# US 7,745,457 B2 · Meridamycin analogues for the treatment of neurodegenerative disorders

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- Number: US 7,745,457 B2
- Document ID: US7745457B2
- Status: Granted
- Kind: B2
- Application number: 11/713,972
- Filed: 2007-03-05
- Published: 2007-09-13
- Granted: 2010-06-29
- Earliest claimed: 2006-03-07
- Assignees: Wyeth
- Inventors: Edmund Idris Graziani; Kevin Pong
- Web page: https://patentgrep.com/patent/US7745457B2

## CPC

- C07D 498/18: Bridged systems
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- 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 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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 498/22: in which the condensed system contains four or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound of the structure is described. This compound and its use for preparing medicines useful in the treatment of neurodegenerative disorders is described.

## Claims

### Claim 1

A compound of the structure:
wherein:
R1 and R2 are, independently selected from the group consisting of, OH, oxo, O(C1 to C6 alkyl), O(substituted C1 to C6 alkyl), O(acyl), O(aryl), O(substituted aryl), O(heterocyclyl), or O(substituted heterocyclyl);
R3, R5, and R6 are independently are selected from the group consisting of OH, oxo, O(C1 to C6 alkyl), O(substituted C1 to C6 alkyl), O(acyl), O(aryl), O(substituted aryl), O(heterocyclyl), and O(substituted heterocyclyl);
R4 is selected from the group consisting of oxo, O(C1 to C6 alkyl), O(substituted C1 to C6 alkyl), O(acyl), O(aryl), O(substituted aryl), O(heterocyclyl), and O(substituted heterocyclyl); or
R3 and R4 and/or R5 and R6 are joined together to form a structure:
or, R4 and R5 are joined to form a structure:
wherein X and Y are independently selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
wherein the alkyl is substituted with one to three substituents each independently selected from halogen, CN, OH, NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
wherein aryl is a carbocyclic aromatic system having a single ring or multiple aromatic rings fused or linked together forming a conjugated aromatic system and wherein the aryl can be optionally substituted with one to four substituents each independently selected from halogen, CN, OH NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
wherein heterocyclyl is a 4- to 7-membered monocyclic or stable multicyclic heterocyclyl ring, which is saturated, partially saturated, or unsaturated, including carbon atoms and from one to four heteroatoms selected from N, O and S; and may be optionally substituted with one to four substituents each independently selected from halogen, CN, OH NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
wherein the acyl is an RCO group, where R is a C1 to C6 alkyl or substituted C1 to C6 alkyl as defined above and the point of attachment is on the carbon atom
R7 is CH2, CHOH, or C═O; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 and R2 are independently oxo, OH or O(acyl).

### Claim 3 (depends on 2)

The compound according to claim 2, wherein said O(acyl) is OC(O)CH3.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R3 and R4 or R4 and R5 are joined, wherein X and Y are CH3.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R7 is C(O).

### Claim 6 (depends on 1)

The compound according to claim 1 which is selected from the group consisting of:

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R1 and R2 are OH; R3 and R4 are joined; R5 and R6 are joined; R7 is C(O); and n is 2.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R1, R2, R3, R4, R5, and R6 are OC(O)CH3; R7 is C(O); and n is 2.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R1, R2, R3, and R4 are OC(O)CH3; R4 and R5 are OH; R7 is C(O); and n is 2.

### Claim 10 (depends on 1)

The compound ac cording to claim 1, wherein R1, R2, R5, and R6 are OH; R3 and R4 are joined; R7 is C(O); and n is 2.

### Claim 11 (depends on 1)

The compound ac cording to claim 1, wherein R1, R2, R3, R4, and R5 are OC(O)CH3; R6 is OH; R7 is C(O); and n is 2.

### Claim 12 (depends on 1)

The compound ac cording to claim 1, wherein R1 and R2 are oxo; R3 and R4 and R5 and R6 are joined; R7 is C(O); and n is 2.

### Claim 13 (depends on 1)

The compound ac cording to claim 1, wherein R1 and R2 are oxo; R3, R4, R5, and R6 are OH; R7 is C(O); and n is 2.

### Claim 14 (depends on 1)

The compound ac cording to claim 1, wherein R1, R2, R3, and R6 are OH; R7 is C(O); n is 2; and R4 and R5 are taken together to form a ring of the structure:

### Claim 15 (depends on 1)

The compound ac cording to claim 1, wherein R1, R2, R3 and R4 are OH; R7 is C(O); n is 2; and R5 and R6 are taken together to form a ring of the structure:

### Claim 16 (depends on 1)

A compound as claimed in claim 1, wherein
R1 and R2 are, independently, OH, oxo, or O(acyl);
R3, R5, and R6 are independently selected from the group consisting of OH and O(acyl);
R4 is O(acyl), or
R3 and R4; R4 and R5; R5 and R6; or a combination thereof are joined to form a structure:
wherein X and Y are independently selected from the group consisting of H and C1 to C6 alkyl;
R7 is C═O; and
n is 2;
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable carriers, excipients, or diluents.

### Claim 18

A method of preparing a compound of the structure:
wherein:
R1, R2, R3, R4, R5, and R6 are, independently, O(C1 to C6 alkyl) or O(substituted C1 to C6 alkyl);
R7 is CH2, CHOH, or C═O; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof
wherein said method comprises reacting meridamycin with an alkylating agent or alkyl anhydride.

### Claim 19 (depends on 18)

The method ac cording to claim 18, wherein said alkylating agent is an alkyl halide, alkyl triflate, or alkyl mesylate.

### Claim 20 (depends on 18)

The method ac cording to claim 18, wherein said alkyl anhydride is acetic anhydride.

### Claim 21

A method of preparing a compound of the structure:
wherein:
R1 and R2 are OH;
R3 and R4 and/or R4 and R5, or R5 and R6, are joined to form a structure:
X and Y are independently selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
R7 is CH2, CHOH, or C═O; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof
wherein, said method comprises reacting meridamycin with a dialkoxyalkane in the presence of an acid catalyst.

### Claim 22 (depends on 21)

The method ac cording to claim 21, wherein said dialkoxyalkane is 2,2-dimethoxypropane.

### Claim 23 (depends on 21)

The method ac cording to claim 21, wherein said acid catalyst is paratoluenesulfonic acid.

### Claim 24 (depends on 21)

A method of preparing a compound of the structure:
wherein:
R1 and R2 are oxo;
R3 and R4 and/or R4 and R5, or R5 and R6, are joined to form a structure:
wherein X and Y are independently selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
wherein the alkyl can be substituted with one to three substituents each independently selected from halogen, CN, OH, NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
wherein aryl is a carbocyclic aromatic system having a single ring or multiple aromatic rings fused or linked together forming a conjugated aromatic system and wherein the aryl can be optionally substituted with one to four substituents each independently selected from halogen, CN, OH NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
wherein heterocyclyl is a 4- to 7-membered monocyclic or stable multicyclic heterocyclyl ring, which is saturated, partially saturated, or unsaturated, including carbon atoms and from one to four heteroatoms selected from N, O and S; and may be optionally substituted with one to four substituents each independently selected from halogen, CN, OH NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
R7 is CH2, CHOH, or C═O; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof
wherein said method comprises reacting the compound prepared according to claim 21 with the Dess-Martin periodinane reagent.

### Claim 25 (depends on 21)

A method of preparing a compound of the structure:
wherein:
R1 is oxo;
R2 is OH;
R3 and R4 and/or R4 and R5, or R5 and R6, are joined to form a structure:
X and Y are independently selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl;
wherein the alkyl is substituted with one to three substituents each independently selected from halogen, CN, OH, NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
wherein aryl is a carbocyclic aromatic system having a single ring or multiple aromatic rings fused or linked together forming a conjugated aromatic system and wherein the aryl can be optionally substituted with one to four substituents each independently selected from halogen, CN, OH NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
wherein heterocyclyl is a 4- to 7-membered monocyclic or stable multicyclic heterocyclyl ring, which is saturated, partially saturated, or unsaturated, including carbon atoms and from one to four heteroatoms selected from N, O and S; and may be optionally substituted with one to four substituents each independently selected from halogen, CN, OH NO2, amino, aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
R7 is CH2, CHOH, or C═O; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof;
wherein said method comprises treating the compound prepared according to claim 21 with tetrapropylammonium ruthenate and N-morpholine oxide.

### Claim 26 (depends on 25)

A method for preparing a compound of the structure:
wherein:
R1 is oxo;
R2 is OH;
R3, R5, and R6 are OH;
R4 is selected from oxo, O(C1 to C6 alkyl), O(substituted C1 to C6 alkyl), O(acyl), O(aryl), O(substituted aryl), O(heterocyclyl), and O(substituted heterocyclyl)
R7 is CH2, CHOH, or C═O; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof
wherein said method comprises reacting the product of claim 25 with a weak acid.

### Claim 27 (depends on 26)

The method ac cording to claim 26, wherein said weak acid is paratoluenesulfonic acid.

### Claim 28

A compound selected from:

### Claim 29 (depends on 28)

A pharmaceutical composition comprising a compound according to claim 28 and one or more pharmaceutically acceptable carriers, excipients, or diluents.