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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Recent Posts

Doglovers, Various types of food can actually be fatal for dogs due to a common, all natural sweetener called xylitol (yikes).


Tis the season for snowball fights, Christmas decorations, and food – SO MUCH FOOD. If you celebrate Christmas (or Hanukkah), chances are you’ll be indulging this holiday season. While I fully support everyone’s right to treat themselves, a lot of kids (and parents) don’t realize that various types of food can actually be fatal for dogs due to a common, all natural sweetener called xylitol (yikes). Because I’m a dog lady, I compiled a list of products that contain xylitol for dog owners to refer to!

https://simplewag.com/xylitol-dogs-a/

 

Xylitol is a sugar alcohol commonly used in candy and chewing gum (and some other products, such as peanut butter.) It is also found in some pharmaceuticals and oral health products such as chewable vitamins and throat lozenges. While Xylitol is safe for humans, xylitol and dogs do not mix. The compound doesn’t affect glucose levels in people, but when ingested by dogs it can cause a dangerous surge of insulin. (In as little as 15 minutes, the blood sugar of a dog that has eaten gum containing Xylitol may register a marked drop in blood sugar.) At higher doses, Xylitol is believed toxic to the canine liver.

Xylitol and Dogs: Statistics

In the past 5 years, Pet Poison Helpline, an animal poison control based out of Minneapolis, MN, has had over 1500 calls for xylitol poisoning, due to the growing awareness of this common kitchen toxin. In both humans and dogs, the level of blood sugar is controlled by the release of insulin from the pancreas. Xylitol does not stimulate the release of insulin from the pancreas in humans.

However, when non-primate species (e.g.,  a dog) eat something containing xylitol, the xylitol is quickly absorbed into the bloodstream, resulting in a potent release of insulin from the pancreas.  This rapid release of insulin results in a rapid and profound decrease in the level of blood sugar (hypoglycemia), an effect that occurs within 10-60 minutes of eating the xylitol. Untreated, this hypoglycemia can be life-threatening.It can also be used in home baking.

Just three grams of Xylitol can kill a 65-pound dog. Because the amount of sweetener used in sugar-free chewing gums varies by manufacturer and product, the number of sticks of gum that would prove fatal to a pooch of that size can’t be stated with precision. As a general rule of thumb, between eight and ten pieces of gum might be deadly to a 65-pound canine, but a smaller dog could easily die after ingesting far less (perhaps as few as two sticks of gum).

If you suspect that your pet has eaten a xylitol-containing product, please contact your veterinarian or Pet Poison Helpline (800-213-6680) immediately. Do not induce vomiting or give anything orally to your dog unless specifically directed to do so by your veterinarian. It is important to get treatment for your dog as quickly as possible.  As some dogs may already be hypoglycemic, inducing vomiting can make them worse!

Xylitol & Dogs: Symptoms

Symptoms of xylitol toxicity develop rapidly, usually within 15-30 minutes of consumption. Signs of hypoglycemia may include any or all of the following:

  • Vomiting
  • Weakness
  • Incoordination or difficulty walking or standing (walking like drunk)
  • Depression or lethargy
  • Tremors
  • Seizures
  • Coma

In severe cases, the dog may develop seizures or liver failure. Dogs that develop liver failure from xylitol poisoning often show signs of hypoglycemia.

Xylitol & Dogs: Diagnosis

A presumptive diagnosis of xylitol poisoning is made if there is a known or possible history that the dog ate something containing xylitol, coupled with symptoms of hypoglycemia. Since toxicity develops rapidly, your veterinarian will not wait for a confirmed diagnosis before beginning treatment. There is no antidote for xylitol toxicity, although treatment with sugar supplementation, IV fluids, and liver protective drugs are beneficial.

Xylitol & Dogs: Treatment

Fast and aggressive treatment by your veterinarian is essential to effectively reverse any toxic effects and prevent the development of severe problems. If your dog has just eaten xylitol but has not yet developed any clinical signs, your veterinarian may induce vomiting to prevent further absorption, depending on what your dog’s blood glucose level is. If clinical signs have developed, treatment will be based on the symptoms that are being shown.

Since xylitol toxicity can cause both low blood glucose and low potassium levels, your veterinarian will perform blood work to determine whether these problems need to be treated. In all cases, your dog will require hospitalization for blood sugar monitoring, dextrose administration, intravenous fluids, liver protectants, and any other supportive care that may be needed. Blood work should be monitored frequently to make sure that blood sugar and liver function remain normal.

Xylitol & Dogs: Prognosis

The prognosis is good for dogs that are treated before symptoms develop, or for dogs that develop uncomplicated hypoglycemia that is reversed rapidly. If liver failure or a bleeding disorder develops, the prognosis is generally poor. If the dog lapses into a coma, the prognosis is very poor. If you personally use products containing xylitol, make sure they are stored safely, out of reach of your pets. Do not share any food that may contain xylitol with your pets. Only use pet toothpaste for pets, never human toothpaste. Keep in mind that there are some veterinary products that contain small amounts of xylitol (e.g., gabapentin medication, mouthwashes). At prescribed doses, these should not result in xylitol poisoning; however, if ingested in large amounts, can potentially result in poisoning.

Xylitol In Products

Many people start a new year with a plan to live a healthier life. But, unbeknownst to some dog owners, a common sugar additive that is used in reduced sugar and diet products has the ability to be lethal to their pup. That sugar additive is called xylitol.

Xylitol is a sugar alcohol commonly used in candy and chewing gum (and some other products, such as peanut butter.) It is also found in some pharmaceuticals and oral health products such as chewable vitamins and throat lozenges.

While Xylitol is safe for humans, it can be harmful to dogs!!

Here is a list of the known products that contain xylitol.

Xylitol In Products: Peanut Butter

Xylitol product list sorted alphabetically by company or distributor
Go Nuts, Co.
Almond Butter
Almond Butter – Chocolate Almond Butter
Peanut Butter – Dark Chocolate Mint
Peanut Butter – Natural Chocolate Flavor
Peanut Butter – Natural Flavor
Peanut Butter – Organic Maple Flavor
Krush Nutrition
Nutty By Nature Peanut Butter Brownie Batter
Nutty By Nature Peanut Butter Cookie Dough
Nutty By Nature Peanut Butter Snickerdoodle Cookie
Nutty By Nature Peanut Butter Thick & Creamy
Nuts ‘N More®
Almond Spread – Almond Butter
High Protein + Almond Spread – Almond Butter
High Protein + Almond Spread – Chocolate Almond
High Protein + Almond Spread – Cinnamon Raisin
High Protein + Peanut Spread – Chocolate Peanut
High Protein + Peanut Spread – Peanut Butter Flavor
High Protein + Peanut Spread – Pumpkin Spice
High Protein + Peanut Spread – Toffee Crunch
Peanut & Protein Spread – Sesame Cranbutter
Peanut Spread – Peanut Butter Flavor
Peanut Spread – Toffee Crunch
P28 Foods
High Protein Spread – Almond Butter
High Protein Spread – Banana Raisin
High Protein Spread – Peanut Spread
High Protein Spread – Signature Blend
Protein Plus PB
Hank’s Protein Plus – Almond Butter
Hank’s Protein Plus – Banana
Hank’s Protein Plus – Caramel Pretzel
Hank’s Protein Plus – Chocolate Chip
Hank’s Protein Plus – Coconut
Hank’s Protein Plus – Honey Maple
Hank’s Protein Plus – Plain
Hank’s Protein Plus – Snickerdoodle

Xylitol In Products: Chocolate

Xylitol product list sorted alphabetically by company or distributor
 Avalon Select
Tru Chocolate – Assorted Flavors
Bulletproof™ 
Chocolate Fuel Bars – Assorted Flavors
Truffled Chocolate Coffee Beans
Dr. John’s
Gourmet Chocolates: Cool Mint, Creamy Peanut Butter, Exotic Coconut, Pecan Caramel Perfection Bars, Pecan Caramel Perfection Clusters, Raspberry Rapture, Sea Salt Caramel, Signature Sampler Collection, Toasted Toffee with Almonds
Healthy Chocolate Co, Inc
Health 4Living™ Xylitol COQ10 Chocolate
Healthy Chocolate – Dark Assorted, Dark Coffee, Dark Coconut, Dark Mint, Dark Orange, Dark Plain, Dark Raspberry
The Raw Chocolate Co
Mint Raw Chocolate
Orange Raw Chocolate

 Xylitol In Products: Cookies, Desserts, Mixes, Ice Cream & Yogurt

Xylitol product list sorted alphabetically by company or distributor

Barry Farm
Sugar Free Pie Filling – Assorted Flavors

Clemmy’s™ Ice Cream
Clemmy’s Rich and Creamy Ice Cream – Chocolate, Chocolate Chip, Orange Creme, Toasted Almond, Vanilla Bean, Coffee
Clemmy’s Rich and Creamy Bars – Cherry Vanilla, Chocolate Fudge, Orange Creme, Strawberries ‘N Creme
Health Garden
Kosher Choc-Oh-Chip Cookies
Jell-O
Jell-O – Boston Cream Pie Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Dulce de leche Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Chocolate Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Chocolate Vanilla Swirls Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Dark Chocolate Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Double Chocolate Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Chocolate Indulgence Mousse Sugar Free
Jell-O – Dark Chocolate Decadence Mousse Sugar Free
Jell-O – Creme Brûlée Rice Pudding Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Rice Pudding Sugar Free / Reduced Calorie Pudding Snacks
Jell-O – Vanilla Sugar Free / Reduced Calorie Pudding Snacks
Sophie Yogurt
Non-Fat Greek Yogurt – Assorted Flavors
SweetDeliverance™
B-Sugarless – Diabetic Cake Mixes – Assorted Flavors
Wegmans
Sugar Free Pudding: Chocolate, Chocolate Vanilla Swirl
Sugar Free Pudding with Calcium : Dark Chocolate
Wheyhey 
Protein Ice Cream – Assorted Flavors

Xylitol In Products: Jams & Syrups

Xylitol product list sorted alphabetically by company or distributor

Focus Nutrition
XyloBurst Sugar-Free Jam: Apricot, Blueberry, Mountain Berry, Peach, Raspberry, Strawberry
Nature’s Hollow
Apricot Sugar-Free Jam Preserves
Blueberry Sugar-Free Jam Preserves
Mountain Berry Sugar-Free Jam Preserves
Peach Sugar-Free Jam Preserves
Raspberry Sugar-Free Jam Preserves
Strawberry Sugar-Free Jam Preserves
Wild Blueberry Sugar-Free Jam Preserves
Maple Sugar-Free Syrup
Raspberry Sugar-Free Syrup
Xylabrands
Xyla Jam – Apricot, Blueberry, Mountain Berry, Peach, Raspberry, Strawberry

 Xylitol in Products- Condiments & Sauces

Xylitol product list sorted alphabetically by company or distributor

Health Garden
Sugar-Free Tomato Ketchup
Nature’s Hollow
Sugar Free Hickory Maple BBQ Sauce
Sugar Free Honey Mustard BBQ Sauce
Sugar-Free Ketchup
Xylabrands
Xyla BBQ Sauce – Original
Xyla Buffalo Wing Sauce
Xyla Chipotle BBQ Sauce
Xyla Ketchup
Xyla Sesame Teriyaki Sauce

Xylitol In Products: Water & Drink Powders

Xylitol product list sorted alphabetically by company or distributor
Designs For Health 
Electrolyte Synergy Grape Flavor
Natural Factors®
SlimStyles® Weight Loss Drink with PGX® – Assorted Flavors
NOW® Foods
Berry Lemonade Slender Sticks
Berry Energy Tea Slender Sticks
Effer-C™ Acai Berry Sticks
Effer-C™ Cranberry Pomegranate Packets
Effer-C™ Elderberry Packets
Grape Slender Sticks
Pomegranate Berry Slender Sticks
Natural Max (no website found)
Skinny Fast Hunger Rescue Chocolate Fix
xyWater
xyWater Nutritional Drink – Assorted Flavors
ZipFizz®
Energy Drink Mix – Assorted Flavors
Immune Fizz – Fruit Punch

Xylitol In Products: Power & Protein Bars, and Powders

Xylitol product list sorted alphabetically by company or distributor

Betty Lou’s™
Low Glycemic Protein Shake: Chocolate, Orange Cream, Vanilla

Designs For Health
PaleoBar Chocolate Coated

Life Extension® 
Pure Plant Protein

NOW® Foods
Berry Lemonade Slender Sticks
Berry Energy Tea Slender Sticks
Effer-C™ Acai Berry Sticks
Effer-C™ Cranberry Pomegranate Packets
Effer-C™ Elderberry Packets
Grape Slender Sticks
Pomegranate Berry Slender Sticks

Natural Max (no website found)
Skinny Fast Hunger Rescue Chocolate Fix

Protocol For Life Balance® 
Plant Protein Complete

Renew Life 
FitSMART Shake – Assorted Flavors
FitSMART Vegan Shake – Assorted Flavors

Xylitol In Products: Candies, Gum & Mints

Xylitol product list sorted alphabetically by company or distributor

Bach Flower
Rescue® Chewing Gum – Orange & Elderflower
Rescue® Pastilles – Assorted Flavors

B Fresh®
B Fresh Energy Mints – Assorted Flavors
B Fresh® Gum – Assorted Flavors

Branam™
Branam™ Xylitol Gum – Hot Cha Cha Cinnamon, Snappy Apple

Designs For Health
Brain Power Sours

Camellix™
MighTeaFlow® Dry Mouth Chewing Gum
MighTeaFlow® Dry Mouth Gel
MighTeaFlow® Dry Mouth Moisturizing Lozenges
MighTeaFlow® Dry Mouth Moisturizing Oral Rinse
MighTeaFlow® Dry Mouth Moisturizing Oral Spray
MighTeaFlow® Green Tea Lozenges

Carifree®
CTx1 Lollies
CTx2 Xylitol Gum

Cleure™
Cleure Fresh Fruit Gum
Cleure Lemon Drops

Cracked Candy™
Cracked Candy – Assorted Flavors

CVS Pharmacy®
CVS Sugar Free Breath Strips Blue Mint

Dentyne®
Dentyne Pure Mint With Citrus Accents
Dentyne Pure Mint With Herbal Accents
Dentyne Pure Mint With Melon Accents

Dr. John’s
Hard Candy: Butterscotch Bliss, Cafe Caramel, Cherry Blossom, Classic Fruits Collection, Cream Soda, Creamsicle Swirl Collection, Fresh Fruits Collection, Luscious Licorice, Mighty Mango, Peppermint Pop, Perfect Pear, Pink Grapefruit, Radiant Rainbow, Signature Sours Collection, Sour Cherry, Sour Lemon, Strawberry Cheesecake, Sunkissed Fruits Collection, Ultimate Hard Candy Collection, Ultimate Sweets Collection

Lollipops: Blue Raspberry Blast, Butterscotch Bliss, Cheeky Cherry, Classic Fruits Collection, Classic Fruits Collection, Creamsicle Swirl Collection, Fresh Fruits Collection, Juicy Grape, Peppermint Pop, Pomegranate Punch, Proudly Patriotic, Radiant Rainbow, Signature Sours Collection, Sunkissed Fruits Collection, Ultimate Lollipop Collection, Ultimate Sweets Collection, Whimsical Watermelon

Soft Candies: Butter Crunch Caramels, Butterscotch Bliss Caramels, Cafe Caramel Caramels, Caramel Lovers Collection, Chocolate Caramel Swirls, Luscious Licorice Taffy, Peppermint Pop Taffy, Ultimate Sweets Collection, Vanilla Caramel Swirls

Sweet Advantage™ Gum – Fruit Punch
Sweet Advantage™ Gum – Peppermint Pop
Sweet Advantage™ Tablet: Peppermint Pop™
Sweet Advantage™ Tablet: Tangy Melon™

Eco-Dent®
Between! Dental Gum – Assorted Flavors

Epic Dental
Xylitol Gum: Cinnamon, Fresh Fruit, Peppermint, Spearmint
Xylitol Mints: Peppermint, Fresh Fruit, Cinnamon

Extra Ice (Wrigley’s)
Extra® Ice – Spearmint
Extra® Ice – Peppermint

Focus Nutrition
XyloBurst Gum: Cinnamon, Fruit, Green Tea, Peppermint, Spearmint,
XyloBurst Xylitol Mints: Berry, Cinnamon, Ginger, Lemon, Licorice, Peppermint, Wintermint
XyloBurst Xylitol Fruit Sours: Cherry, Grape, Orange Citrus, Lemon Lime, Peach Sour, Watermelon
XyloBurst Sugar Free Lollipops with Xylitol: Apple, Orange, Raspberry, Strawberry

Glee Gum
Sugar-Free Glee Gum: Lemon-Lime, Refresh-Mint, Wild Watermelon

Hager Pharma
Hager Pharma Miradent Chewing Gum: Cinnamon, Cranberry, Fresh Fruit, Green Tea, Peppermint, Spearmint

Healthy Grid
Tooth Friendly Xylitol Candies – Assorted Flavors

Hersheys®
Ice Breakers® – Cool Blasts Gum – Assorted Flavors
Ice Breakers® – Ice Cubes Gum – Assorted Flavors

Ice Chips Candy
Ice Chips – Assorted Flavors

Juicy Fruit (Wrigley’s)
Juicy Fruit Fruity Chews – Original

Lotte Confectionery
Lotte Xylitol Gum – Assorted Flavors
Lotte Xylitol Alpha Project Gum – Assorted Flavors
Anytime Candy – Assorted Flavors

Melaleuca
Exceed™ Gum – Assorted Flavors
Exceed™ Mints – Assorted Flavors

Mentos®
Mentos® Pure Gum – Assorted Flavors
Mentos® SugarFree Gum – Assorted Flavors
Mentos® Gum UP2U – Assorted Flavors

Nature’s Stance (XyliChew)
XyliChew Gum: Black Licorice, Cinnamon, Fruit, Peppermint, Spearmint

Nicorette®
Nicorette Stop Smoking Aid – Coated Gum: Cinnamon Surge, Fruit Chill, Mint

Nutraceutical
Zylicious™ Xylitol gum
XyliVita™ Gum

Orbit®
Orbit Gum – Assorted Flavors

Peelu
Cinnamon Sass Chewing Gum with Xylitol
Citrus Breeze Chewing Gum with Xylitol
Peppermint Blast Chewing Gum with Xylitol
Spearmint Chewing Gum with Xylitol

Peppersmith™
Chewing Gum – Assorted Flavors
Fresh Mints – Assorted Flavors

Pür
Pür Gum – Assorted Flavors
Pür Mints – Assorted Flavors

Rainbow Light®
MintAsure™

Rite Aid
Rite Aid Pharmacy Stop Smoking Aid – Sugar Free, Coated Gum: Cinnamon, Mint

Scandinavian Formulas
Salivasure™ Lozenges

Seroyal
Homeofresh Chewing Gum

Starbucks®
Gum
Mints

Stevita
SteviaDent™ Gum: Cinnamon, Peppermint

Stride Gum – Mondalez International
Stride Gum – NonStop Mint, Spark Kinetic Fruit, Spark Kinetic Mint, Spearmint

Supersmile®
Professional Whitening Gum

TheraBreath®
Professional Formula Sugar Free Chewing Gum
TheraBreath® Mouth-Wetting Lozenges
Zox Breath Mints

TheraMints™
100% Xylitol Lozenges

Trident® – Mondalez International
Trident Gum: Blueberry Twist®, Bubblegum, Cinnamon, Minty Sweet Twist, Original Flavor, Passionberry Twist®, Spearmint, Splashing Fruit™, Splashing Mint, Strawberry Twist, Tropical Twist®, Watermelon Twist®, Wintergreen

Walgreens
Walgreens Breath Strips Mint

Xlear®
SparX Candy: Berry, Citrus, Fruit
Spry Dental Defense Gum: Cinnamon, Fresh Fruit, Green Tea, Peppermint, Spearmint, Strawberry
Spry Gem Mints: Berry, Cinnamon, Lemon Creme, Peppermint, Spearmint
Spry Mints: BerryBlast, Cinnamon, Green Tea, Power Peppermint, Spearmint

Xylabrands
Xyla Ballpop Lollipops
Xyla Brand Xylitol Candy: Cherry, Citrus, Grape, Key Lime, Raspberry, Watermelon
Xyla Gum: Cinnamon, Fruit Punch, Peppermint, Spearmint,
Xyla Mints: Cocoa Mint, Fruit Punch, Lemon Lime, Licorice, Peppermint, Wintermint
Xyla Taffy: Assorted Flavors
Xyla Assorted 100% Natural Hard Candies

XyliChew
See Nature’s Stance above for product details

Zellie’s
Zellie’s Naturally Sugar Free Gum: Cinnamon, Fresh Fruit, Peppermint, Spearmint
Zellie’s Naturally Sugar Free Mints: Cool Fruit, Cool Mint, Cinnamon, Spearmint
Zellie’s Polar Bears: Cherry, Tropical Fruit

Zollipops®
Zollipops® Lollipops

Xylitol In Products: Honey, Raw Xylitol & Sweeteners

Xylitol product list sorted alphabetically by company or distributor

Designs For Health
Xylitol Powder 500 gms

Dr. John’s
Simply Xylitol Sweetener

Epic Dental
Xylitol Sweetener

Focus Nutrition
XyloBurst All-Natural Xylitol Sweetener Granuals
XyloBurst All-Natural Xylitol Sweetener Packets

Global Sweet
Smart Sweet Xylitol Granules
Smart Sweet Xylitol Honey

Hager Pharma
Hager Pharma Xylitol Sweetener

Health Garden
Real Birch Xylitol
Real Birch Xylitol Vanilla Sweetener

Jarrow Formulas Inc.
XyliPure Powder
Lo Han Sweet Powder

Life Enhancement
Sugar XE™ Sweetener

Nature’s Hollow
Sugar-Free Honey

NOW® Foods
Now Real Food – Xylitol
Now Real Food – Pure Xylitol Packets

NuNaturals
Sweet X™ Crystals

Nutraceutical
Kal® Xylitol Sweetener

Piping Rock
100%Pure Xylitol Natural Sweetener

Puritan’s Pride
Xylitol Powder

Source Naturals
XyliSmart® Sweetener

Swanson Health Products
Swanson Premium – 100% Pure Non-GMO Xylitol Granules
Swanson Premium – Xylitol Packets

Xlear®
Lite & Sweet
Xylo-Sweet

Xylabrands
Xyla Xylitol Packets
Xyla Xylitol Bulk
Xyla Powdered Xylitol

Zellie’s
Zellie’s Granular Xylitol
Zellie’s Pure Xylitol Packets

 Xylitol in Products: Dental & Nasal: Toothpaste, Floss, Mouthwash & Rinses

Xylitol product list sorted alphabetically by company or distributor

ACT®
Act Advanced Care™ Plaque Guard™ Mouthwash
Act Braces Care™ Mouthwash
Act Dry Mouth Lozenges
Act Dry Mouth Mouthwash
Act Dry Mouth Toothpaste
Act Total Care™ Sensitive Formula Mouthwash

American Biotech Labs
SilverSol Tooth Gel

Aquafresh® – GSK
Aquafresh Training Fluoride-Free Toothpaste

Auromere®
Ayurvedic Mouthwash

Babyganics®
Fluoride Free Toothpaste – Assorted Flavors

Biotene®
Dry Mouth Oral Rinse
Moisturizing Mouth Spray
Oral Balance Gel
PBF Oral Rinse

Branam™
All Natural Xylitol Tooth Gel – Assorted Flavors

Carifree®
CTx2 Spray
CTx3 Gel
CTx3 Rinse
CTx4 Gel 1100
CTx4 Treatment Rinse

Cleure™
Cleure Toothpaste – Assorted Flavors
Cleur Mouthwash – Assorted Flavors

Coral LLC
Coral Kids Toothpaste

Davids
Davids Premium Natural Toothpaste

Dentiste’
Dentiste’ Plus White Nighttime Toothpaste

doTERRA®
On Guard Toothpaste

Dr. Brown’s™
Nose & Face Wipes
Tooth & Gum Wipes

Dr. Collins
All White Toothpaste
Natural Toothpaste

Eco-Dent®
Res-Q-Dent Gel Toothpaste

Epic Dental
Fluoride & Xylitol Toothpaste
Spearmint Xylitol Mouthwash

Grants of Australia
Natural Toothpaste – Assorted Flavors
Natural Toothpaste Single Use Sachets
Xylitol Mint Natural Toothpaste
Xylitol Natural Mouthwash

H2Ocean®
H2Ocean Mouthwash – Assorted Flavors
Nasalzyme Maximum Strength Nasal Spray

Hager Pharma
Hager Pharma Dry Mouth Drops
Hager Pharma Happy Morning Xylitol Disposable Toothbrushes
Hager Pharma Xyli-Spray Sugar Free Fresh Breath Spray

Halo™
Halo Oral Antiseptic, Berry, Citrus

Healing Scents 
Tooth Gel – Assorted Flavors

Hello® 
Breath Spray – Assorted Flavors
Fluoride Toothpaste – Assorted Flavors
Kids Fluoride Toothpaste – Assorted Flavors
Mouthwash – Assorted Flavors

Heritage Store
Hydrogen Peroxide Tooth Powder
Hydrogen Peroxide Mouthwash + White
Hydrogen Peroxide Mouthwash Wintermint
Ipsab Tooth Powder, Cinnamon
Ipsab Whitening Toothpaste

IntelliWHiTE™
IntelliFRESH Breath Gel
IntelliFRESH Oral Rinse Fusion
IntelliWHiTE® CoolBlue Amplifier Gel Pen
IntelliWHiTE® Power Booster & Toothpaste Duo
PM Restore Night Serum
Power Boost Whitening Gel
PRO WhiTE Professional Toothpaste

Jack n’ Jill 
Natural Calendula Toothpaste – Assorted Flavors

Jason®
Healthy Mouth® Tartar Control Anti-Cavity Toothpaste
Healthy Mouth® Tartar Control Cinnamon Clove Mouthwash
Kids Only! Toothpaste – Assorted Flavors
Nutrismile® Enamel Defense Mouthwash
Nutrismile® Enamel Defense Anti-Cavity Toothpaste
Oral Comfort® Soothing Toothpaste
Powersmile® Moutwash: Brightening Peppermint, Strengthening Sea Spearmint, Super Refreshing Cinnamon Powermint
Powersmile® Whitening Anti-Cavity Toothpaste
Sea Fresh® Strengthening Anti-Cavity CoQ10 Gel Toothpaste

Kiss My Face
Obsessively Natural Kids™ Toothpaste – Berry Smart
Obsessively Natural Kids™ Fluoride Free Toothpaste – Berry Smart
Sensitive Fluoride Free Gel
Triple Action Fluoride Free Gel
Triple Action Fluoride Free Toothpaste
Triple Action Anticavity Fluoride Toothpaste
Whitening Gel – Anticavity Fluoride
Whitening Gel – Fluoride Free

Life Extension®
Florassist® Throat Health
Florassist® Oral Hygiene
Life Extension Toothpaste

Logona Naturkosmetik
Kids Dental Gel- Assorted Flavors

Melaleuca
Cool Shot® Breath Spray – Fresh Mint
Koala Pals® Tooth Gel – Assorted Flavors
Mouth Rinse – Assorted Flavors
Sensitive Tooth Polish
Whitening Tooth Polish – Assorted Flavors

MedActive®
Oral Relief Spray
Oral Relief Lozenges

Nature’s Answer 
PerioBrite® Natural Mouthwash – Assorted Flavors

Nature’s Gate
Toothpaste Gel – Cherry, Cool Mint, Wintergreen

NaturallyTaylored
Organic Toothpaste Remineralizing Toothpaste

NOW® Foods
Now Solutions – Activated Nasal Mist
Now Solutions – Xyliwhite™ Mouthwash: Cinnafresh, Neem & Tea Tree, Refreshmint
Now Solutions – Xyliwhite™ Toothpaste Gel: Bubblegum Splash, Cinnafresh, Orange Splash, Neem & Tea Tree, Refreshmint, Strawberry Splash
Now Solutions – Xyliwhite™ Plantinum Mint Toothpaste Gel w/ Baking Soda

Nuk – Gerber®
Grins & Giggles® Gum & Tooth Wipes

Nutraceutical
XyliVita™ Mouthwash
XyliVita™ Toothpaste – Assorted Flavors
XyliVita™ Sensitive Whitening Toothpaste – Cool Mint Chia

Oasis Dry Mouth
Oral Demulcent Moisturizing Spray

OraCoat / OraHealth
Avamin Melts – Healthy Mouth Lining
XyliMelts for Dry Mouth, Regular or Mint-Free
XyliGel with H-B12 for Dry Mouth and Mucositis

Organix South
TheraNeem Naturals – Neem Tooth & gum Powder
TheraNeem Naturals – Tea Tree Toothpaste

Parnell Pharmaceuticals
Mouth Kote Dry Mouth Spray

Peelu
Cinnamon Fluoride
Mint Free Fluoride
Peppermint Fluoride
Spearmint Fluoride

Radius
Cranberry Floss with Natural Xylitol
Vegan Xylitol Mint Floss

Redmond Trading Company
Earthpaste – Assorted Flavors

Seroyal
Homeofresh TP Anisum
Homeofresh TP Chlorophyllum
Homeofresh TP Citrus

Solay Wellness
Solay Smile Natural Tooth Powder – Assorted Flavors

Spiffies®
Lusterbrush Xylitol and Fluoride Tooth Gel
Spiffies Tooth Wipes – Assorted Flavors
Spiffies Tooth Gel – Assorted Flavors
Xyliclean Xylitol Oral Cleansing Solution

Squigle
Squigle Toothpaste
Tooth Builder Toothpaste

Starbrite
Whitening Toothpaste

Swanson Health Products
Swanson Ultra – Tea Tree Mouthwash Peppermint
Swanson Ultra – Whitening Toothpaste with Xylitol, Peelu and Tea Tree Oil
Swanson Ultra – Dry Mouth Relief

Tanner’s Tasty Paste®
Tasty Paste Toothpaste – Assorted Flavors

The Natural Dentist™
All in One Fluoride Toothpaste
Cavity Zapper Fluoride Rinse – Assorted Flavors
Fluoride-Free Toothpaste
Healthy Balance All-Purpose Rinse
Healthy Breath Antiseptic Rinse
Healthy Teeth Fluoride Rinse
Healthy White Pre-Brush Whitening Rinse
Whitening Fluoride Toothpaste

TheraBreath® 
Periotherapy Oral Rinse
Periotherapy Toothpaste
TheraBreath® Plus Oral Rinse
TheraBreath® Icy Mint Oral Rinse
TheraBreath® Soothing Oral Rinse
TheraBrite Plus® Toothpaste

Tom’s of Maine®
Antiplaque & Whitening Toothpaste – Fluoride-Free – Fennel, Peppermint, Spearmint
Antiplaque & Whitening Toothpaste Gel – Fluoride-Free – Spearmint
Cavity Protection Toothpaste – Peppermint Baking Soda, Spearmint
Children’s Anticavity Fluoride Rinse – Juicy Mint
Clean & Gentle Toothpaste – Peppermint
Enamel Strength® Toothpaste – Peppermint
Fluoride-Free Botanically Bright™ Toothpaste – Peppermint, Spearmint
Fluoride-Free Propolis Myrrh Toothpaste – Cinnamint, Fennel, Gingermint Baking Soda, Peppermint Baking Soda, Spearmint
Fluoride-Free Sensitive Toothpaste – Wintermint
Fluoride-Free Travel Natural Toothpaste – Fresh Mint
Maximum Strength Sensitive Toothpaste – Soothing Mint
Simply White Toothpaste – Clean Mint
Simply White Toothpaste Gel – Sweet Mint
Toddler Training Toothpaste – Mild Fruit
Travel Natural Toothpaste – Fresh Mint
Whole Care Toothpaste – Cinnamon Clove, Peppermint, Spearmint, Wintermint
Whole Care Toothpaste Gel – Peppermint
Wicked Fresh™ Mouthwash – Cool Mountain Mint, Peppermint Wave
Wicked Fresh™ Toothpaste – Spearmint Ice, Cool Peppermint

Walgreens®
Walgreens Dry Mouth Mouthwash

Vita-Myr
Children’s Toothpaste with Xylitol & Natural Orange Flavor
Zinc-Plus XTRA Toothpaste with Xylitol & Co Q 10

VMV Hypoallergenics
Essence Skin-Saving Toothpaste

Xlear®
Kid’s Xlear Saline Nasal Spray
Spry Bubble Gum Tooth Gel
Spry Floss with Xylitol
Spry Toothpaste- Cinnamon
Spry Toothpaste- Cinnamon Fluoride
Spry Coolmint Oral Rinse
Spry Spearmint Oral Rinse
Spry Whitening Kit
Spry Wintergreen Oral Rinse
Xlear Saline Nasal Spray with Xylitol
Xlear Sinus Care Rinse

Young Living™ 

Thieves® AromaBright™ Toothpaste
Thieves® Dentarome® Ultra Toothpaste
Thieves® KidScents® Slique™ Toothpaste

Xylitol In Products: Cosmetics & Hair Care

Xylitol product list sorted alphabetically by company or distributor

ApothecaryMuse
Chocolate Lavender Fields Forever Lip Balm

Aroma Naturals®
Therapeutic Lip Care – Assorted Flavors

Bain de Terre
Purité Healthy Color Protect Shampoo
Purité Healthy Moisture Repair Shampoo

Bioderma
Nodé Fluide Shampoo

Etude House
Dear My Jelly Lips-Talk
Sweet Recipe Candy Stick Lip Gloss – Assorted Colors

GlyMed Plus®
Cell Science Lip Science

Holistic Momma Organics
Mauve Melody Shimmer Lip Balm

Laura Mercier
Tinted Moisturizer – Illuminating Broad Spectrum SPF 20 Sunscreen

Lorac
Natural Performance Foundation

Missha
The Style Beautiful Lip Tint – Assorted Colors

NaturallyTaylored
Love Story Wedding Favor Lip Balm
Mason Jar Wedding Favor Lip Balm

True Natural
Natural Liquid Foundation – Assorted Colors

 Xylitol In Products: Final Thoughts

In the past 5 years, Pet Poison Helpline, an animal poison control based out of Minneapolis, MN, has had over 1500 calls for xylitol poisoning, due to the growing awareness of this common kitchen toxin.

If you suspect that your pet has eaten a xylitol-containing product, please contact your veterinarian or Pet Poison Helpline (800-213-6680) immediately.

Do not induce vomiting or give anything orally to your dog unless specifically directed to do so by your veterinarian. It is important to get treatment for your dog as quickly as possible.

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Chelsea Rivera
VP, Content & Media Relations
SimpleWag

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Chelsea Rivera founded SimpleWag with one goal in mind: to help pet owners ensure their pets live the healthiest lives possible! SimpleWag offers its audience access to loads of great content, including expert information provided by staffed vets, trainers, and behavioral specialists. Additionally, SimpleWag offers a pet food alert that notifies you if your pet’s food has been recalled.There is so information out there that it can be overwhelming for well-intentioned pet owners but SimpleWag’s goal is to do the research so you don’t have to! In addition to working for SimpleWag, Chelsea spends her days getting bossed around by her 5 lb. Maltipoo, Baby Rose, in Los Angeles, CA.

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Gedatolisib, гедатолисиб , غيداتوليسيب , 吉达利塞 ,


Image result for GedatolisibImage result for Gedatolisib

Gedatolisib

Pfizer

PF-05212384; PF-5212384; PKI-587

CAS 1197160-78-3
Chemical Formula: C32H41N9O4
Molecular Weight: 615.72

1-(4-{[4-(Dimethylamino)-1-piperidinyl]carbonyl}phenyl)-3-{4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl}urea
3-{4-[bis(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-1-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}urea
N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N’-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea
гедатолисиб [Russian] [INN]
غيداتوليسيب [Arabic] [INN]
吉达利塞 [Chinese] [INN]
  • Phase III Acute myeloid leukaemia
  • Phase II Colorectal cancer; Non-small cell lung cancer
  • Phase I Breast cancer; Solid tumours
  • Discontinued Endometrial cancer

Most Recent Events

  • 22 Nov 2017Pfizer suspends patient enrolment in a phase I/II trial due to drug supply delay in Non-small cell lung cancer (Combination therapy, Inoperable/Unresectable, Metastatic disease, Late-stage disease) in USA (IV) (NCT02920450)
  • 04 Nov 2017No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease, Second-line therapy or greater) in Canada (IV, Infusion)
  • 04 Nov 2017No recent reports of development identified for phase-I development in Solid-tumours(Combination therapy, Late-stage disease, Second-line therapy or greater) in Italy (IV, Infusion)

Gedatolisib, also known as PKI-587 and PF-05212384, is an agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Upon intravenous administration, PI3K/mTOR kinase inhibitor PKI-587 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K.

PKI-587 is a PI3K/mTOR inhibitor, currently being developed by Pfizer. The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. PKI-587  has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously.

PATENT

WO 2009143317

WO 2010096619

WO 2012148540

WO 2014151147

PATENT

US 20170119778

PAPER

Journal of Medicinal Chemistry (2010), 53(6), 2636-2645

http://pubs.acs.org/doi/abs/10.1021/jm901830p

Bis(morpholino-1,3,5-triazine) Derivatives: Potent Adenosine 5′-Triphosphate Competitive Phosphatidylinositol-3-kinase/Mammalian Target of Rapamycin Inhibitors: Discovery of Compound 26 (PKI-587), a Highly Efficacious Dual Inhibitor

 Chemical Sciences
 Oncology
§ Drug Metabolism
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965
J. Med. Chem.201053 (6), pp 2636–2645
DOI: 10.1021/jm901830p
Publication Date (Web): February 18, 2010
Copyright © 2010 American Chemical Society
*To whom correspondence should be addressed. Phone: (845) 602-4023. Fax (845) 602-5561. E-mail: venkata@wyeth.com or venkata699@gmail.com.

Abstract

Abstract Image

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure−activity relationships and the in vitro and in vivo activity of analogues in this series are described.

Preparation of 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4- yl-1,3,5-triazin-2-yl)phenyl]urea (26)

MS (ESI) m/z = 616.7. HRMS: calcd for C32H41N9O4 + H+, 616.335 43; found (ESI-FTMS, [M + H]+), 616.334 24. Purity by analytical HPLC 99.3%. (Prodigy ODS3, 0.46 cm × 15 cm, 20 min gradient acetonitrile in water, trifluoroacetic acid, detector wavelengths, 215 and 254 nm.) 1H NMR (DMSO-d6) δ 1.29−1.36 (m, 6H), 2.6 (m, 4H), 2.9 (m,1H), 3.3 (m, 4H), 3.6 (m, 8H), 3.7 (m, 8H), 7.3 (d, J = 8.3 Hz, 2H), 7.51−7.57 (m, 4H), 8.3 (d, J = 8.3 Hz 2H), 8.9 (s, 1H), 9.0 (s, 1H) ppm. Anal. Calcd for C32H41N9O4: C 62.42%, H 6.71%, N 20.47%. Found: C 62.34%, H 6.67%, N 20.39%.

PAPER

Bioorganic & Medicinal Chemistry Letters (2011), 21(16), 4773-4778.

http://www.sciencedirect.com/science/article/pii/S0960894X11008468

PAPER

New and Practical Synthesis of Gedatolisib

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00298

 College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, China
 Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Hainan Normal University, 99 South Longkun Road, Haina 571158, China
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00298
*Fax: +86 21 67791214. E-mail: yongjun.mao@hotmail.com.

Abstract

Abstract Image

A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.

off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (brs, 2H), 1.89 (brs, 2H), 2.29 (s, 6H), 2.94 (brs, 2H), 3.76 (m, 8H), 3.89 (m, 8H), 7.09 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 8.28 (s, 1H), 8.31 (d, J = 8.6 Hz, 2H), 8.48 (s, 1H). ESI-MS (m/z) 615.9 (M + H). HPLC conditions: Column: Agilent Eclipse XDB-C18 (250 mm × 4.6 mm × 5 μm); Detection: 254 nm; Flow rate: 0.8 mL/min; Temperature: 30 °C; Injection load: 1 μL; Solvent: MeOH; Concentration: 0.5 mg/mL; Run time: 20 min; Mobile phase A: water; Mobile phase B: MeOH/TEA = 100:0.1; Gradient program: time (min): 20; % of mobile phase A: 10; % of mobile phase B: 90; tR = 2.598 min, purity: 99.34%

  • ZhaoX.; TanQ.ZhangZ.ZhaoY. Med. Chem. Res. 2014235188– 5196 DOI: 10.1007/s00044-014-1084-z
  • KhafizovaG.PotoskiJ. R. PCT Int. Appl. WO 2010096619, 2010.
  • VenkatesanA. M.ChenZ.DehnhardtC. M.Dos SantosO.Delos SantosE. G.ZaskA.VerheijenJ. C.KaplanJ. A.RichardD. J.Ayral-KaloustianS.MansourT. S.GopalsamyA.CurranK. J.ShiM. PCT Int. Appl. WO 2009143317, 2009.

REFERENCES

1: Gedaly R, Galuppo R, Musgrave Y, Angulo P, Hundley J, Shah M, Daily MF, Chen C, Cohen DA, Spear BT, Evers BM. PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation. J Surg Res. 2013 Nov;185(1):225-30. doi: 10.1016/j.jss.2013.05.016. Epub 2013 May 25. PubMed PMID: 23769634.

2: Gedaly R, Angulo P, Hundley J, Daily MF, Chen C, Evers BM. PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation. J Surg Res. 2012 Aug;176(2):542-8. doi: 10.1016/j.jss.2011.10.045. Epub 2011 Nov 21. PubMed PMID: 22261591.

3: Dehnhardt CM, Venkatesan AM, Chen Z, Delos-Santos E, Ayral-Kaloustian S, Brooijmans N, Yu K, Hollander I, Feldberg L, Lucas J, Mallon R. Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063. Epub 2011 Jun 21. PubMed PMID: 21763134.

4: Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I. Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15. PubMed PMID: 21325073.

5: Venkatesan AM, Chen Z, dos Santos O, Dehnhardt C, Santos ED, Ayral-Kaloustian S, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Chaudhary I, Mansour TS. PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73. doi: 10.1016/j.bmcl.2010.07.104. Epub 2010 Jul 30. PubMed PMID: 20797855.

6: Venkatesan AM, Dehnhardt CM, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Gibbons J, Abraham RT, Chaudhary I, Mansour TS. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem. 2010 Mar 25;53(6):2636-45. doi: 10.1021/jm901830p. PubMed PMID: 20166697.

????????????PF 05212384, PF 5212384, PKI-587, PF-05212384; PF-5212384; PKI 587, gedatolisib, antitumor agent, PHASE 3, PFIZER, гедатолисиб غيداتوليسيب 吉达利塞 

O=C(NC1=CC=C(C2=NC(N3CCOCC3)=NC(N4CCOCC4)=N2)C=C1)NC5=CC=C(C(N6CCC(N(C)C)CC6)=O)C=C5

 Journal of Medicinal Chemistry (2017), 60(17), 7524-7538 PQR 309

FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome


FDA approves first drug for Eosinophilic Granulomatosis with Polyangiitis, a rare disease formerly known as the Churg-Strauss Syndrome

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA. Continue reading.

December 12, 2017

Release

The U.S. Food and Drug Administration today expanded the approved use of Nucala (mepolizumab) to treat adult patients with eosinophilic granulomatosis with polyangiitis (EGPA), a rare autoimmune disease that causes vasculitis, an inflammation in the wall of blood vessels of the body. This new indication provides the first FDA-approved therapy specifically to treat EGPA.

According to the National Institutes of Health, EGPA (formerly known as Churg-Strauss syndrome) is a condition characterized by asthma, high levels of eosinophils (a type of white blood cell that helps fight infection), and inflammation of small- to medium-sized blood vessels. The inflamed vessels can affect various organ systems including the lungs, gastrointestinal tract, skin, heart and nervous system. It is estimated that approximately 0.11 to 2.66 new cases per 1 million people are diagnosed each year, with an overall prevalence of 10.7 to 14 per 1,000,000 adults.

“Prior to today’s action, patients with this challenging, rare disease did not have an FDA-approved treatment option,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research. “The expanded indication of Nucala meets a critical, unmet need for EGPA patients. It’s notable that patients taking Nucala in clinical trials reported a significant improvement in their symptoms.”

The FDA granted this application Priority Review and Orphan Drug designations. Orphan Drug designation provides incentives to assist and encourage the development of drugs for rare diseases.

Nucala was previously approved in 2015 to treat patients age 12 years and older with a specific subgroup of asthma (severe asthma with an eosinophilic phenotype) despite receiving their current asthma medicines. Nucala is an interleukin-5 antagonist monoclonal antibody (IgG1 kappa) produced by recombinant DNA technology in Chinese hamster ovary cells.

Nucala is administered once every four weeks by subcutaneous injection by a health care professional into the upper arm, thigh, or abdomen.

The safety and efficacy of Nucala was based on data from a 52-week treatment clinical trial that compared Nucala to placebo. Patients received 300 milligrams (mg) of Nucala or placebo administered subcutaneously once every four weeks while continuing their stable daily oral corticosteroids (OCS) therapy. Starting at week four, OCS was tapered during the treatment period. The primary efficacy assessment in the trial measured Nucala’s treatment impact on disease remission (i.e., becoming symptom free) while on an OCS dose less than or equal to 4 mg of prednisone. Patients receiving 300 mg of Nucala achieved a significantly greater accrued time in remission compared with placebo. A significantly higher proportion of patients receiving 300 mg of Nucala achieved remission at both week 36 and week 48 compared with placebo. In addition, significantly more patients who received 300 mg of Nucala achieved remission within the first 24 weeks and remained in remission for the remainder of the 52-week study treatment period compared with patients who received the placebo.

The most common adverse reactions associated with Nucala in clinical trials included headache, injection site reaction, back pain, and fatigue.

Nucala should not be administered to patients with a history of hypersensitivity to mepolizumab or one of its ingredients. It should not be used to treat acute bronchospasm or status asthmaticus. Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, rash, have occurred. Patients should discontinue treatment in the event of a hypersensitivity reaction. Patients should not discontinue systemic or inhaled corticosteroids abruptly upon beginning treatment with Nucala. Instead, patients should decrease corticosteroids gradually, if appropriate.

Health care providers should treat patients with pre-existing helminth infections before treating with Nucala because it is unknown if Nucala would affect patients’ responses against parasitic infections. In addition, herpes zoster infections have occurred in patients receiving Nucala. Health care providers should consider vaccination if medically appropriate.

The FDA granted approval of Nucala to GlaxoSmithKline.

//////////////Nucala, mepolizumab, fda 2017, gsk,  Eosinophilic Granulomatosis, Polyangiitis, Churg-Strauss Syndrome, Priority Review, Orphan Drug

FEVIPIPRANT


Fevipiprant.svg

Fevipiprant.png

FEVIPIPRANT

Molecular Formula: C19H17F3N2O4S
Molecular Weight: 426.41 g/mol

UNII-2PEX5N7DQ4; 2PEX5N7DQ4; NVP-QAW039; QAW039;

CAS 872365-14-5

Product patent WO2005123731A2, NOVARTIS

Image result for novartis

2-[2-methyl-1-[[4-methylsulfonyl-2-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-b]pyridin-3-yl]acetic acid

  • 2-Methyl-1-[[4-(methylsulfonyl)-2-(trifluoromethyl)phenyl]methyl]-1H-pyrrolo[2,3-b]pyridine-3-acetic acid
  • [1-(4-((Methane)sulfonyl)-2-trifluoromethylbenzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]acetic acid

Fevipiprant (INN; code name QAW039) is a drug being developed by Novartis which acts as a selective, orally available antagonistof the prostaglandin D2 receptor 2 (DP2 or CRTh2).[1][2][3]

As of 2016, it is in Phase III[4] clinical trials for the treatment of asthma.[5]

Novartis is developing fevipiprant, a prostaglandin D2 receptor (PD2/CRTh2) antagonist, as an oral capsule formulation for treating asthma and moderate to severe atopic dermatitis.

Image result for FEVIPIPRANT

Inventors Kamlesh BalaCatherine LeblancDavid Andrew SandhamKatharine Louise TurnerSimon James WatsonLyndon Nigel BrownBrian Cox
Applicant Novartis AgNovartis Pharma Gmbh

PATENT

WO2005123731

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005123731

PATENT

CN 106188040

The invention discloses a Fevipiprant and Fevipiprant intermediate preparation method. The method is characterized in that 2-amino-3-bromopyridine and 4-mesyl-2-trifluoromethylbenzaldehyde to condensation reaction to obtain a Schiff base intermediate, then performing reduction reaction to obtain 3-bormo-N-(4-(mesyl)-2-(trifluoromethyl)phenyl)-pyridine-2-amine, subjecting the 3-bormo-N-(4-(mesyl)-2-(trifluoromethyl)phenyl)-pyridine-2-amine to ullmann ring closing reaction with methyl levulinate or ethyl levulinate, and performing saponification reaction or decarboxylic reaction to obtain Fevipiprant namely N[1-(4-((methane)sulfonyl)-2-trifluoromethylphenyl-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-yl] acetic acid. The Fevipiprant and Fevipiprant intermediate preparation method which is a brand new method is short in step, technically convenient in operation, easy in product purification and large-scale production, high yield can be achieved, and Fevipiprant industrial production can be realized easily.

Example 5: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0056] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40 · 9g, 0 · lmo 1) and levulinic acid A ester (13.0g, 0. lmo 1) was added 300 mL N, N- dimethylformamide, was added copper iodide (1 · 9g, 0 · 0lmo 1) and N, N- dimethylglycine (1.0g , 0.01 mol), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, water was added 200mL of saturated sodium chloride solution was cooled and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water , was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give the crude product after recrystallization from ethanol in pure 34.5g, yield 81%.

[0057] · ΜΚ (300ΜΗζ, (16-0Μ50) δ: 12 · 3 (ΐ3Γ, 1Η, α) 2Η), 8.24 (s, lH, PhH), 8.11 ~ 8.12 (d, lH, PhH), 8.00 ~ 8.02 (d, lH, PyH), 7.91 ~ 7.93 (d, lH, PyH), 7.09 ~ 7.10 (d, lH, PhH), 6.46 ~ 6.48 (d, lH, PhH), 5.73 (s, 2H, NCH2) , 3.70 (s, 2H, q ^ C〇2H), 3.30 (s, 3H, CH 3).

[0058] HPLC: 99.9%.

[0059] Example 6: N [l- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0060] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – (. 40.9g, 0 lmo 1) pyridin-2-amine and acetyl malonate methyl ester (18.8g, 0. lmol) was added 300 mL N, N- dimethylformamide, was added copper iodide (1.9g, O.Olmol) and N, N- dimethylglycine (1. (^ , 0.01111〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 1211, 200mL saturated brine was added after cooling, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL of water, was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol, a crude product was obtained from ethanol crystallized to give pure 34. lg, 80% yield.

[0061] HPLC: 99.8%.

[0062] Example 7: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0063] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40 · 9g, 0 · lmo 1) and levulinic acid A ester (13. (^, 0.1111〇1) was added ^ 3,001,111, 1-dimethyl formamide, was added copper iodide (3.88,0.02111〇1) and N, N- dimethylglycine (2. (^, 0.02111〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 1211, 200mL saturated brine was added after cooling, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water , was added sodium hydroxide (8g, 0.2mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure 34. lg, 80% yield billion

[0064] HPLC: 99.9%.

[0065] Example 8: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0066] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 300mL N, N- two after dimethylformamide, was added copper iodide (1.9g, 0.01mol) and 2,2,6,6-tetramethyl-heptane-3,5-dione (3.6g, 0.02mo 1), purged with nitrogen , the reaction temperature was raised to 120 degrees 12h, water was added 200mL of saturated sodium chloride solution was cooled and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water was added sodium hydroxide (8g , 0.2 mol) the reaction temperature was raised to 60 degrees 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 30.2 g, yield 71%.

[0067] HPLC: 99.6%.

[0068] Example 9: Ν [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] P ratio preparation of 3-yl] acetic acid (1).

[0069] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 1’1 ^ 3,001,111, 1 ‘| – dimethylformamide, was added copper iodide (1.98,0.011] 1〇1) and proline (1.28,0.011] 1〇1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, after cooling, 200mL saturated brine, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL ethanol and 100mL water was added sodium hydroxide (8g, 0.2mol) was heated to 60 degrees reaction 2h, cooled to 0 ° C, acidified with 4N hydrochloric acid was added dropwise to pH 2, was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 33.2 g, 78% yield.

[0070] HPLC: 99.8%.

[0071] Example 10: N [1- (4 – ((methane) sulfonyl) -2-trifluoromethyl-phenyl) -2-methyl -1H- pyrrolo [2,3-b] pyridin – preparation of 3- yl] acetic acid (1).

[0072] 3-Bromo -N- (4- (methylsulfonyl) -2- (trifluoromethyl) phenyl) – pyridin-2-amine (40.9 8,0.1111〇1) was added 300mL N, N- two after dimethylformamide, was added copper iodide (1.9g, 0. Olmol) and N, N- dimethylglycine (1.0g, 0.01 mo 1), after nitrogen substitution, the reaction temperature was raised to 120 degrees 12h, cooled was added 200mL saturated brine, and extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated to give a pale yellow powder, was added 100mL of acetic acid and 100mL of concentrated hydrochloric acid was heated to reflux for 6h, cooled to 0 ° C, was added 100mL water analysis crystal was filtered and the solid washed with ethanol to give crude product was recrystallized from ethanol to give pure product 33.2 g, 78% yield.

[0073] HPLC: 99.1%.

PATENT

WO 2017056001

Example 3b: Preparation of Compound A

Production of C8: Compound C6, (3-[2-({[4-Methanesulfonyl-2-(trifluoromethyl)-phenyl]methyl}amino)pyridin-3-yl]prop-2-yn-l-ol) (20 g, 52 mmol) was dissolved in a mixture of methyl isobutyl ketone (MIBK, 125 g), 25.3 g (156 mmol) of 1 , 1 , 1 -triethoxy ethane, and acetic acid (0.625 g, 10 mmol). The mixture was heated within 40 minutes to 140 °C under a N2 over-pressure of 1 – 4 bar. During the reaction ethanol was formed and removed from the vessel by a pressure-regulated valve. After 3.5 h a second portion of acetic acid (0.625g) was added and the mixture was heated for 3.5 h at 140 °C under a N2 over-pressure of 1 – 4 bar. The resultant product was a solution of Ethyl 2-(l- {[4-methanesulfonyl-2-(trifluoromethyl)phenyl]methyl}-2-methyl-lH-pyrrolo[2,3-¾]pyridin-3-yl)acetate and the conversion rate was measured at 98% and the yield 90%. The solution was filtered and 40 g MIBK was added. The solution was heated to IT=80 °C and cooled down within 3 h to

IT=20 °C. At an IT of 65 °C seed crystals were added. At IT 20 °C intermediate C8 was isolated and washed with 40 g MIBK and dried in the oven at IT=60°C/20mbar.

Conversion to Compound A: The intermediate C8 was concentrated under vacuum at

100 °C/200 mbar and water (6000ml). A sodium hydroxide solution (1734 g, 30%, 13 mol) was added to the mixture and heated for 4 h at 50 °C. The solution was distilled again at 100 °C/100 mbar. The phases were separated at 50 °C and the water phase was extracted with methyl isobutyl ketone (2000 ml). Again the phases were separated and the water phase was filtered at 50 °C. To the filtrate methyl isobutyl ketone (5000 ml) was added and the aqueous solution neutralized in 2 portions with hydrochloric acid (963 g, 37%, 9.8 mol) to pH 4 – 4.5. The phases were heated to 80 °C and the organic phases separated. Water (1000 ml) was added to wash the organic phase and after phase separation the organic phase was cooled down to 70 °C. Seed crystals of Compound A were added along with heptane (1000 ml). The resulting suspension was stirred for 30 minutes before cooling further down to 0 °C within 3 h. The suspension was stirred for 3 h at 0 °C and then filtered through a nutsche. The filter cake was washed first with pre-cooled HPTF/methyl isobutyl ketone (1000 g, 5: 1), then with acetone/water (1000 g, 1 :2) and finally with water (1000 g). Wet Compound A was dried in the oven at 60 °C for 8 h under vacuum to isolate 804 g of compound A. The conversion was calculated to be 99%; the yield was 79%.

Example 3 c: Alternative Preparation of Compound A

Molecular Weight: 426 41

Exact Mass: 384.08 Molecular Weight: 453.48

5 g of (3-[2-({[4-Methanesulfonyl-2-(trifluoromethyl)-phenyl]methyl}amino)pyridin-3-yl]prop-2-yn-l-ol), methyl isobutyl ketone (MIBK, 50 ml), and 1 , 1 -dimethoxy-N,N-dimethylethanamine were put together in a 200 ml reactor and stirred for 15 h at 100 °C. The mixture was acidified by addition of hydrochloric acid (15 ml) and kept stirring for 15 h at 100 °C. Then water (25 ml) was added, and the temperature was decreased to 50 °C. Caustic soda (about 15 ml) was added to set the pH around 12. Then, after phase split and a second extraction with water (10 ml), the combined aqueous phases were diluted with methyl isobutyl ketone (25 ml) and acidified at 80 °C to pH 4 with hydrochloric acid. The mixture was cooled to 70 °C, seeded and cooled to 0 °C within 2 h. After 2 h aging at 0 °C, the crystalline solid was collected by filtration, washed with methyl isobutyl ketone (10 ml) and water (10 ml), and dried under vacuum at 60 °C until constant weight. Yield 2.93 g.

PATENT

WO-2017210261

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017210261&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel deuterated analogs of pyrrolo[2,3-b]pyridine compounds, particularly fevipiprant and their salts and compositions and combination comprising them are claimed. Also claims is their use for treating asthma, allergic rhinitis and atopic dermatitis. Compounds are claimed to be a prostaglandin D2 receptor 2 antagonist. Represents first PCT filing from CoNCERT Pharmaceuticals and the inventor on this API.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(5), 582-586

Discovery of Fevipiprant (NVP-QAW039), a Potent and Selective DP2Receptor Antagonist for Treatment of Asthma

Novartis Institutes for Biomedical Research, Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, United Kingdom
ACS Med. Chem. Lett.20178 (5), pp 582–586
DOI: 10.1021/acsmedchemlett.7b00157
*E-mail: david.sandham@novartis.com. Tel: + 1 (617)-871-8000.

Abstract

Abstract Image

Further optimization of an initial DP2 receptor antagonist clinical candidate NVP-QAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11, NVP-QAW039, fevipiprant), which exhibits improved potency on human eosinophils and Th2 cells, together with a longer receptor residence time, and is currently in clinical trials for severe asthma.

RM  sodium methanesulfinate and 4-fluoro-2-(trifluoromethyl)benzaldehyde

Step 1:

4-(methylsulfonyl)-2-(trifluoromethyl)benzaldehyde

A suspension of sodium methanesulfinate (29.6 g, 290 mmol) and 4-fluoro-2-(trifluoromethyl)benzaldehyde (50 g, 260 mmol) in DMSO (200 ml) was heated at 90˚C overnight. The thick yellow suspension was poured onto crushed ice (ca 800 g), diluted with water and the solid reside collected by filtration, washed with water and dried in vacuo to afford 4- (methylsulfonyl)-2-(trifluoromethyl)benzaldehyde as an off-white solid (50.7 g, 77%). LRMS mass ion not detected. 1H NMR (CDCl3) 3.14 (3H s), 8.30 (1H d J=7.5), 8.36 (1H d J=7.5), 8.40 (1H s), 10.49 (1H s).

Step 2:

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol

(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)methanol as an off-white solid (50.7 g, 99%). LRMS mass ion not detected. 1H NMR (CDCl3) 3.11 (3H s), 5.02 (2H s), 8.09 (1H d J=7.5), 8.19 (1H d J=7.5), 8.25 (1H s).

STEP 3

1-(bromomethyl)-4-(methylsulfonyl)-2-(trifluoromethyl)benzene

1-(bromomethyl)-4-(methylsulfonyl)-2- (trifluoromethyl)benzene (47.1 g, 74%) as a white solid. LRMS mass ion not detected. 1H NMR (CDCl3) 3.11 (3H s), 4.67 (2H s), 7.86 (1H d J=7.5), 8.14 (1H d J=7.5), 8.25 (1H s).

STEP 4

methyl 2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate

(83:17) of methyl 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetate (N-1 product) and methyl 2-(2-methyl-7-(4- (methylsulfonyl)-2-(trifluoromethyl)benzyl)-7H-pyrrolo[2,3-b]pyridin-3-yl)acetate (N-7 product) as a white solid (22.5 g 42%). LRMS C20H19F3N2O4S requires M+ 440.4 found [MH]+ m/z 441. 1H NMR (CDCl3) 2.27 (3H s), 3.06 (3H s N-1 product), 3.11 (3H s N-7 product), 3.72 (3H s), 3.77 (2H s), 5.03 (2H s N-7 product), 5.82 (2H s N-1 product), 6.66 (1H d J=8.2), 7.16 (1H dd J=7.8, 4.8), 7.91 (1H d, J=8.3), 7.95 (1H d J=7.7), 8.12 (1H d J=7.8 N-7), 8.19 (1H d J=8.1 N-7), 8.17 (1H s N-7), 8.27 (1H d J=3.6), 8.30 (1H s).

FINAL

2-(2-methyl-1-(4-(methylsulfonyl)-2-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid 11 as needles, m.p. 208˚C (16.3 g, 44%). HRMS C19H18F3N2O4S requires [MH]+ 427.0939 found [MH]+ 427.093. 1H NMR (500 MHz, DMSO-d6) 2.28 (3H s), 3.28 (3H s), 3.73 (2H s), 5.76 (2H s), 6.49 (1H d J=8.3), 7.12 (1H dd J=7.7, 4.8), 7.95 (1H d J=7.8), 8.04 (1H d, J=8.3), 8.14 (1H d J=4.7), 8.26 (1H s), 12.28 (1H br s ). Elemental analysis calcd. for C19H17F3N2O4S: C, 53.52; H, 4.02; N, 6.57; S, 7.52%. Found C, 53.90 ± 0.04; H, 4.28 ± 0.06; N, 6.43 ± 0.02; S, 7.76 ± 0.09%.

PAPER

Drug Metabolism & Disposition (2017), 45(7), 817-825

Patent ID

Patent Title

Submitted Date

Granted Date

US9169251 PYRROLOPYRIDINE DERIVATIVES AND THEIR USE AS CRTH2 ANTAGONISTS
2014-06-26
2014-10-16
Patent ID

Patent Title

Submitted Date

Granted Date

US2016108123 ANTIBODY MOLECULES TO PD-L1 AND USES THEREOF
2015-10-13
2016-04-21
US8455645 Organic compounds
2010-08-19
US8470848 Organic compounds
2010-08-12
US7666878 Pyrrolopyridine Derivatives And Their Use As Crth2 Antagonists
2008-05-15
2010-02-23
US8791256 Pyrrolopyridine derivatives and their use as CRTH2 antagonists
2013-06-05
2014-07-29

References

  1. Jump up to:a b Erpenbeck VJ, Vets E, Gheyle L, Osuntokun W, Larbig M, Neelakantham S, et al. (2016). “Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo-Controlled Studies in Healthy Volunteers”Clin Pharmacol Drug Dev5 (4): 306–13. doi:10.1002/cpdd.244PMC 5071756Freely accessiblePMID 27310331.
  2. Jump up^ Sykes DA, Bradley ME, Riddy DM, Willard E, Reilly J, Miah A, Bauer C, Watson SJ, Sandham DA, Dubois G, Charlton SJ. Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy. Mol Pharmacol. 2016 May;89(5):593-605. doi: 10.1124/mol.115.101832 PMID 26916831
  3. Jump up^ Erpenbeck VJ, Popov TA, Miller D, Weinstein SF, Spector S, Magnusson B, et al. (2016). “The oral CRTh2 antagonist QAW039 (fevipiprant): A phase II study in uncontrolled allergic asthma”. Pulm Pharmacol Ther39: 54–63. doi:10.1016/j.pupt.2016.06.005PMID 27354118.
  4. Jump up^ https://clinicaltrials.gov/ct2/show/NCT02555683
  5. Jump up^ Gonem S, Berair R, Singapuri A, Hartley R, Laurencin M, Bacher G, et al. (2016). “Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial”. Lancet Respir Med4: 699–707. doi:10.1016/S2213-2600(16)30179-5
Fevipiprant
Fevipiprant.svg
Clinical data
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Bioavailability Unaffected by food[1]
Metabolism Hepatic glucuronidation
Biological half-life ~20 hours
Excretion Renal (≤30%)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C19H17F3N2O4S
Molar mass 426.41 g/mol
3D model (JSmol)

////////////////FEVIPIPRANT, QAW039, PHASE 3, asthma, UNII-2PEX5N7DQ4,2PEX5N7DQ4, NVP-QAW039, QAW039, 872365-14-5,

CC1=C(C2=C(N1CC3=C(C=C(C=C3)S(=O)(=O)C)C(F)(F)F)N=CC=C2)CC(=O)O

FDA approves Admelog, the first short-acting “follow-on” insulin product to treat diabetes


FDA approves Admelog, the first short-acting “follow-on” insulin product to treat diabetes

 

The U.S. Food and Drug Administration today approved Admelog (insulin lispro injection), a short-acting insulin indicated to improve control in blood sugar levels in adults and pediatric patients aged 3 years and older with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. Admelog is the first short-acting insulin approved as a “follow-on” product (submitted through the agency’s 505(b)(2) pathway). Continue reading.

 

December 11, 2017

Release

The U.S. Food and Drug Administration today approved Admelog (insulin lispro injection), a short-acting insulin indicated to improve control in blood sugar levels in adults and pediatric patients aged 3 years and older with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. Admelog is the first short-acting insulin approved as a “follow-on” product (submitted through the agency’s 505(b)(2) pathway).

According to the Centers for Disease Control and Prevention, more than 30 million people in the U.S. have diabetes, a chronic disease that affects how the body turns food into energy and the body’s production of natural insulin. Over time, diabetes increases the risk of serious health complications, including heart disease, blindness, and nerve and kidney damage. Improvement in blood sugar control through treatment with insulin, a common treatment, can reduce the risk of some of these long-term complications.

“One of my key policy efforts is increasing competition in the market for prescription drugs and helping facilitate the entry of lower-cost alternatives. This is particularly important for drugs like insulin that are taken by millions of Americans every day for a patient’s lifetime to manage a chronic disease,” said FDA Commissioner Scott Gottlieb, M.D. “In the coming months, we’ll be taking additional policy steps to help to make sure patients continue to benefit from improved access to lower cost, safe and effective alternatives to brand name drugs approved through the agency’s abbreviated pathways.”

Admelog was approved through an abbreviated approval pathway under the Federal Food, Drug, and Cosmetic Act, called the 505(b)(2) pathway. A new drug application submitted through this pathway may rely on the FDA’s finding that a previously approved drug is safe and effective or on published literature to support the safety and/or effectiveness of the proposed product, if such reliance is scientifically justified. The use of abbreviated pathways can reduce drug development costs so products can be offered at a lower price to patients. In the case of Admelog, the manufacturer submitted a 505(b)(2) application that relied, in part, on the FDA’s finding of safety and effectiveness for Humalog (insulin lispro injection) to support approval. The applicant demonstrated that reliance on the FDA’s finding of safety and effectiveness for Humalog was scientifically justified and provided Admelog-specific data to establish the drug’s safety and efficacy for its approved uses. The Admelog-specific data included two phase 3 clinical trials which enrolled approximately 500 patients in each.

Admelog is a short-acting insulin product, which can be used to help patients with diabetes control their blood sugar. Short-acting insulin products are generally, but not always, administered just before meals to help control blood sugar levels after eating. These types of insulin products can also be used in insulin pumps to meet both background insulin needs as well as mealtime insulin needs. This is in contrast to long-acting insulin products, like insulin glargine, insulin degludec and insulin detemir, which are generally used to provide a background level of insulin to control blood sugars between meals, and are administered once or twice a day. While both types of insulin products can play important roles in the treatment of types 1 and 2 diabetes mellitus, patients with type 1 diabetes require both types of insulin while patients with type 2 diabetes may never need a short-acting insulin product.

“With today’s approval, we are providing an important short-acting insulin option for patients that meets our standards for safety and effectiveness,” said Mary T. Thanh Hai, M.D., deputy director of the Office of New Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research.

Admelog can be administered by injection under the skin (subcutaneous), subcutaneous infusion (i.e., via insulin pump), or intravenous infusion. Dosing of Admelog should be individualized based on the route of administration and the patient’s metabolic needs, blood glucose monitoring results and glycemic control goal.

The most common adverse reactions associated with Admelog in clinical trials was hypoglycemia, itching, and rash. Other adverse reactions that can occur with Admelog include allergic reactions, injection site reactions, and thickening or thinning of the fatty tissue at the injection site (lipodystrophy).

Admelog should not be used during episodes of hypoglycemia (low blood sugar) or in patients with hypersensitivity to insulin lispro or one of its ingredients. Admelog SoloStar prefilled pens or syringes must never be shared between patients, even if the needle is changed.

Patients or caregivers should monitor blood glucose in all patients treated with insulin products. Insulin regimens should be modified cautiously and only under medical supervision. Admelog may cause low blood sugar (hypoglycemia), which can be life-threatening. Patients should be monitored more closely with changes to insulin dosage, co-administration of other glucose-lowering medications, meal pattern, physical activity and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness.

Accidental mix-ups between insulin products can occur. Patients should check insulin labels before injecting the insulin product.

Severe, life-threatening, generalized allergic reactions, including anaphylaxis, may occur.

Health care providers should monitor potassium levels in patients at risk of hyperkalemia, a serious and potentially life-threatening condition in which the amount of potassium in the blood is too high.

Admelog received tentative approval from the FDA on Sept. 1, 2017 and is now being granted final approval.

The approval of Admelog was granted to Sanofi-Aventis U.S.

///////////////FDA2017,  Admelog, insulin,  diabetes, insulin lispro, Sanofi-Aventis

PH 46A


str1str1SCHEMBL14669646.png

PH 46A

cas  1421332-97-9

C27 H24 O3, 396.48

Benzoic acid, 4-[[(1S,2S)-2,3-dihydro-1-hydroxy[2,2′-bi-1H-inden]-2-yl]methyl]-, methyl ester
Methyl 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1’H-[2,2′-biinden]-2-yl)methyl)benzoate
str1
FREE ACID CAS  1380445-03-3, Benzoic acid, 4-[[(1S,2S)-2,3-dihydro-1-hydroxy[2,2′-bi-1H-inden]-2-yl]methyl]-
str1
N-Methyl-(D)-Glucamine salt (NMDG)
1380445-04-4
C26 H22 O3 . C7 H17 N O5
D-Glucitol, 1-deoxy-1-(methylamino)-, 4-[[(1S,2S)-2,3-dihydro-1-hydroxy[2,2′-bi-1H-inden]-2-yl]methyl]benzoate (1:1)
PH46A, belonging to a class of 1,2-Indane dimers, has been developed by  Trino Therapeutics Ltd research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases
The new chiral chemical entity PH46A, 6-(methylamino)hexane-1,2,3,4,5-pentanol 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2-biinden]-2-yl)methyl)benzoate, was previously synthesized research group(1X) and shown to have potential therapeutic activity in the areas of inflammation and autoimmune diseases, including inflammatory bowel disease.(2X) PH46A recently completed a first-in-man Phase I clinical trial study.(3X)
  1. 1X  FramptonC.-S.ZhangT.ScalabrinoG.FrankishN.SheridanH. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 201268o323 DOI: 10.1107/S0108270112031265

  2. 2X FrankishN.SheridanH. J. Med. Chem. 2012555497 DOI: 10.1021/jm300390f

  3. 2X TherapeuticsT. A study to assess the safety and tolerability of PH46A in healthy volunteers, to measure drug levels in these subjects and to determine the effect of food on the drug’s absorption. BioMed Central: ISRCTN Registry, EudraCT: 2013-003717-17, 2014.
PH 46A
  • Originator Trino Therapeutics
  • Class Anti-inflammatories; Benzoates; Indans; Muscle relaxants; Small molecules
  • Mechanism of Action Mast cell stabilisers
  • Orphan Drug Status No
  • New Molecular Entity Yes

Highest Development Phases

  • Phase I Ulcerative colitis

Most Recent Events

  • 31 Aug 2014 Trino Therapeutics completes a phase I trial in Ulcerative colitis (In volunteers) in United Kingdom (ISRCTN90725219)
  • 07 Feb 2014 Phase-I clinical trials in Ulcerative colitis (in volunteers) in United Kingdom (PO)
  • 04 Jun 2012 Pharmacodynamics data from a preclinical trial in Ulcerative colitis released by Trino Therapeutics

Cytokines can be produced by various cell populations and have been shown to augment or limit immune responses to pathogens and influence the autoimmune response. One family of cytokines, which uses the common receptor gamma chain (cc), a component of receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21, has been classically defined as growth and survival factors.

IL-2 production can induce an immune response by promoting the proliferation and generation of CD4+ Thl, CD4+ Th2 and CD8+ CTL effector cells. Many of the immunosuppressive drugs used in the treatment of autoimmune diseases and organ transplant rejection, such as corticosteroids and immune suppressive drugs (ciclosporin, tacrolimus) work by inhibiting the production of IL-2 by antigen -activated T cells. Others (sirolimus) block IL-2R signalling, thereby preventing the clonal expansion and function of antigen-selected T cells [ref: Opposing functions of IL-2 and IL-7 in the regulation of immune responses Shoshana D. Katzman, Katrina . Hoyer, Hans Dooms, Iris K. Gratz, Michael D. Rosenblum, Jonathan S. Paw, Sara H. Isakson, Abul K. Abbas. Cytokine 56 (201 1) 1 16-121]

In contrast IL-2 can inhibit the immune response by promoting the survival and functionality of natural (thymic) regulatory T-cells (Tregs), promoting the generation of induced (peripheral) Tregs and inhibiting the generation of CD4+ Thl 7 effector cells [ref: IL-2 and autoimmune disease. Anneliese Schimpl , A., Berberich, I, Kneitz, B., Kramer, S., Santner-Nanan, B., Wagner, S., Wolf, M., Hunig, T. Cytokine & Growth Factor Reviews 13 (2002) 369-378]. Interleukin-2/IL-2R deficiency with time leads to multiorgan inflammation and the formation of autoantibodies of various specificities. Depending on the genetic background, death occurs within a few weeks to a few months, mostly from autoimmune hemolytic anemia or inflammatory bowel disease (IBD) [ref. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 1993;75:253-61]. IL-2 signalling has been shown to be important in both the initiation and regulation of immune responses. In these dual and opposing roles, IL-2 acts to balance immune response, both driving immune cell activation and subsequent reduction. The potential clinical applicability of either augmenting or inhibiting signals mediated by IL-2 is significant and includes cancer, autoimmune inflammatory diseases, organ transplantation and HIV.

Inflammatory bowel disease (IBD) is an autoimmune inflammatory disease that consists of two idiopathic inflammatory diseases, ulcerative colitis (UC) and Crohn’s disease (CD). The greatest distinction between UC and CD is the range of inflamed bowel tissue. Inflammation in CD is discontinuously segmented, known as regional enteritis, while UC is superficial inflammation extending proximally and continuously from the rectum. At present, the exact cause of IBD is unknown. The disease seems to be related to an exaggerated mucosal immune response to infection of the intestinal epithelium because of an imbalance of pro- inflammatory and immune- regulatory molecules. The inheritance patterns of IBD suggest a complex genetic component of pathogenesis that may consist of several combined genetic mutations. Currently no specific diagnostic test exists for IBD, but as an understanding of pathogenesis is improved so will the corresponding testing methods. Treatment of IBD consists of inducing and maintaining remission. IBD patients may be maintained on remission by use of a 5-aminosalycilate. However, while the use of aminosalycilates in UC provides considerable benefit, both in inducing remission in mild to moderate disease and in preventing relapse, the usefulness of these drugs to maintain remission in CD is questionable and is no longer recommended. The mainstay of treatment of active disease is a corticosteroid, commonly used for limited periods to return both UC and CD patients to remission, though budesonide, designed for topical administration with limited systemic absorption, has no benefit in maintaining remission. Alternatives, such as the immunosuppressive drugs azathioprine and mercaptopurine, together with methotrexate and cyclosporine have limited efficacy and the capability of inducing grave adverse effects. Anti- TNFa antibodies, such as infliximab and adalimubab, may be used in those patients unresponsive to standard immunosuppressive therapy. However, many patients fail to respond to anti-TNFa therapy, either due to their particular phenotype or by the production of autoantibodies.

Inventors Helen SheridanNeil Frankish
Applicant Venantius Limited

PATENTS

WO 2013014660

https://encrypted.google.com/patents/WO2013014660A1?cl=en

Compound 6: The N-Methyl-(D)-Glucamine salt (NMDG) of compound 2.

Figure imgf000035_0001

Compound 6 physiochemical properties:

Appearance: Off-white solid

Molecular Weight: 577 (free acid: 382)

Molecular Formula: C33H39O8N (free acid: C26H2203)

Melting Point: 165-167 °C

Compound 6: [a]D:-76.5 (sample concentration: 200 mg/10 ml in Water)

Mass (Da): ES+ only [NMDG+Na] was visible

Elemental analysis: Calc: C (68.61), H (6.80), N (2.42), O (22.16). Found: C (68.44), H

(6.80), N (2.50), 0 (21.98) δΗ(400 MHz, DMSO-d6): 2.48 (3H, apparent s, NCH3), 2.65 (1H, d, J=13.56 Hz, HCH), 2.84-

3.02 (4H, m), 3.16 (1H, d, J= 13.60 Hz, HCH), 3.40-3.70 (7H, m), 3.85-3.92 (l H, m), 5.06 (1H, s, CH-OH), 5.93 (1H, broad s, CH- OH), 6.41 (1H, f, .CH=C), 6.80 (2H, d, J=7.92 Hz, Ar-H), 7.06-7.41 (8H, m, Ar-H), 7.64 (2H, d, J=7.80 Hz, Ar-H).

6c(100 MHz, DMSO): 33.8 (CH3), 37.9 (CH2), 38.2 (CH2), 39.5 (CH2), 51.6 (CH2-N), 55.8

(quat. C), 63.5 (CH2-0), 69.0 (CH-O), 70.3 (CH-O), 70.6 (CH-O), 71.3 (CH-O), 81.1 (CH-OH), 120.1 (tert. C), 123.4 (tert. C), 123.7 (tert. C), 124.3 (tert. C), 124.4 (tert. C), 126.1 (tert. C), 126.3 (tert. C), 127.0 (tert. C), 127.5 (tert. C), 2 x 128.5 (2 x tert. C), 2 x 129.1 (2 x tert. C), 140,4 (quat. C), 141.1 (quat. C), 142.9 (quat. C), 144.5 (quat. C), 145.2 (quat. C), 154.3 (quat. C), 170.4 (C=0).

Synthesis of methyl 4- (lS,2S)-l-hvdroxy-2,3-dihvdro-lHJ’H-f2,2′-biinden1-2-yl)methyl) benzoate (17):

Figure imgf000042_0002

To a solution of 4-(((15,25)-l-hydroxy-2,3-dihydro-lH, l’H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol) and K2C03 (72 mg, 0.52 mmol) in DMF (2.5 mL), was added Mel (148 mg, 1.04 mmol) and then stirred at room temperature for 4 h. The reaction mixture was diluted with 1.5 N HCI (50 mL) and extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with 10 % aq. NaHC03 (25 mL), brine (25 mL), dried over anhydrous Na2S04 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20 % ethyl acetate in chloroform as an eluent to yield 62 mg (59 %) of the title compound as an off white solid.

LCMS (-OH): observed 379.2, calculated 396.17, molecular formula C27H2403

Purity (HPLC): 97 %.

Ή NMR (400 MHz, CDC13): 6 2.84 (1H, d, J = 13.28 Hz, ¾), 3.00 (1H, d, J = 15.64 Hz, CH2), 3.05 (1H, d, J = 15.56 Hz, CPb), 3.27 (lH, d, J = 13.32 Hz, CH ), 3.45 (1H, d, J = 22.52 Hz, CH2), 3.57 (1H, d, J = 22.60 Hz, CH2), 3.89 (3H, s, OCH3), 5.25 (1H, s, CHQH), 6.47 (1H, s, CH=C), 6.96 (2H, d, J = 8.24 Hz, Ar-H), 7.17 (1H, dt, J = 2.04, 9.88 Hz, Ar-H), 7.24-7.33 (5H, m, Ar-H), 7.43 (2H, d, J = 7.60 Hz, Ar-H), 7.83 (2H, dd, J = 1.76, 6.60 Hz, Ar-H).

PATENT

WO 2013174916

PATENT

US 9260376

US 20150141506

PH 46A (S,S & R,R) racemic

Melting point 141–143 °C. 1H NMR (400 MHz, CDCl3) δH (ppm) 6.99 (d, J = 7.72 Hz, 2H), 7.46 (d, J = 7.04 Hz, 2H), 7.20–7.31 (m, 6H), 6.97 (d, J = 7.80 Hz, 2H), 6.50 (s, 1H), 5.29 (d, J = 24.16 Hz, 1H), 3.91 (s, 3H), 3.60 (d, J = 22.68 Hz, 1H), 3.48 (d, J = 22.88 Hz, 1H), 3.28 (d, J = 13.24 Hz, 1H), 3.06 (d, J = 15.64 Hz, 1H), 3.51 (d, J = 16.00 Hz, 1H), 2.86 (d, J = 13.28 Hz, 1H). 13C NMR (100 MHz, CDCl3) δC (ppm) 166.9, 152.3, 144.1, 143.9, 143.4, 142.4, 140.0, 2 × 129.8, 2 × 128.6, 128.1, 128.0, 127.5, 126.6, 126.0, 124.4, 123.9, 123.6, 123.2, 120.2, 82.4, 55.5, 51.6, 39.6, 38.2, 38.0. HRMS (ESI) m/z calculated for C27H24O3 (M + Na)+ , 419.1606; found, 419.1618. Achiral HPLC: Zorbax C18 XDB (150 x 4.6 mm), 20:80:0.1 (v:v:v) water:MeOH:TFA, 1.0 mL/min, 254 nm, RT: 4.31 min. Chiral HPLC: Chiralpak IC, 90:10:0.1 (v:v:v) heptane:IPA:TFA, 1.0 mL/min, 210 nm, RT: 7.98 min & 9.38 min.

PH 46A

1H NMR (400 MHz, dmso-d6) δH (ppm): 7.70 (d, J = 8.4 Hz, 2H, Ar–H), 7.34–7.40 (m, 2H, Ar–H), 7.14–7.25 (m, 5H, Ar–H), 7.07 (t, J = 14.4 Hz, 1H, Ar–H), 6.97 (d, J = 8.4 Hz, 2H, Ar–H), 6.39 (s, 1H, CH = C), 5.85 (d, J = 7.2 Hz, 1H, CHOH), 5.06 (d, J = 6.8 Hz, 1H, CHOH), 3.77 (s, 3H, CH3), 3.56 (d, J = 23.2 Hz, 1H, CH2), 3.42 (d, J = 23.2 Hz, 1H, CH2), 3.20 (d, J = 13.6 Hz, 1H, CH2), 2.96 (s, 2H, CH2), 2.73 (d, J = 13.6 Hz, 1H, CH2).

Figure

clip

Image result for PH46A

https://www.sciencedirect.com/science/article/pii/S0040403916301332

Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent

Celtic Catalysts Ltd, NovaUCD, Belfield, Dublin 4, Ireland
Trino Therapeutics Ltd, The Tower, Trinity Technology & Enterprise Campus, Dublin 2, Ireland
§ Drug Discovery Group, School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute (TBSI), Trinity College, Dublin 2, Ireland
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00258
Publication Date (Web): November 27, 2017
Copyright © 2017 American Chemical Society
*E-mail: hsheridn@tcd.ie.
Abstract Image

PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer 5 and the unwanted enantiomer (R,R)-8 during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A. Significant progress was made on the ketone reduction step, where the use of triisobutylaluminum [TiBA, Al(iBu)3] afforded high selectivity for the target diastereoisomer (rac)-6, compared to the unfavorable ratio obtained using a previous process. This enabled a multikilo scale synthesis of PH46A in a GMP environment. Further, a brief proof-of-principle investigation was carried out using an achiral phase transfer catalyst (PTC) for alkylation at the methine carbon of the parent indanone.

Patent ID

Patent Title

Submitted Date

Granted Date

US2015141506 INDANE DIMERS FOR USE IN THE TREATMENT OF AUTOIMMUNE INFLAMMATORY DISEASE
2013-05-23
2015-05-21
US9260376 COMPOUNDS FOR USE IN THE TREATMENT OF IMMUNE RELATED INFLAMMATORY DISEASE
2012-07-20
2014-04-17

///////////////////////PH46A, PH 46A, phase 1, trino

O=C(OC)c1ccc(cc1)C[C@]3(Cc2ccccc2[C@H]3O)C4=Cc5ccccc5C4

LL 3858, SUDOTERB


SUDOTERB.png

Figure imgf000023_0002

LL 3858, SUDOTERB

UNII-SK2537665A;

CAS 676266-31-2;

N-[2-methyl-5-phenyl-3-[[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methyl]pyrrol-1-yl]pyridine-4-carboxamide;

N-[2-Methyl-5-phenyl-3-[[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]methyl]-1H-pyrrol-1-yl]-4-pyridinecarboxamide

Sudoterb(TM)

Molecular Formula: C29H28F3N5O
Molecular Weight: 519.572 g/mol
  • Originator Lupin
  • Class Antituberculars; Isonicotinic acids; Pyrroles
  • Mechanism of Action Undefined mechanism
  • Orphan Drug Status No
  • New Molecular Entity Yes

Highest Development Phases

  • No development reported Tuberculosis

Most Recent Events

  • 23 Jul 2015 No recent reports on development identified – Phase-II for Tuberculosis in India (unspecified route)
  • 11 Dec 2013 Lupin completes a phase II trial in Tuberculosis in India prior to December 2013 (CTRI2009-091-000741)
  • 31 Jul 2010 Lupin completes enrolment in its phase II trial for Tuberculosis in India (CTRI2009-091-000741)

img

Sudoterb HCl
CAS: 1044503-04-9 (2HCl)
Chemical Formula: C29H30Cl2F3N5O
Molecular Weight: 592.4882

Image result

Image result for sudoterb

SYNTHESIS

WO 2006109323

Tuberculosis (TB) is a contagious disease, which usually runs a protracted course, ending in death in majority of the cases, with relapse being a common feature of the disease. It is one of the most important causes of prolonged disability and chronic ill health. It is caused by the tubercle bacillus Mycobacterium tuberculosis, which is comparatively difficult to control. Drugs such as isoniazid, rifampicin, pyrazinamide, ethambutol streptomycin, para- aminosalisylic acid, ethionamide, cycloserine, capreomycin, kanamycin, thioacetazone etc. have been and are being currently used to treat TB. Amongst these, isoniazid, rifampicin, ethambutol and pyrazinamide are the first-line drugs of choice, which are administrated either as a single drug formulation or as a fixed-dose combination of two or more of the aforesaid drugs. Even though, each of the abovementioned first-line drug regimen is highly effective for treatment of TB, however, they are associated with shortcomings, such as unpleasant side- effects and relatively long course of treatment. The later one results in non-compliance of the patient to the treatment leading often to failure of the treatment and most importantly, development of drug resistance. The development of drug resistance has long constituted a principal difficulty in treating human tuberculosis. The second-line drugs, on the other hand are less effective, more expensive and more toxic.

It is estimated that in the next twenty years over one billion people would be newly infected with TB, with 35 million people succumbing to the disease (WHO Fact Sheet No. 104, Global

Alliance for TB Drug Development- Executive Summary of the Scientific Blueprint for TB

Development : http://www.who.int/inf-fs/en/factl04.hfaiil). With the emergence of HIV related

TB, the disease is assuming alarming proportions as one of the killer diseases in the world today.

A major thrust in research on antimycobacterials in the last decade has witnessed the development of new compounds for treatment of the disease, a) differing widely in structures, b) having different mode/mechanism of action, c) possessing favourable pharmacokinetic properties, d) which are safe and having low incidence of side-effects, and e) which provide a cost-effective dosage regimen.

Several new class of compounds have been synthesized and tested for activity against Mycobacterium tuberculosis, the details of chemistry and biology of which could be found in a recent review by B. N. Roy et. al. in J. Ind. Chem. Soc, April 2002, 79, 320-335 and the references cited therein.

Substituted pyrrole derivatives constitute another class of compounds, which hold promise as antimycobacterial agents. The pyrrole derivatives which have been synthesized and tested for antitubercular as well as non-tubercular activity has been disclosed by : a) D. Deidda et. al. in Antimicrob. Agents and Chemother., Nov 1998, 3035-3037. This article describes the inhibitory activity shown by one pyrrole compound, viz. BM 212 having the structure shown below, against both Mycobacterium tuberculosis including drug-resistant mycobacteria and some non-tuberculosis mycobacteria.

Figure imgf000004_0001

The MIC value (μg/ml) against the M. tuberculosis strain 103471 exhibited by BM 212 was 0.70 as against 0.25 found for isoniazid.

b) M. Biava et. al. in J. Med. Chem. Res., 1999, 19-34 have reported the synthesis of several analogues of BM 212, having the general formula (The compounds disclosed by M. Biava et. al. inJ. Med. Chem. Res., 1999, 19-34.) shown hereunder

Figure imgf000005_0001

wherein,

Figure imgf000005_0002

X is H, . CH2— (Oy-Cl ; CH2-(CH2)4-CH3

Figure imgf000005_0003
Figure imgf000005_0004

Z is H ; Y

and the in vitro antimicrobial activity of the compounds against Candida albicans, Candida sp, Cryptococcus neoforma s, Gram- positive or Gram-negative bacteria, isolates of pathogenic plant fungi, Herpes simplex virus, both HSV1 and HSN2, M. tuberculosis, M. smegmαtis, M. mαrinum and M. αvium.

However, the MIC values (μg/ml) of these compounds against the M. tuberculosis strain 103471 are found to be inferior to BM 212 and are in the range of 4-16.

M. Biava et. al. in Bioorg. & Med. Chem. Lett., 1999, 9, 2983-2988. This article describes the synthesis of pyrrole compounds of formula (: The compounds disclosed by M. Biava et. al. in Bioorg. & Med. Chem. Lett., 1999, 9, 2983-2988) shown hereunder

Figure imgf000006_0001

wherein,

X is H or Cl Y is H or Cl

R is N-methyl piperazinyl or thiomorphinyl

and their respective in vitro activity against M. tuberculosis and non-tuberculosis species of mycobacteria .

However, the MIC values (μg/ml) of these compounds against the M. tuberculosis strain 103471 are found to be inferior to BM 212 and are in the range of 2-4.

d) F. Cerreto et. al. in Eur. J. Med. Chem., 1992, 27, 701-708 have reported the synthesis of certain 3-amino-l,5-diary-2 -methyl pyrrole derivatives and their in vitro anti-fungal activity against Candida albicans and Candida sp. However, there is no report on the activity of such compounds against M. tuberculosis.

e) C. Gillet et. al. in Eur. J. Med. Chem.-Chimica Therapeutica, March- April 1976, ϋ(2), 173-181 report the synthesis of several pyrrole derivatives useful as anti-inflammatory agents and as anti-allergants.

f) R. Ragno et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432. This article reports the synthesis and biological activity of several pyrrole derivatives as well as describes a structure activity relationship between the said pyrrole compounds and antimycobacterial activity. The compounds (The compounds disclosed by R. Rango et. al., Bioorg. & Med. Chem., 2000, 8, 1423-1432)synthesized and tested by the authors is summarized hereunder

Figure imgf000007_0001

wherein,

X is COOH, COOEt, CONHNH2, CH2OH, CH(OH)C6H5, NO2

Figure imgf000007_0002

Y is H, CH3, OCH3, CH2, SO2, or a group of formula

Figure imgf000007_0003

wherein,

R is H, Cl, C2H5, or OCH3 and R1 is H, Cl, F, CH3, or NO2,

A is H or R

Z is a group of formula,

Figure imgf000007_0004

R2 is H, Cl, OH, or OCH3 and R3 is H or Cl

None of the abovementioned disclosures report or suggest the in vivo efficacy including toxicity of any of the compounds described therein against experimental tuberculosis in animal model. Moreover, the higher MIC values of the compounds reported suggest that they may not be very effective in inhibition of Mycobacterium tuberculosis.

NO PIC

Sudershan Kumar Arora

sudershan arora, Formerly: President R&D, Ranbaxy Lab Limited,

Experience

Inventors Sudershan Kumar AroraNeelima SinhaSanjay JainRam Shankar UpadhayayaGourhari JanaShankar AjayRakesh Kumar Sinha
Applicant Lupin Limited

PATENT

WO 2004026828

https://www.google.com/patents/WO2004026828A1?cl=en

PATENT

US 20050256128

PATENT

https://encrypted.google.com/patents/WO2005107809A2?cl=en

Thus the invention relates to an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methy 1-5 -phenyl- pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically acceptable non- toxic salt thereof

Figure imgf000011_0001

and a therapeutically effective amount of one or more first line antitubercular drugs selected from the group consisting of isoniazid, rifampicin, ethambutol and pyrazinamide. Further according to the invention there is provided a process for preparation of an antimycobacterial pharmaceutical composition comprising combining a compound of formula I or a pharmaceutically acceptable salt thereof

Figure imgf000011_0002

and one or more of the first line antitubercular drugs using a dry granulation method, a wet granulation method or a direct compression method. The present invention further provides an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) the compound of formula (I) or a pharmaceutically acceptable non-toxic salt thereof

Figure imgf000012_0001

and a therapeutically effective amount of one or more first line antitubercular drugs selected firom isoniazid, rifampicin, ethambutol and pyrazinamide for treatment of multi-drug resistant tuberculosis including latent tuberculosis. The present invention provides an antimycobacterial combination comprising a therapeutically effective amount of N-(3-[[4-(3-trifluoromethylphenyl)piperazinyl]methyl]-2- methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide of formula (I) or a pharmaceutically acceptable non-toxic salt thereof

Figure imgf000012_0002

and a therapeutically effective amount of one or more first line antitubercular drugs selected from isoniazid, rifampicin, ethambutol and pyrazinamide for treatment and/or inhibition of one or more mycobacterial conditions/ cells including but not limited to sensitive and multi- drug resistant strains of Mycobacterium tuberculosis, Mycobacterium avium – intracellular complex, M. fortutium, M. kansasaii and other related mycobacterial species.

ynthesis of Compound of Formula (I) The compound of formula (I) and the pharmaceutically acceptable salts thereof can be synthesized by any known method including but not limited to the methods disclosed in our PCT Application No. PCT/IN02/00189 (WO 04/026828 Al), which is incorporated herein by reference. An example of the preparation of N-(3-[[4-(3-trifluoromethylphenyl) piperazinyl]methyl]-2-methyl-5-phenyl-pyrrolyl)-4-pyridylcarboxamide is as follows:

Preparation of N-(3 ~[[4-(3 -trifluoromethylphenyl)piperazinyl]methyl)] -2-methyl-5 – phenylpyrrolyl)-4-pyridylcarboxamide

Step l 1 -(4-chlorophenyl)pentane- 1 ,4-dione To a well stirred suspension of anhydrous aluminium chloride (27.0gm, 205.9mmol) in

126ml. of chlorobenzene was added oxopentanoylchloride (23.0gm, 171.6 mmol) drop-wise, over a period of 30-35 minutes at room temperature (25-30EC). The reaction mixture was stirred at the same temperature for 1 hour. After decomposition of the reaction mixture by the addition of solid ice and hydrochloric acid (10ml) the precipitated solid was filtered and the filtrate evaporated on a rotary evaporator to remove all the solvents. The residue was dissolved in ethyl acetate (400 ml), washed with water (2 x 100ml.), brine (100 ml.) and dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained was chromatographed over silica gel (100-200 mesh) using chloroform as eluent to give 8.6gm (24.07%) of the title compound.

Step 2 N-(5-methyl-2-phenylpyrrolyl)-4 pyridylcarboxamide

A mixture of 1- (chlorophenyl)pentane-l,4-dione (6.0g, 28.50 mmol, as obtained in Step-1) and isonicotinic hydrazide (4.30gm, 31.35 mmol) in benzene (6.0 ml.) was refluxed by over molecular sieves. After two hours, benzene was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water (2 x 100 ml.) and brine (1 x 50 ml.). The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product so obtained as purified by column chromatography over silica gel (100-200 mesh) using 0.2% methanol in chloroform as eluent to give 3.50gm (39.42%) of the title compound.

Step 3 N-(3 – { [4-(3-trifuoromethylphenyl)piperazinyl]methyl} -2-methyl-5 -phenylpyrrolyl)-4- pyridylcarboxamide

To a stirred solution of N-(5-methyl-2-phenylpyrrolyl)-4-pyridylcarboxamide (0.300gm, 1.083 mmol, as obtained in Step-2) in acetonitrile (5.0 ml.) was added a mixture of l-(3-trifluoromethylphenyl)piperazine hydrochloride (0.288gm, 1.083mmol), 40% formaldehyde (0.032gm, 1.083 mmol) and acetic acid (0.09 ml), drop-wise. After the completion of addition, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized with sodium hydroxide (20% aq. Soln.) and extracted with ethyl acetate (2 x 50 ml.). The combined ethyl acetate extract was washed with water (2 x 25 ml.), brine (1-χ 20 ml.), and dried over anhydrous sodium sulfate and the solvent evaporated off. TLC of the crude product indicated two spots, which were separated by column chromatography over silica gel (100-200mesh). The more polar compound a eluted out using 80% ethyl acetate- hexane mixture was obtained in 24.34 % (0.130 gm) and was identified as N-(3-{[4-(3- trifluoromethylphenyl)piperazinyl]methyl}-2-methyl-5-phenylpyrrolyl)-4- pyridylcarboxamide m.p.80-82°C, MS: m/z 520 (M+l)

1HNMR(CDC13, *): 2:13 (s, 3H,CH3), 2.60 (bs, 4H, 2xN-CH2), 3.18 (bs, 4H, 2xN-CH2), 3.41 (s, 2H, N-CH2), 6.24 (s, lH,H-4), 6.97-7.03 (4H, m, ArH), 7.22-7.29 (m, 5H,AιΗ), 7.53 (d, 2H, J=6Hz, pyridyl ring), 8.50 (bs, 1H,NH D2O exchangeable), 8.70 (d, 2H, J=6Hz, pyridyl ring).

PATENT

WO 2006109323

Compounds of Formula I are known from PCT International Patent Application WO 2004026828, and were screened for antimycobacterial activity, in various in vitro and in vivo models in mice and guinea pigs. Several compounds exhibited strong antimycobacterial activity against sensitive and MDR strains of Mycobacterium tuberculosis in the in vitro and in vivo experiments. Further the compounds of Formula I were also found to be bioavailable, less toxic and safe compared to available anti TB drugs in various animal models.

Thus compounds of Formula I are useful for the effective treatment of Mycobacterium tuberculosis infection caused by sensitive/MDR strains. PCT International Patent Application WO 2004026828 also discloses the synthesis of compounds of Formula I,

Figure imgf000004_0001

wherein,

Ri is phenyl or substituted phenyl

R2 is selected from a group consisting of i) phenyl which is unsubstituted or substituted with 1 or 2 substituents, each independently selected from Cl, F, or, ii) pyridine, or iii) naphthalene, or iv) NHCOR4 wherein R4 is aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclyl. R3 is selected from a group of formula

/~-\ /-Un

— N N-R5 and — N X

wherein R5 is phenyl which is unsubstituted or substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, Ci-C4 alkyl, Ci-C4 alkoxy, nitro, amino, haloalkyl, haloalkoxy etc.; unsubstituted or substituted benzyl; unsubstituted or substituted heteroaryl; unsubstituted or substituted heteroaroyl; unsubstituted or substituted diphenylmethyl,

n = 0-2 and X = -NCH3, CH2, S, SO, or SO2

Such that when R2 is phenyl, which is unsubstituted or substituted with 1 or 2 substituents, each independently selected from Cl, F; R5 is not Ci-C4 alkyl, or X is not -NCH3, CH2, S, SO, or SO2, when n = 1, or X is not -CH2 when n = 0 which comprises reacting the compound of Formula Il

»o-i >-CH, (H)

O O

with thionyl chloride, followed by reaction with RiH (wherein Ri is phenyl or substituted phenyl) in presence of aluminium chloride, and then condensation with R2NH2 (wherein R2 is as described above) in presence of p-toluenesulphonic acid to yield the corresponding unsubstituted pyrrole derivatives of Formula V,

Figure imgf000005_0001

which on further treatment with suitable secondary amines in the presence of formaldehyde and acetic acid afforded the desired pyrrole derivatives of Formula I,

Figure imgf000006_0001

which, on reacting with hydrochloric acid give a hydrochloride salt of compound of Formula Ia. wherein m = 1-2, Ri, R2 and R3 are the same as defined earlier. The above-mentioned methods in the prior art for the synthesis of compound of the Formula I suffer from the limitations,

1. In methods described in PCT International Patent Application WO 2004026828 for the synthesis of compounds of Formula I, positional isomers, the compound of Formula I’, are formed. The necessity of their removal through column chromatography decreases the yield of final pure product.

Figure imgf000006_0002

2. The synthesis of oxopentanoyl chloride (compound of Formula III) for the synthesis of compound of Formula I has been described in J. Org. Chem.

1960, 25, 390-392. It comprises reaction of levulinic acid with thionyl chloride at 50 0C for 1h, which results in poor yield.

3. In method described in PCT International Patent Application WO 2004026828 for the synthesis of 1-aryl-pentane-1,4-dione (compound of Formula IV), impurities are formed and purification involves column chromatography which decreases the yield of the product. 4. The synthesis of the intermediate of Formula V requires the use of benzene and high temperature conditions, which involves the formation of undesired by- products.

5. The above-mentioned methods in prior art for the synthesis of all the intermediates and final compounds of Formula I involves column chromatography for purification, which is cumbersome, tedious and not practicable on an industrial scale.

Example 1: Preparation of /V-(2-methyl-5-phenyl-3-f4-C3-trifluoromethyl-phenyl)- piperazin-1-ylmethyli-pyrrol-i-ylHsonicotinamide hydrochloride

Step (a): Preparation of 4-oxo-pentanoyl chloride

To a stirred mixture of levulinic acid (340.23 g, 2.93 mol) and Λ/./V- dimethylformamide (6.8 mL, catalytic amount) was added thionyl chloride (367.36 g, 3.087 mol, 1.05 equivalent) drop-wise at 20-30 0C in 1.5-2.0 h. After the complete addition of thionyl chloride, the reaction mixture was stirred at same temperature for 0.5 h (completion of reaction or formation of acid chloride was monitored by GC). After the completion of reaction, thionyl chloride was distilled off under reduced pressure at 20-30 0C. Traces of thionyl chloride were removed by adding benzene (136 mL) under reduced pressure at 30-35 0C and residue was dried at reduced pressure (1-2 mm) at 20-30 0C for 30-60 min to yield 370 g (93.8%) of 4-oxo-pentanoyl chloride as light orange oil. Step (b): Preparation of 1-phenyl-pentane-1,4-dione

Figure imgf000016_0001

(B) (A)

To a stirred suspension of benzene (3700 mL, 10 T w/v of acid chloride) and anhydrous aluminium chloride (440.02 g, 3.30 mol, 1.20 equivalent) was added A- oxo-pentanoyl chloride (370 g, 2.75 mol) drop-wise; the rate of addition was regulated so that the addition required 1.5-2 h and the temperature of the reaction mixture was kept at 25-35 0C. The reaction was completed in 2 h and monitored by GC. After completion of reaction, the reaction mixture was added slowly into cold (5-10 0C) 5% HCI (3700 mL) solution maintaining the temperature below 30 0C. The layers were separated; aqueous layer was extracted with ethyl acetate (1×1850 mL). The combined organic phase was washed with water (1 *1850 mL), 5% NaHCO3 solution (1×1850 mL), water (1×1850 mL), 5% NaCI solution (1×1850 mL), dried (Na2SO4), filtered and concentrated under reduced pressure at 35-40 0C, which was finally dried under reduced pressure (1-2 mm) at 35-400C to yield 185.6 g (38.3%) of 1-phenyl-pentane-1,4-dione as thick oil.

Step (c): Preparation of /V-(2-methyl-5-phenyl-pyrrol-1-yI)-isonicotinamide

A mixture of 1-(phenyl)-pentane-1,4-dione (185 g, 1.05 mol), isonicotinic hydrazide (158.4 g, 1.155 mol, 1.1 equivalent), p-toluenesulphonic acid (1.85 g, 1% w/w) and dichloromethane (1850 ml_) was heated under reflux at 40-50 0C under azeotropic distillation for 2-3 h (water was collected in dean stark apparatus). The completion of reaction was monitored by HPLC. After cooling to 25-30 0C the resulting mixture was washed with saturated NaHCO3 solution (1×925 mL), aqueous layer was back extracted with EtOAc (1×925 ml_). The combined organic layers were washed with water (1×925 mL), 5% brine solution (1×925 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure to obtain the solid product, which was further dried under reduced pressure (1-2 mm) at 35-40 0C. To this, cyclohexane (925 mL) was added and stirred for 25-30 min, solid separated out was filtered washed with cyclohexane (370 mL). This process was repeated two times more with the same amount of cyclohexane and finally solid was dried under reduced pressure (1-2 mm) at 40-500C; yield 162.23 g (55.7%). White solid, mp 177-179 0C. 1H NMR (CDCI3): δ 2.10 (s, 3H), 5.98 (d, J = 3.4 Hz, 1H), 6.22 (d, J = 3.7 Hz, 1H), 7.237.28 (m, 5H), 7.50 (d, J = 5.6 Hz, 2H), 8.55 (d, J = 5.0 Hz, 2H), 9.82 (s, 1H). MS: m/z (%) 278 (100) [M+1]. Anal. Calcd for C17H15N3O (277.32): C, 73.63; H, 5.45; N, 15.15. Found: C, 73.92; H, 5.67; N, 15.29.

Step (d): Preparation of /V-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl- phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide

To a stirred solution of Λ/-(2-methyl-5-phenyl-pyrrol-1-yl)-isonicotinamide (160 g, 0.577 mol) in acetonitrile (1600 mil), was added drop-wise through pressure equalizing funnel a mixture of 1-(3-trifluoromethyl-phenyl)-piperazine monohydrochloride (153.75 g, 0.667 mol, 1.155 equivalent), formaldehyde (17.34 g, 0.577 mol, 1.0 equivalent) and acetic acid (480 mL) at 25-30 0C over a period of 60-90 min. The resulting reaction mixture was stirred for 14-16 h at same temperature and completion of reaction was monitored by TLC. After the completion of reaction, reaction mixture was treated with 20% aqueous NaOH solution (2600 mL). Layers were separated, EtOAc (4000 mL) was added to organic layer, washed with water (2×2000 mL), brine (2×1250 mL), dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure at 35-38 0C and then dried under reduced pressure (1-2 mm) to yield the mixture of Λ/-{5-methyl-2-phenyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-pyrrol- 1-yl}-isonicotinamide (A) and Λ/-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl- phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide (B), yield 289 g (97.8%). The ratio of A and B was determined by reverse phase HPLC, which was found to be 19.4% and 76.7%, respectively.

Step (e): Purification of yV-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)- piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide i) The mixture of A and B obtained from Step (d) (279 g) was dissolved in EtOAc (1960 ml_, 7 times) by heating at 50-60 0C. To this activated charcoal (14 g) was added and stirred for 10 min at the same temperature, filtered the activated charcoal through celite bed at 50-60 0C, washed with EtOAc (560 mL). After cooled to 25-30 0C, cyclohexane (2800 mL) was added to the filtrate and stirred the reaction mixture for 14-15 h at 20-35 0C. Solid separated out was filtered, washed with cyclohexane (3500 mL) and dried under reduced pressure (1-2 mm) for 4-5 hours. Yield 151 g (52%). Ratio of A and B was found to be 1.7% and 96.6%, respectively.

ii) The mixture of A and B obtained from Step (e)(i) (151 g) was dissolved in

EtOAc (755 mL, 5 times) by heating at 50-60 0C. After cooled to 25-30 0C, cyclohexane (1510 mL) was added and stirred the reaction mixture for 14-15 h at 20-35 0C. Solid separated out was frltered, washed with cyclohexane (3000 mL) and dried under reduced pressure (1-2 mm) for 4-5 hours. Yield 140 g (92%). Ratio ofA and B was found to be 0.2% and 98.1%, respectively.

Off white solid, mp 191-193 0C. 1H NMR (CDCI3): δ 2.13 (s, 3H), 2.60 (br s, 4H), 3.13 (br s, 4H), 3.41 (s, 2H), 6.24 (s, 1H), 6.977.29 (m, 9H), 7.53 (d, J = 5.6 Hz, 2H), 8.50 (S, 1H), 8.70 (d, J = 5.6 Hz, 2H). 13C NMR (CDCI3): δ 165.93, 151.77, 150.86, 139.74, 133.02, 131.99, 131.43, 129.92, 129.01, 127.79, 127.49, 121.74, 119.09, 116.18, 115.05, 112.48, 109.51, 54.87, 52.99, 48.93, 9.77. MS: m/z (%) 520 (100) [M+U Anal. Calcd for C29H28F3N5O (519.56): C, 67.04; H, 5.43; N, 13.48. Found: C, 67.36; H, 5.71; N, 13.69.

The free base Λ/-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)-piperazin-1- ylmethyl]-pyrrol-1-yl}-isonicotinamide is obtained in a crystalline form having characteristic powder X-ray diffraction pattern given in Figure 1 with 2Θ values 4.85, 5.99, 6.83, 7.34, 9.15, 9.78, 10.93, 11.98, 13.17, 13.98, 14.33, 14.75, 15.73, 16.42, 17.11. 17.72, 17.95, 18.32, 19.11, 19.75, 20.32, 21.36, 22.04, 23.19, 25.17

Step (f): Preparation of /V-{2-methyl-5-phenyl-3-[4-(3-trifluoromethyl-phenyl)- piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide hydrochloride

To a stirred solution of 6% w/v HCI-EtOAc solution (821.8 mL, 1.351 mol, 7.0 equivalent) in EtOAc (2000 mL) was added a solution of Λ/-{2-methyl-5-phenyl-3- [4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-pyrrol-1-yl}-isonicotinamide (100 g, 0.193 mol) in EtOAc (2000 mL) through dropping funnel at 15-20 0C. When the addition was completed (~60 min), the reaction mixture was stirred at 10-150C for 1 h and then nitrogen gas was passed through reaction mass for 1 h until all the excess HCI fumes were removed. Solid so obtained was filtered through suction in an inert atmosphere, washed with ethyl acetate (2×500 mL), diisopropyl ether (2×500 mL) and dried in vacuum oven under reduced pressure (1-2 mm) at 35-40 0C for 15-20 h. Yield 115 g (99%).

Yellow solid, mp 177-179 0C. 1H NMR (DMSO-d6): δ 2.21 (s, 3H), 3.11-3.42 (m, 6H), 3.93-4.23 (m, 4H), 6.62 (s, 1H), 7.09-7.51 (m, 9H), 8.19-8.21 (d, 2H, J = 4.6 Hz), 8.95-8.97 (d, 2H1 J = 4.6 Hz), 11.30 (br s, 1H), 12.86 (s, 1H). MS: m/z (%) 520 (100) [M+1]. Anal. Calcd for C29H28F3N5O.2HCI.3H2O (646.53): C, 53.87; H, 5.61; N, 10.83. Found: C, 53.67; H, 5.59; N, 10.86.

The product obtained was amorphous in nature having the characteristic X-ray powder diffraction pattern given in Figure 2.

Cited Patent Filing date Publication date Applicant Title
WO2004026828A1 * Sep 20, 2002 Apr 1, 2004 Lupin Limited Pyrrole derivatives as antimycobacterial compounds
WO2005107809A2 * Aug 27, 2004 Nov 17, 2005 Lupin Limited Antimycobacterial pharmaceutical composition comprising an antitubercular drug
US3168532 * Jun 12, 1963 Feb 2, 1965 Parke Davis & Co 1, 5-diarylpyrrole-2-propionic acid compounds
Reference
1 * BIAVA M ET AL: “SYNTHESIS AND MICROBIOLOGICAL ACTIVITIES OF PYRROLE ANALOGS OF BM 212, A POTENT ANTITUBERCULAR AGENT” MEDICINAL CHEMISTRY RESEARCH, BIRKHAEUSER, BOSTON, US, vol. 9, no. 1, 1999, pages 19-34, XP008016949 ISSN: 1054-2523
2 * BIAVA, MARIANGELA ET AL: “Antimycobacterial compounds. New pyrrole derivatives of BM212” BIOORGANIC & MEDICINAL CHEMISTRY , 12(6), 1453-1458 CODEN: BMECEP; ISSN: 0968-0896, 2004, XP002390961
3 * PARLOW J.J.: “synthesis of tetrahydonaphthaenes. part II” TETRAHEDRON, vol. 50, no. 11, 1994, pages 3297-3314, XP002391102
4 * R. RIPS , CH. DERAPPE AND N. BII-HOÏ: “1,2,5-trisubstituted pyrroles of pharmacologic interest” JOURNAL OF ORGANIC CHEMISTRY, vol. 25, 1960, pages 390-392, XP002390960 cited in the application

REFERENCES

1: Didilescu C, Craiova UM. [Present and future in the use of anti-tubercular
drugs]. Pneumologia. 2011 Oct-Dec;60(4):198-201. Romanian. PubMed PMID: 22420168.

2: Nuermberger EL, Spigelman MK, Yew WW. Current development and future prospects
in chemotherapy of tuberculosis. Respirology. 2010 Jul;15(5):764-78. doi:
10.1111/j.1440-1843.2010.01775.x. Review. PubMed PMID: 20546189; PubMed Central
PMCID: PMC4461445.

3: LL-3858. Tuberculosis (Edinb). 2008 Mar;88(2):126. doi:
10.1016/S1472-9792(08)70015-5. Review. PubMed PMID: 18486049.

4: Ginsberg AM. Drugs in development for tuberculosis. Drugs. 2010 Dec
3;70(17):2201-14. doi: 10.2165/11538170-000000000-00000. Review. PubMed PMID:
21080738.

Patent ID

Patent Title

Submitted Date

Granted Date

US2016318925 IMIDAZO [1, 2-a]PYRIDINE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING SAME
2016-02-29
US9309238 IMIDAZO [1, 2-a]PYRIDINE COMPOUNDS, SYNTHESIS THEREOF, AND METHODS OF USING SAME
2010-11-05
2012-08-30
US7491721 Antimycobacterial pharmaceutical composition
2005-11-17
2009-02-17
US2009118509 PREPARATION OF [2-METHYL-5-PHENYL-3-(PIPERAZIN-1-YLMETHYL)] PYRROLE DERIVATIVES
2009-05-07

///////////////LL 3858, SUDOTERB, TB, LUPIN

CC1=C(C=C(N1NC(=O)C2=CC=NC=C2)C3=CC=CC=C3)CN4CCN(CC4)C5=CC=CC(=C5)C(F)(F)F

FDA approves first biosimilar Herceptin (trastuzumab) for the treatment of certain breast and stomach cancers


FDA approves first biosimilar for the treatment of certain breast and stomach cancers

Ogivri, a biosimilar to the cancer drug Herceptin, is approved for HER2+ breast cancer and metastatic stomach cancers

The U.S. Food and Drug Administration today approved Ogivri (trastuzumab-dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+). Ogivri is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second biosimilar approved in the U.S. for the treatment of cancer. Continue reading.

December 1, 2017

Release

The U.S. Food and Drug Administration today approved Ogivri (trastuzumab-dkst) as a biosimilar to Herceptin (trastuzumab) for the treatment of patients with breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma) whose tumors overexpress the HER2 gene (HER2+). Ogivri is the first biosimilar approved in the U.S. for the treatment of breast cancer or stomach cancer and the second biosimilar approved in the U.S. for the treatment of cancer.

As with any treatment, health care professionals should review the prescribing information in the labeling for detailed information about the approved uses.

“The FDA continues to grow the number of biosimilar approvals, helping to promote competition that can lower health care costs. This is especially important when it comes to diseases like cancer, that have a high cost burden for patients,” said FDA Commissioner Scott Gottlieb, M.D. “We’re committed to taking new policy steps to advance our biosimilar pathway and promote more competition for biological drugs.”

Biological products are generally derived from a living organism and can come from many sources, such as humans, animals, microorganisms or yeast. A biosimilar is a biological product that is approved based on data showing that it is highly similar to a biological product already approved by the FDA (reference product) and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

The FDA’s approval of Ogivri is based on review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Ogivri is biosimilar to Herceptin. Ogivri has been approved as a biosimilar, not as an interchangeable product.

Common expected side effects of Ogivri for the treatment of HER2+ breast cancer include headache, diarrhea, nausea, chills, fever, infection, congestive heart failure, difficulty sleeping (insomnia), cough and rash. Common expected side effects of Ogivri for the treatment of HER2+ metastatic stomach cancer include low levels of certain white blood cells (neutropenia), diarrhea, fatigue, low levels of red blood cells (anemia), inflammation of the mouth (stomatitis), weight loss, upper respiratory tract infections, fever, low levels of blood platelets (thrombocytopenia), swelling of the mucous membranes (mucosal inflammation), common cold (nasopharyngitis) and unusual taste sensation (dysgeusia). Serious expected side effects of Ogivri include worsening of chemotherapy-induced neutropenia.

Like Herceptin, the labeling for Ogivri contains a Boxed Warning to alert health care professionals and patients about increased risks of heart disease (cardiomyopathy), infusions reactions, lung damage (pulmonary toxicity) and harm to a developing fetus (embryo-fetal toxicity). Patients should stop taking Ogivri if cardiomyopathy, life-threatening allergic reactions (anaphylaxis), swelling below the skin (angioedema), inflammation of the lungs (interstitial pneumonitis) or fluid in the lungs (acute respiratory distress syndrome) occur. Patients should be advised of the potential risk to a developing fetus and to use effective contraception.

The FDA granted approval of Ogivri to Mylan GmbH. Herceptin was approved in September 1998 and is manufactured by Genentech, Inc.

/////////////Ogivri, biosimilar , cancer, Herceptin, Trastuzumab, FDA 2017

VOXELOTOR


Image result for VOXELOTOR

VOXELOTOR

GBT 440; GTx-011, Treatment of Sickle Cell Disease

RN: 1446321-46-5
UNII: 3ZO554A4Q8

Molecular Formula, C19-H19-N3-O3, Molecular Weight, 337.3771

Benzaldehyde, 2-hydroxy-6-((2-(1-(1-methylethyl)-1H-pyrazol-5-yl)-3-pyridinyl)methoxy)-

2-hydroxy-6-((2-(1-(propan-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde

  • Originator Global Blood Therapeutics
  • Class Antianaemics; Small molecules
  • Mechanism of Action Abnormal haemoglobin modulators; Sickle haemoglobin modulators
  • Orphan Drug Status Yes – Sickle cell anaemia
  • New Molecular Entity Yes

Highest Development Phases

  • Phase III Sickle cell anaemia
  • Phase I Hypoxia; Liver disorders
  • Discontinued Idiopathic pulmonary fibrosis

Most Recent Events

  • 01 Nov 2017 Chemical structure information added
  • 28 Oct 2017 Efficacy and adverse event data from a case study under the compassionate use programme in Sickle cell anaemia released by Global Blood Therapeutics
  • 27 Oct 2017 Discontinued – Phase-II for Idiopathic pulmonary fibrosis in USA (PO)

Voxelotor, also known as GBT-440, is a hemoglobin S allosteric modulator. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.

Image result for VOXELOTORImage result for VOXELOTOR

Image result for VOXELOTOR

PATENT

WO 2013102142

Inventors Brian MetcalfChihyuan ChuangJeffrey WarringtonKumar PAULVANNANMatthew P. JacobsonLan HUABradley Morgan
Applicant Global Blood Therapeutics, Inc.Cytokinetics, Inc.The Regents Of The University Of California

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013102142

Hemoglobin (Hb) is a tetrameric protein in red blood cells that transports up to four oxygen molecules from the lungs to various tissues and organs throughout the body.

Hemoglobin binds and releases oxygen through conformational changes, and is in the tense (T) state when it is unbound to oxygen and in the relaxed (R) state when it is bound to oxygen. The equilibrium between the two conformational states is under allosteric regulation. Natural compounds such as 2,3-bisphosphoglycerate (2,3-BPG), protons, and carbon dioxide stabilize hemoglobin in its de-oxygenated T state, while oxygen stabilizes hemoglobin in its oxygenated R state. Other relaxed R states have also been found, however their role in allosteric regulation has not been fully elucidated.

Sickle cell disease is a prevalent disease particularly among those of African and Mediterranean descent. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing the T state to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. Certain synthetic aldehydes have been found to shift the equilibrium from the polymer forming T state to the non-polymer forming R state (Nnamani et al. Chemistry & Biodiversity Vol. 5, 2008 pp. 1762-1769) by acting as allosteric modulators to stabilize the R state through formation of a Schiff base with an amino group on hemoglobin.

US 7, 160,910 discloses 2-furfuraldehydes and related compounds that are also allosteric modulators of hemoglobin. One particular compound 5-hydroxymethyl-2-furfuraldehyde (5HMF) was found to be a potent hemoglobin modulator both in vitro and in vivo. Transgenic mice producing human HbS that were treated with 5HMF were found to have significantly improved survival times when exposed to extreme hypoxia (5% oxygen). Under these hypoxic conditions, the 5HMF treated mice were also found to have reduced amounts of hypoxia-induced sickled red blood cells as compared to the non-treated mice.

A need exists for therapeutics that can shift the equilibrium between the deoxygenated and oxygenated states of Hb to treat disorders that are mediated by Hb or by abnormal Hb such as HbS. A need also exists for therapeutics to treat disorders that would benefit from having Hb in the R state with an increased affinity for oxygen. Such therapeutics would have applications ranging, for example, from sensitizing hypoxic tumor cells that are resistant to standard radiotherapy or chemotherapy due to the low levels of oxygen in the cell, to treating pulmonary and hypertensive disorders, and to promoting wound healing

Example 18. Preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (Compound 43).

A mixture of 2,6-dihydroxybenzaldehyde (1.58 g, 11.47 mmol, 2 eq.) and K2CO3 (2.4 g, 17.22 mmol, 3 eq.) in DMF (150 mL) was stirred at rt for 10 min. To this mixture was added 3-(chloromethyl)-2-(1-isopropyI-1H-pyrazol-5-yl)pyridine hydrochloride (1.56 g, 5.74 mmol, leq.) at rt. The mixture was heated at 50 °C for 2 h, filtered, concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde (1.71 g, 88%) as a pale yellow solid.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(3), 321-326.

http://pubs.acs.org/doi/full/10.1021/acsmedchemlett.6b00491

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

 Global Blood Therapeutics, Inc., South San Francisco, California 94080, United States
 Cytokinetics, Inc., South San Francisco, California 94080, United States
 Albert Einstein College of Medicine, Bronx, New York 10461, United States
 Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158, United States
§ Tandem Sciences, Inc., Menlo Park, California 94025, United States
ACS Med. Chem. Lett.20178 (3), pp 321–326
DOI: 10.1021/acsmedchemlett.6b00491

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Abstract Image

We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).

Figure

cheme 1. Synthesis of 36a

aReagents and conditions: (a) MOMCl, DIEPA, DCM, 0 °C to rt 2 h, 90%; (b) nBuLi, DMF, THF, −78 to 0 °C, 94%; (c) 12 N HCl, THF, rt, 1.5 h, 81%; (d) Pd(dppf)Cl2, NaHCO3, H2O/dioxane, 100 °C, 12 h, 40%; (e) SOCl2, DCM, rt, 100%; (f) Na2CO3, DMF, 65 °C, 1.5 h, 81%; (g) 12 N HCl, THF, rt, 3 h, 96%.

GBT440 (36) (15.3 g).

HRMS calcd for C19H20N3O3 (M+H + ) 338.1499, found 338.1497; MS (ESI) m/z 338.4 [M+H]+ ;

1H NMR (400 MHz, Chloroform-d) δ 11.94 (s, 1H), 10.37 (d, J = 0.6 Hz, 1H), 8.75 (dd, J = 4.8, 1.7 Hz, 1H), 7.97 (dd, J = 7.8, 1.6 Hz, 1H), 7.63 – 7.57 (m, 1H), 7.46 – 7.33 (m, 2H), 6.57 (dt, J = 8.6, 0.7 Hz, 1H), 6.34 (d, J = 1.9 Hz, 1H), 6.27 (dt, J = 8.3, 1.0 Hz, 1H), 5.07 (s, 2H), 4.65 (hept, J = 6.6 Hz, 1H), 1.47 (d, J = 6.6 Hz, 7H);

13C NMR (101 MHz, DMSO-d6) δ 194.0, 162.9, 161.1, 149.6, 149.1, 139.1, 138.2, 138.2, 138.0, 131.6, 124.0, 111.1, 110.2, 107.4, 103.5, 67.8, 50.5, 23.1.

http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00491/suppl_file/ml6b00491_si_001.pdf

PATENT

WO 2015031285

https://www.google.co.in/patents/WO2015031285A1?cl=en

2-Hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde is a compound having the formula:

Sickle cell disease is a disorder of the red blood cells, found particularly among those of African and Mediterranean descent. The basis for sickle cell disease is found in sickle hemoglobin (HbS), which contains a point mutation relative to the prevalent peptide sequence of hemoglobin (Hb).

[ Hemoglobin (Hb) transports oxygen molecules from the lungs to various tissues and organs throughout the body. Hemoglobin binds and releases oxygen through

conformational changes. Sickle hemoglobin (HbS) contains a point mutation where glutamic acid is replaced with valine, allowing HbS to become susceptible to polymerization to give the HbS containing red blood cells their characteristic sickle shape. The sickled cells are also more rigid than normal red blood cells, and their lack of flexibility can lead to blockage of blood vessels. A need exists for therapeutics that can treat disorders that are mediated by Hb or by abnormal Hb such as HbS, such as 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde hydrochloride.

When used for treating humans, it is important that a crystalline form of a therapeutic agent, like 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde, or a salt thereof, retains its polymorphic and chemical stability, solubility, and other physicochemical properties over time and among various manufactured batches of the agent. If the physicochemical properties vary with time and among batches, the administration of a therapeutically effective dose becomes problematic and may lead to toxic side effects or to ineffective therapy, particularly if a given polymorph decomposes prior to use, to a less active, inactive, or toxic compound. Therefore, it is important to choose a form of the crystalline agent that is stable, is manufactured reproducibly, and has physicochemical properties favorable for its use as a therapeutic agent.

Example ί : Synthesis of Compound 15

OH DIPEA OMOM

(8063J To s solution of 2 >ronao enzsae-i -diol (5 g, 26.45 m ol) m. DCM (50 ml) at 0 *C was added DIPEA (11.54 mL, 66.13 aan l) and MOMCi (4.42 mL. 58.19 ratnoi). The mixture was stirred at 0 °C for 1.5 h, and then warmed to room temperature. The so ntioa was dilated with DCM, washed with sat. NaH€<¾, brum dried and concentrated to give crude product, which was purified by coinran ihexane&/EtOAc~4;l) to give desired product 15.58 g (90%).

14C

Example 2: Synthesis of Compound 13 from 15

[0064] To a solution of 2-bromo-l ,3-bis(methoxymethoxy)benzene (15) (19.9g, 71.8 mmol) in THF (150 mL) at -78 °C was added BuLi (2.5 M, 31.6 mL, 79.0 mmol) dropwise. The solution was stirred at -78 °C for 25 min (resulting white cloudy mixture), then it was warmed to 0 °C and stirred for 25 min. The reaction mixture slowly turns homogenous. To the solution was added DMF at 0 °C. After 25 min, HPLC showed reaction completed. The mixture was quenched with sat. NH4C1 (150 mL), diluted with ether (300 mL). The organic layer was separated, aq layer was further extracted with ether (2X200 mL), and organic layer was combined, washed with brine, dried and concentrated to give crude product, which was triturated to give 14.6 g desired product. The filtrate was then concentrated and purified by column to give additional 0.7 g, total mass is 15.3 g.

Example 3: Synthesis of Compound 13 from resorcinol 11

1.1 R:TMEDA R:BuLi S:THF 2 h -10°C

Journal of Organic Chemistry, 74(1 1), 431 1-4317; 2009

[0065] A three-necked round-bottom flask equipped with mechanical stirrer was charged with 0.22 mol of NaH (50 % suspension in mineral oil) under nitrogen atmosphere. NaH was washed with 2 portions (100 mL) of n-hexane and then with 300 mL of dry diethyl ether; then 80 mL of anhydrous DMF was added. Then 0.09 mol of resorcinol 11, dissolved in 100 mL of diethyl ether was added dropwise and the mixture was left under stirring at rt for 30 min. Then 0.18 mol of MOMCI was slowly added. After 1 h under stirring at rt, 250 mL of water was added and the organic layer was extracted with diethyl ether. The extracts were

15A

washed with brine, dried (Na2S04), then concentrated to give the crude product that was purified by silica gel chromatography to give compound 12 (93 % yield).

15B

[0066] A three-necked round-bottom flask was charged with 110 mL of n-hexane, 0.79 mol of BuLi and 9.4 mL of tetramethylethylendiamine (TMEDA) under nitrogen atmosphere. The mixture was cooled at -10 °C and 0.079 mol of bis-phenyl ether 12 was slowly added. The resulting mixture was left under magnetic stirring at -10 °C for 2 h. Then the temperature was raised to 0 °C and 0.067 mol of DMF was added dropwise. After 1 h, aqueous HC1 was added until the pH was acidic; the mixture was then extracted with ethyl ether. The combined extracts were washed with brine, dried (Na2S04), and concentrated to give aldehyde 13

(84%).

[0067] 2,6-bis(methoxymethoxy)benzaldehyde (13): mp 58-59 °C (n-hexane) ; IR (KBr) n: 1685 (C=0) cm“1; 1H-NMR (400 MHz, CDC13) δ 3.51 (s, 6H, 2 OCH3), 5.28 (s, 4H, 2 OCH20), 6.84 (d, 2H, J = 8.40 Hz, H-3, H-5), 7.41 (t, 1H, J = 8.40 Hz, H-4), 10.55 (s, 1H, CHO); MS, m/e (relative intensity) 226 (M+, 3), 180 (4), 164 (14), 122 (2), 92 (2), 45 (100); Anal. Calc’d. for CnHi405: C,58.40; H, 6.24. Found: C, 57.98; H, 6.20.

Example 4: The Synthesis of Compound 16

13 16

81 %

[0068] To a solution of 2,6-bis(methoxymethoxy)benzaldehyde (13) (15.3 g, 67.6 mmol) in THF (105 mL) (solvent was purged with N2) was added cone. HC1 (12N, 7 mL) under N2, then it was further stirred under N2 for 1.5 h. To the solution was added brine (100 mL) and ether (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×200 mL). The organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (300g,

hexanes/EtOAc=85: 15) to give desired product 16 (9.9 g) as yellow liquid.

Example 5: Synthesis of Compound 17

16

[0069] To a solution of 2-hydroxy-6-(methoxymethoxy)benzaldehyde (16) (10.88 g, 59.72 mmol) in DMF (120 mL) (DMF solution was purged with N2 for 10 min) was added K2C03 (32.05 g, 231.92 mmol) and 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine hydrochloride (10) (15.78 g, 57.98 mmol). The mixture was heated at 65 °C for 1.5 h, cooled to rt, poured into ice water (800 mL). The precipitated solids were isolated by filtration, dried and concentrated to give desired product (17, 18 g).

Example 6: Synthesis of Compound (I)

[0070] To a solution of 2-((2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methoxy)-6-(methoxymethoxy)benzaldehyde (17) (18 g, 47.19 mmol) in THF (135 mL, solution was purged with N2) was added cone. HCI (12N, 20 mL). The solution was stirred at rt for 3 h when HPLC showed the reaction complete. The mixture was added to a solution of NaHC03 (15 g) in water (1.2 L), and the resulting precipitate was collected by filtration, dried to give crude solid, which was further purified by column (DCM/EtOAc=60:40) to give pure product

(15.3 g).

Example 7: Synthesis of Compound I (free base) and its HCI salt form

[0071] Compound (I) free base (40g) was obtained from the coupling of the alcohol intermediate 7 and 2,6-dihydroxybenzaldedhye 9 under Mitsunobu conditions. A procedure is also provided below:

17

Example 8: Synthesis of Compound (I) by Mitsunobu coupling

[0072] Into a 2000-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of [2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methanol (7) (70 g, 322.18 mmol, 1.00 equiv) in tetrahydrofuran (1000 mL). 2,6-Dihydroxybenzaldehyde (9) (49.2 g, 356.21 mmol, 1.10 equiv) and PPh3 (101 g, 385.07 mmol, 1.20 equiv) were added to the reaction mixture. This was followed by the addition of a solution of DIAD (78.1 g, 386.23 mmol, 1.20 equiv) in tetrahydrofuran (200 ml) dropwise with stirring. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 500 ml of H20. The resulting solution was extracted with 3×500 ml of dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA:PE (1 :50-l :3) as eluent to yield the crude product. The crude product was re-crystallized from i-propanol/H20 in the ratio of 1/1.5. This resulted in 40 g (37%) of 2-hydroxy-6-([2-[l-(propan-2-yl)-lH-pyrazol-5-yl]pyridin-3-yl]methoxy)benzaldehyde as a light yellow solid. The compound exhibited a melting point of 80-82 °C. MS (ES, m/z): 338.1 [M+l]. 1H NMR (300 MHz, DMSO-d6) δ 11.72(s, 1H), 10.21(s, 1H), 8.76(d, J=3.6Hz, 1H), 8.24(d, J=2.7Hz, lH),7.55(m, 3H), 6.55(m,3H) ,5.21 (s, 2H), 4.65 (m, 1H), 1.37 (d, J=5.1Hz, 6H). 1H NMR (400 MHz, CDC13) δ 11.96 (s, 1H), 10.40 (s, 1H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.49 – 7.34 (m, 2H), 6.59 (d, J= 8.5 Hz, 1H), 6.37 (d, J= 1.8 Hz, 1H), 6.29 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.67 (sep, J= 6.7 Hz, 1H), 1.50 (d, J= 6.6 Hz, 6H).

[0073] In another approach, multiple batches of Compound (I) free base are prepared in multi gram quantities (20g). The advantage of this route is the use of mono-protected 2,6-dihydroxybenzaldehyde (16), which effectively eliminates the possibility of bis-alkylation side product. The mono-MOM ether of 2,6-dihydroxybenzaldehyde (16) can be obtained from two starting points, bromoresorcinol (14) or resorcinol (11) [procedures described in the Journal of Organic Chemistry, 74(11), 4311-4317; 2009 ]. All steps and procedures are provided below. Due to the presence of phenolic aldehyde group, precautions (i.e., carry out all reactions under inert gas such as nitrogen) should be taken to avoid oxidation of the phenol and/or aldehyde group.

18

Preparation of compound I HC1 salt: A solution of compound I (55.79 g, 165.55 mmol) in acetonitrile (275 mL) was flushed with nitrogen for 10 min, then to this solution was added 3N aqueous HC1 (62 mL) at room temperature. The mixture was stirred for additional 10 min after the addition, most of the acetonitrile (about 200 mL) was then removed by evaporation on a rota

PATENT

WO2017096230

PATENT

WO-2017197083

Processes for the preparation of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (also referred to as voxelotor or Compound (I)) and its intermediates is claimed. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

Disclosed herein are processes for synthesizing 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (Compound (I)) and intermediates used in such processes. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

BACKGROUND

Compound (I) is disclosed in Example 17 of the International Publication No.

WO2013/102142. Compound (I) binds to hemoglobin and increases it oxygen affinity and hence can be useful for the treatment of diseases such as sickle cell disease.

In general, for a compound to be suitable as a therapeutic agent or part of a therapeutic agent, the compound synthesis must be amendable to large scale manufacturing and isolation. The large scale manufacturing and isolation should not impact the physical properties and purity of the compound nor should it negatively impact cost or efficacy of a formulated active ingredient. Accordingly, scale up of manufacturing and isolation may require significant efforts to meet these goals.

ompound (I) has been synthesized by certain methods starting with 2,6-dihydroxbenzaldehyde (compound 1) where each hydroxyl moiety is protected with an unbranched, straight-chain alkyl or alkoxyalkyl such as, for example, methyl or methoxymethyl. Following installation of the aldehyde group, various methods of deprotection of the hydroxyl group were employed to synthesize compound (1) used in the synthesis and production of Compound (I). However, the deprotection processes used lead to unwanted polymerization and decomposition reactions of compound (1) – attributed, in part, to the conditions used for

deprotection of the hydroxy groups. The undesired byproducts yield complex mixtures, lower yields of Compound (I), and require significant effort to purify Compound (I) to a degree acceptable for use as a part of a therapeutic agent, thus rendering the above processes impractical for commercial scale synthesis of Compound (I).

Provided herein are processes for the synthesis of Compound (I):

Examples

Example 1

Synthesis of 2,6-dihydroxybenzaldehyde (Compound (1))

Step 1:

Tetrahydrofuran (700 mL) was added to resorcinol (170g, 1.54 mol, leq.) under inert gas protection, followed by addition of pyridinium tosylate (3.9 g, 15.4 mmol, O.Oleq.), THF 65 mL) and the reaction mixture was cooled down to 0 – 5 °C. Within 1 – 1.5 h ethylvinyl ether (444 mL, 4.63 mol, 3.0 eq.) was added while maintaining a temperature <5°C. After the addition was complete the reaction mixture was allowed to reach room temperature within 1.5 h. The reaction was stirred overnight, cooled down to 10-15 °C, and 510 mL of ½ sat. NaHC03 was added while maintaining the reaction solution below 20 °C. The phases were separated. The organic phase was washed once with 425 mL of water and once with 425 mL 12.5% NaCl solution and evaporated and azeotroped with THF to give bis-EOE-protected resorcinol (401.2 g, 1.55 mol, 102% uncorrected) as a clear colorless to yellowish oil.

Step 2:

Bis-EOE-protected resorcinol (390 g of, actual: 398.6g = 1.53 mol, 1 eq., corrected to 100%) conversion) was added under inert gas protection to a 6 L glass vessel and THF (1170 mL) was added. The reaction mixture was cooled down to -10°C to -5°C and n-BuLi (625 mL, 2.7 M in heptane, 1.687 mol, 1.1 eq.) was added. The reaction mixture was agitated at -5°C- 0°C for 30-40 min and then DMF (153.4 mL, 1.99 mmol, 1.3 eq.) was added starting at -10°C to -5°C. The reaction mixture was stirred until complete and then quenched with lNHCl/EtOAc. It was also discovered, inter alia, that protection with the EOE groups not only resulted in less byproducts but appeared to increase the speed of the formylation reaction to provide 2,6-bis(l-ethoxyethoxy)benzaldehyde (compound (2)).

The mixture was worked up, phase separated and the aqueous washed with MTBE. After aqueous wash to remove salts the organic phase was concentrated to the neat oil to obtain the compound (2) as yellow oil (almost quantitative).

A batch preparation was performed using solvent swap and was completed faster than other known methods for synthesizing Compound (I) with better purity and yield. The deprotection sequence allowed in-situ use of compound (2).

Step 3:

To the reaction solution of Step 2 was added IN HC1 (1755 mL) while maintaining the temperature < 20°C. The pH was of the solution was adjusted to pH = 0.7 – 0.8 with 6 M HC1.

The reaction mixture was stirred for 16 h. After the reaction was complete the organic phase was separated and 1560 mL of methyl tert butyl ether was added. The organic phase was washed once with 1170 mL of IN HC1, once with 780 mL of ½ sat. NaCl solution and once with 780 mL of water and then concentrated to a volume of – 280mL. To the solution was added 780 mL of methyl tert butyl ether and concentrate again to 280 mL [temperature <45°C, vacuo]. To the slurry was added 780 mL of acetonitrile and the solution was concentrated in vacuo at T < 45°C to a final volume of – 280 mL. The slurry was heated to re-dissolve the solids. The solution was cooled slowly to RT and seeded at 60-65 °C to initiate crystallization of the product. The slurry was cooled down to -20°C to -15°C and agitated at this temperature for 1-2 h. The product was isolated by filtration and washed with DCM (pre-cooled to -20°C to -15°C) and dried under a stream of nitrogen to give 2,6-dihydroxybenzaldehyde as a yellow solid. Yield: 138.9 g (1.00 mol, 65.6%).

Example 1A

Alternate Synthesis of 2,6-dihydroxybenzaldehyde compound (1)

Step 1:

In a suitable reactor under nitrogen, tetrahydrofuran (207 L) was added to resorcinol (46 kg, 0.42 kmol, leq.) followed by addition of pyridinium tosylate (1.05 kg, 4.2 mol, O.Oleq.), and the reaction mixture was cooled down to 0 – 5 °C. Within 1 – 1.5 h ethylvinyl ether (90.4 kg, 120.5 L, 125 kmol, 3.0 eq.) was added while maintaining a temperature <5°C. After the addition was complete the reaction mixture was allowed to reach room temperature within 1.5 h. The reaction was stirred overnight, cooled down to 10-15 °C, and 138 L of aqueous 4% NaHC03 was added while maintaining the reaction solution below 20 °C. The phases were separated. The organic phase was washed once with 115 L of water and once with 125.2 kg of a 12.5% NaCl solution. The organic layer was dried by azeotropic distillation with THF to a water content value < 0.05%) (by weight) to yield bis-EOE-protected resorcinol (106.2 kg, 0.42 kmol) as a solution in THF. An advantage over previously reported protection procedures is that the bis-EOE-protected resorcinol product does not need to be isolated as a neat product. The

product-containing THF solution can be used directly in the next reaction step thus increasing throughput and reducing impurity formation.

Step 2:

Bis-EOE-protected resorcinol solution (assumption is 100% conversion) was added under inert gas protection to suitable reactor. The reaction mixture was cooled down to -10°C to -5°C and n-BuLi (117.8 kg, 25% in heptane, 1.1 eq.) was added. The reaction mixture was agitated at -5°C- 0°C for 30-40 min and then DMF (39.7 kg, 0.54 kmol, 1.3 eq.) was added at -10°C to -5°C. The reaction mixture was stirred until complete and then quenched with aqueous HC1 (1M, 488.8 kg) to give 2,6-bis(l-ethoxyethoxy)benzaldehyde. An advantage over previously reported procedures of using EOE protecting group is that the HC1 quenched solution can be used directly in the deprotection step, and 2,6-bis(l-ethoxyethoxy)benzaldehyde does not need to be isolated as a neat oil.

Step 3:

The pH of the quenched solution was adjusted to < 1 with aqueous HC1 (6M, ca 95.9 kg) and the reaction mixture stirred at ambient temperature for 16 h. After the reaction was complete the organic phase was separated and 279.7 kg of methyl tert butyl ether was added. The organic phase was washed once with aqueous IN HC1 (299 kg), once with aqueous 12.5% NaCl (205.8 kg) and once with 189 kg of water and then concentrated to a volume of ca. 69 L. To the slurry was added 164 kg of acetonitrile and the solution was concentrated in vacuo at T < 45°C to a final volume of ca. 69 L. The slurry was heated to re-dissolve the solids. The solution was seeded at 60-65 °C to initiate crystallization of the product and cooled slowly to RT over 8 hrs. The slurry was cooled down to -20 °C to -15°C and agitated at this temperature for l-2h. The product was isolated by filtration and washed with DCM (50.3 kg, pre-cooled to -20 °C to -15 °C) and dried under a stream of nitrogen to yield 2,6-dihydroxybenzaldehyde as a yellow solid. Yield: 37.8 kg (0.27 kmol, 65.4% Yield). The described telescoped approach from deprotection to crystallization increases the throughput and integrity of the product.

Example 2

Synthesis of 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine

dihydrochloride salt

Step 1:

An appropriately sized flask was purged with nitrogen and charged with (2-chloropyridin-3-yl)methanol (1.0 equiv), sodium bicarbonate (3.0 equiv), [1, l ‘-bis(diphenyl-phosphino)-ferrocene]dichloropalladium (5 mol %), l-isopropyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1.2 equiv), and a mixture of 2-MeTHF (17.4 vol) and deionized water (5.2 vol). The resulting solution was heated to 70°C to 75°C and conversion monitored by HPLC. Once the reaction was complete, the reaction mixture was cooled to room temperature, diluted with deionized water, and the phases were separated. The organic layer was extracted with 2 N HC1 (10 vol) and the phases were separated. The aqueous phase was washed with MTBE. The pH of the aqueous phase was adjusted to 8-9 with 6 N NaOH. The product was extracted into EtOAc, treated with Darco G-60 for 30 to 60 min, dried over MgS04, filtered through Celite®, and concentrated to give (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol as a brown oil.

Step 2:

A suitably equipped reactor was charged with (2-(l-isopropyl-lH-pyrazol-5-yl)pyridin-3-yl)methanol hydrochloride salt (1 equivalent) and purified water. An aqueous sodium

bicarbonate solution (8% NaHC03) was added slowly to maintain the solution temperature between 17 °C to 25 °C. After addition was complete, the reaction mixture was stirred at 17 °C to 25 °C and dichloromethane was added and the organic layer was separated. DCM solution was then distilled under atmospheric conditions at approximately 40°C and the volume was reduced. DCM was added the reactor and the contents of the reactor are stirred at 20°C to 30°C until a clear solution is formed. The contents of the reactor were cooled to 0°C to 5°C and thionyl chloride was charged to the reactor slowly to maintain a temperature of < 5 °C. The reaction solution was stirred at 17 °C to 25 °C. When the reaction was complete, a solution of HC1 (g) in 1,4-dioxane (ca. 4 N, 0.8 equiv.) was charged to the reactor slowly to maintain the solution temperature between 17 °C and 25 °C. The product 3-(chloromethyl)-2-(l-isopropyl- lH-pyrazol-5-yl)pyridine dihydrochloride salt was filtered washed with dichloromethane and dried.

Example 3

Synthesis of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde

Form I

(I)

tably equipped reactor was charged with 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine dihydrochloride salt (1 equivalent), sodium iodide (0.05 equivalent), sodium bicarbonate (4 equivalent), l-methyl-2-pyrrolidinone (NMP), and 2,6-dihydroxy-benzaldehyde (1 to 1.05 equiv.). The reaction mixture was heated slowly to 40 °C to 50 °C and stirred until the reaction was complete. Water was then added and the reaction mixture was cooled and maintained at 17 °C to 25 °C. When the water addition was complete, the reaction mixture was stirred at 17 °C to 25 °C and slowly cooled to 0°C to 5°C and the resulting solids were collected by filtration. The solids were washed with a 0 °C to 5 °C 2: 1 water/NMP solution, followed by 0 °C to 5 °C water. The solids were filtered and dried to give 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I or a mixture of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as Form I Form I and NMP solvates.

Alternative Synthesis:

A suitably equipped reactor was charged with 3-(chloromethyl)-2-(l-isopropyl-lH-pyrazol-5-yl)pyridine bishydrochloride salt (1 equivalent), sodium iodide (0.05 equivalent), sodium bicarbonate (3 to 4 equivalent), l-methyl-2-pyrrolidinone (7 equivalent, NMP), and 2,6-dihydoxybenzaldehyde (1.05 equivalent). The reaction mixture was heated to 40 °C to 50° C and stirred until the reaction was complete. Water (5 equivalent) was then added while maintaining the contents of the reactor at 40 °C to 460 C and the resulting clear solution seeded with 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde Form I. Additional water (5 equivalent) was added while maintaining the contents of the reactor at 40 °C to 500 C, the reactor contents cooled to 15 °C to 25 0 C, and the reactor contents stirred for at least 1 hour at 15 °C to 25 0 C. The solids were collected, washed twice with 1 :2 NMP: water and twice with water, and dried to yield 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde Form I devoid of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde as NMP solvates.

Example 4

Preparation of 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)- benzaldehyde Form II

Step 1:

A suitably equipped reactor with an inert atmosphere was charged with crude 2-hydroxy- 6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (from Example 3 above) and MTBE and the contents stirred at 17°C to 25°C until dissolution was achieved. The reaction solution was passed through a 0.45 micron filter and MTBE solvent volume reduced using vacuum distillation at approximately 50 °C. The concentrated solution was heated to 55°C to 60°C to dissolve any crystallized product. When a clear solution was obtained, the solution was cooled to 50 °C to 55 °C and n-heptane was added. 2-Hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde (e.g., Form II) seeds in a slurry of n-heptane were charged and the solution was stirred at 50°C to 55°C. The solution was cooled to 45 °C to 50 °C and n-heptane was added to the reactor slowly while maintaining a reaction solution temperature of 45°C to 50°C. The reaction solution are stirred at 45°C to 50°C and then slowly cooled to 17°C to 25°C. A sample was taken for FTIR analysis and the crystallization was considered complete when FTIR analysis confirmed 2-hydroxy-6-((2-(l-isopropyl-lH-pyrazol-5-yl)-pyridin-3-yl)methoxy)-benzaldehyde (Form II). The contents of the reactor were then cooled to 0°C to 5°C and the solids were isolated and washed with cold n-heptane and dried.

REFERENCES

1: Oksenberg D, Dufu K, Patel MP, Chuang C, Li Z, Xu Q, Silva-Garcia A, Zhou C, Hutchaleelaha A, Patskovska L, Patskovsky Y, Almo SC, Sinha U, Metcalf BW, Archer DR. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016 Oct;175(1):141-53. doi: 10.1111/bjh.14214. PubMed PMID: 27378309.

2: Dufu K, Lehrer-Graiwer J, Ramos E, Oksenberg D. GBT440 Inhibits Sickling of Sickle Cell Trait Blood Under In Vitro Conditions Mimicking Strenuous Exercise. Hematol Rep. 2016 Sep 28;8(3):6637. PubMed PMID: 27757216; PubMed Central PMCID: PMC5062624.

3: Ferrone FA. GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease. Br J Haematol. 2016 Aug;174(4):499-500. doi: 10.1111/bjh.14212. PubMed PMID: 27410726.

4: Oder E, Safo MK, Abdulmalik O, Kato GJ. New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo? Br J Haematol. 2016 Oct;175(1):24-30. doi: 10.1111/bjh.14264. Review. PubMed PMID: 27605087; PubMed Central PMCID: PMC5035193.

////////////VOXELOTOR, GBT 440, GTx-011, Treatment of Sickle Cell Disease, phase 3, gbt, 1446321-46-5, orphan drug

CC(C)n1nccc1c2ncccc2COc3cccc(O)c3C=O

DISCLAIMER

“NEW DRUG APPROVALS ” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Palladium-catalyzed direct C-H ethoxycarbonylation of 2-aryl-1,2,3-triazoles and efficient synthesis of suvorexant


Org. Chem. Front., 2018, Advance Article
DOI: 10.1039/C7QO00945C, Research Article
Rui Sang, Yang Zheng, Hailong Zhang, Xiaohua Wu, Qiantao Wang, Li Hai, Yong Wu
Palladium-catalyzed direct ethoxycarbonylation with diethyl azodicarboxylate was developed and its reaction mechanism was explored by using DFT calculations.

Palladium-catalyzed direct C–H ethoxycarbonylation of 2-aryl-1,2,3-triazoles and efficient synthesis of suvorexant

Abstract

Efficient palladium-catalyzed C–H ethoxycarbonylation of 2-aryl-1,2,3-triazoles was developed by using diethyl azodicarboxylate as the esterification reagent. A wide variety of aryl esters containing 1,2,3-triazoles were obtained in moderate to good yields. In addition, density functional theory calculations were used to enhance the mechanistic studies.

str2

3ea

5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoate

Yellow oil, 1H NMR (600 MHz, Chloroform-d) δ 7.81 (s, 2H), 7.69 – 7.57 (m, 2H), 7.41 (d, J = 8.1 Hz, 8 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, Chloroformd) δ 166.8, 138.8, 136.1, 135.3, 132.2, 130.4, 127.2, 124.4, 61.4, 13.9; IR (cm-1): 2923, 2861, 1723, 1509, 1463, 1410, 1366, 1303, 1285, 1269, 1234, 1201, 1108, 1072, 1044, 1021, 962, 952, 158, 824, 778, 734, 630; HRMS (ESI) Calcd. for C12H13N3O2 [M+Na]+ 254.0905, found 254.0904.

To a round bottom flask charged 4-methyl-2-(2H-1,2,3-triazol-2-yl)benzoate (50 mg, 0.22 mmol), KOH (67.2 mg, 1.2 mmol), EtOH (3 ml) and H2O (0.5 ml), and the system was react at 40 oC for 5 h, and then cooled down to ambient temperature. The pH was adjusted to 1 with 5% HCl, and EtOH was removed under reduced pressure. The residual solvent was extracted with EtOAc (3 x 10 ml), and the solvent was evaporated under reduced pressure. The oily residue was purified by chromatography on a silica gelcolumn (DCM/MeOH) and product 4 was obtained with 90% yield. Suvorexant was synthesised from 4 and 5 according to the literature as previous report. [4, 5] Product 4: 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid: 1H NMR (400 MHz, Chloroform-d) δ 7.83 (s, 2H), 7.76 (d, J = 2.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.50 – 7.42 (m, 1H), 2.47 (s, 3H). [4, 5] Suvorexant: 1H NMR (400 MHz, Chloroform-d) δ 7.90−7.75 (m, 3H), 7.68-7.01 (m, 5H), 5.09 – 4.46 (m, 1H), 4.23 – 3.41 (m, 6H), 3.16-2.31 (m, 4H), 2.20 – 2.01 (m, 1H), 1.91 – 1.16 (m, 3H); [4, 5]

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Suvorexant.svg

suvorexant

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