CZ20003448A3 - Nociceptin antagonist, amide derivative, pharmaceutical preparation, process, use and commercial package - Google Patents

Abstract

The compound represented by the general formula (1 ') and nociceptin antagonists containing compounds (1 ') as the active ingredient wherein R 2 represents preferably hydroxylated lower alkyl, amino, etc .; circle B represents phenyl, thienyl, etc .; E represents a single bond, -O-, - S-, etc .; ring G represents aryl, heterocycle, etc .; R5 represents a halogen atom, a hydroxy group, a lower one an alkyl group preferably substituted by, for example, an atom halogen, etc .; t is 0 or a natural number from 1 to 5, that when t is from 2 to 5, then R5 must be the same or different value; m is 0 or a natural number from 1 to 8; and n is 0 or a natural number from 1 to 4. The compound (1 ') is used for its own analgesic effect on actual pain, such as postoperative pain, nociceptin inhibitory effect. Use specific amide derivatives include compounds (1 ') such as antagonists nociceptin or analgesic agents.

Description

The present invention relates to a nociceptive antagonist comprising a novel amide derivative or a pharmaceutically acceptable salt thereof. In particular, the present invention relates to an analgesic as an active ingredient, a novel amide derivative or a pharmaceutically acceptable salt thereof, which exhibits an analgesic effect as a nociceptive antagonist which selectively acts on the opioid receptor as a 1 receptor and which are useful for treating pain, particularly severe pain or pain caused by nerve abnormality sensors such as hyperalgesia and allodynia. In addition, the present invention relates to a novel use of some kinds of amide derivative as a nociceptive antagonist and analgesic.

BACKGROUND OF THE INVENTION

Pain is a human perception and is an important life signal or a warning signal.

Pain is caused by injury, surgery, inflammation and the like, as well as chronic pain can come from injury, dysfunction and the like, after the recovery of injured nerves and is one of the major clinical problems. Chronic pain sometimes causes spontaneous disorder, dyskensia or mental disorder, where the actual pain is caused by various diseases.

There is also a known existence of pain caused by nerve abnormality sensors, such as hyperalgesia associated with increased support for responses to a common pain stimulus response, allodynia, where pain is felt in response to a stimulus that is not normally caused by pain, and the like.

Analgesics are divided into central analgesics and peripheral analgesics according to their main sites. Because the cause of the pain is a complicated sequence of autonomic nerve reactions, sensations, and the like, a sedative, anxiolytic, antidepressants, hypnotics, anticonvulsant drug, vasodilator drug and the like are used as analgesic adjuvants.

Central analgesics are roughly divided into narcotic analgesics, non-narcotic analgesics and antipyretic analgesics.

Narcotic and non-narcotic opioids are used to treat serious diseases such as post-operative pain and myocardial infarction, burns and the like. These analgesics show

* * remarkable effects resulting from the strong effect of analgesics combined with an effect that eliminates the fear of pain. On the other hand, narcotic analgesics accompany physical dependence and mental dependence and clearly cause drug addiction syndrome. Another side effect is stopping breathing, nausea, vomiting, constipation, dysuria and the like, which limits their use.

The antipyretic analgesic is effective for superficial pain, such as toothache, myalgia and the like, but is considered ineffective for pain within the body. Its antipyretic effect is considered to be the focus at the hypothalamic thermoregulatory center and the analgesic effect is predominantly spread through the peripheral nerves. However, there are many unknown sites in this efficient central mechanism. Its analgesic effect is generally weaker than that provided by narcotic and non-narcotic opioids. Consequently, severe pain is carefully treated with narcotic and non-narcotic opioids in clinical situations to the extent that it causes minor side effects.

Although it has been more than 20 years since the analgesic effect of morphine given to humans in a capsule has been described, morphine was first administered in clinical situations. Pharmaceutical agents overcoming morphine under conditions of various side effects, such as spinal cord histotherapy and the like, which accompany the analgesic effect of morphine have not been found.

Some pain caused by injury and nerve function injury and the like is resistant to commonly administered analgesics in clinical use, such as an antipyretic analgesic and narcotic analgesic, and does not exhibit a significant side effect of the analgesic.

Again, the inventors seek a desire for a safe and effective analgesic, particularly a strong analgesic without side effects, and an analgesic to treat the pain caused by nerve abnormality sensors such as hyperalgesia, allodynia and the like.

The pain is that the nature of the pain that is released in the event of a tissue disorder caused by a nociceptive stimulus (chemical stimulus, mechanical stimulus, thermal stimulus) excites the nociceptors (free nerve endings) on the nerve endings of the sensors and is recognized as pain. Further, gut pain is considered to cause smooth muscle contraction in the gut that mechanically elongates and excites nerve sensors.

Pain perception is usually transmitted by two types of thin nerve fibers Αδ and C fibers, where sharp pain mechanically stimulates the controlling myelin Αδ fiber and blunts the pain of the controlling non-myelin C fiber. Typical painfulness includes bradykinin, serotonin, histamine and the like that acts on the nociceptor at the nerve end. There is an essence that arouses the effect of a painful essence, such as the synthesis of prostaglandin at an inflamed site in the peripheral

9 9 9

9 9 · · ·

9 9 9 9 9 9 • 9 9 999 99 9 tissue. Such afferent fiber pain (primary afferent fiber) creates a synapse on the surface of the dorsicoma layer. The primary afferent fiber excites the nociceptive neuron via neurotransmitters such as the irritating amino acid, the nature of P, and the like, and information is transmitted from dorsicorn to the medulla of the elongated spinal cord, thalamus, and to the cerebral cortex.

The perception of compression and touch is predominantly transmitted by thicker Αβ fibers, which transmit information from terminal nerve sensors to the dorsicoma, the medulla oblongata, thalamus, and to the cerebral cortex such as afferent fiber pain.

Opioid receptors involved in algesia exist in different parts of these spinothalamic tracts. The effect of respiratory depression, the effect of the emetic and the like results from efficacy at the opioid receptor in the medulla of the spinal cord. While the opioid affects the spinal cord, the medulla of the spinal cord, the thalamus and the cerebral cortex to exert a strong analgesic effect, suppressing the thalamus and cerebral cortex is not its main effect. Direct suppression of opioid receptors in dorsicomic neuron and suppression of dorsicomic neuron by decreasing compression across the midbrain and medulla of the medulla oblongata are considered to be the main activity.

Touch perception tends to dull when sustained stimulus of the same intensity. This adaptation is impossible in the case of pain, but in sustained release of neurotransmitters by long-term stimulation of nerve sensors, it is considered to indicate chronic pain by changing exciters or by transmitting nerve cell efficiency efficiently. Further, inhibitors of neurotransmitters, such as γ-aminobutyric acid (GABA), glycine and the like, suppress nerve irritation upon activation of each receptor. While allodynia is considered to be partially induced by the blunting suppression of neurotransmission caused by repeatedly applied stimuli to the nerve sensor, the mechanism of the onset of chronic pain, hyperalgesia and allodynia was only known to some degree.

As already described, the transmissive nerve sensor is controlled by the excitatory nerve fiber and the nerve fiber inhibitor is complicated by interactions with each other and it has been found that there may be many damaged neurotransmitters as disclosed herein. For this reason, there are many useful targets for finding a pharmaceutical agent enhancing effective analgesic activity.

The subsequent discovery of brain morphine receptors in 1973, enkephalin, which is an endogenous pentapeptide having an analgesic effect, was first discovered and isolated in 1975. Today, more than 20 types of morphine-mimetic peptides are known in the category of opioid peptides that inhibit the transmission of algesia information.

• ·

These opioids include a morphine effect on the opioid receptor. The opioid receptor is known to include several subtypes where morphine has a high affinity for the β receptor, enkephalin shows a high affinity for the δ receptor, and dynorphin exhibits a high affinity for the κ receptor, which consists of bases of these substances.

It has long been known that the involvement of μ receptors between these receptors is interesting because of the analgesic effect and the mechanism of these receptors has mostly been elucidated. Studies on the elimination of capability-inducing syndrome and the like of each subtype using an opioid antagonist found to be morphine-dependent is predominantly related to µ receptor activity.

An opioid receptor such as the 1 (ORL-1) receptor has a high similarity to the opioid receptor but is not associated with conventional opioid ligands. This receptor was cloned in 1993. * 1 * 2 in 1995, a 17 amino acid peptide was isolated as an endogenous ORL-1 receptor ligand and structurally characterized and named Nociceptin or Orphanin FQ * 3 * 4 (* 1; FEBS Lett. , 341, 33-38, 1994) (* 2; FEBS Lett., 347, 284-288, 1994) (* 3; Nature, 377, 523-535, 1995) (* 4; Science, 270, 792-794) , 1995).

The nociceptin amino acid sequence is similar to Dynorphin A, which is an endogenous opioid peptide. Dynorphine A is a κ receptor antagonist exerting an analgesic effect but is weakly associated with the ORL-1 receptor and is known not to have * 5 activity. Nociceptin is extremely weakly bound to the opioid receptor * 6 and algesia tests include hot plate test * 7 using the mouse, scratches on the tail with both hind limbs and twitch hind limbs (SBL) test * 8 inducing behavior and the like and have a revealing effect on their supporting the transmission of pain information. These reports show that nociceptin and the ORL-1 receptor have specific affinity for each other and nociceptin was a peptide that induced or enhanced pain and vice versa, depending on the role of the opioid peptide. He is now researching the study of this mechanism's activities. (* 5; Eur. J. Pharmacoal., 321, 97, 1997) (* 6; J. Biol. Chem., 271,23642, 1996) (* 7; Anesthesia, 45, 1060-1066, 1996) (* 8; 18 ^th Analgesic (Opioid Peptide Symposium Abstract, 11-14, 1997).

The ORL-1 receptor is known for more accurate central nervous system activity such as cerebral cortex, hypothalamus, spinal cord and the like * 9 and nociceptin exhibits greater distributability on the dorsicoma superficial layer where the afferent fiber terminates primary pain * 10 and algesia transmission of nociceptin is mainly caused by the central nervous system (* 9; J. Neurochemistry, 64, 34-40,1995) (* 10; Neuro Report 7,3021-3025, 1996).

• · · · · · · · · · · · φφφφφφφφφφφφφφφφφ

5 Φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Nociceptin administration has also been found to induce nociceptive hypersensitivity (hyperalgesia * 3 * 4, allodynia * 11) and to enhance excitatory stimulus by heating and touch (* 11; Molecular Brain Research, 43, 96-104,1996),

According to circumstances, known agents that enhance nociceptin antagonist activity are known to be only nociceptin-like polypeptides and benzoylhydrazone naloxane, both having ORL-1 receptor affinity, and pharmaceutical agents having specific ORL-1 receptor antagonist activity have not yet been discovered.

Known analgesics having a quinoline skeleton include an opioid or anesthetic analgesic antagonist. 63-264460 (EP 277794; BOC Inc.)], analgesics having a different mechanism mechanism [Japanese Patent Unexamined Publication No. 62-503030 (US 5104884; Alkaloida Vegyeszeti Gyar, antifungal activity), WO96 / 13485 (EP 807105; Fujisawa Pharmacutical Industries, Ltd., bradykinin antagonist), WO 96/11930 (Smithkline beecham PLC, serotonin receptor antagonist), Japanese Patent Unexamined Publication no. No. 59-210084 (US 4839366; Chiesi Pharmaceuticals S. p. A., Inhibition of Prostaglandin Synthesis), Japanese Patent Unexamined 54-73784 (US 4293549; Leo Pharmaceutical Products Limited A / S), FR1557928 and FR1543405 (M. Robert ARIES) and the like]. These do not include compounds having the structure of the disclosed compound, nor do they report the activity of nociceptin or ORL-1 receptors, as in the present invention.

A compound having a quinoline skeleton structurally similar to that of the present invention can be used for the effects other than analgesic effects disclosed in DE 831100 and DE 947552 (anti-blood parasitic agent), WO97 / 14681 (therapeutic agent of bone metabolism abnormality), Japanese Patent Unexamined 2167265 (US 5019574; psychoneurotic function enhancing agent), Journal of American Chemistry Society (76, 3703-3708, 1956) (antibacterial agent), HU34479 {discovery of the quinoline skeleton as a synthetic intermediate for the imidazo [4,5-c] quinoline derivative ( analgesic), and the like, although none describes efficacy as an analgesic.

SUMMARY OF THE INVENTION

A pharmaceutical agent having an antagonistic nociceptin effect, as previously described, can provide an effective pain reliever, in particular against acute pain, such as surgical pain or pain caused by nerve abnormality sensors, such as Hyperalgesia and allodynia and the like, and a safe pharmaceutical agent exhibiting a selective effect on the ENT. · · · · · · · · · · · · · -1 receptor and is without significant side effects.

Thus, the present invention provides a pharmaceutical agent having a mechanism effect different from known analgesics and leading to an antagonistic nociceptin effect.

The present invention also provides a novel compound having an antagonistic nociceptin effect, which is useful as an analgesic.

As a result of an intensive study by the inventors of the present invention in an attempt to solve the above problems, the present invention now provides a novel compound having an analgesic effect.

Specifically, the present invention provides the following (1) to (20).

(1) A nociceptin antagonist comprising an amide derivative of the Formula 1

where

R and R are the same or different and each is hydrogen, lower alkyl preferably substituted by hydroxy, amino, lower alkylamino or di (lower) alkylamino;

R ³ and R ⁴ are the same or different and each is hydrogen or lower alkyl;

ring A is aryl or a heterocyclic group;

ring B is phenyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl or cyclohexenyl; and

X is hydrogen, halogen atom, lower alkyl optionally substituted lower alkoxy, lower alkenyl, amino, cyano or a group of formula • · * - (CH _{2) m} -E

wherein E is a single bond, carbonyl, sulfinyl, -O-, -S-, -NHCO-, CH = CR ⁶ -, wherein R ⁶ is hydrogen, aryl or -NR ⁷ , wherein R ⁷ is hydrogen, lower alkyl or lower alkoxycarbonyl; ring G is aryl, heterocyclic, cycloalkyl or fused aryl;

R ⁵ is hydrogen, hydroxy, lower alkyl preferably substituted by any halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy preferably substituted by lower alkoxy, lower alkoxy preferably substituted by lower alkoxy, amino, lower alkylamino, di (lower) alkylamino, nitro, nitro, nitro, lower alkanoyl, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, lower alkylsulfonyl or phenyl;

T is O or a natural number from 1 to 5 which determines the number of substituents on ring G, wherein when t is a natural number from 2 to 5, each R ⁵ may be the same or different;

M is O or a natural number from 1 to 8; and N is 0 or a natural number of from 1 to 4, or a pharmaceutically acceptable salt thereof, as the active ingredient.

(2) A nociceptin antagonist comprising the amide derivative (1) above, wherein Ring A is quinolyl or a pharmaceutically acceptable salt thereof as an active ingredient.

(3) A nociceptin antagonist comprising the amide derivative (1) above, wherein ring B is phenyl and X is a group of the formula (CH ₂ ) mE- (CH ₂ ) _n

G - (R ⁵⁾ _t • · · · · wherein E, ring G, ^R5, t, m and n are as defined in (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

(4) A nociceptin antagonist comprising the amide derivative (3) above, wherein Ring A is

wherein ^R8 is lower alkylthio, or a pharmaceutically acceptable salt thereof as an active ingredient.

(5) an amide derivative of the general formula 1 '

_{(CH2) m} -E- (CH _{2) n}

wherein R ² , ring Β, E, ring G, R ⁵ , t, m and n are as defined in (1) or a pharmaceutically acceptable salt thereof.

(6) the amide derivative (5) above, wherein ring B is phenyl and R ² is lower alkyl or a pharmaceutically acceptable salt thereof.

(7) the amide derivative (6) above, wherein the amino group is substituted at the 4-position with a quinoline backbone, R ² is methyl substituted at the 2-position with a quinoline backbone, E is -O- and ring B is phenyl having a substituent of the general formula · • ·

- (CH _{2) m} -O- (CH _{2) n}

wherein ring G, R ⁵ , t, m and n are as defined in (1) at the 2-position or a pharmaceutically acceptable salt thereof.

(8) the amide derivative (7) above or a pharmaceutically acceptable salt thereof, which is obtained from the group consisting of

N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2 (4-dichlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2- (phenoxymethyl) benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) - 2 - [(4-methoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3,5-dimethylphenoxy) methyl] benzamide hydrochloride, N- (4-amino) 2-methyl-6-quinolyl) -2 - [(3,4-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-nitrophenoxy) methyl] ] benzamide,

N- (4-amino-2-methyl-6-quinolyl) -2 - [(2,3-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2- [ (3-methylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3,5-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl) 6-quinolyl) -2 - [(4-chlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-acetylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-hydroxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-methoxymethoxyphenoxy) ) methyl] benzamide hydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-methoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4 -cyanophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-methylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6- quinolyl) -2 - [(4-trifluoromethylphenoxy) methyl] benzamide hydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2 -nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-acetoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6- quinolyl) -2 - [(2-methoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-aminophenoxy) methyl] benzamide dihydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-chlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4 -fluorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3,4-dichlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl- 6-quinolyl) -2 - [(2-chlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-dimethylaminophenoxy) methyl] benzamide dihydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2 - ((4-tert-butylphenoxy) methyl) benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2- ( 4-Biphenylyloxymethyl) benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-isopropylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) ) -2 - [(4-nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-bromophenoxy) methyl) benzamide hydrochloride, N- (4-amino) 2-methyl-6-quinolyl) -2 - [(4-propylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-fluorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-trifluoromethylphenoxy) methyl) benzamide hydrochloride, methyl 4- [2- {N- (4-amino-2-methyl-6) -quinolyl) carbamoyl} benzyloxy] benzoate hydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-iodophenoxy) methyl] benzamide,

N- (4-amino-2-methyl-6-quinolyl) -2- (3-pyridyloxymethyl) benzamide hydrochloride,

4- (2 - {(4-amino-2-methyl-6-quinolyl) carbamoyl} benzyloxy) benzoate hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-cyanophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-mesylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) - 2 - [(2-chloro-4-ethylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-chloro-3-methylphenoxy) methyl] benzamide hydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2 - [(2-chloro-4-methylphenoxy) methyl] benzamide hydrochloride,

N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide,

N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-chloro-3-methylphenoxy) methyl] benzamide; · · · · · · · · · · · · · · ·

4- [2 - {(4-amino-2-methyl-6-quinolyl) carbamoyl} benzyloxy] benzyl acetate hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-hydroxymethylphenoxy)] methyl] benzamide hydrochloride and

N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide monohydrate hydrochloride.

(9) An amide derivative of formula 1 '

wherein ring A, R ² , R ⁵ and t are as defined in (1) or a pharmaceutically acceptable salt thereof.

(10) A pharmaceutical composition comprising any amide derivative of (5) to (9), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(11) A nociceptin antagonist comprising any amide derivative of (5) to (9) and a pharmaceutically acceptable salt thereof, as an active ingredient.

(12) An analgesic comprising any amide derivative of (1) to (9) and a pharmaceutically acceptable salt thereof, as an active ingredient.

(13) A method for expressing a nociceptin antagonist effect, comprising administering any amide derivative of (1) to (9) or a pharmaceutically acceptable salt thereof.

(14) A method for treating pain comprising administering any amide derivative of (1) to (9) or a pharmaceutically acceptable salt thereof.

(15) Use of any amide derivative of (1) to (9) or a pharmaceutically acceptable salt thereof for the preparation of a nociceptin antagonist.

(16) Use of any amide derivative of (1) to (9) or a pharmaceutically acceptable salt thereof for the preparation of an analgesic.

(17) A pharmaceutical composition for antagonistic nociceptin which comprises any amide derivative of (1) to (9) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

· 9 · 9 9 (9 9 9 9 9 9 9 ((((((((((( 18) A commercial kit comprising the pharmaceutical composition (17) and the instructions included therein, the instructions indicate that the pharmaceutical composition can be used for antagonistic nociceptin.

(19) A pharmaceutical composition for analgesic use comprising any amide derivative of (1) to (9) and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

(20) A commercial kit comprising the pharmaceutical composition of (19) and the instructions included therein, the instructions indicating that the pharmaceutical composition can be used for analgesia.

Each substituent and portion of the molecule used in the present invention is defined as follows.

Halogen is fluorine, chlorine, bromine and iodine. VR ^3, R ^{4, R 5,} and R "is preferably a chlorine atom.

Lower alkyl has a linear or branched chain and has from 1 to 6 carbon atoms.

Specific examples of these include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like.

It is more preferably a linear or branched alkyl having from 1 to 4 carbon atoms. VR ³ , R ⁴ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ and R ² 'are more preferably methyl and R ⁵ ' is more preferably methyl or ethyl.

Lower alkoxy has an alkyl moiety as defined above as lower alkyl. Specific examples include methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy and the like.

Lower alkylthio has an alkyl moiety as defined above as lower alkyl. Specific examples include methylthio, ethylthio, propylthio, isopropylthio, tert-butylthio and the like.

More preferably, the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms.

VR ⁸ is more preferably methylthio.

Lower alkanoyl has an alkyl moiety as defined above as lower alkyl. Specific examples include acetyl, propionyl, butyryl, isobutyryl, pivaloyl and the like.

More preferably, the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms.

VR ⁵ is more preferably acetyl.

Lower alkylsulfonyl has an alkyl moiety as defined above as lower alkyl. Specific examples include mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl and the like.

More preferably, the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms.

VR ⁵ is more preferably mesyl.

Lower alkanoyloxy has an alkyl moiety as defined above as lower alkyl. Specific examples include acetoxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy and the like.

4 · 44 44 4

4444 ··· «4 9 · · e · * · · 4 4 ·

More preferably, the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms.

VR ⁵ is more preferably acetoxy.

Lower alkoxycarbonyl has an alkyl moiety as defined above as lower alkyl. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and the like.

More preferably, the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms.

VR ⁵ is more preferably methoxycarbonyl and R ⁷ is more preferably tert-butoxycarbonyl.

Lower alkyl preferably substituted with hydroxy means that the aforementioned lower alkyl is preferably substituted with one or more hydroxy groups and that the shorter alkyl may be unsubstituted. Specific examples include methyl, ethyl, propyl, isopropyl, hydroxymethyl,

1,2-dihydroxyethyl, 2- (hydroxymethyl) butyl and the like.

R ¹ and R ² are more preferably methyl, ethyl, propyl, isopropyl or hydroxymethyl, and more preferably methyl or ethyl.

Lower alkyl preferably substituted with lower alkoxy means the aforementioned lower alkyl preferably substituted with the aforementioned lower alkyl, which includes unsubstituted alkyl. Specific examples include methyl, ethyl, methoxymethyl, ethoxymethyl, 2- (methoxymethyl) butyl and the like.

More preferably, the base of the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms. X is more preferably methoxymethyl.

Lower alkoxy preferably substituted by lower alkoxy means the aforementioned lower alkoxy group preferably substituted by the aforementioned lower alkoxy group, including unsubstituted alkoxy. Specific examples include methoxy, ethoxy, methoxymethoxy, methoxyethoxy, 2- (methoxymethyl) butyloxy and the like.

More preferably, the base of the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms. VR ⁵ is more preferably methoxy or methoxymethoxy.

Lower alkyl preferably substituted by a halogen atom, a hydroxy group, a lower alkanoyloxy group and preferably a lower alkoxy group by a lower alkoxy group means the aforementioned lower alkyl preferably substituted by one or more of the aforementioned halogen atom, a hydroxy group, aforementioned lower alkanoyloxy group and a lower alkoxy group preferably substituted by each lower alkoxy group. it may be the same or different and the lower alkyl may be unsubstituted. Specific examples include methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, methoxyethoxymethyl and the like.

• · · · · · · · · · · · · ·

More preferably, the base of the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms. VR ⁵ is more preferably methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxymethyl, acetoxymethyl, trifluoromethyl or methoxymethoxymethyl, and more preferably ethyl.

Lower alkylamino is a monoalkylamino group wherein the alkyl moiety is defined above as lower alkyl. Specific examples include methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino and the like.

More preferably, the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms.

In R and R, more preferably methylamino.

Di (lower) alkylamino is a dialkylamino group wherein the alkyl moiety is the same or different and is defined above as lower alkyl. Specific examples include dimethylamino, diethylamino, methylethylamino, N-propyl N-isobutylamino and the like.

More preferably, the alkyl moiety is a linear or branched alkyl having from 1 to 4 carbon atoms.

VR ¹ , R ² and R ⁵ are more preferably dimethylamino.

Shorter alkenyl is a linear chain having from 1 to 6 carbon atoms.

Examples of this include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,

1,3-butadienyl, 2,4-butadienyl, 1-pentenyl, 1,3-pentadienyl and 1,3,5-hexatrienyl and the like.

X is more preferably vinyl.

Aryl is an aromatic hydrocarbon group having from 6 to 18 carbon atoms.

Examples of this include phenyl, naphthyl, anthryl, indezyl, azulenyl, fluorophenyl, phenathryl, pyrenyl and the like.

Ring A is more preferably phenyl, naphthyl, more preferably phenyl. Ring G and R ⁶ are more preferably phenyl.

When ring G is phenyl, R ⁵ is more preferably bonded to the para position.

A heterocyclic ring is a cyclic compound having one or more oxygen, nitrogen, and sulfur atoms as a heteroatom, where multiple heteroatoms may be present and the number of atoms included in the ring ranges from 5 to 20. Specific examples include pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, benzimidazolyl, imidazolidinyl, indolnyl, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, chromanyl, morpholinyl, naphthalinyl, phthalazinyl, ththalazinyl, ththalazinyl, ththalazinyl, ththalazinyl, ththalazinyl, 4H-quinolizinyl, carbazolyl, 1,3,5-triazinyl,

2,3-dihydrobenzofuranyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroacrydinyl, 2,3dihydro-1H-cyclopenta [b] quinolyl and the like.

Ring G is more preferably pyridyl, benzofuranyl or 2,3-dihydrobenzofuranyl, more preferably

2.3- dihydrobenzofuranyl.

Ring A is more preferably a cyclic compound comprising one or more nitrogen atoms as heteroatoms and the number of atoms included in the ring ranges from 9 to 14. More preferably, it is quinolyl, isoquinolyl, quinoxalyl, benzimidazolyl, 5,6,7,8-tetrahydroquinolyl, 5 6,7,8-tetrahydroacrydinyl, 2,3-dihydro-1H-cyclopenta [b] quinolyl, more preferably quinolyl, 5,6,7,8-tetrahydroacrydinyl or 2,3-dihydro-1H-cyclopenta [b] quinolyl.

Ring A is quinolyl, it is preferable that R ^{1 is} an amino group which substitutes at the 4-position,

R ² was lower alkyl which substituted at the 2-position and -NHCO- which substituted at the 6-position.

Cycloalkyl is a saturated cycloalkyl having from 3 to 8 carbon atoms, as illustrated by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Ring G is more preferably cyclohexyl.

Fused aryl is aryl as defined above, wherein the cycloalkyl groups as defined above are fused, which is a cyclic compound wherein the number of ring-forming atoms is from 5 to 18. Specific examples include indanyl, 5,6,7,8-tetrahydro-2-naphthyl, , 6,7,8-tetrahydro-3-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro-2-anthryl, 1,2,3-trihydroazulenyl and the like .

Ring G is more preferably 5,6,7,8-tetrahydro-2-naphthyl.

A protected amino group is an amino group protected by an amino protecting group used in typical chemical syntheses. Specific examples of amino protecting groups include formyl, acetyl, benzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, phthaloyl, benzyl, tosyl and the like.

A carboxy-protecting group is a carboxy-protecting group used in typical chemical syntheses. Specific examples of such agents include methyl, methoxyethoxymethyl, phenacyl, phthalimidomethyl, ethyl, 2,2,2-trichloroethyl, 2-methylthioethyl, tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, tert-butyldimethylsilyl and the like.

A hydroxy protecting group is a hydroxy protecting group that is used in typical chemical syntheses. Specific examples of these include trimethylsilyl, tert-butyldimethylsilyl, methyl, benzyl, p-methoxybenzyl, tert-butyl, trityl, tetrahydropyranyl, methoxymethyl, methoxyethoxyethyl, acetyl, benzoyl and the like.

In the above general formulas [1], [1 '] and [1 ”], each symbol is more preferably the following.

Ring G is more preferably aryl.

R ⁵ is more preferably a halogen atom; lower alkyl preferably substituted by a halogen atom, a hydroxy group, a lower alkanoyloxy group and a lower alkoxy group preferably.

substituted lower alkoxy; lower alkoxy preferably substituted by lower alkoxy; nitro; cyano; or a lower alkanoyl group, and more preferably a lower alkyl group optionally substituted with a halogen atom, a hydroxy group, a lower alkanoyloxy group and a lower alkoxy group preferably substituted with a lower alkoxy group.

T is suitably 0 or the natural number 1 or 2, more preferably 1.

E is more preferably a single bond or -O-, more preferably -O-.

When E is -O-, m is more preferably an integer from 1 to 7, more preferably 1 and n is more suitably 0. When E is a single bond, m + n is more preferably 2.

The compound of general formula [1] includes various isomers. For example, there is a geometric isomerism of E and Z when there is asymmetric carbon atom (s), stereoisomer (s) (e.g., enantiomers and diastereomers). Depending on the case, tautomers may exist in the present invention. For this reason, the present invention encompasses all of these isomers and mixtures thereof.

The pharmaceutical salt of the aforementioned substance may be a salt if it is capable of forming a non-toxic salt with the compound mentioned in the general formula [1], [Γ] and [1 ”]. Examples of such materials include salts of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like; an organic acid salt such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, gluconic acid, ascorbic acid, methylsulfuric acid, benzylsulfuric acid and the like; salts with inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide and the like; salts with inorganic bases such as methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline, cinchonine and the like; or amino acid salts such as lysine, arginine, alanine and the like. The present invention further includes compounds comprising water and hydrates and solvates of each compound.

The present invention further encompasses inactive forms of the drugs and metabolites of each compound. An inactive drug form is a compound of the present invention having a degradable chemical or metabolic group and showing efficacy in forming its original form after administration of the drug to a patient, including complexes without covalent bonds and without salts.

When a compound of the present invention is used as a pharmaceutical formulation, it is normally admixed with a conventionally known pharmaceutically acceptable carrier, excipient, filler, disintegrant, stabilizer, preservative, buffer, buffer.

An emulsifier, flavoring agent, coloring agent, sweetener, thickening agent, flavoring agent, solvent, and more. additives, especially water, vegetable oil, alcohol (e.g. ethanol, benzyl alcohol and the like), polyethylene glycol, glycerol triacetate, gelatin, sugar (e.g. lactose, starch and the like), magnesium stearate, talc, lanolin, petrolatum and the like and are put into tablets, pills, powder, granules, suppositories, injections, eye drops, liquid, capsules, lozenges, aerosols, elixirs, suspensions, emulsions, syrups and the like by conventional methods which can be administered systemically or locally by oral or parenteral administration. administration.

Because the dose is dependent on age, body weight, symptoms of therapeutic effect, route of administration, and the like, it is generally from 0.01 mg to 1 g per dose to be administered once or several times a day to adults.

One example of a production method of a compound of the present invention is shown below, but the present invention is not limited to this production method.

In each step, the processing of reaction products may employ techniques such as isolation and purification, crystallization and recrystallization, silica gel liquid chromatography, preparative HPLC and the like, which may be appropriately used and combined. If necessary, the protecting group may be incorporated into functional groups and the protection may be removed after the reaction has been carried out.

Production method

A synthetic method of a compound of the following formula is shown below in the present invention.

R ¹

[i] q

wherein ring A, R, R and R are as defined above.

When Ring A is a quinoline cycle, the following methods were used for synthesis: the synthetic quinoline method of CAMPS, the synthetic quinoline method of COMBES, the synthetic quinoline method of Friedlander, the synthetic quinoline method of Knorra, Synthetic method of quinoline according to Niementowski and similar methods • Synthetic method of quinoline according to Niementowski and similar methods . Part of the compound can be obtained as a commercially available reagent.

The production methods of the quinoline ring having the substituent are set forth below in this invention.

Production method 1-1

In this production method, the β-keto acid ester and aniline react to form 4-hydroxyquinoline.

Wherein R is as defined above, R is lower alkyl and Y is nitro or protected amino.

Step 1

Compound [1-1] and compound [1-2] are condensed in an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol and the like, at room temperature or with heating to give compound [1-3].

Step 2

Compound [1-3] is obtained by production method 1-1 step 1 is added in portions to the heated solvent and cyclization yields compound [1-4].

A suitable solvent is diphenyl ether or a mixture of diphenyl ether and diphenyl such as Dowtherm A (Fluka trademark).

• · • ·

This production method can be applied to compound [1-1], where the α-position of the β-keto acid ester is substituted with a lower alkyl.

Production method 1-2

According to this production method, quinoline is obtained from isatin.

wherein R ³ and Y are as defined above.

Step 1

Compound [1-5], acetone and aqueous ammonia are reacted under pressure and heating to give compound [1-6].

Step 2

The compound [1-6] obtained by Production Method 1-2, Step 1, is reacted in the presence of an oxidizing agent such as sodium hypochlorite, sodium hypobromite and the like under cooling and the resulting reaction mixture is added dropwise to hot water and further heated to form the compound. [1-7].

The following production method can be used to introduce a specific substituent or specific substitution site.

Production method 1-3

According to this production method, 4-hydroxy-2-methoxycarbonylquinoline is obtained from an acetylenedicarboxylic compound and aniline. The methoxycarbonyl group of this compound can be converted by reduction to a hydroxymethyl group in the next step.

• · l „£

H <=

-►

Step 2

CO ₂ Me

I ⁺

CO ₂ Me [1-8]

Krokl

MeO ₂ C

MeO ₂ C [I-10]

MeOgC

Y

R ³ • 5 wherein R and Y are as defined above.

Step 1

Compound [1-8] and compound [1-9] are condensed in the same manner as in Production Method 1-1, step 1 to give compound [1-10].

Step 2

Compound [1-10] obtained by production method 1-3, step 1 is cyclized in the same manner as in production method 1-1, step 2 to give compound [1-11].

Production method 1-4

According to this production method, the 4,6-diaminoquinoline compound is obtained from 4-nitroquinoline N-oxide.

9 9 9 9 9 • • • • • • • • • • • •

Compound [1-12] and metal iron react in an acidic solvent such as hydrochloric acid, acetic acid and the like, upon heating, and the resulting solution after alkalization gives compound [1-13].

Alternatively, typical reductions using tin or stannous chloride and concentrated hydrochloric acid may be used; an alkali metal sulfide such as aqueous sodium sulfide; catalytic reductions and the like.

Step 2

Compound [1-13] obtained by Production Method 1-4, Step 1, is reacted with bromine in acetic acid under cooling or at room temperature to form a halogenated compound [1-14].

Alternatively, a halogenating agent such as hypohalide (e.g. hypochlorite and the like), N-bromosuccinide and the like can be used in place of bromine for halogenation.

Step 3

Compound [1-14] obtained by Production Method 1-4, Step 2 is nitrated using sulfuric acid as solvent and concentrated nitric acid is added under cooling to produce compound [1-15].

Nitric acid or a mixture of inorganic nitrate with sulfuric acid may be used instead of nitration instead of nitric acid-sulfuric acid.

Step 4 φ φ · · • • • • • φ φ φ φ φ φ · · · · φ φ

The compound [1-15] obtained by production method 1-4, step 3 is subjected to catalytic reduction in the presence of a hydrogenation catalyst in an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol and the like by addition of hydrochloric acid or hydrobromic acid in acid acetic at room temperature or with heating and at normal or high pressure to give compound [1-16].

Examples of the hydrogenation catalyst include palladium on carbon, palladium hydroxide, palladium black, Raney nickel, platinum oxide and the like.

Examples of syntheses wherein Ring A is the isoquinoline cycle are given below in the present invention.

Production method 1-5

According to this production method, 1-halo-7-nitroisoquinoline is obtained from tetrahydroisoquinoline.

[Ι-Π] [1-18]

Step 1

Compound [1-17] is nitrated in the same manner as in Production Method 1-4, step 3 to give compound [1-18].

Step 2

The compound [1-18] obtained in Production Method 1-5, step 1 is subjected to dehydrogenation for several days using Fremy's salt in 4% aqueous sodium carbonate solution at room temperature to give compound [1-1].

Step 3

• φ

ΦΦ ΦΦ

The compound [1-19] obtained in Production Method 1-5, Step 2, is reacted with chloroperbenzoic acid in a halogenated solvent such as dichloromethane, chloroform, carbon dioxide and the like at room temperature by N-oxidation to give compound [1-20].

Step 4

The compound [1-20] obtained in Production Method 1-5, step 3, is reacted with phosphoryl chloride in a hydrocarbon solvent such as toluene, xylene and the like and heating to give compound [1-21].

Production Method 1-6

According to this production method, the condensed quinoline compound with cycloalkyl is obtained by condensation of a saturated cyclic ketone and an anthranilonitrile compound.

[1-22]

wherein Y is as defined above and p is 0 or the natural number 1.

An acid catalyst such as a Lewis acid (e.g., zinc chloride) is added to a mixture of compound [1-22] and compound [1-23] and condensation with heating to give compound [1-24].

Production method 1-7

According to this production method, the substituent of the compound is substituted with amino or substituted amino.

♦ · · · ·

[1-29] q o i n wherein ring A, R, R and Y are as defined above, R is hydrogen or lower alkyl and R is lower alkyl.

Step 1

Compound [1-25] obtained by Production Method 1-1 or a commercially available compound is reacted with chlorosulfonyl isocyanate in acetonitrile or dichloroethane to give compound [1-26],

Step 2

Compound [1-25] obtained by Production Method 1-1 or a commercially available compound is reacted with an alkylating agent in a solvent with heating or at room temperature to give compound [1-27].

Dimethylsulfate or methyl p-toluenesulfonate is used as the alkylating agent to introduce the methoxy group in the scheme.

* Σ ς ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο ο

ZJ ··· ·······································

Examples of a suitable solvent include hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; and ether solvents such as 1,4-dioxane, diethyl ether,

1,2-dimethoxyethane, tetrahydrofuran and the like.

Step 3

Compound [1-25] obtained by Production Method 1-1 or a commercially available compound is reacted with a halogenating agent such as phosphoryl chloride, phosphorus fluoride and the like under heating and the reaction mixture is basified to give compound [1-28].

Step 4

The compound [1-28] obtained by the production method 1-5 or the production method 1-7, step 3 or a commercially available compound is reacted with a metal alkoxide in an alcohol solvent such as methanol, ethanol, propanol, butanol and the like and heating to give compound [ 1-27].

Sodium methoxide is used as the metal alkoxide and methanol is used as the solvent, as the appropriate alcohol solvent to introduce the methoxy group, see scheme.

Step 5

The compound [1-27] obtained by the production method 1-7, step 2 or the production method 1-7, step 4 or a commercially available compound is reacted with an amination agent such as ammonium acetate and the like and heating to give compound [1-26].

Step 6

Compound [1-28] obtained by production method 1-7, step 3 or a commercially available compound is reacted with compound [1-29] in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like and heating to give compound [1-30].

Compound [1-25] in this production method 1-7, compound [1-11] can be obtained by production method 1-3.

Production Method 1-8

According to this production method, the amino protecting group is eliminated or the nitro group is reduced.

R ¹ r ² - £ a \ -nh ₂

f) 2 — L Λ — γ

IN

R ³ [1-31]

R ³ [I] · · * φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ ······· ·· ··

Wherein ring A, R, R, R and Y are as defined above.

When Y is a protected amino group, a typical deprotection method is used.

For example, when the protecting group is acetyl, then concentrated hydrochloric acid is added to compound [1-31] obtained by production method 1-7 or a commercially available compound, and the mixture is deacetylated by heating to give compound [I].

Instead of concentrated hydrochloric acid, heating to concentrated ammonium hydroxide, potassium hydroxide and the like can be used.

When Y is a nitro group, a typical method of converting a reduction of a nitro group to an amino group is used. For example, compound [1-31] obtained by production method 1-7 or a commercially available compound is catalytically reduced in a solvent at room temperature or under heating, at normal or elevated pressure using a hydrogenation catalyst, to give compound [I].

Examples of the solvent include ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone and the like; alcoholic solvents such as methanol, ethanol, propanol, butanol and the like; esters such as ethyl formate, ethyl acetate, butyl acetate and the like; water; or mixtures of the above solvents.

The hydrogenation catalyst may be palladium on carbon, palladium hydroxide, palladium black, Raney nickel, platinum oxide and the like.

Production method

The synthetic method of the compound of formula II is shown below.

R ⁴ wherein ring B, R ⁴ and X are as defined above. When X is a group having the general formula · 4 • 4

4 4

4 • 4444 "wherein ring G, R ⁵ are as defined above at which illustrates the following production method. Production method 2-1

According to this production method, methyl or methyl substituted carboxylic acid is converted to ether.

[II-4] wherein ring B, G, R ⁴ , R ⁵ and t are as defined above and Z is a carboxy protecting group.

Step 1

Compound [Π-1] reacts with a radical initiator such as benzoyl peroxide, azobisisobutyronitrile and the like, and with N-bromosuccinide to form compound [H-2].

Step 2

Compound [Π-2] obtained by Production Method 2-1, Step 1 is reacted with Compound [Π-3] in a solvent in the presence of a base such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, potassium hydride, sodium hydride and the like upon heating to give compound [II-4], 94 99

4 4 43 4 4 4 4 9 4

9 9 9 9 9 9 9 rx _O · 9 9 499 94 9 ··· ······· · · 99 99

Examples of the solvent include hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone and the like; alcoholic solvents such as methanol, ethanol, propanol, butanol and the like.

Many compounds of general formula [II-3] can be readily obtained as commercially available compounds, but hardly available compounds can be synthesized by the following production methods.

Production Method 2-2

According to this production method, the cyclic compound having the substituent is halogen substituted.

r5 «

[Π-5] [Π-6] wherein G is as defined above, R ⁵ is lower alkyl and R ⁵ is a halogen atom.

In the same manner as in Production Method 1-4, step 2, compound [II-5] is halogenated to give compound [II-6].

Using sulforyl chloride as the halogenating agent, the compound is halogenated in a halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrachlorethylene and the like to substitute the chlorine atom for the ortho position of the 4-alkyl-substituted phenol.

Production method 2-3

According to this production method, the cyclic compound is substituted with alkylsulfonyl.

[II-7] [Π-8]

Μ4 · <· «· ···· ♦« • «· · · · · · _λ Α 1 ····» ·· ·· ** ♦ * ····· · <9 99 »·· · Wherein ring G is as defined above, Q is a hydroxyl protecting group, and R ¹¹ is lower alkyl.

Krokl

Compound [β-7] is reacted with an alkylsulfonic anhydride such as methanesulfonyl anhydride in a halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, tetrachlorethylene, and the like, and heating to give compound [II-8].

Step 2

The compound [Π-8] obtained by Production Method 2-3, Step 1 is deprotected by a conventional method to give compound [II-9].

For example, when R ¹¹ is methyl, an aqueous solution of hydrogen bromide is added and the mixture is heated or is heated with sodium cyanide in dimethyl sulfoxide to remove the protecting group.

Production method 2-4

According to this production method, a benzofuran compound or a 2,3-dihydrobenzofuran compound is synthesized from a phenolic compound.

Krokl

[II-12] [II-10] [II-11]

[Π-12]

[11-14] [Π-15] where Q is as defined above.

Step 1

The compound [Π-10] is condensed with compound [II-11] in a polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone and the like in the presence of a base such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide , potassium hydroxide, lithium hydride, potassium hydride, sodium hydride and the like upon heating to give compound [11-12].

Step 2 • 9

The compound [Π-12] obtained by Production Method 2-4, Step 1 is cyclized using a condensing agent such as polyphosphoric acid and the like in a hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like to give [ H-13],

Step 3

The compound [Π-13] obtained by production method 2-4, with cork 2, is catalytically reduced in the same manner as in production method 1-4 of cork 4 to give compounds [H-14] and [H-5].

Examples of solvents include, in addition to alcoholic solvents, ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like and the above mixtures and the like.

Production method 2-5

According to this production method, the carboxyl protecting group is eliminated from the compound.

[Π-16] [Π] where ring B, R ⁴ , X and Z are as defined above.

The carboxyl protecting group may be eliminated by a conventional method to remove a protecting group that is dependent on the type of protecting group.

For example, when Z is methyl, compound [11-16] is reacted in an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol and the like in the presence of a base such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like under heating and the resulting solution is acidified to give compound [II].

Production method

According to this production method, the amine compound and the carboxylic acid are condensed to an amide.

• · · · ·

[1] wherein ring A, ring B, R ¹ , R ² , R ³ , R ⁴ and X are as defined above.

Compound [I]

Obtained by production method 1 or commercially available compound [H] are condensed by production method to form an amide.

For example, compound [Π] is reacted with a halogenating agent such as oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorus pentachloride, and the like, in a solvent at room temperature to form the corresponding acid chloride. Then, the compound is condensed with compound [I] in the presence of a tertiary amine such as triethylamine and the like, or pyridine at room temperature or with cooling to give compound [1].

Examples of suitable solvents include halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like, ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like.

Alternatively, compound [I] and compound [II] are reacted in a solvent in the presence of a condensing agent at room temperature to give compound [1]. The synergist can be used for a smooth reaction.

Examples of condensing agents include Ν, Ν'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide, Ν, Ν'-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and the like, and the like and examples synergists include hydroxysuccinimide, 1-hydroxybenzotriazole and the like.

· · · · · · · · · · · · · · · · · · · · · · · · · ·

Examples of suitable solvents include hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as

1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like, polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like, and mixtures of the above solvents.

To obtain the amide by condensation, an increase in yield, a reduction in cost, an increase in production efficiency, a reduction in deprotection, and the like can be used.

For example, when compound [I] and compound [II] have a nitro group, then the nitro group can be reduced after amide formation by condensation or when compound [I] and compound [Π] have a functional group such as hydroxyl and the like, deprotection may be carried out after amide formation by condensation.

Alternatively, the methoxy carbonyl substituted compound obtained by Production Method 1-3 and Production Method 3 is added to an ether solvent such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like to reduce, lithium borohydride is added in portions under an argon atmosphere while cooling to form a hydroxymethyl substituted compound.

DETAILED DESCRIPTION OF THE INVENTION

The compound of formula (1) of the present invention and the above production method are specifically explained in the examples given on the following pages. It will be appreciated that the present invention is not limited to these examples.

Preparation of Example 1-1

Synthesis of 4,6-diamino-2-methylquinoline

The synthesis was performed according to the following citation (Journal of the American Chemical Society, 70,4065,1948).

Step 1

4-Aminoacetanilide (150.2 g, 1 mol) was added to a solution of methyl acetate (136.8 g, 1.1 mol) in methanol (450 mL) and the mixture was refluxed for 17 hours. The reaction flask was cooled to 0 ° C and the resulting white precipitate was collected by filtration to give methyl p- (p-acetmidophenylamino) crotonate (231.5 g, 93%, white crystals).

Step 2 ····· · · · · · · · · · · · · · · · · · ·

* · · · · ·

JJ · · · ···················································

Methyl p- (p-acetmidophenylamino) crotonate (231.5 g, 0.93 mol) obtained in Preparation of Example 1-1, Step 1 was added in small portions to Dowtherm A (Trade Mark, 600 mL), which was heated under reflux condenser. The mixture was heated to reflux for 10 minutes and the reaction mixture was cooled to room temperature. The resulting precipitate was filtered off and washed with ethyl acetate. The obtained crude crystals were suspended in methanol and filtered to give N- (4-hydroxy-2-methyl-6-quinolyl) acetamide (178.3 g, 88%, deep yellow crystals).

Step 3

To a suspension of N- (4-hydroxy-2-methyl-6-quinolyl) acetamide (100 g, 0.46 mol) obtained by the preparation of Example 1-1, Step 2 in toluene (490 mL) was added dimethyl sulfate (75 mL 0). , 79 mol) and the mixture was refluxed for 8 hours. The resulting precipitate was filtered off, dissolved in water (1350 mL) and heated to 70 ° C. The solution was filtered and to the filtrate was added 35% aqueous sodium hydroxide solution (100 mL). The resulting precipitate was filtered to give N- (4-methoxy-2-methyl-6-quinolyl) acetamide (55.3 g, 52%, pale brown crystals).

Step 4

N- (4-methoxy-2-methyl-6-quinolyl) acetamide (55.6 g, 0.24 mol) obtained by the preparation of Example 1-1, step 3 was mixed with ammonium acetate (279.4 g, 3.62) mol) and the mixture was stirred with heating at 135 ° C for 4 hours. To the reaction mixture were added water (280 mL) and concentrated hydrochloric acid (450 mL), and the mixture was stirred with heating at 90 ° C for 5 hours. The reaction mixture was cooled to 0 ° C and the resulting precipitate was filtered off. The obtained crystals were dissolved in boiling water and after addition of activated carbon the mixture was filtered. A 35% aqueous sodium hydroxide solution was added to the filtrate while cooling with ice. The resulting precipitate was filtered off, washed with water and dried under reduced pressure at 100 ° C to give the title compound (28.4 g, 68%, pale yellow crystals).

Preparation of Example 1-2

Synthesis of 4,6-diamino-2-methylquinoline

Step 1

To 5-nitroisatin (19.21 g, 0.1 mol) was added acetone (36.7 mL, 0.5 mol) and aqueous ammonia (100 mL) and the mixture was heated in an autoclave at 100 ° C for 12 hours . The reaction mixture was cooled to room temperature and the resulting crystals were filtered and washed with water.

• · »

• · · ·

4 4 4 94 94

The obtained crystals were dried by heating under reduced pressure to give 2-methyl-6-nitroquinoline-4-carboxamide (18.30 g, 79%).

Step 2

To 2-methyl-6-nitroquinoline-4-carboxamide (231 mg, 1 mmol) obtained by preparation of Example 1-2, step 1, was added aqueous sodium hypochlorite solution (0.851 mL, 1.2 mmol) and the mixture was heated at 0 ° C for 2.5 hours. The reaction mixture was added dropwise to hot water (10 mL) and refluxed for 20 minutes. The reaction mixture was cooled to room temperature, and the resulting crystals were filtered off and dried by heating under reduced pressure to give 4-amino-2-methyl-6-nitroquinoline (177 mg, 88%).

Step 3

4-Amino-2-methyl-6-nitroquinoline (337 mg, 1.7 mmol) obtained in the same manner as in Preparation of Example 1-2, step 2 was dissolved in methanol (15 mL) and 10% palladium on carbon was added. (200 mg) and the mixture was stirred at room temperature at 3 atm under a hydrogen atmosphere for 15 hours. The reaction mixture was suction filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (200 mg, 70%).

Preparation of Example 1-3

Synthesis of 6-amino-2-methyl-4-methylaminoquinoline

Step 1

N- (4-hydroxy-2-methyl-6-quinolyl) acetamide (4.32 g, 20 mmol) and phosphoryl chloride (9.32 mL, 100 mmol) were heated at 100 ° C for 15 minutes. The reaction mixture was cooled to room temperature and poured onto ice water. Aqueous 28% ammonia was added thereto to make the solution alkaline. The resulting insoluble precipitate was filtered off, washed with ether and water and dried under reduced pressure at 80 ° C to give N- (4-chloro-2-methyl-6-quinolyl) acetamide (6.85 g, crude yellow solid).

Step 2

A suspension of N- (4-chloro-2-methyl-6-quinolyl) acetamide (4 g, crude) obtained by preparation of Example 1-3, step 1 and 85% potassium hydroxide (6.6 g, 100 mmol) in N-methylformamide (100 mL) was heated at 170 ° C for 3 hours, 20 minutes. The reaction mixture was cooled to room temperature, the reaction mixture was diluted with chloroform and water. The chloroform layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained black oil was purified by silica gel column chromatography

9 * 9 9 * 9 9

9 9 9 9 (chloroform: methanol = 85:15 -> chloroform: methanol: 28% aqueous ammonia = 85: 15: 0.1) to give N- (2-methyl-4-methylamino) 6-quinolyl) acetamide (255 mg, 9.5% of N- (4-hydroxy-2-methyl-6-quinolyl) acetamide) as a light brown solid.

Step 3

N- (2-methyl-4-methylamino-6-quinolyl) acetamide (248 mg, 1.08 mmol) obtained by preparation of Example 1-3, step 2 was refluxed for 2 hours in 6N hydrochloric acid (10 mL) ). The reaction mixture was cooled to room temperature and a 4N aqueous sodium hydroxide solution was added such that the pH was not less than 13, and the mixture was subsequently cooled with ice. The resulting insoluble precipitate was filtered off and dried under reduced pressure at 60 ° C to give the title compound (202 mg, 99.7%, light yellow).

Preparation of Example 1-4

Synthesis of 4,6-diaminoquinoline dihydrobromide

The synthesis from step 2 to step 4 was performed according to the following reference (Yakugaku Zasshi,

72, 665 (1952).

Step 1

A suspension of 4-nitroquinoline N-oxide (10 g, 52.5 mmol) and iron metal (26.4 g, 0.47 mol) in acetic acid (500 mL) was stirred with heating at 110 ° C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Aqueous sodium hydroxide solution was added to the residue to make the solution alkaline and further extracted with chloroform (50 mL x 6). The organic layer was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give 4-aminoquinoline (6.0 g, 79%, brown crystals).

Step 2

To a solution of 4-aminoquinoline (2.28 g, 15.8 mmol) obtained in Preparation of Example 1-4, Step 1 in acetic acid (30 mL) was added bromine (2.78 g, 17.4 mmol) with stirring ice cooling and the mixture was further stirred at room temperature for 30 minutes. Diethyl ether was added and the resulting precipitate was filtered to give 4-amino-3-bromoquinoline hydrobromide (4.39 g, 91%). The obtained crystals were dissolved in water and 1N aqueous sodium hydroxide solution was added to make the solution alkaline. The resulting precipitate was filtered off, washed with water and dried under reduced pressure to give 4-amino-3-bromoquinoline (2.91 g, 82%, light gray crystals).

Step 3 t

To a solution of 4-amino-3-bromoquinoline (2.90 g, 13 mmol) obtained in the preparation of Example 14, Step 2 in concentrated sulfuric acid (25 mL) was added 60% nitric acid (1.5 mL, 20 mmol). ) with stirring and ice cooling, and the mixture was further stirred for 1 hour. Sodium hydroxide (40 g) was added to the reaction mixture under ice-cooling, and the resulting precipitate was filtered off. The obtained crystals were dissolved in acetone, charcoal was added, and recrystallization gave 4-amino-3-bromo-6-nitroquinoline (1.65 g, 47%, yellow crystals).

Step 4

To a solution of 4-amino-3-bromo-6-nitroquinoline (0.82 g, 3.05 mmol) obtained in the preparation of Example 1-4, step 3 in ethanol (30 mL) was added a solution of 25% hydrogen bromide in acetic acid ( 0.7 ml, 3.05 mmol) and 10% palladium on carbon catalyst and the mixture was subjected to catalytic reduction at room temperature for 6 hours. The catalyst was filtered off and washed with water. The filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from water-ethanol-ethyl acetate to give the title compound (0.92 g, 94%, green-brown crystals).

Preparation of Example 1-5

Synthesis of 1,7-diaminoquinoline

Step 1

Concentrated sulfuric acid (80 mL) was added in small portions to tetrahydroisoquinoline (24.4 g, 183 mmol) under ice-cooling to dissolve. Then, 60% nitric acid (18 mL) was added dropwise from the funnel, and the mixture was stirred under ice-cooling for 3 hours. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water under ice-cooling and 35% aqueous sodium hydroxide was added to adjust the solution to pH 12. After extraction with chloroform, the organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (180 mL) and concentrated hydrochloric acid (20 mL) was added under ice-cooling. The precipitated brown crystals were filtered off under reduced pressure to give 7-nitrotetrahydroisoquinoline hydrochloride (7.18 g, 22%).

Step 2

To the 7-nitrotetrahydroisoquinoline hydrochloride (7.18 g, 33 mmol) obtained in the preparation of Example 1-5, step 1 was added Fremy's salt (100 g, 280 mmol) in 4% aqueous sodium carbonate (1.5 L). The mixture was stirred at room temperature for 7 days and the reaction mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by neutral alumina column chromatography (hexane: ethyl acetate = 3: 2) to give 7-nitroisoquinoline (3.21 g, 55%).

• 4 4 4 4 4 4 4 4 4 44 4444 44 4444 4444 4444 4444 444444

4 · 44 444 4444 44 4 ·

Step 3

To a solution of 7-nitroisoquinoline (2.38 g, 14 mmol) obtained in Preparation of Example 1-5, Step 2 in chloroform (68 mL) was added m-chloroperbenzoic acid (3.54 g, 21 mmol). The mixture was stirred at room temperature for 21 hours. The chloroform-insoluble material was filtered off with suction and washed with chloroform. The filtrate was washed with aqueous sodium bicarbonate solution, saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 7-nitroisoquinoline N-oxide. The obtained compound was used in the next reaction without purification.

Step 4

To the suspension of the nitroisoquinoline N-oxide obtained in the preparation of Example 1-5, Step 3, toluene (185 mL) was added phosphoryl chloride (3.5 mL, 37 mmol) and the mixture was heated with stirring at 90 ° C for 2 hours . The reaction mixture was cooled to room temperature and the reaction mixture was poured into aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (chloroform: acetone = 30: 1) to give 1-chloro-7-nitroisoquinoline (540 mg, 14%).

Step 5

To a suspension of 1-chloro-7-nitroisoquinoline (670 mg, 3.21 mmol) obtained in Preparation of Example 1-5, Step 4 in methanol (100 mL) was added 1M solution (6.5 mL, 6.5 mmol) of methanolate sodium. The mixture was heated under reflux for 3 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 30: 1) to give 1-methoxy-7-nitroisoquinoline (530 mg, 81%).

Step 6

A mixture of 1-methoxy-7-nitroisoquinoline (530 mg, 2.60 mmol) obtained in the preparation of Example 1-5, step 5 and ammonium acetate (3 g, 39.0 mmol) was heated with stirring at 135 ° C for 4 hours. hours. The reaction mixture was added to aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1-amino-7-nitroisoquinoline (246 mg, 50%).

Step 7

A mixture of 1-amino-7-nitroisoquinoline (246 mg, 1.3 mmol) obtained in the preparation of Example 1-5, step 6 and 5% palladium on carbon (100 mg) in methanol (100 mL) was stirred at room temperature and normal pressure in a hydrogen atmosphere for 8 hours. The reaction mixture was suction filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound (203 mg, 99%).

Preparation of Example 1-6

Synthesis of 7,9-diamino-1,2,3,4-tetrahydroacridine

Step 1

To a mixture of 5-nitroantranilonitrile (1.63 g, 10 mmol) and cyclohexanone (10.3 mL, 100 mmol) was added zinc chloride (1.36 g, 10 mmol) and the mixture was heated under reflux for 20 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, insoluble portions were filtered off. The filtrate was concentrated under reduced pressure and chloroform was added to give a brown oil. The resulting yellow precipitate was filtered off and dried under reduced pressure at 80 ° C. This solid (1.56 g) was diluted with ethyl acetate and 1 N aqueous sodium hydroxide solution and ether were added. The insoluble material was filtered off and dried under reduced pressure at 80 ° C to give 9-amino-7-nitro-1,2,3,4-tetrahydroacridine (810 mg, 33%, as a yellow solid).

Step 2

The 9-amino-7-nitro-1,2,3,4-tetrahydroacridine (773 mg, 3.18 mmol) obtained in the preparation of Example 1-6, step 1, was dissolved in a mixture of solvents tetrahydrofuran (5 mL) and ethanol (5 mL). ml) and 5% palladium on carbon (500 mg) was added followed by hydrogenation at room temperature and normal pressure. After 7 hours, the reaction mixture was filtered through celite, and the filtrate was concentrated to give the title compound (655 mg, 98%, as a yellow oil).

Preparation of Example 2-1

Synthesis of 2 - [(4-ethylphenoxy) methyl] benzoic acid

Step 1

To a solution of o-toluic acid methyl esters (15.0 g, 0.1 mol) in carbon tetrachloride (200 mL) was added N-bromosuccinide (18.7 g, 0.1 mol) and benzoyl peroxide (catalytic amount) and the mixture. was refluxed for 2 hours. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure to give α-bromo-o-toluic acid methyl esters (yellow oil). The obtained oil was used in the next reaction without purification.

• ·

Step 2

To a solution of α-bromo-o-toluic acid methyl ester (2.29 g, 10 mmol) obtained in the preparation of Example 2-1, step 1 and 4-ethylphenol (1.28 g, 10.5 mmol) in dimethylformamide (50 mL) Potassium carbonate (4.15 g, 30 mmol) was added and the mixture was heated to 100 ° C for 1 hour. The reaction mixture was added to ethyl acetate (100 mL) and washed with water and saturated sodium chloride solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 5) to give 2 - [(4-ethylphenoxy) methyl] benzoate (1.96 g, 73%).

Step 3

To a solution of 2 - [(4-ethylphenoxy) methyl] benzoate (1.96 g, 7.3 mmol) obtained in the preparation of Example 2-1, Step 2 in ethanol (20 mL) was added 2 N aqueous potassium hydroxide solution (11 mL). mL, 21.8 mmol) and the mixture was stirred at reflux for 2 hours.

Water (70 mL) and 6 N hydrochloric acid (5 mL) were added to the reaction mixture, and the resulting precipitate was filtered off and washed with water. The obtained solid was dried under reduced pressure to give the title compound (1.75 g, 94%, white crystals).

Preparation of Example 2-2

Synthesis of 2-chloro-4-ethylphenol

A solution of 4-ethylphenol (25.4 g, 0.21 mol) and sulfuryl chloride (18.5 mL, 0.23 mol) in carbon tetrachloride (40 mL) was stirred with heating at 70 ° C for 3 hours. The reaction mixture was diluted with chloroform and washed with water. The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give 2-chloro-4-ethylphenol (25.1 g, 77%).

Preparation of Example 2-3

Synthesis of 4-methylsulfonylphenol

Step 1

To a solution of anisole (3.3 mL, 30 mmol) in carbon tetrachlorethylene (30 mL) was added methylsulfonic anhydride (5.75 g, 33 mmol) and the mixture was stirred with heating at 140 ° C for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) and the crystals obtained were twice 9 9 9 9 • 9 9 9 9

9 9 9 9 9

Recrystallized from hexane-ethyl acetate to give 4-methylsulfonilanisol (505 mg, 9%, colorless crystals).

Step 2

To the 4-methylsulfonilanisol (505 mg, 2.7 mmol) obtained in the preparation of Example 2-3, step 1, 48% hydrogen bromide (3 mL) was added and the mixture was refluxed for 10 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform.

The organic layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give the title compound (256 mg, 55%, colorless crystals).

The obtained compound was used in the next reaction without purification.

Preparation of Example 2-4

Synthesis of methyl 2 - [(5-benzofuranyloxy) methyl] benzoate and methyl 2 - [(2,3-dihydrobenzofuran-5-yloxy) methyl] benzoate

Step 1

To a solution of 4- (benzyloxy) phenol (10.01 g, 50 mmol) and bromoacetaldehyde diethyl acetal (7.52 mL, 50 mmol) in dimethylformamide (100 mL) was added potassium carbonate (10.37 g, 75 mmol) and the mixture was heated to 175 ° C. After 2.5 hours, the reaction mixture was cooled to room temperature. The mixture was diluted with water and ethyl acetate and the aqueous layer was removed. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give 2- [4- (benzyloxy) phenoxy] acetaldehyde diethyl acetal (11.902 g, 75%, light brown oil).

Step 2

2- [4- (Benzyloxy) phenoxy] acetaldehyde diethyl acetal (3.16 g, 10 mmol) obtained in the preparation of Example 2-4, Step 1, and polyphosphoric acid (3.16 g) was heated in toluene (30 mL) at 100 ° C. Noc: 2 ° C. After 40 minutes, the mixture was cooled to room temperature. The reaction mixture was diluted with ether and the supernatant was separated by decantation. The supernatant was concentrated under reduced pressure and was purified by silica gel column chromatography (ethyl hexamacetate =

20: 1) to give 5- (benzyloxy) benzofuran (1.032 g, 46%, light brown oil).

Step 3

The 5- (benzyloxy) benzofuran (1.02 g, 4.55 mmol) obtained in the preparation of Example 2-4, Step 2 was dissolved in a mixture of ethanol (5 mL) and ethyl acetate (5 mL) and 5% palladium was added. on carbon (500 mg) followed by hydrogenation at room temperature and normal pressure. After 2 hours, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethylformamide (20 mL) and α-bromo-o-toluic acid methyl ester (1.042 g, 4.55 mmol) and potassium carbonate (1.26 g, 9.10 mmol) were added. The mixture was heated at 100 ° C for 1.25 hours and cooled to room temperature. The reaction mixture was diluted with water and ethyl acetate and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =

9: 1) to give methyl 2 - [(5-benzofuranyloxy) methyl] benzoate (352 mg, 27%, white crystals) and methyl 2 - [(2,3-dihydrobenzofuran-5-yloxy) methyl] benzoate (220 mg , 17%, light yellow oil).

Example 1

Synthesis of N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide hydrochloride

To a solution of 2 - [(4-ethylphenoxy) methyl] benzoic acid (1.13 g, 4.4 mmol) obtained in the preparation of Example 2-1 in chloroform (20 mL) was added oxalyl chloride (0.6 mL, 6.8 mL). mmol) and the mixture was stirred at room temperature for 1 hour, then the reaction mixture was concentrated under reduced pressure. To obtain the acid chloride, pyridine (20 mL) and 4,6-diamino-2-methylquinoline (623 mg, 4 mmol) obtained in the preparation of Example 1-1 were added and the mixture was stirred at room temperature for 10 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solvent was evaporated. The crude product obtained was dissolved in ethanol, treated with charcoal and the solvent was evaporated. The obtained residue was dissolved in ethyl acetate and a solution of 1 N hydrochloric acid-ether was added. The resulting precipitate was filtered off. The obtained solid was filtered and dried to give the title compound (1.06 g, 59%, pale yellow crystals).

Elemental analysis for C 26 H 25 N 3 O 2 HCl

Calculated; C: 69.71%, H: 5.85%, N: 9.38%

Found; C: 69.77%, H: 5.78%, N: 9.41%

Melting point: 235 ° C

Example 131

Synthesis of N- (4-amino-2-hydroxymethyl-6-quinolyl) -2 - [(4-methylphenoxy) methyl] benzamide hydrochloride

···············

A solution of 4-nitroaniline (6.91 g, 50 mmol) and acetylendicarboxylic acid dimethyl ester (7.82 g, 55 mmol) in methanol (100 mL) was heated at reflux for 24.5 hours. The reaction flask was cooled to room temperature and allowed to stand for one day. The resulting crystals were filtered to give diemethyl 2 - [(4-nitrophenyl) amino] -2-butenedioic acid dimethyl ester (6.43 g, 46%, yellow crystals).

Step 2

To Dowtherm A (trademark, 30 mL) was added dimethyl 2 - [(4-nitrophenyl) amino] -2-butenedioic acid dimethyl ester (6.32 g, 22.6 mmol) obtained in Example 131 under reflux, step 1 in 5 minutes in small portions. The mixture was heated to reflux for 25 minutes and the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ether and the resulting precipitate was filtered off. The resulting crude crystals were suspended in methanol and filtered to give 1,4-dihydro-6-nitro-4-oxo-2-quinoline carboxylic acid methyl ester (4.75 g, 85%, dark brown crystals).

Step 3

To a suspension of 1,4-dihydro-6-nitro-4-oxo-2-quinoline carboxylic acid methyl ester (3.72 g, 15 mmol) obtained in Example 131, Step 2 in acetonitrile (50 mL) was added chlorosulfonyl isocyanate (1, 2). 30 mL, 15 mol) was added and the mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and methanol was added.

Further, the concentration was carried out under reduced pressure. To the residue was added a 2 mol / L aqueous sodium carbonate solution to form a suspension, and the insoluble material was filtered off. The insoluble material was dried under reduced pressure at 80 ° C to give 4-amino-6-nitro-2-quinoline carboxylic acid methyl ester as crude brown crystals (3.23 g). This compound was used in the next reaction without purification.

Step 4

A suspension of crude crystals (494 mg) of 4-amino-6-nitro-2-quinoline carboxylic acid methyl ester obtained in Example 131, step 3, and 5% palladium on carbon (500 mg) in ethanol (10 mL) was hydrogenated at room temperature under normal pressure. The reaction mixture was allowed to cool to room temperature

Filter through celite for 2.5 hours. The filtrate was concentrated under reduced pressure to give the crude 4,6-diamino-2-quinoline carboxylic acid methyl ester product (275 mg, yellow, foam-like substance). This compound was used in the next reaction without purification.

The crude product (270 mg) of 4,6-diamino-2-quinoline carboxylic acid methyl ester obtained in Example 131, step 4 and 2 - [(methylphenoxy) methyl] benzoic acid (363 mg, 1.5 mmol) obtained in the same manner as in Preparing example 2-1 was condensed to form • · φ ·

Φ φ φ φ φ ·

amide obtained in the same manner as in Example 1 to give N- (4-amino-2-methoxycarbonyl-6-quinolyl) -2 - [(4-methylphenoxy) methyl] benzamide (175 mg, 17% from 1,4-dihydro methyl ester) 6-nitro-4-oxo-2-quinolyl carboxylic acid, as a yellow solid).

Step 6

To a solution of N- (4-amino-2-methoxycarbonyl-6-quinolyl) -2 - [(4-methylphenoxy) methyl] benzamide (170 mg, 0.385 mmol) obtained in Example 131, Step 5 in tetrahydrofuran (10 mL) was added after small portions of lithium borohydride (42 mg, 1.927 mmol) under ice-cooling and under argon flow. After 10 minutes, the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with saturated sodium chloride solution and ethyl acetate to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and dried under reduced pressure. The resulting yellow residue was dissolved in ethyl acetate, and a solution (0.5 mL) of 4 N hydrochloric acid-dioxane was added to precipitate the hydrochloride. This salt was filtered and dried under reduced pressure at 80 ° C to give the title compound (116 mg, 67%, pale yellow crystals).

Aminosubstituted compound obtained in the same manner as in the preparation of Examples 1-1 to 1-6 or commercially available amino substituted compounds and carboxylic acid derivatives obtained in the same manner as in the preparation of Examples 2-1 to 2-4 or a commercially available carboxylic acid derivative were prepared in the same manner. as in Example 1 or 131 to give compounds from Example 2 to Example 130 and Example 132. The resulting values are shown in Tables 1 to 44.

Example 133

Synthesis of N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] -2-benzamide hydrochloride monohydrate

Ethanol was added to the crude N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide hydrochloride (24.0 g, 53.7 mmol) obtained in the same manner as in Example 1. (120 mL) and the mixture was dissolved with heating at 55-60 ° C. This solution was filtered, and water (120 mL) was added dropwise to the filtrate with stirring and heating at 55-60 ° C. The reaction mixture was cooled to room temperature and the resulting precipitate was filtered off. The obtained solid was dried at 1 mmHg and 60 ° C for 3 days to give the title compound (22.6 g, 94%, colorless crystals).

Elemental analysis for C 26 H 25 N 3 O 2 HCl. H2O

Calculated; C: 67.02%, H: 6.06%, N: 9.02% Found; C: 66.64%, H: 6.06%, N: 8.99% Melting point: 130 ° C

• 9 9 9 9

9

9

9

99999 98 99

Table 1

Ex. C. General structural formula / property (solvent) b. t .. 1 H NMR (s) ppm MS DMSO-d 6.300MHz 1.10 (3H, U = 7.7Hz) FAB- 447 [M-H +] NB> 2.48 (2Hx}, J = 7.7 Hz) yV 2.59 (3 H, s) 5.30 (2 H, s) (3) A X ° X 6.61 (1H, s) 1 'N 0 AND 235 C 6 ^ 84 (2H, dJ = £ 6Hz) í <Xs 7.05 (2H, dJ = 8.6Hz) HCl f o 7 / 48-7.67 (4HjTt) 7.94 (2 H, s) 8.66 (2 H, br.s) 8.74 (1H, s) 10.86 (1H, s) Colorless crystals 13.93 (1H, br.s) DMSO-d 6.300MHz NH _Z H | ^ jl V r ^ v ^c * 2 X XJ π X X J 262C HCl Cl DMSO-d 6.300MHz 2.59 (311, s) FAB- 5.33 (2 H, s) 418IM-H] - NHg 6.60 (IH, s) 6.87-6.95 (3H, π ») (83) 367 (99) H « 7.21-7.26 (2 H, m) 3 T 1 ^ 245 ~ 7.51-7.70 (4H, m) 1 0 l XJ 246 ”C 7.93 (2 H, s) ⁿ -hcí 8.66 (2 H, br.s) 8.75 (1 H, s) Colorless crystals

Table 2

9999 • 9 9 9 · 9 9 «9 9 999 · · · 9 99 9999

Př.e. General pattern / property (solvent) m.p. 1 H NMR (d 6) ppm MS DMSO-d6,300 MHz 2 _of 59 (3H, s) FAB- 3.65 (3H, s) 448 (M-Hl-) 5.27 (2 H, s) (65) nh ₂ 6.6O (1H, s) 367 (99) H Whose 6 / 77-6.89 (4H, tn) 4 jfSpj O O 276 * C 7.48-7.68 (4 H, m) 7.88-7.96 (2H, m) HCl O/ 8/70 (2H, br.s) 8/74 (IH. S) 10.85 (111, s) 13.78 (1H, s) Colorless crystals DMSO-d 6.300MHz nh ₂ H Γ0Ι AJ 5 aXJ O Ό in Άζ her 265 r HCl DMSO- < 16JOOMHz nh ₂ H ΓΊ) - ^N N < • Οχ 6 X JLJ O 270Γ Sr HCl

ΦΦ ΦΦ φ φ φ φ φ φ »φ φ φ · φ φ

ΦΦΦΦ ΦΦ ΦΦ Φ φ φ φ φ φ φ φ φ φ φ φ φ

Table 3

ΦΦΦΦ

ΦΦ

Ex. 6. General structural formula / property (solvent) m.p. @ 1 H NMR .delta MS 7 Γ ² Η Jk xUsJJ o L a, JI 148 DMSO-d 6.300MHz 8 JT N J0 Y _n XX ° HCl ° \ 196Ό DMSO-d6OOMHz 9 NHzh f ^ j) X. JL J o L Čk DMSO-d6, 300MHz 2 ₍ 20 (3H, s) 2.40 <3H, s) 5.31 (2H, s) 6.45 (3H, s) 6.70-6.76 <3H, m) 7 11.1 (1H, U = 7 _/ 2Hz) 7.47-7.57 (4H.m) 7.62-7.64 (2H, m) 8.390H, s) 10 (KlH.s) FAB + 398 [M + H] (100)

·· * · *

· · * * * * * * * · · · · ·

Table 4 * t t t · · · · · · · · · · · · ·

Ex. δ. General pattern / property (solvent) b. t 1 H NMR (s) ppm MS DMSO-d 6.300MHz FAB- 2.59 (3H.s) 3.62 (611, s) 4791M-H + 1 nh _{2 h} 5.29 (2 H, s) (2) k J 6.04-6, O8 (3H, m) 6.60 (1H, s) 10 0 % 1 7.49-7.69 (4H.m) 7.89-7.97 (2 H, m) HCl Yeah 8 _{out of} 65 (2H, br.s) 8.76 (1H, dJ = 1.5Hz) X 10.85 (1H, s) 13.74 (1H, br.s) Colorless crystals DMSO-d6,300MHz FAB- 2/9 (3Hs) 5.33 (2H, s) 454 [M-H] - _H ř 6/9 (3H, sec.) 6.95 (2H, d, J = 8.9 Hz) 7.27 (211, d, J = 8.9 Hz) (50) 453 (26) 452 (78) 416 11 Í1 ^Z5 IN ^N 245 r 7.49-7.70 (4H. M) O 7.85-7.95 (211 m) N HCl 0 8/7 (2H, br.s) 8.73 (1H, s) Colorless crystals DMSOntóJOOMHz FAB- 2.47 (311, s) 2/8 (3hs) 460 [M-H] 5.44 (2 H, s) 6.59 (1H, s) (18) 459 (99) NH _{2 h} ⁰ 7.03 (211, d, J = 8.9Hz) 12 OC ^ 270 C 7.50-7.71 (411, m) 7.81-7.94 (4H, m) íhci 8.65 (2 H, br.s) 8.72 (1 H, s) 10.88 (111, s) 13.66 (1 H, s) Light yellow crystals

• · l »

Table 5

Ex. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS DMSO-d 6.300MHz 2.58 (3 H, s) N4> β η 5/2 (2H, s) 6.59 (1 H, s) mA Ίί 6/1 (211, dj = 9.611z) A ÁJ L 6.76 (2H, d, J = 9.6 Hz) 13 0 183,0- 7.50-7.65 (4 H, m) Λ 184.0Γ 7 / 9-7.99 (2 H, m) 8/9 (2 H, br.s) HCl Ψ 8.74 (1H.s) 8.94 (1H.s) ΟΗ 10/3 (1H, s) 13.78 (1H, br, s) Colorless crystals DMSO-d 6.300MHz 2.59 (3H, s) FAB- 479 [M-H + 1] Nbfe Η ιΑ 5.05 (2H, s) YrT kJ ¹ 5.28 (2H.s) 6.6O (1H, $) (3) Ο Ό 6.88 (4 H, s) 14 210,0— 7.50-7.69 (4 H, m) 1 Η 212,0Γ 7.93 (2 H, s) HCl IN 8/1 (2H, s) ο 8.73 (1H, s) r 10/6 (1 H, s) / ° 13.91 (1H, br.s) Colorless crystals DMSO-d 6.300MHz P ^H Π 15 Dec Α 224 Γ X N C ) ο HCl

Table 6

Př.e. General structural formula / property (solvent; m.p. 1 H NMR (s) ppm MS DMSO-d 6.300MHz 16 Γ ² M rrr ^Y • HCl O O ^x and ^CN 286Ό 17 NKa h ΙΎΎ ^Νγ • HCl O ^U 0 ' XX 255 r DMSO-d6, 300MHz ^ 18 (3Hs) ^ 59 (311s) 5.29 (2 H, s) 6.60 (1H, s) 6.82 (2H, d, J = 8.4Hz) 7/2 (2H, d, J = 8.4Hz) 7.48-7.88 (6H, m) 8.66 (2H, br.s) ) 8.74 (1 H, s) 1.10, 1H (s) 13.81 (1 H, s) FAB- 4321M-HJ- (8) 107 (99) Light yellow crystals 18 NWa H I ArW •HIM AND of T f 0 ^ ^CF 3 220Γ DMSO-d 6.300MHz 2.60 (3H, s) 5.44 (2 H, s) 6 / ÓK1H, s) 7.13 (2H, d, J = 8.7Hz) 7.53-7.72 (6H, m) 7.95 (2H, s) 8.69 (2H, br.s) 8.72 (1 H, s) FAB- 486 [M-H] (1) 161 (99) Light yellow crystals

Table 7

Φ φ φ φ φ φ φ φ φ φ φ φ · · · · φ · φ φ φ φ φ φ φ φ φ φ

Ex. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS DMSOd6.300MHz 2.59 (3H, s) 5.48 (2 H, s) 6.59 (1H, s) 7.44-7.77 (8H, m) nh ₂ h Ii 7.84-7.93 (2H, m) 19 Dec JL. 0 ^ 0 O w 245 C 8.65 (2 H, br.s) 8.73 (1 H, s) NOz Light yellow crystals DMSO-d 6.300MHz FAB- 2,6O (3H.s) 5.55 (2 H, s) 4641M-H] NH _Z U α D 62 (1H, s) (4) * H JL w aj 7.10 (1H, U = 8.2Hz) ΓϊΥΊί T 7.42 (1H, dJ = 8.2Hz) 20 May Jk · JL AND 200,0- 203,013 7.55-7.86 (6H.m) 7.95 (2H.s) .NOz 8.73 (2 H, br.s) HCl O 8.74 (1H, s) 10.91 (1H, s) 13.99 (1H, br.s) Colorless crystals DMS0- <16,300MHz 2.21 (3H, s) FAB- 4771M-H) _H rifV ^N ' 2.59 (3 H, s) A ³ 5.33 (2 H, s) 6.6O (1H3) (AND) 21 A A ^ J ⁰ % 1 154,0- 6.93-7.00 (4 H, m) 7-4 0-7.70 (4H, m) HCl ° Y ° 155, OC 7.90 (1H, dJ = 9.2Hz) 7.94 (1H, dJ = 9.2Hz) 8.63 (2H, br.s) 8.74 (1H.s) 10.87 (1H, s) 13.85 (1 H, br.s) Colorless crystals

• · · · ·

Table 8

Ex. C. General structural formula / property (solvent) m.p. 1 H NMR (a) ppm MS DMSO-d 6.300MHz FAB + 2.59 (3H.s) 3.65 (3H, s) 449µM-H +) nh ₂ i * 0 5.32 (2H.s) 6.60 (1H, s) (4) T 6.82-6.98 (4H, m) 22nd l 0 148,0- 7.51-7.58 (2 H, m) 'N 149, no 7.66-7.7 L (2H, m) 7.95 (2 H, s) HCl CJ 8.65 (2 H, br.s) 8.75 (1H, s) 10.87 (1H, s) 13.80 (1H, br.s) Colorless crystals DMSO-d6, 300MHz NHj H if 23 _.N. í T H fí NH, 237 C z * O 2HCl DMSO-d 6.300MHz 2.59 (3H, s) FAB- 5.36 (2 H, s) 455IM-H +] NH> ΰ 6.60 (1H, s) 6.90-6.99 (3H, m) (5) Y 7.22-7.28 (1Hn) 24 I JL AND 147,0- 7.50-7.7 L (4H, m) N 149 _of 0 “C 7.89-7.92 (2 H, m) HCl Γ and) 8.61 (2 H, br.s) 8.73 (1H, s) kx 'Sl 10,86OH.s) 13.85 (1H, br.s) Colorless crystals

Table 9 tf tftftftf tf tftftftf tf tftfft tftf tftf tftf tftf

Př.ě. General structural pattern / property (solvent) m.p. 1 H NMR (δ) ppm MS DMSO-d 6.300MHz 2.59 (3 H, s) FAB- 437 [M-H <+>] 5.31 (2 H, s) N J T 6.60 (1H, s) (3) ílf γ Δ 93-7.09 (4H, m) L A 7.49-7 _/ 70 (4H, m) 25 ^K o 14 ^, 0- 7.87-7.95 <2H.m) AND 148.0X3 8.61 (2 H, br.s) 8.73 (1H, s) HCl Y 10.85 (1H, s) 13.80 (1H, br.s) F Colorless crystals DMSO-d 6.300MHz nh ₂ H 26 ΓγΊ in ⁵ rV 223X3 ’O χ * ^ χ! κ. _Λ , 0 Cl HCl DMSCW6, 300Mlz NHj H F ll 27 Mar: _Τ ^Ν γ AND ^J n 165X3 AA. X 0 x 'N ⁰ HCl Cl

• · · · ·

Table 10 · · · · · · · · · · · · · · · · · · · · · · · ·· ·· ··

: κ. C. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS DMSO-d 6.300MHz NH2 H jl 1 at 28 if 5 ϊ jf 233 JI O k • 2 HCl DMSO-d 6.300MHz NHj H C jl 29 if J T H 268Γ 0 HCl DMSO-d 6.300MHz nh ₂ Η f ^ j) Π 30 ΓγΊ j ^ Y 268Γ λ _ν λ> ⁰ t HCl

Table 11 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

ex. General structural formula / property (solvent) b. t. 1 H NMR (¢) ppm MS 31 x ² n j0 i X x XJ * O Χ-ΧΧ • HCl 256 C DMSO-d6,300MHz 32 Η γΠ HCl 23813 DMSO-d 6.300MHz 33 HC ^Ηί Η (Ή νκν ^Ν τΤ ΚΥ ^Β '• HCI) 25213 DMSO-d 6.300MHz

• φ φ φ · · φ φ φ φ φ φ

Table 12

Ex. δ. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS DMSOd6,300MIIz 0.83 (3H, t J = 7.4Hz) FAB- 461 (M-H &lt; + &gt; NHř H 1.48 (2H, q, J = 7.4 Hz) Λ kJ » 2.42 (2H.U = 7.4Hz) 6Q (3H, s) (6) 34 N O 140,0- 5.30 (2H3) 6.61 (1 H, s) Al 142.012 6.84 (2H, d J = 8 Hz) HCl T 7f12 (2H & S = &, SHz) 7.50-7.69 (411, ™) 7.95 (2H.s) 8.68 (2H, br. S) 8.74 (1H.s) Colorless blood 10.87 (1H.s) 14.01 (1H.br.s) DMSO-δ6OOMHz NHa tl I j | 35 AND 255 C 0 k 0 F HCl DMSO-d6, 300MHz NHj H fH) 36 ΓτΤ • ^Ν γ \ / AND 253Γ AtAcF ₃ HCl

• • •

Table 13

Ex. δ. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS DMSO-d 6.300MHz NH _{H H} JrrY Ti 37 -¼. 262 r  HCl DMSO-d6 2.39 (3 H, s) FAB + 510 [M + H <+> Nl · ^ >} 5.33 (2 H, s) L J 6.39 (2H, br. S) 1 (100) Λα ΥΊ 6.44 (1H3) Λ aJ 0 ' in 6.81 (2H, d J = 8.8Hz) 38 O 148,0- 7.49-7.67 (8 H, m) 1 150,0X3 8.36 (1H, s) and Ti 1.0, 49 (1H3) l Ύ AND Her Colorless crystals 1 DMSCM6J00MHZ 2.59 (3H, s) 5.53 (211, s) FAB- 419IM-H] 367 (99) nh ₂ h Jpl 6.60 (111, s) 7.52-7.73 (411, m) 7.85-7.94 (311 m) 39 AV Her. 0 \of? ^k 0 H , N 207X3 8.35 (1 H, m) 8.54 (1H, s) 8.68 (2H, br. S) HCl 8.72 (1H, s) 10.91 (1H, s) 13.94 (111, s) Light yellow crystals

· ♦ · · · · «« «« «« «« «« «« «« · · · · · · ·

Table 14

'Ex. General structural patterns / presence (solvent) m.p. 1 H NMR (ppm) ppm MS DMSO-d 6.300MHz nh ₂ Γ o Ϊ i 40 <5% ^ f ^ OH 225Γ AA οΆ HCl DMSO-d6OOMHz nh ₂ zest il 41 IJ Yeah £ jl 195Γ z * v CN HCl DMSO-d6 2.19 (3 H, s) NHg 2.60 (3H.s) H AND 5.32 (2 H, s) AA ^ γΝ IN IN 6.61 (1H, s) A A L 6.79 (1H, dd4 = ^ 9.8.7Hz) 42 Λ 150,0- or I52 _of: 6.92 (1H, dJ = 2.9Hz) 7.22 (1H, dJ = 8.7Hz) 7.52-7.69 (4H, m) HCl AND 7.93 (2H3) 8.71 (2 H, br.s) Cl 8.74 (1H, s>) 10.90 (1H.s) Colorless crystals 13.91 (1H, s)

φ φ «• • · · · · · · · · · φ φ φ φ

Table 15 φφφφ

Ex. E. General structural formula / property (solvent) b. t. 1 H NMR (d) ppm MS DMSO-d6 2.19 (3H.s) H Π 2.60 (3 H, s) 5.40 <2H.s) ? ΤΎ Ϊ T 6.61 (1 H.s) 7.05 (2H.s) 43 ^k o 159.0 ~ 7.20 (1H, s) XI l60 _of dC 7.53-7.61 (2 H, m) rif 7.69-7.73 (2 H, m) HCl AND 7.95 (2 H, s) 8.66 (2 H, br.s) 8.75 (1H s) 10.89 (1 H.s) Colorless crystals 13.98 (1H, br.s) OMSO-d6 FAB + 1.1 (3H.U = 7 _of 6Hz) 411 Nřfe AA Ar 2.41 (3H.s) IN 2.50 (211, q J = 7.6 Hz) 5.30 (2H, s) (M + H) (100) with 6.45 (1H, s) 44 'N 96,0- 6.56 (2 H, br.s) χζ \. 98,0X3 6 ^ 6 (2H, d J = 8.6Hz) 7.06 (2H4J = 8.6Hz) at 7.48-7.55 (2 H, m) 7.62-7.67 (411 m) 8.41 (1H.s) 10.5 (1H s) Colorless crystals DMSCM6 ^ 21 FAB + 432 [M1 (100) NHj, H (0 2.4O (3H.s) 5.32 (2 H, s) IN in 6.44 (2 H, br.s) 433 [M + 2] (41) II j II 0 6.81 (1H, ddJ = 2.7.8.6Hz) 45 AND 6.95 (1H, dJfc2.7Hz) 7.24 (1H, D, J = 8.6Hz) 7.47-7.67 (6H, m) ςχ 8.38 (1H s) 10.5 (1 H.br.s) Cl Colorless crystals

Table 16 • ♦♦ ·

Ex. C. General structural formula / property (solvent b. t. 1 H NMR (s) ppm MS DMSOd6,300MHz FAB- 2.00 (3 H, s) 2.59 (3 H, s) 490 (M-HJ-) 4.94 (2 H, s) (87) 5.34 (2H, s) 454 (99) fS ^ ^N YT 0 O 6/0 (111, p) 46 ^ γ ^ ο ^ · 25813 6.93 (2H, d, J = 8Hz) 7.24 (2H, d, J = 8.6Hz) N U * HCl 7.49-7.90 (2H, m) 7.85-7.96 (2H, m) 8/3 (2H, br.s) 8.74 (111, s) Light yellow crystals DMSO-d6300MHz FAB- M / z 58 (3H, s) 4.36 (211, d, J = 5.2 Hz) 412 (M-HJ-) ΓγυΟ 5.02 (111, t, J = 5.2 Hz) 5.32 (2H, s) 6.59 (1H s) (100) 47 j ^^ Y ^ OH 27313 6.88 (2H, d, J = 8.6 Hz) o < ₀ HCl 7.16 (2H, d, J = 8.6 Hz) 7.49-7.70 (411, m) 7.85-7.98 (4H. M) 8.67 (2H, Br.s) 8.75 (1 H, s) Light brown crystals DMSO-d 6.300MHz 2.59 (3 H, s) FAB- »4 »M 5.46 (2 H, s) 469 [M-H <+>] Π XJi 6/1 (1 H.s) (2) rW Ύ T 7.13-7.80 (1H, m) l 7.91-7.95 (2 H, m) 48 / '• N O 154,0- 8.67 (2H, br. S) Jy 156,013 8.75 (1H.s) HCl i il 10.91 (1H, s) ÍiT 14.01 (1 H, br.s) Colorless crystals

Table 17 • ·· ·

Ex. δ. General pattern / property (solvent) m.p. 1 H NMR (δ) ppm MS DMSO-d6 FAB- 1,320H, (J = 7,7Hz) 467 (M-H + J) h 1 Π 2.89 (2H, qJ = 7.7Hz) 5.34 (2 H, s) ί ^{ί! ιΙ} Χ Α ζ ^'Ν' > < in 6.66 (1H.s) L 6.96 (2H, d, J = 9 _of 2Hz) 49 0 247,0- 7.26 (2H, dJ = 8 _{out of} 8Hz) HCl rií 249,0X1 7.49-7.7 l (4H.m) 7.95 (1H, dJ = 8.8Hz) 7.99 (1H.dJ-9.2Hz) 8.72 (2H.br.s) Cl 8.73 (1H3) 10.87 (1 $ H) 13.91 (1H.s) Colorless crystals DMSO-d6 FAB- Π 0.96 (3H.U = 7.4Hz) 1 _of 73-1.8 (2H, m) 481 2.8S (2H.U = 7.4Hz) IM-H + K3) Λύ 0 5.34 (2 H, s) 6.65 (1H, s) 50 in 232,0- 6.96 (2H, dJ = 8 _of 8Hz) HCl Φ 233,0X1 7.26 (2hay = 8.8Hz) 7.50-7.71 (4H4n) 7.94 (1ΗΛ1 = 9.2Ηζ) 8.00 (lHAJ = 9.2Hz) 8.73 (2 H, br.s) 8.74 (1H, s) Cl Colorless crystals 10.87 (1H, s) 13 ^ 3 (1 H, s) DMSO20JOOMHz FAB- ^H í 1.32 (3H, t, J = 7.5Hz) 2.88 (2H, q, J = 7.5Hz) 5.44 (2H, s) 6.65 (1H, s) 502 (24) 500 (43) 127 (99) qf 7.22 (1H, d, J = 8.9Hz) 51 li xJt _k , AJ o 163X7 7.34 (IH.dd, > 8,9,2,5Hz) Xz ^ (col HCl 0 Cl 7.51 (1H, d, J = 2.5 Hz) 7.53-7.75 (4H, m) 7.90-7.97 (2H, m) 8.66 (2H, br.s) 8.74 (1 H, s) Light red crystals 10.89 (1H, s) 13.68 (IH $)

Table 18 • ΦΦΦ

Φ • • • • • • · • • • • φ φ

Př.ě. General structural formula / property (solvent) b. t. 1 H NMR (s) ppm MS DMSO-d6 FAB- 1.35 (6H, dJ = 6.9Hz) 482 [M-H +] (28) r- /? 3.22 (1H, o, J = 6.9Hz) 5.34 (2 H, s) 6.69 (1H, s) 1 0 k _6/96 (2H, <U = 9 _/ 0Hz) 52 162,0- 7.26 (2H, d, J = 9.0 Hz) Ϊ _H n rii 164,013 7.52-7.68 (4 H, m) 7.68 (1H, d, J = 9.1Hz) ^HCI LJ 8.04 (1H, dd = 9.1Hz) 8.73 (1 H, s) Cl 8.73 (2 H, br.s) 10.9 (1 H, S) Colorless crystals 13.7 (1H, br.s) DMSO-d6 1.10 (3H, U = 7.6Hz) FAB- 461 NHa 1.32 (3H, t, J = 7.6 Hz) at (yV 2.48 (2H, q, J = 7.6 Hz) [M-H +] řn ^ 89 (2H, q, J = 7 / SH 2) (13) ⁰ k ^ 5.30 (2H _t s) 53 N 0 160,0- 6.66 (1H.s) 161,013 6.84 (2H, <1, J = 8.6 Hz) ^hci u 7.05 (2H, DJ = 8.6 Hz) 7.51-7.69 (4 H, m) 7.96 (2H.s) 8.74 (2 H, br.s) 8.75 (1H) Colorless crystals 10.9 (1H, s) 13.8 (1H, s) DMSO-06 FAB- Η. Π ^ρζΟΗ. ^^ Ηζ) 2.19 (3 H, s) 481 NHj 2.89 (2H, qJ = 7.5Hz) [M-H +] Italy (26) řn 5.32 (2 H, s) 6.66 (1H.s) 54 N ⁰ k 150,0- 6.79 (1H.dd4 = 3.0.8.7Hz) HCl Cl 132 / OC 6.92 (1ΗΑ1 = 3.0Ηζ) 7 ^ 2 (1H, dJ = 8.7Hz) 7.50-7.70 (4Hn) 7.91-7.99 (2H, m) ^ 73 (2H, br .with) 8.74 (1H, s) Colorless crystals (AcOE -Et2O) 10.86 (1H, s) 13.85 (1H, br.s)

«· ·

4 • · · · ·

Table 19 ··· «• · · · · · in

Ex. E. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS 55 '-θ O 83.0— 84.0Γ DMSO-d 6.300MHz 2.41 (3H, s) 4.53 (2H, s) 4.78 (2H, s) 6.46 (1H, s) 6.49 (2H.br.s) 7.22- 7.30 (5H, m) 7.45-7 _of 66 (6H.m) 8.41 (1H, s) 10.45 (1H, s) 398 [M + H +] + (100) 56 DMSO-d6300MHz 2.91 (3 H, s) 5.33 (2H, s) 6.87-6.92 (3H, m) 7.18- 7.23 (2H, m) 7.52-7.68 (4H, m) 7.87 (1H, d, J = 8.7Hz) 8.18- 8.25 (2H, m) 8.79 (1H, s) Δ ^ 2 (1H, d, J = 8.7Hz) 11.0 (1H, s) 57 Γ ² Η Π XyyU A _n EN o DMSO-d 6.300MHz ^ 40 (3H, s) 6.43 (2 H, br.s) 6.45 (1H s) 7.53-7.75 (5 H, m) 8.00 (1H, s) 8.03 (1 H.s) 8.38 (1 HAJ = 2.1 Hz) 10.35 (IH.s) FAB + 278 (M + H + J (100)

ΦΦ «φ« 9

ΦΦΦ Φ Φ

Table 20 φφφφ φφ • ΦΦΦ

ΦΦ ΦΦ Φ «« «« «· ·

Φ Φ Φ Φ

ΦΦ · »

Ex. ¢. General structural formula / property (solvent) m.p. 1 H NMR (s) ppm MS 58 nh ₂ h jA ΛΛ? oX DMSO6.300MHz 2.37 (3H, s) 6.36 (2 H, s) 6.42 (1H, s) 7.29-7.61 (11H, m) 8.25 (1H, d, J = 2.0Hz) 10.33 (1H, s) FAB + 354 (M + H +) (100) 59 (Π rYrW o ,, Colorless crystals DMSO-d6,300MHz 4444 (3H.s) 6.49 (1H, s) 6.68 (2 H, br.s) 7.56-8.30 (7H, m) 10.30 (1H, s) FAB + - 303 [M + H + 1] 60 ς * h jQ JL XJ o L X.Jk J HCl 176Γ

9 9

Table 21

Ex. fi. General structural formula / property (solvent) m.p. 1 H NMR (s) ppm MS NH _and h Π 61 Her. <^ - í? 0 HCl -"O 232Γ Colorless crystals 62 NH ₂ H • HCl Ώ '° O 208 C Yellow crystals νπ ₂ h ( 63 IiVyV ' HCl '° O 212Γ Light yellow crystals

Table 22

Ex. C. General structural formula / property (solvent) m.p. 1 H NMR (s) ppm MS 64 HCl ,.O 253X3 Light yellow crystals 65 H A Χγγγ HCl Colorless crystals 223,0— 225,0X3 DMSO-d6 1.20-1.38 (6H, m) 1.50-1.68 (4H, m) T 57 (3H, s) 2.78 (2H, t, J = 6.5 Hz) 3.79 (2H, tJ = 6 JHz) 6.59 (1H, s) &Lt; 81-6.91 (3H, m) 7.22-7.5 L (6H, m) 7.88-7.94 (2H, m) 8.69 (2H, br.s) 8.79 (1H, s) 10.78 (1H, s) 13.79 (1H, br.s) NH ₂ ti 66 And AA ° kxxz HCl ° O 210X3 Light brown crystals

I

······· ·· ··

Table 23

Ex. E. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS 67 | ^Hi {Η Π • HCl DMSO-d 6.300MHz 2.02 (2H, m) 2.17 (3 H, s) 2/1 (2H, s) Δ 94 (3H, t, J = 8Hz) 3.90 (3H, t4 = 6.4Hz) 6.62 (1H.s) 6.71 (2H, d J = 8.0 Hz) 6.97 (2H, d J = 8 /> Hz) 7.34-7 / 4 (4H, m) 7.95 (2 H, s) 8.50-8.90 (2 H, brs) 8.78 (1H.s) 10/0 (1H.s) 14/2 (1H, s) 68 r * u jQ XXX XX-XX HCl or ci DMSO-d6, 300MHz 2/7 (2H.s) 2.61 (3s.s) 2.97 (2H, t, J = 8.0 Hz) 4.04 (2H, t, J = 0.6Hz) 6.62 7.07 (1H, dJ = 8.9Hz) 7.25 7 / 4-7 / 3 (5H m) 8.50-8.90 (2 H, brs) 8.77 (1H.s) 10.80 (1H.s) 14.00 (1H.s) 69 nh ₂ 8 XX DMSO-d6,300MHz ^ 60 (3H.s) 3.24 (2H, t J = 6Hz) 4.23 (3H, t, J = 6.8 Hz) 6.62 (1H.s) 6.90 (2H, d J = 8.9 Hz) 7/3 (2H, d J = 8.9Hz) 7/9-7.60 (4H, m) 7.95 (2 H, s) 8.50-8.90 (2 H, brs) 8.80 (1H.S) 10.85 (1H, s) 13.94 (1H.s)

Table 24

Př.ě. General structural formula / property (solvent) b. t. 1 H NMR (s) ppm MS 70 NH, μA DMSO-d 6.300MHz 2.38 (3H, s) 4.18 (2 H, s) 6.4I (2H, s) 6.45 (1H, s) 7.14-7.63 (11 H, m) 8.42 (1H, s) 1 ^ 44 (1H, s) FAB- 3661M-HJ- (100) 71 Ji ² N jO? A ° AO DMSO-d 6.300MHz 2.38 (3H, s) 2.88-2.93 (2H, m) 3.03-3.09 (2H, m) 6.43 (2H, s) 6.45 (1H, s) 7.14-7.71 (11 H, m) 8.43 (1H, s) 10.46 (1 H, s) FAB + 382 [M + H] + (100) 72 Γ * H ⁿ * hci Colorless crystals > 300X3

• • •

Table 25 · 9 · 9 · · · · · · · «

Ex. δ. General pattern / property (solvent) b. t. 1 H NMR (δ) ppm MS 73 NH, _H AprWjj. o '--- • HCI uO 280.0282, OC Colorless crystals 74 NH, μ i ^ kl Λ> ϊΫ HCl X) 252.0254, OC Colorless crystals 75 NH ₂ · HCl Yeah 306.0308, OC Colorless crystals

«® ® ® ® ®

Table 26

Ex. C. General structural formula / property (solvent) b. t. 1 H NMR (δ) ppm MS 76 H * h. (QAQ) AAA ° 184, ΟΙ 85.0X3 2.40 (3 H, s) 4.04 (2H.s) 6.44 (1H, s) 6.46 (2 H, br.s) 7.19-7.42 (7 H, m) 7.64 (1H, d, J = 9.3Hz) 7.72 (1H, dd, J = 9.0, Hz) 7.94 (2H, d, J = 7.8 Hz) 8.36 (1H, d, J = 2.1Hz) 10.27 (1H, s) FAB + 368 [M + H] + (100) 77 Α, -Μo 183, ΟΙ 84.013 DMSO-d 6.300MHz 2.4O (3H, s) 2.92-3.0 L (4H, m) 6.43 (2H, br.s) 6.44 (1H, s) 7.16-738 ( 7H, m) 7.65 (111, d, J = 8.9 Hz) 7.73 (1H, ddJ = l1.8.9Hz) 7.94 (2H, dJ = 8 _/ 1Hz) 8p7 (1H. < U = l1Hz) 1.028 (1H3) FAB + 382 [M + H] (100) 78 Ph χτ ^ ο 0 161, ΟΙ 62.013 DMSO-d6,300MHz 1.8-1.6 (2H4tj) 2.40 (3 H, s) 2.63 (2H, U = 8.0Hz) 2.70 (2H, t,) = 8.0Hz) 6.43 (2 H, br.s) 6.44 (1H.s) 7.16-7.40 (7 H, m) 7.65 (lHAJ = 8.8Hz) 7.73 (1H, ddJ = 4,8 4.8.8Hz) 7.95 (2H4J = 8.4Hz) 8.37 (lHAJ = 2.1Hz) 10.28 (1H, s) FAB + 396 (M + H) (100)

• ·

Table 27 «φ φ φ 27 27 27

Př.e. General structural formula / presence (solvent) b. t. 1 H NMR (δ) ppm MS DMSO-d 6.300MHz FAB + 2.40 (3 H, s) 6.43 (2 H, br.s) 380 6.45 (1H, s) (M + H + 1 6.66 (1H.dJ = 12.3Hz) (100) NHj Ί) 6.91 (1H, d Jfel @ 3Hz) 79 rť szA y AA or, οπο, or 7.15-7.21 (6H, m) 7.32 (1H, U = 7.2Hz) JA AA 0 ‘ 7.40 (1H, t, J = 7.2Hz) 7.62-7.65 (3H.m) V2 (1H.S) 10.44 (1 H, s) DMSO-d 6.300MHz FAB + 2.4O (3H, s) 6.45 (2H.s) 380 N4> H AA 7.26-7.66 (12H, ro) [M + H] (100) rif ^ = Y fl-x AA 7.94 (1H.dJ = 7.9Hz) 8.48 (1H, s) 80 A Λ 0 AND 124 0n ^ or 10.54 (1H.s) Γΐ AA nh ₂ H Π 81 clay s < ^N V 233Ό J 0 \ χΆ ^ íhci Colorless crystals

φ • ·

Table 28

9 4 · 4 · 4 · 4 · · · · · · · · · · · · · · · ·

Ex. ¢. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS 82 nh _{2 and 0} • HCl Η fHl O 213TC Colorless crystals 83 NH ₂ HCl O kx DMSO-d6,300MHz 1 _ζ 30-1 _ζ 62 <6Η, m) 2.48 (2H, t, J = 7.8Hz) 2.60 <3H, s) 2.77 (2H, t J = 7) _from 8Hz) 6.61 (1H, s) 7.05-7.51 (9H. m) 7.92 (211, s) 8.65 (2H, br.s) 8.77 (1H, s) 10 , 77 (1H, s) FAB- 459 [M-H] (4) 149 (99) 84 NH ₂ HCl ^h ok XX ⁰ ' 285Γ Light yellow crystals

99 9 9 4

I 9 9 4

Table 29

Ex. E. General structural formula / property (solvent) b. t. 1 H NMR (s) ppm MS DMSO-d 6.300MHz FAB + ^ 41 (3H +) 6.45 (2 H, s) 456 NHL, Η X Ί) 6 _of 73 (2H, br.s) 6.85 (1H, dJ = 7 _of 8Hz) [M + H +] + (100) rť lil ^x Χΐι 7 _{out of} 13-7 _of 36 (13H, m) 85 X X X θ J <5s.Xs J * 7.58-7.72 (313, m) 'N - H X ^ Sl (11U) 10.55 (1H, s) DMSO-d6 FAB- 0.81-0.85 (2H, m), 10-1-1 _of 18 (5H, m) 4231M-H Nbfe H AND 1.43-1.68 (6H, m) (13) XX 6060 (3H, s) ríí 11 2.79 (2H, t = 7.7Hz) 86 X Λ xX 0 270,0- 6.62 (1H, s) 'N 273 ^ 0T 7.31-7.50 (4 H, m) 7.95 (2 H, s) 8.60 (2 H, br.s) HCl Δ ^ 77 (1H, s) 10.77 (1H.s) 13.96 (1 H.br.s) Colorless crystals DMSO-d 6.300MHz NH _Z H 87 || IÍ T fT > 300U XX x ¹ 0 \ HCl

• · · »

Table 30

Ex. General structural formula / property (solvent) b. t. 1 H NMR (δ) ppm MS H AND 88 jiYvV AND 240C A. o HCl Axis / V ¹ Colorless crystals DMSO-d6, 300MHz FAB- l, 10 (3H, t, J = 7.6Hz) 2 _R5O (2H, q, J = 7 _/ 6Hz) 481 (M-H) - N « ₂ H f * ^ 6O (3H, s) 5.41 (2H, s) 6.62 (1H, s) (3) 480 (3) 155 (99) 89 / yVyt 7.08 (2H, s) JB. <JL X l 1 ♦ HCl Ό'ψ ' Cl 245.9C 7.22 (1H, s) 7.50-7.74 (4H, m) 7.94-8.02 (2H, ro) 8/8 (2H, br.s) 8.76 (1H, s) Light brown crystals DMSO-d6 1.10 (3H.tJ = 7.6Hz) Ηζ ^Ηζ H n 1.30 (3H, J = 7.6Hz) 2.49 (2H.q, J = 7.6 Hz) riTY π 2.84 (2H, q, J = 7.6 Hz) JLx c L 5.4O (2H.s) 90 O 1 137.0 ~ 6.62 (1H s) A ¹ 138, no 7.08 (2 H, s) HCl ii 7/2 (2H2) T 7.53-7 / 2 (2H, m) 7.69-7.72 (2 H, m) 7.91 (2 H, s) 8.18 (2H, br.s) Colorless crystals (AcOEt-Et2O) 8.68 (1H, s) 10.82 (1H s)

Φ φ

Table 31 · - · ·

Ex. ¢. General structural formula / property (solvent) b. t. 1 H NMR (δ) ppm MS DMSO-d6 2 ^ 9 (3H2) NI +> AND 3.1 (3H, s) L JI 5.45 (2H.s) Yt 6.60 (1H.s) X X O 7.16 (2H.d4 = 8.9Hz) 91 0 185.0— 7.55-7.72 (4H.m) 186.OC 7.78 (2H, dJ = 8.9Hz) HCl | 7.88 (2HxU = 9.0Hz) in 1 7.93 (2H4J = 9.0Hz) 8.70 (2H.br.s) SOfeCHa 8.72 (1H, s) 10.89 (1H, s) Colorless crystals 13.77 (1H, br.s) DMSO-d 6.300MHz NH ₂ H AND 92 xN-sX ΐ τη ^ 0 269Ό XX ? 0 HCl DMSO-d6.3MHz nh ₂ H AND 93 ^ ^N - ^ X if π γ A ^ .0 233Γ > 0 0 HCl

4 44

4 4 4 4 4 4

4 4 4 4 4

4 4 4 4

4 * · 44 44 44

Table 32 ····

Ex. E. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS 94 H X HCl O 9 o ^z 244X3 Light red crystals 95 DMSO-d6,300MHz 4040 (3H, s) 5.35 (1H, dJ = 11.6Hz) 5.87 (1H, dJ = 17.8Hz) 6.41 (2H, br.s) 6.45 (1H s) 7.04 (1H.dd, J = 11.6, 17.8 Hz) 7.42-7.78 (6H, m) 8.42 (1H s) 10.46 (1H.s) FABí 304 [M + H +] + (100) NH ₂ H and 96 A _n A> o HCl at 325,0— 330,0X3 Colorless crystals

• · ·· ··

Table 33 «« • 9 9 9

9 9 9 • «· 9 9 • 9 9

9 99

Ex. C. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS 97 1SH2 η Λα ^ν υυ 0 ΝγΜ O DMSO-d 6.300MHz 2.55 (3H, s) 5.51 (2 H, s) 6.92 (1H, s) 7.11-7.15 (1H, m) 7.31-7.36 (2H, m) 7.51-7.7I (1H, m) 7.88-7, 90 (2H, m) 8.18 (1H, d, J = 7.2Hz) 8.63 (1H, d, J = 7.5Hz) 10.64 (1H, s) 12.05 (1H, s) FAB + 397 M + H1 + (42) 174 (99) 98 F ² η i ^ a i A A ^cl H H H H H H H H H H H H H H H H H H CI 216C 99 f ^Ηζ H f ^ 1 AY ^CI HCl 0 221C

9

Table 34

9 9 9 9

9

9

998 9 »99

Ex. E. General pattern / property (solvent) m.p. 1 H NMR (ppm) ppm MS NH _Z H 100 ALIGN! ,WHOSE I AJ HCl O w 0 ^ 0 ^ 208 Light yellow kiystaphs 101 nh ₂ AA / H , KLz 0 O Sl ' O zCI 214t 2HCl 1 102 νη ₂ Jfl? r H .Ny O o N ^z 0 · Cl 2741 2HCl H Light yellow crystals

9 9 9 9

99

Table 35 ····

Ex. E. General pattern / property (solvent) m.p. 1 H NMR (δ) ppm MS 103 p ^H z η ΓΛ ιΧν ^Ν γ'Υ °° \ j DMSO-d 6.300MHz 1.83-2.08 (3H, m) 2.30-2.42 (1H, m) 2.57 (3H, s) 3.50-3.75 (211, m) 4.68 (IH, m) 6.57 (1H, s) 7.47-7.58 (5H, m) 7.84- 7.93 (2H, m) 8.64 (211, br.s) 8.68 (1H, s) 10.60 (1H, s) 13/9 (1H, s) 104 P ^h 2 HC ΓΛ ΧσΌΟ • HCl DMSO-d6,300MHz 1.83-? 29 (4H, m) 3 / 7-3? 79 (2H, m) 3.72 (2H, s) 4/5 (1H, m) 6.57 (1H, s) 7.22-7 / 8 (511, m) 7.88-7.93 (2H, m) 8.62 (1H, s) 8.66 (1H, br.s) 10 / 70H, s) 13.88 (1H, s) FAB- 423 [M-H] 127 (99) 105 nh ₂ hr \ fYV τ / • ^hci DMSO-δ 6.300MHz 1.80-2.39 (4H, m) 2/8 (3H, s) 2.79-2.85 (2H, m) 3.48-3.60 (2H, m) 4 52-4 / 4 (111 m) 6.58 (1H, s) 7.1-7 / 0 (5H, tn) 7.89 (2H, s) 8.64 (3H, br. S) 10.52 (1H, s) 13.79 (1 H, s) FAB- 437 [M-HJ03] 127 (99)

· · «· Φ φ φ φ φ φ φ

ΟΛ Φ Φ · Φ ΦΦΦΦΦΦ

Ον ΦΦΦ Φ Φ φφφφ φφφ φφ φφφ φφφφ φφ φφ

Table 36

Ex. δ. General structural formula / property (solvent) m.p. @ 1 H NMR (.delta.) Ppm MS 106 * * ^H 2 Η ΓΛ • HO ^υ DMSO-d 6.300MHz 1.75-40 (6H, m) 2.33 (2H, t, J = 6.9Hz) 2.51-63 (5H, m) 3.49 (2H, m) 4.51- 4.54 (111, m), 57 (1H, s) 7.09-7.31 (5 H, m) 7.89 (1H, s) 8.61 (111, s) 8.64 (2 H, br.s) FAB- 451IM-HJ 127 (99) 107 h r \ Amorphous CDC13,300MHz 1.72-2.07 (4H. M) 2.18-2.49 (2H, m) 2.56-2.82 (3H, m) 2.60 (3H, s) 3.20-3.24 (1H, m) 3.32 (1H, m) 4.86 (2H, br.s) 6.49 (1H, s) 7.16-7.29 (5H, m) 7.32 (1H, d < U = 8.9.2.3Hz) 7.94 (111, d, J = 8, 9Hz) 8.55OH, dJ = 2.3Hz) 9.70 (1H, s) FAB + 389 [M + H] + (100) 108 Η Αγ R / γ r ^ ^0, Y is ^Cl • HCl 219C DMSO-d 6.300MHz

Table 37 • tftf tftfftftff 9 · 99

Ex. E. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS 109 η Ao n ^ jQf ^{cl N} HCl DMSO-d6, 300MHz 2.60 (3s.s) 5.46 (2 H, s) 6.61 (1H, s) 7.07 (2H, ddJ = 7.2.2.4Hz) 7.35 (2H, ddJ = 7.2.2.4Hz) 7.40 (1H.dJ = 44Hz) 7.87 (1H, dJ = 4Hz) 8.60-8.80 (2H.brs) 8.71 (ΙΗλ) 10.57 (1H.s) 14.04 (1H, s) 110 1 ^Ηζ a 1-8 - A _c , DMSO-d 6.300MHz ^ 60 (3H.s) 4.28 (2H, t-like) 4.75 (2H, t-like) 6.17 (1HH) 6.62 (1H.S) 6.92 (2H, dJ = 9.0Hz) 7.18-7.30 (4H.m) 7.98 (1H.dJ = 9.1Hz) 8.05 (1H, dJ = 9.1Hz) 8.40-8.90 (2H, brs) 8.64 (1H.s) 10/32 (H, s) 14.18 (1H.s) 111 nh ₂ η? Λ rVrW Y • HCI DMSO-d6,300MHz ^ 61 (3H.s) 5.42 (2H.s) 6.65 (1H.s) 6.83 (1H, dJ = 1.7Hz) 7.04 (2H, dJ = 8.9Hz) 7.35 (2H, d J = 8.9Hz) 7.99 (1H, dJ = 1.7Hz) 8.50-9.00 (2H.brs) 8.73 (1H, s). 10.73 (1 H, S) 14.4 (UM)

·· ·· · · · · · · · · · · · · · · · · ·

Table 38

Př.e. General structural formula / property (solvent) b. t. 1 H NMR (s) ppm MS 112 nh _{2 h} Ns = L f. J DMSO-d6, 300MHz 2.40 (3H.s) 5.57 (2H.s) 6.44 (1H.s) 6.48 (2H, s) 7.12 (2H.dJ = 7.2Hz) 7.37 (2H.d4 = 7.2Hz) 7.65 (1H.dJ = 8.8Hz) 7.85 (1H.d4 = 8.8Hz) 8.39 (1H.s) 8.69 (1H.s) 10.30 (1H, s) 113 ^{Η Η} 2 Η Γ \ - ² ^ ¹ UL _CI 216X3 Light brown crystals 114 Thread H r \ ♦ 2HCI 211X3 Light yellow crystals

Table 39

Ex. δ. General structural formula / property (solvent) m.p. 1 H NMR (δ) ppm MS 115 NHj Η ΓΛ O <.0 ^ • * ^CI Uc, Light brown crystals 253C 116 p H jO o L xkj) HCl DMSO-d 6.300MHz 1.67 (4H, brs) .delta. 22 (2H, bre) 2.37 (2H, brs) 2/8 (3H, s) 4/1 (2H, s) 6/9 (1 H, s) 6.88-? 92 (3H, m) 7.21-7.28 (2H, m) 7.88 (2 H, s) 8.62 (2 H, brs) 8/8 (1H.s) 10.45 (1H, s) 13.85 (1H, s) 117 HfjX u X XJ ° XXJ HCl 284C DMSO-d 6.300MHz

Φ

Table 40 • ΦΦΦ

· Φ • φ • • • • φ φ φ

Ex. General structural formula / property (solvent) m.p. 1 H NMR (? S) ppm MS CD30D, 300MHz 2.67 (3 H, s) FAJ3- 447 [M-H +] (28) Π 3.39 (6H, s) 5.32 (2 H, s) Sr T 6.79 (1H, s) 6.84-6.90 (3 H, m) 118 7.13-7.19 (2 H, m) 7.48-7.67 (4 H, m) 7.75 (1H, d, J = 9.0Hz) HCl ril 7.91 (1H, ddJ = ^ 0.9.0Hz) 8.95 (1 H, s) Colorless crystals (AcOEt-Ei2O) DMSOd6,300MHz 1.0, 9 (3H, t, J = 7.5Hz) 2.47 (211, q, J-7.5Hz) 5.30 (2H, s) P ^H 2 H lf 6.78 (1H, d, J = 6.9Hz) 6.84 (2H, d, J = 8.7Hz) 119 21913 7.13 (2H, d, J = 8.7Hz) LAJ ó at 7/1-7.69 (4 H, m) N HCl O 7.90-7.99 (2H, m) 8.36 (1H, br.t) 8.79 (1H, s) 8.90 (2 H, br.s) 1.10, 89 (1H, s) Light gray crystals 13.89 (1H, s) DMSO-d 6.300MHz 5.34 (2H, s) 6.79 (1H, d, J = 6.8Hz) 6.96 (2H, d, J = (? 9Hz) NH 'ir r 7.26 (2H, d, J = 6.9 Hz) νΠ2 Η 1 7.50-7.71 (411, m) 120 ΓΤΎ » ^k o 23lC 7.93-8.00 (2 H, m) 8.35 (1H, d, J = 6.8 Hz) 8.78 (1H, s) HCl 8.88 (211, br.s) 10.90 (1H, s) 14.03 (1H, s) Light gray crystals

«9 •

9 9 9

9 9 9

9 9 9

99

999

Table 41

Ex. δ. General pattern / property (solvent) b. t. 1 H NMR (δ) ppm MS DMSO-d 6.300MHz FAB- 2.60 (313, s) 3.26 (3 H, s) 492 (M-HE 4.39 (2H, s) 6 _r 57 (2H, s) (100) HΠί H | TS 5.34 (2 H, s) 121 Α'-Μ O ι _θ • HCl 276X7 ^ 61 (1H, s) (γ92 (2H, d, J = 8.5Hz)) 7.20 (2H, d, J = 8 _of 5Hz) 7.47-7.70 (4H, m) 7.95 (2 H, s) 8.61 (2H, br.s) 8.75 (1H, broad) Light yellow crystals DMSO-d6 5.34 (2 H, s) FAB- 405 IM-H + K6 H O 6.90-6.95 (3H, m) 7.19-7.26 (3H, in) N r T 7.52-7.71 (5H, m) 7.93-7.97 (2 H, m) 122 AJAX AND 11 ^ 0 ~ 8.94 (1H, s) O 117,0X7 9.05 (1H, br.s) 1 11.0 (1H, s) HCl at 13.4 (1H, br.s) AA Colorless crystals DMSO-d 6.300MHz nh _{2 h} Ίι 123 fYjX Y AND W 283X7 kAAz * 0 .A / ¹ • 0 HCl

• 4 44

4 4 4 4

4 4 4 4

4 4 4

44

444

Table 42 «« · «

• 4 4

4 • 4

4

4 4

'Ex. E. General structural formula / property (solvent) b. t. 1 H NMR (s) ppm MS DMSO-d6 ^ 21 (2H.U = 7Hz) FAB- 479 [M-H + K2] NHj> γΎ O ^ 89 (2H.U = 7Hz) 3.18 (2H, t, J = 7.3 Hz) 5.35 (2 H, s) 124 JU N l 164,0- 6.97 (2H.dJ = 9.0Hz) 7.27 (2H, d, J = 9.0 Hz) Λι 165,0X3 7.50-7.71 (4H, 1H) 7.86-7.89 (2H, m)  HCl II 8.45 (2 H, br.s) 8.76 (1H.s) Cl 10.83 (1H.s) 14.24 (1H, br.s) Colorless crystals DMSO-δ 6 5.31 (2 H, s) 6.87-6.93 (3 H, m) aa H 9 7.09 (1H.dJ = 9.2Hz) 7-4-7J5 (2H, m) 7.48-7.64 (4H.m) 125 O Ό AND 1900- 191.0X3 7.69 (1H, d, J = 9.2Hz) 7.94 (1H, dJ = 9.2Hz) HCl AND 8.38 (111, dJ = 9.2Hz) 8.41 (1H, s) • 10.78 (1H, s) 14.11 (1 H, br.s) Colorless crystals DMSO-d 6.300MHz FAB + 2.88 (3H, d, J = 4.8 Hz) 5.31 (2 H, s) 3841M + H &lt; + &gt; AND AND 6.73 (1H, dJ = 8.8Hz) 1 (100) M 6.88-6.96 (4H.m) 7.21-7.27 (2 H / n) 126 - _n and _n and ^ H 0 Λ AND 172 0— 173.0X3 7.46-7.56 (3 H, m) 7.62-7.68 (3 H, m) X 7.78 (3H, d J = 8.8Hz) if 8.1 (1H, d, J = 2Hz) 10.42 (1H, s) Colorless crystals

φφ φφ

Table 43 φφφφ

ΦΦ φ · · ·> φ φ φ φ φ φ φ φ φ φ φ φ

Ex. E. General structural formula / property (solvent) b. t. 1 H NMR (s) ppm MS 127 7¾ o ΥσΧ • ^HCl Φ Cl Colorless crystals (AcOEl-Et2O) 153, ΟΙ 55.0X3 DMSO-d63WMHx 1.68-2.09 (2H, m) 2.39 (3 H, s) ^ 31-2 / 6 (2Hm) 2.73-2.98 (3H.m) 4.21-4.34 (ΙΗ, ιπ) 5.25 (2H, ddJ = 8.9Hz) J = 12.5Hz) 6.50 (1H, s) 6.99 (2H, d J = 8.9 Hz) 7.33 (2H, d J = 8.9Hz) 7.42-7.57 (4 H, m) 7.90-8.14 (2 H, m) 8.60 (1Ηλ14 = 7.6Ηζ) 13, I0 (1H, s) FAB- 457 (M-H + J (58) 128 cXríYo HCl DMSO-d 6.300MHz 5.34 (2H.s) 6.85-6.94 (3H.m) 7.18-7.25 (2H, m) 7.50-7.61 (4H, m) 8.06 (1H, d J = 7Hz) 8.63 (1HH = 1.8Hz) 8.84 (1H, dJ = 1.8Hz) 8.91 (1H, dJ = 1.8Hz) 10.97 (1H.s) 129 nV stQ0 • HCl ^υ 191X3 Colorless crystals

Table 44

Ex. General structural formula / property (solvent) b. t. 1 H NMR (s) ppm MS W ₂ h ΓΊ 130 Χγν XXX 0 Ό O 237C HCl Colorless crystals 131 h fVA Η0χΛ _Ν Λ / 0 n O'' cr 201Γ HCl H 9 0 132 _H2 nA> 0 24132 HCl Colorless crystals

• · · · · · · · · · · · ·

Table 45 • •

Example no. ORL-1 binding μ binding Allodynia COPPER. (mg / kg) Hot plate COPPER. (mg / kg) 50θ50 Ki </ <M) * θ50 (/ zM) Ki (/ zM) 1 0.12 0.007 1.52 0.570 0.3 1 2 0.07 0.004 1.33 0.497 0.3 1 3 1.47 0,079 1.11 0.417 3 30 4 0.23 0.013 1.26 0.453 <1 <3 5 0.52 0,028 1.34 0.505 3 7 0.06 0.003 0.96 0.346 0.3 3 8 0.94 0.050 0.49 0.183 3 9 0.32 0.016 2.03 0,764 1 <3 10 1,02 0,053 0.86 0.324 3 11 0.06 0.003 1.12 0.424 0.3 3 12 0.16 0.008 0.67 0.254 0.3 3 16 0.11 0.006 0.69 0.259 0.1 3 17 0.13 0.007 1,02 0.385 0.3 1

Μ. E. D .: minimum effective dose 9

Table 46

I · t ’» 9 9 4 ··

Example # ORL-1 binding μ binding Allodynia COPPER. (mg / kg) Hot plate COPPER. (mg / kg) IC 50 (yM) Ki (μΜ) IC50 (M _A) Ki (^ M) 18 0.09 0.004 1.04 0.393 0.3 19 Dec 0.16 0.009 1.03 0.388 0.1 3 25 0.15 0.008 1.18 0.464 0,3 < 26 0.08 0.004 1,22 0.479 0/3 1 27 Mar: 0.29 0.015 1.06 0.414 0.3 29 0.16 0.009 1.05 0.414 0,3 < 3 32 0.09 0.005 0.58 0.227 0,3 < - 33 0.09 0.005 1.44 0.565 0.3 34 0.14 0.008 2.37 0.888 0.3 3 38 0.09 0.005 2.67 1,021 0,3 < 42 0.08 0.004 1.99 0.745 0.3 1 43 0.11 0.005 2.10 0.785 0.3 1 49 0.04 0,002 1.26 0.464 0.3 1

Μ. E. D .: Minimum Effective Dose

Table 47

Example # ORL-1 binding μ binding Allodynia COPPER. (mg / kg) Hot plate COPPER. (mg / kg) * θ50 (μΜ) Ki (juM) IC50 (μΜ) Ki (χΜ) 51 0.17 0.008 1.40 0.525 61 1,22 0,063 5.35 2,012 3 62 2.36 0.125 2.00 0,783 3 < 63 1.03 0,054 1.42 0.545 3 < 64 1.39 0,073 3.61 1,382 3 < 65 1.16 0,064 3 < 66 2.00 0,108 3 < 71 1.77 0,089 30 84 2.52 0.129 1.11 0.419 <3 10 < 89 0.13 0.006 1.46 0.548 0.3 1 ⁹⁰ 0.11 0.005 1.18 0.442 - 3 93 0.12 0.007 0,3 < -

Μ. E. D .: Minimum Effective Dose • · · ·

• · · · · · · · · · · · · · · · · · ·

The analgesic effect evaluation method of a compound of the present invention may be explained.

For in vitro evaluation, a compulsory ORL-1 receptor assay was performed and a compulsory µ receptor assay was performed to explain selectivity. For the in vivo evaluation, hot plate and tail twitch tests have been performed for a long time, as well as analgesic effect and touch sensation tests were performed using an allodynic model to evaluate allodynia.

Experimental Example [1]: Mandatory ORL-1 receptor assays

The cell membrane suspension obtained from human ORL-1 expressed cells was treated with Tris buffer so [50 mM Tris, 2 mM EDTA, 0.1 mM (pamidinophenyl) methanesulfonyl fluoride hydrochloride (p-APMCS), 2mM BSA] to make the membrane protein amount 25 pg / ml (2.5 pg per cell). This mixture was mixed with [ ³ H] nociceptin (diluted with Tris buffer to a final concentration of 0.5 nmol) and test compound (diluted with Tris buffer to a final concentration of 10 nmol to 10 pmol) and incubated at room temperature for 60 minutes. The membrane was removed on a G / FB filter (Packard, Unifilter 96 GF / B) and the reaction was terminated. After washing three times, the filter was dried at 24 ° C for 1 hour. Scintillation solution (Packard, Microscin-20) was added and radioactivity was measured (Packard, Topcount, A9912V).

Non-specific binding was binding in the presence of 1 µM nociceptin and the difference between total binding and non-specific binding was taken as specific binding. The IC 50 was calculated from the inhibition of specific binding for the concentration of each compound and the Ki values of the test compound were 0

calculated from this value and the Kd [H] value of nociceptin.

Experimental example [2]: Mandatory μ receptor tests

Standard Rat Brain Membrane Sample (0.755 mg protein / ml), [ ³ H] DAMGO (Tri-DAla-Gly-NMe-Phe-Gly-Ol) [diluted with Tris buffer (50 mM Tris-HCl, 0.1 mM p- APMSF, 2 mg / ml BSA (pH = 7.4)) to a final concentration of 1 nM] and test compound (diluted with Tris buffer to a final concentration of 10 nmol to 10 pmol) were mixed and incubated at room temperature for 90 minutes . The membrane was removed on a G / FB filter (above) and the reaction was complete. After washing three times, the filter was dried at 24 ° C for 1 hour. The scintillation solution (above) was added and the radioactivity (above) was measured.

Non-specific binding was binding in the presence of 10 µM naloxone and the difference between total binding and non-specific binding was taken as specific binding. The IC50 was calculated from the inhibition of the inhibition. The specific binding for the concentration of each compound and the Ki value of the test compound were calculated from this value and from the Kd [ ³ H] DAMGO value.

Experimental example [3]: Hot plate test

Mice (Crj, ICR, 4 weeks old males) were placed on a hot plate (temperature 55.5 ± 0.5 ° C) and the time was measured until the mouse jumped or tried to escape. Mice were grouped by time and body weight so that the groups were equally represented. The test compound was suspended in 0.5% methylcellulose (MC) solution and orally administered to mice. After 60 minutes, the mice were again placed on the hot plate and the time was determined until the mice licked the hind limb or jumped or escaped. A significant difference from the solvent group was analyzed by ANOVA followed by a Dunnett bilateral test.

Experimental example [4]: Tail twitch test

Rats (Crj, SD, 7 or 8 weeks old males) were irradiated from below with thermal rays around the root of the tail and time was measured until the rats moved the tail and escaped, using the analgesic effect caused by tail twitch using a device (manufactured by UGO MASILE) . Prior to administration of the test compound, the measurements were repeated three times and the rats were grouped according to the body weights so that the groups were evenly represented. The test compound was suspended in 0.5% MC solution and orally administered to rats. The same measurement was repeated 30, 60, 90 and 120 minutes after administration. A significant difference from the solvent group was analyzed by ANOVA followed by a Dunnett bilateral test.

Experimental example [5]: Allodynia test

Mice (Crj, ICR, 4 weeks old males) received internally nociceptin (50 pg / 5 μΐ) without killing. 20 minutes after administration and at 5 minute intervals, the side area of the tail of the mice was scraped with a brush and the mouse response was determined. The evaluation had the following criteria; 0 unchanged; 1 escape and shout on the touch stimulus; 2 loud shouting or fleeing on the touch stimulus. The test compound was suspended in 0.5% MC solution and orally administered 60 minutes prior to nociceptin administration. Significant difference of each test group 20 minutes after nociceptin administration from each test group administered with solvent was analyzed by Mann-Whitny U-test.

The results of the experimental examples from [1] to [5] are shown in Tables 45 to 47.

Effects of the invention

As is evident from the above results, the compound of the present invention exhibits a strong analgesic effect via an antagonistic nociceptin effect, and a portion of which exhibits a strong analgesic effect, and some of which exhibits a strong analgesic effect. selective effect on ORL-1 receptors compared to opioid receptors (μ, κ, δ receptors) including μ receptor.

Therefore, the compound of the invention can be used for a pharmaceutical agent effective against pain, especially severe pain such as hyperalgesia, allodynia and the like. Further, since the compound exhibits a selective effect on the ORL-1 receptor, it can be a safe pharmaceutical agent without significant side effects.

This application is based on the invention. No. 100029/1998 issued in Japan, the contents of which are incorporated herein by reference.

• · · · · · · · · · · · · · ·

A nociceptin antagonist comprising an amide derivative of the general formula 1

Claims (20)

PATENT CLAIMS A nociceptin antagonist comprising an amide derivative according to claim 1, wherein Ring A is quinolyl or a pharmaceutically acceptable salt thereof as the active ingredient. A nociceptin antagonist comprising an amide derivative according to claim 1, wherein ring B is phenyl and X is a group of the formula - (CH ₂ ) _m -E wherein E, ring G, R ⁵ , t, m and m are as defined in claim 1 or pharmaceutically acceptable a salt thereof as an active ingredient. 4. The amide derivative containing nociceptin antagonist according to claim 3, wherein ring A is o wherein R is lower alkylthio or a pharmaceutically acceptable salt thereof as an active ingredient. An amide derivative having the general formula 1 '(CH ₂ ) _m -E- (CH ₂ ) _n [i'] wherein R ² , ring Β, E, ring G, R ⁵ , t, man are defined in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The amide derivative according to claim 5, wherein ring B is phenyl and R is lower alkyl or a pharmaceutically acceptable salt thereof as the active ingredient. The amide derivative according to claim 1, wherein the amino group substitutes the 4-position on the quinoline skeleton, R ² is methyl substituting at the 2-position on the quinoline skeleton, E is -O- and ring B is phenyl having a substituent of the general formula - (CH ₂ ) _m —E— (CH ₂ ) _n (R ^) t where ring G, R ⁵ t, m and m are as defined in claim 1, at the 2-position, or a pharmaceutically acceptable salt thereof, as the active ingredient. The amide derivative according to claim 7, or a pharmaceutically acceptable salt thereof, which is obtained from the group consisting of N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2 (4-dichlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2- (phenoxymethyl) benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) - 2 - [(4-methoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3,5-dimethylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3,4-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-nitrophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2,3-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-methylphenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3,5-dimethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-chlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4 -acetylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-hydroxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6- quinolyl) -2 - [(4-methoxymethoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-methoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4 -cyanophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-methylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6- quinolyl) -2 - [(4-trifluoromethylphenoxy) methyl] benzamide hydrochloride, • • • • • • • • • • • • • • • • • • • • • • • • • • φφφφ φφ ·· N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2 -nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-acetoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6- quinolyl) -2 - [(2-methoxyphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-aminophenoxy) methyl] benzamide dihydrochloride, N- (4- amino-2-methyl-6-quinolyl) -2 - [(3-chlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-fluorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3,4-dichlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) - 2 - [(2-chlorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-dimethylaminophenoxy) methyl] benzamide dihydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - ((4-tert-butylphenoxy) methyl) benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2- ( 4-Biphenylyloxymethyl) benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-isopropylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) ) -2 - [(4-nitrophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-bromophenoxy) methyl) benzamide hydrochloride, N- (4-amino) 2-methyl-6-quinolyl) -2 - [(4-propylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-fluorophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-trifluoromethylphenoxy) methyl) benzamide · hydrochloride, methyl 4- [2- {N- (4-amino-2-methyl- 6-quinolyl) carbamoyl} benzyloxy] benzoate hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-iodophenoxy) methyl] benzamide, N- (4-amino-2-methyl-6-quinolyl) -2- (3-pyridyloxymethyl) ) benzamide hydrochloride, 4- (2 - {(4-amino-2-methyl-6-quinolyl) carbamoyl} benzyloxy) benzoate hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(3-cyanophenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-mesylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) - 2 - [(2-chloro-4-ethylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-chloro-3-methylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(2-chloro-4-methylphenoxy) methyl] benzamide hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide; N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-chloro-3-methylphenoxy) methyl] benzamide, 4- [2 - {(4-amino-2-methyl-6-quinolyl) carbamoyl} benzyloxy] benzyl acetate hydrochloride, N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-hydroxymethylphenoxy)] methyl] benzamide hydrochloride and N- (4-amino-2-methyl-6-quinolyl) -2 - [(4-ethylphenoxy) methyl] benzamide monohydrate hydrochloride. An amide derivative according to claim having the general formula 1 "wherein ring A, R ² , R ⁵ and t are as defined in claim 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising an amide derivative according to any one of claims 5 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A nociceptin antagonist comprising an amide derivative according to any one of claims 5 to 9, or a pharmaceutically acceptable salt thereof, which is the active ingredient. An analgesic comprising the amide derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which is the active ingredient. A method for expressing the effect of a nociceptin antagonist comprising administering an amide derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. 14. A method for treating pain comprising administering an amide derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. • 9 «· 98 99 ·· • 9 9 9 9 « 9 9 9 9 9 9 9,999 99 99 Use of an amide derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized in that the production results in a nociceptin antagonist. Use of an amide derivative according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, characterized in that the production results in an analgesic. A pharmaceutical composition for a nociceptin antagonist comprising the amide derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A commercial package comprising a pharmaceutical composition according to claim 17 and instructions included therein, the instructions state that the pharmaceutical composition can be used for a nociceptin antagonist. A pharmaceutical composition for analgesic use comprising an amide derivative according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 20. A commercial package comprising the pharmaceutical composition of claim 19 and instructions included therein, the instructions indicating that the pharmaceutical composition can be used for analgesia.