Peptide derivatives Number:7,001,887 from the United States Patent and Trademark Office (PTO) owispatent

Title: Peptide derivatives

Abstract: A compound of Formula (1):
##STR1##
 
wherein

R₁ represents an amidinophenyl group, etc.;

R₂ represents a hydrogen atom, etc.;

R₃ represents a carbamoylalkyl group, etc.;

R₄ represents a hydrogen atom, etc.;

R₅ represents a benzyl group, etc.;

R₆ represents a hydrogen atom, etc.; and

R₇ represents an alkylsulfonyl group, etc.

A crystal of a complex between factor VIIa/human soluble tissue factor and a low-molecular weight reversible factor VIIa inhibitor. A medium carrying a part or all of structure coordinate data of a complex between human factor VIIa/human soluble tissue factor and a low-molecular weight reversible factor VIIa inhibitor, obtainable by X-ray crystal structure analysis of the crystal. A method for computationally designing a low-molecular weight reversible factor VIIa inhibitor using the coordinate data.

Patent Number: 7,001,887 Issued on 02/21/2006 to Shiraishi,   et al.

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Inventors:	Shiraishi; Takuya (Shizuoka, JP); Kadono; Shojiro (Shizuoka, JP); Haramura; Masayuki (Shizuoka, JP); Sato; Haruhiko (Shizuoka, JP); Kozono; Toshiro (Shizuoka, JP); Koga; Takaki (Shizuoka, JP); Sakamoto; Akihisa (Shizuoka, JP)
Assignee:	Chugai Seiyaku Kabushiki Kaisha (Tokyo, JP)
Appl. No.:	470801
Filed:	February 4, 2002
PCT Filed:	February 4, 2002
PCT NO:	PCT/JP02/00883
371 Date:	August 1, 2003
102(e) Date:	August 1, 2003
PCT PUB.NO.:	WO02/062829
PCT PUB. Date:	August 15, 2002

Foreign Application Priority Data

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Feb 02, 2001[JP]

2001-027474

Current U.S. Class:	514/19; 514/18; 514/258.1; 514/277; 514/311; 514/314; 514/345; 514/395; 530/331; 544/283; 546/113; 546/134; 546/250; 548/305.1
Current Intern'l Class:	C07K 5/06     (20060101); C07D 213/02   (20060101); C07D 235/04   (20060101); C07D 239/86   (20060101); C07D 401/04   (20060101)
Field of Search:	514/18,19,258.1,277,311,314,395 530/331 544/283 546/113,134,250 548/305.1

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References Cited [Referenced By]

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U.S. Patent Documents

5744487	Apr., 1998	Ohshima et al.
6287794	Sep., 2001	Safar et al.
6358960	Mar., 2002	Senokuchi et al.
6365617	Apr., 2002	McComsey et al.
6472393	Oct., 2002	Aliagas-Martin et al.
6586405	Jul., 2003	Semple et al.
Foreign Patent Documents
0669317	Aug., 1995	EP.
0921116	Jun., 1999	EP.
1078917	Feb., 2001	EP.
2791683	Oct., 2000	FR.
WO 00/1565/8	Mar., 2000	WO.
WO 00/3064/6	Jun., 2000	WO.
WO 00/3588/6	Jun., 2000	WO.
WO 00/4153/1	Jul., 2000	WO.
WO 00/5834/6	Oct., 2000	WO.

Other References

Banner, et al. The Crystal Structure of the Complex of Blood Coagulation factor VIIa with Soluble Tissue Factor Nature, vol. 380, No. 7 (Mar. 1996), pp. 41-46. Banner, David. The Factor VIIa/Tissue Factor Complex, Thrombosis and Haemostasis, vol. 78, No. 1, (1997), pp. 512-515. Böhm, Hans-Joachim. LUDI: Rule-Based Automatic Design of New Substituents for Enzyme Inhibitor Leads, Journal of Computer-Aided Molecular Design, vol. 6, (1992), pp. 593-606. Dennis, et al. Peptide Exosite Inhibitors of Factor VIIa as Anticoagulants, Nature, vol. 404, (Mar. 2000), pp. 465-470. Johnson, et al. Crystallization and Preliminary X-Ray Analysis of Active Site-Inhibited Human Coagulation Factor VIIa (des-GIa), Journal of Structural Biology, vol. 125, (1999), pp. 90-93. Kemball-Cook, et al. Crystal Structure of Active Site-Inhibited Human Coagulation Factor VIIa (des-GIa), Journal of Structural Biology, vol. 127, (1999), pp. 213-223. Kirchhofer, et al. Activation of Blood Coagulation Factor VIIa with Cleaved Tissue Factor Extracellular Domain and Crystallization of the Active Complex, PROTEINS, vol. 22, (1995), pp. 419-425. MacKerell Jr. et al. "CHARMM: The Energy Function and its Parameterization." in Encyclopedia of Computational Chemistry. (1998), vol. 1 A-D., pp. 271-277. ISBN: 047196588x.w.set. Pike, et al. Structure of Human Factor VIIa and its Implications for the Triggering of Blood Coagulation, Proc. Natl. Acad. Sci. USA, vol. 96, (Aug. 1999), pp. 8925-8930. Zhang, et al. Structure of Extracellular Tissue Factor Complexed with Factor VIIa Inhibited with a BPTI Mutant, J. Mol. Biol., vol. 285, (1999), pp. 2089-2104.

Primary Examiner: McKane; Joseph K.
Assistant Examiner: Lee; Susannah E.
Attorney, Agent or Firm: Browdy and Neimark, P.L.L.C.

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Claims

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What is claimed is:

1. A compound of Formula (1): ##STR706##

 

wherein

R₁ represents a group selected from the following formulae: ##STR707##

 

wherein R₈ represents an amino group, an aminomethyl group or ##STR708##

 

(wherein R₉ represents a hydrogen atom, an amino group, a hydroxy group, an acyl group or an alkoxycarbonyl group having an optionally substituted linear or branched C₁-C₆ alkyl as its alkyl moiety, R₁₀ represents an amino group, one of X and Y represents ═CH— and the other represents ═N—);

R₂ represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group;

R₃ represents: ##STR709##

 

or

—(CH₂)_m—R₁₁


wherein m represents an integer of 1 to 6, and R₁₁ represents: ##STR710##

 

(wherein R₁₂ represents a hydrogen atom or a linear or branched C₁-C₃ alkyl group) or ##STR711##

 

R₄ represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group;

R₅ represents a linear or branched C₁-C₆ alkyl group or —CH₂—R₁₃ (wherein R₁₃ represents an optionally substituted aryl group or an optionally substituted heterocyclic group);

R₆ represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group; and

R₇ represents an optionally substituted linear or branched C₁-C₆ alkyl group or —SO₂—R₁₄ (wherein R₁₄ represents an optionally substituted linear or branched C₁-C₈ alkyl group)

or a tautomer or enantiomer of the compound, or a hydrate or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein R₅ in Formula (1) is a linear or branched C₁-C₆ alkyl group or —CH₂—R₁₃, in which R₁₃ represents a group selected from the following formulae: ##STR712##

 

wherein

R₁₅ represents a hydrogen atom, an optionally substituted aryl group, a C₁-C₃ alkyl group which may be substituted with a halogen atom, a linear or branched C₁-C₃ alkoxy group, a halogen atom, an arylcarbonyl group, an alkylcarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety, a nitro group, or an amino group;

R₁₆ represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group;

R₁₇ represents a hydrogen atom, a hydroxy group, a linear or branched C₁-C₆ alkyl group, a linear or branched C₁-C₆ alkoxy group, —O—(CH₂)_n—OH (wherein n represents an integer of 1 to 5), —O—(CH₂)_p—COOH (wherein p represents an integer of 1 to 5), —O—(CH₂)_q—NH₂ (wherein q represents an integer of 1 to 5), ##STR713##

 

(wherein R₁₉ represents a hydrogen atom, a hydroxy group, a carboxyl group, a linear or branched C₁-C₆ alkyl group, a halogen atom, a linear or branched C₁-C₆ alkoxy group, or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety), or —OSO₂—R₂₀ (wherein R₂₀ represents a linear or branched C₁-C₆ alkyl group or a benzyl group); and

R₁₈ represents a hydrogen atom, a linear or branched C₁-C₆ alkyl group, a linear or branched C₁-C₆ alkylsulfonyl group, or an optionally substituted arylsulfonyl group.

3. The compound according to claim 1, wherein R₇ in Formula (1) is a linear or branched C₁-C₆ alkyl substituted linear alkyl group or a group of the following formula: ##STR714##

 

wherein k represents an integer of 0 to 3, and R₂₁ represents a hydrogen atom or —NHR₂₂ (wherein R₂₂ represents a linear or branched C₁-C₃ alkyl group or an alkylcarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety) or

—SO₂—R₁₄


wherein R₁₄ represents:

(i) an optionally substituted linear or branched C₁-C₆ alkyl group (wherein said alkyl group may be substituted with a carboxyl group or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety); or

(ii) —CH₂—R₂₃ (wherein R₂₃ represents an optionally substituted phenyl group).

4. The compound according to claim 1, wherein R₃ in Formula (1) is a group of the following formula: ##STR715##

 

or

—(CH₂)_m—R₁₁


wherein m represents an integer of 1 to 3, and R₁₁ represents:

—CONH₂,
##STR716##

 

(wherein R₁₂ represents a hydrogen atom or a methyl group) or ##STR717##

 

5. The compound according to claim 1, wherein R₁ in Formula (1) is a group selected from the following formulae: ##STR718##

 

wherein R₈ represents: ##STR719##

 

(wherein R₉ represents a hydrogen atom, an amino group, a hydroxy group, an acyl group, or an alkoxycarbonyl group having an optionally substituted linear or branched C₁-C₆ alkyl as its alkyl moiety).

6. The compound according to claim 1, wherein R₂ in Formula (1) is a hydrogen atom or a linear or branched C₁-C₃ alkyl group.

7. The compound according to claim 1, wherein R₄ in Formula (1) is a hydrogen atom or a linear or branched C₁-C₃ alkyl group.

8. The compound according to claim 1, wherein R₆ in Formula (1) is a hydrogen atom or a linear or branched C₁-C₃ alkyl group.

9. The compound according to claim 1).

10. The compound according to claim 1, wherein in Formula (1), R₃ is a group of the following formula: ##STR720##

 

and R₇ is —SO₂—R₁₄ (wherein R₁₄ is as defined in claim 1).

11. The compound according to claim 1, wherein in Formula (1),

R₁ is a group selected from the following formulae: ##STR721##

 

wherein R₈ represents: ##STR722##

 

(wherein R₉ represents a hydrogen atom, an amino group, a hydroxy group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, an isovaleryl group, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group or a benzyloxycarbonyl group);

R₂ is a hydrogen atom or a methyl group;

R₃ is a group of the following formula: ##STR723##

 

R₄ is a hydrogen atom or a methyl group;

R₅ is a linear or branched C₁-C₄ alkyl group or —CH₂—R₁₃ wherein R₁₃ represents a group selected from the following formulae: ##STR724##

 

(wherein

R₁₅ represents a hydrogen atom, a t-butyl group, a methoxy group, a bromine atom, a chlorine atom, a benzoyl group, or a phenyl group which may be substituted with a methoxy group or a trifluoromethyl group or a nitro group or an amino group;

R₁₇ represents a hydrogen atom, a hydroxy group, a methyl group, a linear or branched C₁-C₃ alkoxy group, —O—(CH₂)_n—OH (wherein n represents an integer of 1 to 3), —O—(CH₂)_p—COOH (wherein p represents an integer of 1 to 3), —O—(CH₂)_q—NH₂ (wherein q represents an integer of 1 to 3), —OSO₂—R₂₀ (wherein R₂₀ represents an ethyl group, an n-propyl group, an i-propyl group or a benzyl group), a benzyloxy group, a 3- or 4-hydroxybenzyloxy group, or a 3- or 4-carboxybenzyloxy group; and

R₁₈ represents a hydrogen atom, a methyl group, a methanesulfonyl group or a benzenesulfonyl group);

R₆ is a hydrogen atom or a methyl group; and

R₇ is a linear or branched C_l-C₄ alkyl group or a group of the following formula: ##STR725##

 

wherein k represents an integer of 0 to 2, and R₂₁ represents a hydrogen atom or —NHR₂₂ (wherein R₂₂ represents a methyl group or an acetyl group) or

—SO₂—R₁₄


wherein R₁₄ represents a benzyl group, a 2-, 3- or 4-carboxybenzyl group, or an optionally substituted linear or branched C₁-C₄ alkyl group (wherein said alkyl group may be substituted with a carboxyl group or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety).

12. The compound according to claim 1, which is selected from the following formulae: ##STR726## ##STR727## ##STR728##

 

13. A pharmaceutical composition comprising the compound according to claim 1.

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Description

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TECHNICAL FIELD

The present invention relates to peptide derivatives having an inhibitory activity against blood coagulation factor VIIa.

BACKGROUND ART

Blood coagulation is a host defense mechanism provoked in response to vascular injury and/or foreign stimulation. Blood coagulation involves 15 factors including 12 proteinaceous coagulation factors in plasma, along with calcium ion, tissue factor and phospholipid (platelet-derived). This reaction is mediated by a cascade mechanism, in which a series of protease activations occurs successively on the membrane of platelets aggregated at a site of injury or damaged endothelial cells.

The blood coagulation cascade is divided into intrinsic and extrinsic pathways. It is called extrinsic blood coagulation when it occurs with the aid of tissue factor present in tissues, while it is called intrinsic blood coagulation when it occurs without the aid of tissue factor.

Intrinsic blood coagulation is initiated by the contact of blood coagulation factor XII in plasma with the surface of a negatively-charged solid phase or the like. Upon adsorption onto the surface, factor XII is converted through limited hydrolysis into activated factor XII (XIIa), an active protease. In turn, factor XIIa causes the limited hydrolysis of factor XI into activated factor XI (XIa), an active protease. After such a cascade of protease activations, the final protease thrombin causes the limited hydrolysis of fibrinogen into fibrin, leading to the completion of blood coagulation. In downstream reactions after the activation of factor XI, a number of coagulation factors are assembled into complexes to facilitate coagulation factor localization at a site of hemostasis and to ensure efficient activation reactions. Namely, a tenase complex is assembled from phospholipids, factor VIIIa, factor IXa, factor X and Ca²⁺, while a prothrombinase complex is assembled from phospholipids, factor Va, factor Xa, prothrombin and Ca²⁺, resulting in significant promotion of prothrombin activation.

Extrinsic blood coagulation is initiated by the formation of a complex between factor VIIa and tissue factor. This complex between factor VIIa and tissue factor will join the intrinsic pathway at the stage of factor X and IX activation.

In general, extrinsic blood coagulation is reported to be important for hypercoagulation and physiological coagulation under pathological conditions.

Examples of known anticoagulants include a thrombin inhibitor such as heparin, as well as warfarin. However, since a thrombin inhibitor acts on downstream reactions of the blood coagulation cascade and hence cannot control the consumption of coagulation factors that lead to thrombin generation upon excess inhibition of coagulation, such a thrombin inhibitor involves a problem of hemorrhage tendency in clinical use. Likewise, warfarin inhibits the production of many blood coagulation factors and also involves a problem of hemorrhage tendency in clinical use, as in the case of a thrombin inhibitor.

As mentioned above, factor VIIa is located upstream in the extrinsic pathway and hence an inhibitor against factor VIIa will not affect the intrinsic coagulation pathway. That is, such an inhibitor will be able to leave the resistance against hemorrhage. This suggests that a factor VIIa inhibitor is expected to reduce the hemorrhage tendency, a side effect of existing anticoagulants. Thus, a factor VIIa inhibitor is expected to be effective in preventing or treating pathological conditions associated with the extrinsic coagulation pathway, e.g., chronic thrombosis (more specifically, postoperative deep vein thrombosis, post-PTCA restenosis, DIC (disseminated intravascular coagulation), cardioembolic strokes, cardiac infarction and cerebral infarction).

To date, some compounds have been reported as factor VIIa inhibitors (see, e.g., WO00/41531, WO00/35886, WO99/41231, EP921116A, WO00/15658, WO00/30646, WO00/58346).

However, all of these compounds are insufficient to have an inhibitory activity against factor VIIa or a selective inhibitory activity against extrinsic blood coagulation; there is a need to develop an agent having an improved inhibitory activity or an improved selective inhibitory activity.

Recent studies on enzyme inhibitors have tended to employ computational procedures, in which a three-dimensional enzyme model based on X-ray crystal structure analysis or the like is displayed on the screen of a computer to design a candidate compound which may have an inhibitory activity or to perform computer-aided virtual screening. Factor VIIa (hereinafter also referred to as "FVIIa") has also been studied by X-ray structure analysis to determine its three-dimensional structure in free form, in complex with soluble tissue factor (this complex being hereinafter also referred to as "factor VIIa/soluble tissue factor" or "FVIIa/sTF), and in complex with a protein inhibitor (Nature, 380, 41-46, 1996; J. Mol. Biol, 285, 2089-2104, 1999; Proc Natl Acad Sci USA., 96, 8925-8930; J Struct Biol., 127, 213-223, 1999; Nature, 404, 465-470, 2000).

However, computational virtual docking techniques result in inaccurate estimation at present (Guidebook on Molecular Modeling Drug Design, 129-133, 1996, ACADEMIC PRESS); on the other hand, an enzyme molecule frequently undergoes an inhibitor brinding-induced conformational change called induced fit (Guidebook on Molecular Modeling Drug Design, 133-134, 1996, ACADEMIC PRESS). For computer-aided design of inhibitors, it is therefore most desirable to perform X-ray structure analysis on each inhibitor or its structurally similar inhibitor in complex with an enzyme to clarify the details of the binding mode between inhibitor and enzyme at the atomic level. In all previously reported crystals containing factor VIIa, however, irreversible inhibitors or protein inhibitors occupy the active sites of factor VIIa, which may be used as inhibitor-binding sites. Such crystals cannot be used for X-ray crystal structure analysis of a complex between factor VIIa and a low-molecular weight reversible inhibitor (e.g., having a molecular weight less than 1000). Generally, protein crystallization usually requires high purity. A problem of protease cleavage often arises in purifying such high-purity proteins (Crystallization of Nucleic Acids and Proteins, A Practical Approach, 34, 1992, IRL PRESS). In particular, a problem of self-cleavage arises in purifying and crystallizing a protease such as factor VIIa. For this reason, an irreversible inhibitor is often used in purification and crystallization because once binding occurs, the irreversible inhibitor will not be released from the protease and allows complete prevention of self-cleavage during purification and crystallization. However, in the case of a complex with a low-molecular weight reversible inhibitor, it involves technical difficulties because there is no guarantee that self-cleavage is completely prevented during crystallization. Indeed, there has been no report showing the crystallization or three-dimensional structure of a complex between factor VIIa and a low-molecular weight reversible factor VIIa inhibitor.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a peptide derivative useful as a medicament, which has an inhibitory activity against blood coagulation factor VIIa or which has an excellent selective inhibitory effect on extrinsic blood coagulation.

Another object of the present invention is to provide a crystal which can be used for X-ray crystal analysis to clarify the three-dimensional structure of a complex between factor VIIa/soluble tissue factor and a low-molecular weight reversible factor VIIa inhibitor, as well as a method for preparing the crystal. Yet another object of the present invention is to provide a method for designing a novel low-molecular weight reversible factor VIIa inhibitor having an excellent specific or selective inhibitory activity for factor VIIa by using three-dimensional structure information of the complex crystal, as well as a low-molecular weight reversible factor VIIa inhibitor designed by the method.

As a result of extensive and intensive efforts, the inventors of the present invention found that a peptide derivative of Formula (1) had an inhibitory activity against factor VIIa or a selective inhibitory effect on extrinsic blood coagulation, which led to the completion of the invention.

Namely, the present invention provides a compound of Formula (1):
##STR2##
 
wherein

R₁ represents a group selected from the following formulae:
##STR3##
 
[wherein R₈ represents an amino group, an aminomethyl group or
##STR4##
 
(wherein R₉ represents a hydrogen atom, an amino group, a hydroxy group, an acyl group or an alkoxycarbonyl group having an optionally substituted linear or branched C₁-C₆ alkyl as its alkyl moiety, R₁₀ represents an amino group, one of X and Y represents ═CH— and the other represents ═N—)];

R₂ represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group;

R₃ represents:
##STR5##
 

—(CH₂)_m—R₁₁

[wherein m represents an integer of 1 to 6, and R₁₁ represents:

—CONH₂,

##STR6##
 
(wherein R₁₂ represents a hydrogen atom or a linear or branched C₁-C₃ alkyl group) or
##STR7##
 
R₄ represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group;

R₅ represents a linear or branched C₁-C₆ alkyl group or —CH₂—R₁₃ (wherein R₁₃ represents an optionally substituted aryl group or an optionally substituted heterocyclic group);

R₆ represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group; and

R₇ represents an optionally substituted linear or branched C₁-C₆ alkyl group or —SO₂—R₁₄ (wherein R₁₄ represents an optionally substituted linear or branched C₁-C₈ alkyl group)

or a tautomer or enantiomer of the compound, or a hydrate or pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition comprising a compound of Formula (1). Further, the present invention provides an antithrombotic agent comprising the compound. Furthermore, the present invention provides a blood coagulation factor VIIa inhibitor comprising the compound.

In addition, the present invention provides a crystal of a complex between human factor VIIa/human soluble tissue factor and a low-molecular weight reversible factor VIIa inhibitor. In one embodiment, the low-molecular weight reversible factor VIIa inhibitor is a compound of Formula (1) (wherein each symbol is as defined above).

Further, the present invention provides a method for preparing a crystal of a complex between human factor VIIa/human soluble tissue factor and a low-molecular weight reversible factor VIIa inhibitor, which comprises the following steps (i) to (iii):

(i) preparing human factor VIIa/human soluble tissue factor, which is co-crystallizable with the low-molecular weight reversible factor VIIa inhibitor;

(ii) preparing a concentrated sample for crystallization to add the low-molecular weight reversible factor VIIa inhibitor, and

(iii) obtaining the crystal of the complex between human factor VIIa/human soluble tissue factor and the low-molecular weight reversible factor VIIa inhibitor from the concentrated sample for crystallization prepared in (ii) to add a seed crystal of a complex between a low-molecular weight irreversible or reverdible factor VIIa inhibitor and human factor VIIa/human soluble tissue factor. In one embodiment, the low-molecular weight reversible factor VIIa inhibitor is a compound of Formula (1) (wherein each symbol is as defined above).

In addition, the present invention provides a medium carrying a part or all of structure coordinate data of a complex between human factor VIIa/human soluble tissue factor and a low-molecular weight reversible factor VIIa inhibitor, wherein said data are obtainable by performing X-ray crystal structure analysis on the above crystal prepared for the complex between human factor VIIa/human soluble tissue factor and the low-molecular weight reversible factor VIIa inhibitor.

Further, the present invention provides a method for computationally designing a low-molecular weight reversible factor VIIa inhibitor using the above coordinate data. In one embodiment, the low-molecular weight reversible factor VIIa inhibitor is designed to have a substituent capable of interacting with at least one of Asp60 side chain, Tyr94 side chain and Thr98 main chain of the human factor VIIa H chain. In another embodiment, the low-molecular weight reversible factor VIIa inhibitor is designed to have a substituent capable of interacting with Lys192 side chain of the human factor VIIa H chain. In yet another embodiment, the low-molecular weight reversible factor VIIa inhibitor is designed to have a substituent capable of interacting with at least one of Val170E, Gly170F, Asp170G, Ser170H, Pro170I and Gln217 of the human factor VIIa H chain. In yet another embodiment, the low-molecular weight reversible factor VIIa inhibitor is designed to have a substituent capable of interacting with the S4 subsite of the human factor VIIa H chain through a hole extending from the S4 site to the S4 subsite.

Furthermore, the present invention provides a low-molecular weight reversible factor VIIa inhibitor designed by the above method. In one embodiment, the low-molecular weight reversible factor VIIa inhibitor comprises any one of the partial structures shown in the following Class [A-1] or [A-2] as a partial structure capable of interacting with the S2 site of human factor VIIa:

Class [A-1]:

##STR8##

 

(wherein X₁ represents O or NH, and X₂ represents a hydrogen atom or a methyl group) or

Class [A-2]:

##STR9##

 

(wherein R₂₃ represents a 6 or 5-membered aromatic ring containing a heteroatom(s)).

In another embodiment, the low-molecular weight reversible factor VIIa inhibitor comprises any one of the partial structures shown in the following Class [B-1], [B-2], [B-3] or [B-4] as a partial structure capable of interacting with the S1 subsite of human factor VIIa:

Class [B-1]:

##STR10##

 

Class [B-2]:

##STR11##

 

Class [B-3]:

##STR12##

 

(wherein R₂₄ represents the same partial structures defined as Class [B-2], and R₂₅ represents a 6 or 5-membered aromatic ring containing a heteroatom(s)) or

Class [B-4]:

##STR13##

 

(wherein R₂₇ represents a C₁-C₃ alkylene group, R₂₄ represents the same partial structures defined as Class [B-2], and R₂₆ represents the same partial structures defined as Class [B-3]).

In yet another embodiment, the low-molecular weight reversible factor VIIa inhibitor comprises any one of the partial structures shown in the following Class [C-1] or [C-2] as a partial structure capable of interacting with the S4 site of human factor VIIa:

Class [C-1]:

##STR14##

 

(wherein X₃ represents O, NH or CH₂, and R₂₈ represents a 6 or 5-membered aromatic ring containing a heteroatom(s)) or

Class [C-2]:

##STR15##

 

(wherein X₄ represents NH, S or O, and X₅, X₆, X₇, X₈, X₉ and X₁₀ each independently represent N or CH).

In yet another embodiment, the low-molecular weight reversible factor VIIa inhibitor comprises any one of the partial structures shown in the above Class [A-1] or [A-2] as a partial structure capable of interacting with the S2 site of human factor VIIa, any one of the partial structures shown in the above Class [B-1], [B-2], [B-3] or [B-4] as a partial structure capable of interacting with the S1 subsite, and any one of the partial structures shown in the above Class [C-1] or [C-2] as a partial structure capable of interacting with the S4 site.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the three-dimensional conformation of the binding sites between human factor VIIa and Compound (1).

FIG. 2 shows a schematic view of the binding sites between human factor VIIa and Compound (1).

FIG. 3 shows the S4 site of human factor VIIa upon binding to D-Phe-Phe-Arg-cmk (left) or Compound (1) (right).

BEST MODE FOR CARRYING OUT THE INVENTION

In the definition of a compound of Formula (1), the following group defined as R₁:
##STR16##
 
preferably has the following formula:
##STR17##
wherein R₈ preferably represents the following formula:
##STR18##
 

Examples of the acyl group defined as R₉ in the formula for R₈:
##STR19##
 
include alkylcarbonyl groups such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a caproyl group and a phenylacetyl group; alkenylcarbonyl groups such as an acryloyl group, a propioloyl group, a methacryloyl group, a crotonoyl group and an isocrotonoyl group; and arylcarbonyl groups such as a benzoyl group. Preferred is an alkylcarbonyl group having a linear or branched C₁-C₆ alkyl as its alkyl moiety. Particularly preferred are an acetyl group, a propionyl group, a butyryl group, an isobutyryl group and an isovaleryl group.

The alkoxycarbonyl group having an optionally substituted linear or branched C₁-C₆ alkyl as its alkyl moiety, defined as R₉ in the formula for R₈:
##STR20##
 
is preferably an alkoxycarbonyl group having an optionally substituted linear or branched C₁-C₄ alkyl as its alkyl moiety (wherein examples of a substituent include a phenyl group). Particularly preferred are a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group and a benzyloxycarbonyl group.

In the present invention, when expressed as "optionally substituted" or when several substitutions are possible for a given group or moiety, it is meant that the group or moiety may be substituted with one or more substituents.

R₉ in the formula for R₈:
##STR21##
 
is preferably a hydrogen atom, an amino group, a hydroxy group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, an isovaleryl group, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group or a benzyloxycarbonyl group.

The following group defined as R₁:
##STR22##
 
preferably has the following formula:
##STR23##
 

The following group defined as R₁:
##STR24##
 
preferably has the following formula:
##STR25##
 

The following group defined as R₁:
##STR26##
 
preferably has the following formula:
##STR27##
 

The following group defined as R₁:
##STR28##
 
preferably has the following formula:
##STR29##
 

The following group defined as R₁:
##STR30##
 
preferably has the following formula:
##STR31##
 

The following group defined as R₁:
##STR32##
 
preferably has the following formula:
##STR33##
 

The linear or branched C₁-C₆ alkyl group defined as R₂ is preferably a linear or branched C₁-C₃ alkyl group, and particularly a methyl group.

The following group defined as R₃:
##STR34##
 
preferably has the following formula:
##STR35##
 
m in the group —(CH₂)_m—R₁₁ defined as R₃ is preferably an integer of 1 to 3, and particularly 2.

R₁₁ in the group —(CH₂)_m—R₁₁ defined as R₃ is preferably —CONH₂,
##STR36##
 
(wherein R₁₂ preferably represents a hydrogen atom or a linear or branched C₁-C₃ alkyl group, and particularly represents a methyl group).

The linear or branched C₁-C₆ alkyl group defined as R₄ is preferably a linear or branched C₁-C₃ alkyl group, and particularly a methyl group.

The linear or branched C₁-C₆ alkyl group defined as R₅ is preferably a linear or branched C₁-C₄ alkyl group.

The optionally substituted aryl group as R₁₃ in the group —CH₂—R₁₃ defined as R₅ is preferably a group of the following formula:
##STR37##
 
[wherein R₁₅ preferably represents a hydrogen atom, an optionally substituted aryl group (wherein examples of the aryl group include a phenyl group and a naphthyl group, with a phenyl group being preferred, and examples of a substituent include a linear or branched C₁-C₃ alkoxy group, a linear or branched C₁-C₃ alkyl group which may be substituted with a halogen atom, a nitro group and an amino group), a C₁-C₃ alkyl group which may be substituted with a halogen atom, a linear or branched C₁-C₃ alkoxy group, a halogen atom, an arylcarbonyl group (wherein examples of the aryl group include a phenyl group and a naphthyl group, with a phenyl group being preferred), an alkylcarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety, a nitro group, or an amino group, and particularly represents a hydrogen atom, a t-butyl group, a methoxy group, a bromine atom, a chlorine atom, a benzoyl group, or a phenyl group which may be substituted with a methoxy group or a trifluoromethyl group or a nitro group or an amino group] or
##STR38##
 
(wherein R₁₆ preferably represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group, and particularly represents a hydrogen atom).

The optionally substituted heterocyclic group as R₁₃ in the group —CH₂—R₁₃ defined as R₅ contains a 5- to 10-membered monocyclic or condensed ring having at least one nitrogen atom, oxygen atom and/or sulfur atom as a ring member. Examples include furan, thiophene, pyran, pyrrole, pyridine, indole, benzofuran, benzothiophene, benzopyran and benzothiopyran. Examples of a substituent on the optionally substituted heterocyclic group include those listed below for R₁₇ and R₁₈.

The optionally substituted heterocyclic group as R₁₃ in the group —CH₂—R₁₃ defined as R₅ is preferably a group of the following formula:
##STR39##
 
In the above formula, R₁₇ preferably represents a hydrogen atom, a hydroxy group, a linear or branched C₁-C₆ alkyl group, a linear or branched C₁-C₆ alkoxy group, —O—(CH₂)_n—OH (wherein n represents an integer of 1 to 5), —O—(CH₂)_p—COOH (wherein p represents an integer of 1 to 5), —O—(CH₂)_q—NH₂ (wherein q represents an integer of 1 to 5),
##STR40##
 
(wherein R₁₉ represents a hydrogen atom, a hydroxy group, a carboxyl group, a linear or branched C₁-C₆ alkyl group, a halogen atom, a linear or branched C₁-C₆ alkoxy group, or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety), or —OSO₂—R₂₀ (wherein R₂₀ represents a linear or branched C₁-C₆ alkyl group or a benzyl group).

Above all, R₁₇ is preferably a hydrogen atom, a hydroxy group, a methyl group, a linear or branched C₁-C₃ alkoxy group, —O—(CH₂)_n—OH (wherein n represents an integer of 1 to 3), —O—(CH₂)_p—COOH (wherein p represents an integer of 1 to 3), —O—(CH₂)_q—NH₂ (wherein p represents an integer of 1 to 3), —OSO₂—R₂₀ (wherein R₂₀ particularly represents an ethyl group, an n-propyl group, an i-propyl group or a benzyl group), a benzyloxy group, a 3- or 4-hydroxybenzyloxy group, or a 3- or 4-carboxybenzyloxy group.

R₁₈ preferably represents a hydrogen atom, a linear or branched C₁-C₆ alkyl group, a linear or branched C₁-C₆ alkylsulfonyl group, or an optionally substituted arylsulfonyl group (wherein the aryl group is preferably a phenyl group, and examples of a substituent include a linear or branched C₁-C₃ alkoxy group, a linear or branched C₁-C₃ alkyl group which may be substituted with a halogen atom, a nitro group and an amino group), and particularly represents a hydrogen atom, a methyl group, a methanesulfonyl group or a benzenesulfonyl group.

The linear or branched C₁-C₆ alkyl group defined as R₆ is preferably a linear or branched C₁-C₃ alkyl group.

Examples of a substituent on the optionally substituted linear or branched C₁-C₆ alkyl group defined as R₇ include a carboxyl group, an amino group, a mono- or di-substituted alkylamino group having a C₁-C₆ alkyl as its alkyl moiety, and an alkylcarbonylamino group having a C₁-C₆ alkyl as its alkyl moiety.

The alkyl moiety of the optionally substituted linear or branched C₁-C₆ alkyl group defined as R₇ is preferably a linear or branched C₁-C₄ alkyl group.

The optionally substituted linear or branched, C₁-C₆ alkyl group defined as R₇ is preferably a linear or branched C₁-C₄ alkyl group or a group of the following formula:
##STR41##
 
[wherein k represents an integer of 0 to 3, and R₂₁ represents a hydrogen atom or —NHR₂₂ (wherein R₂₂ represents a linear or branched C₁-C₃ alkyl group or an alkylcarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety)].

Above all, in the formula:
##STR42##
 
k is particularly an integer of 0 to 2, and R₂₁ is preferably a hydrogen atom or —NHR₂₂ (wherein R₂₂ represents a methyl group or an acetyl group).

Examples of a substituent on the optionally substituted linear or branched C₁-C₈ alkyl group defined as R₁₄ in the group —SO₂—R₁₄ defined as R₇ include (a) a carboxyl group, (b) an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety, and (c) a phenyl group which may be substituted with a carboxyl group or the like.

The alkyl moiety of the optionally substituted linear or branched C₁-C₈ alkyl group defined as R₁₄ is preferably a linear or branched C₁-C₆ alkyl group.

The optionally substituted linear or branched C₁-C₈ alkyl group defined as R₁₄ is preferably (a) an optionally substituted linear or branched C₁-C₆ alkyl group (wherein said alkyl group may be substituted with a carboxyl group or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety), or (b) —CH₂—R₂₃ (wherein R₂₃ represents an optionally substituted phenyl group, which may be substituted with a carboxyl group or the like).

In particular, R₁₄ is preferably a benzyl group, a 2-, 3- or 4-carboxybenzyl group, or an optionally substituted linear or branched C₁-C₄ alkyl group (wherein said alkyl group may be substituted with a carboxyl group or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety).

R₁ is preferably selected from the following formulae:
##STR43##
 
[wherein R₈ represents:
##STR44##
 
(wherein R₉ represents a hydrogen atom, an amino group, a hydroxy group, an acyl group, or an alkoxycarbonyl group having an optionally substituted linear or branched C₁-C₆ alkyl as its alkyl moiety)].

Above all, R₁ is particularly selected from the following formulae:
##STR45##
 
[wherein R₈ represents:
##STR46##
 
(wherein R₉ represents a hydrogen atom, an amino group, a hydroxy group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, an isovaleryl group, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group or a benzyloxycarbonyl group)].

R₂ is preferably a hydrogen atom or a linear or branched C₁-C₃ alkyl group, and particularly a hydrogen atom or a methyl group.

R₃ is preferably a group of the following formula:
##STR47##
 
or

—(CH₂)_m—R₁₁

[wherein m represents an integer of 1 to 3, and R₁₁ represents:

—CONH₂,

##STR48##
 
(wherein R₁₂ represents a hydrogen atom or a methyl group) or
##STR49##
 

Also preferred is a compound, in which R₃ represents a linear or branched C₁-C₆ alkyl group or —(CH₂)_m—R₁₁ (wherein m and R₁₁ are as defined above).

Also preferred is a compound, in which R₃ represents:
##STR50##
 
and R₇ represents —SO₂—R₁₄ (wherein R₁₄ is as defined above).

In particular, R₃ is preferably a group of the following formula:
##STR51##
 

R₄ is preferably a hydrogen atom or a linear or branched C₁-C₃ alkyl group, and particularly a hydrogen atom or a methyl group.

R₅ is preferably a linear or branched C₁-C₆ alkyl group or —CH₂—R₁₃ [wherein R₁₃ represents a group selected from the following formulae:
##STR52##
 
(wherein

R₁₅ represents a hydrogen atom, an optionally substituted aryl group, a C₁-C₃ alkyl group which may be substituted with a halogen atom, a linear or branched C₁-C₃ alkoxy group, a halogen atom, an arylcarbonyl group, an alkylcarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety, a nitro group, or an amino group;

R₁₆ represents a hydrogen atom or a linear or branched C₁-C₆ alkyl group;

R₁₇ represents a hydrogen atom, a hydroxy group, a linear or branched C₁-C₆ alkyl group, a linear or branched C₁-C₆ alkoxy group, —O—(CH₂)_n—OH (wherein n represents an integer of 1 to 5), —O—(CH₂)_p—COOH (wherein p represents an integer of 1 to 5), —O—(CH₂)_q—NH₂ (wherein q represents an integer of 1 to 5),
##STR53##
 
(wherein R₁₉ represents a hydrogen atom, a hydroxy group, a carboxyl group, a linear or branched C₁-C₆ alkyl group, a halogen atom, a linear or branched C₁-C₆ alkoxy group, or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety), or —OSO₂—R₂₀ (wherein R₂₀ represents a linear or branched C₁-C₆ alkyl group or a benzyl group); and

R₁₈ represents a hydrogen atom, a linear or branched C₁-C₆ alkyl group, a linear or branched C₁-C₆ alkylsulfonyl group, or an optionally substituted-arylsulfonyl group)].

In particular, R₅ is preferably a linear or branched C₁-C₄ alkyl group or —CH₂—R₁₃ [wherein R₁₃ represents a group selected from the following formulae:
##STR54##
 
(wherein

R₁₅ represents a hydrogen atom, a t-butyl group, a methoxy group, a bromine atom, a chlorine atom, a benzoyl group, or a phenyl group which may be substituted with a methoxy group or a trifluoromethyl group or a nitro group or an amino group;

R₁₇ represents a hydrogen atom, a hydroxy group, a methyl group, a linear or branched C₁-C₃ alkoxy group, —O—(CH₂)_n—OH (wherein n represents an integer of 1 to 3), —O—(CH₂)_p—COOH (wherein p represents an integer of 1 to 3), —O—(CH₂)_qNH₂ (wherein q represents an integer of 1 to 3), —OSO₂—R₂₀ (wherein R₂₀ represents an ethyl group, an n-propyl group, an i-propyl group or a benzyl group), a benzyloxy group, a 3- or 4-hydroxybenzyloxy group, or a 3- or 4-carboxybenzyloxy group; and

R₁₈ represents a hydrogen atom, a methyl group, a methanesulfonyl group or a benzenesulfonyl group)].

R₆ is preferably a hydrogen atom or a linear or branched C₁-C₃ alkyl group, and particularly a hydrogen atom or a methyl group.

R₇ is preferably a linear or branched C₁-C₆ alkyl group or a group of the following formula:
##STR55##
 
[wherein k represents an integer of 0 to 3, and R₂₁ represents a hydrogen atom or —NHR₂₂ (wherein R₂₂ represents a linear or branched C₁-C₃ alkyl group or an alkylcarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety)] or

—SO₂—R₁₄

[wherein R₁₄ represents:

(i) an optionally substituted linear or branched C₁-C₆ alkyl group (wherein said alkyl group may be substituted with a carboxyl group or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety); or

(ii) —CH₂—R₂₃ (wherein R₂₃ represents an optionally substituted phenyl group)].

Above all, R₇ is particularly a linear or branched C₁-C₄ alkyl group or a group of the following formula:
##STR56##
 
[wherein k represents an integer of 0 to 2, and R₂₁ represents a hydrogen atom or —NHR₂₂ (wherein R₂₂ represents a methyl group or an acetyl group)] or

—SO₂—R₁₄

[wherein R₁₄ represents a benzyl group, a 2-, 3- or 4-carboxybenzyl group, or an optionally substituted linear or branched C₁-C₄ alkyl group (wherein said alkyl group may be substituted with a carboxyl group or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety)].

Having the definition given above for each symbol, preferred is a compound of Formula (1) wherein

R₁ is a group selected from the following formulae:
##STR57##
 
[wherein R₈ represents:
##STR58##
 
(wherein R₉ represents a hydrogen atom, an amino group, a hydroxy group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, an isovaleryl group, a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group or a benzyloxycarbonyl group)];

R₂ is a hydrogen atom or a methyl group;

R₃ is a group of the following formula:
##STR59##
 

R₄ is a hydrogen atom or a methyl group;

R₅ is a linear or branched C₁-C₄ alkyl group or —CH₂—R₁₃ [wherein R₁₃ represents a group selected from the following formulae:
##STR60##
 
(wherein

R₁₅ represents a hydrogen atom, a t-butyl group, a methoxy group, a bromine atom, a chlorine atom, a benzoyl group, or a phenyl group which may be substituted with a methoxy group or a trifluoromethyl group or a nitro group or an amino group;

R₁₇ represents a hydrogen atom, a hydroxy group, a methyl group, a linear or branched C₁-C₃ alkoxy group, —O—(CH₂)_n—OH (wherein n represents an integer of 1 to 3), —O—(CH₂)_p—COOH (wherein p represents an integer of 1 to 3), —O—(CH₂)_q—NH₂ (wherein q represents an integer of 1 to 3), —OSO₂—R₂₀ (wherein R₂₀ represents an ethyl group, an n-propyl group, an i-propyl group or a benzyl group), a benzyloxy group, a 3- or 4-hydroxybenzyloxy group, or a 3- or 4-carboxybenzyloxy group; and

R₁₈ represents a hydrogen atom, a methyl group, a methanesulfonyl group or a benzenesulfonyl group)];

R₆ is a hydrogen atom or a methyl group; and

R₇ is a linear or branched C₁-C₄ alkyl group or a group of the following formula:
##STR61##
 
[wherein k represents an integer of 0 to 2, and R₂₁ represents a hydrogen atom or —NHR₂₂ (wherein R₂₂ represents a methyl group or an acetyl group)] or

—SO₂—R₁₄

[wherein R₁₄ represents a benzyl group, a 2-, 3- or 4-carboxybenzyl group, or an optionally substituted linear or branched C₁-C₄ alkyl group (wherein said alkyl group may be substituted with a carboxyl group or an alkoxycarbonyl group having a linear or branched C₁-C₃ alkyl as its alkyl moiety)].

Above all, particularly preferred is a compound selected from the following formulae:
##STR62## ##STR63## ##STR64##
 

Compounds of Formula (1) have enantiomers; all individual enantiomers and mixtures thereof are intended to be within the scope of the present invention. Above all, preferred are compounds having the S-configuration at the carbon atom attached to R₃ and having the R-configuration at the carbon atom attached to R₅ in Formula (1).

The compounds of the present invention may also be obtained as hydrates.

Examples of a salt-forming acid include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid and trifluoroacetic acid.

Each compound of Formula (1) may be administered as a pharmaceutical composition in any dosage form suitable for the intended route of administration, in combination with one or more pharmaceutically acceptable diluents, wetting agents, emulsifiers, dispersants, auxiliary agents, preservatives, buffers, binders, stabilizers and the like. It may be administered parenterally or orally.

The dose of the compound can be determined as appropriate for the physique, age and physical condition of a patient, severity of the disease to be treated, elapsed time after onset of the disease, etc. For example, it is usually used at a dose of 1 to 1000 mg/day/person for oral administration and at a dose of 0.1 to 100 mg/day/person for