carbamoylmethylaminoacetic acid derivatives substituted as nep inhibitors

专利摘要:
CARBAMOYLMETHYL-NOACETIC ACID DERIVATIVES REPLACED AS NEP INHIBITORS.The present invention relates to a compound of formula I ';I 'or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R6, A1, A2, X1, s and m are as defined herein. The invention also relates to a process for preparing the compounds of the invention, and their therapeutic applications. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
公开号:BR112012011977A2
申请号:R112012011977-0
申请日:2010-11-18
公开日:2020-09-08
发明作者:Yuki Iwaki；Toshio Kawanami；Gary Michael Ksander；Muneto Mogi
申请人:Novartis Ag；
IPC主号:

专利说明:

Invention Patent Descriptive Report for "DERIVATIVES OF CARBAMOYLMETHYLAMINOACETIC ACID REPLACED AS NEP INHIBITORS ".
BACKGROUND OF THE INVENTION 5 Endogenous atrial natriuretic peptides (ANP), also called atrial natriuretic factors (ANF), have diuretic, natriuffective and vasorelaxative functions in mammals. The natural AFN peptide is metabolically inactivated, in particular by a degradation enzyme that has been recognized for corresponding to the neutral endopeptidase enzyme (NEP) EC 10 3.4.24.11, which is also responsible, for example, for the metabolic inactivation of encephalins. Neutral endopeptidase (EC 3.4.24.11; encephalinase; atriopeptide; NEP) is a zinc-containing metalloprotease that cleaves a variety of peptide substrates on the amino side of hydrophobic residues {see Phar-. "15 macol Rev, Vol. 45, p. 87 (1993)]. Substrates for this enzyme include, but are not limited to, atrial natriuretic peptides (ANP, also known as ANF), brain natriuretic peptides (BNP), met- encephalin and leu-encephaline, bradykinin, neurokinin A, endothelin-1 and substance P. ANP is a potent vasorelaxant and natriuretic agent [see J Hy-20 pertens, Vol. 19, p. 1923 (2001)]. of ANP in normal individuals resulted in a reproducible, marked improvement in natriuresis and diure, including increases in fractional sodium excretion, urinary flow rate and glomerular filtration rate [see JC / in Pharmacol, Vol. 27, p. 927 (1987)]. However, ANP has a short half-life in the circulation, and it has been shown that NEP in membranes of the renal cortex was the main enzyme responsible for degrading this peptide [see Peptides, VOI. 9 , page 173 (1988)]. Therefore, NEP inhibitors (neutral endopeptidase inhibitors, NEP1) should increase r plasma levels of ANP and, in addition, are expected to induce natriuretic and diuretic effects. 30 This enzyme is involved in the breakdown of several bioactive oligopeptides, cleaving peptide bonds on the amino side of hydrophobic amino acid residues. Metabolized peptides include natural peptides
atrial triuretics (ANP), bombesin, bradykinin, calcitonin-related gene peptides, endothelins, encephalins, neurotensin, substance P and vasoactive intestinal peptide. Some of these peptides have powerful vasodilating and neurohormonal functions, diuretic and 5 natriuretic activity or mediate behavioral effects. SUMMARY OF THE INVENTION: The aim of the present invention is to provide new compounds that are useful as inhibitors of neutral endopeptidase, for example, as inhibitors of the degrading enzyme of ANF in mammals, in order to prolong and enhance the diuretic properties, natriuretic and ANF vasodilators in mammals, inhibiting their degradation into less active metabolites. The compounds of this invention are therefore particularly useful. for the treatment of conditions and disorders responsible for the inhibition of "15 neutral endopeptidase (NEP) EC 3.4.24.11. The invention relates to compounds, methods for employing them. and their uses as described here. Examples of compounds of the invention include compounds according to any of formulas I 'and I to IV, or one of pharmaceutically acceptable salts thereof and the compounds of the examples 20. The invention therefore provides a compound of formula (I'):
OO "JY" r "" "R1, R4> C (R ')" <> (R2) "I, where: X1 is OH, -O-C1-7a | quI | a, -NR'Rb, - NHS (O) 2-C1-7a | qui | a ou - 25 NHS (O) 2-benzi | a, where R "and Rb for each occurrence are independently H or C1-7a | qui | a; R1 is H, C1-6 alkyl or C6-1o-ari | -C1-6 alkyl, where alkyl is optional
finally substituted with benzyloxy, hydroxy or C1-6 alkoxy; for each occurrence, R2 is independently C1-6-a | coxy, hydroxy, halo, C1-6-a | chi | a, cyano or trifluoromethyl; A'éOouNR '; 5 R 'and R5 are independently H or Ck6 alkyl; A1 is a C1-3 here link or chain; R3 is a 5- or 6-membered heteroaryl, C6-10-ary | a or C3-7-cycloalkyl, where each heteroaryl, aryl or cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of C1-6a [quj | a, haio, ha | oC1-6a | qui | a, C1-6a | coxy, hydroxy, CO2H and CO, C, -6a | kila; R6 for each occurrence is independently halo, hydroxy, C1-7a | coxy, halo, C1-7alkyl or ha | o-C1-7a | kila; or R4, A1-R3, together with the nitrogen to which R 'and A1-R3 are ¥
"15 linked, form a heterocyclyl with 4 to 7 members or a heteroaryl with 5 to 6 members, each of which is optionally substituted with one or more groups independently selected from the group consisting of C1-6a | qui | a, halo, ha | oC1-6a | qui | a, C1-6a | coxy, hydroxy, CO2H and CO2C1- 6a | qui | a; and 20 méOouuminteirode1at5; séOouuminteirode1até4; or pharmaceutically acceptable salts thereof.
The invention also provides a compound of formula (I): r5 o
"b'ft: ^" ' ^ 4r') ·
/ <»(R2) m I
25 where: X 'represents OH or O-C1-6-a | qui | a; R1éH, C1-6a | chi | aouC6-10-ari | -C1-6a | kila; for each occurrence, R2 is independently C1-6-alkoxy,
doxy, halo, C1.6-a | chi | a, cyano or trifluoromethyl; R4 and R5 are independently H or C1-6 alkyl; A1 is a C1-3a | chi | eny or chain; R3 is a 5- or 6-membered heteroaryl, C6-10-aryl or C3-7-5 cycloalkyl, where each heteroaryl, aryl or cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of C1-6a | chi | a, halo, ha | oC1-6a | quila, C1-6a | coxy, hydroxy, CO2H and CO2C1-6a | qui | a; R 'for each occurrence is independently halo, hydroxy, C1-1O 7a | coxy, halo, C1-7a | chi | a or ha | o-C1-7alkyl; or R4, A1-R3, together with the nitrogen to which R4 and A1-R3 are attached, form a heterocyclyl with 4 to 7 members or a heteroaryl with 5 to 6 members, each of which is optionally substituted with one or more groups independently selected from the group that b "15 consists of C1-6a | qui | a, halo, ha | oC1-6here | a, C1-6a | coxy, hydroxy, CO2H and CO2C1-6a [kila; and méOouuminteirode1até5 ; seOouuminium from 1 to 4; or pharmaceutically acceptable salts thereof.
The compounds of the invention, through the inhibition of neutral endopeptide EC.3.4.24.11, can potentiate the biological effects of bioactive peptides. Therefore, the compounds are particularly useful in the treatment of a number of disorders, including hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, isolated systemic hypertension, peripheral vascular disease, heart failure, concomitant heart failure - gestational, left ventricular hypertrophy, angina, renal failure (diabetic or non-diabetic), renal failure (including edema and salt retention), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulo-nephritis, scleroderma, glomerular sclerosis, eiaproteinurea primary renal disease, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial fluoride, harmful vascular remodeling, plaque stabilization, myocardial infarction dio (Ml), renal fibrosis, polycystic kidney disease (PKD), kidney failure (including edema and salt retention), cyclic edema, Menières disease, hyperaldosteronism 5 (primary and secondary) and hypercalciuria, ascites. In addition, due to their ability to potentiate the effects of ANF, the compounds are useful in the treatment of glaucoma. As another result of their ability to inhibit neutral EC3.4.24.11 endopeptidase, the compounds of the invention may have activity in other therapeutic areas, including for example the treatment of menstrual disorders, premature labor, eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, political ovary syndrome, implant failure). Also, the compounds of the invention should treat asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure ulcers), septic shock, dysfunction of gastric acid secretion, hyperreninemia, cystic fibrosis, restenosis, type-2 diabetes 20, metabolic syndrome , diabetic complications and atherosclerosis, male and female sexual dysfunction In a preferred embodiment the compounds of the invention are useful in the treatment of cardiovascular disorders In another embodiment, the invention relates to a method 25 for treating a disorder or diseases that respond to the inhibition of neutral endopeptidase EC 3.4.24.11 (NEP), in an individual in need of such treatment, comprises nd: administration to the individual of an effective amount of a compound according to any of the formulas I-1V, or pharmaceutically acceptable salts thereof, such as the disorder or disease responsible for the inhibition of neutral EC endopeptidase 3.4.
24.11 (NEP) in the individual is treated. In yet another embodiment, the invention relates to pharmaceutical compositions, comprising a compound according to any of the formulas IV-1, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers. In yet another embodiment, the invention relates to 5 combinations including a compound according to any of the formulas 1-1V, or pharmaceutically acceptable salts thereof, and pharmaceutical combinations of one or more therapeutically active agents. In another embodiment, the invention relates to a method for inhibiting neutral endopeptidase EC 3.4. 24.11 in an individual 10 in need thereof, comprising: administering to the individual a therapeutically effective amount of a compound according to any of the formulas 1-1V, or pharmaceutically acceptable salts thereof, such as the neutral endopeptidase EC 3.4. 24.11 is inhibited.
. DETAILED DESCRIPTION OF THE INVENTION "15 Definition: For the purpose of interpreting this patent application, the following definitions will apply unless otherwise specified and, where appropriate, the terms used in the singular will also include the plural and vice versa 20 As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon portion (straight or linear), comprising 1 to 20 carbon atoms, preferably alkyl comprising 1 to 6 atoms carbon, and more preferably 1 to 4 carbon atoms. Representative examples of alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyla. The term "C1-6a] qui | a" refers to a hydrocarbon containing from one to six carbon atoms. The term "alkylene" refers to an alkyl radical divalent ila, where alkyl is as previously defined. As used herein, the term "haloalkyl" refers to an alkyl as defined herein, which is replaced with one or more halo groups as defined herein.
Preferably, haloalkyl may be monohaloalkyl, dihaloalkyl or pdihaloalkyl including perhaloalkyl.
A mono [oa | qui | a may have an iodine, bromine, chlorine or fluorine within the alkyl group.
Dihaloalkyl and polyhaloalkyl groups have two or more equal haloatoms or a combination of different halo groups within the alkyl.
Preferably the po | po | oa | qui | a contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
Representative examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluorethyl, heptafluorpropyl, difluorchloromethyl, dichlorofluoromethyl, difluorethyl, dichloroethyl dichloropropyl, and dichloroethyl.
A perhaloalkyl refers to an alkyl containing all the hydrogen atoms replaced by haloatoms.
The term "ha | o-C1-6a | qui | a" refers to a hydrocarbon that contains from one to six carbon atoms and is replaced with one or more halo groups. . "15 As used herein, the term" alkoxy "refers to alkyl-O-, where alkyl is defined here above.
Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy, cyclohexyloxy and the like.
Preferably, alkoxy groups have approximately 1-6, more preferably approximately 20 and 1-4 carbons.
As used herein, the term "cycloalkyl" refers to saturated or partially unsaturated, monocyclic, bicyclic or tricyclic groups with 3-12 carbon atoms, preferably 3-8, or 3-7 carbon atoms.
For cycloalkyl, bicyclic and tricyclic systems, all rings are non-aromatic.
Monocyclic hydrocarbon groups in the examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentylene, cyclohexyl and cyclohexenyl.
The bicyclic hydrocarbon groups in the examples include bornyl, decahydronaphthyl, bicycles [2.1.1] hexyl, bicycles [2.2.1] heptyla, bicycles [2.2.1] heptenyl, bicycles [2.2.2] octyl.
The hydroxy tricyclic carbide groups in the examples include adamantyl.
The term "C3-7 cycloalkyl" refers to a cyclic hydrocarbon group containing from 3 to 7 carbon atoms.
The term "aryl" refers to aromatic, monocyclic or bicyclic, hydrocarbon groups containing 6-10 carbon atoms in the ring portion.
The term "aryl" also refers to a group in which the aromatic ring is fused to a cycloalkyl ring, where the linking radical is in the aromatic ring 5 or the fused cycloalkyl ring.
Representative examples of aryl are phenyl, naphthyl, hexahydroindyl, indanyl or tetrahydronaphthyl.
The term "C6-10 aryl" refers to an aromatic hydrocarbon group containing from 6 to 10 carbon atoms in the ring portion.
The term "arylalkyl" is alkyl substituted with aryl.
Representative examples of arylalkyl are benzyl or phenyl | -CH2CH2-. The term "C6-10ari {-C1-6a | qui | a" refers to a hydrocarbon containing from one to six carbon atoms, in which the hydrocarbon is replaced with an aryl containing from 6 to 10 carbon atoms.
The term "heteroaryl" includes monocyclic or bicyclic heteroaryl,>
"15 containing 5-10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatom is independently selected from O, N or S where S and N can be oxidized in various oxidation states.
For bicyclic heteroaryl systems, the system is fully aromatic (i.e. all rings are aromatic). 20 Typical monocyclic heteroaryl groups include thienyl, furyl, pyrrole, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, 1, 2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazole- 5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-
25 4-yl, isoxazol-5-yl, 1,2,4-triazo! -3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazo1-4-yl, 1, 2,3-triazol-5-yl, tetrazolyl, pyrid-2-yl, pyrid-3-yl, or pyridyl-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-3-yl, 2 -pyrazin-2-yl, pyrazin-4-yl, pyrazin-5-yl, 2-pyrimidin-2-yl, 4-pyrimidin-2-yl, or 5-pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl.
The term "heteroaryl" also refers to a group in which a ring
30 teroaromatic is fused to one or more aryl rings, where the radical or attachment point is in the heteroaromatic ring or in the fused aryl ring.
Representative examples of bicyclic heteroaryl are indolyl, isoindolyl, indazolyl, indo-
lyzinyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinaxalinyl, phenanthridinyl, phenatrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzylisoquinolinyl, thi [[2,3]] -pyranyl, 5H-pyrido [2,3-d] -o-oxazinyl, 1 H-pyrazolo [4,3-d] -oxazolyl, 4H-5 imidazo [4,5-d] thiazolyl, pyrazine [2, 3-d] pyridazinyl, im jdazo [2,1-b] thiazo | i] a, im j-dazo [1,2-b] [1,2,4] triazinyl, 7-benzo [b] thienyl, benzoxazolyl , benzoimidazolyl, benzothiazolyl, benzoxapinyl, benzoxazinyl, 1H-pyrrolo [1,2-b] [2] benzazapinyl, benzofuryl, benzothiophenyl, benzotriazolyl, pyrrole [2,3-b] pyridinyl, pyrrole [3,2-c] pyridinyl, pyrrhenium [3,2-c] pyridinyl, pyrrolo [3,2-b] pyridinyl, 10 imidazo [4,5-b] pyridinyl, imidazo [4,5-c] pyridinyl, pyrazolo [4,3-d] pyridinyl , pyrazole [4,3-c] pyridinyl, pyrazolo [3,4-c] pyridinyl, pyrazolo [3,4-d] pyridinyl, pyrazole [3,4-b] pyridinyl, imidazo [1,2 -a] pyridinyl, pyrazolo [1,5-a] pyridinyl, pyrrole [1,2 - "b] pyridazinyl, imidazo [1,2-c] pyrimidinyl, pyrido [3,2-d] pyrimidinyl, pyrido [4,3-
. d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrido [2,3-d] pyrimidinyl, pyrido [2,3- "15 b] pyrazinyl, pyrido [3,4-b] pyrazinyl, pyrimido [5, 4-d] pyrimidinyl, pyrazine [2,3-b] pyrazinyl, or pyrimido [4,5-d] pyrimidinyl.
When a heteroaryl moiety is replaced with hydroxy, the invention also relates to its tautomeric oxo.
For example, a hydroxy substituted oxadiazole also includes oxo-oxadiazoles also known as oxadiazolones.
Tautomerization is represented as follows:
tç / "° '_ NÍ)" ° H
As used herein, the term "heterocyclyl" or "heterocyclic" refers to an optionally substituted, saturated or unsaturated non-aromatic (partially unsaturated) ring that is a monocyclic with 4, 5, 6, 25 or 7 members, and contains at least one heteroatom selected from O, S and N, where N and S can also be optionally oxidized in various oxidation states.
For a bicyclic and tricyclic heterocyclic ring system, a non-aromatic ring system is defined as a ring system that is not totally or partially unsaturated.
Therefore ring systems of bicyclic and tricyclic heterocyclics include ring systems of heterocyclyl where one of the fused rings is aromatic but the other (s) is (are) non-aromatic (s). In one embodiment, the heterocyclyl portion represents a saturated monocyclic ring containing 5-7 ring atoms and optionally containing another heteroatom, selected from O, S or N. The heterocyclic group may be linked to a heteroatom or to a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include dihydrofuranyl, dioxolanyl, dioxanil, di-cyanyl, piperazinyl, pyrroiidine, dihydropyranyl, oxathiolanyl, dithio-iana, oxathianyl, thiomorpholino, oxiranil, aziridinyl, oxetanyl, oxiofila, azetaniline, azetaniline, dinosaur, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanila, oxathinilila, tiepanila, azepanila, dioxepanila, and diazepanila. The term "halogen" includes fluorine, bromine, chlorine and iodine. The term . "perhalogenated" generally refers to a portion where all hydrogens are "replaced by halogen atoms. The term" heteroatom "includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen sulfur and phosphorus In one embodiment the heteroatom is selected from N, O and S. 20 Compound of the invention: Various embodiments of the invention are described here It will be recognized that features specified in each embodiment can be combined with other characteristics specified to provide other modes of execution 25 Certain compounds of formula l 'or l include compounds of formula ll: OR' O ,, AYkDY ^ 'R3 R1 Ê R4 C, | r6)' < »" (R ') m
II or pharmaceutically acceptable salts thereof, where R {R2, R3, R4, R5, R6, X ', A1, s and m have the definition of formula I, supra.
In one embodiment the invention relates to compounds of the formula I ', I or Il where: 5 X 1 represents OH or O-C 1-6 -alkyl; R 'is H or C 1-6 alkyl; for each occurrence, R 'is independently C1-6-a | coxy,
doxy, haio, C1-6-a | chi | a, cyan or trifluoromethyl; R4 and R5 are independently H or C1-6 alkyl;
A1 is a C1-3aiquiene bond or chain; R3 is a 5- or 6-membered heteroaryl or C6-10-ari | a, where each heteroaryl and aryl are optionally substituted with one or more substituents independently selected from the group consisting of C1-
, 6a | kila, halo, ha] oC1-6a | chi | a, C, + alkoxy, hydroxy, CO, H and CO2C1-6alkyl; "15 R6 for each occurrence is independently halo, hydroxy, Cj-
. 7a | coxy, halo, C1-7a | chi | a or ha | o-C1-7a | chi | a; méOouuminteirode1 to 5; seOouuminium from 1 to 4, or pharmaceutically acceptable salts thereof. In another embodiment, the invention relates to compounds of formula r, I or ll where: X1 represents OH or O-C1-6-alkyl; R1 is H or Cl6 alkyl; for each occurrence, R2 is independently C1-6-a |
25 doxy, halo, C1-6-a | chi |, cyano or trifluoromethyl; R4 and R5 are independently H or C1-6 alkyl; A1 is a C1-3a | kilene bond or chain; R3 is a 5- or 6-membered heteroaryl optionally substituted with one or more substituents independently selected from the group consisting of C1-6a | qui | a, halo, haIoC1-6a | qui | a, C1-6a | coxy, hydroxy, CO2H and CO2C1-6 here; R6 for each occurrence is independently halo, hydroxy, Cj-
7a | coxy, halo, C1-7a | chi | a or ha | o-C1-7a | chi | a; méOouuminteirode1at5 seOouuminium from 1 to 4, or pharmaceutically acceptable salts thereof. 5 Certain compounds of formula I 'or I include compounds of the formula lll: O R' O x ') l'lL :: ^' "R ' C, (R') '
<> "(R '),
X2 Ill or pharmaceutically acceptable salts thereof, where R1, R2, R3, R4, R5, R ', X', A'is defined in form | a |, supraeX2éhaloepé0ou a
. 10 integer from 1 to 4. Certain compounds of formula I ', I, ll or | include compounds of formula IV: O R5 O x'AjjL!: ^ "'~ ^ L (R'),
: (R ') p x' lV or pharmaceutically acceptable salts thereof, where R1, R2, R3, R4, R5,
R ', X', A ', X', s and p have the definition of formulas I, ll and lll, supra.
In one embodiment, the invention relates to compounds of formula III or IV, or pharmaceutically acceptable salts thereof, where X2 is a Cl.
In one mode another aspect of this execution p is 0. The following modes of execution can be used independently
dentively, collectively or in any combinations or sub-combinations: In one embodiment, the invention relates to compounds according to any of the formulas I 'and I to lV, or any other 5 classes and subclasses described above, or to pharmaceutically acceptable salts thereof, where A1 is a bond or CH2. In another embodiment A 'is a link- In another embodiment, the invention relates to compounds according to any of formulas I' and I to lV, or any of the other classes and subclasses described above, or pharmaceutically acceptable salts thereof, where R3 is an optionally substituted 5- or 6-membered heteroaryl. In one aspect of this embodiment, R 'is a 6-membered ring heteroaryl selected from the group consisting of pyrazine, pyridine, pyrimidine, pyranone (for example, optionally substituted piran-4-one, pyran -2-one such as 3-hydroxy-pyran-4-one, 3-hydroxy-pyran-2-one), pyrimidinone and pyridinone (for example, optionally substituted pyridin-4-one or pyridin-2-one such as example 3-hydroxy-1-methyl-pyridin-4-one or 1-benzyl-pyridin-2-one). In another aspect of this embodiment R3 is a 5-membered heteroaryl selected from the group consisting of in oxazole, pyrrole, pyrazola, isooxazole, triazole, tetrazole, oxadiazola (for example, 1-oxa-3,4-diazola, 1-oxa-2,4-diazola), oxadiazolone (for example, oxadiazole-2-one) , thiazole, isothiazole, thiophene, imidazole and thiadiazole.Other representative examples of R3 are oxazolone, thiazolone, oxadiazolone, triazolone, oxazolone, imidazolone, pyrazolone. in heteroaryl are independently C1-6a | qui | a, halo, ha | oC1-6a | qui | a, C1-6a | coxy, hydroxy, CO2H or CO2C1-6a | qui | a. In another aspect of the above embodiment, the invention relates to the compounds according to any one of formulas I 'and I 30 to lV, or to any of the other classes and subclasses described above, or pharmaceutically acceptable salts thereof, where R3 is tetrazole.
In another embodiment, the invention refers to the components
placed according to any of formulas I 'and I to IV, or any of any of the other classes and subclasses described above, or to pharmaceutically acceptable salts thereof, where R3 is an optionally substituted phenyl. In another embodiment, the optional 5 substituents on the phenyl are independently C1-6a | chi] a, halo, ha] oC1-6a | quj | a, C1-6a | coxy, hydroxy, CO2H or CO2C1-6a | chi | a. In another embodiment, phenyl is substituted with CO2H and even more optionally substituted. In another embodiment, the invention relates to compounds according to any of formulas I 'and I to IV or to any one of any other classes and subclasses described above, or to pharmaceutically acceptable salts thereof, where R1 is C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl). In another embodiment, the invention relates to compounds according to any of formulas I 'and I through IV or to any of the other classes and subclasses described above, or to pharmaceutically acceptable salts thereof. , where R4 is H.
In another embodiment, the invention relates to compounds according to any of formulas re I to IV or to any of any other classes and subclasses described above, or to pharmaceutically acceptable salts thereof, where R5 is H. In another embodiment, the invention relates to compounds according to any of the formulas ['and I to IV or to any of the other classes and subclasses described above or to pharmaceutically acceptable salts thereof , where s is 0. 25 In another mode of execution groups R1, R ', R3, R', R ', R6, xl A1, X2, m, sep are those defined by groups R', R ', R', R ', R', R6, xI A1, X2, m, sep in the examples section below.
In another embodiment, individual compounds according to the invention are those listed in the examples section below or a pharmaceutically acceptable salt thereof. It will be appreciated that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood, therefore, that isomers resulting from such asymmetry (for example, all enanciomers and diastereomers) are included within the scope of this invention, unless otherwise indicated.
Such isomers can be obtained in substantially pure form by means of classical separation techniques and by stereochemically controlled synthesis.
In addition, the structures and other compounds and moieties discussed in this patent application also include all of their tautomers.
As used here, the term "isomers" refers to different compounds that have the same molecular formula but differ in the structure and arrangement of atoms.
Also as used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention and includes geometric isomers.
It is understood that a substituent may be attached to a chiral center of a "15 carbon atom.
Therefore, the invention includes enanciomers, diastereomers or racemates of the compound. "Enanciomers" are a pair of stereoisomers that are mirrorable images of themselves not overlapping.
A 1: 1 mixture of a pair of enanciomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers-20" are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other.
The absolute stereochemistry is specified according to the Cahn-ingold-Prelog R-S system.
When a compound is a pure enanciomer, the stereochemistry in each chiral carbon can be specified by either R or S.
Resolved compounds whose absolute configuration is unknown can be designated (") or (-) depending on the direction (dextrorotatory or levorotatory) in which they rotate the plane of polarized light on the wavelength of sodium line D.
Certain compounds described here contain one or more asymmetric centers or axes and therefore can give rise to enanciomers, diastereomers and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S). The present invention is intended to include all possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R) and (S) isomers can be prepared using chiral syntones or chiral reagents, or resolved using conventional techniques.
If the compound contains a double bond, the substituent can be an E or Z configuration.
If compound 5 contains a disubstituted cycloalkyl, the cycloalkyl substituent can have a cis or trans configuration.
It is also intended to include all tautomeric forms.
Any asymmetric atom (for example, carbon or the like) of the compound (s) of the present invention can be present in the racemic or enanciomerically enriched configuration, for example the (R) configuration, ( S) or (R, S). In certain embodiments, each asymmetric atom has at least 50 ° /) enanciomeric excess, at least 60 ° /) enanciomeric excess, at least 70 ° /, enanciomeric excess, at least 80 ° /) enanciomeric excess, at least minus 90 ° / 0 of excess enanciomeric, at least 95 ° / 0 of enanciomeric excess, or at least 99 ° /) of enanciomeric excess in the (R) or (S) configuration. Substituents in atoms with unsaturated bonds, if possible , may be present in cis- (Z) or trans- (E) form. Therefore, as used herein, a compound of the present invention may be in the form of a possible isomer, rotamer, atropisomer, tautomer or mixtures thereof, for example, as isomers (cis or trans) substantially geometrically pure, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any mixtures resulting from isomers can be separated, based on the physical-chemical differences of the constituents, in the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and / or fractional crystallization.
Any racemates resulting from final or intermediate products can be resolved in the optical antipodes by known processes, for example, by separating their diastereomeric salts, obtained with an optically active acid or base, and releasing the optically active compound or basic.
In particular, a basic portion can, therefore, be employed to resolve the compounds of the present invention in their optical anti-pruning, for example, by fractional crystallization of a salt formed with an optically active acid, for example, tartaric acid, dibenzoyl acid tartaric acid, diacetyl tartaric acid, di-O, O "-p-toluoyl tartaric, manellic acid, malic acid or camphor-1O — sulfonic acid.
Racemic products can also be resolved by chiral chromatography, for example, high pressure liquid chromatography (HPLC) using a chiral adsorbent.
As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological efficacy and properties of the compounds of this invention, and that are typically not biologically or otherwise undesirable.
In many cases, the compounds of the present invention are capable of forming acidic and / or basic salts by virtue of the presence of amino and / or carboxyl groups or groups similar to them. "15 Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, for example, acetates, aspartates, benzoates, besylates, bromides / hydrobromides, bicarbonates / carbonates, bisulfates / sulfates, camphor sulfonates, chlorides / hydrides, chloroteophilonates, citrates, ethanedisulfonates, fumarates, 20 gluceptates, gluconates, glucuronates, hypurates, hydroiodides / iodides, isethionates, lactates, lactobionates, laurylsulphates, malates, maleates, malonates, mandylates, mesylates, mandylates, mandylates, nanoates, napsylates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, palmoates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, 25 stearates, succinates, sulfosalicylates, tartrates, tartrates, tartrates, tartrates racetatos.
Inorganic acids from which salts can be derived include, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like. 30 Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, acid
tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. 5 Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper, particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium. 10 Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchanger resins, and the like.
Certain organic amines include isopropylamines, benzathines, cholinates, diethanolamines, "15 diethylamines, lysines, meglumines, piperazine and trometamines.
The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical processes.
Generally, such salts can be prepared by reacting free acid forms of these compounds which react with a stoichiometric amount of the appropriate base (such as hydroxides, carbonates, Na, Ca, Mg, or K bicarbonates or the like), or by reaction of the free base forms of these compounds with a stoichiometric amount of the appropriate acid.
Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
Generally, the use of non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, whenever possible.
Additional appropriate salt lists can be found, for example, in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in the "Handbook of Pharmaceutical Salts: Proper- 30 ties, Selection, and Use" by Stahl and Wermuth ( Niley-VCH, Weinheim, Germany, 2002). Any formula indicated here is also intended to represent unmarked forms as well as isotopically marked forms of compounds.
For example, any hydrogen represented by "H" in any of the formulas here is intended to represent all isotopic forms of hydrogen (eg 'H,' H or D, 'H); any carbon represented by
5 "C" in any of the formulas here is intended to represent all isotopic forms of carbon (eg '1ç,' 3C, "C); any nitrogen represented
sitting by "N" is intended to represent all forms of nitrogen (for example "N," N). Other examples of isotopes that are included in the
Conventions include isotopes of oxygen, sulfur, phosphorus, fluorine, iodine and chlorine, such as 18F 31p, 32p, 35S, 36C], 125j.
The invention includes various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes, such as 3H, 13ç, and 14ç are present.
In an execution mode, the atoms in the formulas here occur in their natural abundance.
In another embodiment, one or more hydrogen atoms "15 can be enriched in 2H; and / or one or more carbon atoms can be enriched in 11, 13, or 14C; and / or one or more nitrogen can be enriched. in 14N.
Such isotopically labeled compounds are useful in metabolic studies (with 14C), kinetic reaction studies (with, for example, 2H or 3H), detection or imaging techniques, such as tomography
20 by positron emission (PET) or single photon emission computed tomography (SPECT) including drug or tissue substrate distribution assays, or in radioactive treatment of patients.
In particular, an 18F or labeled compound may be particularly desirable for studying
PET or SPECT.
Isotopically labeled compounds of this invention and their prodrugs can generally be prepared by performing the procedures disclosed in the schemes or in the examples and preparations described below by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent.
In addition, enrichment with heavier isotopes, particularly deuterium (for example, 2H or D) may achieve certain therapeutic advantages resulting from increased metabolic stability, for example, in vivo life requirements or reduced dosage or an
the therapeutic index.
It is understood that deuterium in this context is considered as a substitute for a compound of formulas I to IV.
The concentration of such a heavier isotope, specifically deuterium, can be defined by the isotopic enrichment factor.
The term "isotopic enrichment factor" as used here means the ratio between the isotopic abundance and the natural abundance of a specific isotope.
If a substituent on a compound of this invention is called deuterium, that compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation 10 in each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5 ° / o incorporation deuterium), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), "15 at least 6466.7 (97 ° / o deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) The compounds of formulas I through IV isotopically enriched can generally be prepared by conventional techniques known 20 of those experts in the art or by processes analogous to those described in the attached examples and preparations using an appropriate isotopic enriched reagent in place of the previously unenriched reagent used. Pharmaceutically acceptable solvates according to the invention include those where the crystallization solvent can be isotopically substituted, for example, D2O, d6-acetone, d6-DMSO.
The compounds of the invention, for example, those compounds of formula l ', 1, ll, | j] or lV that contain groups capable of acting as hydrogen bonding donors and / or receptors, may be able to form 30 crystals with formers appropriate crystals.
Such cocrystals can be prepared from compounds of formula I ',], ll, III, IV or V by known cocrystal-forming procedures.
Such procedures include grinding, heating, cosublimation, co-fusion, or contact with the cocrystal former in soluble compounds of formula I ', I, ll, lll or lV under conditions of crystallization and isolation of the crystals thus formed.
Suitable cocrystal builders include those described in WO 2004/078163. Therefore, the invention further provides co-crystals comprising a compound of the formula I, II, II or IV, or pharmaceutically acceptable salts thereof.
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, consequents (eg 10 antibacterial agents, antifungal agents), isotonic agents, absorption, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, dyes and the like and combinations thereof, as would be known to those skilled in the subject "15 (see, for example , Remington's Pharmaceutical Sciences, 18th Ed.
Mack Printing Company, 1990, p. 1289-1329) - Except to the extent that any conventional vehicle is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is considered.
The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit an individual's biological or medical response, for example reduction or inhibition of an enzyme activity or a protein, or improvement of a symptom, alleviation of a condition, delay or delaying the progression of the disease, or prevention of a disease, etc. In a non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to an individual, is effective (1) to at least partially relieve, inhibit , avoid and / or ameliorate a condition, disorder or disease or symptom (i) ameliorated by inhibiting the activity of neutral endopeptidase EC 3.4. 24.11 or (ii) associated with the activity of neutral endo-peptidase EC 3.4. 24.11, or (iii) characterized by abnormal activity of neutral endopeptidase EC 3.4. 24.11; or (2) reduces or inhibits activity
of a neutral EC endopeptidase 3.4. 24.11; or (3) reduces or inhibits the expression of neutral EC endopeptidase 3.4. 24.11. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention which, when administered to a cell or tissue, or biological material non-cellular, or to a medium, is effective to at least partially reduce or inhibit the activity of neutral endopeptidase EC 3.4. 24.11; or at least partially reduce or inhibit the expression of neutral endopeptidase EC 3.4. 24.11 As used herein, the term "individual" refers to an animal.
Typically the animal is a mammal.
An individual also refers to, for example, primates (for example, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
In certain modes of execution, the individual is a primate.
In yet other modes of execution the individual is a human. "15 As used herein, the term" inhibit "," inhibition "or" inhibiting "refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the base activity of a biological activity or process.
As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in a mode of execution to the improvement of the disease or disorder (for example, decrease or stop or reducing the development of the disease or at least one of its clinical symptoms). In another mode of execution "treat", "treating" or "treatment" refers to the relief or improvement of at least one physical parameter, including those that may not be discernible by the patient.
In yet another mode of execution "treat", "treating" or "treatment" refers to the modulation of the disease or disorder, both physically, (for example, stabilization of a discernible symptom), physiologically, (for example , stabilization of a physical parameter), or both.
In yet another embodiment, "treating", "treating or" treatment "refers to preventing or delaying the onset or development or progression of the disease or disorder.
As employed here, an individual is "in need of" treatment if that individual would benefit biologically, in medical terms, or in quality of life, through such treatment.
As used herein, the terms "one," "one," "o / a" and similar terms used in the context of the present invention (especially in the context of the claims) should be considered to cover both the singular and plural, the unless otherwise indicated here or clearly contradicted by the context.
All of the methods described here can be performed in any appropriate order unless otherwise indicated here or otherwise are clearly contradicted by the context.
The use of any and all examples, or Language in the examples (for example, "as is") presented here is intended merely to better clarify the invention and does not represent an Limitation on the scope of the otherwise claimed invention. "15 The compounds of the present invention are obtained either in the free form, as a salt thereof, or as prodrugs derived therefrom.
When a basic group and an acid group are both present in the same molecule, the compounds of the present invention can also form internal salts, for example bipolar ion molecules. The present invention also provides prodrugs of the compounds of the present invention, which convert in vivo into the compounds of the present invention.
A prodrug is an active or inactive compound that is chemically modified through physiological action in vivo, such as hydrolysis, metabolism and the like, to form a compound of this invention, after administration of the prodrug to an individual.
The suitability and techniques involved in preparing and employing prodrugs are well known to those skilled in the art.
Prodrugs conceptually can be divided into two non-exclusive categories, bioprecursor prodrugs and transporter prodrugs.
See The Practice of Medicinal Chemistiy, ca- 30 chapters 31-32 (Ed.
Wermuth, Academic Press, San Diego, Calif., 2001). Generally, bioprecursor prodrugs are compounds that are inactive or have low activity compared to the pharmaceutical compound.
corresponding maco-active, which contains one or more protecting groups and is converted to an active form by metabolism or solvolysis.
Both drug-active forms and any released metabolic product should show acceptably low toxicity.
Transport prodrugs (carrier) 5 are compounds of drugs that contain a carrier portion, for example, that enhance absorption and / or localized delivery to a site (s) of action.
Desirably, for such a transport prodrug, the bond between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or is less active than the drug compound, and any transport moiety. loosened is acceptably non-toxic.
In prodrugs where increased absorption by the carrier portion is targeted, typically the release of the carrier portion should be rapid.
In other cases, it is desirable to use a group that exhibits slow release, for example certain polymers or other groups, such as "cyclodextrin".
Transport prodrugs, for example, can be used to improve one or more of the following properties: greater lipophilicity, longer duration of pharmacological effects, greater specificity, less toxicity and adverse reactions, and / or improvement in the formulation of drugs (eg stability, water solubility, suppression of an undesirable organoleptic or physicochemical property). For example, lipophilicity can be increased by esterifying (a) hydroxyl groups with lipophilic carboxylic acids (for example, a carboxylic acid containing at least a lipophilic moiety), or (b) groups of carboxylic acids with lipophilic alcohols (for example , an alcohol containing at least a lipophilic moiety, for example aliphatic alcohols). Prodrugs of the examples are, for example, esters of free carboxylic acids and S-acyl derived from thiols and O-acyl derived from alcohols or phenols, in which acyl has a meaning as defined herein.
Suitable prodrugs are usually derived from pharmaceutically acceptable esters convertible by solvolysis, under physiological conditions, into the parent carboxylic acid, for example, short chain alkyl esters, low cycloalkyl esters, short chain alkenyl esters, benzyl esters, mono-substituted or di-substituted short-chain alkyl esters, such as the uü- (amino, short-chain monoalkylamino or short-chain di-alkylamino, carboxy, short-chain alkoxycarbonyl) short-chain alkyl esters a- (short-chain alkanoyloxy, short-chain alkoxycarbonyl or short-chain di-alkylaminocarbonyl) short-chain chemicals, such as the pivaloyloxy methyl ester and the like conventionally employed in the art. In addition, amines have been masked as substituted derivatives of methyl arylcarbonyloxy which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundalold, J. Med. Chem. 2503 (1989)) - In addition , drugs containing an acidic NH group, such as imidazole, imide, indole and the like, were masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups were masked as esters and ethers. The EP
039.051 (Sloan and Little) discloses prodrugs of hydroxamic acid in Mannich's base "15, their preparation and use. In addition, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other- other solvents used for their crystallization General Synthetic Scheme: The compounds of the invention can be synthesized using the processes described in the following schemes, examples, and by employing techniques recognized in the art All compounds described herein are included in the invention as compounds. The compounds of the invention can be synthesized according to at least one of the processes described in the 25 schemes 1-3. Within the scope of this text, only a readily removable group that is not a constituent of the particularly desired end product of the compounds of the present invention a "protective group" is designated, unless the context indicates otherwise. The protection of functional groups by such 30 protective groups, the protective groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum
Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York
1999. Salts of the compounds of the present invention containing at least 5 a salt-forming group can be prepared in a properly known manner. For example, salts of compounds of the present invention containing acidic groups can be formed, for example, by treating the compounds with metallic compounds, such as alkali metal salts of appropriate organic carboxylic acids, for example, the sodium salt of acid 2 -ethylhexanoic, with organic compounds of alkali metal or alkaline earth metals, such as the corresponding carbonate hydroxides, carbonates or hydrogen, such as sodium or potassium hydroxides, carbonates or hydrogen carbonates, with corresponding calcium compounds either with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of the compounds of the present invention are obtained in the usual manner, for example , by treating the compounds with an acid or an appropriate anion exchange reagent. Internal salts of the compounds of the present invention contain 20 acid and basic salt-forming groups, for example, a free carboxy group and a free amino group, can be formed, for example, by neutralizing salts, such as acid addition salts, to the isoelectric point, P. ex. with weak bases, or by treatment with ion exchangers. Salts can be converted in the usual way to free compounds; metal and ammonia salts can be converted, for example, by treatment with appropriate acids, and acid addition salts, for example, by treatment with an appropriate basic agent. Mixtures of isomers obtainable according to the invention can be separated, in a properly known manner, into individual isomers; diastereoisomers can be separated, for example, by partitioning between mixtures of polyphasic solvents, recrystallization and / or chromatographic separation, for example in silica gel or for example, by medium pressure liquid chromatography, through a reverse phase column, and racemates can be separated, for example, by forming salts with optically pure salt-forming reagents and separating the mixture of diastereomers thus obtained, for example by means of fractional crystallization, or by chromatography of materials through an optically active column. Intermediates and final products can be worked and / or purified according to standard processes, for example, using chromatographic methods, distribution methods, (re-) crystallization, and the like. 10 The following applies in general to all processes mentioned here before and after.
All process steps mentioned above can be carried out under reaction conditions that are properly known, including those mentioned specifically, in the absence or normally in #
"15 presence of solvents or diluents, including, for example, solvents or diluents that are inert to the reagents used and dissolving them in the absence or presence of catalysts, condensing or neutralizing agents, for example, ion exchangers, such as cation exchangers, for example, in the H + form, depending on the nature of the reaction and / or the reagents at a reduced, normal or elevated temperature, for example in a temperature range of approximately -100 ° C to approximately 190 ° C, including, for example, from approximately -80 ° C to approximately 150 ° C, for example from -80 to -60 ° C, at room temperature, from -20 to 40 ° C or at reflux temperature , under atmospheric pressure or in a closed vessel, if appropriate under pressure, and / or under an inert atmosphere, for example under an atmosphere of argon or nitrogen.
At all stages of the reactions, mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enanciomers, or in any desired mixtures
30 isomers, for example analogously to the processes described under "Additional process steps". The solvents, from which those solvents that are
suitable for any particular reaction can be selected, include those specifically mentioned or, for example, water, esters, such as aliphatic esters, for example diethyl ether or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, 5 such as benzene or toluene, alcohols such as methanol, ethanol or 1-propanol or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamides or dimethyl acetamides , bases, such as heterocyclic nitrogen bases, for example pyridines or N-methylpyrrolidin-2-one,
10 carboxylic acid anhydrides, such as alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methylcyclohexane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated otherwise in the description of the processes.
Such solvent mixtures can also be employed in processing, for example, by chromatography or partition.
The compounds, including their salts, can also be obtained in the form of hydrates, or their crystals, for example, include the solvent used for crystallization.
Different crystalline forms may be present.
The invention also relates to those process forms in which a compound obtainable as an intermediate at any stage of the process is employed as a starting material and the remaining process steps are carried out, or in which a starting material is
25 formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is prepared under the conditions of the process and subsequently processed in situ.
All starting materials, building blocks, reagents, 30 acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are either commercially available or can be prepared by processes of organic synthesis known to those with common knowledge in the art (Houben-Weil 4 "ed. 1952, Methods of Organic Synthesis, Thieme publisher, volume 21). Typically, compounds according to formulas I through IV can be prepared according to the schemes of 1 up to 7 provided
5 below.
The inventive compounds of formulas I 'or 1 where X1 is hydroxy can be prepared by hydrolysis of intermediates A where A', R ', R2, R3, R' and m have the definition of formula I 'or I, supra; and P 'is an appropriate protecting group selected from, but not limited to, methyl, ethyl, or tert-butyl,
10 or benzyl methoxy, or benzyl. o r '(j p'g, ^ rÁ> A, iA' ~ ,,
a k I r ', (r3,
i ~ & "
Intermediate A L ~ / T (R5m
Standard processes can be applied for the hydrolysis of intermediate A using a base selected, but not limited to, Na-OH, KOH, or L1OH, or an acid selected from, but not limited to, TFA,
15 HCl, or BC | 3. When P 'is benzyl or methoxy benzyl, a preferable deprotection process is hydrogenation in the presence of a catalyst such as, but not limited to, palladium-on-carbon.
In some cases, hydrolysis of intermediate A is not required; for example when intermediate A is a compound of the invention of
Formula I 'or 1 where X' is O-alkyl.
Scheme 1 illustrates the synthesis of intermediate A.
Intermediate A can be prepared according to the following general procedures described in scheme 1, where A1, p1, R ', R2, R', R ', R5, R6, S and m are as previously defined. 25
Figure 1 of R '0 Ayjloh,, N ,, ,, rÀrjL °', Rx bgD "fl (Mh» htermediate 2A K ^ w ', m ,, m ,,,) r "k Intermediate 1 A Step 2a Q O
O ,,, Jíf í ° ,, '"° jr'or" OY hÍ yÀqj à' l (Êh htermediate 6A htermediate 6EI ML
C Stage 3a Intermediate 5A Ç} "" K I> 'L HY ^ <R' Intermediate 4A Step 4 & R 'Intermediate 7A
T> hintermediate A In step la, intermediate 3A can be prepared by cross-coupling of intermediate 1A where p2 is an appropriate protecting group selected from, but not limited to, t-butoxycarbonyl, benzyloxycarbonyl, f | uoreni] meti | oxycarbonyl, benzyl, or methoxy benzyl and where L gl is a starting group selected from, but not limited to, haio (eg, bromine, chlorine, or iodine) or trit1uormethanesulfonyloxy with an intermediate 2A where R2 in are as previously described and where BG is an appropriate AO group selected from, but not limited to, boronic acid, trifluorborate or boronic ester. Known binding methods can be applied including Suzuki-Miyaura binding of intermediates 1A with intermediate 2A using palladium species such as, but not limited to, Pd (PPh3) 4, PdC | 2 (dppf), Pd (PPh3) 2C | 2, or Pd (OAc) 2 with a phosphine linker such as P-15 Ph3, dppf, pcy3, or P (t-Bu) 3 and a base such as, but not limited to, Na2CO3, K3PO4, K2CO3, KF, CSF, NaO-t-8u, or KO-t-8u. In step 2a, intermediate 4A can be prepared by appropriately protecting an intermediate 3A where p3 is a protecting group such as, but not limited to, t-butyl, methyl, benzyl, fluorenylmethyl, allyl or 20 benzyl methoxy; followed by an appropriate deprotection of the group P '.
In step 3a, intermediate 5A can be prepared by reacting an intermediate 4A, where R2, R5, R6, s, m, and p3 are as previously defined, with an intermediate 6A, where R 'and P' are as previously defined above and where Lg2 is a starting group selected from, but not limited to, trifluoromethanesulfonyloxy, toluenesulfonyloxy, methanesulfonyloxy, iodine, bromine, and chlorine, followed by deprotection of p3 using an appropriate method. Alternatively, intermediates 5A can be prepared by reacting an intermediate 4A with an intermediate 6B, where R 'and p1 are as defined above, followed by deprotection of p3 using an appropriate process. Known binding processes can be applied, including the alkylation of intermediate 4A to intermediate 6A using a base such as, but not limited to, tertiary amines (e.g. triethylamine or / V, N-diisopropyl ethylamine), pyridine , or K2CO3; or reducing amination condition of intermediate 4A with intermediate 6B, under condition such
W "15 that hydrogenation is carried out in the presence of a catalyst such as palladium-on-carbon or reduction employing a reducing reagent (eg, NaBH4, NaBH (OAc) 3, or NaBH3CN) in the presence of or in the absence of an acid such as acetic acid, TFA, or Ti (i-PrO) 4. In step 4a, intermediate A can be prepared by binding 20 of an intermediate 5A, where p ', R1, R2, R', R6 , without being as previously described, with an intermediate 7A, where A ', R3, and R' are previously described. Known bonding processes can be applied including, but not limited to, conversion of intermediate 5A into a corresponding oxazolidine-2,5-dione, employing reagents, such as triphosgene, 25-carbonyldiimidazole, 4-nitrophenyl chloroformate, or disuccinimidyl carbonate, conversion of intermediate 5A into a corresponding acid halide, using reagents, such as thionyl chloride or oxalyl chloride, or conversion of intermediate 5A to a mixed anhydride with corresponding using reagents such as ClC (O) O-isobutyl, 2,4,6-30 trichlorobenzoyl chloride or cyclic trimer of phosphonic acid propyl anhydride (T3P), followed by reaction of oxazolidine-2,5-dione, acid halide, or anhydrides mixed with intermediate 7A in the presence or absence of a base such as tertiary amine (e.g. triethylamine or NjV-diisopropyl ethylamine) or K2CO3. Alternatively, intermediate 5A can be linked to intermediate 7A using peptide condensing reagents including, but not limited to, dicyclohexylcarbodiimides (DCC), diisopropylcarbodiimides 5 (DlC), 1-etik3- (3- dimethylaminopropyl) carbodiimides (EDC H-Cl), benzotriazola-1-ikoxy-tris-pyrrolidine-phosphonium hexafluorphosphate (Py-BOP), or benzotrjazole-1-i | -oxy-tris- (dimethi | amino) hexafluorophosphate - phosphonium (BOP) in the presence of or in the absence of a reagent, such as 1-hydroxybenzotriazola, 1-hydroxy-7-azabenzotriazola, or dimethylaminopyridine. Scheme 2 illustrates the synthesis of intermediates 5A. Intermediate 5A can also be prepared according to the following procedures described in Scheme 2 where BG, L gl, L g2, p1, p3, R1, R2, and m are as previously defined. Layout 2
GC) 0 d O 'Uly ^': "" oay '° 0 R' 0 hÁyjLo- 'R' N "OYtL: ', Wj $ R% hitermediate 6a Intermediate 6b LG' Stage lb kitermediate 3a <^ - W ltermediate 8A "Y> z poYj> ,, htermediate 2a R 'I (n Step 2b htermediate 5a" I l} 1R'j! IN 15 In step lb, intermediate 9A can be prepared by reacting an intermediate 8A, where in Lg1, R5, R6, if p3 are previously described, with an intermediate 6A, in which R1, p1, and LG 'are as previously described, followed by an appropriate deprotection of the protective group p3.
Alternatively, intermediates 9A can be prepared by reacting an intermediate 8A with an intermediate 6B where p1 and R1 are as previously described, followed by an appropriate deprotection of the protecting group.
tor p3. Known reaction processes can be applied including the alkylation of intermediate 8A with intermediate 6A using a base such as, but not limited to, tertiary amines (e.g., triethylamines or N, N-diisopropyl ethylamines), pyridines, or K2CO3 , or reducing amination condition of intermediate 8A with intermediate 6B, under condition such as hydrogenation in the presence of a catalyst such as palladium-on-carbon or reduction employing a reducing agent (eg, Na-BH4, NaBH (OAc) 3, or NaBH3CN) in the presence of or in the absence of an acid such as acetic acid, TFA, or Ti (i-PrO) 4. In step 2b, intermediate 5A can be prepared by cross-linking an intermediate 9A where L gl, p1, R5, R6, R 's, with an intermediate 2A, where BG, m, and R2 are as previously described .
Known binding processes can be applied including linking Suzuki-Miyaura intermediate 9A with intermediate 2A employing species of W "
"15 palladium such as, but not limited to, Pd (PPh,) 4, PdC | 2 (dppf), or Pd (OAc) 2 with a phosphine linker such as PPhm dppf, PCy3, or P (t-Bu) 3 and a base, such as, but not limited to, Na2CO3, K3PO4, K2CO3, KF, CSF, NaO-t-8u, or KO-t-8u.
Intermediates 9A can also be prepared according to the following general procedure described in Scheme 3, where L G ', p1, p3, R5, R6, R1 and s are as previously described.
Figure 3 0 C) R 'O% YÁ,, PP ,, ,, "" ~ yAoh m + ">, Ayjh Steplc b fj' t! R%
t,;, ,,, "Mermediate 1W Intermediate 11A Intermediate M, <^ - ,,, In step lc, intermediate 9A can be prepared by reducing amination of intermediate IOA where L G ', R6, if p3 are as previously described with intermediate 11A where p ', R5 and R' are as previously
Known reducing amination processes can be applied including a condition such as, but not limited to, hydrogenation in the presence of a catalyst such as palladium-on-carbon or reduction employing a reagent such as, but not limited to, NaBH4 , Na-BH (OAc) 3, or NaBH3CN in the presence of or in the absence of an acid such as acetic acid, TFA, or Ti (i-PrO) 4. The IOA intermediary can be prepared according to the reported procedure. The illustrative example of this chemistry is outlined in WO 2006015885.
Intermediate 5A can also be prepared according to the following general procedures described in Scheme 4, where m, p1, p3, R1, and R2 are as previously described.
10 Scheme 4 fl OR 'O, rt' 0d "" ~ 'Joh "I" ")' _ +" , JJJ '^ P "" I (")' µ i ~ L r 'lrdermediary 5a" A <1 ^ Á ·
W - I ~ 7j (Fi'k lritermediate 1 ia lL = a R "k htermediate 12A In step ld, intermediate 5A can be prepared by reducing amination of intermediate 12A, where m, p3, R ', R', S, m and R2 are as previously described with intermediate 11A, where p1, R5 and R1 are as previously described 15. Known reducing amination processes can be applied including a condition such as, but not limited to, hydrogenation in the presence of a catalyst such as palladium-on-carbon or reduction using a reagent such as, but not limited to, NaBH4, NaBH (OAc) 3, or NaBH3CN in the presence or absence of an acid such as acetic acid, TFA, or Ti (i-PrO) 4. Intermediates 12A can be prepared according to the reported procedure The illustrative example of this chemistry is outlined in WO 2006015885.
Intermediate A can also be prepared according to the following general procedures described in scheme 5, where A1, L g2, 25 p1, p ', R', R2, R3, R ', R', R6, without being as previously described.
Figure 5 d 0 Hn "<r3 R '0
, .AJ ',, k h4yA, A- ,. (R% htermediate 7a, Út m "sEj Stage le l +« 'L l, dermediá ,,, ,, A I 31 "L Hermediário 3a I q o">) Ayj ",," "oAt ° ° Stage &
R 'fi' htermediate 6A htermediate 6b C) R 'O
'"b'rt ::,' Intermediate to i ~
+
In step 1, intermediate 13A can be prepared by linking intermediate 3A with intermediate 7A.
Known binding processes can be applied including, but not limited to, the conversion of intermediate 3A to the corresponding oxazolidine-2,5-dione, using reagents such as triphosgene, carbonyldiimidazole, nitrophenyl 4-chloroformate , or disuccinimidyl carbonate, conversion of intermediate 3A to a corresponding acid halide, using reagents such as thionyl chloride or oxalyl chloride, or conversion of intermediate 3A to a corresponding mixed anhydride using reagents such as ClC chloride (O ) O-isobutyl or 2,4,6-trichlorobenzoyl, followed by reaction of oxazolidine-2,5-dione, acid halide, or mixed anhydride with intermediate 7A in the presence or absence of a base such as tertiary amine (eg, triethylamine or 15 N, N-diisoproplil ethylamine) or K2CO3 and an appropriate deprotection of the p2 protection group. Alternatively, intermediate 3A can be linked with intermediate 7A using peptide condensing reagents including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodimide (DlC), 1-ethyl-3- hydrochloride ( 3-dimethylaminopropyl) carbodiimide 20 (EDC HCl), benzotriazolaj-ikoxy-tris-pyrrolidine-phosphonium hexafluorophosphate
(Py8OP), or benzotriazola-1-ikoxy-tris- (dimethylamino) -phosphonium (BOP) hexafluorphosphate in the presence or absence of a reagent such as 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, or dimethylaminopyridine followed by a deprethylamine protection group P '.
5 In step 2e, intermediate A can be prepared by reacting an intermediate 13A with an intermediate 6A, where L G 'is as previously described. Alternatively, intermediates A can be prepared by reacting an intermediate 13A with an intermediate 6B. Known reaction processes can be applied, including alkylation of an intermediate 13A with an intermediate 6A employing a base such as, but not limited to, tertiary amine (eg, triethylamine or N, N-diisopropyl ethylamine), pyridine, or K2CO3 or reducing amination of intermediate 13A with intermediate 6B under a condition such as, but not limited to hydrogenation in the presence of a catalyst such as palladium-on-. "15 carbon or reduction employing a reagent such as, but not limited to, NaBH4, NaBH (OAc) 3, or NaBH3CN in the presence of or absence of an acid such as acetic acid, TFA, or Ti (i-PrO) 4. Intermediates A can also be prepared according to the following procedures described in scheme 6, where A1, BG, L gl, 20 p1, R1, R2, R3, R4, R5, R6, are as previously described. '0 | HN "<R' O, R 'O," OLrjY <h "> A ^ AN-" Ra R' L. ^, Ç in intermediate 7a W r '' I! ' The Step If lrdermediá, "om <- ^, G 'htermediate 14A ÇÀ, G' 'G" I "! F«' k Et, pa 2F htermediate 2A 0 R 'O' "t'tL: R: i iil1R ' L literary A
In step lf, an intermediate 14A can be prepared by connecting intermediate 9A, where L G ', P', R ', R6, m, s and R1 are as previously
described, with an intermediate 7A.
Known binding methods can be applied including, but not limited to, conversion of intermediate 9A to a corresponding oxazolidine-2,5-dione, using reagents such as triphosgene, carbonyldiimidazole, 4-nitrophenyl chloroformate, or carbonate of disuccinimidyl, conversion of intermediate 9A to a corresponding acid halide, using reagents such as thionyl chloride or oxalyl chloride, or conversion of intermediate 9A to a corresponding mixed anhydride, using reagents such as ClC (O) O- isobutyl or 2,4,6-trichlorobenzoyl, followed by reaction of oxazolidine-2,5-dione, acid halide, or mixed anhydride with intermediate 7A in the presence or "" absence of a base such as tertiary amines (eg example, triethylamine
4 or N, / V-diisoproplil ethylamine) or K2CO3. Alternatively, intermediate 9A ~
"15 may be linked with intermediate 7A employing peptide condensing reagents including, but not limited to, dicyclohexylcarbodimide (DCC), diisopropylcarbodiimide (DlC), 1-ethyl-3- (3-dimethiHaminopropyl hydrochloride) ) carbodiimide (EDC HCl), benzotriazole-1-ikoxy-tris-pyrrolidine-phosphonium hexafluorphosphate (Py8OP), or benzo-20 triazole-1-ikoxy-tris- (dimethylamino) -phosphonium (BOP) hexafluorophosphate (BOP) in the presence of or absence of a reagent such as 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazola, or dimethylaminopyridine.
In step 2f, intermediate A can be prepared by cross-linking an intermediate 14 A, where A ', L gl, p', R ', R3, R5, R6, m, s and R'
25 are as previously described, with an intermediate 2A, where R ', m, and BG are as previously described.
Known binding methods can be applied including Suzuki-Miyaura binding of intermediate 14A with intermediate 2A employing palladium species such as, but not limited to, Pd (PPh3) 4, PdC | 2 (dppf), or Pd ( OAc) 2 with a phosphine linker such as P-30 Ph3, dppf, PCy3, or P (t-Bu) 3 and a base such as, but not limited to, Na, CO3, K3PO4, K2CO3, KF, CSF, NaO -t-8u, or KO-t-8u.
Intermediates 14A can also be prepared according to the following procedures described in scheme 7, where A1, L gl, L g2, p1, p ', R', R ', R', R ', R', R6, without are as previously described.
Figure 7 R '0 Rb q hn "Gr' p2jYjL0h, m, Á 'lrdermediário 7a Step lg" at :::' K ^ lg '<^ LG' htermediário 1a lrdermediário 15a "" 4 "'0 ·'" ° JLj ; °, O> JjJ '° ,, N, ,, lritermediário 6A htermediario 6B R' FÍ ', (R'J b Step 2g Hl intermediate 14a ~ 1 lg', 5 In step lg, an intermediate 15A can be prepared by Bonding of intermediate 1A, where P ', R', R ', if L gl are as previously described, with intermediate 7A, where A {R3, and R4 are as previously described, followed by an appropriate deprotection of the group protection methods P ', known binding methods can be applied including, but not limited to, the conversion of intermediate 1A to a corresponding oxazolidine-2,5-dione, using reagents such as triphosgene, carbonyldiimidazole, 4- nitrophenyl chloroformate, or disuccinimidyl carbonate, conversion of intermediate 1A to a corresponding acid halide, using reagents such as thionyl chloride or oxalyl chloride, or conversion of intermediate 1A to an corresponding mixed oxide using reagents such as ClC (O) O-isobutyl or 2,4,6-trichlorobenzoyl chloride, followed by reaction of oxazolidine-2,5-dione, acid halide, or mixed anhydride with the medium 7A in the presence or absence of a base such as tertiary amines (for example, triethylamine or N, N-diisoproplyl ethylamine) or K2CO3. Alter natively, intermediate 1A can be linked to intermediate 7A using peptide condensing reagents including, but not limited to, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DlC), 1-etii hydrochloride -3- (3-dimethiHaminopropyl) carbodiimide (EDC HCl), hexafluorophosphates-
benzotriazola-1-ikoxy-tris-pyrrolidine-phosphonium (Py8OP), or hexafluorphos-benzotriazola-1-yl-oxy-tris- (dimethylamino) -phosphonium (BOP) in the presence of or absence of a reagent such as 1-hydroxybenzotriazola, 1-hydroxy-7-azabenzotriazola, or dimethylaminopyridine. 5 In step 2g, intermediate 14A can be prepared by reacting an intermediate 15 A, where A1, L gl, R3, R5, R6, if R 'are as previously defined, with an intermediate 6A, where R1, p1 , and L g2 are as previously defined.
Alternatively, intermediates 14A can be prepared by reacting an intermediate 15A, where A ', L gl, R3, R5, R6, s and R4
10 are as previously defined, with an intermediate 6B, where R1 and p1 are as previously described.
Known reaction processes can be applied including the alkylation of intermediate 15A to intermediate 6A using a base such as, but not limited to, tertiary amine (for example, triethylamine or N, N-diisopropyl ethylamine), pyridine, or K2CO3 or amination +
"15 reducing from intermediate 15A to intermediate 6B under a condition such as, but not limited to, hydrogenation in the presence of a catalyst such as palladium-on-carbon or reduction employing a reagent such as, but not limited to, NaBH4, NaBH (OAc) 3, or NaBH3CN in the presence of or absence of an acid such as acetic acid, TFA, or Ti (i-PrO) 4. 20 The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage of it is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are employed in the form of their optically pure salts or antipodes.
The compounds of the invention and intermediates can also be converted to one another according to processes generally known to those skilled in the art.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers.
The pharmaceutical composition can be formulated for particular routes of administration, such as oral administration, parenteral administration, and rectal administration, etc.
In addition, the pharmaceutical compositions of the present invention can be prepared in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations, such as sterilization and / or may contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, wetting agents, emulsifiers and buffering agents, etc.
Typically, pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; «" 15 b) Lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene |; for tablets also C) binders, for example, magnesium aluminum silicates, paste starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or po | ivini | pyrrho | idone; if desired 20 d) disintegrants, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbers, dyes, flavors and sweeteners - Tablets can either be a coated film or enteric film according to the processes known in the art 25 Compositions suitable for administration now include an effective amount of a compound of the invention in the form of tablets, pastilles, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use are prepared according to any process known in the art for the preparation of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents
preservatives to provide pharmaceutically elegant and tasty preparations. Tablets can contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the preparation of tablets. Such excipients are, for example, 5 inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated 10 by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period of time. For example, a delayed release material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be presented as cap- "15 hard gelatin capsules where the active ingredient is mixed with a solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, where the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.20 Certain injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from emulsions or fatty suspensions. Said compositions can be sterilized and / or contain adjuvants, such as preservatives, stabilizers, humectants or emulsifying agents, solution promoters, salts to regulate osmotic pressure and / or buffering agents. they may contain other therapeutically valuable substances. These compositions are prepared according to conventional mixing, granulating or coating processes, r expectantly, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
Compositions suitable for transdermal application include an effective amount of a compound of the invention with a suitable vehicle. Suitable vehicles for transdermal delivery include pharmacologically acceptable absorbable solvents to assist passage through the host's skin.
For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the host's skin at a rate controlled and pre-determined for an extended period of time, and means for securing the device to the skin.
Compositions suitable for topical application, for example, to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, for example, for delivery by aerosol or the like.
Such topical delivery systems will in particular be suitable for dermal application.
They are therefore particularly suitable for use in topical formulations, including cosmetic formulations, well known in the art.
Such systems may contain solubilizers, stabilizers, tonicity-raising agents, buffering agents and preservatives.
As used here, a topical application can also refer to an inhalation application or an intranasal application.
They can conveniently be supplied in the form of a dry powder (either alone or in a mixture, for example a dry mixture with lactose, or as a particle with a mixed component, for example with phospholipids) from a dry powder inhaler or a aerosol spray presentation of a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of an appropriate propellant.
The present invention further provides anhydrous pharmaceutical compositions and dosage forms that comprise the compounds of the present invention as active ingredients, since water can facilitate the degradation of certain compounds.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous ingredients or containing low humidity or low humidity conditions.
An anhydrous pharmaceutical composition can be prepared and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are packaged using known materials to avoid exposure to water, so that they can be included in appropriate formula kits.
Examples of appropriate packaging include, but are not limited to, hermetically sealed films, plastics, unit dose containers (eg vials), blister packs, and strip packs. The invention further relates to pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate at which the compound of the present invention will decompose as an active ingredient.
Such agents, which are referred to herein as "stabilizers", include, but are not limited to, antioxidants, such as ascorbic acid, pH buffers, or saline buffers, etc. "15 The compounds according to any one of formulas I to IV, or pharmaceutically acceptable salts thereof, in free form or in the form of pharmaceutically acceptable salt, exhibit valuable pharmacological properties, for example, modulating properties of the neutral endopeptidase EC 3.4 24.11, for example, as indicated in in vitro and in vivo testing as provided in the following sections, and are therefore indicated for therapy.
The compounds of the invention or pharmaceutically acceptable salts thereof, may be useful in the treatment of a selected indication of hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal failure (diabetic or non-diabetic), renal failure (including edema and salt retention), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma , glomerular sclerosis, primary renal disease proteinurea, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diaphragmatic cardiac myopathy
betic, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial fluoride, harmful vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), kidney failure (including edema and salt retention), cyclic edema, Meniere's disease, hyperaldosteronism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, premature labor, preeclampsia, endometriosis, and reproductive disorders (especially infertility male and female, polycystic ovary syndrome, implant failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition, such as dementia and geriatric confusion , obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure ulcers), septic shock, dysfunction of gastric acid secretion, hyperreninemia, fibrosis
"15 cystic, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and atherosclerosis, male and female sexual dysfunction.
Therefore, as another embodiment, the present invention provides the use of a compound of formula I ', I, ll, | j or lV, or pharmaceutically acceptable salts thereof.
In another mode of execution, therapy is selected from a disease that is associated with neutral endopeptidase activity EC 3.4. 24.11. In another mode of execution, the disease is selected from the previously mentioned list, appropriately hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure , left ventricular hypertrophy, angina, renal failure, renal failure (including edema and salt retention), diabetic nephropathy, non-diabetic nephropathy, type-2 diabetes, and diabetic complications and more appropriately cardiovascular disorders, such as hypertension , renal failure including edema and congestive heart failure. Therefore, as another embodiment, the present invention provides the use of a compound of the formulas I 'I, |, Ili or lV, or pharmaceutically acceptable salts thereof, in therapy.
In another embodiment, therapy is selected from a disease that can be treated by inhibiting the activity of neutral EC endopeptidase. 3.4. 24.11. In another embodiment, the invention provides a method of pretreating a disease that is associated with EC 3.4 neutral endopeptidase activity. 24.11 comprising administering a therapeutically acceptable amount of a compound of the formula I ', I, II, II or IV, or pharmaceutically acceptable salts thereof.
In another mode of execution, the disease is selected from the previously mentioned list, appropriately hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure, hypertrophy left ventricular, angina, renal failure, renal failure (including edema and salt retention), diabetic nephropathy, non-diabetic nephropathy, type-2 diabetes, and diabetic complications and more appropriately cardiac disorders
"15 vascular diseases, such as hypertension, renal failure including edema and congestive heart failure.
The pharmaceutical composition or combination of the present invention can be in a dosage unit of approximately 1-1000 mg of active ingredient (s) for an individual of approximately 50-70 kg, 20 or approximately 1-500 mg, or approximately 1-250 mg, or approximately 1-150 mg or approximately 0.5-100 mg, or approximately 1-50 mg of the active ingredients.
The therapeutically effective dosage of a compound, the pharmaceutical composition or its combinations, is dependent on the species of individual, body weight, age, and individual condition, the disorder or disease or the severity of it being treated .
A general practitioner, doctor or veterinarian of normal knowledge can readily determine the effective amount of each active ingredient needed to prevent, treat or inhibit the progress of the disorder or disease.
The pharmaceutical composition or combination of the present invention can be in a single dosage of approximately 1-1000 mg of active ingredient (s) for an individual of approximately 50-70 kg, or approximately 1-500 or approximately 1-250 mg, or approximately
te 1-150 mg or approximately 0.5-100 mg, or approximately 1-50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or combinations thereof, is dependent on the species of the individual being treated, the body weight, age and condition of the individual, 5 of the disorder or its severity. A general practitioner, doctor or veterinarian of normal knowledge can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease. The properties of the aforementioned dosages are demonstrable in tests in vitro and in vivo using advantageously mammals, for example, mice, rats, dogs, monkeys or isolated organs, tissues and their preparations. The compounds of the present invention can be applied in vitro in the form of solutions, for example, aqueous solutions and, in vivo both internally, parenterally, advantageously intravenously, for example, "15 as a suspension or in aqueous solution. Dosage in in vitro can vary between approximately 10 "3 molar and 10" 9 molar concentrations. A therapeutically effective amount in vivo can vary, depending on the route of administration, between about 0.1-500 mg / kg, or between about 1-100 mg / kg The activity of a compound according to the present invention 20 can be assessed by the following in vitro & in vivo methods and / or by the following in vitro & in vivo methods well described in the art. "A fluorescence lifetime-based assay for protease inhibitor profiling on human kallikrein 7" ("An assay based on the fluorescence lifetime of the protease inhibitor profile on human kallikrein 7") Doering K, Meder G, Hinnenber - 25 ger M, Woelcke J, Mayr LM, Hassiepen UB iomol Screen. 2009 Jan; 14 (1): 1-
9. In particular, the in vitro inhibition of recombinant human neutral endopeptidase (NEP, EC 3.4.24.11) can be determined as follows: Recombinant human neutral endopeptidase (expressed in insect cells and purified using standard processes , final concentration 7 pM) is pre-incubated with test compounds in various concentrations for 1 hour at room temperature in 10 mM sodium phosphate buffer at pH 7.4, containing 150 mM NaCl and 0.05 ° CHAPS) () p / v). The enzymatic reaction is initiated by adding a synthetic peptide substrate Cys (PT14) -Arg-Arg-Leu-Trp-OH to a final concentration of 0.7 µM. The substrate hydrolysis leads to an increase in fluorescence life (FLT) of 5 PT14 measured by means of an FLT reader as described by Doering et al. (2009). The effect of the compound on enzyme activity was determined after 1 hour (t = 60 min) of incubation at room temperature. The lC50 values, corresponding to the inhibitor concentration showing a 50 ° 6 reduction of the FLT values measured in the absence of inhibitor, are calculated from 10 of the percentage vs. inhibition plot. inhibitor concentration using non-linear regression analysis software. Using the test assay (as described above) the compounds of the invention exhibited inhibitory efficacy according to Table 1, provided below.
- 15 Table 1 Inhibitory activity of Compound Compounds: Example NI Human NEP] C5o (nM) Example 3-1 I 0.09 Example 3-2 0.3 Example 3-4 11 Example 3-7 2.4 Example 3-10 I Example 3-12 0.2 Example 3 13 0.2 The compound of the present invention can be administered either simultaneously with, or before, or after, one or more other therapeutic agents. The compound of the present invention can be administered separately, by the same or different route of administration, or together with the same pharmaceutical composition with the other agents. In one embodiment, the invention provides a product that comprises a compound of the formulas I ', I, |, | or IV, or pharmaceutically acceptable salts thereof, and at least one other therapeutic agent as a combined preparation for use in simultaneous, separate or sequential therapy. In one embodiment, therapy is the treatment of a disease or condition associated with EC neutral endopeptidase activity
3.4. 24.11. Products supplied as a combined preparation include a composition comprising the compound of the formula I ', I, Il, II or IV, or 5 pharmaceutically acceptable salts thereof, and O (S) other therapeutic agent (s) ) together (s) in the same pharmaceutical composition, or the compound of formula I ', I, ll, Ill or IV, or pharmaceutically acceptable salts thereof, and the other therapeutic agent (s) ( s) separately, for example, in the form of a kit. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula I ', I, ll, ll or IV, or pharmaceutically acceptable salts thereof, and other therapeutic agent (s) ). Optionally, the pharmaceutical composition can comprise a pharmaceutically acceptable excipient, as described above.
- 15 In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the formula I ', I, Il, | or lV, or pharmaceutically acceptable salts thereof. In an embodiment, the kit comprises means for separately retaining said compositions, such as a container, a divided bottle, or a divided plastic package. An example of such a kit is a blister pack, as typically used for packaging tablets, capsules and the like. The kit of the invention can be used for administration of different dosage forms, for example, oral and parenteral, for administration of the separate compositions at different dosage intervals, or for titration of the compositions separated from each other. To support compliance, the kit of the invention typically comprises instructions for administration. In the combination therapies of the invention, the compound of the invention and the other therapeutic agent can be prepared and / or formulated by the same or different manufacturers. In addition, the compound of the invention and the other therapeutic can be combined into a combination therapy: (i)
before releasing the combination product to clinicians (e.g., in the case of a kit comprising compound A of the invention and the other therapeutic agent); (ii) by the clinicians themselves (or under the clinician's guidance) just before administration; (iii) the patients themselves, for example ,. during sequential administration of the compound of the invention and the other therapeutic agent. Accordingly, the invention provides the use of a compound of formula I ', I, ll, | or lV, or pharmaceutically acceptable salts thereof, for the treatment of a disease or condition associated with the activity of neutral endopeptidase EC 3.4. 24.11, where the medication is prepared for administration with another therapeutic agent. The invention also provides for the use of another therapeutic agent to treat a disease or condition associated with neutral endopeptidase EC 3.4. 24.11, where the drug is administered with a compound of formula I ', I, ll, j | "15 or lV, or pharmaceutically acceptable salts thereof. The invention also provides a compound of formula I ', I, lll, lll or lV, or pharmaceutically acceptable salts thereof, for use in a method of treating a disease or condition associated with the activity of neutral endopeptidase EC 3.4.24.11, where the compound of formula I ', I, Il, lll 20 or lV, or pharmaceutically acceptable salts thereof, is prepared for administration with another therapeutic agent.The invention also provides another agent therapeutic for use in a treatment process of a disease or condition associated with the activity of neutral endopeptidase EC 3.4.
24.11, where the other therapeutic agent is prepared for administration with a compound of formula I ', I, ll, ll or lV, or pharmaceutically acceptable salts thereof. The invention also provides a compound of formula I ', I, Il, j |, or lV, or pharmaceutically acceptable salts thereof, for use in a process of treating a disease or condition associated with neutral EC endopeptidase activity. 3.4. 24.11, where the compound of formula I ', I, ll, | or IV, or pharmaceutically acceptable salts thereof, is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease.
disease or condition associated with neutral endopeptidase activity EC 3.4.
24.11, where the other therapeutic agent is administered with a compound of the formula r, I, li, lll or lV, or pharmaceutically acceptable salts thereof. The invention also provides for the use of a compound of the formula I ', I, ll, II or IV, or pharmaceutically acceptable salts thereof, to treat a disease or condition associated with the neutral endopeptidase EC 3.4 activity. 24.11, where the patient has previously been treated (for example, in the course of 24 hours) with another therapeutic agent. The invention also provides the use of another therapeutic agent to treat a disease or condition associated with the activity of neutral endopeptidase EC 3.4. 24.11, where the patient has previously been treated (for example, in the course of 24 hours) with a compound of the formula I ', I, ll, ll or IV, or pharmaceutically acceptable salts thereof. In one embodiment, the other therapeutic agent is selected from: In one embodiment, the other therapeutic agent is selected from: HMG-CO-A reductase inhibitor, an angiotensin receptor blocker (ARBS, angiotensin ll receptor antagonist), angiotensin converting enzyme (ACE) inhibitor, calcium channel blocker (CCB), endothelin antagonist, renin inhibitor, diuretic, mimetic ApoA-I, antidiabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aidosterone synthase (AS1) inhibitor, a CETP inhibitor and a type 5 phosphodiesterase inhibitor (PDE5). The term "in combination with" a second agent or treatment includes co-administration of the compound of the invention (for example, a compound according to any one of the formulas l-1V or a compound described herein otherwise) with the second agent or treatment, administration of the compound of the invention first, followed by the second agent or treatment and administration of the second agent or treatment first, followed by the compound of the invention. The term "second agent" includes any agent that is known
in the art to treat, prevent, or reduce the symptoms of a disease or disorder described herein, for example, a disorder or disease responsible for inhibiting neutral endopeptidase, such as, for example, hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension , 5 isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal failure (diabetic or non-diabetic), renal failure (including edema and salt retention), diabetic nephropathy, nondiabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of the kidney, primary renal disease, renal vascular hypertension, diabetic retinoplasty and end stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis , atrial fluoride, harmful vascular remodeling, plaque stabilization, myocardial infarction
"15 cardio (Ml), renal fibrosis, polycystic kidney disease (PKD), renal failure (including edema and salt retention), cyclic edema, Menières disease, hyperaldosteronism (primary and secondary) and hypercalciuria, ascites , glaucoma, menstrual disorders, premature labor, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovary syndrome, implant failure), asthma, obstructive sleep apnea , inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition, such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially ulcers) 25 diabetic and venous and pressure wounds), septic shock, modulation of gastric acid secretion, treatment of hyperreninemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, complications diabetic conditions and atherosclerosis, male and female sexual dysfunction.
Examples of second agents include HMG-CO-A reductase inhibitors, angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin, diuretics, ApoA-I
metics, antidiabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase (ASI) inhibitors and CETP inhibitors.
The term "HMG-CO-A reductase inhibitor" (also called 5 beta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors) includes active agents that can be used to lower lipid levels including blood cholesterol.
Examples include atorvastatin, cerivastatin, compactin, dalvastatin, dihyd rocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or pharmaceutically acceptable salts thereof.
The term "ACE inhibitor" (also called angiotensin converting enzyme inhibitor) includes molecules that interrupt the enzymatic degradation of angiotensin I to angiotensin ll.
Such compounds can be used to regulate blood pressure and to
"15 treatment of congestive heart failure.
Examples include alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ra- mipril, spirapril, temocapril, trac- themselves. 20 The term "endothelin antagonist" includes bosentan (cf.
EP 526708 A), Tezosan (cf.
WO 96/19459), or pharmaceutically acceptable salts thereof.
The term "renin inhibitor" includes ditekiren (chemical name: [1S- [1 R *, 2R *, 4R * (1R *, 2R *)]] m - [(1,1-dimethi | ethoxy) carboni |] -L-pro | i | -L-phenyl | anil-N- 25 [2-hydroxy-5-methyl | -1- (2-methyl | propyl) A - [[[2-methyl | -1 - [[ (2-pyridini | methyl) amino] carbonyl] butyl] amino] carbonyl] hexyl] -N-alpha-methyl-L-histidinamide); terlakiren (chemical name: [R- (R *, S *)] - N- (4-morph | ini [carboni]) - L-pheni | a | anil-N- [1- (cic | ohexi | meti | ) -2-hydroxy-3- (1-methyl | ethoxy) -3-oxopropyl]] -S-methyl | -L- cysteine amide); Aliskiren (chemical name: (2S, 4S, 5S, 7S) -5-amino-N- (2- 30 carbamoi | -2,2-dimethi | eti |) -4-hydroxy-7 - {[4-methoxy- 3- (3-methoxypropoxy) phenyl] methyl} -8-methyl-2- (propan-2-yl) nonanamide) and zankiren (chemical name: [lS- [1R * [R * (R *)], 2S *, 3R *]] - N- [1- (cic | ohexylmeti |) -2,3-dihydroxy-5-methyl | hexiI] -a | fa-
[[2 - [[(4-methyl-1-piperazinyl) sulfonyl] methyl] -1-oxo-3-phenylpropyl] -amino] -4-thiazolapropanamide), or their hydrochloride salts, or SPP630, SPP635 and SPP800 as developed by Speedel, or RO 66-1132 and RO 66-1168 of Formulas (A) and (B):
H rN>
H <N> _Ò "°" ° 'Y "° I J" J C Ò. , "°" i '° í, jj / OÔ / OÒ 5 (a) and (b) y or, pharmaceutically acceptable salts thereof. The term "aliskiren", if not specifically defined, should be understood both as the free base and as a salt thereof, especially pharmaceutically acceptable salts thereof, more preferably one, its hemi-fumarate salt. An angiotensin II receptor antagonist or pharmaceutically acceptable salts thereof is understood to be an active ingredient that binds to the angiotensin receptor ATj subtype | but it does not result in activation of the receiver. As a consequence of AT1 receptor inhibition, these antagonists can, for example, be used as antihypertensives or for the treatment of congestive heart failure. The class of ATi receptor antagonists comprises compounds that contain structural characteristics that differ, essentially preferred are non-peptides. For example, mention may be made of compounds that are selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, the compound with the designation E-1477 of the following formula "'S4Á cooh the compound with the designation SC-52458 of the following formula 7 N "N" N ^> ">! H / N = N and the compound with the designation ZD-8731 of the following formula: '| J y
The ~ {'' JA '') N ^ NH / N — N - 5 or, in each case, pharmaceutically acceptable salts thereof. Preferred ATi receptor antagonists are those agents that are marketed, more preferably valsartan or pharmaceutically acceptable salts thereof. The term "calcium channel blockers (CCB)" includes dihydropyridines (DHPS) and non-DHPs (for example, diltiazem-type and verapamil-type CCBs). Examples include amlodipine, felodipine, ryosidine, israipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably a representative of the non-DHP selected from the group that consists of flizar which consists of prenylamine, 15 diltiazem, phendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, or pharmaceutically acceptable salts thereof. CCBS can be used as anti-hypertensive, anti-angina pectoris, or anti-arrhythmic drugs. The term "diuretic" includes thiazide derivatives (e.g., .20 chlorothiazides, hydrochlorothiazides, methylclothiazides and chlorothalone). The term "ApoA-I mimetic" includes D4F peptides (for example, formula D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F) The term "antidiabetic agent" includes insulin secretion enhancers that promote insulin secretion from pancreatic cells
cas.
Examples include derivatives of biguanide (for example, metformin), sulfonylureas (SU) (for example, tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-N - [(1-piro | idini | amino) carboni]] - benzenosu | phonamide (glycopyramide), glibenclamide (glyburide), glycazide, 1-butyl-3-methanylylurea, carbutamide, glibonuride, glipizide, gliquidone, glisoxepide, glibutiazol, glyibuzol, glihexamide, glimidine, and glipamide; pharmaceutically acceptable products.
Other examples include phenylalanine derivatives (for example, nateglinide [N- (trans-4-isopropi [cic | ohexi | carboni |) -D-phenylalanine] (cf.
EP 196222 and EP 526171) of the formula
) '"{7 ::' c: '' h_o); [(S) -2-ethoxy-4- {2 - [[3-methyl-1- [2- (1-piperidinyl) phenyl] repaglinide] butyl] amino] -2-oxoethyl} benzoic] (cf.
EP 589874, EP 147850 A2, in particular example 11 on page 61, and EP 207331 A1); (2S) -2-benzyl-3- (cis-hexahydro-2-isoindo | in | icarboni |) -calcium propionate dihydrate (for example, mitiglinide (cf.
EP 507534)); and glimepiride (cf.
EP 31058). Other examples include DPP-1V, GLP-1 inhibitors and GLP-1 agonists.
DPP-lV is responsible for inactivating GLP-l.
More particularly, DPP-IV generates a GLP-1 receptor antagonist and thus opens the physiological response to GLP-1.
GLP-1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose availability.
The DPP-IV inhibitor can be peptide or, preferably, non-peptide. DPP-IV inhibitors are in each case generically and specifically disclosed, for example, in WO 98/1 9998, DE 196 16 486 A1, WO 00/34241 and WO 95/15309, in each particular case in the claims of the compound and in the final products of the working examples, the subject of the final products, the pharmaceutical preparations and the claims are attached herewith in the present patent application as a reference to those publications.
Preferred are those compounds that are specifically disclosed
in Example 3 of WO 98/19998 and Example 1 of WO 00/34241, respectively. GLP-1 is an insulinotropic protein that is described, for example, by W.E. Schmidt et al. in Diabeto / ogia, 28, 1985, 704-707 and in US 5 5,705,483. The term "GLP-1 agonists" includes variants and analogs of GLP-1 (7-36) NH2 which are disclosed in particular in US 5,120,712, US
5,118,666, US 5,512,549, WO 91/11457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826. Other examples include GLP-1 (7-37), in which the Arg36 terminal amide carboxy functionality is shifted with Gly at the 37 'position of the GLP-1 (7-36) NH2 molecule and variants and their analogs including GL N'-GL P-1 (7-37), D-GL N'-GL P-1 (7-37), acetyl LYS9-GL P- 1 (7-37), LYS "-GLP-1 (7-37) and, in particular, GLP-1 (7-37) OH, VAL '-GL P- 1 (7-37), GLY'-GLP-1 (7-37) , THR'-GLP-1 (7-37), MET'-GLP-1 (7-37) and 4- "15 imidazopropionyl-GLP-1. Special preference is also given to the LPG agonist analogue exendin-4 described by Greig et al. in Diabetologia 1999, 42, 45-50. Also included in the definition of "antidiabetic agent" are insulin sensitivity enhancers that restore improved insulin receptor function to reduce insulin resistance and consequently increase insulin sensitivity. Examples include hypoglycemic thiazolidinedione derivatives (e.g., glitazone, (S) - ((3,4-dihydro-2- (phenyl-methyl) -2H-1-benzopyran-6-i |) meti | -thiazo | idine-2,4-dione (englantazone), 5 - {[4- (3- (5-methyl-2-pheni | -4-oxazo | i |) -1-oxopropi |) -pheni |] -meti |} - 25 thiazolidine-2,4-dione (darglitazone), 5 - {[4- (1-methyl-cyclohexyl) methoxy) - pheni [] meti |} -thiazo | idine-2,4- dione (ciglitazone), 5 - {[4- (2- (1- jindo | i |) ethoxy) pheni |] methyl} -thiazo | idine-2,4-dione (DRF2189), 5- {4- [2 - (5-methyl-2-pheni | -4-oxazoli |) -ethoxy)] benzi | µthiazolidine-2,4-dione (BM-13.1246), 5- (2- naphthi | su | foni |) -thiazo | idine-2,4-dione (AY-31637), bis {4 - [(2,4-dioxo-5- 30 thiazolidinyl) methyl] phenyl} methane (YM268), 5- {4- [2- (5- meti | -2-pheni | A-oxazo | i |) -2-hydroxyethoxy] benzyl} -thiazolidine-2,4-dione (AD-5075), 5- [4- (1-phenyl-1-cycl | opropanecarboni | amino) -benzi |] -thiazo | idine-2,4-dione (DN-I 08) 5 - {[4- (2-
(2,3-dihydroindol-1-yl) ethoxy) pheni [] methyl |} -thiazo | idine-2,4-dione, 5- [3- (4-chloropheni |]) - 2-propine |] -5-pheni | su | foniI) thiazo | idine-2,4-dione, 5- [3- (4-chlorophenyl]) - 2-propynyl] -5- (4-fluorophenyl-ifonyl) thiazolidine- 2,4-d iona, 5 - {[4- (2- (methyl-2-pyridinyl-amino) -ethoxy) phenyl] methyl} -thiazolidine-2,4-dione (rosiglitazone), 5 - {[4- (2- (5-ethyl-2-pyridi |) ethoxy) pheni |] -methyl} thiazo] idine-2,4-dione (pioglitazone), 5 - {[4 - ((3,4-dihydro- 6-hydroxy-2,5,7,8-tetramethi | -2H-1-benzopyran-2-i]) methoxy) -pheni]] -metii} - thiazolidine-2,4-dione (troglitazone), 5- [ 6- (2-f] uor-benzyl | oxy) naphtha | en-2-i | methyl |] - thiazolidine-2,4-dione (MCC555), 5 - {[2- (2-naphthyl) -benzoxazole- 5-yl] - methyl} thiazolidine-2,4-dione (T-174) and 5- (2,4-dioxothiazo | idin-5-i | methyl |) -2-methoxy - N- (4-trifluoromethyl- benzyl) benzamide (KRP297)). Other antidiabetic agents include modulators of the insulin signaling pathway, such as protein tyrosine phosphatase inhibitors (PTPases), non-small molecule antidiabetic mimetic compounds and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors; compounds that influence unregulated hepatic glucose production, such as glucose-6-phosphatase inhibitors (G6Pase), fructose-1, 6-bisphosphatase (Fl, 6-Bpase) inhibitors, glycogen phosphorylase (GP) inhibitors, antagon - glucagon receptor nists and phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDHK) inhibitors; inhibitors of gastric emptying; insulin; GSK-3 inhibitors; retinoid X receptor (RXR) agonists; beta-3 AR agonists; decoupling protein agonists (UCPS); PPARy agonists of the non-glitazone type; double PPARal PPARY agonists; antidiabetic compounds containing vanadium; hormones incretin, glucagon-like peptide-1 (GLP-1) and GLP-1 agonists; beta-cellular imidazoline receptor antagonists; miglitol; a2-adrenergic antagonists; and pharmaceutically acceptable salts thereof.
The term "obesity-reducing agent" includes lipase inhibitors (e.g.,., Orlistat) and appetite inhibitors (e.g., sibutramine and phentermine). An aldosterone synthase inhibitor or pharmaceutically acceptable salts thereof is understood as an active ingredient that has the property of inhibiting the production of aldosterone.
Aldosterone synthase (CYP11B2) is a mitochondrial cytochrome P450 enzyme that catalyzes the last stage of aldosterone production in the adrenal cortex, i.e., the conversion of 11-deoxycorticosterone to aldosterone.
It is known that the inhibition of aldosterone production with so-called aldosterone inhibitors is a successful variant in the treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation or renal failure.
Such aldosterone synthase inhibiting activity is readily determined by those skilled in the art according to standard assays (eg., 10 US 2007/0049616). The class of aldosterone synthase inhibitors comprises both steroidal and non-steroidal synthase inhibitors, the latter being more preferred.
Preference is given to commercially available aldosterone synthase inhibitors or those aldosterone synthase inhibitors that have been approved by health authorities.
The class of aldosterone synthase inhibitors comprises compounds with different structural characteristics.
For example, mention may be made of compounds which are selected from the group consisting of 20 of the non-steroidal aromatase inhibitors anastrozole, fadrozola (including their (+) - enanciomers), as well as the steroidal aromatase inhibitor exemestane, or , in each case where applicable, pharmaceutically acceptable salts thereof.
The most preferred non-steroidal aldosterone synthase inhibitor is 25 o (+) - enantiomer of fadrozola hydrochloride (US Patents 4617307 and 4889861) of formula
'): i HCl or, if appropriate, pharmaceutically acceptable salts thereof.
A preferred steroidal aldosterone antagonist is eplerenone
(cf. EP 122232 A) of the formula ,, O I., .Ó '> and "o ::" r t! r "> 'CH,] Êí The" ro "cH,
O or spironolactone; or, in each case, if appropriate, pharmaceutically acceptable salts thereof. 5 aldosterone synthase inhibitors useful in said combination are compounds and analogues generically and specifically disclosed, for example, in US2007 / 0049616, in particular in the claims of the compounds and in the final products of the working examples, the subject of the final products, pharmaceutical preparations and claims are attached hereto in the present patent application with reference to this publication. Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 4- (6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl) -3-methylbenzonitrile; (4-methoxy benzyl) 5- (2-chloro-4-cyano phenyl) -6,7-dihydro-5H-pyrrho | o [1,2-c] imidazo | a-5-carboxylic acid : 4'-fluoro-6- (6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) biphenyl-3-carbonitrile; 5- (4-cyano-2-methoxy phenyl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-carboxylic acid butyl ester; 4- (6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-ii) -2-methoxy benzonitrile; 5- (2-chloro-4-cyano phenyl) -6,7-dihydro-5h / - pyrrho [o [1,2-c] imidazo | a-5-carboxylic acid 4-fluoro-benzyl ester; 5- (4-cyano-2-trifluoromethoxyphenyl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-carboxylic acid methyl ester; 2- isopropoxyethyl ester of 5- (4-cyano-2-methoxy phenyl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-carboxylic; 4- (6,7-dihydro-5H-pyrrolo [1,2-c] imidazole-5-i |) -2-methyl | benzonitri | a: 4- (6,7-dihydro-5H- pyrrolo [1,2-c] imidazol-5-yl) -3-fluorobenzonitrile; 4- (6,7-dihydro-5H-pyrrho] o [1,2-c] imidazo | -5-i |) -2-methoxy benzonitrile; 3-fluoro-4- (7-methylene-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-5-yl) benzonitrile; cis-3-fNor-4- [7- (4-fluoro-benzyl) -5,6,7,8-tetrahydro-imidazo [1,5- a] pyridin-5-yl] benzonitrile; 4'-Húor-6- (9-methyl-6,7,8,9-tetrahydro-5H-
imidazo [1,5-a] azepin-5-yl) biphenyl-3-carbonitrile; 4'-fluoro-6- (9-methyl-6,7,8,9-tetrahydro-5H-imidazo [1,5-a] azepin-5-yl) biphenyl-3-carbonitrile or in each case, its (R) or (S) enanciomer; or if appropriate, pharmaceutically acceptable salts thereof. The term "aldosterone synthase inhibitors" also includes compounds and analogues disclosed in WO2008 / 076860, WO2008 / 076336, WO2008 / 076862, WO2008 / 027284, WO2004 / 046145, WO2004 / 014914, WO2001 / 076574. In addition, aldosterone synthase inhibitors also include 10 compounds and analogs disclosed in U.S. patent applications.
US2007 / 0225232, US2007 / 0208035, US2008 / 0318978, US2008 / 0076794, US2009 / 0012068, US2009 / 0048241 and in PCT patent applications
- WO2006 / 005726, WO2006 / 128853, WO2006 / 128851, WO2006 / 128852, WO2007 / 065942, WO2007 / 116099, WO2007 / 116908, WO2008 / 119744 and in the "European patent application EP 1886695. Preferred aldosterone inhibitors are suitable for employment in the present invention include, without limitation 8- (4-fluoroen |) -5,6-dihydro-8H-imidazo [5,1-c] [1,4] oxazine; 4- (5,6- di -hydro-8H-imidazo [5,1-c] [1,4] oxazin-8-yl) -2-fNorbenzonitrile; 4- (5,6-dihydro-8H-imidazo [5,1-c] [1, 4] oxazin-8-yl) -2,6-difNorbenzonitrile; 4- (5,6-dihydro-8H-20 imidazo [5,1-c] [1, 4] oxazin-8-yl ) -2-methoxy benzonitrile; 3- (5,6-dihydro-8H-imidazo [5,1-c] [1, 4] oxazin-8-yl) benzonitrile; 4- (5,6-di- hydro-8H-imidazo [5,1- c] [1,4] oxazin-8-yl) phtatonitrile; 4- (8- (4-cyano phenyl) -5,6-dihydro-8H-imidazo [5 , 1- c] [1,4] oxazin-8-yl) benzonitrile; 4- (5,6-dihydro-8H-imidazo [5,1-c] [1,4] oxazin-8-yl) benzonitrile; 4- (5,6-dihydro-8H-imidazo [5,1-c] [1,4] oxazin-8-yl) naphthalene-1- 25 carbon itrila; 8- [4- (1 H -tetrazol-5-yl) phenyl1-5,6-dihydro-8H-imidazo [5,1- C] [1 , 4] oxazine as developed by Speedel, or in each case, its enantiomer (R) or (S); or if appropriate, pharmaceutically acceptable salts thereof.
The term "endothelin receptor blocker" includes bosenta-na.
The term "CETP inhibitor" refers to a compound that inhibits the transport mediated by the cholesteryl ester transfer protein
(CETP) of various cholesteryl esters and triglycerides from HDL to LDL and VL-DL. Such CETP inhibiting activity is readily determined by those skilled in the art according to standard assays (for example, U.S. Pat. No. 6,140,343). Examples include compounds disclosed in U.S. Pat. No. 5 6,140,343 and U.S. Pat. No. 6,197,786 (e.g., [2R, 4S] ethyl acid ester 4 - [(3,5-bis-trif | úormeti | -benzyl) -metoxycarboni | -amino] -2-ethyl | -6- trifluorometik3 , 4-dihydro-2H-quinoline-1-carboxyl (torcetrapib); compounds disclosed in US Pat. No. 6,723,752 (for example, (2R) -3 - {[3- (4-chloro-3- ethyl-phenoxy) -phenyl] - [[3- (1, 1, 2,2-tetrafluoro-ethoxy) -phenyl] -methyl] -amino} -1,1, 1-trifluoro-1O 2-propanol); compounds disclosed in US Ser patent application No. 10 / 807,838; polypeptide derivatives disclosed in US Pat.
5,512,548; rosenonolactone derivatives and analogues containing cholesterylester phosphate disclosed in J. Antibiot., 49 (8): 815- 816 (1996), and Bioorg. Med. Chem. Lett .; 6: 1951-1954 (1996), respectively. In addition, CETP inhibitors also include those disclosed in WO2000 / 017165, WO2005 / 095409 and WO2005 / 097806. A preferred PDE5 inhibitor is Sildenafil. The second agent of particular interest includes endothelin antagonists, renin inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diuretics, antidiabetic agents such as DPPlV inhibitors, and inhibitors of aldosterone synthesis. In one embodiment, the invention provides a combination, in particular a pharmaceutical composition, comprising a therapeutically effective amount of the compound according to the definition of the formula [', I, ll, lll or lV or pharmaceutically acceptable salts thereof, and a or more therapeutically active agents selected from HMG-CO-A reductase inhibitors, angiotensin ll receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, calcium channel blockers (CCB), endothelin antagonists , renin inhibitors, diuretics, Apo-Al mimetics, antidiabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase (ASl) inhibitors and CETP inhibitors.
In one embodiment, the invention provides a method of inhibiting the activity of neutral endopeptidase EC 3.4. 24.11 in an individual, the method comprising administering to the individual a therapeutically effective amount of the compound according to the definition of formula 5 I ', 1, 11, II or IV or pharmaceutically acceptable salts thereof.
In one embodiment, the invention provides a method of treating a disorder or disease in an individual associated with neutral 3.4 endopeptidase activity. 24.11, the method comprising administering to the individual a therapeutically effective amount of the compound according to the definition of formula I ', I, ll, 11 or 11 or pharmaceutically acceptable salts thereof.
In one embodiment, the invention provides a method of treating a disorder or disease in an individual associated with neutral 3.4 endopeptidase activity. 24.11, and the disorder or disease is selected from hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, insufficiency renal (diabetic or non-diabetic), renal failure (including edema and salt retention), diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, primary renal disease proteinurea, renal vascular hypertension, diabetic retinopathy and renal disease final stage (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial fluoride, harmful vascular remodeling, plaque stabilization, myocardial infarction myocardium (Ml), renal fibrosis, polycystic kidney disease (PKD), kidney failure (including ed emu and salt retention), cyclic edema, Menieres disease, hyperaldosteronism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, premature labor, preeclampsia, endometriosis, and reproductive disorders (especially infertility) male and female, polycystic ovary syndrome, implant failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy
asiatic, affective disorders such as depression and psychotic condition, such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure ulcers), shock 5 septic, gastric acid secretion dysfunction, hyperreninemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and atherosclerosis, male and female sexual dysfunction. In one embodiment, the invention provides a compound according to the definition of the formula r, I, Il, lll or lV, for use as a medicine. In one embodiment, the invention provides the use of a compound according to the definition of formula l ', I, II, III or IV or pharmaceutically acceptable salts thereof, for the treatment of a disorder or disease in a individual associated with neutral endopeptidase activity EC 3.4. 24.11. In one embodiment, the invention provides the use of a compound according to the definition of the formula I ', l, ll, Ill or lV, in the preparation of a drug for the treatment of a disorder or disease in a characterized individual by a neutral endopeptidase activity EC 3.4.
24.11, where the said disorder or disease is in particular selected from hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal failure (diabetic or non-diabetic), renal failure (including edema and salt retention), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, primary renal disease proteinurea, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial fluoride, detrimental vascular remodeling, plaque stabilization, myocardial infarction (MI), renal fibrosis, political kidney disease (PKD) ), renal failure (including
edema and salt retention), cyclical edema, Menieres disease, hyperaldosteronism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, premature labor, pre-eclampsia, endometriosis, and reproductive disorders ( especially male infertility and female
5 minina, polycystic ovary syndrome, implant failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition, such as dementia and geriatric confusion, obesity and gastrointestinal disorders ( especially diarrhea and irritable bowel syndrome), wound healing (especially ulcers)
10 Diabetic and venous ras and pressure ulcers), septic shock, dysfunction of gastric acid secretion, hyperreninaemia, cystic fibrosis, restenosis. type-2 diabetes, metabolic syndrome, diabetic and atherosclerotic complications
'clerosis, male and female sexual dysfunction.
In a modality the invention provides the use of a 3
"15 compound according to the definition of the formula I ', I, |, lll or lV, for the treatment of a disorder or disease in an individual characterized by a neutral endopeptidase activity EC 3.4. 24.11, where the disorder or disease are selected from hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal failure (diabetic or non-diabetic), renal failure (including edema and salt retention), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, primary renal disease proteinurea, renal vascular hypertension, retinopathy diabetic and end-stage kidney disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias ares, atrial fibrillation (AF), cardiac fibrosis, atrial fluoride, harmful vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, kidney disease 30 (PKD), renal failure (including edema and salt retention) , cyclical edema, Menieres disease, hyperaldosteronism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, premature labor, preeclampsia, endometriosis, and reproductive disorders (especially male and female infertility, ovarian syndrome polycystic disorders, implant failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition 5 such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and syndrome irritable bowel), wound healing (especially diabetic and venous ulcers and pressure ulcers), septic shock, dysfunction of gas acid secretion trico, hyperreninemia, cystic fibrosis, restenosis, type 2 diabetes, metabolic syndrome, 10 diabetic complications and atherosclerosis, male and female sexual dysfunction. Exemplification of the invention: The following examples are intended to illustrate the invention and should not be considered as being limitations thereon. Temperatures are 15 degrees centigrade. If not mentioned otherwise, all% evaporations are carried out under reduced pressure, typically between
M approximately 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, for example, microanalysis and spectroscopic characteristics, for example, MS, IR, RNM. The abbreviations used are those conventional in the art. All starting materials, building blocks, reagents, acids, bases, dehydrogenating agents, solvents and catalysts used for the synthesis of the compounds of the present invention are either commercially available or can be produced by methods of organic synthesis. - only known to specialists with normal knowledge in the art. (Houben-Weil 4th ed. 1952, "Methods of Organic Synthesis", Thieme publisher, volume 21). In addition, the compounds of the present invention can be prepared by methods of organic synthesis known to anyone with ordinary skill in the art, as shown in the following examples. Exemplification of the invention:
abbreviations: I br: broad bs: broad singlet Ac: acetyl Atm: atmosphere Aq: aqueous calcd: calculated Bn: benzyl Boc: tert-butoxycarbonyl d: doublet dd: doublet of DCM doublets: DME dichloromethane: 1,4-dimethoxy ethane I DMF: N, NAimethylformamide DMSO: dimethylsulfoxide i DAD: diode array detector DTT: dithiothreitol EDTA: te- ESI acid ethylenediamine: ionization by tra-acetic electroborrifide Et and EtOAc: ethyl and ethyl acetate [ÃATU: O- ( 7-azobenzotriazo | -1-i |) - HO8t: 1-hydroxy-7-azabenzotriazola I 1,1,3,3-tetramethyluronium hexafluoro- | phosphate I HPLC: high performance liquid chromatography LC and LCMS: liquid chromatography and pressure I liquid chromatography and mass spectrometry HPLC-RT: high pressure liquid chromatography - retention time H: Hour (s) IR: MeOH infrared: methanol MS: mass spectroscopy m: multiplet min: minutes Me: methyl m / z: mass-to-charge ratio M and mM: Molar and millimole (s) mg: milligram na: not determined NMR: magnetic resonance PMBCI: chloride para-methoxy ben- Pr and iPr: propyl and isopropyl zila ppm: parts per million Pd / C: Palladium on carbon Ph: phenyl q: quartet RP: reverse phase RT: room temperature s: singlet t: triplet TFA: tMúoracético acid THF : tetrahydrofuran TLC: thin layer chromatography t8u: tert-butyl µL, mL and L: microliter, milliliter and liter Tris · HCl: aminotris (hydroxymethyl) methane hydrochloride wt: UV weight: ultraviolet The following examples are intended illustrate the invention and should not be considered as their limitations. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are carried out under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical processes, for example, microanalysis and spectroscopic characteristics, for example, MS, IR, NMR. Abbreviations are those used conventionally in the technique.
, 10 All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are both commercially available. available or can be produced by methods of organic synthesis known to people with ordinary knowledge in the art (Houben-Weil "15 4th Ed. 1952," Methods of Organic Synthesis ", Thieme publisher, voiume 21). the present invention can be prepared by organic synthesis methods known to persons of ordinary skill in the art as shown in the following examples: The compounds of examples 3-1 and 3-2 through 3-20 15 have been found to have | C50 values in the range from approximately 0.001 nM to about 10,000 nM for NEP The conditions for measuring retention times are as follows: HPLC condition A: 25 Column: INERTSIL C8-3, 3 µm x 33 mm x 3.0 mm at 40 ° C. Flow rate: 2 mL / min Mobile phase: A) 0.5 mM ammonium formate in H2O; B) MeOH 5Õ ° / o in CH3CN Gradient: linear gradient from 5 ° / 0 B to 95% B in 2 min 30 Detection: DAD-UV at 210-400 nm
HPLC condition B: Column: INERTSIL C8-3, 3 µm x 33 mm x 3.0 mm at 40 ° C. Flow rate: 2 mL / min Mobile phase: A) 0.1% formic acid in H2O: B) MeOH 50 ° / o in 5 CH, CN Gradient: linear gradient from B 5 ° / 0 to B 95 ° / o in 2 min Detection: DAD-UV at 210-400 nm HPLC condition C: Column: INERTSIL C8-3, 3 µm x 33 mm x 3.0 mm at 40 ° C.
10 Flow rate: 2 mL / min Mobile phase: A) 0.5 mM ammonium formate in H2O; B) MeOH 50 ° 6 in CH3CN Gradient: linear gradient from 4Õ ° / o B to 95% B in 2 min Detection: DAD-UV at 210-400 nm "15 HPLC condition D:% Column: INERTSIL C8-3, 3 µm x 33 mm x 3.0 mm at 40 ° C. Flow rate: 2 mL / min Mobile phase: A) 0.1% formic acid in H2O; B) MeOH 50% in CH, CN 20 Gradient: linear gradient from 40% B to 95% B in 2 min Detection: DAD-UV at 210-400 nm Relative stoichiometry was determined using two-dimensional MRI, under the reaction conditions, the racemization of the stereocenter with the bis group -phenylmethyl is not expected, therefore the absolute stereochemistry was determined based on the relative stereochemistry and the center stereochemistry comprising the bisphenylmethyl group Example 1-1: Synthesis of ethyl acid ester (S) -2 - [(S ) -2- (3'-chloro-biphenyl-4-yl) - 1- (1 H-tetrazo! -5-ylcarbamoyl) -ethylamino] -propionic
Cl
CI ^ i l) sat trifQsgeniQ. NaHCQ, aq, DCM I. ~> I. "lj 2) 5-amino-tetrazole, E% N.
> (ÃX) J "M b) 0 HNj :: ,,, ° rk" "d, ° A a suspension of (S) A- (3'-chloro-biphenyl-4-yl) -2 - (( S) -1- ethoxycarbonyl-ethylamino) -propionic (4.0 g, 10.84 mmol) in dichloromethane (60 mL) and saturated aqueous NaHCO3 (10 mL) was added triphosgene (1.90 g, 5 6.39 After vigorous stirring for 0.5 hour, the reaction mixture was diluted with EtOAC and partially concentrated under reduced pressure. Excess triphosgene was quenched by adding aqueous saturated NaHCO3 and stirred for 0.5 hour. The mixture was extracted with EtOAc and washed with brine. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (50 ml). Triethylamine (1.93 mL, 13.8 mmol) and 5- were added to the mixture. amino-1H-tetrazole (1.18 g, 13.84 mmol) at 0 "C, and the reaction mixture was gradually warmed to room temperature. After stirring for 2 hours, the reaction mixture was concentrated and purified in chromatographic column of silica gel (eluent: 10 ° / MeOH in dichloromethane) to give a mixture of the desired trans isomeric product and the cis isomer The material obtained was recrystallized from CH3CN three times to give ethyl acid ester (S ) -2 - [(S) -2- (3'-c | oro-bipheni | Ai |) -1- (1 H-tetrazo | -5-i | carbamoi |) -eti | amino] - propionic (3 , 92g). 'H RNM (40OMHz, DMSO-C / 6) çj 1.11 (t, 3H, J = 7.1 Hz), 20 1.15 (d, 3H, J = 6.8 Hz), 2.89 (dd, 1H, J = 8.1, 13.7 Hz), 3.02 (dd, 1H, J = 5.8, 14.0 Hz), 3.27-3.36 (m, IH), 3.75-3.83 (m, IH), 4.01 (q, 2H, J = 7.1 Hz), 7.34 (d, 2H, J = 8.3 Hz), 7, 38-7.42 (m, IH), 7.47 (dd, 1H, J = 7.8, 7.8 Hz), 7.60-7.65 (m, 3H), 7.69 (dd, 1H, J = 1.8, 1.8 Hz); MS: m / z (MH ") 443; HRMS: Calculated for C22H23C | N6O3 (M) "442.1, observed 442.1; EA: Calculated 25 for C ,, H ,, C | N6O3: C, 56.95; H, 5.23; N, 18 , 97. Note: C, 56.88; H, 5.07; N, 19.1. Chiral HPLC retention time = 9.26 min. [Condition: Daicel CHIRALCEL OJ-H 4.6x100mm); flow = lml / min .; eluent:
20 ° / EtOH (with 0.1% TFA) in heptane]. The following compounds were prepared using procedures similar to those in Example 1-1 with appropriate intermediates: HHPLC- Exem- RT MMS Product Intermediates pIo N (condi- (M "1) ção) Cl Cl" i ~ ~ r jt, j Cl -tj A »Cl x ° r # ^ d, ° x ° r # ^ Hk: ,,, Acid (S) -2 - ((S) -1- tert-butoxycarbonyl- 1.38 Example 7" 'ethylamino ) -3- (2 ', 5'- min 505 pIo 1-2 Terc-butyl acid-dichloro-biphenyl-4-yl) - (C) do (S) -2 - [(S) -2- (2 ', 5'- dichloro-biphenik4-yl) -1- e (1 H-tetrazol-5- H2N YN · N i | carbamoi [) - ethi | amino] - tl-N' propionic 5-amino- 1H- tetrazole ~: I cP "° r # ^ 2, °
L (S) -3-Biphenyl- "° rll" Hk: N., 4-yl-2 - ((S) -1-ethoxy 1.55 Example "" carbonyl-ethylamino) - min 409 plo 1 -3 Ethyl ester of (S) - propionic acid (A) 2 - [(S) -2-biphenyl-4-yl-1- and (1 H-tetrazok5- H "YN · N ilcarbamoyl) -ethylamino] - # "N" propionic 5-amino-1H- tetrazole
I HHPLC- I Example- RT I MMS Intermediate product | . plo N '(", :::'" I ("" ') f ~ íJ
FA »K, C, l": x ° r # à, ° Acid (S) -2 - ((S) -1- I x ° r # ^ Hk: N ,, tert-butoxycarbon- N-ethylamino) -3- (5'- I 1,27 Example "" fluorine-2'-methoxy - I min I 485 plo 1-4 Terc-butyl acid ester (S) -2 - [(S) - 2- (5'-biphenyl-4-i!) - I (C) fluorine-2'-methoxy-biphenyl-propionic 4-yl) -1- (1H-tetrazol-5- and H2n yn · ni | carbamoi | ) -eti | amino] - tl "N propionic 5-amino-1H- tetrazole ~: j | i <- »~: ix ° r # a, ° x ° r Lo Acid (S) -3-biphenyl- I 4-yl-2 - ((S) -1-tert- 7 -no" butoxycarbonyl- | 1.49 I ethylamino) "I · Exem- Meti! 5- - · propion acid ester [co j m'n I 493 plo 1-5 [(S) -3-biphenyl-4-yl-2- (C) and ((S) -1-tert-butoxycarbonyl- & 7y: - ethylamino) - 5-amino-1H-pyrazole-3-carboxyl-3-carboxylic acid-I propionylamino] -1H-
I HHPLC- l Example- RT I MMS Intermediate product I (condition (| M + 1) plo N tion) Cl
Cl ~:; J I ~ jl L »I., J x ° r # ^ d, °
Example- "° íüj ,, qn (S) -2 - ((S) -1- I tert-butoxycarbonyl- I 1,48 ethylamino) -3- (3'- I min I 486 plo 1-6 Terc- butyl ester of chloro-biphenyl-4-yl) - I (C) of (S) -2 - [(S) -2- (3'-propionic chloro-biphenyl-4- and yl) -1- ( 3-hydroxy- '"r' ° 'isoxazol-5-ylcarbamoyl) - O-N ethylamino] -propionic 5-amino-isoxazo! - I 3-hi Cl
Cl, C, Í) i "I l ~ ~ /" ° rn ° Acid (S) 3 (3 '"° r # ^ Hk: ,, N chloro-biphenyl-4-yl) -2- I
Example-, n-n ((S) -1- I 1.12 I plo 1-7 Ethyl ester of (S) - ethoxycarbonyl- I min I 457
2 - [(S) -2- (3'-chloro-ethylamino) - I (C)
bifeni! -4-i!) - 1- (1-methylpropionic
1H-tetrazol-5- and H2NyN · N i | carbamoi |) -ethi | amino] -, N- N '
propionic 1-methyl-1H-tetrazol-5-ylamine I I HHPLC-;
Example- RT I MMS Intermediate product I (condition I (M "1) plo N tion)
~ Cl I i i C7
! i ^> ">" "° rRá:> - / Ethyl ester of acid I
"° r7" THERE IS ,,, (S) -2 - [(S) -1- carboxy-2- (3'-chloro-I 1.47 I 533 4 Example- 2 "'Ethyl biphenyl-4-yl) "I min. (C) I 'plo 1-8 (S) -2-' ethylamino] -4-phenyl-i [(S) -2- (3'-chloro-biphenyl-butyric acid 4-yl) -1- (1 H-tetrazol-5- and ilcarbamoyl) -ethylamino] - H2NyN · N
4-phenyl-butyric 7 "n
5-amino-1H-
tetrazole
, (JCl I
~ Cl x ° fqg: ° ",, Á) Terc-butyl ester of I x ° r #" THERE: n ,, acid (S) -2 - [(S) -1- I Exem- # "'carboxi- 2- (3'-chloro- 1.27 I 485 pIo 1-9 Acid-biphenyl-4-yl tert-butyl ester) - (C)
do (S) -2 - [(S) -2- (3'-ethylamino] -butyric chloro-biphenyl-4-yl) -1- (1H- and H2NyN · N tetrazol-5-ylcarbamoyl) - ll "N ethylamino] -butyric 5-amino-1H-
tetrazole
HHPLC- Exem- RT MMS Product Intermediates plo N (condi- (M "1) tion)) ~> ci -%: ê" "C), Acid (S) -3- (3'-" ° YANAr ° cIoro- biphenyl-4-yl) -2- oh HNyN · N Exem- # "'((S) -1- 1.31 ethoxycarbonyl-2- (C) 519 pIo1-1O Ethylesterdeacid2- [2- phenyl-ethylamino) - ( 3 "chloro-biphenik4-yl) -1- propionic (1 H-tetrazol-5- and ilcarbamoyl) -ethylamino] -" 2 "YN · N 3-phenyl-propionic # -N 5-amino-1H- tetrazole Experiment 1 -11. (S) -2 - {(S) -2- (3'-chloro-biphenyl-4-yl) -1- [methyl- (1 H-tetrazo | -5-i |) -carbamoyl] ethyl ester -eti | amino} -propionic aa "t 1) triphosgene m. NaHLl4aq. DCÀA ~ Cj ^)] '~ j ~') 'm · m ·" "o' j'b" Lzjy ° [J, »Jl D 'M ,, H TFADCM ujlYQ ,,' '"àj,' LíNjLYo ô H ,, ArN -n 'a'> ynn / htermediate 9 (" j | j "'t, 0
O / A a suspension of (S) -3- (3'-c | oro-bipheni | -4-i |) -2 - ((S) -1- 5 ethoxycarbonyl-ethylamino) -propionic acid (225 mg, 0.599 mmol) in dichloromethane (4 ml) and saturated aqueous NaHCO3 (1 ml) were added triphosgene (178 mg, 0.599 mmol). After vigorous stirring for 10 min, the reaction mixture was diluted with EtOAC and partially concentrated under reduced pressure. Excess triphosgene was eliminated by adding aqueous saturated NaHCO3 and stirred for 0.5 hour. The mixture was extracted with EtOAC and washed with brine. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5 ml). Add
Triethylamine (0.167 ml, 1.177 mmol) and [1- (4-methoxy-benzyl) -1 H-tetrazol-5-yl] -methyl-amine (197 mg, 0.898 mmol) were added to the mixture and stirred at 45 "C at night.
Additional triethylamine (0.167 ml, 1.197 mmol) and [1- (4-methoxy-benzyl) -1 H-tetrazol-54l] -methyl-amine (197 mg, 0.898 mmol) were added and stirred at 45 "C for 30 hours.
The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: 10% MeOH in DCM) to give ethyl ester of (S) -2 - ((S) -2- (3 '- c | oro-bipheni | Ai |) -14 [1- (4-methoxy-benzyl |) -1 H-tetrazok5-yl] -methyl-carbamoyl} - ethylamino) -propionic (261mg). MS: m / z (MH ") 577; H-10 PLC retention time 1.36 min (HPLC condition C). Then (S) -2 - ((S) -2- (3) acid ester '-chloro-biphenyl-4-yl) - 1 - {[1- (4-methoxy-benzyl) -1 H-tetrazo | -5-i [] - methyl | -carbamoy |} -ethi] amino) -propionic (260 mg, 0.451 mmol) was dissolved in TFA (5 ml) and DCM (5 ml) and stirred at 50 "C for 12 hours and at 75 ° C for 5 hours.
The reaction mixture was concentrated under reduced pressure to give (S) -2 - {(S) -2- (3'-chloro-biphenik4-yl) -1- [methyl- (1 H- tetrazo | -5-i |) -carbamoy |] -ethi | amino} -propionic (120 mg). MS: m / z (MH ") 457; HPLC retention time 0.95 min (HPLC condition C) - The following compounds were prepared using a procedure similar to Example 1-1 with appropriate intermediates:
HPLC-RT MS Example N Intermediate product (condition (M + 1) tion) ci Cl ej ÁJ í "" r ": J> O ~" I> ~ ^ r> Ob A »° r # ^ b, ° ° rÁ ^, k: ,,, Acid (S) -2 - ((S) -2- tl "N benzyloxy-1-Example Ethyl ethoxycarbonyl acid ester- 1.31 min 549 1-12 (S) -3- benzyloxy-2-ethylamino) -3- (3'- (C) [(S) -2- (3'-chloro-chloro-biphenyl-4-yl) -biphenyl-4-yl) -1- (1 H - propionic and tetrazole-5- R'y> '· n-ilcarbamoyl) - tl "N ethylamino] - 5-amino-1H- propionic tetrazole
CI Cl ~: J> O- ,, A, »~: J ° r # ^ b, °> L, Jü Acid (S) -3- (3'- ° r7 ^, k: ,, N chloro-biphenik4 -il) -2- # "n ((S) -1- Example .. ethoxycarbonyl-2- 1.29 min 471 1-13 Ettl acid ester (S) -2 - [(S) -2- (3 '- methoxy-ethylamino) - (A) chloro-biphenik4-yl) -1- propionic (1 H-tetrazok5- and ilcarbamoyl) - "2" YN · N ethylamino] -3-methoxy - # -N' propionic 5- amino-1H- tetrazole Example 1-14: Ethyl ester of (S) -2 - [(S) -2- (3'-chloro-biphenyl-4-yl) -1- (1H-tetrazok5-ylcarbamoyl) - ethoxy] -propionic
Cl CI ~
Ü / N> ori "o" j, -o ¢ 'O OH O HNyN · N §-N' To a solution of acid (S) -3- (3'-c | oro-bipheni | -4-i |) -2 - ((S) -1- ethoxycarbonyl-ethoxy) -propionic (62 mg, 0.165 mmol) in THF (5 ml) at room temperature 5-aminotetrazole (38.0 mg, 0.447) was added mmol), D1-5 PEA (0.086 ml, 0.494 mmol) followed by 1,3-diisopropylcarbodiimide (0.060 ml, 0.387 mmol). The reaction was stirred at room temperature for 3 hours. The reaction was cooled ("quenching") with brine and extracted with EtOAC. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. HPLC retention time = 0.99 mi- "10 nutes (condition C); MS (m" 1) = 444. Example 2-1: Ethyl ester of (S) -2 - [(R) -2- ( 3'-c | oro-bipheni | -4-i |) -1- (1H- d tetrazo | -5-i [carbamoi |) -ethylamino1-propionic Cl "I 'or, Êi ::" The cis isomer obtained from the procedure described in Example 1-1 15 was isolated by reverse phase HPLC (Column Sunfire C-18, 0.1% TFA in H2O / CH3CN) giving ethyl ester of (S) -2 - [(R) -2 - (3'-chloro-biphenyl-4-yl) - 1- (1H-tetrazo! -5-ylcarbamoyl) -etüamino] -propionic; 'H NMR (40OMHz, DM-SO-d6) j 1.07 (t, 3H, J = 7.1 Hz), 1.12 (d, 3H, J = 6.8 Hz), 2.88 (dd , 1H, J = 8.1, 13.6 Hz), 3.04 (dd, 1H, J = 6.1, 13.6 Hz), 3.18-3.26 (m, IH), 3, 69-3.78 20 (m, IH), 3.87-4.03 (m, 2H), 7.35 (d, 2H, J = 8.1 Hz), 7.37-7.42 (m , IH), 7.47 (dd, 1H, j = 7.8, 7.8 Hz), 7.58-7.65 (m, 3H), 7.68 7.72 (m, IH); MS: m / z (MH ") 443. The following compounds were prepared using a
similar procedure to Example 1-1 and 2-1 with appropriate intermediates: Example Product Intermediates HPLC- MS N RT (con- (M "1) diction)
CI Example 1.38 min 505 2-2: ', (C) Cl xCj "at X ° Y ^ tiY ° O HNyN · N x ° r # t: acid j-N acid (S) -2 - ((S ) -1- Terc-butyl acid ester (s) -2-j (R) -2- (2 ', 5'-butoxycarbonyl-dichloro-b ifenyl-4-yl) -1- ethylamino) -3- (1 H-tetrazol-5- (2 ', 5'-dichloro-ylcarbamoyl) -ethylamino] - biphenyl-4-yl) - propionic propionic and "" Y'N · N # "N' 5-amino -1 H- tetrazole Example,;, t, 1.46 min 486 2-3 ~ ~ Jj,: :: - "(C)> <» x ° r # ^ :, ° "° l ^ GfÀ ,, Acid (S) -2 - ((S) - o- n l-tert- Ethyl ester of (S) - butoxycarbonyl- 2 - [(R) -2- (3'-chloro-ethylamino) -3- (3 '- biphenyl-4-yl) -1- (3-chloro-biphenyl-4-hydroxy-isoxazol-5-yl) -propionic ilcarbamoyl) -ethylamino] - and propionic h, n)! 77oh 5-amino-isoxazole- 3-hello
Example Intermediate product HPLC- MS N RT (con- (M + 1) diction)
CI Example "1.16 min 457 2-4,:: J (C)" ° rn ° "° rct ;, Acid (S) -3- (3'-zN-N chloro-biphenyl-4-ethyl ester (S) -yl) -2 - ((S) -1- 2 - [(R) -2- (3'-chloro-ethoxycarbonyl-biphenyl-4-yl) -1- (1-methyl-ethylamino) ) - 1 H-tetrazok5- propionic '2 "-rN · N ylcarbamoyl) -ethylamino] - ,, n" n propionic 1-methyl-1 H-tetrazol-5-ylamine Example 3-1: (S) -2 acid - [(S) -2- (3'-chloro-biphenyl-4-yl) -1- (1 H-tetrazol-5- i | carbamoy |) -ethi | amino1-propionic IC and "I / I / ~ / ÇCj> (""> 2m NaOH, EtoH> "- ° rcg ,," '° rág, Ethyl ester of acid (S) -2 - [(S) -2- (3'-chloro-biphenyl- 4-yl) -1- (1 H-tetrazol-5-ylcarbamoyl) -ethylamino] -propionic (100 mg, 0.226 mmol) was treated with 2M aqueous NaOH (2 mL) and EtOH (0.5 mL). stirred at room temperature for 1 hour, the reaction mixture was acidified with 2M HCI to adjust to pH 1. The precipitate was collected by filtration The material obtained was crystallized from EtOl-1 giving (S) -2- [ (S) -2- (3'-chloro-biphenyl-4-yl) -1- (1 H-tetrazol-5-ylcarbamoyl) -ethylamino] -prop ionic (94mg). 'H NMR (40OMHZ, DMSO-C / 6) IjÇi1.15 (d, 3H, J = 7.1 Hz), 2.94 (dd, 1H, j = 7.3.13.7Hz), 3.03 (dd, 1H, j = 6.3,13.6 Hz), 3.26 (dd, 1H, J = 7.1, 13.9 Hz), 3.81 (dd, 1H, J = 6.9 , 6.9 Hz), 7.33 (d, 2H, J = 8.3 Hz), 7.38-
7.42 (m, IH), 7.47 (dd, 1H, J = 7.8, 7.8 Hz), 7.59-7.64 (m, 3H), 7.69 (dd, 1H, J = 1.8, 1.8 Hz), 15.9 (bs, IH); MS: m / z (MH ") 415; HRMS: Calculated for C19H19C | N6O3 (M)" 414.1, observed 414.1 Chiral HPLC retention time = 13.17 min, [condition: Dai-
cell CHIRALPAK IA 4.6x100mm); Flow rate = lml / min .; eluent: 20 ° / EtOH (with 0.1 ° TFA 6) in heptane]. Example 3-2: (S) -2 - [(S) -2- (2 ', 5'-dichloro-biphenylA-yl) -1- (1 H-tetrazole-5- acid
iIcarbamoyl) -ethylamino] -propionic Cl Cl S "
J. ~ I] ~ Citj tfa, triethylsilano, d!] ~ ~ Ci, J t E L o "" - HOU'X, & O j A hGn., '3' HÀy., Yn "#" N "
To a solution of (S) -2 - [(S) -2- (2 ', 5'-dichloro-biphenik4-yl) -1- (1 H-tetrazo | -5-i | carbamoi |) -ethi | amino] -propionic (103 mg, 0.204 mmol) in DCM (2 mL) was added TFA (1 mL) and triethylsilane (0.098 mL, 0.611 mmol). After stirring for 8 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Column Sunfire C-18, eluent: 0.1% TFA in H2O / CH3CN) to give acid (S) -2 - [(S) -2- (2 ', 5'-dichloro-biphenyl-4-yl) -1- (1 H-tetrazoP5-ylcarbamoyl) -ethylamino] -propionic. 'H NMR (40OMHZ, DMSO - & + TFA-Q õ 1.49 (d, 3H, J = 7.1 Hz), 3.29 (dd, 1H, J = 7.6, 13.9 Hz), 3.42 (dd, 1H, J = 7.1, 14.2 HZ), 4.13 (dd, 1H, j = 7.1, 14.0 Hz), 4.62 (dd, 1H, J = 7.3, 7.3 Hz), 7.37 (d, 1H, J = 2.5 Hz), 7.37-7.43 (m, 2H), 7.40 (d, 2H, J = 4 , 3 Hz), 7.48 (dd, 1H, J = 2.5, 8.6 Hz), 7.59 (d, 1H, j = 8.6 Hz), 14.89 (bs, IH); HPLC retention time 1.25 minutes (condition A); MS: m / z (MH ") 449. The following compounds were prepared using a procedure similar to Example 3-1 or 3-2 with departure and appropriate conditions:
Exem- Product Material of Par- Condi- HPLC- MS plo ntation of the RT (M "1) hydroly- (condition) Cl cí Exem- TFA, 1.30 449 plo3-3 y ^ rCI Íj ' triethyl-min. (A) wool, '° M ^ # ^ Y ° O HN YN · NX ° Í # Z:, n DCM, # "N #" n Acid (S) -2-
RT Terc-buti! ester ((R) -2- (2 ', 5'- of (S) -2-dichloro-biphenii- [[(R) -2- (2', 5'- 4-11) -1- (1H - dichloro-biphenyl-4-tetrazol-5- 1I) -1- (1H-ylcarbamoyl) - tetrazol-5-ethylamino] - ilcarbamoyl) - propionic ethylamino] - propionic "1 L1OH 1.28 381 ;;;; ~ yO G, "" 1M, min. (B) "° r # ^ H ;: NN" ° rc ,, ,, tl "N #" N NaOH 2M aq, (S) -2- Ethyl ester of á-EtoH , [(S) -2-biphenyl-4-acid (S) -2 - [(S) - RT 1I-1- (1H- 2-biphenyl-4-yl-1-tetrazol-5- (1 H- tetrazol-5-ilcarbamoyl) - ilcarbamoyl) - ethylamino] - ethylamino] - propionic propionic
Example- Product Material of Par- Condi- HPLC- MS plo N tide of RT (M "1) hydroly- (condition)
F F Example- "i TFA, 1.19 429" i plo3-5 - 6j 2i- ~ A »ò, ~ 1 triethylsin- (A) '° m; , N x ° r # ^ H ;: NN Iano, jj "N DCM, i:" N Acid (S) -2- RT Terc-butyl ester [(S) -2- (5 "fluorine-acid (S ) -2- 2'-methoxy - [(S) -2- (5'-fluoro-biphenyl-4-yl) -1- 2'-methoxy - (1 H-tetrazol-5-biphenyl-4-yl) -1- ilcarbamoyl) - (1 H-tetrazol-5-ethylamino] - ilcarbamoyl) - propionic ethylamino] - propionic Example- <%,: J ~: J NaOH 1.26 423 plo 3-6, JÚ ^ »2M aq , min. (B) '° r'ZLo x "r'tLo EtoH Yn o" # -N OH RT. Acid 5 - [(S) -3- Follic acid methyl ester 5-f (S) -3 - do by biphenyl-4-yl-2-biphenyl-4-yl-2-TFA, ((S) -1-carboxi- ((S) -1-tert-DCM, ethylamino) - butoxycarbonyl- RT propionylami- ethylamino ) - no] -1H- propionylamino] - pyrazola-3- 1H-pyrazola-3-carboxylic carboxylic acid
Exem- Product Material of Par- Condi- HPLC- MS plo ntation of RT (M "1) hydroly- (condi tion) Cl Exem-" TFA, 1.30 430 "I po37 C í) triethylmin - (A) '° r'bj ,, x ° r #' i: jj) lano, DCM, QN
RT (S) -2 - [(S) -2- Terc-butyl ester (3'-Chloro-acid (S) -2-biphenyl-4-yl) -1- [(S) -2- ( 3'-chloro- (3-hydroxy-biphenyl-4-yl) -1- (3-isoxazol-5-hydroxy-isoxazol-ylcarbamoyl) - 5-ylcarbamoyl) - ethylamino] - ethylamino] - propionic propionic Cl Exem-! 1 TFA, 1.40 430% triethylmin. (A) plo 3-8, ÁJ "'° R'y °> r ° O" Y ° lano, ° "Y> -m QN ° '77 °' T DCM, (S) -2- erc-butyl acid ester RT ((R) -2- (3'- (S) -2-chloro-biphenyl-4- [(R) -2- (3'-chloro-yl) -1- (3-hydroxy- biphenyl-4-isoxazol-5-yl) -1- (3-hydroxy-ylcarbamoyl) - isoxazol-5-ethylamino] - ilcarbamoyl) - propionic ethylamino] - propionic
Example- Product Material of Par- Condi- HPLC- MS plo ntation of RT (M "1) hydroly- (condition) Cl a ::" :: I, ÁJ íj,:: J NaOH 2M aq. , 1.16 min. (A) 429 "°; g ^ ti jN: NN" ° Í! Õ,: N N EtoH,
RT ll "N tl" "'EI (S) -2- {2-Tyl (3'-chloro- (S) -2- {2- (3'- | biphenyl-4-yl) acid ester - 1- chloro-biphenyl-4- [methyl- (1 h-yl) -1- [methyl- (1H-1 tetrazol-5-yl) - tetrazol-5-yl) - carbamoyl] - carbamoyl] - ethylamino} - ethylamino} - propionic propionic to Exem- I «t NaOH 1.38 429 po31oj ~ í | i ~" i 2M aq, min. (A) iI i "" jOijY ° EtoH, I "nz: ,,, ° '" Y'j, ,, N "N
RT, N "N i (S) -2- Ethyl ester of ac- | [(S) -2- (3'-chloro-acid (S) -2 - [(S) - | biphenyl-4-yl ) -1- 2- (3'-chloro- (1-methyl-1H-biphenyl-4-yl) -1- (1-tetrazol-5-methyl-1H-! Ylcarbamoyl) - tetrazol-5-ethylamino] - ilcarbamoil) - propionic ethylamino] - propionic
Exem- Product Material of Par- Condi- HPLC- MS plo ntation of RT (M "1) hydroli- (condition) to CI Exem- NaOH 1.43 429 plo3-11 ÁT" 2M aq, min. (A) EtoH, "° rcç ,, / N-N" ° r <,, / N "N
RT (S) -2- Ethyl ester of á- [(R) -2- (3'- acid (S) -2 - [(R) - chloro-biphenik4- 2- (3'-chloro-yl) -1- (1-methyl-biphenyl-4-yl) -1- (1- 1 H-tetrazol-5-methyl-1H-ylcarbamoyl) - tetrazo1-5-ethylamino] - ilcarbamoyl) - propionic ethylamino] - propionic E "" "_ O À> Q í7 ÀJ" "NaOH 0.82 505 plo 3-12 'n-'> ~ / 2M aq., Min. (C) '° r #" KÁ: NN "° r #" THERE: ,, N EtoH, tl-N · ll N RT Acid (S) -2- Ethyl ester of acid (S) -2 - [(S) - [(S) -2- (3'-chloro - 2- (3'-chloro-biphenyl-4-yl) -1- biphenyl-4-yl) -1- (1 H-tetrazol-5- (1 H-tetrazol-5-ylcarbamoyl) - ilcarbamoyl) - ethylamino ] -4- ethylamino] -4- phenyl-butyric phenyl-butyric
Exem- Product Material of Par- Condi- HPLC- MS plo N tide of RT (M "1) hydroly- (condition) Exem- jy ,, Xj" 'TFA, 0.42 429 plo 3-13 DCM , min. (C) -j -j "° r # 'HA: NN x ° r #' H &: ,, N RT jj" N jj-N Acid (S) -2- Terc-butyl ester [(S) -2- (S) -2-biphenyl-4-yl acid 3'-chloro -1- [(S) -2- (3'-chloro- (1 H-tetrazol-5-biphenyl-4-yl) -1- ilcarbamoyl) - (1 H-tetrazol-5-ethylamino] - ilcarbamoyl) - butyric ethylamino] - butyric Exem- jy ,, NaOH 1.25 491 N ° '""' a, çj "°; ç" ti HÇ ,, N ü "N Acid (S) -2- there) tl-N 2M aq., Min. (A) EtoH,
RT Ethyl ester of á- [(S) -2- (3'-chloro-acid 2- [2- (3'-biphenii-4-yl) -1- chloro-biphenyl-4- (1 H-tetrazole- 5- 1i) -1- (1h-ylcarbamoyl) - tetrazol-5-ethylamino] -3-ylcarbamoyl) - phenyl-ethylamino] -3- propionic phenyl-propionic
Example- Product Material of Par- Condi- HPLC- MS plo N tide of RT (M "1) hydroly- (condition) NaOH 1.28 491 p: o ': 75 I to S'" i ~ ~> at 2M aq, min. (A) '° yÀNÀy ° "° yÁNjy ° O" HNyNN O H HN-rNN EtoH, #N # "N
RT I (S) -2- Ethyl ester of á- [(R) -2- (3'- acid 2- [2- (3'- I chloro-biphenyl-4-chloro-biphenyl-4- 1I) -1- (1H-yl) -1- (1 tetrazol-5- H-tetrazol-5-ylcarbamoyl) - ilcarbamoyl) - I ethylamino] -3-ethylamino] -3-phenyl-phenyl-propionic propionic Cl 521 P: The "::" 6 | à + R 27, í ::: ": ', NaOH',: O"; ' ::: '1,35 i "° r # ^, À: NN °" Y "n RT #" rj "8" NI Acid (S) -3- Ethyl ester (S) -3- benzyloxy -2- benzyloxy-2 - [(S) - | [(S) -2- (3'-chloro- 2- (3'-chloro- | biphenyl-4-yl) -1- biphenyl-4-yl) -1- | (1H-tetrazol-5- (1 H-tetrazol-5-ylcarbamoyl) - ilcarbamoyl) - ethylamino] - ethylamino] - propionic propionic
Exem- Product Material of Par- Condi- HPLC- MS plo N tide of RT (M "1) hydroly- (condition) cyc Exem-" I NaOH 0.93 445 plo 3-17,%, d L »- also 2M aq, min. 2 , ("O" "EtoH, (A) '° r # ^, k: NN o hn yn-n RT tl" N tl "N
(S) -2- Ethyl ester of ac- [(S) -2- (3'-chloro-acid (S) -2 - [(S) - biphenyl-4-yl) -1- 2- (3 '-chlor- (1 H-tetrazol-5-biphenyl-4-yl) -1- ylcarbamoyl) - (1H-tetrazol-5-ethylamino] -3-ylcarbamoyl) - methoxy - ethylamino] -3- propionic methoxy - propionic Cl Example-, A NaOH 1.09 416 plo3-18,> ÃO i ~ "i 2M aq, min ^^"> 'L "MeOH, (A)" ° Y "ojY ° ° ir" °' ° ^ rt HNyN · NO HN YN · N
# "N jj-N
(S) -2- Ethyl ester of ac- [(S) -2- (3'-chloro-acid (S) -2 - [(S) - biphenyl-4-yl) -1- 2- (3 '-cioro- (1 H-tetrazo 1-5- biphenyl-4-yl) -1- ylcarbamoyl) - (1 H-tetrazok5-ethoxy] - ilcarbamoyl) - propionic ethoxy] -propionic
Example 3-3: 'H NMR (40OMHz, DMSO-d6 + TFA-Q Ci 1.48 (d, 3H, j = 7.1 Hz), 3.27 (dd, 1H, J = 8.8, 13 , 1 Hz), 3.47 (dd, 1H, j = 6.1, 13.4 Hz), 4.03 (dd, 1H, J = 7.1, 14.1 Hz), 4.47 (dd , 1H, J = 7.3, 7.3 Hz), 7.37-7.42 (m, 5H), 7.47 (dd, 1H, J = 2.8, 8.6 Hz), 7, 58 (d, 1H, J = 8.6 Hz), 14.89 (bs, IH) Example 3-4: 'H NMR (40OMHz, DMSO-c / 6) i5 1.37 (d, 3H, j = 6.8 Hz), 3.20 (d, 2H, J = 6.3 Hz), 3.73-3.87 (bs, IH), 4.25-4.38 (bs, IH), 7 , 33- 7.38 (m, IH), 7.36 (d, 2H, J = 8.1 Hz), 7.45 (dd, 2H, J = 7.4, 7.4 Hz), 7, 60-
w
89/103
7.66 (m, 4H). Example 3-5: 1 H NMR (40OMHZ, DMSOA6) 6 1.35-1.43 (m, 3H), 3.20 (bs, 2H), 3.71 (s, 3H), 3.75-4 .00 (m, IH), 4.36 (bs, IH), 7.05-7.20 (m, 3H), 7.31 (d, 2H, J = 8.3 Hz), 7.45 ( d, 2H, J = 8.3 Hz). 5 Example 3-6: 'H NMR (40OMHz, DMSOA6 + TFA-Q õ 1.48 (d, 3H, J = 7.3 Hz), 3.22 (dd, 1H, J = 7.6, 13, 6 Hz), 3.32 (dd, 1H, J = 6.6, 13.9 Hz), 3.96 (dd, 1H, J = 7.3, 14.4 Hz), 4.50 (dd, 1H, J = 7.3, 7.3 Hz), 6.97 (s, IH), 7.33-7.38 (m, 3H), 7.45 (t, 2H, J = 7.8 Hz ), 7.61-7.67 (m, 4H) Example 3-7: 'H NMR (40OMHZ, DMSOA6) δ 1.37 (bd, 3H, J =
10 4.8 Hz), 3.09-3.26 (m, 2H), 3.67-3.90 (m, IH), 4.10-4.37 (m, IH), 5.83 (s, IH) , 7.34 (d, 2H, J = 8.1 Hz), 7.40- 7.45 (m, IH), 7.48 (dd, 1H, J = 7.8, 7.8 Hz), 7.61-7.66 (m, IH), 7.66-7.73 (m, 3H). Example 3-8: 'H NMR (40OMHz, DMSOA6) δ 1.19-1.39 (m, 3H), 3.05-3.218 (m, 2H), 3.30-4.25 (m, 2H) , 5.83 (s, IH), 7.33 (d, 2H, J = 8.3 Hz), "15 7.40-7.44 (m, IH), 7.48 (dd, 1H, J = 7.8, 7.8 Hz), 7.61-7.73 (m, 4H) Example 3-9: 'H NMR (40OMHz, DMSOA6) 6 1.48-1.57 (m, 3H) , 3.05-3.47 (m, 2H), 3.728 / 3.31 (s "2, total 3H), 4.02-4.21 (m, IH), 5.61-5.82 (m , IH), 7.06-7.27 (m, IH), 7.34-7.76 (m, 7H). Example 3-10: 'H NMR (40OMHz, OMSO-d6) 6 1.35-1.43 (m,
20 3H), 3.13-3.34 (m, 2H), 3.35-3.95 (m, IH), 3.73 (s, 3H), 4.08-4.45 (m, IH ), 7.39-7.45 (m, 3H), 7.49 (dd, 1H, J = 7.8, 7.8 Hz), 7.62-7.75 (m, 4H). Example 3-11: 'H NMR (40OMHz, DMSO-cI6) 6 1.32-1.42 (m, 3H), 3.13-3.34 (m, 2H), 3.35-3.95 ( m, IH), 3.73 (s, 3H), 4.02-4.36 (m, IH), 7.37- 7.45 (m, 3H), 7.49 (dd, 1H, J = 7.8, 7.8 Hz), 7.61-7.74 (m, 4H). Example 3-12: 'H NMR (400 MHz, DMSOAJ ppm 1.67 - 1.90 (m, 2 H), 2.59 (t, j = 7.7 Hz, 2 H), 2.96 (dd, j = 13.6, 7.3 Hz, 1 H), 3.07 (dd, J = 13.6.7.1 Hz, 1H), 3.11 - 3.17 (m, 1H), 3.78 (t, j = 7.1Hz, 1H), 7.07-7.18 (m, 5H), 7.33 (d, j = 8.3Hz, 2H), 7.37-7.42 (m, 1H), 7.46 (t, j = 8, OHz, 1H), 7.61 (d, j = 8.3 HZ, 3 H), 7.68 (t, j = 1.8 Hz , 1 H), 12.02 (br. S, 1 H), 15.89 (br. 30 s., 1 H) Example 3-13: 1 H NMR (400 MHz, DMSOAJ çj ppm 0.91 (t, j = 7.5 Hz, 3 H), 1.67 - 1.80 (m, 2 H), 3.08 - 3.27 (m, 2 H), 3.56 (br. s. , 3 H),
4.16 (br. S., 1 H), 7.34 (d, j = 8.3 Hz, 2 H), 7.41 (ddd, j = 7.8, 2.0, 1.0 Hz , 1 H), 7.47 (t, j = 7.8 Hz, 1H), 7.61 (dt, j = 8.0,1,5,1,1Hz, 1H), 7.64 (d, j = 8.3 Hz, 2 H), 7.68 (t, j = 1.8 Hz, 1H), 12.27 (br.s., 1H), 16.09 (br.s., 1H). Example 3-14: 'H NMR (400 MHz, DMSO-d6) δ ppm 2.83 - 2.91 5 (m, 2 H), 2.91 - 3.11 (m, 2 H), 3.56 (br. s, 2 H), 3.88 (br. s, 1 H), 7.14 - 7.20 (m, 3 H), 7.20 - 7.26 (m, 2 H) , 7.29 (d, j = 8.3 Hz, 2 H), 7.38 - 7.42 (m, 1 H), 7.47 (t, j = 7.8 Hz, 1H), 7.56 -7.63 (m, 3H), 7.68 (t, j = 1.9Hz, 1H), 11.92 (br. S., 1 H), 15.91 (br.s., 1 H) . Example 3-15: 'H NMR (400 MHz, DMso-dj ppm 2.81 - 3.03 10 (m, 4H), 3.51 (t, j = 6.4Hz, 1H), 3.79 ( t, j = 6.2Hz, 1H), 7.14-7.29 (m, 7H), 7.38 - 7.42 (m, 1 H), 7.47 (t, j = 7.8 Hz , 1 H), 7.55 (d, j = 8.1 Hz, 2 H), 7.59 (dt, J = 7.6.1.4 Hz, 1H), 7.66 (t, j = 1 , 9Hz, 1H), 11.78 (br.s., 1H), 15.86 (br-s., 1 - H) Example 3-16: 'H NMR (400 MHz, DMSO-dj Ci ppm 2 , 97 (dd, - "" 15 1H, J = 7.1, 13.6 Hz), 3.07 (dd, 1H, J = 6.3, 13.6 Hz), 3.47 (dd, 1H, J = 5.1,
W 5.1 Hz), 3.58 (d, 2H, J = 5.1 Hz), 3.87 (dd, 1H, J = 6.6 Hz), 4.41 (d, 1H, j = 12 , 4 Hz), 4.46 (d, 1H, J = 12.1 Hz), 7.22-7.36 (m, 7H), 7.38-7.42 (m, IH), 7.47 (t, 1H, j = 7.8 Hz), 7.58-7.64 (m, 3H), 7.68 (t, 1H, J = 1.8 Hz), Example 3-17: 'H NMR (400 MHZ, DMso-dj ppm 2.97-3.13 20 (m, 2H), 3.21 (S, 3H), 3.40-3.61 (m, 3H), 3.76-4 , 01 (m, IH), 7.34 (d, J = 8.34 Hz, 2H), 7.38 7.43 (m, IH), 7.47 (t, J = 8.08 Hz, IH ), 7.59-7.65 (m. 3H), 7.69 (bt, J = 1.77 Hz, IH). Example 3-18: 1H NMR (400 MHZ, DMSO-d6) d ppm 1, 31 (d, j = 6.6Hz, 3H), 3.05-3.18 (m, 2H), 4.03 (q, j = 6.8Hz, 1H), 4.58 (t, j = 6 , 3 25 Hz, 1H), 7.35 (d, j = 8.1 Hz, 2H), 7.37-7.42 (m, 1H), 7.47 (t, j = 7.8 Hz, 1H) , 7.55 -7.65 (m, 3 H), 7.66-7.72 (m, 1 H), 12.13 (br. S., 1 H), 12.69 (br. S. , 1 H), 15.96 (br. S., 1 H) Example 3-19: (S) -2 - [(S) -2- (3'-chloro-biphenyl-4-yl) -1 acid - (1 H-tetrazol-5- icarbamoyl) -ethylamino] -3-hydroxy-propionic 30 Example 3-20: (S) -2 - [(S) -2-biphenyl-4-yl-1- (1 H-tetrazol-5-ylcarbamoyl) - ethylamino] -3-hydroxy-propionic
Cl Cf ~ l (^ <y: J ~ Z) I "~ r: JI,, J ~» HO ~ dj ~ ij HO ~ d- ~ ^ J '° r # ^ H ;: ,,. N "' ° r # ^ Hk: ,,. N '° rM ^ H ;: N ,,, tl "N' tl" '"tl" "To a solution of (S) -3-benzyloxy-2- acid ethyl ester [(S) -2- (3'-chloro-biphenyl-4-yl) -1- (1 H-tetrazoI-5-i | carbamoi |) -ethi | amino] -propionic (47 mg, 0.090 mmol) in EtOAc (1 ml) and EtOH (1 ml) were added 5 ° / 0 Pd-C (9.65 mg, 0.0045 mmol). H2 gas was flasked and the reaction mixture was stirred at 50 ° C. ° C for 6 hours The reaction mixture was filtered through a celite pad and the filtrate was concentrated.The residue was purified by reverse phase HPLC (Column Sunfire C-18, eluent: TFA O, i ° / o in H, O / CH3CN) giving acid (S) -2 - [(S) -2- (3'-c] oro-bipheni | -4-i [) - 1- (1H- "10 tetrazole -5-ylcarbamoyl) -ethylamino] -3-hydroxy-propionic acid (S) -2 - [(S) -2- - .- biphenyl-4-yl-1- (1 H-tetrazok5-ylcarbamoyl) -ethylamino ] -3-hydroxy-propionic. - (S) -2 - [(S) -2- (3'-chloro-biphen ik4-yl) -1- (1 H-tetrazol-5-ylcarbamoyl) -ethylamino] -3-hydroxy-propionic acid; NMR (40OMHz, DMSO- &) çj ppm 2.99-3.14 (m, 2H), 3.50-3.67 (m, 3H), 3.86-3.98 (m, IH), 7 , 34 (d, 2H, j 15 = 8.3 Hz), 7.38-7.42 (m, IH), 7.47 (t, 2H, J = 7.8 Hz), 7.58-7 , 70 (m, 4H)): HPLC retention time 1.17 minutes (condition A); MS: m / z (MH ")
431. (S) -2 - [(S) -2-bipheni | A-i | -1- (1H-tetrazo | -5-ylcarbamoy |) - ethylamino] -3-hydroxy-propionic acid; NMR (40OMHz, DMSO-C16) δ ppm 3.18 (dd, 20 1H, J = 7.6, 13.4 Hz), 3.24-3.36 (m, IH), 3.66-3, 87 (m, 3H), 4.17-4.37 (m, IH), 7.32 (d, 2H, j = 8.1 Hz), 7.32-7.38 (m, IH), 7 , 44 (t, 2H, J = 7.8 Hz), 7.56-7.67 (m, 4H)): HPLC retention time 1.00 minutes (condition A); MS: m / z (MH ") 397. Example 4-1: (S) -3- (3'-c | oro-biphenylA-i |) -2 - ((S) -2-metanosu | foni | amino -1-methyl- 25 2-oxo-ethylamino) -N- (1 H-tetrazol-5-yl) -propionamide
Cl CI,: L} | : ~ I O
HZ 3 '"jjrs,:": ":: r #", k: ,,, S "NO Example 4-1 was prepared using a procedure similar to Example 1-1. NMR (40OMHZ, DMSO-d6 + TFA-Q çjj 1.21 (d, J = 6.32 Hz, 3H), 2.92-3.05 (m, IH), 3.05-3.14 (m, IH), 3.17 ( s, 3H), 3.34-3.46 (m, 5 IH), 3.82-3.95 (m, IH), 7.35 (d, J = 8.08 Hz, 2H), 7, 39-7.43 (m, IH), 7.47 (t, J = 7.83 Hz), 7.60-7.66 (m, 3H), 7.68-7.22 (m, IH) HPLC retention time 1.21 minutes (condition A): MS: m / z (MH ") 492, Starting materials or intermediates were prepared as follows: - 10 intermediate 1: Acid (S ) -3- (3'-chloro-biphenik4-yl) -2 - ((S) -1-ethoxycarbonyl-ethylamino) -propionic Gl Cl ~ b 'ho "b I" ^ ~ ij Ch / ~ .JJ o V pd (pphg ,. Na, CCj, aq. DlidE, & 5 "C., A ~ j, | j ÁjY ^ Z, ° a · p · '" ÁAjy ° oh Cl CI ^ 2 °, Sy: i: I i- "jJ F 1) Bn8r. NaHCO ,, DMF ^ ~ 'EtàN, DCM u> _ ~ ij 2) 4M HCl in dioxane ^ aapa 2 ^ - ° -6 ^ 6 HC' ° ~ Á"> J "" "'° r7" r: ~ j ci - tj Pd / C, EtClAc, A ~ .J ""' "" 1Ír7jY °
The immersed OH 1 Step 1: To a solution of 8oc-L-4-bromophenylalanine (15.0 g,
43.6 mmol), 3-chlorophenylboronic acid (8.52 g, 54.5 mmol), and tetra-cis (triphenylphosphine) palladium (0) (1.51 g, 1.31 mmol) in 1,2-dimethoxyethane (180 mL) 2M aqueous NaCO3 solution (33 mL) was added. The reaction mixture was heated to 85 ° C.
After stirring for 2 hours, reaction mixture 5 was cooled to room temperature and diluted with EtOAC.
The mixture was washed with 1M HCl and brine.
The organic layer was dried with Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 10% MeOH in dichloromethane) to give (S) - 2-tert-butoxycarbonylamino-3- (3'- chloro-biphenyl-4-yl) -propionic (1 3.6 g). 'H 10 NMR (40OMHz, cDcb) δ 1.43 (s, 9H), 3.08-3.17 (m, IH), 3.21-3.31 (m, IH), 4.65 (bs , IH), 5.01 (bs, IH), 7.23-7.32 (m, 3H), 7.45-7.50 (m, 2H), 7.52-7.60 (m, IH ), 7.63-7.70 (m, 2H); MS: m / z (MH ") 376. Step 2: To a solution of (S) -2-tert-butoxycarbonylamino-
- 3- (3'-chloro-biphenyl-4-yl) -propionic (12.9 g, 34.3 mmol) in DMF (130 mL) - benzyl bromide (8.16 mL) was added , 68.6 mmol) and NaHCO3 (5.77 g, 68.6 +
- mmol). After stirring at room temperature overnight, the reaction mixture was diluted with EtOAC.
The mixture was washed with H2O and brine, dried with Na2SO4, and concentrated under reduced pressure.
The residue obtained was treated with 4M HCl in dioxane (30 ml) and stirred for 2 hours.
The reaction mixture was concentrated and the resulting residue was rinsed with / Pr2O to give benzyl ester of (S) -2-amino-3- (3'-chloro-biphenyl-4-yl) -propionic (11.2 g) . 'H NMR (40OMHZ, DMSO-C / 6) ç 3.14 (dd, 1H, J = 7.7, 12.0 Hz), 3.27 (dd, 1H, J = 5.9, 12.0 Hz), 4.38 (dd, 1H, J = 5.9, 7.7 Hz), 5.15 (s, 2H), 7.23-7.27 (m, 2H), 7.30-7 , 34 (m, 5H), 7.42-7.45 (m, IH), 7.51 (dd, 1H, J = 25 7.6, 7.6 Hz), 7.61-7.66 ( m, 3H), 7.69 (dd, 1H, J = 1.8, 1.8 Hz), 8.64 (bs, 2H); MS: m / z (MH ") 366. Step 3: To a solution of benzyl ester of (S) -2-amino-3- (3'-chloro-biphenyl-4-yl) -propionic (10.0 g, 24.9 mmol) in dichloromethane (100 mL) triethylamine (10.4 mL, 74.6 mmol) was added at 0 ° C.
After stirring for 10 min, ethyl (R) -2- (trifluoromethylsulfonyloxy) propionate (9.3 mL, 49.5 mmol) was added at room temperature and stirred for 1 hour.
Triethylamine (10.4 ml, 74.6 mmol) and ethyl (R) -2- (trifNormethylsulfonyloxy) propionate (9.3 ml, 49.5 mmol) were added at room temperature and stirred for an additional 2 hours.
The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure.
The residue obtained was purified by silica gel column chromatography (EtOAc / heptane) to give benzyl ester 5 of (S) -3- (3'-c | oro-bipheni | Ai |) -2 - (( S) -1-ethoxycarboni] -eti | amjno) - propionic (10.6 g). 'H NMR (40OMHZ, CDC | 3) Ci 1.21 (t, 3H, J = 7.3 Hz), 1.27 (d, 3H, J = 6.8 Hz), 1.89 (bs, IH ), 2.95-3.07 (m, 2H), 3.38 (dd, 1H, J = 6.8, 14.8 Hz), 3.69 (dd, 1H, J = 7.1, 7 , 1 Hz), 4.06-4.17 (m, 2H), 5.06 (d, 1H, J = 12.1 Hz), 5.12 (d, 1H, J = 12.1 Hz), 7.20-7.25 (m, 4H), 7.28-7.34 (m, 4H), 10 7.35 (dd, 1H, J = 7.6, 7.6 Hz), 7.41 -7.46 (m, 3H), 7.53 (dd, 1H, J = 1.5, 1.5 Hz); MS: m / z (MH ") 466. Step 4: A suspension of benzyl ester of (S) -3- (3'-chloro-biphenik4-yl) -2 - ((S) -1-ethoxycarbonylketylamino) - propionic (10.0 g, 21.5 mmol) and 5 ° /, of Pd on carbon (0.914 g) in EtOAc (200 mL) was treated with H2 (ba- "15 wool) and stirred at 10-15 ° C for 1.5 hours and at room temperature for 0.5 hours.
The resulting precipitate was dissolved in methanol and filtered through a pad of celite.
The filtrate was concentrated under reduced pressure and the residue obtained was recrystallized from EtOAc to give (S) -3- (3'-chloro-biphenyl-4-yl) -2 - ((S) -1-ethoxycarbonyl- ethylamino) -propionic (5.6 g). The mother liquor was concentrated under reduced pressure and purified by silica gel column chromatography to give an additional amount of (S) -3- (3'-chloro-biphenyl-4-yl) 2 ((S) -1 -etoxycarbonii-ethylamino) propionic (1.4 g). 'H NMR (40OMHz, DMSO-C / 6) 15 1.13 (t, 3H, J = 7.1 Hz), 1.15 (d, 3H, J = 6.8 Hz), 2.85 (dd , 1H, j = 7.1, 14.1 Hz), 2.93 (dd, 1H, j = 6.3.13.6 Hz), 3.30-3.37 (m, IH), 25 3 , 48 (dd, 1H, J = 6.5, 6.5 Hz), 4.03 (q, 2H, J = 7.1 Hz), 7.32 (d, 2H, J = 8.3 Hz) , 7.38-7.43 (m, IH), 7.48 (dd, 1H, j = 7.8, 7.8 Hz), 7.59-7.65 (m, 3H), 7.70 (dd, 1H, J = 2.0, 2.0 Hz); MS: m / z (MH ") 376. Intermediate 2: (S) -2 - ((S) -1-tert-butoxycarbonyl-ethylamino acid) -3- (2 ', 5'-dichloro-biphenyl-4- il) -propionic
: t, jL.H '"u j. ~, JJ 1) Tf2O.
DCM I, "b) J, ~ ,, J djjj Êl Dá '" "'" t, Z, "'t' '" "" °: t.'r "' j '": Z: Áj "" " "Ò" 'O> "" "' b" 'OH °
The same procedures described in step 1 (2,5-dichlorophenylboronic acid was used instead of 3-chlorophenylboronic acid) and in step 2 for the preparation of intermediate 1 were used to prepare 5 benzylester hydrochloride ((S ) -2-amino-3- (2 ', 5'-dichloro-biphenyl-4-yl) - propionic.
Step 3 ': t-butyl (R) -2- (trifluoromethylsulfonyloxy) propionate was prepared from (R) -2-hydroxy-propionic acid tert-butylester (602 mg, 4.12 mmol), triflic anhydride ( 0.696 ml, 4.12 mmol) and 2,6-lutidine (0.480 10 ml, 4.12 mmol) in DCM (5 ml). To a suspension of benzyl hydrochloride ((S) -2-amino-3- (2 ', 5'-dichloro-biphenik4-yl) -propionic acid ester (600 mg,>
. 1.38 mmol) in dichloromethane (10 mL) triethylamine (0.574 mL, 4.12 mmol) was added at 0 "C.
After stirring for 10 min, a half amount of the freshly prepared (R) -2- (triHúormetüsulfonyloxy) t-butyl propionate 15 was added at room temperature and stirred for 1 hour.
Triethylamine (0.574 mL, 4.12 mmol) and the residue of (R) -2- (trif | uormeti | su | foni | oxy) t-butyl propionate were added at room temperature and stirred for 2 hours additional.
The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure.
The residue obtained was purified by silica gel column chromatography (EtO-Ac / heptane) to give benzyl ester of (S) -2 - ((S) -1-tert-butoxycarboni | -ethi | amino) -3 - (2 ', 5'-dic | oro-bipheni | -4-i!) - propionic (580 mg). 1 H NMR (40OMHZ, CDCb) δ 1.24 (t, 3H, J = 6.8 Hz), 1.41 (s, 9H), 3.00-3.07 (m, 2H), 3.26 (dd, 1H, J = 7.1, 13.9 Hz), 3.70 (dd, 1H, J = 7.1, 7.1 Hz), 5.09 (s, 25 2H), 7.20 -7.42 (m, 12H); MS: m / z (MH ") 528. Step 4 ': A suspension of benzyl ester of (S) -2 - ((S) -1- tert-butoxycarbonyl-ethylamino) -3- (2', 5 ' -dic | oro-biphenyl-4-i!) - propionic (580mg, 1.10 mmol) and 5 ° /, Pd on carbon (0.146 g) in EtOAc (10 mL) were treated with H2 (flask) and stirred at RT for 1.5 hours The resulting precipitate was dissolved in methanol and filtered through a pad of celite The filtrate was concentrated under reduced pressure and the residue obtained was recrystallized from EtOAC to give (S) -2 - ((S) acid -1-tert-butoxycarbonyl-ethylamino) -3- (2 ', 5'- dichloro-biphenyl-4-yl) -propionic (438 mg).' H NMR (40OMHz, DMSO-c / 6) õ 1.12 (d, 3H, J = 7.1 Hz), 1.35 (s, 9H), 2.84 (dd, 2H, J = 7.3, 13.6 Hz), 2.95 (dd, 2H, J = 6.1, 13.6 Hz), 3.20 (dd, 1H, j = 6.8, 13.6 Hz), 3.48 (dd, 1H, J = 6.1, 7.3 Hz ), 7.33 (d, 2H, J = 8.6 Hz), 7.37 (d, 2H, J = 8.3 Hz), 7.42-7.49 (m, 2H), 7.60 (d, 2H, J = 8.6 Hz); MS: m / z (MH ") 438. The following intermediates were prepared using a procedure similar to intermediate 1 or intermediate 2 with appropriate reagent: Intermediate Intermediate Reagent HPLC-RT MS | median I (condi- (M "1) river N tion) lnter- Phenylbo acid- 0.71 min 342 | median I CP ronic was (C) river 3 employed" ° r # ^ i, ° instead of Acid (S) -3-biphenyl-4-yl-2-acid 3- ((S) -1-ethoxy chlorophenyl-carbonyl-ethylamino) - ronic in the e- propionic tapa 1 inter-
F Acid 2- 1.07 min 418 median, -O methoxy -5- (C) river 4 -,> L fluorine- x ° r # ^ i, ° phenylboronic acid was used- (S) -2 - (( S) -1-tert- instead butoxycarbonyl-ethylamino) -3- acid 3- (5'-fluorine-2'-methoxy-biphenyl-4-chlorophenyl-yl) -propionic tonic in the e-cover 1 lnter- Intermediate Reagent HPLC-RT MS medium- (condi- (M + 1) river N tion) lnter- "I Phenylbo acid- 1.05 min 370 medium, j" "ronic was (C) river 5 employed x ° r # ^ i: instead of the (S) -3-biphenyl-4-yl-2-acid 3- ((S) -1-tert-butoxycarbonyl-chlorophenylbo-ethylamino) -propionic acid in the 1 Int "e" tapa '- Q íj' c 'Ethyl ester of 1.39 min 466 median / acid (R) -2- (C) river 6 -J r "hydroxy-4-" ° r2 ^ dH ° phenyl-butyric was used - Ethyl ester of (S) -2- acid instead of [(S) -1-carboxy-2- (3'-chloro- of tert-butyl bipheni | -4-i |) -ethi | amino] A- feni | - (R) -2- hydroxy-propionic acid ester in step 3 'inter- Terc-butyl 1.15 min 418 >> ci mediá- (C) rio7 ir "do (R) ) 2- x ° r # ^ bH ° hydroxy- Terc-butyl acid ester (S) - butyric was 2 - [(S) -1-carboxy-2- (3'-chloro- employed biphenyl-4-yl) -ethylamino] - instead of butyric tert-butyl ester- (R) -2 acid -hydroxy- propionic in step 3 '
Inter- Intermediate HPLC-RT MS Reagent medium (condi- (M + 1) river N tion) Inter- Ethyl ester 1.27 min 452 ~ Cl medium-acid (R) -2- (C) river 8 a, C) hydroxy-3- "° r # ^ j: phenyl- (S) -3- (3'-chloro-biphenyl-propionic acid was 4-yl) -2 - ((S) -1-ethoxycarbonyl-2- employed phenyl-ethylamino) -propionic instead of tert-butyl ester- (R) -2-hydroxy-propionic acid in step 3 'intermediate 9: [1- (4-Methoxy-benzyl) -1 H-tetrazole- 5-yl] -methyl-amine '"-n / hY -'" y, N -N paraformaldehyde. / N "N HJY 7" dN N il PMEICI, C * CO ,, DMF (NaOMe, NaBH ", , MeOH »T" (Í) k _f "'
OO / / To a suspension of 5-amino-1H-tetrazole (1.50 g, 17.6 mmol) in DMF (30 mL) were added CS2CO3 (8.62 g, 26.4 mmol) and PMBCI (2, 90 g, 18.5 mmol). After stirring at 60 ° C for 3 hours, the reaction mixture was cooled to room temperature and diluted with EÉOAC. The mixture was washed with H2O and brine, dried with Na2SO4, and concentrated under reduced pressure. The residue was diluted with DCM and the resulting precipitate was collected by filtration to give 1- (4-methoxy-benzyl) -1 H-tetrazol-5-ylamine (0.625 g). 1 H NMR (40OMHZ, DMSO-C / 6) δ 3.73 (s, 3H), 5.27 (s, 2H), 6.78 (s, 2H), 6.92 (d, 2H, J = 8.8 Hz), 7.21 (d, 2H, J = 8.8 Hz). Then, to a suspension of 1- (4-methoxy-benzyl) -1H-tetrazol-5-ylamine (60Omg, 2.92 mmol) in MeOH (10 mL) were added paraformaldehyde (132 mg, 4.39 mmol) and sodium methoxide (632 mg, 25 ° 6 by weight in MeOH). The mixture was refluxed for 30 min until the suspension became a clear solution. The mixture was cooled to room temperature and sodium borohydride (332 mg, 8.77 mmol) was added in portions.
The reaction mixture was refluxed again for 15 min.
After cooling to room temperature, the reaction was terminated with H2Õ.
The mixture was diluted with EtOAC, partially concentrated, and washed with brine.
The organic layer was dried with Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (eluent: MeOH 10 ° / o in DCM) to give [1- (4-methoxy-benzyl) -1H-tetrazol-5-yl] - methyl-amine (0, 63 g). 1 H NMR (40OMHZ, CDCl 3) δ 3.00 (d, 3H, J = 5.3 Hz), 3.61 (bs, IH), 3.82 (S, 3H), 5.25 (S, 2H ), 6.91 (d, 2H, J = 8.8 Hz), 7.16 (d, 2H, j = 8.8 Hz); MS: m / z (MH ") 220. The following intermediates were prepared using a procedure similar to Intermediate 1 or Intermediate 2 with the appropriate reagent: Intermediate- Intermediate HPLC-RT Reagent MS daily N (condi- (M + 1) tion) Intermittent ethyl ester 1.41min 482 daily 9 "J r,; (R) -3- (C)> O ^ d ~ -» benzyloxy-2-hydroxy- r7 ^ c, ° propionic acid was (S) -2 - ((S) -2- used to benzyloxy-l- instead of ethyl és- etoxycarbonyl-ethylamino) - acid ester (R) - 3- (3'- chloro-biphenyl-4-yl) - 2-hydroxy-propionic propionic in step 3 Intermediate- Intermediate HPLC-RT MS Reagent daily N (condi- (M + 1) tion) Intermediate- Ã 'Ethyl ester of á- 0.56min 496 (R) -2- (C) '"" °' ° ~ £)> O ~ A »I hydroxy-3-methoxy-° r7 ^ c, ° propionic acid was (S) -3- (3 ') -chloro- used to biphenyl-4-yl) -2 - ((S) -1- instead of ethyl é- ethoxycarbonyl-2-methoxy-acid (R) - ethylamino) -propionic 2-hydroxy-propionic in step 3 Intermediate 11: (S) -3- (3'-Chloro-biphenylA-yl) -2 - ((S) -1-ethoxycarbonyl-ethoxy acid) ) -propionic
ÇJ Br Cl Pd (PPh}, ÁG "':: 9 L ~ aq. Na, CO, / DME, ojY ° +'> ~» a ,,,, µ Bapa 2 u hojy ° OH OH
OH 3 "c 'a0rL:" 4: íj ,, A L: HMDs / r: F £)' aapa 3 »'°" t: O "° r °' to H2 / Pd / C / EtOAc µ Agjlc | "" "'" ° ÍÍ ^ ° JY °
OH Etapal: To a mixture of 4-bromo-L-phenylanine (2.5 g, 10.24 mmol) and acetic acid solvent (20 ml) and water (75 ml) in an ice bath, was added , a dropwise solution of sodium nitrite (2,120 g,
30.7 mmol) in water (20.00 ml). The mixture was slowly warmed to room temperature and stirred overnight.
Methylamine in THF (20.48 ml, 41.0 mmol) was slowly added dropwise to the suspension and the mixture was clear and stirred at room temperature for 1 hour.
The mixture was concentrated to remove THF and was extracted with EtOAC.
The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as an off-white solid: 1.7 g (yield: 43%). HPLC retention time = 0.83 minutes (condition A); MS (m "2) = 246. 10 Step 2: To a solution of (S) -3- (4-bromo-phenyl) -2-hydroxy-propionic acid (1.5 g, 6.12 mmol) in DME (60 ml) at room temperature, 3-chlorobenzenoboronic acid (1.436 g, 9.18 mmol) and then Na2CO3 aq. (6.12 ml, 12.24 mmol) and Pd (Ph3P) 4 (0.212 g, 0.184 mmol) The mixture was stirred at 85 ° C overnight.
More EtOAC was added to the reaction and "" 15 acidified with 1N HCl to pH-5. The combined organic layers were washed with brine and dried with anhydrous sodium sulfate, filtered and combined.
The residue was purified by HPLC (ACN-H2O 20 to 80% (TFA 0.1 ° / o)) to give the white solid: 550 mg (yield: 32 ° / o). HPLC retention time = 1.23 minutes (condition A); MS (ml) = 275. 20 Step 3: To a solution of benzyl ester of (S) -3- (3'-chloro-biphenyl-4-yl) -2-hydroxy-propionic acid (282 mg, 0.769 mmol) in THF (6 ml) at -78 ° C, L1HMDS / THF (1.999 ml, 1.999 mmol) was added and the resulting yellow mixture was stirred at -78 ° C for 25 minutes, then (R ) -etija-2- (trif | úormeti | su | foni | oxy) (0.860 ml, 4.61 mmol) at -20 ° C.
In 1 hour the reaction was almost complete.
The reaction was quenched with NH4C | sat. and was extracted with EtOAc.
The combined organic layer was washed with brine, filtered and concentrated.
The residue was purified by HPLC (ACN-H2O 75 to 100% (0.1% TFA)) to give the product: 140 mg (yield: 39%). HPLC retention time = 1.57 minutes (condition C); MS (m + 1) 30 = 467. Step 4: A benzylester mixture of (S) -3- (3'-chloro-biphenylA-yl) -2 - ((S) -1-ethoxycarbonyl-ethoxy) - propionic and wet Pd / C 10 ° / o at
EtOAC was hydrogenated under an H2 balloon for 30 minutes. The reaction was filtered from the catalyst and concentrated. The residue was purified by HPLC (ACN-H2 6 to 70% (0.1% TFA)) to give an oil: 128 mg. HPLC retention time = 1.07 minutes (condition C); MS (m-1) = 375.
Intermediate 12: (S) -3- (3'-c | Oro-bipheni | A-yl) -2 - ((S) -2-metanosu | foni | a-mino-1-methyl-2-oxo- ethylamino) -propionic ci Cl "^ ~ ~ j CJ,> 1" J 1) Triphosgene, N.HCO, aq, dcm 4 "T TFA. dc m = V ~ 1 2) Methanesulfonamide, E4 l, dcm ° ú ^ í; WJ "" '' "'° rcto" ""' a Cl Cl ii,,, - ÇÍ ~ "=".,.: F í9 "P: '": r jí: o "" "O "'" "0 y7 d, Step 1: To a benzyl ester solution of (S) -2 - ((S) -1- tert-butoxycarbonj | -ethi | amino) -3- (3'-c | oro-biphenyl-4-i1) -propionic (1.12 g, 2.27 mmol) in DCM (5 mL) was added TFA (5 mL) After being stirred for 3 hours, the reaction mixture was concentrated and purified by silica gel column chromatography (eluent: MeOH 10 ° / o in DCM) to give benzyl ester of (S) -2 - ((S) -1-carboxy-ethyl | amino) -3- (3 '-c | oro-bipheni | Ai |) - propionic. MS: m / z (MH ") 438; HPLC retention time 0.73 min (H-PLC condition C). Step 2: To a benzyl ester solution of (S) -2 - ((S) -1- carboxy-ethylamino) -3- (3'-chloro-biphenyl-4-yl) -propionic (600 mg, 1 , 37 mmol) in DCM (7 mL) and saturated aqueous NaHCO3 solution (2 mL) was added triphosgene (407 mg, 1.37 mmol) - After being stirred for 0.5 hours, the reaction mixture was diluted with EtOAc and stirred for an additional 0.5 hours until gas generation was completed. The organic layer was separated, washed with brine and concentrated. This was dissolved in DCM (7 ml) and methanesulfonamide (195 mg, 2.06 mmol) was added. After being stirred
at RT for 1 hour, the reaction mixture was diluted with EtOAc and washed with brine.
The organic layer was dried with Na2SO4, concentrated and purified by silica gel column chromatography (eluent: MeOH 10 ° / o in DCM) to give benzyl ester of (S) -3- (3'-c | oro) -bifeni | -4-i |) -2 - ((S) -2- 5 methanesulfoni | amino-1-methyl-2-oxo-etj | amino) -propionic.
MS: m / z (M H ") 515; HPLC retention time 1.58 min (HPLC condition A). Step 3: This was dissolved in EtOAC.
Pd-C 5 ° / 0 (146 mg) was added and hydrogenated with H2 balloon at RT for 1 hour.
The reaction mixture was filtered through a pad of celite and the filtrate was concentrated.
The resulting solid 10 was recrystallized from MeOH to give (S) -3- (3'-chloro-bipheni | -4-ii) -2 - ((S) -2-methanesulfoni | amino-1-methyl | - acid 2-oxo-ethyl | amino) -propionic.
MS: m / z (MH ") 425; HPLC retention time 1.14 min (HPLC condition A). Intermediate 12-2: benzyl ester of (S) -2 - ((S) -1-tert- butoxycarbonyl- "15 ethylamino) -3- (3'-chloro-biphenyl-4-i) -propionic Cl / I iI d-G "" - +, g! Y "::: k: n '° 27 to Intermediate 12-2 was prepared using a procedure similar to intermediate 1 and intermediate 2 with the appropriate reagent.
MS: nVz (MH ") 494; HPLC retention time 1.50 min (HPLC condition 20 C). It can be seen that the compounds of the invention are useful as inhibitors of neutral endopeptidase activity (EC 3.4.24.11) and for - they are both useful in the treatment of diseases and conditions associated with neutral endopeptidase activity (EC 3.4.24.11) as well as the diseases reported here.
It will be understood that the invention has been described by way of example only and that modifications can be made even if it remains within the scope and spirit of the invention.

权利要求:
Claims (24)
[1]
1. Compound, characterized by the fact that it presents the formula (I '): oo x'jY "7" ^ gr' R1 I R4 C (R6) " (R2) m / i '5 where: X' is OH, -O-C1-7atqu | la, -NR'R ', -NHS (O) 2-C1-7a | qui | a or -. NHS (O) 2-benzyl | a, where R "e Rb for each occurrence are, independently, H or C1-7a | qui | a; · R 'is H, C1-6 alkyl or C6-10-ari | -C1-6 alkyl, where alkyl is optionally substituted with benzyloxy, hydroxy or C1-6 alkoxy; for each occurrence, R' is , independently, C1-6-a | coxy, hydroxy, halo, C1-6-a | chi | a, cyano or trifluoromethyl; A'éOouNR '; R4 and R5 are independently H or C1-6 alkyl; A1 is a C1-3a | chylene bond or chain; R3 is a 5- or 6-membered heteroaryl, C6-10-aryl or C3-7-cycloalkyl, where each heteroaryl, aryl or cycloalkyl is optionally substituted with one or more groups independently selected from the group consisting of C1-6a | chi | a, halo, ha | oC1-6a | chiI, C1-6a | coxy, hydroxy, 20 CO, H and CO, C, -6here | a; R6 for each occurrence is, independently, halo, hydroxy, Cj-7a | coxy, halo, C1-7here | a or ha | o-C1-7a | qui | a; or R4, A1-R3, together with the nitrogen to which R4 and A1-R3 are linked, form a heterocyclyl with 4 to 7 members or a heteroaryl 25 with 5 to 6 members, each of which is optionally substituted with one or more groups independently selected from the group consisting of C1-6a | qui | a, halo, ha | oC1-6aiqui | a, c1-6a | coj, hydroxy, CO2H and CO2C1-
6a | qui | a; and méOouuminteirode1 to 5; seOouuminium from 1 to 4, or pharmaceutically acceptable salts thereof.
5
[2]
2. Compound according to claim 1, characterized by the fact that it presents the formula I: O R5 O x'À! Jn: ^ '"R' C: l (R ')' <j (R2 ) "j where: ¥" X 'represents OH or O-C1-6-a | qui | a:.
. "10 R 'is H, C1-6 alkyl or C6-10-ari | -C1-6 alkyl; for each occurrence, R2 is, independently, C1-6-a | coxy, hydroxy, halo, C1- 6-a | kyl, cyano or trifluoromethyl; R 'and R5 are, independently, H or C1-6 alkyl; A1 is a C1-3a | chene bond or chain; 15 R3 is a 5- or 6-membered heteroaryl, C6-10-ari | a or C3-7-cic | oa] chi | a, where each heteroaryl, aryia or cycloalkyl are optionally substituted with one or more groups independently selected from the group consisting of C1-6a | qui | a , halo, ha | oC1-6here] a, C1-6a | coxy, hydroxy, CO2H and CO2C1-6a | qui | a; 20 R6 for each occurrence is, independently, halo, hydroxy, Cj-7a | coxy, halo, C1-7a | qui | a or ha | o-C1-7a | qui | a; or R4, A1-R3, together with the nitrogen to which R4 and A1-R3 are attached, form a heterocyclyl with 4 to 7 members or a heteroaryl with 5 to 6 members, each of which is optionally substituted 25 with one or more groups independently selected from the group consisting of C1-6a | qui | a , halo, ha | oC1-6a | qui | a, C1-6a | coxy, hydroxy, CO2H and CO2C1-6a | qui | a; and méOouuminteirode1 to 5; seOouuminium from 1 to 4, or pharmaceutically acceptable salts thereof.
[3]
3. Compound according to claim 1 or 2, characterized by the fact that it has the formula Il: or 'o x1jLrÁDY ^' R3 "" Ú ¢ " <J (R2) m II or pharmaceutically acceptable salts of themselves.
[4]
4. Compound according to claim 1 or 2, characterized by the fact that it has the formula lll: o r 'o - "" AíjL :; ,: (R2) p X2 10 where X2 is halo and p is 0 or an integer from 1 to 4, or pharmaceutically acceptable salts thereof.
[5]
5. Composed according to claim 4, characterized by the fact that it has the formula lV: or 'o, 1ArLjL7 - ^' R3 "'LI' i, (" 3 ' <»" (r'), X2 15 lV or pharmaceutically acceptable salts thereof.
[6]
A compound according to any one of claims 1 to 5, characterized by the fact that:
X 'represents OH or O-C1-6-a | chi | a; R1 is H or C1-6 alkyl; R2 for each occurrence is, independently, C1-6-a | coxy, hydroxy, halo, C1-6-a | chi | a, cyano or trifluoromethyl; R 'and R' are, independently, H or C1g alkyl; A1 is a C1-3aiquiene bond or chain; R3 is a 5- or 6-membered heteroaryl, optionally substituted with one or more substituents independently selected from the group consisting of C1-6a | qui | a, halo, ha | oC1-6a | qui | a, C1-6a | coxy, hydroxy, 10 CO2H and CO2C1-6a | qui | a; R6 for each occurrence is, independently, halo, hydroxy, Cj-7 alkoxy, halo, C1-7a | quila or ha | o-C1-7a | qui | a; méOouuminteirode1 to 5;
P - seOouuminteirode1at4; or '"" 15 pharmaceutically acceptable salts thereof.
R W
[7]
Compound according to any one of claims 1 to 6, characterized in that: A1 is a bond or CH2; or pharmaceutically acceptable salts thereof. 20
[8]
A compound according to any one of claims 1 to 7, characterized in that: R1 is methyl or ethyl, R5 and R4 are H; or pharmaceutically acceptable salts thereof.
[9]
A compound according to any one of claims 1 to 25, characterized by the fact that: R 'is a 5-membered heteroaryl ring selected from the group consisting of oxazole, pyrrole, pyrazola, isooxazole, triazole, tetrazole, o- xadiazole, thiazole, isothiazole, thiophene, imidazole and thiadiazole; each of which is optionally substituted with one or more substituents independently selected from the group consisting of C1-6a | kila, halo, ha] oC1-6a | qui | a, Cj- 6a | coxy, hydroxy, CO2H and CO2C1- 6alkyl; or pharmaceutically acceptable salts thereof.
[10]
A compound according to any one of claims 1 to 9, characterized in that: R3 is tetrazole; or pharmaceutically acceptable salts thereof. 5
[11]
A compound according to any of claims 4 to 10, characterized in that: X2 is Cl, or pharmaceutically acceptable salts thereof.
[12]
12. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 11, or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers.
[13]
13. Combination, characterized by the fact that it comprises: a compound, as defined in any one of claims 1 to 11, or. - pharmaceutically acceptable salts thereof and one or more tera- '"" 15 agents selected from HMG-CO-A reductase inhibitor, one
W angiotensin receptor blocker, angiotensin-converting enzyme inhibitor, calcium channel blocker, endothelin antagonist, renin inhibitor, diuretic, mimic ApoA-I, antidiabetic agent, obesity, an aldosterone receptor blocker 20, an endothelin receptor blocker, an aldosterone synthase inhibitor, a CETP inhibitor and a phosphodiesterase type 5 (PDE5) inhibitor.
[14]
14. Method of inhibiting the activity of neutral EC endopeptidase. 3.4. 24.11. in an individual in need thereof, characterized by the fact that it comprises administering to the individual a therapeutically effective amount of the compound, as defined in any one of claims 1 to 11, or pharmaceutically acceptable salts thereof.
[15]
15. Method of treatment of a disorder or disease associated with the activity of neutral endopeptidase EC. 3.4. 24.11. in an individual 30 in need thereof, characterized by the fact that it comprises: administering to the individual a therapeutically effective amount of the compound, as defined in any of claims 1 to 11, or pharmaceutically acceptable salts thereof.
[16]
16. Method according to claim 15, characterized by the fact that the disorder or disease is selected from hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, 5 isolated systolic hypertension, peripheral vascular disease, heart failure, fa - congestive heart disease, left ventricular hypertrophy, angina, renal failure, renal failure, diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, primary renal disease proteinuria, renal vascular hypertension, diabetic retinopathy and 10 end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial fluoride, © harmful vascular remodeling, stabilization of plaques, myocardial infarction. ·. ' cardio (Ml), renal fibrosis, polycystic kidney disease (PKD), kidney failure, edema "." - 15 cyclic, Menières disease, hyperaldosteronism, hypercalciuria, ascites, «. glaucoma, menstrual disorders, premature labor, preeclampsia, endometriosis, and reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition, such as dementia and confusion geriatric, 20 obesity and gastrointestinal disorders, wound healing, septic shock, dysfunction of gastric acid secretion, hyperreninemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, dysfunction male and female sexual.
[17]
A compound according to any of claims 1 to 25 11, or pharmaceutically acceptable salts thereof, characterized in that it is for use as a medicament.
[18]
18. Use of the compound, as defined in any of claims 1 to 11, or its pharmaceutically acceptable salts thereof, characterized by the fact that it is for the treatment of a disorder or disease 30 associated with the activity of neutral EC endopeptidase. 3.4. 24.11. in an individual in need of such treatment.
[19]
19. Use according to claim 18, characterized by the fact
that the disorder or disease is selected from hypertension, resistant hypertension, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal failure 5 , kidney failure, diabetic nephropathy, nondiabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, primary renal disease proteinuria, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction lytic, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular ventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial fluoride, harmful vascular remodeling, plaque stabilization, myocardial infarction (MI), renal fibrosis, renal disease polycystic kidney disease (PKD), kidney failure, edema
Cyclic w, Menieres disease, hyperaldosteronism, hypercalciuria, ascites, - glaucoma, menstrual disorders, premature labor, pre-: "" 15 eclampsia, endometriosis, and reproductive disorders, asthma, obstructive apnea «. sleep, inflammation, leukemia, pain, epilepsy, affective disorders, depression, psychotic condition, dementia, geriatric confusion, obesity, gastrointestinal disorders, wound healing, septic shock, gastric acid secretion disorders, hyperreninemia, cystic fibrosis, restenosis, type-2 diabetes 20, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction.
[20]
20. Use of the compound, as defined in any one of claims 1 to 11, or pharmaceutically acceptable salts thereof, characterized by the fact that it is for the preparation of a drug for inhibiting the activity of neutral EC endopeptidase. 3.4. 24.11.
[21]
21. Use of the compound, as defined in any of claims 1 to 11, or pharmaceutically acceptable salts thereof, characterized by the fact that it is for the preparation of a medicament for the treatment of a disorder or disease associated with neutral endo-30 peptidase activity EC. 3.4. 24.11.
[22]
22. Use according to claim 21, characterized by the fact that the disorder or disease is selected from hypertension, hypertension
resistant belonging, pulmonary hypertension, pulmonary arterial hypertension, isolated systolic hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal failure, renal failure, diabetic nephropathy, non-diabetic nephropathy, syndrome 5 nephroic, glomerulonephritis, scleroderma, glomerular sclerosis, primary renal disease proteinurea, renal vascular hypertension, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, ventricular arrhythmias and ventricular, atrial fibrillation (AF), cardiac fibrosis, atrial fluoride, 10 harmful vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), kidney failure, cyclic edema, disease de Menières, hyperaldosteronism, hypercalciuria, ascites, m glaucoma, menstrual disorders, pr labor emature, pre-
W · 'eclampsia, endometriosis, and reproductive disorders, asthma, obstructive sleep apnea "" 15, inflammation, leukemia, pain, epilepsy, affective disorders, such as r. depression and psychotic condition, such as dementia and geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, dysfunctions of gastric acid secretion, hyperreninemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome , diabetic complications, atherosclerosis, male and female sexual dysfunction.
[23]
23. A compound according to any one of claims 1 to 11, or pharmaceutically acceptable salts thereof, characterized in that it is for use as an active ingredient in a pharmaceutical composition useful for inhibiting the activity of neutral EC endopeptidase. 3.4. 24.11. 25
[24]
24. A compound according to any one of claims 1 to 11, or pharmaceutically acceptable salts thereof, characterized in that it is for use as an active ingredient in a pharmaceutical composition useful for the treatment of a disorder or disease associated with the activity. - neutrality of neutral EC endopeptidase. 3.4. 24.11. 30 25. Invention, characterized by any of its embodiments or categories of claim encompassed by the material initially disclosed in the patent application or in its examples presented here.

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法律状态:
2020-09-15| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-10-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2021-03-16| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-03-23| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-07-06| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|

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2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US26313709P| true| 2009-11-20|2009-11-20|

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US61/263,137|2009-11-20|

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US35991410P| true| 2010-06-30|2010-06-30|

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US61/359,914|2010-06-30|

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