# US 9,518,152 B2 · Polyamide compound and pharmaceutical composition for treating mitochondrial genetic disease

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- Number: US 9,518,152 B2
- Document ID: US9518152B2
- Status: Granted
- Kind: B2
- Application number: 14/008,982
- Filed: 2012-04-02
- Published: 2015-07-09
- Granted: 2016-12-13
- Earliest claimed: 2011-03-31
- Assignees: Takamitsu Yano
- Applicants: Takamitsu Yano
- Inventors: Takamitsu Yano
- Web page: https://patentgrep.com/patent/US9518152B2

## CPC

- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/785: Polymers containing nitrogen
- A61K 31/787: containing heterocyclic rings having nitrogen as a ring hetero atom
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 3/12: for electrolyte homeostasis
- 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 13/12: of the kidneys
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/14: containing three or more hetero rings
- C08G 73/0611: {with only one nitrogen atom in the ring, e.g. polypyrroles (polysuccinimides C08G73/1092)}
- C08G 73/0616: {with only two nitrogen atoms in the ring}
- A61K 47/595: {Polyamides, e.g. nylon (polyamino acids A61K47/62)}
- C12N 15/1062: {mRNA-Display, e.g. polypeptide and encoding template are connected covalently}
- C12Q 2600/178: miRNA, siRNA or ncRNA
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

The object of the present invention is to provide a fundamental therapy to mitochondrial genetic diseases caused by mutation of the mitochondrial (mt)DNA, and a pharmaceutical composition used for the same. The object can be solved by a polyamide compound binding to a target double-stranded mtDNA comprising A/T pair consisting of first A of the following sense-stranded DNA and the corresponding T, A/T pair consisting of 8th A of the following sense-stranded DNA and the corresponding T, G/C pair consisting of 9th G of the following sense-stranded DNA and the corresponding C, G/C pair consisting of 14th G of the following sense-stranded DNA and the corresponding C, T/A pair consisting of 15th T of the following sense-stranded DNA and the corresponding A, or the like, in the double-stranded DNA consisting of the sense-stranded DNA having base sequence of 5′-ATGGCAGAGCCCGGTAATCGCATAA-3′ (SEQ ID NO: 1) and the antisense-stranded DNA having base sequence of 5′-TTATGCGATTACCGGGCTCTGCCAT-3′ (SEQ ID NO: 2).

## Claims

### Claim 1

A polyamide compound binding to a target double-stranded DNA, wherein said target double-stranded DNA comprises at least one nucleotide pair selected from the group consisting of an A/T pair consisting of the first A of the following sense-stranded DNA and the corresponding T, an A/T pair consisting of the 8th A of the following sense-stranded DNA and the corresponding T, a G/C pair consisting of the 9th G of the following sense-stranded DNA and the corresponding C, a G/C pair consisting of the 14th G of the following sense-stranded DNA and the corresponding C, a T/A pair consisting of the 15th T of the following sense-stranded DNA and the corresponding A, an A/T pair consisting of the 16th A of the following sense-stranded DNA and the corresponding T, an A/T pair consisting of the 17th A of the following sense-stranded DNA and the corresponding T, a C/G pair consisting of the 19th C of the following sense-stranded DNA and the corresponding G, a G/C pair consisting of the 20th G of the following sense-stranded DNA and the corresponding C, a C/G pair consisting of the 21st C of the following sense-stranded DNA and the corresponding G, a T/A pair consisting of the 23rd T of the following sense-stranded DNA and the corresponding A, an A/T pair consisting of the 25th A of the following sense-stranded DNA and the corresponding T, in the double stranded DNA of the following formula(1):
[Chem. 1]
5′-A T G G C A G A G C C C G G T A A T C G C A T
A A-3′
3′-T A C C G T C T C G G G C C A T T A G C G T A
T T-5′ (1)
which consists of the sense-stranded DNA having a base sequence of 5′-ATGGCAGAGCCCGGTAATCGCATAA-3′ (SEQ ID NO: 1) and the antisense-stranded DNA having a base sequence of 5′-TTATGCGATTACCGGGCTCTGCCAT-3′ (SEQ ID NO: 2); and at least one end of said target double-stranded DNA is an A/T or T/A pair;
(1) a residue of the polyamide compound, corresponding to the A/T pair or T/A pair at one end thereof is a turn structure selected from the group consisting of γ-aminobutyric acid residue, (R)2,4-diaminobutyric acid residue, and 5-aminovaleric acid residue, wherein the hydrogen atom of the residues may be substituted with an alkyl group having 1 to 4 carbon atoms, an amino group, a hydroxyl group, a carboxyl group, or —NH3;
(2) the binding region of the polyamide compound, corresponding to the target double-stranded DNA except for the A/T pair or T/A pair at one end thereof, is composed of
(a) Im/Py, or Im/β, corresponding to the G/C pair of the target double-stranded DNA,
(b) Py/Im, or β/Im, corresponding to the C/G pair of the target double-stranded DNA,
(c) Py/Py, Py/Hp, Py/β, β/Py, or β/β corresponding to the A/T pair of the target double-stranded DNA, and
(d) Py/Py, Hp/Py, Py/β, β/Py, or β/β, corresponding to the T/A pair of the target double-stranded DNA,
(wherein Im is N-methylimidazole, Py is N-methylpyrrole, Hp is 3-hydroxy-N-methylpyrrole, and β is β-alanine; and Im/β corresponding to the G/C pair and β/Im corresponding to the C/G pair can be only used in the case of a successive Im•β/Im•β corresponding to a successive G•C/G•C pair or a successive β•Im/β•Im corresponding to a successive C•G/C•G pair; and the hydrogen atom of the Im residue, Py residue, Hp residue, or β residue may be substituted to an alkyl group having 1 to 4 carbon atoms, an amino group, a hydroxyl group, a carboxyl group, or —NH3), and the binding region comprises at least one residue pair of Im/β corresponding to the G/C pair, β/Im corresponding to the C/G pair, β/β corresponding to the A/T pair, or β/β, corresponding to the T/A pair, of the target double-stranded DNA;
(3) an end of the polyamide compound corresponding to the 5′ end of the other end of the target double-stranded DNA is an amino group of Im residue, an amino group of Py residue, an amino group of Hp residue, an amino group of β-alanine, a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, a carboxyl group, or an acyl group having 1 to 4 carbon atoms; an end of the polyamide compound corresponding to the 3′ end of the other end of the target double-stranded DNA is a carboxyl group of Im residue, a carboxyl group of Py residue, a carboxyl group of Hp residue, a carboxyl group of β-alanine, an N,N-dimethylaminopropyl residue, or a β-alanine-N,N-dimethylaminopropyl residue.

### Claim 2 (depends on 1)

The polyamide compound according to claim 1, of the formula selected from the group consisting of
[wherein, R1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an hydroxyl group, an amino group, a carboxyl group, or an acyl group having 1 to 4 carbon atoms,
R2 is independently a hydrogen atom, or a hydroxyl group,
R3, R6, and R7 are independently a hydrogen atom, an amino group, or —NH3,
R4 is a single bond, or β-alanine residue,
R5 is a hydroxyl group, or N,N-dimethylaminopropyl residue; and
the hydrogen atom of the Im residue, Py residue, Hp residue, β residue, γ-aminobutyric acid residue, or (R) 2,4-diaminobutyric acid residue may be substituted with an alkyl group having 1 to 4 carbon atoms, an amino group, a hydroxyl group, or a carboxyl group].

### Claim 3 (depends on 2)

The polyamide compound according to claim 2, of Formula (12):

### Claim 4 (depends on 1)

An agent for promoting replication of wild-type mitochondrial DNA characterized by comprising the polyamide compound according to claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient.

### Claim 5 (depends on 2)

An agent for promoting replication of wild-type mitochondrial DNA characterized by comprising the polyamide compound according to claim 2, or a pharmaceutically acceptable salt thereof, as an active ingredient.

### Claim 6 (depends on 3)

An agent for promoting replication of wild-type mitochondrial DNA characterized by comprising the polyamide compound according to claim 3, or a pharmaceutically acceptable salt thereof, as an active ingredient.