HK1138583B - Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives - Google Patents
Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives Download PDFInfo
- Publication number
- HK1138583B HK1138583B HK10104254.1A HK10104254A HK1138583B HK 1138583 B HK1138583 B HK 1138583B HK 10104254 A HK10104254 A HK 10104254A HK 1138583 B HK1138583 B HK 1138583B
- Authority
- HK
- Hong Kong
- Prior art keywords
- alkyl
- group
- alkylene
- formula
- compound according
- Prior art date
Links
Description
The present invention relates to novel isoquinolone and isoquinolinone 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, BrJ 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 (Fukukoto et al, Heart, 91, 391-2, 2005, Mukai et al, Nature, 389, 990-4) and ocular and intraocular pressure regulation (Hongjo et al, Sci Ophal.42, Eur. J.32, Maskol.32, Maskogawa et al, Maskoshiol J.32, 2000-247, Maskoshikola appl.32, Skoshikoku 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, 49, 2178, Maeda et al, Cell metab.2005, 2, 119-29), sexual dysfunction, e.g. penile erectile dysfunction (Chitaley et al, Nature medicine 2001, 7, 119-122), retinopathy, inflammation, immune disorders, AIDS, osteoporosis, endocrine dysfunction, e.g. hyperaldosteronism, central nervous system disorders such as neuronal degeneration and spinal cord injury (Hara et al, J Neurosurg 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 Sci 2000, 67, 1929; yamamoto et al, J Cardiovasc Pharmacol.2000, 35, 203-; 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, Cen 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 used 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 optional coatings useful as neuroprotective agents
-(CH2)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 describes in general-O- (C) 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 and is preferably substituted by X- [ (C)1-C6) Alkylene radical)]0-1-Y is 5-substituted, wherein X may be oxygen and Y may be aryl or heterocyclyl.
Hagihara et al (bioorg.Med.chem.1999, 7, 2647-2666) disclose 6-benzyloxy-isoquinoline for the treatment of infections caused by H.pylori.
US 5,480,883 discloses broadly compounds of the 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 isoquinolone, Ar II may especially be an optionally substituted C3-7Monocyclic saturated heterocyclic ring systems.
WO 2005/030791(Merck &Co.) broadly describes the use of the compounds as potassium channel inhibitors for the treatment of cardiac arrhythmias, stroke, congestive heart failure and the likeCarbostyril derivatives optionally substituted in the 6-position with a group (CR)eRf)pOR43Substituted, where p may be zero, R43Is, for example, optionally substituted by NR51R52Substituted (C)3-C10) Cycloalkyl, wherein R51And R52Can be hydrogen, (C)1-C6) Alkyl, etc.; or R43Is a radical R defined as a 4-6 membered unsaturated or saturated monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms81(ii) a And is substituted in the 4-position with a directly bonded optionally substituted aryl or heteroaryl group.
WO 2005/030130(Merck &Co.) generally describes isoquinoline derivatives which are potassium channel inhibitors, useful for the treatment of cardiac arrhythmias, stroke, congestive heart failure, etc., which may be substituted at the 1-position with a hydroxy group and optionally at the 6-position with a group (CR)eRf)pOR43Substituted, where p may be zero, R43Is, for example, optionally substituted by NR51R52Substituted (C)3-C10) Cycloalkyl, wherein R51And R52Can be hydrogen, (C)1-C6) Alkyl, etc.; or R43Is a radical R defined as a 4-6 membered unsaturated or saturated monocyclic heterocycle having 1, 2, 3 or 4 heteroatoms81(ii) a And is substituted in the 4-position with a directly bonded optionally substituted aryl or heteroaryl group.
WO 03/053330(Ube) describes in general terms isoquinolone derivatives of the formula
One embodiment of the present invention is a compound of formula (I),
wherein
R1Is H, OH or NH2；
R2Is H, halogen or (C)1-C6) An alkyl group;
R3is that
H，
The halogen(s) are selected from the group consisting of,
(C1-C6) An alkyl group, a carboxyl group,
(C1-C6) An alkylene group-R',
OH，
O-R”，
NH2，
NHR”，
NR "R" or
NH-C(O)-R”，
R4Is that
H，
The halogen(s) are selected from the group consisting of,
a hydroxyl group(s),
CN，
(C1-C6) An alkyl group, a carboxyl group,
R’，
(C1-C6) alkylene-R';
R5is that
H，
The halogen(s) are selected from the group consisting of,
CN，
NO2，
(C1-C6) An alkyl group, a carboxyl group,
(C2-C6) An alkenyl group which is a radical of an alkylene group,
R’，
(C1-C6) Alkylene- (C)6-C10) An aryl group, a heteroaryl group,
(C1-C6) Alkenylene radical- (C)6-C10) An aryl group, a heteroaryl group,
(C1-C6) Alkylene- (C)5-C10) A heterocyclic group,
CH(OH)-(C1-C6) An alkyl group, a carboxyl group,
NH2，
NH-R’，
NH-SO2H，
NH-SO2-(C1-C6) An alkyl group, a carboxyl group,
NH-SO2-R’，
NH-C(O)-(C1-C6) An alkyl group, a carboxyl group,
NH-C(O)-R’，
C(O)N[(C1-C6) Alkyl radical]2，
C (O) OH, or
C(O)O-(C1-C6) An alkyl group;
R6and R6' independently of one another are
H，
R’，
(C1-C8) An alkyl group, a carboxyl group,
(C1-C6) An alkylene group-R',
(C1-C6) alkylene-O- (C)1-C6) An alkyl group, a carboxyl group,
(C1-C6) An alkylene-O-R',
(C1-C6) alkylene-CH [ R']2，
(C1-C6) alkylene-C (O) -R',
(C1-C6) alkylene-C (O) NH2，
(C1-C6) alkylene-C (O) NH-R',
(C1-C6) alkylene-C (O) NH- (C)1-C6) An alkyl group, a carboxyl group,
(C1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2，
(C1-C6) alkylene-C (O) N [ R']2；
(C1-C6) alkylene-C (O) O- (C)1-C6) An alkyl group, a carboxyl group,
C(O)O-(C1-C6) An alkyl group, a carboxyl group,
C(O)OR’，
C(O)(C1-C6) An alkyl group, a carboxyl group,
C(O)R’，
C(O)NH-(C1-C6) An alkyl group, a carboxyl group,
C(O)NHR’，
C(O)N[(C1-C6) Alkyl radical]R’，
C(O)N[(C1-C6) Alkyl radical]2，
C(O)-(C1-C6) An alkylene group-R',
C(O)O(C1-C6) An alkylene group-R',
orR6And R6' together with the N-atom to which they are attached form (C)5-C10) A heterocyclic group;
R7is that
H，
The halogen(s) are selected from the group consisting of,
CN，
NO2，
(C1-C6) An alkyl group, a carboxyl group,
O-(C1-C6) An alkyl group, a carboxyl group,
(C2-C6) An alkenyl group which is a radical of an alkylene group,
R’，
(C1-C6) Alkenylene radical- (C)6-C10) An aryl group, a heteroaryl group,
(C1-C6) An alkylene group-R',
CH(OH)-(C1-C6) An alkyl group, a carboxyl group,
NH2，
NH-R’，
NH-SO2H，
NH-SO2-(C1-C6) An alkyl group, a carboxyl group,
NH-SO2-R’，
SO2-NH2，
SO2-NHR’，
NH-C(O)-(C1-C6) An alkyl group, a carboxyl group,
NH-C(O)-R’，
C(O)N[(C1-C6) Alkyl radical]2，
C (O) OH, or
C(O)O-(C1-C6) An alkyl group;
R8is H, halogen or (C)1-C6) An alkyl group;
n is 1, 2, 3 or 4;
m is 1, 2, 3, 4 or 5, and
l is S (CH)2)p、S(O)(CH2)p、SO2(CH2)p、NH(CH2)p、N(C1-C6) Alkyl- (CH)2)p；
N(C3-C6) Cycloalkyl- (CH)2)p、N[CO(C1-C6) Alkyl radical]-(CH2)pOr N [ (C)1-C3) alkylene-R']-(CH2)p；
p is 0, 1, 2, 3 or 4;
wherein
R' is
(C3-C8) A cycloalkyl group,
(C5-C10) A heterocyclic group,
(C6-C10) An aryl group; and is
R' is
(C3-C8) A cycloalkyl group,
(C5-C10) A heterocyclic group,
(C6-C10) An aryl group, a heteroaryl group,
(C1-C6) An alkyl group, a carboxyl group,
(C1-C6) An alkylene group-R',
(C1-C6) Alkylene oxideradical-O- (C)1-C6) An alkyl group, a carboxyl group,
(C1-C6) alkylene-O-R', or
(C1-C6) alkylene-NRxRy; and is
Wherein Rx and Ry are independently of each other
(C1-C6) An alkyl group, a carboxyl group,
(C5-C10) A heterocyclic group,
(C6-C10) An aryl group, a heteroaryl group,
(C1-C4) Alkylene- (C)5-C10) A heterocyclic group,
(C1-C4) Alkylene- (C)6-C10) An aryl group, a heteroaryl group,
(C1-C4) alkylene-NH (C)1-C6) An alkyl group, a carboxyl group,
(C1-C4) alkylene-N [ (C)1-C6) Alkyl radical]2，
(C1-C4) alkylene-N [ (C)6-C10) Aryl radicals]2Or is or
(C1-C4) alkylene-N [ (C)5-C10) Heterocyclic radical]2；
Wherein in the group R4、R5、R6、R6’、R7And R8In (b), the alkyl, alkylene or cycloalkyl group may be optionally substituted one or more times by: OH, OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONH2、CONHCH3Or CON (CH)3)2；
Wherein in the group R2To R8In (1), the alkyl or alkylene group may beSubstituted one or more times with optionally halogen;
wherein in the group R3To R8In (C)6-C10) Aryl and (C)5-C10) A heterocyclyl is unsubstituted or substituted one or more times with suitable groups independently selected from: halogen, OH, 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, PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) Alkyl radical]2、S-(C1-C6) Alkyl, SO- (C)1-C6) Alkyl, SO2-(C1-C6) Alkyl, SO2-N＝CH-N[(C1-C6) Alkyl 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-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) Alkane (I) and its preparation methodradical-C (O) O- (C)1-C6) Alkyl, N (C)1-C6) alkyl-C (O) -NH- (C)1-C6) Alkyl radical]、(C6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl, O- (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) Heterocyclyl or O- (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group of which (C)6-C10) Aryl or (C)5-C10) The heterocyclic group may be substituted one to three times with groups independently selected from: 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 or O- (C)1-C6) Alkylene- (C)6-C10) An aryl group;
or wherein (C)6-C10) Aryl radicals being in vicinal position by O- (C)1-C4) alkylene-O groups, whereby together with the carbon atom to which the oxygen atom is attached a 5-to 8-membered ring is formed;
and wherein (C)6-C10) Aryl and (C)5-C10) The aryl or heterocyclyl substituent of the heterocyclyl may not be further substituted by an aryl or heterocyclyl containing group;
or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
In one embodiment of the invention, R1Is H, and the compound is characterized by formula (II)：
In another embodiment of the invention, R1Is OH, and the compound is characterized by formula (III):
wherein R is1Isoquinoline derivatives of formula (I) which are OH include the corresponding tautomeric 1-isoquinolone derivatives, characterized by the formula (III'):
this tautomeric form is also an embodiment of the invention.
In another embodiment, R1Is NH2And the compound is characterized by formula (IV):
the following embodiments relate to compounds of formula (I), (II), (III') and (IV).
R1Preferably H or OH.
R3Preferably H, halogen, (C)1-C4) alkylene-R', O-R ", or NHR". More preferred R3Is H or NHR ". Most preferred R3Is H, NH- (C)5-C6) Heterocyclyl or NH-phenyl, particularly preferably H, NH-containing one or more N atoms (C)5-C6) Heteroaryl or NH-phenyl. Most especially preferred R3Is H.
R3Examples of substituents are
Preferably R4Is H, halogen or (C)1-C6) An alkyl group. More preferred R4Is H, halogen or (C)1-C4) An alkyl group. Most preferred R4Is H.
Preferably R5Is H, halogen, CN, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, R', NH- (C)6-C10) Aryl or (C)1-C6) alkylene-R'. More preferably R5Is H, halogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, R', NH- (C)6-C10) Aryl or (C)1-C6) alkylene-R'. Most preferred is R5Is H, halogen, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)6-C10) Aryl, NH- (C)6-C10) Aryl group, (C)1-C2) Alkyl radical- (C)6-C10) Aryl or (C)5-C10) A heteroaryl group. Particularly preferred is R5Is H, halogen, phenyl, (C)1-C6) Alkyl, (C)2-C6) Alkenyl, (C)6-C10) Aryl or (C)5-C6) A heteroaryl group. Most especially preferred R5Is H, halogen, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl.
R5Examples of (a) are hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl, nitrile, nitro, (p-methoxy) -phenyl, N-aniline, benzyl, 2-propenyl, sec-butenyl, cyclopropyl, tetrazole, amino, 4-methoxy-aniline or N-acetyl, preferablySelected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl. More preferred R5Is H, halogen, methyl or ethyl, most preferably R5Is H.
Preferably R6And R6' independently of one another are 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)6-C10) Aryl group, (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C4) alkylene-C (O) - (C)5-C10) Heterocyclic group, (C)1-C4) alkylene-C (O) - (C)6-C10) Aryl group, (C)1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、(C1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) O- (C)1-C6) Alkyl, C (O) R', C (O) (C)1-C6) Alkyl, C (O) O- (C)1-C6) Alkyl, C (O) NH- (C)1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2Or C (O) (C)1-C6) alkylene-R', or R6And R6' together with the N-atom to which they are attached form (C)5-C10) A heterocyclic group.
In a further preferred embodiment, R6And R6' independently of one another are H, (C)1-C6) Alkyl, (C)5-C10) Heterocyclic group, (C)3-C8) Cycloalkyl group, (C)6-C10) Aryl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C4) Alkylene- (C)6-C10) Aryl group, (C)1-C6) Alkylene oxideradical-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、(C1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) O- (C)1-C6) Alkyl, C (O) O- (C)1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) NH- (C)1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2、C(O)(C1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group, C (O) (C)1-C6) Alkylene- (C)6-C10) Aryl, or R6And R6' together with the N-atom to which they are attached form (C)5-C10) A heterocyclic group.
In a more preferred embodiment, R6Is H, (C)1-C6) Alkyl, (C)3-C6) Cycloalkyl or (C)1-C4) Alkylene- (C)3-C6) Cycloalkyl radical, and R6' is H, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)5-C10) Heterocyclic group, (C)5-C10) Aryl group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C4) Alkylene- (C)6-C10) Aryl group, (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, (C)1-C6) alkylene-C (O) N [ (C)1-C6) Alkyl radical]2、(C1-C6) alkylene-C (O) O- (C)1-C6) Alkyl, C (O) O- (C)1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) NH- (C)1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2、C(O)(C1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group, C (O) (C)1-C6) Alkylene- (C)6-C10) Aryl, or R6And R6' together with the N-atom to which they are attached form (C)5-C10) A heterocyclic group.
In a still more preferred embodiment, R6Is H, (C)1-C6) Alkyl, and R6' is H, (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl group, (C)6-C10) Aryl group, (C)5-C10) Heterocyclic group, (C)1-C4) Alkylene- (C)3-C8) Cycloalkyl group, (C)1-C4) Alkylene- (C)5-C10) Heterocyclic group, (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)1-C4) alkylene-O- (C)1-C4) Alkyl, (C)1-C4) alkylene-C (O) N [ (C)1-C4) Alkyl radical]2、(C1-C6) alkylene-C (O) NH- (C)1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl group, or R6And R6' together with the N-atom to which they are attached form (C)5-C10) A heterocyclic group.
In a further even more preferred embodiment, R6Is H, (C)1-C6) Alkyl, and R6' is a hydrogen atom in the presence of a hydrogen atom,
(C1-C6) An alkyl group;
(C3-C8) A cycloalkyl group;
(C1-C4) Alkylene radical-(C3-C8) A cycloalkyl group;
(C1-C4) alkylene-O- (C)1-C4) An alkyl group;
(C1-C4) alkylene-C (O) N [ (C)1-C4) Alkyl radical]2；
(C1-C4) Alkylene- (C)5-C10) A heterocyclic group, or
(C1-C4) Alkylene- (C)6-C10) An aryl group;
C(O)(C1-C4) An alkyl group;
C(O)(C1-C4) Alkylene- (C)5-C10) A heterocyclic group;
or R6And R6' together with the N-atom to which they are attached form (C)5-C6) A heterocyclic group.
Preferably, the heterocyclic group formed is a morpholino, piperidino, pyrrolidino or piperazino group. More preferably the heterocyclyl group is morpholino or piperazinyl.
In the most preferred embodiment, R6Is H, (C)1-C6) Alkyl, and R6' is H, (C)1-C6) Alkyl, (C)3-C8) A cycloalkyl group.
In a further most preferred embodiment, R6Is H and R6' is H, preferably unsubstituted (C)1-C6) Alkyl or preferably unsubstituted (C)3-C8) A cycloalkyl group. Particularly preferred is R6And R6' is H.
As examples of these embodiments, R6Or R6' independently of one another are hydrogen, methyl, ethyl, propyl, isopropyl, 3-methyl-butyl, 2-methyl-propyl, butyl, pentyl, 3, 3, 3-trifluoropropyl, 4-a trifluorobutyl group or a substituent selected from:
the asterisk (@) indicates the attachment of the valence bond to the N-atom of the amine.
Preferably R7Is 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 preferred R7Is H, halogen, CN, (C)1-C4) Alkyl, O- (C)1-C4) Alkyl, (C)1-C4) Alkenyl, phenyl, cyclopropyl or (C)5-C6) A heteroaryl group. Most preferred is R7Is H, fluoro, chloro, bromo, methyl, ethyl, methoxy, phenyl, nitrile, cyclopropyl, thienyl or vinyl, and especially most preferably R7 is H, fluoro, chloro, methyl or methoxy. More particularly preferred R7Is H.
R8Preferably H, halogen or (C)1-C4) An alkyl group. More preferred R8Is H, Cl, F, methyl or ethyl. Most preferred R8Is H.
Preferably R2Is H, halogen or (C)1-C4) An alkyl group. Preferably R2Is H or (C)1-C2) An alkyl group. More preferred R2Is H, methyl or ethyl. Most preferred R2Is H. R2Can be attached to any carbon atom of the ring, including the position to which the linking group L is attached.
Preferably n is 1, 2 or 3. More preferably n is 1 or 2. Most preferably n is 1.
Preferably m is 2, 3 or 4. More preferably m is 3. In another embodiment, m is 1, 2, 4 or 5.
The linking group L may be attached to the ring at any position via a ring carbon atom. In a preferred embodiment, m is 3 and, in all stereochemical forms, L is attached to the 4-position of the aminocyclohexane ring,
or L is linked to the 3-position of the aminocyclohexane ring
In a particularly preferred embodiment, L is attached to the 4-position of the aminocyclohexane ring.
In another embodiment of L, L is S (CH)2)p、S(O)(CH2)pOr SO2(CH2)p. In another embodiment, L is NH (CH)2)p、N(C1-C6) Alkyl- (CH)2)p、N(C3-C6) Cycloalkyl- (CH)2)p N[CO(C1-C6) Alkyl radical]-(CH2)p、N[(C1-C3) Alkylene-aryl radicals]-(CH2)pOr N [ (C)1-C3) Alkylene- (C)1-C6) Heterocyclic radical]-(CH2)pMore preferably NH (CH)2)p、N(C1-C6) Alkyl- (CH)2)p. Preferred is N (C)1-C6) Alkyl is N (C)1-C4) Alkyl, more preferably methyl or ethyl, with methyl being more preferred. Even more preferably L is S (CH)2)pOr NH (CH)2)p. Preferred is N (C)1-C6) Alkyl is N (C)1-C4) Alkyl, more preferably NCH3Or NCH2CH3，NCH3Is more preferred. Most preferably L is S or NH.
Preferably p is 0, 1, 2 or 3, more preferably 0 or 1, most preferably 0.
More preferably m is 3 and L is S or NH and is attached to the 4-position of the aminocyclohexane ring.
At the group R2To R8In (b), the alkyl or alkylene group may be optionally substituted one or more times with halogen. Preferably, the alkyl or alkylene group is substituted one to three times with halogen selected from chlorine or bromine and may also be substituted one or more times with fluorine, and may for example be perfluorinated. Preferably the halogen is fluorine. More preferably, the alkyl or alkylene group is not halogenated.
At the group R4、R5、R6、R6’、R7And R8Wherein alkyl, alkylene or cycloalkyl may be optionally substituted one or more times by a group independently selected from: OH, OCH3、COOH、COOCH3、NH2、NHCH3、N(CH3)2、CONH2、CONHCH3Or CON (CH)3)2. If substituted, the number of substituents is preferably 1, 2, 3 or 4, more preferably 1 or 2, even more preferably 1. Preferably, the alkylene or cycloalkyl group is unsubstituted. More preferably, the alkyl, alkylene or cycloalkyl group is unsubstituted. Preferably R4、R5、R7And R8The alkyl, alkylene or cycloalkyl group in (1) is unsubstituted. In another embodiment, R4、R5、R6、R6’、R7And R8The alkyl, alkylene or cycloalkyl group in (1) is unsubstituted.
In a preferred embodiment of the present invention, one or more or all of the groups comprised in the compounds of formula (I) may have any of the preferred, more preferred or most preferred group definitions indicated above or any one or some of the specific indications covered by the group definitions indicated above independently of each other, all combinations of preferred definitions, more preferred or most preferred and/or specific indications being the subject of the present invention. Furthermore, in respect of all preferred embodiments, the present invention includes all stereoisomeric forms and mixtures of stereoisomeric forms in all ratios of the compounds of formula (I) and pharmaceutically acceptable salts thereof.
The term "in" for substituents in the examples shown (see above) indicates the position at which the substituent is attached, for example,
for R3The substituent isAnd m is 3, which represents a compound of the formula:
a preferred embodiment are compounds of formula (I) wherein:
R1is H or OH
R2Is hydrogen, halogen or (C)1-C6) An alkyl group;
R3is H, halogen, (C)1-C4) alkylene-R', O-R ", or NHR";
R4is H, halogen or (C)1-C6) An alkyl group;
R5is H, (C)1-C6) Alkyl, halogen, CN, (C)2-C6) Alkenyl, (C)6-C10) Aryl, NH- (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl group, (C)5-C10) Heterocyclyl or (C)1-C6) Alkylene- (C)5-C10) A heterocyclic group;
R6and R6'independently of one another are 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) NH2，(C1-C6) alkylene-C (O) NH-R', (C)1-C6) alkylene-C (O) N [ (C)1-C4) Alkyl radical]2、(C1-C6) alkylene-C (O) N [ R']2、C(O)O-(C1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) (C)5-C10) Heterocyclyl, C (O) NH- (C)1-C6) Alkyl, C (O) N [ (C)1-C6) Alkyl radical]2、C(O)-(C1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group, C (O) (C)1-C6) Alkylene- (C)6-C10) Aryl, or R6And R6' together with the N-atom to which they are attached form (C)5-C6) A heterocyclic group;
R7is H, halogen, CN, (C)1-C6) Alkyl, O- (C)1-C6) Alkyl, (C)2-C6) Alkenyl or R';
R8is H, halogen or (C)1-C6) An alkyl group;
m is 2, 3 or 4
n is 1, 2 or 3, and
l is S (CH)2)p、NH(CH2)pOr N (C)1-C6) Alkyl- (CH)2)p(ii) a And is
p is 0, 1 or 2;
and their stereoisomeric and/or tautomeric forms and/or their pharmaceutically acceptable salts.
Another preferred embodiment is a compound of formula (I) wherein:
R1is H or OH;
R2is H or (C)1-C4) An alkyl group;
R3is H, halogen or NHR ", wherein R" is as defined above;
R4is H, halogen or (C)1-C4) An alkyl group;
R5is H, (C)1-C6) Alkyl, halogen, (C)2-C4) Alkenyl, (C)6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl or (C)5-C10) A heterocyclic group;
R6and R6' independently of one another are H, (C)3-C8) Cycloalkyl group, (C)1-C8) Alkyl, (C)1-C6) alkylene-O- (C)1-C6) Alkyl, (C)1-C3) alkylene-R'; c (O) (C)1-C6) Alkyl, C (O) (C)3-C8) Cycloalkyl, C (O) (C)5-C10) Heterocyclic group, C (O) (C)1-C6) Alkylene- (C)3-C8) Cycloalkyl, C (O) (C)1-C6) Alkylene- (C)5-C10) Heterocyclyl or C (O) (C)1-C6) Alkylene- (C)6-C10) An aryl group;
R7is H, halogen, CN, (C)1-C6) Alkyl, O (C)1-C6) Alkyl radical、(C2-C6) Alkenyl or R';
R8is H, halogen or (C)1-C6) An alkyl group;
m is 2, 3 or 4
n is 1, 2 or 3; and is
L is S (CH)2)pOr NH (CH)2)p，
p is 0 or 1;
or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
A particularly preferred embodiment are compounds of formula (I) wherein:
R1is H or OH;
R2is H, (C)1-C4) An alkyl group;
R3is H, NH- (C)5-C6) Heteroaryl or NH-phenyl;
R4is H, halogen or (C)1-C4) An alkyl group;
R5is H, (C)1-C4) Alkyl, halogen, (C)1-C4) Alkenyl, (C)6-C10) Aryl group, (C)1-C2) Alkyl radical- (C)6-C10) Aryl or (C)5-C6) A heteroaryl group;
R6is H, (C)3-C6) Cycloalkyl or (C)1-C4) An alkyl group;
R6' is H, (C)3-C8) Cycloalkyl group, (C)1-C8) Alkyl, (C)1-C3) alkylene-R', C (O) O- (C)1-C6) Alkyl, C (O) (C)1-C6) Alkyl, C (O) (C)3-C6) Cycloalkyl, C (O) (C)5-C6) Heterocyclic group, C (O) (C)1-C3) Alkylene- (C)3-C6) Cycloalkyl, C (O) (C)1-C3) Alkylene- (C)5-C6) Heterocyclyl or C (O) (C)1-C3) Alkylene-phenyl;
R7is H, halogen, CN, (C)1-C4) Alkyl, O (C)1-C4) Alkyl, (C)1-C4) Alkenyl, phenyl, cyclopropyl, (C)5-C6) A heteroaryl group;
R8is H, halogen or (C)1-C4) An alkyl group;
m is 3;
n is 1; and is
L is S or NH;
or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
In an embodiment, the present invention relates to a compound of formula (I) independently selected from:
[4- (isoquinolin-6-ylamino) -cyclohexyl ] -carbamic acid tert-butyl ester,
n-isoquinolin-6-yl-cyclohexane-1, 4-diamine,
36.6-trans- (4-amino-cyclohexylamino) -2H-isoquinolin-1-one,
37.6-cis- (4-amino-cyclohexylamino) -2H-isoquinolin-1-one,
38.6-cis- (4-amino-cyclohexylamino) -7-chloro-2H-isoquinolin-1-one,
39.6-trans- (4-amino-cyclohexylamino) -7-chloro-2H-isoquinolin-1-one,
40.6-cis- (2-amino-cyclohexylamino) -2H-isoquinolin-1-one,
43.6-trans- (2-amino-cyclohexylamino) -2H-isoquinolin-1-one,
44.6-cis- (4-diethyl-amino-cyclohexylamino) -2H-isoquinolin-1-one,
45.6-cis- (4-ethyl-amino-cyclohexylamino) -2H-isoquinolin-1-one,
46.6-cis- (4-dipropyl-amino-cyclohexylamino) -2H-isoquinolin-1-one,
47.6-cis- (4-propyl-amino-cyclohexylamino) -2H-isoquinolin-1-one,
48.6-cis- (4-benzyl-amino-cyclohexylamino) -2H-isoquinolin-1-one,
49.6-cis- (4-isopropyl-amino-cyclohexylamino) -2H-isoquinolin-1-one,
50.6-cis- [4- (3-chloro-benzylamino) -cyclohexylamino ] -2H-isoquinolin-1-one,
51.6-cis- [4- (4-chloro-benzylamino) -cyclohexylamino ] -2H-isoquinolin-1-one,
52.6-cis- {4- [ (piperidin-4-ylmethyl) -amino ] -cyclohexylamino } -2H-isoquinolin-1-one,
53.6-cis- (4-cyclopropylamino-cyclohexylamino) -2H-isoquinolin-1-one,
54.6-cis- (4-bicyclopropyl-amino-cyclohexylamino) -2H-isoquinolin-1-one,
55.7-chloro-6-cis- (4-isopropylamino-cyclohexylamino) -2H-isoquinolin-1-one,
56.7-chloro-6-cis- (4-diethylamino-cyclohexylamino) -2H-isoquinolin-1-one,
57.7-chloro-6-trans- (4-isopropylamino-cyclohexylamino) -2H-isoquinolin-1-one,
61. cis-4- (7-chloro-isoquinolin-6-ylsulfanyl) -cyclohexylamine,
62. cis-4- (7-bromo-isoquinolin-6-ylsulfanyl) -cyclohexylamine, or
64.6-cis- (4-amino-cyclohexylsulfanyl) -7-chloro-2H-isoquinolin-1-one,
or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
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 indications encompassed by their definitions indicated above.
The substitution pattern of isoquinolines is numbered according to the IUPAC rules:
all references below to "a compound of formula (I)" refer to one or more compounds of formulae (I), (II), (III') and (IV) as described above, as well as their pharmaceutically acceptable salts and/or their stereoisomeric forms, polymorphs and solvates. Physiologically functional derivatives as described herein are also included.
Pharmaceutically acceptable salts of the compounds of formula (I) refer to their organic and inorganic salts, as described in Remington's pharmaceutical Sciences (17 th edition, p. 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 pharmaceutically acceptable salts from compounds of formula (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) 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 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 non-pharmaceutically acceptable anions such as trifluoroacetate are likewise within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic applications such as in vitro applications.
The term "physiologically functional derivative" as used herein refers to any physiologically tolerated derivative of a compound of formula (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 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 be active or inactive themselves.
The present invention relates to stereoisomeric forms, including racemates, racemic mixtures, pure enantiomers and diastereomers of the compound of formula (I) and mixtures thereof.
The compounds of the present invention may also exist in various polymorphic forms, 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.
If a group or substituent can occur more than once in a compound of the formula (I), they can all have the meanings indicated independently of one another and can be identical or different.
Term (C)1-C2) Alkyl, (C)1-C4) Alkyl, (C)1-C6) Alkyl, (C)1-C8) Alkyl and corresponding alkylene substituents are understood to be hydrocarbyl residues which may each be linear, e.g. straight-chain, or branched and have 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. This also applies when alkyl is a substituent of 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 or alkylene 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-。
Examples of alkenyl are vinyl, 1-propenyl, 2-propenyl (═ allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1, 3-pentadienyl.
Examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl (═ propargyl) or 2-butynyl.
Halogen means fluorine, chlorine, bromine or iodine.
(C3-C8) Cycloalkyl is a cyclic alkyl radical having 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 ring carbon atomsThe double bond (unsaturated cycloalkyl), such as cyclopentenyl or cyclohexenyl, may be bonded 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. Preferably (C)6-C10) Aryl is phenyl.
(C5-C10) Heterocyclyl means a mono-or bicyclic ring system in which one or more carbon atoms may be replaced by one or more heteroatoms, such as 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulphur 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.
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, chromenyl, chromen-2-onyl, cinnolinyl, decahydroquinolyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b ] furo]Tetrahydrofuran, furyl, furazanyl, homomorpholinyl, homopiperazinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuryl, isochromanyl, isoindolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolyl, furazanyl, homomorpholinyl, indolizinyl, isoindolyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazoAlkyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, oxathianthrenyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, prolyl (prolinyl), pteridinyl, purynyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, tetrahydrofuryl, tetrahydroisoquinolinyl, 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, thiadiazolyl, and the like, Tetrazolyl and xanthenyl. 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. Preferably (C)5-C10) Heterocyclyl is (C)5-C6) A heterocyclic group.
(C6-C10) Aryl and (C)5-C10) The heterocyclyl is unsubstituted or substituted, if not indicated otherwise, one or more times, preferably one to three times, with suitable groups independently selected from: halogen, OH, 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, PO3H2、SO3H、SO2-NH2、SO2NH(C1-C6) Alkyl, SO2N[(C1-C6) Alkyl radical]2、S-(C1-C6) An alkyl group; SO- (C)1-C6) Alkyl, SO2-(C1-C6) Alkyl, SO2-N＝CH-N[(C1-C6) Alkyl 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-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) -NH- (C)1-C6) Alkyl radical]、(C6-C10) Aryl group, (C)1-C6) Alkylene- (C)6-C10) Aryl, O- (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 group, O- (C)1-C6) Alkylene- (C)5-C10) Heterocyclic group of which (C)6-C10) Aryl or (C)5-C10) Hetero compoundThe cyclic group may be substituted once to three times with groups independently selected from: 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) An aryl group; or wherein (C)6-C10) Aryl radicals being in vicinal position by O- (C)1-C4) alkylene-O substituted, thereby forming a 5-to 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 heterocyclyl substituent of a heterocyclyl may not be further substituted by an aryl or heterocyclyl containing group.
To (C)6-C10) Preferred substituents for aryl are (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, SO2-N＝CH-N[(C1-C6) Alkyl radical]2、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、CONH(C1-C6) Alkyl, C (O) NH2、N[(C1-C4) Alkyl radical]2、(C1-C4) Alkylene- (C)6-C10) Aryl group of which (C)6-C10) The aryl group may be further substituted once to three times, preferably once, with the following groups: (C1-C4) Alkyl, (C)1-C4) alkylene-O- (C)1-C6) Alkyl, (C)6-C10) Aryl radical O- (C)1-C6) Alkyl radical- (C)6-C10) Aryl, or may be vicinal by O- (C)1-C4) alkylene-O substituted, thereby forming a 5-to 8-membered ring together with the carbon atom to which the oxygen atom is attached. To (C)6-C10) More preferred substituents for aryl are halogen, CN, phenyl, O-phenyl, NH-C (O) - (C)1-C4) Alkyl and especially NH-C (O) -CH3、C(O)-(C1-C4) Alkyl and especially C (O) -CH3、C(O)-O(C1-C4) Alkyl and especially C (O) -OCH3、(C1-C4) Alkyl and especially CH3Or CF3、O-(C1-C4) Alkyl and especially O-CH3、SO2-NH2、SO2-(C1-C4) Alkyl and especially SO2-CH3Or SO2-CF3(ii) a Or SO2-N＝CH-N[(C1-C4) Alkyl radical]2And especially SO2-N＝CH-N[(CH3)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, such as 1, 2-phenylene, 1, 3-phenylene or 1, 4-phenylene. The above description also applies correspondingly to arylidene groups in arylalkylene. Arylalkylene groups may be unsubstituted or substituted on arylene and alkyleneene groups, examples being benzyl, 1-phenylethylene, 2-phenylethylene, 3-phenylpropylene, 4-phenylbutylene, 1-methyl-3-phenyl-propylene.
To (C)5-C10) Preferred substituents for the heterocyclic group are (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) Aryl may be further substituted by halogen, (C)1-C4) Alkyl, O (C)1-C4) Alkyl, (C)1-C4) alkylene-O- (C)1-C6) Alkyl, O- (C)1-C6) Alkyl radical- (C)6-C10) Aryl radicals, or may be substituted in vicinal position by O- (C)1-C4) alkylene-O substituted, thereby forming a 5-to 8-membered ring together with the carbon atom to which the oxygen atom is attached. To (C)5-C10) More preferred substituents for the heterocyclic group are (C)1-C4) Alkyl, O (C)1-C4) Alkyl, halogen or phenyl, wherein phenyl may be further substituted by halogen, (C)1-C4) Alkyl or O- (C)1-C4) Alkyl is substituted once to three times, preferably once.
(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、R6’、R7、R8N, m and L in combination with the general and preferred definitions.
The invention therefore also relates to the use of a compound of formula (I) and/or their pharmaceutically acceptable salts and/or their prodrugs, a compound of formula (I) and/or their pharmaceutically acceptable salts and/or their prodrugs for the manufacture 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, i.e. for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, 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, 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 invention also relates to a pharmaceutical preparation (or pharmaceutical composition) comprising an effective amount of at least one compound of formula (I) and/or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable carrier substances (or vehicles) and/or additives (or excipients).
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 inert inorganic and/or organic carrier substances and/or additives in addition to the compounds of the formula (I) and/or their pharmaceutically acceptable salts and/or 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 implant sticks are, for example, copolymers of glycolic acid and lactic acid. Pharmaceutical formulations typically contain from about 0.5 to about 90% by weight of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof and/or a prodrug thereof. The amount of the active ingredient of formula (I) and/or a pharmaceutically acceptable salt thereof and/or a prodrug 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) and/or their pharmaceutically acceptable salts and 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, aromatics, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for varying the osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of formula (I) and/or their pharmaceutically acceptable salts. Where a pharmaceutical composition contains two or more compounds of formula (I), the selection of an individual compound may depend on the particular 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) allows for a great deal of control 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) and/or a pharmaceutically acceptable salt thereof, one or more further therapeutically or prophylactically active ingredients.
When using the compounds of the formula (I), the dosage can vary within wide limits and, as is customary and known to the skilled worker, 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. Appropriate 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/kg body weight). The daily dose may be administered in several, e.g. 2, 3 or 4, portions, particularly where larger amounts are administered. 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) can be used as synthesis 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.
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 a 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. In addition, they may then be converted by known methods into pharmaceutically acceptable salts or prodrugs of the compounds of formula (I).
In general, the reaction mixture containing the final compound of formula (I) or (I') or intermediate is worked up and, if desired, the product is then purified by conventional 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.
Isoquinolines and isoquinolinones can be synthesized by a variety of methods. The following general scheme illustrates some possible methods for obtaining isoquinolones, but does not limit the invention.
Scheme 1
Suitably substituted aldehydes, for example X-or Y-substituted aldehydes which are attached in suitable positions and independently of one another are hydrogen, alkyl, alkoxy or halogen, can be reacted with suitable compounds, for example acetals of aminoacetals, for example in solvents such as THF, chloroform or toluene, acid-catalyzed with toluenesulfonic acid or other suitable acids, to give imines (ii) in which Q' can be, for example, methyl or ethyl, which can then be cyclized to isoquinoline (iii) by different methods. This can be done, for example, by lewis acid catalysis with a suitable lewis acid such as a tetrachloro-peptide, iron halide, aluminum halide, etc., at temperatures from ambient to 100 ℃, or by reduction of the 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 and subsequent cyclization to isoquinoline by the action of a suitable lewis acid. The isoquinoline (iii) itself may 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 the appropriate 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.
6-bromoisoquinolines or bromoisoquinolones can be obtained by applying the appropriate bromo derivative in said reaction sequence.
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) can then be converted to the corresponding acid chloride by known methods, and the acid chloride can be converted to the acyl azide by reaction with sodium azide in a suitable solvent such as ether, chloroform or acetone, in the presence or absence 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-isoquinolone (or the corresponding isoquinoline iii) obtained above, e.g. (vi), may be reacted with a suitable compound wherein P1/P2P independently of one another being, for example, hydrogen, alkyl or a protecting group such as Boc or phthaloyl1/P2-reaction of a substituted thiol or amine in the presence of a base such as DBU, cesium carbonate or sodium hydride to give the corresponding alkylthio or alkylamino substituted derivative (xi). Finally, the transformationMay have been carried out at an early stage of the synthesis (e.g. by reaction of suitable intermediates). It should be understood that: in the case of unprotected isoquinolones, this may require protection at the nitrogen or oxygen of the isoquinolone moiety by suitable methods such as reaction with a suitably substituted alkyl or benzyl halide in the presence of a base.
When amine-substituted, the reaction may be accomplished by reacting the appropriate bromo-derivative with the given amine in the presence of a palladium catalyst such as palladium acetate, a ligand such as BINAP, and a base such as cesium carbonate.
The product obtained via this process, e.g. (xi), can then be liberated or, if appropriate amino functions are present, can be reacted with an appropriate aldehyde or ketone in the presence of a reducing agent, e.g. sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, in an appropriate solvent, in the presence of a water-absorbing agent, e.g. molecular sieves or an appropriate orthoester. The amino group may have to be released in an initial step, for example by removal of the Boc-group under acidic conditions. Furthermore, the amino group can be acylated by reaction with a suitable acid chloride in the presence of a base such as triethylamine or Hunig's base or by reaction with a suitable carboxylic acid in the presence of a base such as triethylamine or Hunig's base and a coupling agent such as EDC, PyBOP or TOTU.
In the case of the use of protected isoquinolones, it is necessary to cleave the protecting group used to release the desired isoquinolone (xii). However, this release may be carried out before or after the reductive amination step, depending on the nature of the aldehyde/ketone used and the protecting group used.
Isoquinolone derivatives such as (xii) can be obtained as free bases or as various salts, such as hydrochloride, hydrobromide, phosphate, trifluoroacetate, sulfate 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 isoquinoline derivatives as described above may be readily adapted to prepare compounds of formula (I). In the following examples, the preparation of the compounds of the invention is shown in more detail.
Accordingly, the following examples are part of the present invention and are intended to illustrate, but not to limit the invention.
It is understood that variations that do not substantially affect the activity of the various embodiments of the invention are included within the scope of the invention disclosed herein.
(4-bromo-benzyl) - (2, 2-dimethoxy-ethyl) -amine (1)
50g (270.2mmol) of 4-bromobenzaldehyde are dissolved in 200ml of toluene and 28.4g (270.2mmol) of aminoacetaldehyde dimethyl acetal are added. After addition of 5.1g (27.0mmol) of p-toluenesulfonic acid monohydrate, the reaction mixture is heated at reflux in a Dean Stark apparatus. After 4 hours, the reaction was cooled to room temperature and saturated NaHCO was used3Solutions (2X) and H2And O washing. The combined aqueous layers were extracted with toluene and the combined organic layers were MgSO4Drying and evaporating. The residue is dissolved in 200ml of ethanol and 5.11g (135.1mmol) of sodium borohydride are added in small portions. After stirring at room temperature for 2 hours and standing overnight, 5.0ml of acetic acid was added and the solvent was removed in vacuo. The residue is taken up in dichloromethane and washed with H2O wash (2 ×). With MgSO4After drying and evaporation, 60.5g of the title compound (crude product) were obtained and used without further purification. Rt0.80 min (method C). Actually measured quality: 274.1/276.1(M + H)+)。
N- (4-bromo-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (2)
60.5g of (4-bromo-benzyl) - (2, 2-dimethoxy-ethyl) -amine (1, crude product) are dissolved in 270ml of dichloromethane/pyridine (8: 1). A solution of 76.0g (386.4mmol) of p-toluenesulfonyl chloride in 100ml of dichloromethane was added at 0 ℃ and the solution was stirred at room temperature. After 3 hours, the reaction mixture was washed with 2N HCl and saturated NaHCO3Two washes of the solution. The organic layer was MgSO4Drying and evaporating. Finally, silica gel chromatography (heptane/ethyl acetate 4: 1) was carried out to give 59.9g of the title compound. Rt1.82 minutes (method C). Actually measured quality: 396.1/398.1 (M-OMe)-)。
6-bromo-isoquinoline (3)
To a mechanically stirred solution of 95.2g (699.5mmol) AlCl3To a suspension in 400ml dichloromethane was added a solution of 59.9g (139.8mmol) N- (4-bromo-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (2) in 400ml dichloromethane and the reaction was stirred at room temperature for 4 hours. After standing overnight, the reaction mixture was poured onto ice, the organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane solutions were treated with 1N NaOH (2X) and saturated NaHCO3-solution (2 ×) wash. With MgSO4After drying and evaporation of the solvent, the crude product was purified by silica gel chromatography (heptane/ethyl acetate 1: 1) to yield 17.5g of the title compound. Rt0.68 min (method C). Actually measured quality: 208.1/210.1(M + H)+)。
6-bromo-isoquinoline-2-oxide (4)
Under mechanical stirring 51.0g (245.1mmol) of 6-bromo-isoquinoline (3) are introduced at 800To a solution of 90.6g (367.6mmol) of 3-chloro-perbenzoic acid (70%) was added ml of dichloromethane. After stirring at room temperature for 4 hours and standing overnight, saturated NaHCO was added3Solution until two clear layers are obtained. The dichloromethane solution was separated and washed with saturated NaCl-solution. The aqueous layer was extracted with a chloroform/isopropanol (3: 1) mixture, the organic layers were combined, washed again with saturated NaCl-solution and MgSO4Drying and evaporating. The obtained crude product (53.0g) was used without further purification. RtAfter 0.89 min (method C). Actually measured quality: 226.2(M + H)+)。
6-bromo-1-chloro-isoquinoline (5)
53.0g (236.5mmol) of 6-bromo-isoquinoline-2-oxide (4) are placed in 400ml of POCl3Heating is carried out in two portions under reflux conditions. After 4 hours, the reaction was cooled to room temperature and carefully poured onto ice with mechanical stirring. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were over MgSO4Drying and evaporation gave 42.8g of the title compound, which was used without further purification. Rt1.64 min (method C). Actually measured quality: 242.1/244.2(M + H)+)。
6-bromo-2H-isoquinolin-1-one (6)
To a solution of 42.8g (173.5mmol) 6-bromo-1-chloro-isoquinoline (5) in 700ml acetic acid was added 133.6g (1.74mol) ammonium acetate. After stirring at 100 ℃ for 3 hours, the solution was cooled to room temperature and the solvent was removed in vacuo to a small volume. Pouring the residue into H2In O, the suspension is stirred for several minutes. The precipitate was separated by filtration and dried to yield 28.2g of the title compound. Rt1.30 min (method B)). Actually measured quality: 224.0(M + H)+)。
(4-bromo-3-chloro-benzyl) - (2, 2-dimethoxy-ethyl) -amine (7)
Starting from 4-bromo-3-chloro-benzaldehyde, the title compound was prepared by the method described for (4-bromo-benzyl) - (2, 2-dimethoxy-ethyl) -amine (1). Rt0.94 min (method C). Actually measured quality: 308.3/310.3(M + H)+)。
N- (4-bromo-3-chloro-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (8)
The title compound was prepared by the protocol described for N- (4-bromo-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (2) starting from (4-bromo-3-chloro-benzyl) - (2, 2-dimethoxy-ethyl) -amine (7). Rt1.93 minutes (method C). Actually measured quality: 430.3/432.3 (M-OMe)-)。
6-bromo-7-chloro-isoquinoline (9)
Starting from N- (4-bromo-3-chloro-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (8), the title compound was synthesized by the protocol described for 6-bromo-isoquinoline (3). Rt1.02 minutes (method C). Actually measured quality: 242.2/244.2(M + H)+)。
6-bromo-7-chloro-isoquinoline-2-oxide (10)
The title compound was prepared by the method described for 6-bromo-isoquinoline 2-oxide (4) starting from 6-bromo-7-chloro-isoquinoline (9). Rt1.05 min (method C). Actually measured quality: 258.1/260.2(M + H)+)。
6-bromo-1, 7-dichloro-isoquinoline (11)
Starting from 6-bromo-7-chloro-isoquinoline-2-oxide (10), the desired 6-bromo-1, 7-dichloro-isoquinoline was prepared by the method described for 6-bromo-1-chloro-isoquinoline (5). Rt1.85 min (method C). Actually measured quality: 276.1/278.2(M + H)+)。
6-bromo-7-chloro-2H-isoquinolin-1-one (12)
The title compound was prepared by the method described for 6-bromo-2H-isoquinolin-1-one (6), starting from 6-bromo-1, 7-dichloro-isoquinoline (11). Rt1.26 minutes (method C). Actually measured quality: 258.2/260.2(M + H)+)。
6-bromo-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (13)
28.18g (125.8mmol) 6-bromo-2H-isoquinolin-1-one (6) are dissolved in 200ml dimethylacetamide7.55g (188.7mmol) of sodium hydride (60%) are added at room temperature. After stirring for 30 min, 29.94g (188.7mmol) of 4-methoxy-benzyl chloride were added and stirring was continued at room temperature until conversion was detected to completion. The solvent was removed under reduced pressure and the residue was added saturated NaHCO3-solution, extracted three times with dichloromethane. The organic layer was MgSO4Drying and evaporating. Finally purification was performed by silica gel chromatography. Rt1.93 minutes (method B). Actually measured quality: 344.1(M + H)+)。
6-bromo-7-chloro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (14)
Starting from 6-bromo-7-chloro-2H-isoquinolin-1-one (12), the title compound was prepared by the method described for 6-bromo-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (13). Rt2.12 minutes (method B). Actually measured quality: 378.1/380.1(M + H)+)。
1-benzyloxy-6-bromo-isoquinoline (15)
To a solution of 3.93g (17.5mmol) 6-bromo-2H-isoquinolin-1-one (6) in 150ml toluene was added 12.13g (44.0mmol) Ag2CO3And 3.60g (21.1mmol) of benzyl bromide. The reaction mixture was refluxed for 1.5 hours and then cooled to room temperature. The solution was filtered. H for filtrate2O wash and extract the aqueous phase with ethyl acetate. The combined organic layers were over MgSO4Drying and evaporating. Final purification was performed by preparative HPLC. Rt2.47 minutes (method B). Actually measured quality: 314.1/316.5(M + H)+)。
(4-fluoro-3-chloro-benzyl) - (2, 2-dimethoxy-ethyl) -amine (16)
Starting from 4-fluoro-3-chloro-benzaldehyde, the title compound was prepared by the method described for (4-bromo-benzyl) - (2, 2-dimethoxy-ethyl) -amine (1). RtAfter 0.81 min (method C). Actually measured quality: 248.2(M + H)+)。
N- (4-fluoro-3-chloro-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (17)
The title compound was prepared by the protocol described for N- (4-bromo-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (2) starting from (4-fluoro-3-chloro-benzyl) - (2, 2-dimethoxy-ethyl) -amine (16). Rt1.80 minutes (method C). Actually measured quality: 370.2 (M-OMe)-)。
6-fluoro-7-chloro-isoquinoline (18)
Starting from N- (4-fluoro-3-chloro-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (17), the title compound was synthesized by the protocol described for 6-bromo-isoquinoline (3). RtAfter 0.73 minutes (method C). Actually measured quality: 182.1(M + H)+)。
6-fluoro-7-chloro-isoquinoline-2-oxide (19)
The title compound was prepared by the method described for 6-bromo-isoquinoline-2-oxide (4) starting from 6-fluoro-7-chloro-isoquinoline (18). Rt0.87 min (method C). Actually measured quality: 198.1(M + H)+)。
6-fluoro-1, 7-dichloro-isoquinoline (20)
Starting from 6-fluoro-7-chloro-isoquinoline-2-oxide (19), the desired 6-fluoro-1, 7-dichloro-isoquinoline was prepared by the method described for 6-bromo-1-chloro-isoquinoline (5). Rt2.34 minutes (method B). Actually measured quality: 216.0(M + H)+)。
6-fluoro-7-chloro-2H-isoquinolin-1-one (21)
The title compound was prepared by the method described for 6-bromo-2H-isoquinolin-1-one (6) starting from 6-fluoro-1, 7-dichloro-isoquinoline (20). Rt1.31 min (method B). Actually measured quality: 239.1(M + H)++ACN)。
6-fluoro-7-chloro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (22)
Starting from 6-fluoro-7-chloro-2H-isoquinolin-1-one (21), the title compound was prepared by the method described for 6-bromo-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (13). Rt1.94 minutes (method B). Actually measured quality: 318.1(M + H)+)。
(4-fluoro-3-bromo-benzyl) - (2, 2-dimethoxy-ethyl) -amine (23)
Starting from 4-fluoro-3-bromo-benzaldehyde, the title compound was prepared by the method described for (4-bromo-benzyl) - (2, 2-dimethoxy-ethyl) -amine (1). Rt1.01 min (method B). Actually measured quality: 292.1(M + H)+)。
N- (4-fluoro-3-bromo-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (24)
The title compound was prepared by the protocol described for N- (4-bromo-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (2) starting from (4-fluoro-3-bromo-benzyl) - (2, 2-dimethoxy-ethyl) -amine (23). Rt2.16 minutes (method B). Actually measured quality: 414.1 (M-OMe)-)。
6-fluoro-7-bromo-isoquinoline (25)
Starting from N- (4-fluoro-3-bromo-benzyl) -N- (2, 2-dimethoxy-ethyl) -4-methyl-benzenesulfonamide (24), the title compound was synthesized by the protocol described for 6-bromo-isoquinoline (3). Rt0.80 min (method B). Actually measured quality: 226.0(M + H)+)。
General procedure a for the Hartwig-Buchwald amination reaction:
1.0 equivalent of aryl bromide and 1.5 equivalents of Cs2CO3And 1.2 equivalents of amine in toluene. If the amine is used asFor salt addition, another equivalent of Cs is used2CO3(ii) a Alternatively, if aryl bromide is used as the salt (HCl-or TFA-salt of isoquinoline), an additional 1 equivalent of Cs is used2CO3. The solution was degassed and purged with argon. Then 0.03 eq Pd (OAc)2And 0.045 eq BINAP, the solution was heated at 100 ℃ until the reaction was complete or no further improvement was obtained. To isolate the product, the solution was cooled to room temperature, filtered and the filtrate was evaporated. The residue is taken up in H2In O, extraction was performed with ethyl acetate. Separating the organic layer with MgSO4Drying and removing the solvent in vacuum. The crude product was purified by preparative HPLC.
The following compounds (table 1) were synthesized according to general procedure a:
universal method for deprotection of Boc-groupsB：
The Boc-protected compound was dissolved in methanol and the same volume of 2N HCl was counted. The solution was stirred at room temperature until the reaction was detected to be complete. The solvent was removed in vacuo and the residue was dissolved in H2And (4) in O. Finally, lyophilization afforded the desired product as the hydrochloride salt. According to the general methodBThe following compounds were synthesized as the hydrochloride salts (table 2):
table 2:
general procedure for deprotection of PMB-protected CompoundsC：
In the case of PMB-and Boc-protected compounds, the starting materials were dissolved in trifluoroacetic acid and stirred at room temperature for 1 hour and then in a microwave at 140 ℃ for 3 hours. For isolation, the solvent was removed under reduced pressure and the residue was purified by preparative PHLC. The product fractions were combined and evaporated to give the expected product as the trifluoroacetate salt, which in some cases was dissolved in 2N HCl and evaporated. After final lyophilization of the aqueous solution, the desired product was isolated as the hydrochloride salt.
According to the general methodCThe following compounds were synthesized (table 3):
general procedure for reductive aminationD：
The starting material (1.0eq) was dissolved in anhydrous methanol. Adding fresh dried molecular sieveAfter triethylamine (2.0eq), acetic acid (10.0eq), a carbonyl compound (3.0-6.0eq) and sodium cyanoborohydride (3.0eq), the mixture was stirred at room temperature. To complete the conversion, the reaction was heated to 70 ℃ (bath temperature) in some cases or additional equivalents of carbonyl compound and sodium cyanoborohydride were added. To isolate the product, the solution was filtered and the filtrate was evaporated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with Na2SO4Dried and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC. The product fractions were combined and evaporated to give the expected product as the trifluoroacetate salt, which was dissolved in 2N HCl and evaporated. Finally the aqueous solution was freeze-dried and the expected product was isolated as the hydrochloride salt. The following compound was synthesized as the hydrochloride salt according to general procedure D (table 4):
trans-2- (4-hydroxy-cyclohexyl) -isoindole-1, 3-dione (58)
5g (33mmol) of trans-4-aminocyclohexanol, 4.88g of phthalic acid dimethyl esterThe acid anhydride and 7.85ml tributylamine were stirred at 150 ℃ for 10 hours. The mixture was dissolved in dichloromethane and washed with 1N HCl and saturated sodium bicarbonate solution. The organic phase is treated with Na2SO4Drying and evaporating. Purification over silica gel (50% solution of ethyl acetate in heptane) gave 4.8g of the expected compound.
cis-Thioglycolic acid 4- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -cyclohexyl ester (59)
3g (12.2mmol) trans-2- (4-hydroxy-cyclohexyl) -isoindole-1, 3-dione (58) and 3.51g (13.1 mmol) triphenylphosphine were dissolved in 55ml of anhydrous THF. 2ml (12.2mmol) diethyl azodicarboxylate (15min) was added at 0 ℃ followed by 873. mu.l (12.2mmol) thiolacetic acid and stirring continued at room temperature overnight. After evaporation of all volatiles, the residue was purified over silica gel (2% to 10% solution of ethyl acetate in heptane) to yield 2.56g of the expected compound.
Cis-2- [4- (7-chloro-isoquinolin-6-ylsulfanyl) -cyclohexyl ] -isoindole-1, 3-dione (60)
454mg (1.5mmol) of cis-thiolacetic acid 4- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -cyclohexyl ester (59) and 273mg (1.5mmol) of 6-fluoro-7-chloro-isoquinoline (18) are dissolved in 5ml of degassed DMF. After addition of 675. mu.l (3mmol) of DBU, the mixture was heated at 78 ℃ for 7 hours. The mixture was added to ethyl acetate and washed with brine. The organic phase is treated with Na2SO4Drying and evaporating. Purification over silica gel (30% to 50% solution of ethyl acetate in heptane) gave 220mg of the expected compound.
Cis-4- (7-chloro-isoquinolin-6-ylsulfanyl) -cyclohexylamine (61)
220mg (0.52mmol) of cis-2- [4- (7-chloro-isoquinolin-6-ylsulfanyl) -cyclohexyl]-isoindole-1, 3-dione (60) is treated in 5ml of methanol with 250. mu.l of hydrazine hydrate at room temperature until the conversion is complete. After evaporation, the residue was purified by HPLC. 131mg of cis-4- (7-chloro-isoquinolin-6-ylsulfanyl) -cyclohexylamine were obtained as trifluoroacetate salt. The resulting trifluoroacetate salt was dissolved in 2N HCl. Finally, lyophilization afforded 95mg of the title compound as the hydrochloride salt. Rt0.82 min (method B). Actually measured quality: 293.1/295.1(M + H)+)。
Cis-4- (7-bromo-isoquinolin-6-ylsulfanyl) -cyclohexylamine hydrochloride (62)
The title compound was obtained as the hydrochloride salt from 6-fluoro-7-bromoisoquinoline (25) via its phthalyl protected intermediate by the same reaction sequence as described for cis-4- (7-chloro-isoquinolin-6-ylsulfanyl) -cyclohexylamine (61). RtAfter 0.81 min (method B). Actually measured quality: 337.1(M + H)+)。
6-cis- (4-amino-cyclohexylthio) -7-chloro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (63)
Starting from 7-chloro-6-fluoro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (22), the title compound can be obtained as trifluoroacetate salt via its phthalyl protected intermediate by the same reaction sequence as described for cis-4- (7-chloro-isoquinolin-6-ylsulfanyl) -cyclohexylamine (61).
6-cis- (4-amino-cyclohexylsulfanyl) -7-chloro-2H-isoquinolin-1-one (64)
34mg (0.08mmol) 6-cis- (4-amino-cyclohexylthio) -7-chloro-2- (4-methoxy-benzyl) -2H-isoquinolin-1-one (63) are dissolved in 2ml TFA and stirred in the microwave at 150 ℃ for 1.5H. After evaporation, the residue was taken up in 1N HCl, extracted with dichloromethane and freeze-dried. 11mg of the expected product can be obtained as the hydrochloride salt. RtAfter 0.97 min (method B). Actually measured quality: 309.1/311.1(M + H)+)。
LC/MS-method:
the method A comprises the following steps:
stationary phase: col YMC Jsphere 33X 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 33X 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 H8020X 2
Gradient: ACN: H2O+0.05％TFA
4: 96(0min) to 95: 5(2.0min) to 95: 5(2.4min)
Flow rate 1mL/min
Assay for Rho kinase inhibition
To measure Rho-kinase inhibition, IC was determined according to the following protocol50The value:
active human recombinant ROCKII (N-terminal His 6-tagged recombinant human ROCK-II residues 11-552) was purchased from Apremilast Inc. (Upstate Ltd., Dundee, UK). The Peptide substrate fluorescein-AKRRRLSSLRA-COOH was obtained from JPT Peptide Technologies, Berlin, Germany. Adenosine-5' -triphosphate (ATP), Bovine Serum Albumin (BSA), dimethyl sulfoxide (DMSO), 4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid (Hepes), benzylze-35, and Dithiothreitol (DTT) were purchased from Sigma-Aldrich (Sigma-Aldrich, Munich, Germany). Tris (hydroxymethyl) -aminomethane (Tris), magnesium chloride, NaOH, 1M HCl and EDTA were obtained from Merck Biosciences, Darmstadt, germany. "complete" protease inhibitors were obtained from Roche Diagnostics, Mannheim, Germany.
Test compounds were in buffer 1(25mM Tris-HCl, pH 7.4, 5mM MgCl)22mM DTT, 0.02% (w/v) BSA and 3% DMSO) to the appropriate concentration. ROCK II enzyme was added in buffer 2(25mM Tris-HCl, pH 7.4, 5mM MgCl)22mM DTT and 0.02% (w/v) BSA) to a concentration of 100 ng/ml. The peptide substrate and ATP were diluted in buffer 2 to concentrations of 3. mu.M and 120. mu.M, respectively. Mu.l of the compound solution was mixed with 2. mu.l of the diluted enzyme in 384-well small volume microtiter plates (Greiner, Bio-One, Frickenhausen, Germany) and the kinase reaction was initiated by adding 2. mu.l of a solution containing the peptide substrate and ATP. After incubation at 32 ℃ for 60 minutes, the mixture was incubated by adding 20. mu.l of 100mM Hepes-NaOH, pH 7.4, 0.015% (v/v) benez-35, 45mM EDTA and 0.227%The reaction was terminated by coating the sheet with a solution of reagent 1(chip coating reagent 1) (Kailips Life sciences Inc., Hopkinton, Mass.). Phosphorylation of the substrate peptide was then detected on the Caliper 3000 instrument essentially as described by Pommereau et al (j.biomol. screening 9(5), 409-416, 2004). The separation conditions were as follows: pressure-1.3 psi, upstream voltage-1562V, downstream voltage-500V, and sample aspiration time 200 ms. Positive control (buffer 1 instead of compound) and negative control (buffer 1 instead of compound and buffer 2 instead of ROCK II) were performed in parallel on each plate.
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:
| compound numbering | pIC50 |
| 53 | +++++ |
| 54 | +++++ |
| 52 | +++++ |
| 51 | ++++ |
| 50 | ++++ |
| 48 | ++++ |
| 47 | +++++ |
| 49 | ++++ |
| 45 | +++++ |
| 44 | ++++ |
| 46 | ++++ |
| 40 | +++++ |
| 41 | +++++ |
| 36 | +++++ |
| 61 | +++++ |
| 62 | +++++ |
| 64 | +++++ |
The activities given are expressed as IC as follows50Base 10 negative logarithm (pIC)50)：
+： 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 the formula (I),
wherein
R1Is H or OH;
R2is H;
R3is H;
R4is H;
R5is H;
R6and R6' independently of one another are
H，
(C1-C4) An alkyl group, a carboxyl group,
(C1-C2) An alkylene group-R',
(C3-C4) A cycloalkyl group;
R7is that
H，
Halogen;
R8is H;
n is 1;
m is 3; and is
L is S or NH;
wherein
R' is
C5A heterocyclic group,
C6an aryl group; and is
Wherein in the group R3To R8In, C6Aryl and C5Heterocyclyl is unsubstituted or substituted one or more times by halogen;
the heterocyclic group contains 1 nitrogen atom;
or a stereoisomeric and/or tautomeric form thereof and/or a pharmaceutically acceptable salt thereof.
2. A compound of formula (I) according to claim 1, wherein R1Is H and is characterized by formula (II):
3. a compound of formula (I) according to claim 1, wherein R1Is OH and is characterized by formula (III):
4. a compound of formula (I) according to claim 1 or 3, wherein R1Is OH and is characterized by the formula (III'):
5. a compound according to any one of claims 1 to 3, wherein R7Is H, fluorine, chlorine or bromine.
6. A compound according to any one of claims 1 to 3, wherein R7Is H.
7. A compound according to any one of claims 1 to 3, wherein R6And R6' are independently of each other H, and,
(C1-C4) An alkyl group, a carboxyl group,
(C1-C2) alkylene-C5A heterocyclic group,
(C1-C2) alkylene-C6And (4) an aryl group.
8. A compound according to any one of claims 2-3, wherein
R6Is H, (C)1-C4) Alkyl or (C)3-C4) Cycloalkyl radicals, and
R6' is a hydrogen atom in the presence of a hydrogen atom,
(C1-C4) An alkyl group, a carboxyl group,
(C3-C4) A cycloalkyl group,
(C1-C2) alkylene-C5A heterocyclic group,
(C1-C2) alkylene-C6And (4) an aryl group.
9. A compound according to any one of claims 1 to 3, wherein
R6Is H, (C)1-C4) Alkyl radical, and
R6' is a hydrogen atom in the presence of a hydrogen atom,
(C1-C4) An alkyl group, a carboxyl group,
(C3-C4) A cycloalkyl group,
(C1-C2) alkylene-C5A heterocyclic group,
(C1-C2) alkylene-C6And (4) an aryl group.
10. A compound according to any one of claims 1-3, wherein R6Is H, (C)1-C4) Alkyl and R6' is H, (C)1-C4) Alkyl or (C)3-C4) A cycloalkyl group.
11. A compound according to any one of claims 1-3, wherein R6Is H and R6' is H, (C)1-C4) Alkyl or (C)3-C4) A cycloalkyl group.
12. A compound according to any one of claims 1-3, wherein R6And R6' is H.
13. A compound according to any one of claims 1 to 3 wherein L is attached to the 3-or 4-position of the aminocyclohexane ring.
14. A compound according to any one of claims 1 to 3 wherein L is attached to the 4-position of the aminocyclohexane ring.
15. A compound according to one of claims 1 to 3, wherein L is S.
16. A compound according to one of claims 1 to 3, wherein L is NH.
17. A compound according to claim 1, wherein
R1Is H or OH;
R2is hydrogen;
R3is H;
R4is H;
R5is H;
R6and R6' independently of one another are H, (C)1-C4) Alkyl or (C)1-C2) alkylene-R';
R7is H or halogen;
R8is H;
m is 3
n is a number of 1, and n is,
l is S or NH.
18. A compound according to claim 1, wherein
R1Is H or OH;
R2is H;
R3is H;
R4is H;
R5is H;
R6is H, (C)3-C4) Cycloalkyl or (C)1-C4) An alkyl group;
R6' is H, (C)3-C4) Cycloalkyl group, (C)1-C4) Alkyl or (C)1-C2) alkylene-R';
R7is H or halogen;
R8is H;
m is 3
n is 1; and is
L is S or NH.
19. Use of at least one compound of formula (I) according to any one of claims 1 to 18 and/or a pharmaceutically acceptable salt thereof for the preparation of a medicament.
20. Use of at least one compound of the formula (I) according to one of claims 1 to 18 and/or of a pharmaceutically acceptable salt thereof for the production 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 diseases, ischemic organ failure, fibrotic lung, fibrotic liver, liver failure, nephropathy, renal failure, fibrotic kidney, glomerulosclerosis, 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, premature birth, 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.
21. The use of claim 20, wherein the ischemic organ failure is end organ damage.
22. Medicament comprising an effective amount of at least one compound according to any one of claims 1 to 18 and/or a pharmacologically acceptable salt thereof, pharmaceutically tolerable excipients and carriers and, where appropriate, further additives and/or further active ingredients.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06026895 | 2006-12-27 | ||
| EP06026895.0 | 2006-12-27 | ||
| PCT/EP2007/011166 WO2008077553A1 (en) | 2006-12-27 | 2007-12-19 | Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1138583A1 HK1138583A1 (en) | 2010-08-27 |
| HK1138583B true HK1138583B (en) | 2013-06-28 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101573338B (en) | Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives | |
| US8278294B2 (en) | Substituted isoquinoline and isoquinolinone derivatives as inhibitors of Rho-kinase | |
| CN101228149B (en) | Piperidinyl-substituted isoquinolinone derivatives as Rho-kinase inhibitors | |
| JP5405315B2 (en) | Substituted isoquinoline and isoquinolinone derivatives | |
| JP5313919B2 (en) | Novel substituted isoquinoline and isoquinolinone derivatives | |
| JP5405314B2 (en) | Cycloalkylamine substituted isoquinolone derivatives | |
| EP1912949B1 (en) | Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors | |
| HK1138583B (en) | Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives | |
| HK1140201B (en) | Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase | |
| HK1123035B (en) | Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors | |
| HK1138582A (en) | Substituted isoquinoline and isoquinolinone derivatives | |
| HK1139390B (en) | Cycloalkylamine substituted isoquinolone derivatives |