WO2013146969A1 - Novel disubstituted cyclohexane derivative - Google Patents

Novel disubstituted cyclohexane derivative

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WO2013146969A1
WO2013146969A1 PCT/JP2013/059169 JP2013059169W WO2013146969A1 WO 2013146969 A1 WO2013146969 A1 WO 2013146969A1 JP 2013059169 W JP2013059169 W JP 2013059169W WO 2013146969 A1 WO2013146969 A1 WO 2013146969A1
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PCT/JP2013/059169
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French (fr)
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勝浩 川上
俊宏 木方
厚 天花寺
清水 弘樹
佐藤 厚
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第一三共株式会社
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems

Abstract

Provided are: compounds having a preventive or therapeutic effect against chronic rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, dermatitis, including psoriasis, etc.; a pharmaceutical composition containing said compounds; and a method for preventing or treating inflammatory diseases, characterized in that an effective dose of the pharmaceutical composition is administered to mammals. The present invention involves the compounds represented by general formula (I) or pharmaceutically acceptable salts thereof.

Description

New di-substituted cyclohexane derivatives

The present invention is a quinoline derivative having anti-inflammatory action, a salt thereof or prostaglandin E 2 production inhibitor containing a solvate thereof.

Phospholipase A 2 by liberated from the cell membrane phospholipids arachidonic acid (AA), but it is prostaglandin G 2 prostaglandin H 2 via a (PGG 2) (PGH 2) is synthesized by cyclooxygenase (COX). The PGH 2 prostaglandin D 2 by the respective converting enzyme (PGD 2), prostaglandin E 2 (PGE 2), prostaglandin F 2α (PGF 2α), prostaglandin I 2 (PGI 2) and thromboxane by being converted into hexane a 2 (TXA 2), prostanoids are produced.

Among them, PGE 2, which is thought to prostanoid most abundant in vivo, hyperalgesia, fever, vascular smooth muscle relaxation, gastric acid secretion inhibiting, bronchial smooth muscle relaxation, uterine contractions, versatile from central over peripheral it is known to have physiological activity. Also the biological activity of other prostanoids not only PGE 2 are being elucidated, these are to play an important role in maintaining homeostasis of a living body, while the formation of a variety of pathological conditions, the progress and duration It is thought to be deeply involved.

The COX there are two isozymes of COX-1 and COX-2. Currently, non-steroidal anti-inflammatory drugs which are used as a typical anti-inflammatory agents (NSAIDs) inhibit both COX-1 and COX-2. Since NSAIDs are inhibiting the production of prostanoids from COX-1 which is involved in gastrointestinal protective action, to elicit a gastrointestinal disorder frequently is a problem (Non-Patent Document 1).
Moreover, COX-2 inhibitors showing a selective inhibitory effect on COX-2 that is expressed induced by inflammatory stimuli includes but side effects gastrointestinal disorder is small drug, the risk of cardiovascular events encountered a problem going on. While COX-2 selective inhibitors suppress production of PGI 2 from COX-2, which plays a role in platelet aggregation inhibition and cardioprotection, production of TXA 2 from COX-1 with an opposing effects in the coagulation system it does not inhibit is considered one of the causes (non-patent document 2).

Conventionally, in the treatment of such inflammatory diseases, anti-inflammatory drugs have been used, such as steroids, the expression of their side effects are a problem as symptomatic. Moreover, although non-steroidal anti-inflammatory drugs and the development of new NSAIDs underway in order to avoid such side effects, suffer from still of side effects as described above, development of a fundamental treatment is desired ing.

Against this background, less side effects, it has been attempted to find a compound having excellent anti-inflammatory action. So far, as a background art of the present invention it is known literature shown below.

WO2006 / 063466 WO2007 / 134434 WO2011 / 023812 WO2007 / 042816 WO2008 / 071944 WO2010 / 034796 WO2012 / 022793 WO2010 / 132016 WO2011 / 077313 WO2011 / 131975

.. Jackson LM, Wu KC, Mahida YR, Jenkins D, Hawkey CJ Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa Gut 2000 Dec; 47 (6):.. 762-70 Colin D. .. Funk, Garret A. FitzGerald COX -2 Inhibitors and cardiovascular risk J Cardiovasc Pharmacol 2007; 50:. 470-479.

The present inventors, with respect to novel compounds having anti-inflammatory effects side effects and excellent small, a result of intensive studies for many years, rheumatoid arthritis, osteoarthritis, arthritis associated inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis, including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, nerve, such as diabetic neuralgia neuropathic pain, tumor formation in pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, pain associated with cancer metastasis or familial adenomatous polyposis, colorectal cancer, ovarian epithelial cancer, breast cancer, stomach, strength scleroderma, atherosclerosis, and myocardial infarction associated therewith, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, multiple sex Sclerosis, or found a novel compound useful for Alzheimer's disease or the like, and completed the present invention.

Accordingly, an object of the present invention, novel compounds having anti-inflammatory effects side effects and excellent small, is to provide a pharmacologically acceptable salt thereof.

That is, the present invention is,
(1) compound or pharmacologically acceptable salt thereof represented by the general formula (I).

Figure JPOXMLDOC01-appb-C000002

{Wherein, R 1, R 2, R 3, and R 4 are each independently a hydrogen atom, a halogen atom, a cyano group, C 1 -C 6 optionally substituted by an alkoxy group C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 alkyl optionally ethynyl group optionally substituted with a group, or a phenyl group,
X 1 and X 2 represents a carbon atom or a nitrogen atom,
Y is optionally substituted with 1 to 3 groups selected from Substituent group alpha C 1 -C 6 alkyl group, C 1 -C 6 alkyl optionally substituted by a carboxy group with a group, or a C optionally substituted by 1 -C 6 alkyl group represents a carbamoyl group,
n is 0 or 1,
(I) when n is 0:
Ring A form a heterocyclic ring of unsaturated 5-membered X 1 and X 2 are adjacent, R 2 and R 4, together with the carbon atom or nitrogen atom of the ring to which they are attached, may form a hydrocarbon ring or heterocyclic ring of 5 to 6 membered saturated or unsaturated, hydrocarbon ring or heterocyclic ring formed is optionally substituted with a group selected from substituent group β it may be.
(Ii) when n is 1:
Ring A to form a hydrocarbon ring or heterocyclic ring 6 membered unsaturated, R 3 and R 4, together with the carbon atom or nitrogen atom of the ring to which they are attached, a saturated or unsaturated it may form a hydrocarbon ring or heterocyclic ring of 5-membered to 6-membered, hydrocarbon ring or heterocyclic ring formed may be substituted with a group selected from the substituent group beta.
Substituent group α represents a hydroxyl, C 1 -C 6 alkyl group, C 1 -C 6 alkyl group optionally substituted carboxyl group, and C 1 -C 6 alkyl carbamoyl group which may be substituted with a group representing the.
Substituent group β represents a halogen atom, and 1 to 3 halogen atoms which may be substituted C 1 -C 6 alkyl group. },
Preferably,
(2) X 2 X 1 is a carbon atom is a carbon atom, a compound or a pharmacologically acceptable salt thereof according to (1),
(3) n is 1, any one compound or a pharmacologically acceptable salt thereof according to the above (1) to (2),
(4) salt ring A, which is a heterocycle of 6-membered unsaturated, compound or a pharmacologically acceptable according to any one of the above (1) to (3),
(5) R 3, ring carbon atom or a nitrogen atom of the ring R 4 and they are attached to form together is, furan ring, dihydrofuran ring, thiophene ring, pyrrole ring, pyridine ring, or a benzene is a ring compound or a pharmacologically acceptable salt thereof according to any one of the above (1) to (4),
(6) a compound having the general formula (I) is a compound selected from the following group of compounds, the (1) compound or a pharmacologically acceptable salt thereof according,
N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-ethyl-6-methoxy-3-phenyl-2-yl) piperidine-4-carboxamide,
N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenyl--1H- pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxamide ,
1- (3-chloro-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) -N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide ,
N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide,
2-methyl-2- [cis-4 - ({[1- (6-methyl-3-phenyl-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoic acid,
N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide,
N - [(1S, 3S) -3- carbamoyl cyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide,
2-methyl-2- [cis-4 - ({[1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propane acid, N - [(1S, 3S) -3- carbamoyl cyclohexyl] -1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine - 4-carboxamide, and,
N - [(1S, 3S) -3- carbamoyl cyclohexyl] -1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide (7) In formula (I ) compounds or a pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient having,
(8) prostaglandin E for use to prevent or treat diseases mediated by 2, the pharmaceutical composition described in the above (7),
(9) diseases mediated by prostaglandin E 2 are, rheumatoid arthritis, osteoarthritis, arthritis associated inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis, including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, dysmenorrhea, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, self tumorigenesis pain, colorectal cancer, ovarian carcinoma, breast cancer, in the stomach associated with autoimmune hepatitis, gallstone pain, cancer metastasis or familial adenomatous polyposis, scleroderma, atherosclerosis, and myocardial infarction associated therewith, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, multiple sclerosis, or Alzheimer's disease, the above (8) It is described Pharmaceutical compositions,
(10) diseases mediated by prostaglandin E 2 are, rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis or psoriasis, the dermatitis containing pharmaceutical composition described above (8) to (9), or,
(11) In formula, characterized in that an effective amount of a compound or a pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient has a (I) is administered to a mammal, a method of preventing an inflammatory disease or Method of treatment,
It is.

Compound or a pharmacologically acceptable salt thereof of the present invention have anti-inflammatory effects side effects and excellent small, warm-blooded animals (especially a human) as a prophylactic agent or therapeutic agent for inflammatory diseases or other inflammatory-related diseases against it is useful.

The vertical axis shows the 2 production in inflamed tissue prostaglandin E. It shows the dose-dependent inhibitory effect of example compound 31.

When n is 0, heterocyclic unsaturated 5-membered X 1 and X 2 are adjacent, in particular, a pyrrole ring, a furan ring, or thiophene ring, preferably is a pyrrole ring .

When n is 0, it is formed together with the carbon atom or nitrogen atom of the ring to which they are attached and R 2 and R 4, hydrocarbon ring or heterocyclic 5- to 6-membered saturated or unsaturated ring, specifically, benzene ring, pyridine ring and the like.

When n is 0, X 1 is nitrogen atom, X 2 is preferably a carbon atom, together with the carbon atom or nitrogen atom of the ring to which they are attached and R 2 and R 4 turned in, it is preferable to take the ring structure 6 membered.

When n is 1, specifically, a pyridine ring, a pyrazine ring, or a pyridazine ring, Ring A is X 1 and X 2 are both carbon atoms, a pyridine ring is preferable.

When n is 1, the ring R 3 and R 4 form together with the carbon atom or nitrogen atom of the ring to which they are attached, specifically, a furan ring, thiophene ring, pyrrole ring, or there may be mentioned dihydrofuran ring, a furan ring or a pyrrole ring.

It will be described substituent groups herein below.

Halogen atom is specifically a fluorine atom, a chlorine atom, a bromine atom, or iodine atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

The C 1 -C 6 alkyl group may be a ring structure be branched be linear, containing from 1 to 6 carbon atoms in the chain, an aliphatic hydrocarbon group means. Branched, one or more lower alkyl groups (e.g., methyl group, ethyl group or a propyl group), means that are attached to a linear alkyl chain. Specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, tert- butyl group, a pentyl group, a hexyl group. Preferably, methyl group, ethyl group, propyl group, cyclopropyl group, an isopropyl group, or a tert- butyl group, more preferably a methyl group, an ethyl group, or a cyclopropyl group.

The C 1 -C 6 alkoxy group, the were C 1 -C 6 alkyl group is an oxygen atom bonded to, it means an alkyl -O group, containing from 1 to 6 carbon atoms in the chain. Preferably from 1 to 3 carbon atoms. Specific examples include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, include heptoxy and methyl hydroxy or the like, preferably a methoxy group, an ethoxy group, a propoxy group, or isopropoxy group, more preferably a methoxy group.

C 1 -C 6 optionally C 1 -C 6 alkyl group optionally substituted with an alkoxy group, specifically, methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxymethyl group, a 1-methoxyethyl group, 2-methoxyethyl group, 1-methoxypropyl group, 2-methoxypropyl, 3-methoxypropyl group, 1-methoxybutyl group, 2-methoxybutyl group, 3-methoxybutyl group, 4-methoxybutyl group, 1- methoxypentyl group, 2-methoxybutyl group, 3-methoxy-pentyl group, 4-methoxybutyl group, 5-methoxypentyl group, 1-methoxy-hexyl, 2-methoxy-hexyl group, 3-methoxy-hexyl group, 4-methoxy-hexyl group, a 5-methoxy-hexyl group, or a 6-methoxy hexyl, preferably a methyl group, an ethyl group, propyl Group, or an isopropyl group.

C 1 -C 6 alkyl optionally ethynyl group optionally substituted with a group, specifically, methyl ethynyl group, an ethyl ethynyl, propyl ethynyl group, an isopropyl ethynyl group, butyl ethynyl group, pentyl ethynyl group, or a hexyl ethynyl It can be mentioned groups, preferably a methyl ethynyl group, an ethyl ethynyl group, or a propyl ethynyl group, more preferably a methyl ethynyl group.

Suitably, R 1 is phenyl group, R 2 is hydrogen atom, R 3 is a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, a halogen group, a methyl ethynyl group, or a phenyl a group, R 4 is a cyano group, or a methoxy group.

n is preferably a 1, R 3 and R 4 are preferably taken together with the carbon atom or nitrogen atom of the ring to which they are attached, a 5- to 6-membered saturated or unsaturated to the form a hydrocarbon ring or a heterocyclic ring.

X 1 and X 2 are preferably, are both carbon atoms.

Ring R 3 and R 4 are formed by bonding is preferably a furan ring, dihydrofuran ring, thiophene ring, pyrrole ring, pyridine ring, or a benzene ring. Group substituting these rings is preferably a chlorine atom, a methyl group, dimethyl group, an ethyl group, or a trifluoromethyl group.

C 1 -C 6 alkyl optionally carboxy group optionally substituted with a group, specifically, a carboxy group, a methyl carboxylate group, an ethyl carboxy, propyl carboxy group, an isopropyl carboxy group, butyl carboxy group, pentyl carboxy group, or hexyl carboxy group, preferably a carboxy group, a methyl carboxylate group, or an ethyl carboxylate group.

1 to 3 good C 1 -C 6 alkyl group optionally substituted with a group selected from Substituent group α is preferably a hydroxymethyl group, a carbamoylmethyl group, ethyl carboxymethyl group, a carboxymethyl group, ethyl carboxy (dimethylamino) methyl group, a 1-carboxy-cyclopropyl group, or carboxy (dimethyl) methyl group.

C 1 -C 6 alkyl carbamoyl group which may be substituted with a group, specifically, carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, pentylcarbamoyl group, or hexylcarbamoyl group can be exemplified, preferably a carbamoyl group, methylcarbamoyl group or ethylcarbamoyl group.

Y is preferably a hydroxymethyl group, a carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, a methyl carboxylate group, ethyl carboxymethyl group, ethyl carboxy (dimethylamino) methyl group, a carbamoylmethyl group, a carboxymethyl group, or carboxy ( dimethyl) methyl group.

Examples of the compound having general formula (I), more preferably a compound described in Example.

"Treatment" means to suppress or symptoms to be or improved cure the disease or condition.

By "diseases mediated by prostaglandin E 2", but the onset of the disease is prostaglandin E 2 it is not limited particularly as long as it is believed to be involved, in particular, chronic rheumatoid arthritis, osteoarthritis, arthritis associated inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis, including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, menstrual dysmenorrhea, migraine headache, joint pain, post-herpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis, gallstone pain, to cancer metastasis or familial adenomatous polyposis pain associated with cancer, colorectal cancer, tumor formation in epithelial ovarian cancer, breast cancer, stomach, scleroderma, atherosclerosis, and myocardial infarction associated therewith, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive sex lung disease Sudden infant death syndrome, asthma, fever, inflammatory anorexia, and multiple sclerosis, or or Alzheimer's disease and the like. Preferably, the inflammatory disease, rheumatoid arthritis, osteoarthritis, arthritis associated inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis, including psoriasis, eczema, edema, inflammatory pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine headache, joint pain, post-herpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis, pain associated with gallstone pain, cancer metastasis or familial adenomatous polyposis, asthma, fever, or a compound of inflammatory anorexia present invention is applied, more preferably rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, or dermatitis psoriasis.

The "pharmacologically acceptable salt" refers to salts that can be used as a medicament. In the compounds of the present invention, when having an acidic group or basic group, by reacting with a base or acid, it is possible to the base salts or acid salts, indicating a salt thereof.

As "basic salt" pharmacologically acceptable compounds of the present invention is preferably sodium salts, potassium salts, alkali metal salts such as lithium salts; magnesium salts, alkaline earth metal salts such as calcium salts ; N- methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N- methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, organic base salts or glycine salts such as picoline salt, a lysine salt, arginine salt, ornithine salt, glutamate, an amino acid salt such as aspartate, preferably a alkali metal salt.

The "acid salt" pharmacologically acceptable compounds of the present invention, preferably, hydrofluoride, hydrochloride, hydrobromide, hydrohalide such as hydriodic acid salt, nitrate, perchlorate, sulfate, inorganic salts such as phosphates; methanesulfonate, trifluoromethanesulfonate, lower alkanesulfonates such as ethanesulfonic acid salts, benzenesulfonate, p- ants, such as toluene sulfonic acid salt - Rusuruhon, acetate, malate, fumarate - Le, succinate, citrate, ascorbate, tartrate, oxalate, organic or maleic acid salt salt; and, glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, an amino acid salt such as aspartate, most preferably a hydrohalic acid salt.

Compound or a pharmacologically acceptable salt thereof of the present invention, by the left or or recrystallization in air, absorb moisture, it may be or become or with adsorbed water and hydrates, the present invention encompasses hydrates of such various, also compounds of solvates and crystal polymorphs.

The compound of the present invention, a salt thereof or a solvate thereof, the type and combination of substituents, cis-isomer, geometric isomer trans body or the like, tautomers or d thereof, optical isomers and the like of the l and the like those various isomers can exist, compounds of the present invention, if not specifically limited to all isomers thereof, also encompasses these isomers and stereoisomeric mixture of the stereoisomers and any ratio is there. Mixtures of these isomers may be separated by known resolution means.

Compound represented by the general formula (I) of the present invention may also be in one or more of the atoms that constitute containing atomic isotopes ratio unnatural. The atomic isotopes such as deuterium (2 H), tritium (3 H), iodine-125, and the like (125 I) or carbon -14 (14 C). These compounds are useful in the treatment or prevention agents, research reagents, e.g., assay reagents, and diagnostic agents, for example, is useful as an in vivo diagnostic imaging agent. All isotopic variations of the compound represented by formula (I), regardless of whether it is radioactive, are included within the scope of the present invention.

Further, the present invention, pharmacologically acceptable prodrugs of the compounds of this invention are also encompassed.

The pharmacologically acceptable prodrug, by hydrolysis, or under physiological conditions, is a compound having an amino group, a hydroxyl group, may be converted into a carboxyl group or the like group of the compounds of the present invention, such pro Examples of the group for forming a drag, Prog. Med., Vol. 5, 2157-2161 page, and 1985, "development of pharmaceuticals" (Hirokawa Publishing Company, 1990) described in Volume 7, molecular design 163-198 page it is a group of. As the prodrugs, more specifically, the compounds of the present invention, when there is an amino group, acylation is the amino group, alkylation, phosphorylation compounds (e.g., the amino group is eicosanoylated , alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxy carbonylation, tetrahydrofuranyl reduction, 1,3-dioxolen-4-yl oxy methylation, tert- butylated compounds, etc.) and the like can be given, to the compounds of the present invention, when a hydroxyl group is present, the hydroxyl group is acylated, alkylated, phosphorylated, borated compounds (e.g., its hydroxyl groups acetylated, palmitoylated, propanoyl, pivaloyl, succinylated, fumaryl reduction, alanylated, dimethyl Le aminomethyl carbonylated compounds and the like.), And the like.

Further, the compounds of the present invention, when there is a carboxy group, the carboxy group is esterified, amidated compounds (e.g., the carboxy group with ethyl ester, phenyl ester, carboxymethyl ester, dimethyl aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, an amidation or methylamidated compounds and the like.) and the like.
(Production Method)
The example of the manufacturing method is described below relates to the general formula (I). Although the compounds of the present invention represented by the formula (I) are prepared by various methods, are described illustrates a typical preparation as preferred examples in the following equation, it is not limited thereto. Incidentally, carried protected with a protecting group substituents optionally is in the reaction, the conversion sequence of each substituent group (functional group) is not particularly limited. The compounds of the formula includes the case that forms a salt. When compounds of the formula are commercially available it can also be used as a commercial product.
(Production Method A)
Process A is a process for producing a substituted piperidine carboxylic acid (A21) which can be used as synthetic intermediates in the production of the compound represented by formula (I).

Figure JPOXMLDOC01-appb-C000003

[R 1 ~ R 4 and X 1 ~ X 2 in the formula is the same definition of the substituents of general formula (I). R 5 ~ R 8 represents a hydrogen atom, or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl group and the like. X 3 represents a carbon atom or a sulfur atom. Z 1 represents a hydrogen atom, a cyano group, an amino group, or an alkoxy group, Z 2 represents a hydrogen atom, a chlorine atom, or a nitro group. Z 3 and Z 4 represents a halogen atom (e.g., bromine atom, iodine atom). Z 5 represents a halogen atom (e.g., bromine atom, iodine atom), or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy group. P 1 represents a hydrogen atom or a protecting group of a carboxy group, as a specific protecting group methyl group, an ethyl group, a benzyl group, etc. tert- butyl group. ]
Step (A1) is a compound relative to (A1) and (A6), by performing a substitution reaction between Z 4 is reacted with a piperidine derivative, is a step for preparing a compound (A2) and (A4) . The solvent of the reaction is not particularly limited as long as the reaction proceeds, N- methylpyrrolidone, N, N- dimethylacetamide are preferred.

Step (A2) with respect to the substituent Z 3 in the compound (A2), the presence of a palladium catalyst, exerts a boronic acid or boronic ester and (Suzuki coupling loop ring) conditions, the action of tin compound (Stille coupling) conditions or palladium and copper catalysts presence, such as by the action of terminal alkynes (Sonogashira reaction) conditions is a step of introducing a substituent or substituents which is a precursor thereof corresponding to R 1, compound ( A3) it is a step for preparing a. Further, with respect to the substituent Z 2 in the compound (A5), a step of introducing a substituent or substituents which is a precursor thereof corresponding to Z 5 using similar conditions to produce the compound (A6) it is a process. A step of performing a modification of the deprotection and substituents of the protecting group in R 1 and Z 5 if necessary.

Examples of the Suzuki coupling loop ring, Journal of Organic Chemistry, 68, 20, 2003, 7733-7741, Journal of Organic Chemistry, 70, 6, 2005, 2191-2194, Journal of Organic Chemistry, 68, 24, 2003, 9412 -9415, Bioorganic Medicinal Chemistry, 18, 2, 2010, 707-718, Tetrahedron, 66, 49, 2010, 9552-9559, Synthetic Communications, 30, 19, 2000, 3501-3510, Chemistry A European Journal, 12, 19 it can be carried out according to the method described in 2006, 5142-5148 and the like.

Examples of Stille coupling, Angewandte Chemie, International Edition, 25, 6, 1986, 508-524, Tetrahedron Letters, 35, 19, 1994, 3195-3196, Synthesis, 1986, 7, The method according to 564-565, etc. it can be carried out in accordance with.

Examples of Sonogashira reaction, Chemical. Review, 107, 3, 2007, 874-922, Journal of Organic Chemistry, 68, 9, 2003, 3736-3738, Organic Letters, 2, 12, 2000, 1729-1731. Etc. it can be carried out according to the method described in.

Step (A3) if Z 2 is a hydrogen atom, is a step for preparing the introduced compound substituent Z 5 in the compound (A3) (A4). Compound in dichloromethane (A3), was halogenated by reaction with an electrophilic halide, and Suzuki coupling loop ring condition, Stille coupling conditions for applying a tin compound, corresponding to Z 5 due Sonogashira reaction conditions substituent or a step of introducing a substituent to be a precursor thereof, it is possible to use the same method as step (a-2). The electrophilic halide, such as N- bromosuccinimide, etc. N- iodo succinimide and the like.

Step (A4) is X 2 is a carbon atom, when Z 1 is a tert- butoxy group in dichloromethane for the compound (A4), a step of performing deprotection by the action of trifluoroacetic acid, compound (A7) is a step for preparing a.

Relative Step (A-5) The compound (A7), in dimethylformamide in the presence of a base, a step of performing alkylation by reaction with an alkyl halide, to produce compounds (A8). As the base, for example potassium carbonate, and sodium hydride. Examples of the halogenated alkyl, for example methyl iodide, allyl bromide, 3-bromo-2-methylpropene, and the like Kurochiruburomido.

If Step (A-6) is Z 5 is an iodine atom, with respect to the compound (A8), the presence of a palladium catalyst, a step of intramolecular cyclization by using a Heck reaction conditions, the compound (A9) and ( A10) is a step for preparing a. Examples of the Heck reaction, Chemical. Review, 100, 8, 2000, 3009-3066, Tetrahedron Letters, 45, 33, 2004, 6235-6237, Tetrahedron, 29, 37, 1988, 4687-4690, Tetrahedron Letters, 48, 13, 2007, can be carried out according to a method described in 2307-2310 like.
Step (A-7) is X 2 is a carbon atom, when Z 1 is an amino group of the compound (A4), a step of intramolecular cyclization, a process for producing the compound (A11). A step of performing a modification of the deprotection and substituents of the protecting group in R 5 when necessary.

Relative Step (A-8) The compound (A12), after the substitution reaction with Z 4 is reacted with a piperidine derivative, substituted for the group Z 3, substituents or a precursor corresponding to R 1 a step of introducing a substituent to be a body, a step of producing the compound (A11). A step of performing a modification of the deprotection and substituents of the protecting group in R 5 when necessary. Reaction with piperidine derivatives can be used similar to Step (A-1) method, conversion of the substituents Z 3 can be used in a similar manner as Step (A-2).

Figure JPOXMLDOC01-appb-C000004

[R 1 ~ R 4 and X 1 ~ X 2 in the formula is the same definition of the substituents of general formula (I). n is 1 or 2. X 3 is a nitrogen atom or a sulfur atom. R 7 is a hydrogen atom, a bromine atom, a methyl group, an ethyl group, or a vinyl group, R 8 is a trifluoromethyl group. ]
Relative Step (A-9) the compound (A13) and (A18), after the action of an acid anhydride, a step of adding a piperidine derivative, process for producing the compound (A14) and the (A19) it is. Addition reaction of piperidine derivatives can be used similar to Step (A-1) response.

Relative Step (A-10) The compound (A14), a step of producing a substituent or introduced compound substituent which is a precursor thereof corresponding to the substituent R 7 (A15), the step (A- 3) and can be used in a similar manner.

Step (A-11) is dichloromethane, the presence of a base, after reacting the compound (A16) to the compound (A17), a step of cyclization condensation, to produce compound (A18). It can be used microwave reactor as needed. As the base, for example triethylamine, and the like diisopropylethylamine.

Step (A-12) is a step of deprotecting the protecting group P 1 in the compound (A20), a step of producing the compound (A21). Compound (A20) is compounds in Process A shows a schematic of (A3, A4, A8, A9, A10, A11, A14, A15, A19), the compound (A21) is a schematic of a substituted piperidine carboxylic acid in Process A a representative. Although this reaction varies according to the kind of the protecting group P 1, for example, TW Greene and PG Wuts al, "Protective Groups in Organic Synthesis (third edition, 1999)" can be carried out according to the method described in.
(Production Method B)
Process B is a process for producing a substituted amine (B8) that can be used as synthetic intermediates in preparing compounds of formula (I).

Figure JPOXMLDOC01-appb-C000005

[P 1 are as defined above. X a represents an oxygen atom or NH, Y 1 represents a precursor or a substituent Y itself substituents Y. R 9 represents a hydrogen atom or an optionally substituted alkyl alkenyl, alkynyl, cycloalkyl group and the like. R 10, R 11 is a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, -CH 2 CH 2 - represents a group. ]
P 2 and P 3 represents a protecting group or hydrogen of an amino group, Boc group Specific protecting group (tert- butoxycarbonyl group), Cbz group (benzyloxycarbonyl group), benzylidene group, a diphenylmethylene group and the like and the like. P 2 is benzyl alkylidene group, in the case of diphenylmethylene group P 3 represents a P 2 the same protecting group. Each step comprises a step of performing deprotection of the protecting and protecting group substituents optionally.

Step (B1) compound with respect to (B1), the presence of a suitable condensing agent and a base, a step of condensing a compound having a compound or a hydroxyl group with an amino group, to produce a compound (B2) it is. Adding an additive to accelerate the reaction if necessary. As the condensing agent, for example, WSC (i.e., 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide), DCC (i.e., 1,3-dicyclohexylcarbodiimide), DMT-MM (i.e., 4- (4,6 - dimethoxy-1,3,5-triazin-2-yl) -4-methyl morpholinium chloride), CDI (i.e., 1,1'-carbonyldiimidazole), DEPC (i.e., diethyl phosphonate Russia Nido benzoate), DPPA (i.e., diphenyl phosphorodithioate azide benzoate) and the like. As the base, pyridine, aromatic amines or triethylamine etc. lutidine, diisopropylethylamine, DMAP (4-dimethylaminopyridine), and the like tertiary amines such as. Representative examples of additives, HOAt (3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol), HOBt (1H-benzotriazol-1-ol), HOSu (N - hydroxysuccinimide) and the like. The solvent of the reaction is not particularly limited as long as the reaction proceeds, dichloromethane, N, N-dimethylformamide is preferred.

Relative Step (B-2) The compound (B1), by the action of a suitable reducing agent, to produce compound (B3). In this case, it may be reacted directly reducing agent but, once may be reduced a suitable acylating agent after converted to an acid. Anhydride action. As the reducing agent, borane, and the like sodium borate hydrogen.

Step (B3) compound relative to (B3), after converting the hydroxyl group to a suitable leaving group, a step of substituting with the cyano group, to produce compound (B4). The leaving group, e.g. methylsulfonyloxy group, p- toluenesulfonyloxy group, and a halogen atom.

Step (B4) the compound against (B4), after hydrolysis under acidic conditions cyano group, a step of protecting the resulting carboxy group, to produce compound (B5). Optionally includes a step of protecting the amino group again. Although this reaction varies according to the kind of the protecting group P 1 ~ P 3, for example, TW Greene and PG Wuts al, "Protective Groups in Organic Synthesis (third edition, 1999)" be performed according to the method described in it can.

When the protecting group P 1 is ethyl group, and thionyl chloride is used in ethanol.

When the protecting group P 2 is Boc group, such as di -tert- butyl dicarbonate is used in the presence of a base. As the base, sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, such as triethylamine is used.

When the protecting group P 2 is a Cbz group, in the presence of a base, benzyl chloroformate or N- (benzyloxycarbonyl-oxy) succinimide are used. As the base, sodium hydroxide, potassium hydroxide, potassium hydrogen carbonate, such as triethylamine is used.

For protecting group P 2, P 3 is benzylidene group, the presence of anhydrous magnesium sulfate or sodium sulfate anhydride, benzaldehyde is used as a reactant. The solvent of the reaction is not particularly limited as long as the reaction proceeds, benzene, toluene, and dichloromethane.

When the protecting group P 2, P 3 is a diphenylmethylene group, benzophenone imine is used as a reactant. Bases can be used as needed. The solvent of the reaction is not particularly limited as long as the reaction proceeds, benzene, toluene, and dichloromethane.
Step (B5) of the compound relative to (B5), a step of performing stepwise alkylation is a process for preparing a compound (B6).

Relative Step (B-6) is compound (B7), the protecting group P 2 and P 3 is a step of deprotecting, to produce compound (B8). Compound (B7) represents the outline of the compounds in the production method B (B2, B5, B6), the compound (B8) represents a schematic of a substituted amine in the production method B. Although this reaction varies according to the kind of the protecting group P 2 and P 3, for example, TW Greene and PG Wuts al, "Protective Groups in Organic Synthesis (third edition, 1999)" be performed according to the method described in it can.

When the protecting group P 2 is Boc group, the reactant can be used dioxane or ethyl acetate solution of hydrochloric acid. If necessary, methanol, ethanol, may be added to tetrahydrofuran.

When the protecting group P 2 is a Cbz group and diphenylmethylene group, it can be used under a hydrogen atmosphere, palladium carbon or palladium hydroxide. The solvent of the reaction is not particularly limited as long as the reaction proceeds, methanol, ethanol, tetrahydrofuran is preferred.
When the protecting group P 2, P 3 is a benzylidene group, it can be used diluted hydrochloric acid. The solvent of the reaction is not particularly limited as long as the reaction proceeds, methanol, ethanol is preferred.
(Process C)
Process C is condensation of the compound obtained in Process A (A21) and substituted amine obtained in Process B (B8), is a step for preparing the desired compound of formula (I).

Figure JPOXMLDOC01-appb-C000006

[R 1 ~ R 4 in the formula, X 1 ~ X 2, Y 1 and Y are as defined above substituents. ]
Step (C1) is a compound relative to (A21), the presence of various condensing agent and a base, a step of producing the compound (C1) is reacted with a substituted amine (B8), the step (B-1 ) in a similar manner as can be used.

Step a (C-2) the step of performing a modification of the substituents Y 1 in the compound (C1), hydrolysis, amidation reaction, a known deprotection reaction, oxidation reaction, acylation reaction, sulfonylation reaction, hetero ring formation reaction, hydrogenation reaction, alkylation reaction, reduction reaction, carbon chain extension reaction, by combining alone or two or more thereof a substituent exchange reaction is a process for preparing a compound (I). It can be carried out for removing the protective group in R 1 ~ R 4 if necessary.

The form of a pharmaceutical composition for oral use, tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. The preparation of these forms of medicament, the excipient commonly used as additives, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, preservatives, anti oxidants, colorants, solubilizers, suspending agents, emulsifying agents, sweetening agents, preservatives, buffers, diluents, with a selection appropriately as needed from the wet agent, be performed according to conventional methods can.

The form of pharmaceutical compositions for parenteral, injectable agents, ointments, gels, creams, fomentations, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, inhalation agent, and the like. The preparation of these forms of medicament, the stabilizing agent which is generally used as additives, preservatives, solubilizing agents, humectants, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, soluble adjuvants, buffering agents, isotonic agents, surfactants, colorants, buffering agents, thickening agents, wetting agents, fillers, absorption promoters, suspending agents, appropriately selected as necessary a binder, etc. with the things, it can be carried out by conventional methods.

Compounds having the general formula (I) or a dose of a pharmacologically acceptable salt, symptoms, age, body weight, by an agent of the type and dosage, etc. to be administered in combination, usually, the general formula (I) in terms of amount of a compound having either a range of 0.001 mg ~ 1000 mg per adult human (weighing about 60kg) once, systemically or topically, several times per day, is administered orally or parenterally , or preferably continuously administered intravenously in a range of day 1 to 24 hours.

Furthermore, the pharmaceutical compositions of the present invention, to the extent not to impair the effects of the present invention, if necessary, can be used in combination other active ingredients.

In the present invention, method for preventing and / or treating the disease, which comprises administering acceptable salts compound of the invention or a pharmaceutically also included.
Furthermore, the present invention provides the present compound for the manufacture of the pharmaceutical composition includes the use of a pharmacologically acceptable salt thereof.
[Formulation Example]
The compounds of (Formulation Example 1) Powders present invention 5g, by mixing the lactose 895g and corn starch 100g in a blender to obtain a powder.
The compounds of (Formulation Example 2) Granules invention 5g, after mixing the lactose 865g and low-substituted hydroxypropylcellulose 100 g, it is kneaded by adding a 10% aqueous solution of hydroxypropyl cellulose 300 g. Granulated with a granulating extruder so, obtain the granules by drying.
The compounds of (Formulation Example 3) Tablets invention 5g, lactose 90 g, corn starch 34g, after mixing the crystalline cellulose 20g and magnesium stearate 1g a blender, by tableting on a tablet machine to yield tablets.
[Test Example 1] inflamed tissue in prostaglandins production evaluation
Opas et al report was carried out in the reference (Opas EE, Dallob A, Herold E, Luell S and Humes JL Pharmacological modulation of eicosanoid levels and hyperalgesia in yeast-induced inflammation Biochem Pharmacol 1987.36:... 547-551). The Mycobacterium butyricum dead bacteria suspended in liquid paraffin after sonication was 0.05 ml injected into 5 or male 6-week-old Lewis rats in the right hind footpad (100 ug / paw). The rats were sacrificed 19 days post-treatment, to recover the left leg tissue (untreated paw) was pulverized after flash freezing in liquid nitrogen, and homogenized added Indomethacin, containing EDTA PBS. Homogenization PGE 2, (stable metabolite of PGI 2) PGF 1a in the supernatant and TXB 2 (a stable metabolite of TXA 2) amount was quantified using the EIA kit from Cayman Chemical.


Compounds of this Example 31, as shown in FIG. 1, showing a dose-dependent inhibitory effect on PGE 2 production in inflamed tissue by oral administration of 0.1 ~ 30mg / kg.
[Test Example 2] A549 cells prostanoid production inhibition evaluation A549 cells prostanoid production inhibitory assays were performed with reference to Staffan ThoreAn et al reported (European Journal of Biochemistry, (2000) 267,6428-6434). A549 cells were suspended in 10% FBS added DMEM 25000 was seeded cells /0.1 mL / well and cultured overnight at 37 ° C, 5% CO 2 conditions. The cells were washed once with serum-free DMEM supplemented, serum-free DMEM supplemented after the addition 0.09 mL / well of compound diluted in and incubated for 1 hour. The 10 ng / mL human IL-1beta after the addition 0.01 mL / well and incubated overnight (final concentration 1 ng / mL of IL-1beta). Recovery PGE 2 concentration in the culture supernatants was measured by a commercial ELISA.

As shown in Table 1, compounds of this embodiment with respect to PGE 2 production from A549 cells, showed an excellent inhibitory effect.
[Test Example 3] Rat macrophage prostanoid production evaluation rat macrophages prostanoid production assays were performed with reference to reports of Matsumoto et al (Biochemical and Biophysical Research Communications, (1996) 230,110-114). To 5% Peptone, 3-4 days after the 5% Starch was administered to rats intraperitoneally, peritoneal macrophages were prepared cells infiltrating intraperitoneally solution was collected in 10% FBS added RPMI-1640. After aspirin adjustment macrophages added 0.1 mM final concentration, 96 well plates were added 200,000 cells /0.1 mL / well, 37 ° C , after 2 hours incubation under 5% CO 2, 2 times with RPMI-1640 washed and excluding the non-adherent cells. With 10% FBS added RPMI-1640 was added to 0.05 mL 0.15 mL, 4-fold compound concentrations, and incubated for 1 hour at 37 ° C, 5% CO 2 conditions. Then, LPS was added 0.005 mL (final concentration 0.01 mg / mL), for 24 hours at 37 ° C, 5% CO 2 conditions. It was quantified prostanoids, such as PGE 2 and 200 [mu] L collecting the culture supernatant the next day.

As shown in Table 1, compounds of this embodiment with respect to PGE 2 production from rat macrophages showed an excellent inhibitory effect. Further, the IC 50 value for TXB 2 production of the compounds of the present invention, both also at 1000 ng / mL or more, has been shown to be selectively inhibited PGE 2 production.

Figure JPOXMLDOC01-appb-T000007

(Reference Example 1)
(1S, 3S) -3 - {[(benzyloxy) carbonyl] amino} and cyclohexane carboxylic acid (1R, 3R) -3 - {[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid PCT WO2008 / 075196 filed specification optical in: - according trans -3 {[(benzyloxy) carbonyl] amino} with cyclohexane carboxylic acid (120 g) supercritical fluid chromatography (25 DAICEL CHIRALPAK AD-H, CO / methanol = 75) split was carried out. After collecting the first peak eluting earlier, the solvent was removed under reduced pressure to give the title compound (56.7 g, optical purity> 98% ee) as a solid. Also, after collecting the second peak eluting later, the solvent was removed under reduced pressure to give the title compound (55.4 g, optical purity> 98% ee) as a solid.
(Reference Example 2) benzyl [(1R, 3R) -3 - {[(1S) -1- phenylethyl] carbamoyl} cyclohexyl] dichloromethane first peak obtained in carbamate Reference Example 1 (300 mg, 1.08 mmol) in (11 mL) solution, 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (294mg, 2.16mmol), (1S) -1- phenyl ethanamine (138μL, 1. 08Mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (414 mg, 2.16 mmol), and triethylamine (0.452mL, 3.24mmol) and the mixture was stirred for 20 hours at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 100 / 0-0 / 100) to give the title compound 394mg (96% yield) as a solid. The resulting solid was crystallized from isopropyl alcohol solvent used. Using the obtained crystals were determined absolute conformation by X-ray crystallography. Absolute configuration was determined to be (1S)-1-based three-dimensional arrangement of phenylethanamine (1R, 3R). Therefore, the absolute configuration of a second peak obtained in Reference Example 1 was determined to be (1S, 3S).
(Reference Example 3) benzyl [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] second peak obtained in carbamate Reference Example 1 (1S, 3S) -3 - {[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid (10.5 g, 37.9 mmol) in dichloromethane (10 mL) was added under ice-cooling, commercially available 1,1'-carbonyldiimidazole (7.37 g, 45.5 mmol) and the mixture was stirred for 2 hours . Under ice cooling, a commercially available ethylamine to the reaction mixture (2.0 M tetrahydrofuran solution, 50 mL, 100 mmol) and the mixture was stirred for 15 hours at room temperature. The reaction solution was concentrated under reduced pressure, and diluted with ethyl acetate. The reaction mixture was 1N hydrochloric acid solution, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound 11.9 g.
(Reference Example 4) (1S, 3S) -3- amino -N- ethyl-cyclohexanecarboxamide benzyl obtained in Reference Example 3 [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] carbamate (11.9 g, 37 in ethanol (80 mL) solution of .9mmol equivalent), commercially available 10% palladium carbon (1.97 g) was added, and the mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure to give the title compound 6.73g as a quantitative solid.
(Reference Example 5) benzyl [(1S, 3S) -3- carbamoyl cyclohexyl] obtained in carbamate Reference Example 1 (1S, 3S) -3 - {[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid and commercially available with aqueous ammonia to give the title compound (100% yield) as a solid according to the method of reference example 3.
Ethanol (Reference Example 6) (1S, 3S) -3- amino-cyclohexanecarboxamide hydrochloride benzyl obtained in Reference Example 5 [(1S, 3S) -3- carbamoyl cyclohexyl] carbamate (3.00g, 10.9mol) in (100 mL) solution of commercially available 10% palladium on carbon (300 mg) was added, and the mixture was stirred under hydrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was filtered through Celite, the solvent was removed under reduced pressure. The resulting residue was suspended by the addition of 1N hydrochloric acid ethanol solution, the solvent was removed under reduced pressure. The resulting residue was dried to give the title compound 1.95g (97% yield) as a solid.
(Reference Example 7) Methyl (1S, 3S)-3-amino-cyclohexanecarboxylate was obtained in hydrochloride Reference Example 1 (1S, 3S) -3 - {[(benzyloxy) carbonyl] amino} cyclohexanecarboxylic acid and methanol It was used to give a solid (92% yield) according to the method of reference example 3. The resulting solid was used to obtain the title compound (72% yield) as a solid according to the method of Reference Example 4.
(Reference Example 8) ethyl (cis -4 - {[(1E) - phenylmethylene] amino} cyclohexyl) acetate Izvestiya Akademii Nauk SSSR, SeriyaKhimicheskaya (1980), 10,2374-2379. Ethyl described (cis-4-aminocyclohexyl) acetate hydrochloride (5.60 g, 25.3 mmol) was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with chloroform. Further 0.1N aqueous sodium hydroxide solution was added to the aqueous layer and extracted with chloroform. The organic layers were combined and washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give an oil 3.50g and dried the resulting residue. The resulting oil (1.80 g, 9.72 mmol) in methanol (49 mL) was added stirred for 16 hours at room temperature by adding anhydrous sodium sulfate (9.00 g) and benzaldehyde (0.98 mL, 9.7 mmol) did. The reaction mixture was filtered, the solvent was distilled off under reduced pressure to give the title compound.
(Reference Example 9) 2-methyl-2- (cis -4 - {[(1E) - phenylmethylene] amino} cyclohexyl) propanoate Under nitrogen atmosphere, a tetrahydrofuran solution of 1.14M lithium diisopropylamide (0.353ML, 0 the .402Mmol), a dry ice - under cooling with methanol, ethyl obtained in reference example 8 - - {[phenylmethylene ((1E-aminocyclohexyl) acetate (50.0 mg, 0.183 mmol) cis-4)]} in tetrahydrofuran (0.92 mL) was added. Under ice-cooling, followed by stirring for 20 minutes, dry ice again - cooled with methanol. Methyl iodide (34 [mu] L, 0.55 mmol) and hexamethylphosphoric triamide (70 [mu] L, 0.40 mmol) in tetrahydrofuran solution of (0.92 mL) was added, followed by stirring at room temperature for 2.5 hours. The reaction mixture was added saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. Against the resulting residue was distilled off the solvent under reduced pressure, by performing re-methylation reaction using similar reaction conditions, to quantitatively obtain the title compound.
(Reference Example 10) Ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate Reference Example Ethyl obtained in 9 2-methyl-2- (cis -4 - {[(1E) - phenylmethylene ] amino} cyclohexyl) propanoate (6.51 g, dichloromethane (68 mL) solution of 20.5mmol equivalent), under ice-cooling, followed by stirring at room temperature for 2 hours by the addition of trifluoroacetic acid (2.35 ml, 30.7 mmol). After distilling off the solvent under reduced pressure, commercially available 4N hydrochloric acid - and the solvent was removed under reduced pressure again added ethyl acetate (10 ml). After washed with water was added with toluene, the 4N aqueous sodium hydroxide was added, and extracted with ethyl acetate. The organic layers were combined and washed with brine. After drying over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound 4.02g (92% yield).
(Reference Example 11) Ethyl 1- (3-phenyl-2-yl) piperidine-4-carboxylate PCT WO2006 / 025 783 ethyl filed herein described 1- (3-bromo-2-yl) piperidin-4 carboxylate (980 mg ,, 3.13 mmol) and phenylboronic acid (563 mg, 6.26 mmol) in tetrahydrofuran (20 mL) was added [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) (130mg, 0.16mmol) and potassium phosphate (2.10 g, 9.39 mmol) was added, under an argon atmosphere and heated to reflux for 20 hours. Ethyl acetate was added to the reaction mixture, after the insoluble matter was filtered through Celite, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-4 / 1) to give the title compound 911mg (94% yield) as a solid.
(Reference Example 12) Ethyl 1- (5-bromo-3-phenyl-2-yl) piperidine-4-carboxylate Ethyl 1- (3-phenyl-2-yl) obtained in Reference Example 11 Piperidine - 4-carboxylate (250 mg, 0.81 mmol) in dichloromethane (6 mL) was added under ice-cooling, N- bromosuccinimide (143 mg, 0.81 mmol) was added, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-4 / 1) to give the title compound 300mg (96% yield) as a solid.
(Reference Example 13) 1- (5-bromo-3-phenyl-2-yl) piperidin-4-ethyl-obtained carboxylic acid Reference Example 12 1- (5-bromo-3-phenyl-2-yl ) piperidine-4-carboxylate (87 mg, in a mixed solution of tetrahydrofuran (2 mL) and ethanol (2 mL) of 0.22 mmol), 1N sodium hydroxide solution (1 mL) was added, followed by stirring at room temperature for 13 hours. After adding 1N hydrochloric acid to the reaction mixture was concentrated under reduced pressure. The resulting residue was added water, and extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound.
Reference Example (14) Ethyl 1- (3-phenyl-5-vinyl-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 12 1- (5-bromo-3-phenyl-2- yl) piperidine-4-carboxylate (238 mg, toluene (6 mL) solution of 0.61 mmol), commercially available tri -n- butyl (vinyl) tin (368μL, 1.22mmol) and tetrakis (triphenylphosphine) palladium ( 0) (71mg, 0.06mmol) was added, under argon, was heated and stirred for 23 hours at 90 ° C.. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified by NH silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-17 / 3) to give the title compound 146mg (71% yield).
(Reference Example 15) Ethyl 1- (5-ethyl-3-phenyl-2-yl) piperidine-4-carboxylate Reference Example Ethyl obtained in 14 1- (3-phenyl-5-vinyl-2- yl) piperidine-4-carboxylate (108 mg, in ethanol (6 mL) solution of 0.32 mmol), 10% palladium on carbon (50% water, 50 mg) was added, under hydrogen atmosphere and stirred at room temperature for 16 hours. Of 10% palladium-carbon (50% water, 30 mg) was added and stirred for an additional 26 hours. The reaction mixture was filtered through Celite, and washed with ethanol. The solvent was distilled off under reduced pressure to give the title compound 106mg (98% yield).
(Reference Example 16) Ethyl 1- (3-phenyl-5-prop-l-yn-l-ylpyridin-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 12 1- (5-bromo - 3-phenyl-2-yl) piperidine-4-carboxylate (250 mg, tetrahydrofuran (3.2 mL) solution of 0.64 mmol), dichlorobis (triphenylphosphine) palladium (II) (45 mg, 0.06 mmol), iodide (I) (24mg, 0.13mmol), diisopropylethylamine (443μL, 2.57mmol) and after the addition of 1M fluoride tetra -n- butylammonium, further trimethyl - prop-1 Inirushiran (285μL, 1 .93mmol) was added dropwise. After the reaction system was purged with nitrogen, and microwave irradiated for 30 minutes at 90 ° C.. The reaction mixture was added ethyl acetate, was removed by filtration through celite and the insoluble matter. The filtrate was washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by NH silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-9 / 1) to give 160mg (72% yield) Obtained.
(Reference Example 17) Ethyl 1- (3-bromo-5-chloro-2-yl) piperidine-4-carboxylate commercially available 3-bromo-2,5-dichloropyridine (1.87 g, 8.24 mmol) in N- methylpyrrolidone (4 mL) solution, under ice-cooling, it was added dropwise a commercially available ethyl 4-piperidinecarboxylate (3.81 mL, 24.7 mmol), heated to 120 ° C., for 4 hours heating and stirring. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-9 / 1) to give 2.47 g (86% yield) It was obtained.
(Reference Example 18) Ethyl 1- (6-cyano-3-phenyl-2-yl) piperidine-4-carboxylate Tetrahedron (1990), 46 (16), 6- chloro-5 according to 5715-5732 using phenyl-2-carbonitrile and commercially available ethyl 4-piperidinecarboxylate gave the title compound (87% yield) as a solid according to the method of reference example 17.
(Reference Example 19) Ethyl 1- (5-bromo-6-cyano-3-phenyl-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 18 1- (6-cyano-3-phenyl pyridin-2-yl) piperidine-4-carboxylate (344 mg, dichloromethane (5 mL) and ethanol (5 mL) mixed solution of 1.03 mmol), under ice-cooling, tetra -n- butylammonium tribromide (742 mg, 1. after adding 54 mmol), and stirred at room temperature for 6 hours. The reaction mixture tetra -n- butylammonium tribromide (742 mg, 1.54 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture saturated aqueous sodium bicarbonate solution was added to, and after extraction with dichloromethane. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-9 / 1) to give the title compound 212mg (50% yield).
(Reference Example 20) Ethyl 1- (5-nitro-3-phenyl-2-yl) piperidine-4-carboxylate commercially available 3-bromo-2-chloro-5-nitropyridine and commercially available ethyl 4-piperidinecarboxylate using rate to give an oil (100% yield) according to the method of reference example 17. Using the obtained oil and phenyl boronic acid to give the title compound according to the method of Reference Example 11 (67% yield).
(Reference Example 21) Methyl 1- (5-methoxy-3-phenyl-2-yl) piperidine-4-carboxylate Reference Example Ethyl obtained in 20 1- (5-nitro-3-phenyl-2- yl) piperidine-4-carboxylate (1.11 g, in a mixed solvent of tetrahydrofuran 3.12 mmol) (40 mL), water (10 mL) and ethanol (10 mL), iron powder (1.22 g, 21.9 mmol) and chloride ammonium (501 mg, 9.37 mmol) was added, under a nitrogen atmosphere, followed by stirring at room temperature for 17 hours. After celite filtration, the solvent was removed under reduced pressure. The resulting residue was added water, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 9 / 1-2 / 3) to give a solid 697 mg (69% yield). The resulting solid (250 mg, 0.77 mmol) in a mixture consisting of and water (4 mL), under ice-cooling, after adding sulfuric acid (0.4 mL), sodium nitrite (60 mg, 1.00 mmol) water (1 mL ) was added dropwise. 0 After stirring for 30 min at ° C., under a nitrogen atmosphere, and the mixture was stirred with heating for 2 hours at 90 ° C.. Water was added to the reaction mixture, and around pH7 by addition of a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, and the solvent was removed under reduced pressure. To the resulting mixture consisting of methanol (4 mL) and toluene (4 mL) of the residue under ice cooling, it was added dropwise n- hexane solution of commercially available 2M trimethylsilyldiazomethane (4 mL), and stirred at room temperature for 2 hours. To the reaction mixture was added dropwise an additional of 2M trimethylsilyldiazomethane n- hexane solution (1 mL), and stirred for an additional 2 hours. The reaction mixture was ice-cooled, acetic acid (880μL, 15.4mmol) was slowly added dropwise, and the mixture was stirred 10 min at 0 ° C.. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-3 / 2) to obtain the title compound 42mg (17% yield) solid It was obtained as a.
(Reference Example 22) Ethyl 1- (3-phenyl-5-propyl-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 16 1- (3-phenyl-5-prop-1-yne 1-ylpyridin-2-yl) using piperidine-4-carboxylate, the title compound according to the method of reference example 15 (84% yield) as a solid.
(Reference Example 23) Ethyl 1- (5-isopropyl-3-phenyl-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 12 1- (5-bromo-3-phenyl-2- yl) piperidine-4-carboxylate and 4,4,5,5-tetramethyl-2- (using prop-1-en-2-yl) 1,3,2-dioxaborolane, the method of reference example 11 to give an oil (44% yield) according to. Using the obtained oil, to give the title compound according to the method of Reference Example 15 (40% yield).
(Reference Example 24) Methyl 1- (5-bromo-6-cyano-3-phenyl-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 18 1- (6-cyano-3-phenyl pyridin-2-yl) piperidine -4-carboxylate and methanol solvent, according to the method of reference example 19 to give the title compound (27% yield).
(Reference Example 25) Methyl 1- (6-cyano-5-ethyl-3-phenyl-2-yl) piperidine-4-carboxylate Reference Example Methyl obtained in 24 1- (5-bromo-6-cyano- 3-phenyl-2-yl) piperidine-4-carboxylate (203 mg, tetrahydrofuran (6 mL) solution of 0.51 mmol), tris (dibenzylideneacetone) dipalladium (0) (14 mg, 0.02 mmol) and 1,2,3,4,5-penta-phenyl-1 '- (di -tert- butyl) ferrocene (48 mg, 0.07 mmol) was added and after argon substitution, under ice-cooling, commercial 1.1M It was added dropwise diethyl zinc n- hexane solution (1 mL) over 5 minutes. After 3 hours stirring the reaction mixture at 0 ° C., it was added dropwise 1N aqueous hydrochloric acid solution (6 mL). The reaction mixture was brought to room temperature, saturated aqueous sodium bicarbonate was added. To the resulting mixture, after decantation, were separated, the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-9 / 1) to give the title compound 103 mg (58% yield) It was.
(Reference Example 26) Ethyl 1-(6-tert-butoxy-3-phenyl-2-yl) piperidine-4-carboxylate Commercially available 2-bromo -6-tert Butoxypyridin (7.14 g, 31.0 mmol in dimethylformamide (40 mL) solution of), under ice-cooling, N- bromosuccinimide (6.63 g, 37.2 mmol) was added, and the mixture was stirred with heating for 9 hours at 50 ° C.. Water was added to the reaction mixture, followed by extraction with n- hexane. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-19 / 1), an oil 6.05 g (63% yield) It was obtained. The resulting oil and using a commercially available ethyl 4-piperidinecarboxylate, to give an oil according to the method of Reference Example 17 (104% yield, 96% purity). Using the obtained oil and phenyl boronic acid to give the title compound (86% yield) as a solid according to the method of Reference Example 11.
(Reference Example 27) Ethyl 1- (5-bromo -6-tert-butoxy-3-phenyl-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 26 1- (6-tert-butoxy -3-phenyl-2-yl) piperidine-4-carboxylate to give the title compound (99% yield) as a solid according to the method of reference example 12.
(Reference Example 28) Ethyl 1- (6-tert-butoxy-5-ethyl-3-phenyl-2-yl) piperidin-4-ethyl-obtained carboxylate Reference Example 27 1- (5-Bromo-6 using -tert- butoxy-3-phenyl-2-yl) piperidine-4-carboxylate and potassium ethenyl (trifluoromethyl) borate, was in accordance with the method of reference example 11 to give a solid (61% yield) . The resulting solid was used to obtain the title compound (84% yield) as a solid according to the method of Reference Example 15.
Ethyl obtained in (Reference Example 29) Ethyl 1- (5-ethyl-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate Reference Example 28 1- (6- tert- butoxy-5-ethyl-3-phenyl-2-yl) piperidine-4-carboxylate (830 mg, in dichloromethane (12 mL) solution of 2.02 mmol), trifluoroacetic acid (3 mL) was added, at room temperature the mixture was stirred for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue saturated sodium bicarbonate aqueous solution obtained was added thereto, followed by extraction with dichloromethane. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, it was added n- hexane to the resulting residue. After stirring in suspension, the solution was removed by decantation. Concentrated to dryness the residue to give the title compound 695mg (97% yield) as a solid.
(Reference Example 30) Ethyl 1- (5-ethyl-6-methoxy-3-phenyl-2-yl) piperidine-4-carboxylate Reference ethyl obtained in Example 29 1- (5-ethyl-6-oxo 3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate (150 mg, dimethylformamide (2 mL) solution of 0.42 mmol), potassium carbonate (88 mg, 0.63 mmol) and methyl iodide (105 mg, 1.69 mmol) and the mixture was stirred for 10 hours at 60 ° C.. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by NH silica gel column chromatography (n- hexane / ethyl acetate = 9 / 1-1 / 1) to give 140mg (90% yield) Obtained.
(Reference Example 31) [cis-4 - ({[1- (5-ethyl-3-phenyl-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] ethyl obtained in acetic acid Example 13 [cis-4 - ({[4- 1- (5-ethyl-3-phenyl-2-yl) piperidin-yl] carbonyl} amino) cyclohexyl] acetate (1.01 g, 1.85 mmol equivalent) in ethanol ( in 9.3 mL) suspension, 4N aqueous sodium hydroxide (1.4 mL, 5.6 mmol) and the mixture was stirred for 1.5 hours at 60 ° C.. Water was added to the reaction mixture was concentrated under reduced pressure. 6N aqueous hydrochloric acid was added thereto, followed by extraction with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 100 / 0-0 / 100, chloroform / methanol = 95/590/10) to afford the title compound 337mg (41% yield) as a solid .
(Reference Example 32) Ethyl 1- (6-amino-3-phenyl-2-yl) piperidine-4-carboxylate Commercially available 2-amino-5,6-dibromopyridine and commercially available ethyl 4-piperidinecarboxylate used was in accordance with the method of reference example 17 to give a solid (50% yield). The resulting solid was used to obtain the title compound (39% yield) as a solid according to the method of Reference Example 11.
(Reference Example 33) Ethyl 1- {6-amino-3-phenyl-5 - [(triisopropylsilyl) ethynyl] pyridin-2-yl} piperidine-4-carboxylate Reference Example Ethyl obtained in 32 1- ( using 6-amino-3-phenyl-2-yl) piperidine-4-carboxylate to give a solid (95% yield) according to the method of reference example 12. The resulting solid and commercial using (triisopropylsilyl) acetylene to give the title compound according to the method of Reference Example 16 (81% yield).
(Reference Example 34) Ethyl 1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 33 1- {6-amino - 3-phenyl-5 - [(triisopropylsilyl) ethynyl] pyridin-2-yl} piperidine-4-carboxylate (198 mg, 0.39 mmol) and pyridine (126μL, 1.57mmol) in dichloromethane (4 mL) solution of under ice-cooling, it was added dropwise acetyl chloride (36 [mu] L, 0.51 mmol), after stirring for 20 min at 0 ° C., and stirred for 7 hours at room temperature. Water was added to the reaction mixture, and washed with dichloromethane. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. After azeotropic resulting residue with toluene, the residue was dissolved in tetrahydrofuran (3 mL). To the reaction solution tetra -n- butylammonium fluoride (1M tetrahydrofuran solution, 1.2 mL) was added and stirred for 5 hours at 80 ° C.. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by NH silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-9 / 1) to give 93mg (68% yield) Obtained.
(Reference Example 35) 1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-ethyl-obtained carboxylic acid Reference Example 34 1- (5-phenyl -1H - using the pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate, the title compound was obtained according to the method of reference example 13.
(Reference Example 36) Ethyl 1- (1-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-ethyl-obtained carboxylate Reference Example 34 1- ( 5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylate (101 mg, dehydrated dimethylformamide (2 mL) solution of 0.29 mmol), under ice-cooling, 60% hydrogen after addition of sodium reduction (17mg, 0.43mmol), and stirred for 20 minutes at room temperature. The reaction mixture was again cooled with ice, was added dropwise methyl iodide (54 [mu] L, 0.87 mmol), and stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. , The solvent was removed under reduced pressure, the resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-4 / 1) to give 84mg (80% yield) Obtained.
(Reference Example 37) Ethyl 1- (5-allyl--6-tert-butoxy-3-phenyl-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 27 1- (5-Bromo-6 -tert- butoxy-3-phenyl-2-yl) piperidine-4-carboxylate and a commercial 4,4,5,5-tetramethyl-2- (prop-2-en-1-yl) -1, using 3,2-dioxaborolane to give the title compound (84% yield) as a solid according to the method of reference example 11.
(Reference Example 38) Ethyl 1- [6-tert-butoxy-5- (2-hydroxyethyl) -3-phenyl-2-yl] piperidine-4-carboxylate Ethyl obtained in Reference Example 37 1- ( 5-allyl--6-tert-butoxy-3-phenyl-2-yl) piperidine-4-carboxylate (591 mg, 1.40 mmol) and 50% N-methylmorpholine -N- oxide aqueous solution (871MyuL) acetone ( 4 mL), in a mixed solution of tetrahydrofuran (4 mL) and water (3 mL), under ice-cooling, 4% osmium tetroxide solution (267μL, 0.04mmol) was added and stirred for 5 hours at room temperature. The reaction mixture is again ice-cooled, added dropwise saturated sodium thiosulfate (20 mL), and stirred for 5 minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give an oil. Tetrahydrofuran obtained oil (6 mL), in a mixed solution of methanol (6 mL) and water (6 mL), then added under ice-cooling, sodium periodate (898 mg, 4.20 mmol), 1 hour at room temperature and the mixture was stirred. Ethyl acetate was added to the reaction mixture and insoluble were removed by filtration. The filtrate was washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give an oil. To the resulting oil in methanol (12 mL) solution, under ice-cooling, sodium borohydride (106 mg, 2.80 mmol) was added and stirred for 30 min at 0 ° C.. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-1 / 1) to give the title compound 438mg (73% yield) as a solid.
(Reference Example 39) Ethyl 1- [5- (2-hydroxyethyl) -6-oxo-3-phenyl-1,6-dihydropyridin-2-yl] piperidin-4-ethyl-obtained carboxylate Reference Example 38 using 1- [6-tert-butoxy-5- (2-hydroxyethyl) -3-phenyl-2-yl] piperidine-4-carboxylate, the title compound according to the method of reference example 29 (yield: 84%) as a solid.
(Reference Example 40) Ethyl 1- (5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidin-4-ethyl-obtained carboxylate Reference Example 39 1- [6- tert- butoxy-5- (2-hydroxyethyl) -3-phenyl-2-yl] piperidine-4-carboxylate (252mg, 0.68mmol), 1,1 '- (azodicarbonyl) dipiperidine (343 mg, a mixture consisting of 1.36 mmol) and anhydrous tetrahydrofuran (4 mL), under ice-cooling, tri -n- butyl phosphine (340 [mu] L, 1.36 mmol) was added, and the mixture was stirred for 2 hours at room temperature. The insolubles in the reaction mixture was filtered off and washed with tetrahydrofuran (4 mL). The filtrate and washings were concentrated under reduced pressure, the resulting residue was purified by NH silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-7 / 3). Furthermore, re-purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-4 / 1) to give the title compound 190mg (79% yield) as a solid.
(Reference Example 41) 5-phenyl-thieno [2,3-b] pyridine -6 (7H) - on Journal of Organic Chemistry (2003), 68 (24), 2- bromo-thiophene-3-carba according 9513-9516 aldehyde (2.17 g, 11.4 mmol), 2-phenyl-acetamide (2.00 g, 14.8 mmol), tris (dibenzylideneacetone) dipalladium (0) (312mg, 0.34mmol), 4,5- bis ( diphenylphosphino) -9,9-dimethylxanthene (637 mg, 1.02 mmol), cesium carbonate (6.29 g, 19.3 mmol) and toluene (30 mL) mixture under an argon atmosphere consisting of 15 hours stirring at 100 ° C. did. The reaction mixture was concentrated under reduced pressure, it was collected by filtration insolubles. The resulting insoluble material was dissolved in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound 1.11g (43% yield) as a solid.
(Reference Example 42) 5-phenyl-thieno [2,3-b] pyridin-6-yl obtained in trifluoromethanesulfonate Reference Example 41 5-phenyl-thieno [2,3-b] pyridine -6 (7H) - On (1.11 g, 4.88 mmol) and 2,6-lutidine (1.14 mL, 9.77 mmol) in anhydrous dichloromethane (20 mL) was added under ice-cooling, trifluoromethanesulfonic anhydride (984μL, 5.86mmol) and the mixture was stirred for 1 hour at 0 ℃. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-9 / 1) to give the title compound 661mg (38% yield).
(Reference Example 43) 1- (5-phenyl-thieno [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid Reference 5-phenyl-thieno [2,3-b] obtained in Example 42 pyridine 6-yl using trifluoromethanesulfonate and commercially available ethyl 4-piperidinecarboxylate, in accordance with the method of reference example 17 to give an oil (91% yield). Using the obtained oil, to give the title compound (61% yield) as a solid according to the method of Reference Example 13.
A mixture consisting of (Example 44) 5-bromo-6-chloro-3-methyl -1H- pyrrolo [2,3-b] pyridine dimethylamine hydrochloride (326 mg, 3.80 mmol) and acetic acid (8 mL), ice under cooling, it was added dropwise 30% aqueous formaldehyde solution (268μL, 3.63mmol), and stirred for 20 min at 0 ° C.. To the reaction mixture, PCT WO2010 / 016,490 filed herein described 5-bromo-6-chloro -1H- pyrrolo [2,3-b] pyridine (800 mg, 3.46 mmol) was added followed by 16 hours at 60 ° C. and the mixture was stirred. The reaction mixture the residue obtained by concentration under reduced pressure, was neutralized with saturated aqueous sodium hydrogen carbonate solution, insoluble matter occurred. The insolubles were collected by filtration, was dissolved in acetonitrile (30 mL), was added sodium triacetoxyborohydride (7.11 g, 31.9 mmol). The mixture was stirred for 20 minutes at room temperature, the mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool, add sodium triacetoxyborohydride (7.11 g, 31.9 mmol), was heated under reflux for further 5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution and brine. Dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-4 / 1) to give the title compound 201mg (26% yield) as a solid.
(Reference Example 45) Ethyl 1- {5-bromo-3-methyl-1 - [(4-methylphenyl) sulfonyl]-1H-pyrrolo [2,3-b] pyridin-6-yl} piperidine-4-carboxy the rate reference example 44 obtained in 5-bromo-6-chloro-3-methyl -1H- pyrrolo [2,3-b] pyridine (198 mg, 0.81 mmol) and a mixture consisting of anhydrous tetrahydrofuran (4 mL), ice under cooling, 60% sodium hydride (48 mg, 1.21 mmol) and then was added in portions, and stirred for 1 hour at room temperature. The reaction mixture was again cooled with ice, after addition of 4-methyl-benzenesulfonyl chloride (185 mg, 0.97 mmol) and stirred at room temperature for 15 hours. Water (80 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. After addition the resulting residue n- hexane (10 mL), the solution was removed by decantation. The residue was concentrated under reduced pressure to obtain a solid 300mg (93% yield). The resulting solid and using commercially available ethyl 4-piperidinecarboxylate gave the title compound according to the method of Reference Example 17 (85% yield).
(Reference Example 46) 1- (3-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) ethyl resulting piperidine-4-carboxylic acid Reference Example 45 1- {5 - bromo-3-methyl-1 - [(4-methylphenyl) sulfonyl]-1H-pyrrolo using [2,3-b] pyridin-6-yl} piperidine-4-carboxylate and phenyl boronic acid, reference to give a solid (96% yield) according to the method of example 11. The resulting solid was used to obtain the title compound (25% yield) as a solid according to the method of Reference Example 13.
(Reference Example 47) Ethyl 1- (3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate Organic Letters (2004), 6 (14), 2433-2435. According 3-phenyl-1,8-naphthyridin -2 (1H) - to obtain a triflate according to the method of Reference Example 42 by using an on. The obtained compound and using commercially available ethyl 4-piperidinecarboxylate gave the title compound (62% yield) as a solid according to the method of Reference Example 17.
(Reference Example 48) Ethyl 1- (6-bromo-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate Organic Letters (2004), 6 (14), 2433-2435. According 3-phenyl-1,8-naphthyridin -2 (IH) - using one was according to the method of Reference Example 12 to give a solid (88% yield, about 80% pure). The resulting solid was used to obtain the triflate according to the method of Reference Example 42. The obtained compound and using commercially available ethyl 4-piperidinecarboxylate gave the title compound (74% yield) as a solid according to the method of Reference Example 17.
(Reference Example 49) Ethyl 1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 48 1- (6-bromo-3- phenyl-1,8-naphthyridin-2-yl) piperidine -4-carboxylate and 2,4,6-trimethyl boroxine, the title compound according to the method of reference example 11 (70% yield) solid It was obtained as a.
(Reference Example 50) 1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-ethyl-obtained carboxylic acid Reference Example 49 1- (6-methyl-3-phenyl using 1,8-naphthyridin-2-yl) piperidine-4-carboxylate, the title compound was obtained according to the method of reference example 13.
(Reference Example 51) Ethyl 1- (6-ethyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 48 1- (6-bromo-3- phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate and a commercial tri -n- butyl (vinyl) using tin, a solid (68% yield) according to the method of reference example 14 Obtained. The resulting solid was used to afford the title compound according to the method of Reference Example 15 (75% yield).
(Reference Example 52) 1- (6-methyl-3-phenyl-2-yl) piperidine-4-carboxylic acid Farmaco (1996), 51 (8,9), according 569-577 6-methyl-3 phenylquinoxalines -2 (IH) - with on, to give a triflate according to the method of reference example 42. The obtained compound and using commercially available ethyl 4-piperidinecarboxylate, to give a solid (91% yield) according to the method of Reference Example 17. The resulting solid was used to obtain the title compound (99% yield) as a solid according to the method of Reference Example 13.
(Reference Example 53) Ethyl 1- (5-iodo-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidin-4-ethyl-obtained carboxylate Reference Example 26 1- (6- with tert- butoxy-3-phenyl-2-yl) piperidine-4-carboxylate and N- iodosuccinimide to give a solid (96% yield) according to the method of reference example 12. The resulting solid was used to obtain the title compound (81% yield) as a solid according to the method of Reference Example 29.
(Reference Example 54) Ethyl 1- [6- (allyloxy) -5-iodo-3-phenyl-2-yl] piperidine-4-carboxylate Ethyl obtained in Reference Example 53 1- (5-iodo -6 - oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine -4-carboxylate and allyl bromide to give the title compound according to the method of reference example 30 (100% yield).
(Reference Example 55) Ethyl 1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) ethyl resulting piperidine-4-carboxylate Reference Example 54 1- [6- (allyloxy ) -5-iodo-3-phenyl-2-yl] piperidine-4-carboxylate (6.08 g, in 1,4-dioxane (120 mL) solution of 12.4 mmol), palladium acetate (II) (83 mg, 0.37 mol), cesium carbonate (4.83 g, 14.8 mmol), sodium formate (1.01 g, 14.8 mmol) and tetra -n- butylammonium bromide (4.78 g, 14.8 mmol) was added, an argon atmosphere lower, the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was added ethyl acetate (200 mL). The insolubles were removed by Celite filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 10 / 0-9 / 1) to give the title compound 2.11g (47% yield) as a solid.
(Reference Example 56) 1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) ethyl resulting piperidine-4-carboxylic acid Reference Example 55 1- (3-methyl-5 - phenylfuro using [2,3-b] pyridin-6-yl) piperidine-4-carboxylate to give the title compound (100% yield) as a solid according to the method of reference example 13.
Obtained in (Reference Example 57) Ethyl 1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate Reference Example 53 ethyl using 1- (5-iodo-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine-4-carboxylate and 3-bromo-2-methylpropene, the method of reference example 30 to give an oil (72% yield) according to. Using the obtained oil, according to the method of Reference Example 55 to give the title compound (69% yield) as a solid.
(Reference Example 58) 1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidin-4-ethyl-obtained carboxylic acid Reference Example 57 1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) using piperidine-4-carboxylate, the title in accordance with the method of reference example 13 compound (100% yield) as a solid.
(Reference Example 59) Ethyl 1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylate Ethyl obtained in Reference Example 53 1- (5-iodo - 6-oxo-3-phenyl-1,6-dihydropyridin-2-yl) piperidine -4-carboxylate and a commercial 1-bromo-2-butene, oil in accordance with the method of reference example 30 (yield to obtain the rate 79%). Using the obtained oil, according to the method of Reference Example 55 to give the title compound (68% yield) as a solid.
(Reference Example 60) 1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) ethyl resulting piperidine-4-carboxylic acid Reference Example 59 1- (3-ethyl-5 - phenylfuro using [2,3-b] pyridin-6-yl) piperidine-4-carboxylate to give the title compound (99% yield) as a solid according to the method of reference example 13.
(Reference Example 61) 3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-ol Under a nitrogen atmosphere, the commercially available 2-chloro-2-phenylacetyl chloride (18.8 g, 116 mmol in dichloromethane) under ice-cooling, a commercially available 5-trifluoromethyl-2-aminopyridine (20.1 mL, 127 mmol) and triethylamine (17.7 mL, 127 mmol) and the mixture was stirred for 20 hours at room temperature. Hydrochloric acid solution was added to the reaction mixture, followed by extraction with chloroform. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 9/1) to give a solid 32.0 g (88% yield). The resulting solid (3.00 g, 9.53 mmol) in 2,6-lutidine (10 mL) solution of, 180 ° C., was carried out for 1 hour microwave irradiation. After cooling to room temperature, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution and brine. Dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting solid was washed with ether to give the title compound 1.34g (51% yield) as a solid.
(Reference Example 62) 1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] 3-phenyl obtained piperidine-4-carboxylic acid Reference Example 61 - 6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-ol to give a solid (95% yield) according to the method of reference example 42. The resulting solid and using commercially available ethyl 4-piperidinecarboxylate, to give a solid (21% yield) according to the method of Reference Example 17. The resulting solid was used to obtain the title compound (84% yield) as a solid according to the method of Reference Example 13.
(Reference Example 63) {cis-4 - [({1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl} carbonyl) amino ] cyclohexyl} ethyl obtained in acetic acid example 50 {cis-4 - [({1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidine - using 4-yl} carbonyl) amino] cyclohexyl} acetate gave the title compound (46% yield) as a solid according to the method of reference example 31.
(Reference Example 64) 1- (4,6-diphenyl-3-yl) piperidine-4-carboxylic acid PCT WO2007 / 130383, filed herein described 3-chloro-4,6-diphenyl pyridazine and commercially available ethyl 4 using piperidine carboxylate was obtained according to the method of reference example 17 amorphous product (53% yield). Using the obtained amorphous product was quantitatively give the title compound according to the method of Reference Example 13.
(Reference Example 65) 3-chloro-6-ethyl-4-phenyl-pyridazin PCT WO2005 / 072 740, filed specification described using 3,6-dichloro-4-phenyl pyridazine, according to the method of Reference Example 14 Solid ( 9.9% yield). The resulting solid was used to afford the title compound according to the method of Reference Example 15 (97% yield).
(Reference Example 66) 1- (6-ethyl-4-phenyl-3-yl) piperidin-4-chloro-6-ethyl-4-phenyl-pyridazine and commercial ethyl obtained in carboxylic acid Reference Example 65 using 4-piperidinecarboxylate to yield a solid (61% yield) according to the method of reference example 17. The resulting solid was used to quantitatively give the title compound according to the method of Reference Example 13.

The structural formula of and compounds described in Reference Example shows the physicochemical data are shown below.

Figure JPOXMLDOC01-appb-T000008

Figure JPOXMLDOC01-appb-T000009

Figure JPOXMLDOC01-appb-T000010

Figure JPOXMLDOC01-appb-T000011

Figure JPOXMLDOC01-appb-T000012

Figure JPOXMLDOC01-appb-T000013

Figure JPOXMLDOC01-appb-T000014

Figure JPOXMLDOC01-appb-T000015

Figure JPOXMLDOC01-appb-T000016

Obtained in [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide Reference Example 13 - (Example 1) 1- (5-bromo-3-phenyl-2-yl) -N 1- the (5-bromo-3-phenyl-2-yl) piperidin-4-acetonitrile-carboxylic acid (4 mL) solution obtained in reference example 4 (1S, 3S) -3-amino -N- ethyl cyclohexanecarboxamide (92mg, 0.45mmol), 4- (4,6- dimethoxy-1,3,5-triazin-2-yl) -4-methyl morpholinium chloride (140 mg, 0.45 mmol), triethylamine ( 125 [mu] L, 0.89 mmol) and the mixture was stirred for 14 hours at room temperature. Water (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was added ethyl acetate and triturated. The solid was collected by filtration to give the title compound 103mg (90% yield) as a solid.
Obtained in [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-ethyl-3-phenyl-2-yl) piperidine-4-carboxamide Reference Example 15 - (Example 2) N ethyl 1- using (5-ethyl-3-phenyl-2-yl) piperidine-4-carboxylate, to obtain an amorphous product according to the method of reference example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (38% yield) It was obtained as a solid.
Obtained in [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-methyl-3-phenyl-2-yl) piperidine-4-carboxamide Reference Example 12 - (Example 3) N ethyl 1- (5-bromo-3-phenyl-2-yl) piperidine -4-carboxylate and 2,4,6-trimethyl boroxine, oil in accordance with the method of reference example 11 (yield to obtain the rate 44%). Using the obtained oil, to give an amorphous product according to the method of Reference Example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (58% yield) It was obtained as a solid.
(Example 4) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-phenyl-5-prop-l-yn-l-ylpyridin-2-yl) piperidin-4 carboxamide reference ethyl obtained in example 16 1- (3-phenyl-5-prop-l-yn-l-ylpyridin-2-yl) using piperidine-4-carboxylate, according to the method of reference example 13 to give an oil. Resulting oil and obtained in Reference Example 4 (1S, 3S)-3-amino -N- with ethyl cyclohexanecarboxamide, the title compound according to the method of Example 1 (55% yield) solid It was obtained as a.
Obtained in [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide Reference Example 17 - (Example 5) 1- (5-chloro-3-phenyl-2-yl) -N was with ethyl 1- (3-bromo-5-chloro-2-yl) piperidine-4-carboxylate and phenyl boronic acid according to the method of reference example 11 to give a solid (85% yield) . The resulting solid was used to obtain an amorphous product according to the method of Reference Example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (81% yield) It was obtained as a solid.
(Example 6) 1- (3,5-diphenyl-2-yl) -N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidin-4-carboxamide Ethyl obtained in Reference Example 12 using 1- (5-bromo-3-phenyl-2-yl) piperidine-4-carboxylate and phenyl boronic acid to give a solid (83% yield) according to the method of reference example 11. The resulting solid was used to obtain an amorphous product according to the method of Reference Example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (89% yield) It was obtained as a solid.
(Example 7) 1- (6-cyano-5-methyl-3-phenyl-2-yl) -N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide Reference Example using ethyl 1- 4- (5-bromo-6-cyano-3-phenyl-2-yl) piperidine-carboxylate and tetramethyl tin obtained in 19, oil in accordance with the method of reference example 14 was obtained (96% yield). Using the obtained oil, to give an amorphous product according to the method of Reference Example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (90% yield) It was obtained as a solid.
Obtained in [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-methoxy-3-phenyl-2-yl) piperidine-4-carboxamide Reference Example 21 - (Example 8) N methyl using 1- (5-methoxy-3-phenyl-2-yl) piperidine-4-carboxylate, to obtain an amorphous product according to the method of reference example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (51% yield) It was obtained as a solid.
Obtained in [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-phenyl-5-propyl-2-yl) piperidine-4-carboxamide Reference Example 22 - (Example 9) N using ethyl 1- (3-phenyl-5-propyl-2-yl) piperidine-4-carboxylate was to obtain an amorphous product according to the method of reference example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (59% yield) It was obtained as a solid.
Obtained in [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-isopropyl-3-phenyl-2-yl) piperidine-4-carboxamide Reference Example 23 - (Example 10) N ethyl 1- using (5-isopropyl-3-phenyl-2-yl) piperidine-4-carboxylate, to obtain an amorphous product according to the method of reference example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (47% yield) It was obtained as a solid.
(Example 11) 1- (6-cyano-5-ethyl-3-phenyl-2-yl) -N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] piperidine-4-carboxamide Reference Example using methyl 1- (6-cyano-5-ethyl-3-phenyl-2-yl) piperidine-4-carboxylate obtained in 25, to obtain an amorphous product according to the method of reference example 13 . The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (62% yield) It was obtained as a solid.
(Example 12) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-ethyl-6-methoxy-3-phenyl-2-yl) piperidine-4-carboxamide Reference Example using the obtained ethyl 1- (5-ethyl-6-methoxy-3-phenyl-2-yl) piperidine-4-carboxylate in 30 to afford a solid according to the method of reference example 13. The resulting solid and was obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (71% yield) as a solid Obtained.
Obtained in - [({[1- (5-ethyl-3-phenyl-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl cis -4] acetate Reference Example 15 (Example 13) Ethyl using ethyl 1- (5-ethyl-3-phenyl-2-yl) piperidine-4-carboxylate, to obtain an amorphous product according to the method of reference example 13. The resulting amorphous material and Izvestiya Akademii Nauk SSSR, SeriyaKhimicheskaya (1980), 10, 2374-2379. With ethyl (cis-4-aminocyclohexyl) acetate hydrochloride according was obtained quantitatively as a solid the title compound according to the method of Example 1.
Obtained in - [(oxoethyl 2-amino) cyclohexyl cis-4] -1- (5-ethyl-3-phenyl-2-yl) piperidine-4-carboxamide Reference Example 31 (Example 14) N- [cis-4 - ({[1- (5-ethyl-3-phenyl-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] acetic acid and the commercial 7N ammonia - with methanol, example the title compound (71% yield) as a solid in accordance with the first method.
(Example 15) Ethyl 2- [cis-4 - ({[1- (5-ethyl-3-phenyl-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] -2- Mechirupuropano using the obtained ethyl 1- (5-ethyl-3-phenyl-2-yl) piperidine-4-carboxylate in ate reference example 15, to obtain an amorphous product according to the method of reference example 13. The resulting amorphous substance (450 mg, 1.45 mmol) and dichloromethane ethyl obtained in Reference Example 10 2- (cis-4-aminocyclohexyl) -2-methylpropanoate (309 mg, 1.45 mmol) (14 the .5ML) suspension, triethylamine (607μL, 4.35mmol), 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol (395 mg, 2.90 mmol) and 1-ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (557 mg, 2.91 mmol) and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 100 / 0-0 / 100) to give the title compound 526mg (72% yield) as a solid.
(Example 16) 2- [cis-4 - ({[1- (5-ethyl-3-phenyl-2-yl) piperidin-yl] carbonyl} amino) cyclohexyl] -2-methylpropanoic acid [ ethyl 2 obtained in example 15 [cis-4 - ({[1- (5-ethyl-3-phenyl-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] -2-methylprop Noeto (375 mg, 0.742 mmol) in ethanol (4.1 mL) was added aqueous 4N sodium hydroxide (1.69 mL, 6.76 mmol) was added and subjected to microwave irradiation for 30 minutes at 160 ° C.. 6N hydrochloric acid solution was added to the reaction mixture, followed by extraction with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 10 / 0-9 / 1) to give the title compound 319mg (90% yield) as a solid.
(Example 17) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4 carboxamide reference obtained in example 35 1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) was obtained piperidine-4-carboxylic acid and reference example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, to give the title compound (52% yield) as a solid according to the method of example 1.
(Example 18) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (1-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) using piperidine-4-carboxamide reference example ethyl 1- (1-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) was obtained in 36 piperidine-4-carboxylate, to obtain an amorphous product according to the method of reference example 13. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (63% yield) It was obtained as a solid.
(Example 19) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine - ethyl obtained in 4-carboxamide reference example 40 1- (5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) using piperidine-4-carboxylate, of reference example 13 to give a solid (97% yield) according to the method. The resulting solid and was obtained in Reference Example 4 (1S, 3S)-3-using amino -N- ethyl cyclohexanecarboxamide, to give the title compound (84% yield) as a solid according to the method of Example 1 It was.
(Example 20) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (5-phenyl-thieno [2,3-b] pyridin-6-yl) piperidine-4-carboxamide Reference Example the resulting 1- (5-phenyl-thieno [2,3-b] pyridin-6-yl) was obtained piperidine-4-carboxylic acid and reference example 4 in 43 (1S, 3S) -3- amino -N - with ethyl cyclohexanecarboxamide was obtained the title compound according to the method of example 1 (80% yield).
(Example 21) N - [(1S, 3S) -3- carbamoyl cyclohexyl] -1- (5-phenyl-thieno [2,3-b] pyridin-6-yl) obtained in-4-carboxamide Reference Example 43 obtained 1- (5-phenyl-thieno [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid and obtained in reference example 6 (1S, 3S) -3- amino cyclohexanecarboxamide hydrochloride used to obtain the title compound (80% yield) as a solid according to the method of example 1.
(Example 22) Ethyl 2-methyl-2- [cis-4 - ({[1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl } amino) cyclohexyl] obtained in propanoate reference obtained in example 35 1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid and reference example 10 using ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate, the title compound according to the method of example 1 (77% yield).
(Example 23) 2-Methyl-2- [cis-4 - ({[1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] ethyl obtained in propanoic acid example 22 2-methyl-2- [cis-4 - ({[1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl ) piperidin-4-yl] carbonyl} amino) cyclohexyl] using propanoate to give the title compound (32% yield) as a solid according to the method of example 16.
(Example 24) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenyl--1H- pyrrolo [2,3-b] pyridin-6-yl) in obtained in-4-carboxamide reference example 46 1- (3-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid and reference example 4 the resulting (1S, 3S)-3-using amino -N- ethyl cyclohexanecarboxamide, to give the title compound (80% yield) as a solid according to the method of example 1.
(Example 25) Methyl (1S, 3S) -3 - ({[1- (5- phenyl--1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) cyclohexanecarboxylate reference obtained in example 35 1- (5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid and methyl obtained in reference example 7 (1S , 3S)-3-using aminocyclohexanecarboxylate hydrochloride, the title compound according to the method of example 1 (99% yield).
(Example 26) Methyl (1S, 3S) -3 - ({[1- (3- chloro-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) cyclohexanecarboxylate methyl obtained in example 25 (1S, 3S) -3 - ({[1- (5- phenyl--1H- pyrrolo [2,3-b] pyridin-6-yl) piperidine 4-yl] carbonyl} amino) cyclohexanecarboxylate (120 mg, in dichloromethane (2 mL) solution of 0.26 mmol), under ice-cooling, N- chlorosuccinimide (42 mg, was added to 0.31 mmol), at room temperature 5 hours and the mixture was stirred. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layers were combined, dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n- hexane / ethyl acetate = 9 / 1-1 / 4) to give the title compound 33mg (26% yield).
(Example 27) 1- (3-chloro-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) -N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] methyl obtained in-4-carboxamide example 26 (1S, 3S) -3 - ({[1- (3- chloro-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl ) using piperidine-4-yl] carbonyl} amino) cyclohexanecarboxylate was obtained an amorphous-like material in accordance with the method of reference example 31. The resulting amorphous material and using a commercially available ethylamine (2.0 M tetrahydrofuran) to give the title compound according to the method of Example 1 (12% yield).
(Example 28) Ethyl [cis-4 - ({[1- (3-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino ) cyclohexyl] acetate reference example was obtained in 46 1- (3-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid and Izvestiya Akademii Nauk SSSR, SeriyaKhimicheskaya (1980), 10, 2374-2379. With ethyl (cis-4-aminocyclohexyl) acetate hydrochloride according to quantitatively obtain the title compound according to the method of Example 1.
(Example 29) [cis-4 - ({[1- (3-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] ethyl obtained in acetic acid example 28 [cis-4 - ({[1- (3-methyl-5-phenyl -1H- pyrrolo [2,3-b] pyridin-6-yl) piperidin-4 using yl] carbonyl} amino) cyclohexyl] acetate, the title compound according to the method of reference example 31 (64% yield).
(Example 30) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] obtained in 1- (3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide Reference Example 47 with resulting ethyl 1- (3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate, to obtain a solid according to the method of reference example 13. The resulting solid and was obtained in Reference Example 4 (1S, 3S)-3-using amino -N- ethyl cyclohexanecarboxamide was obtained the title compound according to the method of Example 1 (85% yield) .
(Example 31) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide Reference obtained in example 50 1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) obtained piperidine-4-carboxylic acid and reference example 4 (1S, 3S) -3-amino using -N- ethyl cyclohexanecarboxamide was obtained the title compound according to the method of example 1 (86% yield).
(Example 32) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-ethyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxamide Reference using the obtained ethyl 1- (6-ethyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylate in example 51, an amorphous product according to the method of reference example 13 Obtained. The resulting amorphous material and obtained in Reference Example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound according to the method of Example 1 (62% yield) Obtained.
(Example 33) Methyl (1S, 3S) -3 - ({[1- (6- methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexanecarboxylate rate reference example was obtained in 50 1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine-4-carboxylic acid and methyl obtained in reference example 7 (1S, 3S) - using 3-amino-cyclohexanecarboxylate hydrochloride, the title compound was obtained according to the method of example 1 (109% yield, 91% purity).
(Example 34) N - [(1S, 3S) -3- (methylcarbamoyl) cyclohexyl] -1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-carboxamide methyl obtained in example 33 (1S, 3S) -3 - ({[1- (6- methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexane with carboxylate was obtained according to the method of reference example 31 amorphous product (yield 95%). The resulting amorphous material and commercially available methylamine (2.0 M tetrahydrofuran solution) was used to afford the title compound according to the method of Example 1 (79% yield).
(Example 35) Ethyl 2-methyl-2- [cis-4 - ({[1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl} amino ) cyclohexyl] propanoate obtained 1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl obtained in reference example 50) piperidine-4-carboxylic acid and ethyl obtained in reference example 10 2- ( using cis-4-aminocyclohexyl) -2-methylpropanoate, the title compound according to the method of example 1 (97% yield).
(Example 36) 2-Methyl-2- [cis-4 - ({[1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidin-4-yl] carbonyl} amino) ethyl obtained cyclohexyl] propanoic acid example 35 2-methyl-2- [cis-4 - ({[1- (6-methyl-3-phenyl-1,8-naphthyridin-2-yl) piperidine -4 - using yl] carbonyl} amino) cyclohexyl] propanoate to give the title compound (75% yield) as a solid according to the method of example 16.
(Example 37) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] obtained in 1- (6-methyl-3-phenyl-2-yl) piperidine-4-carboxamide Reference Example 52 1- (6-methyl-3-phenyl-2-yl) piperidin-4-obtained carboxylic acid and reference example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, the title compound (83% yield) as a solid according to the method of example 1.
(Example 38) N - [(1S, 3S) -3- carbamoyl cyclohexyl] -1- (6-methyl-3-phenyl-2-yl) was obtained piperidin-4-carboxamide Reference Example 52 1- using (6-methyl-3-phenyl-2-yl) piperidine-4-carboxylic acid and obtained in reference example 6 (1S, 3S) -3-amino-cyclohexanecarboxamide hydrochloride the process of example 1 to give the title compound (86% yield) according to.
(Example 39) Ethyl 2-methyl-2- [cis-4 - ({[1- (6-methyl-3-phenyl-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoate Reference obtained in example 52 1- (6-methyl-3-phenyl-2-yl) piperidine-4-carboxylic acid and ethyl obtained in reference example 10 2- (cis-4-aminocyclohexyl) -2- using methyl propanoate, the title compound according to the method of example 1 (95% yield).
(Example 40) 2-Methyl-2- [cis-4 - ({[1- (4-6-methyl-3-phenyl-2-yl) piperidin-yl] carbonyl} amino) cyclohexyl] Embodiment propanoic acid ethyl obtained in example 39 2-methyl-2- [cis-4 - ({[1- (6-methyl-3-phenyl-2-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] propanoate It was used to obtain the title compound (77% yield) as a solid according to the method of example 16.
(Example 41) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4 carboxamide reference example 56 obtained in 1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) was obtained piperidine-4-carboxylic acid and reference example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, according to the method of example 1 to give the title compound (79% yield) as a solid.
(Example 42) N - [(1S, 3S) -3- carbamoyl cyclohexyl] -1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide Reference Example 1 obtained in 56 (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) was obtained piperidine-4-carboxylic acid and reference example 6 (1S, 3S) -3- using amino cyclohexanecarboxamide hydrochloride, according to the method of example 1 to give the title compound (56% yield).
(Example 43) Ethyl 2-methyl-2- [cis-4 - ({[1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl } amino) cyclohexyl] obtained in propanoate reference example 56 obtained in 1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid and reference example 10 using ethyl 2- (cis-4-aminocyclohexyl) -2-methylpropanoate, the title compound according to the method of example 1 (90% yield).
(Example 44) 2-Methyl-2- [cis-4 - ({[1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4-yl] carbonyl} amino) cyclohexyl] ethyl obtained in propanoic acid example 43 2-methyl-2- [cis-4 - ({[1- (3-methyl-5-phenylfuro [2,3-b] pyridin-6-yl ) piperidin-4-yl] carbonyl} amino) cyclohexyl] using propanoate to give the title compound (67% yield) as a solid according to the method of example 16.
(Example 45) 1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) -N - [(1S, 3S) -3- (ethyl carbamoyl) cyclohexyl] obtained in-4-carboxamide reference example 58 1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine -4 - obtained in the carboxylic acid and reference example 4 (1S, 3S)-3-using amino -N- ethyl cyclohexanecarboxamide, according to the method of example 1 to give the title compound (70% yield).
(Example 46) N - [(1S, 3S) -3- carbamoyl cyclohexyl] -1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl ) was obtained piperidin-4-carboxamide reference example 58 1- (3,3-dimethyl-5-phenyl-2,3-dihydrofuro [2,3-b] pyridin-6-yl) piperidine-4-carboxylic acid and using obtained in reference example 6 (1S, 3S)-3-amino-cyclohexanecarboxamide hydrochloride, according to the method of example 1 to give the title compound (47% yield).
(Example 47) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidin-4 carboxamide reference example 60 obtained in 1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) was obtained piperidine-4-carboxylic acid and reference example 4 (1S, 3S) using 3-amino -N- ethyl-cyclohexanecarboxamide, according to the method of example 1 to give the title compound (75% yield).
(Example 48) N - [(1S, 3S) -3- carbamoyl cyclohexyl] -1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) piperidine-4-carboxamide Reference Example 60 obtained in 1- (3-ethyl-5-phenylfuro [2,3-b] pyridin-6-yl) was obtained piperidine-4-carboxylic acid and reference example 6 (1S, 3S) -3- using amino cyclohexanecarboxamide hydrochloride, according to the method of example 1 to give the title compound (83% yield) as a solid.
(Example 49) N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl ] obtained 1 piperidin-4-carboxamide reference example 62 [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidine-4-carboxylic acid and reference examples using obtained in 4 (1S, 3S)-3-amino -N- ethyl-cyclohexanecarboxamide, to give the title compound (83% yield) as a solid according to the method of example 15.
(Example 50) Ethyl {cis-4 - [({1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl} carbonyl) amino] cyclohexyl} was obtained in acetate reference example 62 1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidine-4-carboxylic acid and Izvestiya Akademii Nauk SSSR, SeriyaKhimicheskaya (1980), using ethyl (cis-4-aminocyclohexyl) acetate hydrochloride according 10,2374-2379, gave the title compound according to the method of example 1 (84% yield).
(Example 51) N-[cis-4- (2-amino-2-oxoethyl) cyclohexyl] -1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2 yl] was obtained piperidin-4-carboxamide reference example 63 {cis-4 - [({1- [3-phenyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-2-yl] piperidin-4-yl} carbonyl) amino] cyclohexyl} acetic acid and commercial 7N ammonia - methanol solution was used to obtain the title compound according to the method of example 1 (59% yield) as a solid.
(Example 52) 1- (4,6-diphenyl-3-yl) -N - [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] 1 obtained in-4-carboxamide Reference Example 64 - (4,6-diphenyl-3-yl) obtained piperidine-4-carboxylic acid and reference example 4 (1S, 3S) -3- using amino -N- ethyl cyclohexanecarboxamide, example 15 the title compound according to the method (64% yield) as a solid.
Obtained in [(1S, 3S) -3- (ethylcarbamoyl) cyclohexyl] -1- (6-ethyl-4-phenyl-pyridazin-3-yl) piperidine-4-carboxamide Reference Example 66 - (Example 53) N 1- using (6-ethyl-4-phenyl-3-yl) piperidine-4-carboxylic acid and obtained in reference example 4 (1S, 3S) -3-amino -N- ethyl-cyclohexanecarboxamide, to give the title compound (80% yield) according to the method of example 15.

The structural formulas and physicochemical data of the compounds described in the Examples below.

Figure JPOXMLDOC01-appb-T000017

Figure JPOXMLDOC01-appb-T000018

Figure JPOXMLDOC01-appb-T000019

Figure JPOXMLDOC01-appb-T000020

Figure JPOXMLDOC01-appb-T000021

Figure JPOXMLDOC01-appb-T000022

Figure JPOXMLDOC01-appb-T000023

Figure JPOXMLDOC01-appb-T000024

Claims (10)

  1. Compound or pharmacologically acceptable salt thereof represented by the general formula (I).
    Figure JPOXMLDOC01-appb-C000001

    {Wherein, R 1, R 2, R 3, and R 4 are each independently a hydrogen atom, a halogen atom, a cyano group, C 1 -C 6 optionally substituted by an alkoxy group C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 alkyl optionally ethynyl group optionally substituted with a group, or a phenyl group,
    X 1 and X 2 represents a carbon atom or a nitrogen atom,
    Y is optionally substituted with 1 to 3 groups selected from Substituent group alpha C 1 -C 6 alkyl group, C 1 -C 6 alkyl optionally substituted by a carboxy group with a group, or a C optionally substituted by 1 -C 6 alkyl group represents a carbamoyl group,
    n is 0 or 1,
    (I) when n is 0:
    Ring A form a heterocyclic ring of unsaturated 5-membered X 1 and X 2 are adjacent, R 2 and R 4, together with the carbon atom or nitrogen atom of the ring to which they are attached, may form a hydrocarbon ring or heterocyclic ring of 5 to 6 membered saturated or unsaturated, hydrocarbon ring or heterocyclic ring formed is optionally substituted with a group selected from substituent group β it may be.
    (Ii) when n is 1:
    Ring A to form a hydrocarbon ring or heterocyclic ring 6 membered unsaturated, R 3 and R 4, together with the carbon atom or nitrogen atom of the ring to which they are attached, a saturated or unsaturated it may form a hydrocarbon ring or heterocyclic ring of 5-membered to 6-membered, hydrocarbon ring or heterocyclic ring formed may be substituted with a group selected from the substituent group beta.
    Substituent group α represents a hydroxyl, C 1 -C 6 alkyl group, C 1 -C 6 alkyl group optionally substituted carboxyl group, and C 1 -C 6 alkyl carbamoyl group which may be substituted with a group representing the.
    Substituent group β represents a halogen atom, and 1 to 3 halogen atoms which may be substituted C 1 -C 6 alkyl group. }
  2. X 2 X 1 is a carbon atom is a carbon atom, a compound or a pharmacologically acceptable salt thereof according to claim 1.
  3. n is 1, compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 2.
  4. Ring A is a heterocyclic 6-membered unsaturated compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3.
  5. R 3, ring carbon atoms or a hydrogen atom of the ring R 4 and they are attached to form together is, is a furan ring, dihydrofuran ring, thiophene ring, pyrrole ring, pyridine ring, or a benzene ring the compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4.
  6. Compound or pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient having the general formula (I).
  7. For use for preventing or treating a disease mediated by prostaglandin E 2, the pharmaceutical composition according to claim 6.
  8. Diseases mediated by prostaglandin E 2 are, rheumatoid arthritis, osteoarthritis, arthritis associated inflammatory disease, inflammatory bowel disease, ulcerative colitis, dermatitis, including psoriasis, eczema, edema, inflammation sexual pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine headache, joint pain, post-herpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with osteoarthritis, headache, autoimmune hepatitis , gallstone pain, tumorigenesis pain, colorectal cancer, ovarian carcinoma, breast cancer, in the stomach associated with cancer metastasis and familial adenomatous polyposis, scleroderma, atherosclerosis, and myocardial infarction associated therewith, stroke, abdominal aortic aneurysm, apnea syndrome, respiratory distress syndrome, chronic obstructive pulmonary disease, sudden infant death syndrome, asthma, fever, inflammatory anorexia, multiple sclerosis, or Alzheimer's disease, a pharmaceutical according to claim 7 Narubutsu.
  9. Diseases mediated by prostaglandin E 2 are, rheumatoid arthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease, ulcerative colitis, inflammatory pain, autoimmune hepatitis, multiple sclerosis, or psoriasis a dermatitis containing pharmaceutical composition according to claim 7 or claim 8.
  10. An effective amount of a compound or a pharmaceutical composition containing a pharmacologically acceptable salt thereof as an active ingredient having the general formula (I) which comprises administering to a mammal, prevention or treatment method for inflammatory diseases.
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