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HK1123035B - Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors - Google Patents

Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors Download PDF

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HK1123035B
HK1123035B HK08114021.6A HK08114021A HK1123035B HK 1123035 B HK1123035 B HK 1123035B HK 08114021 A HK08114021 A HK 08114021A HK 1123035 B HK1123035 B HK 1123035B
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Hong Kong
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alkyl
alkylene
halogen
group
compound according
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HK08114021.6A
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Chinese (zh)
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HK1123035A1 (en
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Oliver Plettenburg
Armin Hofmeister
Dieter Kadereit
Joachim Brendel
Matthias Loehn
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Sanofi-Aventis
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Priority claimed from PCT/EP2006/007139 external-priority patent/WO2007012421A1/en
Publication of HK1123035A1 publication Critical patent/HK1123035A1/en
Publication of HK1123035B publication Critical patent/HK1123035B/en

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piperidinyl-substituted isoquinolinone derivatives as Rho-kinase inhibitors
The present invention relates to novel isoquinolinone and isoquinoline derivatives as described in the claims, their preparation and their use in the treatment and/or prevention of diseases associated with Rho-kinase inhibition and/or Rho-kinase mediated inhibition of myosin light chain phosphatase phosphorylation.
Small GTPase RhoA is activated by agonist stimulation, resulting in the conversion of RhoA from an inactive GDP-bound form to an active GTP-bound form, which subsequently binds to and activates Rho-kinase. Two isoforms, Rho-kinase 1 and Rho-kinase 2, are known. Rho-kinase 2 is expressed in vascular smooth muscle cells and endothelial cells. Rho-kinase 2 activation by active GTP-bound RhoA leads to calcium sensitization of smooth muscle cells by phosphorylation-mediated inhibition of myosin light chain phosphatase activity and upregulation of light chain activity regulated by myosin accordingly (Uehata et al, Nature 1997, 389, 990-994).
Rho-kinase is known to be involved in vasoconstriction, including the development of myogenic tension and smooth muscle over-contraction (Gokina et al, J.Appl.physiol.2005, 98, 1940-8), bronchial smooth muscle contraction (Yoshii et al, am.J.Resp.cell mol.biol.20, 1190-1200), asthma (Setoguchi et al, Br J Pharmacol.2001, 132, 111-8; Nakahara et al, Eur J2000, 389, 103) and chronic obstructive pulmonary disease (COPD, Maruoka, Nippon Rinsho, 1999, 57, 1982-7), hypertension, pulmonary hypertension (Fukumoto et al, Heart, 91, 391-2, 2005, Mukai et al, Nature, 389, 990-4) and ocular and intraocular pressure regulation (Hongjo et al, Ciothaff, Ophal.2001, 1997-42, Massach.42, Massach.247, Skoshii et al, Maskol.97-5, Skoshikoshii et al, Skoku et al, Skoku et al, Skoku, S, Renal diseases, including Hypertension-induced, non-Hypertension-induced and diabetic nephropathy, renal failure and Peripheral Arterial Occlusive Disease (PAOD) (Wakino et al, Drug News Perspectrum. 2005, 18, 639-43), myocardial infarction (Demiryurek et al, Eur J Pharmacol.2005, 527, 129-40, Hattori et al, Circulation, 2004, 109, 2234-9), cardiac hypertrophy and failure (Yamakawa et al, Hypertension 2000, 35, 313-318, Liao et al, Am J Physiol Cell physiol.2006, 290, C661-8, Kishi et al, circle, 111, 2741-2747), coronary heart disease, atherosclerosis, restenosis (Pacaud et al, Arch. major. Diabetes 2005, 98, FEtt 254, Restt et al, Reishi et al, 2000, Diabetes mellitus 466, Diabetes mellitus, Hypertension, Diabetes mellitus, 49, 2178, Maeda et al, Cell metab.2005, 2, 119-29), sexual dysfunction, e.g. penile erectile dysfunction (Chitaley et al, Nature Medicine2001, 7, 119-122), retinopathy, inflammation, immune disorders, AIDS, osteoporosis, endocrine dysfunction, e.g. aldosteronism, central nervous system disorders such as neuronal degeneration and spinal cord injury (Hara et al, JNeurosurg 2000, 93, 94), cerebral ischemia (Uehata et al, Nature 1997, 389, 990; satoh et al, Life Sci.2001, 69, 1441-53; hitomi et al, Life Sci2000, 67, 1929; yamamoto et al, J Cardiovasc Pharmacol.2000, 35, 203-11), cerebral vasospasm (Sato et al, Circ Res 2000, 87, 195; kim et al neurosurgey 2000, 46, 440), pain, e.g. neuropathic pain (Tatsumi et al Neuroscience 2005, 131, 491; inoue et al, Nature Medicine 2004, 10, 712), gut bacterial infections (WO 98/06433), carcinogenesis and progression, neoplasias where Rho kinase inhibition has been shown to inhibit tumor cell growth and metastasis (Itoh et al, Nature Medicine1999, 5, 221; somlyo et al, Res Commun 2000, 269, 652), angiogenesis (Uchida et al, Biochem Biophys Res 2000, 269, 633-40; gingras et al, Biochem J2000, 348, 273), vascular smooth muscle cell proliferation and motility (Tammy et al, circ. res.1999, 84, 1186-1193; tangkijvanch et al, Atherosclerosis 2001, 155, 321-; yamashiro et al, j.cell biol.2000, 150, 797-; bauer et al, Blood1999, 94, 1665-; retzer et al, Cell Signal 2000, 12, 645) and leukocyte recruitment (Kawaguchi et al, Eur J pharmacol.2000, 403: 203-8; Sanchez-Madrid et al, J Immunol.2003, 171: 1023-34, Sanchez-Madrid et al, J Immunol.2002, 168: 400-10) and bone resorption (chelliaah et al, J Biol chem.2003, 278: 29086-97). Activation of the Na/H exchange transport system (Kawaguchi et al, Eur J Pharmacol.2000, 403: 203-8), Alzheimer's disease (Zhou et al, Science 2003, 302, 1215-.
Thus, compounds having inhibitory effects on Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase may be useful in the treatment and/or prevention of cardiovascular and non-cardiovascular diseases involving Rho-kinase as the primary or secondary cause, such as hypertension, pulmonary hypertension, ocular hypertension, retinopathy and glaucoma, peripheral circulation disorders, Peripheral Arterial Occlusive Disease (PAOD), coronary heart disease, angina pectoris, cardiac hypertrophy, heart failure, ischemic disease, ischemic organ failure (terminal organ damage), fibrotic lung, fibrotic liver, liver failure, renal disease, including hypertension-induced, non-hypertension-induced and diabetic nephropathy, renal failure, fibrotic kidney, glomerulosclerosis, organ hypertrophy, asthma, Chronic Obstructive Pulmonary Disease (COPD), adult respiratory distress syndrome, Thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain, neuronal degeneration, spinal cord injury, alzheimer's disease, premature labor, erectile dysfunction, endocrine dysfunction, arteriosclerosis, prostatic hypertrophy, diabetes and diabetic complications, metabolic syndrome, vascular restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, bone diseases such as osteoporosis, bacterial infections of the digestive tract, sepsis, cancer development and progression, cancer of e.g. the breast, colon, prostate, ovary, brain and lung and metastases thereof.
WO 01/64238 describes optionally substituted- (CH) compounds useful as neuroprotective agents2)1-6-O-(CH2)0-6-、-(CH2)0-6-S-(CH2)0-6-or- (CH)2)0-6-a linked heterocyclyl substituted isoquinoline-5-sulfonamide derivative.
WO 2004/106325(Schering AG) describes prodrugs of the Rho-kinase inhibitor fasudil carrying an ether or ester group at position 1 of the isoquinoline ring.
WO 2001/039726 generally describes-O- (C) s useful for the treatment of microbial infections0-C10) Alkyl-heteroaryl substituted cyclohexyl derivatives.
JP 10087629 a describes isoquinoline derivatives useful for the treatment of diseases caused by helicobacter pylori (Heliobacter pylori), such as gastritis cancer or ulcer. The isoquinoline derivative may be substituted at the 1-position by OH, preferably by X- [ (C)1-C6) Alkylene radical)]0-1-Y5-wherein X may be oxygen and Y may be aryl or heterocyclyl.
Yoshida et al (bioorg.Med.chem.1999, 7, 2647-2666) disclose 6-benzyloxy-isoquinoline for the treatment of infections caused by helicobacter pylori.
US 5,480,883 discloses in general compounds of formula "Ar I-X-Ar II" useful as EGF and/or PDGF receptor inhibitors for inhibiting cell proliferation, wherein X may be (CHR)1)m-Z-(CHR1)nE.g. Z-CH2Wherein Z may be O, R1Is hydrogen or alkyl, ArI may especially be an optionally substituted isoquinolinone, Ar II may especially be an optionally substituted C3-7Monocyclic saturated heterocyclic ring systems.
WO 2005/030791(Merck&Co.) generally disclosed as potassium channel inhibitors for the treatment of cardiac arrhythmias, stroke, congestive heart failureEtc., optionally substituted at the 6-position with a group (CR)eRf)pOR43Substituted, where p may be zero, R43Is, for example, a radical R81Defined as a 4-6 membered unsaturated or saturated monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O or S; and is substituted in the 4-position with a directly bonded optionally substituted aryl or heteroaryl group.
WO 2005/030130(Merck&Co.) generally discloses isoquinolinone derivatives which may be substituted in the 1-position by hydroxy and optionally by a group in the 6-position (CR) as potassium channel inhibitors for the treatment of cardiac arrhythmias, stroke, congestive heart failure etceRf)pOR43Substituted, where p may be zero, R43Is, for example, a radical R81Defined as a 4-6 membered unsaturated or saturated monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O or S; and is substituted in the 4-position with a directly bonded optionally substituted aryl or heteroaryl group.
WO 03/053330(Ube) describes isoquinolinone derivatives of the formula
One embodiment of the present invention is a compound of formula (I),
wherein
R2Is H, (C)1-C6) Alkyl, [ (C)1-C6) Alkylene radical]0-1-R’、[(C1-C6) Alkylene radical]0-1-O-(C1-C6) Alkyl, [ (C)1-C6) Alkylene radical]0-1-O-R’、[(C1-C6) Alkylene radical]0-1-NH2、[(C1-C6) Alkylene radical]0-1-NH(C1-C6) Alkyl, [ (C)1-C6) Alkylene radical]0-1-N[(C1-C6) Alkyl radical]2、[(C1-C6) Alkylene radical]0-1-CH[R’]2、[(C1-C6) Alkylene radical]0-1-C(O)-R’、[(C1-C6) Alkylene radical]0-1-C(O)NH2、[(C1-C6) Alkylene radical]0-1-C (O) NH-R' or [ (C)1-C6) Alkylene radical]0-1-C(O)N[R’]2；
R3Is H, halogen, CN, (C)1-C6) Alkyl, (C)1-C6) alkylene-R ', OH, O-R', NH2NHR ', NR' R 'or NH-C (O) -R',
R4is H, halogen, hydroxy, CN, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C6) alkylene-R';
R5is H, halogen, CN, NO2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)2-C6) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)5-C10) Heterocyclic radical, NH2、NH-R’、NH-SO2H、NH-SO2-(C1-C6) Alkyl, NH-SO2-R’、NH-C(O)-(C1-C6) Alkyl, NH-C (O) -R', C (O) N [ (C)1-C6) Alkyl radical]2C (O) OH or C (O) O- (C)1-C6) An alkyl group;
R6is H, R', (C)1-C8) Alkyl, (C)1-C6) alkylene-R', (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-O-R', (C)1-C6) alkylene-CH [ R']2、(C1-C6) alkylene-C (O) -R', (C)1-C6) alkylene-C (O) NH2、(C1-C6) alkylene-C (O) NH-R' or (C)1-C6) alkylene-C (O) N [ R']2；
R7And R8Independently of one another H, halogen, CN, NO2、(C1-C6) Alkyl, O- (C)1-C6) Alkyl, O- [ (C)1-C6) Alkylene radical]0-1-R’、(C2-C6) Alkenyl, R', (C)2-C6) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C6) alkylene-R', NH2、NH-R’、NH-SO2H、NH-SO2-(C1-C6) Alkyl, NH-SO2-R’、SO2-NH2、SO2-NHR’、NH-C(O)-(C1-C6) Alkyl, NH-C (O) -R', C (O) N [ (C)1-C6) Alkyl radical]2C (O) OH or C (O) O- (C)1-C6) An alkyl group;
R9is halogen or (C)1-C6) An alkyl group;
n is 0, 1, 2, 3 or 4; and is
L is O or O- (C)1-C6) An alkylene group;
wherein R' is (C)3-C8) Cycloalkyl group, (C)5-C10) Heterocyclyl or (C)6-C10) An aryl group; and is
R' is (C)3-C8) Cycloalkyl group, (C)5-C10) Heterocyclic group, (C)6-C10) Aryl group, (C)1-C6) Alkyl, (C)1-C6) alkylene-R', (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-O-R' or (C)1-C6) alkylene-NRxRy(ii) a And is
Wherein R isxAnd RyIndependently of one another are (C)1-C6) Alkyl, (C)5-C10) Heterocyclic group, (C)6-C10) Aryl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C4) Alkylene- (C)6-C10) Aryl group, (C)1-C4) alkylene-NH (C)1-C6) Alkyl, (C)1-C4) alkylene-N [ (C)1-C6) Alkyl radical]2、(C1-C4) alkylene-N [ (C)6-C10) Aryl radicals]2Or (C)1-C4) alkylene-N [ (C)5-C10) Heterocyclic radical]2(ii) a And is
Wherein at the residue R4、R5、R7And R8In (1), one alkyl or alkylene hydrogen atom may be optionally substituted by OH, OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONH2，、CONHCH3Or CON (CH)3)2Substituted, or the alkyl or alkylene group may be halogenated one or more times; or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
In another embodiment of the compounds of formula (I), at residue R4、R5、R7And R8In (1), one alkyl or alkylene hydrogen atom may be optionally substituted by OH, F, OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONH2、CONHCH3Or CON (CH)3)2And (4) substitution.
Stereoisomeric forms of isoquinolinone derivatives of formula (I) include the corresponding tautomeric 1-hydroxy-substituted isoquinoline derivatives of formula (I'),
wherein R is1Is H, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)2-C6) Alkynyl [ (C)1-C6) Alkylene radical]0-1-(C3-C8) Cycloalkyl, [ (C)1-C6) Alkylene radical]0-1-(C5-C10) Heterocyclyl group, [ (C)1-C6) Alkylene radical]0-1-(C6-C10) Aryl, C (O) - (C)1-C6) Alkyl, C (O) (C)2-C6) Alkenyl, C (O) - (C)2-C6) Alkynyl, C (O) - [ (C)1-C6) Alkylene radical]0-1-(C3-C8) Cycloalkyl, C (O) - [ (C)1-C6) Alkylene radical]0-1-(C5-C10) Heterocyclyl or C (O) - [ (C)1-C6) Alkylene radical]0-1-(C6-C10) Aryl radical, and
wherein R is3、R4、R5、R6、R7、R8、R9N and L are as defined above.
In a preferred embodiment, R in the compound of formula (I)2Is H, which compound is thus characterized by the compound of formula (II)
In a further preferred embodiment, R in the compound of formula (I') is1Is H, which compound is therefore characterized by a compound of formula (II'),
compounds (II) and (II') are in tautomeric form with each other.
For example, compounds of the formula
Is a tautomer of a compound of the formula.
The following preferred embodiments relate to compounds of formula (I), (I '), (II) and (II').
R3Preferably H, halogen, (C)1-C6) Alkyl, (C)1-C4) alkylene-R', O-R ", or NHR". More preferably R3Is H, (C)1-C6) Alkyl or NHR ". Most preferred is R3Is H, (C)1-C4) Alkyl, NH- (C)5-C6) Heterocyclyl or NH-phenyl, especially preferably R3Is H, (C)1-C4) Alkyl, NH-containing one or more N atoms (C)5-C6) Heteroaryl or NH-phenyl. Most especially preferred is R3Is H.
Preferably, R4Is H, halogen, CN, (C)1-C6) Alkyl, NH- (C)6-C10) Aryl or (C)1-C6) alkylene-R'. More preferably, R4Is H, halogen, (C)1-C6) Alkyl, NH- (C)6-C10) Aryl or (C)1-C6) alkylene-R'. In a further preferred embodiment, R4Is H, halogen, (C)1-C6) Alkyl, NH- (C)6-C10) Aryl or (C)1-C2) Alkylene- (C)6-C10) And (4) an aryl group. Most preferred is R4Is H, halogen or (C)1-C6) An alkyl group. Particularly preferred is R4Is H, halogen or (C)1-C6) An alkyl group. Most especially preferred is R4Is H.
Preferably, R5Is H, halogen, CN, (C)1-C6) Alkyl, R', NH- (C)6-C10) Aryl or (C)1-C6) alkylene-R'. More preferably, R5Is H, halogen, (C)1-C6) Alkyl, R', NH- (C)6-C10) Aryl or (C)1-C6) alkylene-R'. In a further preferred embodiment, R5Is H, halogen, (C)6-C10) Aryl, NH- (C)6-C10) Aryl group, (C)1-C2) Alkylene- (C)6-C10) Aryl group, (C)1-C6) Alkyl or (C)5-C10) A heteroaryl group. Most preferred is R5Is H, halogen, phenyl, (C)1-C6) Alkyl or (C)5-C6) A heteroaryl group. Particularly preferred is R5Is H, halogen or (C)1-C6) An alkyl group. More particularly, R is preferred5Is H or halogen. Most especially preferred is R5Is H.
Preferably, R6Is H, (C)1-C6) Alkyl, R', (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C4) alkylene-C (O) - (C)5-C10) Heterocyclic group, (C)1-C4) alkylene-C (O) - (C)6-C10) Aryl or (C)1-C6) Alkylene- (C)6-C10) And (4) an aryl group. In a further preferred embodiment, R6Is H, (C)1-C6) Alkyl, (C)5-C10) Heterocyclic group, (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclyl or (C)1-C6) Alkylene- (C)6-C10) And (4) an aryl group. More preferably R6Is H, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclyl or (C)1-C6) Alkylene- (C)6-C10) And (4) an aryl group.
In a more preferred embodiment, R6Is H, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclyl, wherein heterocyclyl is unsubstituted or substituted by (C)1-C4) Alkyl is substituted, or is (C)1-C4) Alkylene- (C)6-C10) Aryl, wherein aryl is unsubstituted or substituted, preferably 1 to 3 times, by: halogen, (C)1-C4) Alkyl, especially methyl, ethyl, isopropyl or 3, 3, 3-trifluoromethyl, O- (C)1-C4) Alkyl, especially methoxy, SO2-(C1-C4) Alkyl, especially SO2-CH3Or SO2-CF3Or by N [ (C)1-C4) Alkyl radical]2In particular N (CH)3)2And (4) substitution. In a more particularly preferred embodiment, R6Is H, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C2) Alkylene-thienyl, (C)1-C2) Alkylene-pyridyl group, (C)1-C2) Alkylene-piperidinyl radicals, (C)1-C2) Alkylene-pyrrolidinyl (C)1-C2) Alkylene-1-methyl-pyrrolyl, (C)1-C2) Alkylene-1-methyl-pyrazolyl, (C)1-C2) Alkylene-furyl group, (C)1-C2) Alkylene-tetrahydrofuryl or (C)1-C2) alkylene-1H-indazolyl group, (C)1-C2) Alkylene-naphthyl or (C)1-C2) Alkylene-phenyl, wherein phenyl is unsubstituted or substituted by halogen, methyl, ethyl, isopropyl, 3, 3, 3-trifluoromethyl, methoxy, SO2-CH3、SO2-CF3Or N (CH)3)2Substituted, preferably (C)1-C2) Alkylene is methylene. In a more particularly preferred embodiment, R6Is H, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl or (C)1-C4) Alkylene- (C)3-C6) A cycloalkyl group. In yet another more particularly preferred embodiment, R6Is H, (C)1-C6) An alkyl group. In the most preferred embodiment, R6Is H. R6Examples of radicals are hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, 3-methyl-butyl, sec-butyl, 3, 3, 3-trifluoropropyl or a substituent selected from the group consisting of:
the asterisk (—) indicates the N atom to which the bond is attached to the piperidine ring.
Preferably, R7And R8Independently of one another, H, halogen, CN, (C)1-C6) Alkyl, O- (C)1-C6) Alkyl, (C)2-C6) Alkenyl, R' or (C)1-C6) Alkylene- (C)3-C8) A cycloalkyl group. More preferably R7And R8Independently of one another, H, halogen, CN, (C)1-C4) Alkyl, O- (C)1-C4) Alkyl, (C)2-C4) Alkenyl, phenyl, (C)3-C6) Cycloalkyl group, (C)1-C4) Alkylene- (C)3-C6) Cycloalkyl or (C)5-C6) A heteroaryl group. Even more preferably R7And R8Independently of one another, H, halogen, (C)1-C4) Alkyl, O- (C)1-C4) Alkyl or (C)3-C6) A cycloalkyl group. Most preferably, R7Is H, halogen, (C)1-C4) Alkyl or O- (C)1-C4) Alkyl and R8Is H, in another even more preferred embodiment, R7And R8Independently of one another, H, halogen, (C)1-C4) Alkyl, O- (C)1-C4) Alkyl or phenyl. Particularly preferred is R7And R8Is H.
R9Preferably halogen or (C)1-C4) An alkyl group. More preferably R9Is Cl, F, methyl or ethyl. More preferably R9Is methyl.
Preferably, n is 0, 1, 2 or 3. More preferably n is 0 or 1. Most preferably n is 0.
The linking group L may be attached to any position of the piperidine ring via a piperidine ring carbon atom, thereby forming the (R) -or (S) -stereoisomer of the compounds of the present invention.
In a preferred embodiment, L is attached to the 4-position of the piperidine ring in all stereochemical forms
Or
L is linked to the 3-position of the piperidine ring,
in a particularly preferred embodiment, L is attached at the 4-position of the piperidine ring.
Preferably, L is O-methylene, O-ethylene or O. More preferably, L is O-methylene, O-ethylene or most preferably O attached at the 4-position of the piperidine ring.
Most preferably, L is O.
In a preferred embodiment of the present invention, one or more or all of the groups comprised in the compounds of formula (I) or (Γ) may have any of the preferred, more preferred or most preferred group definitions indicated above or any one or some of the specific representations covered by the group definitions indicated above independently of each other, all combinations of preferred definitions, more preferred or most preferred and/or specific representations being the subject of the present invention. Furthermore, the present invention includes, for all preferred embodiments, all stereoisomeric forms and mixtures of stereoisomeric forms in all ratios of the compounds of formula (I) or (I') and/or their physiologically acceptable salts.
A preferred embodiment of the present invention are compounds of formula (I), (I '), (II) or (II'), wherein
R3Is H, halogen, CN, (C)1-C6) Alkyl, (C)1-C6) alkylene-R ', OH, O-R', NH2Or NHR ";
R4is H, halogen, hydroxy, CN, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C6) alkylene-R';
R5is H, halogen, CN, NO2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)2-C6) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)5-C10) Heterocyclic radical, NH2、NH-R’、NH-SO2H、NH-SO2-(C1-C6) Alkyl, NH-SO2-R’、NH-C(O)-(C1-C6) Alkyl, NH-C (O))-R’、C(O)N[(C1-C6) Alkyl radical]2C (O) OH or C (O) O- (C)1-C6) An alkyl group;
R6is H, (C)3-C8) Cycloalkyl group, (C)1-C8) Alkyl, (C)1-C6) alkylene-R', (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-O-R', (C)1-C6) alkylene-CH [ R']2、(C1-C6) alkylene-C (O) NH2、(C1-C6) alkylene-C (O) NH-R' or (C)1-C6) alkylene-C (O) N [ R']2；
R7And R8Independently of one another H, halogen, CN, NO2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)2-C6) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C6) alkylene-R', NH2、NH-R’、NH-SO2-(C1-C6) Alkyl, NH-SO2-R’、SO2-NH2、SO2-NHR’、NH-C(O)-(C1-C6) Alkyl, NH-C (O) -R', C (O) N [ (C)1-C6) Alkyl radical]2C (O) OH or C (O) O- (C)1-C6) An alkyl group;
R9is halogen or (C)1-C6) An alkyl group;
n is 0, 1, 2, and
l is O or O- (C)1-C3) An alkylene group;
wherein R is1、R2、R’、R”、RxAnd RyAs defined above;
or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
A further preferred embodiment of the present invention are compounds of the formula (I), (I '), (II) or (II'), in which
R3Is H, halogen, CN, (C)1-C6) Alkyl, (C)1-C2) alkylene-R' or NHR ";
R4is H, halogen, CN, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C2) alkylene-R';
R5is H, halogen, CN, NO2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)2-C6) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)5-C10) Heterocyclic radical, NH2、NH-R’、NH-C(O)-(C1-C6) Alkyl or C (O) N [ (C)1-C6) Alkyl radical]2；
R6Is H, (C)3-C8) Cycloalkyl group, (C)1-C8) Alkyl or (C)1-C3) alkylene-R';
R7and R8Independently of one another H, halogen, CN, NO2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)2-C3) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C3) alkylene-R', NH-SO2-(C1-C6) Alkyl or SO2-NH2；
R9Is halogen or (C)1-C6) An alkyl group;
n is 0 or 1, and
l is O or O-methylene;
wherein R is1、R2、R’、R”、RxAnd RyAs defined above; or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
The most preferred embodiment of the present invention are compounds of formula (I), (I '), (II) or (II'), wherein
R3Is H, halogen, CN, (C)1-C6) Alkyl, (C)1-C2) alkylene-R' or NHR ";
R4is H, halogen, CN, (C)1-C4) Alkyl, (C)3-C6) Cycloalkyl group, (C)1-C2) alkylene-R';
R5is H, halogen, CN, NO2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)2-C6) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl, NH-R';
R6is H, (C)3-C6) Cycloalkyl or (C)1-C4) An alkyl group;
R7and R8Independently of one another H, halogen, CN, NO2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)2-C3) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C3) alkylene-R', NH-SO2-(C1-C6) Alkyl or SO2-NH2；
n is 0 and R9Is absent, or
n is 1 and R9Is halogen or (C)1-C4) An alkyl group; and is
L is O;
wherein R is1、R2、R’、R”、RxAnd RyAs defined above; or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
In another preferred embodiment of the invention, the compounds of the invention are compounds of formula (I), (I '), (II) or (II'), wherein
R3Is H, halogen, CN, (C)1-C6) Alkyl, (C)1-C6) alkylene-R ', OH, O-R', NH2Or NHR ";
R4is H, halogen, hydroxy, CN, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C6) alkylene-R';
R5is H, halogen, CN, NO2、(C1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)2-C6) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)5-C10) Heterocyclic radical, NH2、NH-R’、NH-SO2H、NH-SO2-(C1-C6) Alkyl, NH-SO2-R’、NH-C(O)-(C1-C6) Alkyl, NH-C (O) -R', C (O) N [ (C)1-C6) Alkyl radical]2C (O) OH or C (O) O- (C)1-C6) An alkyl group;
R6is H, (C)3-C8) Cycloalkyl group, (C)1-C8) Alkyl, (C)1-C6) alkylene-R', (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-O-R', (C)1-C6) alkylene-CH [ R']2、(C1-C6) alkylene-C (O) NH2、(C1-C6) alkylene-C (O) NH-R' or (C)1-C6) alkylene-C (O) N [ R']2；
R7And R8Independently of one another H, halogen, CN, NO2、(C1-C6) Alkyl, O- (C)1-C6) Alkyl, (C)2-C6) Alkenyl, R', (C)2-C6) Alkenylene radical- (C)6-C10) Aryl group, (C)1-C6) alkylene-R', NH2、NH-R’、NH-SO2-(C1-C6) Alkyl, NH-SO2-R’、SO2-NH2、SO2-NHR’、NH-C(O)-(C1-C6) Alkyl, NH-C (O) -R', C (O) N [ (C)1-C6) Alkyl radical]2C (O) OH or C (O) O- (C)1-C6) An alkyl group;
R9is halogen or (C)1-C6) An alkyl group;
n is 0, 1, 2; and is
L is O or O- (C)1-C4) An alkylene group;
wherein R is1、R2、R’、R”、RxAnd RyAs defined above; or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
A further preferred embodiment of the present invention are compounds of the formula (I), (I '), (II) or (II'), in which
R3Is H, halogen, CN, (C)1-C6) Alkyl or (C)1-C2) alkylene-R';
R4is H, halogen, CN, (C)1-C6) Alkyl or (C)1-C2) alkylene-R';
R5is H, halogen, CN, NO2、(C1-C6) An alkyl group;
R6is H, (C)3-C8) Cycloalkyl group, (C)1-C8) Alkyl, (C)1-C3) Alkylene- (C)3-C6) Cycloalkyl group, (C)1-C3) Alkylene- (C)6-C10) Aryl or (C)1-C3) Alkylene- (C)5-C10) A heterocyclic group;
R7and R8Independently of one another H, halogen, CN, NO2、(C1-C6) Alkyl, O- (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl or phenyl;
R9is halogen or (C)1-C6) An alkyl group;
n is 0 or 1; and is
L is O or O-methylene;
wherein R is1、R2R' is as defined above, or a pharmaceutically acceptable salt and/or stereoisomeric form and/or physiologically functional derivative thereof.
The most preferred embodiment of the present invention are compounds of formula (I), (I '), (II) or (II'), wherein
R3Is H;
R4is H, halogen or (C)1-C4) An alkyl group;
R5is H, halogen or (C)1-C6) An alkyl group;
R6is H, (C)3-C6) Cycloalkyl group, (C)1-C4) Alkyl, (C)1-C2) Alkylene- (C)3-C6) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclyl, wherein heterocyclyl is unsubstituted or substituted by (C)1-C4) Alkyl is substituted, or is (C)1-C4) Alkylene- (C)6-C10) Aryl, wherein aryl is unsubstituted or substituted by halogen, (C)1-C4) Alkyl, O- (C)1-C4) Alkyl, SO2-(C1-C4) Alkyl or N [ (C)1-C4) Alkyl radical]2Substitution;
R7and R8Independently of one another, H, halogen, (C)1-C4) Alkyl, O- (C)1-C4) Alkyl or phenyl;
R9is (C)1-C4) An alkyl group;
n is 0 or 1; and is
L is O;
wherein R is1、R2As defined above, R is preferred1Is H and R2Is H; or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
As in any embodiment of the invention, in the preceding embodiments containing preferred, more preferred, most preferred or exemplary definitions of the compounds of the invention, one or more or all of the groups may have any of the above preferred, more preferred, most preferred definitions, or any one or some of the specific representations covered by their definitions shown above.
Physiologically acceptable salts of the compounds of formulae (I) and (I ') mean organic and inorganic salts thereof, as described, for example, in Remington's Pharmaceutical Sciences (17 th edition, page 1418 (1985)). Due to physical and chemical stability and solubility, sodium, potassium, calcium and ammonium salts are particularly preferred for acidic groups and salts of maleic, fumaric, succinic, malic, tartaric, methanesulfonic, hydrochloric, sulfuric, phosphoric or carboxylic or sulfonic acids, such as hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, acetate, lactate, maleate, fumarate, malate, gluconate, and salts of amino acids, trona or carboxylic acids, are particularly preferred for basic groups. The preparation of physiologically acceptable salts from the compounds of the formulae (I) and (I') capable of salt formation, including their stereoisomeric forms, is carried out in a manner known per se. The compounds of formula (I) form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic agents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases such as trimethylamine or triethylamine, ethanolamine, diethanolamine or triethanolamine, tromethamine or other basic amino acids such as lysine, ornithine or arginine. When formula (I) or (I') has a basic group, stable acid addition salts can also be prepared with strong acids. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid and of organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid.
Salts with physiologically unacceptable anions, such as trifluoroacetate, are likewise within the framework of the present invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic, e.g. in vitro, applications.
The term "physiologically functional derivative" as used herein refers to any physiologically tolerated derivative of a compound of formula (I) or (I ') according to the invention, for example an N-oxide, which on administration to a mammal, for example a human, is capable of forming (directly or indirectly) a compound of formula (I) or (I') or an active metabolite thereof.
Physiologically functional derivatives include prodrugs of the compounds of the invention, as described, for example, in H.Okada et al, chem.pharm.Bull.1994, 42, 57-61. Such prodrugs can be metabolized in vivo to the compounds of the invention. These prodrugs may themselves be active or inactive.
The invention relates to racemates, racemic mixtures and pure enantiomeric forms of the compounds of formula (I) or (I') as well as diastereomers and mixtures thereof.
If a group or substituent can occur once or more than once in a compound of the formula (I) or (I'), they can all have the meanings indicated independently of one another and can be identical or different.
The compounds of the present invention may also exist in various polymorphic forms and/or solvates, for example, as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the invention are within the framework of the invention and are a further aspect of the invention.
All references below to "a compound of formula (I)" or "a compound of formula (I ') refer to one or more compounds of formula (I) or (I') as described above, as well as their physiologically acceptable salts, solvates and physiologically functional derivatives as described herein.
The terms alkyl and corresponding alkylene substituent are to be understood as meaning hydrocarbyl residues which may each, where appropriate, be linear, for example straight-chain, or branched and have 1, 2, 3, 4, 5 or 6 carbon atoms. This also applies when alkyl is a substituent for another group, for example in alkoxy (O-alkyl), S-alkyl or-O (C)1-C6) alkylene-O-, alkoxycarbonyl, or arylalkyl. Examples of alkyl are methyl, ethyl, propyl, butyl, pentyl or hexyl, the n-isomers of all these radicals, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl. If not otherwise indicated, the alkyl group may be halogenated one or more times, for example the alkyl group may be fluorinated, for example perfluorinated. Examples of haloalkyl are CF3And CH2CF3、OCF3、SCF3or-O- (CF)2)2-O-。
Alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl (═ allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1, 3-pentadienyl.
Alkynyl is, for example, ethynyl, 1-propynyl, 2-propynyl (═ propargyl) or 2-butynyl.
Halogen means fluorine, chlorine, bromine or iodine.
(C3-C8) Cycloalkyl is a cyclic alkyl group containing 3, 4, 5, 6, 7 or 8 ring carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl, which may also be substituted and/or contain 1 or 2 double bonds (unsaturated cycloalkyl), for example cyclopentenyl or cyclohexenyl, may be bound via any carbon atom.
(C6-C10) Aryl means an aromatic ring or a ring system comprising two fused or otherwise connected aromatic rings, for example phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha-or beta-tetralone-, indanyl-or indan-1-one groups. Preferably (C)6-C10) Aryl is phenyl.
(C5-C10) By heterocyclyl is meant a mono-or bicyclic ring system which, in addition to carbon atoms, contains one or more heteroatoms, such as 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or a combination of different heteroatoms. The heterocyclyl residue may be bonded at any position, for example, 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position. (C)5-C10) The heterocyclic group may be (1) aromatic [ ═ heteroaryl]Or (2) saturated or (3) mixed aromatic/saturated heterocyclic groups.
Is suitably (C)5-C10) Heterocyclic groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomorpholinyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, furyl, quinazolinyl, quinolyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, benzopyranyl, benzopyran-2-onyl, cinnolinyl, decahydroquinolyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b ] amino]Tetrahydrofuran, furyl, furazanyl, homomorpholinyl, homopiperazinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuryl, isobenzodihydropyranyl, isoindolyl, isoquinolinyl (phenylglyoxal)And imidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, prolyl (prolinyl), pteridinyl, purynyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, pyrazolidinyl, pyridoxalyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolin, Tetrahydroquinolinyl, 6H-1, 2, 5-thiadiazinyl, thiazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thienyl, triazolyl, tetrazolyl, and xanthyl. Pyridyl represents 2-, 3-and 4-pyridyl. Thienyl represents 2-and 3-thienyl. Furyl represents 2-and 3-furyl. Also included are the corresponding N-oxides of these compounds, such as 1-oxy-2-, 3-, or 4-pyridyl.
(C5-C10) The substitution of the heterocyclyl residue may occur at a free carbon atom or at a nitrogen atom.
(C5-C10) Preferred examples of heterocyclyl residues are pyrazinyl, pyridyl, pyrimidinyl, pyrazolyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl, benzofuranyl, quinolinyl, tetrazolyl and triazolyl.
(C6-C10) Aryl and (C)5-C10) The heterocyclyl is unsubstituted or substituted one or more times with suitable groups independently selected from: halogen, CF3、NO2、N3、CN、C(O)-(C1-C6) Alkyl, C (O) - (C)1-C6) Aryl, COOH, COO (C)1-C6) Alkyl, CONH2、CONH(C1-C6) Alkyl, CON [ (C)1-C6) Alkyl radical]2、(C3-C8) Cycloalkyl group, (C)1-C6) Alkyl, (C)1-C6) alkylene-OH, (C)1-C6) alkylene-NH2、(C1-C6) alkylene-NH (C)1-C6) Alkyl, (C)1-C6) alkylene-N [ (C)1-C6) Alkyl radical]2、(C2-C6) Alkenyl, (C)2-C6) Alkynyl, O- (C)1-C6) Alkyl, O-C (O) - (C)1-C6) Alkyl, O-C (O) - (C)6-C10) Aryl, O-C (O) - (C)5-C10) Heterocyclic group, PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) Alkyl radical]2、S-(C1-C6) An alkyl group; s- (C)1-C6) Alkylene- (C)6-C10) Aryl, S- (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group, SO- (C)1-C6) Alkyl, SO- (C)1-C6) Alkylene- (C)6-C10) Aryl, SO- (C)1-C6) Alkylene- (C)5-C10) Heterocyclic radical, SO2-(C1-C6) Alkyl, SO2-(C1-C6) Alkylene- (C)6-C10) Aryl, SO2-(C1-C6) Alkylene- (C)5-C10) Heterocyclic radical, SO2-NH(C1-C6) Alkylene- (C)6-C10) Aryl, SO2-NH(C1-C6) Alkylene- (C)5-C10) Heterocyclic radical, SO2-N[(C1-C6) Alkyl radical][(C1-C6) Alkylene- (C)6-C10) Aryl radicals]、SO2-N[(C1-C6) Alkyl radical][(C1-C6) Alkylene- (C)5-C10) Heterocyclic radical]、SO2-N[(C1-C6) Alkylene- (C)6-C10) Aryl radicals]2、SO2-N[(C1-C6) Alkylene- (C)5-C10) Heterocyclic radical]2、C(NH)(NH2)、NH2、NH-(C1-C6) Alkyl, N [ (C)1-C6) Alkyl radical]2、NH-C(O)-(C1-C6) Alkyl, NH-C (O) O- (C)1-C6) Alkyl, NH-C (O) - (C)6-C10) Aryl, NH-C (O) - (C)5-C10) Heterocyclyl, NH-C (O) O- (C)6-C10) Aryl, NH-C (O) O- (C)5-C10) Heterocyclyl, NH-C (O) -NH- (C)1-C6) Alkyl, NH-C (O) -NH- (C)6-C10) Aryl, NH-C (O) -NH- (C)5-C10) Heterocyclyl radical, NH-SO2-(C1-C6) Alkyl, NH-SO2-(C6-C10) Aryl, NH-SO2-(C5-C10) Heterocyclic group, N (C)1-C6) alkyl-C (O) - (C)1-C6) Alkyl, N (C)1-C6) alkyl-C (O) O- (C)1-C6) Alkyl, N (C)1-C6) alkyl-C (O) - (C)6-C10) Aryl, N (C)1-C6) alkyl-C (O) -heterocyclyl, N (C)1-C6) alkyl-C (O) O- (C)6-C10) Aryl, N (C)1-C6) alkyl-C (O) O- (C)5-C10) Heterocyclic group, N (C)1-C6) alkyl-C (O) -NH- (C)1-C6) Alkyl radical]、N(C1-C6) alkyl-C (O) -NH- (C)6-C10) Aryl, N (C)1-C6) alkyl-C (O) -NH- (C)5-C10) Heterocyclic group, N [ (C)1-C6) Alkyl radical]-C(O)-N[(C1-C6) Alkyl radical]2、N[(C1-C6) Alkyl radical]-C(O)-N[(C1-C6) Alkyl radical]-(C6-C10) Aryl, N [ (C)1-C6) Alkyl radical]-C(O)-N[(C1-C6) Alkyl radical]-(C5-C10) Heterocyclic group, N [ (C)1-C6) Alkyl radical]-C(O)-N[(C6-C10) Aryl radicals]2、N[(C1-C6) Alkyl radical]-C(O)-N[(C5-C10) Heterocyclic radical]2、N[(C6-C10) Aryl radicals]-C(O)-(C1-C6) Alkyl, N [ (C)5-C10) Heterocyclic radical]-C(O)-(C1-C6) Alkyl, N [ (C)6-C10) Aryl radicals]-C(O)O-(C1-C6) Alkyl, N [ (C)5-C10) Heterocyclic radical]-C(O)O-(C1-C6) Alkyl, N (aryl) -C (O) - (C)6-C10) Aryl, N [ (C)5-C10) Heterocyclic radical]-C(O)-(C6-C10) Aryl, N [ (C)6-C10) Aryl radicals]-C(O)O-(C6-C10) Aryl, N [ (C)5-C10) Heterocyclic radical]-C(O)O-(C6-C10) Aryl, N [ (C)6-C10) Aryl radicals]-C(O)-NH-(C1-C6) Alkyl, N [ (C)5-C10) Heterocyclic radical]-C(O)-NH-(C1-C6) Alkyl, N (aryl) -C (O) -NH- (C)6-C10) Aryl, N [ (C)5-C10) Heterocyclic radical]-C(O)-NH-(C6-C10) Aryl, N [ (C)6-C10) Aryl radicals]-C(O)-N[(C1-C6) Alkyl radical]2、N[(C5-C10) Heterocyclic radical]-C(O)-N[(C1-C6) Alkyl radical]2、N[(C6-C10) Aryl radicals]-C(O)-N[(C1-C6) Alkyl radical]-(C6-C10) Aryl, N [ (C)5-C10) Heterocyclic radical]-C(O)-N[(C1-C6) Alkyl radical]-(C6-C10) Aryl, N [ (C)6-C10) Aryl radicals]-C(O)-N[(C6-C10) Aryl radicals]2、N[(C5-C10) Heterocyclic radical]-C(O)-N[(C6-C10) Aryl radicals]2、(C6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl, O- (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)5-C10) Heterocyclic group, (C)1-C6) Alkylene- (C)5-C10) Heterocyclic radical、O-(C1-C6) Alkylene- (C)5-C10) Heterocyclic group of which (C)6-C10) Aryl or (C)5-C10) The heterocyclic radical may be substituted by halogen, OH, NO2、CN、O-(C1-C6) Alkyl, (C)1-C6) Alkyl, NH2、NH(C1-C6) Alkyl, N [ (C)1-C6) Alkyl radical]2、SO2CH3、COOH、C(O)O-(C1-C6) Alkyl, CONH2、(C1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-O- (C)6-C10) Aryl, O- (C)1-C6) Alkylene- (C)6-C10) Aryl is substituted 1 to 3 times; or wherein (C)6-C10) Aryl is O- (C)1-C4) alkylene-O is ortho-substituted, thereby forming a 5-8-membered ring together with the carbon atom to which the oxygen atom is attached. (C)6-C10) Aryl and (C)5-C10) The aryl or heteroaryl substituents of a heterocyclyl group may not be further substituted by aryl or heterocyclyl containing groups.
If substituted, (C)6-C10) A preferred substituent for aryl is (C)1-C4) Alkyl, O- (C)1-C4) Alkyl, O-phenyl, C (O) O- (C)1-C6) Alkyl, C (O) OH, C (O) - (C)1-C4) Alkyl, halogen, NO2、SO2NH2、CN、SO2-(C1-C4) Alkyl, NH-SO2-(C1-C4) Alkyl, NH2、NH-C(O)-(C1-C4) Alkyl, (C)3-C8) Cycloalkyl group, (C)1-C4) alkyl-OH, C (O) N [ (C)1-C4) Alkyl radical]2、C(O)NH2、N[(C1-C4) Alkyl radical]2、(C1-C4) Alkenylene radical- (C)6-C10) Aryl group of which (C)6-C10) The aryl group may be further substituted by (C)1-C4) Alkyl, (C)1-C4) alkylene-O- (C)1-C6) Alkyl, O- (C)1-C6) Alkyl radical- (C)6-C10) Aryl substituted or may be substituted by O- (C)1-C4) The alkylene-O group is ortho-substituted, thereby forming a 5-8-membered ring together with the carbon atom to which the oxygen atom is attached. More preferably, (C)6-C10) Aryl substituents are halogen, (C)1-C4) Alkyl, especially methyl, ethyl, isopropyl or 3, 3, 3-trifluoromethyl, O- (C)1-C4) Alkyl, especially methoxy, SO2-(C1-C4) Alkyl, especially SO2-CH3Or SO2-CF3Or N [ (C)1-C4) Alkyl radical]2In particular N [ (CH)3)2。
In monosubstituted phenyl, the substituents may be in the 2-, 3-or 4-position, preferably in the 3-and 4-position. If the phenyl group carries two substituents, they may be in the 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-positions. In phenyl groups carrying three substituents, the substituents may be in the 2, 3, 4-position, 2, 3, 5-position, 2, 3, 6-position, 2, 4, 5-position, 2, 4, 6-position or 3, 4, 5-position.
The above description relating to phenyl applies correspondingly to divalent radicals derived from phenyl, i.e. phenylene which may be unsubstituted or substituted 1, 2-phenylene, 1, 3-phenylene or 1, 4-phenylene. The above description also applies correspondingly to arylidene groups in arylalkylene. Examples of arylalkylene groups, which may also be unsubstituted or substituted in the arylene group as well as in the alkyleneene group, are benzyl, 1-phenylethylene, 2-phenylethylene, 3-phenylpropylene, 4-phenylbutylene, 1-methyl-3-phenyl-propylene.
If substituted, (C)5-C10) A preferred substituent for the heterocyclic group is (C)1-C4) Alkyl, O- (C)1-C4) Alkyl, (C)1-C4) Alkylene-phenyl, halogen, (C)1-C4) alkylene-O- (C)1-C4) Alkyl, (C)5-C10) Heterocyclic group, (C)1-C4) alkylene-N [ (C)1-C4) Alkyl radical]2Or (C)6-C10) Aryl group of which (C)6-C10) The aryl group may be further substituted by (C)1-C4) Alkyl, (C)1-C4) alkylene-O- (C)1-C6) Alkyl, O- (C)1-C6) Alkyl radical- (C)6-C10) Aryl substituted or may be substituted by O- (C)1-C4) The alkylene-O group is ortho-substituted, thereby forming a 5-8-membered ring with the carbon atom to which the oxygen atom is attached. More preferably (C)5-C10) The heterocyclyl substituent is (C)1-C4) An alkyl group.
(C6-C10) Aryl and (C)5-C10) General and preferred substituents for heterocyclyl groups may be as defined above for R1、R2、R3、R4、R5、R6、R7、R8、R9N and L in combination with the general and preferred definitions.
The invention therefore also relates to the use of a compound of formula (I) or (I') or a physiologically acceptable salt and/or stereoisomeric form thereof, as a medicament for the treatment and/or prophylaxis of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, i.e. for the treatment and/or prophylaxis of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulatory disorders, Peripheral Arterial Occlusive Disease (PAOD), coronary heart disease, angina pectoris, cardiac hypertrophy, heart failure, ischemic disease, ischemic organ failure (terminal organ damage), fibrotic lung, fibrotic liver, liver failure, hepatic failure, Renal diseases, including hypertension-induced, non-hypertension-induced and diabetic nephropathy, renal failure, fibrotic kidney, glomerulosclerosis, organ hypertrophy, asthma, Chronic Obstructive Pulmonary Disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g., neuropathic pain, neuronal degeneration, spinal cord injury, alzheimer's disease, preterm labor, erectile dysfunction, endocrine dysfunction, arteriosclerosis, prostatic hypertrophy, diabetes and diabetic complications, metabolic syndrome, vascular restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, bone diseases such as osteoporosis, bacterial infections of the digestive tract, sepsis, cancer development and progression, cancer of, e.g., the breast, colon, prostate, ovary, brain and lung, and metastases thereof.
The treatment and/or prophylaxis of human diseases is a preferred embodiment, but warm-blooded animals such as cats, dogs, rats, horses, etc. can also be treated with the compounds of the invention.
The invention also relates to a pharmaceutical preparation (or pharmaceutical composition) containing an effective amount of at least one compound of formula (I) or (I') or a physiologically acceptable salt and/or stereoisomeric form thereof and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable carrier substances (or vehicles) and/or additives (or excipients).
Optionally, physiologically functional derivatives of formula (I) or (I'), including prodrugs, are useful for the uses and pharmaceutical formulations described above.
The medicaments may be administered orally, for example in the form of pills, tablets, spray-coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. However, the application can also be carried out as follows: rectally, e.g. in the form of suppositories, or parenterally, e.g. intravenously, intramuscularly or subcutaneously, in the form of injection or infusion solutions, microcapsules, implants or implant sticks, or transdermally or topically, e.g. in the form of ointments, solutions or tinctures, or by other routes, e.g. in the form of aerosols or nasal sprays.
The pharmaceutical preparations according to the invention are prepared in a manner known per se and familiar to the person skilled in the art, using pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives, in addition to the compounds of the formula (I) or (I') or their physiologically acceptable salts and/or their stereoisomeric forms and their prodrugs. For the preparation of pills, tablets, coated tablets and hard gelatine capsules it is possible to use, for example, lactose, maize starch or derivatives thereof, talc, stearic acid or its salts and the like. Carrier materials for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils and the like. Suitable carrier materials for the preparation of solutions, e.g. injection solutions or emulsions or syrups, are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils and the like. Suitable carrier materials for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. Pharmaceutical preparations usually contain from about 0.5 to about 90% by weight of a compound of formula (I) or (Γ) or a physiologically acceptable salt thereof and/or a stereoisomeric form thereof. The amount of active ingredient of formula (I) or (I') and/or a physiologically acceptable salt thereof and/or a stereoisomeric form thereof in the pharmaceutical preparation is generally from about 0.5 to about 1000mg, preferably from about 1 to about 500 mg.
In addition to the active ingredients of the formula (I) or (I') and/or their physiologically acceptable salts and/or stereoisomeric forms and the carrier substances, the pharmaceutical preparations can contain one or more additives, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorants, aromas, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of the formula (I) and/or (I') and/or their physiologically acceptable salts and/or their stereoisomeric forms. Where a pharmaceutical composition contains two or more compounds of formula (I) and/or (Γ), the selection of an individual compound may depend on the specific overall pharmacological properties of the pharmaceutical formulation. For example, highly potent compounds with shorter duration of action may be combined with long acting compounds with lower efficacy. The flexibility allowed with respect to the choice of substituents in the compounds of formula (I) or (I') allows for a multitude of controls over the biological and physicochemical properties of the compounds, thereby enabling the selection of such desired compounds. Furthermore, the pharmaceutical preparations may contain, in addition to at least one compound of the formula (I) or (I') and/or a physiologically acceptable salt and/or a stereoisomeric form thereof, one or more further therapeutically or prophylactically active ingredients.
When using the compounds of the formula (I) or (I'), the dosage can vary within wide limits and, as is customary and known to the skilled practitioner, the dosage should be adapted to the individual case in each case. Depending on, for example, the particular compound employed, the nature and severity of the disease being treated, the mode and regimen of administration, or whether an acute or chronic condition is being treated or prevented. Suitable dosages may be established using clinical methods known in the medical arts. In general, the daily dose to achieve the desired result in an adult human weighing about 75kg is from about 0.01 to about 100mg/kg, preferably from about 0.1 to about 50mg/kg, in particular from about 0.1 to about 10mg/kg (in each case in mg per kg of body weight). Especially in the case of administration of larger amounts, the daily dose can be divided into several, e.g. 2, 3 or 4, portions. It may be necessary to deviate upwards or downwards from the indicated daily dose, usually depending on the individual behaviour.
Furthermore, the compounds of formula (I) or (I') can be used as synthetic intermediates for the preparation of further compounds, in particular further pharmaceutically active ingredients which can be obtained from the compounds of formula I, for example by introducing substituents or modifying functional groups.
It should be understood that: modifications that do not materially affect the activity of the various embodiments of the invention are included within the scope of the invention disclosed herein.
The compounds of formula (I) or (Γ) may be prepared according to the following illustrative compounds without departing from the scope of the claims.
In general, the protecting groups still present in the product obtained from the coupling reaction are then removed by standard methods. For example, a tert-butyl protecting group, particularly tert-butoxycarbonyl group, as an amino-protected form may be deprotected, i.e., converted to an amino group, by treatment with trifluoroacetic acid. As already explained, it is also possible to generate functional groups from suitable precursor groups after the coupling reaction. Furthermore, the conversion into physiologically acceptable salts or prodrugs of the compounds of the formula (I) or (I') can then be carried out by known methods.
In general, the reaction mixture containing the final product of formula (I) or (I') or intermediates is worked up and, if desired, the product is purified by customary methods known to those skilled in the art. For example, the synthesized compounds can be purified using well known methods such as crystallization, chromatography, or reverse phase high performance liquid chromatography (RP-HPLC) or other separation methods based on, for example, compound size, charge, or hydrophobicity. Similarly, well-known methods such as amino acid sequence analysis, NMR, IR and Mass Spectrometry (MS) can be used to characterize the compounds of the invention.
Isoquinolinone compounds can be synthesized by a variety of methods. The following general scheme illustrates some of the possible methods for obtaining isoquinolinones, but does not limit the invention.
Scheme 1.
An appropriately substituted aldehyde, for example an X-or Y-substituted aldehyde attached in suitable positions, independently of one another as hydrogen, alkyl, alkoxy or halogen, can be reacted with a suitable compound, for example an acetal of aminoacetaldehyde, in a solvent such as THF, chloroform or toluene, under catalysis by toluenesulfonic acid or another suitable acid, to give the imine (ii) where Q' can be, for example, methyl or ethyl, which can then be cyclized to isoquinoline (iii) by different methods. This may be done, for example, by Lewis acid catalysis with a suitable Lewis acid such as a peptide tetrachloride, iron halide, aluminum halide, etc., at temperatures of from ambient to 100 deg.C, or by reduction of an imine to the corresponding amine by the action of a suitable reducing agent such as sodium borohydride, conversion of the amine to an amide or sulfonamide by reaction with a suitable acid chloride, followed by cyclization to isoquinoline by the action of a suitable Lewis acid. The isoquinoline itself (iii) can then be converted to the corresponding N-oxide (iv) by the action of a suitable oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid, and the like, at room or elevated temperature. The N-oxide (iv) may then be converted to the 1-chloro-isoquinoline derivative (v) by reaction with a reagent such as phosphorus oxychloride in the presence or absence of phosphorus pentachloride. This derivative (v) can then be converted into a suitable 1-alkoxy-derivative by reaction with various alcohols Q-OH such as methanol, ethanol or benzyl alcohol in the presence of a suitable base such as sodium hydride in a suitable solvent such as dimethylformamide, dimethylacetamide and the like. Alternatively, (v) can be converted directly to isoquinolinone derivatives (vii) by reaction with a reagent such as ammonium acetate.
Scheme 2.
Alternatively, the isoquinoline may be obtained as follows: reaction of a suitable 3-formylated or acetylated fluorobenzene (viii) where Z is for example H or an alkyl group such as methyl or ethyl with a reagent such as triethyl phosphonate acetate in the presence of a suitable base such as sodium hydride gives the corresponding cinnamate ester which is subsequently cleaved in a suitable solvent by the action of a suitable base such as potassium hydroxide, sodium hydroxide or lithium hydroxide to give the acid (ix). (ix) The corresponding acid chloride can then be converted by known methods, which can be converted to the acyl azide by reaction with sodium azide in a suitable solvent such as ether, chloroform or acetone, with or without the presence of water. The corresponding azide can then be converted to isoquinolinone (x) by reaction in a suitable solvent such as diphenylmethane or diphenyl ether at a suitable temperature.
Scheme 3.
The 6-fluoro-isoquinolinone obtained above, e.g. (vi), can be reacted with a suitable P-substituted aminoalcohol wherein P is e.g. hydrogen, alkyl or a protecting group such as Boc, in the presence of a base such as DBU, cesium carbonate or sodium hydride to give the corresponding alkoxy-substituted derivative (xi). Finally, the conversion may have been carried out at an early stage of the synthesis (e.g. by a suitable intermediate reaction). It should be understood that: in the case of unprotected isoquinolinones, this may require protection at the nitrogen or oxygen of the isoquinolinone moiety by suitable methods such as reaction with an appropriately substituted alkyl or benzyl halide in the presence of a base.
If a suitable amino functionality is present, the product obtained via this process, e.g. (xi), can then be reacted with a suitable aldehyde or ketone in the presence of a reducing agent, e.g. sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, in a suitable solvent, in the presence of a water absorbing agent, e.g. molecular sieves or a suitable orthoester. The amino group may have to be released in an initial step, e.g. removal of the Boc-group under acidic conditions.
In the case of protected isoquinolinones, it is necessary to cleave the protecting group used to release the desired isoquinolinone (xii). However, this release can be carried out before or after the reductive amination step, depending on the nature of the aldehyde/ketone used and the protecting group used.
Isoquinolinone derivatives such as (xii) can be obtained as free bases or as various salts, such as hydrochloride, hydrobromide, phosphate, sulphate or fumarate salts. The resulting salts can be converted into the corresponding free bases, for example by subjecting them to ion exchange chromatography or, for example, by treatment with aqueous base, followed by treatment with a suitable organic solvent such as methyl tert-butyl ether, chloroform, ethyl acetate or an isopropanol/dichloromethane mixture, followed by evaporation to dryness.
The general procedures for preparing substituted isoquinolinones as described above can be readily adapted to prepare compounds of formula (I) or formula (I'). In the following examples, the preparation of the compounds of the invention is shown in more detail. The following examples are, therefore, part of the present invention and are intended to illustrate, but not to limit the invention.
(2, 2-dimethoxy-ethyl) - (4-fluoro-benzyl) -amine (1)
12.4g of 4-fluorobenzaldehyde are dissolved in 100mL of toluene and reacted with 10.5g of 2-aminoacetaldehyde dimethyl acetal and 1.90g (10mmol) of p-toluenesulfonic acid monohydrate in a dean Stark apparatus for 2 hours. The solution was cooled, extracted with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated to dryness. The crude product was dissolved in 100mL of ethanol. 1.89g of sodium borohydride were added in portions. Stirring was continued overnight. For the work-up, acetic acid was added until no gas evolution was observed. The solution was then evaporated to dryness, taken up in dichloromethane and washed twice with water. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness. The resulting crude product (20g) was used for further reaction without purification. Rt0.86min (method B). And (3) detecting quality: 182.1 (M-OMe)-)，214.2(M+H+)。
N- (2, 2-dimethoxy-ethyl) -N- (4-fluoro-benzyl) -4-methyl-benzenesulfonamide (2)
20g of (2, 2-dimethoxy-ethyl) - (4-fluoro-benzyl) -amine (1) are dissolved in 120mL of dichloromethane. 20mL of pyridine was added. A solution of 23.8g of p-toluenesulfonyl chloride in dichloromethane is added dropwise at 0 ℃. The reaction was allowed to warm to room temperature and stirring was continued until conversion was complete. For workup, the reaction mixture was extracted twice with 2M hydrochloric acid, twice with sodium bicarbonate and once with brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and the resulting crude product was purified by silica gel chromatography to give 22.95g of compound 2 as an orange oil. Rt1.71min (method C). And (3) detecting quality: 336.1 (M-OMe)-)。
6-fluoro-isoquinoline (3)
41.6g AlCl3Suspended in 400mL of dichloromethane. A solution of 22.95g N- (2, 2-dimethoxy-ethyl) -N- (4-fluoro-benzyl) -4-methyl-benzenesulfonamide (2) in 150mL of dichloromethane was added at room temperature. Stirring was continued overnight at room temperature, the solution was poured onto ice, the organic layer was separated, the aqueous phase was extracted twice with dichloromethane, then the organic layers were combined and extracted twice with sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness and the resulting crude product (8.75g) was purified by silica gel chromatography to give 2.74g of compound (3), Rt0.30min (method C). And (3) detecting quality: 148.1(M + H)+)。
7-chloro-6-fluoro-isoquinoline (4)
Starting from 3-chloro-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). Rt0.77min (method a). And (3) detecting quality: 182.1/184.1(M + H)+)。
7-chloro-6-fluoro-isoquinoline 2-oxide (5)
25g (137.7mmol) of 7-chloro-6-fluoro-isoquinoline (4) are dissolved in 500mL of dichloromethane. 50.9g (206.5mmol) of m-chloroperbenzoic acid (70%) are added at room temperature and the mixture is stirred at room temperature until complete conversion is obtained. For working up, the precipitate is filtered off and washed with dichloromethane. The filtrate was washed twice with sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic phase is over MgSO4Drying and evaporating. The solid material thus obtained (18.4g) was used without further purification. Rt0.87min (method C). And (3) detecting quality: 198.1/200.1(M+H+)。
1, 7-di-chloro-6-fluoro-isoquinoline (6)
2.6g (12.0mmol) of 7-chloro-6-fluoro-isoquinoline 2-oxide (5) are placed in 40mL of POCl3Heated at medium reflux for 4 hours. After the mixture had cooled to room temperature, it was poured onto ice. The aqueous solution was extracted three times with dichloromethane. The organic layers were combined and MgSO4Drying and evaporation gave 2.91g of the title compound which was used without further purification. Rt2.34min (method a). And (3) detecting quality: 216.0/218.0(M + H)+)。
4- (isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (7)
7.49g of tert-butyl 4-hydroxy-piperidine-1-carboxylate were dissolved in 20mL of anhydrous dimethylacetamide. 1.49g of sodium hydride (60%) was added. Then a solution of 3.65g of 6-fluoroisoquinoline (3) in dimethylacetamide was added dropwise. The solution was heated at 80 ℃ for 2 hours, then the solvent was removed and the residue was taken up in dichloromethane. The organic layer was extracted twice with water, then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to give 6.22g of 4- (isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (7). Rt1.32min (method B). And (3) detecting quality: 329.1(M + H)+)。
4- (2-oxy-isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (8)
3.97g (12.1mmol) of 4- (isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (7) are dissolved in 100mL of dichloromethane, and 4.47g (18.1mmol) of m-chloroperbenzoic acid (70%) are added at room temperature. The reaction mixture was stirred for 1 hour and then washed with saturated sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to give 4.19g of crude product which was used for further conversion without purification. Rt1.46min (method B). And (3) detecting quality: 345.2(M + H)+)。
1-chloro-6- (piperidin-4-yloxy) -isoquinoline-hydrochloride (9)
3.5g (10.16mmol) of 4- (2-oxy-isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (8) are dissolved in 250mL of HCl-saturated ethanol at 50 ℃. The clear solution was concentrated in vacuo and the residue was taken up in 50mL of POCl3And (4) refluxing. After 3 hours, the POCl was removed under vacuum3The residue was taken up in water. The pH was adjusted to 11 by addition of sodium hydroxide and the aqueous solution was extracted twice with dichloromethane. The organic layers were combined, dried over magnesium sulfate and evaporated to dryness. The residue was purified by preparative HPLC, whereby the trifluoroacetate salt of the title compound was obtained. The product was converted to the corresponding hydrochloride salt by dissolving it in 2N HCl followed by lyophilization. Yield: 950mg. Rt1.03min (method B). And (3) detecting quality: 263.1/265.1(M + H)+)。
4- (1-chloro-isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (10)
1.23g (4.11mmol) of 1-chloro-6- (piperidin-4-yloxy) -isoquinoline hydrochloride (9) are dissolved in 50mL of bisMethyl chloride, 0.85mL (6.15mmol) triethylamine was added. A solution of 1.09g (5.0mmol) of di-tert-butyl dicarbonate in 10mL of dichloromethane is added dropwise at 0 ℃ and the mixture is left overnight at room temperature. For workup, the mixture was washed twice with water, dried over magnesium sulfate and evaporated to give 1.1g of the desired product, which was used without further purification. Rt1.86min (method C). And (3) detecting quality: 363.1/365.2(M + H)+)。
4- (1-benzyloxy-isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (11)
0.70g (6.49mmol) of benzyl alcohol was dissolved in 10mL of dimethylacetamide. 260mg (6.49mmol) of sodium hydride (60%) are added and the solution is stirred at room temperature. After 30min, a solution of 1.57g (4.33mmol) of 4- (1-chloro-isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (10) in 10mL of dimethylacetamide was added and the resulting mixture was heated at 90 deg.C (bath temperature). After 8 hours and standing overnight at room temperature, an additional 1.0 equivalent of benzyl alcohol and sodium hydride was added and heating continued at 90 ℃ for 8 hours. For working up, the solvent is removed in vacuo and the residue is dissolved in dichloromethane. The organic solution was washed twice with water, over MgSO4Drying and evaporating. The resulting crude product was purified by preparative HPLC. Rt2.13min (method C). And (3) detecting quality: 435.2(M + H)+)。
6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (12)
Compound (11) is dissolved in ethanol/2N HCl (1: 1) and stirred at room temperature until complete conversion is obtained. The solvent was removed under vacuum and the residue was purified by preparative HPLC. The resulting trifluoroacetate salt was dissolved in 2N HCl and lyophilized. In addition fromAfter lyophilization in water, 850mg of the hydrochloride salt of the title compound was obtained. Rt0.75min (method B). And (3) detecting quality: 245.1(M + H)+)。
An alternative synthesis method:
6-fluoro-isoquinolinone (13)
4.8mL (90.3mmol, 1.5 equivalents) of thionyl chloride are added dropwise in portions to a solution of 10g (60.2mmol) of 3-fluorocinnamic acid in 44mL of chloroform and 1mL of DMF. The reaction was heated to reflux for 2.5 hours. The solvent was then distilled off to give 11.4g of crude acid chloride, which was used without any further purification.
The acid chloride was dissolved in 45mL of acetone. 8.03g of NaN were added in portions at 0 DEG.C3(123.5mmol, 2 eq.). 41mL of water was then added while maintaining the temperature below 5 ℃. The reaction was stirred for an additional 1.5 hours. Then 55mL of chloroform was added. The mixture was extracted with 80mL of water followed by 40mL of brine. Through Na2SO4After drying and filtration, 14mL of diphenyl ether was added and most of the chloroform was removed in vacuo (no heating). Complete removal of chloroform should be avoided.
The solution containing azide, diphenyl ether and remaining chloroform was added portionwise to a solution of 10mL tributylamine in 97mL diphenyl ether at 260 ℃ over 15 minutes. A vigorous reaction was observed during the addition. The reaction was stirred at 260 ℃ for an additional 20 minutes. After cooling to room temperature, 270mL of n-heptane were added. The precipitated product was filtered off and washed with ether to yield 5.65g of the title compound. Ms (dci) detection quality: 164.0(M + H)+)。
6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (14)
169 uL of p-methoxybenzyl chloride (1.24mmol, 1.1 eq) was added to 200mg of 6-fluoro-isoquinolinone (13) (1.13mmol) and 368mg of Cs2CO3(1.36mmol, 1.2eq) in 3mL DMF. The mixture was stirred for 2 hours and then poured onto ice. The precipitate was filtered, washed with water and dried to yield 300mg of the title compound. LCMS method B, retention time 1.76min, Mass detection 284.14[ M + H [ ]]+。
6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (12)
117mg (0.58mmol) of tert-butyl 4-hydroxy-piperidine-1-carboxylate are dissolved in 2mL of N, N-dimethylacetamide. Under an argon atmosphere, 63.6mg (2.7mmol) of sodium hydride were added, and the mixture was stirred at room temperature. After 30min, 150mg (0.53mmol) 6-fluoro-2- (4-methoxybenzyl) -2H-isoquinolin-1-one (14) are added and the solution is heated to 80 ℃ for 1H. The mixture was poured into water and extracted with chloroform. The organic layers were combined and washed with Na2SO4Drying, filtering and evaporating. The crude intermediate was purified by preparative HPLC. The protected intermediate was dissolved in 2mL TFA and the reaction was heated to 150 ℃ in a microwave reactor for 2 hours to remove the protecting group. The reaction mixture was quenched with methanol and evaporated to dryness. The remaining residue was taken up in dichloromethane, extracted three times with 1N HCl, the aqueous layers combined and extracted once with dichloromethane. The combined aqueous layers were lyophilized and the residue was treated twice with water and lyophilized again to give the product as the HCl salt. The purity of the product obtained is sufficient, but the impurities which ultimately occur can be removed by chromatography on silica gel or HPLC.
7-bromo-6-fluoro-isoquinoline (15)
The title compound was prepared starting from 3-bromo-4-fluoro-benzaldehyde through the same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). Rt0.91min (method B). And (3) detecting quality: 226.0/228.0(M + H)+)。
7-methyl-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (16)
a) 6-fluoro-7-methyl-2H-isoquinolin-1-one
To a solution of 10.0g (55.5mmol) of 3-fluoro-4-methyl-cinnamic acid in 80mL of acetone at 0 ℃ were added successively 10mL of acetone containing 6.74g (66.6mmol) of triethylamine and 7.83g (72.2mmol) of ethyl chloroformate. After stirring for 2 hours at 0 to 5 deg.C, a solution of 4.0g (61.1mmol) of sodium azide in 9.5mL of water was added. After stirring for another 1 hour, the reaction mixture was poured onto 200mL of ice-water and extracted twice with chloroform. The organic phase is dried over magnesium sulfate, 40mL of diphenyl ether are added and the chloroform is carefully removed in vacuo. The residue was then added dropwise to 50mL of diphenyl ether which had been preheated to 245 ℃. After complete addition, it was stirred for an additional 1 hour at 230 ℃ and 250 ℃. After cooling to 150 ℃ the reaction mixture is poured into 270mL heptane, after further cooling in an ice bath, the precipitated product is filtered off with suction to give 4.1g 6-fluoro-7-methyl-2H-isoquinolin-1-one.
b) 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one
To a solution of 9.17g (51.8mmol) 6-fluoro-7-methyl-2H-isoquinolin-1-one in 80mL DMF was added 20.2g (62.1mmol) cesium carbonate followed by 8.92g (56.9mmol) 4-methoxybenzyl chloride. After stirring at room temperature for 90 minutes, the reaction mixture was poured into 600mL of water, stirred for 1 hour, and the precipitated product was filtered off with suction. Additional product was isolated from the mother liquor by heptane/ethyl acetate (80: 20) chromatography. The combined product was recrystallized from ethyl acetate to yield 8.39g 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one.
c)4- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester
A solution of 3.2g (15.9mmol) of 1-tert-butoxycarbonyl-4-hydroxypiperidine in 110mL of dimethylacetamide is stirred with 1.36g (45.4mmol) of 80-% sodium hydride at room temperature for 1 hour. A suspension of 4.5g (15.1mmol) 6-fluoro-2- (4-methoxy-benzyl) -7-methyl-2H-isoquinolin-1-one in dimethylacetamide is then added. The reaction mixture was heated to 80 ℃ for 2 hours, during which time a clear solution was obtained. The reaction mixture was slowly added to 160mL of water, stirred for 1 hour, and after separation the product was filtered and dried in vacuo overnight. 6.4g of 4- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester are obtained.
d) 7-methyl-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one hydrochloride
6.4g (13.4mmol)4- [2- (4-methoxy-benzyl) -7-methyl-1-oxo-1, 2-dihydro-isoquinolin-6-yloxy-are reacted]Tert-butyl-piperidine-1-carboxylate was dissolved in 30.5g (267.4mmol) of trifluoroacetic acid. After 1 hour at room temperature, the mixture was heated in a microwave oven at 150 ℃ for 2 hours. The excess trifluoroacetic acid is then distilled off in vacuo and the residue is diluted with 130mL of 1M hydrochloric acid. The aqueous phase was washed three times with dichloromethane and then lyophilized to give the hydrochloride salt which was crystallized from isopropanol. This afforded 3.2g of 7-methyl-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (16) as the hydrochloride salt. Rt1.24min (method B). And (3) detecting quality: 259.1(M + H)+)。
7-bromo-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (17)
a)3- (4-bromo-3-fluoro-phenyl) -acrylic acid ethyl ester
To a solution of 13.4g (60mmol) triethyl phosphonate acetate in 80mL toluene at 0 deg.C was added 1.8g (60mmol) 80% sodium hydride. After 30 minutes, 40mL of toluene containing 11.0g (54mmol) of 4-bromo-3-fluorobenzaldehyde was added and the resulting thick mixture was stirred with a mechanical stirrer overnight. After dilution with 500mL of ethyl acetate and 200mL of water, the organic phase is separated and washed with sodium bicarbonate solution and brine. After drying over magnesium sulfate followed by evaporation and purification by flash chromatography, 10.6g of 3- (4-bromo-3-fluoro-phenyl) -acrylic acid ethyl ester is obtained.
b)3- (4-bromo-3-fluoro-phenyl) -acrylic acid
10.5g (38.6mmol) of 3- (4-bromo-3-fluoro-phenyl) -acrylic acid ethyl ester are dissolved in 100mL of methanol and stirred with 97mL of 1M aqueous sodium hydroxide solution overnight. After removal of the methanol in vacuo, the residue was acidified with concentrated hydrochloric acid. The precipitate was separated by suction and dried at 50 ℃ in vacuo to give 8.0g of 3- (4-bromo-3-fluoro-phenyl) -acrylic acid.
c) 7-bromo-6-fluoro-2H-isoquinolin-1-one
To a solution of 4.0g (16.3mmol) of 3- (4-bromo-3-fluoro-phenyl) -acrylic acid in 60mL of acetone at 0-5 deg.C were added successively 10mL of acetone containing 2.0g (19.6mmol) of triethylamine and 10mL of acetone containing 2.3g (21.2mmol) of ethyl chloroformate. After stirring for 1 hour at 0-5 deg.C, a solution of 1.6g (24.5mmol) of sodium azide in 9mL of water was added. After stirring for another 1 hour, the reaction mixture was poured into 200mL of ice water and extracted twice with chloroform. The organic phase is dried over magnesium sulfate, 24mL of diphenyl ether are added and the chloroform is carefully removed in vacuo. The residue was then added dropwise to 60mL of diphenyl ether which had been preheated to 250 ℃. After complete addition, the reaction mixture was stirred at 230 ℃ and 250 ℃ for an additional 30 minutes. After cooling to 100 ℃ the reaction mixture is poured into 100mL heptane, after further cooling in an ice bath, the precipitated product is filtered off with suction to give 2.4g of crude 7-bromo-6-fluoro-2H-isoquinolin-1-one.
d) 7-bromo-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one
In analogy to the procedure described in example 16 step b, from 2.4g of crude 7-bromo-6-fluoro-2H-isoquinolin-1-one, 3.9g (11.9mmol) cesium carbonate and 1.7g (10.9mmol) 4-methoxybenzyl chloride was obtained 0.93g 7-bromo-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one.
e) 7-bromo-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one-hydrochloride
In analogy to the procedure described in example 16 steps c and d, from 0.93g (2.6mmol) 7-bromo-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one and 0.54g (2.7mmol) 1-tert-butoxycarbonyl-4-hydroxypiperidine 0.35g 7-bromo-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one was obtained as the hydrochloride salt.
Rt0.80min (method a). And (3) detecting quality: 323.1/325.1(M + H)+)。
Cis and trans N-Boc-2-methyl-piperidin-4-ol (18 and 19)
213mg (5.6mmol) of NaBH are introduced at 0 DEG.C4Add portionwise to a solution of 1.0g (4.7mmol) 1-boc-2-methyl-piperidin-4-one in 10mL ethanol. The mixture was stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was dissolved in water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with Na2SO4And (5) drying. After filtration, the solvent was distilled off and the crude product was purified by column chromatography (n-heptane/ethyl acetate 1/1) to yield 367mg (36%) of cis-isomer 18 and 205mg (20%) of trans-isomer 19, as well as 97mg (10%) of a mixture of the two isomers.
Cis-isomer (18):
1H-NMR(CDCl3): δ 4.28(1H, m), 4.17(1H, m), 3.82(1H, m), 3.26(1H, m), 1.85(1H, ddd, J14.7, 6.6 and 3.4Hz), 1.77(1H, m), 1.66(2H, m), 1.33(3H, d, J7.1 Hz).
Trans-isomer (19):
1H-NMR(CDCl3): δ 4.50(1H, m), 4.04(1H, m), 3.95(1H, m), 2.87(1H, dt, J ═ 2.9 and 13.6Hz), 1.93(1H, m), 1.83(1H, m), 1.53(1H, m), 1.32(1H, m), 1.14(3H, d, J ═ 7.1 Hz).
1-cyclopropyl-piperidin-4-ol (20)
5g of 4-hydroxypiperidine are dissolved in methanol. 23.8mL of 1[ (1-ethoxycyclopropyl) oxy ] trimethylsilane and 5.8g of sodium cyanoborohydride were added, and the mixture was reacted at 60 ℃ for 12 hours. The same amounts of the two reagents were added again and stirring was continued at 60 ℃ for 12 hours.
The mixture was diluted with methanol, filtered through celite and evaporated to dryness. The residue was taken up in ethyl acetate, extracted twice with 2N sodium hydroxide, once with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography to give 2g of product 20, MS: 141 (M)+)。
Starting from the acids and amines listed in table 1 below, in a similar manner as described in the synthesis of 12, 16 or 17, the hydrochloride salt of the following compound was obtained.
The acrylic acid used is commercially available or synthesized from the corresponding aldehyde in a manner analogous to that described in the literature (see, e.g., j.med. chem.2005, 48, 71-90). One example is described in the synthesis of step 17, step a.
TABLE 1
4-bromo-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (52)
200mg (12) was suspended in 25mL of chloroform. 100 μ L of triethylamine was added and stirring was continued for 2 hours. The solution is evaporated and the residue is purified by chromatography on silica gel (dichloromethane: methanol: triethyl)Amine 10: 1: 0.1). Another HPLC purification was performed and the anion was changed to HBr to give 73mg of product as the hydrobromide salt. Rt1.35min (method a). And (3) detecting quality: 407.1/409.1(M + H)+)。
4- (1-benzyloxy-7-chloro-isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (53)
289.8mg (1.44mmol) of tert-butyl 4-hydroxy-piperidine-1-carboxylate are dissolved in 10mL of dimethylacetamide, and 57.6mg (1.44mmol) of sodium hydride (60%) are added. The reaction mixture was stirred at room temperature. After 30min, a solution of 310mg (1.44mmol)1, 7-di-chloro-6-fluoro-isoquinoline (6) in 3mL dimethylacetamide was added and the mixture was stirred at room temperature for 1h to complete the conversion. Then 155.7mg (1.44mmol) of benzyl alcohol and 57.6mg (1.44mmol) of sodium hydride (60%) were successively added, and stirring was continued at room temperature. To achieve complete conversion, after 2 hours, 0.5 equivalents of benzyl alcohol and sodium hydride are added twice and left to stand overnight. For working up, the solvent is evaporated, the residue is taken up in dichloromethane, washed twice with water and over MgSO4Drying and evaporating. Final purification was done by preparative HPLC.
7-chloro-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (54)
254mg (0.52mmol) of 4- (1-benzyloxy-7-chloro-isoquinolin-6-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (53) are stirred in methanol/2N HCl (1: 1) at room temperature overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC. The product fractions were evaporated and dissolved in 2N HCl. Lyophilization afforded 57mg of the desired compound as the hydrochloride salt. Rt0.95min (method B). And (3) detecting quality: 279.1(M + H)+)。
7-chloro-6- (1-isopropyl-piperidin-4-yloxy) -2H-isoquinolin-1-one (55)
64mg (0.23mmol) of 7-chloro-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one-hydrochloride (54) are dissolved in 5mL of methanol. 41.4mg (0.41mmol) of triethylamine was added, and the mixture was stirred at room temperature for 10 minutes. After addition of freshly dried molecular sieve, 122.4mg (2.04mmol) of acetic acid, 26.7mg (0.46mmol) of acetone and 43.3mg (0.69mmol) of sodium cyanoborohydride, the reaction mixture is refluxed for 8 hours. After addition of 2 equivalents of acetone and 2 equivalents of sodium cyanoborohydride at room temperature, the reaction was refluxed for an additional 2 hours to complete the conversion. For working up, the mixture is filtered and the filtrate is evaporated. The residue was dissolved in dichloromethane, washed twice with 2N NaOH and water, over MgSO4And (5) drying. After evaporation of the solvent and purification by preparative HPLC, 13mg of the title compound are obtained as the trifluoroacetate salt. Rt0.96min (method B). And (3) detecting quality: 321.1/323.2(M + H)+)。
General procedure a for reductive amination:
0.243mmol of 6- (piperidin-4-yloxy) -2H-isoquinolin-1-one-hydrochloride (12) or another suitable amine, 0.243mmol of aldehyde and 0.365mmol of triethylamine in 3mL of HC (OMe)3The mixture was stirred at room temperature for 1 hour. The mixture was cooled to-10 deg.C and 1.75mL of freshly prepared solution containing 1.215mmol of NaHB (OAc) was added3And 1.215mmol of HOAc in DMF. Stirring was continued for 30 minutes at-10 ℃ and the mixture was warmed to room temperature and left at room temperature overnight. 0.5mL of water was added, the mixture was evaporated, dissolved in DMF and purified by preparative HPLC. The purified product was dissolved in 1mL of HCl-containing isopropanol (5-6M) and left overnight at room temperature (cleaving off some of the BOC/tBu ester groups of the product). 2mL of water was added and the solution was lyophilized to give the product hydrochloride.
The following compounds shown in table 2 were then synthesized in a manner similar to that described in the general procedure to give the hydrochloride salt.
TABLE 2
General procedure B for reductive amination:
100mg (0.25mmol) of 7-chloro-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one trifluoroacetate (54, trifluoroacetate) are dissolved in 5mL of methanol. After addition of molecular sieve 4A, 51.5mg (0.51mmol) triethylamine, 152.9mg (2.55mmol) acetic acid and 0.32mmol of the corresponding aldehyde, 48.0mg (0.76mmol) sodium cyanoborohydride solution are added dropwise and the mixture is stirred at room temperature until complete conversion is obtained. In some cases, it is necessary to heat the mixture at 60 ℃ to obtain complete conversion. Upon isolation of the product, the solution was filtered and the solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with 1N NaOH and saturated NaCl-solution, dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC. The resulting trifluoroacetate salt is stirred in 2N HCl/methanol, evaporated, dissolved in water and freeze dried to give the desired product as the hydrochloride salt.
By this procedure, using compound 54, the compounds in table 3 below were synthesized and obtained as the hydrochloride salts.
TABLE 3
7-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -4-methyl-2H-isoquinolin-1-one (308)
Alkylation of 50mg of 7-fluoro-4-methyl-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (22) with isopropyl bromide in the presence of triethylamine at 60 ℃ C. gave 31mg of 7-fluoro-6- (1-isopropyl-piperidin-4-yloxy) -4-methyl-2H-isoquinolin-1-one. Rt0.93min (method B). And (3) detecting quality: 319.2(M + H)+)。
5-chloro-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (309)
60mg (0.21mmol) of 6- (piperidin-4-yloxy) -2H-isoquinolin-1-one-hydrochloride (12) are dissolved in 5mL of concentrated sulfuric acid. 28.6mg (0.21mmol) of N-chlorosuccinimide are added at 0 ℃ and the mixture is stirred at 50 ℃. After 2 hours, the solution was poured onto ice and the pH was adjusted to about 12 by adding solid NaOH. The aqueous solution was extracted twice with dichloromethane. The organic layer was MgSO4Drying and evaporating. The crude product was purified by preparative HPLC. The resulting trifluoroacetate salt was dissolved in 2N HCl and the solvent was removed in vacuo. The residue was dissolved in water followed by lyophilization to give the desired compound as HCl-salt. Rt0.86min (method A). And (3) detecting quality: 279.1/281.1(M + H)+)。
7-bromo-6-fluoro-isoquinoline 2-oxide (310)
The title compound was prepared following the procedure described for 7-chloro-6-fluoro-isoquinoline 2-oxide (5), starting from 7-bromo-6-fluoro-isoquinoline (15). Rt0.93min (method C). And (3) detecting quality: 242.2/244.2(M + H)+)。
7-bromo-1-chloro-6-fluoro-isoquinoline (311)
The desired product was synthesized starting from 7-bromo-6-fluoro-isoquinoline 2-oxide (310) following the protocol described for 1, 7-dichloro-6-fluoro-isoquinoline (6). Rt1.70min (method C). And (3) detecting quality: 260.0/262.0(M + H)+)。
7-bromo-6-fluoro-2H-isoquinolin-1-one (312)
12.9g (49.5mmol) of 7-bromo-1-chloro-6-fluoro-isoquinoline (311) are dissolved in 250mL of acetic acid. After addition of 38.7g (0.5mol) of ammonium acetate, the solution is stirred at 100 ℃. After 3 hours, the solvent was removed in vacuo and the residue was poured onto water. The precipitate was filtered and dried to yield 9.91g (83%) of the title compound. Rt1.15min (method C). And (3) detecting quality: 242.2/244.1(M + H)+)。
7-bromo-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (313)
9.66g (39.9mmol) of 7-bromo-6-fluoro-2H-isoquinolin-1-one (312) are dissolved in 180mL of dimethylacetamide and 1.92g (48.0mmol) of sodium hydride (60%) are added. After 1 hour at room temperature, a solution of 7.50g (48.0mmol) of 4-methoxybenzyl chloride in 25mL of dimethylacetamide is added. The mixture was stirred at room temperature until complete conversion was obtained. For the separation operation, the solvent was removed in vacuo and the residue was taken up in saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic layer was MgSO4Drying and evaporation gave 16.8g of dark oil as crude product, which was stirred in methanol. The precipitate was filtered to give 6.56g of the title compound as a yellow solid. The mother liquor was evaporated and the residue was purified by preparative HPLC to give a further 2.62g of the desired product. Rt1.71min (method C). And (3) detecting quality: 362.3/364.3(M + H)+)。
4- [ 7-bromo-2- (4-methoxy-benzyl) -1-oxo-1, 2-dihydro-isoquinolin-6-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester (314)
126mg (0.625mmol) of tert-butyl 4-hydroxy-piperidine-1-carboxylate are dissolved in 2.5mL of dimethylacetamide, and 30mg (0.75mmol) of NaH (60% purity) are added at room temperature. After 15min 181mg (0.5mmol) 7-bromo-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (313) were added and stirring continued at room temperature. After 5.5 hours, the solvent was removed in vacuo and after addition of saturated sodium bicarbonate solution, the mixture was extracted twice with dichloromethane. The organic layer was MgSO4Drying and evaporating. After final purification by preparative HPLC, 182mg of product could be isolated. Rt1.93min (method C). And (3) detecting quality: 543.5/545.5(M + H)+)。
7-bromo-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (17)
182mg of 4- [ 7-bromo-2- (4-methoxy-benzyl) -1-oxo-1, 2-dihydro-isoquinolin-6-yloxy-phenyl]Tert-butyl-piperidine-1-carboxylate (314) was dissolved in 5mL of trifluoroacetic acid. After 2 hours at room temperature, the mixture was heated in a microwave oven at 140 ℃ for 2 hours. The solvent was removed in vacuo and the residue was dissolved in 2n hcl. The aqueous solution was washed twice with dichloromethane and the organic layer was extracted with 2N HCl. The aqueous solutions were combined, evaporated in vacuo and the residue dissolved in water. After lyophilization, the title compound was isolated as the HCl-salt. Rt0.80min (method B). And (3) detecting quality: 323.1/325.1(M + H)+)。
6-fluoro-2- (4-methoxy-benzyl) -7-phenyl-2H-isoquinolin-1-one (315)
453mg (1.25mmol) of 7-bromo-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (313), 432mg (3.125mmol) of K2CO3And 190.5mg (1.56mmol) of phenylboronic acid in 12.5mL of toluene.Under argon, 72mg (0.062mmol) Pd (Ph) were added3)4The solution was stirred at 100 ℃. After complete conversion, the solvent was removed in vacuo and saturated sodium bicarbonate solution was added. The aqueous solution was extracted three times with dichloromethane and the organic layer was over MgSO4And (5) drying. After evaporation, the crude product was purified by preparative HPLC. Rt1.80min (method C). And (3) detecting quality: 360.4(M + H)+)。
4- [2- (4-methoxy-benzyl) -1-oxo-7-phenyl-1, 2-dihydro-isoquinolin-6-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester (316)
168mg (0.83mmol) of tert-butyl 4-hydroxy-piperidine-1-carboxylate are dissolved in 5mL of dimethylacetamide, and 20mg (0.83mmol) of sodium hydride (60%) are added. The mixture was stirred at room temperature. After 30min, a solution of 240mg (0.67mmol) 6-fluoro-2- (4-methoxy-benzyl) -7-phenyl-2H-isoquinolin-1-one (315) in 5mL dimethylacetamide is added and stirring is continued at room temperature. After standing overnight, 20mg (0.83mmol) of sodium hydride (60%) were added and the solution was stirred at 100 ℃. After 1 hour, the solvent was removed in vacuo and saturated sodium bicarbonate solution was added. The aqueous phase was extracted three times with dichloromethane. The organic layer was purified over MgSO4Drying and evaporating. The crude product was purified by preparative HPLC. Rt1.98min (method C). And (3) detecting quality: 541.7(M + H)+)。
7-phenyl-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (317)
4- [2- (4-methoxy-benzyl) -1-oxo-7-phenyl-1, 2-dihydro-isoquinolin-6-yloxy) according to the procedure described for 7-bromo-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (17)]-piperidine-1-carboxylic acid tert-butyl ester (316)And (4) deprotection. Similar work up was carried out to give the title compound as HCl-salt. Rt1.05min (method B). And (3) detecting quality: 321.1(M + H)+)。
7-Ethyl-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (318)
The title compound was synthesized following the procedure described for 6-fluoro-2- (4-methoxy-benzyl) -7-phenyl-2H-isoquinolin-1-one (315), starting from 7-bromo-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (313) and ethylboronic acid. Rt1.69min (method C). And (3) detecting quality: 312.4(M + H)+)。
4- [ 7-Ethyl-2- (4-methoxy-benzyl) -1-oxo-1, 2-dihydro-isoquinolin-6-yloxy ] -piperidine-1-carboxylic acid tert-butyl ester (319)
According to p-4- [2- (4-methoxy-benzyl) -1-oxo-7-phenyl-1, 2-dihydro-isoquinolin-6-yloxy]-tert-butyl piperidine-1-carboxylate (316) the title compound was synthesized starting from 7-ethyl-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (318) and tert-butyl 4-hydroxy-piperidine-1-carboxylate. Rt1.91min (method C). And (3) detecting quality: 493.6(M + H)+)。
7-Ethyl-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (320)
According to the method described for 7-bromo-6- (piperidin-4-yloxy) -2H-isoquinolin-1-one (17), the reaction mixture is prepared4- [ 7-Ethyl-2- (4-methoxy-benzyl) -1-oxo-1, 2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (319) deprotection. Final purification by preparative HPLC gave the title compound as the trifluoroacetate salt. Rt0.92min (method A). And (3) detecting quality: 273.2(M + H)+)。
The method A comprises the following steps:
stationary phase: col YMC Jsphere 33 x 2
Gradient: ACN + 0.05% TFA: h2O+0.05％TFA
5: 95(0min) to 95: 5(3.4min) to 95: 5(4.4min)
Flow rate 1mL/min
The method B comprises the following steps:
stationary phase: col YMC Jsphere 33 x 2
Gradient: ACN + 0.05% TFA: h2O+0.05％TFA
5: 95(0min) to 95: 5(2.5min) to 95: 5(3.0min)
Flow rate 1mL/min
The method C comprises the following steps:
stationary phase: col YMC Jsphere ODS H8020 x 2
Gradient: ACN: h2O+0.05％TFA
4: 96(0min) to 95: 5(2.0min) to 95: 5(2.4min)
Flow rate 1mL/min
The method D comprises the following steps:
stationary phase: col YMC Jsphere 33 x 2.1
Gradient: grad ACN + 0.08% FA: h2O + 0.1% FA (formic acid)
5: 95(0min) to 95: 5(2.5min) to 95: 5(3min)
Flow rate 1.3mL/min
Assay for Rho kinase inhibition
To measure Rho-kinase inhibition, IC50 values were determined according to the following protocol:
buffer solution: 25mM Tris pH7.5; 0.02% BSA; 5% of glycerol; 0.008% TritonX 100; 2% DMSO; 1mM DTT; 1mM MgCl2(ii) a 0, 5. mu. Ci/well. gamma33P ATP
Enzyme: ROCKII or ROK α) (Upstate, catalog #14-451 Lot #24880U)0.1 ng/. mu.l
Final concentration of ATP in the reaction mixture: 40 μ M
Biotinylated substrate, diluted to 0.25. mu.M (no ATP) with the above buffer
1.10. mu.l Tris buffer (+ -inhibitor)
2. Add 30. mu.L of enzyme solution
3. The reaction was started with 30. mu.L of mixed substrate/ATP/ATP 33
4. Incubate at room temperature for 20 minutes
5. The reaction was stopped with 30. mu.L of 50mM EDTA
6. Transfer 50. mu.L of stop solution to streptavidin Flash Plate plus, Perkinelmer, SMP 103A
7. Incubate for 30min at room temperature
8. Four washes with 300. mu.l PBS/0.1% Tween 20
9. Determination of radioactivity in wells
In the assay, the following products/compounds were determined and the following activities were measured using the various forms (salts or free bases) obtained in the above examples:
No. pIC50
12 +++++
17 +++++
21 +++++
23 +++++
25 ++++
28 +++++
31 +++++
32 ++++
40 +++++
45 +++++
49 ++++
52 +++++
54 +++++
55 +++++
58 +++++
101 +++++
265 +++++
266 +++++
275 +++++
276 +++++
309 +++++
the activities given are expressed as negative log base 10 (pIC50) of IC50 as follows:
+： pIC50≤3.0
++： 3.0≤pIC50＜4.0
+++ 4.0≤pIC50＜5.0
++++： 5.0≤pIC50＜6.0
+++++：6.0≤pIC50

Claims (22)

1. A compound of formula (I)
Wherein
R2Is H;
R3is H;
R4is H, halogen, CN or (C)1-C6) An alkyl group;
R5is H, halogenCN or NO2；
R6Is H, (C)1-C8) Alkyl or (C)1-C6) alkylene-R';
R7and R8Independently of one another H, halogen, CN, NO2、(C1-C6) Alkyl, O- (C)1-C6) Alkyl or NH2；
n is 0; and is
L is O or O- (C)1-C6) An alkylene group;
wherein R' is (C)3-C8) Cycloalkyl group, (C)5-C10) Heterocyclyl or (C)6-C10) An aryl group; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R6Is H, (C)1-C6) Alkyl, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclyl or (C)1-C6) Alkylene- (C)6-C10) And (4) an aryl group.
3. A compound according to claim 2, wherein R6Is H, (C)1-C6) Alkyl or (C)1-C4) Alkylene- (C)3-C6) A cycloalkyl group.
4. A compound according to claim 3, wherein R6Is H or (C)1-C6) An alkyl group.
5. A compound according to claim 4, wherein R6Is H.
6. A compound according to claim 1, wherein R5Is H or halogen.
7. A compound according to claim 6, wherein R5Is H.
8. A compound according to claim 1, wherein R4Is H, halogen or (C)1-C6) An alkyl group.
9. A compound according to claim 8, wherein R4Is H.
10. A compound according to claim 1, wherein R7And R8Independently of one another, H, halogen, (C)1-C4) Alkyl or O- (C)1-C4) An alkyl group.
11. A compound according to claim 10, wherein R7And R8Is H.
12. A compound according to claim 1, wherein L is attached to the cyclohexyl ring at the 4-position,
l is connected to the 3-position of the cyclohexyl ring,
13. the compound according to claim 12, wherein L is attached to the 4-position of the cyclohexyl ring.
14. A compound according to claim 1, wherein L is O-methylene or O.
15. The compound according to claim 14, wherein L is O attached to the cyclohexyl ring at the 4-position.
16. The compound according to claim 14, wherein L is O.
17. A compound according to claim 1, wherein
R4Is H, halogen or (C)1-C6) An alkyl group;
R5is H or halogen;
R6is H, (C)1-C8) Alkyl or (C)1-C3) alkylene-R';
R7and R8Independently of one another, H, halogen or (C)1-C6) An alkyl group; and is
L is O or O-methylene;
or a pharmaceutically acceptable salt thereof.
18. A compound according to claim 1, wherein
R4Is H, halogen or (C)1-C4) An alkyl group;
R5is H or halogen;
R6is H or (C)1-C4) An alkyl group;
R7and R8Independently of one another, H, halogen or (C)1-C6) An alkyl group; and is
L is O;
or a pharmaceutically acceptable salt thereof.
19. A compound selected from
Or a pharmaceutically acceptable salt thereof.
20. Use of at least one compound of formula (I) according to any one of claims 1 to 19 or a physiologically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase.
21. Use of at least one compound of the formula (I) according to any one of claims 1 to 19 or of a physiologically acceptable salt thereof for the preparation of a medicament for the treatment and/or prophylaxis of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulatory disorders, peripheral arterial occlusive disease, coronary heart disease, angina pectoris, cardiac hypertrophy, heart failure, ischemic disease, ischemic organ failure, fibrotic lung, fibrotic liver, liver failure, nephropathy, organ hypertrophy, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, neuronal degeneration, spinal cord injury, alzheimer's disease, premature labor, erectile dysfunction, endocrine dysfunction, arteriosclerosis, prostatic hypertrophy, diabetes and diabetic complications, Metabolic syndrome, vascular restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, bone disease, bacterial infections of the digestive tract, sepsis, cancer development and progression.
22. The use of claim 21, wherein the renal disease is selected from renal failure, fibrotic kidney or glomerulosclerosis.
HK08114021.6A 2005-07-26 2006-07-20 Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors HK1123035B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05016154 2005-07-26
EP05016154.6 2005-07-26
PCT/EP2006/007139 WO2007012421A1 (en) 2005-07-26 2006-07-20 Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors

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HK1123035A1 HK1123035A1 (en) 2009-06-05
HK1123035B true HK1123035B (en) 2013-09-19

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