CN1780838A - Azabicyclononene derivatives - Google Patents

Azabicyclononene derivatives Download PDF

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CN1780838A
CN1780838A CNA2004800116500A CN200480011650A CN1780838A CN 1780838 A CN1780838 A CN 1780838A CN A2004800116500 A CNA2004800116500 A CN A2004800116500A CN 200480011650 A CN200480011650 A CN 200480011650A CN 1780838 A CN1780838 A CN 1780838A
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mixture
alkyl group
low alkyl
compound
racemic mixture
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奥利维尔·贝曾康
丹尼尔·比尔
瓦尔特·菲施利
尤博斯·雷门
西尔维娅·理查德-比洛斯泰恩
托马斯·韦勒
蒂埃里·西费朗
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Actelion Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

The invention relates to novel 3,9-diazabicyclo[3.3.1]nonene derivatives and related compounds and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more of those compounds and especially their use as inhibitors of renin.

Description

Azabicyclononene derivatives
The present invention relates to the new compound of general formula I.The invention still further relates to these compounds the preparation method, comprise the pharmaceutical composition of one or more formulas I compound and particularly they in cardiovascular disorder and renal insufficiency as the purposes of renin inhibitor.In addition, these compounds can be considered to the inhibitor of other aspartyl protease, thereby and can be used as the plasmepsins inhibitor for the treatment of malaria thus and as the inhibitor treatment fungi infestation of Candida albicans excretory aspartyl protease.
In renin-angiotensin system (RAS), bioactive Angiotensin II (Ang II) produces by a kind of two step mechanism.The feritin enzymatic breaking angiotensinogen of high degree of specificity becomes angiotensin I (Ang I), and it forms Ang I by low specificity angiotensin-converting enzyme (ACE) then.Known Ang II acts at least two receptor subtypes that are called as AT1 and AT2.As if wherein AT1 transmits the most known function of Ang II, and the effect of AT2 is still unknown.
The main progress in the treating cardiovascular disease has been represented in the adjusting of RAS.ACE inhibitor and AT1 retarding agent have been used to treat hypertension (Waeber B. etc. " The renin-angiotensin system:role inexperimental and human hypertension ", in Berkenhager W.H., Reid J.L. (eds): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1996,489-519; Weber M.A., Am.J.Hypertens., 1992,5,247S).In addition, ACE inhibitor is used to protect kidney (Rosenberg M.E. etc., Kidney International, 1994,45,403; Breyer J.A. etc., Kidney International, 1994,45, S156), be used to prevent congestive heart failure (Vaughan D.E. etc., Cardiovasc.Res., 1994,28,159; Fouad-Tarazi F. etc., Am.J.Med., 1988,84 (Suppl.3A), 83) and myocardial infarction (Pfeffer M.A.et al., N.Engl.J.Med., 1992,327,669).
The principle of exploitation renin inhibitor is the specificity (Kleinert H.D., Cardiovasc.Drugs, 1995,9,645) of feritin.The unique known substrate of feritin is a proangiotensin, and it only is subjected to feritin effect (under physiological condition).On the contrary, ACE except the Ang I that can rupture, also can rupture bradykinin and with chymase (a kind of serine protease) function intersect (Husain A., J.Hypertens., 1993,11,1155).In the patient, the inhibition of ACE can cause causing the bradykinin accumulation (5～20%) of cough and life-threatening acute essential edema (0.1～0.2%) (Israili Z.H.et al., Annals of Internal Medicine, 1992 of potentiality, 117,234).Rennin is not to suppress by ACE inhibitor.Therefore, in the patient who accepts the ACE inhibitor treatment, still may form Ang II.On the other hand, in Ang II, the concentration of Ang II is improved significantly by the blocking-up of AT1 acceptor with other AT-receptor subtype over-exposure in the blocking-up of AT1 acceptor (for example passing through losartan).This can produce serious problem aspect the safety of AT1 receptor antagonist body and efficiency characteristic.In a word, wish that not only renin inhibitor is different from ACE inhibitor and AT1 retarding agent in security, but the more important thing is, also wish to stop also to be different from ACE inhibitor and AT1 retarding agent aspect the effectiveness of RAS at them.
Because renin inhibitor has the peptide of plan feature (Kleinert H.D., Cardiovasc.Drugs, 1995,9,645) cause oral cavity activity deficiency, thereby only renin inhibitor has been carried out limited clinical practice (AziziM.et al., J.Hypertens., 1994,12,419; Neutel J.M.et al., Am.Heart, 1991,122,1094).There has been the clinical development of several compounds to be terminated owing to there is the high problem of cost in they.Only there is a compound to enter clinical trial (Rahuel J.et al., Chem.Biol., 2000,7,493 with 4 chiral centres; Mealy N.E., Drugs of the Future, 2001,26,1139).Therefore, but but expectation and at the metabolic stability per os biological utilisation of seeking a kind of mass preparation and the renin inhibitor of sufficiently soluble.Recently, first non-peptide renin inhibitor (Oefner C.et al., Chem.Biol., 1999,6,127 that demonstrate higher external activity are disclosed; Patent application WO97/09311; M  rki H.P.et al., Il Farmaco, 2001,56,21).Yet the research and development state of these compounds is still unknown.
The present invention relates to a kind of non-peptide and discovery low-molecular-weight blood vessel tension peptide protoenzyme inhibitor.And described: in the indication of the blood vessel tension peptide protoenzyme inhibitor of the orally active of long-acting outside blood pressure regulation is effective, in this blood pressure regulation indication, can be with the renin-rennin system activation of tissue, thereby the local function that causes physiopathology to change, for example kidney, heart and blood vessel remodeling, atherosclerosis and possible restenosis.
The invention describes non-peptide class renin inhibitor.
Especially, the present invention relates to the novel cpd of general formula I,
Figure A20048001165000091
General formula I
Wherein
W is hexavalent, non-benzo-fused, phenyl or heteroaryl, is replaced by V in a position or contraposition;
V representative-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-;
U represents aryl, heteroaryl;
T representative-CONR 1-,-(CH 2) pOCO-,-(CH 2) pN (R 1) CO-,-(CH 2) pN (R 1) SO 2-or-COO-;
Q represents low-grade alkylidene, lower alkenylene;
M represents hydrogen, cycloalkyl, aryl, heterocyclic radical, heteroaryl;
L representative-R 3,-COR 3,-COOR 3,-CONR 2R 3,-SO 2R 3,-SO 2NR 2R 3,-COCH (aryl) 2
R 1Represent hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, aryl, cycloalkyl-low alkyl group;
R 2And R 2' independent hydrogen, low alkyl group, low-grade alkenyl, cycloalkyl, the cycloalkyl-low alkyl group represented;
R 3Represent hydrogen, low alkyl group, low-grade alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical, cycloalkyl-low alkyl group, aryl lower alkyl, heteroaryl-low alkyl group, heterocyclic radical-low alkyl group, aryloxy-low alkyl group, heteroaryloxy-low alkyl group, wherein these groups can be unsubstituted or by hydroxyl ,-OCOR 2,-COOR 2, lower alkoxy, cyano group ,-CONR 2R 2' ,-CO-morpholine-4-base ,-CO-((4-low alkyl group) piperazine-1-yl) ,-NH (NH) NH 2,-NR 4R 4' or low alkyl group list-, two-or three replace, condition is that this carbon atom links to each other with a heteroatoms at the most when carbon atom is sp3-hydridization;
R 4And R 4' independent represent hydrogen, low alkyl group, cycloalkyl, cycloalkyl-low alkyl group, hydroxy lower alkyl ,-COOR 2,-CONH 2
K is integer 0 or 1;
M and n represent integer 0 or 1, and condition is when m represents integer 1, and n is an integer 0, and when n represented integer 1, m was an integer 0, and when k represented integer 0, n represented integer 0;
P is an integer 1,2,3 or 4;
And the mixture of optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and this meso-form and pharmacy acceptable salt, solvent complex and the crystalline form of non-mapping racemic mixture of racemic mixture, diastereomer, diastereomer.
The term " low alkyl group " that in the definition of general formula I,---unless other explanation arranged---, when combining separately or with other group, be meant contain 1～7, preferred 1～4 can by the optional carbon atom that replaces of halogen saturated, the straight or branched group.The example of low alkyl group is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl and heptyl.Be preferably methyl, ethyl and sec.-propyl.
Term " lower alkoxy " is the R-O-group, and wherein R is a low alkyl group.The example of lower alkoxy is methoxyl group, oxyethyl group, propoxy-, isopropoxy, isobutoxy, sec-butoxy and tert.-butoxy.
Term " low-grade alkenyl ", when combining separately or with other group, be meant comprise 2～7, preferred 2～4 can be by the optional carbon atom that replaces of halogen and the straight or branched group of an ethylene linkage.The example of low-grade alkenyl is vinyl, propenyl or butenyl.
Term " low-grade alkynyl ", when combining separately or with other group, be meant comprise 2～7, preferred 2～4 can be by optional carbon atom and the triple-linked straight or branched groups that replace of halogen.The example of low-grade alkynyl is ethynyl, proyl or butynyl.
Term " low-grade alkylidene ", separately or other group in conjunction with the time, be meant comprise 1～7, preferred 1～4 can be by optional carbon atom straight chain or the side chain divalence chain group that replaces of halogen.The example of low-grade alkylidene is ethylidene, propylidene or butylidene.
Term " lower alkenylene ", separately or other group in conjunction with the time, be meant comprise 2～7, preferred 2～4 can be by the optional carbon atom that replaces of halogen and the straight or branched divalence chain group of an ethylene linkage.The example of lower alkenylene is vinylidene, propenylidene and crotonylidene.
Term " low-grade alkylidene dioxy base " is meant the low-grade alkylidene that is replaced by a Sauerstoffatom at each end.The example of low-grade alkylidene dioxy base is preferably methylene-dioxy and ethylenedioxy.
Term " low-grade alkylidene oxygen base " is meant the low-grade alkylidene that is replaced by Sauerstoffatom at an end.The example of low-grade alkylidene oxygen base is preferably inferior methoxyl group, inferior ethoxyl and inferior propoxy-.
Term " halogen " is meant fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine and bromine.
Term " cycloalkyl " is separately or when being used in combination, be meant the stable hydrocarbon loop systems that contains 3～7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl, and can randomly singly be replaced independently or polysubstituted by following radicals: low alkyl group, low-grade alkenyl, lower alkenylene, lower alkoxy, low-grade alkylidene oxygen base, low-grade alkylidene dioxy base, hydroxyl, halogen ,-CF 3,-NR 1R 1' ,-NR 1C (O) R 1' ,-NR 1S (O) 2R 1' ,-C (O) NR 1R 1', lower alkylcarbonyl ,-COOR 1,-SR 1,-SOR 1,-SO 2R 1,-SO 2NR 1R 1', R wherein 1' represent hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, aryl, cycloalkyl-low alkyl group.Preferred group is a cyclopropyl.
Term " aryl ", separately or when being used in combination, be meant phenyl, naphthyl or indanyl, preferred phenyl, and preferably singly replaced independently or polysubstituted by following radicals: thus low alkyl group, low-grade alkenyl, low-grade alkynyl, lower alkenylene or low-grade alkylidene and aromatic ring form five Yuans or six-ring, lower alkoxy, low-grade alkylidene dioxy base, low-grade alkylidene oxygen base, hydroxyl, hydroxy lower alkyl, halogen, cyano group ,-CF 3,-OCF 3,-NR 1R 1' ,-NR 1R 1'-low alkyl group ,-NR 1C (O) R 1' ,-NR 1S (O) 2R 1' ,-C (O) NR 1R 1' ,-NO 2, lower alkylcarbonyl ,-COOR 1,-SR 1,-SOR 1,-SO 2R 1,-SO 2NR 1R 1', benzyloxy, wherein R 1' definition as above.Preferred substituted be halogen, lower alkoxy, low alkyl group ,-CF 3,-OCF 3
Term " aryloxy " is meant the Ar-O-group, and wherein Ar is an aryl.The example of aryloxy is a phenoxy group.
Term " heterocyclic radical ", separately or when being used in combination, be meant saturated or unsaturated (but nonaromatic) five of comprising nitrogen, oxygen or sulphur atom that one or two can be identical or different-, six-or seven-unit ring, and should ring optional can replacement by low alkyl group, hydroxyl, lower alkoxy and halogen are optional.Nitrogen-atoms, if exist, can be by COOR 2Replace.The example of this ring is piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, THP trtrahydropyranyl, dihydro pyranyl, 1,4-dioxane base, pyrrolidyl, tetrahydrofuran base, pyrrolin base, imidazolidyl, pyrazoline base, pyrazolidyl, dihydroquinoline base, tetrahydric quinoline group, tetrahydro isoquinolyl.
Term " heteroaryl " separately or when being used in combination, is meant six Yuans aromatic rings that comprise 1～4 nitrogen-atoms; The six Yuans aromatic rings of benzo that comprise 1～3 nitrogen-atoms; Five Yuans aromatic rings that comprise 1 Sauerstoffatom, 1 nitrogen-atoms or 1 sulphur atom; The five Yuans aromatic rings of benzo that comprise 1 Sauerstoffatom, 1 nitrogen-atoms or 1 sulphur atom; The five Yuans aromatic rings and the benzo derivative thereof that comprise 1 Sauerstoffatom and 1 nitrogen-atoms; The five Yuans aromatic rings and the benzo derivative thereof that comprise 1 sulphur atom and 1 nitrogen-atoms or 1 Sauerstoffatom; The five Yuans aromatic rings and the benzo derivative thereof that comprise 2 nitrogen-atoms; The five Yuans aromatic rings and the benzo derivative thereof that comprise 3 nitrogen-atoms, or tetrazole ring.The example of this loop systems is furyl, thiophenyl, pyrryl, pyridyl, pyrimidyl, indanyl, quinolyl, isoquinolyl, imidazolinyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, tonka bean camphor base, benzo thiophenyl, quinazolyl, quinoxalinyl.This class ring can fully be replaced by following substituting group institute: low alkyl group, low-grade alkenyl, low-grade alkynyl, low-grade alkylidene, lower alkenylene, low-grade alkylidene dioxy base, rudimentary alkylene oxide group, hydroxy lower alkyl, lower alkoxy, hydroxyl, halogen, cyano group ,-CF 3,-OCF 3,-NR 1R 1' ,-NR 1R 1'-low alkyl group ,-N (R 1) COR 1,-N (R 1) SO 2R 1,-CONR 1R 1' ,-NO 2, lower alkylcarbonyl ,-COOR 1,-SR 1,-SOR 1,-SO 2R 1,-SO 2NR 1R 1', another aryl, another heteroaryl or another heterocyclic radical etc., wherein R 1' definition as above.
Term " heteroaryl oxygen base " is meant the Het-O group, and wherein Het is a heteroaryl.
Term " sp3-hydridization " is meant a kind of carbon atom and refers to that this carbon atom forms four keys with tetrahedron pattern and four substituting groups around this carbon atom.
Term " pharmacy acceptable salt " comprises with mineral acid or all example hydrochloric acids of organic acid or Hydrogen bromide, sulfuric acid, phosphoric acid, citric acid, formic acid, acetate, toxilic acid, tartrate, phenylformic acid, methylsulfonic acid, tosic acid etc. formed to the avirulent salt of living organisms, and when the compound of formula I is the tart compound and mineral alkali such as basic metal or alkaline-earth metal formed salt such as sodium hydroxide, potassium hydroxide, calcium hydroxide for example.
Compound of the present invention also be included in one or more sites for example oxygen (hydroxyl condensation), sulphur (sulfydryl condensation) and/or nitrogen by the nitrosylation compound of the general formula I of nitrosylation.Can use ordinary method known in the art to prepare nitrosylation compound of the present invention.For example with the method for compound nitrosylation such as the US5 of United States Patent (USP), 380,758 and US5,703,073, WO 97/27749, WO 98/19672, WO 98/21193, WO99/00361 and Oae etc., Org.Prep.Proc.Int., 15 (3): 165-198 (1983) is described, and the disclosed content of these documents is drawn in full at this and is reference.
The compound of general formula I can also comprise two or more unsymmetrical carbons, and the mixture that can be prepared into optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and the meso-form and the pharmacy acceptable salt thereof of diastereomeric racemic mixture of racemic mixture, diastereomer, diastereomer.
The present invention comprises all these forms.Can be by known mode itself, for example column chromatography, tlc, HPLC or crystallization process separate mixture.
The compound of one group of preferred general formula I is that wherein W, V, U, T, Q, L and M definition are as the compound of general formula I, and wherein
K is 1
N is 0, and
M is 1.
Another compound of organizing preferred general formula I for wherein W, V, U, T, Q, M, k, m and n definition as the compound of general formula I, and
L represent H ,-COR 3" ,-COOR 3" ,-CONR 2" R 3";
Wherein
R 2" and R 3" independent represent low alkyl group, low-grade cycloalkyl-low alkyl group, its low alkyl group and low-grade cycloalkyl-low-grade alkyl group is not substituted or by halogen, cyano group, hydroxyl ,-OCOCH 3,-CONH 2,-COOH ,-NH 2The single replacement,, condition is that when carbon atom was sp3-hydridization, this carbon atom linked to each other with a heteroatoms at most.
Another compound of organizing preferred general formula I for wherein W, V, U, L, k, m and n definition as the compound of general formula I, and
T is-CONR 1-;
Q is a methylene radical;
M is aryl, heteroaryl.
The compound of the general formula I that another group is more preferably is that wherein W, U, L, T, Q, M, k, m and n define the as above compound of general formula I, and
V representative-O-CH 2-CH (CH 3)-CH 2-O-,-O-CH 2-C (CH 3) 2-CH 2-O-.
The compound of the general formula I that another group is more preferably is that wherein V, U, T, Q, M, L, k, m and n define the as above compound of general formula I, and
W represents 1, the dibasic phenyl ring of 4-.
The compound of the general formula I that another group is more preferably is that wherein W, V, Q, T, M, L, k, m and n define the as above compound of general formula I, and
U be single-, two-or three-phenyl or the heteroaryl that replace, wherein substituting group is halogen, low alkyl group, lower alkoxy, CF 3
Particularly preferred compound of Formula I is:
(1R, 5S)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-]-phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2, the 3-dichloro benzyl) acid amides;
(1S, 5R)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-] phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2, the 3-dichloro benzyl) acid amides;
(1R, 5S)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-]-phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2, the 3-dichloro benzyl) acid amides and (1S, 5R)-7-{4-[(2S)-and 2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-] phenyl }-3, the mixture of 9-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2, the 3-dichloro benzyl) acid amides.
The compound of general formula I and pharmacy acceptable salt thereof for example can be used as healing potion with the form of pharmaceutical composition.These compounds that comprise at least a general formula I can be used in particular for prevention and the insufficiency of accommodation relevant illness of treatment with renin-angiotensin system (RAS) with the common solid support material and the pharmaceutical composition of auxiliary, comprise cardiovascular disorder and ephrosis.The example of this disease is hypertension, coronary artery disease, cardiac insufficiency, renal insufficiency, kidney or myocardial ischemia and renal failure.They also can be used for preventing air bag or support angioplasty restenosis afterwards, are used for the treatment of erective dysfunction, glomerulonephritis, renal colic and glaucoma.In addition, they also can be used to treat the complication with prevent diabetes complication, blood vessel or heart art or organ transplantation infectious-related complication, cyclosporin treatment, and at present known other and RAS relative disease.
In another specific examples, the present invention relates to a kind of method of preventing and/or treating with the RAS relative disease of being used for, the RAS relative disease is hypertension for example, congestive heart failure, pulmonary hypertension, cardiac insufficiency, renal insufficiency, kidney or myocardial ischemia, atherosclerosis, renal failure, erective dysfunction, glomerulonephritis, renal colic, glaucoma, the diabetic complication, blood vessel or postcardiac surgery complication, restenosis, the complication of using immunosuppressant treatment to cause after the organ transplantation, and other present known and RAS relative disease, this method comprises to the human or animal takes a kind of formula I compound.
In another specific examples, the compound that the present invention relates to the general formula I of above-mentioned definition is used for the treatment of and/or the purposes of prevention and RAS relative disease, and the RAS relative disease is hypertension for example, congestive heart failure, pulmonary hypertension, cardiac insufficiency, renal insufficiency, kidney or myocardial ischemia, atherosclerosis, renal failure, erective dysfunction, glomerulonephritis, renal colic, glaucoma, the diabetic complication, blood vessel or postcardiac surgery complication, restenosis, the complication of using immunosuppressant treatment to cause after the organ transplantation, and other present known and RAS relative disease.
In addition, the compound that the invention still further relates to above-mentioned definition is used to prepare the purposes that treats and/or prevents with the medicine of RAS relative disease, with RAS relative disease for example hypertension, coronary artery disease, cardiac insufficiency, renal insufficiency, kidney and myocardial ischemia and renal failure.Can prepare these medicaments by known method.
Formula I compound also can be used to unite use with one or more other pharmacological active substance, for example with other renin inhibitor, ACE-inhibitor, angiotensin-ii receptor antagonist, endothelin receptor antagonist, vasodilator, calcium antagonist, potassium activator, diuretic(s), sympatholytic agent, beta-adrenergic antagonist, alpha-adrenergic antagonist and neutral endopeptidase inhibitor, unite use, to treat above-mentioned disease.
The prodrug that is included in the active ingredient in the general formula I that causes of form of ownership is also included among the present invention.
Can make the compound of general formula I by method given among the following embodiment or similar approach.
Chemical part
The necessary chemical process of included compound can be with reference to patent application formerly for example WO03/093267 or WO 04/002957 in the preparation general formula I.The glycerol derivative that can get from commerce, the 3-hydroxyl-2 that can get from commerce, 2-dimethylated methyl propionate, from (R)-or (S)-3-hydroxy-2-methyl propionic acid (Locher, T.; Et al.; PCT Int.Appl.WO 0022153 A1 20000420,2000; Vogel, G.; Et al.; Chemistry and Physics of Lipids, 1990,52,99; Seebach, D.; Et al.; Helv.Chim.Acta, 1986,69,1147) or from (R)-or (S)-3-hydroxyl-2-(trifluoromethyl) propionic acid (Goetzoe, S.P.; Et al.; Chimia, 1996,50,20) can prepare the included connection portion of V in the general formula I.Any derivative of 1-hydroxyl-1-methyl cyclopropanecarboxylate or lactic acid can be used as starting raw material in addition.All starting raw materials can be by the protection step, be converted into the segmental precursor of V-U with the combination of coupling step (usually through the Mitsunobu coupling), reduction step and/or the deprotection steps of phenol derivatives, hydroxyl heterocycle, hydroxyl cycloalkyl or cyanoheteroaryl.For example, can prepare A type compound, wherein R according to above-mentioned a kind of compound a-and R b-group such as general formula I definition (or this group precursor), and COOR cBe the ester that suits, be generally methyl esters, ethyl ester or benzyl ester.Ester reduction can generate the Type B compound, can generate C type compound through the Mitsunobu coupling then.In this process, and protecting group that can rupture (PG) and alternative protecting group with suitable more following chemical process (PG '), thus D type compound generated.The known trifluoromethanesulfonic acid vinyl acetate of coupling (vinyl triflate) E can generate F type Bicyclononene.Can generate G type compound through the blocking group processing, deprotection obtains H type Bicyclononene then.In next step, for example Mitsunobu coupling can generate J type Bicyclononene, and wherein fragment V-U is in the appropriate location.Saponification can generate K type compound, forms L type compound through the acid amides coupling then.Remove the Boc-protecting group, alkylation or acylations can form M type Bicyclononene then, and deprotection obtains required N type end product then.
Flow process 1
Figure A20048001165000171
Formula I compound and pharmaceutically-acceptable acid addition useful as drug thereof for example are the pharmaceutical dosage forms of administration in the intestines, parenteral admin or topical.These medicines can oral (for example being the form of tablet, coating tablet, lozenge, hard capsule or soft capsule, solution, emulsion or suspension), rectal administration (for example suppository form), parenteral admin (for example being injection liquid or perfusion liquid form) or topical (for example being ointment, emulsion or oils form).
Can make pharmaceutical preparation in the mode that those skilled in the art know, promptly, by a kind of currently known methods mode, with described formula I compound and pharmaceutically-acceptable acid addition thereof, randomly there is the material of therapeutic value to mix with other, with compatible solid or liquid carrier materials in suitable, non-toxicity, inertia, the treatment, and if desired, common medicine auxiliary is made a kind of galenic form of medication.
When solid support material not only can be inorganic carrier material, also can be organic support material.Therefore, for example lactose, W-Gum or derivatives thereof, talcum powder, stearic acid or its salt etc. can be used as for example solid support material of tablet, coated tablet, lozenge and hard capsule.The appropriate carriers material that is used for soft capsule is for example vegetables oil, wax, fat and semisolid and liquid polyol (character that depends on activeconstituents, yet, do not need carrier in soft capsule).The solution and the syrup appropriate carriers material that are used for this manufacturing are for example water, polyvalent alcohol, sucrose, Nulomoline or the like.The appropriate carriers material that is used for injection liquid is for example water, alcohol, polyvalent alcohol, glycerine and vegetables oil.The appropriate carriers material that is used for suppository for natural or sclerosis oils for example, wax, fat and partly-liquid or liquid polyol.The preparation appropriate carriers material that is used for topical is glyceryl ester, half-synthetic and synthetics glyceryl ester, winterized stearin, liquid wax, whiteruss, liquid aliphatic alcohol, sterol, polyoxyethylene glycol and derivatived cellulose.
Can consider common stablizer, sanitas, wetting agent and emulsifying agent, denseness activator, smell activator, the salt that is used to change seepage water pressure, buffer reagent, solubilizing agent, tinting material and sequestering agent and antioxidant as the medicine auxiliary.
The dosage of formula I compound can in very large range change and depend on disease, patient's age and individual instances and the mode of administration of being controlled, and should be adapted to individual requirement in each concrete situation.For adult patients, acceptable per daily dose is about 1mg～about 1000mg, is preferably about 50mg～about 500mg especially.For children, should adjust dosage according to body weight and age.
The medicine preparation preparation is fit to comprise about 1～500mg, the formula I compound of preferred 5～200mg.
Following embodiment is used to be described more specifically the present invention.But these embodiment are not to be any restriction to scope of the present invention.
Embodiment
Abbreviation
The ACE angiotensin-converting enzyme
AcOH acetate
The Ang Angiotensin
Aq. the aqueous solution
The Bn benzyl
Uncle Boc-butoxy carbonyl
The BSA bovine serum albumin
The BuLi n-Butyl Lithium
The DIBAL diisobutyl aluminium hydride
The DIPEA diisopropyl ethyl amine
DMAP 4-N, the N-dimethyl aminopyridine
The DMSO dimethyl sulfoxide (DMSO)
EDC HCl ethyl-N, N-dimethylaminopropyl carbodiimide hydrochloride
The EIA enzyme immunoassay
Eq. equivalent
The Et ethyl
The EtOAc ethyl acetate
The FC flash chromatography
HOBt hydroxybenzotriazole base
The LC-MS liquid chromatography-mass spectrography
MeOH methyl alcohol
Org. organic
The PG protecting group
The Ph phenyl
The RAS renin-angiotensin system
The rt room temperature
Sol. solution
TBAF chlorination four-just-the butyl ammonium
TBDMS tert-butyl dimethylsilane
The Tf trifyl
The THF tetrahydrofuran (THF)
TMAD N, N, N ', N '-tetramethyl-azodicarboamide
Precursor
(R)-3-(tert-butyl phenylbenzene siloxy)-2 Methylpropionic acid methyl esters (A)
To (-)-D-beta-hydroxy methyl isobutyrate (5.54mL, 50mmol) and imidazoles (8.51g is 125mmol) at CH 2Cl 2Adding chlorination tert-butyl diphenyl silane in the mixture (150mL) (19.5mL, 75mmol).After stirring 18h, this mixture is through CH 2Cl 2The dilution and through saturated NH 4Cl solution and salt water washing.Organic extract is through MgSO 4Drying is filtered, and this solvent is removed in decompression.Obtain title compound (15.32g, 86%) through FC (hexane/EtOAc 100: 0 → 90: 10) purifying.
(S)-3-(tert-butyl phenylbenzene siloxy)-2-methyl-prop-1-alcohol (B)
In-78 ℃, to the DIBAL (hexane solution of 1M; 113.2mL, 113.2mmol) in the solution, further, add compd A (13.44g, THF 37.7mmol) (150mL) solution through THF (400mL) dilution.This solution stirs 30min in-78 ℃ and slowly adds MeOH (11.3mL) then.Allow this mixture to heat up.Slowly add saturated NH 4The Cl aqueous solution is until forming granular solids.This mixture is at Na 2SO 4Filter on the bed course.(hexane/EtOAc 98/2 → 95/5 → 90: 10 → 80: 20) purifying obtains title compound (11.6g, 93%) through FC.LC-MS；R t＝1.12，ES+：329.28.
(S)-[3-(4-bromine phenoxy group)-2-methyl propoxy-]-tert-butyl diphenyl silane (C)
With the 4-bromophenol (7.07g, 40.2mmol) and DIPEA (0.58mL, 3.3mmol add compd B, and (11g is in toluene 33.48mmol) (335mL) solution.In 0 ℃ add azo-dicarboxylic two piperidines (12.67g, 50.2mmol) and subsequently just adding-tributylphosphine (16.52ml, 67mmol).This reaction mixture of stirring at room 1h stirs 2h in 60 ℃ then.Allow to be chilled to room temperature, add entry then.This mixture extracts through EtOAc.Organic extract is through MgSO 4Drying is filtered, and this solvent is removed in decompression.Obtain title compound (16.0g, 99%) through FC (hexane/EtOAc 95/5) purifying.LC-MS；R t＝1.29min.
(S)-[3-(4-bromine phenoxy group)-2-methyl propoxy-]-tert-butyl dimethylsilane (D)
In 0 ℃ to C (13.1g, add in THF 27mmol) (200mL) solution TBAF (the THF solution of 1M, 54mL, 54mmol).Remove cryostat and stir this reaction mixture 2h.Add AcOEt and saturated NH 4The Cl aqueous solution.Water through AcOEt extraction and organic phase through MgSO 4Drying is filtered, and removal of solvent under reduced pressure.Obtain title compound (3.79g, 57%) through FC (hexane/EtOAc 80/20 → 50/50 → 0/100) purifying.
(3.79mL, 15.5mmol) (2.63g is 38.7mmol) at CH with imidazoles to the compound of previous acquisition 2Cl 2Adding tert-butyl dimetylsilyl muriate in the mixture (45mL) (3.5g, 23.2mmol).After stirring 3h, this mixture is through CH 2Cl 2The dilution and through saturated NH 4The Cl aqueous solution and salt water washing.Organic extract is through MgSO 4Drying is filtered, and this solvent is removed in decompression.Obtain title compound (3.1g, 56%) through FC (hexane/EtOAc 98/2 → 95/5) purifying.LC-MS；R t＝.1.24min.
1:1 (1R, 5S)-and 7-{ (2S)-4-[3-(tert-butyl dimethylsilyl bis)-2-methyl propoxy-] phenyl }-9-methyl-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6-dicarboxylic acid uncle 3--butyl ester 6-ethyl ester and (1S, 5R)-and 7-{ (2S)-4-[3-(tert-butyl dimethylsilyl bis)-2-methyl propoxy-] phenyl }-9-methyl-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3, the mixture (F) of 6-dicarboxylic acid uncle 3--butyl ester 6-ethyl ester
Under-78 ℃, ((1.8g is in THF 5mmol) (4mL) solution 5.12mmol) to add Compound D for the hexane solution of 1.6M, 3.2mL with BuLi.This mixture is in stirring at room 30, and adding ZnCl 2(the THF solution of 1M is pursuant to the ZnCl of 160 ℃ of dry 3h 2With the THF preparation, 6mL, 6mmol).Allow this mixture to rise to room temperature and add Bicyclononene E (0.91g, THF 2mmol) (6ml) solution adds Pd (PPh then 3) 4(58mg, 0.05mmol).This mixture heating up to 40 ℃ also stirred 30 minutes under this temperature.Add saturated NH 4The Cl aqueous solution.This mixture is through EtOAc (3 times) and through the salt water washing.Organic extract is through MgSO 4Drying is filtered, and removal of solvent under reduced pressure.Obtain title compound (0.49g, 41%) through FC (hexane/AcOEt 50: 50 → 0/100 is EtOAc/MeOH 95/5 then) purifying.LC-MS；R t＝1.03?ES+：589.36.
1:1 (1R, 5S)-and 7-{ (2S)-4-[3-(tert-butyl dimethylsilyl bis)-2-methyl-propoxy-] phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6,9-tricarboxylic acid uncle 3--butyl ester 6-ethyl ester 9-(2,2,2-three chloro-1,1-dimethyl ethyl) ester and (1S, 5R)-7-{ (2S)-4-[3-(tert-butyl dimethylsilyl bis)-2-methyl-propoxy-]-phenyl-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6,9-tricarboxylic acid uncle 3--butyl ester 6-ethyl ester 9-(2,2,2-three chloro-1,1-dimethyl ethyl) mixture (G) of ester
With Bicyclononene F (0.49g, 0.83mmol) and β, β, β-three chloro-tert-butyl chloro-formic ester (1g, CH 4.15mmol) 2ClCH 2Cl (10ml) vlil 4h.Allow this mixture to be chilled to room temperature and removal of solvent under reduced pressure.Residue obtains title compound (0.40g, 61%) through FC (EtOAc/ hexane 5/95 → 10/90) purifying.LC-MS：R t＝1.33?ES+：777.25.
1:1 (1R, S)-7-[4-((2R) 3-hydroxy-2-methyl propoxy-) phenyl]-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6,9-tricarboxylic acid uncle 3--butyl ester 6-ethyl ester 9-(2,2,2-three chloro-1,1-dimethyl ethyl) ester and (1S, 5R)-7-[4-(2S)-3-hydroxy-2-methyl propoxy-) phenyl]-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6,9-tricarboxylic acid uncle 3--butyl ester 6-ethyl ester 9-(2,2,2-three chloro-1,1-dimethyl ethyl) mixture (H) of ester
In 0 ℃ to Bicyclononene G (0.40g, add in THF 0.51mmol) (5mL) solution TBAF (the THF solution of 1M, 0.76mL, 0.76mmol).Remove ice bath and stir this reaction mixture 4h.Add AcOEt and saturated NH 4The Cl aqueous solution.Water through AcOEt extraction and organic phase through MgSO 4Drying is filtered, and removal of solvent under reduced pressure.Obtain title compound (0.26g, 78%) through (hexane/EtOAc 30/70 → 50/50 → 2/1) purifying.
LC-MS；R t＝1.95min.
1:1 (1R, 5S)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base)-and propoxy-] phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6,9-tricarboxylic acid uncle 3--butyl ester 6-ethyl ester 9-(2,2,2-three chloro-1, the 1-dimethyl ethyl) ester and (1S, 5R)-7-{4-[(2S)-and 2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-] phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6,9-tricarboxylic acid uncle 3--butyl ester 6-ethyl ester 9-(2,2,2-three chloro-1,1-dimethyl ethyl) mixture (J) of ester
With 2,3, the 6-trifluoromethyl phenol (0.07g, 0.48mmol) and DIPEA (0.007mL, (0.26g is in toluene 0.4mmol) (5mL) solution 0.04mmol) to add compound H.In 0 ℃ add azo-dicarboxylic two piperidines (0.15g, 0.6mmol), add subsequently tributylphosphine (0.20ml, 0.8mmol).This reaction mixture of stirring at room 20min. stirs 1h in 80 ℃ then.Allow this reaction mixture to be chilled to room temperature and add entry.This mixture extracts through EtOAc.Organic extract is through MgSO 4Drying is filtered, and removal of solvent under reduced pressure.(hexane/EtOAc20/80) purifying obtains title compound (0.28g, 89%) through FC.
LC-MS；R t＝1.26，ES+：795.08.
1:1 (1R, 5S)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base)-and propoxy-] phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6,9-tricarboxylic acid uncle 3--butyl ester 9-(2,2,2-three chloro-1, the 1-dimethyl ethyl) ester and (1S, 5R)-7-{4-[(2S)-and 2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base)-propoxy-] phenyl }-3,9-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,6,9-tricarboxylic acid uncle 3--butyl ester 9-(2,2,2-three chloro-1,1-dimethyl ethyl) mixture (K) of ester
Stir Bicyclononene J (0.28g, the mixture 2.5h of (5ml) solution of EtOH 0.36mmol) and 1M NaOH (3.6mL, the 3.6mmol)) aqueous solution in 80 ℃.Allow this mixture to be chilled to room temperature and use 1M HCl acidified aqueous solution.This mixture is through EtOAc (3x) extraction and through MgSO 4Drying is filtered, and removal of solvent under reduced pressure.Crude product obtains title compound (0.20g 72%) through FC (hexane/EtOAc 30/70 → 50/50) purifying.LC-MS：R t＝1.19；MS-：765.17.
1:1 (1R; 5S)-6-[cyclopropyl-(2; the 3-dichloro benzyl) formamyl]-7-{4-[(2S)-and 2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-] phenyl }-3; 9-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-6-alkene-3; 9-dicarboxylic acid uncle 3--butyl ester 9-(2,2,2-three chloro-1; the 1-dimethyl ethyl) ester and (1S; 5R)-6-[cyclopropyl-(2, the 3-dichloro benzyl)-formamyl]-7-{4-[(2S)-2-methyl-3-(2,3; 6-trifluoromethoxy phenoxy base) propoxy-] phenyl }-3; 9-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-6-alkene-3,9-dicarboxylic acid uncle 3--butyl ester 9-(2,2; 2-three chloro-1,1-dimethyl ethyl) mixture (L) of ester
Stir Bicyclononene K (0.20g, 0.26mmol), (2, the 3-dichloro benzyl) cyclopropylamine (0.17mg, 0.78mmol), DMAP (0.004g, 0.06mmol), DIPEA (0.18mL, 1.0mmol), HOBt (0.04g, 0.32mmol) and EDCHCl (0.074g is 0.39mmol) at CH 2Cl 2Mixture (5mL) 2 days.Add then EDC.HCl (0.074g, 0.39mmol) and DIPEA (0.07mL, 0.39mmol) and continue to stir 2 days.This mixture is through CH 2Cl 2The dilution and through 1M HCl (2x) solution washing.This organic extract is through MgSO 4Drying is filtered, and removal of solvent under reduced pressure.Obtain title compound (0.11g, 44%) through FC (hexane/EtOAc 20: 80 → 30/70) purifying.LC-MS：R t＝1.34；ES+：964.19.
Embodiment
1:1 (1R, 5S)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base)-and propoxy-] phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2, the 3-dichloro benzyl) acid amides and (1S, 5R)-7-{4-[(2S)-and 2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-] phenyl }-3, the mixture of 9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2, the 3-dichloro benzyl) acid amides
(0.11g 0.11mmol) is dissolved among THF (3mL) and the AcOH (0.3mL) and uses zinc (0.14g 2.2mmol.) handles with Bicyclononene L.Stir this suspension 2h and pass through the filtration of Titan  HPLC strainer.Reduction vaporization filtrate, residue need not to be further purified and are used for following step.
To before obtain material (0.08g, CH 0.11mmol) 2Cl 2(2mL) solution is chilled to 0C.Add 4MHCl/ dioxane (2mL).Behind room temperature 2.5h, removal of solvent under reduced pressure and dried residue under high vacuum.Title compound is through preparation-HPLC purifying.LC-MS：R t＝0.80；ES+：660.38
Carried out following mensuration in order to measure compound of Formula I and salt thereof.
The compounds of this invention is for the recombinate inhibition of feritin of people
Carrying out external enzymatic in 384-hole polypropylene board (Nunc) measures.Measuring damping fluid is made up of the 10mM PBS that comprises 1mMEDTA and 0.1%BSA (Gibco BRL).The hatching thing is by the DMSO solution composition of the enzyme mixture and the 2.5 μ L renin inhibitors in the every hole of 50 μ L.This enzyme mixture is grouped into by following one-tenth in 4 ℃ of premixs merging:
People's feritin (0.16ng/mL) synthetic human angiotensin (1-14) (0.5 μ M) of recombinating
Hydroxyquinoline Sulfate (1mM)
Then in 37 ℃ of this mixture of hatching 3h.
In order to measure enzymatic activity and restraining effect thereof, in 384-orifice plate (Nunc), detect cumulative Ang I by enzyme immunoassay (EIA).5 μ L hatching thing or standard substance are transferred in the immune plate, be coated with the covalent complex (Ang I-BSA) of Ang I and bovine serum albumin(BSA) on this plate in advance.The above-mentioned test damping fluid that adds the 75 μ L Ang I-antibody that comprise 0.01%Tween 20, and under 4 ℃, cultivate preliminary the hatching a whole night.The PBS that use comprises 0.01%Tween 20 washs immune plate 3 times, and (WA 934, Amersham) at room temperature hatch 2 hours to use anti-rabbit-peroxidase coupling antibody then.After washing 3 times, adding peroxidase substrate ABTS (2.2 '-azino-two-(3-ethyl-benzothiazole sulfonate moiety ester), and at room temperature hatched this plate 60 minutes.Using pH is after 4.3 the 0.1M citric acid termination reaction, in microplate in this plate of 405nm place evaluation.Calculate the inhibition per-cent of each concentration point and be determined at enzymic activity and be suppressed 50% (IC 50) time the feritin inhibition concentration.The IC of all compounds of being measured 50-value all is lower than 100nM.Selected mixture demonstrates very good bioavailability and more stable in metabolism than the compound of prior art.

Claims (12)

1. compound of Formula I
General formula I
Wherein
W is hexavalent, non-benzo-fused, phenyl ring or hetero-aromatic ring, is replaced by V in a position or contraposition;
V representative-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-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-;
U represents aryl, heteroaryl;
T representative-CONR 1-,-(CH 2) pOCO-,-(CH 2) pN (R 1) CO-,-(CH 2) pN (R 1) SO 2-or-COO-;
Q represents low-grade alkylidene, lower alkenylene;
M represents hydrogen, cycloalkyl, aryl, heterocyclic radical, heteroaryl;
L representative-R 3,-COR 3,-COOR 3,-CONR 2R 3,-SO 2R 3,-SO 2NR 2R 3,-COCH (aryl) 2
R 1Represent hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, cycloalkyl, aryl, cycloalkyl-low alkyl group;
R 2And R 2' independent hydrogen, low alkyl group, low-grade alkenyl, cycloalkyl, the cycloalkyl-low alkyl group represented;
R 3Represent hydrogen, low alkyl group, low-grade alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical, cycloalkyl-low alkyl group, aryl lower alkyl, heteroaryl-low alkyl group, heterocyclic radical-low alkyl group, aryloxy-low alkyl group, heteroaryloxy-low alkyl group, wherein these groups can be unsubstituted or by hydroxyl ,-OCOR 2,-COOR 2, lower alkoxy, cyano group ,-CONR 2R 2' ,-CO-morpholine-4-base ,-CO-((4-low alkyl group) piperazine-1-yl) ,-NH (NH) NH 2,-NR 4R 4' or low alkyl group list-, two-or three replace, condition is that this carbon atom links to each other with a heteroatoms at the most when carbon atom is sp3-hydridization;
R 4And R 4' independent represent hydrogen, low alkyl group, cycloalkyl, cycloalkyl-low alkyl group, hydroxy lower alkyl ,-COOR 2,-CONH 2
K is integer 0 or 1;
M and n represent integer 0 or 1, and condition is when m represents integer 1, and n is an integer 0, and when n represented integer 1, m was an integer 0, and when k represented integer 0, n represented integer 0;
P is an integer 1,2,3 or 4;
And the mixture of optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and this meso-form and pharmacy acceptable salt, solvent complex and the crystalline form of non-mapping racemic mixture of racemic mixture, diastereomer, diastereomer.
2. according to the compound of claim 1, wherein W, V, U, T, Q, L and M such as general formula I define, and
K is 1
N is 0
M is 1,
And the mixture of optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and this meso-form and pharmacy acceptable salt, solvent complex and the crystalline form of non-mapping racemic mixture of racemic mixture, diastereomer, diastereomer.
3. according to the compound of claim 1, wherein W, V, U, T, Q, M, k, m and n such as general formula I define, and
L representative-COR 3" ,-COOR 3" ,-CONR 2" R 3";
R 2" and R 3" independent low alkyl group, the low-grade cycloalkyl-low alkyl group represented, wherein low alkyl group and low-grade cycloalkyl-low alkyl group be not substituted or by halogen ,-CN ,-OH ,-OCOCH 3,-CONH 2,-COOH or-NH 2The single replacement,, condition is, when carbon atom was sp3-hydridization, this carbon atom linked to each other with a heteroatoms at the most,
And the mixture of optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and this meso-form and pharmacy acceptable salt, solvent complex and the crystalline form of non-mapping racemic mixture of racemic mixture, diastereomer, diastereomer.
4. according to the compound of claim 1, wherein W, V, U, L, k, m and n such as general formula I define, and
T representative-CONR 1-;
Q represents methylene radical;
M represents aryl, heteroaryl;
And the mixture of optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and this meso-form and pharmacy acceptable salt, solvent complex and the crystalline form of non-mapping racemic mixture of racemic mixture, diastereomer, diastereomer.
5. according to the compound of claim 1, wherein W, U, L, T, Q, M, k, m and n such as general formula I define, and
V representative-O-CH 2-CH (CH 3)-CH 2-O-,-O-CH 2-C (CH 3) 2-CH 2-O-;
And the mixture of optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and this meso-form and pharmacy acceptable salt, solvent complex and the crystalline form of non-mapping racemic mixture of racemic mixture, diastereomer, diastereomer.
6. according to the compound of claim 1, wherein V, U, T, Q, M, L, k, m and n such as general formula I define, and
W represents 1, the dibasic phenyl ring of 4-,
And the mixture of optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and this meso-form and pharmacy acceptable salt, solvent complex and the crystalline form of non-mapping racemic mixture of racemic mixture, diastereomer, diastereomer.
7. according to the compound of claim 1, wherein W, V, Q, T, M, L, m and n such as general formula I define, and
U by phenyl or heteroaryl list-, two-or three replace, wherein substituting group is halogen, low alkyl group, lower alkoxy, CF 3,
And the mixture of optically pure enantiomorph, enantiomorph for example mixture, diastereomeric racemic mixture, mixture and this meso-form and pharmacy acceptable salt, solvent complex and the crystalline form of non-mapping racemic mixture of racemic mixture, diastereomer, diastereomer.
8. according to each compound of claim 1 to 7, be selected from
(1R, 5S)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-]-phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2,3-two chloro-benzyls) acid amides;
(1S, 5R)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-] phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2,3-two chloro-benzyls) acid amides;
(1R, 5S)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-]-phenyl }-3,9-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2, the 3-dichloro benzyl) acid amides and (1S, 5R)-7-{4-[(2S)-and 2-methyl-3-(2,3,6-trifluoromethoxy phenoxy base) propoxy-] phenyl }-3, the mixture of 9-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-6-alkene-6-carboxylic acid cyclopropyl-(2, the 3-dichloro benzyl) acid amides.
9. pharmaceutical composition, it comprises at least a as claim 1 to 8 compound and common solid support material and auxiliary as described in each, and be used for the treatment of or the relevant disorder of insufficiency of accommodation of prevention and renin-angiotensin system (RAS), described disorder comprises: cardiovascular disorder and ephrosis, hypertension, congestive heart failure, pulmonary hypertension, cardiac insufficiency, renal insufficiency, kidney or myocardial ischemia, atherosclerosis, renal failure, erective dysfunction, glomerulonephritis, renal colic, glaucoma, the diabetic complication, blood vessel or postcardiac surgery complication, restenosis, the complication of using immunosuppressant treatment to cause after the organ transplantation, and other present known and RAS relative disease.
10. one kind is used to prevent or the method for treatment and RAS relative disease, wherein said disease comprises hypertension, congestive heart failure, pulmonary hypertension, cardiac insufficiency, renal insufficiency, kidney or myocardial ischemia, atherosclerosis, renal failure, erective dysfunction, glomerulonephritis, renal colic, glaucoma, the diabetic complication, blood vessel or postcardiac surgery complication, restenosis, the complication of using immunosuppressant treatment to cause after the organ transplantation, and other present known and RAS relative disease, this method comprises to the human or animal takes each described compound of a kind of claim 1 to 8.
11. each described compound of claim 1 to 8 is used for the treatment of or the purposes of prevention and RAS relative disease, described disease comprises: the complication and other the present known and RAS relative disease that use immunosuppressant treatment to cause after hypertension, congestive heart failure, pulmonary hypertension, cardiac insufficiency, renal insufficiency, kidney or myocardial ischemia, atherosclerosis, renal failure, erective dysfunction, glomerulonephritis, renal colic, glaucoma, diabetic complication, blood vessel or postcardiac surgery complication, restenosis, the organ transplantation.
12. as claim 1 to 8 as described in each compound and one or more other pharmacological active substances linked together with the purposes of treatment as disease as described in the claim 9 to 11, described pharmacological active substance comprises ACE-inhibitor, angiotensin-ii receptor antagonist, endothelin receptor antagonist, vasodilator, calcium antagonist, potassium activator, diuretic(s), sympatholytic agent, beta-adrenergic antagonist, alpha-adrenergic antagonist and neutral endopeptidase inhibitor.
CNA2004800116500A 2003-05-02 2004-04-26 Azabicyclononene derivatives Pending CN1780838A (en)

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