# US 2010/0168154 A1 · 1-substituted tetrahydroisoquinoline compound

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- Number: US 2010/0168154 A1
- Document ID: US20100168154A1
- Status: Published application
- Kind: A1
- Application number: 12/600,503
- Filed: 2008-05-20
- Published: 2010-07-01
- Earliest claimed: 2007-05-22
- Assignees: Astellas Pharma Inc.
- Inventors: Jun-Ichi Shishikura; Makoto Inoue; Takashi Ogiyama; Koichi Yonezawa; Susumu Yamaki; Kazuhiro Yokoyama; Shuichirou Kakimoto; Hidetsugu Okada
- Web page: https://patentgrep.com/patent/US20100168154A1

## CPC

- C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 13/10: of the bladder
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/10: for petit-mal
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 217/14: other than aralkyl radicals
- C07D 217/16: substituted by oxygen atoms
- C07D 221/20: Spiro-condensed ring systems
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 491/06: Peri-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided is a compound useful as an N-type Ca2+ channel blocker. As a result of intensive studies of compounds having an action of blocking N-type Ca2+ channels, the present inventors found that a tetrahydroisoquinoline compound of the present invention having a substituent at the 1-position has an action of blocking the N-type Ca2+ channels, an antinociceptive pain action, an antineuropathic pain action, an abdominal pain-inhibitory action and an opioid-induced constipation-improving action, and the present invention has been completed based on these findings. The compound of the present invention can be used as a pharmaceutical composition for preventing and/or treating various pains such as neuropathic pain and nociceptive pain, headaches such as migraine and cluster headache, central nervous system diseases such as anxiety, depression, epilepsy, cerebral stroke and restless legs syndrome, abdominal symptoms such as abdominal pain and abdominal distension, stool abnormalities such as diarrhea and constipation, digestive system diseases such as irritable bowel syndrome, urinary system diseases such as overactive bladder and interstitial cystitis, etc.

## Claims

### Claim 1

A compound of the formula (I):
wherein the symbols in the formula have the following meanings:
R1a and R1b: are the same or different and may be —H, C1-6 alkyl which may be substituted, cycloalkyl which may be substituted, aryl which may be substituted, or an aromatic hetero ring which may be substituted, provided that both of R1a and R1b cannot be —H, and R1a and R1b, when taken together with the carbon atom to which they are attached, may represent cycloalkyl which may be substituted,
R3a, R3b, R4a and Rab: are the same or different and may be —H, or C1-6 alkyl,
R5, R6, R7 and R8: are the same or different and may be —H, C1-6 alkyl which may be substituted, —O—(C1-6alkyl) which may be substituted, cyano, carbamoyl which may be substituted with one or two C1-6alkyl, or halogen, and any two adjacent groups of R5, R6, R7 and R8 when taken together may form —O—CH2—O— or —O—(CH2)2—O—,
R11, R12, R13, R15 and R16: are the same or different and may be —H or C1-6alkyl,
R21: is —H, C1-6 alkyl which may be substituted, or cycloalkyl which may be substituted,
R22: is
(1) cycloalkyl which is substituted with one or more groups selected from the group consisting of —OH and —CH2OH and which may be further substituted;
(2) C1-8 alkyl substituted with one or two —OH, wherein the C1-8 alkyl may further have a substituent, and one or two methylene groups (—CH2—) contained in this alkyl chain may be replaced with —O—; or
(3) C1-6 alkyl substituted with cycloalkyl which is substituted with one or more groups selected from the group consisting of —OH and —CH2OH and which may be further substituted, wherein the C1-6 alkyl may be substituted with —OH, and one or two methylene groups (—CH2—) contained in this alkyl chain may be replaced with —O—; and
n and m: are the same or different and are 0 or 1,
wherein R12 and R21 when taken together may form methylene, ethylene, or trimethylene, and in this case, R11 may represent —OH, or
R21 and R22, when taken together with the nitrogen atom to which they are attached, may form azetidine, pyrrolidine, piperidine, azepane, azocane, morpholine, tetrahydroisoquinoline or thiomorpholine which are substituted with —OH or C1-6 alkyl substituted with —OH; or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein m is 0, n is 0, and R1a, R3a, R3b, R4a, R4b, R11, R12 and R21 are each —H; or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein R1b is isopropyl, methoxymethyl, phenyl, 2-(trifluoromethyl)benzyl, or cyclohexyl; or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 2)

The compound according to claim 2, wherein R5, R6, R7 and R8 are the same or different and are independently selected from the group consisting of —H, methyl, ethyl, methoxy, and fluoro; or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 2)

The compound according to claim 2, wherein R22 is 2-hydroxypropan-1-yl, 2-hydroxy-3-methoxypropan-1-yl, or (1-hydroxycyclohexyl)methyl; or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound according to claim 1, which is
1-[({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
(2S)-1-({2-[(1S)-1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)-3-methoxy propan-2-ol,
1-({[2-(1(1S)-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,
(2R)-1-({2-[(1S)-8-methoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)propan-2-ol,
1-[({2-[(1R)-7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
(2S)-1-methoxy-3-[(2-oxo-2-{1(1S)-[2-(trifluoromethyl)benzyl]-3,4-dihydroisoquinolin-2(1H)-yl}ethyl)amino]propan-2-ol,
1-({[3-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxo propyl]amino}methyl)cyclohexanol,
(2R)-1-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,
(2R)-1-[(2-oxo-2-{1-[2-(trifluoromethyl)phenyl]-3,4-dihydroisoquinolin-2(1H)-yl}ethyl)amino]propan-2-ol,
(2S)-1-{[2-(1-cyclohexyl-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}-3-methoxy propan-2-ol,
(2R)-1-({2-oxo-2-[(1S)-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}amino)propan-2-ol,
1-[({2-[7-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
1-[({2-[7-ethyl-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
1-({[2-(1-isopropyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,
1-[({2-[5-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
1-[({2-[1-(methoxymethyl)-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
(1S,2S)-2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}-1-phenyl propane-1,3-diol,
1-({(2R)-2-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]pyrrolidin-1-yl}methyl)cyclohexanol,
(2R)-1-{[2-(1-cyclohexyl-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,
1-({[2-(3′,4′-dihydro-2′H-spiro[cyclohexane-1,1′-isoquinolin]-2′-yl)-2-oxoethyl]amino}methyl)cyclohexanol,
(2R)-1-[(2-oxo-2-{1-[2-(trifluoromethoxy)phenyl]-3,4-dihydroisoquinolin-2(1H)-yl}ethyl)amino]propan-2-ol,
(2R)-1-{[2-(1-cyclohexyl-7-ethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}propan-2-ol,
1-({[2-(6-fluoro-1-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,
1,1-dicyclopropyl-2-({2-[6-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)ethanol,
1-({[2-(1-tert-butyl-8-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,
1-({[2-(1-isopropyl-6-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,
1-({[2-(6-fluoro-1-propyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,
1-[({2-[1-(methoxymethyl)-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
1-({[2-(5-fluoro-1-propyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}methyl)cyclohexanol,
1-[({2-[5-fluoro-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
1-[({2-[8-methoxy-1-(methoxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol,
1-[({2-[1-(ethoxymethyl)-7-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)methyl]cyclohexanol, or
(1R,2S)-2-({2-[(1R)-1-(2-methoxyphenyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-oxoethyl}amino)cyclopentanol; or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

### Claim 8 (depends on 1)

An N-type Ca2+ channel blocker comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A pharmaceutical composition for preventing or treating pain, neuropathic pain, abdominal symptom, spastic constipation, opioid-induced constipation, irritable bowel syndrome, or constipation-type irritable bowel syndrome, comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The pharmaceutical composition according to claim 9, which is a pharmaceutical composition for preventing or treating pain.

### Claim 11 (depends on 10)

The pharmaceutical composition according to claim 10, which is a pharmaceutical composition for preventing or treating neuropathic pain.

### Claim 12 (depends on 9)

The pharmaceutical composition according to claim 9, which is a pharmaceutical composition for preventing or treating abdominal symptom.

### Claim 13 (depends on 9)

The pharmaceutical composition according to claim 9, which is a pharmaceutical composition for preventing or treating spastic constipation.

### Claim 14 (depends on 13)

The pharmaceutical composition according to claim 13, which is a pharmaceutical composition for preventing or treating opioid-induced constipation.

### Claim 15 (depends on 9)

The pharmaceutical composition according to claim 9, which is a pharmaceutical composition for preventing or treating irritable bowel syndrome.

### Claim 16 (depends on 15)

The pharmaceutical composition according to claim 15, which is a pharmaceutical composition for preventing or treating constipation-type irritable bowel syndrome.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and an opioid as active ingredients.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the composition is used in combination with an opioid.

### Claim 19 (depends on 1)

A method for the manufacture of a pharmaceutical composition for preventing or treating pain, neuropathic pain, abdominal symptom, spastic constipation, opioid-induced constipation, irritable bowel syndrome, or constipation-type irritable bowel syndrome comprising incorporating into said composition a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

An active ingredient of a pharmaceutical composition for preventing or treating pain, neuropathic pain, abdominal symptom, spastic constipation, opioid-induced constipation, irritable bowel syndrome, or constipation-type irritable bowel syndrome comprising the compound of claim 1.

### Claim 21 (depends on 1)

A method for preventing or treating pain, neuropathic pain, abdominal symptom, spastic constipation, opioid-induced constipation, irritable bowel syndrome, or constipation-type irritable bowel syndrome, comprising administering to a patient in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.