# US 7,745,665 B2 · Substituted phenethylamines

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- Number: US 7,745,665 B2
- Document ID: US7745665B2
- Status: Granted
- Kind: B2
- Application number: 12/132,147
- Filed: 2008-06-03
- Published: 2008-12-04
- Granted: 2010-06-29
- Earliest claimed: 2007-06-04
- Assignees: Auspex Pharmaceuticals, Inc.
- Inventors: Thomas G. Gant; Sepehr Sarshar
- Web page: https://patentgrep.com/patent/US7745665B2

## CPC

- C07C 215/60: the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- 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 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 25/06: Antimigraine agents
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Disclosed herein are substituted phenethylamine alpha adrenergic receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

## Claims

### Claim 1

A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or enantiomer thereof.

### Claim 2 (depends on 1)

The compound as recited in claim 1, wherein each of said positions represented as D have deuterium enrichment of at least 98%.

### Claim 3 (depends on 1)

The compound as recited in claim 1, wherein each of said positions represented as D have deuterium enrichment of at least 90%.

### Claim 4 (depends on 1)

The compound as recited in claim 1, wherein each of said positions represented as D have deuterium enrichment of at least 50%.

### Claim 5 (depends on 1)

The compound as recited in claim 1, wherein each of said positions represented as D have deuterium enrichment of at least 20%.

### Claim 6 (depends on 1)

The compound as recited in claim 1, wherein each of said positions represented as D have deuterium enrichment of at least 10%.

### Claim 7 (depends on 1)

The compound as recited in claim 1, wherein each of said positions represented as D have deuterium enrichment of at least 5%.

### Claim 8 (depends on 1)

The compound as recited in claim 1, wherein each of said positions represented as D have deuterium enrichment of at least 1%.

### Claim 9

A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a compound selected from the group consisting of:
or a pharmaceutically acceptable salt or enantiomer thereof.

### Claim 10 (depends on 9)

A pharmaceutical composition as recited in claim 9, further comprising one or more release-controlling excipients.

### Claim 11 (depends on 9)

The pharmaceutical composition as recited in claim 9, further comprising one or more non-release controlling excipients.

### Claim 12 (depends on 9)

The pharmaceutical composition as recited in claim 9, wherein the composition is suitable for oral, parenteral, or intravenous infusion administration.

### Claim 13 (depends on 12)

The pharmaceutical composition as recited in claim 12, wherein the oral dosage form is a tablet or capsule.

### Claim 14 (depends on 12)

The pharmaceutical composition as recited in claim 12, wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram.

### Claim 15 (depends on 9)

The pharmaceutical composition as recited in claim 9, further comprising another therapeutic agent.

### Claim 16 (depends on 15)

The pharmaceutical composition as recited in claim 15, wherein the therapeutic agent is selected from the group consisting of calcium channel blockers, adenosine, Beta-blockers, digitoxin, anti-arrhythmic agents, sympathomimetic drugs, steroidal drugs, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, anesthetics, mydriasis agents, anti-histamines, decongestants, expectorants, anti-tussives, sepsis agents, anti-bacterials, anti-fungals, anti-coagulants, thrombolytics, endothelin converting enzyme (ECE) inhibitors, thromboxane enzyme antagonists, potassium channel openers, thrombin inhibitors, growth factor inhibitors, platelet activating factor (PAF) antagonists, anti-platelet agents, Factor VIIa Inhibitors, Factor Xa Inhibitors, renin inhibitors, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, anti-atherosclerotic agents, MTP Inhibitors, potassium channel activators, alpha-PDE5 agents, beta-PDE5 agents, diuretics, anti-diabetic agents, PPAR-gamma agonists, mineralocorticoid enzyme antagonists, aP2 inhibitors, protein tyrosine kinase inhibitors, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents, cytotoxic agents, antimetabolites, farnesyl-protein transferase inhibitors, hormonal agents, microtubule-disruptor agents, microtubule-stabilizing agents, topoisomerase inhibitors, prenyl-protein transferase inhibitors, cyclosporins, TNF-alpha inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gold compounds, antalarmin, Z-338 and platinum coordination complexes.

### Claim 17 (depends on 16)

The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is a calcium channel blocker.

### Claim 18 (depends on 17)

The pharmaceutical composition as recited in claim 17, wherein the calcium channel blocker is selected from the group consisting of amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine, mibefradil, verapamil, gallopamil, diltiazem, fendiline, bepridil, lidoflazine, and perhexiline.

### Claim 19 (depends on 16)

The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is adenosine.

### Claim 20 (depends on 16)

The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is a Beta-blocker.

### Claim 21 (depends on 20)

The pharmaceutical composition as recited in claim 20, wherein the Beta-blocker is selected from the group consisting of alprenolol, oxprenolol, pindolol, propranolol, timolol, sotalol, nadolol, mepindolol, carteolol, tertatolol, bopindolol, bupranolol, penbutolol, cloranolol, practolol, metoprolol, atenolol, acebutolol, betaxolol, bevantolol, bisoprolol, celiprolol, esmolol, epanolol, s-atenolol, nebivolol, talinolol, labetalol, and carvedilol.

### Claim 22 (depends on 16)

The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is an anti-arrhythmic agent.

### Claim 23 (depends on 22)

The pharmaceutical composition as recited in claim 22, wherein the anti-arrhythmic agent is selected from the group consisting of quinidine, procainamide, disopyramide, sparteine, ajmaline, prajmaline, lorajmine, lidocaine, mexiletine, tocainide, aprindine, propafenone, flecainide, lorcainide, encainide, amiodarone, bretylium tosilate, bunaftine, dofetilide, ibutilidem, moracizine, and cibenzoline.

### Claim 24 (depends on 16)

The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is an opioid.

### Claim 25 (depends on 24)

The pharmaceutical composition as recited in claim 24, wherein the opioid is selected from the group consisting of morphine, codeine, thebain, diacetylmorphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, nicomorphine, fentanyl, 3-methylfentanyl, alfentanil, sufentanil, remifentanyl, carfentanyl, ohmefentanyl, pethidine, ketobemidone, propoxyphene, dextropropoxyphene, methadone, loperamide, pentazocine, buprenorphine, etorphine, butorphanol, nalbufine, levorphanol, naloxone, naltrexone, and tramadol.

### Claim 26 (depends on 16)

The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is a sympathomimetic drug.

### Claim 27 (depends on 26)

The pharmaceutical composition as recited in claim 26, wherein the sympathomimetic drug is selected from the group consisting of cyclopentamine, ephedrine, phenylephrine, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, phenylpropanolamine, and pseudoephedrine.

### Claim 28 (depends on 16)

The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is a mydriasis agent.

### Claim 29 (depends on 28)

The pharmaceutical composition as recited in claim 28, wherein the mydriasis agent is selected from the group consisting of atropine, scopolamine, methylscopolamine, cyclopentolate, homatropine, and tropicamide.

### Claim 30 (depends on 16)

The pharmaceutical composition as recited in claim 16, wherein the therapeutic agent is a steroidal drug.

### Claim 31 (depends on 30)

The pharmaceutical composition as recited in claim 30, wherein the steroidal drug is selected from the group consisting of aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone acetate, hydrocortisone (cortisol), prednisolone, prednisone, methylprenisolone, dexamethasone, and triamcinolone.

### Claim 32

A method for the treatment, prevention, or amelioration of one or more symptoms of an alpha adrenergic receptor-mediated disorder, in a subject, comprising administering a therapeutically effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt or enantiomer thereof.

### Claim 33 (depends on 32)

The method as recited in claim 32, wherein the alpha adrenergic receptor-mediated disorder is selected from the group consisting of nasal congestion, migraine, asthma, chronic obstructive pulmonary disorders, ischemic heart disorder, and hypotension.

### Claim 34 (depends on 32)

The method as recited in claim 32, wherein the symptoms of the alpha adrenergic receptor-mediated disorder can be lessened, alleviated, or prevented by administering an alpha adrenergic receptor modulator.

### Claim 35 (depends on 32)

The method as recited in claim 32, wherein said compound has at least one of the following properties:
a) decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;
b) increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;
c) decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;
d) increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and
e) an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

### Claim 36 (depends on 32)

The method as recited in claim 32, wherein said compound has at least two of the following properties:
a) decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;
b) increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;
c) decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;
d) increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and
e) an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

### Claim 37 (depends on 32)

The method as recited in claim 32, wherein the method affects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound.

### Claim 38 (depends on 37)

The method as recited in claim 37, wherein the cytochrome P450 isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

### Claim 39 (depends on 32)

The method as recited in claim 32, wherein said compound is characterized by decreased inhibition of at least one cytochrome P450 or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

### Claim 40 (depends on 39)

The method as recited in claim 39, wherein said cytochrome P450 or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAOA, and MAOB.

### Claim 41 (depends on 32)

The method as recited in claim 32, wherein the method affects the treatment of the disease while reducing or eliminating a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound.

### Claim 42 (depends on 41)

The method as recited in claim 41, wherein the diagnostic hepatobiliary function endpoint is selected from the group consisting of alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST,” “SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein.

### Claim 43 (depends on 1)

A compound as recited in claim 1 having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 44 (depends on 1)

A compound as recited in claim 1 having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 45

A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a compound having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 46 (depends on 1)

A compound as recited in claim 1 having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 47 (depends on 1)

A compound as recited in claim 1 having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 48

A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a compound having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 49 (depends on 1)

A compound as recited in claim 1 having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 50 (depends on 1)

A compound as recited in claim 1 having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 51

A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a compound having the structural formula:
or a pharmaceutically acceptable salt thereof.

### Claim 52 (depends on 9)

A pharmaceutical composition as recited in claim 9, wherein said pharmaceutical composition is a solid oral dosage form.

### Claim 53 (depends on 45)

A pharmaceutical composition as recited in claim 45, wherein said pharmaceutical composition is a solid oral dosage form.

### Claim 54 (depends on 48)

A pharmaceutical composition as recited in claim 48, wherein said pharmaceutical composition is a solid oral dosage form.

### Claim 55 (depends on 51)

A pharmaceutical composition as recited in claim 51, wherein said pharmaceutical composition is a solid oral dosage form.