens, a phenyl group, C 1-5 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, C 2-6 alkoxyalkyl, C 1-4 alkyl (which is -NR ¹³ R ¹⁴ , -CF ₃ , -NO ₂ , -SO ₂ R ¹³ or -S (= O) R ^13a ), an aryl group substituted with 0-2 R ¹² , or C 1-8 -alkyl substituted with 0-2 R ¹¹ , » - 207 - 1) R ³² is other than -C (= O) -, or C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1-3 and w is 1 - (2v + 1) R ⁴⁰ is hydrogen, (C 1 -C 5) alkyl, or benzyl, provided that at least one of the following conditions is met: C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N (R ¹³ ) ₂ , - 205 -CO ₂ R ¹³ , -C (= O) N (R ¹³ ) ₂ and / or C _V F _W , wherein v is 1-3 and w is 1- (2v + 1), c) an aryl group having 0-2 halogens, a phenyl group, C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH , -N (R ¹³⁾ 2, -CO2R ^13, -C (= O) N ^(R13) may be substituted by a group of formula 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v +1) R ³⁹ is represented a) a hydrogen atom, b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be (i) C 1-6 alkyl, (ii) C 1-6 alkoxy, (iii) aryl having 0-2 halo, phenyl, C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, may be substituted by a group of formula -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V F _W where v = 1 to 3 and w = 1 to (2v + 1) b) an aryl group having 0-2 halogens, a phenyl group, C 1-6 alkyl, C 1-6 alkoxy, -NO ₂ , -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO ₂ (C 1-5 alkyl), -OH, -N ^(R13) 2, substituted by a group of formula -CO2R ^13, -C (= O) N ^(R13) 2 and / or C _V M _W a, wherein v is 1 to 3 and w = 1 to (2v + 1) R ³⁸ is as defined a) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, where the substituent may be i) C 1-4 alkyl; - 204 - (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl, C 1-6 -alkyl, C 1-6 -alkoxy, -NO ₂ , -S (C 1-5 -alkyl), -SO (C 1-5 -alkyl), -SO ₂ (C 1-5 -alkyl), -OH, -N ^(R13) 2, -CO2R ^13, -C (= O) N ^(R13) 2 and / or C may be substituted by a group of formula _v Fw where v = 1 to 3 and w is 1 - (2v + 1 ) c) an aryl group having 0-2 halogens, a phenyl group, C 1-8 -alkyl substituted with 0-2 R ¹¹ , C1-C4 alkyl optionally substituted with one to six halogens and benzyl, R ² is hydrogen or C 1-8 alkyl, R ¹⁰ and R ^10a are each independently phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halo, hydroxy, nitro, cyano, C 1-6 alkyl, 3-6 -C - 197 cycloalkyl, C3-6 cycloalkyl-methyl group, a C7-10 arylalkyl group, C 1-6 alkoxy, -CO ₂ R ^13, -C (= O) NHOR ^13a, -C (= O ) N (R ¹³ ) 2, -C (= O) NHN (R ¹³ ) 2, = NOR ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -OC (= O). ) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ^13a , -NR ¹³ C (= O) N (R ¹³ ) ₂ , SO2N -NR ¹³ (R ¹³⁾ 2 R ^13, -NR SO2R ^13a, -SO 3 H, -SO ₂ R ^13a, -S (= O) R ^13a, -SR ¹³ or -SO 2 N (R ¹³⁾ 2, 2-6 C 1-4 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyloxy C 1-4 alkylcarbonyl, C 1-4 alkylcarbonylamino, -OCH ₂ CO ₂ H, 2- (1-morpholino) ethoxy, or C 1-4 alkyl ( alkyl substituted with -N (R ¹³ ) ₂ , -CF ₃ , -NO ₂ or -S (= O) R ^13a ), J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) C (R ⁴ ) (R ⁵ ) C (= O) -, wherein R ³ is hydrogen or C 1-8 alkyl, R ⁴ is hydrogen or C 1-3 alkyl, R ⁵ is hydrogen, C 1 -C 5 alkyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 2 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl ( the alkyl group is substituted with 1 to 5 substituents selected from the group consisting of -NR ¹³ R ¹⁴ , -CF 3, -NO ² , -SO ² R ^13a or -S (= O) R ^13a ), an aryl group having 0-2 R ¹² substituted, 5-10 membered heterocyclic ring system containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, substituted with 0-2 R ¹² , R ¹² is phenyl, benzyl, phenethyl, phenoxy, benzyloxy -halo, hydroxy, nitro, cyano, C 1-5 -alkyl, C 3-6 -cycloalkyl, C 3-6 -cycloalkylmethyl, C 7-10-arylalkyl, C 1-5 -alkoxy, - CO2R ¹³ , -C (= O) NHOR ^13a , -C (= O) NHN (R ¹³ ) ₂ , -OR ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ^13a, -NR ¹³ C (= O) N (R ¹³⁾ 2, -NR ¹³ SO2N ^(R13) 2, NR ¹³ SO2R ^13a, -SO ₃ H, -SO ₂ R ^13a , -S (= O) R ^13a , -SR ¹³ or -SO ₂ N (R ¹³ ) 2, C 2 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 A haloalkoxy group of 196 mos, a C 1-4 alkylcarbonyloxy group, a C 1-4 alkylcarbonyl group, a C 1-4 alkylcarbonylamino group, a -OCH 2 CO 2 H group, 2- ( 1-morpholino) ethoxy, (C 1 -C 4) alkyl (the alkyl group being substituted with -N (R ¹³ ) 2, -CF ₃ , -NO ₂ or -S (= O) R ¹³ '), R ¹³ is independently hydrogen, (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 4 -C 12) alkylcycloalkyl, aryl, - (C 1 -C 10) alkyl-aryl-aryl, or (C 3 -C 10) -alkoxy-alkyl-. group, R ^13a is C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl, or C 3 -C 10 alkoxyalkyl for the same nitrogen atom bonded two R ¹³ groups together - (CH ₂ ) ₂ . ₅ - or - _(CH2) O _(CH2) - form a group of formula R ¹⁴ is hydroxy, hydrogen, C 1 -C 4 alkyl or benzyl, R ²¹ and R ²³ are each independently hydrogen, C 1-8 alkyl substituted with 0-2 R ¹¹ , CLAIMS 1. Compounds of formula (I) and pharmaceutically acceptable salts or prodrugs thereof R ³¹ is a C 6-14 saturated, partially unsaturated or aromatic carbocyclic ring system substituted with 0-4 R ¹⁰ or R ^10a , R ³² is -C (= O) -, -C (= S) -, -S (= O) ₂ -, -S (= O) - or -P (= Z) (ZR ¹³ ) -, Z is sulfur or oxygen, n and n 'are independently 0-2, R ¹ and R ²² are independently hydrogen, 2- 8 alkynyl substituted with 0-2 R ¹¹ groups, C2-8 alkenyl substituted with 0-2 R ¹¹ groups, The compound of claim 1, or a pharmacologically acceptable salt or prodrug thereof, wherein R ^{31 is} attached to the (C (R ²³ ) R ²² ) n and (C (R ²¹ ) R ¹ ) n · moiety on the two carbocyclic rings. different atoms. - 206 - 2) p 'is different from 0, or 2- 8 alkynyl substituted with 0-2 R ¹¹ groups, 2- 8 alkenyl substituted with 0-2 R ¹¹ groups, • * · · · · - 198 - 2- (1-morpholino) ethoxy, 2- 8 alkynyl substituted with 0-2 R ¹¹ groups, 2- 8 alkenyl substituted with 0-2 R ¹¹ groups, - (C 3 -C 7 alkyl) -NH- (C 1 -C 6 alkyl), (ae) - (CH ₂ ) _m -O- (C 1 -C 4 alkyl) -NH- (C 1 -C 6 alkyl). C 1 -C 6 alkyl, where m is 1 or 2, and - (CH ₂ ) _m -S- (C 1 -C 4 alkyl) -ΝH- (C 1 -C 6 alkyl) where m is 1 or 2, X is -NH ₂ or -NH-C (= NH) (NH ₂ ), or R ⁶ and R ⁷ together form a group of formula (c) wherein n is 0 or 1, X is -NH ₂ or -NHC - (= NH) (NH ₂ ) L is -Y (CH ₂ ) _V C (= O) -, wherein Y is -NH-, O or S, v is 1 or 2, M is the D or L isomeric amino acid of formula (i) wherein q 'is 0-2, R ¹⁷ is hydrogen or C 1-3 alkyl, R ⁸ is -CO ₂ R ^13b , R ^13b is a) C2-C8 alkenyl, b) C2-C8 alkynyl, c) substituted C 1 -C 8 -alkyl, where the substituent may be <* • · · 99 - 223 - i) aryl optionally substituted with 1 to 2 halogen atoms, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO ₂ , -S (O) ₀ -2- (C 1 -C 5 alkyl), -OH, -N (R ¹³ ) 2, -CO 2 R ¹³ , -CON (R ¹³ ) 2, and / or -C _V F _W , wherein v is 1 to 3 and w is 1 (2v + 1), ii) C3-C8 cycloalkyl, iii) j), e) aryl substituted by 1-2 halogen, phenyl, C1-5 alkyl, C1-5 alkoxy port, -NO _2, -S (O) _0-2 - (1 -5 carbon atoms) alkyl, -OH, - N (R ¹³ ) 2, -CO 2 R ¹³ , -CON (R ¹³ ) 2, and / or -C _V F _W , wherein v is 1-3 and w is 1- (2v + 1), f) C2-C8-alkyl, alkenyl or alkynyl, which may be substituted with 1-2 identical or different substituents, which may be C1-C4-alkyl, C3-C8-cycloalkyl, C1-C5-alkoxy, phenoxy, benzyloxy; -halo, -NO ₂ , -CN, -CO ₂ R ¹³ , -CON (R ¹³ ) 2, or -N (R ³⁶ ) COR ³⁶ , morpholino, 2- (1-morpholino) ethoxy group, -N ^(R13) 2, -N ^{+ (R13)} _3, OCOCH _3, -CF ₃ or -S (0) _o-2-R ^13a group of the formula g) -CH (R ³⁶ ) OR ³⁸ , h) -CH (R ³⁶ ) OC (= O) R ³⁷ ; i) -CH (R ³⁶ ) OC (= O) OR ³⁸ , - 224 ··· «·· ·· ♦ ·· ·· • 4 4 · 4 * ··· ··· 44 ·· •« · · ··· 4 · «* 4 j) -CH (R ³⁶ ) OC (= O) N (R ³⁷ ) ₂ ; k) -CH (R ³⁶ ) CO ₂ R ³⁷ , (l) a group of the formula (k) or m) a group of the formula m; R ³⁶ is independently hydrogen, (C 1 -C 8) -alkyl, (C 3 -C 10) -cycloalkyl, phenyl or benzyl, R ³⁷ is a) a hydrogen atom, b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be (i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl, 3- to 8 carbon atoms which is substituted with 0-2 R ¹¹ groups, The compound of claim 1, or a pharmacologically acceptable salt or prodrug thereof, wherein n is 0 and n 'is 0, n is 0 and n' is 1, n is 0 and n 'is 2, n is 1 and n. 'is 0, n is 1 and n' is 1, n is 1 and n 'is 2, n is 2 and n' is 0, n is 2 and n 'is 1 or n is 2 and n' is 2. 3) q 'is different from 0, or 3- 10 carbon atoms, cycloalkyl having 0-2 ^R11 group bowl substituted, aryl substituted with 0-2 R ¹² groups, 5-10 membered heterocyclic ring system comprising one to four heteroatoms selected from nitrogen, sulfur and / or oxygen atom and substituted with 0-2 R ¹² , oxygen, fluorine, chlorine, bromine or iodine, -CF ₃ , -CN, -CO ₂ R ¹³ , -C (= O) R ¹³ , -C (= O) N (R ¹³ ) 2, -CHO, -CH 2 OR ¹³ , -OC (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , -OC (= O) N (R ^13). ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹⁴ C (= O) OR ^13a , -NR ¹³ C (= O) N (R ¹³ ) 2, -NR ¹⁴ SO 2 N (R ¹³ ) 2, -NR ¹⁴ SO ² R ^13a , -SO ³ H, -SO 2 R ^13a , -SR ¹³ , -S (= O) R ^13a , -SO ² N (R ¹³ ) 2i -N (R ¹³ ) 2i -NHC (= NH) NHR ¹³ , - C (= NH) NHR ¹³ , = NOR ¹³ , -NO 2, -C (= O) NHOR ¹³ , -C (= O) NHNR ¹³ R ^13a , = NOR ¹³ , -B (R ³⁴ ) (R ³⁵ ) or -OCH ₂ CO ₂ H, 2- (1-morpholino) ethoxy, -SC (= NH) NHR ¹³ , -N ₃ , -Si (CH ₃ ) ₃ , - (C 1 -C 5) alkyl - NHR ¹⁶ , - (C 0 -C 6 alkyl) -X or (a) in general wherein q is independently 0 or 1 and b is, or - (CH ₂ ) _m S (O) p (CH ₂ ) ₂ X, wherein m is 1 or 2, and p 'is 0 to 2, or R ³ and R ^{4 taken} together form a group of formula (c) wherein n is 0 or 1, ···· ·············································· · · · · · · · · · 9 * · - 199 X is a group of formula (d), or R ³ and R ⁵ together form - (CH 2) _t - or - (CH ₂ ) S (O) _P C (CH ₃ ) ₂ -, wherein t is 2-4 and p 'is 0-2, or R ⁴ and R ⁵ together form a group - (CH ₂ ) _U - wherein u is 2-5, R ¹⁶ is an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group, K is the D or L isomeric amino acid of formula -N (R ⁶ ) CH (R ⁷ ) C (= O) -, wherein R ⁶ is hydrogen or C 1-8 alkyl, R ⁷ is - (C 1 -C 7 alkyl) -X, a group of the formula (e) wherein q is independently 0-2 and the substituent is in the 3- or 4-position of the phenyl ring; wherein q is independently 0-2 and the substituent is in the 3- or 4-position of the cyclohexyl group; - (CH ₂ ) _m O- (C 1 -C 4 alkyl) -X wherein m is 1 or 2 and - (CH ₂ ) _m S (O) p - (C 1 -C 4 alkyl) -X a group of general formula where • · · - 200 m is 1 or 2 and p 'is 0 to 2, X is a group of formula (d), -N (R ¹³ ) R ¹³ , -C (= NH) (NH 2), -SC (= NH) -NH 2, -NH-C (= NH) (NHCN), - NH-C (= NCN) (NH 2) or -NH-C (= N-OR ¹³ ) (NH 2), or R ⁶ and R ⁷ together form a group of formula (h) wherein q is independently 1 or 2, n is 0 or 1 and X is -NH ₂ or a group of formula (d), L is -Y (CH ₂ ) _v C (= O) -, wherein Y is -NH, -N- (C 1 -C 3 alkyl), oxygen or sulfur, v is 1 or 2, M is an amino acid D or L isomeric amino acid of formula (i) wherein q 'is 0-2, R ¹⁷ is hydrogen or C 1-3 alkyl, R ^{8 is} -CO ² R ¹³ , -SO 3 R ¹³ , -SO ² NHR ¹⁴ , -B (R ³⁴ ) (R ³⁵ ), -NHSO 2 CF _3i. -CONHNHSO ₂ CF _3i -PO (OR ¹³ ) 2, -PO (OR ¹³ ) R ¹³ or -SO 2 NH-heteroaryl (the heteroaryl group having 5-10 members and containing 1-4 heteroatoms nitrogen, sulfur and / or oxygen), and -SO ₂ NHCOR ^13, -CONHSO2R ^{13a, 13b} -CH2CONHSO group is ₂ R ^{13a, 13a} -NHSO2NHCOR, -NHCONHSO2R ^13a, -SO2NHCONHR or -CO2R ^13, R ³⁴ and R ³⁵ are independently -OH, -F, -N (R ¹³ ) _2, or C 1 -C 8 alkoxy, or - 201 ···· ···· ·· ·· • · · · · · · · · · · · · · • · • · «· · · · · ·· ·· R ³⁴ and R ³⁵ together form a C 2-20 cyclic boronic ester which may optionally contain 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, or a C 2-20 cyclic divalent cyclic boramide, optionally containing 1 to 4 heteroatoms nitrogen, it may contain a sulfur atom and / or an oxygen atom or form a cyclic boramide ester of 2 to 20 carbon atoms optionally containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, R ^13b is a) C 1-8 alkyl; b) C2-C8 alkenyl, c) C 2-8 alkynyl, d) C3-C8 cycloalkyl, e) C 1-8 alkyl substituted with optionally substituted substituents i) aryl optionally substituted with 1 to 2 halogens, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO ₂ , -S (O) ₀ . It may be substituted by (1 -5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, CON ^(R13) 21 and / or -C _V F _W group of formula wherein v is _1-2 - 3 and w are 1- (2v + 1), ii) C3-8cycloalkyl, iii) j), f) aryl optionally substituted with 1 to 2 halogens, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO ₂ , -S (O) ₀ . _2- (C 1 -C 5) - 202 alkyl), -OH, -N (R ¹³ ) 2, -CO 2 R ¹³ , -CON (R ¹³ ) 2, and / or -C _V F _W where v is 1 to 3 and w is 1- (2v + 1); g) C 2-8 alkyl, alkenyl or alkynyl having 1 to 2 C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, phenoxy, benzyloxy, halogen, -NO _2, -CN -CO ₂ R ¹³ , -CON (R ¹³ ) 2, -N (R ³⁶ ) COR ³⁶ , morpholino, 2- (1-morpholino) ethoxy, -N (R ¹³ ) 2, -N ^{+ (R13)} _3, OCOCH _3, -CF _3, and / or -S (O) _0th Substituted with ₂ -R ^13a , h) -CH (R ³⁶ ) OR ³⁸ ; i) -CH (R ³⁶ ) OC (= O) R ³⁷ ; j) -CH (R ³⁶ ) OC (= O) OR ³⁸ , k) -CH (R ³⁶ ) OC (= O) N (R ³⁷ ) ₂ ; l) -CH (R ³⁶ ) N (R ³⁶ ) C (= O) R ³⁶ ; m) -CH (R ³⁶ ) CO ₂ R ³⁷ , n) -CH (R ³⁶ ) CON (R ¹³ ) ₂ ; o) -CH (R ³⁶ ) N (R ¹³ ) ₂ ; q) a group of formula (k), r) a group of the formula I, s) a group of the formula m; t) a group of the formula n; u) a group of the formula o; R ³⁶ is independently hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl, phenyl, or benzyl; - 203 R ^{37 has the} meaning a) a hydrogen atom, b) C 1-8 alkyl or C 3-8 cycloalkyl, which may be substituted with 1-2 substituents, wherein the substituent may be (i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl, 3- 10 carbon atoms which is substituted with 0-2 R ¹¹ aryl group substituted with 0-2 R ¹² groups, 5-10 membered heterocyclic ring system containing one to four heteroatoms selected from nitrogen, sulfur and / or oxygen atom, and substituted with 0-2 R ¹² , oxygen, fluorine, chlorine, bromine or iodine, -CF ₃ , -CN, -CO ₂ R ¹³ , -C (= O) R ¹³ , -C (= O) N (R ¹³ ) 2, -CHO, -CH 2 OR ¹³ , -OC (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , -OC (= O) N (R ¹³ ) 2 . - 194 νν · ι ·· / ··· »· •« · · · · · · · · · · · · · · · ··· -NR ¹³ C (= O) R ¹³ , -NR ¹⁴ C (= O) OR ^13a , -NR ¹³ C (= O) N (R ¹³ ) 2, -NR ¹⁴ SO 2 N (R ¹³ ) 2, -NR ¹⁴ SO2R ^13a, -SO3H, -SO2R ^13a, -SR ^13, -S (= 0) ^{R 13a,} -SO 2 N (R ¹³⁾ 2, -N ^(R13) 2, -NHC (= NH) ^NHR13, -C ( = NH) NHR ¹³ , = NOR ¹³ , -NO 2, -C (= O) NHOR ¹³ , -C (= O) NHNR ¹³ R ^13a , or -OCH ₂ CO ₂ H, or 2- (1-morpholino) ethoxy. or R ¹ and R ²¹ together form a 3-7 membered carbocyclic ring substituted with 0-2 R ¹² groups, and n '= 2, R ¹ or R ²¹ on the adjacent carbon, together with ^R1 or ^R21 -gyel -gyel forms a direct bond and thus forms a double bond or a triple bond between the carbon atoms, R ²² and R ²³ together form a 3-7 membered carbocyclic ring substituted with 0-2 R ¹² groups, or n = 2 case, direct or together R ²² R ²³ on the adjacent carbon with R ²² or R ²³ malate forms a bond to form a double bond or a triple bond between the carbon atoms, or R ²¹ = in the case of hydrogen, R ¹ and R ² together form a 5-8 membered carbocyclic ring substituted with 0-2 R ¹² , R ¹¹ is oxygen, fluoro, chloro, bromo or iodo, -CF ₃ , -CN, -CO ₂ R ¹³ , -C (= O) R ¹³ , -C (= O) N (R ¹³ ) 2i. -CHO, -CH ² OR ¹³ , -OC (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ^13, -NR ¹⁴ C (= O) OR ^13a, -NR ¹³ C (= O) N (R ¹³⁾ 2, -NR ¹⁴ SO2N ^(R13) 2, NR ¹⁴ SO2R ^{13 a,} -SO3H, -SO2R ^13a, -SR ^13, -S (= O) R ^13a, -SO 2 N (R ¹³⁾ 2, -N ^(R13) 2, -NHC (= NH) ^NHR13, -C (= NH) ^NHR13, = NOR ¹³ , -NO ₂ , -C (= O) NHOR ¹³ , - 195 C (= O) NHNR ¹³ R ¹³ ', -OCH ₂ CO ₂ H, or A compound according to claim 1, or a pharmacologically acceptable salt or prodrug thereof, wherein R ⁶ is methyl, ethyl or propyl. 4) q is different from 0-1 or (5) X is -NH-C (= NH) NHCN, -NH-C (= NCN) (NH ₂ ) or -NH-C (= NOR ¹³ ) NH Or ₂ A 5 to 10 membered heterocyclic ring system containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, substituted with 0-2 R ¹² , R ¹² is phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halo, hydroxy. - 209 dusts, nitro, cyano, C 1-5 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, C 7-10 arylalkyl, C 1-5 alkoxy, -CO ₂ R ¹³ , -C (= O) NHO R ¹³ ', -C (= O) NHN (R ¹³ ) ₂ , -OR ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, - OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ^13a , -NR ¹³ C (= O) N (R ¹³ ) 2, - NR ¹³ SO 2 N (R ¹³ ) 2, -NR ¹³ SO 2 R ^13a , -SO ₃ H, -SO ₂ R ^13a , -S (= O) R ^13a , -SR ¹³ or -SO ₂ N (R ¹³ ) 2, C 6 -C 6 alkoxyalkyl, methylenedioxy, ethylenedioxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylcarbonyl oxy, (C 1 -C 4) alkylcarbonyl, (C 1 -C 4) alkylcarbonylamino, -OCH ₂ CO ₂ H, 2- (1-morpholino) -eto xi group, a C 1-4 alkyl group (the alkyl group is -N ^(R13) _2, -CF _{3i -NO2,} -S (= O) R ^13a is substituted by a group of formula); R ¹³ is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl, or C 3 -C 10 alkoxyalkyl; group, R ^13a is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 4 -C 12) alkylcycloalkyl, aryl, (C 1 -C 10) alkylaryl, or (C 3 -C 10) alkoxyalkyl, or • · · - two R ¹³ groups bonded to 210 identical nitrogen atoms together - (CH ₂ ) ₂ . ₅ - or - _(CH2) O _(CH2) - to form a group of formula, R ¹⁴ is hydroxy, hydrogen, C 1 -C 4 alkyl or benzyl, R ²¹ and R ²³ are each independently hydrogen, C 1-4 alkyl optionally substituted with 1 to 6 halogens, or benzyl, R ² is hydrogen or C 1-8 alkyl, R ¹⁰ and R ^10a are each independently phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halo, hydroxy, nitro, cyano, C 1-5 alkyl, 3-6 C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 7 -C 10 arylalkyl, C 1 -C 5 alkoxy, -CO 2 R ¹³ , -C (= O) NHOR ^13a , -C (= O) NHN ( R ¹³ ) 2, = NOR ¹³ or -B (R ³⁴ ) (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , - (C 1 -C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -OC (= O) N (R ¹³ ) 2i -NR ¹³ C ( = O) R ^13, -NR ¹³ C (= O) OR ^13a, -NR ¹³ C (= O) N (R ¹³⁾ 2, -NR ¹³ SO2N ^(R13) 2, NR ¹³ SO2R ^13a, -SO ₃ H, -SO ₂ R ^13a, -S (= O) R ^13a, -SR ¹³ or -SO 2 N (R ¹³⁾ 2, C 2-6 alkoxyalkyl group, a methylenedioxy group, an ethylene group Dioxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, (1-4C) alkylcarbonyloxy, (1-4C) alkylcarbonyl, (1-4C) alkylcarbonylamino, -OCH ₂ CO ₂ H, 2- (1-morpholino) ethoxy or C 1 -C 4 Alkyl group (substituted with -N (R ¹³ ) ₂ , -CF ₃ , -NO ₂ or -S (= O) R ¹³ *), J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) C (R ⁴ ) (R ⁵ ) C (= O) -, wherein R ³ is hydrogen or methyl, R ⁴ is hydrogen or C 1-3 alkyl, R ⁵ is hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, C 1-6 cycloalkylethyl, phenyl, phenyl, methyl, -CH ₂ OH, -CH ₂ SH, -CH ₂ OCH ₃ , -CH ₂ SCH ₃ , -CH ₂ CH ₂ SCH ₃ , - (CH ₂ ) _S NH ₂ , - (CH ₂ ) _S NHC (= NH) (NH ₂ ) or - (CH ₂ ) _S NHR ¹⁶ where s is 3-5, or R ³ and R ⁵ together form - (CH ₂ ) _t - (t = 2-4) or - (CH ₂ ) SC (CH ₃ ) ₂ -, or R ⁴ and R ⁵ together form - (CH ₂ ) _U - wherein u is 2-5, R ¹⁶ is an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group, K is the D or L isomeric amino acid of formula -N (R ⁶ ) CH (R ⁷ ) C (= O) -, wherein R ⁶ is hydrogen or C 1-8 alkyl, R ⁷ is - (C 1 -C 7) alkyl-X, (e) wherein q is independently 0-2 and the substituent is in the 3- or 4-position of the phenyl, - 212 - (f) wherein q is independently 0-2 and the substituent is at the 3- or 4-position of the cyclohexyl group, (g), - (CH ₂ ) m O- (C 1 -C 4 alkyl) -X wherein m is 1 or 2, or - (CH ₂ ) _m S- (C 1 -C 4 alkyl) -X where m is its value is 1 or 2, X is -NH-C (= NH) (NH ₂ ), -NHR ¹³ , -C (= NH) (NH ₂ ) or -SC (NH) -NH ₂ , or R ⁶ and R ⁷ together (h *) -group wherein n is 0 or 1, X is -NH ₂ or -NH-C (= NH) (NH ₂ ) L is -Y (CH ₂ ) _V C (= O) -, wherein Y is -NH, -N (C 1 -C 3 alkyl) -, oxygen or sulfur, v is 1 or 2, M is the D or L isomeric amino acid of formula (i) wherein q 'is 0-2, R ¹⁷ is hydrogen or C 1-3 alkyl, ^{R8 13} -CO2R, -SO3R ^13, -SO 2 NHR ^14, -B (R ³⁴⁾ (R ^35), -NHSO2CF _3, -CONHNHSO ₂ CF _3, -PO ^(OR13) 2, -PO (OR ^{13) R13,} -SO2NH-heteroaryl group of formula (a heteroaryl «· •« • ···· · · · · · · ··· ··· ··· "·« « - 213 ports having 5 to 10 members and containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen), -SO ₂ NH-heteroaryl (heteroaryl having 5 to 10 members and 1-4 heteroatoms of nitrogen, sulfur and / or oxygen) contains) and -SO ₂ NHCOR ^13, -CONHSO2R ^13a -CH2CONHSO ₂ R ^{13a, 13a} -NHSO2NHCOR, -NHCONHSO2R ^13a, -SO2NHCONHR ¹³ or -CO2R group of formula ^13b, R ³⁴ and R ³⁵ are each independently hydroxy, fluoro, -NR ¹³ R ^14, or C 1 -C 8 alkoxy, or R ³⁴ and R ³⁵ together form a C 2-20 cyclic boron ester optionally containing 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, or a C 2-20 divalent cyclic boronamide, optionally containing 1 to 4 heteroatoms nitrogen, contains a sulfur atom and / or an oxygen atom or forms a cyclic boramide ester of 2 to 20 carbon atoms optionally containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen atoms, R ^13b is a) C 1-8 alkyl; b) C2-C8 alkenyl, c) C 2-8 alkynyl, d) C3-C8 cycloalkyl, e) C 1-8 substituted alkyl, where the substituent may be i) an aryl group optionally substituted with 1 to 2 halogen atoms, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkyl, C 1 -C 5 alkyl, C 1 -C 5 alkyl, C 1 -C 5 alkyl; · · ·· «·· · ·· - 214 C 1-5 alkoxy, -NO ₂ , -S (O) ₀ . ₂ - (1 -5 alkyl), -OH, -N ^(R13) 2, -CO2R ^13, CON ^(R13) 2, and _V F can / or C substituted by a group of formula _W where v is 1 -3 and w are 1- (2v + 1), ii) C3-C8 cycloalkyl, iii) j), f) aryl optionally substituted with 1 to 2 halogens, phenyl, C 1 -C 5 alkyl, C 1 -C 5 alkoxy, -NO ₂ , -S (O) ₀ -2- (C 1 -C 5 alkyl), -OH, -N (R ¹³ ) 2, -CO 2 R ¹³ , -CON (R ¹³ ) 2, and / or -C _V F _W , wherein v is 1 to 3 and w is 1 (2v + 1), g) C 2-8 alkyl, alkenyl or alkynyl having 1 to 2 C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, phenoxy, benzyloxy, halogen, -NO _2, -CN , -CO ₂ R ¹³ , -CON (R ¹³ ) 2, -N (R ³⁶ ) COR ³⁶ , morpholino, 2- (1-morpholino) ethoxy, -N (R ¹³ ) 2, -N ^{+ (R13)} _3, OCOCH _3, -CF _3, and / or -S (O) ₀ 2-R ^13a are substituted by a group of formula h) -CH (R ³⁶ ) OR ³⁸ ; i) -CH (R ³⁶ ) OC (= O) R ³⁷ ; j) -CH (R ³⁶ ) OC (= O) OR ³⁸ ; k) -CH (R ³⁶ ) OC (= O) N (R ³⁷ ) ₂ ; l) -CH (R ³⁶ ) N (R ³⁶ ) C (= O) R ³⁶ , ··· · - 215 - m) -CH (R ³⁶ ) CO ₂ R ³⁷ , n) -CH (R ³⁶ ) CON (R ¹³ ) ₂ ; o) -CH (R ³⁶ ) N (R ¹³ ) ₂ ; q) a group of formula (k), r) a group of the formula I, s) a group of the formula m; t) a group of the formula n; u) a group of the formula (o), R ³⁶ is independently hydrogen, (C 1 -C 8) -alkyl, (C 3 -C 10) -cycloalkyl, phenyl or benzyl, R ³⁷ is a) a hydrogen atom, b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be (i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl, Compounds of formula (I) according to claim 1 and pharmacologically acceptable salts or prodrugs thereof, wherein R ³¹ is a C 6-14 saturated, partially saturated or aromatic carbocyclic ring substituted with 0-4 R ¹⁰ or R ^10a , R ³² is -C (= O) -, -C (= S) - or -S (= O) ₂ -, n and n 'are independently 0-2, R ¹ and R ²² are independently hydrogen, 5) R ⁸ is -B (R ³⁴ ) (R ³⁵ ) or -CO ₂ R ^13b . The compound of claim 5, or a pharmacologically acceptable salt or prodrug thereof, of the formula R ³¹ is as defined (a) a 6-membered saturated, partially unsaturated or aromatic carbocyclic ring substituted with 0-3 R ¹⁰ or R ^10a , b) an 8-11 membered saturated, partially saturated, or aromatic fused bicyclic carbocyclic ring substituted with 0-4 R ¹⁰ or R ^10a , or c) a 14-membered saturated, partially saturated, or aromatic tricyclic carbocyclic ring substituted with 0-4 R ¹⁰ or R ^10a . C 6 -C 10 bicycloalkyl substituted with 0-2 R ¹¹ , aryl substituted with 0-2 R ¹² , 5-10 membered heterocyclic ring system containing from 1 to 4 heteroatoms nitrogen, sulfur and / or oxygen, and substituted with 0-2 R ¹² and oxygen, fluorine, chlorine, bromine or iodine, -CF ₃ , -CN, -CO ₂ R ¹³ , -C (= O) R ¹³ , -C ( = O) N ^(R13) 2, -CHO, -CH20R ^13, -OC (= O) R ^13, -OC (= O) OR ^13a, -OR ^13, -OC (= O) N ^(R13) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹⁴ C (= O) OR ^13a , -NR ¹³ C (= O) N (R ¹³ ) 2, -NR ¹⁴ SO 2 N (R ¹³ ) 2, - NR ¹⁴ SO2R ¹³ ', -SO3H, -SO2R ^13a, -SR ^13, -S (= O) R ^13a, -SO 2 N (R ¹³⁾ 2, -CH 2 N (R ¹³⁾ 2, -N ^(R13) 2i - NHC (= NH) NHR ¹³ , -C (= NH) NHR ¹³ , or -NO 2, or R ¹ and R ²¹ together form a 5-7-membered carbocyclic ring which may be substituted with 0-2 R ¹² groups, and n '= 2, R ¹ or R ²¹ together with R ¹ or R -gyel -gyel ²¹ on the adjacent carbon forms a direct bond so that a double bond or a triple bond is formed between the carbon atoms, or R ²² and R ^{23 taken} together form a 3- to 7-membered carbocyclic ring which may be substituted with 0-2 R ¹² or - In 208 n = 2, R ²² or R ^{23 is on} the adjacent carbon atom Forms a direct bond with R ²² or R ^{23 to} form a double bond or a triple bond between the carbon atoms, or R ²¹ = in the case of hydrogen, R ¹ and R ² together form a 5-8 membered carbocyclic ring which may be substituted with 0-2 R ¹² , R ¹¹ is oxygen, fluorine, chlorine, bromine or iodine, CF3, -CN, -CO2R ^13, -C (= O) ^R13, -C (= O) N ^(R13) 2, -CHO , -CH ₂ OR ¹³ , -OC (= O) R ¹³ , -O C (= O) 0 R ^13a , -OR ¹³ , -OC (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ^13, -NR ¹⁴ C (= O) OR ¹³ ·, -NR ¹³ C (= O) N ^(R13) 2i -NR ¹⁴ SO ² N ^(R13) 2i -NR ¹⁴ so2r ¹³ ', -SO3H, ¹³ · -SO2R, -SR ^13, -S (= O) R ^13a, -SO 2 N (R ¹³⁾ 2, -CH 2 N (R ¹³⁾ 2 R, -N ^(R13) 2, -NHC (= NH) NHR ^13, -C (= NH) NHR ¹³ , = NOR ¹³ , -NO 2, or The compound of claim 1, or a pharmacologically acceptable salt or prodrug thereof, of the formula R ³¹ is as defined a) a 6-membered, saturated, partially saturated or aromatic carbocyclic ring of formula (p) wherein any bond forming the carbocyclic ring may be a single bond or a double bond and is independently substituted with 0-4 R ¹⁰ , b) A 10-membered, saturated, partially saturated, or aromatic bicyclic carbocyclic ring of formula (r) wherein any bond forming the carbocyclic ring may be a single bond or a double bond and may be independently substituted with 0-4 R ¹⁰ or R ^10a groups. . (c) a 9-membered, saturated, partially saturated, or aromatic bicyclic carbocyclic ring of formula (s) or (t) wherein any bond that forms the carbocyclic ring may be a single ring; · ··· • · · * ··· · »· ·· - 219 bonds or double bonds, which may be independently substituted with 0-4 R ¹⁰ or R ¹⁰ '. The compound of claim 1, or a pharmacologically acceptable salt or prodrug thereof, of the formula R ³¹ is a group of the formula (u), (v), (x) or (y) wherein the dashed line can be a single bond or a double bond independently substituted with 0-3 R ¹⁰ or R ^10a , n is 0. or 1, n 'is 0-2. The compound of claim 1, or a pharmacologically acceptable salt or prodrug thereof, of the formula R ¹ and R ²² are each independently phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, hydroxy, nitro, cyano, C 1-5 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, 7- C 10 arylalkyl, C 1 -C 5 alkoxy, -CO 2 R ¹³ , -C (= O) NHOR ^13a , -C (= O) NHN (R ¹³ ) 2, -OR ¹³ or -B (R ³⁴ ). (R ³⁵ ), C 3 -C 6 cycloalkoxy, -OC (= O) R ¹³ , -C (= O) R ¹³ , -OC (= O) OR ^13a , -OR ¹³ , - (1- C 4 alkyl) -OR ¹³ , -N (R ¹³ ) 2, -O C (= O) N (R ¹³ ) 2, -NR ¹³ C (= O) R ¹³ , -NR ¹³ C (= O) OR ^13a , -NR ¹³ C (= O) N (R ¹³⁾ 2, -NR ¹³ SO2N ^(R13) 2, NR ¹³ SO2R ^13a, -SO ₃ H, -SO ₂ R ^13a, -S (= O) R ^13a , -SR ¹³ or -SO 2 N (R ¹³ ) 2, C 2 -C 6 alkoxyalkyl, methylenedioxy, - 220 ethylenedioxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkylcarbonyloxy, C 1-4 alkylcarbonyl, C 1 -C 4 alkylcarbonylamino, -OCH 2 CO 2 H, 2- (1-morpholino) ethoxy, or C 1 -C 4 alkyl (the alkyl group is -N (R ¹³ ) 2, -CFR ³ , -NO 2 or -S (= O) R ^13a . 10. A compound according to claim 1, a pharmaceutically acceptable salt or prodrug thereof, which is a pharmaceutically acceptable salt or prodrug thereof, wherein the phenyl ring is optionally substituted with 0-3 R ¹⁰ , R ¹⁰ is independently hydrogen, C 1-8 alkyl. a phenyl group, a halogen atom or a C 1-4 alkoxy group, R ¹ is hydrogen, C 1-4 alkyl, phenyl, benzyl or C 1-4 phenylalkyl, R ² is hydrogen or methyl, R ¹³ is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl, or C 3 -C 10 alkoxy. alkyl, R ^13a is C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl or C 3 -C 10 alkoxyalkyl, or • · ·. ♦ ♦ ♦ · ♦ * *. «· · * Two R ¹³ groups bonded to 221 identical nitrogen atoms together - (CH ₂ ) ₂ . ₅ - or - _(CH2) O _(CH2) - to form a group of formula, R ¹⁴ is hydroxy, hydrogen, C 1-4 alkyl, or benzyl, J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) C (R ⁴ ) (R ⁵ ) C (= O) -, wherein R ³ is hydrogen or methyl, R ⁴ is hydrogen or C 1-3 alkyl, R ⁵ is hydrogen, (C 1 -C 8) -alkyl, (C 3 -C 6) -cycloalkyl, (C 3 -C 6) -cycloalkylmethyl, (C 1 -C 6) -cycloalkylethyl, phenyl, phenylmethyl, -CH ₂ OH, -CH SH _2, -CH2OCH3, -CH ₂ SCH _{3 (CH 2} CH ₂ SCH _{3 R} - _{(CH2) s NH2,} - _{(CH2) s} NHC (= NH) (NH ₂₎ - (CH _{2) s} -NHR ₆ group, wherein s is 3-5, R ^1G is an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group, or R ³ and R ⁵ together form -CH ₂ CH ₂ CH ₂ -, or R ⁴ and R ⁵ together form - (CH ₂ ) _u - wherein u is 2-5, K is the L-isomeric amino acid of the formula -N (R ⁶ ) CH (R ⁷ ) C (= O) - wherein R ⁶ is hydrogen or C 1-8 alkyl, ^R7 is (aa) R, group (b) wherein q is 0 or 1; - (CH ₂ ) _r -X, where r is 3-6, (c), (d), """4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «* · · 9 - 222 - (CH ₂ ) _m S (CH ₂ ) ₂ X where m is 1 or 2, The compound of claim 10, or a pharmacologically acceptable salt or prodrug thereof, wherein the phenyl ring is substituted with 0-2 R ¹⁰ or R ^10a , - 227 R ¹⁰ or R ¹⁰ * independently of one another are hydrogen, C 1 -C 8 alkyl, phenyl, halo or C 1 -C 4 alkoxy, R ¹ is hydrogen, R ² is hydrogen, R ¹³ is independently hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 4 -C 12 alkylcycloalkyl, aryl, C 1 -C 10 alkyl-aryl, or C 3 -C 10 alkoxyalkyl; group, R ^13a is (C 1 -C 10) alkyl, (C 3 -C 10) cycloalkyl, (C 4 -C 12) alkylcycloalkyl, aryl, (C 1 -C 10 alkyl) -aryl, or (C 3 -C 10) alkoxyalkyl, or two R ¹³ groups bound to the same nitrogen atom together - (CH ₂ ) ₂ . ₅ - or - _(CH2) O _(CH2) - to form a group of formula, R ¹⁴ is hydroxy, hydrogen, C 1 -C 4 alkyl or benzyl, J is the L-isomer or D-isomeric amino acid of formula A-Ala or -N (R ³ ) CH (R ^S ) C (= O) -, wherein R ³ is hydrogen and R ⁵ is hydrogen, -CH ₃ , -CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ CH (CH ₃ ) ₂ , - (CH ₂ ) ₄ NH ₂ or - (C 3 -C 5 alkyl) -NHR ¹⁶ , or R ³ is methyl and ^R5 is hydrogen, or R ³ and R ⁵ together form -CH ₂ CH ₂ CH ₂ -, - 228 R ¹⁶ is an amine protecting group, 1-2 amino acids or 1-2 amino acids substituted with an amine protecting group, K is the L-isomeric amino acid of the formula -N (CH ₃ ) CH (R ⁷ ) C (= O) - wherein R ⁷ is - (CH ₂ ) ₃ NHC (= NH) (NH ₂ ) L is -NHCH ₂ C (= O) -, wherein M is the D isomer or the L isomeric amino acid of formula (i) wherein q 'is 1 R ⁴ is hydrogen or methyl, R ¹⁷ is hydrogen, R ^{8 is} -CO ₂ R ^13b , R ^13b is -CH (R ³⁶ ) OC (= O) R ³⁷ , -CH (R ³⁶ ) OC (= O) OR ³⁸ or a group of formula (I), R ³⁶ is C 1 -C 4 straight alkyl or hydrogen, R ³⁷ is a) a hydrogen atom, b) C 1-8 alkyl or C 3-8 cycloalkyl substituted with 1-2 identical or different substituents, wherein the substituent may be (i) C1-C4 alkyl, (ii) C3-C8 cycloalkyl, (iii) C1-C5 alkoxy, (iv) aryl having 0-2 halogens, phenyl, The compound of claim 10, or a pharmacologically acceptable salt thereof, of the formula ^R1 and ^R2 are each independently hydrogen or methyl, J is D-Val, D-2-aminobutyric acid, D-Leu, D-Ala, Gly, DPro, D-Ser, D-Lys, beta-Ala, Pro, Phe, NMeGly, D-NIe, DPhg, D- Ile, D-Phe, D-Tyr, Ala, ^ε- β-Azidobenzoyl-D-Lys, N ⁶ -Benzoyl-Benzoyl-D-Lys, NM-Tryptophanyl-D-Lys, N- ^E -O-Benzyl-Benzoyl-D Lys, N ^E -p-acetylbenzoyl-D-Lys, IST-dansyl-D-Lys, N ^{E-glycyl-D-Lys,} N ^E glycyl-p-benzoylbenzoyl-D-Lys, ^Ν ε -ρ-phenyl-benzoyl-D-Lys, Ν- ^ε- m-benzoyl-benzoyl-D-Lys, Ν- ^ε- o-benzoyl-benzoyl-D-Lys, D-norwayin, K is NMeArg or Arg, L is Gly, beta-Ala or Ala, M is Asp (methylcarbonyloxymethyl), Asp (ethylcarbonyloxymethyl), Asp (t-butylcarbonyloxymethyl), · · · · • · ·· · · · -231Asp- (cyclohexylcarbonyloxymethyl ester), Asp (1- (methylcarbonyloxy) ethyl ester), Asp (1- (ethylcarbonyloxy) ethyl ester), Asp (1- (t-b-1-carbonyloxy) ethyl ester), Asp (1- (cyclohexylcarbonyloxy) ethyl ester), Asp (i-propyloxycarbonyloxymethyl ester), Asp (cyclohexylcarbonyloxymethyl ester) ), Asp (t-butyl 1-oxycarbonyl-oxy-methyl ester), Asp (1- (i-propyloxycarbonyloxy) ethyl ester), Asp (1- (cyclohexyl 1-oxycarbonyl-oxy) ethyl ester), Asp (1- (t-butyloxycarbonyloxy) ethyl ester), Asp (dimethylamino-ethyl ester), Asp (diethylamino-ethyl ester), Asp - ((1,3-dioxa-5-methyl-cyclopenten-2-on-4-yl) methyl ester); Asp - ((5- (t-butyl) -1,3-dioxa-cyclopenten-2-on-4-yl) methyl ester); Asp - ((1,3-dioxa-5-phenylcyclopenten-2-one-4-yl) methyl ester) or Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester). The compound of claim 10, or a pharmacologically acceptable salt thereof, of the formula R ¹ and R ² are each independently hydrogen or methyl, J is D-Val, D-2-aminobutyric acid, D-norvaline, D-Leu, D-Ala, Gly, D-Pro, D-Ser, D-Lys, Beta-Ala, Pro, Phe, NMeGly, D-NIe, D-Phg, D-IIe, D-Phe, D-Tyr, Ala, K means NMeArg, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · p · - 232 L is Gly, M is Asp (methylcarbonyloxymethyl), Asp (ethylcarbonyloxymethyl), Asp (t-butylcarbonyloxymethyl), Asp (cyclohexylcarbonyl) oxymethyl ester), Asp (1- (methylcarbonyloxy) ethyl ester), Asp (1- (ethylcarbonyloxy) ethyl ester), Asp (1- (t-butylcarbonyloxy) ethyl ester, Asp (1- (cyclohexylcarbonyloxy) ethyl ester), Asp (i-propyloxy-carbonyloxymethyl). ester), As p- (cyclohexylcarbonyloxymethyl ester), Asp- (t-butyloxycarbonyloxymethyl ester), Asp- (1- (i- propyloxycarbonyloxy) ethyl ester), Asp (1- (cyclohexyloxycarbonyloxy) ethyl ester), Asp (1- (t-butyloxycarbonyloxy)) ethyl ester), Asp (dimethylaminoethyl ester), Asp (diethylaminoethyl ester), Asp - ((1,3-dioxa-5-methylcyclopenten-2-one-4-yl) methyl ester), Asp - ((5- (t-butyl) -1,3-dioxa-cyclopenten-2-on-4-yl) methyl ester); Asp - ((1,3-dioxa-5-phenyl-1-cyclopenten-2-O-n-4-yl) methyl ester) or Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester). Compounds according to claim 10, or a pharmaceutically acceptable salt thereof, as follows: • · · · · · · · · · · · · · · · · · - 233 - - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (methylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J represents D-Val ,, K is NMeArg, L is Gly and M is Asp (ethylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (t-butylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (cyclohexylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and - 234 • · · · · ··· · «· · · · · · M is Asp (1- (methylcarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (1- (ethylcarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (1- (t-butylcarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (1- (cyclohexylcarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (isopropyloxycarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K means NMeArg, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· · - 235 L is Gly and M is Asp (cyclohexylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (t-butyloxycarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (1- (isopropyloxycarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (1- (cyclohexyloxycarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (1- (t-butyloxycarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J means D-Val, ···· ·····························································································• - 236 Κ for NMeArg, L is Gly and M is Asp (dimethylaminoethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (diethylaminoethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp - ((1,3-dioxa-5-methylcyclopenten-2-one-4-yl) methyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp - ((5- (t-butyl) -1,3-dioxa-cyclopenten-2-one-4-yl) -methyl-ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp - ((1,3-dioxa-5-phenylcyclopenten-2-one-4-yl) • · * - 237-methyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-Val, K is NMeArg, L is Gly and M is Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (methylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (ethylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (t-butylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, · 9 · · · · ··· - 238 K is NMeArg, L is Gly and M is Asp (cyclohexylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (1- (methylcarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (1- (ethylcarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (1- (t-butylcarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (1- (cyclohexylcarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² represent a hydrogen atom, * - 239 J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (isopropyloxycarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (cyclohexylcarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (t-butyloxycarbonyloxymethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (1- (isopropyloxycarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (1- (cyclohexyloxycarbonyloxy) ethyl ester); - Compound of Formula (II) wherein · · · · · · · · · · · · · • · · • * ··· · · * · - R ¹ 240 and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (1- (t-butyloxycarbonyloxy) ethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (dimethylaminoethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (diethylaminoethyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp - ((1,3-dioxa-5-methylcyclopenten-2-one-4-yl) methyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L stands for Gly and ··· »··· ··· · · · · · · ··· - 241 M is Asρ - ((5- (t-butyl) -1,3-dioxa-cyclopentene-2-one-4-yl) -methyl); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp - ((1,3-dioxa-5-phenylcyclopenten-2-one-4-yl) methyl ester); - A compound of formula II wherein R ¹ and R ² is hydrogen, J is D-2-aminobutyric acid, K is NMeArg, L is Gly and M is Asp (1- (2- (2-methoxypropyl) carbonyloxy) ethyl ester). 15. A pharmaceutical composition comprising a therapeutically effective amount of 1-14. A compound according to claim 1 together with a pharmaceutical carrier.