Factor VIIa inhibitory (thio)urea derivatives, their preparation and their use Number:6,743,790 from the United States Patent and Trademark Office (PTO) owispatent The present invention relates to compounds of the formula I, ##STR1##in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, A, X, m and n have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of thromboembolic diseases and restenoses. They are reversible inhibitors of the blood clotting enzyme factor VIIa and can in general be applied in conditions in which an undesired activity of factor VIIa is present or for the cure or prevention of which an inhibition of factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, for example as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.<H preparation, derivatives, Factor, VIIa, inh, 6743790.html, Patent, pto, 6743790

Title: Factor VIIa inhibitory (thio)urea derivatives, their preparation and their use

Abstract: The present invention relates to compounds of the formula I, ##STR1##in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, A, X, m and n have the meanings indicated in the claims. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of thromboembolic diseases and restenoses. They are reversible inhibitors of the blood clotting enzyme factor VIIa and can in general be applied in conditions in which an undesired activity of factor VIIa is present or for the cure or prevention of which an inhibition of factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, for example as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

Patent Number: 6,743,790 Issued on 06/01/2004 to Klingler, et al.

Inventors: Klingler; Otmar (Rodgau, DE), Schudok; Manfred (Eppstein/Ts., DE), Nestler; Hans-Peter (Kelkheim, DE), Matter; Hans (Langenselbold, DE), Schreuder; Herman (Hofheim-Lorsbach, DE)
Assignee: Aventis Pharma Deutschland GmbH (Frankfurt am Main, DE)

Appl. No.: 09/874,318

Filed: June 6, 2001

Foreign Application Priority Data


Jun 06, 2000 [EP]			00112116

Current U.S. Class: 514/230.8 ; 514/237.8; 514/327; 514/330; 514/331; 514/354; 514/357; 514/364; 514/371; 514/452; 514/586; 514/597; 544/159; 544/160; 544/162; 544/165; 546/224; 546/233; 546/237; 546/332; 548/185; 549/366; 564/27; 564/28; 564/29; 564/51

Current International Class: C07C 275/42 (20060101); C07C 275/00 (20060101); C07D 211/00 (20060101); C07D 213/40 (20060101); C07D 211/96 (20060101); C07D 213/00 (20060101); C07D 319/00 (20060101); C07D 319/18 (20060101)

Field of Search: 564/38,27,28,29,51 546/235,227,233,237,224,332 514/330,586,597,452,369,371,327,331,354,357,230.8,237.8 544/159,165,160,162,105 549/366 548/185

References Cited [Referenced By]

U.S. Patent Documents


5273982	December 1993	Alig et al.
5314902	May 1994	Tjoeng et al.
5703050	December 1997	Klingler et al.

Foreign Patent Documents


0 987 274	Mar., 2000	EP
WO 92/06711	Apr., 1992	WO
WO 94/17041	Aug., 1994	WO
WO 94/22907	Oct., 1994	WO
WO 96/12800	May., 1996	WO
WO 97/47651	Dec., 1997	WO

Other References

GJ. Broze, Jr., "Tissue factor pathway inhibitor and the current concept of blood coagulation" Blood Coagulation and Fibrionolysis 6(1):S7-S13 (1995). .
Y.-C. Cheng and W.H. Prusoff, "Relationship between the inhibition constant (K.sub.1) and the concentration of inhibitor which causes 50 per cent inhibition (I.sub.50) of an enzymatic reaction" Biochemical Pharmacology 22:3099-3108 (1973). .
H. Cole, "The tissue factor pathway of coagulation" Australian Journal of Medical Science 16:87-93 (1995). .
L.A. Harker, et al., "Antithrombotic Benefits and Hemorrhagic Risks of Direct Thrombin Antagonists" Thrombosis and Haemostasis 74(1):464-472 (1995). .
L.A. Harker, et al., "Antithrombotic and Antilesion Benefits without Hemorrhagic Risks by Inhibiting Tissue Factor Pathway" Haemostasis 26(Suppl. 1):76-82 (1996). .
J.A. Ostrem et al., "Discovery of a Novel, Potent, and Specific Family of Factor Xa Inhibitors via Combinatorial Chemistry" Biochemistry 37:1053-1059 (1998). .
I,H. Segel, Chapter 3, "Simple Inhibition Systems," in Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems, John Wiley & Sons, New York, p. 100-125 (1975). .
Jang, Y. et al. "Influence of Blockade at Specific Levels of the Coagulation Cascade on Restenosis in a Rabbit Atherosclerotic Femoral Artery Injury Model" Circulation 92:3041-50 (1995)..

Primary Examiner: Seaman; D. Margaret
Assistant Examiner: Covington; Raymond
Attorney, Agent or Firm: Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.

Parent Case Text

This application claims the benefit of priority under 35 U.S.C. .sctn.119(a) to European Patent Application No. 00112116.9, filed Jun. 6, 2000, the disclosure of which is hereby incorporated by reference.

Claims

What is claimed is:

1. A compound of the formula I, ##STR23## wherein m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; A is halogen; X is sulfur or oxygen; R.sup.1 is chosen from hydrogen, hydroxy, (C.sub.1 -C.sub.12)-alkoxycarbonyl-,(C.sub.6 -C.sub.14)- aryl-(C.sub.1 -C.sub.4)-alkoxycarbonyl-, and (C.sub.6 -C.sub.14)-aryloxycarbonyl-, wherein each of the aryl groups is unsubstituted or substituted by at least one identical or different substituent chosen from (C.sub.1 -C.sub.12)-alkyl, halogen and (C.sub.1 -C.sub.12)-alkoxy; R.sup.2 is chosen from hydrogen, (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, R.sup.20 -(C.sub.6 -C.sub.12)-alkyl-, R.sup.20 -(C.sub.1 -C.sub.14)-aryl-, and R.sup.20 -(C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, wherein R.sup.20 is chosen from hydroxycarbonyl-, aminocarbonyl-, (C.sub.1 -C.sub.12)-alkoxycarbonyl-, and (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkoxycarbonyl-; R.sup.3 is chosen from hydrogen, cyano, hydroxy, and (C.sub.1 -C.sub.12)-alkyl; R.sup.4 is chosen from (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14),-aryl, (C.sub.8 -C.sub.14 -aryl-(C.sub.1 -C.sub.4)-alkyl-, Het, and Het-(C.sub.1 -C.sub.4)-alkyl-, wherein the alkyl, aryl and Het groups are unsubstituted or substituted by at least one identical or different substituent R.sup.10 ; R.sup.5 is chosen from hydrogen, (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, Het, Het-(C.sub.1 -C.sub.4)-alkyl-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-aminocarbonyl-, and Het-(C.sub.1 -C.sub.4)-alkyl-aminocarbonyl-, wherein the alkyl, aryl and Het groups are unsubstituted or substituted by at least one identical or different substituent R.sup.10 ;

or R.sup.4 and R.sup.5 together with the carbon atom to which they are bonded form a saturated or unsaturated 3-membered to 8-membered ring which is a carbocyclic ring or a heterocyclic ring containing 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, and which is optionally condensed to one or two saturated or unsaturated carbocyclic ring systems or heterocyclic ring systems containing 5 to 10 ring atoms of which 1, 2 or 3 are identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, wherein the resulting R.sup.4 (R.sup.5)C group is unsubstituted or substituted by at least one identical or different substituent R.sup.10 ; R.sup.6 is chosen from hydrogen, hydroxy, (C.sub.1 -C.sub.8)-alkoxy, and (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkoxy-; R.sup.10 is chosen from (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.1 -C.sub.4)-alkoxy-(C.sub.2 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryloxy-, Het-oxy-, Het-(C.sub.1 -C.sub.4)-alkoxy-, (C.sup.6 -C.sub.14)-aryl, Het, Het-(C.sub.1 -C.sub.4,-alkyl-, trifluoromethoxy, trifluoromethyl, halogen, oxo, hydroxy, amino, (C.sub.1 -C.sub.12)-alkylcarbonylamino-, aminocarbonylamino-, (C.sub.6 -C.sub.14)-arylcarbonylamino-, Het-carbonylamino-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylcarbonylamino-, Het-(C.sub.1 -C.sub.4)-alkylcarbonylamino-, (C.sub.1 -C.sub.8)-alkylcarbonyl-, (C.sub.6 -C.sub.14)-arylcarbonyl-, (C.sub.1 -C.sub.8)-alkylaminocarbonyl-, (C.sub.6 -C.sub.14)-arylaminocarbonyl-, (C.sub.6 -C.sub.14 -aryl-(C.sub.1 -C.sub.4)-alkylaminocarbonyl-, Het-aminocarbonyl-, Het-(C.sub.1 -C.sub.4)-alkylaminocarbonyl-, aminocarbonyl-, (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl-, cyano, nitro, amidino, acetimino, tri-((C.sub.1 -C.sub.4)-alkyl)ammonio-, (C.sub.1 -C.sub.8)-alkylamino-, di-((C.sub.1 -C.sub.8)-alkyl)amino-, hydroxycarbonylmethoxy-, (C.sub.1 -C.sub.8)-alkylsulfonyl-, (C.sub.6 -C.sub.14)-arylsulfonyl-, (C.sub.1 -C.sub.8)-alkylaminosulfonyl-, (C.sub.6 -C.sub.14)-arylaminosulfonyl-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylaminosulfonyl-, Het-aminosulfonyl, Het-(C.sub.1 -C.sub.4)-alkylaminosulfonyl-, (C.sub.1 -C.sub.8)-alkylsulfonylamino-, (C.sub.6 -C.sub.14)-arylsulfonylamino-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylsulfonylamino-, Het-sulfonylamino-, and Het-(C.sub.1 -C.sub.4)-alkylsulfonylamino-, wherein (C.sub.1 -C.sub.12)-alkylcarbonylamino- representing R.sup.10 is unsubstituted or substituted in the alkyl group by a substituent chosen from amino, hydroxy and (C.sub.1 -C.sub.4)-alkoxy, and wherein (C.sub.1 -C.sub.12)-alkyl and (C.sub.1 -C.sub.8)-alkoxy representing R.sup.10 are unsubstituted or substituted by at least one identical or different substituent chosen from (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl- and aminocarbonyl-, wherein each of the aryl groups and Het group in a group R.sup.10 is unsubstituted or substituted by at least one identical or different substituent chosen from halogen, nitro, oxo, hydroxy, (C.sub.1 -C.sub.8)-alkyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.1 -C.sub.4)-alkoxy-(C.sub.2 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryloxy-, (C.sub.6 -C.sub.14 -aryl-(C.sub.1 -C.sub.4)-alkoxy-, Het-oxy-, Het-(C.sub.1 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, Het, Het-(C.sub.1 -C.sub.4)-alkyl-, trifluoromethyl, cyano, trifluoromethoxy, (C.sub.1 -C.sub.8)-alkylsulfonyl-, (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl-, aminocarbonyl-, amino, (C.sub.1 -C.sub.8)-alkylamino-, di-((C.sub.1 -C.sub.8)-alkyl)amino-, (C.sub.1 -C.sub.8)-alkylcarbonylamino-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylcarbonylamino-, (C.sub.6 -C.sub.14)-arylcarbonylamino-, Het-carbonylamino-, Het-(C.sub.1 -C.sub.4)-alkylcarbonylamino-, and (C.sub.1 -C.sub.8)-alkylcarbonyl-, wherein (C.sub.1 -C.sub.8)-alkyl and (C.sub.1 -C.sub.8)-alkoxy representing a substituent on an aryl group or Het group in a group R.sup.10 are unsubstituted or substituted by at least one identical or different substituent chosen from (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl- and aminocarbonyl-, with the proviso that, when a substituent R.sup.10 is bonded to an alkyl group, it cannot be (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl-, aminocarbonyl-, (C.sub.1 -C.sub.8)-alkylaminocarbonyl-, or (C.sub.1 -C.sub.8)-alkylaminosulfonyl-, and that, when a substituent R.sup.10 is bonded to an alkyl group, it cannot be (C.sub.1 -C.sub.8)-alkyl which is substituted by at least one identical or different substituent chosen from (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl- and aminocarbonyl-; Het is a residue of a saturated or unsaturated monocyclic or bicyclic, 3-membered to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur; or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.

2. The compound of the formula I as claimed in claim 1, in which X is oxygen, or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.

3. The compound of the formula I as claimed in claim 1, in which R.sup.1 is chosen from hydrogen, hydroxy and (C.sub.1 -C.sub.4)-alkoxycarbonyl-, or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.

4. The compound of the formula I as claimed in claim 1, in which R.sup.2 is hydrogen, or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.

5. The compound of the formula I as claimed in claim 1, in which R.sup.6 is chosen from hydrogen and hydroxy, or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.

6. The compound of the formula I as claimed in claim 1, in which n is 0, R.sup.3 is hydrogen and R.sup.5 is chosen from methyl, ethyl and phenyl, wherein the phenyl group is unsubstituted or substituted by at least one identical or different substituent R.sup.10 ; or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.

7. A process for the preparation of at least one compound of formula I as claimed in claim 1, comprising linking the compounds of formulae II, III and IV with formation of a (thio)urea bridge between the groups G.sup.1 and G.sup.2 in formulae II and III and an amide bond between the COZ group in formula II and the NH2 group In formula IV, ##STR24## wherein (a) G.sup.1 is NH.sub.2 and G.sup.2 is chosen from iso(thio)cyanato, (C.sub.1 -C.sub.6)-alkoxycarbonylamino, trichloromethylcarbonylamino, and azolyl-N-(thio)carbonylamino, wherein these groups contain the group R.sup.6 ; or (b) G.sup.1 is chosen from iso(thio)cyanato, (C.sub.1 -C.sub.8)-alkoxycarbonylamino, trichloromethylcarbonylamino, and azolyl-N-(thio)carbonylamino and G.sup.2 is NHR.sup.6 ; and Z in the compound of formula III is chosen from hydroxy and a nucleophilically substitutable leaving group; R.sup.0 in the compound of formula II is chosen from R.sup.1 NH--C(.dbd.NH)-, a protected form thereof, and a precursor group thereof; and m, n, A, R.sup.1, R.sup.2, R.sup.3 ; R.sup.4, R.sup.5 and R.sup.6 are defined as in claim 1, but wherein functional groups can also be present in protected form or in the form of precursor groups.

8. A pharmaceutical composition, comprising at least one compound chosen from the compounds of the formula I as claimed in claim 1 and their physiologically tolerable salts, and a pharmaceutically acceptable carrier.

9. A method of inhibiting factor VIIa, comprising administering to a patient an effective amount of at least one compound chosen from the compounds of the formula I as claimed in claim 1 and their physiologically tolerable salts.

10. A method of inhibiting factor VIIa, comprising contacting a sample which contains factor VIIa with at least one compound chosen from the compounds of the formula I as claimed in claim 1 and their physiologically tolerable salts.

11. A method of inhibiting or reducing blood clotting or inflammatory response, comprising administering to a patient an effective amount of at least one compound chosen from the compounds of the formula I as claimed in claim 1 and their physiologically tolerable salts.

12. A method of treating cardiovascular disorders, thromboembolic diseases or restenoses, comprising administering to a patient an effective amount of at least one compound chosen from the compounds of the formula I as claimed in claim 1 and their physiologically tolerable salts.

Description

TECHNICAL FIELD

The present invention relates to compounds of the formula I, ##STR2##

in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, A, X, m and n have the meanings indicated below. The compounds of the formula I are valuable pharmacologically active compounds. They exhibit a strong antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of thromboembolic diseases and restenoses. They are reversible inhibitors of the blood clotting enzyme factor VIIa and can in general be applied in conditions in which an undesired activity of factor VIIa is present or for the cure or prevention of which an inhibition of factor VIIa is intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, for example as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

BACKGROUND OF THE INVENTION

The ability to form blood clots is vital to survival. The formation of a blood clot or a thrombus is normally the result of tissue injury which initiates the coagulation cascade and has the effect of slowing or preventing blood flow in wound healing. Other factors which are not directly related to tissue injury like atherosclerosis and inflammation may also initiate the coagulation cascade. In general, a relationship exists between inflammation and the coagulation cascade. Inflammation mediators regulate the coagulation cascade and coagulation components influence the production and activity of inflammation mediators. However, in certain disease states the formation of blood clots within the circulatory system reaches an undesired extent and is itself the source of morbidity potentially leading to pathological consequences. It is nevertheless not desirable in such disease states to completely inhibit the blood clotting system because life threatening hemorrhage would ensue. In the treatment of such states a well-balanced intervention into the blood clotting system is required, and there is still a need for substances exhibiting a suitable pharmacological activity for achieving such a result.

Blood coagulation is a complex process involving a progressively amplified series of enzyme activation reactions in which plasma zymogens are sequentially activated by limited proteolysis. Mechanistically the blood coagulation cascade has been divided into intrinsic and extrinsic pathways, which converge at the activation of factor X; subsequent generation of thrombin proceeds through a single common pathway (see Scheme 1). Present evidence suggests that the intrinsic pathway plays an important role in the maintenance and growth of fibrin formation, while the extrinsic pathway is critical in the initiation phase of blood coagulation (H. Cole, Aust. J. Med. Sci. 16 (1995) 87; G. J. Broze, Blood Coagulation and Fibrinolysis 6, Suppl. 1 (1995) S7; which is incorporated herein by reference). It is generally accepted that blood coagulation is physically initiated upon formation of a factor VIIa/tissue factor (TF) complex. Once formed, this complex rapidly initiates coagulation by activating factors IX and X. The newly generated activated factor X, i.e. factor Xa, then forms a one-to-one complex with factor Va and phospholipids to form a prothrombinase complex, which is responsible for converting soluble fibrinogen to insoluble fibrin via the activation of thrombin from its precursor prothrombin. As time progresses, the activity of the factor VIIa/tissue factor complex (extrinsic pathway) is suppressed by a Kunitz-type protease inhibitor protein, TFPI, which, when complexed to factor Xa, can directly inhibit the proteolytic activity of factor VIIa/tissue factor. In order to maintain the coagulation process in the presence of an inhibited extrinsic system, additional factor Xa is produced via the thrombin-mediated activity of the intrinsic pathway. Thus, thrombin plays a dual autocatalytic role, mediating its own production and the conversion of fibrinogen to fibrin. The autocatalytic nature of thrombin generation is an important safeguard against uncontrolled bleeding and it ensures that, once a given threshold level of prothrombinase is present, blood coagulation will proceed to completion. Thus, it is most desirable to develop agents that inhibit coagulation without directly inhibiting thrombin but by inhibiting other steps in the coagulation cascade like factor VIIa activity. ##STR3##

In many clinical applications there is a great need for the prevention of intravascular blood clots or for some anticoagulant treatment. For example, nearly 50% of patients who have undergone a total hip replacement develop deep vein thrombosis (DVT). The currently available drugs like heparin and derivatives thereof are not satisfactory in many specific clinical applications. The currently approved therapies include fixed dose low molecular weight heparin (LMWH) and variable dose heparin. Even with these drug regimes 10% to 20% of patients develop DVT, and 5% to 10% develop bleeding complications.

Another clinical situation for which better anticoagulants are needed concerns subjects undergoing transluminal coronary angioplasty and subjects at risk for myocardial infarction or suffering from crescendo angina. The present, conventionally accepted therapy which consists of administering heparin and aspirin, is associated with a 6% to 8% abrupt vessel closure rate within 24 hours of the procedure. The rate of bleeding complications requiring transfusion therapy due to the use of heparin also is approximately 7%. Moreover, even though delayed closures are significant, administration of heparin after termination of the procedures is of little value and can be detrimental.

The widely used blood-clotting inhibitors like heparin and related sulfated polysaccharides like LMWH and heparin sulfate exert their anti-clotting effects by promoting the binding of a natural regulator of the clotting process, anti-thrombin III, to thrombin and to factor Xa. The inhibitory activity of heparin primarily is directed toward thrombin which is inactivated approximately 100 times faster than factor Xa. Hirudin and hirulog are two additional thrombin-specific anticoagulants presently in clinical trials. However, these anticoagulants which inhibit thrombin also are associated with bleeding complications. Preclinical studies in baboons and dogs have shown that targeting enzymes involved at earlier stages of the coagulation cascade, such as factor Xa or factor VIIa, prevents clot formation without producing the bleeding side effects observed with direct thrombin inhibitors (L. A. Harker et al., Thromb. Haemostas. 74 (1995) 464; incorporated herein by reference).

Specific inhibition of the factor VIIa/tissue factor catalytic complex using monoclonal antibodies (for example, WO-A-92/06711; incorporated herein by reference) or a protein such as chloromethyl ketone inactivated factor VIIa (for example, WO-A-96/12800 and WO-A-97/47651; both of which are incorporated herein by reference) is an extremely effective means of controlling thrombus formation caused by acute arterial injury or the thrombotic complications related to bacterial septicemia. There is also experimental evidence suggesting that inhibition of factor VIIa/tissue factor activity inhibits restenosis following balloon angioplasty (L. A. Harker et al., Haemostasis 26 (1996) S1:76; incorporated herein by reference). Bleeding studies have been conducted in baboons and indicate that inhibition of the factor VIIa/tissue factor complex has the widest safety window with respect to therapeutic effectiveness and bleeding risk of any anticoagulant approach tested including thrombin, platelet and factor Xa inhibition (L. A. Harker et al., Thromb. Haemostas. 74 (1995) 464; incorporated herein by reference).

A specific inhibitor of factor VIIa which has a favorable property profile would have substantial practical value in the practice of medicine. In particular, a factor VIIa inhibitor would be effective under circumstances where the present drugs of choice, like heparin and related sulfated polysaccharides, are ineffective or only marginally effective. Certain inhibitors of factor VIIa have already been described. EP-A-987274 (incorporated herein by reference), for example, discloses compounds containing a tripeptide unit which inhibit factor VIIa. However, the property profile of these compounds is still not ideal, and there is a need for further low molecular weight factor VIIa-specific blood clotting inhibitors that are effective and do not cause unwanted side effects. The present invention satisfies this need by providing novel factor VIIa activity inhibiting urea derivatives and thiourea derivatives of the formula I. Other (thio)urea derivatives have already been described, for example, in U.S. Pat. No. 5,314,902 (corresponding to WO-A-94/17041) and U.S. Pat. No. 5,703,050 (corresponding to WO-A-94/22907), the disclosures of which are herein incorporated by reference, however, the disclosed compounds are antagonists of integrin receptors like the fibrinogen receptor GPIIb/IIIa.

SUMMARY AND DETAILED DESCRIPTION

Thus, a subject of the present invention is a compound of the formula I ##STR4##

wherein m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; A is halogen; X is sulfur or oxygen; R.sup.1 is chosen from hydrogen, hydroxy, (C.sub.1 -C.sub.12)-alkoxycarbonyl-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkoxycarbonyl-, and (C.sub.6 -C.sub.14)-aryloxycarbonyl-, wherein each of the aryl groups is unsubstituted or substituted by at least one identical or different substituent chosen from (C.sub.1 -C.sub.12)-alkyl, halogen, and (C.sub.1 -C.sub.12)-alkoxy; R.sup.2 is chosen from hydrogen, (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, R.sup.20 --(C.sub.1 -C.sub.12)-alkyl-, R.sup.20 --(C.sub.6 -C.sub.14)-aryl-, and R.sup.20 --(C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, wherein R.sup.20 is chosen from hydroxycarbonyl-, aminocarbonyl-, (C.sub.1 -C.sub.12)-alkoxycarbonyl-, and (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkoxycarbonyl-; R.sup.3 is chosen from hydrogen, cyano, hydroxy, and (C.sub.1 -C.sub.12)-alkyl; R.sup.4 is chosen from (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, Het, and Het-(C.sub.1 -C.sub.4)-alkyl-, wherein the alkyl, aryl and Het groups are unsubstituted or substituted by at least one identical or different substituent R.sup.10 ;

R.sup.5 is chosen from hydrogen, (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, Het, Het-(C.sub.1 -C.sub.4)-alkyl-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-aminocarbonyl-, and Het-(C.sub.1 -C.sub.4)-alkyl-aminocarbonyl-, wherein the alkyl, aryl and Het groups are unsubstituted or substituted by at least one identical or different substituent R.sup.10 ;

or R.sup.4 and R.sup.5 together with the carbon atom to which they are bonded form a saturated or unsaturated 3-membered to 8-membered ring which is a carbocyclic ring or a heterocyclic ring containing 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, and which is optionally condensed to one or two saturated or unsaturated carbocyclic ring systems or heterocyclic ring systems containing 5 to 10 ring atoms of which 1, 2 or 3 are identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur, wherein the resulting R.sup.4 (R.sup.5)C group is unsubstituted or substituted by at least one identical or different substituent R.sup.10 ; R.sup.6 is chosen from hydrogen, hydroxy, (C.sub.1 -C.sub.8)-alkoxy, and (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkoxy-; R.sup.10 is chosen from (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.1 -C.sub.4)-alkoxy-(C.sub.2 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryloxy-, Het-oxy-, Het-(C.sub.1 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryl, Het, Het-(C.sub.1 -C.sub.4)-alkyl-, trifluoromethoxy, trifluoromethyl, halogen, oxo, hydroxy, amino, (C.sub.1 -C.sub.12)-alkylcarbonylamino-, aminocarbonylamino-, (C.sub.6 -C.sub.14)-arylcarbonylamino-, Het-carbonylamino-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylcarbonylamino-, Het-(C.sub.1 -C.sub.4)-alkylcarbonylamino-, (C.sub.1 -C.sub.8)-alkylcarbonyl-, (C.sub.6 -C.sub.14)-arylcarbonyl-, (C.sub.1 -C.sub.8)-alkylaminocarbonyl-, (C.sub.6 -C.sub.14)-arylaminocarbonyl-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylaminocarbonyl-, Het-aminocarbonyl-, Het-(C.sub.1 -C.sub.4)-alkylaminocarbonyl-, aminocarbonyl-, (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl-, cyano, nitro, amidino, acetimino, tri-((C.sub.1 -C.sub.4)-alkyl)ammonio-, (C.sub.1 -C.sub.8)-alkylamino-, di-((C.sub.1 -C.sub.8)-alkyl)amino-, hydroxycarbonylmethoxy-, (C.sub.1 -C.sub.8)-alkylsulfonyl-, (C.sub.6 -C.sub.14)-arylsulfonyl-, (C.sub.1 -C.sub.5)-alkylaminosulfonyl-, (C.sub.6 -C.sub.14)-arylaminosulfonyl-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylaminosulfonyl-, Het-aminosulfonyl-, Het-(C.sub.1 -C.sub.4)-alkylaminosulfonyl-, (C.sub.1 -C.sub.8)-alkylsulfonylamino-, (C.sub.6 -C.sub.14)-arylsulfonylamino-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylsulfonylamino-, Het-sulfonylamino-, and Het-(C.sub.1 -C.sub.4)-alkylsulfonylamino-, wherein (C.sub.1 -C.sub.12)-alkylcarbonylamino- representing R.sup.10 is unsubstituted or substituted in the alkyl group by a substituent chosen from amino, hydroxy and (C.sub.1 -C.sub.4)-alkoxy, and wherein (C.sub.1 -C.sub.12)-alkyl and (C.sub.1 -C.sub.8)-alkoxy representing R.sup.10 are unsubstituted or substituted by at least one identical or different substituent chosen from (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl-, and aminocarbonyl-, wherein each of the aryl groups and Het group in a group R.sup.10 is unsubstituted or substituted by at least one identical or different substituent chosen from halogen, nitro, oxo, hydroxy, (C.sub.1 -C.sub.8)-alkyl, (C.sub.1 -C.sub.8)-alkoxy, (C.sub.1 -C.sub.4)-alkoxy-(C.sub.2 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryloxy-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkoxy-, Het-oxy-, Het-(C.sub.1 -C.sub.4)-alkoxy-, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, Het, Het-(C.sub.1 -C.sub.4)-alkyl-, trifluoromethyl, cyano, trifluoromethoxy, (C.sub.1 -C.sub.8)-alkylsulfonyl-, (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl-, aminocarbonyl-, amino, (C.sub.1 -C.sub.8)-alkylamino-, di-((C.sub.1 -C.sub.8)-alkyl)amino-, (C.sub.1 -C.sub.8)-alkylcarbonylamino-, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkylcarbonylamino-, (C.sub.6 -C.sub.14)-arylcarbonylamino-, Het-carbonylamino-, Het-(C.sub.1 -C.sub.4)-alkylcarbonylamino-, and (C.sub.1 -C.sub.8)-alkylcarbonyl-, wherein (C.sub.1 -C.sub.8)-alkyl and (C.sub.1 -C.sub.8)-alkoxy representing a substituent on an aryl group or Het group in a group R.sup.10 are unsubstituted or substituted by at least one identical or different substituent chosen from (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl-, and aminocarbonyl-, with the proviso that, when a substituent R.sup.10 is bonded to an alkyl group, it cannot be (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl-, aminocarbonyl-, (C.sub.1 -C.sub.8)-alkylaminocarbonyl- or (C.sub.1 -C.sub.8)-alkylaminosulfonyl-, and that, when a substituent R.sup.10 is bonded to an alkyl group, it cannot be (C.sub.1 -C.sub.8)-alkyl which is substituted by at least one identical or different substituents chosen from (C.sub.1 -C.sub.8)-alkoxycarbonyl-, hydroxycarbonyl- and aminocarbonyl-; Het is a residue of a saturated or unsaturated monocyclic or bicyclic, 3-membered to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms chosen from nitrogen, oxygen and sulfur; or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.

All groups, substituents, residues etc. which can occur several times in the compounds of the formula I, for example A, R.sup.10 or Het, can each independently of one another have the meanings indicated, and can in each case be identical or different.

As used herein, the term alkyl is to be understood in the broadest sense to mean hydrocarbon residues which can be linear, i.e. straight-chain, or branched and which can be acyclic or cyclic groups or comprise any combination of acyclic and cyclic subunits. Further, the term alkyl as used herein expressly includes saturated groups as well as unsaturated groups which latter groups contain one or more, for example one, two or three, double bonds and/or triple bonds, provided that the double bonds are not located within a cyclic alkyl group in such a manner that an aromatic system results. All these statements also apply if an alkyl group occurs as a substituent on another group or is substituted, for example in an alkoxy group (alkyl-O--), an alkoxycarbonyl- group or an arylalkyl- group. Non limiting examples of alkyl groups containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, the n-isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl, tert-pentyl, 2,3,4-trimethylhexyl, and isodecyl.

Unsaturated alkyl groups are, for example, alkenyl groups such as vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, or 1,3-pentadienyl, or alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl (=propargyl), or 2-butynyl. Alkyl groups can also be unsaturated when they are substituted.

Non-limiting examples of cyclic alkyl groups are cycloalkyl groups containing 3, 4, 5, 6, 7, or 8 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, which can also be substituted and/or unsaturated. Unsaturated cyclic alkyl groups and unsaturated cycloalkyl groups such as, for example, cyclopentenyl or cyclohexenyl, can be bonded via any carbon atom. The term alkyl as used herein also comprises cycloalkyl-substituted alkyl groups such as cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cycloheptylmethyl-, 1-cyclopropylethyl-, 1-cyclobutylethyl-, 1-cyclopentylethyl-, 1-cyclohexylethyl-, 2-cyclopropylethyl-, 2-cyclobutylethyl-, 2-cyclopentylethyl-, 2-cyclohexylethyl-, 3-cyclopropylpropyl-, 3-cyclobutylpropyl-, 3-cyclopentylpropyl-, and others, in which groups the cycloalkyl subgroup as well as acyclic subgroup can be unsaturated and/or substituted.

Of course, a cyclic alkyl group has to contain at least three carbon atoms, and an unsaturated alkyl group has to contain at least two carbon atoms. Thus, a group like (C.sub.1 -C.sub.8)-alkyl is to be understood as comprising, among others, saturated acyclic (C.sub.1 -C.sub.8)-alkyl, (C.sub.3 -C.sub.8)-cycloalkyl, cycloalkyl-alkyl- groups like (C.sub.3 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.3)-alkyl- wherein the total number of carbon atoms can range from 4 to 8, and unsaturated (C.sub.2 -C.sub.8)-alkyl like (C.sub.2 -C.sub.8)-alkenyl or (C.sub.2 -C.sub.8)-alkynyl. Similarly, a group like (C.sub.1 -C.sub.4)-alkyl is to be understood as comprising, among others, saturated acyclic (C.sub.1 -C.sub.4)-alkyl, (C.sub.3 -C.sub.4)-cycloalkyl, cyclopropyl-methyl- and unsaturated (C.sub.2 -C.sub.4 -alkyl like (C.sub.2 -C.sub.4)-alkenyl or (C.sub.2 -C.sub.4)-alkynyl.

Unless stated otherwise, in one embodiment of the invention the term alkyl comprises acyclic saturated hydrocarbon residues which have from one to six carbon atoms and which can be linear or branched. A particular group of saturated acyclic alkyl groups is formed by (C.sub.1 -C.sub.4)-alkyl groups like methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The above statements relating to alkyl groups do not only apply to monovalent residues but correspondingly to divalent and polyvalent residues like alkanediyl groups, alkylene groups or polymethylene groups, some examples of which are methylene, 1,2-ethylene (=ethane-1,2-diyl), 1,1-ethylene (=1-methyl-methylene), 1-isobutyl-methylene, 1,3-propylene, 2,2-dimethyl-1,3-propylene, 1,4-butylene, but-2-en-1,4-diyl, 1,2-cyclopropylene, 1,2-cyclohexylene, 1,3-cyclohexylene, and 1,4-cyclohexylene.

Examples of (C.sub.1 -C.sub.4)-alkoxy-(C.sub.2 -C.sub.4)-alkoxy- groups are 2-methoxyethoxy-, 2-ethoxyethoxy-, 2-isopropoxyethoxy-, 3-methoxypropoxy-, and 4-ethoxybutoxy-.

The term aryl refers to a monocyclic or polycyclic hydrocarbon residue in which residue at least one carbocyclic ring is present which has a conjugated pi electron system, i.e., which is an aromatic ring, and which residue is attached via a carbon atom contained in a ring which has a conjugated pi electron system. In a (C.sub.6 -C.sub.14)-aryl group from 6 to 14 ring carbon atoms are present. Examples of (C.sub.6 -C.sub.14)-aryl groups are phenyl, naphthyl, biphenylyl, fluorenyl, anthracenyl, indenyl, indanyl, 1,2,3,4-tetrahydronaphthyl or 2,3,4,5-tetrahydro-1H-benzocycloheptenyl. Examples of (C.sub.6 -C.sub.10)-aryl groups are phenyl, naphthyl, indenyl, indanyl or 1,2,3,4-tetrahydronaphthyl. Unless stated otherwise, and irrespective of any specific substituents bonded to aryl groups which are indicated in the definition of the compounds of the formula I, aryl groups, for example phenyl, naphthyl or fluorenyl, can in general be unsubstituted or substituted by one or more, for example one, two, three, or four, identical or different substituents, for example by the substituents listed below.

Aryl groups can be bonded via any desired position in an aromatic ring. In substituted aryl groups the substituents can be located in any desired position. In monosubstituted phenyl groups the substituent can be located in the 2-position, the 3-position or the 4-position, such as in the 3-position or the 4-position. If a phenyl group carries two substituents, they can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenyl groups carrying three substituents the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position, or 3,4,5-position. Naphthyl groups can be 1-naphthyl (=naphthalen-1-yl) and 2-naphthyl (=naphthalen-2-yl). In substituted naphthyl groups the substituents can be located in any positions, for example in monosubstituted 1-naphthyl groups in the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position and in monosubstituted 2-naphthyl groups in the 1-, 3-, 4-, 5-, 6-, 7-, or 8-position. 1,2,3,4-Tetrahydronaphthyl, when attached via a carbon atom in the aromatic ring and comprised by the term aryl, can be 1,2,3,4-tetrahydronaphthalen-5-yl or 1,2,3,4-tetrahydronaphthalen-6-yl. Biphenylyl groups can be biphenyl-2-yl, biphenyl-3-yl or biphenyl-4-yl. Fluorenyl groups, when comprised by the term aryl, can be bonded via the 1-, 2-, 3-, or 4-position, otherwise via the 1-, 2-, 3-, 4-, or 9-position. In one embodiment of the invention, in monosubstituted fluorenyl groups bonded via the 9-position, the substituent can be present in the 1-, 2-, 3-, or 4-position.

The above statements relating to aryl groups correspondingly apply to divalent and polyvalent groups derived from aryl groups, e.g. to arylene groups like phenylene which can be unsubstituted or substituted 1,2-phenylene, 1,3-phenylene or 1,4-phenylene, or naphthylene which can be unsubstituted or substituted 1,2-naphthalenediyl, 1,3-naphthalenediyl, 1,4-naphthalenediyl, 1,5-naphthalenediyl, 1,6-naphthalenediyl, 1,7-naphthalenediyl, 1,8-naphthalenediyl, 2,3-naphthalenediyl, 2,6-naphthalenediyl, or 2,7-naphthalenediyl. The above statements also correspondingly apply to the aryl subgroup in arylalkyl- groups. Examples of arylalkyl- groups, which can also be unsubstituted or substituted in the aryl subgroup as well as in the alkyl subgroup, are benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 4-phenylbutyl, 1-methyl-3-phenyl-propyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, and 9-fluorenylmethyl. All the above explanations also apply to aromatic rings which may be condensed (or fused) to a ring formed by the groups R.sup.4 and R.sup.5 and the carbon atom to which these groups are attached.

The Het group comprises groups containing 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms in the parent monocyclic or bicyclic heterocyclic ring system. In monocyclic Het groups the heterocyclic ring may comprise a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered ring, such as a 5-membered or 6-membered ring. In bicyclic Het groups two fused rings may be present, one of which is a 5-membered ring or 6-membered heterocyclic ring and the other of which is a 5-membered or 6-membered heterocyclic or carbocyclic ring. For example, a bicyclic ring Het may contain 8, 9 or 10 ring atoms, for example, 9 or 10 ring atoms.

Het comprises saturated heterocyclic ring systems which do not contain any double bonds within the rings, as well as unsaturated heterocyclic ring systems including mono-unsaturated and poly-unsaturated heterocyclic ring systems which contain one or more, for example one, two, three, four, or five, double bonds within the rings provided that the resulting system is stable. Unsaturated rings may be partially unsaturated or non-aromatic, or they may be aromatic and thus may contain double bonds arranged in such a manner that a conjugated pi electron system results. Aromatic rings in a Het group may be 5-membered or 6-membered rings. For example, aromatic groups in a Het group contain 5 to 10 ring atoms. Aromatic rings in a Het group thus comprise 5-membered and 6-membered monocyclic heterocycles and bicyclic heterocycles composed of two 5-membered rings, one 5-membered ring and one 6-membered ring, or two 6-membered rings. In bicyclic aromatic groups in a Het group one or both rings may contain heteroatoms. Aromatic Het groups may also be referred to by the customary term heteroaryl for which all the definitions and explanations above and below relating to Het correspondingly apply. These explanations relating to the saturation/unsaturation in heterocyclic ring systems representing the Het group corresponding apply to any other heterocyclic ring system that can be present in a compound of the formula I, for example to a ring formed by R.sup.4 and R.sup.5 together with the carbon atom to which these groups are bonded, and the ring systems that may be condensed to this ring.

In a Het group and any other heterocyclic group, for example, 1 or 2 identical or different ring heteroatoms selected from nitrogen, oxygen and sulfur atoms may be present. In general, the ring heteroatoms can be present in any desired combination and in any desired positions with respect to each other provided that the resulting heterocyclic system is known in the art and is stable and suitable as a subgroup in a drug substance. Examples of parent structures of heterocycles from which the Het group any other heterocyclic groups can be derived are aziridine, oxirane, azetidine, pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine, 1,4-dioxine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, indole, isoindole, benzofuran, benzothiophene, 1,3-benzodioxole, benzo[1,4]dioxine, 4H-benzo[1,4]oxazine, indazole, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, chromane, isochromane, cinnoline, quinazoline, quinoxaline, phthalazine, pyridoimidazoles, pyridopyridines, and pyridopyrimidines, and others, as well as ring systems which result from the listed heterocycles by fusion (or condensation) of a carbocyclic ring, for example benzo-fused, cyclopenta-fused, cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles.

The fact that many of the before-listed names of heterocycles are the chemical names of unsaturated or aromatic ring systems does not imply that the Het groups and other heterocyclic groups could only be derived from the respective unsaturated ring system. The names here only serve to describe the ring system with respect to ring size and the number of the heteroatoms and their relative positions. As explained above, for example a Het group can be saturated or partially unsaturated or aromatic, and can thus be derived not only from the before-listed heterocycles themselves but also from all of their partially or completely hydrogenated analogues as well as from their more highly unsaturated analogues, if applicable. As examples of completely or partially hydrogenated analogues of the before-listed heterocycles from which a Het group and any other heterocyclic group may be derived the following may be mentioned: pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane, 2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazole, 1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxine (=1,4-dioxane), piperazine, perhydro-1,4-oxazine (=morpholine), 2,3-dihydrobenzo[1,4]dioxine (=1,4-benzodioxane), 3,4-dihydro-2H-benzo[1,4]oxazine, perhydro-1,4-thiazine (=thiomorpholine), perhydroazepine, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline, and others.

The Het group and any other heterocyclic group may be bonded via any ring carbon atom, and in the case of nitrogen heterocycles via any suitable ring nitrogen atom, if applicable. Thus, for example, a pyrrolyl group can be pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl, a pyrrolidinyl group can be pyrrolidin-1-yl (=pyrrolidino), pyrrolidin-2-yl or pyrrolidin-3-yl, a pyridinyl group can be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, a piperidinyl group can be piperidin-1-yl (=piperidino), piperidin-2-yl, piperidin-3-yl or piperidin-3-yl. Furyl can be furan-2-yl or fur-3-yl, thienyl can be thiophen-2-yl or thiophen-3-yl, imidazolyl can be imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl, 1,3-oxazolyl can be 1,3-oxazol-2-yl, 1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl can be 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, or 1,3-thiazol-5-yl, pyrimidinyl can be pyrimidin-2-yl, pyrimidin-4-yl (=pyrimidin-6-yl) or pyrimidin-5-yl, piperazinyl can be piperazin-1-yl (=piperazin-4-yl=piperazino) or piperazin-2-yl. Indolyl can be indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, or indol-7-yl. Similarly benzimidazolyl, benzoxazolyl and benzothiazolyl groups can be bonded via the 2-position and via any of the positions 4, 5, 6, and 7, and in the case of benzimidazolyl, also via the 1-position. Quinolinyl can be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, or quinolin-8-yl, isoqinolinyl can be isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, or isoquinolin-8-yl. In addition to being bonded via any of the positions indicated for quinolinyl and isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl can also be bonded via the nitrogen atoms in 1-position and 2-position, respectively.

Unless stated otherwise, and irrespective of any specific substituents in aryl groups, Het groups or any other heterocyclic groups which are indicated in the definition of the compounds of the formula I, aryl groups, Het groups and other heterocyclic groups can be unsubstituted or substituted on ring carbon atoms with one or more, for example one, two, three, four or five, identical or different substituents like (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, halogen, nitro, amino, (C.sub.1 -C.sub.4)-alkylamino, di-((C.sub.1 -C.sub.4)-alkyl)amino, ((C.sub.1 -C.sub.4)-alkyl)carbonylamino such as, for example, acetylamino, trifluoromethyl, trifluoromethoxy, hydroxy, oxo, hydroxymethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, methylsulfonyl, optionally substituted phenyl, optionally substituted phenoxy, benzyl optionally substituted in the phenyl group, benzyloxy optionally substituted in the phenyl group, and others. The substituents can be present in any desired position provided that a stable molecule results. An oxo substituent (.dbd.O) can of course not be present in an aromatic ring, but can be present if the Het group or any other heterocyclic or carbocyclic group is saturated or partially unsaturated. Examples of oxo-substituted heterocyclic groups are 4H-benzo[1,4]oxazin-3-one, 3H-isobenzofuran-1-one, benzo[1,4]dioxin-2-one, chroman-2-one, and others. Examples of the group Het-oxy-, i.e. the group Het-O--, are pyridinyloxy including pyridin-3-yloxy and pyridin4-yloxy, pyrimidinyloxy including pyrimidin-2-yloxy, piperidinyloxy including piperidin-3-yloxy and piperidin-4-yloxy, and pyrrolidin-3-yloxy. In some embodiments of the invention, not more than two nitro groups are present in the compounds of the formula I.

Further, unless stated otherwise, and irrespective of any specific substituents in Het groups or any other heterocyclic groups which are indicated in the definition of the compounds of the formula I, Het groups and other heterocyclic groups can on each suitable ring nitrogen atom independently of one another be unsubstituted, i.e. carry a hydrogen atom, or be substituted, for example, by (C.sub.1 -C.sub.8)-alkyl, for example (C.sub.1 -C.sub.4)-alkyl such as methyl or ethyl, optionally substituted phenyl, phenyl-(C.sub.1 -C.sub.4)-alkyl-, for example benzyl, optionally substituted in the phenyl group, hydroxy-(C.sub.2 -C.sub.4)-alkyl- such as, for example 2-hydroxyethyl, acetyl or another acyl group, methylsulfonyl or another sulfonyl group, etc. Another group that may occur as a substituent on a suitable ring nitrogen atom is the acetimino group CH.sub.3 --C(.dbd.NH)--. Suitable nitrogen heterocycles can also be present as N-oxides or as quaternary salts. Ring sulfur atoms can be oxidized to the sulfoxide or to the sulfone. Thus, for example, a tetrahydrothienyl residue may be present as S,S-dioxotetrahydrothienyl residue or a thiomorpholinyl residue like thiomorpholin-4-yl may be present as 1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl.

The explanations relating to the Het group correspondingly apply to divalent and polyvalent Het groups including divalent and polyvalent heteroaromatic groups which may be bonded via any ring carbon atoms and in the case of nitrogen heterocycles via any carbon atoms and any suitable ring nitrogen atoms or via any suitable ring nitrogen atoms. For example, a pyridinediyl group can be pyridin-2,3-diyl, pyridin-2,4-diyl, pyridin-2,5-diyl, pyridin-2,6-diyl, pyridin-3,4-diyl, or pyridin-3,5-diyl, a piperidinediyl group can be, among others, piperidin-1,2-diyl, piperidin-1,3-diyl, piperidin-1,4-diyl, piperidin-2,3-diyl, piperidin-2,4-diyl, or piperidin-3,5-diyl, a piperazinediyl group can be, among others, piperazin-1,3-diyl, piperazin-1,4-diyl, piperazin-2,3-diyl, piperazin-2,5-diyl, and others. The above statements also correspondingly apply to the Het subgroup in the groups Het-alkyl-. Examples of such groups Het-alkyl- which can also be unsubstituted or substituted in the Het subgroup as well as in the alkyl subgroup, are (pyridin-2-yl)-methyl, (pyridin-3-yl)-methyl, (pyridin-4-yl)-methyl, 2-(pyridin-2-yl)-ethyl, 2-(pyridin-3-yl)-ethyl, and 2-(pyridin-4-yl)-ethyl.

Halogen is fluorine, chlorine, bromine or iodine, in some embodiments being fluorine, chlorine or bromine.

Optically active carbon atoms present in the compounds of the formula I can independently of each other have R configuration or S configuration. The compounds of the formula I can be present in the form of pure enantiomers or pure diastereomers or in the form of mixtures of enantiomers and/or diastereomers, for example in the form of racemates. The present invention relates to pure enantiomers and mixtures of enantiomers as well as to pure diastereomers and mixtures of diastereomers. The invention comprises mixtures of two or of more than two stereoisomers of the formula I, and it comprises all ratios of the stereoisomers in the mixtures. In case the compounds of the formula I can be present as E isomers or Z isomers (or cis isomers or trans isomers) the invention relates both to pure E isomers and pure Z isomers and to E/Z mixtures in all ratios. The invention also comprises all tautomeric forms of the compounds of the formula I, for example the form in which instead of the group R.sup.1 --NH--C(.dbd.NH)-- depicted in formula I the tautomeric group R.sup.1 --N.dbd.C(--NH.sub.2)-- is present.

Diastereomers, including E/Z isomers, can be separated into the individual isomers, for example, by chromatography. Racemates can be separated into the two enantiomers by customary methods, for example by chromatography on chiral phases or by resolution, for example by crystallization of diastereomeric salts obtained with optically active acids or bases. Stereochemically uniform compounds of the formula I can also be obtained by employing stereochemically uniform starting materials or by using stereoselective reactions.

The choice of incorporating into a compound of the formula I a building block with R configuration or S configuration, or in the case of an amino acid unit present in a compound of the formula I of incorporating a building block designated as D-amino acid or L-amino acid, can depend, for example, on the desired characteristics of the compound of the formula I. For example, the incorporation of a D-amino acid building block can confer increased stability in vitro or in vivo. The incorporation of a D-amino acid building block also can achieve a desired increase or decrease in the pharmacological activity of the compound. In some cases it can be desirable to allow the compound to remain active for only a short period of time. In such cases, the incorporation of an L-amino acid building block into the compound can allow endogenous peptidases in an individual to digest the compound in vivo, thereby limiting the individual's exposure to the active compound. A similar effect may also be observed in the compounds of the invention by changing the configuration in another building block from S configuration to R configuration or vice versa. By taking into consideration the medical needs one skilled in the art can determine the desirable characteristics, for example a favorable stereochemistry, of the required compound of the invention.

Physiologically tolerable salts of the compounds of formula I are nontoxic salts that are physiologically acceptable, such as pharmaceutically utilizable salts. Such salts of compounds of the formula I containing acidic groups, for example a carboxy group COOH, are, for example, alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions such as tetramethylammonium or tetraethylammonium, and acid addition salts with ammonia and physiologically tolerable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine. Basic groups contained in the compounds of the formula I, for example amino groups or amidino groups, form acid addition salts, for example with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. The present invention also includes acid addition salts of compounds of the formula I which contain, for example, two basic groups with one acid equivalent or with two acid equivalents.

Salts of compounds of the formula I can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the formula I with an inorganic or organic acid or base in a solvent or diluent, or from other salts by cation exchange or anion exchange. The present invention also includes all salts of the compounds of the formula I which, because of low physiological tolerability, are not directly suitable for use in pharmaceuticals but are suitable, for example, as intermediates for carrying out further chemical modifications of the compounds of the formula I or as starting materials for the preparation of physiologically tolerable salts.

The anions of the mentioned acids that may be present in acid addition salts of the compounds of the formula I, are also examples of anions that may be present in the compounds of the formula I if they contain one or more positively charged groups like trialkylammonio-substituents, i.e. groups of the formula (alkyl).sub.3 N.sup.+ bonded via the positively charged nitrogen atom, which groups may represent R.sup.10, or quaternized ring nitrogen atoms in heterocyclic groups. In general a compound of the formula I contains one or more physiologically tolerable anions or anion equivalents as counterions if it contains one or more permanently positively charged groups like trialkylammonio. Compounds of the formula I which simultaneously contain a basic group or a positively charged group and an acidic group, for example an amidino group and a carboxy group, can also be present as zwitterions (or betaines or inner salts) which are likewise included in the present invention.

The present invention furthermore includes all solvates of compounds of the formula I, for example hydrates or adducts with alcohols. The invention also includes derivatives and modifications of the compounds of the formula I, for example protected forms, prodrugs, i.e. compounds which in vitro do not necessarily exhibit pharmacological activity but which in vivo are converted into active compounds, and other physiologically tolerable derivatives including esters and amides of acid groups, as well as active metabolites of the compounds of the formula I.

The structural elements in the compounds of formula I have the following example denotations which they can have independently of the denotations of other elements.

The number m, i.e. the number of halogen atoms that are present as substituents on the phenylene group depicted in formula I, in some embodiments can be 0, 1 or 2, such as 0 or 1, or 0. Those positions of the phenylene group depicted in formula I which do not carry a substituent A carry hydrogen atoms. Thus, if m is zero and accordingly no substituent A is present, said phenylene group carries four hydrogen atoms. If 1, 2, 3, or 4 substituents A are present, said phenylene group carries 3, 2, 1, or 0 hydrogen atoms, respectively.

The number n, i.e. the number of the CH.sub.2 groups in the polymethylene chain connecting the nitrogen of the amido group C(.dbd.O)--NH depicted in formula I and the group --CR.sup.3 R.sup.4 R.sup.5, is 0 or 1 in some embodiments, for example, 0. Thus, the group --(CH.sub.2).sub.n -- in some embodiments can be a direct bond or the group --CH.sub.2 --. For example, the group --(CH.sub.2).sub.n -- can be a direct bond, i.e. the nitrogen atom of the amido group --C(.dbd.O)--NH-- is directly bonded to the --CR.sup.3 R.sup.4 R.sup.5 group.

The substituents A, which in general can be identical or different, are, in some embodiments, selected from fluorine, chlorine and bromine, such as from fluorine and chlorine. As outlined above with respect to aryl groups and phenyl groups in general, the substituents A can be present in any desired position on the phenyl ring to which they are bonded. If only one substituent A is present, it can be located in the 2-position or in the 3-position with respect to the (thio)urea group, if two substituents A are present, they can be located in the 2,3-position, 2,5-position, 2,6-position and 3,5-position with respect to the (thio)urea group.

In some embodiments of the invention, X can be oxygen.

R.sup.1 can be hydrogen, hydroxy or (C.sub.1 -C.sub.12)-alkoxycarbonyl- in some embodiments. In other embodiments it can be hydrogen, hydroxy or (C.sub.1 -C.sub.4)-alkoxycarbonyl-, such as hydrogen or hydroxy, and such as hydrogen.

If an aryl group present in a group R.sup.1 is substituted by one or more identical or different substituents selected from (C.sub.1 -C.sub.12)-alkyl, halogen and (C.sub.1 -C.sub.12)-alkoxy, it can be substituted by 1, 2 or 3, such as by 1 or 2, identical or different substituents, for example by one substituent. An alkyl group or alkoxy group present in a substituent in a group R.sup.1 can be a (C.sub.1 -C.sub.4)-alkyl group or (C.sub.1 -C.sub.4)-alkoxy group, respectively.

In some embodiments of the invention, R.sup.2 can be selected from hydrogen, (C.sub.1 -C.sub.12)-alkyl, (C.sub.6 -C.sub.14)-aryl, and (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl-, such as from hydrogen, (C.sub.1 -C.sub.8)-alkyl, (C.sub.6 -C.sub.10)-aryl and (C.sub.6 -C.sub.10)-aryl-(C.sub.1 -C.sub.4)-alkyl-. In other embodiments R.sup.2 is hydrogen.

In some embodiments, R.sup.3 can be hydrogen.

If a group R.sup.4 or R.sup.5 or a cyclic group formed by R.sup.4 and R.sup.5 together with the carbon atom to which they are bonded is substituted by one or more substituents R.sup.10, it may carry, for example, 1, 2, 3, 4, or