JP2009502756A - Substituted pyridocarboxamides as inhibitors of plasminogen activator inhibitor 1 - Google Patents

Abstract

  The present invention relates to substituted pyridocarboxamides, methods for their production, and their use for the manufacture of a medicament for the treatment and / or prevention of human and animal diseases (particularly thrombotic disorders).

Description

  The present invention relates to substituted pyridinecarboxamides, methods for their production, and their use for the manufacture of medicaments for the treatment and / or prevention of diseases (particularly thrombotic disorders) in humans and animals.

  Plasminogen activator inhibitor-1 (PAI-1) is the most important regulatory component in the plasminogen-plasmin system. The fibrinolytic system contains the enzyme precursor plasminogen, which is converted to the active enzyme plasmin by two plasminogen activators tPA and uPA. PAI-1 is a major physiological inhibitor of both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). One of the main tasks of plasmin in the fibrinolytic system is to degrade fibrin at the site of vascular injury. However, the fibrinolytic system is not only responsible for removing fibrin from the circulation, but is also involved in a variety of other processes including ovulation, embryogenesis, intimal proliferation, angiogenesis, tumorigenesis and atherosclerosis To do.

  Elevated plasma PAI-1 levels are associated with a number of disorders and symptoms that lead to defects in the fibrinolytic system. Thus, for example, an increase in plasma PAI-1 levels, for example, a thrombotic disorder characterized by the occurrence of a thrombus that locally impairs blood flow in a blood vessel or detaches and forms a thrombus to block downstream blood flow (Krishnamurti, Blood, 69, 798 (1987); Reilly, Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal of Clinical Investigations, 92, 2756 (1993); Rocha, Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis, 24, 243 (1994)). Neutralizing antibodies with PAI-1 activity result in faster endogenous fibrinolysis and perfusion (Biemond, Circulation, 91, 1175 (1995); Levi, Circulation, 85, 305 (1992)).

  Accordingly, one object of the present invention is to provide novel PAI-1 inhibitors for the treatment of thrombotic disorders in humans and animals.

  Structures similar to the compounds of the present invention are disclosed in WO03 / 080060 and WO03 / 080564 as PAI-1 inhibitors for the treatment of thrombotic disorders. In particular, WO95 / 33750 discloses substituted pyridinecarboxamides as corticotropin releasing factor (CRF) antagonists for the treatment of central nervous system disorders, and WO03 / 061387 is based on the use of substituted pyridinecarboxamides. A method for controlling algae is disclosed.

［式中、
Ｘは、式

（式中、＊は、カルボニル基への結合点であり、
＃は、酸素原子への結合点であり、
そして、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、相互に独立して、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、トリフルオロメチル、Ｃ_１−Ｃ_４−アルキル、Ｃ_１−Ｃ_４−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_４−アルコキシカルボニルまたはＣ_１−Ｃ_６−アルキルアミノカルボニルである）
の基であり、
Ｙは、フェニルまたはピリジルであり
（ここで、フェニルおよびピリジルは、１個ないし３個の置換基により置換されていてもよく、ここで、置換基は、ハロゲン、ヒドロキシ、アミノ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ヒドロキシカルボニル、アミノカルボニル、Ｃ_１−Ｃ_６−アルキル、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニルおよびＣ_１−Ｃ_６−アルキルアミノカルボニルからなる群から相互に独立して選択される）、
ｎは、０、１、２または３の数であり、
Ｒ^１は、フェニルである
（ここで、フェニルは、１個ないし３個の置換基により置換されていてもよく、ここで、置換基は、ハロゲン、ヒドロキシ、アミノ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ヒドロキシカルボニル、アミノカルボニル、Ｃ_１−Ｃ_６−アルキル、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、Ｃ_１−Ｃ_６−アルキルアミノカルボニルおよびＣ_１−Ｃ_６−アルキルスルホニルアミノからなる群から相互に独立して選択される）］
の化合物、並びにそれらの塩、水和物、塩の水和物および溶媒和物に関する。 The present invention has the formula

[Where:
X is the formula

(In the formula, * is the point of attachment to the carbonyl group,
# Is the point of attachment to the oxygen atom,
R ² , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C ₁ -C ₄ -alkyl, C ₁ -C _4. - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₄ - alkoxycarbonyl or _C 1 -C ₆ - alkylaminocarbonyl)
The basis of
Y is phenyl or pyridyl (wherein phenyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are halogen, hydroxy, amino, cyano, trifluoro; , trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C Selected from the group consisting of ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl independently of each other),
n is a number 0, 1, 2 or 3;
R ¹ is phenyl (wherein phenyl may be substituted by 1 to 3 substituents, where the substituents are halogen, hydroxy, amino, cyano, trifluoromethyl, tri trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxy Selected from the group consisting of carbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkylsulfonylamino)]
As well as their salts, hydrates, salt hydrates and solvates.

  The compounds according to the invention comprise compounds of the formula (I) and their salts, solvates and solvates of the salts, compounds of the formulas mentioned below which are encompassed by the formula (I) and their salts, solvates and salts And the compounds described below as embodiments included in formula (I) and their salts, solvates and solvates of salts (compounds included in formula (I) described below are already Salt, solvate and salt solvate).

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or diastereomers and their respective mixtures. From a mixture of such enantiomers and / or diastereomers, a stereomerically pure component can be isolated by known methods.
Where the compounds of the invention can exist in tautomeric forms, the present invention includes all tautomeric forms.

For the purposes of the present invention, preferred salts are physiologically acceptable salts of the compounds of the present invention. However, salts are also included which are not themselves suitable for pharmaceutical applications, but can be used, for example, for the isolation or purification of the compounds of the invention.

  Physiologically acceptable salts of the compounds of the present invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, Examples include toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, and benzoic acid salts.

  Physiologically acceptable salts of the compounds of the present invention also include conventional base salts such as, and preferably, alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts (eg, calcium and magnesium). Salt), and ammonia or an organic amine having 1 to 16 C atoms (eg, and preferably ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethyl) Ammonium salts derived from aminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine).

For the purposes of the present invention, a solvate is a form of the compound of the invention that forms a complex by coordination with solvent molecules in the solid or liquid state. Hydrates are a special form of solvates where coordination occurs with water.

For the purposes of the present invention, unless otherwise indicated, the substituents have the following meanings:
Alkyl itself, as well as “alk” and “alkyl” in alkoxy, alkylamino, alkylcarbonyl, alkylaminocarbonyl, alkoxycarbonyl and alkylsulfonylamino are usually one to six, preferably one to A straight-chain or branched alkyl radical having 4 and particularly preferably 1 to 3 carbon atoms, for example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and represents n-hexyl.

Alkoxy by way of example and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino is an alkylamino radical having one or two alkyl substituents (selected independently of each other), for example and preferably methylamino, ethylamino, n-propylamino, isopropylamino, tert -Butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N, N-diethylamino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-Nn -Propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino. For example, C ₁ -C ₄ -alkylamino represents a monoalkylamino radical having 1 to 4 carbon atoms or a dialkylamino radical having 1 to 4 carbon atoms in each alkyl substituent. .

Alkylcarbonyl by way of example and preferably represents methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.

Alkylaminocarbonyl represents an alkylaminocarbonyl radical having one or two alkyl substituents (selected independently of one another). C ₁ -C ₃ -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl having 1 to 3 carbon atoms in each alkyl substituent. Represents a radical. For example and preferably, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, N-tert -Butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl.

Alkoxycarbonyl by way of example and preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylsulfonylamino by way of example and preferably represents methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, n-pentylsulfonylamino and n-hexylsulfonylamino.

Heteroaryl usually has 5 or 6 ring atoms and has an aromatic monocyclic radical having up to 4, preferably up to 3, heteroatoms from the group of S, O and N, for example And preferably, it represents thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl and pyridazinyl.
Halogen represents fluorine, chlorine, bromine and iodine.

In the formula of the group representing X, the end points of the straight lines each having * or # do not represent a carbon atom or a CH ₂ group, but represent a part of the bond to the carbonyl group or oxygen atom to which X is bonded. Forming.

When radicals in the compounds of the invention are substituted , the radicals may be substituted with one or more substituents, identical or different, unless otherwise specified. Substitution with up to 3 identical or different substituents is preferred. Very particular preference is given to substitution with one substituent.

（式中、＊は、カルボニル基への結合点であり、
＃は、酸素原子への結合点であり、
そして、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は、相互に独立して、水素、ハロゲン、ヒドロキシ、アミノ、シアノ、ニトロ、トリフルオロメチル、Ｃ_１−Ｃ_４−アルキル、Ｃ_１−Ｃ_４−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_４−アルコキシカルボニルまたはＣ_１−Ｃ_６−アルキルアミノカルボニルである）
の基であり、
Ｙが、フェニルであり
（ここで、フェニルは、１個ないし３個の置換基により置換されていてもよく、ここで、置換基は、ハロゲン、ヒドロキシ、アミノ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ヒドロキシカルボニル、アミノカルボニル、Ｃ_１−Ｃ_６−アルキル、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニルおよびＣ_１−Ｃ_６−アルキルアミノカルボニルからなる群から相互に独立して選択される）、
ｎが、０または１の数であり、
Ｒ^１が、フェニルである
（ここで、フェニルは、１個ないし３個の置換基により置換されていてもよく、ここで、置換基は、ハロゲン、ヒドロキシ、アミノ、シアノ、トリフルオロメチル、トリフルオロメトキシ、ヒドロキシカルボニル、アミノカルボニル、Ｃ_１−Ｃ_６−アルキル、Ｃ_１−Ｃ_６−アルコキシ、Ｃ_１−Ｃ_６−アルキルアミノ、Ｃ_１−Ｃ_６−アルキルカルボニル、Ｃ_１−Ｃ_６−アルコキシカルボニル、Ｃ_１−Ｃ_６−アルキルアミノカルボニルおよびＣ_１−Ｃ_６−アルキルスルホニルアミノからなる群から相互に独立して選択される）
式（Ｉ）の化合物、並びにそれらの塩、水和物、塩の水和物および溶媒和物である。 Preference is given to:
X is the formula

(In the formula, * is the point of attachment to the carbonyl group,
# Is the point of attachment to the oxygen atom,
R ² , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C ₁ -C ₄ -alkyl, C ₁ -C _4. - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₄ - alkoxycarbonyl or _C 1 -C ₆ - alkylaminocarbonyl)
The basis of
Y is phenyl (wherein phenyl is optionally substituted by 1 to 3 substituents, where the substituents are halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoro methoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl And C ₁ -C ₆ -alkylaminocarbonyl selected from each other independently)
n is a number of 0 or 1,
R ¹ is phenyl (wherein the phenyl may be substituted by 1 to 3 substituents, where the substituents are halogen, hydroxy, amino, cyano, trifluoromethyl, tri trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxy Selected independently from the group consisting of carbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkylsulfonylamino)
Compounds of formula (I) and their salts, hydrates, hydrates of salts and solvates.

（式中、＊は、カルボニル基への結合点であり、
＃は、酸素原子への結合点であり、
そして、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５は水素である）
の基であり、
Ｙが、フェニルであり
（ここで、フェニルは、１個ないし２個の置換基により置換されていてもよく、ここで、置換基は、ハロゲンおよびＣ_１−Ｃ_４−アルコキシからなる群から相互に独立して選択される）、
ｎが、０または１の数であり、
Ｒ^１が、フェニルである
（ここで、フェニルは、１個ないし３個の置換基により置換されていてもよく、ここで、置換基は、ハロゲン、シアノ、トリフルオロメチル、メチル、メトキシおよびメチルスルホニルアミノからなる群から相互に独立して選択される）
式（Ｉ）の化合物、並びに、それらの塩、水和物、塩の水和物および溶媒和物である。 Preference is given to:
X is the formula

(In the formula, * is the point of attachment to the carbonyl group,
# Is the point of attachment to the oxygen atom,
And R ² , R ³ , R ⁴ and R ⁵ are hydrogen)
The basis of
Y is phenyl (wherein phenyl may be substituted by 1 to 2 substituents, wherein the substituents are selected from the group consisting of halogen and C ₁ -C ₄ -alkoxy; Selected independently),
n is a number of 0 or 1,
R ¹ is phenyl (wherein phenyl is optionally substituted by 1 to 3 substituents, where the substituents are halogen, cyano, trifluoromethyl, methyl, methoxy and methyl Independently selected from the group consisting of sulfonylamino)
Compounds of formula (I) and their salts, hydrates, salt hydrates and solvates.

（式中、＊は、カルボニル基への結合点であり、
＃は、酸素原子への結合点である）
の基であり、
Ｒ^２およびＲ^３が水素である、
式（Ｉ）の化合物である。 Preference is given to:
X is the formula

(In the formula, * is the point of attachment to the carbonyl group,
# Is the point of attachment to the oxygen atom)
The basis of
R ² and R ³ are hydrogen,
It is a compound of formula (I).

Also preferred are compounds of formula (I), wherein R ² and R ³ are hydrogen.
Also preferred are compounds of formula (I), wherein R ⁴ and R ⁵ are hydrogen.
Also preferred are compounds of formula (I), wherein Y is phenyl.
Also preferred are compounds of formula (I), wherein n is a number of zero.
Also preferred are compounds of formula (I), wherein R ¹ is phenyl and the phenyl is substituted by one trifluoromethyl.

（式中、ＸおよびＲ^１は、上記の意味を有する）
の化合物を、式

（式中、Ｘおよびｎは、上記の意味を有する）
の化合物と反応させることを特徴とする。 The invention further relates to a process for the preparation of a compound of formula (I), which comprises a compound of formula

(Wherein X and R ¹ have the above meanings)
A compound of the formula

(Wherein X and n have the above meanings)
It is made to react with the compound of this.

  This reaction is generally carried out in an inert solvent in the presence of a base, preferably at room temperature to the reflux temperature of the solvent at atmospheric pressure.

  Examples of inert solvents are ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, or other solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide or acetonitrile, with dimethyl sulfoxide being preferred.

  Examples of bases are sodium or potassium methanolate or sodium or potassium ethanolate or alcoholates such as potassium tert-butoxide or amides such as sodium amide, lithium bis (trimethylsilyl) amide or lithium diisopropylamide, Or an organic metal compound such as butyl lithium or phenyl lithium, or another base such as sodium hydride or DBU, preferably sodium hydride.

（式中、Ｒ^１は上記の意味を有する）
の化合物を、式

（式中、Ｘは上記の意味を有する）
の化合物と反応させることにより製造できる。 Compounds of formula (II) are known or have the formula

(Wherein R ¹ has the above meaning)
A compound of the formula

(Wherein X has the above meaning)
It can manufacture by making it react with the compound of.

  This reaction is generally carried out in an inert solvent in the presence of a dehydrating agent, optionally in the presence of a base, preferably in the temperature range of −30 ° C. to 50 ° C. under atmospheric pressure.

  Examples of inert solvents are halohydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene, nitromethane, dioxane, dimethylformamide or acetonitrile. It is likewise possible to use mixtures of these solvents. Dichloromethane or dimethylformamide is particularly preferred.

  Examples of bases are alkali metal carbonates such as sodium or potassium carbonate or bicarbonate, or trialkylamines such as triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or Organic bases such as diisopropylethylamine.

  In this regard, examples of suitable dehydrating agents are, for example, N, N′-diethyl-, N, N′-dipropyl-, N, N′-diisopropyl-, N, N′-dicyclohexylcarbodiimide, N- (3-dimethyl Carbodiimides such as aminoisopropyl) -N′-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide), carbonyl compounds such as carbonyldiimidazole, or 2 1,2-oxazolium compounds such as ethyl-5-phenyl-1,2-oxazolium 3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or 2-ethoxy-1-ethoxycarbonyl Acylamino such as -1,2-dihydroquinoline Compound, or propanephosphonic anhydride, or isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride or O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O -(Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) or 1-hydroxybenzotriazole (HOBt), Or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or N-hydroxysuccinimide Or a mixture with these bases.

  This condensation is preferably carried out using TBTU in the presence of diisopropylethylamine.

  The compounds of formula (III), (IV) and (V) are known per se to the person skilled in the art or can be prepared by conventional methods known from the literature.

スキーム２：

The production of the compounds of the present invention can be clarified by the following synthetic scheme.
Scheme 1:

Scheme 2:

The compounds of the present invention exhibit a range of valuable pharmaceutical and pharmacokinetic effects that could not have been anticipated.
They are therefore suitable for use as medicaments for the treatment and / or prevention of diseases in humans and animals.
The pharmaceutical activity of the compounds of the present invention can be explained by their action as PAI-1 inhibitors.
The invention further relates to the use of the compounds according to the invention for the treatment and / or prevention of disorders, preferably thrombotic disorders.

  The compounds of the present invention may be used for example for thrombotic disorders such as venous and arterial thrombosis, pulmonary thrombosis, cerebral thrombosis, thromboembolism and deep vein thrombosis, or coronary heart disease, cardiac fibrillation, pulmonary fibrosis Fibrosis, complications of thromboembolism, or stroke such as, for example, thrombotic and thromboembolic stroke, or transient ischemic attacks, reocclusion and restenosis after coronary procedures (percutaneous Reocclusion and restenosis after coronary angioplasty, reocclusion and restenosis after coronary artery bypass surgery), disseminated intravascular coagulation, or surgery, eg, pulmonary embolism, stroke, vascular surgery, vascular replacement Stenting, organ, tissue and cell implementation and transplantation, or cardiovascular disorders such as myocardial infarction, atherosclerotic atheroma, cardiac infarction, stable angina and unstable angina, Or chronic obstructive Lung disease, renal fibrosis, polycystic ovary syndrome, Alzheimer's disease, osteolysis induced by estrogen deficiency, diabetes, obesity, chronic periodontitis, lymphoma, disorders related to extracellular matrix accumulation, eg asthma Inflammatory disorders such as, septic shock, kidney disorders, obesity, insulin resistance, angiogenesis-related disorders, or cancer, eg, blood vessel damage due to leukemia, malignancy, or infection, and breast cancer and Suitable for the prevention and / or treatment of disorders associated with elevated uPA levels such as ovarian cancer.

  The compounds of the present invention may also be used to influence thrombolytic therapy, to affect wound healing, for example, atherosclerotic vessels such as restenosis, coronary heart disease, cerebral ischemia and peripheral arterial occlusion. Disorders, heart failure, hypertension, eg, asthma, inflammatory lung disorder, glomerulonephritis, inflammatory bowel disorder, and other inflammatory disorders, and rheumatic disorders of the motor system, eg, degenerative disorders, such as neurodegenerative disorders, and It can be used in the prevention and treatment of osteoporosis.

  The compounds of the invention can also be used in the treatment of blood and blood products used for dialysis and blood storage in the liquid phase, in particular for ex vivo platelet aggregation. The compounds can also be added to human plasma during chemical blood analysis under hospital conditions to determine fibrinolytic ability.

  The compounds of the present invention can also be used in combination with prothrombolytic agents, fibrinolytic agents and anticoagulants.

The invention further relates to the use of the compounds according to the invention for the prevention and / or treatment of disorders, in particular the above mentioned pathologies.
The invention further relates to the use of the compounds according to the invention for the manufacture of a medicament for the prevention and / or treatment of disorders, in particular the above mentioned pathologies.
The invention further relates to a method for the prevention and / or treatment of disorders, in particular the above mentioned pathologies, by using an amount of a compound of the invention having cardiovascular activity.
The invention further relates to a medicament comprising a compound of the invention in combination with one or more further active ingredients, in particular for the prevention and / or treatment of the disorders mentioned above.

The compounds of the invention can act systemically and / or locally. For this purpose, they are suitable, for example, orally, parenterally, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or It can be administered by the otic route or as an implant or stent.
The compounds according to the invention can be administered in administration forms suitable for these administration routes.

  Suitable for oral administration functions according to the prior art, delivers the compounds of the invention in a rapid and / or modified manner, and comprises the compounds of the invention in crystalline and / or amorphous and / or dissolved forms Dosage forms, such as tablets (uncoated or coated tablets, such as enteric coatings, or those that are insoluble or have a coating that dissolves slowly and controls the release of the compounds of the invention), in the oral cavity Rapidly disintegrating tablets or films / oblates, film / lyophilizers, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions It is.

  Parenteral administration avoids the absorption phase (eg, intravenous, intraarterial, intracardiac, spinal or lumbar) or includes absorption (eg, intramuscular, subcutaneous, intradermal, transdermal) Skin or intraperitoneal). Suitable dosage forms for parenteral administration are, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

  Examples suitable for other routes of administration are eg pharmaceutical forms for inhalation (especially powder inhalers, nebulizers), nasal drops, liquids, sprays; tablets, films / oblates or capsules for tongue, sublingual or buccal administration Suppositories, ophthalmic or otic formulations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, Foam, dusting powder, implant or stent.

  The compounds of the invention can be converted into the stated administration forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These adjuvants include, among others, carriers (eg, microcrystalline cellulose, lactose, mannitol), solvents (eg, liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (eg, sodium dodecyl sulfate, polyoxysorbitan oleate), Binders (eg polyvinylpyrrolidone), synthetic and natural polymers (eg albumin), stabilizers (eg antioxidants such as ascorbic acid), colorants (eg inorganic pigments such as iron oxide) and flavors and / or odors Concealing agents are included.

  The present invention further relates to medicaments comprising at least one compound of the invention, preferably together with one or more inert, non-toxic pharmaceutically suitable auxiliaries, and their use for the purposes mentioned above. .

  In general, in both human medicine and veterinary medicine, a total amount of about 0.01 to about 700, preferably about 0.01 to 100 mg / kg body weight per 24 hours, optionally in the form of multiple single doses. It has been found that administering the compounds of the present invention is advantageous to achieve the desired results. A single dose comprises a compound of the invention preferably in an amount of about 0.1 to about 80, in particular 0.1 to 30 mg / kg body weight.

  Nevertheless, if necessary, it may be necessary to deviate from the above-mentioned amounts depending on the body weight, route of administration, individual response to the active ingredient, the nature of the formulation and the time or interval at which it is administered. Thus, it may be sufficient to make less than the above-mentioned minimum amount, while in other cases the upper limit mentioned must be exceeded. If administered in large quantities, it may be desirable to divide these into several individual doses over the day.

  The percentage data in the following tests and examples are percentages by weight unless otherwise indicated; parts are parts by weight. Liquid / liquid solution solvent ratio, dilution ratio and concentration data are in each case based on volume.

A. Example
Abbreviations:

２−フルオロニコチン酸３００ｍｇ（２.０６ｍｍｏｌ）を、丸底フラスコ中のジクロロメタン１０ｍｌに導入し、ＴＢＴＵ９９３ｍｇ（３.０９ｍｍｏｌ）を添加する。ジイソプロピルエチルアミン０.５３９ｍｌ（３.０９ｍｍｏｌ）を滴下して添加し、続いて室温で１０分間撹拌し、次いで４−トリフルオロメチルアニリン３６９ｍｇ（２.２７ｍｍｏｌ）を添加する。混合物を室温で１６時間撹拌し、溶媒を完全に除去し、分取ＨＰＬＣにより残渣を精製する。生成物４２８ｍｇ（理論値の７３％）を固体として単離する。
MS (ESIpos): m/z = 285 (M+H)⁺.
¹H-NMR (400MHz, DMSO-d₆): δ = 10.93 (s, 1H), 8.43 (d, 1H), 8.29 (t, 1H), 7.92 (d, 2H), 7.75 (d, 2H), 7.54(t, 1H). Starting compound
Example 1A
2-Fluoro-N- [4- (trifluoromethyl) phenyl] nicotinamide

300 mg (2.06 mmol) of 2-fluoronicotinic acid are introduced into 10 ml of dichloromethane in a round bottom flask and 993 mg (3.09 mmol) of TBTU is added. 0.539 ml (3.09 mmol) of diisopropylethylamine are added dropwise, followed by stirring at room temperature for 10 minutes, and then 369 mg (2.27 mmol) of 4-trifluoromethylaniline are added. The mixture is stirred at room temperature for 16 hours, the solvent is completely removed and the residue is purified by preparative HPLC. 428 mg (73% of theory) of product are isolated as a solid.
MS (ESIpos): m / z = 285 (M + H) ⁺ .
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.93 (s, 1H), 8.43 (d, 1H), 8.29 (t, 1H), 7.92 (d, 2H), 7.75 (d, 2H), 7.54 (t, 1H).

２−フルオロニコチン酸３００ｍｇ（２.０６ｍｍｏｌ）を、４−フルオロアニリン２５４.６ｍｇ（２.２７ｍｍｏｌ）と、実施例１Ａの製造方法と同様に反応させ、対応するアミドを得る。分取ＨＰＬＣにより精製し、生成物４１９ｍｇ（理論値の８７％）を得る。
MS (TOF): m/z = 234 (M)⁺.
¹H-NMR (400MHz, DMSO-d₆): δ =10.61 (s, 1H), 8.41 (d, 1H), 8.25 (t, 1H), 7.77 (dd, 2H), 7.53 (t, 1H), 7.22 (t, 2H). Example 2A
2-Fluoro-N- (4-fluorophenyl) nicotinamide

300 mg (2.06 mmol) of 2-fluoronicotinic acid is reacted with 254.6 mg (2.27 mmol) of 4-fluoroaniline in the same manner as in the production method of Example 1A to obtain the corresponding amide. Purification by preparative HPLC gives 419 mg (87% of theory) of product.
MS (TOF): m / z = 234 (M) ⁺ .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 10.61 (s, 1H), 8.41 (d, 1H), 8.25 (t, 1H), 7.77 (dd, 2H), 7.53 (t, 1H), 7.22 (t, 2H).

２−フルオロニコチン酸３００ｍｇ（２.０６ｍｍｏｌ）を、アニリン２１３.４ｍｇ（２.２７ｍｍｏｌ）と、実施例１Ａの製造方法と同様に反応させ、対応するアミドを得る。分取ＨＰＬＣにより精製し、生成物４１１ｍｇ（理論値の９２％）を固体として得る。
MS (DCI, NH₃): m/z = 234 (M+NH₄)⁺.
¹H-NMR (400MHz, DMSO-d₆): δ = 10.55 (s, 1H), 8.40 (d, 1H), 8.25 (t, 1H), 7.70 (d, 2H), 7.52 (t, 1H), 7.37 (t, 2H), 7.13 (t, 1H). Example 3A
2-Fluoro-N-phenylnicotinamide

300 mg (2.06 mmol) of 2-fluoronicotinic acid is reacted with 213.4 mg (2.27 mmol) of aniline in the same manner as in the production method of Example 1A to obtain the corresponding amide. Purification by preparative HPLC gives 411 mg (92% of theory) of the product as a solid.
MS (DCI, NH ₃ ): m / z = 234 (M + NH ₄ ) ⁺ .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 10.55 (s, 1H), 8.40 (d, 1H), 8.25 (t, 1H), 7.70 (d, 2H), 7.52 (t, 1H), 7.37 (t, 2H), 7.13 (t, 1H).

２−フルオロ−４−ピリジンカルボン酸１５０ｍｇ（１.０４ｍｍｏｌ）を、丸底フラスコ中のジクロロメタン１０ｍｌに導入し、ＴＢＴＵ５０２ｍｇ（１.５６ｍｍｏｌ）を添加する。ジイソプロピルエチルアミン０.２７２ｍｌ（１.５６ｍｍｏｌ）を滴下して添加し、続いて室温で１０分間撹拌し、次いで、４−フルオロアニリン１７５.４ｍｇ（１.５６ｍｍｏｌ）を添加する。混合物を室温で１６時間撹拌し、溶媒を完全に除去し、分取ＨＰＬＣにより残渣を精製する。生成物１９６ｍｇ（理論値の７９％）を固体として単離する。
MS (DCI, NH₃): m/z = 251 (M+NH₄)⁺.
¹H-NMR (400MHz, DMSO-d₆): δ = 10.62 (s, 1H), 8.45 (d, 1H), 7.82 (d, 1H), 7.78 (dd, 2H), 7.66 (s, 1H), 7.24 (t, 2H). Example 4A
2-Fluoro-N- (4-fluorophenyl) iso-nicotinamide

150 mg (1.04 mmol) of 2-fluoro-4-pyridinecarboxylic acid are introduced into 10 ml of dichloromethane in a round bottom flask and 502 mg (1.56 mmol) of TBTU are added. 0.272 ml (1.56 mmol) of diisopropylethylamine is added dropwise, followed by stirring at room temperature for 10 minutes, and then 175.4 mg (1.56 mmol) of 4-fluoroaniline are added. The mixture is stirred at room temperature for 16 hours, the solvent is completely removed and the residue is purified by preparative HPLC. 196 mg (79% of theory) of product are isolated as a solid.
MS (DCI, NH ₃ ): m / z = 251 (M + NH ₄ ) ⁺ .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 10.62 (s, 1H), 8.45 (d, 1H), 7.82 (d, 1H), 7.78 (dd, 2H), 7.66 (s, 1H), 7.24 (t, 2H).

２−フルオロ−４−ピリジンカルボン酸１５０ｍｇ（１.０４ｍｍｏｌ）を、３−トリフルオロメチルアニリン２５６.９ｍｇ（１.５６ｍｍｏｌ）と、実施例６Ａの製造方法と同様に反応させ、対応するアミドを得る。分取ＨＰＬＣによる精製により、生成物２０２ｍｇ（理論値の６８％）を得る。
MS (ESIpos): m/z = 285 (M+H)⁺.
¹H-NMR (300MHz, DMSO-d₆): δ = 10.82 (s, 1H), 8.47 (d, 1H), 8.22 (s, 1H), 8.03 (d, 1H), 7.83 (m, 1H), 7.68 (s, 1H), 7.64 (t, 1H), 7.53 (d, 1H). Example 5A
2-Fluoro-N- [3- (trifluoromethyl) phenyl] isonicotinamide

150 mg (1.04 mmol) of 2-fluoro-4-pyridinecarboxylic acid is reacted with 256.9 mg (1.56 mmol) of 3-trifluoromethylaniline in the same manner as in the production method of Example 6A to obtain the corresponding amide. . Purification by preparative HPLC gives 202 mg (68% of theory) of product.
MS (ESIpos): m / z = 285 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.82 (s, 1H), 8.47 (d, 1H), 8.22 (s, 1H), 8.03 (d, 1H), 7.83 (m, 1H), 7.68 (s, 1H), 7.64 (t, 1H), 7.53 (d, 1H).

２−フルオロ−４−ピリジンカルボン酸１０００ｍｇ（７.０９ｍｍｏｌ）を、アニリン７９２ｍｇ（８.５１ｍｍｏｌ）と、実施例６Ａの製造方法と同様に反応させ、対応するアミドを得る。粗製のバッチを飽和クエン酸溶液と混合し、塩化メチレンで３回抽出する。合わせた有機相を飽和塩化ナトリウム溶液で１回洗浄し、溶媒を完全に除去する。これにより、生成物１.３６ｇ（理論値の８８％）を得る。
MS (ESIpos): m/z = 217 (M+H)⁺.
¹H-NMR (300MHz, DMSO-d₆): δ = 10.53 (s, 1H), 8.44 (d, 1H), 7.83 (dt, 1H), 7.76 (d, 2H), 7.66 (s, 1H), 7.39 (t, 2H), 7.16 (t, 1H). Example 6A
2-Fluoro-N-phenylisonicotinamide

1000 mg (7.09 mmol) of 2-fluoro-4-pyridinecarboxylic acid is reacted with 792 mg (8.51 mmol) of aniline in the same manner as in the production method of Example 6A to obtain the corresponding amide. The crude batch is mixed with saturated citric acid solution and extracted three times with methylene chloride. The combined organic phases are washed once with saturated sodium chloride solution and the solvent is completely removed. This gives 1.36 g (88% of theory) of product.
MS (ESIpos): m / z = 217 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.53 (s, 1H), 8.44 (d, 1H), 7.83 (dt, 1H), 7.76 (d, 2H), 7.66 (s, 1H), 7.39 (t, 2H), 7.16 (t, 1H).

４−ヒドロキシ安息香酸４６.６５ｍｇ（０.３４ｍｍｏｌ）を、乾燥ＤＭＳＯ４ｍｌに導入し、水素化ナトリウム（６０％）２８.１５ｍｇ（０.７ｍｍｏｌ）を添加する。室温、アルゴン下で１０分間撹拌した後、実施例１Ａ由来のフルオロニコチンアミド８０ｍｇ（０.２８ｍｍｏｌ）を添加する。混合物を８０℃で１時間、１２０℃でさらに１６時間加熱する。水約１ｍｌを注意深く添加し、粗生成物を分取ＨＰＬＣにより精製する。生成物２３ｍｇ（理論値の１９％）を固体として単離する。
MS (ESIpos): m/z = 403 (M+H)⁺.
¹H-NMR (300MHz, DMSO-d₆): δ = 11.7 (s, 1H), 7.7 (m, 4H), 7.6 (d, 1H), 7.45 (d, 2H), 7.3 (d, 1H), 7.1 (d, 2H), 6.1 (t, 1H). Exemplary Embodiment
Example 1
4-{[3-({[4- (trifluoromethyl) phenyl] amino} carbonyl) pyridin-2-yl] oxy} benzoic acid

46.65 mg (0.34 mmol) of 4-hydroxybenzoic acid are introduced into 4 ml of dry DMSO and 28.15 mg (0.7 mmol) of sodium hydride (60%) are added. After stirring for 10 minutes at room temperature under argon, 80 mg (0.28 mmol) of fluoronicotinamide from Example 1A are added. The mixture is heated at 80 ° C. for 1 hour and at 120 ° C. for an additional 16 hours. About 1 ml of water is carefully added and the crude product is purified by preparative HPLC. 23 mg (19% of theory) of product are isolated as a solid.
MS (ESIpos): m / z = 403 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 11.7 (s, 1H), 7.7 (m, 4H), 7.6 (d, 1H), 7.45 (d, 2H), 7.3 (d, 1H), 7.1 (d, 2H), 6.1 (t, 1H).

実施例２Ａ由来の２−フルオロニコチンアミド２.８９ｇ（１２.３４ｍｍｏｌ）を、４−ヒドロキシ安息香酸２.０５ｇ（１４.８１ｍｍｏｌ）および水素化ナトリウム（６０％）１.２３４ｇ（３０.８５ｍｍｏｌ）と、実施例１の製造方法と同様に反応させ、対応するエーテル誘導体をＮ−メチルピロリドン１００ｍｌ中に得る。塩化メチレンから再結晶し、生成物４.０９ｇ（理論値の９４％）を固体として得る。
MS (ESIpos): m/z = 353 (M+H)⁺.
¹H-NMR (300MHz, DMSO-d₆): δ = 12.92 (s, 幅広い, 1H), 10.66 (s, 1H), 8.28 (dd, 1H), 8.14 (dd, 1H), 7.98 (d, 2H), 7.73 (dd, 2H), 7.32 (m, 3H), 7.20 (t, 2H). Example 2
4-[(3-{[(4-Fluorophenyl) amino] carbonyl} pyridin-2-yl) oxy] benzoic acid

2.89 g (12.34 mmol) of 2-fluoronicotinamide from Example 2A was combined with 2.05 g (14.81 mmol) of 4-hydroxybenzoic acid and 1.234 g (30.85 mmol) of sodium hydride (60%). In the same manner as in the production method of Example 1, the corresponding ether derivative is obtained in 100 ml of N-methylpyrrolidone. Recrystallization from methylene chloride gives 4.09 g (94% of theory) of the product as a solid.
MS (ESIpos): m / z = 353 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.92 (s, broad, 1H), 10.66 (s, 1H), 8.28 (dd, 1H), 8.14 (dd, 1H), 7.98 (d, 2H ), 7.73 (dd, 2H), 7.32 (m, 3H), 7.20 (t, 2H).

実施例３Ａ由来の２−フルオロニコチンアミド８０ｍｇ（０.３７ｍｍｏｌ）を、４−ヒドロキシ安息香酸６１.３２ｍｇ（０.４４ｍｍｏｌ）および水素化ナトリウム（６０％）３７ｍｇ（０.９３ｍｍｏｌ）と、実施例１の製造方法と同様に反応させ、対応するエーテル誘導体をＤＭＳＯ（４ｍｌ）中に得る。分取ＨＰＬＣにより精製し、生成物２３.５ｍｇ（理論値の１９％）を得る。
MS (ESIpos): m/z = 335 (M+H)⁺.
¹H-NMR (300MHz, DMSO-d₆): δ = 10.47 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 8.86 (d, 2H), 7.72 (d, 2H), 7.35 (d, 2H), 7.27 (m, 1H), 7.04-7.13 (m, 3H). Example 3
4-{[3- (anilinocarbonyl) pyridin-2-yl] oxy} benzoic acid

80 mg (0.37 mmol) of 2-fluoronicotinamide from Example 3A was replaced with 61.32 mg (0.44 mmol) of 4-hydroxybenzoic acid and 37 mg (0.93 mmol) of sodium hydride (60%). To give the corresponding ether derivative in DMSO (4 ml). Purification by preparative HPLC affords 23.5 mg (19% of theory) of product.
MS (ESIpos): m / z = 335 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.47 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 8.86 (d, 2H), 7.72 (d, 2H), 7.35 (d, 2H), 7.27 (m, 1H), 7.04-7.13 (m, 3H).

４−ヒドロキシ安息香酸７０.７７ｍｇ（０.５１２ｍｍｏｌ）を、乾燥ＤＭＳＯ４ｍｌに導入し、水素化ナトリウム（６０％）４２.７ｍｇ（１.０７ｍｍｏｌ）を添加する。室温、アルゴン下で１０分間撹拌した後、実施例４Ａ由来のイソニコチンアミド１００ｍｇ（０.４３ｍｍｏｌ）を添加する。混合物を１３０℃で１６時間加熱し、冷却後、１Ｎ塩酸で中和する。粗生成物を分取ＨＰＬＣにより精製する。生成物４１ｍｇ（理論値の２７％）を固体として単離する。
MS (ESIpos): m/z = 353 (M+H)⁺.
¹H-NMR (300MHz, DMSO-d₆): δ = 12.88 (s, 幅広い, 1H), 10.55 (d, 1H), 8.37 (d, 1H), 8.0 (d, 2H), 7.79 (dd, 2H), 7.66 (dd, 1H), 7.59 (s, 1H), 7.27 (d, 2H), 7.20 (d, 2H). Example 4
4-[(4-{[(4- (Fluorophenyl) amino] carbonyl} pyridin-2-yl) oxy] benzoic acid

70.77 mg (0.512 mmol) of 4-hydroxybenzoic acid are introduced into 4 ml of dry DMSO and 42.7 mg (1.07 mmol) of sodium hydride (60%) are added. After stirring for 10 minutes at room temperature under argon, 100 mg (0.43 mmol) of isonicotinamide from Example 4A are added. The mixture is heated at 130 ° C. for 16 hours, cooled and neutralized with 1N hydrochloric acid. The crude product is purified by preparative HPLC. 41 mg (27% of theory) of product are isolated as a solid.
MS (ESIpos): m / z = 353 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.88 (s, broad, 1H), 10.55 (d, 1H), 8.37 (d, 1H), 8.0 (d, 2H), 7.79 (dd, 2H ), 7.66 (dd, 1H), 7.59 (s, 1H), 7.27 (d, 2H), 7.20 (d, 2H).

実施例５Ａ由来のイソニコチンアミド１００ｍｇ（０.３５２ｍｍｏｌ）を、４−ヒドロキシ安息香酸５８.３ｍｇ（０.４２２ｍｍｏｌ）および水素化ナトリウム（６０％）３５.２ｍｇ（０.８８ｍｍｏｌ）と、実施例１の製造方法と同様に反応させ、対応するエーテル誘導体をＤＭＳＯ４ｍｌ中に得る。分取ＨＰＬＣにより精製し、生成物９１ｍｇ（理論値の６２％）を得る。
MS (ESIpos): m/z = 403 (M+H)⁺.
¹H-NMR (300MHz, DMSO-d₆): δ = 12.88 (s, 幅広い, 1H), 10.79 (s, 1H), 8.39 (d, 1H), 8.24 (s, 1H), 8.0 (m, 3H), 7.61-7.68 (m, 3H), 7.51 (d, 1H), 7.27 (d, 2H). Example 5
4-{[4-({[3- (trifluoromethyl) phenyl] amino} carbonyl) pyridin-2-yl] oxy} benzoic acid

100 mg (0.352 mmol) of isonicotinamide derived from Example 5A, 58.3 mg (0.422 mmol) of 4-hydroxybenzoic acid and 35.2 mg (0.88 mmol) of sodium hydride (60%) The corresponding ether derivative is obtained in 4 ml of DMSO. Purification by preparative HPLC gives 91 mg (62% of theory) of product.
MS (ESIpos): m / z = 403 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.88 (s, broad, 1H), 10.79 (s, 1H), 8.39 (d, 1H), 8.24 (s, 1H), 8.0 (m, 3H ), 7.61-7.68 (m, 3H), 7.51 (d, 1H), 7.27 (d, 2H).

実施例６Ａ由来のイソニコチンアミド３７ｍｇ（０.１６９ｍｍｏｌ）を、３−フルオロ−４−ヒドロキシフェニル酢酸３４.５ｍｇ（０.２０３ｍｍｏｌ）および水素化ナトリウム（６０％）１６.９ｍｇ（０.４２ｍｍｏｌ）と、実施例１の製造方法と同様に反応させ、対応するエーテル誘導体をＤＳＭＯ４ｍｌ中に得る。分取ＨＰＬＣにより精製し、生成物６ｍｇ（理論値の９％）を得る。
MS (ESIneg): m/z = 365 (M-H)⁺.
¹H-NMR (300MHz, DMSO-d₆): δ = 10.53 (s, 1H), 8.28 (d, 1H), 7.78 (d, 2H), 7.56 (m, 2H), 7.38 (t, 2H), 7.08-7.20 (m, 3H), 7.00 (d, 1H), 3.17 (s, 2H). Example 6
(4-{[4- (anilinocarbonyl) pyridin-2-yl] oxy} -3-fluorophenyl) acetic acid

37 mg (0.169 mmol) of isonicotinamide from Example 6A was combined with 34.5 mg (0.203 mmol) of 3-fluoro-4-hydroxyphenylacetic acid and 16.9 mg (0.42 mmol) of sodium hydride (60%). In the same manner as in the production method of Example 1, the corresponding ether derivative is obtained in 4 ml of DSMO. Purification by preparative HPLC gives 6 mg (9% of theory) of product.
MS (ESIneg): m / z = 365 (MH) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.53 (s, 1H), 8.28 (d, 1H), 7.78 (d, 2H), 7.56 (m, 2H), 7.38 (t, 2H), 7.08-7.20 (m, 3H), 7.00 (d, 1H), 3.17 (s, 2H).

実施例６Ａ由来のイソニコチンアミド３７ｍｇ（０.１６９ｍｍｏｌ）を、４−ヒドロキシ安息香酸２８ｍｇ（０.２０３ｍｍｏｌ）および水素化ナトリウム（６０％）１６.９ｍｇ（０.４２ｍｍｏｌ）と、実施例１の製造方法と同様に反応させ、対応するエーテル誘導体をＤＳＭＯ４ｍｌ中に得る。分取ＨＰＬＣにより精製し、生成物３９ｍｇ（理論値の６９％）を得る。
MS (ESIpos): m/z = 335 (M+H)⁺.
¹H-NMR (400MHz, DMSO-d₆): δ = 12.93 (s, 幅広い, 1H), 10.52 (s, 1H), 8.37 (d, 1H), 8.01 (d, 2H), 7.77 (d, 2H), 7.65 (dd, 1H), 7.60 (s, 1H), 7.39 (t, 2H), 7.27 (d, 2H), 7.15 (t, 1H). Example 7
4-{[4- (4-anilinocarbonyl) pyridin-2-yl] oxy} benzoic acid

Preparation of Example 1 with 37 mg (0.169 mmol) of isonicotinamide from Example 6A, 28 mg (0.203 mmol) of 4-hydroxybenzoic acid and 16.9 mg (0.42 mmol) of sodium hydride (60%) The reaction is carried out analogously to the method and the corresponding ether derivative is obtained in 4 ml of DSMO. Purification by preparative HPLC gives 39 mg (69% of theory) of product.
MS (ESIpos): m / z = 335 (M + H) ⁺ .
¹ H-NMR (400MHz, DMSO-d ₆ ): δ = 12.93 (s, broad, 1H), 10.52 (s, 1H), 8.37 (d, 1H), 8.01 (d, 2H), 7.77 (d, 2H ), 7.65 (dd, 1H), 7.60 (s, 1H), 7.39 (t, 2H), 7.27 (d, 2H), 7.15 (t, 1H).

B. Assessment of physiological activity
Abbreviations:

The in vitro effects of the compounds of the invention can be demonstrated in the following assays:
1. Plasma fibrinolysis assay Identification of inhibitors of plasminogen activator inhibitor-1 (PAI-1) in rats, and quantification of the activity of the substances described herein is based on plasma-based fibrin Perform using a lysis assay. Inhibition of fibrinolysis system, alpha ₂ - antiplasmin, or alpha ₂ - in the macroglobulin plasmin levels, or by PAI-1 can be carried out at the level of plasminogen activator.

  The addition of human α-thrombin leads to the development of a three-dimensional structured fibrin network through several intermediate steps. This fibrin network is broken by the serine protease plasmin, which is formed by the plasminogen activator tPA from the previously inactive enzyme precursor plasminogen. The activity of tPA is controlled by plasminogen activator inhibitor-1PAI-1. Inhibition of PAI-1 leads to an increase in the dissolution rate of the fibrin network.

Assay method: Recombinant rat plasminogen activator inhibitor 1 (PAI-1; Molecular Innovations Inc., MI, USA) (final concentration: 8.25 nM; 50 mM HEPES, pH 6.2; 50 mM NaCl; 0.1) % PEG 6000) is incubated for 3 minutes at room temperature in a 96-well microtiter plate with a substance to be tested or a suitable solvent in a concentration range of 100 μM to 10 nM in a volume of 12 μl. Human platelet-deficient plasma (Blutspendedienst Deutsches Rotes Kreuz, Hagen, Germany) is diluted with buffer (150 mM NaCl; 20 mM HEPES, pH 7.4) at a ratio of 1: 3. Add 183 μl of plasma / buffer mixture to the protein / substance mixture in batches. Calcium chloride (final concentration: 10 mM), human tissue plasminogen activator (tPA; final concentration: 7.5 nM; Chromogenix, Moelndal, Sweden) and α-thrombin (final concentration: 25 nM; Kordia, Leiden, Netherlands) 8 μl of the mixture of), mix vigorously and transfer 80 μl portions twice to a 384-well microtiter plate. Following the formation of the fibrin clot and its subsequent lysis, the absorbance is measured at a wavelength of 405 nm. The reaction rate is measured at 37 ° C. at 2 minute intervals for at least 3 hours (Tecan Saphire, Tecan Germany GmbH, Crailsheim, Germany).

Data analysis: The clot lysis time (CLT) is the time at which the absorbance reaches an intermediate value between the highest and lowest absorbance. CLT values found in the absence of PAI-1 are defined as “0% PAI-1 activity” and those in the presence of 8.25 nM are defined as “100% activity”. The CLT ₅₀ value represents the concentration of the test substance at which the clot lysis time was reduced by a factor of two.

2. Selectivity comparison with other serine proteases
2.1 Plasminogen activator t-PA and urokinase
Assay Method: Substances are characterized for their effect on tPA (tissue plasminogen activator) and urokinase. For this purpose, a PAI-1 inhibitor is combined with human tPA (Sigma Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 1 nM) or human urokinase (Sigma Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 2.5 nM), Incubate for 10 minutes at room temperature in a buffer containing 50 mM TRIS pH 7.5, 140 mM NaCl and 0.1% PEG6000. Enzymatic activity is measured with SPECTRAFluor Plus (Tecan, Maennedorf, Switzerland) as an increase in fluorescence due to cleavage of specific peptide substrates (final concentration 10 μM; 444XF for tPA and 244XF for urokinase; American Diagnostica). . The maximum substance concentration is 10 μM.

Analysis: The value of fluorescence obtained without addition of substance is set equal to 100% and then all other values are associated with this 100%. Dose-activity plots and IC ₅₀ values are calculated from these percentages using the GraphPad Prism computer program.

2.2. Coagulation factors FX, FXa, FIXaβ, FVIIa, FXIa and serine proteases plasmin and trypsin
Assay Method: Clotting Factor Factor X (FX), Factor Xa (FXa), Factor IXaβ (FIXaβ), Factor VIIa (FVIIa), Factor XIa (FXIa) and thrombin, and serine protease plasmin and trypsin Used for testing. Common fluorogenic substrates are I-1100 (Boc-Ile-Glu-Gly-Arg-AMC), I-1575 (Boc-Glu (OBzl) -Ala-Arg-AMC HCl), I-1560 (Boc- Asp (OBzl) -Pro-Arg-AMC HCl) and I-1275 (MeOSuc-Ala-Phe-Lys-AMC TFA). All of these substrates are available from Bachem (Bubendorf, Switzerland). All experiments are performed in 50 millimolar (mM) Tris, 100 mM sodium chloride, 5 mM calcium chloride, 0.1% BSA, pH 7.4, room temperature. The final volume in all experiments is 100 microliters (μl).

  For each mixture, 10 nM FXa 5 μM substrate I-1100, 0.3 nM FXIa 5 μM I-1575, 0.1 nM trypsin 5 μM I-1100, 0.002 nM thrombin 5 μM I-1560, and , 0.012 nM plasmin is mixed with 50 μM I-1275. For combined assay systems, 8.8 nM FIXaβ or 1 pM FVIIa is mixed with 9.5 nM FXa and 50 μM substrate I-1100 in each case. The test compound is a 10 mmol (mM) solution in dimethyl sulfoxide (DMSO). These 10 mM stock solutions are first diluted 1: 5 with DMSO and then 1: 100 with assay medium. Eight serial dilutions are made from this 20 μM solution, each subsequent concentration corresponding to 1/3 of the original concentration. 30 μl of these individual dilution mixtures are 10 μM with the highest substance concentration in the enzyme / substance mixture followed by 3.3 μM, 1.1 μM, 0.37 μM, 0.12 μM, 0.04 μM, 0.04 Add to 30 μl cells, corresponding to 012 μM and 0.004 μM. These test substances are diluted in this way and added to the individual enzyme assay system. After incubation for 60 minutes, the amidolytic activity of the enzyme is measured in SPECTRAFluor Plus (Tecan, Maennedorf, Switzerland) at wavelengths of 360 nm (excitation) and 465 nm (emission).

Analysis: The value of fluorescence obtained without the addition of substance is set equal to 100% and then all other values are associated with these 100%. Thus, it is possible to compare experiments performed on different days. Dose-activity plots and IC ₅₀ values are calculated from these percentages using the GraphPad Prism computer program.

2.3 Inhibition of serine protease
2.3.1α ₂ - Other macroglobulin, serine protease inhibitors alpha ₂ - - antiplasmin alpha ₂ antiplasmin can inhibit serine protease plasmin.
Assay Method: Human α ₂ -antiplasmin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 50 nM; 50 mM TrisHCl pH 7.3; 200 mM NaCl; 0.2% BSA) in a volume of 10 μl with a concentration range of 100 Incubate for 5 minutes at room temperature in a 96-well microtiter plate with 10 μM of the substance to be tested or a suitable solvent. For each batch, 20 μl of human plasmin (Merck Biosciences, Schwalbach / Taunus, Germany; final concentration: 5 nM) is added to the α ₂ -antiplasmin / substance mixture and incubated at 37 ° C. for 15 minutes. The fluorogenic plasmin substrate I1275 (Bachem, Weil am Rhein, Germany; final concentration: 15 μM; 50 mM TRIS pH 7.3, 200 mM NaCl; 0.02% BSA) is then added. After incubation for 40 minutes at a temperature of 37 ° C., the fluorescence signal is measured (Tecan Saphire, Tecan Deutschland GmbH, Crailsheim, Germany; excitation: 360 nm; emission: 465 nm; gain 50).

Data analysis: The value of fluorescence found in the absence of α ₂ -antiplasmin (emission at 465 nm) is defined as “0% inhibition” and in the presence of 50 nM as “100% inhibition”. Define. The IC ₅₀ value represents the concentration of the test substance at which the emitted fluorescence is reduced by a factor of two.

2.3.2α ₁ - α ₁ antitrypsin serine protease inhibitors - antitrypsin can inhibit serine proteases trypsin.
Assay Method: Human α ₁ -antitrypsin (Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany; final concentration: 2 μM; 50 mM TrisHCl pH 7.3; 100 mM NaCl; 5 mM calcium chloride; 0.5% BSA) in a volume of 10 μl Incubate with the substance to be tested in a concentration range of 100-10 μM or in a suitable solvent in a 96-well microtiter plate at room temperature for 5 minutes. For each batch, 20 μl of human trypsin (Sigma-Aldrich, Taufkirchen, Germany; final concentration: 500 nM) is added to the α ₁ -antitrypsin / substance mixture and incubated at 37 ° C. for 15 minutes. The fluorogenic trypsin substrate I1100 (Bachem, Weil am Rhein, Germany; final concentration: 1 μM; 50 mM TRIS pH 7.3, 200 mM NaCl; 0.02% BSA) is then added. After incubation for 40 minutes at a temperature of 37 ° C., the fluorescence signal is measured (Tecan Saphire, Tecan Deutschland GmbH, Crailsheim, Germany; excitation: 360 nm; emission: 465 nm; gain 50).

Data analysis: The value of fluorescence found in the absence of α ₁ -antitrypsin (emission at 465 nm) is defined as “0% inhibition” and the presence in the presence of 2 μM as “100% inhibition”. Define. The IC ₅₀ value represents the concentration of the test substance at which the emitted fluorescence is reduced by a factor of two.

The suitability of the compounds of the invention for the treatment of thrombotic disorders can be demonstrated in the following animal models:
The compounds of the invention can be examined in a thrombosis model in which fibrinolysis is mediated by a PAI-1-dependent mechanism (Clozel, J Cardiovasc Pharmacol 12: 520-5 (1998); Levi, Circulation 85: 305 -12 (1992); Biemond, Circulation 91: 1175-81 (1995); compare Friederich, Circulation 96: 916-21 (1997)). Furthermore, it is possible to characterize the compounds of the invention with respect to their inhibition or reduction of PAI-1 activity in vivo (compare Crandall, BBRC 311: 904-908 (2003)).

The half-life of the compounds of the invention can be shown in the following assay:
In order to determine the apparent half-life in vivo, the test substance is dissolved in various formulation compositions (eg plasma, ethanol, DMSO, PEG400, etc.) or a mixture of these solubilizers to male Wistar rats. Administer intravenously. The dosage is in the range of 0.1 to 1 mg / kg. Blood samples are taken at various time points over a period of 26 hours using a catheter or as slaughtered plasma. Quantitative measurements of substances in the test sample are made in the plasma using a calibration sample conditioned in the plasma. Proteins present in the plasma are removed by precipitation with acetonitrile. The samples are then fractionated on a 2300 HTLC system (Cohesive Technologies, Franklin, MA, USA) by HPLC using a reverse phase column. The HPLC system is combined with an API 3000 Triple Quadropole mass spectrometer (Applied Biosystems, Darmstadt, Germany) via a turbo ion spray interface. The time course of plasma concentration is analyzed using a validated kinetic analysis program.

C. Exemplary Embodiments of Pharmaceutical Compositions Compounds of the present invention can be converted to pharmaceutical formulations in the following manner:
tablet:
composition:
100 mg of the compound of the invention, 50 mg lactose (monohydrate), 50 mg corn starch (natural), 10 mg polyvinylpyrrolidone (PVP25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
Tablet weight 212 mg. Diameter 8mm, curvature radius 12mm.
Manufacturing:
A mixture of the compound of the invention, lactose and starch is granulated with 5% strength aqueous PVP solution (m / m). The granules are dried and then mixed with magnesium stearate for 5 minutes. This mixture is compressed with a conventional tableting machine (see above for tablet shape). As a guideline, a tableting force of 15 kN is used for tableting.

Oral suspension:
composition:
1000 mg of the compound of Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, USA) and 99 g of water.
10 ml of oral suspension is equivalent to a single dose of 100 mg of a compound of the invention.
Manufacturing:
Rhodigel is suspended in ethanol and the compound of the invention is added to the suspension. Add water with stirring. The mixture is stirred for about 6 hours until the Rhodigel swells.

Solutions that can be administered intravenously:
composition:
1 mg of the compound of the invention, 15 g of polyethylene glycol 400 and 250 g of water for injection.
Manufacturing:
The compound of the present invention is dissolved in polyethylene glycol 400 with stirring. The solution is sterilized by filtration (pore diameter 0.22 μm) and distributed under sterile conditions into heat-sterilized infusion bottles. These are sealed with an infusion stopper and a crimp cap.

Claims (11)

formula

[Where:
X is the formula

(In the formula, * is the point of attachment to the carbonyl group,
# Is the point of attachment to the oxygen atom,
R ² , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C ₁ -C ₄ -alkyl, C ₁ -C _4. - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₄ - alkoxycarbonyl or _C 1 -C ₆ - alkylaminocarbonyl)
The basis of
Y is phenyl or pyridyl (wherein phenyl and pyridyl may be substituted by 1 to 3 substituents, where the substituents are halogen, hydroxy, amino, cyano, trifluoro; , trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C Selected from the group consisting of ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl independently of each other),
n is a number 0, 1, 2 or 3;
R ¹ is phenyl (wherein phenyl may be substituted by 1 to 3 substituents, where the substituents are halogen, hydroxy, amino, cyano, trifluoromethyl, tri trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxy Selected from the group consisting of carbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkylsulfonylamino)]
Or one of its salts, solvates or solvates of salts thereof. Where
X is the formula

(In the formula, * is the point of attachment to the carbonyl group,
# Is the point of attachment to the oxygen atom,
R ² , R ³ , R ⁴ and R ⁵ are independently of each other hydrogen, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, C ₁ -C ₄ -alkyl, C ₁ -C _4. - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₄ - alkoxycarbonyl or _C 1 -C ₆ - alkylaminocarbonyl)
The basis of
Y is phenyl (wherein phenyl is optionally substituted by 1 to 3 substituents, where the substituents are halogen, hydroxy, amino, cyano, trifluoromethyl, trifluoro methoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxycarbonyl And C ₁ -C ₆ -alkylaminocarbonyl selected from each other independently)
n is a number of 0 or 1,
R ¹ is phenyl (wherein the phenyl may be substituted by 1 to 3 substituents, where the substituents are halogen, hydroxy, amino, cyano, trifluoromethyl, tri trifluoromethoxy, hydroxycarbonyl, _{aminocarbonyl,} C 1 -C ₆ - _alkyl, C 1 -C ₆ - _alkoxy, C 1 -C ₆ - _alkylamino, C 1 -C ₆ - _{alkylcarbonyl,} C 1 -C ₆ - alkoxy Selected independently from the group consisting of carbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkylsulfonylamino)
A compound according to claim 1, or one of its salts, solvates or solvates of salts. Where
X is the formula

(In the formula, * is the point of attachment to the carbonyl group,
# Is the point of attachment to the oxygen atom,
And R ² , R ³ , R ⁴ and R ⁵ are hydrogen)
The basis of
Y is phenyl (wherein phenyl may be substituted by 1 to 2 substituents, wherein the substituents are selected from the group consisting of halogen and C ₁ -C ₄ -alkoxy; Selected independently),
n is a number of 0 or 1,
R ¹ is phenyl (wherein phenyl is optionally substituted by 1 to 3 substituents, where the substituents are halogen, cyano, trifluoromethyl, methyl, methoxy and methyl Independently selected from the group consisting of sulfonylamino)
A compound according to claim 1 or claim 2, or one of its salts, solvates or solvates of salts. A process for the preparation of a compound of formula (I) according to claim 1 or a salt, solvate or solvate of a salt thereof,

(Wherein X and R ¹ have the meaning of claim 1)
A compound of the formula

(Wherein X and n have the meaning of claim 1)
A process comprising reacting with a compound of:   4. A compound according to any one of claims 1 to 3 for the treatment and / or prevention of disease.   Use of a compound according to any of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prevention of diseases.   Use of a compound according to any of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prevention of thrombotic disorders.   A medicament comprising at least one compound according to any one of claims 1 to 3 in combination with a further active ingredient.   A medicament comprising at least one compound according to any one of claims 1 to 3 in combination with at least one inert, non-toxic pharmaceutically suitable adjuvant.   The medicament according to claim 8 or 9, for the treatment and / or prevention of thrombotic disorders.   In humans and animals by administering a pharmaceutically effective amount of at least one compound according to any one of claims 1 to 3 or a medicament according to any one of claims 8 to 10. A method for controlling thrombotic disorders.