# US 9,434,753 B2 · Modified creatine compounds

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- Number: US 9,434,753 B2
- Document ID: US9434753B2
- Status: Granted
- Kind: B2
- Application number: 14/345,503
- Filed: 2012-09-18
- Published: 2015-01-01
- Granted: 2016-09-06
- Earliest claimed: 2011-09-19
- Assignees: Gencia Corporation
- Applicants: Gencia Corporation
- Inventors: Shaharyar M. Khan; Robert Gadwood; Arthur Glenn Romero
- Web page: https://patentgrep.com/patent/US9434753B2

## CPC

- C07F 9/5456: {Arylalkanephosphonium compounds}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- 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 13/00: Drugs for disorders of the urinary system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- 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
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F 9/22: Amides of acids of phosphorus
- C07F 9/5442: {Aromatic phosphonium compounds (P-C aromatic linkage)}
- C07F 9/6506: having the nitrogen atoms in positions 1 and 3
- C07F 9/6552: {the oxygen atom being part of a six-membered ring}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention discloses creatine derivatives that are represented by Formula (I), Formula (II), and Formula (III); wherein Z is a functional group; Y is a mitochondrial targeting agent, a cationic ammonium group, or a polypeptide containing at least one positively charged amino acid residue; each R1 is independently hydrogen, alkyl, or a phosphate group; R2 a linker; R3 is a spacer group; R4 is hydrogen, alkyl, aryl, or heterocyclic; or R4 and R1, or R4 and R3, together with the nitrogen atoms to which they are attached form a heterocyclic ring, and W is hydrogen or alkyl.

## Claims

### Claim 1

A compound of Formula I
or a pharmaceutically acceptable salt thereof wherein
Z is —C(═O)NR5—;
wherein R5 is hydrogen, alkyl, aryl, or heterocyclic;
Y is a phosphonium group;
each R1 is independently hydrogen, alkyl, or a phosphate group;
R2 is alkyl;
R3 is alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl;
R4 is hydrogen, or alkyl;
at each occurrence, an alkyl is optionally substituted with 1-3 substituents independently selected from halo, haloalkyl, hydroxyl, amino, thio, ether, ester, oxo, aldehyde, cycloalkyl, nitrile, urea, amide, carbamate and aryl;
at each occurrence, an aryl is optionally substituted with 1-5 substituents independently selected from halogen, azide, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, and CN;
W is hydrogen or alkyl; and with the provisos that Z and Y are not substituted on the same R2 carbon; and that Z and the —NR4— moiety are not substituted on the same R3 carbon.

### Claim 2 (depends on 1)

A compound or pharmaceutically acceptable salt of claim 1 wherein
Z is —C(═O)NR5, and R5 is hydrogen or C1-6 alkyl;
Y is a phosphonium group;
each R1 is independently hydrogen, alkyl, or a phosphate group;
R2 is alkyl;
R3 is alkyl, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, or alkylheterocycloalkyl; and
R4 is hydrogen, or C1-6 alkyl; and W is hydrogen.

### Claim 3 (depends on 2)

A compound or pharmaceutically acceptable salt of claim 2 wherein the phosphonium group is selected from —P+(R′)3X−, wherein R′ is alkyl or aryl; and X− is an anion.

### Claim 4 (depends on 3)

A compound or pharmaceutically acceptable salt of claim 3 wherein R′ is phenyl; and X− is chloride, or trifluoroacetate.

### Claim 5 (depends on 2)

A compound or pharmaceutically acceptable salt of claim 2 wherein each R1 is hydrogen, or one R1 is hydrogen, the other R1 is —PO32−M, wherein M is a cation having one or two position charges.

### Claim 6 (depends on 2)

A compound or pharmaceutically acceptable salt of claim 2 wherein R2 is C3-8 alkyl.

### Claim 7 (depends on 2)

A compound or pharmaceutically acceptable salt of claim 2 wherein R3 is C1-8 alkyl or R3 is C1-6 alkylheterocycloalkyl wherein heterocycloalkyl is a cyclic ring of 3-10 atoms having at least one hetero atom selected from non-peroxide oxygen, or nitrogen.

### Claim 8 (depends on 2)

A compound or pharmaceutically acceptable salt of claim 2 wherein R4 is hydrogen or C1-4 alklyl.

### Claim 9 (depends on 8)

A compound or pharmaceutically acceptable salt of claim 8 wherein R4 is methyl.

### Claim 10 (depends on 8)

A compound or pharmaceutically acceptable salt of claim 8 wherein
Z is —C(═O)NH—,
Y is —P+(Phenyl)3X−, wherein X− is chloride, or trifluoroacetate;
R1 is hydrogen;
R2 is C1-8 alkyl;
R3 is C1-6 alkyl, C1-6 alkylcycloalkyl wherein cycloalkyl comprising 3-6 carbon atoms, or C1-6 alkylheterocycloalkyl wherein heterocycloalkyl is a cyclic ring of 5-6 atoms having a nitrogen atom; and
R4 is methyl.

### Claim 11

A compound selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 12

A compound or a pharmaceutically acceptable salt thereof selected from:
wherein each X— is chloride or trifluoroacetate.

### Claim 13

A compound or a pharmaceutically acceptable salt thereof selected from:
wherein each X— is chloride or trifluoroacetate.

### Claim 14

A compound or a pharmaceutically acceptable salt thereof selected from:
wherein each X— is chloride or trifluoroacetate.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1.

### Claim 16 (depends on 15)

A method of enhancing mitochondrial function in a patient in need thereof, comprising administering the pharmaceutical composition of claim 15 in an amount effective to enhance mitochondrial function in a patient.

### Claim 17 (depends on 15)

A method of increasing ATP production in mitochondria of a patient, comprising administering the pharmaceutical composition of claim 15 in an amount effective to increase ATP production in the mitochondria of the patient.

### Claim 18 (depends on 15)

A method of treating a mitochondrial myopathy in a patient, comprising administering the pharmaceutical composition of claim 15 in an amount effective to treat one or more symptoms of the mitochondrial myopathy in the patient.