WO2012128582A2 - Composé capable d'inhiber la 11-bêta-hydroxystéroïde déshydrogénase de type 1 humaine et composition pharmaceutique en contenant - Google Patents

Composé capable d'inhiber la 11-bêta-hydroxystéroïde déshydrogénase de type 1 humaine et composition pharmaceutique en contenant Download PDF

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WO2012128582A2
WO2012128582A2 PCT/KR2012/002100 KR2012002100W WO2012128582A2 WO 2012128582 A2 WO2012128582 A2 WO 2012128582A2 KR 2012002100 W KR2012002100 W KR 2012002100W WO 2012128582 A2 WO2012128582 A2 WO 2012128582A2
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mmol
compound
nmr
morpholine
mhz
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PCT/KR2012/002100
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English (en)
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WO2012128582A3 (fr
Inventor
In Hee Lee
Chang Min Park
Se Hoan Kim
Hee Il Chae
Doo Hyeok PYEON
Myoung Hyeon SHIN
Jeong Un HWANG
Soon Young Moon
Tae Young Ha
So Youn Kim
Hyuk Joon Choi
Myoung Hyun YOO
Jong Chan Lee
Young Seok Kim
Jae Keol Rhee
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Hyundai Pharm Co., Ltd.
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Priority claimed from KR1020110025926A external-priority patent/KR20120108999A/ko
Priority claimed from KR1020120020455A external-priority patent/KR20120109297A/ko
Application filed by Hyundai Pharm Co., Ltd. filed Critical Hyundai Pharm Co., Ltd.
Publication of WO2012128582A2 publication Critical patent/WO2012128582A2/fr
Publication of WO2012128582A3 publication Critical patent/WO2012128582A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for inhibiting human 11- ⁇ -Hydroxy Steroid Dehydrogenase Type 1(11 ⁇ -HSD1) comprising the same.
  • a glucocorticoid (cortisol in human, corticosterone in rodents) is a reversely regulatory hormone, namely is against the action of insulin (Dallman MF, Strack AM, Akana SFetal., 1993; Front Neuroendocrinol 14, 303-347). It regulates the expression of liver enzymes associated with the gluconeogenesis, and increses the substrate supply by releasing amino acids from muscle (decrease of protein synthesis and increase of protein decomposition) and releasing glycerols from adipose tissue (increase of lipid decomposition).
  • the glucocorticoid is also important in dividing a preadipocyte into mature adipocytes that can store triglycerids (Bujalska IJ et al., 1999; Endocrinology 140, 3188-3196). It can be important in disease status in which the glucocorticoid derived by "stress" as itself is associated with the central obesity that is a strong risk factor of type 2 diabetes, hypertension and cardiovascular disease (Bjorntorp P and Rosmond R, 2000; Int. J. Obesity 24, S80-S85).
  • glucocorticoid not only can be regulated by the secretion of cortisol, but also is regulated in tissue level according to the intracellular interconversion of inactive cortisone and active cortisol by 11 ⁇ -Hydroxy Steroid Dehydrogenase, 11 ⁇ HSD1 (that activates cortisone) and 11 ⁇ HSD2 (that deactivates cortisol) (Sandeep TC and Walker BR, 2001 Trends in Endocrinol & Metab. 12, 446-453).
  • An isoform of 11 ⁇ -Hydroxy Steroid Dehydrogenase Type 1(11 ⁇ HSD1) is expressed in a liver, adpose tissues, a brain, lungs and other tissues of glucocorticoid, and is a potential target for treatment of numerous diseases that can be improved by the decrease of action of glucocorticoid, such as diabetes, obesity and age-related cognitive impairment (Seckl et al., 2001; Endocrinology 142, 1371-1376).
  • Cushing's syndrome is associated with excess of cortisol, and this is associated with sugar tolerence, central obesity (which is caused by stimulation of differentiation of preadipocyte in depot), dyslipidemia and hypertension. Cushing's syndrome shows a number of obvious similarities with the metabolic syndrome. Although the metabolic syndrome is not generally associated with excessive levels of circulating cortisol (Jessop DS et al., 2001; J. Clin. Endocrinol. Metab. 86, 4109-4114), it is expected that the abnormally high activity of 11 ⁇ HSD1 in tissue has the same effect.
  • 11 ⁇ HSD1 knock-out mice represent an attenuated glucocorticoid-derived activation of gluconeogenesis enzyme as a reaction to sugar concentration in plasma, which is meager and is reduced in response to stress or obesity (Kotelevtsev Y et al., 1997; Proc. Natl. Acad. Sci USA 94, 14924-14929), and this implies an usefulness of 11 ⁇ HSD1 inhibition in output degradation of plasma sugar and liver sugar in type 2 diabetes.
  • these mice express an anti-arteriosclerotic lipoprotein profile, in which triglyceride decreases, HDL colesterol increases and apo-lipoprotein AI level increases (Morton NM et al., 2001; J. Biol.
  • 11 ⁇ HSD1 The most obvious proof of relationship between a metabolic syndrome and 11 ⁇ HSD1 is derived from a recent study on an excessive expression of 11 ⁇ HSD1 of transgenic mouse (Masuzaki H et al., 2001; Science 294, 2166-2170). When it is expressed under the regulation of adipocyte-specific promoting genes, 11 ⁇ HSD1 transgenic mouse shows corticosterone with high fat level, central obesity, insulin resistant diabetes, hyperlipidemia and sitomania. Most importantly, the increase of 11 ⁇ HSD1 level in fat of this mouse is similar with that observed in diabetes object. The activity of 11 ⁇ HSD1 in fat and corticosterone level in plasma were normal, but the corticosterone level in hepatic portal vein increased to 3 times. It is thought that this is a cause of metabolic effects in liver.
  • the distribution of tissues of 11 ⁇ HSD1 is widespread and is overlapped with the acceptor of glucocorticoid.
  • the inhibition of 11 ⁇ HSD1 can potentially counter the effect of glucocorticoid in numerous physiological/pathological roles.
  • the 11 ⁇ HSD1 is present in skeletal muscle of human, and the opposite action of glucocorticoid to assimilation effect of insulin which effects on protein conversion and glucose metabolism was widely disclosed (Whorwood CB et al., 2001; J. Clin. Endocrinol. Metab. 86, 2296-2308). Therefore, the skeletal muscle is an important target for the treatment of 11 ⁇ HSD1-class.
  • the glucocorticoid can also reduce the insulin secretion and degrade the effect of insulin resistance derived from glucocorticoid.
  • Pancreatic islets can express 11 ⁇ HSD1 and carbene oxolones can inhibit the effect of 11-dehydrocorticosterone on insulin release (Davani B et al., 2000; J. Biol. Chem. 275, 34841-34844).
  • 11 ⁇ HSD1 inhibitor not only can act on insulin resistance at the tissue level, but also can increase the insulin secretion itself.
  • the skeletal development and bone action are also regulated by the action of glucocorticoid.
  • the 11 ⁇ HSD1 is present in human bone osteoclasts and osteoclasts and results of healthy volunteers treated with carbene oxolones show reduction in bone absorption without changes in markers of bone formation (Cooper MS et al. 2000; Bone 27, 375-381).
  • the inhibition of activity of 11 ⁇ HSD1 can be used as a protection mechanism in a treatment of osteoporosis.
  • the glucocorticoid can be also associated with an eye disease such as glaucoma. It was shown that the 11 ⁇ HSD1 influences person's intraocular pressure and it can be expected that the inhibition of 11 ⁇ HSD1 can reduce the increase of intraocular pressure associated with glaucoma (Rauz S et al., 2001; Investigative Opthalmology & Visual Science 42, 2037-2042).
  • the 11 ⁇ HSD1 in human brain is inhibited, the reactivation of cortisone into cortisol can be inhibited, and the glucocorticoid-mediated effects, which is harmful to other aspects of survival of nerve and function of nerve, comprising cognitive impairment, depression and increased appetite are prevented.
  • metabolic syndrome of adult treatment panel indicates the presence when a patient has 3 or more symptoms of the following symptoms:
  • a blood sugar (serum glucose) of 110 mg/dl(6.1 mmol/l) or more.
  • ITT impaired glucose tolerance
  • the present invention provides a compound which has more excellent activity and solubility and is more efficient in formulation and transmission and a pharmaceutical composition for inhibiting human 11- ⁇ -Hydroxy Steroid Dehydrogenase Type 1 comprising the same for this.
  • the present invention provides a novel compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for inhibiting human 11- ⁇ -Hydroxy Steroid Dehydrogenase Type 1(11 ⁇ -HSD1) comprising the same.
  • An embodiment of the present invention provides a compound represented by the following Chemical Formula 1 or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R' and R'' are each independently H or a C 1 -C 3 alkyl and may be taken together to form a 5- or 6-membered saturated or unsaturated ring;
  • X is any one selected from the group consisting of -NR 1 R 2 , -NHSO 2 R 1 , -C(O)OR 1 , -NHC(O)R 1 , -OC(O)R 1, -C(O)NR 1 R 2 , -NHC(O)NR 1 R 2 , and -C(O)NHNR 1 R 2 ;
  • L is a bond or a C 1 - C 3 alkylene group, wherein each carbon atom constituting the C 1 - C 3 alkylene group may be independently substituted with one or more C 1 - C 6 alkyl groups;
  • R 1 and R 2 are each independently any one selected from the group consisting of hydrogen, -OH, a substituted or unsubstituted C 1 - C 6 alkyl, a substituted or unsubstituted C 3 - C 12 cycloalkyl, a substituted or unsubstituted C 6 - C 12 aryl, and a substituted or unsubstituted C 5 - C 12 heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S;
  • R 1 and R 2 may be taken together with the nitrogen atom to which they are attached to form a 5- to 8-membered saturated or unsaturated ring, wherein the saturated or unsaturated ring may be substituted with one or more groups selected from the group consisting of -OH, a C 1 - C 6 alkoxy, a C 1 - C 6 haloalkoxy, a substituted or unsubstituted C 1 - C 6 alkyl, -NO 2 , halo, -COOH, a -C 1 - C 6 alkyloxycarbonyl, a C 6 - C 10 aryl, -NH 2 , a mono- or di- C 1 - C 6 alkylamino, and a mono- or di- C 1 - C 6 alkylcarbamoyl;
  • L‘ is a bond, -C(O)-, -C(O)O-, -C(O)NH-, -NHC(O)-, C 1 - C 3 alkylene, -SO 2 -, C 1 - C 3 alkylene-C(O)-, or -C(O)-C 1 - C 3 alkylene, wherein each carbon atom constituting the C 1 - C 3 alkylene may be each independently substituted with one or more groups selected from the group consisting of C 1 - C 6 alkyl, -CN, -COOH, and C 1 - C 6 alkyloxycarbonyl;
  • P is any one selected from the group consisting of a substituted or unsubstituted C 1 - C 6 alkyl, a substituted or unsubstituted C 3 - C 12 cycloalkyl, a substituted or unsubstituted C 6 - C 12 aryl, a substituted or unsubstituted C 5 - C 12 heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S, a C 1 - C 6 alkyloxycarbonyl, -COOH, and -NR 1 R 2 ;
  • carbon atoms constituting the alkyl group may be taken together to form a 5- or 6-membered saturated or unsaturated ring, wherein the ring may be substituted with one or more groups selected from the group consisting of -OH, C 1 - C 6 alkoxy, C 1 - C 6 haloalkoxy, C 1 - C 6 alkyl, -NO 2 , halo, -COOH, -C 1 - C 6 alkyloxycarbonyl, C 6 - C 10 aryl, -NH 2 , mono or di C 1 - C 6 alkylamino, and mono- or di- C 1 - C 6 alkylcarbamoyl, and one or more of the carbon atoms constituting the ring may be substituted with one or more selected from the group consisting of
  • substituted C 1 - C 6 alkyl, substituted C 3 - C 12 cycloalkyl, substituted C 6 - C 12 aryl and substituted C 5 - C 12 heteroaryl mean that said C 1 - C 6 alkyl, C 3 - C 12 cycloalkyl, C 6 - C 12 aryl and C 5 - C 12 heteroaryl may be independently substituted with one or more groups selected from the group consisting of a C 1 - C 6 alkyl which may be substituted with -CN, halo or -OH; a C 3 - C 12 cycloalkyl; a C 2 - C 6 alkenyl; a substituted or unsubstituted C 5 - C 12 heteroaryl having one or more ring heteroatom selected from the group consisting of N, O and S; a C 6 - C 10 aryl; a C 1 - C 6 alkylsulfonyl; a C 6 - C 12 aryls
  • one or more carbon atoms constituting the C 1 - C 6 alkyl and the C 3 - C 12 cycloalkyl may be substituted with one or more of N, O and S;
  • alkyl or alkenyl in said C 1 - C 6 alkyl, C 2 - C 6 alkenyl, C 1 - C 6 alkylsulfonyl, C 1 - C 6 alkoxy, C 1 - C 6 haloalkoxy, -C 1 - C 6 alkylcarbonyl, -C 1 - C 6 alkyloxycarbonyl, C 1 - C 6 alkylamino and C 1 - C 6 alkylcarbamoyl may be straight or branched-chain; and
  • C 3 - C 12 cycloalkyl, C 6 - C 12 aryl and C 5 - C 12 heteroaryl have a single ring or a multiple ring structure.
  • an embodiment of the present invention provides a compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof characterized in that X is -C(O)NR 1 R 2 and R 1 and R 2 are the same as defined above.
  • an embodiment of the present invention provides a compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof characterized in that in the Chemical Formula 1 X is , and the cycloalkyl moiety is substituted with one or more groups selected from the group consisting of a C 1 - C 6 alkyl which may be substituted with -CN, halo or -OH; a C 3 - C 12 cycloalkyl; a C 2 - C 6 alkenyl; a substituted or unsubstituted C 5 - C 12 heteroaryl having one or more ring heteroatoms selected from the group consisting of N, O and S; a C 6 - C 10 aryl; a C 1 - C 6 alkylsulfonyl; a C 6 - C 12 arylsulfonyl; a C 1 - C 6 alkylthio; mercapto; -OH; a C 1 - C 6 alkoxy; a
  • an embodiment of the present invention provides a compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof characterized in that the compound of the Chemical Formula 1 is any one selected from the group consisting of the following compounds.
  • an embodiment of the present invention provides a compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof characterized in that the compound of the Chemical Formula 1 is any one selected from the group consisting of the following compounds.
  • the present invention provides a pharmaceutical composition for inhibiting human 11- ⁇ -Hydroxy Steroid Dehydrogenase Type 1(11 ⁇ -HSD1), comprising the compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof of the present invention as an active ingredient.
  • the present invention provides a pharmaceutical composition for treating or preventing any one disease selected from the group consisting of hypertension, heart failure, renal failure, liver failure, peripheral vascular disease, coronary artery disease, myocardial infraction, hyderlipidemia, diabetes, hyperglycemia, obesity, ischemic heart disease, diabetic nephropathy, diabetic heart failure, dyslipidemia, stroke, arteriosclerosis, inflammation, adult respiratory distress syndrome, renal disease, Raynaud syndrome, obstructive pulmonary disease, interstitial pulmonary disease, asthma and arthritis, comprising the compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof of the present invention as an active ingredient.
  • the present invention provides a pharmaceutical composition for treating or preventing any one disease selected from the group consisting of diabetes, metabolic syndrome, obesity, polycystic ovary syndrome, eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, hyderlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low high-density lipoprotein level (HDL), high low-density lipoprotein level (LDL), hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, arteriosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, nerve disorder, muscle wasting, cognitive impairment, dementia, psoriasis, glaucoma, osteoporosis, viral infection, inflammatory disease, and immune disease, comprising the compound or a stereoisomer thereof or a pharmacuetically acceptable salt thereof of the present invention as an active ingredient.
  • any one disease selected from
  • pharmaceutically acceptable means that a carrier, a diluent, or an excipient should be harmonizable with other ingredient of dosage form, and not harmful to a consumer thereof.
  • alkyl used in the present invention means a saturated hydrocarbon radical, which can be linear or branched. This definition applies to both when the term is used alone, and when the term is used as a part of a compound term, such as “arylalkyl”, “alkylamino” and the like. It is intended that in the present specification and claims all numerical ranges comprise an upper end and a lower end thereof.
  • cycloalkyl and cycloalkylene represent a saturated hydrocarbon ring, and comprise noncyclic and polycyclic rings.
  • a cycloalkyl and cycloalkylene group having a hetero atom (for example, N, O or S) instead of carbon ring atom can be mentioned as “heterocycloalkyl” and “heterocycloalkylene", respectively.
  • a part of the cycloalkyl and heterocycloalkyl can be also substituted or not be substituted with a halogen atom or another group, for example, nitro, alkyl, alkylamino, carboxyl, alkoxy, aryloxy and so on.
  • halo or halogen means fluorine, chlorine, bromine or iodine atom unless otherwise noted.
  • hetero represents a molecule, a coupler or a substituent, in which one or more than one of carbon atom is substituted with any one atom other than carbon, for example, nitrogen, oxygen, sulfur, phosphorus or silicon, generally nitrogen, oxygen or sulfur or more than one of noncarbon atom.
  • heteroalkyl represents a hetero atom-containing alkyl substituent
  • heterocyclic represents a hetero atom-containing or aromatic or nonaromatic cyclic substituent or group.
  • heteroaryl and “heteroaromatic” each represents a hetero atom-containing “aryl” and “aromatic” substituent.
  • heterocyclic and “heterocyclyl” comprise the terms “heteroaryl” and “heteroaromatic”.
  • substituted represents that an atom or a group of atoms of any one compound is substituted with another atom or another group of atoms.
  • an atom or a group of atoms can be substituted with one or more than one of that from among the following substituents or groups: halo, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkylamino, hydroxyC 1 -C 8 alkyl, haloC 1 -C 8 alkyl, carboxyl, hydroxyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyC 1 -C 8 alkoxy, thioC 1 -C 8 alkyl, aryl, aryloxy, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl C 1 -C 8 alkyl, heteroaryl, arylC 1 -C 8 alkyl, heteroarylC 1 -C 8 alkyl, heteroarylC 1 -
  • unsubstituted means an original compound not substituted with any atom or group of atoms.
  • a total daily dosage to be administered to host as a single dosage or a separate dosage is preferably 1 to 100 mg, particularly preferably 3 to 10 mg, per 1 kg body weight, but a specific dosage level for each patient can change according to a specific compound to be used, a body weight, a gender, a health status, a diet of patient, a time of administration, a method of administration of drug, an excretion rate, mixing drugs and a severity of disease and so on.
  • An injectable formulation for example a sterile injectable aqueous or oily suspension can be prepared by using a suitable dispersant, wetting agent or suspending agent according to the known technology. Solvents which can be used for this comprise water, Ringer's solution and isotonic NaCl solution, and a sterile fixed oil is also normally used as a solvent or a suspension medium. Any nonirritating fixed oil comprising mono-, di-glyceride can be also used for this purpose, and also a fatty acid such as oleic acid can be used in an injectable formulation.
  • Examples of a form of solid administration for oral administration comprise capsules, tablets, pills, powders and granules, and particularly capsules and tablets are useful. It is preferable to prepare tablets and pills into a form of long shell.
  • the form of solid administration can be prepared by mixing the active compound of the Chemical Formula 1 according to the present invention with one or more inert diluent, such as sucrose, lactose, starch and so on, lubricants such as magnesium stearate, carriers such as disintegrants, binders and so on.
  • the compound of the present invention and the pharmaceutical composition for inhibiting human 11- ⁇ -Hydroxy Steroid Dehydrogenase Type 1 comprising the same have excellent activity and solubility, and are more efficient in formulation and transmission.
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • N-(adamantane-2-yl)-4-benzylmorpholine-2-carboxamide 500 mg, 1.41 mmol was dissolved in EtOH (10 ml), and added with 10 % Pd/C (50mg). The resultant mixture was stirred under a hydrogen atmosphere for 12 hours, and filtered through celite to remove 10 % Pd/C. Then, N-(adamantane-2-yl)morpholine-2-carboxamide (279.7 mg, 1.25 mmol, 75 %) was obtained.
  • N -2-adamantyl-morpholine-2-carboxyamide hydrochloride (100 mg, 0.33 mmol), 1-bromo-4-fluoro-2-trifluoro)benzene (80 mg, 0.33 mmol), BINAP (8 mg, 0.013 mmol), t-BuONa (64 mg, 0.66 mmol), and Pd 2 (dba) 3 (6 mg, 0.007 mmol) were dissolved in toluene (1 ml), and stirred at 100°C for 5 hours. After the reaction was completed, the resultant product was filtered through celite, and an organic layer was separated by Et 2 O and EA. The organic layer was dried and filtered with MgSO 4 .
  • a desired compound was obtained in the same manner as described in Preparation Example 3 in Example 1 except that 1-bromo-4-chlorobenzene was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 3 in Example 1 except that 1-bromo-2-chlorobenzene was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 3 in Example 1 except that 1-bromo-2-fluorobenzene was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 3 in Example 1 except that 1-bromo-4-trifluoromethylbenzene was used.
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • N-(adamantane-2-yl)-4-benzylmorpholine-2-carboxamide 500 mg, 1.41 mmol was dissolved in EtOH (10 ml), and added with 10 % Pd/C (50mg). The resultant mixture was stirred under a hydrogen atmosphere for 12 hours, and filtered through celite to remove 10 % Pd/C. Then, N-(adamantane-2-yl)morpholine-2-carboxamide (279.7 mg, 1.25 mmol, 75 %) was obtained.
  • N-2-adamantyl-morpholine-2-carboxyamide hydrochloride 100 mg, 0.33 mmol
  • 2-bromo-1-phenylethanone 99 mg, 0.5 mmol
  • DMF 1 ml
  • K 2 CO 3 92 mg, 0.66 mmol
  • an organic layer was separated by H 2 O and EA. The organic layer was dried and filtered with MgSO 4 .
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-(2-methoxyphenyl)ethanone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-(4-fluorophenyl)ethanone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-(3-nitrophenyl)ethanone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-phenylpropane-1-one was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 2-bromo-1-phenylpropane-1-one was used.
  • N-2-adamantyl-ethyl-2-(2-(carbamoyl)morpholino)acetate (100 mg, 0.29 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and then was added with LiOH (61 mg, 1.45 mmol) dissolved in H 2 O (1 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2 N -HCl to pH 2, and extracted with EA.
  • N-2-adamantyl-ethyl-2-(2-(carbamoyl)morpholino)acetic acid 50 mg, 0.16 mmol was dissolved in CH 2 Cl 2 (1 ml), and added with BOP (70 mg, 0.16 mmol) and DIPEA (60 mg, 0.47 mmol), followed by stirring. The resultant mixture was added with 4-fluoroaniline (20 mg, 0.19 mmol), and stirred at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH 2 Cl 2 and H 2 O, and dried and filtered with MgSO 4 .
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that ethyl 2-bromo-2-methylpropanoate was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 8 in Example 2 except that 2-chloroaniline was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that 1-(2-bromoethyl)-4-fluorobenzene was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that (2-bromoethyl)benzene was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that (2-bromopropyl)benzene was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that ethyl 2-chloro-2-phenylacetate was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 7 in Example 2 except that ethyl 2-bromo-2-methylpropanoate was used.
  • N-2-adamantyl-morpholine-2-carboxyamide hydrochloride (245 mg, 0.816 mmol) was dissolved in CH 2 Cl 2 (5 ml), and added with BOP (300 mg, 0.68 mmol) and DIPEA (264 mg, 2.04 mmol), followed by stirring. The resultant mixture was added with 4-cyanobenzoic acid (100 mg, 0.68 mmol), and stirred at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH 2 Cl 2 and H 2 O, and dried and filtered with MgSO 4 .
  • N-2-adamantyl-morpholine-2-carboxyamide hydrochloride 200 mg, 0.66 mmol
  • 4-nitrophenyl carbonochloridate 133 mg, 0.66 mmol
  • DMF 10 ml
  • triethylamine 200 mg, 1.98 mmol
  • the organic layer was separated by H 2 O and CH 2 Cl 2 , and dried and filtered with MgSO 4 .
  • N-2-adamantyl-morpholine-2-carboxyamide 100 mg, 0.38 mmol
  • 4-(1-chloroethyl)-1,2-difluorobenzene 201 mg, 1.14 mmol
  • DMF 1 ml
  • K 2 CO 3 158 mg, 1.14 mmol
  • KI 189 mg, 1.14 mmol
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-cyanoacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 2-pyridineacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 3-pyridineacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-pyridineacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-fluoroacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that benzoylcyanide was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-propionylbenzonitrile was used.
  • N-2-adamantyl-morpholine-2-carboxyamide hydrochloride (382 mg, 1.27 mmol) and 5-(bromomethyl)picolinonitrile (500 mg, 2.54 mmol) were dissolved in DMF (10 ml), added with K 2 CO 3 (526 mg, 3.81 mmol) and KI (632 mg, 3.81 mmol), and stirred at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by H 2 O and CH 2 Cl 2 , and dried and filtered with MgSO 4 .
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-chloroacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-bromo-3-pyridine acetone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-bromo-3-pyridine acetone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 2-methoxy-3-pyridine aldehyde was used.
  • Methyl 2-(4-benzylmorpholine-2-yl)acetate (500 mg, 2.00 mmol) was dissolved in 70% MeOH aqueous solution (10 ml), added with KOH (189 mg, 3.37 mmol), and stirred for 12 hours at room temperature.
  • the resultant product was added with 2N HCl so that its acidity can be adjusted to pH 7.
  • vacuum distillation was carried out in such a manner that only 1ml of water remained.
  • N-(adamantane-2-yl)-2-(4-benzylmorpholine-2-yl)acetamide (500 mg, 1.56 mmol) was dissolved in EtOH (10 ml), and added with 10 % Pd/C (50mg). The resultant mixture was stirred under a hydrogen atmosphere for 12 hours, and filtered through celite to remove 10 % Pd/C. Then, N-(adamantane-2-yl)-2-(morpholine-2-yl)acetamide (347.4 mg, 1.25 mmol, 80 %) was obtained.
  • N-2-adamantyl-2-(morpholine-2-yl)acetamide 50 mg, 0.18 mmol
  • 3,4-difluorobenzaldehyde 25 mg, 0.18 mmol
  • DCE dimethyl methoxyethyl
  • acetic acid 21 mg, 0.36 mmol
  • sodium triacetoxy borohydride 76 mg, 0.36 mmol was added thereto, followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by H 2 O and CH 2 Cl 2 , and dried and filtered with MgSO 4 .
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-pyridinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that cyclohexanecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-nitrobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-methylbenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-cyanobenzaldehyde was used.
  • Methyl isobutyrate (500 mg, 4.9 mmol) was dissolved in THF (10 ml), and slowly added with 2M LDA (2.95 ml, 5.9 mmol) at -78°C. The temperature of the mixture was raised to 0°C, and then after 30-min stirring, it was lowered to -78°C. The resultant mixture was slowly added with N-Boc-2-aminoacetealdehyde (936 mg, 5.9 mmol) dissolved in THF (5 ml). The mixture was stirred at -78°C for 3 hours, and the reaction was terminated through addition of H 2 O. Then, the temperature was slowly raised to room temperature.
  • the resultant mixture was extracted (X3) with CH 2 Cl 2 , and dried and filtered with MgSO 4 . After the solvent was removed by vacuum distillation, the mixture was purified by column chromatography so as to provide methyl 4-(t-butoxycarbonyl)amino)-3-hydroxy-2,2-dimethylbutanoate compound (768 mg, 2.94 mmol, 60 %).
  • Methyl 4-amino-3-hydroxy-2,2-dimethylbutanoate hydrochloride compound (106.7 mg, 0.54 mmol) was dissolved in CH 2 Cl 2 (4 ml), and added with 2-nitrobenzenesulfonyl chloride (119.7 mg, 0.54 mmol) and triethylamine (120.2 mg, 1.19 mmol), followed by stirring at room temperature for 3 hours.
  • the resultant solution was added with H 2 O, extracted (X3) with CH 2 Cl 2 , and dried and filtered with MgSO 4 .
  • Methyl 3-hydroxy-2,2-dimethyl-4-(2-nitrophenylsulfonamido)butanoate (520 mg, 1.50 mmol) was dissolved in DMF (10 ml), and added with K 2 CO 3 (415 mg, 3.00 mmol) and 1,2-dichloroethane (1.3 ml, 0.1.5 mmol), followed by stirring at room temperature for 12 hours. Then, the resultant mixture was cooled to 0°C, and added with 60% NaH (158 mg, 3.00 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H 2 O, extracted (X3) with CH 2 Cl 2 , and dried and filtered with MgSO 4 .
  • Methyl 2-methyl-2-(4-((2-nitrophenyl)sulfonyl)morpholine-2-yl)propanoate 141.5 mg, 0.38 mmol was dissolved in THF (3 ml) and MeOH (3 ml), and added with LiOH (84.5 mg, 2.0 mmol) dissolved in H 2 O (1 ml), followed by stirring at room temperature for 12 hours.
  • the resultant solution was concentrated through vacuum distillation, acidified by the addition of 2 N -HCl aqueous solution to pH 2, and extracted with CH 2 Cl 2 .
  • the organic layer was dried and filtered with MgSO 4 .
  • N-(adamantane-2-yl)-2-methyl-2-(4-((2-nitrophenyl)sulfonyl)morpholine-2-yl)propanamide (380 mg, 0.77 mmol) was dissolved in DMF (15 ml), and added with K 2 CO 3 (213 mg, 1.54 mmol) and benzenethiol (238 ul, 2.32 mmol), followed by stirring at room temperature for 12 hours. The resultant solution was added with H 2 O, extracted (X3) with CH 2 Cl 2 , and dried and filtered with MgSO 4 .
  • N-2-adamantyl-2-methyl-2-(morpholine-2-yl)propanamide hydro chloride 50 mg, 0.18 mmol
  • 4-cyanobenzaldehyde(40 mg, 0.3 mmol) were dissolved in DCE (1 ml), and added with acetic acid (36 mg, 0.6 mmol), followed by stirring at room temperature for 10 minutes.
  • the resultant mixture was added with sodium triacetoxy borohydride (127 mg, 0.6 mmol), and stirred at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by H 2 O and CH 2 Cl 2 , and dried and filtered with MgSO 4 .
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • N-(adamantane-2-yl)-4-benzylmorpholine-2-carboxamide 500 mg, 1.41 mmol was dissolved in EtOH (10 ml), and added with 10 % Pd/C (50mg). The resultant mixture was stirred under a hydrogen atmosphere for 12 hours, and filtered through celite to remove 10 % Pd/C. Then, N-(adamantane-2-yl)morpholine-2-carboxamide (279.7 mg, 1.25 mmol, 75 %) was obtained.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-cyanobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that cyclohexanecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-bromobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-naphthaaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-morpholinobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 6-methoxy-2-naphthabenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-methylbenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-(methylthio)benzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-methylbenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 6-methyl-2-pyritincarboxyaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-(trifluoromethyl)benzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-(trifluoromethyl)benzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that biphenyl-4-carboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that methyl 4-formylbenzoate was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 7 in Example 2 except that methyl 4-formylbenzoate was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 1H-indole-5-carboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2,3-dihydrobenzo[b][1,4]dioxine-6-carboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-fluoro-3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-bromo-3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 5-bromo-3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-bromo-3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-trifluoromethyl-3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 1H-pyrrole-2-carboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 6-methoxypicolinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-methoxy-3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 1-methyl-1H-pyrrole-2-carboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-bromoisonicotinaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-methyl-3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-cyanobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4,6-dichloropyrimidine-5-carboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-methylpicolinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-cyanobenzaldehyde was used.
  • N-2-adamantyl-4-(3-chlorobenzyl)morpholine-2-carboxyamide 100 mg, 0.25 mmol was dissolved in DCM (30 ml), and added with 1,4-dioxane (11 mg, 0.3 mmol) including 4M HCl dissolved therein, followed by stirring at room temperature for 4 hours. After the reaction was completed, the solid was caught by DCM and EA. Then, through filtering, N-2-adamantyl-4-(3-chlorobenzyl)morpholine-2-carboxyamide hydrochloride (109 mg, 0.16 mmol, 82%) was obtained.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-chloro-3-pyridinecarboaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3,4-difluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-nitrobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-trifluoromethoxybenzaldehyde was used.
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • 4-benzylmorpholine-2-carboxylic acid hydrochloride (162.0 mg, 0.63 mmol) was dissolved in CH 2 Cl 2 (5 ml), added with EDCI (121 mg, 0.63 mmol) and DMAP (154 mg, 1.26 mmol), and stirred for 30 minutes. The resultant mixture was added with cyclohexaneamine (86 ul, 0.75 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H 2 O, extracted (X3) with CH 2 Cl 2 , and dried and filtered with MgSO 4 . Through vacuum distillation, the solvent was removed. The resultant mixture was purified by column chromatography so as to provide 4-benzyl-N-cyclohexylmorpholine-2-carboxamide (172.4 mg, 0.57 mmol, 90 %).
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 3-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 2-fluorobenzaldehyde was used.
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • the resultant mixture was purified by column chromatography so as to provide (4-benzylmorpholine-2-yl)(3-hydroxy-8-azabicyclo[3.2.1]ontane-8-yl)methanone (152.0 mg, 0.46 mmol, 73 %).
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 3 except that 4-cyanobenzaldehyde was used.
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 7 except that 1-adamantylamine-3-ol was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 7 except that 2-adamantylamine-5-ol was used.
  • N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide 120 mg, 0.33 mmol was dissolved in EtOH (1 ml), added with 5% Pd/C (24 mg), and stirred at room temperature for 12 hours under a H 2 (g) atmosphere. After the reaction was completed, the resultant product was subjected to celite filtration, and concentration so as to provide N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide mixture (50 mg, 0.18 mmol, 54 %).
  • N-[5-(alcohol)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide (50 mg, 0.18 mmol) and 4-cyanobenzaldehyde (24 mg, 0.18 mmol) were dissolved in dichloroethane (1 ml), and added with acetic acid (21 mg, 0.36 mmol), followed by stirring at room temperature for 10 minutes.
  • the resultant mixture was added with sodium triacetoxy borohydride (76 mg, 0.36 mmol), followed by stirring at room temperature for 12 hours. After the reaction was completed, the organic layer was separated by CH 2 Cl 2 and H 2 O, and dried and filtered with MgSO 4 .
  • Methyl 2-(4-belzylmorpholine-2-yl)acetate (500 mg, 2.00 mmol) was dissolved in 70% MeOH aqueous solution (10 ml), and added with KOH (189 mg, 3.37 mmol), followed by stirring for 12 hours at room temperature. The resultant mixture was added with 2N HCl so that its acidity can be adjusted to pH 7. Then, vacuum distillation was carried out in such a manner that only 1ml of water remained.
  • N-(adamantane-2-yl)-2-(4-benzylmorpholine-2-yl)acetamide (500 mg, 1.56 mmol) was dissolved in EtOH (10 ml), and added with 10 % Pd/C (50mg). The resultant mixture was stirred under a hydrogen atmosphere for 12 hours, and filtered through celite to remove 10 % Pd/C. Then, N-(adamantane-2-yl)-2-(morpholine-2-yl)acetamide (347.4 mg, 1.25 mmol, 80 %) was obtained.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 2 except that ethyl 2-bromo-2-methylpropanoate was used.
  • N-2-adamantyl-2-(morpholine-2-yl)acetamide 100 mg, 0.36 mmol
  • ethyl 2-bromo-2-phenylacetate 216 mg, 1.08 mmol
  • K 2 CO 3 149 mg, 1.08 mmol
  • KI 180 mg, 1.08 mmol
  • a desired compound was obtained in the same manner as described in Preparation Example 7 in Example 2 except that ethyl 2-bromo-2-methylpropanoate was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 13 in Example 2 except that 4-cyanoacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 7 in Example 2 except that 4-pyridineacetophenone was used.
  • Ethyl 4-benzyl-5-methylmorpholine-2-carboxylate (500 mg, 1.9 mmol) was dissolved in THF (3 ml) and MeOH (3 ml), and added with LiOH (399 mg, 9.5 mmol) dissolved in H 2 O (3 ml), followed by stirring at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2 N -HCl to pH 2, and extracted with EA. The organic layer was dried and filtered with MgSO 4 , and concentrated so as to provide 4-benzyl-5-methylmorpholine-2-carboxylic acid mixture.
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • 4-oxo-adamantane-1-carboxyacid (10 g, 51.5 mmol) was dissolved in 7 N NH 3 in MeOH (50 ml), and added with 10% Pd/C (1 g, 10%), followed by stirring under a hydrogen gas atmosphere for 12 hours. After the reaction was completed, the resultant product was added with H 2 O and filtered so as to provide 4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).
  • N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (100 mg, 0.24 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), and then was added with LiOH (50 mg, 1.2 mmol) dissolved in H 2 O (1 ml), and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2 N -HCl to pH 5, and extracted with EA.
  • N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide 70 mg, 0.176 mmol was dissolved in CH 2 Cl 2 (2 ml), and added with EDCI (68 mg, 0.35 mmol) and HOBt (46 mg, 0.26 mmol), followed by stirring. Then, an ammonium hydroxide solution (1.88 ml) was added thereto, followed by stirring at room temperature for 5 hours. After the reaction was completed, the organic layer was separated by CH 2 Cl 2 and H 2 O, and dried and filtered with MgSO 4 .
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • 4-oxo-adamantane-1-carboxyacid (10 g, 51.5 mmol) was dissolved in 7 N NH 3 in MeOH (50 ml), and added with 10% Pd/C (1 g, 10%), followed by stirring under a hydrogen gas atmosphere for 12 hours. After the reaction was completed, the resultant product was added with H 2 O and filtered so as to provide 4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).
  • N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide 200 mg, 0.49 mmol was dissolved in EtOH (10 ml), added with 5% Pd/C (40 mg), and stirred at room temperature for 5 hours under a H 2 (g) atmosphere. After the reaction was completed, the resultant product was subjected to celite filtration, and concentration so as to provide N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide mixture(100 mg, 0.31 mmol, 63 %).
  • N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide 100 mg, 0.31 mmol
  • 4-cyanobenzaldehyde 41 mg, 0.31 mmol
  • acetic acid 37 mg, 0.62 mmol
  • sodium triacetoxy borohydride 131 mg, 0.62 mmol was added thereto, followed by stirring at room temperature for 12 hours.
  • the organic layer was separated by H 2 O and CH 2 Cl 2 , and dried and filtered with MgSO 4 .
  • N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (40 mg, 0.09 mmol) was dissolved in THF (1 ml) and MeOH (1 ml), added with LiOH (11 mg, 0.27 mmol) dissolved in H 2 O (1 ml) and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2 N -HCl to pH 5, and extracted with EA.
  • N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-cyanobenzyl)morpholine-2-carboxyamide (20 mg, 0.047 mmol) was dissolved in CH 2 Cl 2 (1 ml), and added with EDCI (18 mg, 0.094 mmol) and HOBt (11 mg, 0.071 mmol), followed by stirring. The resultant mixture was added with ammonium hydroxide solution (0.6 ml), followed by stirring at room temperature for 5 hours.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 4-chloro-3-pyridinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-chloro-3-pyridinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-fluoro-4cyanobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-bromo-4-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-bromo-3-pyridinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 5-methoxy-6-pyridinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 5-methoxy-6-pyridinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 3-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 4-methoxybenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-methoxybenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 5-methyl-6pyridinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-chlorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-chloro-4-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-methylbenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 4-nitrobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 4-nitrobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 13 except that 4-pyridinealdehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-nitrobenzaldehyde was used.
  • N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-nitrobenzyl)morpholine-2-carboxyamide (40 mg 0.09 mmol) was dissolved in ethanol (3 ml), added with, Pd/C 5% (12 mg, 30%), and stirred under a hydrogen gas atmosphere. After the reaction was completed, the resultant product was subjected to filtration, and concentration so as to provide N-[5-(aminocarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(2-aminobenzyl)morpholine-2-carboxyamide (30 mg, 0.07 mmol, 81%).
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that isoquinoline-5-aldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-trifluoromethylbenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2,4,6-trifluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-methylbenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-fluorobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-cyanobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2-fluoro-4-bromobenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-bromo-4-hydroxybenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 2,4,6-trimethylbenzaldehyde was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 2 in Example 13 except that 3-fluorobenzaldehyde was used.
  • 4-benzylmorpholine-2-carbonitrile (64.1 g, 316.9 mmol) was dissolved in 6N HCl aqueous solution (600 mL), refluxed for 2.5 hours, and cooled to -10°C. The produced solid was filtered, and washed with acetone (300 ml, cooled to -10°C). The resultant solid compound was dried in a 60°C oven so as to provide 4-benzylmorpholine-2-carboxylic acid hydrochloride compound (78.7 g, 305.4 mmol, 96 %).
  • 4-oxo-adamantane-1-carboxyacid (10 g, 51.5 mmol) was dissolved in 7 N NH 3 in MeOH (50 ml), and added with 10% Pd/C (1 g, 10%), followed by stirring under a hydrogen gas atmosphere for 12 hours. After the reaction was completed, the resultant product was added with H 2 O and filtered so as to provide 4-amino-adamantane-1-carboxyacid (8.17 g, 41.8 mmol, 81%).
  • N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide 200 mg, 0.49 mmol was dissolved in EtOH (10 ml), added with 5% Pd/C (40 mg), and stirred at room temperature for 5 hours under a H 2 (g) atmosphere. After the reaction was completed, the resultant product was subjected to celite filtration, and concentration so as to provide N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide mixture(100 mg, 0.31 mmol, 63 %).
  • N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]morpholine-2-carboxamide 300 mg, 0.836 mmol
  • (1-chloroethyl)benzene 235 mg, 1.672 mmol
  • K 2 CO 3 347 mg, 2.508 mmol
  • KI 416 mg, 2.508 mmol
  • N-[5-(methoxycarbonyl)tricyclo[3,3,1,13,7]dec-2-yl]-4-(1-phenylethyl)morpholine-2-carboxyamide (520 mg, 1.22 mmol) was dissolved in THF (5 ml) and MeOH (5 ml), added with LiOH (256 mg, 6.1 mmol) dissolved in H 2 O (5 ml), and stirred at room temperature for 4 hours. After the reaction was completed, the solvent was concentrated. The resultant product was acidified by the addition of 2 N -HCl to pH 5, and extracted with EA.
  • N-[5-(carboxylic acid)tricyclo[3,3,1,13,7]dec-2-yl]-4-(4-benzyl)morpholine-2-carboxyamide (542 mg, 1.31 mmol) was dissolved in CH 2 Cl 2 (15 ml), and added with EDCI (502 mg, 2.62 mmol) and HOBt (401 mg, 2.62 mmol), followed by stirring. The resultant mixture was added with ammonium hydroxide solution (6 ml), followed by stirring at room temperature for 4 hours. After the reaction was completed, the organic layer was separated by CH 2 Cl 2 and H 2 O, and dried and filtered with MgSO 4 .
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 4-cyanoacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 4-trifluoromethoxyacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 4-trifluoromethylacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 2-methylacetophenone was used.
  • a desired compound was obtained in the same manner as described in Preparation Example 1 in Example 14 except that 2-methylacetophenone was used.

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Abstract

La présente invention concerne un composé inédit, ou un stéréo-isomère, ou un sel pharmaceutiquement acceptable de celui-ci et une composition pharmaceutique capable d'inhiber la 11-bêta-hydroxystéroïde déshydrogénase de type 1 (11β-HSD1) humaine en contenant. L'invention concerne un composé présentant une activité et une solubilité remarquables et pouvant être très efficacement formulé et administré, ainsi qu'une composition pharmaceutique capable d'inhiber la 11-bêta-hydroxystéroïde déshydrogénase de type 1 humaine en contenant.
PCT/KR2012/002100 2011-03-23 2012-03-23 Composé capable d'inhiber la 11-bêta-hydroxystéroïde déshydrogénase de type 1 humaine et composition pharmaceutique en contenant WO2012128582A2 (fr)

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KR20110025920 2011-03-23
KR10-2011-0025920 2011-03-23
KR10-2011-0025926 2011-03-23
KR1020110025926A KR20120108999A (ko) 2011-03-23 2011-03-23 인간 11-베타-히드록시스테로이드 탈수소효소 타입 1을 억제하는 화합물 및 이를 포함하는 약학조성물
KR1020120020455A KR20120109297A (ko) 2011-03-23 2012-02-28 인간 11-베타-히드록시스테로이드 탈수소효소 타입 1을 억제하는 화합물 및 이를 포함하는 약학조성물
KR10-2012-0020455 2012-02-28

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US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10000477B2 (en) 2014-10-31 2018-06-19 Indivior Uk Limited Dopamine D3 receptor antagonist compounds
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
WO2020079042A1 (fr) * 2018-10-17 2020-04-23 Boehringer Ingelheim International Gmbh Dérivés de 4-pyridinylméthyl-morpholine et leur utilisation comme médicament
JP2022505082A (ja) * 2018-10-17 2022-01-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４－ピリミジン－５－イルメチル－モルホリン誘導体および医薬としてのその使用
JP2022505080A (ja) * 2018-10-17 2022-01-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４－ピラジン－２－イルメチル－モルホリン誘導体および医薬としてのその使用
CN114276280A (zh) * 2021-10-30 2022-04-05 苏州汉酶生物技术有限公司 一种手性苯丁胺醇磺酰胺类化合物的制备方法、制备其的中间体及制备方法
WO2022263820A1 (fr) * 2021-06-15 2022-12-22 Z Factor Limited COMPOSÉS ET LEUR UTILISATION DANS LE TRAITEMENT D'UNE DÉFICIENCE EN α1-ANTITRYPSINE

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Cited By (18)

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Publication number Priority date Publication date Assignee Title
US10087174B2 (en) 2013-10-14 2018-10-02 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
USRE47193E1 (en) 2013-10-14 2019-01-08 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US9663486B2 (en) 2013-10-14 2017-05-30 Eisai R&D Management Co., Ltd. Selectively substituted quinoline compounds
US10654842B2 (en) 2014-10-31 2020-05-19 Indivior Uk Limited Dopamine D3 receptor antagonist compounds
US10000477B2 (en) 2014-10-31 2018-06-19 Indivior Uk Limited Dopamine D3 receptor antagonist compounds
US10239870B2 (en) 2014-10-31 2019-03-26 Indivior Uk Limited Dopamine D3 receptor antagonists
JP2022505082A (ja) * 2018-10-17 2022-01-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４－ピリミジン－５－イルメチル－モルホリン誘導体および医薬としてのその使用
CN112867508A (zh) * 2018-10-17 2021-05-28 勃林格殷格翰国际有限公司 4-吡啶基甲基-吗啉衍生物及其作为药物的用途
WO2020079042A1 (fr) * 2018-10-17 2020-04-23 Boehringer Ingelheim International Gmbh Dérivés de 4-pyridinylméthyl-morpholine et leur utilisation comme médicament
JP2022505080A (ja) * 2018-10-17 2022-01-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４－ピラジン－２－イルメチル－モルホリン誘導体および医薬としてのその使用
JP2022505081A (ja) * 2018-10-17 2022-01-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４－ピリジニルメチル－モルホリン誘導体および医薬としてのその使用
JP7093469B2 (ja) 2018-10-17 2022-06-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４－ピリジニルメチル－モルホリン誘導体および医薬としてのその使用
JP7093468B2 (ja) 2018-10-17 2022-06-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４－ピラジン－２－イルメチル－モルホリン誘導体および医薬としてのその使用
JP7093470B2 (ja) 2018-10-17 2022-06-29 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ４－ピリミジン－５－イルメチル－モルホリン誘導体および医薬としてのその使用
CN112867508B (zh) * 2018-10-17 2023-09-15 勃林格殷格翰国际有限公司 4-吡啶基甲基-吗啉衍生物及其作为药物的用途
WO2022263820A1 (fr) * 2021-06-15 2022-12-22 Z Factor Limited COMPOSÉS ET LEUR UTILISATION DANS LE TRAITEMENT D'UNE DÉFICIENCE EN α1-ANTITRYPSINE
CN114276280A (zh) * 2021-10-30 2022-04-05 苏州汉酶生物技术有限公司 一种手性苯丁胺醇磺酰胺类化合物的制备方法、制备其的中间体及制备方法
CN114276280B (zh) * 2021-10-30 2023-10-31 苏州汉酶生物技术有限公司 一种手性苯丁胺醇磺酰胺类化合物的制备方法、制备其的中间体及制备方法

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