Cycloalkylamine-substituted isoquinolone derivatives

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 6-substituted isoquinolone derivatives of formula

or , or stereoisomeric forms and/or pharmaceutically acceptable salts thereof, where R2 denotes H or (C1-C6)alkyl; R3, R4 and R5 denote H; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R', (C1-C6)alkylene-C(O)O-(C1-C6)alkyl, C(O)-(C1-C6)alkylene-R', or R6 and R6', together with a N atom with which they are bonded form a (C5-C6)heterocyclyl group in which one or more carbon atoms can be substituted with 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or a combination of different heteroatoms; R7 denotes H, halogen, (C1-C6)alkyl; R8 denotes H; n equals 1; m equals 1, 2, 3, 4 or 5, and L denotes O or O-(C1-C6)alkylene; where, R' denotes (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl; where in residues R6 and R6' alkyl or alkylene can optionally be substituted one or more times with COOH groups; and where in residues R6 and R6' (C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times with suitable groups independently selected from a group comprising CONH2 and (C1-C6)alkyl; where if m equals 3, R6 cannot denote H; where if m equals 3 and R6 denotes (C1-C8)alkyl, then the alkyl is substituted once or more times, preferably one to three times, with a COOH group. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the disclosed compounds.

EFFECT: novel isoquinolone derivatives which inhibit Rho-kinase and/or Rho-kinase mediated phosphorylation of the myosin light-chain phosphate.

31 cl, 6 tbl

 

This invention relates to new derivatives isohedron described by the claims, receipt and use of these derivatives for the treatment and/or prevention of diseases associated with inhibition of Rho-kinase and/or mediated by Rho-kinase phosphorylation phosphatase light chain of myosin.

Activation of RhoA small GTP by agonist stimulation leads to the transformation of RhoA inactivated GDP-bound form to the active GTP-bound form with the subsequent binding of Rho-kinase and activation of Rho-kinase. There are two isoforms of Rho-kinase 1 and Rho-kinase 2. Rho-kinase 2 is expressed in the smooth muscle cells of blood vessels and endothelial cells. Activation of Rho-kinase 2 under the action of the active GTP-bound RhoA leads to calcium sensitization of smooth muscle cells is mediated through phosphorylation inhibition of phosphatase activity light chain of myosin and thus increasing regulation of the activity of the regulatory light chain of myosin (Uehata et al., Nature 1997, 389, 990-994).

It is known that Rho-kinase is involved in vasoconstriction, including violations such as the development of myogenic tone and hyperactivity smooth muscle (Gokina et al. J. Appl. Physiol. 2005, 98, 1940-1948), 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, 111-118; Nakahara, et al. Eur J 2000, 389, 103) and chronic obstructive ill the of the lungs (COPD, Maruoka, Nippon Rinsho, 1999, 57, 1982-1987), hypertension, pulmonary hypertension (Fukumoto et al. Heart, 91, 391-392, 2005, Mukai et al. Nature 1997, 389, 990-994) and ocular hypertension and regulation of intraocular pressure (Honjo et al. Invest. Ophthalmol. Visual Sci. 2001, 42, 137-144), endothelial dysfunction (Steioff et al. Eur. J. Pharmacol. 2005, 512, 247-249), angina (Masumoto et al. Circ 2002, 105, 1545-1547, Shimokawa et al. JCP, 2002, 40, 751-761), nephropathy, including hypertension-induced, regimentation-induced and diabetic nephropathy, renal failure, and occlusive peripheral artery disease (PAOD) (Wakino et al. Drug News Perspect. 2005, 18, 639-643), myocardial infarction (Demiryurek et al. Eur J Pharmacol. 2005, 527, 129-140, Hattori et al. Circulation, 2004, 109,2234-2239), cardiac hypertrophy and heart failure (Yamakawa, et al. Hypertension 2000, 35, 313-318, Liao et al. Am J Physiol Cell Physiol. 2006, 290, C661-668, Kishi et al. Circ 2005, 111, 2741-2747), coronary heart disease, arteriosclerosis, restenosis (Pacaud et al. Arch. Mal. Coeur 2005, 98, 249-254, Retzer, et al. FEBS Lett 2000, 466, 70, Negoro, et al. Biochem Biophys Res Commun 1999, 262, 211), diabetes, diabetic complications, glucose disposal and metabolic syndrome (Sandu et al. Diabetes 2000, 49, 2178, Maeda et al. Cell Metab. 2005, 2, 119-129), sexual dysfunction, such as erectile dysfunction penis (Chitaley et al. Nature Medicine 2001, 7, 119-122), retinopathy, inflammation, immune diseases, AIDS, osteoporosis, disorders of the endocrine glands, for example giperaldosteronizm, disorders of the Central nervous system, such as Narona the degeneration and damage to the spinal cord (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, 203-211), spasm of cerebral vessels (Sato et al. Circ Res 2000, 87, 195; Kim et al. Neurosurgery 2000, 46, 440), pain, such as neuropathic pain (Tatsumi et al. Neuroscience 2005, 131, 491, Inoue et al. Nature medicine 2004, 10, 712), infection of digestive tract bacteria (WO 98/06433), the development and progression of cancer, neoplasia, in which, as shown, inhibition of Rho-kinase inhibits tumor cell growth and metastasis (Itoh et al. Nature Medicine 1999, 5, 221; Somlyo, et al. Res Commun 2000, 269, 652), angiogenesis (Uchida et al. Biochem Biophys Res 2000, 269, 633-640 ; Gingras et al. Biochem J 2000, 348, 273), proliferation and motility of smooth muscle cells of blood vessels (Tammy et al. Circ. Res. 1999, 84, 1186-1193; Tangkijvanich et al. Atherosclerosis 2001, 155, 321-327), proliferation of endothelial cells, the retraction and motility of endothelial cells (Oikawa et al. Biochem. Biophys. Res. Commun. 2000, 269. 633-640), the formation of stress fibers (Kimura et al. Science 1997, 275, 1308-1311; Yamashiro et al. J. Cell Biol. 2000, 150, 797-806), thrombotic disorders (Kikkawa et al. FEBS Lett. 2000, 466, 70-74; Bauer et al. Blood 1999, 94, 1665-1672, Klages et al. J Cell Biol 1999,144, 745; Retzer et al. Cell Signal 2000, 12, 645) and the aggregation of cells (Kawaguchi et al. Eur J Pharmacol. 2000, 403, 203-208; Sanchez-Madrid et al. J Immunol. 2003, 171, 1023-1034, Sanchez-Madrid et al. J Immunol. 2002, 168, 400-410), and bone resorption (Chellaiah et al. J Biol Chem. 2003, 278, 29086-29097), activation of the system of transport of Na/H exchange (Kawaguchi et al. Eur J Pharmacol. 2000, 403, 203-208), Alzheimer's disease (Zhou et al. Science 003, 302, 1215-1217), activation of adducin (Fukata et al. J. Biol. Chem. 1998, 273, 5542-5548) and SREB- (Sterol-response binding element) signal system and the impact of this system on lipid metabolism (Lin et al. Circ. Res. 2003, 92, 1296-1304).

Thus, the compounds having inhibitory effect on Rho-kinase and/or mediated by Rho-kinase phosphorylation of the phosphatase light chain of myosin, and are useful for treatment and/or prevention of cardiovascular and not cardiovascular disease with involvement of Rho-kinase as a cause of primary or secondary disease, such as hypertension, pulmonary hypertension, ocular hypertension, retinopathy and glaucoma, impaired peripheral circulation, occlusive peripheral artery disease (PAOD), coronary heart disease, angina, cardiac hypertrophy, heart failure, ischemic diseases, ischemic organ failure (damage end of the body), pneumovirus, liver fibrosis, liver failure, nephropathy, including hypertension-induced, regimentation-induced and diabetic nephropathy, renal failure, fibrosis of the kidney, renal glomerulosclerosis, hypertrophy of the body, asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome of adults, thrombotic disorders, stroke, causes the brain to the courts, cerebral ischemia, pain, such as neuropathic pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, disorders of endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and diabetic complications, metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, infection of digestive tracts with bacteria, sepsis, development and progression of cancer, such as malignant neoplasms of the breast, colon, prostate, ovarian, brain and lung, and corresponding metastases.

WO 01/64238 describes derivatives of isoquinoline-5-sulfonamida, optionally substituted -(CH2)1-6-O-(CH2)0-6-, -(CH2)0-6-S-(CH2)0-6- or -(CH2)0-6-linked heterocyclic group, useful as neuroprotective funds.

WO 2004/106325 (Schering AG) describes prodrugs of inhibitors of Rho-kinase fasudil containing ether or ester group at the 1-position of the isoquinoline ring.

WO 2001/039726 mainly describes substituted-O-(C0-C10)alkylglycerol cyclohexyl derivatives, useful for the treatment of microbial infections./p>

JP 10087629 A describes derivatives of isoquinoline, useful for treatment of diseases caused by Heliobacter pylori, such as, for example, gastritis, cancer or ulcer. Derivatives of isoquinoline can be substituted by OH in the 1-position and preferably are 5-substituted by-X - [(C1-C6)alkylen)]0-1-Y, where X can mean oxygen, and Y may denote aryl or heterocyclic group.

Hagihara et al. (Bioorg. Med. Chem. 1999, 7, 2647-2666) describe 6-benzyloxyethanol, useful for the treatment of infections caused by Heliobacter pylori.

US 5480883 mainly describes as inhibitors of EGF and/or PDGF receptor, are useful for inhibiting cell proliferation, the compounds of formula Ar I-X-Ar II”, where X may mean (CHR1)m-Z-(CHR1)n, for example, Z-CH2in which Z may denote O, R1means hydrogen or alkyl, Ar I may mean, among other things, optionally substituted isohedron and Ar II may mean, among other things, optionally substituted C3-7-monocyclic saturated heterocyclic system.

WO 2005/030791 (Merck & Co.) mainly describes as inhibitors of potassium channels for the treatment of cardiac arrhythmias, stroke, congestive heart failure and other derivatives isohedron, optionally substituted in the 6-position by the group (CReRf)pOR43where p is aviatica zero and R 43means, for example, (C3-C10)cycloalkenyl residue, optionally substituted NR51R52where R51and R52can denote hydrogen, (C1-C6)alkyl, etc.; or R43means the group R81defined as 4-6-membered unsaturated or saturated monocyclic heterocyclic ring with 1, 2, 3 or 4 heteroatoms; substituted directly connected, optionally substituted aryl or heteroaryl ring in 4-position.

WO 2005/030130 (Merck & Co.) mainly describes as inhibitors of potassium channels for the treatment of cardiac arrhythmias, stroke, congestive heart failure and other derivatives isohedron, which can be substituted by hydroxyl at the 1-position and optionally substituted in the 6-position by the group (CReRf)pOR43where p may be zero, and R43means, for example, (C3-C10)cycloalkenyl residue, optionally substituted NR51R52where R51and R52can denote hydrogen, (C1-C6)alkyl, etc.; or R43means the group R81defined as 4-6-membered unsaturated or saturated monocyclic heterocyclic ring with 1, 2, 3 or 4 heteroatoms; substituted directly connected, optionally substituted aryl or heteroaryl ring in 4-position.

WO 03/05330 (Ube) mainly describes derivatives isohedron formula

as inhibitors of Rho-kinase.

Variant implementation of the present invention is a compound of formula (I)

where R2denotes H, halogen or (C1-C6)alkyl,

R3means

H,

halogen,

(C1-C6)alkyl,

(C1-C6)alkylene-R',

OH,

O-R",

NH2,

Other",

NR"R" or

NH-C(O)-R",

R4means

H,

halogen,

hydroxy,

CN,

(C1-C6)alkyl,

R',

(C1-C6)alkylene-R',

R5means

H,

halogen,

CN,

NO2,

(C1-C6)alkyl,

(C2-C6)alkenyl,

R',

(C1-C6)alkylene-(C6-C10)aryl,

(C1-C6)albaniles-(C6-C10)aryl,

(C1-C6)alkylene-(C5-C10)heterocyclyl,

CH(OH)-(C1-C6)alkyl,

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]2,

C(O)OH or

C(O)O-(C1-C6)alkyl;

R6and R6' independently from each other mean

H,

R',

(C1-C8)alkyl,

(C1-C6)alkylene-R',

(C1-C6)alkylen-O-(C1-C6)alkyl,

(C1-C )alkylen-O-R',

(C1-C6)alkylene-CH[R']2,

(C1-C6)alkylen-C(O)-R',

(C1-C6)alkylen-C(O)NH2,

(C1-C6)alkylen-C(O)NH-R',

(C1-C6)alkylen-C(O)NH-(C1-C6)alkyl,

(C1-C6)alkylen-C(O)N[(C1-C6)alkyl]2,

(C1-C6)alkylen-C(O)N[R']2;

(C1-C6)alkylen-C(O)O-(C1-C6)alkyl,

C(O)O-(C1-C6)alkyl,

C(O)OR',

C(O)(C1-C6)alkyl,

C(O)R',

C(O)NH-(C1-C6)alkyl,

C(O)other',

C(O)N[(C1-C6)alkyl]R'

C(O)N[(C1-C6)alkyl]2,

C(O)-(C1-C6)alkylene-R',

C(O)O(C1-C6)alkylene-R',

or R6and R6'together with the N-atom to which they are attached, form a (C5-C10)heterocyclyl group;

R7means

H,

halogen,

CN,

NO2,

(C1-C6)alkyl,

O-(C1-C6)alkyl,

(C2-C6)alkenyl,

R',

(C1-C6)albaniles-(C6-C10)aryl,

(C1-C6)alkylene-R',

CH(OH)-(C1-C6)alkyl,

NH2,

NH-R',

NH-SO2H,

NH-SO2-(C1-C6)alkyl,

NH-SO2-R',

SO2-NH2,

SO2-Other',

NH-C(O)-(C1-C6)alkyl,

NH-C(O)-R',

C(O)N[(C1-C6)alkyl]2,

C(O)OH is whether

C(O)O-(C1-C6)alkyl;

R8denotes H, halogen or (C1-C6)alkyl;

n is 1, 2, 3 or 4;

m is 1, 2,3, 4, or 5, and

L means O or O-(C1-C6)alkylen,

where

R' means

(C3-C8)cycloalkyl,

(C5-C10)heterocyclyl,

(C6-C10)aryl and

R" means

(C3-C8)cycloalkyl,

(C5-C10)heterocyclyl,

(C6-C10)aryl,

(C1-C6)alkyl,

(C1-C6)alkylene-R',

(C1-C6)alkylen-O-(C1-C6)alkyl,

(C1-C6)alkylen-O-R' or

(C1-C6)alkylene-NRxRy; and

where Rxand Ryindependently from each other mean

(C1-C6)alkyl,

(C5-C10)heterocyclyl,

(C6-C10)aryl,

(C1-C4)alkylene-(C5-C10)heterocyclyl,

(C1-C4)alkylene-(C6-C10)aryl,

(C1-C4)alkylene-NH(C1-C6)alkyl,

(C1-C4)alkylene-N[(C1-C6)alkyl]2,

(C1-C4)alkylene-N[(C6-C10)aryl]2or

(C1-C4)alkylene-N[(C5-C10)heterocyclyl]2,

where in the residues R4, R5, R6, R6', R7and R8alkyl, alkylen or cycloalkyl optionally may be substituted by one who is not a more time OH, OCH3, COOH, COOCH3, NH2, NHCH3N(CH3)2, CONHCH3or CON(CH3)2;

where in the residues R2-R8alkyl or alkylene optionally can be substituted one or more times by halogen;

where in the residues R3-R8(C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times by suitable groups, independently selected from the group comprising OH, halogen, NO2N3, CN, C(O)-(C1-C6)alkyl, C(O)-(C1-C6)aryl, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2,(C3-C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)alkylene-OH, (C1-C6)alkylene-NH2, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)quinil, O-(C1-C6)alkyl, O-C(O)-(C1-C6)alkyl, PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl, SO-(C1-C6)alkyl, SO2-(C1-C6)alkyl, SO2-N=CH-N[(C1-C6)alkyl]2C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH-C(O)-(C 1-C6)alkyl, NH-C(O)O-(C1-C6)alkyl, NH-SO2-(C1-C6)alkyl, NH-SO2-(C6-C10)aryl, NH-SO2-(C5-C10)heterocyclyl, N(C1-C6)alkyl-C(O)-(C1-C6)alkyl, N(C1-C6)alkyl-C(O)O-(C1-C6)alkyl, N(C1-C6)alkyl-C(O)-NH-(C1-C6)alkyl], (C6-C10)aryl, (C1-C6)alkylene-(C6-C10)aryl, O-(C6-C10)aryl, O-(C1-C6)alkylene-(C6-C10)aryl, (C5-C10)heterocyclyl, (C1-C6)alkylene-(C5-C10)heterocyclyl or O-(C1-C6)alkylene-(C5-C10)heterocyclyl,

where (C6-C10)aryl or (C5-C10)heterocyclyl can be substituted one to three times by a group independently selected from the group including halogen, OH, NO2, CN, O-(C1-C6)alkyl, (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, SO2CH3, COOH, C(O)O-(C1-C6)alkyl, CONH2, (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-O-(C6-C10)aryl, or O-(C1-C6)alkylene-(C6-C10)aryl;

or where (C6-C10)aryl vicinal substituted O-(C1-C4)alkylene-O group, resulting in a 5-8-membered ring is formed together with the carbon atoms is kind, which are attached to atoms of oxygen;

and where the aryl or heterocyclyl substituents (C6-C10)aryl and (C5-C10)heterocyclyl groups can be optionally substituted containing aryl or heterocyclyl group;

and where, if m is 3, R6cannot mean H, (C5-C10)heterocyclyl or (C6-C10)aryl; and

where, if m is 3 and R6mean residue selected from the group including

(C1-C8)alkyl,

(C3-C8)cycloalkyl,

(C1-C6)alkylene-R',

(C1-C6)alkylen-O-(C1-C6)alkyl,

(C1-C6)alkylen-O-R',

(C1-C6)alkylene-CH[R']2,

(C1-C6)alkylen-C(O)-R',

(C1-C6)alkylen-C(O)NH2,

(C1-C6)alkylen-C(O)NH-R', or

(C1-C6)alkylen-C(O)N[R']2;

alkyl, alkylen or cycloalkyl in the specified residue substituted one or more times, preferably one to three times, OH, OCH3, COOH, COOCH3, NH2, NHCH3N(CH3)2, CONHCH3or CON(CH3)2;

or the corresponding stereoisomeric and/or tautomeric forms and/or pharmaceutically acceptable salts.

In another embodiment, the compound of formula (I) differs in that it is a compound of formula (I)

Compounds of formula (I) and (I) are tautomeric forms of each other and are part of this invention. The following variants of implementation relate to compounds of formula (I) and (I).

R3preferably denotes H, halogen, (C1-C4)alkylene-R', O-R" or other". More preferably, R3means H or other". Most preferably, R3means H, NH-(C5-C6)heterocyclyl or NH-phenyl, in particular, preferred are H, NH-(C5-C6)heteroaryl containing one or more N atoms, or NH-phenyl. Particularly preferred R3means H.

Examples R3deputies are

Preferably, R4denotes H, halogen or (C1-C6)alkyl. More preferably, R4denotes H, halogen or (C1-C4)alkyl. Most preferably, R4means H.

Preferably, R5means H, halogen, CN, (C1-C6)alkyl, (C2-C6)alkenyl, R', NH-(C6-C10)aryl or (C1-C6)alkylene-R'. More preferably, R5means H, halogen, (C1-C6)alkyl, (C2-C6)alkenyl, R', NH-(C6-C10)aryl or (C1-C6)alkylene-R'. Most preferably, R5means H, halogen, (C1-C6)alkyl, (C2-C6)Elke the sludge, (C6-C10)aryl, NH-(C6-C10)aryl, (C1-C2)alkyl-(C6-C10)aryl or (C5-C10)heteroaryl. In particular, preferably R5means H, halogen, phenyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C6-C10)aryl or (C5-C6)heteroaryl. Most preferably R5means H, halogen, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl.

Examples R5are hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl, nitrile, nitro, (p-methoxy)phenyl, N-aniline, benzyl, 2-propenyl,Deutbutenyl, cyclopropyl, tetrazol, amino, 4-methoxyaniline or N-acetyl, preferably hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, vinyl, phenyl, thienyl or pyridyl. More preferably, R5means H, halogen, methyl or ethyl, most preferably, R5means H.

Preferably R6and R6' independently from each other mean

H, (C1-C6)alkyl, R', (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-(C6-C10)aryl, (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C4)alkylen-C(O)-(C5-C10)heterocyclyl, (C1-C4)alkylen-C(O)-(C6-C10)aryl, (C1-C6)al the ilen-C(O)N[(C 1-C6)alkyl]2, (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl,(C1-C6)alkylen-C(O)O-(C1-C6)alkyl, C(O)R C(O)(C1-C6)alkyl, C(O)O-(C1-C6)alkyl, C(O)NH-(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2or C(O)(C1-C6)alkylene-R', or

R6and R6'together with the N-atom to which they are attached, form a (C5-C10)heterocyclyl group.

In another preferred embodiment, R6and R6' independently from one another mean H, (C1-C6)alkyl, (C5-C10)heterocyclyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-(C6-C10)aryl, (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-C(O)N[(C1-C6)alkyl]2, (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl, (C1-C6)alkylen-C(O)O-(C1-C6)alkyl, C(O)O-(C1-C6)alkyl, C(O)(C1-C6)alkyl, C(O)(C3-C8)cycloalkyl, C(O)NH-(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2C(O)(C1-C6)alkylene-(C3-C8)cycloalkyl, C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl, C(O)( 1-C6)alkylene-(C6-C10)aryl, or R6and R6'together with the N-atom to which they are attached, form a (C5-C10)heterocyclyl group.

In a more preferred embodiment, R6means H, (C1-C6)alkyl, (C3-C6)cycloalkyl or (C1-C4)alkylene-(C3-C6)cycloalkyl and

R6' means H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C5-C10)aryl, (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-(C6-C10)aryl, (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl, (C1-C6)alkylen-C(O)N[(C1-C6)alkyl]2, (C1-C6)alkylen-C(O)O-(C1-C6)alkyl, C(O)O-(C1-C6)alkyl, C(O)(C1-C6)alkyl, C(O)(C3-C8)cycloalkyl, C(O)NH-(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2C(O)(C1-C6)alkylen-C3-C8)cycloalkyl, C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl, C(O)(C1-C6)alkylene-(C6-C10)aryl, or

R6and R6'together with the N-atom to which they are attached, form a (C5-C10g is teracycline group.

In an even more preferred embodiment, R6means H, (C1-C6)alkyl and R6' means H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (C5-C10)heterocyclyl, (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C4)alkylen-O-(C1-C4)alkyl, (C1-C4)alkylen-C(O)N[(C1-C4)alkyl]2, (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl, C(O)(C1-C6)alkyl, C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl, or

R6and R6'together with the N-atom to which they are attached, form a (C5-C10)heterocyclyl group.

Further, an even more preferred embodiment, R6means H, (C1-C6)alkyl and R6' means

H;

(C1-C6)alkyl;

(C3-C8)cycloalkyl;

(C1-C4)alkylene-(C3-C8)cycloalkyl;

(C1-C4)alkylen-O-(C1-C4)alkyl;

(C1-C4)alkylen-C(O)N[(C1-C4)alkyl]2;

(C1-C4)alkylene-(C5-C10)heterocyclyl where heterocyclyl is unsubstituted or substituted one or more times before occhialino, from one to three times, more preferably one or two times by a group independently selected from the group comprising (C1-C4)alkyl, O(C1-C4)alkyl, halogen or phenyl, or substituted once (C5-C6)heterocyclyl,

where phenyl or (C5-C6)heterocyclyl is unsubstituted or substituted one to three times by halogen, (C1-C4)alkyl or O(C1-C4)alkyl; or

(C1-C4)alkylene-(C6-C10)aryl, where aryl is unsubstituted or substituted one or more times, preferably one to three times, more preferably one or two times by a group independently selected from the group comprising halogen, (C1-C4)alkyl, preferably CH3or CF3, O-(C1-C4)alkyl, CN, SO2-NH2; SO2-(C1-C4)alkyl, preferably SO2-CH3or SO2-CF3; SO2-N=CH-N[(C1-C4)alkyl]2preferably SO2-N=N-N(CH3)2, NH-CO-(C1-C4)alkyl, preferably NH-CO-CH3or CO-O-(C1-C4)alkyl, or (C6-C10)aryl substituted once unsubstituted phenyl, unsubstituted O-phenyl or unsubstituted (C5-C6)heterocyclyl;

C(O)(C1-C4)alkyl;

C(O)(C1-C4)alkylene-(C5-C10)heterocyclyl;

p> or R6and R6'together with the N-atom to which they are attached, form a (C5-C6)heterocyclyl group, which is unsubstituted or substituted one to three times, preferably once, (C1-C4)alkyl or C(O)O(C1-C4)alkyl;

where (C1-C4)alkyl or (C1-C6)alkyl residue is unsubstituted or substituted one to three times by halogen, preferably fluorine.

Preferably formed heterocyclyl group is morpholino, piperidino, pyrrolidino or piperazine derivatives, which can be unsubstituted or substituted as indicated above. More preferably, heterocyclyl group is morpholino or 4-ethylpiperazine.

In the most preferred embodiment, R6means H, (C1-C6)alkyl and R6' means H, (C1-C6)alkyl, (C3-C8)cycloalkyl,

In another most preferred embodiment, R6means H and R6' means H, preferably unsubstituted (C1-C6)alkyl or preferably unsubstituted (C3-C8)cycloalkyl. Particularly preferably, R6and R6' mean H.

In one of the embodiments, R6not may meantertbutyloxycarbonyl, in which osobennosti, if m equals 3.

As examples of such embodiments, R6or R6'denote, independently of one another, hydrogen, methyl, ethyl, propyl, isopropyl, 3-methylbutyl, 2-methylpropyl, butyl, pentyl, 3,3,3-cryptochromes, 4,4,4-triptorelin or Deputy selected from the group including

or

The asterisk (*) are presented as examples of the substituents shows where the link is connected with the N-atom.

Examples of residues, where NR6and NR6form a heterocyclic ring, are

or

The asterisk (*) are presented as examples of the substituents shows where the link connects to the carbon atom of carbocycle.

Preferably, R7means H, halogen, CN, (C1-C6)alkyl, O-(C1-C6)alkyl, (C2-C6)alkenyl, R', or (C1-C6)alkylene-(C3-C8)cycloalkyl. More preferably, R7means H, halogen, CN, (C1-C4)alkyl, O-(C1-C4)alkyl, (C1-C4)alkenyl, phenyl, cyclopropyl or (C5-C6)heteroaryl. Most preferably, R7 means H, fluorine, chlorine, bromine, methyl, ethyl, methoxy, phenyl, nitrile, cyclopropyl, thienyl or vinyl, particularly preferably, R7means H, fluorine, chlorine, methyl or methoxy. More preferably, R7means H.

R8preferably denotes H, halogen or (C1-C4)alkyl. More preferably, R8denotes H, Cl, F, methyl or ethyl. Most preferably, R8means H.

Preferably, R2denotes H, halogen or (C1-C4)alkyl. Preferably, R2means H or (C1-C2)alkyl. More preferably, R2denotes H, methyl or ethyl. Most preferably, R2means H. R2may be bonded to any carbon atom of the ring, including the position, according to which is attached a connecting group L.

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 connected with the ring in any position via a carbon atom of the ring. In a preferred embodiment, m is 3 and L is attached at the 4-position aminocyclohexanol rings

or L is attached at the 3-position aminocyclohexanol ring

all stereochemical forms.

In a particularly preferred embodiment, L is attached at the 4-position aminocyclohexanol rings.

In another preferred embodiment, L is O-methylene, O-ethylene or preferably O. More preferably, m is 3 and L is O-methylene, O-ethylene or O, is attached at the 4-position aminocyclohexanol rings.

In the residues R2-R8alkyl or alkylene optionally can be substituted one or more times by halogen. Preferably, the alkyl or alkylene substituted one or more times by halogen selected from chlorine or bromine, but may be replaced by fluorine once, or more times, for example, be perfluorinated. Preferably, the halogen means fluorine. More preferably, the alkyl or alkylen is not halogenated.

In the residues R4, R5, R6, R6', R7and R8alkyl, alkylen or cycloalkyl optionally can be substituted one or more times by a group independently selected from OH, OCH3, COOH, COOCH3, NH2, NHCH3N(CH3)2, CONHCH3or CON(CH3)2.

In the case of substitution, the number of the substituents are preferably selected from 1, 2, 3 or 4, more preferably 1 or 2 and, more preferably, the number of substituents is 1. Pre is respectfully alkylen or cycloalkyl is unsubstituted. More preferably, the alkyl, alkylen or cycloalkyl is unsubstituted. Preferably alkyl, alkylen or cycloalkyl R4, R5, R7and R8is unsubstituted. In another embodiment, alkyl, alkylen or cycloalkyl R4, R5, R6, R7and R8is unsubstituted.

In preferred embodiments of this invention, one or more, or all groups contained in the compounds of formula (I) or (I), independently from each other can have any of the preferred, more preferred or most preferred definitions of the above groups, or any one or some of the definitions included in the definition of groups and above all the combinations, more preferred or most preferred and/or private definitions are the subject of this invention. Also, with regard to all the preferred embodiments, the invention includes compounds of formula (I) or (Iin all stereoisomeric forms and mixtures of stereoisomeric forms in all ratios, and their pharmaceutically acceptable salts.

The term “ * “ are presented as examples of the substituents, see above, means the place of connection of the Deputy, which implies, for example, for R3Deputy

and m is 3, the compound of the formula

The preferred embodiment is a compound of formula (I),

where R2means hydrogen, halogen or (C1-C6)alkyl;

R3means H, halogen, (C1-C4)alkylene-R', O-R" or other";

R4denotes H, halogen or (C1-C6)alkyl;

R5means H, (C1-C6)alkyl, halogen, CN, (C2-C6)alkenyl, (C6-C10)aryl, NH-(C6-C10)aryl, (C1-C6)alkylene-(C6-C10)aryl, (C5-C10)heterocyclyl or (C1-C6)alkylene-(C5-C10)heterocyclyl;

R6and R6' independently from one another mean H, R', (C1-C8)alkyl, (C1-C6)alkylene-R', (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-O-R', (C1-C6)alkylene-CH[R']2, (C1-C6)alkylen-C(O)NH2, (C1-C6)alkylen-C(O)NH-R', (C1-C6)alkylen-C(O)N[(C1-C4)alkyl]2, (C1-C6)alkylen-C(O)N[R']2C(O)O-(C1-C6)alkyl, C(O)(C1-C6)alkyl, C(O)(C3-C8)cycloalkyl, C(O)(C5-C10)heterocyclyl, C(O)NH-(C1-C6)alkyl, C(O)N[(C1-C6)alkyl]2C(O)-(C1-C6)alkylene-(C3-C8)cycloalkyl, C(O)(C1-C6)alkyl is n-(C 5-C10)heterocyclyl, C(O)(C1-C6)alkylene-(C6-C10)aryl,

or R6and R6'together with the N-atom to which they are attached, form a (C5-C6)heterocyclyl group;

R7means H, halogen, CN, (C1-C6)alkyl, O-(C1-C6)alkyl, (C2-C6)alkenyl or R';

R8denotes H, halogen or (C1-C6)alkyl;

m is 2, 3 or 4,

n is 1, 2 or 3, and

L is O, O-methylene or O-ethylene;

and their pharmaceutically acceptable salts.

Another preferred embodiment is a compound of formula (I),

where R2means H or (C1-C4)alkyl;

R3denotes H, halogen or other", where R takes values above;

R4denotes H, halogen or (C1-C4)alkyl;

R5means H, (C1-C6)alkyl, halogen, (C2-C4)alkenyl, (C6-C10)aryl, (C1-C6)alkylene-(C6-C10)aryl or (C5-C10)heterocyclyl;

R6and R6' independently from one another mean H, (C3-C8)cycloalkyl, (C1-C8)alkyl, (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C3)alkylene-R', C(O)(C1-C6)alkyl, C(O)(C3-C8)cycloalkyl, C(O)(C5-C10)heterocyclyl, C(O)(C1-C6)alkylene-(C3 -C8)cycloalkyl, C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl or C(O)(C1-C6)alkylene-(C6-C10)aryl;

R7means H, halogen, CN, (C1-C6)alkyl, O(C1-C6)alkyl, (C2-C6)alkenyl or R';

R8denotes H, halogen or (C1-C6)alkyl;

m is 2, 3 or 4;

n is 1, 2 or 3, and

L means O;

and their pharmaceutically acceptable salts.

In particular, the preferred embodiment is a compound of formula (I),

where R2means H, (C1-C4)alkyl;

R3means H, NH-(C5-C6)heteroaryl or NH-phenyl;

R4denotes H, halogen or (C1-C4)alkyl;

R5means H, (C1-C4)alkyl, halogen, (C1-C4)alkenyl, (C6-C10)aryl, (C1-C2)alkyl-(C6-C10)aryl or (C5-C6)heteroaryl;

R6means H, (C3-C6)cycloalkyl or (C1-C4)alkyl;

R6' means H, (C3-C8)cycloalkyl, (C1-C8)alkyl, (C1-C3)alkylene-R', C(O)O-(C1-C6)alkyl, C(O)(C1-C6)alkyl, C(O)(C3-C6)cycloalkyl, C(O)(C5-C6)heterocyclyl, C(O)(C1-C3)alkylene-(C3-C6)cycloalkyl, C(O)(C1-C3)alkylene-(C5-C6)heterocyclyl Il is C(O)(C 1-C3)alkylester;

R7means H, halogen, CN, (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)alkenyl, phenyl, cyclopropyl, (C5-C6)heteroaryl;

R8denotes H, halogen or (C1-C4)alkyl;

m is 3;

n is 1 and

L means O;

and their pharmaceutically acceptable salts.

In the embodiment, this invention concerns the compounds of formula (I) or formula (I)independently selected from the group

15 Amide 1-[4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)cyclohexyl]piperidine-4-carboxylic acid,

16 7-Chloro-6-(4-piperidine-1-enciclopedias)-2H-isoquinoline-1-he,

17 7-Chloro-6-(4-(morpholine-4-enciclopedias)-2H-isoquinoline-1-he,

19 7-Chloro-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he,

21 7-Chloro-6-[4-(4-methylpiperazin-1-yl)cyclohexyloxy]-2H-isoquinoline-1-he,

23 Ethyl ester [4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexylamino]acetic acid,

24 [4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexylamino]acetic acid,

27 7-Methyl-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he,

28 N-[4-(7-Methyl-1-oxo-1,2-dihydroisoquinoline-6-yloxy)TRANScyclohexyl]-3-piperidine-4-ylpropionic,

29 N-[4-(7-Methyl-1-oxo-1,2-dihydroisoquinoline-6-yloxy)TRANScyclohexyl]-2-piperidine-4-ylacetamide,

3 N-[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy) CIS-cyclohexyl]-3-piperidine-4-ylpropionic,

31 N-[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexyl]-2-piperidine-4-ylacetamide,

43 6-((1S,3S)-3-Aminocyclopentane)-2H-isoquinoline-1-he,

44 6-((1S,3S)-3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,

45 6-((1S,3R)-3-Aminocyclopentane)-2H-isoquinoline-1-he,

46 6-((1S,3R)-3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,

47 6-((CIS-4-Aminocyclohexane)-7-methyl-2H-isoquinoline-1-he /

48 7-Chloro-6-(CIS-4-aminocyclohexane)-2H-isoquinoline-1-he,

or their stereoisomeric forms and/or pharmaceutically acceptable salts.

In another embodiment, this invention concerns the compounds of formula (I) or formula (I)independently selected from the group

49 6-(CIS-4-Aminocyclohexane)-2H-isoquinoline-1-he,

54 6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,

55CIS-6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,

56TRANS6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,

62 6-(5-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,

65 5-(1-Benzyloxy-7-chloroisoquinoline-6-yloxy)-1-propylcyclohexane,

66 6-(5-Amino-5-propylcyclohexyl)-7-chloro-2H-isoquinoline-1-he,

68 6-(5-Benzylamino-5-propylcyclohexyl)-7-chloro-2H-isoquinoline-1-he,

69 7-Chloro-6-(5-ethylamino-5-propylcyclohexyl)-2H-isoquinoline-1-he,

70 7-Chloro-6-(CIS-3-from the propylenecarbonate)-2H-isoquinoline-1-he,

71 6-(3-CIS-Benzylaminocarbonyl)-7-chloro-2H-isoquinoline-1-he,

72 6-(3-TRANSBenzylaminocarbonyl)-7-chloro-2H-isoquinoline-1-he,

73 7-Chloro-6-(3-CIS-dibenzylidineacetone)-2H-isoquinoline-1-he,

74 7-Chloro-6-(3-TRANSdibenzylidineacetone)-2H-isoquinoline-1-he /

75 7-Chloro-6-(3-TRANSdiethylaminoethoxy)-2H-isoquinoline-1-he,

or their stereoisomeric forms and/or pharmaceutically acceptable salts.

(The number of connections shown for reference)

As in any of the embodiments of the invention, in previous versions of the implementation, including the preferred, more preferred, preferred or typical examples of the definitions of the compounds according to this invention, one or more, or all groups can have any of the preferred, more preferred or most preferred of the above definitions, or any one or some of the definitions included in the definition of the groups above.

The equivalent circuit of isoquinoline numbered according to the IUPAC rules:

All references to “compound (compounds) of the formula (I) or (I)” refers hereinafter to the compound (compounds) of the above formula (I) or (I), and their pharmaceutically acceptable salts, and/or stereoisomeric forms, polymorphs and SOLV there. Also included are described here physiologically functional derivatives.

Under the pharmaceutically acceptable salts of compounds of formula (I) or (I) refers to both organic and inorganic salts, as described in Remington''s Pharmaceutical Sciences (17th edition, page 1418 (1985)). Because of the physical and chemical stability and solubility are preferred for acid groups, inter alia, salts of sodium, potassium, calcium and ammonium; preference is given to the major groups, inter alia, salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or carboxylic acid, or sulfonic acids, such as, for example, hydrochloride, hydrobromide, phosphates, sulphates, methansulfonate, acetates, lactates, maleate, fumarate, malate, gluconate, and salts of amino acids, natural substrates or carboxylic acids. Getting pharmaceutically acceptable salts of compounds of formula (I) or (I)capable of salt formation, including the corresponding stereoisomeric forms, carry out, essentially, in a known manner. The compounds of formula (I) form stable alkali metal salts, alkaline earth metal or optionally substituted ammonium with basic reagents such as hydroxides, to rbonate, the bicarbonate, the alcoholate and ammonia, or organic bases such as trimethyl - or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or other basic amino acids, for example lysine, ornithine or arginine. When the compounds of formula (I) or (Ihave basic groups, stable acid salt additive can also be obtained with strong acids. Suitable pharmaceutically acceptable acid additive salts of the compounds according to the invention are salts of inorganic acids such as hydrochloric acid, Hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and organic acids, such as, for example, acetic acid, benzolsulfonat, benzoic, citric, econsultancy, fumaric, gluconic, glycolic, setinova, lactic, lactobionic, maleic, malic, methansulfonate, succinic, p-toluensulfonate and tartaric acid.

Salts with a pharmaceutically unacceptable anion, such as, for example, triptorelin, also included in the scope of the invention as useful intermediates for obtaining or purification of pharmaceutically acceptable salts and/or for use in non-therapeutic purposes, for example in vitro.

The term “physiologically functional derivative”used herein means any physiologically the ski acceptable derivative compounds of formula (I) or (I ) according to the invention, for example, N-oxide, which when administered to a mammal, for example, such as people, are able to form (directly or indirectly) a compound of formula (I) or (I), or its active metabolite.

Physiologically functional derivative includes prodrugs of the compounds according to the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be converted into the exchange process in vivo in the connection according to the invention. Such prodrugs may themselves be active or not.

The invention relates to compounds of formula (I) or (I) in the form of their stereoisomeric forms, which include the racemates, racemic mixtures, pure enantiomers and diastereomers, and mixtures of these forms.

Compounds according to the invention may also exist in different polymorphic forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention are included in the scope of the present invention and constitute a further aspect of the invention.

If radicals or substituents are present repeatedly in the compounds of formula (I) or (I), all independently of each other, have a specified value and are the same or different.

Terms (C1-C2)alkyl, (C1-C4)alkyl, (C1-C6)alkyl, (C1-C 8)alkyl and the corresponding alkylene deputies mean a hydrocarbon residue, which may be linear, i.e. unbranched, or branched, and contains 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, respectively. The term is also used if an alkyl group exists as a Deputy to another group, for example in alkoxygroup (O-alkyl, S-alkyl or-O(C1-C6)alkylen-O-, alkoxycarbonyl group or arylalkyl group. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl or hexyl, n-isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl,Deutbutyl,tertbutyl ortertpencil. Alkyl or alkylene group - unless otherwise noted - to be halogenated once or several times, for example, alkyl groups may be fluorinated, for example perfluorinated. Examples of halogenated alkyl groups are CF3and CH2CF3, OCF3SCF3or-O-(CF2)2-O-.

Alkenyl are, 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.

The quinil are, for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL (= propargyl) or 2-butynyl./p>

Halogen means fluorine, chlorine, bromine or iodine.

(C3-C8)cycloalkyl groups are cyclic alkyl group containing 3, 4, 5, 6, 7 or 8 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl, which can also be substituted and/or contain 1 or 2 double bonds (unsaturated cycloalkyl group), as, for example, cyclopentenyl or cyclohexenyl can be connected through any carbon atom.

(C6-C10)aryl group means an aromatic ring or ring system containing two aromatic rings are condensed, or otherwise associated, for example phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha - or beta-tetralone, indanyl or indan-1-anilina group. Preferred (C6-C10)aryl group is phenyl.

(C5-C10)heterocyclyl group means mono - or bicyclic system of rings, where 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 sulfur atoms or combinations of various heteroatoms. Heterocyclyl residues can be attached in any position, for example, in the 1-position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-state is, or 8-position. (C5-C10)heterocyclyl groups can be (1) aromatic [= heteroaryl group], or (2) saturated, or (3) mixed aromatic/saturated.

Suitable (C5-C10)heterocyclyl group includes acridines, azocines, benzimidazolyl, benzofuran, benzomorphans, benzothiazyl, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, asterisell, benzisoxazole, benzisothiazole, carbazole, 4H-carbazolyl, carbolines, furanyl, hintline, chinoline, 4H-hemolysins, honokalani, hinokitiol, bromanil, bromanil, chromen-2-IMT, cinnoline, decahydroquinoline, 2H,6H-1,5,2-detainer, dihydrofuro[2,3-b]tetrahydrofuran, furyl, furutani, homomorpholine, homopiperazine, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindolines, isoindolyl, ethenolysis (benzimidazolyl), isothiazolin, isoxazolyl, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridines, phenanthrolines, phenazines, phenothiazines, phenoxathiin, phenoxazines, phthalazine, piperazinil, piperidinyl, prolinol, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine pyrazolines, pyrazolyl, pyridazinyl, pyridinyl, paradoxicaly, predominately, peridotite, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 6H-1,2,5-thiadiazine, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xantinol. Pyridyl is 2-, 3 - and 4-pyridyl. Thienyl means both 2-and 3-thienyl. Furyl means both 2-and 3-furyl. Also included are the corresponding N-oxides of these compounds, for example 1-hydroxy-2-, 3 - or 4-pyridyl. Substitution in (C5-C10)heterocyclyl residues can be carried out free carbon atoms or nitrogen atoms.

Preferred examples of (C5-C10)heterocyclyl residues are pyrazinyl, pyridyl, pyrimidinyl, pyrazolyl, morpholinyl, pyrrolidinyl, piperazinil, piperidinyl, thienyl, benzofuran, chinoline, tetrazolyl and triazolyl. Preferred (C5-C10)heterocyclyl the remainder is (C5-C6)heterocyclyl.

(C6-C10)aryl and (C5-C10)heterocyclyl groups are unsubstituted or, if not stated otherwise, substituted one or more times, preferably one to three times by suitable groups, independently selected from the group comprising halo is Yong, OH, NO2N3, CN, C(O)-(C1-C6)alkyl, C(O)-(C1-C6)aryl, COOH, COO(C1-C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2,(C3-C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)alkylene-OH, (C1-C6)alkylene-NH2, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)quinil, O-(C1-C6)alkyl, O-C(O)-(C1-C6)alkyl, PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2S-(C1-C6)alkyl; SO-(C1-C6)alkyl, SO2-(C1-C6)alkyl, SO2-N=CH-N[(C1-C6)alkyl]2C(NH)(NH2), NH2, NH-(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH-C(O)-(C1-C6)alkyl, NH-C(O)O-(C1-C6)alkyl, NH-SO2-(C1-C6)alkyl, NH-SO2-(C6-C10)aryl, NH-SO2-(C5-C10)heterocyclyl, N(C1-C6)alkyl-C(O)-(C1-C6)alkyl, N(C1-C6)alkyl-C(O)O-(C1-C6)alkyl,

N(C1-C6)alkyl-C(O)-NH-(C1-C6)alkyl],

(C6-C10)aryl, (C1-C6)alkylene-(C6-C10)aryl, O-(C6-C10)aryl,

O-(C1C 6)alkylene-(C6-C10)aryl, (C5-C10)heterocyclyl,

(C1-C6)alkylene-(C5-C10)heterocyclyl,

O-(C1-C6)alkylene-(C5-C10)heterocyclyl,

where (C6-C10)aryl or (C5-C10)heterocyclyl can be substituted one to 3 times by a group independently selected from the group including halogen, OH, NO2, CN, O-(C1-C6)alkyl, (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, SO2CH3, COOH, C(O)O-(C1-C6)alkyl, CONH2, (C1-C6)alkylen-O-(C1-C6)alkyl, (C1-C6)alkylen-O-(C6-C10)aryl, O-(C1-C6)alkylene-(C6-C10)aryl; or where (C6-C10)aryl vicinal substituted O-(C1-C4)alkylene-O group, resulting in a 5-8-membered ring is formed together with the carbon atoms to which are attached oxygen atoms. Aryl or heterocyclyl substituents (C6-C10)aryl and (C5-C10)heterocyclyl groups can be optionally substituted containing aryl or heterocyclyl group.

Preferred substituents for (C6-C10)aryl groups are (C1-C4)alkyl, O-(C1-C4)alkyl, O-phenyl, phenyl, C(O)O-(C1-C6)alkyl, C(O)OH, C(O)-(C1-C4 )alkyl, halogen, NO2, SO2NH2CN, SO2-(C1-C4)alkyl, SO2-N=CH-N[(C1-C6)alkyl]2, NH-SO2-(C1-C4)alkyl, NH2, NH-C(O)-(C1-C4)alkyl, (C3-C8)cycloalkyl, (C1-C4)alkyl-OH, C(O)N[(C1-C4)alkyl]2C(O)NH(C1-C6)alkyl, C(O)NH2N[(C1-C4)alkyl]2, (C1-C4)alkylene-(C6-C10)aryl, where (C6-C10)aryl may be optionally substituted one to three times, preferably once, by substituents selected from the group comprising (C1-C4)alkyl, (C1-C4)alkylen-O-(C1-C6)alkyl, (C6-C10)aryl-O-(C1-C6)alkyl-(C6-C10)aryl, or may be substituted vicinal group O-(C1-C4)alkylen-O, resulting in a 5-8-membered ring is formed together with the carbon atoms to which are attached oxygen atoms. More preferred substituents for (C6-C10)aryl are halogen, CN, phenyl, O-phenyl, NH-C(O)-(C1-C4)alkyl, in particular NH-C(O)-CH3C(O)-(C1-C4)alkyl, in particular C(O)-CH3C(O)-O(C1-C4)alkyl, in particular C(O)-OCH3, (C1-C4)alkyl, in particular CH3or CF3, O-(C1-C4)alkyl, in particular O-CH3, SO2-NH2, SO2 -(C1-C4)alkyl, in particular SO2-CH3or SO2-CF3; or SO2-N=CH-N[(C1-C4)alkyl]2in particular, SO2-N=CH-N[(CH3)2.

In monosubstituted phenyl groups Deputy may be located in the 2-position, 3-position or 4-position, preferred are 3-position and 4-position. If the phenyl group contains two substituent, the substituents can be located in the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. Phenyl groups containing three substituent, the substituents can be located 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 provisions phenyl groups, respectively, applicable to the divalent groups derived from phenyl groups, i.e. phenylene, which may be unsubstituted or substituted as 1,2-phenylene, 1,3-phenylene or 1,4-phenylene. The above provisions of the respectively applicable to aryl subgroup in arylalkylamine groups. Examples arylalkylamine groups, which may be unsubstituted or substituted in the aryl subgroup, as well as in alkalinous subgroup, are benzyl, 1-phenylethylene, 2-phenylethylene, 3-phenylpropyl, 4-phenylbutyl, 1-methyl-3-phenylpropyl.

Preferred z is Mascitelli for (C 5-C10)heterocyclyl groups are (C1-C4)alkyl, O-(C1-C4)alkyl, (C1-C4)alkylether, halogen, (C1-C4)alkylen-O-(C1-C4)alkyl, (C5-C10)heterocyclyl, (C1-C4)alkylene-N[(C1-C4)alkyl]2or (C6-C10)aryl, where (C6-C10)aryl may be optionally substituted by a Deputy chosen from the group comprising halogen, (C1-C4)alkyl, O(C1-C4)alkyl, (C1-C4)alkylen-O-(C1-C6)alkyl, O-(C1-C6)alkyl-(C6-C10)aryl, or may be substituted vicinal group O-(C1-C4)alkylen-O, resulting in a 5-8-membered ring is formed together with the carbon atoms to which are attached oxygen atoms. More preferred substituents for (C5-C10)heterocyclyl groups are (C1-C4)alkyl, O(C1-C4)alkyl, halogen or phenyl, where phenyl may be optionally substituted one to three times, preferably once, Deputy chosen from the group comprising halogen, (C1-C4)alkyl or O-(C1-C4)alkyl.

Common and preferred substituents (C6-C10)aryl and (C5-C10)heterocyclyl groups can be combined with common and preferred definitions of the R 1, R2, R3, R4, R5, R6, R6', R7, R8n, m and L, as described above.

Thus, this invention also relates to compounds of formula (I) or (Iand/or their pharmaceutically acceptable salts and/or prodrugs for use as pharmaceuticals (or drugs), use of compounds of formula (I) or (Iand/or their pharmaceutically acceptable salts and/or prodrugs, to obtain pharmaceutical products for the treatment and/or prevention of diseases associated with Rho-kinase and/or mediated by Rho-kinase phosphorylation phosphatase light chain of myosin, i.e. for the treatment and/or prevention of diseases such as hypertension, pulmonary hypertension, ocular hypertension, retinopathy and glaucoma, impaired peripheral circulation, occlusive peripheral artery disease (PAOD), coronary heart disease, angina, cardiac hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end damage body), pneumovirus, liver fibrosis, liver failure, nephropathy, including hypertension-induced, regimentation-induced and diabetic nephropathy, renal failure, fibrosis of the kidney, renal glomerulosclerosis, hypertrophy of the body, as the mA chronic obstructive pulmonary disease (COPD), respiratory distress syndrome of adults, thrombotic disorders, stroke, spasm of cerebral vessels, cerebral ischemia, pain, such as neuropathic pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, disorders of endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and diabetic complications, metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, infection of digestive tracts with bacteria, sepsis, development and progression of cancer, for example, malignant neoplasms of the breast, colon, prostate, ovarian, brain and lung, and corresponding metastases.

In addition, this invention relates to pharmaceutical preparations (or pharmaceutical compositions)containing an effective amount of at least one of the compounds of formula (I) or (Iand/or their pharmaceutically acceptable salts, and pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable substances-carriers (or solvents), and/or auxiliary substances (or excipients).

Pharmaceutical among the STV can be administered orally, for example, in such form, as pills, tablets, coated tablets, coated tablets, granules, hard or soft gelatine capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. The introduction, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or transdermally or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention receives, in fact, in a known manner and is familiar to the person skilled in the art, pharmaceutically acceptable inert inorganic and/or organic matter-carriers and/or excipients used in addition to the compound (compounds) of the formula (I) or (Iand/or their pharmaceutically acceptable salts and/or prodrugs. For the manufacture of pills, tablets, coated tablets and hard gelatin capsules can be used, for example, lactose, corn starch or derivatives, corn starch, talc, stearic acid or salts of stearic acid, and so on. Substances-carriers for soft gelatin capsules and supposit the holders, are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable substances-carriers to obtain solutions, such as solutions for injection, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable substances-carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to 90 mass % of compounds of formula (I) or (Iand/or their pharmaceutically acceptable salts and/or prodrugs. The amount of active ingredient of formula (I) or (Iand/or their pharmaceutically acceptable salts and/or prodrugs in the pharmaceutical preparations normally is from about 0.5 to 1000 mg, preferably, from about 1 to 500 mg

In addition to the active ingredients of formula (I) or (Iand/or their pharmaceutically acceptable salts and substances-the media, the pharmaceutical preparations can contain one or more auxiliary substances, such as, for example, fillers, disintegrant, binders, lubricants, humectants, stabilizers, emulsifiers, preservatives, sweeteners, to acitelli, the corrigentov, aromatizers, thickeners, diluents, buffer substances, solvents, soljubilizatory, means to achieve a depot effect, salts for modifying the osmotic pressure, forming a coating agents or antioxidants. The pharmaceutical preparations can also contain two or more compounds of the formula (I) or (Iand/or their pharmaceutically acceptable salts. In the case of a pharmaceutical product containing two or more compounds of the formula (I), the choice of individual compounds allows to achieve a specific overall pharmacological profile of a pharmaceutical product. For example, high-performance connection of short-term actions can be combined with the connection of long-term action less effective. The flexibility provided by the choice of substituents of formula (I) or (I), greatly to regulate biological and physico-chemical properties of compounds and thus to carry out the selection of such desired connections. Furthermore, in addition to at least one compound of formula (I) and/or their pharmaceutically acceptable salts, pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.

When using compounds of formula (I) or (I) dose can in order to reroute in a wide range and, as conventional and known to the attending physician must meet specific conditions in each individual case. The dose depends on the specific compound, the nature and severity of treatable diseases, from ways and schemes, or cured, whether acute or chronic disease, or prevention. The appropriate dosage can be determined using clinical approaches that are well known in the field of medicine. In General, the daily dose required to achieve the desired results in an adult weighing about 75 kg is approximately from 0.01 to 100 mg/kg, preferably from about 0.1 to 50 mg/kg, in particular from about 0.1 to 10 mg/kg (in each case in mg per 1 kg of body weight). The daily dose may be divided, in particular, in the case of the introduction of relatively large amounts, for example, 2, 3, or 4 separate injections. Usually, depending on the individual reactions may require deviation up or down from a specified daily dose.

In addition, the compounds of formula (I) can be used as intermediate products of synthesis for the preparation of other compounds, in particular of other pharmaceutical active ingredients derived from compounds of the formula I, for example, by the in troduction the possible substituents or modification of functional groups.

Typically, protective groups that may still be present in the products obtained in the reaction of binding, then remove the standard ways. For example,tertbutylene protective group, in particulartertbutoxycarbonyl group, which is a protective form amino groups, can be removed, i.e. converted into the amino group, by treatment with triperoxonane acid. As already mentioned, after the reaction of the binding functional group can also be generated from the corresponding groups predecessors. In addition, the transformation into a pharmaceutically acceptable salt or prodrug of the compounds of formula (I) or (I') can then be performed by known methods.

Usually the reaction mixture containing the target compound of formula (I) or (I') or intermediate product, process, and optionally, the product is then purified by standard methods known to the person skilled in the art. For example, the synthesized compound can be purified using well known methods such as crystallization, chromatography or obremenitve-high performance liquid chromatography (RP-HPLC), or other methods of separation based on, for example, on the size, charge or hydrophobicity of the compounds. Similarly, well-known methods, such as amino acid analysis consequently the STI, NMR, IR and mass spectrometry (MS) can be used to characterize the compounds according to the invention.

Athinaikon can be synthesized in a number of ways. The following General schemes illustrate some possible ways of obtaining athinodorou, but do not limit the invention.

Scheme 1:

Accordingly substituted aldehyde, for example substituted by X or Y, independently from each other mean a hydrogen, alkyl, alkoxy or halogen is attached in a suitable position, can be subjected to interaction with the appropriate connection, such as, for example, acetal of aminoacetaldehyde, for example, in a solvent such as THF, chloroform or toluene, under conditions of acid catalysis by toluensulfonate acid or other suitable acid with the formation of the imine (ii), where Q' can mean, for example, methyl or ethyl, which, in turn, can be cycletour different ways to of isoquinoline (iii). For example, the cyclization may be accomplished by catalysis by a Lewis acid with the use of Lewis acids such as titanium tetrachloride, ferrous iron halides, the halides of aluminum, and so forth, in the temperature range from ambient temperature to 100°C, or by restoring imine decouvertes amine under the action of a suitable reducing agent, such as sodium borohydride, with the conversion of amine to amide or a sulfonamide in the interaction with the appropriate acid chloride acid and subsequent cyclization to the isoquinoline under the action of an appropriate Lewis acid. Himself isoquinoline (iii) can then be converted into the corresponding N-oxide (iv) under the action of a suitable oxidizing agent such as hydrogen peroxide, m-chloroperbenzoic acid or other, at room temperature or elevated temperature. N-oxide (iv) can then be transformed into 1-chloroisoquinoline derivative (v) in collaboration with a reagent such as phosphorus oxychloride, in the presence or absence of pentachloride phosphorus. Derivative (v) can then be converted into the corresponding 1-alkoxy-derivatives in the interaction with various alcohols Q-OH, such as methanol, ethanol or benzyl alcohol, in the presence of a suitable base such as sodium hydride and in a suitable solvent, such as dimethylformamide, dimethylacetamide or other. Alternatively, (v) can be directly transformed into izohinolinove derivative (vii) in collaboration with the same reagent as ammonium acetate.

Scheme 2:

Alternatively, athinaikon can be obtained by the reaction of 3-formirovanii or acetylated fermentelos (viii)g is e z means, for example, H or alkyl, such as methyl or ethyl, with a reagent such as triethylphosphate, in the presence of a suitable base such as sodium hydride, which gives the corresponding esters of cinnamic acid, which subsequently decompose under the action of a suitable base, such as potassium hydroxide, sodium hydroxide or lithium hydroxide, in a suitable solvent that gives the acid (ix). (ix) may then be converted into the corresponding acid chloride of the acid is well known methods, which can be converted to azide acid by interaction with sodium azide in a suitable solvent, such as a simple ether, chloroform or acetone in the presence or absence of water. The corresponding azide can then be converted into athinaikon (x) when interacting in a suitable solvent, such as difenilmetana or simple diphenyl ether, at a corresponding temperature.

Scheme 3:

Obtained as above 6-foreskinlacy, for example (vi), can be subjected to interaction with P1/P2-substituted aminoalcohols, where P1/P2independently from each other mean, for example, hydrogen, alkyl or a protective group such as, for example, Boc or phthaloyl, in the presence of a base, such as DBU, cesium carbonate or sodium hydride, with the formation of the appropriate the appropriate alkoxy-substituted derivative (xi). In the end, this conversion was carried out in the initial stages of the synthesis (for example, when the engagement with a suitable intermediate product). It is clear that this transformation may require in the case of unprotected athinodorou protection by nitrogen or oxygen izohinolinove group using suitable methods, such as, for example, interaction with appropriately substituted alkyl or benzyl halides in the presence of a base.

Products of type (xi)obtained in this way can then be either selected or, if present at the amino-functionality, subjected to interaction with aldehydes or ketones in the presence of a reducing agent, such as triacetoxyborohydride sodium, sodium borohydride or cyanoborohydride sodium in a suitable solvent and in the presence of photodamage agent such as molecular sieves, or a suitable complex orthoepy. This amino group can be released at an early stage, for example, acidic removal of the Boc-group. In addition, the amino group may be azetilirovanna by communicating with the appropriate acid chloride acid in the presence of a base such as triethylamine or base Hunig'a, or by interaction with a suitable carboxylic acid in the presence of a base, that the CSOs as triethylamine or base Hunig'a, and linking reagent, such as EDC, PyBOP or TOTU.

In the case of protected athinodorou requires the removal of used protective groups for the release of the desired isohedron (xii). This release, however, may be performed before or after the stage of recovery amination, depending on the nature of the aldehyde/ketone and used protective group.

Derivatives isohedron, such as (xii)can be obtained as free bases or in the form of various salts, such as, for example, hydrochloride, hydrobromide, phosphates, triptoreline, sulfates or fumarate. The salts can be converted into the corresponding free base or by ion-exchange chromatography, or, for example, treatment of water with alkali and subsequent extraction with suitable organic solvents, such as, for example, methyltertbutyl ether, chloroform, ethyl acetate, or a mixture of isopropanol/dichloromethane, followed by evaporation to dryness.

The above General methods of obtaining derivatives of athinaikon can easily be adapted to obtain compounds of formula (I) or (I`). In the following examples, obtaining the compounds according to this invention are described in more detail.

Therefore, the following examples are included in the scope of the present invention and considered what are stated as illustrative and but not limiting the invention.

It is clear that modifications that do not significantly affect the activity of different embodiments of the compounds according to the invention, are included in the scope of the disclosed invention here.

LC/MS methods:

Method A:

Stationary phase: Col YMC Jsphere 33×2

Gradient: ACN+0.05% of TFA: H2O+0.05% of TFA 5:95 (0 min) to 95:5 (by 3.4 min) to 95:5 (4,4 min)

A flow rate of 1 ml/min

Method B:

Stationary phase: Col YMC Jsphere 33×2

Gradient: ACN+0.05% of TFA: H2O+0.05% of TFA 5:95 (0 min) to 95:5 (2.5 minutes) to 95:5 (3,0 min)

A flow rate of 1 ml/min

Method C:

Stationary phase: Col YMC Jsphere ODS H80 20×2

Gradient: ACN:H2O+0.05% of TFA from 4:96 (0 min) to 95:5 (2,0 min) to 95:5 (2,4 min)

A flow rate of 1 ml/min

Method D:

Stationary phase: Col YMC Jsphere 33×2,1

Gradient: ACN+0,08% FA:H2O+0,1%FA (formic acid) 5:95 (0 min) to 95:5 (2.5 minutes) to 95:5 (3 min)

The flow rate of 1.3 ml/min

Method E:

Stationary phase: Col YMC Jsphere 33×2

Gradient: ACN+0.05% of TFA:H2O+0.05% of TFA 5:95 (0 min) to 95:5 (2.5 minutes) to 95:5 (3.2 min)

The flow rate of 1.3 ml/min

Method F:

Stationary phase: Col YMC-Pack Pro C18 RS 33×2,1

Gradient: ACN+0.1% of FA:H2O+0,1% FA (formic acid) 5:95 (0 min) to 95:5 (2.5 minutes) to 95:5 (3 min)

The flow rate of 1.3 ml/min

Method G:

Stationary phase: Col YMC Jsphere 33×2,1

Gradient: ACN+0.05% of TFA:H2O+0.05% of TFA from 2:98 (0 min) to 2:98 (1 min) to 95:5 (5 min) to 95:5 (6,25 min)

A flow rate of 1 ml/min

Method H:

Stationary phase: Col YMC Jsphere ODS H80 20×2

Gradient: ACN:H2O+0.05% of TFA from 7:93 (0 min) to 95:5 (1,2 min) to 95:5 (1,4 min)

The flow rate of 1.1 ml/min

Method I:

Stationary phase: Waters XBridge C18 4

Gradient: ACN+0.05% of TFA:H2O+0.05% of TFA 5:95 (0 min) to 5:95 (0,3 min) to 95:5 (3.5 minutes) to 95:5 (4 min)

The flow rate of 1.3 ml/min

Method J:

Stationary phase: Col YMC Jsphere 33×2

Gradient: ACN+0.05% of TFA:H2O+0.05% of TFA 5:95 (0 min) to 5:95 (0.5 min) to 95:5 (3.5 minutes) to 95:5 (4 min)

The flow rate of 1.3 ml/min

(2.2-Dimethoxymethyl)-(4-terbisil)amine (1)

12.4 g of 4-forbindelse dissolved in 100 ml of toluene and subjected to interaction with 10.5 g of dimethylacetal 2-aminoacetaldehyde and 1.90 g of the monohydrate of p-toluensulfonate acid for two hours in the office of Dean stark. The solution is allowed to cool, extracted with saturated sodium bicarbonate solution, water and saturated salt solution, dried over magnesium sulfate and evaporated to dryness. The crude product is dissolved in 100 ml of ethanol. Add portions 1,89 g of sodium borohydride. Stirring is continued over night. For the purpose of processing, add acetic acid until then, until you cease to be a gas. Then the solution is evaporated to dryness, absorb dichloromethane and washed twice with water. The organic layer is extracted with saturated the salt solution, dried over magnesium sulfate and evaporated to dryness. The resulting crude product (20 g) is used for further interactions without purification. Rt=0,86 min (method B). Installed weight: 182,1 (M-OMe-), 214,2 (M+H+).

N-(2,2-Dimethoxymethyl)-N-(4-terbisil)-4-methylbenzenesulfonamide (2)

20 g (2,2-dimethoxymethyl)-(4-terbisil)amine (1) is dissolved in 120 ml of dichloromethane. Add 20 ml of pyridine. At 0°C is added dropwise a solution of 23.8 g of acid chloride of p-toluensulfonate acid in dichloromethane. The reaction mixture is allowed to warm to room temperature and stirring is continued until complete conversion. For the purpose of processing, the reaction mixture was twice washed with 2M hydrochloric acid, twice with sodium bicarbonate solution and once with saturated salt solution. The organic layer is dried over magnesium sulfate, evaporated to dryness and the resulting crude product is purified by chromatography on silica gel, receiving 22, 95mm g of compound 2 as an orange oil. Rt=1,71 min (method C). Installed weight: 336,1 (M-OMe-).

6-Forsakenly (3)

of 41.6 g of AlCl3suspended in 400 ml of dichloromethane. At room temperature add a solution of 22, 95mm g of N-(2,2-dimethoxymethyl)-N-(4-terbisil)-4-methylbenzenesulfonamide (2) in 150 ml of dichloromethane. Stirring is continued at room is the temperature during the night, the solution was poured on ice, the layers separated, the aqueous phase is twice extracted with dichloromethane and the combined organic layer is then extracted twice with sodium bicarbonate solution. The organic layer is dried over magnesium sulfate, evaporated to dryness and the resulting crude product (8,75 g) purified by chromatography on silica gel, getting to 2.74 g of compound 3. Rt=0,30 min (method C). Installed weight: 148,1 (M+H+).

7-Chloro-6-forsakenly (4)

On the basis of 3-chloro-4-forventelige specified in the header of the connection are using the same reaction sequence as that used for the synthesis of 6-vtoritchnaia (3). Rt=0,77 min (method A). Installed weight: 182,1/184,1 (M+H+).

7-Chloro-6-forsakenly-2-oxide (5)

25 g (137,7 mmol) 7-chloro-6-vtoritchnaia (4) is dissolved in 500 ml of dichloromethane. At room temperature add up 50.9 g (206,5 mmol) m-chloroperbenzoic acid (70%), and the mixture is stirred at room temperature to achieve complete conversion. For the purpose of processing, the precipitate was separated by filtration and washed with dichloromethane. The filtrate is washed twice with sodium bicarbonate solution. The layers are separated and the aqueous phase is twice extracted with dichloromethane. The organic phase is dried with magnesium sulfate and evaporated. The thus obtained solid prophetic the TWT (18,4 g) used without further purification. Rt=0,87 min (method C). Installed weight: 198,1/200,1 (M+H+).

1,7-Dichloro-6-forsakenly (6)

2.6 g (12,0 mmol) 7-chloro-6-forsakenly-2-oxide (5) is heated in 40 ml of POCl3the boiling point under reflux for 4 hours the Mixture is cooled to room temperature and then poured on ice. The aqueous solution extracted three times with dichloromethane. The combined organic layers dried with magnesium sulfate and evaporated, receiving only 2.91 g specified in the title compound, which was used without further purification. Rt=2,34 min (method A). Installed weight: 216,0/218,0 (M+H+).

7-Chloro-6-fluoro-2H-isoquinoline-1-he (7)

41,13 g (190,4 mmol) of 1,7-dichloro-6-vtoritchnaia (6) are dissolved in 670 ml of acetic acid. After adding 148, 8 persons g (1,90 mol) of ammonium acetate solution stirred at 100°C. After 3 h the solvent is removed under reduced pressure and the residue poured into water. The aqueous phase is extracted three times with dichloromethane, the combined organic layer was washed with saturated sodium bicarbonate solution and saturated salt solution, dried over sodium sulfate and evaporated to dryness. The crude product is crystallized from a mixture of ethyl acetate/heptane, getting 14,85 g of the desired product. Another 4.5 g can be obtained by evaporation and chromatography on silica gel maticnog the solution.

The precipitate is filtered and dried, obtaining to 9.91 g specified in the connection header. Rt=1,33 min (method B). Installed weight: 198,0 (M+H+).

6 Verizononline (8)

4.8 ml (90,3 mmol, 1.5 EQ.) thionyl chloride are added in portions to a solution of 10 g (60,2 mmol) 3-tortorice acid in 44 ml of chloroform and 1 ml of DMF. The reaction mixture is heated to boiling point under reflux for 2.5 hours and Then the solvent is distilled off, getting 11.4 g of crude carboxylic acid which is used without any additional purification.

The acid chloride of the acid is dissolved in 45 ml of acetone. At 0°C add portions 8,03 g (123,5 mmol, 2 EQ.) NaN3. Then added 41 ml of water while maintaining the temperature below 5°C. the Reaction mixture is stirred for another 1.5 hours Then add 55 ml of chloroform. The mixture was washed with 80 ml of water and then 40 ml of saturated salt solution. After drying over Na2SO4and filtering add 14 ml simple diphenyl ether and most of the chloroform is removed in vacuo (without heating). Avoid complete removal of chloroform.

The solution containing azide, simple diphenyl ether and residual chloroform is added dropwise, at 260°C, for 15 minutes, to a solution of 10 ml of tributylamine in 97 ml simple diphenyl ether. While adding may be EN Lichna reaction. The reaction mixture was stirred another 20 minutes at 260°C. After cooling to room temperature, add 270 ml of n-heptane. The precipitated product is filtered and washed with diethyl ether, receiving 5,65 g specified in the connection header. MS (DCI) Installed weight: 164,0 (M+H+).

6-fluoro-2-(4-methoxybenzyl)-2H-isoquinoline-1-he (9)

169 μl (1,24 mmol, 1.1 EQ.) p-methoxybenzylamine added to a suspension of 200 mg (1.13 mmol) of 6-pteriskingiana (8) and 368 mg (1,36 mmol, 1.2 EQ.) Cs2CO3in 3 ml of DMF. The mixture is stirred for 2 h and then poured on ice. The precipitate is filtered, washed with water and dried, receiving 300 mg specified in the connection header. Rt=1,76 min (method B). Installed weight: 284,14 (M+H+).

7-Chloro-6-fluoro-2-(4-methoxybenzyl)-2H-isoquinoline-1-he (10)

On the basis of 7-chloro-6-fluoro-2H-isoquinoline-1-it (7) is specified in the header connection receive according to the Protocol described for 6-fluoro-2-(4-methoxybenzyl)-2H-isoquinoline-1-it (9). Rt=1,66 min (method C). Installed weight: 318,3 (M+H+).

1-Benzyloxy-7-chloro-6-forsakenly (11)

14,74 g (74,6 mmol) 7-chloro-6-fluoro-2H-isoquinoline-1-it (7) is dissolved in 150 ml of toluene. After adding 30,86 g (111,9 mmol) of silver carbonate and 15,31 g (89,5 mmol) benzylbromide, the mixture is stirred at 80°C in accordance with the s 3 o'clock After cooling to room temperature the reaction mixture is filtered and the filtrate evaporated. The residue is dissolved in dichloromethane and washed with water, dried with magnesium sulfate and evaporated. Final purification by the method of preparative HPLC gives 11,63 g specified in the connection header. Rt=of 2.51 min (method B). Installed weight: grass 288,1/290,1 (M+H+).

6-(CIS-4 Aminocyclohexane)-7-chloro-2H-isoquinoline-1-he (12)

2,19 g (10.2 mmol)oftertbutyl etherCIS-(4-hydroxycyclohexyl)carbamino acid was dissolved in 20 ml of dimethylacetamide. In an argon atmosphere add 814 mg (from 20.4 mmol) of sodium hydride (60%) and the mixture is stirred at room temperature. After 30 minutes add a solution of 2.0 g (9,26 mmol) of 1,7-dichloro-6-vtoritchnaia (6) in 5 ml of dimethylacetamide and stirring is continued at room temperature. After 1 h, add 2.0 g (18.5 mmol) of benzyl alcohol and 740 mg (18.5 mmol) of sodium hydride (60%). The reaction mixture was stirred for 2 h at room temperature and 30 minutes at 80°C to achieve full conversion. The solvent is removed in vacuo and the residue absorb dichloromethane and washed twice with water. After drying over magnesium sulfate the organic layer is evaporated, giving 4.44 g of crude intermediate product,tertbutyl etherCIS-[4-(1-benzyloxy-7-chlorothieno the in-6-yloxy)cyclohexyl]carbamino acid. The intermediate product is dissolved in methanol and treated with 2 N. HCl at room temperature. After stirring for 2 d pH of the reaction mixture is adjusted to an alkaline value by adding sodium hydroxide. The solvent is removed in vacuum and the residue is stirred in ethanol. Filtration and evaporation of the filtrate gives a solid, which was purified preparative HPLC. The resulting triptorelin dissolved in 2 N. HCl. The final lyophilization give 433 mg specified in the title compound as hydrochloride. Rt=0,89 min (method B). Installed weight: 293,2/295,2 (M+H+).

1-Benzyloxy-7-chloro-6-(1,4-dioxaspiro[4.5]Dec-8-yloxy)isoquinoline (13)

1.26 g (a 8.34 mmol) of dioxaspiro[4.5]Decan-8-ol dissolved in 50 ml of dimethylacetamide and add 695,2 mg a (17.4 mmol) of sodium hydride (60%). After stirring for 30 minutes at room temperature add a solution of 2.0 g (6.95 mmol) of 1-benzyloxy-7-chloro-6-vtoritchnaia (11) in 50 ml of dimethylacetamide and stirring is continued at room temperature. After 1 h the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane and washed with water. The organic layer is dried with magnesium sulfate and evaporated, giving 3,30 g of crude product used without further purification. Rt=2,05 min (Method C). Installed weight: 426,5 (M+H +).

7-Chloro-6-(4-oxocyclohexyl)-2H-isoquinoline-1-he (14)

3,30 g of 1-benzyloxy-7-chloro-6-(1,4-dioxaspiro[4.5]Dec-8-yloxy)isoquinoline (13, crude product) is stirred in 30 ml of a mixture of 6 n HCl/acetone (1:2) at room temperature. After 3 h the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer is dried with magnesium sulfate and evaporated. The crude product is purified preparative HPLC. Rt=1,34 min (method B). Installed weight: 292,0 (M+H+).

On the basis of 7-chloro-6-(4-oxocyclohexyl)-2H-isoquinoline-1-she (14), the following compounds are synthesized in the form of hydrochloride by analogy with the General procedure described below.

A General method of performing the reaction of reductive amination

0.46 mmol of the corresponding amine dissolved in 10 ml of methanol. After adding molecular sieves 4 Å, was 92.3 mg (or 0.57 mmol) of triethylamine, 273,8 mg (4,56 mmol) of acetic acid and 0.57 mmol of ketone (14) is added dropwise a solution of 86,0 mg (1.37 mmol) of cyanoborohydride sodium and the mixture is stirred at room temperature to achieve complete conversion. In some cases, to achieve full conversion is necessary to heat the mixture to 70°C. For selection of products the solution is filtered and the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane, raybaut 1 N. NaOH and saturated sodium chloride solution, dried with magnesium sulfate and evaporated. Mono - or bis-alkylated products, if formed, purified preparative HPLC or precipitated from methanol HCl.

The resulting triptoreline stirred mixture of 2 N. HCl/methanol, evaporated, dissolved in water and dried by sublimation, getting the required products in the form of hydrochloride.

Removing the protective groups are Boc-protected products takes place during evaporation containing product HPLC fractions containing 0.1% of TFA, or during subsequent stirring in a mixture of 2 N. HCl/methanol. Cm. table 1

Table 1
If-
measures
AminProductNoteChemical name[M+H+]/
[g/mol]
Rt/
min
Method
15CIS/TRANSmixtureamide 1-[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)cyclohexyl]-piperidine-4-carboxylic acid 404,10,92B
16CIS/TRANSmixture7-Chloro-6-(4-piperidine-1-enciclopedias)-2H-isoquinoline-1-he361,11,08B
17TRANSisomer, isolated by stirring the crude product reset. aminer. using 2n. HCl. Filtration of the precipitate gives pureTRANSisomer.7-Chloro-6-(4-(morpholine-4-enciclopedias)-2H-isoquinoline-1-he363,21,07B
18The mother liquor from example 17, purified prep. HPLC, whereby the resulting ratio (CIS:TRANS) 2:1.7-Chloro-6-(4-(morpholine-4-enciclopedias)-2H-isoquinoline-1-he363,1 0,95B
19CIS-andTRANSthe isomers are separated by prep. HPLC;TRANSthe isomer obtained approx. with a purity of 80%.7-Chloro-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he347,11,02B
20CIS-andTRANSthe isomers are separated by prep. HPLC;CIS-the isomer obtained with a purity >95%.7-Chloro-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he347,10,97B
21CIS-andTRANSthe isomers are separated by prep. HPLC;TRANSthe isomer obtained approx. with a purity of 80%.7-Chloro-6-[4-(4-methylpiperazin-1-yl)cyclohexyloxy]-2H-isoquinoline-1-he376,2 0,81B
22CIS-andTRANSthe isomers are separated by prep. HPLC;CIS-the isomer obtained approx. with a purity of 75%.7-Chloro-6-[4-(4-methylpiperazin-1-yl)cyclohexyloxy]-2H-isoquinoline-1-he376,10,82B

Ethyl ester [4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexylamino]acetic acid (23)

300 mg (of 0.91 mmol) 6-CIS-(4 aminocyclohexane)-7-chloro-2H-isoquinoline-1-she (12) was dissolved in 20 ml of methanol and treated with 258 mg (1,14 mmol) of ethyl ester of Glyoxylic acid according to the General methodology of the implementation of the reactions of the reductive amination. To achieve complete conversion of the additional 5.0 equivalents of ethyl ester of Glyoxylic acid and 0.5 equivalent of cyanoborohydride sodium add portions for 34 hours and after 5 h reaction time the temperature was raised to 60°C until the reaction will not go to completion. After filtration of the reaction solution is evaporated. The residue is dissolved in dichloromethane, washed with 1 N. NaOH and saturated NaCl solution, drying is over MgSO 4and evaporated. Thus obtained crude product is used for subsequent interactions without additional purification. Rt=0,81 min (method C). Installed weight: 365,4 (M+H+, methyl ester as the solvent used methanol), 0,87 min (method C). Installed weight: 379,4 (M+H+, ethyl ester, specified in the header of the connection).

[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexylamino]acetic acid (24)

185 mg of ethyl ester [4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexylamino]acetic acid (23, crude product) are dissolved in 2 ml of methanol. After adding 2 ml of 2 N. NaCO3solution, the solution was stirred at room temperature for 1.5 hours, the Solvent is evaporated in vacuo and the residue purified preparative HPLC, giving specified in the title compound in the form of triptoreline. Rt=0,91 min (method B). Installed weight: to 351.3 (M+H+).

6-(TRANS4 Aminocyclohexane)-7-methyl-2H-isoquinoline-1-he (25)

a) 6-Fluoro-7-methyl-2H-isoquinoline-1-he

To a solution of 10.0 g (of 55.5 mmol) 3-fluoro-4-methylcatechol acid in 80 ml of acetone successively added at 0°C 6,74 g (66,6 mmol) of triethylamine in 10 ml of acetone and then 7,83 g (72.2 mmol) of ethylchloride. After stirring for t the value of 2 h at 0-5°C, add a solution of 4.0 g (61,1 mmol) of sodium azide in 9.5 ml of water. After stirring for additional 1 h, the reaction mixture was poured into 200 ml ice water and extracted twice with chloroform. The organic phase is dried over magnesium sulfate, add 40 ml simple diphenyl ether and chloroform thoroughly removed in vacuum. The residue is then applied dropwise in 50 ml of simple diphenyl ether, pre-heated to 245°C. Upon completion of addition, the reaction mixture is stirred for further 1 h at 230-250°C. After cooling to 150°C, the reaction mixture was poured into 270 ml of heptane and after further cooling in an ice bath, the precipitated product is filtered with suction and obtain 4.1 g of 6-fluoro-7-methyl-2H-isoquinoline-1-it.

b) 6-fluoro-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-he

To a solution 9,17 g (51,8 mmol) 6-fluoro-7-methyl-2H-isoquinoline-1-she's in 80 ml DMF added 20.2 g (62,1 mmol) of cesium carbonate and then of 8.92 g (56,9 mmol) of 4-methoxybenzylamine. After stirring at room temperature for 90 minutes the reaction mixture is poured into 600 ml of water, stirred for 1 h and then precipitated product produce by sucking. From the mother liquor an additional amount of the product emit chromatography using a mixture of heptane/ethyl acetate (80:20). United products is recrystallized from ethyl acetate and get 8,39 g of 6-fluoro-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-it.

c) 6-(TRANS 4 Aminocyclohexane)-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-he

To a solution of 1.48 g (of 9.75 mmol)TRANS4-aminocyclohexanecarboxylic in 20 ml of dimethylacetamide add 1,95 g (48,77 mmol) of sodium hydride (60%) and the mixture is stirred for 15 minutes. Subsequently add 2,90 g (of 9.75 mmol) 6-fluoro-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-she's in 30 ml of dimethylacetamide, and the reaction mixture is heated to 80°C for 2 days. After cooling, the mixture was poured into 300 ml ice water and the precipitated crude product is purified by chromatography. The first residual starting material elute with a mixture of ethyl acetate/heptane (2:1) and finally the desired product elute pure methanol, getting 1.98 g of 6-(TRANS4 aminocyclohexane)-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-it.

d) 6-(TRANS4 Aminocyclohexane)-7-methyl-2H-isoquinoline-1-he (25)

2.64 g (6.7 mmol) of 6-(TRANS4 aminocyclohexane)-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-she and 15.3 g (134,5 mmol) triperoxonane acid is heated for 2 h in a high-frequency electric furnace at 150°C. Then the excess triperoxonane acid is distilled off in vacuum and the residue diluted with 130 ml of 1 M hydrochloric acid. The aqueous phase is washed 3 times with dichloromethane and then dried by sublimation, getting hydrochloride, which is recrystallized from isopropanol. This gives 1.1 g of 6-(TRANS4-aminocyclo is hexyloxy)-7-methyl-2H-isoquinoline-1-it (25) as hydrochloride. Rt=0,92 min (method B). Installed weight: 273,22 (M+H+).

6-(CIS-4 Aminocyclohexane)-7-methyl-2H-isoquinoline-1-he (26)

a)CIS-4-Aminocyclohexanol

To a solution of 30.0 g (0,265 mol) cyclohexasiloxane in 300 ml of dichloromethane and 38 ml of ethanol is added slowly at 0°C to 34.5 g (0,318 mol)tertbutylhypochlorite. The obtained dark blue solution is cooled to -20°C and then add to 31.9 g (0,398 mol) of 1,3-cyclohexadiene and the mixture was stored in a refrigerator at 5°C for 2 days before the disappearance of the blue color. The reaction mixture is concentrated to 50% volume and then slowly add 600 ml of diethyl ether. After stirring over night the precipitate is separated by suction, getting 29.0 G. of 2-oxa-3-azabicyclo[2.2.2]Oct-5-ene in the form of hydrochloride. 5.0 g (0.045 mol) of the obtained substances hydronaut 3.0 g (0,013 mol) of platinum oxide under a hydrogen pressure of 2 bar. After 7 h, the catalyst was separated by filtration and add a solution of 20 ml of 4 M hydrochloric acid in dioxane. After evaporation the residue is recrystallized from 30 ml of isopropanol, obtaining 3.1 gCIS-4-aminocyclohexanol as hydrochloride.

b) 6-(CIS-4 Aminocyclohexane)-7-methyl-2H-isoquinoline-1-he (26)

Of 2.55 g (16,8 mmol)CIS-4-aminocyclohexanecarboxylic and 5.0 g (16,8 mmol) 6-fluoro-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-he is (25, stage b) receive and 0.98 g of 6-(CIS-4 aminocyclohexane)-7-methyl-2H-isoquinoline-1-he hydrochloride as described in example 25 (stages c and d). Rt=0,99 min (method B). Installed weight: 273,18 (M+H+).

7-Methyl-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he (27)

a) 2-(4-Methoxybenzyl)-7-methyl-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he

To a solution of 0.4 g (1 mmol) 6-(CIS-4 aminocyclohexane)-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-it (26, stage b), 0.31 g (2 mmol) of sodium iodide and 0.35 g (2.5 mmol) of potassium carbonate in 40 ml of DMF is added dropwise 0.24 g (1.1 mmol) of 1,4-dibromobutane. After stirring at room temperature for 2 days the mixture was diluted with water and extracted with ethyl acetate. After drying and evaporation the residue is purified by chromatography, getting 182 mg of 2-(4-methoxybenzyl)-7-methyl-6-(4-pyrrolidin-1-yl-cyclohexyloxy)-2H-isoquinoline-1-it.

b) 7-Methyl-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he (27)

180 mg (0.4 mmol) of 2-(4-methoxybenzyl)-7-methyl-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-it is heated with 0.9 g triperoxonane acid in the high-frequency electric furnace at 150°C. After treatment with water, 58 mg of 7-methyl-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-get it in the form of hydrochloride. Rt=1,07 min (method B). Installed weight: 327,2 (M+H+).

About the General technique to obtain amide:

0.6 mmol of the corresponding amine (hydrochloride) is suspended in 7.5 ml of dry DMF. After cooling to 0°C add 0.6 mmol of triethylamine and 0.6 mmol of O-((etoxycarbonyl)cyanomethylene)-N,N,N',N'-tetramethylethylenediamine). The resulting solution was added to a solution of the appropriate carboxylic acid (0.6 mmol) and 1 EQ. of triethylamine in 7.5 ml of DMF. The mixture is heated to room temperature and stirred for 2H. Monitor the development of the reaction by HPLC and, if necessary, add an additional equivalent of TOTU and triethylamine. The mixture is evaporated, the crude product is absorbed by ethyl acetate and filtered through celite, the solvent is evaporated. The product was then purified by chromatography on silica gel.

The obtained product is dissolved in 10 ml of dichloromethane and add triperoxonane acid (1 ml). The mixture is stirred for 2 hours at ambient temperature, evaporated, absorbed 1M HCl and lyophilized. Final double dissolving the crude product in water, followed by lyophilization, to give the desired product as hydrochloride.

Table 2
ExampleAminAldehydeProduct[M+H+] Rt/minMethodChemical name
2825412,41,07BN-[4-(7-Methyl-1-oxo-1,2-dihydroisoquinoline-6-yloxy)TRANS-cyclohexyl]-3-piperidine-4-ylpropionic
2925397,21,01BN-[4-(7-Methyl-1-oxo-1,2-dihydroisoquinoline-6-yloxy)TRANS-cyclohexyl]-2-piperidine-4-ylacetamide
3012432,21,06BN-[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexyl]-3-piperidine-4-ylpropionic
3112 418,31,02InN-[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexyl]-2-piperidine-4-ylacetamide

(1R,3S)-3-(tertButyldimethylsilyloxy)Cyclopentanol (32)

A solution of 2.0 g (was 9.33 mmol) of (1S,4R)-4-(tertbutyldimethylsilyloxy)cyclopent-2-enol (Curran, et al. Tetrahedron 1997, 53, 1983-2004) in 10 ml of ethyl acetate is treated with 66 mg of 20% palladium hydroxide on charcoal and the mixture is stirred overnight in a hydrogen atmosphere (1 ATM) at room temperature. The catalyst was removed by filtration and the filtrate evaporatedin the vacuumgetting 2.0 g specified in the connection header (32). Rt=1,72 min (method C). Installed weight: 217,2 (M+H+).

(1S,3S)-3-(tertButyldimethylsilyloxy)cyclopentylamine (33)

720 mg of 3.33 mmol) of (1R,3S)-3-(tertbutyldimethylsilyloxy)Cyclopentanol (32) and 2.18 g (8,32 mmol) of triphenylphosphine are dissolved in 15 ml of tetrahydrofuran and cooled to -20°C. and Then added dropwise to 1.05 ml (of 6.65 mmol) of diethylazodicarboxylate and after 3 min 717 μl of 3.33 mmol) diphenylphosphinite and the mixture is stirred at room temperature overnight. EXT the keys diethyl ether and a saturated solution of sodium chloride, and the aqueous phase is extracted three times with diethyl ether. The combined organic layers dried over sodium sulfate, filtered and evaporated.

The crude product is dissolved in 15 ml of tetrahydrofuran and added 1.47 g (of 1.80 mmol) of triphenylphosphine polystyrene (1.2 mmol/g). After adding 2 ml of water the reaction mixture is stirred at room temperature until completion of the interaction. The resin is removed by filtration and the filtrate evaporatedin the vacuum. The resulting product, 256 mg specified in the header of the compound (33), pure enough for further transformations. Rt=1,11 min (method C). Installed weight: to 216.2 (M+H+).

(1S,3S)-3-Aminocyclopentane (34)

To a solution of 95 mg (0.44 mmol) of (1S,3S)-3-(tertbutyldimethylsilyloxy)cyclopentylamine (33) in 1 ml of 2-propanol was added 1 ml of 2n. hydrochloric acid and the mixture is stirred at room temperature to achieve complete conversion. The reaction mixture was thrice washed with diethyl ether, the aqueous phase is concentratedin the vacuumand lyophilized. The remainder absorb water and again lyophilized, receiving 68 mg of (1S,3S)-3-aminocyclopentane (34) in the form of hydrochloride. Rt=0,13 min (method C). The installed weight of 102.3 (M+H+).

((1R,4S)-4-Azidocillin-2-enyloxy)tertbutyldimethylsilyl (35)

At asanee header connection get combining a solution of 630 mg (2,46 mmol) of (1S,4R)-4-(tertbutyldimethylsilyloxy)cyclopent-2-enrobage ester acetic acid [synthesized by sellerbuyer industrial output (1S,4R)-4-hydroxycyclopent-2-enrobage ether acetic acid (Curran, et al. Tetrahedron 1997, 53, 1983-2004)] in 6 ml of tetrahydrofuran solution of 320 mg (4,91 mmol) of sodium azide in 1.3 ml of water. To the resulting two-phase mixture is added a solution of 112 mg (0.12 mmol) of Tris(dibenzylideneacetone)diplegia(0) and 258 mg (0.98 mmol) of triphenylphosphine in 2 ml of tetrahydrofuran and the reaction mixture is heated to 50°C for 6 h during which the reaction is finished. Add a saturated solution of sodium chloride and the aqueous phase re-extracted with diethyl ether. The combined organic phase is dried over sodium sulfate, filtered and evaporated. The crude substance is purified by chromatography on silica gel, getting 475 mg specified in the header of the compound (35).

1H NMR (400 MHz, DMSO) δ=0,09 (s, 3H), of 0.10 (s, 3H), from 0.88 (s, 9H), 1,49 (dt, J=3,9, of 14.0 Hz, 1H), 2,69 (dt, J=7,4, a 14.1 Hz, 1H), 4,22-4.26 deaths (m, 1H), 4.75 V-rate 4.79 (m, 1H), of 5.92-5,95 (m, 1H), equal to 6.05 (dt, J=1,8, a 5.4 Hz, 1H).

(1S,4R)-4-(tertButyldimethylsilyloxy)cyclopent-2-enylamine (36)

934 mg (3.90 mmol) of ((1R,4S)-4-azidocillin-2-enyloxy)tertbutyldimethylsilyl (35) is dissolved in 16 ml of tetrahydrofuran and added 1.13 g (4,29 mmol) of triphenylphosphine. After adding 2 ml of the odes, the reaction mixture was stirred at room temperature until completion of the reaction. Add a saturated solution of sodium chloride, the layers separated and the organic layer evaporatedin the vacuum. The crude product is purified by chromatography on silica gel, receiving 890 mg specified in the connection header (36). Rt=1,02 min (method C). Installed weight: 214,3 (M+H+).

(1R,3S)-3-(tertButyldimethylsilyloxy)cyclopentylamine (37)

The way A

To a solution of 135 mg (0,56 mmol) of ((1R,4S)-4-azidocillin-2-enyloxy)tertbutyldimethylsilyl (35) in 2 ml of methanol, add 60 mg of 5% palladium on charcoal and the suspension is stirred overnight in a hydrogen atmosphere (1 ATM) at room temperature over night. The catalyst was removed by filtration and the filtrate evaporatedin the vacuum. The residue is purified by chromatography on silica gel, receiving 98 mg specified in the connection header (37). Rt=1,15 min (method C). Installed weight: 216,3 (M+H+).

Method B

A solution of 330 mg (1.55 mmol) of (1S,4R)-4-(tertbutyldimethylsilyloxy)cyclopent-2-enylamine (36) in 4 ml of ethanol is treated with 164 mg of 5% palladium on charcoal and the mixture is stirred in hydrogen atmosphere (1 ATM) at room temperature for 5 hours, the Catalyst was removed by filtration and the filtrate is evaporated, getting 227 mg specified in the header of the compound (37) with a purity sufficient for further conversion.

(S,3R)-3-Aminocyclopentane (38)

On the basis of 486 mg (of 2.26 mmol) of (1R,3S)-3-(tertbutyldimethylsilyloxy)cyclopentylamine (37), 229 mg specified in the title compounds are synthesized as hydrochloride following the Protocol described for (1S,3S)-3-aminocyclopentane (34). Rt=0,14 min (method C). The installed weight of 102.3 (M+H+).

2-(4-Methoxybenzyl)-6-((1S,3S)-3-aminocyclopentane)-2H-isoquinoline-1-he (39)

106 mg (4.20 mmol) of sodium hydride (95%) are suspended in 3 ml of dimethylacetamide and added dropwise 193 mg (1,40 mmol) (1S,3S)-3-aminocyclopentane (34), dissolved in 1 ml of dimethylacetamide. After 1 h, add 402 mg (1,42 mmol) of 2-(4-methoxybenzyl)-6-fluoro-2H-isoquinoline-1-it (9)dissolved in the other 3 ml of dimethylacetamide. The reaction mixture was stirred at 80°C until completion of the interaction. The mixture was poured into water, extracted three times with a mixture of dichloromethane and 2-propanol (3:1) and the combined organic layers evaporated. Add water and make lyophilization the crude product to remove residual dimethylacetamide. The resulting crude product was then purified by chromatography on silica gel, receiving 250 mg specified in the header of the compound (39). Rt=1,20 min (method E). Installed weight: 365,2 (M+H+).

The following three product is obtained by the same method described for the synthesis of 39 using suitable is e-2 - (4-methoxybenzyl)-6-fluoro-2H-isoquinoline-1-ones and 3-aminocyclopentane.

399,1
Table 3
ExampleIshino-
line
AminProductChemical name[M+H+]Rt/minMethod
4010342-(4-Methoxybenzyl)-6-((1S,3S)-3-aminocyclopentane)-7-chloro-2H-isoquinoline-1-he399,11,32E
419382-(4-Methoxybenzyl)-6-((1S,3R)-3-aminocyclopentane)-7-chloro-2H-isoquinoline-1-he365,21,23E
4210382-(4-Methoxybenzyl)-6-((1S,3R)-3-aminocyclopentane)-7-chloro-2H-isoquinoline-1-he1,25E

6-((1S,3S)-3-Aminocyclopentane)-2H-isoquinoline-1-he (43)

125 mg (0.34 mmol) of 2-(4-methoxybenzyl)-6-((1S,3S)-3-aminocyclopentane)-2H-isoquinoline-1-it (39) dissolved in 1 ml of TFA and heated in a high frequency electric furnace at 150°C for 3 hours Add methanol and the reaction mixture is evaporated. The solution absorb 1H. HCl and extracted three times with dichloromethane. The combined dichloromethane layers are extracted twice 1H. HCl and the combined HCl layers lyophilized. The residue is dissolved in water and again lyophilized, receiving 42 mg of 6-((1S,3S)-3-aminocyclopentane)-2H-isoquinoline-1-it (43) as hydrochloride. Rt=0,86 min (method E). Installed weight: 245,1 (M+H+).

These three products will get hydrochloride by the same method described for the synthesis of 43, on the basis of the corresponding 2-(4-methoxybenzyl)-2H-isoquinoline-1-ones (table 4).

Table 4
ExampleThe original connectionProductChemical name[M+H+]Rt/minMethod
44406-((1S,3S)-3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he279,11,00F
45416-((1S,3R)-3-Aminocyclopentane)-2H-isoquinoline-1-he245,20,64C
46426-((1S,3R)-3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he279,10,90E

6-(CIS-4 Aminocyclopentane)-7-methyl-2H-isoquinoline-1-he (47)

a)CIS-4-Aminocyclohexanol

To a solution of 16.8 g (0,149 mol) cyclohexasiloxane in 240 ml of methylene chloride is added slowly at 0°C and 19.4 g (0,178 mol)tertbutylhypochlorite. The obtained dark blue solution is cooled to -20°C and then add 30 ml of ethanol and 20.0 g (0,212 mol) of 1,3-cycloheptadiene and the mixture was stored in a refrigerator at 5°C for 2 days before the disappearance of the blue color. The reaction with the feature added to 30 ml of isopropanol and then add 300 ml of diethyl ether and after stirring for 3 h, the precipitate is separated by suction, getting to 18.6 g of 6-oxa-7-azabicyclo[3.2.2]non-8-anhydroglucitol. 9.0 g (0,072 mol) obtained substances hydronaut using palladium on charcoal under 5 bar of hydrogen. After complete conversion, the catalyst is separated by filtration and add a solution of 30 ml of 4 M hydrochloric acid in dioxane. After evaporation the residue is crystallized from 20 ml of isopropanol and 500 ml of diethyl ether, obtaining 7.5 gCIS-4-aminocyclohexanol as hydrochloride.

b) 6-(CIS-4 Aminocyclopentane)-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-he

A solution of 223 mg (1.35 mmol)ofCIS-4-aminocyclohexanol in 5 ml of dimethylacetamide is stirred with 242 mg (8.1 mmol) of 80% sodium hydride in 15 minutes at room temperature. Then add a solution of 0.4 g (1.35 mmol) of 6-fluoro-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-it (25, step b) in 10 ml of dimethylacetamide. The reaction mixture is heated to 80°C for 8 h, and after the specified time, add an additional 30% of the initial amount ofCIS-4-amino-cycloheptanol and sodium hydride. After another 8 h at 80°C the reaction mixture was added to water and extracted with dichloromethane. Purification of the crude product by chromatography using a mixture of dichloromethane/methanol (100:0-97:3) to give 134 mg of 6-(CIS-4 aminocyclopentane)-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-it.

c) 6-(CIS-4 Aminocyclopentane)-7-methyl-H-isoquinoline-1-he (47)

130 mg (0.32 mmol) of 6-(CIS-4 aminocyclopentane)-2-(4-methoxybenzyl)-7-methyl-2H-isoquinoline-1-she dissolved in 730 mg (6.4 mmol) triperoxonane acid and the mixture is heated for 2 h in a high-frequency electric furnace at 150°C. Then the excess triperoxonane acid is distilled off in vacuo, the residue diluted with water and the solution is alkalinized. After extraction with dichloromethane, drying over magnesium sulfate and evaporation obtain 24 mg of 6-(CIS-4 aminocyclopentane)-7-methyl-2H-isoquinoline-1-it (47). Rt=0,96 min (method B). Installed weight: 287,3 (M+H+).

7-Chloro-6-(CIS-4 aminocyclopentane)-2H-isoquinoline-1-it (48)

Specified in the header of the product is obtained in the form of the hydrochloride in the same way as described for the synthesis of 6-(CIS-4 aminocyclopentane)-7-methyl-2H-isoquinoline-1-she (47), usingCIS-4-aminotetrahydrofuran (47, step a) and 7-chloro-6-fluoro-2-(4-methoxybenzyl)-2H-isoquinoline-1-it (10). Rt=1,05 min (method B). Installed weight: 307,12 (M+H+).

6-(CIS-4 Aminocyclopentane)-2H-isoquinoline-1-he (49)

Specified in the header of the product is obtained in the form of the hydrochloride in the same way as described for the synthesis of 6-(CIS-4 aminocyclopentane)-7-methyl-2H-isoquinoline-1-she (47), usingCIS-4-aminotetrahydrofuran (47, step a) and 6-f the PR-2-(4-methoxybenzyl)-2H-isoquinoline-1-he (9). Rt=0,81 min (method C). Installed weight: 273,2 (M+H+).

3-Aminocyclohexanol (50)

To a cooled to 0°C solution of 2.00 g (10,8 mmol) butyl methyl ether (3-oxacyclobutane)carbamino acid in 20 ml ethanol add portions 204 mg (5.40 mmol) of sodium borohydride. The reaction mixture was stirred at room temperature to achieve complete conversion. The solvent is evaporated, the crude product absorb dichloromethane and treated with saturated sodium bicarbonate solution. The phases are separated and the aqueous phase is twice extracted with dichloromethane. The combined organic phases, dried over magnesium sulfate and concentrated give crude tributyl ether (3-hydroxycyclopent)carbamino acid. Rt=0,76 min (method C). Installed weight: 132,2 (M-tBu+H+).

The crude alcohol was dissolved in 90 ml of dichloromethane and added dropwise 11 ml triperoxonane acid. After stirring overnight at room temperature add 100 ml of 2n. hydrochloric acid, the phases are separated and the aqueous phase is concentratedin the vacuum. After the double dissolution of the residue in water and subsequent lyophilization 980 mg specified in the connection header 50 is isolated in the form of the hydrochloride as a mixture of diastereoisomers. Rt=0,19 min (method C). Installed weight: 88,35 (M+H+).

3-(1-Benzyloxy-7-harithi the Olin-6-yloxy)cyclobutylamine (51)

To a suspension 459 mg (11.5 mmol) of sodium hydride (60%) in 16 ml of dimethylacetamide add a solution of 333 mg (3,82 mmol) 3-aminocyclohexanol (50) in 8 ml of dimethylacetamide. After stirring for 60 min at room temperature add a solution of 1.00 g (3,48 mmol) of 1-benzyloxy-7-chloro-6-vtoritchnaia (11) in 16 ml of dimethylacetamide and stirring is continued first at room temperature, then for 2 h at 50°C to end the interaction. The reaction is quenched by addition of water and the reaction mixture is shaken out three times with a mixture of dichloromethane and 2-propanol (3:1). The combined organic layers evaporated, water is added and the crude product lyophilized to remove residual dimethylacetamide. The resulting crude product was then purified by chromatography on silica gel, giving 377 mg specified in the connection header (51) in the form of a mixture of diastereoisomers. Rt=0,85 min (method H). Installed weight: 355,1 (M+H+).

The following two product is obtained by the same method described for the synthesis of 51 using 1-benzyloxy-7-chloro-6-forsakenly (11) and the corresponding (3-aminocinnamate)methanol.

Table 5
ExampleSource
connection
Product is t Chemical name[M+H+]Rt/minMethod
52CIS-(3-aminocinnamate) methanolCIS-3-(1-Benzyloxy-7-chloroisoquinoline-6-intoximeter)cyclobutylamine369,21,26C
53TRANS(3-aminocinnamate) methanolTRANS3-(1-Benzyloxy-7-chloroisoquinoline-6-intoximeter)cyclobutylamine369,21,22C

6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he (54)

A solution of 377 mg (1.06 mmol) of 3-(1-benzyloxy-7-chloroisoquinoline-6-yloxy)cyclobutylamine (51) in 8 ml of 2-propanol is treated with 8 ml of 2n. aqueous hydrochloric acid and stirred until complete conversion. The reaction mixture is evaporated, double-lyophilized out of the water and recrystallized from 2-propanol. 195 mg specified in the title compound can be isolated as hydrochloride, to provide the Commissioner inseparable mixture of diastereoisomers. Rt=1,92 min (method G). Installed weight: 265,1 (M+H+).

PureCIS-andTRANSthe isomers can be obtained in the form of hydrochloride by the same method described for the synthesis of 6-(3-aminocyclopentane)-7-chloro-2H-isoquinoline-1-it (54), respectively, using the appropriateCIS-orTRANSisomer 3-aminocyclohexanol (50).CIS-Isomer (54a): Rt=1,85 min (method I). Installed weight: 265,1 (M+H+);TRANSisomer (54b): Rt=1,90 min (method I). Installed weight: 265,1 (M+H+).

CIS-6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he (55)

Based on 756 mg (2.05 mmol)ofCIS-6-(3-aminocyclopentane)-7-chloro-2H-isoquinoline-1-she (52), 460 mgCIS-6-(3-aminocyclopentane)-7-chloro-2H-isoquinoline-1-she (55) in the form of the hydrochloride can be obtained as described for compound 54. Rt=1,91 min (method I). Installed weight: 279,1 (M+H+).

TRANS6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he (56)

Based on 778 mg (2,11 mmol)TRANS6-(3-aminocyclopentane)-7-chloro-2H-isoquinoline-1-it (53), 353 mgTRANS6-(3-aminocyclopentane)-7-chloro-2H-isoquinoline-1-she (56) in the form of the hydrochloride can be obtained as described for compound 54. Rt=1,87 min (method I). Installed weight: 279,2 (M+H+).

CIS-5-(tertbutyl is methylcellulose)cyclooctanol (57)

21,4 g (312 mmol) of imidazole, 34,5 g (229 mmol)oftertbutyldimethylsilyloxy and 10 mg of DMAP are added to a solution ofCIS-1,5-cyclooctadiene in 500 ml of THF. The reaction mixture was stirred for 2 h, then quenched with water followed by extraction with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride and dried over magnesium sulfate. Filtration and evaporation under reduced pressure to give the crude product, which was purified by chromatography on silica gel (mixture of n-heptane/ethyl acetate, 4:1)getting to 26.0 g of the desired product as a colorless oil. Rt=3,00 min (method J). Installed weight: 259,2 (M+H+).

5-(tertBUTYLPEROXY)cyclooctane (58)

A solution of 4.5 g (58 mmol) of dimethyl sulfoxide in 25 ml of dichloromethane is added dropwise to a stirred solution of 3.7 g (29 mmol) of oxalicacid in 50 ml of dichloromethane at -78°C. the Solution is stirred for 30 minutes at -78°C and then 5.0 g (19,3 mmol)CIS-5-(tertBUTYLPEROXY)cyclooctanol (57) in 30 ml of dichloromethane is added dropwise, maintaining the temperature at -78°C. After stirring for 30 minutes, added dropwise to 9.8 g (97 mmol) of triethylamine and the temperature allowed to rise to -30°C. Add an additional 50 ml of dichloromethane and the solution stirred for 1 h at -30°. Add portions, with stirring, 300 ml of saturated solution of ammonium chloride and then separating the organic layer. After washing with additional quantity of a solution of ammonium chloride the organic phase is dried over magnesium sulfate, filtered and evaporated, receiving 5.0 g of the desired product as a yellow oil, used without further purification. Rt=1,96 min (method C). Installed weight: 257,3 (M+H+).

5-(tertBUTYLPEROXY)cyclooctylamine (59)

11,0 g (38,6 mmol) isopropoxide titanium are added to a solution of 5.0 g (19,3 mmol) 5-(tertbutyldimethylsilyloxy)cyclooctanone (58) to 48.3 ml (96,5 mmol) of a 2M solution of ammonia in ethanol and stirred for 6 hours. After adding 1.1 g (29 mmol) of sodium borohydride, the mixture is stirred at room temperature for 4 days. The reaction is quenched by adding 50 ml of 2M aqueous solution of ammonia. A white precipitate is removed by filtration and washed with ethyl acetate. The filtrate is extracted with ethyl acetate and the combined organic layers are dried over magnesium sulfate, filtered and evaporated, receiving 4.5 g of 5-(tertbutyldimethylsilyloxy)cyclooctylamine (59), as a mixture of diastereomers in the form of a yellow oil, used without further purification. Rt=2,14 min (method J). Installed weight: 258,2 (M+H+).

5-Aminocyclohexanol (60)

35 ml of 2n. aqueous hydrochloric acid are added to a solution of 3.5 g (to 13.6 mmol) 5-(tertBUTYLPEROXY)cyclooctylamine (59) in 35 ml of 2-propanol, and the resulting solution was stirred at room temperature overnight. The isopropanol is removed under reduced pressure and the resulting aqueous solution was washed with a simpletertbutylmethylamine ether. 2.7 g of crude 5-aminocyclohexanol (60) are obtained as hydrochloride, sublimation of the water layer, as diastereomer mixture is used without further purification. Rt=0,18 min (Method C). Installed weight: 144,2 (M+H+).

5-(1-Benzyloxy-7-chloroisoquinoline-6-yloxy)cyclooctylamine (61)

1.3 g specified in the title compounds are synthesized on the basis of 0.8 g (2,78 mmol) of 1-benzyloxy-7-chloro-6-vtoritchnaia (11), 417 mg (14.4 mmol) of sodium hydride (60%) and 0.63 g (3.5 mmol) of 5-aminocyclohexanol (60)according to the Protocol described for 3-(1-benzyloxy-7-chloroisoquinoline-6-yloxy)cyclobutylamine (51). Purification by chromatography on silica gel (mixture of dichloromethane:methanol:aq. ammonia - 100:7:0,75) give 0.35 g of the desired product as a mixture of diastereoisomers. Rt=1,41 min (method C). Installed weight: 413,1 (M+H+).

6-(5-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he (62)

According to 0.22 g (0.54 mmol) -(1-benzyloxy-7-chloroisoquinoline-6-yloxy)cyclooctylamine (61), 124 mg of 6-(5-aminocyclopentane)-7-chloro-2H-isoquinoline-1-he (62) can be obtained as hydrochloride using the method described for connection 54. Rt=1,85 min (method I). Installed weight: 321,1 (M+H+).

1-Allyl-5-(tertbutyldimethylsilyloxy)cyclooctylamine (63)

To a solution of 1.5 g (of 5.85 mmol) 5-(tertbutyldimethylsilyloxy)cyclooctanone 8.4 ml (58,5 mmol) in 7n ammonia in methanol, pre-mixed for 15 min at room temperature, is added dropwise 1.7 ml (9,36 mmol) of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The reaction mixture was stirred for 18 h at room temperature. Volatile substances are removedin the vacuumand the residue re-dissolved in 100 ml of diethyl ether. Then added dropwise 100 ml of 1N. aqueous HCl and the resulting biphasic mixture is stirred for 30 minutes, the Layers separated, the aqueous layer washed with diethyl ether and the pH adjusted to pH 9 by adding sodium hydroxide. Then the suspension is extracted with a mixture of 3:1 dichloromethane and 2-propanol and the combined organic extracts are concentratedin the vacuumgetting 0,89 g specified in the title compounds as a mixture of diastereoisomers. Rt=0,44 min, 0,49 min (method C). Installed weight: 184,3 (M+H+).

5-Amino-5-propylcyclohexane (64)

A solution of 895 mg (4,88 mmol) of 1-allyl-5-(tertbutyldimethylsilyloxy)cyclooctylamine (63) in 15 ml of methanol is treated with 52 mg of 10% palladium on charcoal and the mixture is stirred overnight in a hydrogen atmosphere (1 ATM) at room temperature. The catalyst was removed by filtration and the filtrate evaporatedin the vacuumgetting 0,794 g specified in the connection header (64). Rt=0,56 min, and 0.62 min (method C). Installed weight: 186,3 (M+H+).

5-(1-Benzyloxy-7-chloroisoquinoline-6-yloxy)-1-propylcyclohexane (65)

572 mg specified in the title compounds as a mixture of diastereoisomers synthesized on the basis of 1,11 g (3,86 mmol) of 1-benzyloxy-7-chloro-6-vtoritchnaia (11), 514 mg (12.9 mmol) of sodium hydride (60%) and 794 mg (4,29 mmol) 5-amino-5-propylcyclohexanone (64), according to the Protocol described for 3-(1-benzyloxy-7-chloroisoquinoline-6-yloxy)cyclobutylamine (51). Rt=1,52 min, and 1.56 min (method C). Installed weight: 453,3 (M+H+).

6-(CIS-5-Amino-5-propylcyclohexyl)-7-chloro-2H-isoquinoline-1-he 6-(TRANS5-amino-5-propylcyclohexyl)-7-chloro-2H-isoquinoline-1-he (66/67)

On the basis of 396 mg (0.87 mmol) of 5-(1-benzyloxy-7-chloroisoquinoline-6-yloxy)-1-propylcyclohexanone (65), 6-(5-amino-5-propylcyclohexyl)-7-chloro-2H-isoquinoline-1-it can be obtained in hydrochloride with the application is receiving method, described for connection 54. 182 mg and 86 mg of pure diastereomers 66 and 67, respectively, obtained by separation of the mixture by preparative HPLC and lyophilization of the remnants of 2n. HCl and water. Stereoisomer 1 (66): Rt=2,31 min (method I). Installed weight: 363,2 (M+H+), 346,2 (M-NH3+H+). The stereoisomer 2 (67): Rt=2,52 min (method G). Installed weight: 363,2 (M+H+), 346,2 (M-NH3+H+). The relative stereochemistry of the two derivatives is assigned arbitrarily.

The following products are obtained in the form of hydrochloride according to the General reaction technique reductive amination described for the synthesis of compounds 15-22, using the appropriate athinaikon and aldehydes or ketones. (Table 6)

Table 6
ExampleThe original connectionAldehyde/ketoneProductChemical name[M+H+]Rt/minMethod
6866benzaldehyde6-(5-Benzylamino the-5-propylcyclohexyl)-7-chloro-2H-isoquinoline-1-he 453,32,62I
6966acetaldehyde7-Chloro-6-(5-ethylamino-5-propylcyclohexyl)-2H-isoquinoline-1-he391,31,06C
7054aacetone7-Chloro-6-(CIS-3-isopropylaminocarbonyl)-2H-isoquinoline-1-heto 307.1to 2.06I
7154abenzaldehyde6-(3-CIS-Benzylaminocarbonyl)-7-chloro-2H-isoquinoline-1-he355,12,40I
7254bbenzaldehyde6-(3-TRANS-Benzylaminocarbonyl)-7-chloro-2H-isoquinoline-1-the n 355,12,43I
7354abenzaldehyde7-Chloro-6-(3-CIS-dibenzylidineacetone)-2H-isoquinoline-1-he445,12,72I
7454bbenzaldehyde7-Chloro-6-(3-TRANS-dibenzylideneacetone)-2H-isoquinoline-1-he445,12,88I
7554bacetaldehyde7-Chloro-6-(3-TRANS-diethylaminoethoxy)-2H-isoquinoline-1-he321,12,14I

Determination of the inhibition of Rho-kinase

To assess inhibition of Rho-kinase values IC50determined according to the following Protocol.

Active recombinant ROCK II human (N-terminal His6-tagged remnants of recombinantly ROCK II human 11-552) acquire from Upstate Ltd., Dundee, UK. The peptide substrate, Fluorescein-AKRRRLSSLRA-COOH, buy from JPT Peptide Technologies, Berlin, Germany. Adenosine-5'-triphosphate (ATP), bovine serum albumin (BSA), dimethylsulfoxide (DMSO), 4-(2-hydroxyethyl)piperazine-1-econsultancy acid (Hepes), Brij-35 and dithiothreitol (DTT) purchase from Sigma-Aldrich, Munich, Germany. Tris(hydroxymethyl)aminomethan (Tris), magnesium chloride, NaOH, 1M HCl and EDTA purchase from Merck Biosciences, Darmstadt, Germany. "Complete" protease inhibitor buy Roche Diagnostics, Mannheim, Germany.

Compound diluted to the appropriate concentrations of buffer 1 (25 mm Tris-HCl, pH of 7.4, 5 mm MgCl2, 2 mm DTT, 0.02 percent (m/o) BSA and 3% DMSO). The enzyme ROCK II was diluted to a concentration of 100 ng/ml of buffer 2 (25 mm Tris-HCl, pH of 7.4, 5 mm MgCl2, 2 mm DTT and 0.02% (m/o) BSA). The peptide substrate and ATP was diluted to concentrations of 3 μm and 120 μm, respectively buffer 2. 2 μl of a solution of the compound mixed with 2 ál of diluted enzyme in 384-well titration the microplate small volume (Greiner, Bio-One, Frickenhausen, Germany) and initiate the kinase reaction by adding 2 ál of a solution containing the peptide substrate and ATP. After incubation for 60 min at 32°C the reaction is stopped by adding 20 μl of solution containing 100 mm Hepes-NaOH, pH 7,4, 0,015% (o/o) Brij-35, 45 mm EDTA and 0,227% reagent 1 to cover the chip (Caliper Lifescience Inc, Hopkinton, MA). Phosphorylation of the peptide substrate registering device Caliper 3000, mainly the AK described Pommereau et al. (J. Biomol. Screening 2004, 9(5), 409-416). The separation conditions are: pressure of 1.3 psi (0,091 kg/cm2), the upper voltage -1562, the lower the voltage of -500 V, the time of selection of a sample of 200 MS. Positive controls (buffer 1 instead of the connection) and negative controls (buffer 1 instead of the compound and buffer 2 instead of ROCK II) parallel use on each tablet.

This test subjected to the following products/connections using the appropriate form (salt or free base), obtained as described above, and has the following activity.

Connection # pIC50Connection # pIC50
15+++++31+++++
16+++++44+++++
17+++++45+++++
18+++++47+++++
19+++++ 48+++++
20+++++54+++++
21+++++56+++++
22+++++66+++++
24+++++67+++++
28++++
29++++
30+++++

Activity data, expressed through the negative logarithm IC50(pIC50conform to the following:

+: pIC50≤ 3,0

++: 3,0 ≤ pIC50< 4,0

+++ 4,0 ≤ pIC50< 5,0

++++: 5,0 ≤ pIC50< 6,0

+++++: 6,0 ≤ pIC50

1. The compound of formula (I)

or formula (I')

where R2means H or (C1-C6)alkyl;
R 3means N;
R4means N;
R5means N;
R6and R6' independently from each other mean
N, (C1-C8)alkyl, (C1-C6)alkylene-R', (C1-C6)alkylen-C(O)O-(C1-C6)alkyl, C(O)-(C1-C6)alkylene-R',
or R6and R6' together with the N-atom to which they are attached, form a (C5-C6)heterocyclyl group in which one or more carbon atoms may be substituted by 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or a combination of various heteroatoms;
R7means H, halogen, (C1-C6)alkyl;
R8means N;
n = 1;
m = 1, 2, 3, 4 or 5, and
L means O or O-(C1-C6)alkylen;
where R' means (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl;
where in the residues R6and R6' alkyl or alkylene optionally can be substituted one or more times with COOH group;
and
where in the residues R6and R6' (C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times by suitable groups, independently selected from the group comprising CONH2and (C1-C6)alkyl;
and
where, if m = 3, R6cannot mean N;
where, if m = 3 and R6means (C1-C8)Ala is l, the alkyl substituted one or more times, preferably one to three times by a group COOH;
or their stereoisomeric forms and/or pharmaceutically acceptable salts.

2. The compound according to claim 1, where R7means halogen or (C1-C6)alkyl.

3. The compound according to claim 1, where R7denotes H, halogen or (C1-C4)alkyl.

4. The compound according to claim 1, where R7means H, fluorine, chlorine, bromine, methyl or ethyl.

5. The compound according to claim 1, where R7means H, fluorine, chlorine, bromine or methyl.

6. The compound according to claim 1, where R7means N.

7. The compound according to claim 1, where m = 2, 3, or 4.

8. The compound according to claim 1, where m = 3.

9. The compound according to claim 1, where R2means H or (C1-C4)alkyl.

10. The compound according to claim 1, where R2means H or (C1-C2)alkyl.

11. The compound according to claim 1, where R2denotes H, methyl or ethyl.

12. The compound according to claim 1, where
R6and R6' independently from one another mean H,
(C1-C6)alkyl,
(C1-C4)alkylene-(C3-C8)cycloalkyl,
(C1-C4)alkylene-(C5-C10)heterocyclyl,
(C1-C4)alkylene-(C6-C10)aryl,
(C1-C6)alkylen-C(O)O-(C1-C6)alkyl
or
C(O)(C1-C6)alkylene-R',
R6and R6' together with the N-atom to which they are attached, form a (C5-C6

13. The compound according to claim 1, where
R6and R6' independently from each other mean
N, (C1-C6)alkyl, (C1-C4)alkylene-(C3-C8)cycloalkyl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-(C6-C10)aryl, (C1-C6)alkylen-C(O)O-(C1-C6)alkyl, C(O)(C1-C6)alkylene-(C3-C8)cycloalkyl, C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl, C(O)(C1-C6)alkylene-(C6-C10)aryl, or
R6and R6' together with the N-atom to which they are attached, form a (C5-C6) heterocyclyl group in which one or more carbon atoms may be substituted by 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or combinations of various heteroatoms.

14. The compound according to claim 1, where
R6means H, (C1-C6)alkyl or (C1-C4)alkylene-(C3-C6)cycloalkyl and
R6' means N
(C1-C6)alkyl,
(C1-C4)alkylene-(C3-C8)cycloalkyl,
(C1-C4)alkylene-(C5-C10)heterocyclyl,
(C1-C4)alkylene-(the 6-C10)aryl,
(C1-C6)alkylen-C(O)O-(C1-C6)alkyl,
C(O)(C1-C6)alkylene-(C3-C8)cycloalkyl,
C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl,
C(O)(C1-C6)alkylene-(C6-C10)aryl, or
R6and R6' together with the N-atom to which they are attached, form a (C3-C6) heterocyclyl group in which one or more carbon atoms may be substituted by 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or combinations of various heteroatoms.

15. The compound according to claim 1, where
R6means H, (C1-C6)alkyl and
R6' means N
(C1-C6)alkyl,
(C1-C4)alkylene-(C3-C8)cycloalkyl,
(C1-C4)alkylene-(C5-C10)heterocyclyl,
(C1-C6)alkylene-(C6-C10)aryl,
C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl, or
R6and R6' together with the N-atom to which they are attached, form a (C5-C6) heterocyclyl group in which one or more carbon atoms may be substituted by 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or combinations of various heteroatoms.

16. The compound according to claim 1, where
R6means H, (C1-C6)alkyl and
R6' means N;
(C1-C6)alkyl;
(C1-C4)alkylene-(C3-C8)cycloalkyl;
(C1-C4)alkylene-(C5-C10)heterocyclyl where heterocyclyl is unsubstituted or substituted one or more times by a group independently selected from (C1-C4)alkyl
(C1-C4)alkylene-(C6-C10)aryl, where aryl is unsubstituted or substituted one or more times by a group independently selected from (C1-C4)alkyl;
C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl;
or R6and R6' together with the N-atom to which they are attached, form a (C5-C6) heterocyclyl group in which one or more carbon atoms may be substituted by 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or combinations of various heteroatoms, which is unsubstituted.

17. The compound according to claim 1, where R6means H, (C1-C6)alkyl and R6' means H or (C1-C6)alkyl.

18. The compound according to claim 1, where R6mean N and R6' means H or (C1-C6)alkyl.

19. The compound according to claim 1, where R6and R6' mean N.

20. The compound according to claim 1, where m = 3 and L attached at the 3-position or 4-position aminocyclohexanol rings.

21. The compound according to claim 1, where m = 3 and L is attached at the 4-position iminocyclohexa the new ring.

22. The compound according to claim 1, where L is O-methylene, O-ethylene or O.

23. The compound according to claim 1, where L is O.

24. The compound according to claim 1, where
R2means hydrogen or (C1-C4)alkyl;
R6and R6' independently from one another mean H, (C1-C8)alkyl, (C1-C6)alkylene-R', (C(O)-(C1-C6)alkylene-(C3-C8)cycloalkyl, C(O)(C1-C6)alkylene-(C5-C10)heterocyclyl, C(O)(C1-C6)alkylene-(C6-C10)aryl,
or R6and R6' together with the N-atom to which they are attached, form a (C5-C6)heterocyclyl group in which one or more carbon atoms may be substituted by 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or combinations of different heteroatoms;
R7denotes H, halogen or (C1-C4)alkyl;
m = 2, 3, or 4; and
L is O-methylene or O-ethylene.

25. The compound according to claim 1, where
R2means H or (C1-C4)alkyl;
R6and R6' independently from one another mean H, (C1-C8)alkyl, (C1-C3)alkylene-R', C(O)(C1-C6)alkylene-(C3-C8)cycloalkyl, C(O)(C1-C6)alkylene-(C5-C6)heterocyclyl or C(O)(C1-C6)alkylene-(C6-C10)aryl;
R7denotes H, halogen or (C1-C4 )alkyl;
m = 2, 3, or 4; and
L means Acting

26. The compound according to claim 1, where
R2means H, (C1-C4)alkyl;
R6means H or (C1-C4)alkyl;
R6' means H, (C1-With8)alkyl, (C1-C3)alkylene-R', C(O)(C1-C3)alkylene-(C3-C6)cycloalkyl, C(O)(C1-C3)alkylene-(C5-C6)heterocyclyl or C(O)(C1-C3)alkylester;
R7denotes H, halogen or (C1-C4)alkyl;
m = 3 and
L means Acting

27. The compound according to claim 1, independently selected from the group including
Amide 1-[4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)-cyclohexyl]piperidine-4-carboxylic acid,
7-Chloro-6-(4-piperidine-1-enciclopedias)-2H-isoquinoline-1-he,
7-Chloro-6-(4-(morpholine-4-enciclopedias)-2H-isoquinoline-1-he,
7-Chloro-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he,
7-Chloro-6-[4-(4-methylpiperazin-1-yl)cyclohexyloxy]-2H-isoquinoline-1-he,
Ethyl ester [4-(7-chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexylamino]acetic acid,
[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexylamino]acetic acid,
7-Methyl-6-(4-pyrrolidin-1 enciclopedias)-2H-isoquinoline-1-he,
N-[4-(7-Methyl-1-oxo-1,2-dihydroisoquinoline-6-yloxy)TRANS-cyclohexyl]-3-piperidine-4-ylpropionic,
N-[4-(7-Methyl-1-oxo-1,2-dihydroisoquinoline-6-yloxy)transcellular]-2-piperidine-4-ylacetamide,
N-[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexyl]-3-piperidine-4-ylpropionic,
N-[4-(7-Chloro-1-oxo-1,2-dihydroisoquinoline-6-yloxy)CIS-cyclohexyl]-2-piperidine-4-ylacetamide,
6-((1S,3S)-3-Aminocyclopentane)-2H-isoquinoline-1-he,
6-((1S,3S)-3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,
6-((1S,3R)-3-Aminocyclopentane)-2H-isoquinoline-1-he,
6-((1S,3R)-3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,
6-((CIS-4-Aminocyclohexane)-7-methyl-2H-isoquinoline-1-it
or
7-Chloro-6-(CIS-4-aminocyclohexane)-2H-isoquinoline-1-he,
or their stereoisomeric forms and/or pharmaceutically acceptable salts.

28. The compound according to claim 1, independently selected from the group including
6-(CIS-4-Aminocyclohexane)-2H-isoquinoline-1-he,
6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,
CIS-6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,
TRANS-6-(3-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,
6-(5-Aminocyclopentane)-7-chloro-2H-isoquinoline-1-he,
6-(5-Amino-5-propylcyclohexyl)-7-chloro-2H-isoquinoline-1-he,
6-(5-Benzylamino-5-propylcyclohexyl)-7-chloro-2H-isoquinoline-1-he,
7-Chloro-6-(5-ethylamino-5-propylcyclohexyl)-2H-isoquinoline-1-he,
7-chloro-6-(CIS-3-isopropylaminocarbonyl)-2H-ethanolic-1-he,
6-(3-CIS-Benzylaminocarbonyl)-7-chloro-2H-isoquinoline-1-he,
6-(3-TRANS-Benzylaminocarbonyl)-7-chloro-2H-isoquinoline-1-he,
7-Chloro-6-(3-C is with dibenzylidineacetone)-2H-isoquinoline-1-he,
7-Chloro-6-(3-TRANS-dibenzylideneacetone)-2H-isoquinoline-1-it
or
7-Chloro-6-(3-grans-diethylaminoethoxy)-2H-isoquinoline-1-he,
or their stereoisomeric forms and/or pharmaceutically acceptable salts.

29. The use of the compounds of formula (I) and/or its pharmaceutically acceptable salt according to one of claims 1 to 28 for receiving the drug, which inhibits Rho-kinase and/or mediated by Rho-kinase phosphorylation of the phosphatase light chain of myosin.

30. The use of the compounds of formula (I) and/or its pharmaceutically acceptable salt according to one of claims 1 to 28 for obtaining a medicinal product for the treatment and/or prevention of diseases such as hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, impaired peripheral circulation, peripheral arterial occlusive disease (PAOD), coronary heart disease, angina, cardiac hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end damage body), pneumovirus, liver fibrosis, liver failure, nephropathy, renal failure, fibrosis of the kidney, renal glomerulosclerosis, hypertrophy of the body, asthma, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome of adults, thrombotic disorders, stroke, causes mozgovynosa, cerebral ischemia, pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, disorders of endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and diabetic complications, metabolic syndrome, restenosis of blood vessels, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy, infection of digestive tracts with bacteria, sepsis, development and progression of cancer.

31. Drug, which inhibits Rho-kinase and/or mediated by Rho-kinase phosphorylation of the phosphatase light chain of myosin, comprising an effective amount of a compound according to any one of claims 1 to 28 and/or its pharmaceutically acceptable salt, pharmaceutically acceptable excipients and carriers, and require auxiliary substances.



 

Same patents:

New compounds // 2456273

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula: wherein B is specified in a group consisting of pyridine, pyridazine, pyrimidine and oxazole which can be optionally substituted by halogen, C1-7-alkyl or a C1-7-alkoxy group; L1 is specified in a group consisting of -NH-, -C(O)NH- and -NHC(O)-, A means C3-C12-cycloalkyl, C6-C12-aryl, a 4-7-member monocyclic heterocyclic group consisting of 1-3 heteroatoms optionally specified in O N and S, or a bicyclic heterocyclyl specified in a group consisting of benzimidazolyl, benzoxazolyl, benzothiazolyl, wherein cycloalkyl, aryl, mono- or bicyclic heterocyclyl can be optionally substituted by one or more substitutes optionally specified in a group consisting of a cyano group, halogen, an oxo group, C1-7-alkyl, C1-7-halogenalkyl, a C1-7-alkoxy group, C1-7-halogenalkoxy group, an amino group, a di-C1-7-alkylamino group, a C1-7-alkylthio group and C3-8-cycloalkyl, 1-2- means a bivalent residue specified in a group consisting of: - a bivalent alkyl group consisting of 1 to 4 carbon atoms, a bivalent alkenyl group consisting of 2 to 3 carbon atoms, - -C(O)-, - -C(O)-[R4]c-R5- wherein c is equal to 0, and R5 is specified in a group consisting of a bivalent C1-C4-alkyl group optionally substituted by another C1-4-alkyl, a C4-C8-cycloalkyl group, a phenyl group and a 5- or 6-member heterocyclyl group consisting of N heteroatoms, - -C(O)-NH-, - -(CH2)1-3-C(O)-NH-(CH2)1-3-, - -C(O)-NH-R4- wherein R4 is specified in a group consisting of a bivalent C1-C7-alkyl group optionally substituted by another C1-4-alkyl, a cyclohexyl group and a cyclopentyl group, and E is specified in a group consisting of: - COOH, - a ester group of carboxylic acid, or to its pharmaceutically acceptable salts. What is also described is a pharmaceutical composition exhibiting DGAT1 modulatory activity, on the basis of the presented compounds, and also a method of treating pathological conditions or disorders associated with DGAT1 activity.

EFFECT: there are prepared and described new compounds applicable for treating or preventing the pathological conditions or disorders associated with DGAT1 activity.

22 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 6-substituted isoquinoline and isoquinolone derivatives of formula (I) where R1 denotes OH; R2 denotes H; R3 denotes H; R4 denotes H, (C1-C6)alkyl; R5 denotes H, halogen; R6 denotes H, (C1-C8)alkyl, (C1-C6)alkyleneR', (C1-C6)alkylene-C(O)NH-(C1-C6)alkyl, (C1-C6)alkylene-C(O)O-(C1-C6)alkyl, C(O) (C1-C6)alkyl, C(O)R1 or C(O)-(C1-C6)alkyleneR'; R7 denotes H, halogen, (C1-C6)alkyl; R8 denotes H; n equals 1, 2, 3 or 4; m equals 1, 2, 3, 4 or 5; and L denotes O or O-(C1-C6)alkylene; where R' denotes (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl; where in residues R4, R6 and R7 alkyl or alkylene can optionally be substituted once or several times with OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONHCH3 or CON(CH3)2; where in residues R4, R6 and R7 alkyl or alkylene can optionally be substituted once or several times with halogen; where in residue R6(C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted once or several times with suitable groups independently selected from halogen; where, if m equals 3, R6 does not denote H; and where, if m equals 3 and R6 denotes a residue selected from (C1-C8)alkyl, (C1-C6)alkylene-R'; alkyl, alkylene in said residue is substituted with once or several times, preferably once to three times, with OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONHCH3 or CON(CH3)2; or stereoisomeric forms thereof and/or tautomeric forms thereof and/or pharmaceutically acceptable salts thereof. The invention also relates to use of compounds of formula I to prepare a medicinal agent which inhibits Rho-kinase, as well as to the medicinal agent itself.

EFFECT: novel compounds which can be useful when treating and/or preventing diseases associated with Rho-kinase and/or Rho-kinase-mediated myosin light chain phosphatase phosphorylation are obtained and described.

34 cl, 75 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidine-sulphone)-N'-isonictinoyl hydrazide used as substance for medicinal agents for treating and preventing immunodeficiency during infectious and somatic pathology ('Isofon'), treating mycobacterial and viral infections ('Tubosan'). The method involves reaction of 6-methyluracil-5-sulphochloride with isonicotinic acid hydrazide in equimolar amounts in the medium of a mixture of ethyl acetate and alcohol - ethyl or isopropyl or methyl alcohol, taken in ratio 95-90:5-10 vol. % at temperature 40-73°C for not less than two hours, followed by distillation of the solvent from the reaction mass, dissolution and purification of the reaction product in aqueous ammonia solution and neutralisation of the purified solution to pH not higher than 5. All steps of the process of producing the end product are carried out in a single cycle without extracting intermediate products.

EFFECT: method enables to reduce the cost of raw materials, avoid loss of the end product during intermediate operations, increase output of a pharmaceutically pure agent, cut the duration of the process and reduce labour input.

6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine of formula (I) in which R1 denotes a methyl group, R2 denotes a R21NR22 group, where R21 denotes an ethyl group which is substituted with an ethoxycarbonyl group, and R22 denotes a pyridin-2-yl group, R3 denotes an n-hexyloxycarbonyl group, where at step (a) phenyldiamine of formula (II) where R1 and R2 assume values given for formula (I), which reacts with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, to obtain a product of formula (III) where R1 and R2 assume values given for formula (I), which is hydrogenated at temperature from 30 to 60°C at hydrogen pressure from 1 to 10 bar, over palladium on activated charcoal (Pd/C) in a mixture of tetrahydrofuran and water, and then, without any preliminary extraction of the hydrogenation product, the obtained compound of formula (I), in which R3 denotes hydrogen, in the presence of potassium carbonate reacts with a compound of formula (IV) R3-X (IV), where R3 assumes values given for formula (I), and X denotes a suitable splitting group.

EFFECT: simple method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine.

3 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (1): R1 means haloalkyl containing 1-6 fluorine atoms; R2 means C1-C6alkyl or halogen; R3 means -L-NR4R5, -X-NR-C(O)R8 or -X-NR-C(O)NR4R5 wherein L means -X-C(O), -(CR2)j, -O(CR2)1-4 or and X means (CR2)j or [C(R)(CR2OR)]; R4 and R5 independently mean H, C1-C6alkyl, halogen-substituted C1-C6alkyl, hydroxy group-substituted C1-C6alkyl, or (CR2)k-R6; R8 independently means (CR2)k-R6 or C1-C6alkyl, or halogen-substituted C1-C6alkyl; R7 means H; alternatively, R4 and R5 together with N atom in each NR4 R5 form a 4-7-member heterocyclic ring containing 1 -2 heteroatoms independently specified in N and O substituted by 0-3 groups R11; R11 means R8, (CR2)k-OR7, CO2R7, (CR2)k-C(O)-(CR2)k-R8, (CR2)kC(O)NR7R7 or (CR2)kS(O)1-2R8; each R means H or C1-C6alkyl; each k is equal to 0-6; and j and m are independently equal to 0-4; provided R1 does not mean trifluoromethoxygroup, provided R3 means C(O)NH2, C(O)NR12R13; wherein R12 and R13 together form piperazinyl; the values of the radical R6 are presented in the patent claim. The invention also refers to the pharmaceutical composition containing said compounds.

EFFECT: producing new 5-(4-(halogenalkoxy)phenyl)pyrimidin-2-amine derivatives showing c-kit, PDGFRα, PDGFRβ kinase inhibitory activity, optionally in the form of isomers or pharmaceutically acceptable salts.

12 cl, 77 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new piperazine amide derivatives of formula wherein X represents N or CH; Y represents N or CH; R1 represents lower alkyl, phenyl, phenyl-lower alkyl wherein phenyl can be optionally substituted by 1-2 substitutes independently specified in a group consisting of halogen, lower alkyl; R2 represents lower alkyl, phenyl, naphthyl or heteroaryl specified in dimethylisoxazolyl, quinolinyl, thiophenyl or pyridinyl wherein phenyl or heteroaryl are optionally substituted by 1 substitute optionally specified in a group consisting of halogen, lower alkoxy group, fluor-lower alkyl, lower alkoxy-carbonyl and phenyl; R3 represents phenyl, pyridinyl or pyrazinyl wherein phenyl, pyridinyl or pyrazinyl are substituted by 1-2 substituted optionally specified in a group consisting of halogen, lower alkyl and fluor-lower alkyl; R4, R5, R6, R7, R8, R9, R10 and R11 independently represent hydrogen, as well as to their physiologically acceptable salts. These compounds are bound with LXR alpha and LXR beta, and are applicable as therapeutic agents for treatment and/or prevention of high lipid levels, high cholesterol levels, low HDL cholesterol, high LDL cholesterol, atherosclerotic diseases, diabetes, non insulin dependent diabetes mellitus, metabolic syndrome, dislipidemia, sepsis, inflammatory diseases, infectious diseases, skin diseases, colitis, pancreatitis, cholestasis, liver fibrosis, psoriasis, Alzheimer's disease, etc.

EFFECT: preparing new piperazine amide derivatives.

15 cl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to quinoline derivatives of formula I

, or to its pharmaceutically acceptable salts, wherein X1 represents O; p represents 0, 1 or 2; each group R1 which can be identical or different and which can be located only in positions of 6- and/or 7-quinoline ring, specified in halogen, cyano, carboxy, (1-6C)alkoxycarbonyl, carbamoyl, (1-6C)alkoxy, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, or in a group of formula: Q1-X2-, wherein X2 represents CO and Q1 represents pyrrolidine, q represents 0 or 1; R2 represents (1-6C)alkoxy; R3 represents hydrogen or (1-6C)alkyl; R4 represents hydrogen; R5 represents hydrogen, methyl, ethyl, propyl, allyl, 2-propynyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, cyanomethyl, 2-cyanoethyl or 3-cyanopropyl; the ring A represents a 5-membor monocyclic heteroaryl ring with up to three ring heteroatoms specified in oxygen, nitrogen and sulphur; r represents 0, 1 or 2; and each group R6 which can be identical or different is specified in amino, (1-6C)alkyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, or in a group of formula: -X6-R15 wherein X6 represents a single link and R15 represents (1-6C)alkoxy-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl or in a group of formula: -X7-Q3 wherein X7 represents C(R17)2N(R17) wherein each R17 represents hydrogen and Q3 represents (3-8C)cycloalkyl, and wherein any CH2 group within the R6 group optionally carries a hydroxy group on each said group. Also, the invention refers to methods for making the compound of formula I, to a pharmaceutical composition on the basis of the compound of formula I, to applying the compound of formula I and the combinations on the basis of the compound of formula I and additional anticancer drugs.

EFFECT: there are produced new quinoline derivatives effective in treating diabetic retinopathy and disturbed cell proliferation.

15 cl, 6 tbl, 32 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyridine derivatives of formula (I), where R denotes a linear alkyl with 4-8 carbon atoms. The invention also relates to a pharmaceutical composition based on a compound of formula (I), use of the compound of formula (I), a method of preventing or treating diseases caused by Helicobacter pyroli bacteria and/or diseases associated with secretion of gastric juice, and a method of producing a pyridine derivative of formula (I).

EFFECT: novel pyridine derivatives of formula (I), having useful biological properties, are obtained.

9 cl, 2 dwg, 8 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or formula (I') where values of the substitutes are disclosed in the patent claim. The present compounds are able to inhibit Rho-kinase.

EFFECT: making the compounds effective for treating and/or preventing the Rho-kinase-associated and/or Rho-kinase-mediated diseases by phosphorylation of myosin light chain phosphatise.

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry, specifically to novel derivatives of 3,4-dihydroisoquinoline of general formula III where: R=H, Alk1=Alk2=Me, Ar=Ph (a), Ar=C6H4Me-n (b), Alk1Me, Alk2=Bu, Ar=Ph (c), Ar=C6H4Me-n (d), R=OMe, Alk1=Alk2=Me, Ar=Ph (e), Ar=C6H4Me-n (f), R=OEt, Alk1=Alk2=Me, Ar=Ph (g) The invention also relates to a method of producing compounds of general formula III, involving reaction of 6-aryl-2,2-dimethyl-4H-1,3-dioxin-4-ones with 3,3-dialkyl-3,4-dihydroisoquinolines in an absolute toluene medium at temperature 108-110°C, followed by extraction of the desired product.

EFFECT: obtaining novel derivatives of 3,4-dihydroisoquinoline of general formula III, having fluorescent properties, which are resistant to UV light.

4 cl, 8 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to new compounds (2Z,5Z)-1-aryl-3-hydroxy-5-(3,3-dialkyl-3,4-dihydroisoquinolin-1(2N)-ylidene)-pent-2-ene-1,4-diones with general formula:

III: R=H, Ar=Ph (a), C6H4F-n (b), R=OMe, Ar=Ph (c), C6H4OMe-n (d), C6H4F-n (e), C6H4NO2-n (f). The invention also relates to a method of producing said compounds.

EFFECT: obtaining new compounds which can be used as primary products in synthesis of new heterocyclic systems.

2 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to new compounds (1Z,3Z)-4-aryl-4-hydroxy-1-(3,3-dialkyl-3,4-dihydroisoquinolin-1(2N)-ylidene)-but-3-en-4-ones with general formula:

III: R=H, Alk1=Alk2=Me, Ar=Ph (a), Ar=C6H4Me-p (b), Alk1=Me, Alk2=Bu, Ar=Ph (c), Ar=C6H4Me-p (d), R=OMe, Alk1=Alk2=Me, Ar=Ph (e), Ar=C6H4Me-p (f), R=OEt, Alk1=Alk2=Me, Ar=Ph (g). The invention also relates to a method of producing said compounds.

EFFECT: obtaining new compounds with analgetic activity and which can be used as primary products in synthesis of new heterocyclic systems.

4 cl, 1 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in the new compounds with formula I Ar is a bivalent group, formed by removal of two hydrogen atoms from benzol, pyrimidine or pyridine (this bivalent group can also be substituted with a halogen atom, inferior alkoxy (this inferior alkoxy group can also be substituted with a halogen), hydroxyl or inferior alkyl); X1 is an oxygen atom; R1 is a straight or branched inferior alkyl (this inferior alkyl group can also be substituted with hydroxy, halogen, alkoxy, allyloxy or aralkyloxy ), phenyl, aralkyl or alkoxy; ring A is a 5- or 6- member heteroaryl ring, containing 1 or 2 nitrogen atoms or a sulphur atom in the ring, or a benzene ring; R2 and R3 can be identical or different from each other, and each represents hydrogen, amino, alkylamino, hydroxyl, inferior alkylsulphonyl, halogen, inferior alkyl (this inferior alkyl group can also be substituted with a halogen), inferior cycloalkyl (this inferior cycloalkyl group can also be substituted with a halogen), inferior alkoxy (this inferior alkoxy group can also be substituted with a halogen), aryl, heteroaryl, mono inferior alkylcarbamoyl, inferior alkylcarboxamide, arylcarboxamide, inferior alkylsulphonylamino, alkylaminosulphonyl, aralkyl or alkanoylakylamino or; Y is CH or a nitrogen atom; -X2 is a group with formula (II) (where R4 and R5 and a the nitrogen atom, taken together, can form a 5-8-member monocyclic ring (this monocyclic ring can be substituted with a halogen atom, oxo group or inferior alkyl group, which can be substituted by a halogen itself), or a 6-10-member bicyclo-ring, n is an integer, which assumes values 3 or 4, and (CH2)n can be substituted with an inferior alkyl group, containing 1-3 carbon atoms), with formula (III) (where m is and integer which assumes values from 0 to 4, and R6 is an inferior alkyl or cycloalkyl group) or formula (IV) , where symbols assume values given above. The invention also relates to agents for preventing or curing metabolic diseases, blood circulatory diseases or diseases of the nervous system, containing formula I compounds.

EFFECT: new compounds can be used in medicine.

18 cl, 279 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of the formula (I): , where R1 is -COOH or -(CH2)n-R14; R2 is or , where X is -CH or -N; each of R3, R4, R5 and R6 is selected out of group including -H, -(lower) alkyl, -N(CH3)2, -O-(lower) alkene, -(lower) alcoxy, or where R5 and R6 are substitutes in adjoining carbon atoms in ring, R5 and R6 optionally form 5- or 6-member saturated carbocyclic ring together with adjoining carbon atoms, R14 is unsaturated 5-member substituted or non-substituted heterocyclic ring including 1 to 4 heteroatoms selected out of N, O and S, n is 0 or 1, or their pharmaceutically acceptable salts or complex ethers. Invention also concerns pharmaceutical composition.

EFFECT: obtaining new bioactive compounds and pharmaceutical composition based on them, with inhibition effect on glutamine fructose-6-phosphate amidotransferase (GFAT).

16 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula (I): and/or all stereoisomer forms of compound of the formula (I) and/or mix of these forms at any ratio, and/or physiologically acceptable salt of compound of the formula (I), where A is -(C0-C4)-alkylene; B is -(C0-C4)-alkylene or residue -B1-B2-B3-, where B1 is -(CH2)n-, where m is integer 0; B3 is -(CH2)m-, where m is integer 0; so that amount of n and m is 0; and B2 is -O-; cycle 1 or cycle 2 are equal or differ and denote independently 1) covalent link, 2)-(C6-C14)-aryl which is an aromatic hydrocarbon residue with 6-14 carbon atoms in a cycle, where the said aryl is unsubstituted or independently monosubstituted by G, or 3) 4-15-member heterocycle which is a cyclic system with 4-15 carbon atoms located in one, two or three interconnected cyclic systems, and containing one heteroatom selected out of nitrogen or oxygen, where the said heterocycle is unsubstituted or independently monosubstituted by G; G is 1) hydrogen atom, 2) halogen atom, 3)-O-R12, where R12 is a) hydrogen atom, b)-(C1-C6)-alkyl, where alkyl is unsubstituted or trisubstituted by halogen atom, c)-C(O)-O-R13, where R13 is c)1)-(C1-C6)-alkyl, where alkyl is unsubstituted, 4)-NO2, 5)-CN, 6)-N(R15)-R12, where R15 is 6)1)hydrogen atom, X stands for -OH or -NH-OH; n1 is integer 2; n2 is integer 3; together with that, that the sum of n1 and n2 is 5; R1, R2, R3, R4 and R5 are equal or different and independently from each other stand for 1) hydrogen atom, 2)-C(O)-R8, where R8 is 2)1) hydrogen atom, 2)2)-(C1-C6)-alkyl, where alkyl is unsubstituted. The invention also concerns method of obtaining compounds of the formula (I) and medical preparation for matrix metalloproteinase inhibition.

EFFECT: new derivatives of saturated bicyclic iminoacids with useful biological properties.

4 cl, 1 tbl, 29 ex

FIELD: organic chemistry.

SUBSTANCE: description is given of compounds with formula (I) and their pharmaceutical salts, in which n, X, Y, R1, R2, R3, R4 and R5 are defined in this invention. The obtained compounds have modulating action relative to "5-НТ6" receptors. Description is also given of a pharmaceutical composition based on compounds with formula (I), used as "5-НТ6" modulators for treating damages to the central nervous system.

EFFECT: obtaining of new compounds, with useful biological properties.

10 cl, 1 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I): wherein Y means >C=O or -CH2; Z means >C=O or -CH2; R1 means hydrogen atom or group of the formula: -CR3R4R5; R2 is chosen independently from group comprising halogen atom, halogen-(C1-C6)-alkyl, cyano-group; m = 1-3. Also, invention relates to medicinal agents containing these compounds possessing selective inhibitory properties with respect to monoaminooxidase B activity and used in treatment and prophylaxis of Alzheimer's disease and senile feeblemindedness.

EFFECT: valuable medicinal properties of compounds.

23 cl, 1 tbl, 64 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, more specifically to a new chemical compound, a 3-(2,2,2-trimethylhydrazinium)propionate-5-nicotinate hydroxide 3-(2,2,2-trimethylhydrazinium)potassium propionate derivative, (CH3)3N+HCH2CH2COOKRCOO- wherein exhibiting antiischemic activity.

EFFECT: what is produced and described is the new compound which may be effective as an agent showing antiischemic activity.

1 cl, 1 ex, 1 tbl

Up!