JP2006525259A - New diazabicyclononene derivatives - Google Patents

Abstract

The present invention provides new 3,9-diazabicyclo [3.3.1] nonene derivatives and related compounds and the use of the derivatives and related compounds as active ingredients in the manufacture of pharmaceutical compositions.
Novel 3,9-diazabicyclo [3.3.1] nonene derivatives and related compounds, and use of the derivatives and related compounds as active ingredients in the manufacture of pharmaceutical compositions, methods for preparing the derivatives and related compounds, It is achieved by pharmaceutical compositions comprising one or more of the above derivatives or related compounds, in particular their use as renin inhibitors.

Description

The present invention relates to novel compounds of general formula I. The present invention also provides a process for the preparation of the compounds, pharmaceutical compositions containing one or more of the compounds of formula I and the use of these compounds as renin inhibitors, especially in cardiovascular disorders and renal dysfunction Related aspects including In addition, these compounds can be regarded as inhibitors of other aspartyl proteases, and therefore as a plasmepsin inhibitor for the treatment of malaria and as a Candida albicans secreted aspartyl for the treatment of fungal infections. It would be useful as a protease inhibitor.

In the renin-angiotensin system (RAS), a physiologically active substance, angiotensin II (Ang II), is produced by a two-step mechanism. Renin, which is a highly specific enzyme, cleaves angiotensinogen to produce angiotensin I (AngI). This is further processed by the less specific angiotensin converting enzyme (ACE) to Ang II. Ang II is known to act on at least two receptor subtypes called AT ₁ and AT ₂ . AT ₁ appears to transmit most of the known functions of Ang II, but the role of AT ₂ is still unknown.

The regulation of RAS represents a major advance in the treatment of cardiovascular diseases. ACE inhibitors and AT ₁ blockers have already been accepted for the treatment of hypertension (see, for example, Non-Patent Documents 1 and 2). Further, ACE inhibitors are used for renal protection (see Non-Patent Documents 3 and 4), for prevention of congestive heart failure (for example, see Non-Patent Documents 5 and 6) and for prevention of myocardial infarction (for example, non-patent documents). (See Patent Document 7).
WH Berkenhager, JL Reid (eds.): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1996, 489-519 Weber et al., “The Renin-Angiotensin System: Role in Experimental and Human Hypertension” MA Weber, American Journal of Hypertens., 1992, 5, 247S M.E. Rosenberg et al., Kidney International, 1994, 45, 403 JA Breyer et al., Kidney International, 1994, 45, S156. Vaughan et al., Cardiovasc. Res., 1994, 28, 159 Fouad-Tarazi et al., American Journal of Medicine (Am. J. Med.), 1988, 84 (Appendix 3A), 83. M. A. Pfeffer et al., New England Journal of Medicine (N. Eengl. J. Med.), 1992, 327, 669.

The rationale for the development of renin inhibitors is the specificity of renin (see, for example, Non-Patent Document 8). The only known substrate for renin is angiotensinogen, which can only be processed (under physiological conditions) by renin. In contrast, ACE can cleave bradykinin in addition to AngI, and can be replaced by chymase, which is a serine protease (see, for example, Non-Patent Document 9). Thus, ACE inhibition in patients leads to bradykinin accumulation, which causes cough (5-20%) and potentially fatal angioedema (0.1-0.2%) ( For example, refer nonpatent literature 10.). Chymase is not inhibited by ACE inhibitors. Therefore, AngII production is still possible in ACE inhibitor-treated patients. On the other hand, AT ₁ receptor (e.g., by losartan) is cut off, thus to overexposure other AT- receptor subtype AngII whose concentration was dramatically increased by the blockade of AT ₁ receptors. This may pose a serious problem regarding the safety and efficacy profile of AT ₁ receptor antagonists. In short, renin inhibitors are not only expected to differ from ACE inhibitors and AT ₁ blockers in terms of safety, but more importantly, they are also expected to differ in their RAS blocking effects.
KD Kleinert, Cardiovasc. Drugs, 1995, 9,645. A. Hussain, Journal of Hypertension (J. Hypertens), 1993, 11, 1155 ZH Israili et al., Anals of Internal Medicine, 1992, 117, 234.

Since renin inhibitors have insufficient oral activity due to their peptidomimeticity (see, for example, Non-Patent Document 11), very limited clinical experience with them (for example, Non-Patent Document 12 and Only 13) is obtained. The clinical development of several compounds has been discontinued due to this problem and the high price of the product. Only one compound with four chiral centers has entered clinical trials (see, for example, Non-Patent Documents 14 and 15). Thus, a renin inhibitor that can be produced on a large scale, is stable against metabolism, has a high oral bioavailability, and is sufficiently soluble has not been found and is being searched. Recently, the first non-peptide renin inhibitors that exhibit high vitreous activity have been described (see, for example, Non-Patent Document 16, Patent Document 1, and Non-Patent Document 17). However, the development status of these compounds is unknown.
HD Kleinert, Cardiovascular Drags, 1995, 9, 645 M. Azizi et al., Journal of High Patent, 1994, 12, 419 JM Neutel et al., American Heart (1991), 122, 1094 J. et al. Rahuel et al., Chem. Biol., 2000, 7, 493 NE Mealy, Drugs of the Future, 2001, 26, 1139 C. Oefner et al., Chemistry and Biology, 1999, 6, 127. International Publication No. 97/09311 HP P. Marki et al., Il Farmaco, 2001, 56, 21

The present invention relates to the identification and confirmation of a non-peptide, low molecular weight renin inhibitor. Activation of the tissue renin-chymase system can lead to a range of blood pressure regulation that can lead to pathologically altered local functions such as renal, cardiac and vascular remodeling, atherosclerosis, or restenosis Describes a long-acting orally active renin inhibitor active in a number of indications.

The present invention describes non-peptide renin inhibitors.

式中、

Ｗは、Ｖがメタまたはパラ位で置換された６員の非ベンゼン縮合のフェニルまたはヘテロアリール環であり;

Ｖ は、-Ｏ-ＣＨ_２-ＣＨ(ＯＣＨ_３)-ＣＨ_２-Ｏ-; -Ｏ-ＣＨ_２-ＣＨ(ＣＨ_３)-ＣＨ_２-Ｏ-; -Ｏ-ＣＨ_２-ＣＨ(ＣＦ_３)-ＣＨ_２-Ｏ-; -Ｏ-ＣＨ_２-Ｃ(ＣＨ_３)_２-ＣＨ_２-Ｏ-; -Ｏ-ＣＨ_２-Ｃ(ＣＨ_３)_２-Ｏ-; -Ｏ-Ｃ(ＣＨ_３)_２-ＣＨ_２-Ｏ-; -Ｏ-ＣＨ_２-ＣＨ(ＣＨ_３)-Ｏ-; -Ｏ-ＣＨ(ＣＨ_３)-ＣＨ_２-Ｏ-; -Ｏ-ＣＨ_２-Ｃ(ＣＨ_２ＣＨ_２)-Ｏ-; -Ｏ-Ｃ(ＣＨ_２ＣＨ_２)-ＣＨ_２-Ｏ-を表し;

Ｕ は、アリール; ヘテロアリールを表し;

Ｔ は、-ＣＯＮＲ^１-; -(ＣＨ_２)_ｐＯＣＯ-; -(ＣＨ_２)_ｐＮ(Ｒ^１)ＣＯ-; -(ＣＨ_２)_ｐＮ(Ｒ^１)ＳＯ_２-; または-ＣＯＯ-を表し;

Ｑ は、低級アルキレン; 低級アルケニレンを表し;

Ｍ は、水素; シクロアルキル; アリール; ヘテロシクリル; ヘテロアリールを表し;

Ｌ は、-Ｒ^３; -ＣＯＲ^３; -ＣＯＯＲ^３; -ＣＯＮＲ^２Ｒ^３; -ＳＯ_２Ｒ^３; -ＳＯ_２ＮＲ^２Ｒ^３;-ＣＯＣＨ(アリール)_２を表し;

Ｒ^１ は、水素; 低級 アルキル; 低級 アルケニル; 低級 アルキニル; シクロアルキル; アリール; シクロアルキル - 低級 アルキルを表し;

Ｒ^２ および Ｒ^２' は、水素; 低級 アルキル; 低級 アルケニル; シクロアルキル; シクロアルキル-低級アルキルを独立に表し;

Ｒ^３ は、水素; 低級アルキル; 低級アルケニル; シクロアルキル; アリール; ヘテロアリール; ヘテロシクリル; シクロアルキル-低級アルキル; アリール-低級ルキル; ヘテロアリール-低級アルキル; ヘテロシクリル-低級アルキル; アリールオキシ-低級 アルキル; ヘテロアリールオキシ-低級アルキルを表し、 これらの基は、未置換またはモノ-、 ジ-またはトリ置換されていてもよく、置換基としてはヒドロキシ、 -ＯＣＯＲ^２、 -ＣＯＯＲ^２、 低級 アルコキシ、 シアノ、 -ＣＯＮＲ^２Ｒ^２'、 -ＣＯ-モルホリン-４-イル、 -ＣＯ-((４-低級アルキル)ピペラジン-１-イル)、 -ＮＨ(ＮＨ)ＮＨ_２、 -ＮＲ^４Ｒ^４' または低級 アルキルが挙げられる、 但し、炭素原子がｓｐ３-混成軌道の場合、この炭素原子は多くても１個のヘテロ原子と結合していることを条件とする;

Ｒ^４ および Ｒ^４' は、水素; 低級アルキル; シクロアルキル; シクロアルキル-低級アルキル; ヒドロキシ-低級アルキル; -ＣＯＯＲ^２; -ＣＯＮＨ_２を独立に表し;

ｋ は、整数０または１であり;

ｍおよびｎ は、整数０または１を表し、 但し、ｍが整数１を表す場合、 ｎは整数０であり、 ｎが整数１を表す場合、 ｍは整数０であり; ｋが整数０を表す場合、 ｎは整数０を表す;

ｐ は、整数１、 ２、 ３ または ４である;

および医薬品として許容可能な塩類、溶媒コンプレックスおよび形態学的形状と同様に、光学的に純粋なエナンチオマー、ラセミ体などのエナンチオマーの混合物、ジアステレオマー、ジアステレオマーの混合物、ジアステレオマーラセミ体、ジアステレオマーラセミ体の混合物、およびそのメソ形。 In particular, the present invention relates to novel compounds of general formula I.

Where

W is a 6-membered non-benzene fused phenyl or heteroaryl ring in which V is substituted at the meta or para position;

V _{is, -O-CH 2 -CH (OCH} 3) -CH 2 -O-; -O-CH 2 -CH (CH 3) -CH 2 -O-; -O-CH 2 -CH (CF 3) _{-CH 2 -O-; -O-CH 2} -C (CH 3) 2 -CH 2 -O-; -O-CH 2 -C (CH 3) 2 -O-; -O-C (CH 3) ₂ —CH ₂ —O—; —O—CH ₂ —CH (CH ₃ ) —O—; —O—CH (CH ₃ ) —CH ₂ —O—; —O—CH ₂ —C (CH ₂ CH ₂ ) —O—; represents —O—C (CH ₂ CH ₂ ) —CH ₂ —O—;

U represents aryl; represents heteroaryl;

T is -CONR ¹ -;-(CH ₂ ) _p OCO-;-(CH ₂ ) _p N (R ¹ ) CO-;-(CH ₂ ) _p N (R ¹ ) SO _2- ; or -COO- Represents;

Q represents lower alkylene; lower alkenylene;

M represents hydrogen; cycloalkyl; aryl; heterocyclyl; heteroaryl;

L ^{is, -R 3; -COR 3; -COOR} 3; -CONR 2 R 3; -SO 2 R 3; represents -COCH ^{_{(aryl) 2; -SO 2 NR 2 R}} 3;

R ¹ represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl; cycloalkyl; aryl; cycloalkyl-lower alkyl;

R ² and R ² ′ are independently hydrogen; lower alkyl; lower alkenyl; cycloalkyl; cycloalkyl-lower alkyl;

R ³ is hydrogen; lower alkyl; lower alkenyl; cycloalkyl; aryl; heteroaryl; heterocyclyl; cycloalkyl-lower alkyl; aryl-lower alkyl; heteroaryl-lower alkyl; heterocyclyl-lower alkyl; aryloxy-lower alkyl; Represents a heteroaryloxy-lower alkyl, these groups may be unsubstituted or mono-, di- or tri-substituted, including hydroxy, -OCOR ² , -COOR ² , lower alkoxy, cyano, -CONR ² R ² ', -CO- morpholin-4-yl, -CO - ((4- lower alkyl) _{piperazin-1-yl), -NH (NH) NH 2} , -NR 4 R 4' or lower alkyl However, when the carbon atom is sp3-hybrid orbital, this carbon atom is bonded to at most one heteroatom. With the proviso Rukoto;

R ⁴ and R ⁴ ′ represent hydrogen; lower alkyl; cycloalkyl; cycloalkyl-lower alkyl; hydroxy-lower alkyl; —COOR ² ; —CONH ₂ independently;

k is an integer 0 or 1;

m and n represent the integer 0 or 1, provided that when m represents the integer 1, n is the integer 0, and when n represents the integer 1, m is the integer 0; k represents the integer 0 Where n represents the integer 0;

p is an integer 1, 2, 3 or 4;

And pharmaceutically acceptable salts, solvent complexes and morphological forms, as well as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, A mixture of diastereomeric racemates and their meso forms.

In the definition of general formula I, unless stated otherwise, the term lower alkyl, alone or in combination with other groups, is 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Saturated straight-chain and branched-chain groups having the formula: are optionally substituted with halogen. Examples of lower alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl and heptyl. Methyl, ethyl and isopropyl groups are preferred.

The term lower alkoxy is indicated by the group R—O, where R is lower alkyl. Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.

The term lower alkenyl, alone or together with other groups, means straight and branched groups comprising 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, containing an olefinic bond, These may be optionally substituted with halogen. Examples of lower alkenyl are vinyl, propenyl or butenyl.

The term lower alkynyl, alone or together with other groups, means straight-chain and branched groups consisting of 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms, including triple bonds, These may be optionally substituted with halogen. Examples of lower alkynyl are ethynyl, propynyl or butynyl.

The term lower alkylene, alone or together with other groups, means straight and branched divalent groups of 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, which are halogenated May be optionally substituted. Examples of lower alkylene are ethylene, propylene or butylene.

The term lower alkenylene, alone or together with other groups, has an olefinic bond and is a straight and branched divalent group consisting of 2 to 7 carbon atoms, preferably 2 to 4 carbon atoms. And optionally substituted with halogen. Examples of lower alkenylene are vinylene, propenylene and butenylene.

The term lower alkylenedioxy means that each end of lower alkylene is substituted with an oxygen atom. Examples of lower alkylenedioxy groups are preferably methylenedioxy and ethylenedioxy.

The term lower alkyleneoxy means that one end of lower alkylene is substituted with an oxygen atom. Examples of lower alkyleneoxy groups are preferably methyleneoxy, ethyleneoxy and propyleneoxy.

The term halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

The term cycloalkyl, alone or in combination, means a saturated cyclic hydrocarbon ring system having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, Are lower alkyl, lower alkenyl, lower alkenylene, lower alkoxy, lower alkyleneoxy, lower alkylenedioxy, hydroxy, halogen, —CF ₃ , —NR ¹ R ^{1 ′} , —NR ¹ C (O) R ^{1 ′} , —NR ¹ S (O ₂ ) R ^{1 ′,} C (O) NR ¹ R ^{1 ′} , lower alkylcarbonyl, —COOR ¹ , —SR ¹ , —SOR ¹ , —SO ₂ R ¹ , SO ₂ NR ¹ R ^{1 ′} It may optionally be mono- or polysubstituted. R ^{1 ′} represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl; cycloalkyl; aryl; cycloalkyl-lower alkyl. A cyclopropyl group is a preferred group.

The term aryl, alone or in combination, refers to a phenyl, naphthyl or indanyl group, preferably a phenyl group, which is a lower alkyl, lower alkenyl, lower alkynyl, lower ring that forms a 5- or 6-membered ring with the aryl ring. Alkenylene or lower alkylene, lower alkoxy, lower alkylenedioxy, lower alkyleneoxy, hydroxy, hydroxy-lower alkyl, halogen, cyano, —CF ₃ , —OCF ₃ , —NR ¹ R ^{1 ′} , —NR ¹ R ^{1 ′} − Lower alkyl, —NR ¹ C (O) R ^{1 ′} , —NR ¹ S (O ₂ ) R ¹ , —C (O) NR ¹ R ^{1 ′} , —NO ₂ , lower alkylcarbonyl, —COOR ¹ , —SR _{^{1, -SOR 1, -SO 2 R}} 1, -SO 2 NR 1 R 1 ', benzyloxy, optionally mono - be or polysubstituted . R ^{1 ′} has the meaning defined above. Preferred substituents are halogen, lower alkoxy, lower alkyl, CF ₃ , OCF ₃ .

The term aryloxy refers to the group Ar-O, where Ar is aryl. An example of a lower aryloxy group is phenoxy.

The term heterocyclyl alone or in combination contains one or two nitrogen, oxygen or sulfur atoms, which may be the same or different and are saturated or unsaturated (but not aromatic) 5, 6- or 7-membered rings are meant, and these rings may be optionally substituted with lower alkyl, hydroxy, lower alkoxy and halogen. A nitrogen atom, if present, may be substituted with a —COOR ² group. Examples of such rings are piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroquinolinyl , Tetrahydroquinolinyl and tetrahydroisoquinolinyl.

The term heteroaryl, alone or in combination, is a 6-membered aromatic ring containing 1 to 4 nitrogen atoms; a benzene-fused 6-membered aromatic ring containing 1 to 3 nitrogen atoms; 5-membered aromatic ring containing one oxygen, one nitrogen or one sulfur atom; one benzene-fused five-membered aromatic ring containing one nitrogen, one nitrogen or one sulfur atom; one oxygen And 5-membered aromatic rings containing one nitrogen atom and their benzene condensed derivatives; 5-membered aromatic rings containing sulfur and nitrogen or oxygen atoms and their benzene-condensed derivatives; 5-membered aromatic containing two nitrogen atoms Means a 5-membered aromatic ring containing 3 nitrogen atoms and a benzene condensed derivative thereof, or a tetrazolyl ring. Examples of such ring systems are furanyl, thiophenyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, coumarinyl, benzothiophenyl, quinazolinyl Quinoxalinyl. These rings are lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, lower alkenylene, lower alkylenedioxy, lower alkyleneoxy, hydroxy-lower alkyl, lower alkoxy, hydroxy, halogen, cyano, —CF ³ , —OCF _3. , —NR ¹ R ^{1 ′} , —NR ¹ R ^{1 ′} -lower alkyl, —N (R ¹ ) COR ¹ , —N (R ¹ ) SO ₂ R ¹ , —CONR ¹ R ^{1 ′} , —NO ₂ , lower Suitably substituted with alkylcarbonyl, —COOR ¹ , —SR ¹ , —SOR ¹ , —SO ₂ R ¹ , —SO ₂ NR ¹ R ^{1 ′} , another aryl, another heteroaryl, another heterocyclyl, or the like; May be. R ^{1 ′} has the same meaning as defined above.

The term heteroaryloxy refers to a Het-O group, where Het is heteroaryl.

The term sp3-hybrid orbit refers to a carbon atom, which forms four bonds for four substituents arranged in a tetragonal form around this atom.

The term pharmaceutically acceptable salts are hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. A salt with an inorganic or organic acid that is non-toxic to living organisms, or where the compound of general formula I is acidic in nature, an inorganic base such as an alkali or alkaline earth base, such as sodium hydroxide, It includes either a salt with potassium hydroxide, calcium hydroxide or the like.

The compounds of the present invention also include nitroso compounds of the general formula I which are nitrosated via one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfuryl condensation) and / or nitrogen. The nitrosated compounds of the present invention can be prepared by conventional methods known to those skilled in the art. For example, known methods for nitrosating compounds include US Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; WO 98/21193; 99/00361 and Oae et al., Org. Prep. Proc. Int., 15 (3): 165-198 (1983). The disclosures of each of these documents are hereby incorporated by reference in their entirety.

The compounds of the general formula I can contain two or more asymmetric carbon atoms and are optically pure enantiomers, enantiomer mixtures such as racemates, diastereomers, diastereomeric mixtures, diastereomers It may be prepared in the form of mar racemates, diastereomeric racemic mixtures, and meso forms thereof, and pharmaceutically acceptable salts thereof.

The present invention encompasses all these forms. The mixture can be separated by methods known per se, ie column chromatography, thin layer chromatography, HPLC or crystallization.

Preferred groups of compounds of general formula I are those in which W, V, U, T, Q, L, and M are as defined in general formula I above, k is 1 and n is 0 And m is 1.

Another group of preferred compounds of general formula I is that W, V, U, T, Q, M, k, m, and n are as defined above for general formula I, and L is ^{, H; -COR 3 '';} -COOR 3 ''; -CONR 2 ' ^{represents' R 3 ''; R 2} '' and R ³ '' is lower alkyl; lower cycloalkyl - independently lower alkyl It is a compound to represent. The lower alkyl and the lower cycloalkyl-lower alkyl may be unsubstituted or monosubstituted by halogen, cyano, hydroxy, —OCOCH ₃ , —CONH ₂ , —COOH, or —NH ₂ . However, in the case where the carbon atom is sp3-hybrid orbital, it is a condition that this carbon atom is bonded to at most one heteroatom.

Another group of preferred compounds of general formula I are those wherein W, V, U, L, k, m, and n are as defined in general formula I, and T is -CONR ^1- A compound in which Q represents methylene; and M represents an aryl or heteroaryl.

Another group of more preferred compounds of general formula I is that W, U, L, T, Q, M, k, m, and n are as defined above for general formula I, and V is A compound representing —O—CH ₂ —CH (CH ₃ ) —CH ₂ —O—; —O—CH ₂ —C (CH ₃ ) ₂ —CH ₂ —O—.

Another group of even more preferred compounds of general formula I are those in which V, U, T, Q, M, L, k, m, and n are as defined above for general formula I, and W Is a compound representing a 1,4-disubstituted phenyl ring.

Another group of even more preferred compounds of general formula I is that W, V, Q, T, M, L, m, and n are as defined above for general formula I, and U is A compound that is mono-, di-, or tri-substituted phenyl or heteroaryl, and the substituent is halogen, lower alkyl, lower alkoxy, CF ₃ .

Particularly preferred compounds of the general formula I are compounds selected from the following group:

(1R, 5S) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) propoxy] -phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl) amide;

(1S, 5R) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluoro-phenoxy) propoxy] phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl) amide;

(1R, 5S) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) propoxy] -phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl) amide and (1S, 5R) -7- {4-[(2S) -2-methyl-3- (2,3 , 6-Trifluoro-phenoxy) propoxy] phenyl} -3,9-diazabicyclo- [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl) amide .

The compounds of general formula I and pharmaceutically acceptable salts of the compounds can be used therapeutically, eg in the form of pharmaceutical compositions. These pharmaceutical compositions comprise at least one compound of general formula I and usual carrier substances and adjuvants, in particular related to dysregulation of the renin-angiotensin system (RAS) including cardiovascular disease and nephropathy It can be used for treatment or prevention of disease. Examples of such diseases are hypertension, coronary heart disease, heart failure, renal dysfunction, renal or myocardial ischemia, renal failure. These pharmaceutical compositions can also be used for the prevention of restenosis after angioplasty with balloons or stents, the treatment of erectile dysfunction, glomerulonephritis, renal colic and glaucoma. In addition, they are associated with diabetic complications, complications after vascular or cardiac surgery, restenosis, complications of treatment with immunosuppressants after organ transplantation, complications of cyclosporine treatment, and RAS It can also be used for the treatment and prevention of other currently known diseases.

In another embodiment, the invention relates to hypertension, congestive heart failure, pulmonary hypertension, heart failure, renal dysfunction, renal or myocardial ischemia, atherosclerosis, renal failure, erectile dysfunction, glomerulonephritis, necrosis Diseases associated with RAS, including pain, glaucoma, diabetic complications, complications after vascular or cardiac surgery, restenosis, complications of treatment with immunosuppressants after organ transplantation, and others related to RAS For the treatment and / or prophylaxis of these diseases, the method comprises administering to a human or animal a compound according to general formula I.

In addition, the present invention provides for the manufacture of a medicament for the treatment and / or prevention of diseases associated with RAS, such as hypertension, coronary disease, heart failure, renal dysfunction, kidney or myocardial ischemia, and renal failure. Relates to the use of the same compounds as defined in. These medicaments can be produced in a manner known per se.

The compounds of general formula I are also used for the treatment of the diseases mentioned above, together with one or more pharmacologically active compounds, such as other renin inhibitors, ACE inhibitors, angiotensin II receptor antagonists. , Endothelin receptor antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympathetic blockers, β-adrenergic antagonists, α-adrenergic antagonists, and neutral endopeptidase inhibitors You can also

Any form of prodrug that results in an active ingredient encompassed by Formula I above is included in this invention.

The compounds of general formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.

Chemistry

The chemistry necessary to produce the compounds contained in general formula 1 can be obtained from prior patent applications, such as WO 03/093267 or 04/002957. Linkers included under V of general formula I are commercially available glycerin, commercially available 3-hydroxy-2,2-dimethylpropionic acid methyl ester, (R)-or (S ) -3-hydroxy-2-methylpropionic acid (T. Locher et al .; PCT Int. Appl. WO 0022153 A1 20000420, 2000; G. Vogel et al .; Chemistry and Physics of Lipids, 1990, 52, 99; D. Seebach et al. Helv. Chim. Acta, 1986, 69, 1147), or (R)-or (S) -3-hydroxy-2- (trifluoromethyl) propionic acid (SP Goetzoe et al; Chimia, 1996, 50, 20) Can be manufactured from. Similarly, methyl 1-hydroxy-1-cyclopropanecarboxylate or any lactic acid derivative can be used as starting material. All of these starting materials are protected, phenolic, hydroxyheterocyclic, hydroxycycloalkyl, or hydroxyheteroaryl coupling (typically by Mitsunobu coupling), reduction, and / or desorption. By combining protective means, it can be converted into a VU precursor for the segment. For example, a type A compound can be prepared from one of the above compounds. Where R ^a -and R ^b -groups are as defined in general formula I (or precursors to such groups) and COOR ^c is a suitable ester, typically methyl, ethyl Or a benzyl ester. Reduction of the ester can lead to a compound of type B and then to a compound of type C by Mitsunobu coupling. In the course of this reaction procedure, the protecting group (PG) can be cleaved and replaced with a more suitable protecting group (PG ′) for the next chemical reaction leading to a type D compound. Coupling to the known vinyl triflate E can lead to type F bicyclononene. Treatment of the protecting group can lead to a compound of type G, which can then be deprotected to a type H bicyclononene. The following means can be led to type J bicyclononene by means of Mitsunobu coupling, for example, where the VU segment is in a perfectly defined location. Saponification can lead to a compound of type K, which can then be led to a compound of type L, for example by amide coupling. The Boc-protecting group can be removed and then alkylated or acylated to type M bicyclononene, followed by deprotection to the desired final compound of type N.

The compounds of formula I and the pharmaceutically acceptable acid addition salts thereof can be used as medicaments, for example in the form of enteral, parenteral or topical medicaments. For example, these are orally in the form of tablets, coated tablets, dragees, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions, etc., from the rectum in the form of suppositories, and in the form of injections and infusions. And can be administered (applied) parenterally or in the form of an ointment, cream or oil.

The manufacture of a medicament is well known to those skilled in the art by combining the described compounds of formula I and pharmaceutically acceptable acid addition salts thereof, optionally with other therapeutically useful substances. In known manner, along with a suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier material, if necessary, the usual pharmaceutical adjuvants are added to form the dosage form. Can be achieved.

Suitable carrier materials include not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used as carrier materials for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carrier materials for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid polyols and liquid polyols (although soft gelatin capsules may not require a carrier depending on the nature of the active ingredient). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suitable suppositories are, for example, natural and hardened oils, waxes, fats and semisolid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Considered as a pharmaceutical adjunct is the usual stabilizers, preservatives, wetting agents and emulsifiers, consistency improvers, flavor improvers, salts for changing osmotic pressure, buffers, solubilizers, colorings Agents, masking agents and antioxidants.

The dose of the compound of formula I will vary within a wide range depending on the disease to be controlled, the age and personal condition of the patient, the method of administration and, of course, will be adapted to the individual requirements of each particular case become. In the case of an adult patient, a daily dose of about 1 mg to about 1000 mg, particularly about 50 mg to about 500 mg is considered.

Formulations usually contain about 1 to 500 mg, preferably 5 to 200 mg, of a compound of formula I.

The following examples serve to illustrate the invention in more detail. However, they are not intended to limit the scope in any way.

Abbreviation

ACE angiotensin converting enzyme AcOH acetic acid Ang angiotensin aq. Aqueous, water-containing Bn benzyl Boc tert-butyloxycarbonyl BSA bovine serum albumin BuLi n-butyllithium DIBAL hydrogenated diisobutyaluminum DIPEA diisopropylethylamine DMAP 4-N, N-dimethyl Aminopyridine DMSO dimethyl sulfoxide EDC.HCl ethyl-N, N-dimethylaminopropylcarbodiimide hydrochloride EIA enzyme immunoassay eq. Equivalent Et Ethyl EtOAc Ethyl Acetate FC Flash Chromatography HOBt Hydroxybenzotriazole LC-MS Liquid Chromatography Mass Spectrometry MeOH Methanol org. Organic, Organic PG Protecting Group Ph Phenyl RAS Renin Angiotensin System rt Room Temperature Sol. Liquid TBAF Tetra-n-butylammonium fluoride TBDMS tert-butyldimethylsilyl Tf trifluoromethylsulfonyl THF Tetrahydrofuran TMAD N, N, N ′, N′-Tetramethylazodicarboxamide

precursor

(R) -3- (tert-butyldiphenylsilanyloxy) -2-methylpropionic acid methyl ester (A)

To a mixture of (−)-methyl D-β-hydroxyisobutyrate (5.54 mL, 50 mmol) and imidazole (8.51 g, 125 mmol) in CH ₂ Cl ₂ (150 mL) was added tert- Butyldiphenylsilyl chloride (19.5 mL, 75 mmol) was added. After stirring for 18 hours, the mixture was diluted with CH ₂ Cl ₂ and washed with saturated aqueous NH ₄ Cl and brine. The organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. Purification by FC (heptane / EtOAc 100: 0 → 90: 10) gave the title compound (15.32 g, 86%).

(S) -3- (tert-butyldiphenylsilanyloxy) -2-methylpropan-1-ol (B)

A solution of DIBAL (1M in hexane; 113.2 mL, 113.2 mmol) was further diluted with THF (400 mL) before compound A (13.44 g, 37.7 mmol) was dissolved in THF (150 The solution dissolved in mL) was added at -78 ° C. The solution was stirred for 30 minutes at −78 ° C., then MeOH (11.3 mL) was added slowly. The mixture was allowed to warm. Saturated aqueous NH ₄ Cl was added slowly until a finely divided solid was formed. The mixture was filtered through a pad of Na ₂ SO ₄ . Purification by FC (heptane / EtOAc 98/2 → 95/5 → 90: 10 → 80: 20) gave the title compound (11.6 g, 93%). _{LC-MS; R t = 1.12} , ES +: 329.28.

(S)-[3- (4-Bromophenoxy) -2-methylpropoxy] -tert-butyldiphenylsilane (C)

A solution of 4-bromophenol (7.07 g, 40.2 mmol) and DIPEA (0.58 mL, 3.3 mmol) and compound B (11 g, 33.48 mmol) in toluene (335 mL). Added to. Azodicarboxylic acid dipiperidide (12.67 g, 50.2 mmol) was added followed by n-tributylphosphine (16.52 ml, 67 mmol) at 0 ° C. The reaction mixture was stirred for 1 hour at room temperature and then for 2 hours at 60 ° C. The mixture was left to cool to room temperature and then water was added. This mixture was extracted with EtOAc. The organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. Purification by FC (heptane / EtOAc 95/5) gave the title compound (16.0 g, 99%). LC-MS; R _t = 1.29 min.

(S)-[3- (4-Bromophenoxy) -2-methylpropoxy] -tert-butyldimethylsilane (D)

To a solution of compound C (13.1 g, 27 mmol) dissolved in THF (200 mL), TBAF (1M solution in THF, 54 mL, 54 mmol) was added at 0 ° C. The cooling bath was removed and the reaction mixture was stirred for 2 hours. AcOEt and saturated aqueous NH ₄ Cl were added. The aqueous phase was extracted with AcOEt, the organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. Purification by FC (heptane / EtOAc 80/20 → 50/50 → 0/100) gave the title compound (3.79 g, 57%).

To a mixture of the previously obtained compound (3.79 mL, 15.5 mmol) and imidazole (2.63 g, 38.7 mmol) in CH ₂ Cl ₂ (45 mL) was added tert-butyldimethylsilyl chloride. (3.5 g, 23.2 mmol) was added. After stirring for 3 hours, the mixture was diluted with CH ₂ Cl ₂ and washed with saturated aqueous NH ₄ Cl and brine. The organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. Purification by FC (heptane / EtOAc 98/2 → 95/5) gave the title compound (3.1 g, 56%). LC-MS; R _t = 1.24 min.

(1R, 5S) -7-{(2S) -4- [3- (tert-Butyldimethylsilanyloxy) -2-methylpropoxy] phenyl} -9-methyl-3,9-diazabicyclo [3.3. 1] non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester and (1S, 5R) -7-{(2S) -4- [3- (tert-butyldimethylsilanyl) Of (oxy) -2-methylpropoxy] phenyl} -9-methyl-3,9-diazabicyclo [3.3.1] non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester 1: 1 mixture (F)

BuLi (1.6M in hexanes, 3.2 mL, 5.12 mmol) was added to a solution of compound D (1.8 g, 5 mmol) in THF (4 mL) at −78 ° C. . The mixture was stirred for 30 minutes at this temperature and ZnCl ₂ (prepared from ZnCl ₂ and THF dried in THF at 1M, 160 ° C. for 3 hours, 6 mL, 6 mmol) was added. The mixture was allowed to warm to room temperature and a solution of bicyclononene E (0.91 g, 2 mmol) in THF (6 ml) was added followed by Pd (PPh ₃ ) ₄ (58 mg, 0. 05 mmol) was added. The mixture was heated to 40 ° C. and stirred at this temperature for 30 minutes. Saturated aqueous NH ₄ Cl was added. The mixture was extracted 3 times with EtOAc and washed with brine. The organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. Purification by FC (heptane / AcOEt 50: 50 → 0/100 further EtOAc / MeOH 95/5) gave the title compound (0.49 g, 41%). _{LC-MS; R t = 1.03} ES +: 589.36.

(1R, 5S) -7-{(2S) -4- [3- (tert-Butyldimethylsilanyloxy) -2-methyl-propoxy] phenyl} -3,9-diazabicyclo [3.3.1] non 6-ene-3,6,9-tricarboxylic acid 3-tert-butyl ester 6-ethyl ester 9- (2,2,2-trichloro-1,1-dimethylethyl) ester and (1S, 5R) -7 -{(2S) -4- [3- (tert-butyldimethylsilanyloxy) -2-methyl-propoxy] -phenyl} -3,9-diazabicyclo [3.3.1] non-6-ene-3 , 6,9-Tricarboxylic acid 3-tert-butyl ester 6-ethyl ester 9- (2,2,2-trichloro-1,1-dimethylethyl) ester 1: 1 mixture (G)

Bicyclononene F (0.49 g, 0.83 mmol) and tert-butyl β, β, β-trichloro-chloroformate (1 g, 4.15 mmol) dissolved in CH ₂ ClCH ₂ Cl (10 ml) The resulting solution was heated to reflux for 4 hours. The mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was purified by FC (EtOAc / heptane 5/95 → 10/90) to give the title compound (0.40 g, 61%). _{LC-MS: R t = 1.33} ES +: 777.25.

(1R, 5S) -7- [4-((2R) -3-Hydroxy-2-methylpropoxy) phenyl] -3,9-diazabicyclo [3.3.1] non-6-ene-3,6, 9-tricarboxylic acid 3-tert-butyl ester 6-ethyl ester 9- (2,2,2-trichloro-1,1-dimethylethyl) ester and (1S, 5R) -7- [4-((2S)- 3-hydroxy-2-methylpropoxy) phenyl] -3,9-diazabicyclo [3.3.1] non-6-ene-3,6,9-tricarboxylic acid 3-tert-butyl ester 6-ethyl ester 9- 1: 1 mixture of (2,2,2-trichloro-1,1-dimethylethyl) ester (H)

To a solution of bicyclononene G (0.40 g, 0.51 mmol) in THF (5 mL) was added TBAF (1M solution in THF, 0.76 mL, 0.76 mmol) at 0 ° C. . The ice bath was removed and the reaction mixture was stirred for 4 hours. AcOEt and saturated aqueous NH ₄ Cl were added. The aqueous phase was extracted with AcOEt, the organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. Purification by FC (heptane / EtOAc 30/70 → 50/50 → 2/1) gave the title compound (0.26 g, 78%).
LC-MS; R _t = 1.95 min.

(1R, 5S) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) -propoxy] phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-3,6,9-tricarboxylic acid 3-tert-butyl ester 6-ethyl ester 9- (2,2,2-trichloro-1,1-dimethylethyl) ester and (1S, 5R) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) propoxy] phenyl} -3,9-diazabicyclo [3.3.1] non-6-ene 3-, 6,9-tricarboxylic acid 3-tert-butyl ester 6-ethyl ester 9- (2,2,2-trichloro-1,1-dimethylethyl) 1: 1 mixture of esters (J)

2,3,6-trifluorophenol (0.07 g, 0.48 mmol) and DIPEA (0.007 mL, 0.04 mmol) were added to compound H (0.26 g, 0.4 mmol) in toluene. To the solution dissolved in (5 mL). Azodicarboxylic acid dipiperidide (0.15 g, 0.6 mmol) was added. Tributylphosphine (0.20 ml, 0.8 mmol) was then added at 0 ° C. The reaction mixture was stirred for 20 minutes at room temperature and then for 1 hour at 80 ° C. The reaction mixture was allowed to cool to room temperature and water was added. The mixture was extracted with EtOAc. The organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. Purification by FC (heptane / EtOAc 20/80) gave the title compound (0.28 g, 89%).
LC-MS; R _t = 1.26, ES +: 795.08.

(1R, 5S) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) -propoxy] phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-3,6,9-tricarboxylic acid 3-tert-butyl ester 9- (2,2,2-trichloro-1,1-dimethylethyl) ester and (1S, 5R) -7- { 4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) -propoxy] phenyl} -3,9-diazabicyclo- [3.3.1] non-6-ene-3 1: 1 mixture of 9,6-tricarboxylic acid 3-tert-butyl ester 9- (2,2,2-trichloro-1,1-dimethylethyl) ester (K)

A mixture of bicyclononene J (0.28 g, 0.36 mmol) in EtOH (5 ml) and 1M aqueous NaOH (3.6 mL, 3.6 mmol)) was stirred at 80 ° C. for 2.5 hours. The mixture was allowed to cool to room temperature and acidified with 1M aqueous HCl. The mixture was extracted 3 times with EtOAc, the organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. The crude product was purified by FC (heptane / EtOAc 30/70 → 50/50) to give the title compound (0.20 g 72%). _{LC-MS: R t = 1.19} ; MS-: 765.17.

(1R, 5S) -6- [cyclopropyl- (2,3-dichlorobenzyl) carbamoyl] -7- {4-[(2S) -2-methyl-3- (2,3,6-trifluorophenoxy) Propoxy] phenyl} -3,9-diazabicyclo- [3.3.1] non-6-ene-3,9-dicarboxylic acid 3-tert-butyl ester 9- (2,2,2-trichloro-1,1 -Dimethylethyl) ester and (1S, 5R) -6- [cyclopropyl- (2,3-dichlorobenzyl) -carbamoyl] -7- {4-[(2S) -2-methyl-3- (2,3 , 6-Trifluorophenoxy) propoxy] phenyl} -3,9-diazabicyclo- [3.3.1] non-6-ene-3,9-dicarboxylic acid 3-tert-butyl ester 9- (2,2, 1: 1 mixture of 2-trichloro-1,1-dimethylethyl) ester (L)

Bicyclononene K (0.20 g, 0.26 mmol), (2,3-dichlorobenzyl) cyclopropylamine (0.17 mg, 0.78 mmol), DMAP (0.004 g, 0.06 mmol), DIPEA (0.18 mL, 1.0 mmol) , HOBt (0.04 g, 0.32 mmol) , and ^{EDC. HCl (0.074 g, 0.39} mmol) to _{CH 2} Cl 2 (5 mL) in The mixture contained in was stirred for 2 days. EDC.HCl (0.074 g, 0.39 mmol) and DIPEA (0.07 mL, 0.39 mmol) were then added and stirring was continued for 2 days. The mixture was diluted with CH ₂ Cl ₂ and washed twice with 1M aqueous HCl. The organic extract was dried over MgSO ₄ , filtered and the solvent removed under reduced pressure. Purification by FC (heptane / EtOAc 20: 80 → 30/70) gave the title compound (0.11 g, 44%). _{LC-MS: R t = 1.34} ; ES +: 964.19.

Example

(1R, 5S) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) -propoxy] phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl) amide and (1S, 5R) -7- {4-[(2S) -2-methyl-3- (2,3 , 6-Trifluorophenoxy) propoxy] phenyl} -3,9-diazabicyclo [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl) amide 1: 1 blend

Bicyclononene L (0.11 g, 0.11 mmol) was dissolved in THF (3 mL) and AcOH (0.3 mL) and treated with zinc (0.14 g, 2.2 mmol.). The suspension was stirred for 2 hours and filtered through a Titan® → HPLC filter. The filtrate was evaporated under reduced pressure and the residue was used in the next step without further purification.
A solution of the previously obtained material (0.08 g, 0.11 mmol) dissolved in CH ₂ Cl ₂ (2 mL) was cooled to 0 ° C. 4M HCl / dioxane (2 mL) was added. After 2.5 hours at room temperature, the solvent was removed under reduced pressure and the residue was dried under high vacuum. The title compound was purified by preparative HPLC. _{LC-MS: R t = 0.80} ; ES +: 660.38

The following test methods were carried out to determine the activity of the compounds of general formula I and their salts.

Inhibition of human recombinant renin by the compounds of the invention

In-vessel enzyme assays were performed using 384 well polypropylene plates (Nunk). The assay buffer consisted of 10 mM PBS (Gibco BRL) containing 1 mM EDTA and 0.1% BSA. The culture consisted of 50 μL enzyme-containing mixture per well and 2.5 μL renin inhibitor in DMSO. The enzyme-containing mixture was premixed at 4 ° C. It consists of the following ingredients:
・ Recombinant human renin (0.16 ng / mL)
Synthetic human angiotensin (1-14) (0.5 μM)
-Hydroxyquinoline sulfate (1 mM).
The mixtures were then incubated for 3 hours at 37 ° C.
Accumulated AngI was detected by enzyme immunoassay (EIA) in 384-well plates (Nunk) to determine enzyme activity and its inhibition rate. 5 μL of culture or standard was transferred to an immunoplate previously coated with a covalent complex of AngI and bovine serum albumin (AngI-BSA). 75 μL of AngI antibody solution in the above assay buffer containing 0.01% Tween 20 was added and primary incubation was performed overnight at 4 ° C. Plates were washed 3 times with PBS containing 0.01% Tween 20, and then incubated with anti-rabbit peroxidase conjugated antibody (WA934, Amersham) for 2 hours at room temperature. After washing the plate three times, the peroxidase substrate ABTS (2,2′-azino-di (3-ethylbenzthiazoline sulfonate) was added and the plate was incubated for 60 minutes at room temperature.The reaction was performed with 0.1 M citric acid pH 4.3. After stopping, the plates were evaluated using a microplate reader at 405 nm.The percentage inhibition was calculated for each concentration point to determine the renin inhibitory concentration (IC ₅₀ ) that inhibits enzyme activity by 50%. The IC ₅₀ value of the compound is less than 100 nM However, the selected compound exhibits a very good bioavailability and has a higher stability compared to metabolically known compounds. It was.

Claims (12)

Compounds of general formula I

In the formula

W is a 6-membered non-benzene fused phenyl or heteroaryl ring in which V is substituted at the meta or para position;

V represents —O—CH ₂ —CH (OCH ₃ ) —CH ₂ —O: —O—CH ₂ —CH (CH ₃ ) —CH ₂ —O—; —O—CH ₂ —CH (CF ₃ ) — _{CH 2 -O-; -O-CH 2} -C (CH 3) 2 -O-; -O-C (CH 3) 2 -CH 2 -O-; -O-CH 2 -CH (CH 3) - _{O-; -O-CH (CH 3} ) -CH 2 -O-; -O-CH 2 -C (CH 2 CH 2) -O-; -O-C (CH 2 CH 2) -CH 2 -O -Represents;

U represents aryl; represents heteroaryl;

T represents -CONR ¹ -;-(CH ₂ ) _p OCO-;-(CH ₂ ) _p N (R ¹ ) CO-;-(CH ₂ ) _p N (R ¹ ) SO _2- ; or -COO- Represents;

Q represents lower alkylene; lower alkenylene;

M represents hydrogen; cycloalkyl; aryl; heterocyclyl; heteroaryl;

L ^{is, -R 3; -COR 3; -COOR} 3; -CONR 2 R 3; -SO 2 R 3; represents -COCH ^{_{(aryl) 2; -SO 2 NR 2 R}} 3;

R ¹ represents hydrogen; lower alkyl; lower alkenyl; lower alkynyl; cycloalkyl; aryl; cycloalkyl-lower alkyl;

R ² and R ² ′ are independently hydrogen; lower alkyl; lower alkenyl; cycloalkyl; cycloalkyl-lower alkyl;

R ³ is hydrogen; lower alkyl; lower alkenyl; cycloalkyl; aryl; heteroaryl; heterocyclyl; cycloalkyl-lower alkyl; aryl-lower alkyl; heteroaryl-lower alkyl; heterocyclyl-lower alkyl; aryloxy-lower alkyl; Represents heteroaryloxy-lower alkyl, these groups may be unsubstituted or hydroxy, —OCOR ² , —COOR ² , lower alkoxy, cyano, —CONR ² R ² ′, —CO-morpholin-4-yl, It may be mono-, di-, or trisubstituted with —CO — ((4-lower alkyl) piperazin-1-yl), —NH (NH) NH ₂ , —NR ⁴ R ⁴ ′ or lower alkyl. Provided that when the carbon atom is sp3-hybrid orbital, this carbon atom is bonded to at least one heteroatom;

R ⁴ and R ⁴ 'of hydrogen; lower alkyl; cycloalkyl; cycloalkyl - lower alkyl; hydroxy - lower alkyl; -COOR ^2; represents a -CONH ₂ independently;

k is an integer 0 or 1;

m and n are integers 0 or 1, provided that when m represents the integer 1, n is the integer 0, and when n represents the integer 1, m is the integer 0; k is the integer 0 N represents the integer 0;

p is an integer 1, 2, 3 or 4;

And pharmaceutically acceptable salts, solvent complexes and morphological forms, as well as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, A mixture of diastereomeric racemates and their meso forms.
A compound of general formula I according to claim 1, wherein W, V, U, T, Q, L and M are as defined in general formula I,

k is 1,
n is 0,
m is 1.

And pharmaceutically acceptable salts, solvent complexes and morphological forms, as well as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, A mixture of diastereomeric racemates and their meso forms.
A compound of general formula I according to claim 1, wherein W, V, U, T, Q, M, k, m and n are as defined for general formula I,

L is, -COR ^{3 'represents -CONR 2''R3''} ;'; -COOR 3 '';

R ² ″ and R ³ ″ each independently represent lower alkyl; lower cycloalkyl-lower alkyl, wherein lower alkyl and lower cycloalkyl-lower alkyl may be unsubstituted or halogen, —CN, —OH, Mono-substituted with —OCOCH ₃ , —CONH ₂ , —COOH, or —NH ₂ . Provided that when the carbon atom is sp3-hybrid orbital, this carbon atom is bonded to at least one heteroatom,

And pharmaceutically acceptable salts, solvent complexes and morphological forms, as well as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, A mixture of diastereomeric racemates and their meso forms.
A compound of general formula I according to claim 1, wherein W, V, U, L, k, m and n are as defined in general formula I,

T represents —CONR ¹ —;
Q represents methylene;
M represents aryl or heteroaryl;

And pharmaceutically acceptable salts, solvent complexes and morphological forms, as well as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, A mixture of diastereomeric racemates and their meso forms.
A compound of general formula I according to claim 1, wherein W, U, L, T, Q, M, k, m and n are as defined for general formula I,

V _{is, -O-CH 2 -CH (CH} 3) -CH 2 -O-; -O-CH 2 -C (CH 3) 2 represents a -CH ₂ -O-;

And pharmaceutically acceptable salts, solvent complexes and morphological forms, as well as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, A mixture of diastereomeric racemates and their meso forms.
A compound of general formula I according to claim 1, wherein V, U, T, Q, M, L, k, m and n are as defined in general formula I,

W represents a 1,4-disubstituted phenyl ring,

And pharmaceutically acceptable salts, solvent complexes and morphological forms, as well as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, A mixture of diastereomeric racemates and their meso forms.
A compound of general formula I according to claim 1, wherein W, V, Q, T, M, L, m and n are as defined for general formula I,

U is mono-, di-, or tri-substituted phenyl or heteroaryl, and the substituent is halogen, lower alkyl, lower alkoxy, CF ₃ ,

And pharmaceutically acceptable salts, solvent complexes and morphological forms, as well as optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, A mixture of diastereomeric racemates and their meso forms.
The compound according to any one of claims 1 to 7, which is selected from the following group:

(1R, 5S) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) propoxy] -phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl) amide;

(1S, 5R) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluoro-phenoxy) propoxy] phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichloro-benzyl) amide;

(1R, 5S) -7- {4-[(2S) -2-Methyl-3- (2,3,6-trifluorophenoxy) propoxy] -phenyl} -3,9-diazabicyclo [3.3.1 ] Non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl) amide and (1S, 5R) -7- {4-[(2S) -2-methyl-3- (2,3 , 6-Trifluoro-phenoxy) propoxy] phenyl} -3,9-diazabicyclo- [3.3.1] non-6-ene-6-carboxylic acid cyclopropyl- (2,3-dichlorobenzyl) amide .
Cardiovascular disease and nephropathy, hypertension, congestive heart failure, pulmonary hypertension, heart failure, renal dysfunction, renal or myocardial ischemia, atherosclerosis, renal failure, erectile dysfunction, glomerulonephritis, renal colic, glaucoma, Diseases associated with dysregulation of the renin-angiotensin system (RAS), including diabetic complications, complications after vascular or cardiac surgery, restenosis, complications due to the use of immune response inhibitors after organ transplantation, and RAS A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 8 and a usual carrier substance and adjuvant for the treatment or prevention of other known diseases.
Hypertension, congestive heart failure, pulmonary hypertension, heart failure, renal dysfunction, renal or myocardial ischemia, atherosclerosis, renal failure, erectile dysfunction, glomerulonephritis, renal colic, glaucoma, diabetic complications, blood vessels or heart A method for the treatment or prevention of diseases associated with RAS, including complications after surgery, restenosis, complications due to the use of immune response inhibitors after organ transplantation, and other diseases associated with RAS, The method comprises administering to a human or animal a compound according to any one of claims 1-8.
High blood pressure, congestive heart failure, pulmonary hypertension, heart failure, renal dysfunction, renal or myocardial ischemia, atherosclerosis, renal failure, erectile dysfunction, glomerulonephritis, renal colic, glaucoma, diabetic complications, blood vessels or heart Claims 1 to 3 for the treatment or prevention of diseases related to RAS and other known diseases related to RAS, including complications after surgery, restenosis, complications due to the use of immune response inhibitors after organ transplantation 9. Use of a compound according to any one of 8.
An ACE inhibitor, an angiotensin II receptor antagonist, an endothelin receptor antagonist, a vasodilator, a calcium antagonist, a potassium activator, for the treatment of the disease according to any one of claims 9 to 11. 9. Any one of claims 1 to 8 in combination with other pharmacologically active compounds including diuretics, sympatholytic agents, β-adrenergic antagonists, α-adrenergic antagonists, and neutral endopeptidase inhibitors. Use of one or more compounds described in 1.