# US 7,612,091 B2 · Caspase inhibitors and uses thereof

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- Number: US 7,612,091 B2
- Document ID: US7612091B2
- Status: Granted
- Kind: B2
- Application number: 10/743,563
- Filed: 2003-12-22
- Published: 2004-09-30
- Granted: 2009-11-03
- Earliest claimed: 2002-12-20
- Assignees: Vertex Pharmaceuticals Incorporated
- Inventors: Jean-Damien Charrier; Michael Mortimore; John R. Studley
- Web page: https://patentgrep.com/patent/US7612091B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/16: Central respiratory analeptics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/10: for petit-mal
- A61P 25/12: for grand-mal
- 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
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- 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 217/24: Oxygen atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound of formula I: wherein: X is —OR1 or —N(R5)2, Y is halo, trifluorophenoxy, or tetrafluorophenoxy; R1 is: C1-6 straight chained or branched alkyl, alkenyl, or alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with optionally substituted aryl, CF3, Cl, F, OMe, OEt, OCF3, CN, or NMe2; C1-6 cycloalkyl, wherein 1-2 carbon atoms in the cycloalkyl is optionally replaced with —O— or —NR5—; R2 is C1-6 straight chained or branched alkyl; R3 is hydrogen, halo, OCF3, CN, or CF3; R4 is hydrogen, halo, OCF3, CN, or CF3; and each R5 is independently H, C1-6 straight chained or branched alkyl, aryl, —O—C1-6 straight chained or branched alkyl, or —O-aryl. The present invention also provides pharmaceutical compositions and methods using such compositions for treating a caspase-mediated disease, particularly in the central nervous system.

## Claims

### Claim 1

A compound of formula I:
wherein:
X is —OR1 or —N(R5)2,
Y is halo, trifluorophenoxy, or tetrafluorophenoxy;
R1 is:
C1-6 straight chained or branched alkyl, or C2-6 straight chained or branched alkenyl or alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with optionally substituted phenyl, CF3, Cl, F, OMe, OEt, OCF3, CN, or NMe2;
C3-6 cycloalkyl, wherein 1-2 carbon atoms in the cycloalkyl is optionally replaced with —O— or NR5—;
R2 is C1-6 straight chained or branched alkyl;
R3 is hydrogen, halo, OCF3, CN, or CF3;
R4 is hydrogen, halo, OCF3, CN, or CF3; and
each R5 is independently H, C1-6 straight chained or branched alkyl, aryl, —O—C1-6 straight chained or branched alkyl, or —O-aryl.

### Claim 2

A compound of formula I:
wherein:
X is —OR1 or —N(R5)2,
Y is halo, trifluorophenoxy, or tetrafluorophenoxy;
R1 is:
C1-6 straight chained or branched alkyl, or C2-6 straight chained or branched alkenyl or alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with phenyl or CF3, or
C3-6 cycloalkyl, wherein 1-2 carbon atoms in the cycloalkyl is optionally replaced with —O— or —NR5—;
R2 is C1-6 straight chained or branched alkyl;
R3 is hydrogen, halo, OCF3, CN, or CF3;
R4 is hydrogen, halo, OCF3, CN, or CF3; and
R5 is H, C1-6 straight chained or branched alkyl, or —O—C1-6 straight chained or branched alkyl; provided that if:
Y is F;
R2 is isopropyl, R3 is hydrogen, and R4 is Cl; or
R2 is ethyl, R3 is hydrogen, and R4 is Cl or CF3; or
R2 is ethyl, R3 is Cl or CF3, and R4 is hydrgen; then
R1 is not t-butyl; and if
Y is 2,3,5,6-tetrafluorophenoxy;
R2 is ethyl; and
R3 and R4 are each hydrogen; or
R3 is hydrogen and R4 is Cl or CF3; or
R3 and R4 are each Cl; then
R1 is not t-butyl.

### Claim 3 (depends on 1, 2)

The compound according to claim 1 or claim 2, wherein R2 is ethyl, n-propyl, or isopropyl.

### Claim 4 (depends on 1, 2)

The compound according to claim 1 or claim 2, wherein Y is F, trifluorophenoxy, or tetrafluorophenoxy.

### Claim 5 (depends on 1)

The compound according to claim 1, having formula IA′:
R2 is ethyl, n-propyl, or isopropyl;
R3 is hydrogen, halo, OCF3, CN, or CF3; and
R4 is hydrogen, halo, OCF3, CN, or CF3.

### Claim 6 (depends on 1)

The compound according to claim 1, having formula IA:
R1 is C1-6 straight chained or branched alkyl optionally substituted with phenyl or CF3;
R2 is ethyl, n-propyl, or isopropyl;
R3 is hydrogen, halo, OCF3, CN, or CF3; and
R4 is hydrogen, halo, OCF3, CN, or CF3.

### Claim 7 (depends on 2)

The compound according to claim 2, having formula IA′:
R2 is ethyl, n-propyl, or isopropyl;
R3 is hydrogen, halo, OCF3, CN, or CF3; and
R4 is hydrogen, halo, OCF3, CN, or CF3.

### Claim 8 (depends on 2)

The compound according to claim 2, having formula IA:
R1 is C1-6 straight chained or branched alkyl optionally substituted with phenyl or CF3;
R2 is ethyl, n-propyl, or isopropyl;
R3 is hydrogen, halo, OCF3, CN, or CF3; and
R4 is hydrogen, halo, OCF3, CN, or CF3.

### Claim 9 (depends on 1)

The compound according to claim 1, having the formula IB′:
wherein:
R2 is ethyl, n-propyl, or isopropyl;
R3 and R4 are each independently hydrogen, halo, OCF3, CN, or CF3; and
Ar is tritluorophenyl or tetrafluorophenyl.

### Claim 10 (depends on 1)

The compound according to claim 1, having the formula IB:
wherein:
R1 is C1-6 straight chained or branched ailkyl optionally substituted with phenyl or CF3;
R2 is ethyl, n-propyl, or isopropyl;
R3 and R4 are each independently hydrogen, halo, OCF3, CN, or CF3; and
Ar is trifluorophenyl or tetrafluorophenyl.

### Claim 11 (depends on 2)

The compound according to claim 2, having the formula IB′:
wherein:
R2 is ethyl, n-propyl, or isopropyl;
R3 and R4 are each independently hydrogen, halo, OCF3, CN, or CF3; and
Ar is tntluorophenyl or tetrafluorc phenyl.

### Claim 12 (depends on 2)

The compound according to claim 2, having the formula IB:
wherein:
R1 is C1-6 straight chained or branched alkyl optionally substituted with phenyl or CF3;
R2 is ethyl, n-propyl, or isopropyl;
R3 and R4 are each independently hydrogen, halo, OCF3, CN, or CF3; and
Ar is trifluorophenyl or tetrafluorcphenyl.

### Claim 13 (depends on 10, 12)

The compound according to claim 10 or claim 12, wherein Ar is 2,3,5,6-tetrafluorophenyl.

### Claim 14 (depends on 5, 6, 7, 8, 9, 10, 11, 12)

The compound according to any one of claims 5-12, wherein R2 is ethyl.

### Claim 15 (depends on 5, 6, 7, 8, 9, 10, 11, 12)

The compound according to any one of claims 5-12, wherein R3 is H, and R4 is F, Cl, or CF3.

### Claim 16 (depends on 5, 6, 7, 8, 9, 10, 11, 12)

The compound according to any one of claims 5-12, wherein when Y is halo, then R3 and R4, are not simultaneously hydrogen.

### Claim 17 (depends on 14)

The compound according to claim 14 wherein when Y is halo, then R3 and R4, are not simultaneously hydrogen.

### Claim 18 (depends on 15)

The compound according to claim 15 wherein when Y is halo, then R3 and R4, are not simultaneously hydrogen.

### Claim 19 (depends on 6, 8, 10)

The compound according to any one of claims 6, 8, 10, or 12, wherein X is —OR1 and the R1 is an alkyl group that is not substituted with phenyl or CF3.

### Claim 20 (depends on 17)

The compound according to claim 17 wherein X is —OR1 and the R1 is ethyl or propyl.

### Claim 21 (depends on 5, 7, 9)

The compound according to any one of claims 5, 7, 9, or 11, wherein X is —N(R5)2.

### Claim 22 (depends on 21)

The compound according to claim 21, wherein R5 is methyl, ethyl, or propyl.

### Claim 23 (depends on 21)

The compound according to claim 21, wherein X is —N(R5)2 and one R5 is C1-6 straight chained or branched alkyl and the other R5 is —O—C1-6 straight chained or branched alkyl.

### Claim 24 (depends on 21)

The compound according to claim 21, wherein X is —N(R5)2 and one R5 is H or —C1-6 straight chained or branched alkyl and the other R5 is —C1-6 straight chained or branched alkyl.

### Claim 25 (depends on 24)

The compound according to claim 24, wherein the C1-6 straight chained or branched alkyl is methyl, ethyl, or propyl.

### Claim 26

A compound selected from the following compounds:

### Claim 27 (depends on 1, 2)

A pharmaceutical composition comprising:
a) a compound according to claim 1 or claim 2; and
b) a pharmaceutically acceptable carrier, adjuvant or vehicle.

### Claim 28

A process for preparing a corn pound of formula I:
wherein:
X is —OR1 or —N(R5)2,
Y is halo, trifluorophenoxy, or tetrafluorophenoxy;
R1 is:
C1-6 straight chained or branched alkyl, or C2-6 straight chained or branched alkenyl or alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with optionally substituted phenyl, CF3, Cl, F, OMe, OEt, OCF3, CN, or NMe2;
C3-6 cycloalkyl, wherein 1-2 carbon atoms in the cycloalkyl is optionally replaced with —O— or —NR5—;
R2 is C1-6 straight chained or branched alkyl;
R3 is hydrogen, halo, OCF3, CN, or CF3;
R4 is hydrogen, halo, OCF3, CN, or CF3; and
R5 is H, C1-6 straight chained orbianched alkyl, aryl, —O—C1-6 straight chained or branched alkyl, or —O-aryl;
comprising the step of reacting a compound of formula I′:
wherein X, Y, R2, R3, and R4 are as defined for formula I; under conditions forming an ester or aniide bond to provide a compound of formula I.

### Claim 29

A process for preparing a compound of formula I:
wherein:
X is —OR1 or —N(R5)2,
Y is halo, trifluorophenoxy, or tetrafluorophenoxy;
R1 is:
C1-6 straight chained or branched alkyl, or C2-6 straight chained or branched alkenyl or alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with optionally substituted phenyl, CF3, Cl, F, OMe, OEt, OCF3, CN, or NMe2;
C3-6 cycloalkyl, wherein 1-2 carbon atoms in the cycloalkyl is optionally replaced with —O— or NR5—;
R2 is C1-6 straight chained or branched alkyl;
R3 is hydrogen, halo, OCF3, CN, or CF3;
R4 is hydrogen, halo, OCF3, CN, or CF3; and
R5 is H, C1-6 straight chained or branched alkyl, aryl, —O—C1-6 straight chained or branched alkyl, or —O-aryl;
comprising the step of coupling a compound of formula A and a compound of formula K:
to provide a compound of formula L:
wherein X, Y, R1, R2, R3, and R4 are as defined in formula I and wherein the hydroxy group in K is optionally protected.

### Claim 30

A process for preparing a compound of formula I:
wherein:
X is —OR1 or —N(R5)2,
Y is halo, trifluorophonoxy, or tetrafluorc phenoxy;
R1 is:
C1-6 straight chained or branched alkyl, or C2-6 straight chained or branched alkenyl or alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with optionally substituted phenyl, CF3, Cl, F, OMe, OEt, OCF3, CN, or NMe2;
C3-6 cycloalkyl, wherein 1-2 carbon atoms in the cycloalkyl is optionally replaced with —O— or —NR5—;
R2 is C1-6 straight chained or branched alkyl;
R3 is hydrogen, halo, OCF3, CN, or CF3;
R4 is hydrogen, halo, OCF3, CN, or CF3; and
R5 is H, C1-6 straight chained or bianched alkyl, aryl, —O—C1-6 straight chained or branched alkyl, or —O-aryl;
comprising the step of oxidizing a compound of fonnula L:
wherein X, Y, R1, R2, R3, and R4 are as defined for formula I; to provide a compound of formula I.

### Claim 31 (depends on 13)

The compound according to claim 13, wherein R2 is ethyl.