# US 9,040,506 B2 · 7,11-methanocycloocta [B] quinoline derivative as highly functionalizable acetylcholinesterase inhibitors

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- Number: US 9,040,506 B2
- Document ID: US9040506B2
- Status: Granted
- Kind: B2
- Application number: 13/640,182
- Filed: 2011-04-08
- Published: 2013-01-31
- Granted: 2015-05-26
- Earliest claimed: 2010-04-09
- Assignees: Universite De Rouen
- Applicants: Cyril Ronco; Pierre Yves Renard; Ludovic Jean; Florian Nachon; Anthony Romieu
- Inventors: Cyril Ronco; Pierre Yves Renard; Ludovic Jean; Florian Nachon; Anthony Romieu
- Web page: https://patentgrep.com/patent/US9040506B2

## CPC

- C12N 9/18: Carboxylic ester hydrolases {(3.1.1)}
- A61P 25/00: Drugs for disorders of the nervous system
- 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 25/22: Anxiolytics
- 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
- C07D 221/22: Bridged ring systems
- C07D 401/08: linked by a carbon chain containing alicyclic rings
- C07D 401/14: containing three or more hetero rings
- C12Y 301/01008: Cholinesterase (3.1.1.8), i.e. butyrylcholine-esterase
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12Y: ENZYMES

## Abstract

New highly functionalizable Huprine derivatives of formula I: and a method for preparing such compounds and their use for treating neurological diseases in which the level of acetylcholine is affected such as Alzheimer's disease.

## Claims

### Claim 1

A compound of formula I:
wherein,
R is a moiety of formula -A-Y—Z,
wherein,
A is C1-C4 alkylene;
Y is a single bond, —O—, —C(O)—, —C(O)O—, —OC(O)—, —OS(O)2—, —NH—, —N(R4)— or
Z is H, halo, cyano, hydroxyl, azide, hydrazinyl, —OR5, —C(O)OR6, —NR6R7, —N+R6R7R8, —CH(COOR6)2, —CH(CH2OH)2, CH2—OC(O)—R9, C1-C4 alkyl, C1-C4 alkyl substituted with halogen or hydroxyl, C2-C4 alkenyl or C2-C4 alkenyl substituted with halogen or hydroxyl;
R4 and R5 are C1-C4 alkyl or C1-C4 alkyloxycarbonyl;
R6, R7 and R8 are independently H or C1-C4 alkyl; and
R9 is C1-C4 alkyl or C1-C4 alkyl substituted with halogen;
with the proviso that R is not alkyl;
Ra, Rb, Rc and Rd are independently H, halogen, cyano, carboxyl, —O(C1-C4 alkyl), —S(C1-C4 alkyl), or —CH2S(C1-C4 alkyl);
R1 is H or ═CH2; and
R2 is Cl or NR3R′3 wherein R3 and R′3 are independently H, acetyl, C1-C4 alkyl, or —CO(C1-C4 alkyl);
and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R is selected from the group consisting of:
—CH2—COO—C2H5,
—(CH2)2—OH,
—(CH2)2—OCO—CH3,
—(CH2)2—OCO—CF3,
—(CH2)2—O—CH3,
—(CH2)2—I,
—(CH2)2—CN,
—(CH2)2—Cl,
—(CH2)2—F,
—CH2—COOH,
—(CH2)2—N3,
—(CH2)2—OSO2—CH3,
—(CH2)2—NH—NH2,
—(CH2)2—NH—OH,
—(CH2)2—N(boc)-O(boc),
—(CH2)2—OCO—NH2,
—(CH2)2—OCO—CH═CH2,
—CH2—CO—N(CH3)2,
—CH2—CONH2,
—(CH2)2—N+H(CH3)2,
—(CH2)2—(C2H2N3)—COOCH3,
—(CH2)2—(C2H2N3)—CH2OH,
—(CH2)2—N+H3,
—(CH2)2—N+(CH3)3,
—(CH2)2—CH—(COOCH3)2,
—(CH2)2—CH—(COOC2H5)2,
—(CH2)2—CH—(CH2OH)2,
—(CH2)3—COO—CH3,
—(CH2)4—OH,
—(CH2)4—OSO2—CH3,
—(CH2)4—N3,
—(CH2)4—(C2H2N3)—COOCH3,
—(CH2)4—(C2H2N3)—CH2OH,
—(CH2)4—(C2H2N3)—CH2OCOCF3,
—(CH2)3—COO—C2H5.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R2 is NR3R′3.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein Ra, Rb, Rd and Rc are H or Ra, Rb and Rd are H and Rc is Cl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R1 is H.

### Claim 6 (depends on 1)

The compound according to claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 7

A compound selected from the group consisting of:

### Claim 8 (depends on 1)

A method of producing the compound according to claim 1 wherein said method comprises the steps of:
a) contacting the diketone of formula 1
with an α-haloester, to obtain the compound of formula 2
wherein R′ is a C1-C4 alkyl;
b) transforming the alcoholic group of the compound of formula 2 into a leaving group to obtain the compound of formula 3
wherein R″ is a leaving group;
b′) eventually converting the compound of formula 3 into the compound of formula 4
c) contacting the compound of formula 3 or 4 with the compound of formula 5
wherein Ra, Rb, Rc and Rd are as defined in formula I, and Re is CN or COOH, to obtain the compound of formula HUP
wherein R′ is a C1-C4 alkyl and R10 is NH2 or Cl.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a compound according claim 1.

### Claim 10 (depends on 1)

A resin for affinity chromatography comprising the compound according to claim 1.

### Claim 11 (depends on 1)

An enantioselective catalyst, comprising the compound according to claim 1.