JP2001512742A - Selective factor Xa inhibitor - Google Patents

Abstract

(57) SUMMARY Disclosed are novel compounds having activity against mammalian factor Xa, their salts and compositions related thereto. These compounds are useful in the prevention or treatment of coagulation diseases in vitro or in vivo and have formula (I).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a new class of bicyclic arylazepinones that are potent and highly selective inhibitors of factor Xa when associated with factor Xa or prothrombinase complexes For compounds. These compounds are composed of factor Xa and other coagulation-related proteases (eg, thrombin, fVIIa, fI
Shows selectivity for Xa) or a protease involved in the fibrinolytic cascade (eg, plasminogen activator, plasmin).

[0002]

[Prior art]

Blood coagulation protects mammalian species when vascular wall integrity is compromised and dysregulated blood loss threatens survival. Clotting is the result of the blood clotting and is an important component of hemostasis. Under normal haemostatic conditions, a delicate balance between clot formation and clot removal (fibrinolysis) is maintained. The blood clotting cascade involves the conversion of various inactive enzymes (enzyme sources) to active enzymes, which ultimately convert the soluble plasma protein fibrinogen into an insoluble matrix of highly cross-linked fibrin. (Dav
IE et al., "The Coagulation Cascade: Initiat."
ion, Maintenance and Regulation "Bio chemistry 30:. 10363-10370 (1991) refer) platelets adhere to damaged vessel is activated, that is incorporated into the clot, stable and initial formation of hemostatic" plug " Play an important role in In certain diseases of the cardiovascular system, when a thrombus blocks blood flow in the coronary vessels (myocardial infarction) or limb and pulmonary veins (venous thrombosis), normal hemostasis does not occur, and clot formation and clotting occur. The balance of the clot lysis is forced to promote life-threatening thrombus formation. Although platelets and blood clotting are both involved in thrombus formation, certain components of the coagulation cascade are the primary cause of the expansion or acceleration of the processes involved in platelet aggregation and fibrin deposition.

[0003] An important enzyme in the coagulation cascade and hemostasis is thrombin. Although thrombin is closely related to the process of thrombus formation, it also plays an anticoagulant role during hemostasis because under normal circumstances it can convert protein C to active protein C in a thrombomodulin-dependent manner be able to. Thrombin plays a central role in thrombosis by being able to act as a catalyst for the penultimate stage of the conversion of fibrinogen to fibrin and by its potent, platelet-activating activity. Fulfill. Direct or indirect inhibition of thrombin activity is described by Claesson in "Synthetic Peptides and
Peptidomimetics as Substrates and I
nhibitors of Thrombin and Other Prot
eases in the Blood Coagulation System
m ", Blood Coag Fibrinol .5: . 411-436 (1
994) has been the focus of recent various anticoagulation methods. recent years,
Many classes of anticoagulants used directly or indirectly in the clinic affect thrombin (ie, heparin, low molecular weight heparin and coumarin). Thrombin is produced by prothrombinase complexes at the meeting points of the intrinsic and extrinsic coagulation pathways. The prothrombinase complex is described in Mann et al.
ace-Dependent Reactions of the Vitam
in K-Dependent Enzymes ", Blood 76: 1-1.
6 (1990), when activated factor X (factor Xa) and its non-enzymatic cofactor, factor Va, associate at the phospholipid surface in a Ca ⁺² -dependent manner. Is done. The prothrombinase complex converts the enzyme source, prothrombin, into active procoagulant thrombin.

The location of prothrombinase at the confluence of intrinsic and extrinsic coagulation pathways and a significant increase in thrombin generation mediated by a limited number of target catalytic units present at the site of vascular injury (uncomplexed Xa A factor of over 393,000) suggests that inhibition of thrombin generation is an ideal way to block uncontrolled procoagulant activity. Unlike thrombin, which acts on a variety of protein substrates and specific receptors, factor Xa appears to have a single physiological substrate, namely prothrombin.

[0005] Plasma contains endogenous inhibitors of both Factor VIIa-Tissue Factor (TF) complex and Factor Xa, termed Tissue Factor Pathway Inhibitor (TFPI). TFPI is a Kunitz-type protease inhibitor with three tandem Kunitz domains. TFPI is T
Inhibiting the F / fVIIa complex by a two-step mechanism, which involves first inhibiting the proteolytic activity of Xa by the interaction of the second Kunitz domain of TFPI with the active site of factor Xa. Including. The second step is Gir
Ard et al., “Functional Significance of
the Kunitz-type Inhibitory Domains o
f Lipoprotein-associated Coagulation
Inhibitor ", Nature 338: 518-520 (1989).
As well as inhibiting TF / fVIIa by forming a quaternary complex TF / fVIIa / TFPI / fXa, as described in US Pat. Polypeptides from phagocytic organisms have been reported to be specific inhibitors with high potency against factor Xa. U.S. Pat. No. 4,588,5 to Gasic
No. 87 describes the anticoagulant activity of the saliva of Mexican hill Haementeria Officinalis. The main component of this saliva is “The Amino Acid Sequence of Antistas” by Nutt et al.
in, a Potent Inhibitor of Factor Xa
Reveals a Repeated Internal Structur
e ", J. Biol . Chem . 263: 10162-10167 (1988).
Has been shown to be a polypeptide factor Xa antistasin.

[0006] A tick anticoagulant peptide, another potent and highly specific inhibitor of factor Xa,
"Tick Anticoagulant Peptid" by Waxman et al.
e (TAP) is a Novel Inhibitor of Blood
Coagulation Factor Xa ", Science 248:
593-596 (1990), the soft mite Ornithi.
isolated from a whole body extract of doros moubata.

[0007] Other polypeptide-type inhibitors of factor Xa include the following:
Contra et al., “Isolation and Stru.
Cultural Characterization of a Potent
Inhibitor of Coagulation Factor Xaf
rom the Leech Hamenteria ghilianii ", Thromb .Haemost. 61: 437-441 (1989); Blan.
Kenship et al., “Amino Acid Sequence of Ghi
lanten: Anti-coagulant-antimetastati
c Principle of the South American Le
ech, Haementeria ghilianii ",Biochem .Biophys.Res.Commun. 166: 1384-1389 (19
90); Blankamp et al., "Ghilantens: Anticoagu
lants, Antimetastatic Proteins from
the South American Leach Haementeria
ghilianii ",J.Lab.Clin.Med. 115: 89-97
(1990); Jacobs et al., "Isolation and Charac.
teration of a Coagulation Factor X
a Inhibitor from Black Fly Salivary
Grands ",Thromb.Haemost. 64: 235-238 (1
990); Rigbi et al., "Bovine Factor Xa Inhibi.
ting Factor and Pharmaceutical Compo
situations Holding the same ", European Patent
Application No. 352,903 (1990); Cox, "Coagulation F.
actor X Inhibitor From the Hundred-p
ace Snake Deinagikistrodon acutus ven
om ”,Toxicon 31: 1445-1457 (1993); Cape.
Ilo et al., “Ancylostoma Factor Xa Inhibito
r: Partial Purification and it's Iden
Tification as a Major Hookworm-deriv
ed Anticoagulant In Vitro ”,J.Infect .Dis. 167: 1474-1477 (1993); Seemour et al., "E.
cotin is a Potent Anticoagulant and
Reversible Tight-binding Inhibitor o
f Factor Xa ",Biochemistry 33: 3949-3
958 (1994).

[0008] Factor Xa inhibitor compounds that are not large polypeptide type inhibitors include:
It has been reported including the following references: Tidwell et al., "Strategi
es for Anticoagulation With Syntheti
c Protease Inhibitors. Xa Inhibitors
Versus Thrombin Inhibitors, " Thromb . RES . 19: 339-349 (1980); Turner et al.," P-Am.
idino Esters as Irreversible Inhibit
ors of Factor IXa and Xa and Thrombin
", Biochemistry 25: 4929-4935 (1986); H.
Itomi et al., “Inhibitory Effect of New Syn.
thetic Protease Inhibitor (FUT-175) o
n the Coagulation System ", Haemostas is 15: 164-168 (1985); Sturzebecher other," S
Synthetic Inhibitors of Bovine Factor
Xa and Thrombin. Comparison of Their
Anticoagulant Efficiency "., Thromb Re s .54: 245-252 (1989); Kam other," Mechanism B
used Isocoumarin Inhibitors for Tryp
sin and Blood Coagulation Serine Pro
teases: New Anticoagulants ", Biochem istry 27: 2547-2557 (1988); Hauptmann other,
“Comparison of the Anticoagulant and
Antithrombotic Effects of Synthetic
.. Thrombin and Factor Xa Inhibitors " T hromb Haemost 63: 220-223 (1990); Miy
adera et al., Japanese Patent Application No. 6327488 (1994); Nagahar
a, et al., “Dibasic (Amidinoaryl) propanoic Ac
id Derivatives as Novel Blood Coagul
ation Factor Xa Inhibitors ".., J Med C hem .37: 1200-1207 (1994); Vlasuk other," INHI
bits of Thrombosis ", WO 93/15756; Br
unck et al., “Novel Inhibitors of Factor Xa
"WO 94/13693. Al-Obeidi et al.," Factor Xa.
Inhibitors ", WO 95/29189, discloses pentapeptide X1-YIR-X2 derivatives as factor Xa inhibitors.
It helps to inhibit blood clotting when treating thrombosis, stroke and myocardial infarction.

[0009]

[Problems to be solved by the invention]

The present invention relates to novel peptidomimetic analogs, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives.

[0010] In another aspect, the invention includes a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the invention, and a pharmaceutically acceptable carrier. These compositions are useful as specific inhibitors that have an effect on blood coagulation in mammals.

[0011] In still another aspect, the present invention relates to the use of these inhibitors as a therapeutic agent for a disease state of a mammal having a coagulation disease as described below, which comprises unstable angina, intractable angina, and myocardium. In the treatment of infarction, transient ischemic attacks, thrombotic attacks, embolic attacks, sporadic intravascular coagulation, including the treatment of septic shock, pulmonary embolism, or the treatment of reperfusion coronary reocclusion or restenosis The present invention relates to a method for treating or preventing deep vein thrombosis or the like. Such compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.

[0012] In another aspect of the present invention, there is provided a compound useful as a diagnostic agent.

[0013]

[Means to solve the problem]

In a preferred embodiment, the present invention provides compounds of general formula I:

[0014] [wherein, R ¹ and R ² are independently, H, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-3 alkylaryl, C _1-3 alkyl -C _3-8 R ³ is H, C _1-6 alkyl, or R ² and R ³ together form a cyclic carbon, q is an integer from 0 to 2, r is an integer of 0 to 4, s is an integer of 0 to 1, t is an integer of 0 to 4, A is R ⁸ , —NR ⁸ R ⁹ ,

Wherein R is selected from the group consisting of:⁸, R⁹, R^TenAnd R¹¹Is independently H, -OH, C_1-6Alkyl, aryl and C_1-4R is selected from the group consisting of alkylaryl;¹²Is H, C_1-6 Alkyl, aryl and C_1-4Selected from the group consisting of alkylaryl, or R^TenOr R¹¹And R can form a 5- to 6-membered ring with¹³Is H, C _1-6 Alkyl, aryl and C_1-4Selected from the group consisting of alkylaryl
Or R¹¹Can form a 5- or 6-membered ring together with D);_3-8Cycloalkyl, C_1-6Alkenyl, C_1-6Alkenyl aryl, aryl and 1 to 4 selected from the group consisting of N, O and S
Wherein E is a direct bond, -CO-, -SO_Two-, -O-CO-, -NR¹⁴-SO_Two-Oh
And -NR¹⁴-CO- (where R¹⁴Is H, -OH, C_1-6Alkyl, aryl and C_1-4G is a direct bond, C is selected from the group consisting of_3-85- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of cycloalkyl, aryl and N, O and S
J is selected from the group consisting of^Fifteen, -NR^FifteenR¹⁶,

Wherein R is selected from the group consisting of^Fifteen, R¹⁶, R¹⁷And R¹⁸Is independently H, -OH, C_1-6Alkyl, aryl and C_1-4R is selected from the group consisting of alkylaryl;¹⁹Is H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl
Or R¹⁷Or R¹⁸And can form a 5- to 6-membered ring with²⁰Is
, H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl
Selected or R¹⁸And a 5- or 6-membered ring can be formed (provided that J is R^Fifteenso
In some cases, G must include at least one N atom)]; K ′, K ″, K ″ ″ and K ″ ″ are independently —CH—, —CR^Four-, -CR^Five -And -N-, where K ', K ", K"' and K "
Only one of '' is -CR^FourAnd only one of K ', K ", K"' and K "" is -CR^FiveWherein R is^FourAnd R^FiveIs independently C_1-6Alkyl, aryl, C_1-6Alkyl
Aryl, C_1-4Alkyloxy, halogen, -NO_Two, -NR⁶R⁷, -NR⁶COR⁷, -OR⁶, -OCOR⁶, -COOR⁶, -CONR⁶R⁷, -CN, -CF _Three , -SO_TwoNR⁶R⁷And C_1-6Alkyl-OR⁶Selected from the group consisting of
Where R⁶And R⁷Is independently H, C_1-6Alkyl, C_1-3Alkylaryl
And Q is H,

Wherein R ²¹ and R ²² are independently selected from the group consisting of H, C _1-3 alkyl and aryl; and T is H, —COOR ²³ , -CONR ²³ R ²⁴ , -C
F ₃ , —CF ₂ CF ₃ and the formula

[0018] is selected from the group consisting of groups having a (wherein, R ²³ and R ²⁴ are independently selected H, C _1-6 alkyl, from the group consisting of aryl and C _{1 -4} alkyl aryl U ′ and U ″ are independently selected from the group consisting of —O—, —S—, —N— and —NH—, provided that at least one of U ′ or U ″ is -N- or -NH-); R ²⁵ is, H, C _{1- 6} alkyl, C _2-6 alkenyl, C _0-6 alkylaryl, C _2-6 alkenylaryl, C _0-6 alkyl heterocycloalkyl , C _2-6 alkenyl heterocycloalkyl, selected from the group consisting of -CF ₃ and -CF ₂ CF _3; V is, -S -, - SO -, - SO 2 -, -O- and -NR ²⁶ - (wherein, R ²⁶ is, H, C _1-6 is selected from alkyl and the group consisting of benzyl Le) selected from the group consisting of It is; and W is,

And 1 to 4 substituted by R ²⁹ and R ³⁰ and selected from N, S and O
Is selected from C _6-10 group consisting hetero ring system comprising pieces of heteroatom; wherein, a is is 0 to 2 integer; R ²⁷ and R ²⁸ are independently, H, C _1-6 Alkyl, aryl, C _1-6 alkylaryl, —COOR ³¹ , —CONR ³¹ R ³² , —CN and —CF ₃ ; and R ²⁹ and R ³⁰ are independently H 2, C _1-6 alkyl, aryl, C _1-6 alkylaryl, C _1-4 alkyloxy, _{^{halogen, -NO 2, -NR 31 R 32}} , -NR 31 COR 32, -OR 31, -OCOR 3 1, - ^{COOR 31, -CONR 31 R 32,} -CN, -CF 3, is selected from the group consisting of -SO ₂ NR ³¹ R ³² Contact and C _1-6 alkyl -OR ³¹ (wherein, R ³¹ and R ^{3 2} is independently, H, C _1-6 alkyl, or C _1-3 alkyl and aryl or Ranaru group Compounds represented by the selected are)]], as well as all pharmaceutically acceptable salts and their optical isomers.

Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless otherwise indicated.

The term “alkyl” includes straight chain, branched chain, cyclic groups and combinations thereof, and includes the specified number of carbon atoms, or up to 12 carbon atoms if no number is specified. Means a saturated aliphatic group having The term "cycloalkyl" means a monocyclic, bicyclic, or tricyclic aliphatic ring having 3 to 12 carbon atoms, preferably 3 to 7 carbon atoms.

The term “alkenyl” includes straight-chain, branched-chain, cyclic groups and combinations thereof,
An unsaturated aliphatic group having at least one double bond and having the specified number of carbon atoms is meant.

The term "aryl" is an unsubstituted or substituted aromatic ring, but is referred to as an example, but are not limited to, C _1-6 alkoxy, C _1-6 alkyl, C _{1- 6} alkylamino, hydroxy, halogen, cyano (-CN), mercapto, nitro (-NO _2), thioalkoxy, carboxyanhydride monkey aldehyde, carboxyl, mosquitoes Ruboarukokishi, carboxamide, -NR'R '', - NR'COR '', -O
R, -OCOR, -COOR, -CONR'R '', - CF 3, -SO 2 NR'R
'' And C _1-6 alkyl-OR; aryl, C _1-6 alkylaryl wherein R
Groups can be H, C _1-6 alkyl, C _1-3 alkylaryl, and aryl), and are substituted with one, two, or three substituents, such as carbocyclic aryl,
Including, but not limited to, heterocyclic aryl, biaryl and triaryl groups, any of these means an aromatic ring which may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, C _1-6 alkylphenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and aromatic heterocyclic or heteroaryl, and the like, the latter being nitrogen, oxygen and sulfur. And an aryl group containing 1 to 4 heteroatoms selected from the group consisting of The aryl group preferably has 5 to 14 carbon atoms forming a cyclic structure, while the heteroaryl group has 1 to 4 heteroatoms and the remaining 4 to 10 carbon atoms.
It is preferable to have the following atom.

As used herein, the terms “heterocyclo” and “heterocyclic system” refer to nitrogen,
Means any saturated or unsaturated mono- or bicyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of oxygen and sulfur. A typical heterocyclic ring system is 5-
It has 10 members, of which 1-4 members are heteroatoms. Typical examples of monocyclic systems include piperidinyl, pyrrolidinyl, pyridinyl, piperidonyl, pyrrolidonyl and thiazolyl, while examples of bicyclic systems include benzimidazolyl, benzothiazolyl and benzoxazolyl, all of which may be substituted.

As used herein, the term “cyclic carbon” refers to any saturated or unsaturated ring containing 3 to 6 carbon atoms.

As used herein, the terms “alkylaryl” and “alkenylaryl” are alkyl or alkenyl groups, each having the indicated number of carbon atoms and having one, two, or three Means an alkyl or alkenyl group to which two aryl groups have been added. As used herein, the term "benzyl" refers, -CH ₂ - means the C ₆ H _5.

[0027] As used herein, the term "alkyloxy" refers to an alkyl group attached to an oxygen atom, such as methoxy, ethoxy, and the like.

As used herein, the term “halogen” refers to a Cl, Br, F or I substituent.

As used herein, the term “direct link” means a bond that directly connects the substituents on each side of the direct link. When two adjacent substituents are each defined as being "directly linked", they are considered to be a single bond.

“Two substituents together form a 5- or 6-membered ring” means that an ethylene or propylene bridge is formed between each two substituents.

The term “pharmaceutically acceptable salts” includes salts of the compounds that are derived from combinations of the compounds with organic or inorganic acids. These compounds are both useful in free base and salt form. In practice, the use of the salt form is equivalent to the use of the base form, and both acid and base addition salts are within the scope of the invention.

“Pharmaceutically acceptable acid addition salt” refers to salts that retain the biological effectiveness and properties of the free bases, and are not biologically or otherwise undesirable, and include hydrochloric acid, bromide Inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, silica It means salts formed with organic acids such as cinnamate, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

“Pharmaceutically acceptable base addition salt” refers to those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum bases. Including. Particularly preferred are the salts of ammonium, potassium, sodium, calcium and manganese. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, tertiary and substituted amines, including naturally-occurring substituted amines, cyclic amines and basic ion exchange resins. Amines, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine Glucosamine, methylglucamine, theobromine, purine, piperidine, piperidine, N-ethylpiperidine, polyamine resin and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimetamine, dicyclohexylamine, choline and caffeine.

For the purposes of the present invention, “biological property” means the function or activity of an in vivo effector or antigen performed directly or indirectly by a compound of the present invention. Effector functions include receptor or ligand binding, all enzymatic or enzymatic modulating activities, all carrier binding activities, all hormonal activities, all activities that promote or inhibit the attachment of cells to the extracellular matrix or cells Or all structural roles. Antigen function includes possession of an epitope or antigenic site capable of reacting with an antibody raised against the epitope or antigenic site. The biological properties of the compounds of the present invention can be readily determined by the methods described in Examples 13 and 14 and by methods well known in the art.

In addition, the following abbreviations are used herein. "Bn" means benzyl. "Boc" means t-butoxycarbonyl. "BOP" means benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate. "Bu" means butyl. "CBZ" means carbobenzyloxy. "DCM" means dichloromethane. "DIEA" means diisopropylethylamine. "DMF" means N, N-dimethylformamide. "EDC" means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. "Et" means ethyl. “Et ₂ O” means diethyl ether. "EtOAc" means ethyl acetate. "EtOH" means ethanol. "HF" means hydrogen fluoride. "Me" means methyl. “MeOH” means methanol. "NHS" means N-hydroxysuccinimide. "Ph" means phenyl. "P-TsOH" means p-toluenesulfonic acid monohydrate. "TFA" means trifluoroacetic acid. "THF" means tetrahydrofuran. "Tos" means p-toluenesulfonyl.

In the compounds of the present invention, the carbon atoms bonded to the four non-identical substituents are asymmetric. Thus, the compounds of the present invention may exist as diastereoisomers, enantiomers, or mixtures thereof. The syntheses described herein include:
Racemates, enantiomers or diastereoisomers may be used as starting materials or intermediates. The diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization techniques, or other methods known in the art. Similarly, enantiomeric product mixtures may be separated in the same manner or by other methods known in the art. Each asymmetric carbon atom, when present in a compound of the present invention, is in one of two configurations (R or S), both configurations being within the scope of the invention. In the above process, the final product may sometimes contain small amounts of diastereomeric or enantiomeric products, but these products do not affect their therapeutic or diagnostic use.

In all the peptides of the present invention, one or more amide bonds (—CO—NH—) are replaced by —CH ₂ NH—, —CH ₂ S—, —CH ₂ —O—, —CH ₂ —CH ₂ -, - CH = CH- (cis and _{trans), - COCH 2 -, -} CH (OH) CH 2 -, - C
It may be arbitrarily substituted with another bond represented by an equivalent formula such as H ₂ SO— and —CH ₂ SO ₂ —. This substitution can be performed by a method known in the art. The following references describe the preparation of peptide analogs containing these alternative linking groups. Spatola, "Peptide Backbone Modi
Sociola, "Chemistry" (General Review) Vega Data , Vol. 1, Issue 3, (March 1983); Spatola, "Chemist.
ry and Biochemistry of Amino Acids,
Peptides and Proteins "(General Review), B. Wein
stein eds. , Marcel Dekker, New York,
p. 267 (1983); Morley, Trends Pharm . S ci (general review) pp. 463-468 (1980); Hudson other I nt. J. Pept . Prot . Res . 14: 177-185 (1979) (-CH 2 NH -, - CH 2 CH 2 -); Spatola other, Life Sci. Three
8: 1243-1249 (1986) (- CH 2 -S); Hann, J. C hem. Soc . Perkin Trans . I pp. 307-314 (19 82) (- CH = CH-, cis and trans); Almquist other, J. M ed. Chem . 23: 1392-1398 (1980) (- COCH 2 -);
Jennings-White et al., Tetrahedron Lett . _{23: 2533 (-COCH 2 -)} (1982); Szelke et European Patent Application No. 45665; CA: 97: 39405 ( 1982) (- CH (OH) CH 2 -); Holladay et Tetrahedron Lett. 2 4: 4401-4404 (1983) ( - CH (OH) CH 2 -); and Hr uby, Life Sci. 31: 189-199 (1982) (- CH 2 -
S).

[0038]

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides compounds of general formula I, which are potent and specific Xa inhibitors:

[0039] [wherein, R ¹ and R ² are independently, H, C _1-6 alkyl, C _3-8 cycloalkyl, C _1-3 alkylaryl, C _1-3 alkyl -C _3-8 R ³ is H, C _1-6 alkyl, or R ² and R ³ together form a cyclic carbon, q is an integer from 0 to 2, r is an integer of 0 to 4, s is an integer of 0 to 1, t is an integer of 0 to 4, A is R ⁸ , —NR ⁸ R ⁹ ,

Wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently H, —OH, C _1-6 alkyl, aryl and C _1-4 alkylaryl R ¹² is selected from the group consisting of H 2, C _1-6 alkyl, aryl and C _1-4 alkylaryl, or forms a 5- to 6-membered ring with R ¹⁰ or R ¹¹ And R ¹³ is
H is selected from the group consisting of H, C _1-6 alkyl, aryl and C _1-4 alkylaryl or can form a 5- or 6-membered ring with R ¹¹ ]; D is a direct bond, C _3-8 cycloalkyl The group consisting of alkyl, C _1-6 alkenyl, C _1-6 alkenyl aryl, aryl and 5 to 10 membered heterocyclic ring systems containing 1 to 4 heteroatoms selected from the group consisting of N, O and S It is selected from; E is a direct _{bond, -CO -, - SO 2 -} , - O-CO -, - NR 14 -SO 2 - and -NR ¹⁴ -CO- (wherein, R ¹⁴ is H, - G is selected from the group consisting of OH, C _1-6 alkyl, aryl and C _1-4 alkylaryl); G is a direct bond, C _3-8 cycloalkyl, aryl and N, 1 to 4 heads selected from the group consisting of O and S Includes atoms, selected from the group consisting of 5 to 10-membered ring heterocyclic system; J ^{is, R 15, -NR 15 R 16} ,

Wherein R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are independently H, —OH, C _1-6 alkyl, aryl and C _1-4 alkyl R ¹⁹ is selected from the group consisting of H, C _1-6 alkyl, aryl and C _1-4 alkylaryl, or forms a 5- to 6-membered ring together with R ¹⁷ or R ^18. And R ²⁰ is selected from the group consisting of H, C _1-6 alkyl, aryl and C _1-4 alkylaryl, or can form a 5- to 6-membered ring with R ¹⁸ , wherein J is If R ¹⁵ , G must contain at least one N atom)]; K ′, K ″, K ″ ″ and K ″ ″ are independently —CH—, — CR ⁴ -, - CR ⁵ - is selected from the group consisting of and -N- (However, K ', K'', Oyo K''' K ''
'' Only one is -CR ⁴ - a, K ', K'',K' only one '' and K '''' is -CR ⁵ - and is); wherein, R ⁴ And R ⁵ are independently C _1-6 alkyl, aryl, C _1-6 alkylaryl, C _1-4 alkyloxy, halogen, —NO ₂ , —NR ⁶ R ⁷ , —NR ⁶ COR ⁷ , ^{OR 6, -OCOR 6, -COOR 6} , -CONR 6 R 7, -CN, -C
Selected from the group consisting of F ₃ , —SO ₂ NR ⁶ R ⁷ and C _1-6 alkyl-OR ⁶ (
Wherein R ⁶ and R ⁷ are independently selected from the group consisting of H, C _1-6 alkyl, C _1-3 alkylaryl and aryl);

Wherein R ²¹ and R ²² are independently selected from the group consisting of H, C _1-3 alkyl and aryl; and T is H, —COOR ²³ , -CONR ²³ R ²⁴ , -C
F ₃ , —CF ₂ CF ₃ and the formula

[0043] is selected from the group consisting of groups having a (wherein, R ²³ and R ²⁴ are independently selected H, C _1-6 alkyl, from the group consisting of aryl and C _{1 -4} alkyl aryl U ′ and U ″ are independently selected from the group consisting of —O—, —S—, —N— and —NH—, provided that at least one of U ′ or U ″ is -N- or -NH-); R ²⁵ is, H, C _{1- 6} alkyl, C _2-6 alkenyl, C _0-6 alkylaryl, C _2-6 alkenylaryl, C _0-6 alkyl heterocycloalkyl , C _2-6 alkenyl heterocycloalkyl, selected from the group consisting of -CF ₃ and -CF ₂ CF _3; V is, -S -, - SO -, - SO 2 -, -O- and -NR ²⁶ - (wherein, R ²⁶ is, H, C _1-6 is selected from alkyl and the group consisting of benzyl Le) selected from the group consisting of It is; and W is,

And 1 to 4 substituted by R ²⁹ and R ³⁰ and selected from N, S and O
Is selected from C _6-10 group consisting hetero ring system comprising pieces of heteroatom; wherein, a is is 0 to 2 integer; R ²⁷ and R ²⁸ are independently, H, C _1-6 Alkyl, aryl, C _1-6 alkylaryl, —COOR ³¹ , —CONR ³¹ R ³² , —CN and —CF ₃ ; and R ²⁹ and R ³⁰ are independently H 2, C _1-6 alkyl, aryl, C _1-6 alkylaryl, C _1-4 alkyloxy, _{^{halogen, -NO 2, -NR 31 R 32}} , -NR 31 COR 32, -OR 31, -OCOR 3 1, - ^{COOR 31, -CONR 31 R 32,} -CN, -CF 3, is selected from the group consisting of -SO ₂ NR ³¹ R ³² Contact and C _1-6 alkyl -OR ³¹ (wherein, R ³¹ and R ^{3 2} is independently, H, C _1-6 alkyl, or C _1-3 alkyl and aryl or Ranaru group And a new class of bicyclic arylazepinone compounds selected from all pharmaceutically acceptable salts thereof and optical isomers thereof, and pharmaceutically acceptable salts thereof. Compositions and their use as therapeutics for disease states in mammals characterized by abnormal thrombosis.

The compounds of the preferred embodiments of general structural formula I have the following stereochemistry:

Preferred R ¹ and R ² substituents are H and C _1-6 alkyl, more preferably H and methyl; most preferably H. R ³ is preferably H.

The integer “r” is preferably 3.

The integer “s” is preferably 0.

The integer “t” is preferably 0-1.

Various “A” substituents include R⁸, R⁹, R^Ten, And R¹¹Is independently H or C _1-6 Preferably selected from the group consisting of alkyl; more preferably independently selected from the group consisting of H or methyl. R¹²Is H, or
C_1-6Alkyl or R^TenOr R¹¹Preferably form a 5- or 6-membered ring together with H; and more preferably, H or methyl. R¹³But H, C_1-6 Alkyl or R^TenPreferably forms a 5- or 6-membered ring together with
More preferably, it is H or methyl.

D is preferably 5 to 10 containing 1 to 4 heteroatoms selected from the group consisting of a direct bond, C _3-8 cycloalkyl, aryl and N, O and S.
Selected from the group consisting of membered heterocyclic ring systems.

E is preferably a direct bond, —CO— or —SO ₂ —.

G is preferably a direct bond.

In the “J” substituent, R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are independently selected from the group consisting of H and C _1-6 alkyl; more preferably H and methyl.

Preferably at least three of K ′, K ″, K ″ ″ and K ″ ″ are —CH—; more preferably K ′, K ″, K ′ ″ and K '''' Is all CH-. K
One is -CR ⁴ - or -CR ⁵ - if it is, R ⁴ or R ⁵ is preferably a halogen.

Q is preferably

Wherein R ²¹ is preferably H and R ²² is preferably H.

T is preferably H, —COOR ²³ , —CONR ²³ R ²⁴ or a formula:

Is a group having

R ²³ is preferably H. R ²⁴ is preferably C _1-4 alkylaryl. V is preferably, -S -, - is O- or -NR ²⁶ (wherein R ²⁶ is preferably H or methyl, more preferably H). W is preferably

Is selected from the group consisting of:

W is more preferably of the formula:

Is shown.

R²⁹And R³⁰Is preferably H, -OR³¹, -COOR³¹, -CONR ³¹ R³²Or -CF_ThreeSelected from the group consisting of; more preferably H.

W is the formula:

Where R ²⁷ is preferably H and R ²⁸ is preferably H.

T is the formula:

Where U ′ is preferably O, U ″ is preferably N, and R ²⁵ is preferably —CF ₃ or —CF ₂ CF ₃ .

In one preferred embodiment of the invention, s is 0; R ² and R ³ are H; K ′, K ″, K ′ ″ and K ″ ″ are —CH Q is -C (O)-
T. It also has the general structure II:

Are shown as a preferred group of compounds defined by

Preferred embodiments of the compounds of general structural formula II have the following stereochemistry:

In another preferred embodiment of the invention, s is 0; r is 3; ¹ , R^TwoAnd R^ThreeIs H; K ′, K ″, K ″ ″ and K ″ ″ are —CH—; G is a bond;

Wherein R ¹⁵ , R ¹⁷ , R ¹⁸ and R ¹⁹ are all H; and Q is —C (O) —T. It also has the general structural formula III:

Are shown as a preferred group of compounds defined by

Preferred embodiments of the compounds of general structural formula III have the following stereochemistry:

The present invention also includes all pharmaceutically acceptable isomers, salts, hydrates and solvates of the compounds of formulas I, II and III. Further, formulas I, II,
And the compounds of formula III may exist in various isomeric and tautomeric forms, and all such forms are pharmaceutically acceptable salts of such isomers and tautomers , And hydrates and solvates.

The compounds of the present invention may be isolated as free acids or bases or may be converted into various inorganic and organic acids and bases. Such salts are within the scope of the present invention. Non-toxic, physiologically compatible salts are particularly useful, but other less desirable salts may be utilized in the isolation and purification steps.

A number of methods are useful for preparing the above salts and are known to those skilled in the art. For example,
The free acid or free base of one compound of the above formula is dissolved in a solvent or solvent mixture in which the salt is insoluble, or in a solvent such as water where the solvent is subsequently removed by evaporation, distillation or lyophilization. It can be reacted with one or more molar equivalents of the desired acid or base. Alternatively, the product in free acid or free base form may be passed through an ion exchange resin to form the desired salt, or one salt form of the product may be separated using the same general steps. May be converted to the form.

[0079] The present invention also includes prodrug derivatives of the compounds included herein. The term “prodrug” refers to a pharmaceutically inactive derivative of a parent drug molecule that requires either spontaneous or enzymatic biotransformation in an organism to release the active drug. Prodrugs are variants or derivatives of the compounds of the present invention which have groups cleavable under metabolic conditions. Prodrugs become pharmaceutically active compounds of the present invention in vivo when they undergo solvolysis or enzymatic degradation under physiological conditions. The prodrug compounds of the present invention are sometimes referred to as monovalent, divalent, trivalent, etc., depending on the number of biotransformation steps required to release the active agent in the organism, the number of Shows the number of functional groups present in the form. Prodrug forms often provide benefits, such as solubility, histocompatibility, or delayed release, in mammalian tissues (Bundgard, Design of Prodrugs, pp. 147-146).
7-9, 21-24 Elsevier, Amsterdam 1985;
Silverman, The Organic Chemistry of
Drug Design and Drug Action, pp. 352
-401, Academic Press, San Diego, CA,
1992). In general, prodrugs known in the art include acid derivatives well known to those skilled in the art, such as esters prepared by the reaction of a suitable alcohol with a parent acid, amides prepared by the reaction of an amine with a parent acid compound, or And amides which are produced by the reaction of an amine or base which reacts to form an acylated base derivative with a parent acid compound. Further, the prodrug derivative of the present invention
It may be combined with other features taught herein to increase bioavailability.

The following structures are illustrative of the compounds of the present invention, but are not intended to be limiting in any way. It should be noted that in the compounds of the present invention, certain substituents are between two other substituents. For example, D is A- and-(
CH ₂ ) _t -E-. Thus, a substituent such as D is a substituent A-
And coupling the left showing the direct connection to the - (CH ₂₎ are illustrated below as having two "suspension" binding right binding indicating a direct connection to _t -E-. Accordingly, the general formula D is _{phenyl, A-D- (CH 2)} t -E- can be described as follows.

D, the phenyl group, can be described in the following table as follows:

In the tables below, other substituents could be presented as having one or more similar “suspended” bonds. It will be appreciated that these show a direct link to the adjacent substituent. It will be understood that the compounds shown below exist as other isomers, and that the forms of the isomers exemplified herein are not intended to be limiting in any way.

The present invention provides compounds of the general formula IV

Wherein R ¹ , R ² and R ³ are H; q is 1; r is 3; s is 0; G is a direct bond; be _{C (NH) NH 2; K} ', K'',K''' and K '''' is -CH-; and Q is Is included].

[0085]

[0086] In the table, "direct bond" refers to "direct bond".

The present invention provides a compound of general structural formula V

[0088] [wherein, R ^1, R ² and R ³ are H; q 2; t is located at 1; A is an H; D is phenyl; E is -SO ₂ - K ′, K ″, K ″ ″ and K ″ ″ are —CH—; and Q is Is included].

[0089]

[0090]

The present invention provides a compound of general structural formula VI

[0092] [wherein, q is an 1; r is an 3; s is an 0; t is an 1; A is an H; D is phenyl; E is -SO ₂ - in Yes; G be a direct bond; J is an _{-NH-C (NH) NH 2} ; K ', K'',K''' and K '''' is -CH-; and Q is Is included].

[0093]

[0094]

The present invention provides compounds of formula VII

Wherein R ¹ , R ² and R ³ are H; q is 0; r is 3; s is 0; t is 1; D is phenyl; E is -SO ₂ - and and; G is a direct bond; J is an _{-NH-C (NH) NH 2} ; and K ', K'', K
'''AndK''''are -CH-].

[0097]

The present invention provides compounds of the general structural formula VIII

Wherein R ¹ , R ² and R ³ are H; q and t are 1; r is 3; s is 0; A is H; There; E is -SO ₂ - and and; G is a direct bond; J is an _{-NH-C (NH) NH 2} ; and Q is Is included].

[0100]

As mentioned above, the compounds of the invention may be used, for example, for the treatment of unstable angina, refractory angina, myocardial infarction, transient ischemic stroke, thrombotic stroke, embolic stroke, septic shock. Pathology of mammals having coagulation disorders such as treatment or prevention of deep vein thrombosis or the like in the prevention of diffuse intravascular coagulation, pulmonary embolism, or reperfusion coronary artery reocclusion or restenosis It has uses as a therapeutic agent for conditions. In addition, these compounds are Xa
Useful for treating or preventing the above-mentioned diseases involving the formation and action of factor / prothrombinase complexes. This includes multiple thrombotic and prothrombotic conditions in which the coagulation cascade is activated, including, but not limited to, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and the complications of surgical thromboembolism And occlusion of peripheral arteries.

Accordingly, a method of preventing or treating a condition in a mammal characterized by unwanted thrombosis comprises administering to said mammal a therapeutically effective amount of a compound of the present invention. In addition to the above-mentioned pathological conditions, other conditions that can be treated or prevented by administration of the compounds of the present invention include, but are not limited to, either thrombolytic therapy or percutaneous transluminal coronary angioplasty. Obstructive coronary thrombus formation, thrombosis of venous vasculature, sporadic intravascular coagulation disease, rapid consumption of coagulation factors, systemic coagulation forms life-threatening thrombi throughout microvessels, resulting in extensive organs Failure, hemorrhagic stroke, renal dialysis, oxygen administration to blood, conditions leading to the application of cardiac catheterization, and the like.

The compounds of the present invention are also useful in a method for preventing coagulation of a biological sample, the method comprising administering a compound of the present invention.

The compounds of the present invention can also be used in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of the present invention may include other compounds typically prescribed for these conditions according to generally accepted medical methods, such as anticoagulants, thrombolytics, or other compounds. Antithrombotic agents, such as platelet aggregation inhibitors, tissue plasminogen activator, urokinase, prourokinase, streptokinase, heparin, aspirin or warfarin
) And the like. The compounds of the present invention may also act in a synergistic manner to prevent reocclusion after successful thrombolytic treatment and to reduce the time to reperfusion. These compounds can reduce the dose of thrombolytic used and also minimize possible bleeding side effects. The compounds of the invention can be used in vivo, usually in mammals, such as primates (such as humans), sheep, horses, cows, pigs, dogs, cats, rats, and mice, or in vitro.

The biological properties of the compounds of the invention can be determined by methods well known in the art, such as in vitro protease assays and in vivo tests, as shown in the Examples below, as well as their antithrombolytic potency, and The effect on hemostasis and hematological parameters can be assessed and easily characterized.

To adapt the compounds of the present invention for diagnosis, formulations in the form of solutions or suspensions, are typically utilized. In the management of thrombotic disorders, the compounds of the present invention are used in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions, or injectable dosage forms. Or it may be incorporated into a shaped article. A subject in need of treatment using a compound of the present invention can be administered a dose that provides optimal efficacy. Dosage and method of administration will vary from subject to subject, and will include the type of mammal being treated, sex, weight, diet, co-administered drugs, overall clinical conditions, the particular compound used, It will depend on factors such as the particular use of the compound and other factors which those skilled in the medical arts will recognize.

Formulations containing a compound of the present invention are prepared for storage or administration by mixing a compound having the desired purity with a physiologically acceptable carrier, excipient, stabilizer and the like. It may also be provided as a delayed or time release formulation.
Therapeutically acceptable carriers or diluents are well known in the pharmaceutical art, and include, for example, Remington's Pharmceutical Science.
s, Mack Publishing Co., Ltd. , (AR Gennaro). Such substances are non-toxic to recipients at the dosages and concentrations employed, e.g., buffers such as phosphoric acid, citric acid, acetic acid and other organic acid salts, antioxidants such as ascorbic acid, poly (organic acid). Low molecular weight such as arginine (about 1
Less than 0 residues) peptides, proteins such as serum albumin, gelatin or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid or arginine, monosaccharides, disaccharides and cellulose or Derivatives thereof, glucose, other carbohydrates including mannose or dextrin, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counter ions such as sodium, and nonionic surfactants such as tween, pluronic or polyethylene glycol Is mentioned.

Dosage formulations of a compound of the present invention for use in therapeutic administration must be sterile. Sterility can be readily achieved by filtration through sterile membranes, such as 0.2 micron membranes, or by other conventional methods. The formulation is typically stored in lyophilized form or as an aqueous solution. PH of the administration agent of the present invention
Is typically 3-11, more preferably 5-9, and most preferably 7-8. It will be appreciated that certain of the foregoing excipients, carriers, or stabilizers that result in the formation of cyclic polypeptide salts. The preferred route of administration is by injection, but other modes of administration, such as oral, intravenous (pills and / or infusion), subcutaneous, intramuscular, colon, rectal, or through the nose, transdermally or intraperitoneally The way
It is also expected to be carried out using various dosage forms, for example, suppositories, implanted pellets or small cylinders, aerosols, microcapsules, oral preparations, and topical preparations such as ointments, drops, and skin patches. The compounds of the present invention are desirably incorporated into shaped articles such as implants employing inert materials such as biodegradable polymers or synthetic silicones, such as silastic silicone rubber, or other commercially available polymers.

The compounds of the present invention can also be administered in the form of liposome delivery systems such as small unilamellar cells, large unilamellar cells and multilamellar cells. Liposomes can be formed from various lipids, such as cholesterol, stearoylamine, or phosphatidylcholine.

The compounds of the present invention may be delivered using an antibody, antibody fragment, growth factor, hormone, or other targeting moiety, to which the compound molecule is attached. The compounds of the present invention may be conjugated to a suitable polymer as a targetable drug carrier. Such polymers include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-propyl-methacrylamide phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention are useful in providing a class of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon caprolactone, polyhydroxy Butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and may be linked to block copolymers of crosslinked or amphiphilic hydrogels. The polymer and semipermeable polymer matrix may be formed into shaped articles such as valves, stents, tubes, prostheses, and the like.

Generally, liquid preparations of a therapeutic compound will be packaged in a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
Can be put in.

The therapeutically effective dose can be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual decisions will be made to determine the optimum dosage required. The therapeutically effective dose range depends on the route of administration, the purpose of the treatment, and the condition of the patient. In the case of injection with a hypodermic injection needle, it can be assumed that the administered agent is delivered to a body fluid. For other routes of administration, the absorption efficiency must be determined individually for each compound by methods well known in pharmacy. Thus, it will also be necessary for the treating individual to titrate the dosage form and alter the route of administration necessary to obtain the optimal therapeutic effect. Determination of an effective dose level, ie, the dose level necessary to achieve the desired result, will be readily determined by one skilled in the art. Typically, application of the compound is initiated initially at low dose levels, and is escalated until the desired effect is finally achieved.

The compounds of the present invention can be administered orally or parenterally in an effective amount, ie, about 0,1.
1 to 100 mg / kg, preferably about 0.5 to 50 mg / kg, more preferably about 1 to 20 mg / kg, in a single dose or in 2 to 4 doses per day, or continuously. It can be administered in a therapeutic mode in which it is injected.

Typically, from about 5 to 500 mg of a compound or mixture of compounds of the present invention comprises
Physiologically acceptable vehicles, carriers, excipients, in free acid or base form or as pharmaceutically acceptable salts, as required by acceptable pharmaceutical practice.
It is formulated together with binders, preservatives, stabilizers, coloring agents, fragrances and the like. The amount of active ingredient in these compositions is such that a suitable dosage in the range recited is obtained.

Typical adjuvants that can be incorporated into tablets, capsules, etc. are binders such as acacia, corn starch or gelatin, and excipients such as microcrystalline cellulose, disintegrants such as corn starch and alginic acid, magnesium stearate. And sweeteners such as sucrose and lactose, or fragrances. When the dosage form is a capsule, it may contain, in addition to the above materials, liquid carriers such as water, saline, fatty oils, and the like. Various other materials may be used as coatings or modifiers in physical form for a dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension in a vehicle such as oil or a synthetic fat vehicle such as ethyl oleate or in liposomes is desirable. Buffers, preservatives, antioxidants and the like may be incorporated according to acceptable pharmaceutical practice.

Preparation of the Disclosed Compounds The compounds of the present invention can be synthesized by either the solid phase method or the liquid phase method, or a combination of both methods, described in standard texts and cited in the literature. Is also good.
These methods are well-known in the art. Bodanszky, "T
he Principles of Peptide Synthesis "
Hanfer, et al. , Eds. , Springer-Verla
g, Berlin, 1984.

The starting materials used in any of these methods are also Aldrich, Sigma
, Nova Biochemicals, Bachem Bioscience
It can be obtained commercially from chemical suppliers such as s or can be easily synthesized by known procedures.

Reactions are performed under standard temperature and pressure reaction conditions, in standard laboratory glassware and reaction vessels, unless otherwise noted. The reaction product is isolated and purified by conventional methods, typically by solvent extraction into a suitable solvent. The product can be purified by column chromatography or other suitable methods. Most compounds are purified by reverse phase HPLC and can be characterized by ion spray mass chromatography.

During the synthesis of these compounds, the functional groups of the amino acid derivatives used in these methods are protected by protecting groups to prevent side reactions during the coupling operation. For examples of suitable protecting groups and their use, see “The Peptide: Anal.
ysis, Synthesis, Biology ", Academic
Press, Vol. 3 (Gross et al., 1981) and Vol. 9 (198
7), the disclosure of which is incorporated herein by reference.

The compounds of the present invention are preferably prepared by standard amide bond formation methods using the formula (a)
) Can be produced by coupling the carboxylic acid of the formula (b) to the amine of the formula (b).

Compounds of formula (b) wherein Q is H are described in WO 96/01338, WO 96/246
09, Feng et al., WO 96/31504, and WO 96/32110. These disclosures are incorporated herein by reference.

Compounds of formula (b) wherein Q is a boron-containing compound are described in J. Org . Chem . 6
0: 3717-3722 (1995), and EP by de Nanteuil et al.
688, 788. These disclosures are incorporated herein by reference.

Compounds of formula (b) wherein Q is —C (O) —T, where T is H, are described in WO 93/15756, Vlasuk et al., WO 94/17817, Abelman
Other WO94 / 21673, Webb other WO94 / 08941, Verber other W
O94 / 25051, Levy et al. WO95 / 35312, Simple et al. WO9
5/35313, Abelman et al. WO 95/28420, and Abelma
n, etc. by the method disclosed in WO 96/19493. These disclosures are incorporated herein by reference.

Compounds of formula (b) wherein Q is —C (O) —T, wherein T is COOR ²³ or CONR ²³ R ²⁴ are described in WO 94/25051, WO 94/089
41 and the above-mentioned WO 94/21673. These disclosures are incorporated herein by reference.

Compounds of formula (b) wherein Q is —C (O) —T, wherein T is —CF ₃ or —CF ₂ CF ₃ , may be prepared by the method disclosed in Schacht et al. GB 2287027. Can be. These disclosures are incorporated herein by reference.

Q is —C (O) —T, where T is the following formula:

And V is —SO—, —SO—, —O—, or —SO ₂ —. Compounds of formula (b) are described in Constanzo et al., US Pat. No. 5,223,308, Di.
Maio Other WO96 / 19483, U.S. Pat. No. 5,164,371, J. A m. Chem . Soc . 114: 1854-1863 (1992), J . Med . Chem . 38: 76-85 (1995), and, J. Med . Chem .
37: 3492-3502 (1994). Finally, fragments wherein V is -NR ^21- where R ²¹ is H, C _1-6 alkyl or benzyl are described in J. Am . Med . Chem . 37:34
92-3502 (1994). All of these references are incorporated herein by reference.

Q is —C (O) —T, where T is the following formula

And U ′ and U ″ are various substituents (—O—, —S—, —N—, —
Is NH-) compound of formula (b) is, J. Med . Chem . 38: 1355-
1371 (1995) and J. Med . Chem . 37: 2421-2436
(1994). These disclosures are incorporated herein by reference.

The starting compounds of formula (a) are known compounds or can be prepared by known methods (Heisch et al., Canadian Patent 2,071,744; Sugihara et al., Canadian Patent 2,126,026). Baker et al., EP 365,992, U.S. Pat. No. 4,251,438; Carr et al., U.S. Pat. No. 4,341,698, Gol.
US Patent No. 5,120,718, Biswanath et al. US Patent No. 5,164,388, Dugan et al. US Patent No. 5,281,585, Sugihara et al. US Patent No. 5,294,713, Bobby et al. WO95 / 06038, W
O95 / 35308, J. Chem . Soc . Perkin . Trans . I
1687-1689 (1989), and Int. J. Peptide. Pro
tein. Res. 37: 468-47 (1991)) or by a method represented by the following reaction formula.

The following reaction diagram shows the above reaction formula more specifically. The chemistry shown in each figure can be easily modified and combined by other techniques well known in the art to produce other compounds within the scope of the invention. Scheme I

[0132]

The reagents used in the eight steps in the scheme are synthesized as follows.

Without further elaboration, it is believed that one skilled in the art can utilize the present invention to its fullest extent. Accordingly, the following preferred specific embodiments should be construed as illustrative only and are not limiting of the remaining disclosure in any way.

[0135]

【Example】

(Example 1) Manufacturing of

Boc-L-Arg (Tos) —OH (2 g, 4.7 mmol) in DMF (2
0 mL) to a suspension (0 ° C.) was added MeNHOMe · HCl (1 g, 10.3 mmol).
), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol) were added.
The solution was stirred at 0 ° C. for 10 hours. DMF was evaporated under reduced pressure. The oily residue was dissolved in EtOAc (200 mL) and water (20 mL). The organic layer was washed with saturated NaHCO ₃ , water (20 mL), 1 M hydrochloric acid (10 ml), and saturated saline (2 × 20 mL). The organic layer was dried over MgSO _4, filtered, to obtain a suspension by emitted steam. The suspension was filtered and the solid was cooled to cold EtOAc (10 mL
) And dried to obtain the above Boc-Arg (Tos) -N (Me) OMe (1.5 g, yield 70%). FAB-MS (M + H) + = 472

(Example 2) Manufacturing of

A solution of thiazole (2.5 g, 29 mmol) in THF (25 mL) (−78 ° C.)
) Was added dropwise to n-BuLi (1.6 mL in 19 mL hexane). The mixture was stirred for 30 minutes. Next, the Boc-Arg (Tos) -N (Me) OMe from Example 1 (1.7 g, 3.6 mm) was added to the lithiozole mixture at −78 ° C.
ol) in THF (50 mL). The solution was stirred for 2 hours. 1 M hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was heated to room temperature. This mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated brine (30 mL), dried over MgSO _4, filtered and evaporated. The crude oily residue was subjected to flash column chromatography on SiO ₂ (50% EtOAc in CH ₂ Cl ₂ ) to give the above Boc-Arg (Tos) -thiazole as a powder (1
. 5 g, 84% yield). DCI-MS (M + H) + = 496

(Example 3) Manufacturing of

Boc-Arg (Tos) -thiazole from Example 2 (300 mg, 0.6
(mmol) in CH ₂ Cl ₂ (10 mL) (0 ° C.) was added TFA (10 mL). The solution was stirred at 0 ° C. for 2 hours. Evaporation of the solvent and excess TFA gave an oily residue which was used directly without further purification.

Example 4 (S) -N- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl] glycine Manufacturing of

The title compound was prepared with minor modifications to the method described in Biopolymers (38) 1-12 (1996).

Under argon, N-phthaloyl-L-phenylalanine (10.0 g, 33.9 m
mol), EDC (15.9 g, 83.0 mmol) and NHS (8.77 g, 76.2 mmol) in DCM (100 mL) was stirred overnight at ambient temperature. The reaction mixture was then concentrated to give a residue, which was treated with dioxane (1
00 mL). To this mixture was added glycine (6.35 g, 84.7 mmol)
And an aqueous solution (100 mL) of sodium bicarbonate (5 g) was added and the reaction was stirred overnight. Most of the solvent was removed by concentration and the residue was acidified with 1N hydrochloric acid to give a white, opaque mixture. This was extracted with EtOAc (3 × 50 mL) and the combined organic layers were washed several times with 1N hydrochloric acid and water alternately. The organic matter was dried over magnesium sulfate and concentrated to give a white solid. This was triturated several times with a minimum of Et ₂ O and the crude desired product was recovered as a white solid using filtration (9.78 g).

Example 5 (S) -3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -1-oxo-3-phenylpropyl]- Production of 5-oxazolidinone

The title compound was prepared with minor modifications to the method described in Biopolymers (38) 1-12 (1996).

The dipeptide from Example 4 (9.62 g, 27.3 mmol), paraformaldehyde (20.5 g, 25 eq) and p-TsOH (550 mg, 0.1 eq)
A solution of this mixture in toluene (555 mL) was heated to reflux using a Dean-Stark water separator. Over the course of 4 hours, three more aliquots of paraformaldehyde (4 g, 5 eq) were added every hour. Thereafter, all the dipeptide starting material had been consumed by TLC analysis. Residue in EtOAc (500 mL)
And saturated aqueous sodium bicarbonate (250 mL) and the solids were removed by decantation. The layers were separated and the organic was washed with saturated sodium bicarbonate and saturated sodium chloride, and then dried over magnesium sulfate. Filtration and concentration provided the desired product as an off-white solid (6.77 g). This material was used for the next step without further purification.

Example 6 (S) -4- (1,3-Dihydro-1,3-dioxo-2H-isoindole-
Production of 2-yl) -1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetic acid

The title compound was prepared by the method described in Biopolymers (38) 1-12 (1996).

A solution of the oxazolidinone from Example 5 (924 mg, 2.54 mmol) in dry DCM (6 mL) was treated with trifluoromethanesulfonic acid (5 g) at ambient temperature. The reaction mixture turned dark brown and was stirred overnight at ambient temperature. DCM (5
0 mL) was added, the mixture was cooled in an ice-water bath, and about 10 g of ice was added. The organic layer was washed with water (2 × 30 mL) and saturated sodium chloride (50 mL), and then extracted with a 6% aqueous sodium bicarbonate solution (3 × 50 mL). PH of aqueous layer with concentrated hydrochloric acid
Acidified to 2 and extracted with DCM (3 × 50 mL). The organics were dried over sodium sulfate and concentrated to give a slightly sticky yellow solid. Upon treatment with DCM, the product could be isolated as a pale yellow powder solid (799mg).

Example 7 Production of (S) -4-Amino-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetic acid

The title compound was produced by the method described in Biopolymers (38) 1-12 (1996).

A solution of the phthalimidic acid from Example 6 (720 mg, 1.98 mmol) and hydrazine monohydrate (593 mg, 12 mmol) in absolute ethanol (25 mL) was gently heated to reflux for 2 hours, then cooled and concentrated did. The residue was washed with water (20
mL) and the solution was acidified to pH 5 with glacial acetic acid. The mixture is stirred for one hour,
Filtration then yielded 180 mg of a white solid, which was determined by HPLC analysis to be a mixture of the desired product and phthaloylhydrazine. The solid was stirred for 10 minutes with 1N acetic acid, filtered and the filtrate was concentrated to give 461 mg of a white solid, which was determined by HPLC to be 90% of the desired product and 10% of phthaloylhydrazide. Was. This mixture was used for the next reaction without further purification.

Example 8 Production of (S) -4-Amino-1,3,4,5-tetrahydro-3-oxo-2H-2-benzazepine-2-acetic acid, methyl ester

The MeOH (5 mL) was cooled in an ice-acetone bath and thionyl chloride (60 μL) was added. The solution was stirred for 1 minute and then the amino acid from Example 7 (163 m
g, 0.70 mmol) were added all at once. After removing the cooling bath, the reaction was stirred while warming to ambient temperature over 1 hour and then heated to 40 ° C. for an additional 1.5 hours. The reaction mixture was concentrated to dryness and the residue was subjected to HPLC analysis,
The reaction was shown to be incomplete, so the above reaction sequence was repeated, but this time the reaction was finally heated for 0.5 hour. The reaction mixture was concentrated to dryness to give the product (168 mg, 97%) as a pale yellow solid.

(Example 9) Manufacturing of

A solution of the aminomethyl ester from Example 8 (168 mg, 0.70 mmol) in dichloromethane (5 mL) was cooled to −78 ° C. and DIEA (410 mL, 3.5 eq) and α-toluenesulfonyl chloride ( 143 mg, 0.75 mmol) were added. The reaction was then warmed to ambient temperature over 3 hours. The reaction was incomplete, so the reaction was cooled again to -78 ° C and additional α-toluenesulfonyl chloride (52 mg, 0.27 mmol) was added. The reaction was then stirred overnight while warming to ambient temperature. The reaction mixture is concentrated to dryness and the residue is purified by flash column chromatography on silica gel (30% ethyl acetate in hexane then 50% ethyl acetate in hexane) to give the desired product as a white solid (182 mg, 67%) was gotten.

(Example 10) Manufacturing of

A mixture of the sulfonamide methyl ester from Example 9 (58 mg, 0.14 mmol), 1 N hydrochloric acid (10 mL) and MeOH (3 mL) was heated at 70 ° C. for 24 hours and the progress of the reaction was monitored by HPLC. Upon completion of the reaction, the mixture was lyophilized to give a gummy residue. This material was again lyophilized from water (5 mL) to give the solid, crude form of the desired product (85 mg). This material was used for the next step without further purification.

(Example 11) Manufacturing of

To a solution of Boc-Arg (Tos) -thiazole from Example 2 (89 mg, 0.18 mmol) in DCM (2 mL) was added TFA (2 mL) and the reaction was stirred at ambient temperature for 40 minutes. Concentration gave a residue, which was taken up in DCM (5 mL),
Concentration again provided the free amine of the TFA salt. Add this material to DMF (1 mL)
And the crude product from Example 10 was added to a solution of the acid in DMF (2 mL).
The pH of the solution was raised to 9 using DIEA (200 μL) and the reaction mixture was placed in an ice-water bath. BOP reagent (80 mg, 0.18 mmol) was added and the reaction mixture was checked on pH paper to confirm that it remained basic and stirred overnight while warming to ambient temperature. The solution was then partitioned between ethyl acetate (50 mL) and 0.1 N hydrochloric acid (25 mL), the organics were washed with saturated sodium bicarbonate (2 × 25 mL), saturated sodium chloride (25 mL), and finally sulfuric anhydride Dried with sodium.
Filtration and concentration gave a crude product (105 mg) as an orange solid, which was used for the next reaction without further purification. APCI-MS (M + H ^< + ^> ) = 766.

Example 12 Compound VI (4): Manufacturing of

A mixture of the crude product from Example 11, anisole (1 mL) and ethyl methyl sulfide (250 mL) and 500 mg of Merrifield resin were cooled with liquid nitrogen and treated with HF (5 mL). The reaction was stirred in an ice water bath for 1 hour, then HF was removed under vacuum. The residue was washed with ether (2 × 50 mL) and the dried resin was extracted twice with 2M aqueous acetic acid (25 mL, then 5 mL). Lyophilization of the aqueous solution provided a crude solid product, which was purified by reverse phase HPLC to give the desired product as a white solid (12 mg). APCI-MS (M
+ H ⁺ ) = 612

Example 13 Determination of IC ₅₀ First, a compound of the invention is dissolved in a buffer to obtain a solution containing a concentration such that the assay concentration ranges from 0 to 100 μM. In assays for thrombin, prothrombinase and factor Xa, a synthetic chromogenic substrate is added to a solution containing a test compound and the enzyme in question, and the residual catalytic activity of the enzyme is measured spectrophotometrically.

The IC ₅₀ of a compound is determined from the substrate turnover. IC ₅₀ is the concentration of test compound that inhibits substrate turnover by 50%. Preferred compounds of the invention are desirably less than 500 nM, preferably less than 200 nM, in factor Xa assays.
It has an IC ₅₀ of less than nM, more preferably less than 100 nM. Preferred compounds of the present invention desirably have an IC ₅₀ in the prothrombinase assay of less than 4.0 μM, preferably less than 200 nM, more preferably less than 10 nM. Preferred compounds of the present invention desirably have an IC ₅₀ in the thrombin assay of greater than 1.0 μM, preferably greater than 10.0 μM, more preferably greater than 100.0 μM.

Amide Degradation Assay to Measure Protease Inhibitory Activity The factor Xa and thrombin assay contains 0.15 M NaCl at room temperature,
Performed in 0.02 M Tris-HCl buffer, pH 7.5. Para-nitroanilide substrate S-2765 (Chromogenix) for factor Xa and Chromozym TH (Boehringer Man) for thrombin
heim) was pre-incubated with the enzyme and test compound for 5 minutes at room temperature, followed by S
oftmax 96-well plate reader (Molecular Devi)
Using ce), monitor at 405 nm and determine the time-dependent appearance of p-nitroanilide.

A prothrombinase inhibition assay is described in Sinha et al., Trom . Res . ,
75: 427-436 (1994), with a modification of the method described in the plasma release system. The activity of the prothrombinase complex is determined by measuring the time course of thrombin generation using the p-nitroanilide substrate Chromozym TH. The assay consists of 0.15 M NaCl at pH 7.5,
From factor Xa (0.5 nM), factor Va (2 nM), phosphatidylserine: phosphatidylcholine (25:75, 20 μM) in 20 mM Tris-HCL buffer containing 5 mM CaCl ₂ and 0.1% bovine serum albumin. It consists of preincubating the complex formed and the selected compound to be tested as an inhibitor for 5 minutes. Aliquots of the mixture of complex and test compound were added to prothrombin (1 nM)
And Chtomozym TH (0.1 mM). Substrate cleavage rate of 405
Measure in nm for 2 minutes. Multiple concentrations of a given test compound are assayed in duplicate. The percent inhibition is determined using a standard curve of thrombin generation by an equivalent amount of untreated complex.

The compounds of the present invention showed inhibitory activity in the above factor Xa assay. Preferred compounds of the present invention have an IC ₅₀ value of less than 100 nM.

Example 14 The antithrombotic effect of the compound of the present invention can be easily evaluated by performing a series of tests on rabbits as described below. These tests are also useful when assessing a compound's hemostasis and its effect on hematological parameters. Antithrombotic effects in a rabbit model of venous thrombosis Hollenbach et al., Thromb . Haemost . 71: 357-
362 (1994) using a rabbit severe thrombosis model to measure the in vivo antithrombotic activity of the compounds of the invention. Rabbits were anesthetized by intramuscular injection of a cocktail of ketamine, zirazine, and acepromazine.

A standardized protocol consists of inserting a clot-forming cotton thread and a copper wire device into the abdominal vena cava of anesthetized rabbits. Non-occlusive thrombi are developed in the central venous circulation and then thrombus growth inhibition is used as a measure of the antithrombotic activity of the compound being evaluated. The test agent and the subject saline are administered via a marginal ear vein catheter. A femoral vein catheter is used to draw blood before and during steady state infusion of the compound being evaluated. The onset of thrombus formation occurs shortly after the cotton thread device is delivered to the central venous circulation. The compound to be evaluated is administered for a period of 150 minutes starting at 30 minutes, at which point the experiment is terminated. Rabbits are euthanized and thrombus is dissected by surgical resection and characterized by weight and histology. The blood sample is then analyzed for changes in hematological and coagulation parameters.

While the invention has been described with reference to disclosed embodiments, it will be readily apparent to one skilled in the art that the specific experiments detailed are merely illustrative of the invention. I can do it. It should be understood that various changes can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Scarborough, Robert, M. United States, Belmont, California, Belmont Canyon Road 2544 F Term (Reference) 4C084 AA02 AA07 BA01 BA14 BA25 DC17 NA05 ZA402 ZA542 ZC202 4H045 AA10 AA30 BA05 BA11 BA12 BA51 DA56 EA24 GA25 HA02

Claims (49)

[Claims] 1. The formula:[Where R¹And R^TwoIs independently H, C_1-6Alkyl, C_3-8Cycloalkyl, C_{1- Three} Alkylaryl, C_1-3Alkyl-C_3-8R is selected from the group consisting of cycloalkyl and aryl;^ThreeIs H, C_1-6Alkyl or R^TwoAnd R^ThreeTogether form a cyclic carbon
Q is an integer of 0 to 2, r is an integer of 0 to 4, s is an integer of 0 to 1, t is an integer of 0 to 4, A is R⁸, -NR⁸R⁹,Selected from the group consisting of⁸, R⁹, R^TenAnd R¹¹Is independently H, -OH, C_1-6Alkyl, aryl and C_1-4R is selected from the group consisting of alkylaryl;¹²Is H, C_1-6Alkyl, aryl and C_1-4Selected from the group consisting of alkylaryls
Or R^TenOr R¹¹And can form a 5- to 6-membered ring with¹³Is
H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl
Or R¹¹Can form a 5- or 6-membered ring together with D);_3-8Cycloalkyl, C_1-6Alkenyl, C_1-6Alkenyl aryl, aryl and 1 to 4 selected from the group consisting of N, O and S
Wherein E is a direct bond, -CO-, -SO_Two-, -O-CO-, -NR¹⁴-SO_Two-Oh
And -NR¹⁴-CO- [where R¹⁴Is H, -OH, C_1-6Alkyl, aryl and C_1-4G is a direct bond, C is selected from the group consisting of_3-85- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of cycloalkyl, aryl and N, O and S
J is selected from the group consisting of^Fifteen, -NR^FifteenR¹⁶,Selected from the group consisting of^Fifteen, R¹⁶, R¹⁷And R¹⁸Is independently H, -OH, C_1-6Alkyl, aryl and C_1-4R is selected from the group consisting of alkylaryl;¹⁹Is H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl
Or R¹⁷Or R¹⁸And can form a 5- to 6-membered ring with²⁰Is
, H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl
Selected or R¹⁸And a 5- or 6-membered ring can be formed (provided that J is R^Fifteenso
In some cases, G must include at least one N atom)]; K ′, K ″, K ″ ″ and K ″ ″ are independently —CH—, —CR^Four-, -CR^Five -And -N-, where K ', K ", K"' and K "
Only one of '' is -CR^FourAnd only one of K ', K ", K"' and K "" is -CR^FiveWherein R is^FourAnd R^FiveIs independently H, C_1-6Alkyl, aryl, C_1-6Al
Killaryl, C_1-4Alkyloxy, halogen, -NO_Two, -NR⁶R⁷, -NR ⁶ COR⁷, -OR⁶, -OCOR⁶, -COOR⁶, -CONR⁶R⁷, -CN, -CF_Three, -SO_TwoNR⁶R⁷And C_1-6Alkyl-OR⁶Selected from the group consisting of
(Where R⁶And R⁷Is independently H, C_1-6Alkyl, C_1-3Alkyl ants
And Q is H,Selected from the group consisting of^{twenty one}And R^{twenty two}Is independently H, C_1-3Selected from the group consisting of alkyl and aryl; and T is H, -COOR^{twenty three}, -CONR^{twenty three}R^{twenty four}, -C
F_Three, -CF_TwoCF_ThreeAnd expressionsSelected from the group consisting of groups having the formula:^{twenty three}And R^{twenty four}Is independently H, C_1-6Alkyl, aryl and C_{1 -Four} U ′ and U ″ are independently selected from the group consisting of —O—, —S—, —N— and —NH—, provided that U ′ or At least one of U ″ is —N— or —NH—);^{twenty five}Is H, C _1-6 Alkyl, C_2-6Alkenyl, C_0-6Alkylaryl, C_2-6Alkenyl ant
, C_0-6Alkyl heterocyclo, C_2-6Alkenylheterocyclo, -CF_ThreeAnd -CF_TwoCF_ThreeV is -S-, -SO-, -SO_Two -, -O- and -NR²⁶− (Where R²⁶Is H, C_1-6W is selected from the group consisting of alkyl and benzyl; and W isAnd R²⁹And R³⁰1 to 4 selected from N, S and O
C heteroatoms_6-10Selected from the group consisting of heterocyclic ring systems; wherein a
Is an integer from 0 to 2;²⁷And R²⁸Is independently H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, -COOR³¹, -CONR³¹R³², -CN and -CF_ThreeAnd R is selected from the group consisting of²⁹And R³⁰Is, independently, H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, C_1-4Alkyloxy, halogen, -NO_Two, -NR³¹R³², -NR³¹COR³², -OR³¹, -OCOR³¹, -COOR³¹, -CONR³¹R³², -CN, -CF_Three, -SO_TwoNR³¹R³² And C_1-6Alkyl-OR³¹Selected from the group consisting of³¹And R³²Is independently H, C_1-6Alkyl, C_1-3Alkylaryl and aryl
Selected from the group consisting of:)]], and all pharmaceutically acceptable salts thereof and their optics
Isomer. 2. R ¹ is selected from the group consisting of H and C _1-6 alkyl;
A compound according to claim 1. 3. The compound according to claim 2, wherein R ¹ is selected from the group consisting of H and methyl. 4. The compound according to claim 3, wherein R ¹ is H. 5. The compound according to claim 1, wherein R ² is selected from the group consisting of H and C _1-6 alkyl. 6. The compound according to claim 5, wherein R ² is selected from the group consisting of H and methyl. 7. The compound according to claim 6, wherein R ² is H. 8. The compound according to claim 1, wherein R ³ is H. 9. The compound according to claim 1, wherein R ⁴ is halogen. 10. The compound according to claim 1, wherein R ⁵ is halogen. 11. The compound according to claim 1, wherein the integer “r” is 3. 12. The compound according to claim 1, wherein the integer “s” is 0. 13. The compound according to claim 1, wherein the integer “t” is 0-1. 14. The compound of claim 1, wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of H and C _1-6 alkyl. 15. The compound according to claim 14, wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of H and methyl. 16. The compound according to claim 1, wherein R ¹² is H or C _1-6 alkyl, or forms a 5- or 6-membered ring with R ¹⁰ or R ¹¹ . 17. The compound according to claim 16, wherein R ¹² is H or methyl. 18. The compound according to claim 1, wherein R ¹³ is H or C _1-6 alkyl, or forms a 5- or 6-membered ring with R ¹⁰ . 19. The compound according to claim 18, wherein R ¹³ is H or methyl. 20. A 5 to 10 membered heterocyclic ring system wherein D is a direct bond, C _3-8 cycloalkyl, aryl and from 1 to 4 heteroatoms selected from the group consisting of N, O and S. 2. The compound according to claim 1, wherein the compound is selected from the group consisting of: 21. E is a direct bond, -CO- or -SO ₂ - A compound according to claim 1. 22. The compound of claim 1, wherein G is a direct bond. 23. R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are independently:
It is selected from the group consisting of H and C _1-6 alkyl, A compound according to claim 1. 24. R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are independently:
24. The compound of claim 23, wherein the compound is selected from the group consisting of H and methyl. 25. At least three of K ′, K ″, K ″ ″ and K ″ ″ are —CH
2. The compound according to claim 1, which is-. 26. The compound of claim 25, wherein K ′, K ″, K ″ ″ and K ″ ″ are all —CH—. 27. Q is 2. The compound according to claim 1, which is 28. The compound according to claim 27, wherein R ²¹ is H. 29. The compound according to claim 28, wherein R ²² is H. 30. T is H, -COOR ²³ , -CONR ²³ R ²⁴ or a formula 28. The compound according to claim 27, which is a group having 31. The compound according to claim 30, wherein R ²³ is H. 32. The compound of claim 30, wherein R ²⁴ is C _1-4 alkylaryl. 33. The method according to claim 30, wherein V is —S—, —O—, or —NR ²⁶ —.
The compound according to the above. 34. The compound according to claim 33, wherein R ²⁶ is H or methyl. 35. The compound according to claim 34, wherein R ²⁶ is H. 36. W is 31. The compound of claim 30, wherein the compound is selected from the group consisting of: 37. W is 37. The compound of claim 36, which is 38. R ²⁹ and R ³⁰ are independently H, —O—R ³¹ , —COO
R ^31, is selected from the group consisting of -CONR ³¹ R ³² or -CF _3, A compound according to claim 36. 39. The compound according to claim 38, wherein R ²⁹ is H. 40. The compound according to claim 38, wherein R ³⁰ is H. 41. W is The compound of claim 1, wherein R ²⁷ is H. 42. The compound according to claim 41, wherein R ²⁸ is H. 43. T is In and, U 'is O, U''is N, R ²⁵ is -CF ₃ or -CF ₂ CF _3, A compound according to claim 37. 44. The formula:[Where R¹Is H, C_1-6Alkyl, C_3-8Cycloalkyl, C_1-3Alkylaryl,
C_1-3Alkyl-C_3-8Selected from the group consisting of cycloalkyl and aryl; q is an integer from 0 to 2; r is an integer from 0 to 4; t is an integer from 0 to 4;⁸, -NR⁸R⁹,Selected from the group consisting of⁸, R⁹, R^TenAnd R¹¹Is independently H, -OH, C_1-6Alkyl, aryl and C_1-4R is selected from the group consisting of alkylaryl;¹²Is H, C_1-6Alkyl, aryl and C_1-4Selected from the group consisting of alkylaryls
Or R^TenOr R¹¹And can form a 5- to 6-membered ring with¹³Is
H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl
Or R¹¹Can form a 5- or 6-membered ring together with D);_3-8Cycloalkyl, C_1-6Alkenyl, C_1-6Alkenyl aryl, aryl and 1 to 4 selected from the group consisting of N, O and S
Wherein E is a direct bond, -CO-, -SO_Two-, -O-CO-, -NR¹⁴-SO_Two-Oh
And -NR¹⁴-CO- (where R¹⁴Is H, -OH, C_1-6Alkyl, aryl and C_1-4G is a direct bond, C is selected from the group consisting of_3-85- to 10-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of cycloalkyl, aryl and N, O and S
J is selected from the group consisting of^Fifteen, -NR^FifteenR¹⁶,Wherein R is selected from the group consisting of^Fifteen, R¹⁶, R¹⁷And R¹⁸Is independently H, -OH, C_1-6Alkyl, aryl and C_1-4R is selected from the group consisting of alkylaryl;¹⁹Is H, C_{1 -6} Alkyl, aryl and C_1-4Selected from the group consisting of alkylaryl, or R¹⁷Or R¹⁸And can form a 5- to 6-membered ring with²⁰Is H,
C_1-6Alkyl, aryl and C_1-4Selected from the group consisting of alkylaryl
Or R¹⁸And a 5- or 6-membered ring can be formed (provided that J is R^FifteenPlace that is
G must contain at least one N atom), T is H, -COOR^{twenty three}, -CONR^{twenty three}R^{twenty four}, -CF_Three, -CF_TwoCF_ThreeAnd expressionIs selected from the group consisting of:^{twenty three}And R^{twenty four}Is independently H, C_1-6Alkyl, aryl and C_{1 -Four} U ′ and U ″ are independently selected from the group consisting of —O—, —S—, —N— and —NH—, provided that U ′ or At least one of U ″ is —N— or —NH—);^{twenty five}Is H, C _1-6 Alkyl, C_2-6Alkenyl, C_0-6Alkylaryl, C_2-6Alkenyl ant
, C_0-6Alkyl heterocyclo, C_2-6Alkenylheterocyclo, -CF_ThreeAnd -CF_TwoCF_ThreeV is -S-, -SO-, -SO_Two -, -O- and -NR²⁶− (Where R²⁶Is H, C_1-6W is selected from the group consisting of alkyl and benzyl; and W isAnd R²⁹And R³⁰1 to 4 selected from N, S and O
Containing two heteroatoms_6-10Selected from the group consisting of heterocyclic ring systems; wherein a is
An integer from 0 to 2; R²⁷And R²⁸Is independently H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, -COOR³¹, -CONR³¹R³², -CN and -CF_ThreeAnd R is selected from the group consisting of²⁹And R³⁰Is independently H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, C_1-4Alkyloxy, halogen, -NO_Two, -NR³¹R³², -NR³¹COR³², -OR³¹, -OCOR^{Three 1} , -COOR³¹, -CONR³¹R³², -CN, -CF_Three, -SO_TwoNR³¹R³²And C_1-6Alkyl-OR³¹Selected from the group consisting of³¹And R^{Three Two} Is independently H, C_1-6Alkyl, C_1-3Selected from the group consisting of alkylaryl and aryl)]]], and all pharmaceutically acceptable salts thereof and their optics
Isomer. 45. The formula:[Wherein, q is an integer of 0 to 2, t is an integer of 0 to 4, A is R⁸, -NR⁸R⁹,Selected from the group consisting of⁸, R⁹, R^TenAnd R¹¹Is independently H, -OH, C_1-6Alkyl, aryl and C_1-4R is selected from the group consisting of alkylaryl;¹²Is H, C_1-6Alkyl, aryl and C_1-4Selected from the group consisting of alkylaryls
Or R^TenOr R¹¹And can form a 5- to 6-membered ring with¹³Is
H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl
Or R¹¹Can form a 5- or 6-membered ring together with D);_3-8Cycloalkyl, C_1-6Alkenyl, C_1-6Alkenyl aryl, 1 to 4 members selected from the group consisting of aryl and N, O and S
Wherein E is a direct bond, -CO-, -SO_Two-, -O-CO-, -NR¹⁴-SO_Two-Oh
And -NR¹⁴-CO- (where R¹⁴Is H, -OH, C_1-6Alkyl, aryl and C_1-4Selected from the group consisting of alkylaryl); T is H, -COOR^{twenty three}, -CONR^{twenty three}R^{twenty four}, -CF_Three, -CF_TwoCF_ThreeAnd expressionWherein R is selected from the group consisting of:^{twenty three}And R^{twenty four}Is independently H, C_1-6Alkyl, aryl and C_{1 -Four} U ′ and U ″ are independently selected from the group consisting of —O—, —S—, —N— and —NH—, provided that U ′ or At least one of U ″ is —N— or —NH—);^{twenty five}Is H, C _1-6 Alkyl, C_2-6Alkenyl, C_0-6Alkylaryl, C_2-6Alkenyl ant
, C_0-6Alkyl heterocyclo, C_2-6Alkenylheterocyclo, -CF_ThreeAnd -CF_TwoCF_ThreeV is -S-, -SO-, -SO_Two -, -O- and -NR²⁶− (Where R²⁶Is H, C_1-6W is selected from the group consisting of alkyl and benzyl; and W isAnd R²⁹And R³⁰1 to 4 selected from N, S and O
C heteroatoms_6-10Selected from the group consisting of heterocyclic ring systems; wherein a
Is an integer from 0 to 2;²⁷And R²⁸Is independently H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, -COOR³¹, -CONR³¹R³², -CN and -CF_ThreeAnd R is selected from the group consisting of²⁹And R³⁰Is, independently, H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, C_1-4Alkyloxy, halogen, -NO_Two, -NR³¹R³², -NR³¹COR³², -OR³¹, -OCOR³¹, -COOR³¹, -CONR³¹R³², -CN, -CF_Three, -SO_TwoNR³¹R³² And C_1-6Alkyl-OR³¹Selected from the group consisting of³¹And R³²Is independently H, C_1-6Alkyl, C_1-3Alkylaryl and aryl
Selected from the group consisting of:)]], and all pharmaceutically acceptable salts thereof and their optics
Isomer. 46. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesirable thrombosis, comprising the step of combining a pharmaceutically acceptable carrier with the compound of claim 1. The pharmaceutical composition comprising: 47. A method for preventing or treating a condition in a mammal characterized by unwanted thrombosis, wherein the mammal is administered a therapeutically effective amount of a compound according to claim 1. The method for prevention or treatment described above. 48. Scattered intravascular coagulation, including the treatment of unstable angina, refractory angina, myocardial infarction, transient ischemic stroke, thrombotic stroke, embolic stroke, septic shock;
Thromboembolism of deep vein thrombosis, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, surgery and peripheral arterial occlusion in the prevention of pulmonary embolism or treatment of reperfusion coronary artery reocclusion or restenosis Treatment or prevention of sexual complications, intravascular coagulation syndrome, from thrombolytic therapy or percutaneous transluminal coronary angioplasty surgery, occlusive coronary thrombosis, thrombosis of venous tract structure and disseminated intravascular coagulation disorders 48. The method of claim 47, wherein said condition is selected from the group consisting of: 49. A method for inhibiting coagulation of a biological sample, which comprises administering the compound according to claim 1.