# US 9,752,149 B2 · Matriptase inhibitors and uses thereof against orthomyxoviridae infections

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- Number: US 9,752,149 B2
- Document ID: US9752149B2
- Status: Granted
- Kind: B2
- Application number: 14/943,716
- Filed: 2015-11-17
- Published: 2016-04-07
- Granted: 2017-09-05
- Earliest claimed: 2011-06-02
- Assignees: Socpra Sciences Sante Et Humaines S.E.C.
- Applicants: Socpra Sciences Sante Et Humaines S.E.C.
- Inventors: Martin Richter; Richard Leduc; Eloic Colombo; Eric Marsault
- Web page: https://patentgrep.com/patent/US9752149B2

## CPC

- C12N 15/1131: {against viruses}
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/06: Tripeptides
- A61K 38/07: Tetrapeptides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- A61P 35/00: Antineoplastic agents
- C07K 5/06026: {the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala}
- C07K 5/06095: {Arg-amino acid}
- C07K 5/06104: {with the first amino acid being acidic}
- C07K 5/0817: {the first amino acid being Arg}
- C07K 5/0819: {with the first amino acid being acidic}
- C07K 5/1019: {with the first amino acid being basic}
- C07K 16/40: against enzymes
- C12N 9/6424: {Serine endopeptidases (3.4.21)}
- A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles}
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K 2039/505: {comprising antibodies}
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C12N 2310/14: interfering nucleic acids [NA]
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The present invention provides matriptase inhibitors and compositions for treating and preventing orthomyxovirus infections such as flu infections. The present invention also provides novel compounds, compositions, methods of use, uses and kits thereof for inhibiting matriptase. Such compounds are useful for treating and preventing orthomyxovirus infections, such as flu infections, and for inhibiting tumor growth, progression and/or metastasis.

## Claims

### Claim 1

A method of treating an influenza type A, B or C infection in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of formula (1) or a composition comprising said compound of formula (1) to said subject, wherein said compound of formula (1) is:
or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein
R12 is H, NH2 or NHR7; wherein R7 is
R13 is H, NH2 or NHR7; wherein R7 is an alkyl, aryl, (C═O)-alkyl, (C═O)-aryl, SO2-alkyl or SO2-aryl, C(═NH)—NH2, C(═NH)—NHalkyl, C(═NH)—NHaryl or one or more amino acids residues in (L) or (D) configuration;
R1 is H, NH2 or NHR7; wherein R7 is an alkyl, aryl, (C═O)-alkyl, (C═O)-aryl, SO2-alkyl or SO2-aryl, C(═NH)—NH2, C(═NH)—NHalkyl, C(═NH)—NHaryl or one or more amino acids residues in (L) or (D) configuration;
R2 and R5 are independently —CH2—R8 or
wherein R8 is (CH2)n-NH(C═NH)NH—R14 or (CH2)n-NH—R14, wherein,
n is 1 to 4;
m is 0 to 3;
R10 is —C(═NH)—NH2, NH2 or NH alkyl; and
R14 is H, alkyl, NH2, NO2 or COalkyl;
R3 is a linear alkyl; an alkyl substituted with (CO)NH2, (CO)OH, NH2, NHCO-alkyl, NHCO-aryl, NHSO2-alkyl, NHSO2-aryl or heteroaryl; an aryl, a substituted aryl, an heteroaryl or a substituted heteroaryl;
R4 is an alkyl, an aryl, a substituted alkyl, a substituted aryl, an heteroaryl or a substituted heteroaryl;
R6 is
wherein W, X, Y and Z are independently N or CH;
V is independently O, NH, NCH3 or S;
R11 is H, CO2H, CONH-alkyl, CONH-aryl, aryl, heteroaryl, halide or CO-(amino acid residue in (L) or (D) configuration)q, wherein q is 1 or 2; and
wherein the one or more amino acids residue is isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, arginine, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, proline, serine, tyrosine, beta-alanine, 3-amino-propionic acid, 2,3-diamino propionic acid, alpha-aminoisobutyric acid, 4-amino-butyric acid, N-methylglycine, hydroxyproline, ornithine, citrulline, t-butylalanine, t-butylglycine, N-methylisoleucine, phenylglycine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, cyclohexylglycine, cyclopentylglycine, cyclobutylglycine, cyclopropylglycine, norleucine, norvaline, 2-napthylalanine, pyridylalanine, 3-benzothienyl alanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, penicillamine, 1,2,3,4-tetrahydro-isoquinoline-3-carboxylix acid, beta-2-thienylalanine, methionine sulfoxide, homoarginine, N-acetyl lysine, 2-amino butyric acid, 2-amino butyric acid, 2,4,-diaminobutyric acid, p-aminophenylalanine, N-methylvaline, selenocysteine, homocysteine, homoserine, cysteic acid, epsilon-amino hexanoic acid, delta-amino valeric acid, or 2,3-diaminobutyric acid.

### Claim 2 (depends on 1)

The method of claim 1, wherein said composition further comprises
(a) an additional therapeutic agent for treating or preventing an influenza Type A, B or C infection;
(b) a pharmaceutically acceptable excipient; or
(c) a combination of (a) and (b).

### Claim 3 (depends on 1)

The method of claim 1, wherein the influenza infection is an influenza type A infection.

### Claim 4 (depends on 1)

The method of claim 1, wherein
R7 is

### Claim 5 (depends on 1)

The method of claim 1, wherein
(i) R1 is —H or —NH2;
(ii) R2 is
(iii) m is 1;
(iv) W is CH;
(v) X is CH;
(vi) Y is CH;
(vii) R10 is —C(═NH)NH2; or
(viii) any combination of (i) to (vii).

### Claim 6 (depends on 1)

The method of claim 1, wherein
(i) R1 is —NH2;
(ii) R2 is the side chain of arginine;
(iii) R3 is an alkyl substituted with (CO)NH2, (CO)OH, NH2, NHCO-alkyl, NHCO-aryl, NHSO2-alkyl, NHSO2-aryl or heteroaryl;
(iv) R4 is an alkyl;
(v) R5 is —CH2—R8;
(vi) R6 is
(vii) R8 is —(CH2)3NH(C═NH)NH2;
(viii) W is CH;
(ix) X is CH;
(x) Y is CH;
(xi) Z is CH;
(xii) V is S;
(xiv) R11 is H; or
(xiii) any combination of (i) to (xiii).

### Claim 7 (depends on 1)

The method of claim 1, wherein R3 is an alkyl substituted with (CO)NH2, (CO)OH, NH2, NHCO-alkyl, NHCO-aryl, NHSO2-alkyl, NHSO2-aryl or heteroaryl.

### Claim 8 (depends on 1)

The method of claim 1, wherein R3 is —(CH2)2C(═O)NH2.

### Claim 9 (depends on 1)

The method of claim 1, wherein R4 is a C1 to C6 alkyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein R4 is a C1 to C3 alkyl.

### Claim 11 (depends on 1)

The method of claim 1, wherein R4 is —CH3.

### Claim 12 (depends on 1)

The method of claim 1, wherein R2 and R5 have the (S) configuration.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is of formula (1.1):
wherein
R12 is NHR7, wherein R7 is
and
wherein R1, R2, R3, R4, R5, R6, R8, R10, R11 and R13 are as defined in claim 1.

### Claim 14 (depends on 13)

The method of claim 13, wherein the influenza infection is an influenza type A infection.

### Claim 15 (depends on 1)

The method of claim 1, wherein the compound is: