# US 7,608,617 B2 · Naphthaline derivatives as H3 inverse agonists

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- Number: US 7,608,617 B2
- Document ID: US7608617B2
- Status: Granted
- Kind: B2
- Application number: 11/821,263
- Filed: 2007-06-22
- Published: 2007-11-15
- Granted: 2009-10-27
- Earliest claimed: 2004-06-02
- Assignees: Hoffmann-La Roche Inc.
- Inventors: Silvia Gatti McArthur; Cornelia Hertel; Matthias Heinrich Nettekoven; Jean-Marc Plancher; Susanne Raab; Olivier Roche; Rosa Maria Rodriguez-Sarmiento; Franz Schuler
- Web page: https://patentgrep.com/patent/US7608617B2

## CPC

- C07D 401/10: linked by a carbon chain containing aromatic rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- 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 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/06: with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 207/12: Oxygen or sulfur atoms
- C07D 207/14: Nitrogen atoms not forming part of a nitro radical
- C07D 209/44: Iso-indoles; Hydrogenated iso-indoles
- C07D 211/22: by oxygen atoms
- C07D 211/38: Halogen atoms or nitro radicals
- C07D 211/42: attached in position 3 or 5
- C07D 211/46: having a hydrogen atom as the second substituent in position 4
- C07D 217/06: with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 295/088: to an acyclic saturated chain
- C07D 295/192: from aromatic carboxylic acids
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of formula I: and pharmaceutically acceptable salts thereof, to the preparation of such compounds and pharmaceutical compositions containing them. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

## Claims

### Claim 1

A compound of the formula I:
wherein:
R1 is selected from the group consisting of hydrogen,
lower alkyl,
phenyl unsubstituted or substituted with one or two groups independently selected from the group consisting of lower alkyl, lower halogenalkoxy and lower hydroxyalkyl,
lower phenylalkyl, wherein the phenyl ring is unsubstituted or substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, and
lower alkoxyalkyl;
R2 is selected from the group consisting of hydrogen,
lower alkyl,
cycloalkyl,
lower cycloalkylalkyl,
lower hydroxyalkyl,
lower alkoxyalkyl,
lower alkylsulfanylalkyl,
lower dialkylaminoalkyl,
phenyl unsubstituted or substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,
lower phenylalkyl, wherein the phenyl ring is unsubstituted or substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,
pyrrolidinyl unsubstituted or substituted with a group selected lower alkyl or halogen,
lower heteroarylalkyl, wherein the heteroaryl ring is unsubstituted or substituted with one or two lower alkyl groups, and
lower heterocyclylalkyl, wherein the heterocyclyl ring is unsubstituted or substituted with one or two lower alkyl groups; or
R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur,
said saturated heterocyclic ring
being unsubstituted or substituted by one, two or three groups independently selected from the group consisting of lower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl, and lower halogenalkylcarbonylamino, or
being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen;
A is
wherein:
m is 0, 1 or 2;
n is 0, 1 or 2;
R3 is hydrogen or lower alkyl;
R9 and R10 are independently from each other selected from hydrogen or lower alkyl;
t is 1 or 2;
R4 is hydrogen or lower alkyl;
X is O, S or N—R8; with R8 being hydrogen or lower alkyl;
p is 0, 1 or 2;
R5 is lower alkyl or cycloalkyl;
q is 0, 1 or 2;
R6 is lower alkyl;
s is 0, 1 or 2;
R7 is lower alkyl;
and pharmaceutically acceptable salts thereof,
wherein if A is A1, then R1 and R2 together with the nitrogen atom to which they are attached do not form a 4-, 5-, 6-, or 7-membered saturated or partly unsaturated heterocyclic ring.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein:
R1 is selected from the group consisting of hydrogen,
lower alkyl,
phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower halogenalkoxy or lower hydroxyalkyl, and
lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl;
R2 is selected from the group consisting of hydrogen,
lower alkyl,
phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl, and
lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy or lower hydroxyalkyl; or
R1 and R2 together with the nitrogen atom to which they are attached form a 5-or 6-membered saturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and oxo, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen;
A is
wherein:
m is 0, 1 or 2;
n is 0, 1 or 2;
R3 is hydrogen or lower alkyl;
t is 1 or 2;
R4 is hydrogen or lower alkyl;
X is O, S or N—R8; with R8 being hydrogen or lower alkyl;
p is 0, 1 or 2;
R5 is lower alkyl;
q is 0, 1 or 2;
R6 is lower alkyl;
s is 0, 1 or 2;
R7 is lower alkyl;
and pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R1 is is selected from the group consisting of hydrogen, lower alkyl, phenyl unsubstituted or substituted with one or two groups independently selected from lower alkyl, lower halogenalkoxy and lower hydroxyalkyl, and lower phenylalkyl wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl and R2 is hydrogen or lower alkyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R1 is lower phenylalkyl, wherein the phenyl ring may be unsubstituted or substituted with one or two groups independently selected from lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R2 is selected from the group consisting of
hydrogen, lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower hydroxyalkyl,
lower alkoxyalkyl, lower alkylsulfanylalkyl, lower dialkylaminoalkyl,
phenyl unsubstituted or substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,
lower phenylalkyl, wherein the phenyl ring is unsubstituted or substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,
pyrrolidinyl unsubstituted or substituted with a group selected lower alkyl or halogen,
lower heteroarylalkyl, wherein the heteroaryl ring is unsubstituted or substituted with one or two lower alkyl groups, and
lower heterocyclylalkyl, wherein the heterocyclyl ring is unsubstituted or substituted with one or two lower alkyl groups.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R2 is selected from the group consisting of hydrogen,
lower alkyl,
phenyl unsubstituted or substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl,
lower phenylalkyl, wherein the phenyl ring is unsubstituted or substituted with one or two groups independently selected from the group consisting of lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, and
pyrrolidinyl unsubstituted or substituted with a group selected lower alkyl or halogen.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from the group consisting of lower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl, and lower halogenalkylcarbonylamino, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from the group consisting of piperidine, piperazine, pyrrolidine, thiomorpholine, morpholine and azepane, said heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from the group consisting of lower alkyl, halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl, and lower halogenalkylcarbonylamino, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R1 and R2 together with the nitrogen atom to which they are attached form a 5-or 6-membered saturated heterocyclic ring optionally containing a further heteroatom selected from nitrogen, oxygen or sulfur, said saturated heterocyclic ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and oxo, or being condensed with a phenyl ring, said phenyl ring being unsubstituted or substituted by one, two or three groups independently selected from lower alkyl, lower alkoxy and halogen.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein A is of the formula A1:
wherein m is 0, 1 or 2; n is 0, 1 or 2; R3 is hydrogen or lower alkyl, and R9 and R10 are independently from each other selected from hydrogen or lower alkyl.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein R9 and R10 are hydrogen.

### Claim 12 (depends on 10)

The compound according to claim 10, wherein m is 1 and n is 1.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein A is of the formula A2:
wherein m is 0, 1 or 2; t is 1 or 2; R4 is hydrogen or lower alkyl; and X is O, S or N—R8; with R8 being hydrogen or lower alkyl.

### Claim 14 (depends on 13)

The compound according to claim 13, wherein t is 1 and X is O.

### Claim 15 (depends on 13)

The compound according to claim 13, wherein m is 1.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein A is of the formula A3:
wherein p is 0, 1 or 2 and R5 is lower alkyl or cycloalkyl.

### Claim 17 (depends on 16)

The compound according to claim 16, wherein R5 is lower alkyl.

### Claim 18 (depends on 16)

The compound according to claim 16, wherein p is 0.

### Claim 19 (depends on 16)

The compound according to claim 16, wherein p is 1.

### Claim 20 (depends on 1)

The compound according to claim 1, wherein A is of the formula A4:
wherein q is 0, 1 or 2; and R6 is lower alkyl.

### Claim 21 (depends on 20)

The compound according to claim 20, wherein q is 0.

### Claim 22 (depends on 20)

The compound according to claim 20, wherein q is 1.

### Claim 23 (depends on 1)

The compound according to claim 1, wherein A is of the formula A5:
wherein s is 0, 1 or 2; and R7 is lower alkyl.

### Claim 24 (depends on 23)

The compound according to claim 23, wherein s is 1.

### Claim 25 (depends on 1)

The compound according to claim 1, wherein said compound is selected from the group consisting of:
(4-isopropyl-piperazin-1-yl)-{6-[2-(1-methyl-piperidin-2-yl)-ethoxy]-naphthalen-2-yl}-methanone,
[6-(1-isopropyl-piperidin-4-yloxy)-naphthalen-2-yl]-(4-methyl-piperidin-1-yl)-methanone,
[6-(1-isopropyl-piperidin-4-yloxy)-naphthalen-2-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,
(3,4-dihydro-1H-isoquinolin-2-yl)-{6-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-naphthalen-2-yl}-methanone,
(3,4-dihydro-1H-isoquinolin-2-yl)-[6-(1-isopropyl-piperidin-4-yloxy)-naphthalen-2-yl]-methanone,
6-(1-isopropyl-piperidin-4-yloxy)-naphthalene-2-carboxylic acid benzyl-methyl-amide,
[6-(1-isopropyl-piperidin-4-yloxy)-naphthalen-2-yl]-thiomorpholin-4-yl-methanone,
6-(1-isopropyl-piperidin-4-yloxy)-naphthalene-2-carboxylic acid 3-methoxy-benzylamide,
[6-(1-isopropyl-piperidin-4-yloxy)-naphthalen-2-yl]-morpholin-4-yl-methanone,
(4-isopropyl-piperazin-1-yl)-[6-(1-isopropyl-pyrrolidin-3-yloxy)-naphthalen-2-yl]-methanone,
[6-(1-isobutyl-piperidin-4-yloxy)-naphthalen-2-yl]-(4-isopropyl-piperazin-1-yl)-methanone,
[6-(1-isopropyl-piperidin-4-yloxy)-naphthalen-2-yl]-piperidin-1-yl-methanone,
6-(3-piperidin-1-yl-propoxy)-naphthalene-2-carboxylic acid methyl-phenethyl-amide 1:1 hydrochloride,
6-(3-piperidin-1-yl-propoxy)-naphthalene-2-carboxylic acid benzyl-isopropyl-amide 1:1 hydrochloride,
6-(3-piperidin-1-yl-propoxy)-naphthalene-2-carboxylic acid ethyl-(2-fluoro-benzyl)-amide 1:1 hydrochloride,
6-(3-piperidin-1-yl-propoxy)-naphthalene-2-carboxylic acid (2-dimethylamino-ethyl)-ethyl-amide 1:2 hydrochloride,
6-(1-isopropyl-piperidin-4-yloxy)-naphthalene-2-carboxylic acid methyl-(1-methyl-pyrrolidin-3-yl)-amide 1:2 hydrochloride,
[6-(1-isopropyl-piperidin-4-yloxy)-naphthalen-2-yl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone 1:1 hydrochloride,
[6-(1-cyclopropyl-piperidin-4-yloxy)-naphthalen-2-yl]-morpholin-4-yl-methanone,
and pharmaceutically acceptable salts thereof.

### Claim 26 (depends on 1)

A process for the manufacture of a compound according to claim 1, comprising the steps of:
a) reacting a compound of the formula II:
wherein R1 and R2 are as defined in claim 1,
with an alcohol of the formula III:
HO-A III
wherein A is as defined in claim 1,
in the presence of a trialkylphosphine or triphenylphosphine and of a diazo compound to obtain a compound of the formula I:
and if desired,
converting the compound obtained into a pharmaceutically acceptable acid addition salt, or, alternatively,
b) coupling a compound of formula VII:
wherein A is as defined in claim 1,
with an amine of the formula V:
H—NR1R2 V
wherein R1 and R2 are as defined in claim 1,
under basic conditions to obtain a compound of the formula I:
and if desired,
converting the compound obtained into a pharmaceutically acceptable acid addition salt.

### Claim 27 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 as well as a pharmaceutically acceptable carrier and/or adjuvant.