# US 9,750,737 B2 · METAP2 inhibitors and methods of treating obesity

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- Number: US 9,750,737 B2
- Document ID: US9750737B2
- Status: Granted
- Kind: B2
- Application number: 15/226,258
- Filed: 2016-08-02
- Published: 2016-12-01
- Granted: 2017-09-05
- Earliest claimed: 2013-04-10
- Assignees: SynDevRx, Inc.
- Applicants: SynDevRx, Inc.
- Inventors: John S. Petersen; James Shanahan
- Web page: https://patentgrep.com/patent/US9750737B2

## CPC

- A61K 31/485: Morphinan derivatives, e.g. morphine, codeine
- A61K 31/336: having three-membered rings, e.g. oxirane, fumagillin
- A61K 31/77: of oxiranes
- A61K 38/06: Tripeptides
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/50: for increasing or potentiating the activity of insulin
- 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 relates to modified or polymer conjugated MetAP2 inhibitors. The present invention also relates to methods of preventing, inducing, causing or increasing weight loss, treating obesity and/or treating metabolic syndrome utilizing the modified or polymer conjugated MetAP2 inhibitors. The present invention also relates to methods of improving insulin sensitivity and glycemic control, reducing insulin levels and/or improving leptin sensitivity utilizing the modified or polymer conjugated MetAP2 inhibitors.

## Claims

### Claim 1

A method for improving or restoring leptin sensitivity in a subject in need thereof comprising administering at least one compound, or a pharmaceutically acceptable salt, thereof, selected from the group consisting of
in a therapeutically effective amount to the subject.

### Claim 2

A method for improving or restoring leptin sensitivity in a subject in need thereof comprising administering at least one compound, or a pharmaceutically acceptable salt, thereof, of the Formula
wherein, independently for each occurrence,
R4 is H or C1-C6 alkyl;
R5 is H or C1-C6 alkyl;
R6 is C2-C6 hydroxyalkyl;
Z is —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or —NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X—Y—C(O)—W;
AA1 is glycine, alanine, or H2N(CH2)mCO2H, wherein m is 2, 3, 4 or 5;
AA2 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA3 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA4 is a bond, or alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, threonine, valine, tryptophan, or tyrosine;
AA5 is a bond, or glycine, valine, tyrosine, tryptophan, phenylalanine, methionine, leucine, isoleucine, or asparagine;
AA6 is a bond, or alanine, asparagine, citrulline, glutamine, glycine, leucine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, or H2N(CH2)mCO2H, wherein m is 2, 3, 4 or 5;
L is —OH, —O-succinimide, —O-sulfosuccinimide, alkoxy, aryloxy, acyloxy, aroyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, —NH2, —NH(C2-C6 hydroxyalkyl), halide or perfluoroalkyloxy;
Q is NR, O, or S;
X is M-(C(R)2)p-M-J-M-(C(R)2)p-M-V;
M is a bond, or C(O);
J is a bond, or ((CH2)qQ)r, C5-C8 cycloalkyl, aryl, heteroaryl, NR, O, or S;
Y is NR, O, or S;
R is H or alkyl;
V is a bond or
R9 is alkyl, aryl, aralkyl, or a bond; or R9 taken together with Y forms a heterocyclic ring;
R10 is amido or a bond;
R11 is H or alkyl;
W is a methionine aminopeptidase-2 inhibitor moiety or alkyl;
x is in the range of 1 to about 450;
y is in the range of 1 to about 30;
n is in the range of 1 to about 50;
p is 0 to 20;
q is 2 or 3; and
r is 1, 2, 3, 4, 5, or 6;
in a therapeutically effective amount to the subject.

### Claim 3 (depends on 2)

The method of claim 2, wherein R4 is methyl.

### Claim 4 (depends on 2)

The method of claim 2, wherein R5 is methyl.

### Claim 5 (depends on 2)

The method of claim 2, wherein R6 is 2-hydroxypropyl.

### Claim 6 (depends on 2)

The method of claim 2, wherein Z is —NH-AA6-C(O)-Q-X—Y—C(O)—W.

### Claim 7 (depends on 6)

The method of claim 6, wherein AA6 is glycine.

### Claim 8 (depends on 2)

The method of claim 2, wherein Z is —NH-AA5-AA6-C(O)-Q-X—Y—C(O)—W.

### Claim 9 (depends on 8)

The method of claim 8, wherein AA5 is leucine and AA6 is glycine.

### Claim 10 (depends on 8)

The method of claim 8, wherein AA5 is valine and AA6 is glycine.

### Claim 11 (depends on 8)

The method of claim 8, wherein AA5 is phenylalanine and AA6 is glycine.

### Claim 12 (depends on 8)

The method of claim 8, wherein AA5 is glycine and AA6 is glycine.

### Claim 13 (depends on 2)

The method of claim 2, wherein Z is —NH-AA3-AA4-AA5-AA6-C(O)-Q-X—Y—C(O)—W.

### Claim 14 (depends on 13)

The method of claim 13, wherein AA5 is leucine and each of AA3, AA4, or AA6 is glycine.

### Claim 15 (depends on 13)

The method of claim 13, wherein AA5 is valine and each of AA3, AA4, or AA6 is glycine.

### Claim 16 (depends on 13)

The method of claim 13, wherein AA5 is phenylalanine and each of AA3, AA4, or AA6 is glycine.

### Claim 17 (depends on 13)

The method of claim 13, wherein AA3 is glycine, AA4 is phenylalanine, AA5 is leucine and AA6 is glycine.

### Claim 18 (depends on 13)

The method of claim 13, wherein each of AA3, AA4, AA5 and AA6 is glycine.

### Claim 19 (depends on 2)

The method of claim 2, wherein -Q-X-Y is

### Claim 20 (depends on 2)

The method of claim 2, wherein W is

### Claim 21 (depends on 2)

The method of claim 2, wherein the ratio of x to y is in the range of about 20:1 to about 4:1.

### Claim 22 (depends on 2)

The method of claim 2, wherein the ratio of x to y is about 11:1.

### Claim 23 (depends on 2)

The method of claim 2, wherein the subject has a BMI of 25 kg/m2 to 29.9 kg/ m2.

### Claim 24 (depends on 2)

The method of claim 2, wherein the subject has a BMI of 30 kg/m2 or greater.

### Claim 25 (depends on 2)

The method of claim 2, wherein the subject has a BMI of 35 kg/m2 or greater.

### Claim 26 (depends on 2)

The method of claim 2, wherein the subject has a BMI of 40 kg/m2 or greater.

### Claim 27 (depends on 2)

The method of claim 2, wherein the subject has at least one disorder selected from the group consisting of diabetes, non-insulin dependent diabetes mellitus-type II, impaired glucose tolerance, impaired fasting glucose, elevated plasma insulin concentrations, insulin resistance syndrome, hyperlipidemia, dyslipidemia, hypertension, hyperuricacidemia, gout, coronary artery disease, cardiac disease, myocardial infarction, angina pectoris, sleep apnea, obstructive sleep apnea, Pickwickian syndrome, fatty liver, cerebral infarction, stroke, cerebral thrombosis, respiratory complications, cholelithiasis, gallbladder disease, kidney disease, gastro-esophageal reflux, stress urinary incontinence, arteriosclerosis, heart disease, abnormal heart rhythms, heart arrhythmias, transient ischemic attack, orthopedic disorders, osteoarthritis, arthritis deformans, lumbodynia, emmeniopathy, endocrinopathies, hormonal imbalances and infertility.

### Claim 28 (depends on 27)

The method of claim 27, wherein administration of the compound treats or ameliorates said at least one disorder.

### Claim 29 (depends on 2)

The method of claim 2, further comprising treating, decreasing or improving one or more cardiometabolic risk factors in said subject.

### Claim 30 (depends on 29)

The method of claim 29, wherein said cardiometabolic risk factors are selected from plasma triglyceride levels, LDL-cholesterol levels, C-reactive protein (CRP) levels, systolic blood pressure and diastolic blood pressure.

### Claim 31 (depends on 2)

The method of claim 2, further comprising administering a second active agent.

### Claim 32 (depends on 2)

The method of claim 2, further comprising decreasing body weight in said subject, wherein said body weight is decreased from about 1% to about 50%.

### Claim 33 (depends on 32)

The method of claim 32, wherein decreasing body weight comprises decreasing body fat in said subject.

### Claim 34 (depends on 33)

The method of claim 33, comprising decreasing body fat while substantially maintaining muscle mass in said subject.

### Claim 35 (depends on 32)

The method of claim 32, wherein decreasing body weight comprises decreasing adipocytes in said subject.

### Claim 36 (depends on 32)

The method of claim 32, wherein decreasing body weight comprises decreasing food intake in said subject.

### Claim 37 (depends on 2)

The method of claim 2, wherein said subject does not have cancer or a hyper-proliferative disorder.

### Claim 38 (depends on 2)

The method of claim 2, wherein said therapeutically effective amount is from about 0.0001 mg/kg to about 5 mg/kg of body weight per day.

### Claim 39 (depends on 2)

The method of claim 2, wherein said therapeutically effective amount is from or about 0.001 to about 1 mg/kg of body weight per day.

### Claim 40 (depends on 2)

The method of claim 2, wherein said compound is administered from about 1 to about 5 times per week.

### Claim 41 (depends on 2)

The method of claim 2, wherein said compound is administered in a q4d dosing schedule.

### Claim 42 (depends on 2)

The method of claim 2, wherein said compound is administered in a q7d dosing schedule.

### Claim 43 (depends on 2)

The method of claim 2, wherein said compound is administered once every two weeks.

### Claim 44 (depends on 2)

The method of claim 2, wherein said subject is treated for at least about six months.

### Claim 45 (depends on 2)

The method of claim 2, wherein said subject is treated for at least about two years.

### Claim 46 (depends on 2)

The method of claim 2, wherein said compound is administered parenterally.

### Claim 47 (depends on 2)

The method of claim 2, wherein said compound is administered subcutaneously.

### Claim 48 (depends on 2)

The method of claim 2, wherein said compound is provided as a pharmaceutical composition comprising said compound and a pharmaceutically acceptable carrier.

### Claim 49 (depends on 2)

The method of claim 2, wherein Z is represented by:

### Claim 50 (depends on 2)

The method of claim 2, wherein Z is represented by

### Claim 51 (depends on 2)

The method of claim 2, wherein the compound has a molecular weight of less than about 60 kDa.