US 7,253,153 B2 · Derivatives of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl] phosphonic acid and methods of use thereof

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof are provided where at least one of R2 or R3 is not hydrogen. The compounds of the present invention are N-methyl-D-aspartate (NMDA) receptor antagonists and are useful in treating a variety of conditions present in a mammal that benefit from inhibiting the NMDA receptor.

Drawings

Drawings are temporarily unavailable. Open the PDF at USPTO

Drawings

Claims11

Dependent claims

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
R1 is hydrogen, a C1 to C6 alkyl group, a C2 to C7 acyl group, a C1 to C6 alkanesulfonyl group, or a C6 to C14 aroyl group;
A is alkylene of 1 to 4 carbon atoms or alkenylene of 2 to 4 carbon atoms;
R2 and R3 are independently selected from hydrogen, or
with the proviso that at least one of R2 and R3 is not hydrogen;
R4 and R5 are independently selected from hydrogen, a C1 to C4 alkyl group, a C5 to C7 aryl group, a C6 to C15 alkylaryl group having 5 to 7 carbon atoms in the aryl ring, a C2 to C7 alkenyl group, or C2 to C7 alkynyl group, or R4 and R5 may together form a spiro C3 to C8 carbocyclic ring;
R6 is a C1 to C12 linear or branched alkyl group, a C2 to C7 linear or branched alkenyl or alkynyl group, a C5 to C13 aryl group, a C6 to C21 alkylaryl group having 5 to 13 carbon atoms in the aryl moiety;
a 5 to 13 membered heteroaryl group, a 6 to 21 membered alkylheteroaryl group having 5 to 13 members in the heteroaryl moiety, a C4 to C8 cycloalkyl group, a C5 to C16 alkylcycloalkyl group having 4 to 8 carbon atoms in the cycloalkyl ring;
R7 and R8 are independently selected from hydrogen, a C1 to C12 linear or branched alkyl group, a C2 to C7 linear or branched alkenyl or alkynyl group, a C5 to C13 aryl group, a C6 to C21 alkylaryl group having 5 to 13 carbon atoms in the aryl moiety, a 5 to 13 membered heteroaryl group, a 6 to 21 membered alkylheteroaryl group having 5 to 13 members in the heteroaryl moiety, or R7 and R8 may together form a cycloalkyl or heterocycloalkyl group having in the ring 4 to 8 carbon atoms and optionally one to two atoms selected from nitrogen, oxygen or sulfur;
wherein any R1 to R8 group having an aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety may optionally be substituted on the aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety with 1 to about 5 substituents independently selected from a halogen atom, a cyano, nitro or hydroxyl group, a C1-C6 alkyl group, or a C1-C6 alkoxy group.

7 more elements

A product made by the process comprising:

a) reacting a compound of formula (II)
and at least one ester selected from
wherein
R1 is hydrogen, a C1 to C6 alkyl group, a C2 to C7 acyl group, a C1 to C6 alkanesulfonyl group, or a C6 to C14 aroyl group;
A is alkylene of 1 to 4 carbon atoms or alkenylene of 2 to 4 carbon atoms;
Y is a leaving group;
R4 and R5 are independently selected from hydrogen, a C1 to C4 alkyl group, a C5 to C7 aryl group, a C6 to C15 alkylaryl group having 5 to 7 carbon atoms in the aryl ring, a C2 to C7 alkenyl group, or C2 to C7 alkynyl group, or R4 and R5 may together form a spiro C3 to C8 carbocyclic ring;
R6 is a C1 to C12 linear or branched alkyl group, a C2 to C7 linear or branched alkenyl or alkynyl group, a C5 to C13 aryl group, a C6 to C21 alkylaryl group having 5 to 13 carbon atoms in the aryl moiety;
a 5 to 13-membered heteroaryl group, a 6 to 21 membered alkylheteroaryl group having 5 to 13 members in the heteroaryl moiety, a C4 to C8 cycloalkyl group, a C5 to C16 alkylcycloalkyl group having 4 to 8 carbon atoms in the cycloalkyl ring;
and
R7 and R8 are independently selected from hydrogen, a C1 to C12 linear or branched alkyl group, a C2 to C7 linear or branched alkenyl or alkynyl group, a C5 to C13 aryl group, a C6 to C21 alkylaryl group having 5 to 13 carbon atoms in the aryl moiety;
a 5 to 13 membered heteroaryl group, a 6 to 21 membered alkylheteroaryl group having 5 to 13 members in the heteroaryl moiety, or R7 and R8 may together form a cycloalkyl or heterocycloalkyl group having in the ring 4 to 8 carbon atoms and optionally one to two atoms selected from nitrogen, oxygen or sulfur;
and
b) forming a product of formula (I) or a pharmaceutically acceptable salt thereof
wherein:
R2 and R3 are independently selected from hydrogen, or
with the proviso that at least one of R2 and R3 is not hydrogen;
R1, A, R4, R5, and R6 in formula (I) are defined as in formula (II);
wherein any R1 to R8 group in formula (I) or (II) having an aryl, heteroaryl, cycloalkyl or heterocycloalkyl moiety may optionally be substituted with 1 to about 5 substituents independently selected from a halogen atom, a cyano, nitro or hydroxyl group, a C1-C6 alkyl group, or a C1-C6 alkoxy group.

16 more elements

Dependencies are inferred from the claim text.

Description10,134 words

Summary1,111 words

#The present invention relates to derivatives of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl]phosphonic acid and methods of use thereof. The compounds of the present invention are particularly useful as N-methyl-D-aspartate (NMDA) receptor antagonists.

#Glutamate and aspartate play dual roles in the central nervous system as essential amino acids and as the principal excitatory neurotransmitters. There are at least four classes of excitatory amino acid receptors: NMDA, AMPA (2-amino-3-(methyl-3-hydroxyisoxazol-4-yl)propanoic acid), kainate and metabotropic receptors. These excitatory amino acid receptors regulate a wide range of signaling events that impact physiological brain functions. For example, activation of the NMDA receptor has been shown to be the central event which leads to excitotoxicity and neuronal death in many disease states, as well as a result of hypoxia and ischaemia following head trauma, stroke and following cardiac arrest. It is also known that the NMDA receptor plays a major role in the synaptic plasticity that underlies many higher cognitive functions, such as memory and learning, certain nociceptive pathways, and in the perception of pain. In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain which underlies consciousness itself.

#NMDA receptors are localized throughout the central nervous system. NMDA receptors are ligand-gated cation channels that modulate sodium, potassium and calcium ions flux when they are activated by glutamate in combination with glycine. Structurally, the NMDA receptor is thought to be comprised of heteromultimeric channels containing two major subunits designated as NR1 and NR2. These subunits contain a glycine binding site, a glutamate binding site and polyamine binding site. For the NR1 subunit, multiple splice variants have been identified, whereas for the NR2 subunit, four individual subunit types (NR2A, NR2B, NR2C, and NR2D) have been identified. The NMDA receptor also contains an Mg++ binding site located inside the pore of the ionophore of the NMDA receptor/channel complex, which blocks the flow of ions.

Detailed description9,023 words

#This invention provides compounds of formula (I)

#where:

#R1 is hydrogen, a C1 to C6 alkyl group, a C2 to C7 acyl group, a C1 to C6 alkanesulfonyl group, or a C6 to C14 aroyl group;

Facts

Application

10/820,216Filed 7 Apr 2004 · us provisional application

Priority

9 Apr 2003

Published

US 2005/0004080 A16 Jan 2005

Granted

7 Aug 2007

Term ended

10 Mar 2025

Estimated · how

20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment, including 337 days of adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification29 codes

C07F 9/645
Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom: having two nitrogen atoms as the only ring hetero atoms
A61P 3/08
Drugs for disorders of the metabolism: for glucose homeostasis
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Timeline

9 Apr 2003Priority claimedParent application 60/461,490
7 Apr 2004Application filedUS 10/820,216
14 Jul 2004Assigned to Wyethassignment of assignor's interest
6 Jan 2005PublishedUS 2005/0004080 A1
7 Aug 2007GrantedUS 7,253,153 B2
10 Mar 2025Term endedEstimated, includes 337 days of adjustment

Derivatives of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl] phosphonic acid and methods of use thereof

Life of this patent

Derivatives of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl] phosphonic acid and methods of use thereof

Life of this patent

Life of this patent

Abstract

Drawings

Drawings

Claims11

Description10,134 words

Drawings

Classification29 codes

Life of this patent

Description10,134 words