# US 2014/0194416 A1 · N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

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- Number: US 2014/0194416 A1
- Document ID: US20140194416A1
- Status: Published application
- Kind: A1
- Application number: 14/204,636
- Filed: 2014-03-11
- Published: 2014-07-10
- Earliest claimed: 2007-09-26
- Assignees: Cardioxyl Pharmaceuticals, Inc.; The Johns Hopkins University
- Applicants: Cardioxyl Pharmaceuticals, Inc.; The Johns Hopkins University
- Inventors: John P. Toscano; Frederick Arthur Brookfield; Andrew D. Cohen; Stephen Martin Courtney; Lisa Marie Frost; Vincent Jacob Kalish
- Web page: https://patentgrep.com/patent/US20140194416A1

## CPC

- C07C 317/48: the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/10: Antioedematous agents; Diuretics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/06: Antiarrhythmics
- 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 311/48: having nitrogen atoms of sulfonamide groups further bound to another hetero atom
- C07D 295/155: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 295/16: acylated on ring nitrogen atoms
- C07D 295/192: from aromatic carboxylic acids
- C07D 295/26: Sulfur atoms
- C07D 333/26: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 333/36: Nitrogen atoms
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention relates to N-hydroxylsulfonamide derivatives that donate nitroxyl (HNO) under physiological conditions and are useful in treating and/or preventing the onset and/or development of diseases or conditions that are responsive to nitroxyl therapy, including heart failure and ischemia/reperfusion injury. Novel N-hydroxylsulfonamide derivatives release NHO at a controlled rate under physiological conditions, and the rate of HNO release is modulated by varying the nature and location of functional groups on the N-hydroxylsulfonamide derivatives.

## Claims

### Claim 1

A compound of the formula (I), (II) or (III):
wherein:
R1 is H;
R2 is H, aralkyl or heterocyclyl;
m and n are independently an integer from 0 to 2;
x is an integer from 0 to 4 and y is an integer from 0 to 3, provided that at least one of x and y is greater than 0;
b is an integer from 1-4;
R3, R4, R5, R6 and R7 are independently selected from the group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, carboxyl, carboxyl ester, acylamino and sulfonylamino, provided that at least one of R3, R4, R5, R6 and R7 is carboxyl, carboxyl ester, acylamino or sulfonylamino;
each R8 and R9 is independently selected from the group consisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH2, OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH2, NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH2, OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH2, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, arylsulfinyl, carbonylamino and sulfonylamino, provided that: (1) at least one R8 is carbonylamino or sulfonylamino when the compound is of the formula (III) and (2) at least one of R8 and R9 is carbonylamino or sulfonylamino when the compound is of the formula (II);
A is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q1, Q2, Q3 and Q4, which are taken together with V and W to form ring A;
B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containing ring moieties Q5, Q6, Q7 and Q8, which are taken together with the V and W to form ring B;
V and W are independently C, CH, N or NR10;
Q1, Q2, Q3, Q4, Q5, Q6, Q7 and Q8 are independently selected from the group consisting of C, CH2, CH, N, NR10, O and S;
C is a heteroaromatic ring containing ring moieties Q9, Q10, Q11, Q12, Q13 and Q14 that are independently selected from the group consisting of C, CH2, CH, N, NR10, O and S, provided that at least one of Q9, Q10, Q11, Q12, Q13 and Q14 is N, NR10, O or S, and
R10 is H, alkyl, acyl or sulfonyl
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R2 is H.

### Claim 3 (depends on 1)

The compound of claim 1, wherein x and y are both 1.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is of the formula (I).

### Claim 5 (depends on 4)

The compound of claim 4 wherein the compound is of the formula (I) and at least one of R3 and R7 is other than H.

### Claim 6 (depends on 4)

The compound of claim 4, wherein the compound is of the formula (I) and at least one of R3 and R7 is an electron withdrawing group.

### Claim 7 (depends on 4)

The compound of claim 4, wherein the compound is of the formula (I) and at least one of R3, R4, R5, R6 and R7 is carboxyl, —COO-alkyl, —C(O)NH2, —C(O)NRaRb where Ra is hydrogen and Rb is alkyl, —C(O)NRaRb where Ra and Rb are independently alkyl, —C(O)NRaRb where Ra and Rb are taken together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic ring, —SO2NH2, —SO2NR-alkyl where R is hydrogen, —SO2NR-alkyl where R is alkyl, —SO2NR2, where the two R groups are taken together with the nitrogen to which they are attached to form a heterocyclic or substituted heterocyclic ring.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is of the formula (II).

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound is of the formula (III).

### Claim 10 (depends on 1)

A method of modulating the in vivo nitroxyl levels in an individual in need thereof, the method comprising administering to the individual an N-hydroxysulfonamide of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A method of treating, preventing or delaying the onset or development of a disease or condition that is responsive to nitroxyl therapy, comprising administering to an individual in need thereof a compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 13 (depends on 1)

A kit comprising a compound of the claim 1 and instructions for use in the treatment of a disease or condition that is responsive to nitroxyl therapy.