# US 8,772,326 B2 · Methods and compositions of small molecule modulators of hepatocyte growth factor (scatter factor) activity

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- Number: US 8,772,326 B2
- Document ID: US8772326B2
- Status: Granted
- Kind: B2
- Application number: 13/003,514
- Filed: 2009-07-09
- Published: 2011-07-28
- Granted: 2014-07-08
- Earliest claimed: 2008-07-10
- Assignees: Anigion Biomedica Corp.
- Applicants: Weizhong Cai; Prakash Narayan; Bijoy Panicker; David E. Smith
- Inventors: Weizhong Cai; Prakash Narayan; Bijoy Panicker; David E. Smith
- Web page: https://patentgrep.com/patent/US8772326B2

## CPC

- C07D 409/14: containing three or more hetero rings
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/145: {with organic compounds}
- A61K 9/146: {with organic macromolecular compounds}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 31/415: 1,2-Diazoles
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- 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 25/32: Alcohol-abuse
- A61P 31/14: for RNA viruses
- A61P 31/20: for DNA viruses
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/14: containing three or more hetero rings
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The present invention provides compositions and formulations of compounds having formula (I) and pharmaceutically acceptable derivatives thereof, wherein p, R1, R2 and B are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of injuries, conditions or diseases in which HGF/SF or the activities thereof, or agonists or antagonists thereof have a therapeutically useful role. In addition, methods are provided for treating such diseases or diseases starting at a time after the onset of the injury, condition or disease.

## Claims

### Claim 1

A pharmaceutical composition comprising a compound having the structure of Formula (A):
a tautomer thereof; or a pharmaceutically acceptable derivative thereof;
wherein C=C is cis or trans;
A represents an optionally substituted aromatic or non-aromatic 5-6 membered monocyclic ring, optionally containing 1-4 heteroatoms selected from N, O or S; or an optionally substituted aromatic or non-aromatic 8-12 membered bicyclic ring, optionally containing 1-6 heteroatoms selected from N, O or S;
q is one or two; and
each R is independently selected from the group consisting of hydrogen, halogen, hydroxyl, —NO2, —CN, an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety; —ORR, —S(═O)nRd, —NRbRc, and —C(═O)Ra; wherein n is 0-2, RR is an optionally substituted aliphatic, heteroaliphatic, aromatic, heteroaromatic moiety;
Ra, for each occurrence, is independently selected from the group consisting of hydrogen, hydroxy, optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl;
Rb and Rc, for each occurrence, are independently selected from the group consisting of hydrogen; hydroxy; SO2Rd; optionally substituted aliphatic, heteroaliphatic, aryl and heteroaryl;
Rd, for each occurrence, is independently selected from the group consisting of hydrogen; —N(Re)2; optionally substituted aliphatic, aryl and heteroaryl; and
Re, for each occurrence, is independently hydrogen or optionally substituted aliphatic;
in an aqueous buffered saline containing about 40% to about 60% (v/v) polyethylene glycol 300 and about 5% to about 15% polysorbate 80;
wherein the compound of Formula A has HGF/SF activity.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the polyethylene glycol 300 is present at about 50% (v/v).

### Claim 3 (depends on 1)

The composition of claim 1, wherein the polysorbate 80 is present at about 10% (v/v).

### Claim 4 (depends on 1)

The composition of claim 1, wherein the aqueous buffer is phosphate-buffered saline.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the pH is about 7.4.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the compound of Formula (A) is present at about 0.8 to about 10 milligrams per milliliter.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the polyethylene glycol 300 is present at about 50% (v/v), the polysorbate 80 is present at about 10% (v/v), the buffer is phosphate-buffered saline, pH 7.4, and the compound of Formula (A) is present at about 0.8 to about 10 milligrams per milliliter.

### Claim 8 (depends on 1)

The composition of claim 1, wherein A is phenyl or naphthyl.

### Claim 9 (depends on 1)

The composition of claim 1, wherein A is a heterocyclic moiety.

### Claim 10 (depends on 9)

The composition of claim 9, wherein the compound of Formula (A) has the structure:
tautomer thereof; or a prodrug, salt, hydrate, or ester thereof;
wherein X is O, S or NRN wherein RN is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl or a nitrogen protecting group; and
each R is independently selected from the group consisting of hydrogen, halogen; hydroxy; nitro; CN; aryl; heteroaryl; —C(═O)Ra; —NRbRc; —S(O)nRd where n =0-2; C1-6alkoxy optionally substituted with one or more substituents independently selected from halogen and C1-6 alkyl; an optionally substituted fused bicyclic 8-12-membered aromatic or alicyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of N,O, and S; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 cycloalkyl, each independently optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-5 alkoxy, nitro, and N(Re)2;
wherein each occurrence of Ra is independently selected from the group consisting of hydrogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, aryl, heteroaryl, and NRbRc, wherein C1-6 alkyl and C1-6 alkoxy are optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-5 alkoxy, nitro, and N(Re)2;
each occurrence of Rb and Rc is independently selected from the group consisting of hydrogen; hydroxy; SO2Rd; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-5 alkoxy, nitro, and N(Re)2; C1-6 alkoxy optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-5 alkoxy, nitro and N(Re)2; aryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-4 alkyl, C1-5 alkoxy, nitro, and N(Re)2; and heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-4 alkyl, C1-5 alkoxy, nitro, and N(Re)2;
each occurrence of Rd is independently selected from the group consisting of hydrogen; N(Re)2; C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-5 alkoxy, nitro, and N(Re)2; aryl and heteroaryl; and
each occurrence of Re is independently hydrogen or C1-6 alkyl.

### Claim 11 (depends on 10)

The composition of claim 10, wherein the compound of Formula (A) has the structure:
a tautomer thereof; or a prodrug, salt, hydrate, or ester thereof.

### Claim 12 (depends on 10)

The composition of claim 10, wherein the compound of Formula (A) has the structure:
a tautomer thereof; or a prodrug, salt, hydrate, or ester thereof.

### Claim 13 (depends on 10)

The composition of claim 10, wherein the compound of Formula (A) has the structure:
a tautomer thereof; or a prodrug, salt, hydrate, or ester thereof;
wherein RN is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, acyl, or a nitrogen protecting group.

### Claim 14 (depends on 1)

The composition of claim 1, wherein the compound is (E)-3(5)-[2-(2,3-methylenedioxyphenyl)vinyl]-1H-pyrazole, (Z)-3(5)-[2-(2,3-methylenedioxyphenyl)vinyl]-1H-pyrazole, (E)-3(5)-[2-(2-chloro-5-trifluoromethylphenyl)vinyl]-1H-pyrazole, (Z)-3(5)- [2-(2-chloro-5-trifluoromethylphenyl)vinyl]-1H-pyrazole, (E)-3(5)-[2-(2-trifluoromethylphenyl)vinyl]-1H-pyrazole, (Z)-3(5)-[2-(2-trifluoromethylphenyl)vinyl]-1H-pyrazole, (E)-3(5)-[2-(2-furyl)vinyl]-1H-pyrazole, (Z)-3(5)-[2-(2-furyl)vinyl]-1H-pyrazole, (E)-3(5)-[2-(2-thienyl)vinyl]-1H-pyrazole, (Z)-3(5)-[2-(2-thienyl)vinyl]-1 H-pyrazole, (E)-3-(2(5-nitrofuran-2-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(5-nitrofuran-2-yl)vinyl)-1H-pyrazole, (E)-3-styryl-1H-pyrazole, (Z)-3-styryl-1H-pyrazole, (E)-2-(2-(1H-pyrazol-3-yl)vinyl)-1H-indole, (Z)-2-(2-(1H-pyrazol-3-yl)vinyl)-1H-indole, (E)-4-(2-(1H-pyrazol-3-yl)vinyl)-N,N-dimethylaniline, (Z)-4-(2-(1H-pyrazol-3-yl)vinyl)-N,N-dimethylaniline, (E)-3-(4-methoxystyryl)-1H-pyrazole, (Z)-3-(4-methoxystyryl)-1H-pyrazole, (E)-3-(2,6-dichlorostyryl)-1H-pyrazole, (Z)-3-(2,6-dichlorostyryl)-1H-pyrazole, (E)-3-(2-(naphthalen-2-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(naphthalen-2-yl)vinyl)-1H-pyrazole, (E)-3-(2-(1H-pyrrol-2-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(1H-pyrrol-2-yl)vinyl)-1H-pyrazole, (E)-3-(2-(thiophen-3-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(thiophen-3-yl)vinyl)-1H-pyrazole, (E)-3-(2-(1H-pyrrol-3-yl)vinyl)-1H-pyrazole, (Z)-3-(2-(1H-pyrrol-3-yl)vinyl)-1H-pyrazole, (E)-3-(2-(furan-3-yl)vinyl)-1H-pyrazole , or (Z)-3-(2-(furan-3-yl)vinyl)-1H-pyrazole.