# US 7,411,091 B2 · N-acyl-N′-benzyl-alkylendiamino derivatives

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- Number: US 7,411,091 B2
- Document ID: US7411091B2
- Status: Granted
- Kind: B2
- Application number: 10/580,367
- Filed: 2004-11-12
- Published: 2007-06-21
- Granted: 2008-08-12
- Earliest claimed: 2003-11-24
- Assignees: Newron Pharmaceuticals S.p.A.
- Inventors: Florian Thaler; Cibele Maria Sabido David; Laura Faravelli; Stefania Gagliardi; Elena Colombo; Patricia Salvati
- Web page: https://patentgrep.com/patent/US7411091B2

## CPC

- C07D 207/27: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/12: Antidiarrhoeals
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/12: of the kidneys
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- 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
- C07C 233/36: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

This invention is related to compounds and use of N-Acyl-N′-benzyl-alkylendiamino derivatives of the following general formula (I), wherein A is a straight or branched C2-C8 alkyl chain; X is a methylene, oxygen, sulphur or a NR7 group; R1 is a straight or branched C1-C8 alkyl or C3-C8 alkenylene or C3-C8 alkynylene chain, optionally substituted with CF3, phenyl, phenoxy or naphthyl, the aromatic rings optionally substituted by one or more C1-C4 alkyl, halogens, trifluoromethyl, hydroxy or C1-C4 alkoxy groups; R2, R3 are independently hydrogen, a C1-C3 alkyl chain, halogen, trifluoromethyl, hydroxy or C1-C4 alkoxy groups; R4, R5 are independently hydrogen or C1-C6 alkyl; R6 is a hydrogen or a straight or branched C1-C8 alkyl or linked to R5 can form a five to seven membered lactam; R7 is hydrogen or C1-C6 alkyl; and the pharmaceutically acceptable salts thereof that are active as sodium and/or calcium channel modulators and therefore useful in preventing, alleviating and curing a wide range of pathologies, including, but not limited to, neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urologic, metabolic and gastrointestinal diseases, where the above mechanisms have been described as playing a pathological role

## Claims

### Claim 1

A compound of general formula I
wherein
A is a straight or branched C2-C8 alkyl chain;
X is a methylene, oxygen, sulphur or a NR7 group;
R1 is a straight or branched C1-C8 alkyl or C3-C8 alkenylene or C3-C8 alkynylene chain, optionally substituted with CF3, phenyl, phenoxy or naphthyl, the aromatic rings optionally substituted by one or more C1-C4 alkyl, halogens, trifluoromethyl, hydroxy or C1-C4 alkoxy groups;
R2, R3 are independently hydrogen, a C1-C3 alkyl chain, halogen, trifluoromethyl, hydroxy or C1-C4 alkoxy groups;
R4, R5 are independently hydrogen or C1-C6 alkyl;
R6 is a hydrogen or a straight or branched C1-C8 alkyl or linked to R5 can form a five to seven membered lactam;
R7 is hydrogen or C1-C6 alkyl;
and the pharmaceutically acceptable salts thereof, with the proviso that when A is —CH2CH2—, R1-X is ortho-benzylthio, R2, R3 and R5 are hydrogen and R6 methyl, R4 is other than hydrogen or methyl;
when A is —CH2CH2—, R1—X 4-methoxy, R2 2-methoxy, R3 and R5 hydrogen and R6 methyl, R4 is other than hydrogen, and
when A is —CH2CH2—, R1—X 3-methoxy, R2 5-methoxy, R3 and R5 hydrogen and R6 methyl, R4 is other than hydrogen.

### Claim 2 (depends on 1)

A compound of general formula I as defined in claim 1, where A is ethylene or propylene, X is oxygen, methylene, NH or NCH3, R1 is C1—C8 alkyl chain, optionally substituted with CF3, phenyl or phenoxy group, where the aromatic ring in R1 is optionally substituted by one or two methoxy, fluoro, chloro or trifluoromethyl groups, R2 and R3 are hydrogen, methyl, methoxy, fluorine, chlorine or bromine, R4 and R5 are hydrogen or methyl, R6 is methyl or ethyl or linked to R5 form a five or six membered lactam.

### Claim 3

A compound selected from the group consisting of:
N-2- (4-Butyloxy-benzylamino)-ethyl-acetamide;
N-2-[4-(4-triFluorobutyloxy)-benzylamino]-ethyl-acetamide;
N-2-(4-Pentyloxy-benzylamino)-ethyl-acetamide;
N-2-[4-(5-triFluoropentyloxy)-benzylamino]-ethyl-acetamide;
N-2-(2-Benzyloxy-benzylamino)-ethyl-acetamide;
N-2-(3-Benzyloxy-benzylamino)-ethyl-acetamide;
N-2-(4-Benzyloxy-benzylamino)-ethyl-acetamide;
N-2-[4-(5-Phenyl-pentyloxy)-benzylamino]-ethyl-acetamide;
N-2-[4-(2-Phenethyl)-benzylamino]-ethyl-acetamide;
N-{2-[2-(2-Fluoro-benzyloxy)-benzylamino]-ethyl}-acetamide;
N-{2-[3-(2-Fluoro-benzyloxy)-benzylamino]-ethyl}-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-benzylamino]-ethyl}-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-2-methoxy-benzylamino]-ethyl }-acetamide;
N-{2-[4-(2-Fluaro-benzyloxy)-2-methyl-benzylamino]-ethyl }-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-3-fluoro-benzylamino]-ethyl }-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-3-chloro-benzylamino]-ethyl }-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-3-methoxy-benzylamino]-ethyl }-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-3-methyl-benzylamino]-ethyl }-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-3,5-dimethoxy-benzylamino]-ethyl }-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-3, 5-dimethyl-benzylamino]-ethyl }-acetamide;
N-{2-[4-(2-Fluoro-benzyloxy)-3-bromo-5-methoxy-benzylamino]-ethyl }-acetamide;
N-3-(4-Pentyloxy-benzylamino)-propyl-acetamide;
N-2-[4-(5-trifluoropentyloxy)-benzylamino]-propyl acetamide;
N-3-(4-Benzyloxy-benzylamino)-propyl-acetamide;
N-3-[4-(2-Phenethyl)-benzylamino]-propyl-acetamide;
N-3-[4-(5-Phenyl-pentyloxy)-benzylamino]-propyl-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-2-methoxy-benzylamino]-propyl }-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-2-methyl-benzylamino]-propyl}-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-3-fluoro-benzylamino]-propyl }-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-3-chloro-benzylamino]-propyl }-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-3-methoxy-benzylamino]-propyl}-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-3-methyl-benzylamino]-propyl }-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-3,5-dimethoxy-benzylamino]-propyl}-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-3,5-dimethyl-benzylamino]-propyl}-acetamide;
N-{3-[4-(2-Fluoro-benzyloxy)-3-bromo-5-methoxy-benzylamino]-propyl}-acetamide;
1-[2-(4-Butyloxy-benzylamino)-ethyl]-pyrrolidin-2-one;
l-{2-[4-(4-triFluorobutyloxy-benzylamino]-ethyl}-pyrrolidin-2-one;
1-[2-(4-Pentyloxy-benzylamino)-ethyl]-pyrrolidin-2-one;
l-{2-[4-(5-triFluoropentyloxy-benzylamino]-ethyl}-pyrrolidin-2-one;
1-[2-(2-Benzyloxy-benzylamino)-ethyl]-pyrrolidin-2-one;
1-[2-(3-Benzyloxy-benzylamino)-ethyl]-pyrrolidin-2-one;
1-[2-(4-Benzyloxy-benzylamino)-ethyl]-pyrrolidin-2-one;
1-[2-(4-Benzylthio-benzylamino)-ethyl]-pyrrolidin-2-one;
1-[2-(4-Benzylamino-benzylamino)-ethyl]-pyrrolidin-2-one;
l-{2-[4-(5-Phenyl-pentyloxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
1- {2-[4-(2-Phenoxy-ethoxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
1- {2-[4-(Naphthalen-1-ylmethoxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
l-{2-[2-(3-Fluorobenzyloxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
l-{2-[3-(3-Fluorobenzyloxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
l-{2-[4-(3-Fluorobenzyloxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(4-tert-Butyl-benzyloxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(4-triFluoromethyl-benzyloxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2,6-Dichloro-benzyloxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(3,5-Dimethoxy-benzyloxy)-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2-Fluoro-benzyloxy)-2-methoxy-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2-Fluoro-benzyloxy)-2-methyl -benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4- C2-Fluoro-benzyloxy)-3-fluoro-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2-Fluoro-benzyloxy)-3-methoxy-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2-Fluoro-benzyloxy)-3-methyl-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2-Fluoro-benzyloxy)-3-chloro-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2-Fluoro-benzyloxy)-3,5-dimethoxy-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2-Fluoro-benzyloxy)-3,5-dimethyl-benzylamino]-ethyl}-pyrrolidin-2-one;
1-{2-[4-(2-fluoro-benzyloxy)-3-bromo-5-methoxy-benzylamino]-ethyl}-pyrrolidin-2-one;
1-[3-(4-Pentyloxy-benzylamino)-propyl]-pyrrolidin-2-one;
1-[3-(2-Benzyloxy-benzylamino)-propyl]-pyrrolidin-2-one;
1-[3-(3-Benzyloxy-benzylamino)-propyl]-pyrrolidin-2-one;
1-[3-(4-Benzyloxy-benzylamino)-propyl]-pyrrolidin-2-one;
1-{3-[4-(5-Phenyl-pentyloxy)-benzylamino]-propyl}-pyrrolidin-2-one;
1- {3-[4-(2-Phenoxy-ethoxy)-benzylamino]-propyl}-pyrrolidin-2-one;
1-{3-[4-(Naphthalen-1-ylmethoxy)-benzylamino]-propyl)-pyrrolidin-2-one;
1-{3-[4-(4-tert-Butyl-benzyloxy)-benzylamino]-propyl)-pyrrolidin-2-one;
1- {3-[4-(4-triFluoromethyl-benzyloxy)-benzylamino]-propyl }-pyrrolidin-2-one;
1-(3-[4-(2,6-Dichloro-benzyloxy)-benzylamino]-propyl}-pyrrolidin-2-one;
1-{3-[4-(3, 5-Dimethoxy-benzyloxy)-benzylamino}-propyl}-pyrrolidin-2-one;
1-{3-[4-(2-Fluoro-benzyloxy)-2-methoxy-benzylamino]-propyl}-pyrrolidin-2-one;
1-{3-[4-(2-Fluoro-benzyloxy)-2-methyl-benzylamino]-propyl}-pyrrolidin-2-one;
1-{3-[4-(2-Fluoro-benzyloxy)-3-fluoro-benzylamino]-propyl}-pyrrolidin-2-one;
1-{3-[4-(2-Fluoro-benzyloxy)-3-methoxy-benzylamino]-propyl }-pyrrolidin-2-one;
1-{3-[4-(2-Fluoro-benzyloxy)-3-methyl-benzylamino]-propyl }-pyrrolidin-2-one;
1-{3-[4-(2-Fluoro-benzyloxy)-3-chloro-benzylamino]-propyl }-pyrrolidin-2-one;
1-{3-[4-(2-Fluoro-benzyloxy)-3,5-dimethoxy-benzylamino]-propyl}-pyrrolidin-2-one;
1-{3-[4-(2-Fluoro-benzyloxy)-3,5-dimethyl-benzylamino]-propyl}-pyrrolidin-2-one;
1-{3-[4-(2-f Fluoro-benzyloxy)-3-bromo-5-methoxy-benzylamino]-propyl}-pyrrolidin-2-one;
or pharmaceutically acceptable salts thereof.

### Claim 4 (depends on 1)

A process for the preparation of a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, the process comprising:
a) reaction of compounds of formula II
wherein R1, R2, R3and X are as defined above
with compounds of formula III, in the presence of a reducing agent
wherein R4, R5, R6 and A are as defined previously thus obtaining a compound of formula I; or
b) reaction of compounds of formula IV
wherein R1, R2 R3 and X are as defined above and Y is a halogen atom or a O-EWG group, where the EWG means an electron withdrawing group, like e.g. mesyl, tosyl or trifluoroacetyl groups, able to transform the oxygen which they are linked to, in a good leaving group
with compounds of formula III thus obtaining a compound of formula I; or
c) reacting of a compound of formula Ia
wherein R1, R2, R3, R5 and R6, X and A are as defined above, with compounds of formula V or VI
R4Y V
R8CHO VI
wherein Y is as defined above; R4 is a C1-C6 alkyl and R8 is hydrogen or C1-C5 alkyl, thus obtaining a compound of the invention in which R4 is C1-C6 alkyl; and, if desired, converting a compound of the invention into another compound of the invention and/or, if desired, converting a compound of the invention into a pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers of compounds of the invention into a single isomer.

### Claim 5 (depends on 1)

A pharmaceutical composition containing a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof in admixture with a suitable carrier and/or diluent and optionally to other therapeutic agents.

### Claim 6 (depends on 1)

A compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use as an active therapeutic substance.

### Claim 7 (depends on 1)

A method of preparing a medicament having sodium and/or calcium channel modulating activity, comprising:
mixing a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable, therapeutically inert organic and/or inorganic carrier material.