NZ618912B2 - Trpv1 antagonists including dihydroxy substituent and uses thereof - Google Patents
Trpv1 antagonists including dihydroxy substituent and uses thereof Download PDFInfo
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- NZ618912B2 NZ618912B2 NZ618912A NZ61891212A NZ618912B2 NZ 618912 B2 NZ618912 B2 NZ 618912B2 NZ 618912 A NZ618912 A NZ 618912A NZ 61891212 A NZ61891212 A NZ 61891212A NZ 618912 B2 NZ618912 B2 NZ 618912B2
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Abstract
Provided are N-(benzo[d]thiazol-2-yl)-4-{5-[1,2-dihydroxyethyl]-3-halo/trifluoromethylpyridin-2-yl}-piperazin-1-yl-carboxamide derivative compounds of the general formula (I), wherein the variables are as defined in the specification. An example of the compounds is (5)-4-{5-[(5)-1,2-Dihydroxyethyl]-3-fluoropyridin-2-y1)-N-(5-fluorobenzo[d]thiazol-2-y1)- 2-methylpiperazine-1-carboxamide. The compounds are antagonists of Transient Receptor Potential Vanilloid 1 (TRPV1). The compounds may be useful in the treatment of pain, osteoarthritis, urinary incontinence, ulcers, inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS). 3-fluoropyridin-2-y1)-N-(5-fluorobenzo[d]thiazol-2-y1)- 2-methylpiperazine-1-carboxamide. The compounds are antagonists of Transient Receptor Potential Vanilloid 1 (TRPV1). The compounds may be useful in the treatment of pain, osteoarthritis, urinary incontinence, ulcers, inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS).
Description
TRPV1 ANTAGONISTS INCLUDING DIHYDROXY SUBSTITUENT
AND USES THEREOF
1. FIELD
The disclosure relates to Compounds of Formula (I), and pharmaceutically acceptable
derivatives thereof, compositions comprising an effective amount of a Compound of Formula
(I) and methods for treating or preventing a condition such as pain, e.g., pain associated with
osteoarthritis, osteoarthritis, UI, an ulcer, IBD, and IBS, comprising administering to an animal
in need thereof an effective amount of a Compound of Formula (I).
2. BACKGROUND
Pain is the most common symptom for which patients seek medical advice and treatment. Pain
can be acute or chronic. While acute pain is usually self-limited, chronic pain persists for three
months or longer and can lead to significant changes in a patient's personality, lifestyle,
functional ability and overall quality of life (Foley, "Pain," in Cecil Textbook of Medicine, pp.
100-107 (Bennett and Plum eds., 20th ed. 1996)).
Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain
includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis.
Neuropathic pain is caused by damage to the peripheral or central nervous system and is
maintained by aberrant somatosensory processing. There is a large body of evidence relating
activity at vanilloid receptors (Di Marzo et al., "Endovanilloid signaling in pain," Current
Opinion in Neurobiology 12:372-379 (2002)) to pain processing.
Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such
as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen,
diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone,
methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the above-
listed treatments, neuropathic pain, which can be difficult to treat, has also been treated with
anti-epileptics (e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenytoin), NMDA
antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia),
and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline).
UI is uncontrollable urination, generally caused by bladder-detrusor-muscle instability. UI
affects people of all ages and levels of physical health, both in health care settings and in the
community at large. Physiologic bladder contraction results in large part from acetylcholine-
induced stimulation of post-ganglionic muscarinic-receptor sites on bladder smooth muscle.
Treatments for UI include the administration of drugs having bladder-relaxant properties,
which help to control bladder-detrusor-muscle overactivity.
None of the existing commercial drug treatments for UI has achieved complete success in all
classes of UI patients, nor has treatment occurred without significant adverse side effects.
Treatment of ulcers often involves reducing or inhibiting the aggressive factors. For example,
antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium
bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis,
leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of
other drugs into the blood stream and cause diarrhea.
H antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine, are also used to treat
ulcers. H antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme
secretion elicited by histamine and other H agonists in the stomach and duodenum. H
antagonists, however, can cause breast enlargement and impotence in men, mental changes
(especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.
H , K - ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers.
H , K - ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete
acid. Side effects associated with H , K - ATPase inhibitors include nausea, diarrhea,
abdominal colic, headache, dizziness, somnolence, skin rashes, and transient elevations of
plasma activities of aminotransferases.
Inflammatory-bowel disease ("IBD") is a chronic disorder in which the bowel becomes
inflamed, often causing recurring abdominal cramps and diarrhea. The two types of IBD are
Crohn's disease and ulcerative colitis.
Crohn's disease, which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a
chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is
more common in Jews of eastern-European ancestry. Most cases of Crohn's disease begin
before age 30 and the majority start between the ages of 14 and 24. The disease often affects
the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the
small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract.
Cramps and diarrhea, side effects associated with Crohn's disease, can be relieved by
anticholinergic drugs, diphenoxylate, loperamide, deodorized opium tincture, or codeine.
When Crohn's disease causes the intestine to be obstructed or when abscesses or fistulas do not
heal, surgery can be necessary to remove diseased sections of the intestine. Surgery, however,
does not cure the disease, and inflammation tends to recur where the intestine is rejoined. In
almost half of the cases a second operation is needed. Berkow et al., eds., "Crohn's Disease,"
Merck Manual of Medical Information, pp. 528-530 (1997).
Ulcerative colitis is a chronic disease in which the large intestine becomes inflamed and
ulcerated, leading to episodes of bloody diarrhea, abdominal cramps, and fever. Ulcerative
colitis usually begins between ages 15 and 30; however, a small group of people have their first
attack between ages 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the
small intestine and does not affect the full thickness of the intestine. The disease usually begins
in the rectum and the sigmoid colon and eventually spreads partially or completely throughout
the large intestine. The cause of ulcerative colitis is unknown.
Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and
replacing lost fluids and nutrients. Anticholinergic drugs and low doses of diphenoxylate or
loperamide are administered for treating mild diarrhea. For more intense diarrhea higher doses
of diphenoxylate or loperamide, or deodorized opium tincture or codeine are administered.
Irritable-bowel syndrome ("IBS") is a disorder of motility of the entire gastrointestinal tract,
causing abdominal pain, constipation, and/or diarrhea. IBS affects three-times more women
than men. In IBS, stimuli such as stress, diet, drugs, hormones, or irritants can cause the
gastrointestinal tract to contract abnormally. During an episode of IBS, contractions of the
gastrointestinal tract become stronger and more frequent, resulting in the rapid transit of food
and feces through the small intestine, often leading to diarrhea. Cramps result from the strong
contractions of the large intestine and increased sensitivity of pain receptors in the large
intestine.
Treatment of IBS often involves modification of an IBS-patient's diet. Often it is
recommended that an IBS patient avoid beans, cabbage, sorbitol, and fructose. A low-fat, high-
fiber diet can also help some IBS patients. Regular physical activity can also help keep the
gastrointestinal tract functioning properly. Drugs such as propantheline that slow the function
of the gastrointestinal tract are generally not effective for treating IBS. Antidiarrheal drugs,
such as diphenoxylate and loperamide, help with diarrhea. Berkow et al., eds., "Irritable Bowel
Syndrome," Merck Manual of Medical Information, pp. 525-526 (1997).
International publication no. WO 98/31677 describes a class of aromatic amines derived from
cyclic amines that are useful as antidepressant drugs. International publication no. WO
01/027107 describes a class of heterocyclic compounds that are sodium/proton exchange
inhibitors. International publication no. WO 99/37304 describes substituted
oxoazaheterocyclic compounds useful for inhibiting factor Xa. U.S. Patent No. 6,248,756 to
Anthony et al. and international publication no. WO 97/38665 describe a class of piperidine-
containing compounds that inhibit farnesyl-protein transferase (Ftase). International
publication no. WO 98/31669 describes a class of aromatic amines derived from cyclic amines
useful as antidepressant drugs. International publication no. WO 97/28140 describes a class of
piperidines derived from 1-(piperazinyl)aryl(oxy/amino)carbonylaryl-piperidine that are
useful as 5-HT receptor antagonists. International publication no. WO 97/38665 describes a
class of piperidine containing compounds that are useful as inhibitors of farnesyl-protein
transferase.
U.S. Patent No. 4,797,419 to Moos et al. describes a class of urea compounds for stimulating
the release of acetylcholine and useful for treating symptoms of senile cognitive decline. U.S.
Patent No. 5,891,889 to Anthony et al. describes a class of substituted piperidine compounds
that are useful as inhibitors of farnesyl-protein transferase, and the farnesylation of the
oncogene protein Ras. U.S. Patent No. 6,150,129 to Cook et al. describes a class of dinitrogen
heterocycles useful as antibiotics. U.S. Patent No. 5,529,998 to Habich et al. describes a class
of benzooxazolyl- and benzothiazolyloxazolidones useful as antibacterials.
International publication no. WO 01/57008 describes a class of 2-benzothiazolyl urea
derivatives useful as inhibitors of serine/threonine and tyrosine kinases. International
publication no. WO 02/08221 describes aryl piperazine compounds useful for treating chronic
and acute pain conditions, itch, and urinary incontinence. International publication no. WO
00/59510 describes aminopyrimidines useful as sorbitol dehydrogenase inhibitors.
Japanese patent application no. 11-199573 to Kiyoshi et al. describes benzothiazole derivatives
that are neuronal 5HT3 receptor agonists in the intestinal canal nervous system and useful for
treating digestive disorders and pancreatic insufficiency. German patent application no 199 34
799 to Rainer et al. describes a chiral-smectic liquid crystal mixture containing compounds
with 2 linked (hetero)aromatic rings or compounds with 3 linked (hetero)aromatic rings.
Chu-Moyer et al., J. Med. Chem. 45:511-528 (2002) describes heterocycle-substituted
piperazino-pyrimidines useful as sorbitol dehydrogenase inhibitors. Khadse et al., Bull. Haff.
Instt. 1(3):27-32 (1975) describes 2-(N -substituted-N -piperazinyl) pyrido(3,2-d)thiazoles and
-nitro(N -substituted-N -piperazinyl)benzthiazoles useful as anthelmintic agents.
U.S. Patent Application Publication No. US 2004/0186111 A1 and International publication no.
A1 describe a class of compounds that are useful for treating pain. U.S.
Patent Application Publication No. US 2006/0199824 A1 and International publication no. WO
2005/009987 A1 describe a class of compounds that are useful for treating pain. U.S. Patent
Application Publication No. US 2006/0128717 A1 and International publication no. WO
2005/009988 A1 describe a class of compounds that are useful for treating pain. U.S. Patent
Application Publication Nos. US 2009/0170867 A1, US 2009/0170868 A1, and 2009/0176796
A1 and International publication no. A2 describe a class of compounds that
are useful for treating pain.
There remains, however, a clear need in the art for new drugs useful for treating or preventing
pain, e.g., pain associated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, and IBS.
Citation of any reference in Section 2 of this application is not to be construed as an admission
that such reference is prior art to the present application.
3. SUMMARY
In a first aspect of the disclosure, new compounds that exhibit affinity for the TRPV1 receptor
are described.
In some embodiments, such new compounds exhibit antagonist activity at the TRPV1 receptor.
In other embodiments, such new compounds exhibit partial antagonist activity at the TRPV1
receptor.
Certain new compounds of the disclosure can be used to treat an animal suffering from pain,
e.g., chronic or acute pain.
In another aspect of the disclosure, methods of treating chronic or acute pain in an animal by
administering one or more Compounds of Formula (I) to an animal in need of such treatment
are described. In certain embodiments, such new Compounds of Formula (I) effectively treat
chronic or acute pain in the animal, while producing fewer or reduced side effects compared to
previously available compounds.
Compounds of Formula (I) are herein disclosed:
or a pharmaceutically acceptable derivative thereof, where:
R is -halo or -CF ;
R is -H or -CH ;
each R and R is independently -H, -halo, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
8 9 3 3 3 3 2 3 2 3
or -C(O)OR ;
R is -(C -C )alkyl;
1 4
each halo is independently -F, -Cl, -Br, or -I; and
m is the integer 0 or 1;
(1) provided that if R is -H then m is 1; and
(2) provided that if R is -H and the carbon atom at the a position of the a-b bond is in the (S)
configuration, then the methyl group bonded to the piperazine ring is a (S)methyl group, a
(S)methyl group, or a (R)methyl group,
and wherein the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, polymorph, solvate, co-crystal, radiolabeled form and/or tautomer.
In another embodiment in connection with a Compound of Formula (I), it is further provided
that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group;
(4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and/or
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group or a (R)methyl group.
Compounds of Formula (I) are potent at TRPV1 receptors, and are soluble in aqueous solutions
at either pH 6.8 or pH 1.2.
A Compound of Formula (I), or a pharmaceutically acceptable derivative thereof, is useful for
treating or preventing pain, e.g., pain associated with osteoarthritis, osteoarthritis, UI, an ulcer,
IBD, or IBS (each being a "Condition") in an animal.
The disclosure also relates to compositions comprising an effective amount of a Compound of
Formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically
acceptable carrier or excipient. The compositions are useful for treating or preventing a
Condition in an animal.
The disclosure further relates to methods for treating a Condition comprising administering to
an animal in need thereof an effective amount of a Compound of Formula (I), or a
pharmaceutically acceptable derivative thereof.
The disclosure further relates to a Compound of Formula (I), a pharmaceutically acceptable
derivative thereof, a composition containing a Compound of Formula (I), and/or a composition
containing a pharmaceutically acceptable derivative of a Compound of Formula (I) for use in
the treatment of pain, e.g., pain associated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD,
or IBS in an animal.
The disclosure further relates to use of a Compound of Formula (I), or a pharmaceutically
acceptable derivative thereof, in the manufacture of a medicament for treating and/or
preventing a Condition, such as pain and/or osteoarthritis. The disclosure further relates to a
Compound of Formula (I), or a pharmaceutically acceptable derivative thereof, for use in the
treatment and/or prevention of a Condition, such as pain and/or osteoarthritis.
The disclosure further relates to methods for preventing a Condition comprising administering
to an animal in need thereof an effective amount of a Compound of Formula (I), or a
pharmaceutically acceptable derivative thereof.
The disclosure still further relates to methods for inhibiting Transient Receptor Potential
Vanilloid 1 ("TRPV1," formerly known as Vanilloid Receptor 1 or VR1) function in a cell,
comprising contacting a cell capable of expressing TRPV1 with an effective amount of a
Compound of Formula (I), or a pharmaceutically acceptable derivative thereof.
The disclosure still further relates to a method for preparing a composition comprising the step
of admixing a Compound of Formula (I), or a pharmaceutically acceptable derivative thereof,
and a pharmaceutically acceptable carrier or excipient.
The disclosure still further relates to a kit comprising a container containing an effective
amount of a Compound of Formula (I), or a pharmaceutically acceptable derivative thereof.
In one embodiment, preferred Compounds of Formula (I) are Compounds of Formula (II):
(II)
or a pharmaceutically acceptable derivative thereof, where:
R is -H or -CH ;
R is -H, -F, or -CH ;
R is -H, -halo, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH ; and
9 3 3 3 3 2 3 2 3 2 3
each halo is independently -F, -Cl, -Br, or -I;
(1) provided that if R is -H and the carbon atom at the a position of the a-b bond is in the (S)
configuration, then the methyl group bonded to the piperazine ring is a (S)methyl group, a
(S)methyl group, or a (R)methyl group,
and wherein the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, polymorph, solvate, co-crystal, radiolabeled form and/or tautomer.
In another embodiment in connection with a Compound of Formula (II), it is further provided
that:
(2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group;
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and/or
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group or a (R)methyl group.
Many Compounds of Formula (II) are soluble, in some cases highly soluble, in aqueous
solutions at either pH 6.8 or pH 1.2, are potent at TRPV1 receptors, are orally bioavailable,
have a good therapeutic index, and are believed to be highly efficacious in animals for the
treatment of pain and/or osteoarthritis. Moreover, Compounds of Formula (II) are capable of
ameliorating undesirable side effects, such as an increase in body temperature that can occur
upon in vivo administration of some compounds which modulate the TRPV1 receptor.
The disclosure can be understood more fully by reference to the following detailed description
and illustrative examples, which are intended to exemplify non-limiting embodiments of the
disclosure.
3.1. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the PXRD pattern (CuK radiation) of the product prepared with Compound
A155(a) and fumaric acid.
Figure 2 depicts N NMR CP/MAS spectra of the product prepared with Compound A155(a)
and fumaric acid, the dihydrochloride-salt of Compound A155(a) and the free base of
Compound A155(a).
Figure 3 depicts the C NMR CP/MAS spectrum of the product prepared with Compound
A155(a) and fumaric acid.
4. DETAILED DESCRIPTION
The invention includes the following:
(1.) A Compound of Formula (I):
or a pharmaceutically acceptable derivative thereof, wherein:
R is -halo or -CF ;
R is -H or -CH ;
each R and R is independently -H, -halo, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
8 9 3 3 3 3 2 3 2 3
or -C(O)OR ;
R is -(C -C )alkyl;
1 4
each halo is independently -F, -Cl, -Br, or -I; and
m is the integer 0 or 1;
(1) provided that if R is -H then m is 1; and
(2) provided that if R is -H and the carbon atom at the a position of the a-b bond is in
the (S) configuration, then the methyl group bonded to the piperazine ring is a (S)
methyl group, a (S)methyl group, or a (R)methyl group,
and wherein the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, polymorph, solvate, co-crystal, radiolabeled form and/or tautomer.
(2.) The compound of the above (1.) or a pharmaceutically acceptable derivative thereof,
wherein it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, R is -H, and R is -halo, then the methyl group bonded to the piperazine
ring is a (R)methyl group;
(4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, R is -F, and R is -F, then the methyl group bonded to the piperazine
ring is a (S)methyl group or a (S)methyl group; and/or
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d
bond are each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl
group bonded to the piperazine ring is a (S)methyl group or a (R)methyl group.
(3.) The compound of the above (1.) or (2.) or a pharmaceutically acceptable derivative
thereof, wherein R is -F, -Cl, or -CF .
(4.) The compound of any one of the above (1.) to (3.) or a pharmaceutically acceptable
derivative thereof, wherein R is -F.
(5.) The compound of any one of the above (1.) to (4.) or a pharmaceutically acceptable
derivative thereof, wherein R is -CH or -CH CH .
3 2 3
(6.) The compound of any one of the above (1.) to (5.) or a pharmaceutically acceptable
derivative thereof, wherein R is -CH CH .
2 3
(7.) The compound of any one of the above (1.) to (6.) or a pharmaceutically acceptable
derivative thereof, wherein R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , or -C(O)OCH CH .
2 3 2 3
(8.) The compound of any one of the above (1.) to (7.) or a pharmaceutically acceptable
derivative thereof, wherein R is -H, -F, or -CH .
(9.) The compound of any one of the above (1.) to (8.) or a pharmaceutically acceptable
derivative thereof, wherein R is -F or -CH .
(10.) The compound of any one of the above (1.) to (9.) or a pharmaceutically acceptable
derivative thereof, wherein R is -H.
(11.) The compound of any one of the above (1.) to (10.) or a pharmaceutically acceptable
derivative thereof, wherein R is -CH and the carbon atoms at the a and c positions of the a-b
bond and the c-d bond are each in the (S) configuration.
(12.) The compound of any one of the above (1.) to (10.) or a pharmaceutically acceptable
derivative thereof, wherein R is -CH and the carbon atoms at the a and c positions of the a-b
bond and the c-d bond are each in the (R) configuration.
(13.) The compound of any one of the above (1.) to (10.) or a pharmaceutically acceptable
derivative thereof, wherein R is -H and the carbon atom at the a position of the a-b bond is in
the (S) configuration.
(14.) The compound of any one of the above (1.) to (10.) or a pharmaceutically acceptable
derivative thereof, wherein R is -H and the carbon atom at the a position of the a-b bond is in
the (R) configuration.
(15.) The compound of any one of the above (1.) to (14.) or a pharmaceutically acceptable
derivative thereof, wherein m is 1 and the methyl group bonded to the piperazine ring is a (S)-
2-methyl group.
(16.) The compound of the above (1.) to (15.), wherein the pharmaceutically acceptable
derivative is a pharmaceutically acceptable salt, radiolabeled form, a co-crystal, or a
combination thereof.
(17.) The compound of the above (15.) or (16.), wherein the pharmaceutically acceptable
derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-toluenesulfonic acid salt,
a fumaric acid-salt, or a fumarate co-crystal.
(18.) The compound of any one of the above (15.) to (16.), wherein the pharmaceutically
acceptable derivative is a fumaric acid-salt, a fumarate co-crystal, or a combination thereof.
(19.) The compound of any one of the above (1.) to (12.) or a pharmaceutically acceptable
derivative thereof, wherein m is 0.
(20.) The compound of the above (19.), wherein the pharmaceutically acceptable derivative is
a pharmaceutically acceptable salt, radiolabeled form, or a hydrochlorate, tartrate,
benzenesulfonate, p-toluenesulfonate, or fumarate co-crystal.
(21.) The compound of the above (19.) or (20.), wherein the pharmaceutically acceptable
derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-toluenesulfonic acid salt,
a fumaric acid-salt, or a fumarate co-crystal.
(22.) The compound of the above (19.), wherein the pharmaceutically acceptable derivative is
a fumaric acid-salt, a fumarate co-crystal, or a combination thereof.
(23.) The compound of any one of the above (1.) to (8.), (11.), or (19.) or a pharmaceutically
acceptable derivative thereof, which is
.
(24.) The compound of any one of the above (1.) to (3.), (5.) to (8.), (11.), or (19.) or a
pharmaceutically acceptable derivative thereof, which is
(25.) The compound of any one of the above (1.) to (8.), (11.), or (19.) or a pharmaceutically
acceptable derivative thereof, which is
(26.) The compound of any one of the above (1.) to (9.), (11.), or (19.) or a pharmaceutically
acceptable derivative thereof, which is
(27.) The compound of any one of the above (23.) to (26.), which is a free base.
(28.) The compound of any one of the above (23.) to (26.), which is a fumaric acid-salt, a
fumarate co-crystal, or a combination thereof.
(29.) A composition comprising the compound of any one of the above (1.) to (28.) or a
pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or
excipient.
(30.) A method for treating pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer,
IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective
amount of the compound of any one of the above (1.) to (28.) or a pharmaceutically acceptable
derivative thereof.
(31.) A method for treating pain, pain associated with osteoarthritis, UI, an ulcer, IBD, or IBS
in an animal, comprising administering to an animal in need thereof, an effective amount of the
compound of any one of the above (1.) to (28.) or a pharmaceutically acceptable derivative
thereof.
(32.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, or IBS in an animal,
comprising administering to an animal in need thereof, an effective amount of the compound of
any one of the above (1.) to (28.) or a pharmaceutically acceptable derivative thereof.
(33.) A method for treating pain, UI, an ulcer, IBD, or IBS in an animal, comprising
administering to an animal in need thereof, an effective amount of the compound of any one of
the above (1.) to (28.) or a pharmaceutically acceptable derivative thereof.
(34.) A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of
expressing TRPV1 with an effective amount of the compound of any one of the above (1.) to
(28.) or a pharmaceutically acceptable derivative thereof.
(35.) The product of combining the compound of any one of the above (1.) to (28.) with
fumaric acid, where the molar ratio in the product is about 1:0.5 of (the Compound of Formula
(I)):(fumaric acid).
(36.) A composition comprising the product of the above (35.) and a pharmaceutically
acceptable carrier or excipient.
(37.) A method for treating pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer,
IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective
amount of the product of the above (35.).
(38.) A method for treating pain, pain associated with osteoarthritis, UI, an ulcer, IBD, or IBS
in an animal, comprising administering to an animal in need thereof, an effective amount of the
product of the above (35.).
(39.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, or IBS in an animal,
comprising administering to an animal in need thereof, an effective amount of the product of
the above (35.).
(40.) A method for treating pain, UI, an ulcer, IBD, or IBS in an animal, comprising
administering to an animal in need thereof, an effective amount of the product of the above
(35.).
(41.) A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of
expressing TRPV1 with an effective amount of the product of the above (35.).
(42.) The compound of any one of the above (1.), (4.), (6.), or (8.), which is a compound of
formula (II):
(II)
or a pharmaceutically acceptable derivative thereof, wherein:
R is -H or -CH ;
R is -H, -F, or -CH ;
R is -H, -halo, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH ; and
9 3 3 3 3 2 3 2 3 2 3
each halo is independently -F, -Cl, -Br, or -I;
(1) provided that if R is -H and the carbon atom at the a position of the a-b bond is in
the (S) configuration, then the methyl group bonded to the piperazine ring is a (S)
methyl group, a (S)methyl group, or a (R)methyl group,
and wherein the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, polymorph, solvate, co-crystal, radiolabeled form and/or tautomer.
(43.) The compound of the above (42.) or a pharmaceutically acceptable derivative thereof,
wherein it is further provided that:
(2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, R is -H, and R is -halo, then the methyl group bonded to the piperazine
ring is a (R)methyl group;
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, R is -F, and R is -F, then the methyl group bonded to the piperazine
ring is a (S)methyl group or a (S)methyl group; and/or
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d
bond are each in the (S) configuration, R is -H, and R is -halo, then the methyl group
bonded to the piperazine ring is a (S)methyl group or a (R)methyl group.
(44.) The compound of the above (42.) or (43.) or a pharmaceutically acceptable derivative
thereof, wherein R is -CH and the carbon atoms at the a and c positions of the a-b bond and
the c-d bond are each in the (S) configuration.
(45.) The compound of the above (42.) or (43.) or a pharmaceutically acceptable derivative
thereof, wherein R is -CH and the carbon atoms at the a and c positions of the a-b bond and
the c-d bond are each in the (R) configuration.
(46.) The compound of the above (42.) or (43.) or a pharmaceutically acceptable derivative
thereof, wherein R is -H and the carbon atom at the a position of the a-b bond is in the (S)
configuration.
(47.) The compound of the above (42.) or (43.) or a pharmaceutically acceptable derivative
thereof, wherein R is -H and the carbon atom at the a position of the a-b bond is in the (R)
configuration.
(48.) The compound of any one of the above (42.) to (47.) or a pharmaceutically acceptable
derivative thereof, wherein the methyl group bonded to the piperazine ring is a (S)methyl
group.
(49.) The compound of the above (48.) or a pharmaceutically acceptable derivative thereof,
wherein R is -H.
(50.) The compound of the above (48.) or (49.) or a pharmaceutically acceptable derivative
thereof, wherein R is -F.
(51.) The compound of any one of the above (48.) to (50.), wherein the pharmaceutically
acceptable derivative is a pharmaceutically acceptable salt, or a fumarate co-crystal.
(52.) The compound of any one of the above (48.) to (51.), wherein the pharmaceutically
acceptable derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-
toluenesulfonic acid salt, a fumaric acid-salt, or a fumarate co-crystal.
(53.) The compound of any one of the above (48.) to (50.), wherein the pharmaceutically
acceptable derivative is a fumaric acid-salt, a fumarate co-crystal, or a combination thereof.
(54.) The compound of any one of the above (42.) to (47.) or a pharmaceutically acceptable
derivative thereof, wherein the methyl group bonded to the piperazine ring is a (S)methyl
group.
(55.) The compound of the above (54.) or a pharmaceutically acceptable derivative thereof,
wherein R is -H.
(56.) The compound of the above (54.) or (55.) or a pharmaceutically acceptable derivative
thereof, wherein R is -F.
(57.) The compound of any one of the above (54.) to (56.), wherein the pharmaceutically
acceptable derivative is a pharmaceutically acceptable salt, or a fumarate co-crystal.
(58.) The compound of any one of the above (54.) to (57.), wherein the pharmaceutically
acceptable derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-
toluenesulfonic acid salt, a fumaric acid-salt, or a fumarate co-crystal.
(59.) The compound of any one of the above (54.) to (56.), wherein the pharmaceutically
acceptable derivative is a fumaric acid-salt, a fumarate co-crystal, or a combination thereof.
(60.) The compound of any one of the above (42.) to (47.) or a pharmaceutically acceptable
derivative thereof, wherein the methyl group bonded to the piperazine ring is a (R)methyl
group.
(61.) The compound of the above (60.) or a pharmaceutically acceptable derivative thereof,
wherein R is -H.
(62.) The compound of the above (60.) or (61.) or a pharmaceutically acceptable derivative
thereof, wherein R is -F.
(63.) The compound of any one of the above (60.) to (62.), wherein the pharmaceutically
acceptable derivative is a pharmaceutically acceptable salt, or a fumarate co-crystal.
(64.) The compound of any one of the above (60.) to (63.), wherein the pharmaceutically
acceptable derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-
toluenesulfonic acid salt, a fumaric acid-salt, or a fumarate co-crystal.
(65.) The compound of any one of the above (60.) to (62.), wherein the pharmaceutically
acceptable derivative is a fumaric acid-salt, a fumarate co-crystal, or a combination thereof.
(66.) The compound of any one of the above (42.), (43.), (46.), (54.), (55.), or (57.) to (59.) or
a pharmaceutically acceptable derivative thereof, which is
(67.) The compound of any one of the above (42.) to (44.), (60.), or (62.) to (65.) or a
pharmaceutically acceptable derivative thereof, which is
(68.) The compound of any one of the above (42.), (43.), (47.), or (54.) to (59.) or a
pharmaceutically acceptable derivative thereof, which is
.
(69.) The compound of any one of the above (42.), (43.), (46.), or (54.) to (59.) or a
pharmaceutically acceptable derivative thereof, which is
(70.) The compound of any one of the above (42.), (43.), (46.), (54.), or (57.) to (59.) or a
pharmaceutically acceptable derivative thereof, which is
(71.) The compound of any one of the above (42.), (43.), or (47) or a pharmaceutically
acceptable derivative thereof, which is
(72.) The compound of any one of the above (42.), (43.), (46.), (54.), or (56.) to (59.) or a
pharmaceutically acceptable derivative thereof, which is
(73.) The compound of any one of the above (42.), (43.), (46.), (60.), or (63.) to (65.) or a
pharmaceutically acceptable derivative thereof, which is
(74.) The compound of any one of the above (66.) to (73.), which is a free base.
(75.) The compound of any one of the above (66.) to (73.), which is a fumaric acid-salt, a
fumarate co-crystal, or a combination thereof.
(76.) A composition comprising the compound of any one of the above (42.) to (75.) or a
pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or
excipient.
(77.) A method for treating pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer,
IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective
amount of the compound of any one of the above (42.) to (75.) or a pharmaceutically
acceptable derivative thereof.
(78.) A method for treating pain, pain associated with osteoarthritis, UI, an ulcer, IBD, or IBS
in an animal, comprising administering to an animal in need thereof, an effective amount of the
compound of any one of the above (42.) to (75.) or a pharmaceutically acceptable derivative
thereof.
(79.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, or IBS in an animal,
comprising administering to an animal in need thereof, an effective amount of the compound of
any one of the above (42.) to (75.) or a pharmaceutically acceptable derivative thereof.
(80.) A method for treating pain, UI, an ulcer, IBD, or IBS in an animal, comprising
administering to an animal in need thereof, an effective amount of the compound of any one of
the above (42.) to (75.) or a pharmaceutically acceptable derivative thereof.
(81.) A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of
expressing TRPV1 with an effective amount of the compound of any one of the above (42.) to
(75.) or a pharmaceutically acceptable derivative thereof.
(82.) The product of combining the compound of any one of the above (42.) to (74.) with
fumaric acid, where the molar ratio in the product is about 1:0.5 of (the Compound of Formula
(I)):(fumaric acid).
(83.) A composition comprising the product of the above (82.) and a pharmaceutically
acceptable carrier or excipient.
(84.) A method for treating pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer,
IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective
amount of the product of the above (82.).
(85.) A method for treating pain, pain associated with osteoarthritis, UI, an ulcer, IBD, or IBS
in an animal, comprising administering to an animal in need thereof, an effective amount of the
product of the above (82.).
(86.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, or IBS in an animal,
comprising administering to an animal in need thereof, an effective amount of the product of
the above (82.).
(87.) A method for treating pain, UI, an ulcer, IBD, or IBS in an animal, comprising
administering to an animal in need thereof, an effective amount of the product of the above
(82.).
(88.) A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of
expressing TRPV1 with an effective amount of the product of the above (82.).
(89.) A compound which is
or a pharmaceutically acceptable derivative thereof.
(90.) A composition comprising the compound of the above (89.) or a pharmaceutically
acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient.
(91.) A method for treating pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer,
IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective
amount of the compound of the above (89.) or a pharmaceutically acceptable derivative thereof.
(92.) A method for treating pain, pain associated with osteoarthritis, UI, an ulcer, IBD, or IBS
in an animal, comprising administering to an animal in need thereof, an effective amount of the
compound of the above (89.) or a pharmaceutically acceptable derivative thereof.
(93.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, or IBS in an animal,
comprising administering to an animal in need thereof, an effective amount of the compound of
the above (89.) or a pharmaceutically acceptable derivative thereof.
(94.) A method for treating pain, UI, an ulcer, IBD, or IBS in an animal, comprising
administering to an animal in need thereof, an effective amount of the compound of the above
(89.) or a pharmaceutically acceptable derivative thereof.
(95.) A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of
expressing TRPV1 with an effective amount of the compound of the above (89.) or a
pharmaceutically acceptable derivative thereof.
(96.) The compound of any one of the above (1.) to (95.) or a pharmaceutically acceptable
derivative thereof, wherein the % ee of the compound is at least about 90%.
(97.) The compound of any one of the above (1.) to (96.) or a pharmaceutically acceptable
derivative thereof, wherein the % ee of the compound is at least about 93%.
(98.) A compound, product or a pharmaceutically acceptable derivative thereof or composition
of any one of the above (1.) to (29.), (35.), (36.), (42.) to (76.), (82.), (83.), (89.), (90.), (96.), or
(97.) for use in the treatment of pain, pain associated with osteoarthritis, osteoarthritis, UI, an
ulcer, IBD, or IBS in an animal.
(99.) A compound, product or a pharmaceutically acceptable derivative thereof or composition
of any one of the above (1.) to (29.), (35.), (36.), (42.) to (76.), (82.), (83.), (89.), (90.), or (96.)
to (98.) for use in the treatment of pain in an animal.
(100.) A compound, product or composition of any one of the above (1.) to (29.), (35.), (36.),
(42.) to (76.), (82.), (83.), (89.), (90.), or (96.) to (98.) for use in the treatment of pain
associated with osteoarthritis in an animal.
(101.) A compound, product or a pharmaceutically acceptable derivative thereof or
composition of any one of the above (1.) to (29.), (35.), (36.), (42.) to (76.), (82.), (83.), (89.),
(90.), or (96.) to (98.) for use in the treatment of osteoarthritis in an animal.
(102.) Use of a compound, product or composition of any one of the above (1.) to (29.), (35.),
(36.), (42.) to (76.), (82.), (83.), (89.), (90.), or (96.) to (98.) or a pharmaceutically acceptable
derivative thereof in the manufacture of a medicament for the treatment of pain, pain associated
with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, or IBS
4.1 Compounds of Formula (I)
The disclosure encompasses Compounds of Formula (I):
or a pharmaceutically acceptable derivative thereof,
(1) provided that if R is -H then m is 1, and
(2) provided that if R is -H and the a-b bond is in the (S) configuration, then the methyl group
bonded to the piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl
group,
where R , R , R , R , and m are as defined above for Compounds of Formula (I).
1 4 8 9
Certain embodiments of formula (I) are presented below.
In one embodiment, a Compound of Formula (I) is a free base.
In another embodiment, a Compound of Formula (I) is a pharmaceutically acceptable
derivative of a Compound of Formula (I).
In another embodiment, the pharmaceutically acceptable derivative of a Compound of Formula
(I) is a pharmaceutically acceptable salt. In another embodiment, the pharmaceutically
acceptable derivative of a Compound of Formula (I) is a fumaric acid-salt. In another
embodiment, the pharmaceutically acceptable derivative of a Compound of Formula (I) is a
fumaric acid-salt where the molar ratio of the Compound of Formula (I):fumaric acid is about
1:0.5.
In another embodiment, the pharmaceutically acceptable derivative of a Compound of Formula
(I) is a co-crystal. In another embodiment, the pharmaceutically acceptable derivative of a
Compound of Formula (I) is a fumarate co-crystal. In another embodiment, the
pharmaceutically acceptable derivative of a Compound of Formula (I) is a fumarate co-crystal
where the molar ratio of the Compound of Formula (I):fumarate is about 1:0.5.
In another embodiment, the pharmaceutically acceptable derivative of a Compound of Formula
(I) is a fumaric acid-salt, a fumarate co-crystal, or a combination thereof. In another
embodiment, the molar ratio of the Compound of Formula (I):(fumaric acid and/or fumarate) is
about 1:0.5.
Other embodiments relate to the product of combining a Compound of Formula (I) with
fumaric acid, where the molar ratio in the product is about 1:0.5 of (the Compound of Formula
(I)):(fumaric acid); a composition comprising that product and a pharmaceutically acceptable
carrier or excipient; a method for treating pain, e.g., pain associated with osteoarthritis,
osteoarthritis, UI, an ulcer, IBD, or IBS in an animal, comprising administering to an animal in
need thereof, an effective amount of that product; and a method of inhibiting TRPV1 function
in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of
that product.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group.
In another embodiment, it is further provided that:
(4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group.
In another embodiment, it is further provided that:
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group or a (R)methyl group.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group; and
(4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group; and
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group or a (R)methyl group.
In another embodiment, it is further provided that:
(4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group or a (R)methyl group.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group;
(4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group or a (R)methyl group.
In another embodiment, it is further provided that:
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group; and
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group.
In another embodiment, it is further provided that:
(4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group;
(4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and
(5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to
the piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group.
In another embodiment, R is -F, -Cl, -Br, or -CF .
In another embodiment, R is -F, -Cl, or -CF .
In another embodiment, R is -F or -CF .
In another embodiment, R is -Cl or -CF .
In another embodiment, R is -F or -Cl.
In another embodiment, R is -F.
In another embodiment, R is -Cl.
In another embodiment, R is -CF .
In another embodiment, R is -Br.
In another embodiment, R is -CH or -CH CH .
3 2 3
In another embodiment, R is -CH CH .
2 3
In another embodiment, R is -CH .
3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH .
2 3 2 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH .
9 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH .
9 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH .
2 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH .
9 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH .
9 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF .
9 3 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF .
9 3 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF .
9 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH .
9 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF .
9 3 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH .
9 3 3
In another embodiment, R is -H, -F, -Cl, or -CH .
In another embodiment, R is -H, -F, -Cl, or -OCH .
In another embodiment, R is -H, -F, -Cl, or -OCF .
In another embodiment, R is -H, -F, or -CH .
In another embodiment, R is -H, -F, or -OCH .
In another embodiment, R is -H, -F, or -OCF .
In another embodiment, R is -H, -F, or -Cl.
In another embodiment, R is -H or -F.
In another embodiment, R is -H or -Cl.
In another embodiment, R is -H or -CH .
In another embodiment, R is -F or -CH .
In another embodiment, R is -F or -Cl.
In another embodiment, R is -Cl or -CH .
In another embodiment, R is -H.
In another embodiment, R is -F.
In another embodiment, R is -Cl.
In another embodiment, R is -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH .
2 3 2 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
8 3 3 3 3 2 3
or -CH OCH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH .
8 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH .
8 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
8 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH .
2 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
8 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
8 3 3 3 3 2 3
or -CH OCH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH .
8 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH .
8 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF .
8 3 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF .
8 3 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF .
8 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH .
8 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF .
8 3 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH .
8 3 3
In another embodiment, R is -H, -F, -Cl, or -CH .
In another embodiment, R is -H, -F, -Cl, or -OCH .
In another embodiment, R is -H, -F, -Cl, or -OCF .
In another embodiment, R is -H, -F, or -CH .
In another embodiment, R is -H, -F, or -OCH .
In another embodiment, R is -H, -F, or -OCF .
In another embodiment, R is -H, -F, or -Cl.
In another embodiment, R is -H or -F.
In another embodiment, R is -H or -Cl.
In another embodiment, R is -H or -CH .
In another embodiment, R is -F or -CH .
In another embodiment, R is -F or -Cl.
In another embodiment, R is -Cl or -CH .
In another embodiment, R is -H.
In another embodiment, R is -F.
In another embodiment, R is -Cl.
In another embodiment, R is -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH and R is -H, -F, or -CH .
2 3 2 3 3 2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH and R is -H, -F, or -CH .
2 3 2 3 2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -H, -F, or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -H, -F, or -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -H, -F, or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH and R is -H, -F, or -CH .
2 3 3 2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH and R is -H, -F, or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -H, -F, or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -H, -F, or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -H, -F, or -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF and R is -H, -F, or
9 3 3 3 3 8
-CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF and R is -H, -F,
9 3 3 3 3 8
or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF and R is -H, -F, or -CH .
9 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH and R is -H, -F, or -CH .
9 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF and R is -H, -F, or -CH .
9 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH and R is -H, -F, or -CH .
9 3 3 8 3
In another embodiment, R is -H, -F, -Cl, or -CH and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, or -OCH and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, or -OCF and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -CH and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -OCH and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -OCF and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -Cl and R is -H, -F, or -CH .
9 8 3
In another embodiment, R is -H or -F and R is -H, -F, or -CH .
9 8 3
In another embodiment, R is -H or -Cl and R is -H, -F, or -CH .
9 8 3
In another embodiment, R is -H or -CH and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -F or -CH and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -F or -Cl and R is -H, -F, or -CH .
9 8 3
In another embodiment, R is -Cl or -CH and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -H and R is -H, -F, or -CH .
9 8 3
In another embodiment, R is -F and R is -H, -F, or -CH .
9 8 3
In another embodiment, R is -Cl and R is -H, -F, or -CH .
9 8 3
In another embodiment, R is -CH and R is -H, -F, or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH and R is -F or -CH .
2 3 2 3 3 2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH and R is -F or -CH .
2 3 2 3 2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -F or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -F or -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -F or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH and R is -F or -CH .
2 3 3 2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH and R is -F or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -F or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -F or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -F or -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF and R is -F
9 3 3 3 3 8
or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF and R is -F or -CH .
9 3 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF and R is -F or -CH .
9 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH and R is -F or -CH .
9 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF and R is -F or -CH .
9 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH and R is -F or -CH .
9 3 3 8 3
In another embodiment, R is -H, -F, -Cl, or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, or -OCH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, or -OCF and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -OCH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -OCF and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -Cl and R is -F or -CH .
9 8 3
In another embodiment, R is -H or -F and R is -F or -CH .
9 8 3
In another embodiment, R is -H or -Cl and R is -F or -CH .
9 8 3
In another embodiment, R is -H or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -F or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -F or -Cl and R is -F or -CH .
9 8 3
In another embodiment, R is -Cl or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H and R is -F or -CH .
9 8 3
In another embodiment, R is -F and R is -F or -CH .
9 8 3
In another embodiment, R is -Cl and R is -F or -CH .
9 8 3
In another embodiment, R is -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH and R is -F.
2 3 2 3 3 2 3 8
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH and R is -F.
2 3 2 3 2 3 8
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -F.
2 3 8
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -F.
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -F.
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH and R is -F.
2 3 3 2 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH and R is -F.
2 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -F.
2 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -F.
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -F.
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF and R is -F.
9 3 3 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF and R is -F.
9 3 3 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF and R is -F.
9 3 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH and R is -F.
9 3 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF and R is -F.
9 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH and R is -F.
9 3 3 8
In another embodiment, R is -H, -F, -Cl, or -CH and R is -F.
9 3 8
In another embodiment, R is -H, -F, -Cl, or -OCH and R is -F.
9 3 8
In another embodiment, R is -H, -F, -Cl, or -OCF and R is -F.
9 3 8
In another embodiment, R is -H, -F, or -CH and R is -F.
9 3 8
In another embodiment, R is -H, -F, or -OCH and R is -F.
9 3 8
In another embodiment, R is -H, -F, or -OCF and R is -F.
9 3 8
In another embodiment, R is -H, -F, or -Cl and R is -F.
In another embodiment, R is -H or -F and R is -F.
In another embodiment, R is -H or -Cl and R is -F.
In another embodiment, R is -H or -CH and R is -F.
9 3 8
In another embodiment, R is -F or -CH and R is -F.
9 3 8
In another embodiment, R is -F or -Cl and R is -F.
In another embodiment, R is -Cl or -CH and R is -F.
9 3 8
In another embodiment, R is -H and R is -F.
In another embodiment, R is -F and R is -F.
In another embodiment, R is -Cl and R is -F.
In another embodiment, R is -CH and R is -F.
9 3 8
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH , R is -F or -CH , and R is -Cl or -
2 3 2 3 3 2 3 8 3 1
CF .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH , R is -F or -CH , and R is -Cl or -CF .
2 3 2 3 2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH , R is -F or -CH , and R is -Cl or -CF .
2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH , R is -
9 3 3 3 3 2 3 8
F or -CH , and R is -Cl or -CF .
3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH , R is -
9 3 3 3 3 2 3 8
F or -CH , and R is -Cl or -CF .
3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH , R is -F or -CH , and R is -Cl or -CF .
2 3 3 2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH , R is -F or -CH , and R is -Cl or -CF .
2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH , R is -F or -CH , and R is -Cl or -CF .
2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH , R is -F or
9 3 3 3 3 2 3 8
-CH , and R is -Cl or -CF .
3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH , R is -F or
9 3 3 3 3 2 3 8
-CH , and R is -Cl or -CF .
3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF , R is -F or -CH ,
9 3 3 3 3 8 3
and R is -Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF , R is -F or -CH , and
9 3 3 3 3 8 3
R is -Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF , R is -F or -CH , and R is -Cl
9 3 3 3 8 3 1
or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH , R is -F or -CH , and R is -Cl
9 3 3 3 8 3 1
or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF , R is -F or -CH , and R is -Cl
9 3 3 8 3 1
or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH , R is -F or -CH , and R is -Cl
9 3 3 8 3 1
or -CF .
In another embodiment, R is -H, -F, -Cl, or -CH , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, or -OCH , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, or -OCF , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, or -CH , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, or -OCH , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, or -OCF , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, or -Cl, R is -F or -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -H or -F, R is -F or -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -H or -Cl, R is -F or -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -H or -CH , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -F or -CH , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -F or -Cl, R is -F or -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -Cl or -CH , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, R is -F or -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -F, R is -F or -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -Cl, R is -F or -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -CH , R is -F or -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH , R is -F, and R is -Cl or -CF .
2 3 2 3 3 2 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH , R is -F, and R is -Cl or -CF .
2 3 2 3 2 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH , R is -F, and R is -Cl or -CF .
2 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH , R is -
9 3 3 3 3 2 3 8
F, and R is -Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH , R is -
9 3 3 3 3 2 3 8
F, and R is -Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH , R is -F, and R is -Cl or -CF .
2 3 3 2 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH , R is -F, and R is -Cl or -CF .
2 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH , R is -F, and R is -Cl or -CF .
2 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH , R is -F,
9 3 3 3 3 2 3 8
and R is -Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH , R is -F,
9 3 3 3 3 2 3 8
and R is -Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF , R is -F, and R is
9 3 3 3 3 8 1
-Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF , R is -F, and R is -Cl
9 3 3 3 3 8 1
or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF , R is -F, and R is -Cl or -CF .
9 3 3 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH , R is -F, and R is -Cl or -CF .
9 3 3 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF , R is -F, and R is -Cl or -CF .
9 3 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH , R is -F, and R is -Cl or -CF .
9 3 3 8 1 3
In another embodiment, R is -H, -F, -Cl, or -CH , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -H, -F, -Cl, or -OCH , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -H, -F, -Cl, or -OCF , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -H, -F, or -CH , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -H, -F, or -OCH , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -H, -F, or -OCF , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -H, -F, or -Cl, R is -F, and R is -Cl or -CF .
9 8 1 3
In another embodiment, R is -H or -F, R is -F, and R is -Cl or -CF .
9 8 1 3
In another embodiment, R is -H or -Cl, R is -F, and R is -Cl or -CF .
9 8 1 3
In another embodiment, R is -H or -CH , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -F or -CH , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -F or -Cl, R is -F, and R is -Cl or -CF .
9 8 1 3
In another embodiment, R is -Cl or -CH , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -H, R is -F, and R is -Cl or -CF .
9 8 1 3
In another embodiment, R is -F, R is -F, and R is -Cl or -CF .
9 8 1 3
In another embodiment, R is -Cl, R is -F, and R is -Cl or -CF .
9 8 1 3
In another embodiment, R is -CH , R is -F, and R is -Cl or -CF .
9 3 8 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH , R is -CH , and R is -Cl or -CF .
2 3 2 3 3 2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH , R is -CH , and R is -Cl or -CF .
2 3 2 3 2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH , R is -CH , and R is -Cl or -CF .
2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH , R is -
9 3 3 3 3 2 3 8
CH , and R is -Cl or -CF .
3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH , R is -
9 3 3 3 3 2 3 8
CH , and R is -Cl or -CF .
3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH , R is -CH , and R is -Cl or -CF .
2 3 3 2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH , R is -CH , and R is -Cl or -CF .
2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH , R is -CH , and R is -Cl or -CF .
2 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH , R
9 3 3 3 3 2 3 8
is -CH , and R is -Cl or -CF .
3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH , R
9 3 3 3 3 2 3 8
is -CH , and R is -Cl or -CF .
3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF , R is -CH , and R
9 3 3 3 3 8 3 1
is -Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF , R is -CH , and R
9 3 3 3 3 8 3 1
is -Cl or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF , R is -CH , and R is -Cl
9 3 3 3 8 3 1
or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH , R is -CH , and R is -Cl
9 3 3 3 8 3 1
or -CF .
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF , R is -CH , and R is -Cl or -CF .
9 3 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH , R is -CH , and R is -Cl or -CF .
9 3 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, or -CH , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, or -OCH , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, or -OCF , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, or -CH , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, or -OCH , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, or -OCF , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, or -Cl, R is -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -H or -F, R is -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -H or -Cl, R is -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -H or -CH , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -F or -CH , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -F or -Cl, R is -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -Cl or -CH , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, R is -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -F, R is -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -Cl, R is -CH , and R is -Cl or -CF .
9 8 3 1 3
In another embodiment, R is -CH , R is -CH , and R is -Cl or -CF .
9 3 8 3 1 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , -C(O)OCH , or -C(O)OCH CH , R is -F, and R is -Cl.
2 3 2 3 3 2 3 8 1
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH , R is -F, and R is -Cl.
2 3 2 3 2 3 8 1
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH , R is -F, and R is -Cl.
2 3 8 1
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH , R is -
9 3 3 3 3 2 3 8
F, and R is -Cl.
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH , R is -
9 3 3 3 3 2 3 8
F, and R is -Cl.
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -
9 3 3 3 3 2 3
CH OCH , -C(O)OCH , or -C(O)OCH CH , R is -F, and R is -Cl.
2 3 3 2 3 8 1
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH , R is -F, and R is -Cl.
2 3 8 1
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH , R is -F, and R is -Cl.
2 3 8 1
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH , R is -F,
9 3 3 3 3 2 3 8
and R is -Cl.
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH , R is -F,
9 3 3 3 3 2 3 8
and R is -Cl.
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF , R is -F, and R is
9 3 3 3 3 8 1
-Cl.
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF , R is -F, and R is -Cl.
9 3 3 3 3 8 1
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF , R is -F, and R is -Cl.
9 3 3 3 8 1
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH , R is -F, and R is -Cl.
9 3 3 3 8 1
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF , R is -F, and R is -Cl.
9 3 3 8 1
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH , R is -F, and R is -Cl.
9 3 3 8 1
In another embodiment, R is -H, -F, -Cl, or -CH , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -H, -F, -Cl, or -OCH , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -H, -F, -Cl, or -OCF , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -H, -F, or -CH , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -H, -F, or -OCH , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -H, -F, or -OCF , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -H, -F, or -Cl, R is -F, and R is -Cl.
9 8 1
In another embodiment, R is -H or -F, R is -F, and R is -Cl.
9 8 1
In another embodiment, R is -H or -Cl, R is -F, and R is -Cl.
9 8 1
In another embodiment, R is -H or -CH , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -F or -CH , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -F or -Cl, R is -F, and R is -Cl.
9 8 1
In another embodiment, R is -Cl or -CH , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -H, R is -F, and R is -Cl.
9 8 1
In another embodiment, R is -F, R is -F, and R is -Cl.
9 8 1
In another embodiment, R is -Cl, R is -F, and R is -Cl.
9 8 1
In another embodiment, R is -CH , R is -F, and R is -Cl.
9 3 8 1
In another embodiment, R is -H.
In another embodiment, R is -CH .
In another embodiment, R is -H and R is -F, -Cl, or -CF .
4 1 3
In another embodiment, R is -CH and R is -F, -Cl, or -CF .
4 3 1 3
In another embodiment, R is -H and R is -F or -CF .
4 1 3
In another embodiment, R is -CH and R is -F or -CF .
4 3 1 3
In another embodiment, R is -H and R is -F or -Cl.
In another embodiment, R is -CH and R is -F or -Cl.
4 3 1
In another embodiment, R is -H and R is -Cl or -CF .
4 1 3
In another embodiment, R is -CH and R is -Cl or -CF .
4 3 1 3
In another embodiment, R is -CH and m is 0.
In another embodiment, R is -CH , R is -F, -Cl, or -CF and m is 0.
4 3 1 3
In another embodiment, R is -H and m is 1.
In another embodiment, R is -CH and m is 1.
In another embodiment, R is -H, R is -F, -Cl, or -CF , and m is 1
4 1 3
In another embodiment, R is -CH , R is -F, -Cl, or -CF , and m is 1
4 3 1 3
In another embodiment, R is -CH , R is -Cl or -CF , and m is 0.
4 3 1 3
In another embodiment, R is -H, R is -Cl or -CF , and m is 1
4 1 3
In another embodiment, R is -CH , R is -Cl or -CF , and m is 1
4 3 1 3
In another embodiment, R is -CH , R is -F or -CF , and m is 0.
4 3 1 3
In another embodiment, R is -H, R is -F or -CF , and m is 1
4 1 3
In another embodiment, R is -CH , R is -F or -CF , and m is 1
4 3 1 3
In another embodiment, R is -CH , R is -F or -Cl, and m is 0.
4 3 1
In another embodiment, R is -H, R is -F or -Cl, and m is 1
In another embodiment, R is -CH , R is -F or -Cl, and m is 1
4 3 1
In another embodiment, R is -CH , R is -Cl, and m is 0.
4 3 1
In another embodiment, R is -H, R is -Cl, and m is 1.
In another embodiment, R is -CH , R is Cl, and m is 1.
4 3 1
In another embodiment, R is -CH , R is -CF , and m is 0.
4 3 1 3
In another embodiment, R is -H, R is -CF , and m is 1.
4 1 3
In another embodiment, R is -CH , R is -CF , and m is 1.
4 3 1 3
In another embodiment, R is -H and the carbon atom at the a position of the a-b bond is in the
(S) configuration.
In another embodiment, R is -H, R is -F, -Cl, or -CF , and the carbon atom at the a position of
4 1 3
the a-b bond is in the (S) configuration.
In another embodiment, R is -H, R is -F or -CF , and the carbon atom at the a position of the
4 1 3
a-b bond is in the (S) configuration.
In another embodiment, R is -H, R is -F or -Cl, and the carbon atom at the a position of the a-
b bond is in the (S) configuration.
In another embodiment, R is -H, R is -Cl or -CF , and the carbon atom at the a position of the
4 1 3
a-b bond is in the (S) configuration.
In another embodiment, R is -H, m is 1, and the carbon atom at the a position of the a-b bond
is in the (S) configuration.
In another embodiment, R is -H, R is -F, -Cl, or -CF , m is 1, and the carbon atom at the a
4 1 3
position of the a-b bond is in the (S) configuration.
In another embodiment, R is -H, R is -Cl or -CF , m is 1, and the carbon atom at the a position
4 1 3
of the a-b bond is in the (S) configuration.
In another embodiment, R is -H, R is -F or -CF , m is 1, and the carbon atom at the a position
4 1 3
of the a-b bond is in the (S) configuration.
In another embodiment, R is -H, R is -F or -Cl, m is 1, and the carbon atom at the a position
of the a-b bond is in the (S) configuration.
In another embodiment, R is -H, R is -Cl, m is 1, and the carbon atom at the a position of the
a-b bond is in the (S) configuration.
In another embodiment, R is -H, R is -CF , m is 1, and the carbon atom at the a position of the
4 1 3
a-b bond is in the (S) configuration.
In another embodiment, R is -H and the carbon atom at the a position of the a-b bond is in the
(R) configuration.
In another embodiment, R is -H, R is -F, -Cl, or -CF , and the carbon atom at the a position of
4 1 3
the a-b bond is in the (R) configuration.
In another embodiment, R is -H, R is -F or -CF , and the carbon atom at the a position of the
4 1 3
a-b bond is in the (R) configuration.
In another embodiment, R is -H, R is -F or -Cl, and the carbon atom at the a position of the a-
b bond is in the (R) configuration.
In another embodiment, R is -H, R is -Cl or -CF , and the carbon atom at the a position of the
4 1 3
a-b bond is in the (R) configuration.
In another embodiment, R is -H, m is 1, and the carbon atom at the a position of the a-b bond
is in the (R) configuration.
In another embodiment, R is -H, R is -F, -Cl, or -CF , m is 1, and the carbon atom at the a
4 1 3
position of the a-b bond is in the (R) configuration.
In another embodiment, R is -H, R is -Cl or -CF , m is 1, and the carbon atom at the a position
4 1 3
of the a-b bond is in the (R) configuration.
In another embodiment, R is -H, R is -F or -CF , m is 1, and the carbon atom at the a position
4 1 3
of the a-b bond is in the (R) configuration.
In another embodiment, R is -H, R is -F or -Cl, m is 1, and the carbon atom at the a position
of the a-b bond is in the (R) configuration.
In another embodiment, R is -H, R is -Cl, m is 1, and the carbon atom at the a position of the
a-b bond is in the (R) configuration.
In another embodiment, R is -H, R is -CF , m is 1, and the carbon atom at the a position of the
4 1 3
a-b bond is in the (R) configuration.
In another embodiment, R is -CH and the carbon atoms at the a and c positions of the a-b
bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F, -Cl, or -CF , and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F or -CF , and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F or -Cl, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -Cl or -CF , and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , m is 0, and the carbon atoms at the a and c positions of the
a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F, -Cl, or -CF , m is 0, and the carbon atoms at the a
4 3 1 3
and c positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , m is 1, and the carbon atoms at the a and c positions of the
a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F, -Cl, or -CF , m is 1, and the carbon atoms at the a
4 3 1 3
and c positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -Cl or -CF , m is 0, and the carbon atoms at the a and
4 3 1 3
c positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -Cl or -CF , m is 1, and the carbon atoms at the a and
4 3 1 3
c positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F or -CF , m is 0, and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F or -CF , m is 1, and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F or -Cl, m is 0, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -F or -Cl, m is 1, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -Cl, m is 0, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is Cl, m is 1, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -CF , m is 0, and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH , R is -CF , m is 1, and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH and the carbon atoms at the a and c positions of the a-b
bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F, -Cl, or -CF , and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F or -CF , and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F or -Cl, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -Cl or -CF , and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , m is 0, and the carbon atoms at the a and c positions of the
a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F, -Cl, or -CF , m is 0, and the carbon atoms at the a
4 3 1 3
and c positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , m is 1, and the carbon atoms at the a and c positions of the
a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F, -Cl, or -CF , m is 1, and the carbon atoms at the a
4 3 1 3
and c positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -Cl or -CF , m is 0, and the carbon atoms at the a and
4 3 1 3
c positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -Cl or -CF , m is 1, and the carbon atoms at the a and
4 3 1 3
c positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F or -CF , m is 0, and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F or -CF , m is 1, and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F or -Cl, m is 0, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -F or -Cl, m is 1, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -Cl, m is 0, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is Cl, m is 1, and the carbon atoms at the a and c
4 3 1
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -CF , m is 0, and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, R is -CH , R is -CF , m is 1, and the carbon atoms at the a and c
4 3 1 3
positions of the a-b bond and the c-d bond are each in the (R) configuration.
In another embodiment, m is 1 and the methyl group bonded to the piperazine ring is a
(S)methyl group.
In another embodiment, m is 1 and the methyl group bonded to the piperazine ring is a
(S)methyl group.
In another embodiment, m is 1 and the methyl group bonded to the piperazine ring is a
(R)methyl group.
Aqueous solubility of compounds is often a desirable feature. For example, aqueous solubility
of a compound permits that compound to be more easily formulated into a variety of dosage
forms that can be administered to an animal. When a compound is not fully soluble in
biological fluids, e.g., blood, it can precipitate and the animal's exposure to the drug will
accordingly not correspond to the administered dose. Aqueous solubility increases the
likelihood that a compound will have higher dissolution and, for compounds with good
permeability, it results in high exposure in an animal's blood, and increases the ability to predict
exposure at the target sight of the compound.
Many Compounds of Formula (I) are soluble, and in some cases highly soluble, in aqueous
solution. For example, at either pH 6.8 or pH 1.2, compound 200 is insoluble in aqueous
solution, i.e., has an aqueous solubility <0.1 μM. In contrast, the aqueous solubility at pH 1.2
of the following Compounds of Formula (I) is >50 μM: A126(a), A155(a), A155(d), A155(e),
A158(a), C125(r), and C126(r). The aqueous solubility at pH 6.8, in μM, of Compounds of
Formula (I) A126(a), A155(a), A155(d), A155(e), A158(a), C125(r), and C126(r) is 14, 17, 4.0,
5.0, 5.0, 3.0, and 4.0, respectively. Additionally, the aqueous solubility at either pH 1.2 or pH
6.8 of Compound of Formula (I) A122(a) is >50 μM. The aqueous solubility, in μM, at pH 1.2
of compounds 209, 210, 211, 212, 213, 214, and 215 is 9.3, 2.0, 1.3, 10.3, 39.6, >50 and 9.6,
respectively. The following compounds are aqueous insoluble at pH 6.8: 203, 207, 200, and
208. The following compounds have low aqueous solubility at pH 6.8: 209, 210, 211, 212,
213, 214, and 215 have aqueous solubility, in μM, of 1.0, 0.4, 0.4, 1.9, 0.8, 1.8, and 0.6,
respectively.
The following chemical structures relate to certain of the above-discussed compounds:
4.2 Compounds of Formula (II)
Preferred Compounds of Formula (I) are Compounds of Formula (II):
(II)
or a pharmaceutically acceptable derivative thereof,
(1) provided that if R is -H and the carbon atom at the a position of the a-b bond is in the (S)
configuration, then the methyl group bonded to the piperazine ring is a (S)methyl group, a
(S)methyl group, or a (R)methyl group,
where R , R , and R are as defined above for Compounds of Formula (II).
4 8 9
Certain embodiments of formula (II) are presented below.
In one embodiment, a Compound of Formula (II) is a free base.
In another embodiment, a Compound of Formula (II) is a pharmaceutically acceptable
derivative of a Compound of Formula (II).
In another embodiment, the pharmaceutically acceptable derivative of a Compound of Formula
(II) is a pharmaceutically acceptable salt. In another embodiment, the pharmaceutically
acceptable derivative of a Compound of Formula (II) is a fumaric acid-salt. In another
embodiment, the pharmaceutically acceptable derivative of a Compound of Formula (II) is a
fumaric acid-salt where the molar ratio of the Compound of Formula (II):fumaric acid is about
1:0.5.
In another embodiment, the pharmaceutically acceptable derivative of a Compound of Formula
(II) is a co-crystal. In another embodiment, the pharmaceutically acceptable derivative of a
Compound of Formula (II) is a fumarate co-crystal. In another embodiment, the
pharmaceutically acceptable derivative of a Compound of Formula (II) is a fumarate co-crystal
where the molar ratio of the Compound of Formula (II):fumarate is about 1:0.5.
In another embodiment, the pharmaceutically acceptable derivative of a Compound of Formula
(II) is a fumaric acid-salt, a fumarate co-crystal, or a combination thereof. In another
embodiment, the molar ratio of the Compound of Formula (II):(fumaric acid and/or fumarate)
is about 1:0.5.
Other embodiments relate to the product of combining a Compound of Formula (II) with
fumaric acid, where the molar ratio in the product is about 1:0.5 of (the Compound of Formula
(II)):(fumaric acid); a composition comprising that product and a pharmaceutically acceptable
carrier or excipient; a method for treating pain, e.g., pain associated with osteoarthritis,
osteoarthritis, UI, an ulcer, IBD, or IBS in an animal, comprising administering to an animal in
need thereof, an effective amount of that product; and a method of inhibiting TRPV1 function
in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of
that product.
In another embodiment, it is further provided that:
(2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group.
In another embodiment, it is further provided that:
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group or a (R)methyl group.
In another embodiment, it is further provided that:
(2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group; and
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group.
In another embodiment, it is further provided that:
(2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group; and
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group or a (R)methyl group.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group or a (R)methyl group.
In another embodiment, it is further provided that:
(2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group;
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group or a (R)methyl group.
In another embodiment, it is further provided that:
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group.
In another embodiment, it is further provided that:
(2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group; and
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group.
In another embodiment, it is further provided that:
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group.
In another embodiment, it is further provided that:
(2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl
group;
(3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is
-F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or
a (S)methyl group; and
(4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are
each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the
piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group.
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH .
9 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH .
9 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH .
9 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH .
9 3 3 3 3 2 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF .
9 3 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF .
9 3 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF .
9 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH .
9 3 3 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF .
9 3 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH .
9 3 3
In another embodiment, R is -H, -F, -Cl, or -CH .
In another embodiment, R is -H, -F, -Cl, or -OCH .
In another embodiment, R is -H, -F, -Cl, or -OCF .
In another embodiment, R is -H, -F, or -CH .
In another embodiment, R is -H, -F, or -OCH .
In another embodiment, R is -H, -F, or -OCF .
In another embodiment, R is -H, -F, or -Cl.
In another embodiment, R is -H or -F.
In another embodiment, R is -H or -Cl.
In another embodiment, R is -H or -CH .
In another embodiment, R is -F or -CH .
In another embodiment, R is -F or -Cl.
In another embodiment, R is -Cl or -CH .
In another embodiment, R is -H.
In another embodiment, R is -F.
In another embodiment, R is -Cl.
In another embodiment, R is -CH .
In another embodiment, R is -H or -F.
In another embodiment, R is -H or -CH .
In another embodiment, R is -F or -CH .
In another embodiment, R is -H.
In another embodiment, R is -F.
In another embodiment, R is -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH and R is -F or -CH .
2 3 2 3 2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -F or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -F or -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -F or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH and R is -F or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -F or -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -F or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -F or -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF and R is -F
9 3 3 3 3 8
or -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF and R is -F or -CH .
9 3 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF and R is -F or -CH .
9 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH and R is -F or -CH .
9 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF and R is -F or -CH .
9 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH and R is -F or -CH .
9 3 3 8 3
In another embodiment, R is -H, -F, -Cl, or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, or -OCH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, or -OCF and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -OCH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -OCF and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -Cl and R is -F or -CH .
9 8 3
In another embodiment, R is -H or -F and R is -F or -CH .
9 8 3
In another embodiment, R is -H or -Cl and R is -F or -CH .
9 8 3
In another embodiment, R is -H or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -F or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -F or -Cl and R is -F or -CH .
9 8 3
In another embodiment, R is -Cl or -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H and R is -F or -CH .
9 8 3
In another embodiment, R is -F and R is -F or -CH .
9 8 3
In another embodiment, R is -Cl and R is -F or -CH .
9 8 3
In another embodiment, R is -CH and R is -F or -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH and R is -F.
2 3 2 3 2 3 8
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -F.
2 3 8
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -F.
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -F.
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH and R is -F.
2 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -F.
2 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -F.
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -F.
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF and R is -F.
9 3 3 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF and R is -F.
9 3 3 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF and R is -F.
9 3 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH and R is -F.
9 3 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF and R is -F.
9 3 3 8
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH and R is -F.
9 3 3 8
In another embodiment, R is -H, -F, -Cl, or -CH and R is -F.
9 3 8
In another embodiment, R is -H, -F, -Cl, or -OCH and R is -F.
9 3 8
In another embodiment, R is -H, -F, -Cl, or -OCF and R is -F.
9 3 8
In another embodiment, R is -H, -F, or -CH and R is -F.
9 3 8
In another embodiment, R is -H, -F, or -OCH and R is -F.
9 3 8
In another embodiment, R is -H, -F, or -OCF and R is -F.
9 3 8
In another embodiment, R is -H, -F, or -Cl and R is -F.
In another embodiment, R is -H or -F and R is -F.
In another embodiment, R is -H or -Cl and R is -F.
In another embodiment, R is -H or -CH and R is -F.
9 3 8
In another embodiment, R is -F or -CH and R is -F.
9 3 8
In another embodiment, R is -F or -Cl and R is -F.
In another embodiment, R is -Cl or -CH and R is -F.
9 3 8
In another embodiment, R is -H and R is -F.
In another embodiment, R is -F and R is -F.
In another embodiment, R is -Cl and R is -F.
In another embodiment, R is -CH and R is -F.
9 3 8
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH and R is -CH .
2 3 2 3 2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH and R is -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , -OCH CH ,
9 3 3 3 3 2 3
or -CH OCH and R is -CH .
2 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -OCH CH and R
9 3 3 3 3 2 3 8
is -CH .
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , -OCF , or -CH OCH and R
9 3 3 3 3 2 3 8
is -CH .
In another embodiment, R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , or -OCF and R is -CH .
9 3 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , -OCH , or -OCF and R is -CH .
9 3 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCF and R is -CH .
9 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , -CF , or -OCH and R is -CH .
9 3 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCF and R is -CH .
9 3 3 8 3
In another embodiment, R is -H, -F, -Cl, -CH , or -OCH and R is -CH .
9 3 3 8 3
In another embodiment, R is -H, -F, -Cl, or -CH and R is -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, or -OCH and R is -CH .
9 3 8 3
In another embodiment, R is -H, -F, -Cl, or -OCF and R is -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -CH and R is -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -OCH and R is -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -OCF and R is -CH .
9 3 8 3
In another embodiment, R is -H, -F, or -Cl and R is -CH .
9 8 3
In another embodiment, R is -H or -F and R is -CH .
9 8 3
In another embodiment, R is -H or -Cl and R is -CH .
9 8 3
In another embodiment, R is -H or -CH and R is -CH .
9 3 8 3
In another embodiment, R is -F or -CH and R is -CH .
9 3 8 3
In another embodiment, R is -F or -Cl and R is -CH .
9 8 3
In another embodiment, R is -Cl or -CH and R is -CH .
9 3 8 3
In another embodiment, R is -H and R is -CH .
9 8 3
In another embodiment, R is -F and R is -CH .
9 8 3
In another embodiment, R is -Cl and R is -CH .
9 8 3
In another embodiment, R is -CH and R is -CH .
9 3 8 3
In another embodiment, R is -H.
In another embodiment, R is -CH .
In another embodiment, R is -H and the carbon atom at the a position of the a-b bond is in the
(S) configuration.
In another embodiment, R is -H and the carbon atom at the a position of the a-b bond is in the
(R) configuration.
In another embodiment, R is -CH and the carbon atoms at the a and c positions of the a-b
bond and the c-d bond are each in the (S) configuration.
In another embodiment, R is -CH and the carbon atoms at the a and c positions of the a-b
bond and the c-d bond are each in the (R) configuration.
In another embodiment, the methyl group bonded to the piperazine ring is a (S)methyl
group.
In another embodiment, the methyl group bonded to the piperazine ring is a (S)methyl
group.
In another embodiment, the methyl group bonded to the piperazine ring is a (R)methyl
group.
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, and the methyl group bonded to the piperazine ring is a (S)methyl group.
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, and the methyl group bonded to the piperazine ring is a (S)methyl group.
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, and the methyl group bonded to the
piperazine ring is a (S)methyl group.
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, and the methyl group bonded to the
piperazine ring is a (S)methyl group.
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, and the methyl group bonded to the piperazine ring is a (S)methyl group.
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, and the methyl group bonded to the piperazine ring is a (S)methyl group.
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, and the methyl group bonded to the
piperazine ring is a (S)methyl group.
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, and the methyl group bonded to the
piperazine ring is a (S)methyl group.
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, and the methyl group bonded to the piperazine ring is a (R)methyl group.
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, and the methyl group bonded to the piperazine ring is a (R)methyl group.
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, and the methyl group bonded to the
piperazine ring is a (R)methyl group.
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, and the methyl group bonded to the
piperazine ring is a (R)methyl group.
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, and R is
-F or -CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, and R is
-F or -CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, and R is -F or -CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, and R is -F or -CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, and R is
-F or -CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, and R is
-F or -CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, and R is -F or -CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, and R is -F or -CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, and R
is -F or -CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, and R
is -F or -CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, and R is -F or -CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, and R is -F or -CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, and R is
-H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, and R is
-H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, and R is -H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, and R is -H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, and R is
-H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, and R is
-H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, and R is -H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, and R is -H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, and R
is -H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, and R
is -H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, and R is -H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, and R is -H, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH ,
9 3 3 3 3 2 3 2 3
or -C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -F
or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -F
or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -F or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -
8 3 9 3 3 3
OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -F or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -
8 3 9 3 3 3
OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -F
or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -F
or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -F or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -
8 3 9 3 3 3
OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -F or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -
8 3 9 3 3 3
OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, R is -F
or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, R is -F
or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, R is -F or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -
8 3 9 3 3 3
OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, R is -F or -CH , and R is -H, -Cl, -Br, -CH , -CF , -OCH , -
8 3 9 3 3 3
OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -F,
and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
9 3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -F,
and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
9 3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -F, and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -F, and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -F,
and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
9 3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -F,
and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
9 3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -F, and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -F, and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, R is -F,
and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
9 3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, R is -F,
and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -C(O)OCH CH .
9 3 3 3 3 2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, R is -F, and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, R is -F, and R is -H, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -
CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -
CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 3 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 3 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -
CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (S)methyl group, R is -
CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 3 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (S)methyl group, R is -CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -
8 3 9 3 3 3 3
OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (S)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, R is -
CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -H, the carbon atom at the a position of the a-b bond is in the (R)
configuration, the methyl group bonded to the piperazine ring is a (R)methyl group, R is -
CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or -
3 9 3 3 3 3 2 3 2 3
C(O)OCH CH .
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (S) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, R is -CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF ,
8 3 9 3 3 3 3
-OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
In another embodiment, R is -CH , the carbon atoms at the a and c positions of the a-b bond
and the c-d bond are each in the (R) configuration, the methyl group bonded to the piperazine
ring is a (R)methyl group, R is -CH , and R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , -OCF ,
8 3 9 3 3 3 3
-OCH CH , -CH OCH , or -C(O)OCH CH .
2 3 2 3 2 3
Illustrative Compounds of Formulae (I) and/or (II) are listed below in Tables 1-3.
Table 1
and pharmaceutically acceptable derivatives thereof, where:
Compound R R R
1 8 9
A1a, b, c, d, e, f or g -Cl -H -H
A2 b, d, e, f or g -Cl -H -Cl
A3 b, d, e, f or g -Cl -H -Br
A4 b, d, e, f or g -Cl -H -F
A5 a, b, c, d, e, f or g -Cl -H -CH
A6 a, b, c, d, e, f or g -Cl -H -OCH
A7 a, b, c, d, e, f or g -Cl -H -OCH CH
A8 a, b, c, d, e, f or g -Cl -H -CF
A9 a, b, c, d, e, f or g -Cl -H -OCF
A10 a, b, c, d, e, f or g -Cl -H -CH OCH
A11 a, b, c, d, e, f or g -Cl -H -C(O)OCH CH
Compound R R R
1 8 9
A12 a, b, c, d, e, f or g -Cl -Cl -H
A13 a, b, c, d, e, f or g -Cl -Cl -Cl
A14 a, b, c, d, e, f or g -Cl -Cl -Br
A15 a, b, c, d, e, f or g -Cl -Cl -F
A16 a, b, c, d, e, f or g -Cl -Cl -CH
A17 a, b, c, d, e, f or g -Cl -Cl -OCH
A18 a, b, c, d, e, f or g -Cl -Cl -OCH CH
A19 a, b, c, d, e, f or g -Cl -Cl -CF
A20 a, b, c, d, e, f or g -Cl -Cl -OCF
A21 a, b, c, d, e, f or g -Cl -Cl -CH OCH
A22 a, b, c, d, e, f or g -Cl -Cl -C(O)OCH CH
A23 a, b, c, d, e, f or g -Cl -Br -H
A24 a, b, c, d, e, f or g -Cl -Br -Cl
A25 a, b, c, d, e, f or g -Cl -Br -Br
A26 a, b, c, d, e, f or g -Cl -Br -F
A27a, b, c, d, e, f or g -Cl -Br -CH
A28 a, b, c, d, e, f or g -Cl -Br -OCH
A29 a, b, c, d, e, f or g -Cl -Br -OCH CH
A30 a, b, c, d, e, f or g -Cl -Br -CF
A31 a, b, c, d, e, f or g -Cl -Br -OCF
A32 a, b, c, d, e, f or g -Cl -Br -CH OCH
A33 a, b, c, d, e, f or g -Cl -Br -C(O)OCH CH
A34 a, b, c, d, e, f or g -Cl -F -H
A35 a, b, c, d, e, f or g -Cl -F -Cl
A36 a, b, c, d, e, f or g -Cl -F -Br
A37 a, c, d, e, f or g -Cl -F -F
A38 a, b, c, d, e, f or g -Cl -F -CH
A39 a, b, c, d, e, f or g -Cl -F -OCH
A40 a, b, c, d, e, f or g -Cl -F -OCH CH
A41 a, b, c, d, e, f or g -Cl -F -CF
A42 a, b, c, d, e, f or g -Cl -F -OCF
A43 a, b, c, d, e, f or g -Cl -F -CH OCH
Compound R R R
1 8 9
A44 a, b, c, d, e, f or g -Cl -F -C(O)OCH CH
A45 a, b, c, d, e, f or g -Cl -CH -H
A46 a, b, c, d, e, f or g -Cl -CH -Cl
A47 a, b, c, d, e, f or g -Cl -CH -Br
A48 a, b, c, d, e, f or g -Cl -CH -F
A49 a, b, c, d, e, f or g -Cl -CH -CH
A50 a, b, c, d, e, f or g -Cl -CH -OCH
A51 a, b, c, d, e, f or g -Cl -CH -OCH CH
3 2 3
A52 a, b, c, d, e, f or g -Cl -CH -CF
A53a, b, c, d, e, f or g -Cl -CH -OCF
A54 a, b, c, d, e, f or g -Cl -CH -CH OCH
3 2 3
A55 a, b, c, d, e, f or g -Cl -CH -C(O)OCH CH
3 2 3
A56 a, b, c, d, e, f or g -Cl -OCH -H
A57 a, b, c, d, e, f or g -Cl -OCH -Cl
A58 a, b, c, d, e, f or g -Cl -OCH -Br
A59 a, b, c, d, e, f or g -Cl -OCH -F
A60 a, b, c, d, e, f or g -Cl -OCH -CH
A61 a, b, c, d, e, f or g -Cl -OCH -OCH
A62 a, b, c, d, e, f or g -Cl -OCH -OCH CH
3 2 3
A63 a, b, c, d, e, f or g -Cl -OCH -CF
A64 a, b, c, d, e, f or g -Cl -OCH -OCF
A65 a, b, c, d, e, f or g -Cl -OCH -CH OCH
3 2 3
A66 a, b, c, d, e, f or g -Cl -OCH -C(O)OCH CH
3 2 3
A67 a, b, c, d, e, f or g -Cl -OCH CH -H
A68 a, b, c, d, e, f or g -Cl -OCH CH -Cl
A69 a, b, c, d, e, f or g -Cl -OCH CH -Br
A70 a, b, c, d, e, f or g -Cl -OCH CH -F
A71 a, b, c, d, e, f or g -Cl -OCH CH -CH
2 3 3
A72 a, b, c, d, e, f or g -Cl -OCH CH -OCH
2 3 3
A73 a, b, c, d, e, f or g -Cl -OCH CH -OCH CH
2 3 2 3
A74 a, b, c, d, e, f or g -Cl -OCH CH -CF
2 3 3
A75 a, b, c, d, e, f or g -Cl -OCH CH -OCF
2 3 3
Compound R R R
1 8 9
A76 a, b, c, d, e, f or g -Cl -OCH CH -CH OCH
2 3 2 3
A77 a, b, c, d, e, f or g -Cl -OCH CH -C(O)OCH CH
2 3 2 3
A78 a, b, c, d, e, f or g -Cl -CF -H
A79a, b, c, d, e, f or g -Cl -CF -Cl
A80 a, b, c, d, e, f or g -Cl -CF -Br
A81 a, b, c, d, e, f or g -Cl -CF -F
A82 a, b, c, d, e, f or g -Cl -CF -CH
A83 a, b, c, d, e, f or g -Cl -CF -OCH
A84 a, b, c, d, e, f or g -Cl -CF -OCH CH
3 2 3
A85 a, b, c, d, e, f or g -Cl -CF -CF
A86 a, b, c, d, e, f or g -Cl -CF -OCF
A87 a, b, c, d, e, f or g -Cl -CF -CH OCH
3 2 3
A88 a, b, c, d, e, f or g -Cl -CF -C(O)OCH CH
3 2 3
A89 a, b, c, d, e, f or g -Cl -OCF -H
A90 a, b, c, d, e, f or g -Cl -OCF -Cl
A91 a, b, c, d, e, f or g -Cl -OCF -Br
A92 a, b, c, d, e, f or g -Cl -OCF -F
A93 a, b, c, d, e, f or g -Cl -OCF -CH
A94 a, b, c, d, e, f or g -Cl -OCF -OCH
A95 a, b, c, d, e, f or g -Cl -OCF -OCH CH
3 2 3
A96 a, b, c, d, e, f or g -Cl -OCF -CF
A97 a, b, c, d, e, f or g -Cl -OCF -OCF
A98 a, b, c, d, e, f or g -Cl -OCF -CH OCH
3 2 3
A99 a, b, c, d, e, f or g -Cl -OCF -C(O)OCH CH
3 2 3
A100 a, b, c, d, e, f or g -Cl -CH OCH -H
A101 a, b, c, d, e, f or g -Cl -CH OCH -Cl
A102 a, b, c, d, e, f or g -Cl -CH OCH -Br
A103 a, b, c, d, e, f or g -Cl -CH OCH -F
A104 a, b, c, d, e, f or g -Cl -CH OCH -CH
2 3 3
A105a, b, c, d, e, f or g -Cl -CH OCH -OCH
2 3 3
A106 a, b, c, d, e, f or g -Cl -CH OCH -OCH CH
2 3 2 3
A107 a, b, c, d, e, f or g -Cl -CH OCH -CF
2 3 3
Compound R R R
1 8 9
A108 a, b, c, d, e, f or g -Cl -CH OCH -OCF
2 3 3
A109 a, b, c, d, e, f or g -Cl -CH OCH -CH OCH
2 3 2 3
A110 a, b, c, d, e, f or g -Cl -CH OCH -C(O)OCH CH
2 3 2 3
A111 a, b, c, d, e, f or g -Cl -C(O)OCH CH -H
A112 a, b, c, d, e, f or g -Cl -C(O)OCH CH -Cl
A113 a, b, c, d, e, f or g -Cl -C(O)OCH CH -Br
A114 a, b, c, d, e, f or g -Cl -C(O)OCH CH -F
A115 a, b, c, d, e, f or g -Cl -C(O)OCH CH -CH
2 3 3
A116 a, b, c, d, e, f or g -Cl -C(O)OCH CH -OCH
2 3 3
A117 a, b, c, d, e, f or g -Cl -C(O)OCH CH -OCH CH
2 3 2 3
A118 a, b, c, d, e, f or g -Cl -C(O)OCH CH -CF
2 3 3
A119 a, b, c, d, e, f or g -Cl -C(O)OCH CH -OCF
2 3 3
A120 a, b, c, d, e, f or g -Cl -C(O)OCH CH -CH OCH
2 3 2 3
A121 a, b, c, d, e, f or g -Cl -C(O)OCH CH -C(O)OCH CH
2 3 2 3
A122 a, b, c, d, e, f or g -F -H -H
A123 b, d, e, f or g -F -H -Cl
A124 b, d, e, f or g -F -H -Br
A125 b, d, e, f or g -F -H -F
A126 a, b, c, d, e, f or g -F -H -CH
A127 a, b, c, d, e, f or g -F -H -OCH
A128 a, b, c, d, e, f or g -F -H -OCH CH
A129 a, b, c, d, e, f or g -F -H -CF
A130 a, b, c, d, e, f or g -F -H -OCF
A131a, b, c, d, e, f or g -F -H -CH OCH
A132 a, b, c, d, e, f or g -F -H -C(O)OCH CH
A133 a, b, c, d, e, f or g -F -Cl -H
A134 a, b, c, d, e, f or g -F -Cl -Cl
A135 a, b, c, d, e, f or g -F -Cl -Br
A136 a, b, c, d, e, f or g -F -Cl -F
A137 a, b, c, d, e, f or g -F -Cl -CH
A138 a, b, c, d, e, f or g -F -Cl -OCH
A139 a, b, c, d, e, f or g -F -Cl -OCH CH
Compound R R R
1 8 9
A140 a, b, c, d, e, f or g -F -Cl -CF
A141 a, b, c, d, e, f or g -F -Cl -OCF
A142 a, b, c, d, e, f or g -F -Cl -CH OCH
A143 a, b, c, d, e, f or g -F -Cl -C(O)OCH CH
A144 a, b, c, d, e, f or g -F -Br -H
A145 a, b, c, d, e, f or g -F -Br -Cl
A146 a, b, c, d, e, f or g -F -Br -Br
A147 a, b, c, d, e, f or g -F -Br -F
A148 a, b, c, d, e, f or g -F -Br -CH
A149 a, b, c, d, e, f or g -F -Br -OCH
A150 a, b, c, d, e, f or g -F -Br -OCH CH
A151 a, b, c, d, e, f or g -F -Br -CF
A152 a, b, c, d, e, f or g -F -Br -OCF
A153 a, b, c, d, e, f or g -F -Br -CH OCH
A154 a, b, c, d, e, f or g -F -Br -C(O)OCH CH
A155 a, b, c, d, e, f or g -F -F -H
A156 a, b, c, d, e, f or g -F -F -Cl
A157a, b, c, d, e, f or g -F -F -Br
A158 a, c, d, e, f or g -F -F -F
A159 a, b, c, d, e, f or g -F -F -CH
A160 a, b, c, d, e, f or g -F -F -OCH
A161 a, b, c, d, e, f or g -F -F -OCH CH
A162 a, b, c, d, e, f or g -F -F -CF
A163 a, b, c, d, e, f or g -F -F -OCF
A164 a, b, c, d, e, f or g -F -F -CH OCH
A165 a, b, c, d, e, f or g -F -F -C(O)OCH CH
A166 a, b, c, d, e, f or g -F -CH -H
A167 a, b, c, d, e, f or g -F -CH -Cl
A168 a, b, c, d, e, f or g -F -CH -Br
A169 a, b, c, d, e, f or g -F -CH -F
A170 a, b, c, d, e, f or g -F -CH -CH
A171 a, b, c, d, e, f or g -F -CH -OCH
Compound R R R
1 8 9
A172 a, b, c, d, e, f or g -F -CH -OCH CH
3 2 3
A173 a, b, c, d, e, f or g -F -CH -CF
A174 a, b, c, d, e, f or g -F -CH -OCF
A175 a, b, c, d, e, f or g -F -CH -CH OCH
3 2 3
A176 a, b, c, d, e, f or g -F -CH -C(O)OCH CH
3 2 3
A177 a, b, c, d, e, f or g -F -OCH -H
A178 a, b, c, d, e, f or g -F -OCH -Cl
A179 a, b, c, d, e, f or g -F -OCH -Br
A180 a, b, c, d, e, f or g -F -OCH -F
A181 a, b, c, d, e, f or g -F -OCH -CH
A182 a, b, c, d, e, f or g -F -OCH -OCH
A183a, b, c, d, e, f or g -F -OCH -OCH CH
3 2 3
A184 a, b, c, d, e, f or g -F -OCH -CF
A185 a, b, c, d, e, f or g -F -OCH -OCF
A186 a, b, c, d, e, f or g -F -OCH -CH OCH
3 2 3
A187 a, b, c, d, e, f or g -F -OCH -C(O)OCH CH
3 2 3
A188 a, b, c, d, e, f or g -F -OCH CH -H
A189 a, b, c, d, e, f or g -F -OCH CH -Cl
A190 a, b, c, d, e, f or g -F -OCH CH -Br
A191 a, b, c, d, e, f or g -F -OCH CH -F
A192 a, b, c, d, e, f or g -F -OCH CH -CH
2 3 3
A193 a, b, c, d, e, f or g -F -OCH CH -OCH
2 3 3
A194 a, b, c, d, e, f or g -F -OCH CH -OCH CH
2 3 2 3
A195 a, b, c, d, e, f or g -F -OCH CH -CF
2 3 3
A196 a, b, c, d, e, f or g -F -OCH CH -OCF
2 3 3
A197 a, b, c, d, e, f or g -F -OCH CH -CH OCH
2 3 2 3
A198 a, b, c, d, e, f or g -F -OCH CH -C(O)OCH CH
2 3 2 3
A199 a, b, c, d, e, f or g -F -CF -H
A200 a, b, c, d, e, f or g -F -CF -Cl
A201 a, b, c, d, e, f or g -F -CF -Br
A202 a, b, c, d, e, f or g -F -CF -F
A203 a, b, c, d, e, f or g -F -CF -CH
Compound R R R
1 8 9
A204 a, b, c, d, e, f or g -F -CF -OCH
A205 a, b, c, d, e, f or g -F -CF -OCH CH
3 2 3
A206 a, b, c, d, e, f or g -F -CF -CF
A207 a, b, c, d, e, f or g -F -CF -OCF
A208 a, b, c, d, e, f or g -F -CF -CH OCH
3 2 3
A209a, b, c, d, e, f or g -F -CF -C(O)OCH CH
3 2 3
A210 a, b, c, d, e, f or g -F -OCF -H
A211 a, b, c, d, e, f or g -F -OCF -Cl
A212 a, b, c, d, e, f or g -F -OCF -Br
A213 a, b, c, d, e, f or g -F -OCF -F
A214 a, b, c, d, e, f or g -F -OCF -CH
A215 a, b, c, d, e, f or g -F -OCF -OCH
A216 a, b, c, d, e, f or g -F -OCF -OCH CH
3 2 3
A217 a, b, c, d, e, f or g -F -OCF -CF
A218 a, b, c, d, e, f or g -F -OCF -OCF
A219 a, b, c, d, e, f or g -F -OCF -CH OCH
3 2 3
A220 a, b, c, d, e, f or g -F -OCF -C(O)OCH CH
3 2 3
A221 a, b, c, d, e, f or g -F -CH OCH -H
A222 a, b, c, d, e, f or g -F -CH OCH -Cl
A223 a, b, c, d, e, f or g -F -CH OCH -Br
A224 a, b, c, d, e, f or g -F -CH OCH -F
A225 a, b, c, d, e, f or g -F -CH OCH -CH
2 3 3
A226 a, b, c, d, e, f or g -F -CH OCH -OCH
2 3 3
A227 a, b, c, d, e, f or g -F -CH OCH -OCH CH
2 3 2 3
A228 a, b, c, d, e, f or g -F -CH OCH -CF
2 3 3
A229 a, b, c, d, e, f or g -F -CH OCH -OCF
2 3 3
A230 a, b, c, d, e, f or g -F -CH OCH -CH OCH
2 3 2 3
A231 a, b, c, d, e, f or g -F -CH OCH -C(O)OCH CH
2 3 2 3
A232 a, b, c, d, e, f or g -F -C(O)OCH CH -H
A233 a, b, c, d, e, f or g -F -C(O)OCH CH -Cl
A234 a, b, c, d, e, f or g -F -C(O)OCH CH -Br
A235a, b, c, d, e, f or g -F -C(O)OCH CH -F
Compound R R R
1 8 9
A236 a, b, c, d, e, f or g -F -C(O)OCH CH -CH
2 3 3
A237 a, b, c, d, e, f or g -F -C(O)OCH CH -OCH
2 3 3
A238 a, b, c, d, e, f or g -F -C(O)OCH CH -OCH CH
2 3 2 3
A239 a, b, c, d, e, f or g -F -C(O)OCH CH -CF
2 3 3
A240 a, b, c, d, e, f or g -F -C(O)OCH CH -OCF
2 3 3
A241 a, b, c, d, e, f or g -F -C(O)OCH CH -CH OCH
2 3 2 3
A242 a, b, c, d, e, f or g -F -C(O)OCH CH -C(O)OCH CH
2 3 2 3
A243 a, b, c, d, e, f or g -CF -H -H
A244 b, d, e, f or g -CF -H -Cl
A245 b, d, e, f or g -CF -H -Br
A246 b, d, e, f or g -CF -H -F
A247 a, b, c, d, e, f or g -CF -H -CH
A248 a, b, c, d, e, f or g -CF -H -OCH
A249 a, b, c, d, e, f or g -CF -H -OCH CH
3 2 3
A250 a, b, c, d, e, f or g -CF -H -CF
A251 a, b, c, d, e, f or g -CF -H -OCF
A252 a, b, c, d, e, f or g -CF -H -CH OCH
3 2 3
A253 a, b, c, d, e, f or g -CF -H -C(O)OCH CH
3 2 3
A254 a, b, c, d, e, f or g -CF -Cl -H
A255 a, b, c, d, e, f or g -CF -Cl -Cl
A256 a, b, c, d, e, f or g -CF -Cl -Br
A257 a, b, c, d, e, f or g -CF -Cl -F
A258 a, b, c, d, e, f or g -CF -Cl -CH
A259 a, b, c, d, e, f or g -CF -Cl -OCH
A260 a, b, c, d, e, f or g -CF -Cl -OCH CH
3 2 3
A261a, b, c, d, e, f or g -CF -Cl -CF
A262 a, b, c, d, e, f or g -CF -Cl -OCF
A263 a, b, c, d, e, f or g -CF -Cl -CH OCH
3 2 3
A264 a, b, c, d, e, f or g -CF -Cl -C(O)OCH CH
3 2 3
A265 a, b, c, d, e, f or g -CF -Br -H
A266 a, b, c, d, e, f or g -CF -Br -Cl
A267 a, b, c, d, e, f or g -CF -Br -Br
Compound R R R
1 8 9
A268 a, b, c, d, e, f or g -CF -Br -F
A269 a, b, c, d, e, f or g -CF -Br -CH
A270 a, b, c, d, e, f or g -CF -Br -OCH
A271 a, b, c, d, e, f or g -CF -Br -OCH CH
3 2 3
A272 a, b, c, d, e, f or g -CF -Br -CF
A273 a, b, c, d, e, f or g -CF -Br -OCF
A274 a, b, c, d, e, f or g -CF -Br -CH OCH
3 2 3
A275 a, b, c, d, e, f or g -CF -Br -C(O)OCH CH
3 2 3
A276 a, b, c, d, e, f or g -CF -F -H
A277 a, b, c, d, e, f or g -CF -F -Cl
A278 a, b, c, d, e, f or g -CF -F -Br
A279 a, c, d, e, f or g -CF -F -F
A280 a, b, c, d, e, f or g -CF -F -CH
A281 a, b, c, d, e, f or g -CF -F -OCH
A282 a, b, c, d, e, f or g -CF -F -OCH CH
3 2 3
A283 a, b, c, d, e, f or g -CF -F -CF
A284 a, b, c, d, e, f or g -CF -F -OCF
A285 a, b, c, d, e, f or g -CF -F -CH OCH
3 2 3
A286 a, b, c, d, e, f or g -CF -F -C(O)OCH CH
3 2 3
A287a, b, c, d, e, f or g -CF -CH -H
A288 a, b, c, d, e, f or g -CF -CH -Cl
A289 a, b, c, d, e, f or g -CF -CH -Br
A290 a, b, c, d, e, f or g -CF -CH -F
A291 a, b, c, d, e, f or g -CF -CH -CH
3 3 3
A292 a, b, c, d, e, f or g -CF -CH -OCH
3 3 3
A293 a, b, c, d, e, f or g -CF -CH -OCH CH
3 3 2 3
A294 a, b, c, d, e, f or g -CF -CH -CF
3 3 3
A295 a, b, c, d, e, f or g -CF -CH -OCF
3 3 3
A296 a, b, c, d, e, f or g -CF -CH -CH OCH
3 3 2 3
A297 a, b, c, d, e, f or g -CF -CH -C(O)OCH CH
3 3 2 3
A298 a, b, c, d, e, f or g -CF -OCH -H
A299 a, b, c, d, e, f or g -CF -OCH -Cl
Compound R R R
1 8 9
A300 a, b, c, d, e, f or g -CF -OCH -Br
A301 a, b, c, d, e, f or g -CF -OCH -F
A302 a, b, c, d, e, f or g -CF -OCH -CH
3 3 3
A303 a, b, c, d, e, f or g -CF -OCH -OCH
3 3 3
A304 a, b, c, d, e, f or g -CF -OCH -OCH CH
3 3 2 3
A305 a, b, c, d, e, f or g -CF -OCH -CF
3 3 3
A306 a, b, c, d, e, f or g -CF -OCH -OCF
3 3 3
A307 a, b, c, d, e, f or g -CF -OCH -CH OCH
3 3 2 3
A308 a, b, c, d, e, f or g -CF -OCH -C(O)OCH CH
3 3 2 3
A309 a, b, c, d, e, f or g -CF -OCH CH -H
3 2 3
A310 a, b, c, d, e, f or g -CF -OCH CH -Cl
3 2 3
A311 a, b, c, d, e, f or g -CF -OCH CH -Br
3 2 3
A312 a, b, c, d, e, f or g -CF -OCH CH -F
3 2 3
A313a, b, c, d, e, f or g -CF -OCH CH -CH
3 2 3 3
A314 a, b, c, d, e, f or g -CF -OCH CH -OCH
3 2 3 3
A315 a, b, c, d, e, f or g -CF -OCH CH -OCH CH
3 2 3 2 3
A316 a, b, c, d, e, f or g -CF -OCH CH -CF
3 2 3 3
A317 a, b, c, d, e, f or g -CF -OCH CH -OCF
3 2 3 3
A318 a, b, c, d, e, f or g -CF -OCH CH -CH OCH
3 2 3 2 3
A319 a, b, c, d, e, f or g -CF -OCH CH -C(O)OCH CH
3 2 3 2 3
A320 a, b, c, d, e, f or g -CF -CF -H
A321 a, b, c, d, e, f or g -CF -CF -Cl
A322 a, b, c, d, e, f or g -CF -CF -Br
A323 a, b, c, d, e, f or g -CF -CF -F
A324 a, b, c, d, e, f or g -CF -CF -CH
3 3 3
A325 a, b, c, d, e, f or g -CF -CF -OCH
3 3 3
A326 a, b, c, d, e, f or g -CF -CF -OCH CH
3 3 2 3
A327 a, b, c, d, e, f or g -CF -CF -CF
3 3 3
A328 a, b, c, d, e, f or g -CF -CF -OCF
3 3 3
A329 a, b, c, d, e, f or g -CF -CF -CH OCH
3 3 2 3
A330 a, b, c, d, e, f or g -CF -CF -C(O)OCH CH
3 3 2 3
A331 a, b, c, d, e, f or g -CF -OCF -H
Compound R R R
1 8 9
A332 a, b, c, d, e, f or g -CF -OCF -Cl
A333 a, b, c, d, e, f or g -CF -OCF -Br
A334 a, b, c, d, e, f or g -CF -OCF -F
A335 a, b, c, d, e, f or g -CF -OCF -CH
3 3 3
A336 a, b, c, d, e, f or g -CF -OCF -OCH
3 3 3
A337 a, b, c, d, e, f or g -CF -OCF -OCH CH
3 3 2 3
A338 a, b, c, d, e, f or g -CF -OCF -CF
3 3 3
A339a, b, c, d, e, f or g -CF -OCF -OCF
3 3 3
A340 a, b, c, d, e, f or g -CF -OCF -CH OCH
3 3 2 3
A341 a, b, c, d, e, f or g -CF -OCF -C(O)OCH CH
3 3 2 3
A342 a, b, c, d, e, f or g -CF -CH OCH -H
3 2 3
A343 a, b, c, d, e, f or g -CF -CH OCH -Cl
3 2 3
A344 a, b, c, d, e, f or g -CF -CH OCH -Br
3 2 3
A345 a, b, c, d, e, f or g -CF -CH OCH -F
3 2 3
A346 a, b, c, d, e, f or g -CF -CH OCH -CH
3 2 3 3
A347 a, b, c, d, e, f or g -CF -CH OCH -OCH
3 2 3 3
A348 a, b, c, d, e, f or g -CF -CH OCH -OCH CH
3 2 3 2 3
A349 a, b, c, d, e, f or g -CF -CH OCH -CF
3 2 3 3
A350 a, b, c, d, e, f or g -CF -CH OCH -OCF
3 2 3 3
A351 a, b, c, d, e, f or g -CF -CH OCH -CH OCH
3 2 3 2 3
A352 a, b, c, d, e, f or g -CF -CH OCH -C(O)OCH CH
3 2 3 2 3
A353 a, b, c, d, e, f or g -CF -C(O)OCH CH -H
3 2 3
A354 a, b, c, d, e, f or g -CF -C(O)OCH CH -Cl
3 2 3
A355 a, b, c, d, e, f or g -CF -C(O)OCH CH -Br
3 2 3
A356 a, b, c, d, e, f or g -CF -C(O)OCH CH -F
3 2 3
A357 a, b, c, d, e, f or g -CF -C(O)OCH CH -CH
3 2 3 3
A358 a, b, c, d, e, f or g -CF -C(O)OCH CH -OCH
3 2 3 3
A359 a, b, c, d, e, f or g -CF -C(O)OCH CH -OCH CH
3 2 3 2 3
A360 a, b, c, d, e, f or g -CF -C(O)OCH CH -CF
3 2 3 3
A361 a, b, c, d, e, f or g -CF -C(O)OCH CH -OCF
3 2 3 3
A362 a, b, c, d, e, f or g -CF -C(O)OCH CH -CH OCH
3 2 3 2 3
A363 a, b, c, d, e, f or g -CF -C(O)OCH CH -C(O)OCH CH
3 2 3 2 3
Table 2
and pharmaceutically acceptable derivatives thereof, where:
Compound R R R
1 8 9
B1h, i, j, k, m, n, o or p -Cl -H -H
B2 j, k, o or p -Cl -H -Cl
B3 j, k, o or p -Cl -H -Br
B4 j, k, o or p -Cl -H -F
B5 h, i, j, k, m, n, o or p -Cl -H -CH
B6 h, i, j, k, m, n, o or p -Cl -H -OCH
B7 h, i, j, k, m, n, o or p -Cl -H -OCH CH
B8 h, i, j, k, m, n, o or p -Cl -H -CF
B9 h, i, j, k, m, n, o or p -Cl -H -OCF
B10 h, i, j, k, m, n, o or p -Cl -H -CH OCH
B11 h, i, j, k, m, n, o or p -Cl -H -C(O)OCH CH
B12 h, i, j, k, m, n, o or p -Cl -Cl -H
B13 h, i, j, k, m, n, o or p -Cl -Cl -Cl
B14 h, i, j, k, m, n, o or p -Cl -Cl -Br
B15 h, i, j, k, m, n, o or p -Cl -Cl -F
B16 h, i, j, k, m, n, o or p -Cl -Cl -CH
B17 h, i, j, k, m, n, o or p -Cl -Cl -OCH
B18 h, i, j, k, m, n, o or p -Cl -Cl -OCH CH
B19 h, i, j, k, m, n, o or p -Cl -Cl -CF
B20 h, i, j, k, m, n, o or p -Cl -Cl -OCF
Compound R R R
1 8 9
B21 h, i, j, k, m, n, o or p -Cl -Cl -CH OCH
B22 h, i, j, k, m, n, o or p -Cl -Cl -C(O)OCH CH
B23 h, i, j, k, m, n, o or p -Cl -Br -H
B24 h, i, j, k, m, n, o or p -Cl -Br -Cl
B25 h, i, j, k, m, n, o or p -Cl -Br -Br
B26 h, i, j, k, m, n, o or p -Cl -Br -F
B27h, i, j, k, m, n, o or p -Cl -Br -CH
B28 h, i, j, k, m, n, o or p -Cl -Br -OCH
B29 h, i, j, k, m, n, o or p -Cl -Br -OCH CH
B30 h, i, j, k, m, n, o or p -Cl -Br -CF
B31 h, i, j, k, m, n, o or p -Cl -Br -OCF
B32 h, i, j, k, m, n, o or p -Cl -Br -CH OCH
B33 h, i, j, k, m, n, o or p -Cl -Br -C(O)OCH CH
B34 h, i, j, k, m, n, o or p -Cl -F -H
B35 h, i, j, k, m, n, o or p -Cl -F -Cl
B36 h, i, j, k, m, n, o or p -Cl -F -Br
B37 h, i, j, k, m, n, o or p -Cl -F -F
B38 h, i, j, k, m, n, o or p -Cl -F -CH
B39 h, i, j, k, m, n, o or p -Cl -F -OCH
B40 h, i, j, k, m, n, o or p -Cl -F -OCH CH
B41 h, i, j, k, m, n, o or p -Cl -F -CF
B42 h, i, j, k, m, n, o or p -Cl -F -OCF
B43 h, i, j, k, m, n, o or p -Cl -F -CH OCH
B44 h, i, j, k, m, n, o or p -Cl -F -C(O)OCH CH
B45 h, i, j, k, m, n, o or p -Cl -CH -H
B46 h, i, j, k, m, n, o or p -Cl -CH -Cl
B47 h, i, j, k, m, n, o or p -Cl -CH -Br
B48 h, i, j, k, m, n, o or p -Cl -CH -F
B49 h, i, j, k, m, n, o or p -Cl -CH -CH
B50 h, i, j, k, m, n, o or p -Cl -CH -OCH
B51 h, i, j, k, m, n, o or p -Cl -CH -OCH CH
3 2 3
B52 h, i, j, k, m, n, o or p -Cl -CH -CF
Compound R R R
1 8 9
B53h, i, j, k, m, n, o or p -Cl -CH -OCF
B54 h, i, j, k, m, n, o or p -Cl -CH -CH OCH
3 2 3
B55 h, i, j, k, m, n, o or p -Cl -CH -C(O)OCH CH
3 2 3
B56 h, i, j, k, m, n, o or p -Cl -OCH -H
B57 h, i, j, k, m, n, o or p -Cl -OCH -Cl
B58 h, i, j, k, m, n, o or p -Cl -OCH -Br
B59 h, i, j, k, m, n, o or p -Cl -OCH -F
B60 h, i, j, k, m, n, o or p -Cl -OCH -CH
B61 h, i, j, k, m, n, o or p -Cl -OCH -OCH
B62 h, i, j, k, m, n, o or p -Cl -OCH -OCH CH
3 2 3
B63 h, i, j, k, m, n, o or p -Cl -OCH -CF
B64 h, i, j, k, m, n, o or p -Cl -OCH -OCF
B65 h, i, j, k, m, n, o or p -Cl -OCH -CH OCH
3 2 3
B66 h, i, j, k, m, n, o or p -Cl -OCH -C(O)OCH CH
3 2 3
B67 h, i, j, k, m, n, o or p -Cl -OCH CH -H
B68 h, i, j, k, m, n, o or p -Cl -OCH CH -Cl
B69 h, i, j, k, m, n, o or p -Cl -OCH CH -Br
B70 h, i, j, k, m, n, o or p -Cl -OCH CH -F
B71 h, i, j, k, m, n, o or p -Cl -OCH CH -CH
2 3 3
B72 h, i, j, k, m, n, o or p -Cl -OCH CH -OCH
2 3 3
B73 h, i, j, k, m, n, o or p -Cl -OCH CH -OCH CH
2 3 2 3
B74 h, i, j, k, m, n, o or p -Cl -OCH CH -CF
2 3 3
B75 h, i, j, k, m, n, o or p -Cl -OCH CH -OCF
2 3 3
B76 h, i, j, k, m, n, o or p -Cl -OCH CH -CH OCH
2 3 2 3
B77 h, i, j, k, m, n, o or p -Cl -OCH CH -C(O)OCH CH
2 3 2 3
B78 h, i, j, k, m, n, o or p -Cl -CF -H
B79h, i, j, k, m, n, o or p -Cl -CF -Cl
B80 h, i, j, k, m, n, o or p -Cl -CF -Br
B81 h, i, j, k, m, n, o or p -Cl -CF -F
B82 h, i, j, k, m, n, o or p -Cl -CF -CH
B83 h, i, j, k, m, n, o or p -Cl -CF -OCH
B84 h, i, j, k, m, n, o or p -Cl -CF -OCH CH
3 2 3
Compound R R R
1 8 9
B85 h, i, j, k, m, n, o or p -Cl -CF -CF
B86 h, i, j, k, m, n, o or p -Cl -CF -OCF
B87 h, i, j, k, m, n, o or p -Cl -CF -CH OCH
3 2 3
B88 h, i, j, k, m, n, o or p -Cl -CF -C(O)OCH CH
3 2 3
B89 h, i, j, k, m, n, o or p -Cl -OCF -H
B90 h, i, j, k, m, n, o or p -Cl -OCF -Cl
B91 h, i, j, k, m, n, o or p -Cl -OCF -Br
B92 h, i, j, k, m, n, o or p -Cl -OCF -F
B93 h, i, j, k, m, n, o or p -Cl -OCF -CH
B94 h, i, j, k, m, n, o or p -Cl -OCF -OCH
B95 h, i, j, k, m, n, o or p -Cl -OCF -OCH CH
3 2 3
B96 h, i, j, k, m, n, o or p -Cl -OCF -CF
B97 h, i, j, k, m, n, o or p -Cl -OCF -OCF
B98 h, i, j, k, m, n, o or p -Cl -OCF -CH OCH
3 2 3
B99 h, i, j, k, m, n, o or p -Cl -OCF -C(O)OCH CH
3 2 3
B100 h, i, j, k, m, n, o or p -Cl -CH OCH -H
B101 h, i, j, k, m, n, o or p -Cl -CH OCH -Cl
B102 h, i, j, k, m, n, o or p -Cl -CH OCH -Br
B103 h, i, j, k, m, n, o or p -Cl -CH OCH -F
B104 h, i, j, k, m, n, o or p -Cl -CH OCH -CH
2 3 3
B105h, i, j, k, m, n, o or p -Cl -CH OCH -OCH
2 3 3
B106 h, i, j, k, m, n, o or p -Cl -CH OCH -OCH CH
2 3 2 3
B107 h, i, j, k, m, n, o or p -Cl -CH OCH -CF
2 3 3
B108 h, i, j, k, m, n, o or p -Cl -CH OCH -OCF
2 3 3
B109 h, i, j, k, m, n, o or p -Cl -CH OCH -CH OCH
2 3 2 3
B110 h, i, j, k, m, n, o or p -Cl -CH OCH -C(O)OCH CH
2 3 2 3
B111 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -H
B112 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -Cl
B113 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -Br
B114 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -F
B115 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -CH
2 3 3
B116 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -OCH
2 3 3
Compound R R R
1 8 9
B117 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -OCH CH
2 3 2 3
B118 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -CF
2 3 3
B119 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -OCF
2 3 3
B120 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -CH OCH
2 3 2 3
B121 h, i, j, k, m, n, o or p -Cl -C(O)OCH CH -C(O)OCH CH
2 3 2 3
B122 h, i, j, k, m, n, o or p -F -H -H
B123 j, k, o or p -F -H -Cl
B124 j, k, o or p -F -H -Br
B125 j, k, o or p -F -H -F
B126 h, i, j, k, m, n, o or p -F -H -CH
B127 h, i, j, k, m, n, o or p -F -H -OCH
B128 h, i, j, k, m, n, o or p -F -H -OCH CH
B129 h, i, j, k, m, n, o or p -F -H -CF
B130 h, i, j, k, m, n, o or p -F -H -OCF
B131h, i, j, k, m, n, o or p -F -H -CH OCH
B132 h, i, j, k, m, n, o or p -F -H -C(O)OCH CH
B133 h, i, j, k, m, n, o or p -F -Cl -H
B134 h, i, j, k, m, n, o or p -F -Cl -Cl
B135 h, i, j, k, m, n, o or p -F -Cl -Br
B136 h, i, j, k, m, n, o or p -F -Cl -F
B137 h, i, j, k, m, n, o or p -F -Cl -CH
B138 h, i, j, k, m, n, o or p -F -Cl -OCH
B139 h, i, j, k, m, n, o or p -F -Cl -OCH CH
B140 h, i, j, k, m, n, o or p -F -Cl -CF
B141 h, i, j, k, m, n, o or p -F -Cl -OCF
B142 h, i, j, k, m, n, o or p -F -Cl -CH OCH
B143 h, i, j, k, m, n, o or p -F -Cl -C(O)OCH CH
B144 h, i, j, k, m, n, o or p -F -Br -H
B145 h, i, j, k, m, n, o or p -F -Br -Cl
B146 h, i, j, k, m, n, o or p -F -Br -Br
B147 h, i, j, k, m, n, o or p -F -Br -F
B148 h, i, j, k, m, n, o or p -F -Br -CH
Compound R R R
1 8 9
B149 h, i, j, k, m, n, o or p -F -Br -OCH
B150 h, i, j, k, m, n, o or p -F -Br -OCH CH
B151 h, i, j, k, m, n, o or p -F -Br -CF
B152 h, i, j, k, m, n, o or p -F -Br -OCF
B153 h, i, j, k, m, n, o or p -F -Br -CH OCH
B154 h, i, j, k, m, n, o or p -F -Br -C(O)OCH CH
B155 h, i, j, k, m, n, o or p -F -F -H
B156 h, i, j, k, m, n, o or p -F -F -Cl
B157h, i, j, k, m, n, o or p -F -F -Br
B158 h, i, j, k, m, n, o or p -F -F -F
B159 h, i, j, k, m, n, o or p -F -F -CH
B160 h, i, j, k, m, n, o or p -F -F -OCH
B161 h, i, j, k, m, n, o or p -F -F -OCH CH
B162 h, i, j, k, m, n, o or p -F -F -CF
B163 h, i, j, k, m, n, o or p -F -F -OCF
B164 h, i, j, k, m, n, o or p -F -F -CH OCH
B165 h, i, j, k, m, n, o or p -F -F -C(O)OCH CH
B166 h, i, j, k, m, n, o or p -F -CH -H
B167 h, i, j, k, m, n, o or p -F -CH -Cl
B168 h, i, j, k, m, n, o or p -F -CH -Br
B169 h, i, j, k, m, n, o or p -F -CH -F
B170 h, i, j, k, m, n, o or p -F -CH -CH
B171 h, i, j, k, m, n, o or p -F -CH -OCH
B172 h, i, j, k, m, n, o or p -F -CH -OCH CH
3 2 3
B173 h, i, j, k, m, n, o or p -F -CH -CF
B174 h, i, j, k, m, n, o or p -F -CH -OCF
B175 h, i, j, k, m, n, o or p -F -CH -CH OCH
3 2 3
B176 h, i, j, k, m, n, o or p -F -CH -C(O)OCH CH
3 2 3
B177 h, i, j, k, m, n, o or p -F -OCH -H
B178 h, i, j, k, m, n, o or p -F -OCH -Cl
B179 h, i, j, k, m, n, o or p -F -OCH -Br
B180 h, i, j, k, m, n, o or p -F -OCH -F
Compound R R R
1 8 9
B181 h, i, j, k, m, n, o or p -F -OCH -CH
B182 h, i, j, k, m, n, o or p -F -OCH -OCH
B183h, i, j, k, m, n, o or p -F -OCH -OCH CH
3 2 3
B184 h, i, j, k, m, n, o or p -F -OCH -CF
B185 h, i, j, k, m, n, o or p -F -OCH -OCF
B186 h, i, j, k, m, n, o or p -F -OCH -CH OCH
3 2 3
B187 h, i, j, k, m, n, o or p -F -OCH -C(O)OCH CH
3 2 3
B188 h, i, j, k, m, n, o or p -F -OCH CH -H
B189 h, i, j, k, m, n, o or p -F -OCH CH -Cl
B190 h, i, j, k, m, n, o or p -F -OCH CH -Br
B191 h, i, j, k, m, n, o or p -F -OCH CH -F
B192 h, i, j, k, m, n, o or p -F -OCH CH -CH
2 3 3
B193 h, i, j, k, m, n, o or p -F -OCH CH -OCH
2 3 3
B194 h, i, j, k, m, n, o or p -F -OCH CH -OCH CH
2 3 2 3
B195 h, i, j, k, m, n, o or p -F -OCH CH -CF
2 3 3
B196 h, i, j, k, m, n, o or p -F -OCH CH -OCF
2 3 3
B197 h, i, j, k, m, n, o or p -F -OCH CH -CH OCH
2 3 2 3
B198 h, i, j, k, m, n, o or p -F -OCH CH -C(O)OCH CH
2 3 2 3
B199 h, i, j, k, m, n, o or p -F -CF -H
B200 h, i, j, k, m, n, o or p -F -CF -Cl
B201 h, i, j, k, m, n, o or p -F -CF -Br
B202 h, i, j, k, m, n, o or p -F -CF -F
B203 h, i, j, k, m, n, o or p -F -CF -CH
B204 h, i, j, k, m, n, o or p -F -CF -OCH
B205 h, i, j, k, m, n, o or p -F -CF -OCH CH
3 2 3
B206 h, i, j, k, m, n, o or p -F -CF -CF
B207 h, i, j, k, m, n, o or p -F -CF -OCF
B208 h, i, j, k, m, n, o or p -F -CF -CH OCH
3 2 3
B209h, i, j, k, m, n, o or p -F -CF -C(O)OCH CH
3 2 3
B210 h, i, j, k, m, n, o or p -F -OCF -H
B211 h, i, j, k, m, n, o or p -F -OCF -Cl
B212 h, i, j, k, m, n, o or p -F -OCF -Br
Compound R R R
1 8 9
B213 h, i, j, k, m, n, o or p -F -OCF -F
B214 h, i, j, k, m, n, o or p -F -OCF -CH
B215 h, i, j, k, m, n, o or p -F -OCF -OCH
B216 h, i, j, k, m, n, o or p -F -OCF -OCH CH
3 2 3
B217 h, i, j, k, m, n, o or p -F -OCF -CF
B218 h, i, j, k, m, n, o or p -F -OCF -OCF
B219 h, i, j, k, m, n, o or p -F -OCF -CH OCH
3 2 3
B220 h, i, j, k, m, n, o or p -F -OCF -C(O)OCH CH
3 2 3
B221 h, i, j, k, m, n, o or p -F -CH OCH -H
B222 h, i, j, k, m, n, o or p -F -CH OCH -Cl
B223 h, i, j, k, m, n, o or p -F -CH OCH -Br
B224 h, i, j, k, m, n, o or p -F -CH OCH -F
B225 h, i, j, k, m, n, o or p -F -CH OCH -CH
2 3 3
B226 h, i, j, k, m, n, o or p -F -CH OCH -OCH
2 3 3
B227 h, i, j, k, m, n, o or p -F -CH OCH -OCH CH
2 3 2 3
B228 h, i, j, k, m, n, o or p -F -CH OCH -CF
2 3 3
B229 h, i, j, k, m, n, o or p -F -CH OCH -OCF
2 3 3
B230 h, i, j, k, m, n, o or p -F -CH OCH -CH OCH
2 3 2 3
B231 h, i, j, k, m, n, o or p -F -CH OCH -C(O)OCH CH
2 3 2 3
B232 h, i, j, k, m, n, o or p -F -C(O)OCH CH -H
B233 h, i, j, k, m, n, o or p -F -C(O)OCH CH -Cl
B234 h, i, j, k, m, n, o or p -F -C(O)OCH CH -Br
B235h, i, j, k, m, n, o or p -F -C(O)OCH CH -F
B236 h, i, j, k, m, n, o or p -F -C(O)OCH CH -CH
2 3 3
B237 h, i, j, k, m, n, o or p -F -C(O)OCH CH -OCH
2 3 3
B238 h, i, j, k, m, n, o or p -F -C(O)OCH CH -OCH CH
2 3 2 3
B239 h, i, j, k, m, n, o or p -F -C(O)OCH CH -CF
2 3 3
B240 h, i, j, k, m, n, o or p -F -C(O)OCH CH -OCF
2 3 3
B241 h, i, j, k, m, n, o or p -F -C(O)OCH CH -CH OCH
2 3 2 3
B242 h, i, j, k, m, n, o or p -F -C(O)OCH CH -C(O)OCH CH
2 3 2 3
B243 h, i, j, k, m, n, o or p -CF -H -H
B244 j, k, o or p -CF -H -Cl
Compound R R R
1 8 9
B245 j, k, o or p -CF -H -Br
B246 j, k, o or p -CF -H -F
B247 h, i, j, k, m, n, o or p -CF -H -CH
B248 h, i, j, k, m, n, o or p -CF -H -OCH
B249 h, i, j, k, m, n, o or p -CF -H -OCH CH
3 2 3
B250 h, i, j, k, m, n, o or p -CF -H -CF
B251 h, i, j, k, m, n, o or p -CF -H -OCF
B252 h, i, j, k, m, n, o or p -CF -H -CH OCH
3 2 3
B253 h, i, j, k, m, n, o or p -CF -H -C(O)OCH CH
3 2 3
B254 h, i, j, k, m, n, o or p -CF -Cl -H
B255 h, i, j, k, m, n, o or p -CF -Cl -Cl
B256 h, i, j, k, m, n, o or p -CF -Cl -Br
B257 h, i, j, k, m, n, o or p -CF -Cl -F
B258 h, i, j, k, m, n, o or p -CF -Cl -CH
B259 h, i, j, k, m, n, o or p -CF -Cl -OCH
B260 h, i, j, k, m, n, o or p -CF -Cl -OCH CH
3 2 3
B261h, i, j, k, m, n, o or p -CF -Cl -CF
B262 h, i, j, k, m, n, o or p -CF -Cl -OCF
B263 h, i, j, k, m, n, o or p -CF -Cl -CH OCH
3 2 3
B264 h, i, j, k, m, n, o or p -CF -Cl -C(O)OCH CH
3 2 3
B265 h, i, j, k, m, n, o or p -CF -Br -H
B266 h, i, j, k, m, n, o or p -CF -Br -Cl
B267 h, i, j, k, m, n, o or p -CF -Br -Br
B268 h, i, j, k, m, n, o or p -CF -Br -F
B269 h, i, j, k, m, n, o or p -CF -Br -CH
B270 h, i, j, k, m, n, o or p -CF -Br -OCH
B271 h, i, j, k, m, n, o or p -CF -Br -OCH CH
3 2 3
B272 h, i, j, k, m, n, o or p -CF -Br -CF
B273 h, i, j, k, m, n, o or p -CF -Br -OCF
B274 h, i, j, k, m, n, o or p -CF -Br -CH OCH
3 2 3
B275 h, i, j, k, m, n, o or p -CF -Br -C(O)OCH CH
3 2 3
B276 h, i, j, k, m, n, o or p -CF -F -H
Compound R R R
1 8 9
B277 h, i, j, k, m, n, o or p -CF -F -Cl
B278 h, i, j, k, m, n, o or p -CF -F -Br
B279 h, i, j, k, m, n, o or p -CF -F -F
B280 h, i, j, k, m, n, o or p -CF -F -CH
B281 h, i, j, k, m, n, o or p -CF -F -OCH
B282 h, i, j, k, m, n, o or p -CF -F -OCH CH
3 2 3
B283 h, i, j, k, m, n, o or p -CF -F -CF
B284 h, i, j, k, m, n, o or p -CF -F -OCF
B285 h, i, j, k, m, n, o or p -CF -F -CH OCH
3 2 3
B286 h, i, j, k, m, n, o or p -CF -F -C(O)OCH CH
3 2 3
B287h, i, j, k, m, n, o or p -CF -CH -H
B288 h, i, j, k, m, n, o or p -CF -CH -Cl
B289 h, i, j, k, m, n, o or p -CF -CH -Br
B290 h, i, j, k, m, n, o or p -CF -CH -F
B291 h, i, j, k, m, n, o or p -CF -CH -CH
3 3 3
B292 h, i, j, k, m, n, o or p -CF -CH -OCH
3 3 3
B293 h, i, j, k, m, n, o or p -CF -CH -OCH CH
3 3 2 3
B294 h, i, j, k, m, n, o or p -CF -CH -CF
3 3 3
B295 h, i, j, k, m, n, o or p -CF -CH -OCF
3 3 3
B296 h, i, j, k, m, n, o or p -CF -CH -CH OCH
3 3 2 3
B297 h, i, j, k, m, n, o or p -CF -CH -C(O)OCH CH
3 3 2 3
B298 h, i, j, k, m, n, o or p -CF -OCH -H
B299 h, i, j, k, m, n, o or p -CF -OCH -Cl
B300 h, i, j, k, m, n, o or p -CF -OCH -Br
B301 h, i, j, k, m, n, o or p -CF -OCH -F
B302 h, i, j, k, m, n, o or p -CF -OCH -CH
3 3 3
B303 h, i, j, k, m, n, o or p -CF -OCH -OCH
3 3 3
B304 h, i, j, k, m, n, o or p -CF -OCH -OCH CH
3 3 2 3
B305 h, i, j, k, m, n, o or p -CF -OCH -CF
3 3 3
B306 h, i, j, k, m, n, o or p -CF -OCH -OCF
3 3 3
B307 h, i, j, k, m, n, o or p -CF -OCH -CH OCH
3 3 2 3
B308 h, i, j, k, m, n, o or p -CF -OCH -C(O)OCH CH
3 3 2 3
Compound R R R
1 8 9
B309 h, i, j, k, m, n, o or p -CF -OCH CH -H
3 2 3
B310 h, i, j, k, m, n, o or p -CF -OCH CH -Cl
3 2 3
B311 h, i, j, k, m, n, o or p -CF -OCH CH -Br
3 2 3
B312 h, i, j, k, m, n, o or p -CF -OCH CH -F
3 2 3
B313h, i, j, k, m, n, o or p -CF -OCH CH -CH
3 2 3 3
B314 h, i, j, k, m, n, o or p -CF -OCH CH -OCH
3 2 3 3
B315 h, i, j, k, m, n, o or p -CF -OCH CH -OCH CH
3 2 3 2 3
B316 h, i, j, k, m, n, o or p -CF -OCH CH -CF
3 2 3 3
B317 h, i, j, k, m, n, o or p -CF -OCH CH -OCF
3 2 3 3
B318 h, i, j, k, m, n, o or p -CF -OCH CH -CH OCH
3 2 3 2 3
B319 h, i, j, k, m, n, o or p -CF -OCH CH -C(O)OCH CH
3 2 3 2 3
B320 h, i, j, k, m, n, o or p -CF -CF -H
B321 h, i, j, k, m, n, o or p -CF -CF -Cl
B322 h, i, j, k, m, n, o or p -CF -CF -Br
B323 h, i, j, k, m, n, o or p -CF -CF -F
B324 h, i, j, k, m, n, o or p -CF -CF -CH
3 3 3
B325 h, i, j, k, m, n, o or p -CF -CF -OCH
3 3 3
B326 h, i, j, k, m, n, o or p -CF -CF -OCH CH
3 3 2 3
B327 h, i, j, k, m, n, o or p -CF -CF -CF
3 3 3
B328 h, i, j, k, m, n, o or p -CF -CF -OCF
3 3 3
B329 h, i, j, k, m, n, o or p -CF -CF -CH OCH
3 3 2 3
B330 h, i, j, k, m, n, o or p -CF -CF -C(O)OCH CH
3 3 2 3
B331 h, i, j, k, m, n, o or p -CF -OCF -H
B332 h, i, j, k, m, n, o or p -CF -OCF -Cl
B333 h, i, j, k, m, n, o or p -CF -OCF -Br
B334 h, i, j, k, m, n, o or p -CF -OCF -F
B335 h, i, j, k, m, n, o or p -CF -OCF -CH
3 3 3
B336 h, i, j, k, m, n, o or p -CF -OCF -OCH
3 3 3
B337 h, i, j, k, m, n, o or p -CF -OCF -OCH CH
3 3 2 3
B338 h, i, j, k, m, n, o or p -CF -OCF -CF
3 3 3
B339h, i, j, k, m, n, o or p -CF -OCF -OCF
3 3 3
B340 h, i, j, k, m, n, o or p -CF -OCF -CH OCH
3 3 2 3
Compound R R R
1 8 9
B341 h, i, j, k, m, n, o or p -CF -OCF -C(O)OCH CH
3 3 2 3
B342 h, i, j, k, m, n, o or p -CF -CH OCH -H
3 2 3
B343 h, i, j, k, m, n, o or p -CF -CH OCH -Cl
3 2 3
B344 h, i, j, k, m, n, o or p -CF -CH OCH -Br
3 2 3
B345 h, i, j, k, m, n, o or p -CF -CH OCH -F
3 2 3
B346 h, i, j, k, m, n, o or p -CF -CH OCH -CH
3 2 3 3
B347 h, i, j, k, m, n, o or p -CF -CH OCH -OCH
3 2 3 3
B348 h, i, j, k, m, n, o or p -CF -CH OCH -OCH CH
3 2 3 2 3
B349 h, i, j, k, m, n, o or p -CF -CH OCH -CF
3 2 3 3
B350 h, i, j, k, m, n, o or p -CF -CH OCH -OCF
3 2 3 3
B351 h, i, j, k, m, n, o or p -CF -CH OCH -CH OCH
3 2 3 2 3
B352 h, i, j, k, m, n, o or p -CF -CH OCH -C(O)OCH CH
3 2 3 2 3
B353 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -H
3 2 3
B354 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -Cl
3 2 3
B355 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -Br
3 2 3
B356 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -F
3 2 3
B357 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -CH
3 2 3 3
B358 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -OCH
3 2 3 3
B359 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -OCH CH
3 2 3 2 3
B360 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -CF
3 2 3 3
B361 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -OCF
3 2 3 3
B362 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -CH OCH
3 2 3 2 3
B363 h, i, j, k, m, n, o or p -CF -C(O)OCH CH -C(O)OCH CH
3 2 3 2 3
Table 3
and pharmaceutically acceptable derivatives thereof, where:
Compound R R R
1 8 9
C1q, r, s or t -Cl -H -H
C2 q, r, s or t -Cl -H -Cl
C3 q, r, s or t -Cl -H -Br
C4 q, r, s or t -Cl -H -F
C5 q, r, s or t -Cl -H -CH
C6 q, r, s or t -Cl -H -OCH
C7 q, r, s or t -Cl -H -OCH CH
C8 q, r, s or t -Cl -H -CF
C9 q, r, s or t -Cl -H -OCF
C10 q, r, s or t -Cl -H -CH OCH
C11 q, r, s or t -Cl -H -C(O)OCH CH
C12 q, r, s or t -Cl -Cl -H
C13 q, r, s or t -Cl -Cl -Cl
C14 q, r, s or t -Cl -Cl -Br
C15 q, r, s or t -Cl -Cl -F
C16 q, r, s or t -Cl -Cl -CH
C17 q, r, s or t -Cl -Cl -OCH
C18 q, r, s or t -Cl -Cl -OCH CH
C19 q, r, s or t -Cl -Cl -CF
Compound R R R
1 8 9
C20 q, r, s or t -Cl -Cl -OCF
C21 q, r, s or t -Cl -Cl -CH OCH
C22 q, r, s or t -Cl -Cl -C(O)OCH CH
C23 q, r, s or t -Cl -Br -H
C24 q, r, s or t -Cl -Br -Cl
C25 q, r, s or t -Cl -Br -Br
C26 q, r, s or t -Cl -Br -F
C27q, r, s or t -Cl -Br -CH
C28 q, r, s or t -Cl -Br -OCH
C29 q, r, s or t -Cl -Br -OCH CH
C30 q, r, s or t -Cl -Br -CF
C31 q, r, s or t -Cl -Br -OCF
C32 q, r, s or t -Cl -Br -CH OCH
C33 q, r, s or t -Cl -Br -C(O)OCH CH
C34 q, r, s or t -Cl -F -H
C35 q, r, s or t -Cl -F -Cl
C36 q, r, s or t -Cl -F -Br
C37 q, r, s or t -Cl -F -F
C38 q, r, s or t -Cl -F -CH
C39 q, r, s or t -Cl -F -OCH
C40 q, r, s or t -Cl -F -OCH CH
C41 q, r, s or t -Cl -F -CF
C42 q, r, s or t -Cl -F -OCF
C43 q, r, s or t -Cl -F -CH OCH
C44 q, r, s or t -Cl -F -C(O)OCH CH
C45 q, r, s or t -Cl -CH -H
C46 q, r, s or t -Cl -CH -Cl
C47 q, r, s or t -Cl -CH -Br
C48 q, r, s or t -Cl -CH -F
C49 q, r, s or t -Cl -CH -CH
C50 q, r, s or t -Cl -CH -OCH
C51 q, r, s or t -Cl -CH -OCH CH
3 2 3
Compound R R R
1 8 9
C52 q, r, s or t -Cl -CH -CF
C53q, r, s or t -Cl -CH -OCF
C54 q, r, s or t -Cl -CH -CH OCH
3 2 3
C55 q, r, s or t -Cl -CH -C(O)OCH CH
3 2 3
C56 q, r, s or t -Cl -OCH -H
C57 q, r, s or t -Cl -OCH -Cl
C58 q, r, s or t -Cl -OCH -Br
C59 q, r, s or t -Cl -OCH -F
C60 q, r, s or t -Cl -OCH -CH
C61 q, r, s or t -Cl -OCH -OCH
C62 q, r, s or t -Cl -OCH -OCH CH
3 2 3
C63 q, r, s or t -Cl -OCH -CF
C64 q, r, s or t -Cl -OCH -OCF
C65 q, r, s or t -Cl -OCH -CH OCH
3 2 3
C66 q, r, s or t -Cl -OCH -C(O)OCH CH
3 2 3
C67 q, r, s or t -Cl -OCH CH -H
C68 q, r, s or t -Cl -OCH CH -Cl
C69 q, r, s or t -Cl -OCH CH -Br
C70 q, r, s or t -Cl -OCH CH -F
C71 q, r, s or t -Cl -OCH CH -CH
2 3 3
C72 q, r, s or t -Cl -OCH CH -OCH
2 3 3
C73 q, r, s or t -Cl -OCH CH -OCH CH
2 3 2 3
C74 q, r, s or t -Cl -OCH CH -CF
2 3 3
C75 q, r, s or t -Cl -OCH CH -OCF
2 3 3
C76 q, r, s or t -Cl -OCH CH -CH OCH
2 3 2 3
C77 q, r, s or t -Cl -OCH CH -C(O)OCH CH
2 3 2 3
C78 q, r, s or t -Cl -CF -H
C79q, r, s or t -Cl -CF -Cl
C80 q, r, s or t -Cl -CF -Br
C81 q, r, s or t -Cl -CF -F
C82 q, r, s or t -Cl -CF -CH
C83 q, r, s or t -Cl -CF -OCH
Compound R R R
1 8 9
C84 q, r, s or t -Cl -CF -OCH CH
3 2 3
C85 q, r, s or t -Cl -CF -CF
C86 q, r, s or t -Cl -CF -OCF
C87 q, r, s or t -Cl -CF -CH OCH
3 2 3
C88 q, r, s or t -Cl -CF -C(O)OCH CH
3 2 3
C89 q, r, s or t -Cl -OCF -H
C90 q, r, s or t -Cl -OCF -Cl
C91 q, r, s or t -Cl -OCF -Br
C92 q, r, s or t -Cl -OCF -F
C93 q, r, s or t -Cl -OCF -CH
C94 q, r, s or t -Cl -OCF -OCH
C95 q, r, s or t -Cl -OCF -OCH CH
3 2 3
C96 q, r, s or t -Cl -OCF -CF
C97 q, r, s or t -Cl -OCF -OCF
C98 q, r, s or t -Cl -OCF -CH OCH
3 2 3
C99 q, r, s or t -Cl -OCF -C(O)OCH CH
3 2 3
C100 q, r, s or t -Cl -CH OCH -H
C101 q, r, s or t -Cl -CH OCH -Cl
C102 q, r, s or t -Cl -CH OCH -Br
C103 q, r, s or t -Cl -CH OCH -F
C104 q, r, s or t -Cl -CH OCH -CH
2 3 3
C105q, r, s or t -Cl -CH OCH -OCH
2 3 3
C106 q, r, s or t -Cl -CH OCH -OCH CH
2 3 2 3
C107 q, r, s or t -Cl -CH OCH -CF
2 3 3
C108 q, r, s or t -Cl -CH OCH -OCF
2 3 3
C109 q, r, s or t -Cl -CH OCH -CH OCH
2 3 2 3
C110 q, r, s or t -Cl -CH OCH -C(O)OCH CH
2 3 2 3
C111 q, r, s or t -Cl -C(O)OCH CH -H
C112 q, r, s or t -Cl -C(O)OCH CH -Cl
C113 q, r, s or t -Cl -C(O)OCH CH -Br
C114 q, r, s or t -Cl -C(O)OCH CH -F
C115 q, r, s or t -Cl -C(O)OCH CH -CH
2 3 3
Compound R R R
1 8 9
C116 q, r, s or t -Cl -C(O)OCH CH -OCH
2 3 3
C117 q, r, s or t -Cl -C(O)OCH CH -OCH CH
2 3 2 3
C118 q, r, s or t -Cl -C(O)OCH CH -CF
2 3 3
C119 q, r, s or t -Cl -C(O)OCH CH -OCF
2 3 3
C120 q, r, s or t -Cl -C(O)OCH CH -CH OCH
2 3 2 3
C121 q, r, s or t -Cl -C(O)OCH CH -C(O)OCH CH
2 3 2 3
C122 q, r, s or t -F -H -H
C123 q, r, s or t -F -H -Cl
C124 q, r, s or t -F -H -Br
C125 q, r, s or t -F -H -F
C126 q, r, s or t -F -H -CH
C127 q, r, s or t -F -H -OCH
C128 q, r, s or t -F -H -OCH CH
C129 q, r, s or t -F -H -CF
C130 q, r, s or t -F -H -OCF
C131q, r, s or t -F -H -CH OCH
C132 q, r, s or t -F -H -C(O)OCH CH
C133 q, r, s or t -F -Cl -H
C134 q, r, s or t -F -Cl -Cl
C135 q, r, s or t -F -Cl -Br
C136 q, r, s or t -F -Cl -F
C137 q, r, s or t -F -Cl -CH
C138 q, r, s or t -F -Cl -OCH
C139 q, r, s or t -F -Cl -OCH CH
C140 q, r, s or t -F -Cl -CF
C141 q, r, s or t -F -Cl -OCF
C142 q, r, s or t -F -Cl -CH OCH
C143 q, r, s or t -F -Cl -C(O)OCH CH
C144 q, r, s or t -F -Br -H
C145 q, r, s or t -F -Br -Cl
C146 q, r, s or t -F -Br -Br
C147 q, r, s or t -F -Br -F
Compound R R R
1 8 9
C148 q, r, s or t -F -Br -CH
C149 q, r, s or t -F -Br -OCH
C150 q, r, s or t -F -Br -OCH CH
C151 q, r, s or t -F -Br -CF
C152 q, r, s or t -F -Br -OCF
C153 q, r, s or t -F -Br -CH OCH
C154 q, r, s or t -F -Br -C(O)OCH CH
C155 q, r, s or t -F -F -H
C156 q, r, s or t -F -F -Cl
C157q, r, s or t -F -F -Br
C158 q, r, s or t -F -F -F
C159 q, r, s or t -F -F -CH
C160 q, r, s or t -F -F -OCH
C161 q, r, s or t -F -F -OCH CH
C162 q, r, s or t -F -F -CF
C163 q, r, s or t -F -F -OCF
C164 q, r, s or t -F -F -CH OCH
C165 q, r, s or t -F -F -C(O)OCH CH
C166 q, r, s or t -F -CH -H
C167 q, r, s or t -F -CH -Cl
C168 q, r, s or t -F -CH -Br
C169 q, r, s or t -F -CH -F
C170 q, r, s or t -F -CH -CH
C171 q, r, s or t -F -CH -OCH
C172 q, r, s or t -F -CH -OCH CH
3 2 3
C173 q, r, s or t -F -CH -CF
C174 q, r, s or t -F -CH -OCF
C175 q, r, s or t -F -CH -CH OCH
3 2 3
C176 q, r, s or t -F -CH -C(O)OCH CH
3 2 3
C177 q, r, s or t -F -OCH -H
C178 q, r, s or t -F -OCH -Cl
C179 q, r, s or t -F -OCH -Br
Compound R R R
1 8 9
C180 q, r, s or t -F -OCH -F
C181 q, r, s or t -F -OCH -CH
C182 q, r, s or t -F -OCH -OCH
C183q, r, s or t -F -OCH -OCH CH
3 2 3
C184 q, r, s or t -F -OCH -CF
C185 q, r, s or t -F -OCH -OCF
C186 q, r, s or t -F -OCH -CH OCH
3 2 3
C187 q, r, s or t -F -OCH -C(O)OCH CH
3 2 3
C188 q, r, s or t -F -OCH CH -H
C189 q, r, s or t -F -OCH CH -Cl
C190 q, r, s or t -F -OCH CH -Br
C191 q, r, s or t -F -OCH CH -F
C192 q, r, s or t -F -OCH CH -CH
2 3 3
C193 q, r, s or t -F -OCH CH -OCH
2 3 3
C194 q, r, s or t -F -OCH CH -OCH CH
2 3 2 3
C195 q, r, s or t -F -OCH CH -CF
2 3 3
C196 q, r, s or t -F -OCH CH -OCF
2 3 3
C197 q, r, s or t -F -OCH CH -CH OCH
2 3 2 3
C198 q, r, s or t -F -OCH CH -C(O)OCH CH
2 3 2 3
C199 q, r, s or t -F -CF -H
C200 q, r, s or t -F -CF -Cl
C201 q, r, s or t -F -CF -Br
C202 q, r, s or t -F -CF -F
C203 q, r, s or t -F -CF -CH
C204 q, r, s or t -F -CF -OCH
C205 q, r, s or t -F -CF -OCH CH
3 2 3
C206 q, r, s or t -F -CF -CF
C207 q, r, s or t -F -CF -OCF
C208 q, r, s or t -F -CF -CH OCH
3 2 3
C209q, r, s or t -F -CF -C(O)OCH CH
3 2 3
C210 q, r, s or t -F -OCF -H
C211 q, r, s or t -F -OCF -Cl
Compound R R R
1 8 9
C212 q, r, s or t -F -OCF -Br
C213 q, r, s or t -F -OCF -F
C214 q, r, s or t -F -OCF -CH
C215 q, r, s or t -F -OCF -OCH
C216 q, r, s or t -F -OCF -OCH CH
3 2 3
C217 q, r, s or t -F -OCF -CF
C218 q, r, s or t -F -OCF -OCF
C219 q, r, s or t -F -OCF -CH OCH
3 2 3
C220 q, r, s or t -F -OCF -C(O)OCH CH
3 2 3
C221 q, r, s or t -F -CH OCH -H
C222 q, r, s or t -F -CH OCH -Cl
C223 q, r, s or t -F -CH OCH -Br
C224 q, r, s or t -F -CH OCH -F
C225 q, r, s or t -F -CH OCH -CH
2 3 3
C226 q, r, s or t -F -CH OCH -OCH
2 3 3
C227 q, r, s or t -F -CH OCH -OCH CH
2 3 2 3
C228 q, r, s or t -F -CH OCH -CF
2 3 3
C229 q, r, s or t -F -CH OCH -OCF
2 3 3
C230 q, r, s or t -F -CH OCH -CH OCH
2 3 2 3
C231 q, r, s or t -F -CH OCH -C(O)OCH CH
2 3 2 3
C232 q, r, s or t -F -C(O)OCH CH -H
C233 q, r, s or t -F -C(O)OCH CH -Cl
C234 q, r, s or t -F -C(O)OCH CH -Br
C235q, r, s or t -F -C(O)OCH CH -F
C236 q, r, s or t -F -C(O)OCH CH -CH
2 3 3
C237 q, r, s or t -F -C(O)OCH CH -OCH
2 3 3
C238 q, r, s or t -F -C(O)OCH CH -OCH CH
2 3 2 3
C239 q, r, s or t -F -C(O)OCH CH -CF
2 3 3
C240 q, r, s or t -F -C(O)OCH CH -OCF
2 3 3
C241 q, r, s or t -F -C(O)OCH CH -CH OCH
2 3 2 3
C242 q, r, s or t -F -C(O)OCH CH -C(O)OCH CH
2 3 2 3
C243 q, r, s or t -CF -H -H
Compound R R R
1 8 9
C244 q, r, s or t -CF -H -Cl
C245 q, r, s or t -CF -H -Br
C246 q, r, s or t -CF -H -F
C247 q, r, s or t -CF -H -CH
C248 q, r, s or t -CF -H -OCH
C249 q, r, s or t -CF -H -OCH CH
3 2 3
C250 q, r, s or t -CF -H -CF
C251 q, r, s or t -CF -H -OCF
C252 q, r, s or t -CF -H -CH OCH
3 2 3
C253 q, r, s or t -CF -H -C(O)OCH CH
3 2 3
C254 q, r, s or t -CF -Cl -H
C255 q, r, s or t -CF -Cl -Cl
C256 q, r, s or t -CF -Cl -Br
C257 q, r, s or t -CF -Cl -F
C258 q, r, s or t -CF -Cl -CH
C259 q, r, s or t -CF -Cl -OCH
C260 q, r, s or t -CF -Cl -OCH CH
3 2 3
C261q, r, s or t -CF -Cl -CF
C262 q, r, s or t -CF -Cl -OCF
C263 q, r, s or t -CF -Cl -CH OCH
3 2 3
C264 q, r, s or t -CF -Cl -C(O)OCH CH
3 2 3
C265 q, r, s or t -CF -Br -H
C266 q, r, s or t -CF -Br -Cl
C267 q, r, s or t -CF -Br -Br
C268 q, r, s or t -CF -Br -F
C269 q, r, s or t -CF -Br -CH
C270 q, r, s or t -CF -Br -OCH
C271 q, r, s or t -CF -Br -OCH CH
3 2 3
C272 q, r, s or t -CF -Br -CF
C273 q, r, s or t -CF -Br -OCF
C274 q, r, s or t -CF -Br -CH OCH
3 2 3
C275 q, r, s or t -CF -Br -C(O)OCH CH
3 2 3
Compound R R R
1 8 9
C276 q, r, s or t -CF -F -H
C277 q, r, s or t -CF -F -Cl
C278 q, r, s or t -CF -F -Br
C279 q, r, s or t -CF -F -F
C280 q, r, s or t -CF -F -CH
C281 q, r, s or t -CF -F -OCH
C282 q, r, s or t -CF -F -OCH CH
3 2 3
C283 q, r, s or t -CF -F -CF
C284 q, r, s or t -CF -F -OCF
C285 q, r, s or t -CF -F -CH OCH
3 2 3
C286 q, r, s or t -CF -F -C(O)OCH CH
3 2 3
C287q, r, s or t -CF -CH -H
C288 q, r, s or t -CF -CH -Cl
C289 q, r, s or t -CF -CH -Br
C290 q, r, s or t -CF -CH -F
C291 q, r, s or t -CF -CH -CH
3 3 3
C292 q, r, s or t -CF -CH -OCH
3 3 3
C293 q, r, s or t -CF -CH -OCH CH
3 3 2 3
C294 q, r, s or t -CF -CH -CF
3 3 3
C295 q, r, s or t -CF -CH -OCF
3 3 3
C296 q, r, s or t -CF -CH -CH OCH
3 3 2 3
C297 q, r, s or t -CF -CH -C(O)OCH CH
3 3 2 3
C298 q, r, s or t -CF -OCH -H
C299 q, r, s or t -CF -OCH -Cl
C300 q, r, s or t -CF -OCH -Br
C301 q, r, s or t -CF -OCH -F
C302 q, r, s or t -CF -OCH -CH
3 3 3
C303 q, r, s or t -CF -OCH -OCH
3 3 3
C304 q, r, s or t -CF -OCH -OCH CH
3 3 2 3
C305 q, r, s or t -CF -OCH -CF
3 3 3
C306 q, r, s or t -CF -OCH -OCF
3 3 3
C307 q, r, s or t -CF -OCH -CH OCH
3 3 2 3
Compound R R R
1 8 9
C308 q, r, s or t -CF -OCH -C(O)OCH CH
3 3 2 3
C309 q, r, s or t -CF -OCH CH -H
3 2 3
C310 q, r, s or t -CF -OCH CH -Cl
3 2 3
C311 q, r, s or t -CF -OCH CH -Br
3 2 3
C312 q, r, s or t -CF -OCH CH -F
3 2 3
C313q, r, s or t -CF -OCH CH -CH
3 2 3 3
C314 q, r, s or t -CF -OCH CH -OCH
3 2 3 3
C315 q, r, s or t -CF -OCH CH -OCH CH
3 2 3 2 3
C316 q, r, s or t -CF -OCH CH -CF
3 2 3 3
C317 q, r, s or t -CF -OCH CH -OCF
3 2 3 3
C318 q, r, s or t -CF -OCH CH -CH OCH
3 2 3 2 3
C319 q, r, s or t -CF -OCH CH -C(O)OCH CH
3 2 3 2 3
C320 q, r, s or t -CF -CF -H
C321 q, r, s or t -CF -CF -Cl
C322 q, r, s or t -CF -CF -Br
C323 q, r, s or t -CF -CF -F
C324 q, r, s or t -CF -CF -CH
3 3 3
C325 q, r, s or t -CF -CF -OCH
3 3 3
C326 q, r, s or t -CF -CF -OCH CH
3 3 2 3
C327 q, r, s or t -CF -CF -CF
3 3 3
C328 q, r, s or t -CF -CF -OCF
3 3 3
C329 q, r, s or t -CF -CF -CH OCH
3 3 2 3
C330 q, r, s or t -CF -CF -C(O)OCH CH
3 3 2 3
C331 q, r, s or t -CF -OCF -H
C332 q, r, s or t -CF -OCF -Cl
C333 q, r, s or t -CF -OCF -Br
C334 q, r, s or t -CF -OCF -F
C335 q, r, s or t -CF -OCF -CH
3 3 3
C336 q, r, s or t -CF -OCF -OCH
3 3 3
C337 q, r, s or t -CF -OCF -OCH CH
3 3 2 3
C338 q, r, s or t -CF -OCF -CF
3 3 3
C339q, r, s or t -CF -OCF -OCF
3 3 3
Compound R R R
1 8 9
C340 q, r, s or t -CF -OCF -CH OCH
3 3 2 3
C341 q, r, s or t -CF -OCF -C(O)OCH CH
3 3 2 3
C342 q, r, s or t -CF -CH OCH -H
3 2 3
C343 q, r, s or t -CF -CH OCH -Cl
3 2 3
C344 q, r, s or t -CF -CH OCH -Br
3 2 3
C345 q, r, s or t -CF -CH OCH -F
3 2 3
C346 q, r, s or t -CF -CH OCH -CH
3 2 3 3
C347 q, r, s or t -CF -CH OCH -OCH
3 2 3 3
C348 q, r, s or t -CF -CH OCH -OCH CH
3 2 3 2 3
C349 q, r, s or t -CF -CH OCH -CF
3 2 3 3
C350 q, r, s or t -CF -CH OCH -OCF
3 2 3 3
C351 q, r, s or t -CF -CH OCH -CH OCH
3 2 3 2 3
C352 q, r, s or t -CF -CH OCH -C(O)OCH CH
3 2 3 2 3
C353 q, r, s or t -CF -C(O)OCH CH -H
3 2 3
C354 q, r, s or t -CF -C(O)OCH CH -Cl
3 2 3
C355 q, r, s or t -CF -C(O)OCH CH -Br
3 2 3
C356 q, r, s or t -CF -C(O)OCH CH -F
3 2 3
C357 q, r, s or t -CF -C(O)OCH CH -CH
3 2 3 3
C358 q, r, s or t -CF -C(O)OCH CH -OCH
3 2 3 3
C359 q, r, s or t -CF -C(O)OCH CH -OCH CH
3 2 3 2 3
C360 q, r, s or t -CF -C(O)OCH CH -CF
3 2 3 3
C361 q, r, s or t -CF -C(O)OCH CH -OCF
3 2 3 3
C362 q, r, s or t -CF -C(O)OCH CH -CH OCH
3 2 3 2 3
C363 q, r, s or t -CF -C(O)OCH CH -C(O)OCH CH
3 2 3 2 3
4.3 Definitions
As used herein, the terms used above having following meaning:
"-(C -C )alkyl" means a straight chain or branched non-cyclic hydrocarbon having 1, 2, 3, or 4
carbon atoms. Representative straight chain -(C -C )alkyls include -methyl, -ethyl, -n-propyl,
and -n-butyl. Representative branched -(C -C )alkyls include -iso-propyl, -sec-butyl, -iso-
butyl, and -tert-butyl.
"-Halogen" or "-halo" means -F, -Cl, -Br, or -I.
In connection with the methyl substituent of the piperazine ring of, e.g., compounds of formula
(I), "2-methyl group", "2-position methyl group", and the like means
where R , R , R , and R are as defined above for Compounds of Formula (I), and where the
1 4 8 9
numbers designate the position of each atom in the piperazine ring.
In connection with the methyl substituent of the piperazine ring of, e.g., compounds of formula
(I), "(R)methyl group", "(R)position methyl group", and the like means
where R , R , R , and R are as defined above for Compounds of Formula (I), where the
1 4 8 9
numbers designate the position of each atom in the piperazine ring.
In connection with the methyl substituent of the piperazine ring of, e.g., compounds of formula
(I), "(S)methyl group", "(S)position methyl group", and the like means
where R , R , R , and R are as defined above for Compounds of Formula (I), where the
1 4 8 9
numbers designate the position of each atom in the piperazine ring.
In connection with the methyl substituent of the piperazine ring of, e.g., compounds of formula
(I), "3-methyl group", "3-position methyl group", and the like means
where R , R , R , and R are as defined above for Compounds of Formula (I), and where the
1 4 8 9
numbers designate the position of each atom in the piperazine ring.
In connection with the methyl substituent of the piperazine ring of, e.g., compounds of formula
(I), "(R)methyl group", "(R)position methyl group", and the like means
where R , R , R , and R are as defined above for Compounds of Formula (I), where the
1 4 8 9
numbers designate the position of each atom in the piperazine ring.
In connection with the methyl substituent of the piperazine ring of, e.g., compounds of formula
(I), "(S)methyl group", "(S)position methyl group", and the like means
where R , R , R , and R are as defined above for Compounds of Formula (I), where the
1 4 8 9
numbers designate the position of each atom in the piperazine ring.
In connection with the substituent of the pyridine ring containing R , the phrase "wherein R is
-CH and the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in
the (S) configuration" and the like means
where the lower-case letters are used to designate a particular C-O bond in that substituent.
In connection with the substituent of the pyridine ring containing R , the phrase "wherein R is
-CH and the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in
the (R) configuration" and the like means
where the lower-case letters are used to designate a particular C-O bond in that substituent.
In connection with the substituent of the pyridine ring containing R , the phrase "wherein R is
-CH , the carbon atom at the a position of the a-b bond in the (R) configuration, and the carbon
atom at the c position of the c-d bond is in the (S) configuration" and the like means
where the lower-case letters are used to designate a particular C-O bond in that substituent.
In connection with the substituent of the pyridine ring containing R , the phrase "wherein R is
-CH , the carbon atom at the a position of the a-b bond in the (S) configuration, and the carbon
atom at the c position of the c-d bond is in the (R) configuration" and the like means
where the lower-case letters are used to designate a particular C-O bond in that substituent.
In connection with the substituent of the pyridine ring containing R , the phrase "wherein R is
-H and the carbon atom at the a position of the a-b bond is in the (S) configuration" and the like
means
where the lower-case letters are used to designate a particular C-O bond in that substituent.
In connection with the substituent of the pyridine ring containing R , the phrase "wherein R is
-H and the carbon atom at the a position of the a-b bond is in the (R) configuration" and the like
means
where the lower-case letters are used to designate a particular C-O bond in that substituent.
The term "animal," includes, but is not limited to, a cow, monkey, baboon, chimpanzee, horse,
sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, and human.
The phrase "pharmaceutically acceptable derivative", as used herein, includes any
pharmaceutically acceptable salt, polymorph, pseudopolymorph, solvate, co-crystal, prodrug,
radiolabeled form, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic
mixture, geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the
disclosure.
In one embodiment, the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, polymorph, pseudopolymorph, solvate, co-crystal, prodrug, radiolabeled form,
stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic mixture, geometric
isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the disclosure. In another
embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt,
polymorph, pseudopolymorph, solvate, co-crystal, radiolabeled form, stereoisomer, enantiomer,
diastereomer, other stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,
e.g., of a Compound of Formula (I) of the disclosure. In another embodiment, the
pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph,
pseudopolymorph, solvate, co-crystal, prodrug, stereoisomer, enantiomer, diastereomer, other
stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer, e.g., of a Compound
of Formula (I) of the disclosure. In another embodiment, the pharmaceutically acceptable
derivative is a pharmaceutically acceptable salt, polymorph, pseudopolymorph, solvate, co-
crystal, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic mixture,
geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the disclosure. In
another embodiment, the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, polymorph, co-crystal, radiolabeled form, stereoisomer, enantiomer,
diastereomer, other stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,
e.g., of a Compound of Formula (I) of the disclosure. In another embodiment, the
pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph, co-
crystal, prodrug, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic
mixture, geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the
disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, polymorph, co-crystal, stereoisomer, enantiomer,
diastereomer, other stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,
e.g., of a Compound of Formula (I) of the disclosure. In another embodiment, the
pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, co-crystal,
radiolabeled form, stereoisomer, enantiomer, diastereomer, other stereoisomeric form, racemic
mixture, geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the
disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, co-crystal, prodrug, stereoisomer, enantiomer, diastereomer,
other stereoisomeric form, racemic mixture, geometric isomer, and/or tautomer, e.g., of a
Compound of Formula (I) of the disclosure. In another embodiment, the pharmaceutically
acceptable derivative is a pharmaceutically acceptable salt, co-crystal, stereoisomer,
enantiomer, diastereomer, other stereoisomeric form, racemic mixture, geometric isomer,
and/or tautomer, e.g., of a Compound of Formula (I) of the disclosure.
In another embodiment, the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, polymorph, pseudopolymorph, solvate, co-crystal, radiolabeled form,
stereoisomer, geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the
disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, polymorph, pseudopolymorph, solvate, co-crystal, prodrug,
stereoisomer, geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the
disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, polymorph, pseudopolymorph, solvate, co-crystal,
stereoisomer, geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the
disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, polymorph, co-crystal, radiolabeled form, stereoisomer,
geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of the disclosure. In
another embodiment, the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, polymorph, co-crystal, prodrug, stereoisomer, geometric isomer, and/or
tautomer, e.g., of a Compound of Formula (I) of the disclosure. In another embodiment, the
pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph, co-
crystal, stereoisomer, geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) of
the disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, co-crystal, radiolabeled form, stereoisomer, geometric isomer,
and/or tautomer, e.g., of a Compound of Formula (I) of the disclosure. In another embodiment,
the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, co-crystal,
prodrug, stereoisomer, geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I)
of the disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, co-crystal, stereoisomer, geometric isomer, and/or tautomer,
e.g., of a Compound of Formula (I) of the disclosure. In another embodiment, the
pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, co-crystal,
stereoisomer, and/or tautomer, e.g., of a Compound of Formula (I) of the disclosure. In another
embodiment, the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt,
polymorph, stereoisomer, and/or tautomer, e.g., of a Compound of Formula (I) of the
disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pharmaceutically acceptable salt, stereoisomer, and/or tautomer, e.g., of a Compound of
Formula (I) of the disclosure.
In another embodiment, the pharmaceutically acceptable derivative is a pharmaceutically
acceptable salt, e.g., of a Compound of Formula (I) of the disclosure. In another embodiment,
the pharmaceutically acceptable derivative is a polymorph, e.g., of a Compound of Formula (I)
of the disclosure. In another embodiment, the pharmaceutically acceptable derivative is a
pseudopolymorph, e.g., of a Compound of Formula (I) of the disclosure. In another
embodiment, the pharmaceutically acceptable derivative is a solvate, e.g., of a Compound of
Formula (I) of the disclosure. In another embodiment, the pharmaceutically acceptable
derivative is a co-crystal, e.g., of a Compound of Formula (I) of the disclosure. In another
embodiment, the pharmaceutically acceptable derivative is a prodrug, e.g., of a Compound of
Formula (I) of the disclosure. In another embodiment, the pharmaceutically acceptable
derivative is a radiolabeled form, e.g., of a Compound of Formula (I) of the disclosure. In
another embodiment, the pharmaceutically acceptable derivative is a stereoisomer, e.g., of a
Compound of Formula (I) of the disclosure. In another embodiment, the pharmaceutically
acceptable derivative is an enantiomer, e.g., of a Compound of Formula (I) of the disclosure.
In another embodiment, the pharmaceutically acceptable derivative is a diastereomer, e.g., of a
Compound of Formula (I) of the disclosure. In another embodiment, the pharmaceutically
acceptable derivative is a stereoisomeric form other than a stereoisomer, an enantiomer and a
diastereomer, e.g., of a Compound of Formula (I) of the disclosure. In another embodiment,
the pharmaceutically acceptable derivative is a racemic mixture, e.g., of a Compound of
Formula (I) of the disclosure. In another embodiment, the pharmaceutically acceptable
derivative is a geometric isomer, e.g., of a Compound of Formula (I) of the disclosure. In
another embodiment, the pharmaceutically acceptable derivative is a tautomer, e.g., of a
Compound of Formula (I) of the disclosure.
The phrase "pharmaceutically acceptable salt", as used herein, is any pharmaceutically
acceptable salt that can be prepared from a Compound of Formula (I) including a salt formed
from an acid and a basic functional group, such as a nitrogen group, of a Compound of Formula
(I). Illustrative salts include, but are not limited, to sulfate, citrate, acetate, trifluoroacetate,
oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,
lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,
succinate, maleate, gentisinate, fumarate, gluconate, glucoronate, saccharate, formate, benzoate,
glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and
pamoate (i.e., 1,1'-methylene-bis-(2-hydroxynaphthoate)) salts. The term "pharmaceutically
acceptable salt" also includes a salt prepared from a Compound of Formula (I) having an acidic
functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable
inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali
metals such as sodium, potassium, cesium, and lithium; hydroxides of alkaline earth metal such
as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia
and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines;
dicyclohexylamine; tributyl amine; pyridine; picoline; N-methyl-N-ethylamine; diethylamine;
triethylamine; mono-, bis-, or tris-(2-hydroxy-(C -C )alkyl amines), such as mono-, bis-, or tris-
(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,
N,N-di-[(C -C )alkyl]-N-(hydroxy-(C -C )alkyl)-amines, such as N,N-dimethyl-
1 3 1 3
N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino
acids such as arginine, lysine, and the like. In one embodiment, the pharmaceutically
acceptable salt is a hydrochloride-salt, a sulfate-salt, a sodium-salt, a potassium-salt, a benzene
sulfonic acid-salt, a para-toluenesulfonic acid-salt, or a fumaric acid-salt. In another
embodiment, the pharmaceutically acceptable salt is a hydrochloride-salt or a sulfate-salt. In
another embodiment, the pharmaceutically acceptable salt is a hydrochloride-salt. In another
embodiment, the pharmaceutically acceptable salt is a sulfate-salt. In another embodiment, the
pharmaceutically acceptable salt is a sodium-salt. In another embodiment, the
pharmaceutically acceptable salt is a potassium-salt. In another embodiment, the
pharmaceutically acceptable salt is a para-toluenesulfonic acid-salt. In another embodiment,
the pharmaceutically acceptable salt is a fumaric acid-salt. In another embodiment, the
pharmaceutically acceptable fumaric acid-salt contains about one equivalent of a Compound of
Formula (I) and about 0.5 equivalents of fumaric acid, e.g., from about 0.3 to about 0.7
equivalents of fumaric acid in one embodiment, from about 0.4 to about 0.6 equivalents of
fumaric acid in another embodiment, from about 0.44 to about 0.56 equivalents of fumaric acid
in another embodiment, or from about 0.47 to about 0.53 equivalents of fumaric acid in another
embodiment. In another embodiment, the pharmaceutically acceptable fumaric acid-salt
contains one equivalent of a Compound of Formula (I) and 0.5 equivalents of fumaric acid.
One skilled in the art will recognize that, e.g., acid addition salts, of a Compound of Formula
(I) can be prepared by reaction of the compounds with the appropriate acid by a variety of
known methods.
The compounds of the disclosure provided herein also encompass all polymorphs and
pseudopolymorphs of the Compounds of Formula (I). "Polymorphs" are known in the art (see,
e.g., Giron, "Investigations of Polymorphism and Pseudo-polymorphism in Pharmaceuticals by
Combined Thermoanalytical Techniques," J. Thermal Anal. Cal. 64:37-60 (2001)) and are
considered to be different crystalline phases in which a Compound of Formula (I) is capable of
existing. The crystalline phases can have different arrangements ("packing polymorphism")
and/or conformations ("conformational polymorphism") of the molecules in the crystal lattice.
For example, in two distinct polymorphs of a Compound of Formula (I), each polymorph can
have the molecules arranged in a different fundamental crystal system - triclinic, monoclinic,
orthorhombic, tetragonal, trigonal, hexagonal, or cubic. The term "anhydrate" as used herein, is
any crystalline form of a Compound of Formula (I) in which water molecules are a non-integral
part of the crystal. An anhydrate of a Compound of Formula (I) can be prepared, for example,
by crystallization from a solvent substantially free of water. In one embodiment, the
Compound of Formula (I) is present as an anhydrate, i.e., as a free base where the crystal lattice
is substantially free of water molecules and any water molecules present are present as "surface
water" (e.g., loosely bound to the crystal's surface) as would be discernable and distinguishable
to those in the art by, e.g., thermogravimetric analysis (TGA) and/or differential scanning
calorimetry (DSC), from water molecules that are an integral part of the crystal (e.g., a
hydrate). An anhydrate of a Compound of Formula (I) has less than about 0.2 mole water in
one embodiment, less than about 0.15 mole water in another embodiment, less than about 0.12
mole water in another embodiment, less than about 0.1 mole water in another embodiment, less
than about 0.085 mole water in another embodiment, less than about 0.075 mole water in
another embodiment, less than about 0.06 mole water in another embodiment, less than about
0.057 mole water in another embodiment, less than about 0.05 mole water in another
embodiment, less than about 0.03 mole water in another embodiment, less than about 0.025
mole water in another embodiment, less than about 0.02 mole water in another embodiment,
less than about 0.01 mole water in another embodiment, less than about 0.005 mole water in
another embodiment, and less than about 0.001 mole water in another embodiment, each said
embodiment taking into account the presence of surface water and each said embodiment being
per 1 mole of a Compound of Formula (I).
The compounds of the disclosure provided herein also encompass all solvates of the
Compounds of Formula (I). "Solvates" are known in the art and are considered to be a
combination, physical association and/or solvation of a Compound of Formula (I) with a
solvent molecule. This physical association can involve varying degrees of ionic and covalent
bonding, including hydrogen bonding. When the solvate is of the stoichiometric type, there is a
fixed ratio of the solvent molecule to Compound of Formula (I), e.g., a disolvate, monosolvate
or hemisolvate when the solvent molecule:Compound of Formula (I) molecule molar ratio is
2:1, 1:1 or 1:2, respectively. In other embodiments, the solvate is of the nonstoichiometric
type. For example, the Compound of Formula (I) crystal can contain solvent molecules in the
structural voids, e.g., channels, of the crystal lattice. In certain instances, the solvate can be
isolated, for example when one or more solvent molecules are incorporated into the crystal
lattice of a crystalline solid. Thus, "solvate", as used herein, encompasses both solution-phase
and isolatable solvates. As the crystalline form of a solvate can also be referred to as a
"pseudopolymorph", the compounds of the disclosure provided herein also encompass all
pseudopolymorphs of the Compounds of Formula (I). A Compound of Formula (I) of the
disclosure can be present as a solvated form with a pharmaceutically acceptable solvent, such
as water, methanol, ethanol, and the like, and it is intended that the disclosure include both
solvated and unsolvated Compound of Formula (I) forms. As "hydrate" relates to a particular
subgroup of solvates, i.e., where the solvent molecule is water, hydrates are included within the
solvates of the disclosure. In one embodiment, the Compound of Formula (I) is present as a
monohydrate, i.e., as a free base where the water:Compound of Formula (I) molar ratio is about
1:1, e.g., from 0.91:1 to 1.09:1 in one embodiment, from 0.94:1 to 1.06:1 in another
embodiment, from 0.97:1 to 1.03:1 in another embodiment, and from 0.985:1 to 1.015:1 in
another embodiment, each said embodiment taking no account of surface water that might be
present, if any.
Preparation of solvates is known in the art. For example, Caira et al., "Preparation and Crystal
Characterization of a Polymorph, a Monohydrate, and an Ethyl Acetate Solvate of the
Antifungal Fluconazole," J. Pharmaceut. Sci., 93(3):601-611 (2004), describes the preparation
of solvates of fluconazole with ethyl acetate and with water. Similar preparations of solvates,
hemisolvate, hydrates, and the like are described by Van Tonder et al., "Preparation and
Physicochemical Characterization of 5 Niclosamide Solvates and 1 Hemisolvate," AAPS
Pharm. Sci. Tech., 5(1):Article 12 (2004), and Bingham et al., "Over one hundred solvates of
sulfathiazole," Chem. Comm., pp. 603-604 (2001). In one embodiment, a non-limiting, process
involves dissolving the Compound of Formula (I) in a desired amount of the desired solvent
(organic, water or mixtures thereof) at temperatures above about 20°C to about 25°C, cooling
the solution at a rate sufficient to form crystals, and isolating the crystals by known methods,
e.g., filtration. Analytical techniques, for example, infrared spectroscopy, can be used to show
the presence of the solvent in a crystal of the solvate.
The compounds of the disclosure provided herein also encompass all co-crystals of the
Compounds of Formula (I). "Co-crystals" are known in the art; a co-crystal is considered to be
a structurally homogeneous crystalline material that contains two or more neutral building
blocks, e.g., a Compound of Formula (I) with a co-former material, that are present in definite
stoichiometric amounts. Aakeroy et al., "Co-crystal or Salt: Does it Really Matter?" Mol.
Pharmaceutics 4(3):317-322 (2007). As used herein, a "co-crystal" includes all polymorphs of
that co-crystal, i.e., all different crystalline phases of that co-crystal. The main difference
between solvates and co-crystals is the physical state of the isolated pure components. For,
e.g., a two component system, if one component is a liquid at a temperature of about 25°C then
the crystal containing both components is designated as a solvate; if both components are solids
at that temperature then the crystal containing both components is designated as a co-crystal.
Sekhon, "Pharmaceutical Co-crystals - A Review," Ars. Pharm. 50(3):99-117 (2009).
Furthermore, co-crystals and salts can be considered as opposite "extremes" on the scale of the
multi-component structures possible. Salts are formed through ionization, e.g., an acid-base
reaction or proton donation occurring between the active pharmaceutical ingredient and an
acidic or basic substance. In contrast, when the active pharmaceutical ingredient(s) lacks an
ionizable site amenable to salt formation, a co-crystal can be formed through unionization, e.g.,
hydrogen bonding, - , or van der Waals interactions between the components. The
differences in structure among a co-crystal, salt, and hydrate are illustrated in, e.g., Figures 1
and 2 of Schultheiss et al., "Pharmaceutical Co-crystals and their Physicochemical Properties,"
Crystal Growth & Design 9(6):2950-2967 (2009), which is hereby incorporated by reference.
Preparation of co-crystals is known in the art; for example, as described in the above-cited
references and in U.S. Patent Nos. 7,452,555 B2 and 7,935,817 B2.
In one embodiment, a co-crystal with a Compound of Formula (I) comprises hydrochloric acid,
tartaric acid, benzenesulfonic acid, toluenesulfonic acid, succinic acid, fumaric acid, citric acid,
oxalic acid, benzoic acid, or any mixture thereof. In another embodiment, a co-crystal with a
Compound of Formula (I) comprises hydrochloric acid, benzenesulfonic acid, toluenesulfonic
acid, L-tartaric acid, fumaric acid, or any mixture thereof. In another embodiment, the co-
crystal is of a Compound of Formula (I) and hydrochloric acid. In another embodiment, the co-
crystal is of a Compound of Formula (I) and benzenesulfonic acid. In another embodiment, the
co-crystal is of a Compound of Formula (I) and toluenesulfonic acid. In another embodiment,
the co-crystal is of a Compound of Formula (I) and L-tartaric acid. In another embodiment, the
co-crystal is of a Compound of Formula (I) and fumaric acid. In another embodiment, the co-
crystal contains about one equivalent of a Compound of Formula (I) and about 0.5 equivalents
of fumaric acid, e.g., from about 0.3 to about 0.7 equivalents of fumaric acid in one
embodiment, from about 0.4 to about 0.6 equivalents of fumaric acid in another embodiment,
from about 0.44 to about 0.56 equivalents of fumaric acid in another embodiment, or from
about 0.47 to about 0.53 equivalents of fumaric acid in another embodiment. In another
embodiment, the co-crystal contains one equivalent of a Compound of Formula (I) and 0.5
equivalents of fumaric acid. Analytical techniques, for example, infrared spectroscopy, single
crystal x-ray diffraction (XRD), powder x-ray diffraction (PXRD), melting point determination,
DSC, differential thermal analysis (DTA), TGA, solid-state NMR (SSNMR), and x-ray
photoelectron spectroscopy (XPS), can be used to elucidate the structure of a co-crystal. In
certain embodiments, XRD, SSNMR, and/or XPS is used to determine whether a co-crystal or
a salt is present. In certain embodiments when a sufficiently large single crystal cannot be
grown, SSNMR or XPS is used to determine whether a co-crystal or a salt is present.
However, the art recognizes that "the exact classification of a compound as a salt or a co-crystal
can at times be somewhat ambiguous." Aakeroy et al., at page 321. For example, Aakeroy et
al. describe a study where x-ray and neutron diffraction were used to study hydrogen bonding
between urotropine N-oxide and formic acid as a function of temperature in which the exact
location of the proton was found to change with temperature and, under certain conditions, the
system displayed partial proton transfer from the acid to the N-oxide moiety, i.e., the system
possessed characteristics intermediate between a salt and a co-crystal. Id. Moreover, Pop et al.
describe tiotropium fumarate as, simultaneously, a salt and a co-crystal with a stoichiometry of
cation:anion:co-former of 2:1:1. Pop et al., "Tiotropium Fumarate: An Interesting
Pharmaceutical Co-crystal," J. Pharma. Sci. 98(5):1820-1834 (2009). The structure,
determined by XRD, is described as "made up of two monovalent tiotropium cations combined
with a divalent fumarate anion to make the salt, plus a nonionized free fumaric acid moiety to
make the co-crystal." Id. Thus in connection with the absence of an indisputably clear
distinction between a salt and a co-crystal, it should be understood that the phrase "and
combinations thereof", when used in the context of a salt and/or a co-crystal, means that a
characteristic attributable to a salt and another characteristic attributable to a co-crystal are
simultaneously present in one embodiment; in another embodiment, a characteristic
intermediate between the characteristic attributable to a salt and the characteristic attributable to
a co-crystal is present.
The compounds disclosed herein also comprise all prodrugs of the Compounds of Formula (I).
"Prodrugs" are known in the art and, while not necessarily possessing any pharmaceutical
activity as such, are considered to be any covalently bonded carrier(s) that releases the active
parent drug in vivo. In general, such prodrugs will be a functional derivative of a Compound of
Formula (I) which is readily convertible in vivo, e.g., by being metabolized, into the required
Compound of Formula (I). Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described in, for example, H. Bundgaard ed., Design of
Prodrugs, Elsevier (1985); "Drug and Enzyme Targeting, Part A," Widder et al., eds., Vol. 112
in Methods in Enzymology, Academic Press (1985); Bundgaard, "Design and Application of
Prodrugs," Chapter 5, pp. 113-191 in A Textbook of Drug Design and Development,
Krogsgaard-Larsen and Bundgaard Eds., Harwood Academic Publishers (1991); Bundgaard et
al., "(C) Means to Enhance Penetration (1) Prodrugs as a means to improve the delivery of
peptide drugs," Adv. Drug Delivery Revs. 8:1-38 (1992); Bundgaard et al., "Glycolamide Esters
as Biolabile Prodrugs of Carboxylic Acid Agents: Synthesis, Stability, Bioconversion, and
Physicochemical Properties," J. Pharmaceut. Sci. 77(4):285-298 (1988); and Kakeya et al.,
"Studies on Prodrugs of Cephalosporins. I. Synthesis and Biological Properties of
Glycyloxygenzoyloxymethyl and Glycylaminobenzoyloxymethyl Esters of 7β-[2-(2-
Aminothiazolyl)-(Z)methoxyiminoacetamido]3-methylcephemcarboxylic Acid,"
Chem. Pharm. Bull. 32:692-698 (1984).
In addition, one or more hydrogen, carbon or other atoms of a Compound of Formula (I) can be
replaced by a radioactive isotope of the hydrogen, carbon or other atoms. Such a
"radiolabeled", "radiolabeled form", and the like of a Compound of Formula (I), each of which
is encompassed by the disclosure, is useful as a research and/or diagnostic tool in metabolism
pharmacokinetic studies and in binding assays. "Radioactive", as used herein with respect to an
atom, means an atom that comprises a radioactive atom and therefore the specific radioactivity
thereof is above the background level of radioactivity. Examples of radioactive isotopes that
can be incorporated into a Compound of Formula (I) of the disclosure include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromine, and
2 3 11 13 14 15 17 18 31 32 35 18 19 36 37 76 77
iodine, such as H, H, C, C, C, N, O, O, P, P, S, F, F, Cl, Cl, Br, Br,
81 123 124 125 131
Br, I, I, I, and I, respectively. In one embodiment, a radiolabeled Compound of
Formula (I) contains 1, 2, 3, 4, or more radioactive isotopes, each of which is independently
selected from hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine,
bromine, and iodine. In another embodiment, a radiolabeled Compound of Formula (I)
contains 1 or 2 radioactive isotopes, each of which is independently selected from hydrogen,
carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, bromine, and iodine. In
another embodiment, a radiolabeled Compound of Formula (I) contains 1 radioactive isotope
which is selected from hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine,
chlorine, bromine, and iodine. In another embodiment, a radiolabeled Compound of Formula
(I) contains 1, 2, 3, 4, or more radioactive isotopes, each of which is independently selected
2 3 11 13 14 15 17 18 31 32 35 18 19 36 37 76 77 81 123
from H, H, C, C, C, N, O, O, P, P, S, F, F, Cl, Cl, Br, Br, Br, I,
124 125 131
I, I, and I. In another embodiment, a radiolabeled Compound of Formula (I) contains 1
2 3 11 13 14
or 2 radioactive isotopes, each of which is independently selected from H, H, C, C, C,
17 18 31 32 35 18 19 36 37 76 77 81 123 124 125 131
N, O, O, P, P, S, F, F, Cl, Cl, Br, Br, Br, I, I, I, and I. In another
embodiment, a radiolabeled Compound of Formula (I) contains 1 radioactive isotope which is
2 3 11 13 14 15 17 18 31 32 35 18 19 36 37 76 77
selected from H, H, C, C, C, N, O, O, P, P, S, F, F, Cl, Cl, Br, Br,
81 123 124 125 131
Br, I, I, I, and I. In another embodiment, a radiolabeled Compound of Formula (I)
contains 1, 2, 3, 4, or more radioactive isotopes, each of which is independently selected from
2 3 13 14 15 18 32 125
H, H, C, C, N, O, P, and I. In another embodiment, a radiolabeled Compound of
Formula (I) contains 1 or 2 radioactive isotopes, each of which is independently selected from
3 14 15 18 32 125
H, C, N, O, P, and I. In another embodiment, a radiolabeled Compound of Formula
3 14 15 18 32 125
(I) contains 1 radioactive isotope which is selected from H, C, N, O, P, and I.
Radiolabeled compounds of the disclosure can be prepared by methods known in the art. For
example, tritiated Compounds of Formula (I) can be prepared by introducing tritium into the
particular Compound of Formula (I), for example, by catalytic dehalogenation with tritium.
This method can include reacting a suitably halogen-substituted precursor of a Compound of
Formula (I) with tritium gas in the presence of a suitable catalyst, for example, Pd/C, in the
presence or absence of a base. Other suitable methods for preparing tritiated compounds can be
found in Filer, "The Preparation and Characterization of Tritiated Neurochemicals," Chapter 6,
pp. 155-192 in Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds
(Part A) (1987). C-labeled compounds can be prepared by employing starting materials
14 13
having a C carbon. Compounds containing piperazine isotopcially enriched with C and/or
N can be prepared as described in, e.g., Figure 5A and the associated description, of U.S.
Patent No. 7,355,045 B2.
A Compound of Formula (I) can contain one or more asymmetric centers and can thus give rise
to enantiomers, diastereomers, and other stereoisomeric forms. Unless specifically otherwise
indicated, the disclosure encompasses compounds with all such possible forms as well as their
racemic and resolved forms or any mixture thereof. When a Compound of Formula (I) contains
an olefinic double bond or other center of geometric asymmetry, and unless specifically
otherwise indicated, it is intended to include all "geometric isomers", e.g., both E and Z
geometric isomers. Unless specifically otherwise indicated, all "tautomers", e.g., ketone-enol,
amide-imidic acid, lactam-lactim, enamine-imine, amine-imine, and enamine-enimine
tautomers, are intended to be encompassed by the disclosure as well.
As used herein, the terms "stereoisomer", "stereoisomeric form", and the like are general terms
for all isomers of individual molecules that differ only in the orientation of their atoms in space.
It includes enantiomers and isomers of compounds with more than one chiral center that are not
mirror images of one another ("diastereomers").
The term "chiral center" refers to a carbon atom to which four different groups are attached.
The term "enantiomer" or "enantiomeric" refers to a molecule that is nonsuperimposeable on its
mirror image and hence optically active where the enantiomer rotates the plane of polarized
light in one direction and its mirror image rotates the plane of polarized light in the opposite
direction.
The term "racemic" refers to a mixture of equal parts of enantiomers which is optically
inactive.
The term "resolution" refers to the separation or concentration or depletion of one of the two
enantiomeric forms of a molecule. Optical isomers of a Compound of Formula (I) can be
obtained by known techniques such as chiral chromatography or formation of diastereomeric
salts from an optically active acid or base.
Optical purity can be stated in terms of enantiomeric excess (% ee), which is determined by the
formula:
The term "MeOH" means methanol, i.e., methyl alcohol.
The term "EtOH" means ethanol, i.e., ethyl alcohol.
The term "t-BuOH" means tert-butyl alcohol, i.e., 2-methylpropanol.
The term "THF" means tetrahydrofuran.
The term "DMF" means N,N-dimethylformamide.
The term "DCM" means methylene chloride, i.e., dichloromethane.
The term "DCE" means dichloroethane.
The term "DME" means 1,2-dimethoxyethane, i.e., ethylene glycol dimethyl ether.
The term "EtOAc" means ethyl acetate.
The term "NH OH" means ammonium hydroxide.
The term "TEA" means triethylamine.
The term "MeCN" means acetonitrile.
The term "NaH" means sodium hydride.
The term "AcOH" means acetic acid.
The term "DMSO" means dimethylsulfoxide, i.e., methylsulfinylmethane.
The term "DIEA" means diisopropylethylamine, i.e., N-ethyl-N-isopropylpropanamine.
The term "BuLi" means butyl lithium.
The term "BOC" means tert-butyloxycarbonyl:
The term "HOBT" means 1-hydroxybenzotriazole hydrate.
The term "EDCI" means 1-ethyl[3-(dimethylamino)propyl]carbodiimide.
The term "IBD" means inflammatory-bowel disease.
The term "IBS" means irritable-bowel syndrome.
The term "ALS" means amyotrophic lateral sclerosis.
The phrase "effective amount," when used in connection with a Compound of Formula (I)
means an amount effective for: (a) treating or preventing a Condition or symptom thereof; (b)
detectably inhibiting TRPV1 receptor function in a cell, or (c) detectably activating TRPV1
receptor function in a cell.
The phrase "effective amount," when used in connection with an other therapeutic agent or a
second therapeutic agent means an amount for providing the therapeutic effect of the second
therapeutic agent.
The phrase "therapeutic index," describes the gap between the dose that is effective, and the
dose that induces adverse effects.
The terms "modulate", "modulating", and the like as used herein with respect to the TRPV1
receptor mean the mediation of a pharmacodynamic response (e.g., analgesia) in an animal
from (i) inhibiting or activating the receptor, or (ii) directly or indirectly affecting the normal
regulation of the receptor activity. Compounds that modulate the receptor activity include
agonists, partial agonists, antagonists, mixed agonists/antagonists, mixed partial
agonists/antagonists and compounds which directly or indirectly affect regulation of the
receptor activity.
As used herein, a compound that binds to a receptor and mimics the regulatory effect(s) of an
endogenous ligand is defined as an "agonist". As used herein, a compound that binds to a
receptor and is only partly effective as an agonist is defined as a "partial agonist". As used
herein, a compound that binds to a receptor but produces no regulatory effect, but rather blocks
binding of another agent to the receptor is defined as an "antagonist". (See Ross and Kenakin,
Pharmacodynamics: Mechanisms of Drug Action and the Relationship Between Drug
Concentration and Effect, Chapter 2 in Goodman & Gilman's The Pharmacological Basis of
Therapeutics 31-32 (Hardman et al., eds., 10 ed. 2001).
The phrases "treatment of," "treating" and the like include the amelioration or cessation of a
Condition or a symptom thereof. In one embodiment, treating includes inhibiting, for example,
decreasing the overall frequency of episodes of a Condition or a symptom thereof.
The phrases "prevention of," "preventing" and the like include the avoidance of the onset of a
Condition or a symptom thereof.
A "disorder" includes, but is not limited to, the Conditions defined above.
In the event of doubt as to the agreement of a depicted chemical structure and a chemical name,
the depicted chemical structure governs.
It is appreciated that various features of the disclosure which are, for clarity, described in the
context of separate embodiments, can also be provided in combination in a single embodiment
unless otherwise specifically herein excluded. Conversely, various features of the disclosure
which are, for brevity, described in the context of a single embodiment, can also be provided
separately and/or in any suitable subcombination unless otherwise specifically herein excluded.
4.4 Methods for Making Compounds of Formula (I)
The Compounds of Formula (I) can be made using conventional organic synthesis or by the
illustrative methods shown in the Schemes below.
4.4.1 Methods for Installing a Vinyl Group on Substituted Pyridine
4.4.1.1 Suzuki Coupling
The introduction of a vinyl group by a Suzuki cross-coupling reaction is exemplified in Scheme
1 below, where R and R are as defined above, L is a -halo, and each R is independently
1 4 5
selected from
-(C -C )alkyl or both R groups together form a -CH -CH - or a -CH -CH -CH - group linking
1 4 5 2 2 2 2 2
each oxygen atom and the boron atom to which they are attached into a ring, which ring can be
optionally substituted by one or more -CH groups.
Scheme 1
In one embodiment, the leaving groups (L) at the 2-position and 5-position on the pyridine ring
of a compound of formula 1 can be selected to be the same halogen atom, e.g., each is bromine,
or, in another embodiment, can be selected to be different halogen atoms. For example, the
leaving group in the 2-position of the pyridine ring of the compound of formula 1 can be -Cl
while the leaving group in the 5-position of the pyridine ring can be -Br. Examples of boronate
esters 2 include, but are not limited to, 4,4,6-trimethylvinyl-1,3,2-dioxaborinane, 4,4,5,5-
tetramethylvinyl-1,3,2-dioxaborolane, and di-n-butyl vinyl boronic ester. The reaction is
carried out in a suitable organic solvent (e.g., THF or DMF) in the presence of an excess of
tetra(n-butyl)ammonium fluoride (TBAF). In an alternative embodiment, CsF can be used
instead of TBAF. Examples of palladium catalysts include, but are not limited to, [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(DPPF)Cl ) and
bis(triphenylphosphine)dichloropalladium(II) (Pd(PPh ) Cl ). The reaction can be carried out
3 2 2
in the presence of a base, such as potassium carbonate. The compounds of formula 1 are
commercially available or can be prepared by procedures known in the art.
4.4.1.2 Oxidation Followed by Wittig Olefination
An alternative technique for installation of a vinyl group is shown in Scheme 2 below, where
R and L are as defined above.
Scheme 2
The first step involves the oxidation of an alcohol group of the compound of formula 4 to an
aldehyde, thereby producing a compound of formula 5. The aldehyde group of the compound
of formula 5 is then converted into a vinyl group by a Wittig olefination reaction to provide the
compound of formula 6. The compounds of formula 4 are commercially available or can be
prepared by procedures known in the art.
4.4.1.3 Reduction Followed by Dehydration
An alternative technique for installation of a vinyl group is shown in Scheme 3 below, where
R , R , and L are as defined above.
Scheme 3
The first step involves the reduction of the ketone group of the compound of formula 7 to the
hydroxyl group of a compound of formula 8. Following addition of p-toluene sulfonic acid, the
compound of formula 8 is dehydrated to produce a compound of formula 3. The compounds of
formula 7 are commercially available or can be prepared by procedures known in the art.
4.4.2 Methods for Preparing Diols
4.4.2.1 Asymmetric Dihydroxylation of Vinyl Substituted Pyridines
Asymmetric dihydroxylation can be carried out as illustrated in Scheme 4 below, where a
compound of formula 3 is shown as the starting material and where R , R , and L are as defined
above. The compound of formula 6 could also serve as the starting material in Scheme 4.
Scheme 4
As demonstrated in Scheme 4, the stereochemistry of the resulting diol depends upon the
chirality of the ligand used in the AD mix as described in, e.g., Sharpless et al., J. Org. Chem.
57:2768-2771 (1992) and Schemes 1.14 and 1.15 of U.S. Patent Application Publication No.
2009/0170868 A1. AD-mix is composed of the following components: potassium osmate
(K OsO (OH) ), potassium ferricyanide (K Fe(CN) ), potassium carbonate (K CO ), and the
2 2 4 3 6 2 3
chiral ligands as shown in Scheme 5. In one embodiment, the reaction produces a chiral diol
having an enantiomeric excess (ee) of at least about 80%. In another embodiment, the reaction
produces a chiral diol having a % ee of at least about 90%. In another embodiment, the
reaction produces a chiral diol having a % ee of at least about 93%. In another embodiment,
the reaction produces a chiral diol having a % ee of at least about 94%. In another
embodiment, the reaction produces a chiral diol having a % ee of at least about 95%. In
another embodiment, the reaction produces a chiral diol having a % ee of greater than 95%
(e.g., 95.1% to 99.9%). In another embodiment, the reaction produces a chiral diol having a %
ee of at least about 96%. In another embodiment, the reaction produces a chiral diol having a
% ee of greater than 96% (e.g., 96.1% to 99.9%). In another embodiment, the reaction
produces a chiral diol having a % ee of at least about 97%. In another embodiment, the
reaction produces a chiral diol having a % ee of greater than 97% (e.g., 97.1% to 99.9%).
Scheme 5
4.4.2.2 Preparation of Chiral Diols Via Weinreb Amides
Diastereomers of the compounds of formulas 10a and 10b can be prepared by an alternative
synthetic route. An example of such an alternative route is depicted in Schemes 6-10, below.
A Weinreb amide of formula 14 is first prepared by conventional means, as shown in Scheme
Scheme 6
In Scheme 6, protection of the hydroxyl group of the compound of formula 11 with a tert-
butyldimethylsilyl (TBS) group followed by hydrolysis provides a compound of formula 12.
Reaction of a compound of formula 12 with a compound of formula 13 (where WSC is 1-(3-
(dimethylamino)propylethyl-carbodiimide) provides a compound of formula 14. The
compounds of formulae 11 and 13 are commercially available or can be prepared by procedures
known in the art.
The compound of formula 14 is then reacted with a compound of formula 1 in the presence of
iso-propylmagnesium chloride and lithium chloride to produce a compound of formula 15, as
shown in Scheme 7, where R and L are as defined above.
Scheme 7
Diastereoselective reduction of the compound of formula 15 with the organoborane reducing
agent L-selectride produces a compound of formula 16, as shown in Scheme 8.
Scheme 8
The reaction is preferentially carried out in a mixed solvent system such as hexane/THF at a
low temperature (e.g., -78°C).
The compound of formula 16 is then reacted with 4-nitrobenzoic acid in the presence of
triphenylphosphine and diethyl azodicarboxylate (DEAD) to produce a compound of formula
17, as shown in Scheme 9.
Scheme 9
Basic hydrolysis of the compound of formula 17 followed by removal of the TBS group
provides a compound of formula 10c' as shown in Scheme 10, where the "prime" suffix
(" ' ") denotes that R is -CH . The enantiomeric excess (ee) of the compound of formula 10c'
is at least about 80% and/or the % ee values as set forth above with respect to Scheme 4.
Scheme 10
It will be appreciated that when the enantiomer of the compound of formula 11 (see Scheme 6),
i.e., compound 11a, is used as a starting material, then the enantiomer of the compound of
formula 10c', i.e., compound 10d', is produced as shown in Scheme 11 by following the steps as
depicted in Schemes 6-10.
Scheme 11
The enantiomeric excess (ee) of the compound of formula 10d' is at least about 80% and/or the
% ee values as set forth above with respect to Scheme 4. The compounds of formula 11a are
commercially available or can be prepared by procedures known in the art.
4.4.2.3 Preparation of Racemic Diols
Racemic diols can be prepared by methods known in the art using osmium tetroxide (OsO ) and
N-methyl morpholine N-oxide (NMO) in an aqueous acetone solution.
4.4.3 Methods for Coupling Substituted Pyridines to Piperazines
A compound of formula 18 can be prepared by addition of a compound of formula 10 to a
compound of formula 19 in the presence of a palladium catalyst, as depicted in Scheme 12,
where R , R , m, and L are as defined above.
Scheme 12
It will be appreciated that in accordance with the disclosure, the compound of formula 19 has
one of the following structures:
.
The compounds of formula 19 are commercially available or can be prepared by procedures
known in the art. It will be further appreciated that the compound of formula 19 can be reacted
with a compound of formula 10a, 10b, 10c', or 10d' to produce a compound of formula 18a,
18b, 18c', or 18d', respectively.
In an alternative embodiment, the compound of formula 18 can be obtained as shown in
Scheme 13, where R , R , m, and L are as defined above and P is a nitrogen protecting group
1 4 N
(e.g., BOC).
Scheme 13
In this embodiment, the hydroxyl groups of the compound of formula 10 are protected to
provide a compound of formula 20 prior to coupling the compound of formula 20 to the
compound of formula 21. Such protection is accomplished through the addition to the
compound of formula 10 of 2,2-dimethoxypropane in the presence of para-toluene sulfonic
acid monohydrate (PTSA) to provide the compound of formula 20. The compound of formula
is then reacted with a compound of formula 21 in the presence of a palladium catalyst and a
base to provide a compound of formula 22. The compound of formula 22 is then reacted with
an excess of acid, e.g., HCl, to provide the deprotected compound of formula 18. It will be
appreciated that in accordance with the disclosure, the compound of formula 21 has one of the
following structures:
The compounds of formula 21 are commercially available or can be prepared by procedures
known in the art. It will be further appreciated that the compound of formula 10 can be
replaced with the compound of formula 10a, 10b, 10c', or 10d' in Scheme 13 to produce a
compound of formula 18a, 18b, 18c', or 18d', respectively. In these embodiments, the
enantiomeric excess (ee) of the compound of formula 18a (or 18b or 18c' or 18d') is at least
about 80% and/or the % ee values as set forth above with respect to Scheme 4.
4.4.4 Methods for Preparing BenzothiazolAmines of Formula 23
A compound of formula 23 can be prepared by the addition of potassium thiocyanate, bromine,
and acetic acid to a compound of formula 24 as depicted in Scheme 14, where R and R are as
defined above. The compound of formula 23 is precipitated from solution following the
addition of ammonium hydroxide. The compounds of formula 24 are commercially available
or can be prepared by procedures known in the art.
Scheme 14
4.4.5 Methods for Preparing Carboxamides of Formula 26
A compound of formula 26 can be prepared by adding a compound of formula 23 to a
compound of formula 25 in the presence of a base, such as TEA or DIEA, as depicted in
Scheme 15, where R , R , R , R , and m are as defined above and each L is a leaving group
1 4 8 9 2
independently selected from phenyl, 4-nitrophenyl, and imidazolyl. The compounds of
formula 25 are commercially available or can be prepared by procedures known in the art.
Scheme 15
4.4.6 Methods for Preparing Piperazine Derivatives of Formula (I)
A Compound of Formula (I) can be prepared by adding a compound of Formula 26 to a
compound of formula 18 as depicted in Scheme 16, where R , R , R , R , m, and L are as
1 4 8 9 2
defined above.
Scheme 16
In certain embodiments, the reaction is carried out in DCM or an aprotic organic solvent. In
certain embodiments, a compound of formula 18a, 18b, 18c', or 18d' is treated with a
compound of formula 26 to produce an enantiomerically enriched diol, as exemplified in non-
limiting Scheme 17 for a compound of formula 18a, where R , R , R , R , m, and L are as
1 4 8 9 2
defined above. In these embodiments, the enantiomeric excess (ee) of the Compound of
Formula (I) is at least about 80%. In another embodiment, the reaction produces a Compound
of Formula (I) having a % ee of at least about 90%. In another embodiment, the reaction
produces a Compound of Formula (I) having a % ee of at least about 93%. In another
embodiment, the reaction produces a Compound of Formula (I) having a % ee of at least about
94%. In another embodiment, the reaction produces a Compound of Formula (I) having a % ee
of at least about 95%. In another embodiment, the reaction produces a Compound of Formula
(I) having a % ee of greater than 95% (e.g., 95.1% to 99.9%). In another embodiment, the
reaction produces a Compound of Formula (I) having a % ee of at least about 96%. In another
embodiment, the reaction produces a Compound of Formula (I) having a % ee of greater than
96% (e.g., 96.1% to 99.9%). In another embodiment, the reaction produces a Compound of
Formula (I) having a % ee of at least about 97%. In another embodiment, the reaction produces
a Compound of Formula (I) having a % ee of greater than 97% (e.g., 97.1% to 99.9%).
Scheme 17
It will be appreciated that alternative methods can be used to prepare Compounds of Formula
(I). For example, as shown in Scheme 18 a compound of formula 3 can be added to a
compound of formula 21 to produce a compound of formula 27, e.g., by the method of step 2 of
Scheme 13, where R , R , m, and P are as defined above.
1 4 N
Scheme 18
The compound of formula 27 is then dihydroxylated, e.g., by the method of Scheme 4,
Schemes 6-10, or Scheme 11, to produce a compound of formula 28 as shown in Scheme 19,
where R , R , m, and P are as defined above.
1 4 N
Scheme 19
For example, the reaction depicted in Scheme 19 can be carried out in enantioselective manner
using reaction conditions described in Scheme 4. Alternatively, a racemic diol can be prepared
by methods known in the art using osmium tetroxide (OsO ) and N-methyl morpholine N-oxide
(NMO) in an aqueous acetone solution.
As depicted in Scheme 20, where R , R , R , R , m, P , and L are as defined above, the
1 4 8 9 N 2
compound of formula 28 is deprotected with an excess of acid, e.g., HCl, to provide a
compound of formula 18, e.g., by the method of step 3 of Scheme 13. Reaction of the
compound of formula 18 with a compound of formula 26 in the presence of a base (see, e.g.,
Schemes 16 and 17) provides a Compound of Formula (I).
Scheme 20
The progress of the reaction(s) above can be monitored using conventional analytical
techniques including, but not limited to, high pressure liquid chromatography (HPLC), column
chromatography, thin-layer chromatography (TLC), gas chromatography (GC), mass
spectrometry (MS), and nuclear magnetic resonance spectroscopy (NMR) such as H NMR and
C NMR. Compounds of Formula (I) can be isolated and further treated if desired. In one
embodiment, the Compound of Formula (I) is isolated by removing the solvent under reduced
pressure. In another embodiment, the Compound of Formula (I) is isolated by extraction.
Compounds of Formula (I) can be further treated, for example, by column chromatography or
recrystallization.
Suitable aprotic organic solvents for use in the illustrative methods include, but are not limited
to, DCM, DMSO, chloroform, toluene, benzene, acetonitrile, carbon tetrachloride, pentane,
hexane, ligroin, and diethyl ether. In one embodiment, the aprotic organic solvent is DCM.
One or more hydrogen, carbon, or other atom(s) of a Compound of Formula (I) can be replaced
by an isotope of the hydrogen, carbon, or other atom(s). Such compounds, which are
encompassed by the disclosure, are useful, e.g., as research and diagnostic tools in metabolism
pharmacokinetic studies and in binding assays.
4.5 Therapeutic Uses of Compounds of Formula (I)
In accordance with the disclosure, the Compounds of Formula (I) are administered to an animal
in need of treatment or prevention of a Condition.
In one embodiment, an effective amount of a Compound of Formula (I) can be used to treat or
prevent any condition treatable or preventable by inhibiting TRPV1. Examples of Conditions
that are treatable or preventable by inhibiting TRPV1 include, but are not limited to, pain, e.g.,
pain associated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, and/or IBS.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
used to treat or prevent acute or chronic pain. Examples of pain that can be treated or
prevented using a Compound of Formula (I) include, but are not limited to, cancer pain,
neuropathic pain, labor pain, myocardial infarction pain, pancreatic pain, colic pain, post-
operative pain, headache pain, muscle pain, arthritic pain, and pain associated with a
periodontal disease, including gingivitis and periodontitis.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can also
be used for treating or preventing pain associated with inflammation or with an inflammatory
disease in an animal. Such pain can arise where there is an inflammation of the body tissue
which can be a local inflammatory response and/or a systemic inflammation. For example, the
Compounds of Formula (I) can be used to treat or prevent pain associated with inflammatory
diseases including, but not limited to: organ transplant rejection; reoxygenation injury resulting
from organ transplantation (see Grupp et al., "Protection against Hypoxia-reoxygenation in the
Absence of Poly (ADP-ribose) Synthetase in Isolated Working Hearts," J. Mol. Cell Cardiol.
31:297-303 (1999)) including, but not limited to, transplantation of the heart, lung, liver, or
kidney; chronic inflammatory diseases of the joints, including arthritis, rheumatoid arthritis,
osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel
diseases, such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease;
inflammatory lung diseases, such as asthma, adult respiratory distress syndrome, and chronic
obstructive airway disease; inflammatory diseases of the eye, including corneal dystrophy,
trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic
inflammatory diseases of the gum, including gingivitis and periodontitis; tuberculosis; leprosy;
inflammatory diseases of the kidney, including uremic complications, glomerulonephritis and
nephrosis; inflammatory diseases of the skin, including sclerodermatitis, psoriasis and eczema;
inflammatory diseases of the central nervous system, including chronic demyelinating diseases
of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer s
disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease,
amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune diseases,
including Type I and Type II diabetes mellitus; diabetic complications, including, but not
limited to, diabetic cataract, glaucoma, retinopathy, nephropathy (such as microalbuminuria
and progressive diabetic nephropathy), polyneuropathy, mononeuropathies, autonomic
neuropathy, gangrene of the feet, atherosclerotic coronary arterial disease, peripheral arterial
disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, and a skin
or mucous membrane complication (such as an infection, a shin spot, a candidal infection or
necrobiosis lipoidica diabeticorum); immune-complex vasculitis, and systemic lupus
erythematosus (SLE); inflammatory diseases of the heart, such as cardiomyopathy, ischemic
heart disease hypercholesterolemia, and atherosclerosis; as well as various other diseases that
can have significant inflammatory components, including preeclampsia, chronic liver failure,
brain and spinal cord trauma, and cancer. The Compounds of Formula (I) can also be used for
inhibiting, treating, or preventing pain associated with inflammatory disease that can, for
example, be a systemic inflammation of the body, exemplified by gram-positive or gram
negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy
in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory
cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent that is adminstered as
a treatment for cancer.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can also
be used to treat or prevent pain associated with nerve injury (i.e., neuropathic pain). Chronic
neuropathic pain is a heterogenous disease state with an unclear etiology. In chronic
neuropathic pain, the pain can be mediated by multiple mechanisms. This type of pain
generally arises from injury to the peripheral or central nervous tissue. The syndromes include
pain associated with spinal cord injury, multiple sclerosis, post-herpetic neuralgia, trigeminal
neuralgia, phantom pain, causalgia, and reflex sympathetic dystrophy and lower back pain.
The chronic pain is different from acute pain in that chronic neuropathic pain patients suffer the
abnormal pain sensations that can be described as spontaneous pain, continuous superficial
burning and/or deep aching pain. The pain can be evoked by heat-, cold-, and mechano-
hyperalgesia, or by heat-, cold-, or mechano-allodynia.
Chronic neuropathic pain can be caused by injury or infection of peripheral sensory nerves. It
includes, but is not limited to, pain from peripheral nerve trauma, herpes virus infection,
diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.
Neuropathic pain can also be caused by nerve damage from chronic alcoholism, human
immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. Stroke
(spinal or brain) and spinal cord injury can also induce neuropathic pain. Cancer-related
neuropathic pain results from tumor growth compression of adjacent nerves, brain, or spinal
cord. In addition, cancer treatments, including chemotherapy and radiation therapy, can cause
nerve injury. Neuropathic pain includes but is not limited to pain caused by nerve injury such
as, for example, the pain from which diabetics suffer.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
used to treat or prevent a migraine including, but not limited to, migraine without aura
("common migraine"), migraine with aura ("classic migraine"), migraine without headache,
basilar migraine, familial hemiplegic migraine, migrainous infarction, and migraine with
prolonged aura.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
used to treat or prevent pain associated with osteoarthritis. Osteoarthritis (OA), also known as
osteoarthrosis, degenerative arthritis, or degenerative joint disease, is a group of mechanical
abnormalities involving degradation of joints, including articular cartilage and subchondral
bone. Examples of OA treatable or preventable using the Compounds of Formula (I) include,
but are not limited to, joint pain, joint stiffness, joint tenderness, joint locking, and joint
effusion.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
used to treat or prevent UI. Examples of UI treatable or preventable using the Compounds of
Formula (I) include, but are not limited to, urge incontinence, stress incontinence, overflow
incontinence, neurogenic incontinence, and total incontinence.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
used to treat or prevent an ulcer. Examples of ulcers treatable or preventable using the
Compounds of Formula (I) include, but are not limited to, a duodenal ulcer, a gastric ulcer, a
marginal ulcer, an esophageal ulcer, or a stress ulcer.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
used to treat or prevent IBD, including Crohn's disease and ulcerative colitis.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
used to treat or prevent IBS. Examples of IBS treatable or preventable using the Compounds of
Formula (I) include, but are not limited to, spastic-colon-type IBS and constipation-
predominant IBS.
Applicants believe that the Compounds of Formula (I), or a pharmaceutically acceptable
derivative thereof, are antagonists for TRPV1. The disclosure also relates to methods for
inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1
with an effective amount of a Compound of Formula (I), or a pharmaceutically acceptable
derivative thereof. This method can be used in vitro, for example, as an assay to select cells
that express TRPV1 and, accordingly, are useful as part of an assay to select compounds useful
for treating or preventing pain, e.g., pain associated with osteoarthritis, osteoarthritis, UI, an
ulcer, IBD, or IBS. The method is also useful for inhibiting TRPV1 function in a cell in vivo,
in an animal, a human in one embodiment, by contacting a cell, in an animal, with an effective
amount of a Compound of Formula (I), or a pharmaceutically acceptable derivative thereof. In
one embodiment, the method is useful for treating or preventing pain in an animal. In another
embodiment, the method is useful for treating or preventing UI in an animal. In another
embodiment, the method is useful for treating or preventing an ulcer in an animal. In another
embodiment, the method is useful for treating or preventing IBD in an animal. In another
embodiment, the method is useful for treating or preventing IBS in an animal.
Examples of tissue comprising cells capable of expressing TRPV1 include, but are not limited
to, neuronal, brain, kidney, urothelium, and bladder tissue. Methods for assaying cells that
express TRPV1 are known in the art.
4.6 Therapeutic/Prophylactic Administration and Compositions of the Disclosure
Due to their activity, Compounds of Formula (I), or a pharmaceutically acceptable derivative
thereof, are advantageously useful in veterinary and human medicine. As described above,
Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, are useful for
treating or preventing a Condition.
When administered to an animal, Compounds of Formula (I), or a pharmaceutically acceptable
derivative thereof, are, in one embodiment, administered as a component of a composition that
comprises a pharmaceutically acceptable carrier or excipient. The compositions, which
comprise a Compound of Formula (I), or a pharmaceutically acceptable derivative thereof, can
be administered orally. Compounds of formula (I), or a pharmaceutically acceptable derivative
thereof, can also be administered by any other convenient route, for example, by infusion or
bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal,
and intestinal mucosa, etc.) and can be administered together with another therapeutically
active agent. Administration can be systemic or local. Various delivery systems are known,
e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used
to administer the Compound of Formula (I), or a pharmaceutically acceptable derivative
thereof.
Methods of administration include, but are not limited to, intradermal, intramuscular,
intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral,
intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or
skin. The mode of administration is left to the discretion of the practitioner. In most instances,
administration will result in the release of Compounds of Formula (I), or a pharmaceutically
acceptable derivative thereof, into the bloodstream.
In specific embodiments, it can be desirable to administer the Compounds of Formula (I), or a
pharmaceutically acceptable derivative thereof, locally. This can be achieved, for example, and
not by way of limitation, by local infusion during surgery, topical application, e.g., in
conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means
of a suppository or enema, or by means of an implant, said implant being of a porous,
non-porous, or gelatinous material, including membranes, such as sialastic membranes, or
fibers.
In certain embodiments, it can be desirable to introduce the Compounds of Formula (I), or a
pharmaceutically acceptable derivative thereof, into the central nervous system or
gastrointestinal tract by any suitable route, including intraventricular, intrathecal, and epidural
injection, and enema. Intraventricular injection can be facilitated by an intraventricular
catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and
formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic
pulmonary surfactant. In certain embodiments, the Compounds of Formula (I) can be
formulated as a suppository, with traditional binders and excipients such as triglycerides.
In another embodiment, the Compounds of Formula (I), or a pharmaceutically acceptable
derivative thereof, can be delivered in a vesicle, in particular a liposome (see Langer, "New
Methods of Drug Delivery," Science 249:1527-1533 (1990); Lopez-Berestein, "Treatment of
Systemic Fungal Infections with Liposomal-Amphotericin B," Liposomes in the Therapy of
Infectious Disease and Cancer, pp. 317-327 (1989); and Treat et al., "Liposome encapsulated
doxorubicin - preliminary results of phase I and phase II trials" Liposomes in the Therapy of
Infectious Disease and Cancer, pp. 353-365 (1989).
In yet another embodiment, the Compounds of Formula (I), or a pharmaceutically acceptable
derivative thereof, can be delivered in a controlled-release system or sustained-release system
(see, e.g., Goodson, "Dental Applications," pp. 115-138 in Medical Applications of Controlled
Release, Vol. 2, Applications and Evaluation, Langer and Wise, eds., CRC Press (1984),
hereafter "Goodson"). Other controlled- or sustained-release systems discussed in the review
by Langer, Science 249:1527-1533 (1990) can be used. In one embodiment, a pump can be
used (Langer, Science 249:1527-1533 (1990); Sefton, "Implantable Pumps," in CRC Crit. Rev.
Biomed. Eng. 14(3):201-240 (1987); Buchwald et al., "Long-term, Continuous Intravenous
Heparin Administration by an Implantable Infusion Pump in Ambulatory Patients with
Recurrent Venous Thrombosis," Surgery 88:507-516 (1980); and Saudek et al., "A Preliminary
Trial of the Programmable Implantable Medication System for Insulin Delivery," New Engl. J.
Med. 321:574-579 (1989)). In another embodiment, polymeric materials can be used (see
Goodson; Smolen et al., "Drug Product Design and Performance," Controlled Drug
Bioavailability Vol. 1, John Wiley & Sons, New York (1984); Langer et al., "Chemical and
Physical Structure of Polymers as Carriers for Controlled Release of Bioactive Agents: A
Review," J. Macromol. Sci. Rev. Macromol. Chem. C23(1):61-126 (1983); Levy et al.,
"Inhibition of Calcification of Bioprosthetic Heart Valves by Local Controlled-Release
Diphosphonate," Science 228:190-192 (1985); During et al., "Controlled Release of Dopamine
from a Polymeric Brain Implant: In Vivo Characterization," Ann. Neurol. 25:351-356 (1989);
and Howard et al., "Intracerebral drug delivery in rats with lesion-induced memory deficits,"
J. Neurosurg. 71:105 (1989)). In yet another embodiment, a controlled- or sustained-release
system can be placed in proximity of a target of the Compounds of Formula (I), e.g., the spinal
column, brain, or gastrointestinal tract, thus requiring only a fraction of the systemic dose.
The compositions can optionally comprise a suitable amount of a pharmaceutically acceptable
excipient so as to provide the form for proper administration to the animal. Such a
pharmaceutical excipient can be a diluent, suspending agent, solubilizer, binder, disintegrant,
preservative, coloring agent, lubricant, and the like. The pharmaceutical excipient can be a
liquid, such as water or an oil, including those of petroleum, animal, vegetable, or synthetic
origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. The
pharmaceutical excipient can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal
silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and
coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipient is
sterile when administered to an animal. Water is a particularly useful excipient when a
Compound of Formula (I) is administered intravenously. Saline solutions and aqueous
dextrose and glycerol solutions can also be employed as liquid excipients, particularly for
injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc,
sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. The
compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or
pH buffering agents. Specific examples of pharmaceutically acceptable carriers and excipients
that can be used to formulate oral dosage forms are described in the Handbook of
Pharmaceutical Excipients, (Amer. Pharmaceutical Ass'n, Washington, DC, 1986),
incorporated herein by reference.
The compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets,
multiparticulates, capsules, capsules containing liquids, powders, multiparticulates,
sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any
other form suitable for use. In one embodiment, the composition is in the form of a capsule
(see e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are
described by Radebough et al., "Preformulation," pp. 1447-1676 in Remington's
Pharmaceutical Sciences Vol. 2 (Gennaro, ed., 19 ed., Mack Publishing, Easton, PA, 1995),
incorporated herein by reference.
In one embodiment, the Compounds of Formula (I) are formulated in accordance with routine
procedures as a composition adapted for oral administration to human beings. A Compound of
Formula (I) to be orally delivered can be in the form of tablets, capsules, gelcaps, caplets,
lozenges, aqueous or oily solutions, suspensions, granules, powders, emulsions, syrups, or
elixirs, for example. When a Compound of Formula (I) is incorporated into oral tablets, such
tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, multiply
compressed or multiply layered. Techniques and compositions for making solid oral dosage
forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman et al., eds., 2 ed.,
Marcel Dekker, Inc., 1989 & 1990). Techniques and compositions for making tablets
(compressed and molded), capsules (hard and soft gelatin) and pills are also described by King,
"Tablets, Capsules, and Pills," pp. 1553-1593 in Remington's Pharmaceutical Sciences (Osol,
ed., 16 ed., Mack Publishing, Easton, PA, 1980).
Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, suspensions,
and solutions and/or suspensions reconstituted from non-effervescent granules, optionally
containing one or more suitable solvents, preservatives, emulsifying agents, suspending agents,
diluents, sweeteners, coloring agents, flavoring agents, and the like. Techniques and
composition for making liquid oral dosage forms are described in Pharmaceutical Dosage
Forms: Disperse Systems (Lieberman et al., eds., 2 ed., Marcel Dekker, Inc., 1996 & 1998).
When a Compound of Formula (I) is to be injected parenterally, it can be, e.g., in the form of an
isotonic sterile solution. Alternatively, when a Compound of Formula (I) is to be inhaled, it
can be formulated into a dry aerosol or can be formulated into an aqueous or partially aqueous
solution.
An orally administered Compound of Formula (I) can contain one or more agents, for example,
sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as
peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a
pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the
compositions can be coated to delay disintegration and absorption in the gastrointestinal tract
thereby providing a sustained action over an extended period of time. Selectively permeable
membranes surrounding an osmotically active driving compound are also suitable for orally
administered compositions. In these latter platforms, fluid from the environment surrounding
the capsule is imbibed by the driving compound, which swells to displace the agent or agent
composition through an aperture. These delivery platforms can provide an essentially zero
order delivery profile as opposed to the spiked profiles of immediate release formulations. A
time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral
compositions can include standard excipients such as mannitol, lactose, starch, magnesium
stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the
excipients are of pharmaceutical grade.
In another embodiment, the Compounds of Formula (I) can be formulated for intravenous
administration. In one embodiment, compositions for intravenous administration comprise
sterile isotonic aqueous buffer. Where necessary, the compositions can also include a
solubilizing agent. A Compound of Formula (I) for intravenous administration can optionally
include a local anesthetic such as benzocaine or prilocaine to lessen pain at the site of the
injection. Generally, the ingredients are supplied either separately or mixed together in unit
dosage form, for example, as a dry lyophilized powder or water free concentrate in a
hermetically sealed container such as an ampule or sachette indicating the quantity of active
agent. Where a Compound of Formula (I) is to be administered by infusion, it can be
dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or
saline. Where a Compound of Formula (I) is administered by injection, an ampule of sterile
water for injection or saline can be provided so that the ingredients can be mixed prior to
administration.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
administered by controlled-release or sustained-release means or by delivery devices that are
known to those of ordinary skill in the art. Examples include, but are not limited to, those
described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719;
,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566,
each of which is incorporated herein by reference. Such dosage forms can be used to provide
controlled- or sustained-release of one or more active ingredients using, for example,
hydropropylmethyl cellulose, ethylcellulose, other polymer matrices, gels, permeable
membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or
a combination thereof to provide the desired release profile in varying proportions. Suitable
controlled- or sustained-release formulations known to those of ordinary skill in the art,
including those described herein, can be readily selected for use with the active ingredients of
the disclosure. The disclosure thus encompasses single unit dosage forms suitable for oral
administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are
adapted for controlled- or sustained-release.
Controlled- or sustained-release pharmaceutical compositions can have a common goal of
improving drug therapy over that achieved by their non-controlled or non-sustained release
counterparts. In one embodiment, a controlled- or sustained-release composition comprises a
minimal amount of a Compound of Formula (I) to cure or control the condition in a minimum
amount of time. Advantages of controlled- or sustained-release compositions include extended
activity of the drug, reduced dosage frequency, and increased patient compliance. In addition,
controlled- or sustained-release compositions can favorably affect the time of onset of action or
other characteristics, such as blood levels of the Compound of Formula (I), and can thus reduce
the occurrence of adverse side effects.
Controlled- or sustained-release compositions can be designed to immediately release an
amount of a Compound of Formula (I), or a pharmaceutically acceptable derivative thereof,
that promptly produces the desired therapeutic or prophylactic effect, and gradually and
continually release other amounts of the Compound of Formula (I) to maintain this level of
therapeutic or prophylactic effect over an extended period of time. To maintain a constant level
of the Compound of Formula (I) in the body, the Compound of Formula (I) can be released
from the dosage form at a rate that will replace the amount of Compound of Formula (I) being
metabolized and excreted from the body. Controlled- or sustained-release of an active
ingredient can be stimulated by various conditions, including but not limited to, changes in pH,
changes in temperature, concentration or availability of enzymes, concentration or availability
of water, or other physiological conditions or compounds.
The amount of the Compound of Formula (I), or a pharmaceutically acceptable derivative
thereof, that is effective in the treatment or prevention of a Condition can be determined by
standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed
to help identify optimal dosage ranges. The precise dose to be employed will also depend on
the route of administration, and the seriousness of the Condition and can be decided according
to the judgment of a practitioner and/or each animal's circumstances. Suitable effective dosage
amounts, however, will, in one embodiment, range from about 0.01 mg/kg of body weight to
about 2500 mg/kg of body weight, although they are, in another embodiment, about 100 mg/kg
of body weight or less. In one embodiment, the effective dosage amount ranges from about
0.01 mg/kg of body weight to about 100 mg/kg of body weight of a Compound of Formula (I);
in another embodiment, about 0.02 mg/kg of body weight to about 50 mg/kg of body weight;
and in another embodiment, about 0.025 mg/kg of body weight to about 20 mg/kg of body
weight.
In one embodiment, an effective dosage amount is administered about every 24 h until the
Condition is abated. In another embodiment, an effective dosage amount is administered about
every 12 h until the Condition is abated. In another embodiment, an effective dosage amount is
administered about every 8 h until the Condition is abated. In another embodiment, an
effective dosage amount is administered about every 6 h until the Condition is abated. In
another embodiment, an effective dosage amount is administered about every 4h until the
Condition is abated.
The effective dosage amounts described herein refer to total amounts administered; that is, if
more than one Compound of Formula (I), or a pharmaceutically acceptable derivative thereof,
is administered, the effective dosage amounts correspond to the total amount administered.
Where a cell capable of expressing TRPV1 is contacted with a Compound of Formula (I) in
vitro, the amount effective for inhibiting the TRPV1 receptor function in a cell will range from
about 0.01 μg/L to about 5 mg/L; in one embodiment, from about 0.01 μg/L to about 2.5 mg/L;
in another embodiment, from about 0.01 μg/L to about 0.5 mg/L; and in another embodiment,
from about 0.01 μg/L to about 0.25 mg/L, of a solution or suspension of a pharmaceutically
acceptable carrier or excipient. In one embodiment, the volume of solution or suspension
comprising the Compound of Formula (I), or a pharmaceutically acceptable derivative thereof,
is from about 0.01 μL to about 1mL. In another embodiment, the volume of solution or
suspension is about 200 μL.
The Compounds of Formula (I), or a pharmaceutically acceptable derivative thereof, can be
assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in
humans. Animal model systems can be used to demonstrate safety and efficacy.
The methods for treating or preventing a Condition in an animal in need thereof can further
comprise administering to the animal being administered a Compound of Formula (I), or a
pharmaceutically acceptable derivative thereof (i.e., a first therapeutic agent) a second
therapeutic agent. In one embodiment, the second therapeutic agent is administered in an
effective amount. In one embodiment, the second therapeutic agent is administered in an
effective amount.
The methods for inhibiting TRPV1 function in a cell capable of expressing TRPV1 can further
comprise contacting the cell with an effective amount of a second therapeutic agent.
An effective amount of the second therapeutic agent(s) will be known to those skilled the art
depending on the agent. However, it is well within the skilled artisan's purview to determine
the second therapeutic agent's optimal effective-amount range. A Compound of Formula (I)
and the second therapeutic agent combined can act either additively or synergistically to treat
the same Condition, or they can act independently of each other such that the Compound of
Formula (I) treats or prevents a first Condition and the second therapeutic agent treats or
prevents a second disorder, which can be the same as the first Condition or another disorder. In
one embodiment of the disclosure, where a second therapeutic agent is administered to an
animal for treatment of a Condition (e.g., pain), the minimal effective amount of the Compound
of Formula (I) will be less than its minimal effective amount would be where the second
therapeutic agent is not administered. In this embodiment, the Compound of Formula (I) and
the second therapeutic agent can act synergistically to treat or prevent a Condition. In one
embodiment, a Compound of Formula (I) is administered concurrently with a second
therapeutic agent as a single composition comprising an effective amount of a Compound of
Formula (I) and an effective amount of the second therapeutic agent. Alternatively, a
composition comprising an effective amount of a Compound of Formula (I) and a second
composition comprising an effective amount of the second therapeutic agent are concurrently
administered. In another embodiment, an effective amount of a Compound of Formula (I) is
administered prior or subsequent to administration of an effective amount of the second
therapeutic agent. In this embodiment, the Compound of Formula (I) is administered while the
second therapeutic agent exerts its therapeutic effect, or the second therapeutic agent is
administered while the Compound of Formula (I) exerts its therapeutic effect for treating or
preventing a Condition.
The second therapeutic agent can be, but is not limited to, an opioid agonist, a non-opioid
analgesic, a non-steroid anti-inflammatory agent, an antimigraine agent, a Cox-II inhibitor, an
antiemetic, a β-adrenergic blocker, an anticonvulsant, an antidepressant, a Ca -channel
blocker, an anticancer agent, an agent for treating or preventing UI, an agent for treating or
preventing an ulcer, an agent for treating or preventing IBD, an agent for treating or preventing
IBS, an agent for treating addictive disorder, an agent for treating Parkinson's disease and
parkinsonism, an agent for treating anxiety, an agent for treating epilepsy, an agent for treating
a stroke, an agent for treating a seizure, an agent for treating a pruritic condition, an agent for
treating psychosis, an agent for treating Huntington's chorea, an agent for treating ALS, an
agent for treating a cognitive disorder, an agent for treating a migraine, an agent for treating
vomiting, an agent for treating dyskinesia, an agent for treating depression, a pharmaceutically
acceptable derivative thereof, or any mixture thereof.
Examples of useful opioid agonists include, but are not limited to, alfentanil, allylprodine,
alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,
clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone,
dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,
ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,
isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,
meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine,
nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium,
oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, proheptazine, promedol, properidine,
propiram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable derivatives
thereof, or any mixture thereof.
In certain embodiments, the opioid agonist is codeine, hydromorphone, hydrocodone,
oxycodone, dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone,
pharmaceutically acceptable derivatives thereof, or any mixture thereof.
Examples of useful non-opioid analgesics include, but are not limited to, non-steroidal
anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen,
flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,
pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,
bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin,
fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic
acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, a pharmaceutically
acceptable derivative thereof, or any mixture thereof. Other suitable non-opioid analgesics
include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal
anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate,
choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and
olsalazin; para-aminophenol derivatives including acetaminophen and phenacetin; indole and
indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids,
including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including
mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam,
tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); alkanones,
including nabumetone; a pharmaceutically acceptable derivative thereof; or any mixture
thereof. For a more detailed description of the NSAIDs, see Insel, "Analgesic-Antipyretic and
Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout," pp. 617-657 in
Goodman & Gilman's The Pharmacological Basis of Therapeutics (Goodman et al., Eds., 9
Ed., McGraw-Hill, New York 1996), and Hanson, "Analgesic, Antipyretic and Anti-
Inflammatory Drugs," pp. 1196-1221 in Remington: The Science and Practice of Pharmacy Vol
2 (Gennaro, ed., 19 ed., Mack Publishing, Easton, PA, 1995), which are hereby incorporated
by reference in their entireties.
Examples of useful antimigraine agents include, but are not limited to, alpiropride,
bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine,
ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine,
methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol,
risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, a pharmaceutically
acceptable derivative thereof, or any mixture thereof.
Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations
thereof, are described in U.S. Patent No. 6,136,839, which is hereby incorporated by reference
in its entirety. Examples of useful Cox-II inhibitors include, but are not limited to, celecoxib,
DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone, nimesulide, NS-
398, SC-5766, T-614, L-768277, GR-253035, JTE-522, RS000, SC-58125, SC-078,
PD-138387, NS-398, flosulide, D-1367, SC-5766, PD-164387, etoricoxib, valdecoxib,
parecoxib, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
The second therapeutic agent can also be an agent useful for reducing any potential side effects
of a Compound of Formula (I). For example, the second therapeutic agent can be an antiemetic
agent. Examples of useful antiemetic agents include, but are not limited to, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,
ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,
diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,
pipamazine, scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine, thioproperazine,
tropisetron, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful β-adrenergic blockers include, but are not limited to, acebutolol, alprenolol,
amosulabol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol,
bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,
carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol,
indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol,
nadoxolol, nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, practolol,
pronethalol, propranolol, sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol, toliprolol,
xibenolol, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful anticonvulsants include, but are not limited to, acetylpheneturide, albutoin,
aloxidone, aminoglutethimide, 4-aminohydroxybutyric acid, atrolactamide, beclamide,
buramate, calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,
decimemide, diethadione, dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide,
ethotoin, felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine, magnesium
bromide, magnesium sulfate, mephenytoin, mephobarbital, metharbital, methetoin,
methsuximide, 5-methyl(3-phenanthryl)-hydantoin, 3-methylphenylhydantoin,
narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione, phenacemide,
phenetharbital, pheneturide, phenobarbital, phensuximide, phenylmethylbarbituric acid,
phenytoin, phethenylate sodium, potassium bromide, pregabaline, primidone, progabide,
sodium bromide, solanum, strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,
topiramate, trimethadione, valproic acid, valpromide, vigabatrin, zonisamide, a
pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful antidepressants include, but are not limited to, binedaline, caroxazone,
citalopram, (S)-citalopram, dimethazan, fencamine, indalpine, indeloxazine hydrocholoride,
nefopam, nomifensine, oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,
benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin, phenelzine, cotinine,
rolicyprine, rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam,
amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine, demexiptiline,
desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imipramine
N-oxide, iprindole, lofepramine, melitracen, metapramine, nortriptyline, noxiptilin, opipramol,
pizotyline, propizepine, protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,
benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate,
femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin, hypericin,
levophacetoperane, medifoxamine, milnacipran, minaprine, moclobemide, nefazodone,
oxaflozane, piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,
sulpiride, tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine, L-tryptophan,
venlafaxine, viloxazine, zimeldine, a pharmaceutically acceptable derivative thereof, or any
mixture thereof.
Examples of useful Ca -channel blockers include, but are not limited to, bepridil, clentiazem,
diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil,
amlodipine, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,
felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine,
nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine,
lomerizine, bencyclane, etafenone, fantofarone, perhexiline, a pharmaceutically acceptable
derivative thereof, or any mixture thereof.
Examples of useful anticancer agents include, but are not limited to, acivicin, aclarubicin,
acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin,
ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,
asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene
hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium,
bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin,
carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin,
cisplatin, cladribine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine,
dactinomycin, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine,
dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,
droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate,
eflornithine hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine, epirubicin
hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate
sodium, etanidazole, etoposide, etoposide phosphate, etoprine, fadrozole hydrochloride,
fazarabine, fenretinide, floxuridine, fludarabine phosphate, fluorouracil, flurocitabine,
fosquidone, fostriecin sodium, gemcitabine, gemcitabine hydrochloride, hydroxyurea,
idarubicin hydrochloride, ifosfamide, ilmofosine, interleukin II (including recombinant
interleukin II or rIL2), interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon
alpha-n3, interferon beta-I a, interferon gamma-I b, iproplatin, irinotecan hydrochloride,
lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium,
lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine
hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaril, mercaptopurine,
methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide, mitocarcin,
mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone
hydrochloride, mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, paclitaxel,
pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman,
piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,
porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin
hydrochloride, pyrazofurin, riboprine, rogletimide, safingol, safingol hydrochloride, semustine,
simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustine,
spiroplatin, streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium, tegafur,
teloxantrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, thiamiprine,
thioguanine, thiotepa, tiazofurin, tirapazamine, toremifene citrate, trestolone acetate, triciribine
phosphate, trimetrexate, trimetrexate glucuronate, triptorelin, tubulozole hydrochloride, uracil
mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,
vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine
tartrate, vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin
hydrochloride, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of other anticancer drugs include, but are not limited to, 20-epi-1,25
dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;
adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;
angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic
protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense
oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;
apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III
derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;
beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;
bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate;
bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin
derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole;
CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors
(ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide;
cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;
crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab;
decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane;
dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydroazacytidine;
9-dihydrotaxol; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron;
doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;
edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue;
estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane;
fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone;
fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase
inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine;
ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth
factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane;
iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B;
itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha
interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear
polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds;
lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin
A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;
miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol;
mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone;
mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin;
monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene
inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide
B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides;
nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;
nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide
modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone;
oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer;
ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel
derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;
parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate;
phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A;
placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds;
platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;
prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C
inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors;
purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated
hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl
protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated;
rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine;
romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense
oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain
antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate;
solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine;
splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors;
stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide
antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium;
telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide;
tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin;
thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl
etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell
factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin;
tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide;
variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;
vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatin
stimalamer, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing UI include, but are not limited
to, propantheline, imipramine, hyoscyamine, oxybutynin, dicyclomine, a pharmaceutically
acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing an ulcer include, antacids such
as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate;
sucraflate; bismuth compounds such as bismuth subsalicylate and bismuth subcitrate; H
antagonists such as cimetidine, ranitidine, famotidine, and nizatidine; H , K - ATPase
inhibitors such as omeprazole, iansoprazole, and lansoprazole; carbenoxolone; misprostol;
antibiotics such as tetracycline, metronidazole, timidazole, clarithromycin, and amoxicillin; a
pharmaceutically acceptable derivative thereof; or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing IBD include, but are not
limited to, anticholinergic drugs; diphenoxylate; loperamide; deodorized opium tincture;
codeine; broad-spectrum antibiotics such as metronidazole; sulfasalazine; olsalazie;
mesalamine; prednisone; azathioprine; mercaptopurine; methotrexate; a pharmaceutically
acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing IBS include, but are not
limited to, propantheline; muscarine receptor antogonists such as pirenzapine, methoctramine,
ipratropium, tiotropium, scopolamine, methscopolamine, homatropine, homatropine
methylbromide, and methantheline; antidiarrheal drugs such as diphenoxylate and loperamide;
a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing an addictive disorder include,
but are not limited to, methadone, desipramine, amantadine, fluoxetine, buprenorphine, an
opiate agonist, 3-phenoxypyridine, levomethadyl acetate hydrochloride, serotonin antagonists,
a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing Parkinson's disease and
parkinsonism include, but are not limited to, carbidopa/levodopa, pergolide, bromocriptine,
ropinirole, pramipexole, entacapone, tolcapone, selegiline, amantadine, trihexyphenidyl
hydrochloride, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing anxiety include, but are not
limited to, benzodiazepines, such as alprazolam, brotizolam, chlordiazepoxide, clobazam,
clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam,
halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam,
temazepam, and triazolam; non-benzodiazepine agents, such as buspirone, gepirone,
ipsapirone, tiospirone, zolpicone, zolpidem, and zaleplon; tranquilizers, such as barbituates,
e.g., amobarbital, aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,
pentobarbital, phenobarbital, secobarbital, and thiopental; propanediol carbamates, such as
meprobamate and tybamate; a pharmaceutically acceptable derivative thereof; or any mixture
thereof.
Examples of useful therapeutic agents for treating or preventing epilepsy include, but are not
limited to, carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenytoin,
primidone, valproic acid, trimethadione, benzodiazepines, γ vinyl GABA, acetazolamide,
felbamate, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing stroke include, but are not
limited to, anticoagulants such as heparin, agents that break up clots such as streptokinase or
tissue plasminogen activator, agents that reduce swelling such as mannitol or corticosteroids,
acetylsalicylic acid, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing a seizure include, but are not
limited to, carbamazepine, ethosuximide, gabapentin, lamotrignine, phenobarbital, phenytoin,
primidone, valproic acid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinyl
GABA, acetazolamide, felbamate, a pharmaceutically acceptable derivative thereof, or any
mixture thereof.
Examples of useful therapeutic agents for treating or preventing a pruritic condition include,
but are not limited to, naltrexone; nalmefene; danazol; tricyclics such as amitriptyline,
imipramine, and doxepin; antidepressants such as those given below, menthol; camphor;
phenol; pramoxine; capsaicin; tar; steroids; antihistamines; a pharmaceutically acceptable
derivative thereof; or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing psychosis include, but are not
limited to, phenothiazines such as chlorpromazine hydrochloride, mesoridazine besylate, and
thoridazine hydrochloride; thioxanthenes such as chloroprothixene and thiothixene
hydrochloride; clozapine; risperidone; olanzapine; quetiapine; quetiapine fumarate;
haloperidol; haloperidol decanoate; loxapine succinate; molindone hydrochloride; pimozide;
ziprasidone; a pharmaceutically acceptable derivative thereof; or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing Huntington's chorea include,
but are not limited to, haloperidol, pimozide, a pharmaceutically acceptable derivative thereof,
or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing ALS include, but are not
limited to, baclofen, neurotrophic factors, riluzole, tizanidine, benzodiazepines such as
clonazepan, dantrolene, a pharmaceutically acceptable derivative thereof, or any mixture
thereof.
Examples of useful therapeutic agents for treating or preventing cognitive disorders include,
but are not limited to, agents for treating or preventing dementia such as tacrine; donepezil;
ibuprofen; antipsychotic drugs such as thioridazine and haloperidol; antidepressant drugs such
as those given above; a pharmaceutically acceptable derivative thereof; or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing a migraine include, but are not
limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,
ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine,
ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan,
oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,
zolmitriptan, a pharmaceutically acceptable derivative thereof, or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing vomiting include, but are not
limited to, 5-HT receptor antagonists such as ondansetron, dolasetron, granisetron, and
tropisetron; dopamine receptor antagonists such as prochlorperazine, thiethylperazine,
chlorpromazin, metoclopramide, and domperidone; glucocorticoids such as dexamethasone;
benzodiazepines such as lorazepam and alprazolam; a pharmaceutically acceptable derivative
thereof; or any mixture thereof.
Examples of useful therapeutic agents for treating or preventing dyskinesia include, but are not
limited to, reserpine, tetrabenazine, a pharmaceutically acceptable derivative thereof, or any
mixture thereof.
Examples of useful therapeutic agents for treating or preventing depression include, but are not
limited to, tricyclic antidepressants such as amitryptyline, amoxapine, bupropion,
clomipramine, desipramine, doxepin, imipramine, maprotilinr, nefazadone, nortriptyline,
protriptyline, trazodone, trimipramine, and venlaflaxine; selective serotonin reuptake inhibitors
such as citalopram, (S)-citalopram, fluoxetine, fluvoxamine, paroxetine, and setraline;
monoamine oxidase inhibitors such as isocarboxazid, pargyline, phenelzine, and
tranylcypromine; psychostimulants such as dextroamphetamine and methylphenidate; a
pharmaceutically acceptable derivative thereof; or any mixture thereof.
A Compound of Formula (I), or a pharmaceutically acceptable derivative thereof, and the
second therapeutic agent can act additively or, in one embodiment, synergistically. In one
embodiment, a Compound of Formula (I) is administered concurrently with a second
therapeutic agent; for example, a composition comprising an effective amount of a Compound
of Formula (I) and an effective amount of a second therapeutic agent can be administered.
Alternatively, a composition comprising an effective amount of a Compound of Formula (I)
and a different composition comprising an effective amount of a second therapeutic agent can
be concurrently administered. In another embodiment, an effective amount of a Compound of
Formula (I) is administered prior or subsequent to administration of an effective amount of a
second therapeutic agent. In this embodiment, the Compound of Formula (I) is administered
while the second therapeutic agent exerts its therapeutic effect, or the second therapeutic agent
is administered while the Compound of Formula (I) exerts its therapeutic effect for treating or
preventing a Condition.
A composition of the disclosure is prepared by a method comprising admixing a Compound of
Formula (I) or a pharmaceutically acceptable derivative thereof with a pharmaceutically
acceptable carrier or excipient. Admixing can be accomplished using methods known for
admixing a compound (or derivative) and a pharmaceutically acceptable carrier or excipient. In
one embodiment, the Compound of Formula (I) is present in the composition in an effective
amount.
4.7 Kits
The disclosure further provides kits that can simplify the handling and administration of a
Compound of Formula (I) to an animal.
In one embodiment, a kit of the disclosure comprises a unit dosage form of a Compound of
Formula (I). In one embodiment, the unit dosage form comprises a first container, which can
be sterile, containing an effective amount of a Compound of Formula (I) and a
pharmaceutically acceptable carrier or excipient. The kit can further comprise a label or printed
instructions instructing the use of the Compound of Formula (I) to treat or prevent a Condition.
The kit can further comprise a unit dosage form of a second therapeutic agent, for example, a
second container containing an effective amount of the second therapeutic agent and a
pharmaceutically acceptable carrier or excipient. In another embodiment, the kit comprises a
container containing an effective amount of a Compound of Formula (I), an effective amount of
a second therapeutic agent and a pharmaceutically acceptable vehicle, carrier, or excipient.
Examples of second therapeutic agents include, but are not limited to, those listed above.
Kits of the disclosure can further comprise a device that is useful for administering the unit
dosage forms. Examples of such a device include, but are not limited to, a syringe, a drip bag,
a patch, an inhaler, and an enema bag.
The following examples are set forth to assist in understanding the invention and should not be
construed as specifically limiting the invention described and claimed herein. Such variations
of the invention, including the substitution of all equivalents now known or later developed,
that would be within the purview of those skilled in the art, and changes in formulation or
changes in experimental design, are to be considered to fall within the scope of the invention
incorporated herein.
. EXAMPLES
Certain Examples below relate to the synthesis of illustrative Compounds of Formulae (I)
and/or (II).
.1 Example 1: Preparation of Compound C126(r)
Tert-butyl 4-(5-bromofluoropyridinyl)-piperazinecarboxylate (103)
A reaction mixture of 5-bromochlorofluoropyridine (101, 8.0 g, 38.02 mmol, Oakwood
Products, Inc., West Columbia, SC) and tert-butyl piperazinecarboxylate (102, 7.08 g, 38.02
mmol, Sigma-Aldrich) in DMSO (32 mL) was heated at 100°C for 16h. The mixture was
cooled to a temperature of about 25°C, poured onto cold 10% aqueous sodium carbonate, and
extracted with EtOAc. The organic layer was washed with water, washed with brine, dried
over sodium sulfate, and concentrated to provide 15.5 g of a semi-solid. The semi-solid was
washed with hexanes and filtered. The filtrate was concentrated to provide 7.5 g of a residue.
The residue was chromatographed on a silica gel column eluted with a gradient of from 100%
hexanes to 10:90 EtOAc:hexanes to provide 103 as a solid (24% yield).
(E)-tert-butyl 4-(3-fluoro(propenyl)pyridinyl)piperazinecarboxylate (105)
Under an argon atmosphere, to a solution of 103 (3.30 g, 9.16 mmol) and (E)-prop
enylboronic acid (104, 0.95 g, 11.0 mmol, Sigma-Aldrich) was added a 1M solution of tetra(n-
butyl)ammonium fluoride (TBAF) in THF (22 mL, 22.0 mmol, Sigma-Aldrich) and [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(DPPF)Cl , 0.075 g, 0.092 mmol,
Sigma-Aldrich). The resulting reaction mixture was stirred at reflux for 2 hours, cooled to a
temperature of about 25°C, diluted with water, and extracted with EtOAc. The organic layer
was washed with brine and concentrated to provide 3.6 g of a residue. The residue was
chromatographed on a silica gel column eluted with EtOAc:hexanes to provide 105 (91%
yield).
Tert-butyl 4-(5-((1S,2S)-1,2-dihydroxypropyl)fluoropyridinyl)piperazinecarboxylate
(106)
To a solution of 105 (2.67 g, 8.29 mmol ) in tert-butanol (80 mL) and water (80 mL) was added
methanesulfonamide (0.79 g, 8.29 mmol, Sigma-Aldrich). The mixture was cooled to 5°C and
AD-mix-α (11.50 g, 8.29 mmol) was added to form a reaction mixture. After warming the
reaction mixture to a temperature of about 25°C and stirring for 16 hours, excess solid sodium
sulfite was added and the resulting slurry was allowed to stir at 15°C for 30 min. The mixture
was extracted twice with EtOAc. The organic portions were combined, washed with brine,
dried (Na SO ), and concentrated under reduced pressure. The residue was chromatographed
on a silica gel column eluted with 50:50 EtOAc:hexanes and 70:30 EtOAc:hexanes to provide
106 as a solid (>99% yield).
(1S,2S)(5-fluoro(piperazinyl)pyridinyl)propane-1,2-diol (107)
To a solution of 106 (3.0 g, 8.65 mmol) in DCM (25 mL) was added 4N HCl in dioxane (2.51
mL, 43.2 mmol). The resulting reaction mixture was stirred at a temperature of about 25°C in a
closed vessel for 16h; a suspension formed. The suspension was stirred with diethyl ether; a
solid precipitated. The precipitate was collected by filtration and washed several times with
ether to provide 107 (91% yield) as a tan solid which, being >99% pure as analyzed by LC/MS,
was used directly in the next step.
4-[5-((1S,2S)-1,2-Dihydroxy-propyl)fluoro-pyridinyl]piperazinecarboxylic acid
(6-methyl-benzothiazolyl)-amide (Compound C126(r))
A suspension of 107 (200 mg, 0.61mmol) and N-(6-methylbenzo[d]thiazolyl)-1H-imidazole-
1-carboxamide (108, 160 mg, 0.61mmol) in DCM (6.0 mL) was cooled in an ice bath.
Diisopropylethylamine (DIEA, 2.0 mL, Sigma-Aldrich) was added to form a reaction mixture.
The reaction mixture was stirred at a temperature of about 25°C for 16 hours; a precipitate
formed. The precipitate was filtered and washed with DCM. Thereafter, the precipitate was
dissolved in 20:80 MeOH:DCM, concentrated on silica, and chromatographed on a silica gel
column eluted with a gradient of from 30:70 EtOAc:DCM to 80:20 EtOAc:DCM to provide
C126(r) as a white solid (24% yield). H NMR (DMSO-d ) δ: 0.88 (3H, d, J=6.4Hz), 2.37
(3H, s), 3.38 (4H, m), 3.69 (5H, m), 4.37 (1H, t, J=4.8Hz), 4.65 (1H, d, J=4.6Hz), 5.28 (1H, d,
J=4.4Hz), 7.18 (1H, m), 7.44 (1H, d, J=14.3Hz), 7.52 (1H, br s), 7.66 (1H, br s), 7.97 (1H, s),
11.20 (1H, br s). LC/MS (M+1): m/z = 446.
Compound 108 was prepared as follows:
To a solution of 6-methylbenzo[d]thiazolamine (109, 328 mg, 2 mmol, Sigma-Aldrich) in
DMF (5 mL) was added di(1H-imidazolyl)methanone (110, 357 mg, 2.2 mmol, Sigma-
Aldrich) at 0ºC. Under vigorous stirring, the resulting reaction mixture was slowly allowed to
warm to a temperature of about 25ºC over 14 h. A white precipitate formed. The precipitate
was collected by filtration under reduced pressure, washed twice with EtOAc (10 mL for each
wash), and dried under reduced pressure to provide 108 (yield >99%).
.2 Example 2: Preparation of Compounds B122(j), B122(k), B122(o), B122(p),
B125(j), B125(k), B125(o), B125(p), B155(h), B155(j), B155(o), B158(j),
B158(o), C4(r), C123(r), C125(r), and C170(r)
Using procedures similar to those described in Example 1 above, the following Compounds of
Formula (I) were prepared.
B122(j): (R)-N-(benzo[d]thiazolyl){5-[(1S,2S)-1,2-dihydroxypropyl]fluoropyridin-
2-yl}methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 0.87 (3H, d, J=6.1Hz), 1.07
(3H, d, J=6.4Hz), 3.08-3.45 (3H, m), 3.75-3.54 (2H, m), 3.94-4.30 (3H, m), 4.35 (1H, t,
J=5.0Hz), 4.66 (1H, d, J=4.6Hz), 5.28 (1H, d, J=4.4Hz), 7.20 (1H, t, J=7.4Hz), 7.70-7.28 (3H,
m), 7.72-7.91 (1H, m), 7.96 (1H, s), 11.33 (1H, br s). LC/MS (M+1): m/z = 447.
B122(k): (S)-N-(benzo[d]thiazolyl){5-[(1S,2S)-1,2-dihydroxypropyl]fluoropyridin-
2-yl}methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 0.87 (3H, d, J=6.4Hz), 1.07
(3H, d, J=6.6Hz), 3.28-3.39 (3H, m), 3.60-3.70 (2H, m), 4.20-4.22 (3H, m), 4.34 (1H, d,
J=5.5Hz), 4.67 (1H, br s), 5.25 (1H, br s), 7.20 (1H, t, J=7.5Hz), 7.32-7.51 (3H, m), 7.80 (1H,
br s), 7.96 (1H, s), 11.32 (1H, br s). LC/MS (M+1): m/z = 447.
B122(o): (R)-N-(benzo[d]thiazolyl){5-[(1R,2R)-1,2-dihydroxypropyl]fluoropyridin-
2-yl}methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 0.88 (3H, d, J=6.3Hz), 1.05
(3H, d, J=6.4Hz), 2.99-3.46 (3H, m), 3.50-3.60 (1H, m), 3.61-3.75 (1H, m), 4.00-4.31 (3H, m),
4.33 (1H, d, J=5.3Hz), 4.66 (1H, br s), 5.27 (1H, br s), 6.89 (1H, t, J=7.4Hz), 7.11 (1H, t,
J=7.1Hz), 7.25 (1H, d, J=7.9Hz), 7.39 (1H, dd, J=1.8, 14.5Hz), 7.54 (1H, d, J=7.2Hz), 7.95
(1H, s). LC/MS (M+1): m/z = 447.
B122(p): (S)-N-(benzo[d]thiazolyl){5-[(1R,2R)-1,2-dihydroxypropyl]fluoropyridin-
2-yl}methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 0.87 (3H, d, J=6.3Hz), 1.07
(3H, d, J=6.6Hz), 3.21-3.35 (3H, m), 3.62-3.66 (2H, m), 4.03-4.36 (4H, m), 4.66 (1H, d,
J=4.0Hz), 5.28 (1H, d, J=4.0Hz), 7.20 (1H, t, J=7.5Hz), 7.33-7.50 (3H, m), 7.80 (1H, br s),
7.95 (1H, s), 11.27 (1H, br s). LC/MS (M+1): m/z = 447.
B125(j): (R){5-[(1S,2S)-1,2-dihydroxypropyl]fluoropyridinyl}-
N-(6-fluorobenzo[d]thiazolyl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ:
0.87 (3H, d, J=6.3Hz), 1.07 (3H, d, J=6.6Hz), 3.10-3.46 (3H, m), 3.55-3.75 (2H, m), 4.03 (1H,
d, J=13.9Hz), 4.11-4.28 (2H, m), 4.35 (1H, t, J=4.7Hz), 4.66 (1H, d, J=4.6Hz), 5.28 (1H, d,
J=4.4Hz), 7.20 (1H, td, J=2.7, 9.1Hz), 7.41 (1H, dd, J=1.6, 14.4Hz), 7.50-7.59 (1H, m), 7.77
(1H, dd, J=2.6, 8.5Hz), 7.95 (1H, s), 11.43 (1H, br s). LC/MS (M+1): m/z = 465.
B125(k): (S){5-[(1S,2S)-1,2-dihydroxypropyl]fluoropyridinyl}-
N-(5-fluorobenzo[d]thiazolyl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ:
0.87 (3H, d, J=6.3Hz), 1.07 (3H, d, J=6.4Hz), 3.24-3.40 (3H, m), 3.71-3.60 (2H, m), 4.04-4.20
(3H, m), 4.35 (1H, t, J=4.6Hz), 4.65 (1H, d, J=4.6Hz), 5.27 (1H, d, J=4.6Hz), 7.24-7.38 (3H,
m), 7.82 (1H, br s), 7.96 (1H, s), 11.27 (1H, br s). LC/MS (M+1): m/z = 465.
B125(o): (R){5-[(1R,2R)-1,2-dihydroxypropyl]fluoropyridinyl}-
N-(6-fluorobenzo[d]thiazolyl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ:
0.87 (3H, d, J=6.4Hz), 1.07 (3H, d, J=6.6Hz), 3.43-3.08 (3H, m), 3.55-3.74 (2H, m), 3.97-4.08
(1H, m), 4.13-4.26 (2H, m), 4.34 (1H, d, J=5.0Hz), 4.66 (1H, br s), 5.28 (1H, br s), 7.15 (1H,
td, J=2.7, 9.1Hz), 7.41 (1H, dd, J=1.6, 14.4Hz), 7.48 (1H, dd, J=4.7, 8.7Hz), 7.70 (1H, dd,
J=2.6, 8.7Hz), 7.95 (1H, s). LC/MS (M+1): m/z = 465.
B125(p): (S)Z{5-[(1R,2R)-1,2-dihydroxypropyl]fluoropyridinyl}-
N-(5-fluorobenzo[d]thiazolyl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ:
0.87 (3H, d, J=6.3Hz), 1.07 (3H, d, J=6.6Hz), 3.21-3.35 (3H, m), 3.62-3.69 (2H, m), 4.02-4.20
(3H, m), 4.34 (1H, t, J=4.6Hz), 4.66 (1H, d, J=4.6Hz), 5.28 (1H, d, J=4.6Hz), 7.21 (1H, dt,
J=1.7, 9.0Hz), 7.41 (1H, dd, J=1.7, 14.3Hz), 7.55 (1H, br s), 7.77 (1H, d, J=9.0Hz), 7.95 (1H,
s), 11.30 (1H, br s). LC/MS (M+1): m/z = 465.
B155(h): (S){5-[(1S,2S)-1,2-dihydroxypropyl]fluoropyridinyl}-
N-(5-fluorobenzo[d]thiazolyl)methylpiperazinecarboxamide. H NMR (CDCl ) δ:
1.16 (3H, d, J=6.3Hz), 1.31 (3H, d, J=6.7Hz), 2.97-2.92 (1H, m), 3.11-3.16 (2H, m), 3.39 (1H,
dt, J=3.5, 12.6Hz), 3.89-4.01 (4H, m), 4.40-4.42 (3H, m), 6.99 (1H, dt, J=2.4, 8.8Hz), 7.30-
7.34 (2H, m), 7.65 (1H, dd, J=5.2, 8.5Hz), 7.98 (1H, s), 9.31 (1H, br s). LC/MS (M+1): m/z =
465.
B155(j): (R){5-[(1S,2S)-1,2-dihydroxypropyl]fluoropyridinyl}-
N-(5-fluorobenzo[d]thiazolyl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ:
0.87 (3H, d, J=6.3Hz), 1.07 (3H, d, J=6.4Hz), 3.10-3.44 (3H, m), 3.76-3.52 (2H, m), 4.04 (1H,
d, J=13.9Hz), 4.13-4.26 (2H, m), 4.29-4.38 (1H, m), 4.61-4.69 (1H, m), 5.28 (1H, d, J=4.3Hz),
7.02 (1H, td, J=9.1, 2.4Hz), 7.25-7.35 (1H, m), 7.41 (1H, dd, J=14.3, 1.5Hz), 7.81 (1H, dd,
J=5.5, 8.7Hz), 7.95 (1H, s), 11.60 (1H, br s). LC/MS (M+1): m/z = 465.
B155(o): (R){5-[(1R,2R)-1,2-dihydroxypropyl]fluoropyridinyl}-
N-(5-fluorobenzo[d]thiazolyl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ:
0.87 (3H, d, J=6.3Hz), 1.07 (3H, d, J=6.6Hz), 3.08-3.47 (3H, m), 3.56-3.74 (2H, m), 4.04 (1H,
d, J=12.7Hz), 4.27-4.13 (2H, m), 4.34 (1H, d, J=5.0Hz), 4.66 (1H, br s), 5.27 (1H, br s), 6.98
(1H, td, J=2.2, 9.0Hz), 7.26 (1H, dd, J=2.1, 10.1Hz), 7.41 (1H, dd, J=1.3, 14.4Hz), 7.77 (1H,
dd, J=5.6, 8.5Hz), 7.95 (1H, s). LC/MS (M+1): m/z = 465.
B158(j): (R)-N-(5,6-difluorobenzo[d]thiazolyl){5-[(1S,2S)-1,2-dihydroxypropyl]-
3-fluoropyridinyl}methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 0.87 (3H,
d, J=6.3Hz), 1.06 (3H, d, J=6.4Hz), 3.04-3.42 (4H, m), 3.51-3.76 (2H, m), 3.97-4.10 (1H, m),
4.11-4.25 (1H, m), 4.30-4.38 (1H, m), 4.65 (1H, d, J=4.3Hz), 5.27 (1H, d, J=4.6Hz), 7.35-7.51
(2H, m), 7.80-7.98 (2H, m), 11.52 (1H, br s). LC/MS (M+1): m/z = 483.
B158(o): (R)-N-(5,6-difluorobenzo[d]thiazolyl){5-[(1R,2R)-1,2-dihydroxypropyl]-
3-fluoropyridinyl}methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 0.87 (3H,
d, J=6.3Hz), 1.06 (3H, d, J=6.6Hz), 3.06-3.44 (3H, m), 3.52-3.74 (2H, m), 3.94-4.08 (1H, m),
4.10-4.26 (2H, m), 4.29-4.40 (1H, m), 4.58-4.72 (1H, m), 5.19-5.34 (1H, m), 7.34-7.52 (2H,
m), 7.81-7.99 (2H, m), 11.49 (1H, br s). LC/MS (M+1): m/z = 483.
C4(r): 4-{3-Chloro[(1S,2S)-1,2-dihydroxypropyl]pyridinyl}-N-(6-fluorobenzo[d]thiazol-
2-yl)piperazinecarboxamide. H NMR (DMSO-d ) δ: 0.89 (3H, d, J=6.2Hz), 3.24-3.31
(4H, m), 3.69-3.73 (5H, m), 4.40 (1H, d, J=4.4Hz), 4.67 (1H, br s), 5.34 (1H, br s), 7.14 (1H,
dt, J=8.6, 1.7Hz), 7.47 (1H, dd, J=8.6, 4.6Hz), 7.67-7.71 (2H, m), 8.15 (1H, d, J=1.7Hz), 11.52
(1H, br s). LC/MS (M+1): m/z = 466.
C123(r): N-(6-chlorobenzo[d]thiazolyl)(5-((1S,2S)-1,2-dihydroxypropyl)-
3-fluoropyridinyl)piperazinecarboxamide. H NMR (DMSO-d ) δ: 0.88 (3H, d,
J=6.4Hz), 3.40 (4H, m), 3.70 (5H, m), 4.37 (1H, t, J=4.8Hz), 4.65 (1H, d, J=6.8Hz), 5.28 (1H,
d, J=4.7Hz), 7.39 (1H, d, J=7.5Hz), 7.44 (1H, d, J=14.3Hz), 7.63 (1H, br s), 7.97 (1H, s), 8.03
(1H, br s), 11.40 (1H, br s). LC/MS (M+1): m/z = 466.
C125(r): 4-(5-((1S,2S)-1,2-dihydroxypropyl)fluoropyridinyl)-
N-(6-fluorobenzo[d]thiazolyl)piperazinecarboxamide. H NMR (DMSO-d ) δ: 0.88 (3H,
d, J=6.4Hz), 3.39 (4H, m), 3.69 (5H, m), 4.37 (1H, t, J=4.82Hz), 4.66 (1H, d, J=4.6Hz), 5.28
(1H, d, J=4.6Hz), 7.22 (1H, t, J=9.4Hz), 7.44 (1H, d, J=14.2Hz), 7.64 (1H, br s), 7.81 (1H, br
s), 7.97 (1H, s), 11.33 (1H, br s). LC/MS (M+1): m/z = 450.
C170(r): 4-(5-((1S,2S)-1,2-dihydroxypropyl)fluoropyridinyl)-
N-(5,6-dimethylbenzo[d]thiazolyl)piperazinecarboxamide. H NMR (DMSO-d ) δ: 0.88
(3H, d, J=6.4Hz), 2.28 (6H, d, J=5.7Hz), 3.38 (4H, m), 3.70 (5H, m), 4.36 (1H, d, J=5.5Hz),
4.66 (1H, br s), 5.28 (1H, br s), 7.44 (1H, d, J=12.7Hz), 7.46 (1H, br s), 7.56 (1H, br s), 7.97
(1H, s), 11.17 (1H, br s). LC/MS (M+1): m/z = 460.
.3 Example 3: Preparation of Compound BB
Using procedures similar to those described in Example 1 above, the Compound BB was
prepared.
BB: (S){5-[(1S,2S)-1,2-dihydroxypropyl]fluoropyridinyl}-
N-(6-fluorobenzo[d]thiazolyl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ:
0.86 (3H, d, J=6.1Hz), 1.24 (3H, d, J=6.6Hz), 2.85 (1H, t, J=11.6Hz), 3.05 (1H, d, J=11.6Hz),
3.24-3.33 (1H, m), 3.65-3.73 (1H, m), 3.77 (1H, d, J=12.9Hz), 3.93 (1H, d, J=12.3Hz), 4.16
(1H, br s), 4.36 (1H, t, J=4.6Hz), 4.57 (1H, br s), 4.66 (1H, d, J=4.8Hz), 5.29 (1H, d, J=4.6Hz),
7.21 (1H, t, J=8.8Hz), 7.43 (1H, d, J=14.3Hz), 7.64 (1H, br s), 7.79 (1H, br s), 7.95 (1H, s),
11.30 (1H, br s). LC/MS (M+1): m/z = 464.
.4 Example 4: Preparation of Compound A155(a)
2-Chlorofluorovinylpyridine (112)
To a solution of 101 (5.00g, 23.8 mmol) and 4,4,6-trimethylvinyl-1,3,2-dioxaborinane (111,
3.29 g, 21.39 mmol, Sigma-Aldrich) in a mixture of TBAF (30.0 mL) and THF (64.0 mL)
under an argon atmosphere was added bis(triphenylphosphine)dichloropalladium(II) catalyst
(Pd(PPh ) Cl , 1.33 g, 1.90 mmol, Sigma-Aldrich) and K CO (8.20 g, 59.4 mmol). The
3 2 2 2 3
resulting reaction mixture was heated to 60°C and held for 16 hrs in a sealed bottle. The
mixture was cooled to a temperature of about 25°C, diluted with water, and extracted with
EtOAc. The organic layer was separated, washed with brine, and concentrated. The residue
was chromatographed on a silica gel column eluted with EtOAc:hexanes to provide 3.2 g of
112 as a colorless oil (85% yield). H NMR (CDCl ) δ: 5.48 (1H, d, J=10.97Hz), 5.83 (1H, d,
J=17.62Hz), 6.68 (1H, dd, J=10.97, 17.62Hz), 7.52 (1H, d, J=1.60Hz), 8.20 (1H, d, J=1.60Hz).
LC/MS (M+1): m/z = 158.
(S)(6-Chlorofluoropyridinyl)ethane-1,2-diol (113)
To a solution of 112 (5.00 g, 31.75 mmol) in water (162 mL) and tert-butanol (162 mL) cooled
to 0ºC with an ice bath was added AD-mix α (54.6 g, Sigma-Aldrich) to form a reaction
mixture. With the bath ice left in place, the reaction mixture was allowed to warm to a
temperature of about 25°C. After 16 hrs, excess solid sodium sulfite (60 g) was added and the
resulting slurry was allowed to stir at a temperature of about 25°C for 30 min. The mixture was
extracted twice with EtOAc. The organic portions were combined, washed with brine, dried
(Na SO ), and concentrated under reduced pressure. The resulting mixture was
chromatographed on a silica gel column eluted with a gradient of from 50:50 EtOAc:hexanes to
100% EtOAc to provide 5.39 g of 113 as a white solid (89% yield). H NMR (CDCl ) δ: 2.16
(1H, t, J=5.60Hz), 2.88 (1H, d, J=3.54Hz), 3.66 (1H, m), 3.84 (1H, m), 4.91 (1H, m), 7.59 (1H,
dd, J=1.61, 8.73Hz), 8.29 (1H, d, J=1.88Hz). LC/MS (M+1): m/z = 192.
(S)Chloro(2,2-dimethyl-1,3-dioxolanyl)fluoropyridine (114)
A suspension of 113 (5.39 g, 28.2 mmol) in 2,2-dimethoxypropane (58 mL, Sigma-Aldrich)
was cooled with an ice bath. Para-toluene sulfonic acid monohydrate (PTSA, 0.54 g, 2.82
mmol, Sigma-Aldrich) was added to form a reaction mixture. The ice bath was removed and
the reaction mixture was stirred at a temperature of about 25°C for 16 hrs. Thereafter, the
mixture was cooled with an ice bath, treated with saturated aqueous sodium bicarbonate, and
extracted with EtOAc. The organic layer was separated, washed with brine, dried (Na SO ),
and concentrated to provide 5.65 g of 114 as an oil (87% yield). H NMR (CDCl ) δ: 1.48
(3H, s), 1.54 (3H, s), 3.71 (1H, m), 4.37 (1H, m), 5.11 (1H, t, J=6.76Hz), 7.53 (1H, dd, J=1.93,
8.63Hz), 8.18 (1H, d, J=1.88Hz). LC/MS (M+1): m/z = 232.
(S)-Tert-butyl{5-[(S)-2,2-dimethyl-1,3-dioxolanyl]fluoropyridinyl}-
2-methylpiperazinecarboxylate (116)
To a solution of 114 (1.60 g, 6.91 mmol) in toluene (21.1 mL) under an argon atmosphere was
added (S)-tert-butyl 2-methylpiperazinecarboxylate (115, 1.38 g, 6.91 mmol, AK Scientific,
Inc., Union City, CA), sodium tert-butoxide (0.73 g, 7.60 mmol, Sigma-Aldrich), and 2-
dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (i.e., "X-Phos," 0.49 g, 1.04 mmol, Sigma-
Aldrich). The mixture was degassed under argon and then tris(dibenzylideneacetone)
dipalladium (Pd (DBA) , 0.63 g, 0.69 mmol, Sigma-Aldrich) was added to form a reaction
mixture. The reaction mixture, heated in an oil bath maintained at temperature within the range
of from 80°C to 85°C, was stirred for 1.5 hours. Thereafter, the mixture was cooled to a
temperature of about 25°C, poured onto cold water, and extracted with EtOAc. The organic
layer was separated, washed with brine, and concentrated to an oil which was chromatographed
on a silica gel column eluted with 10:90 EtOAc:hexanes and 20:80 EtOAc:hexanes to provide
1.71 g of 116 as a solid (63% yield). H NMR (CDCl ) δ: 1.25 (3H, d, J=6.80Hz), 1.46 (3H,
s), 1.48 (9H, s), 1.53 (3H, s), 2.89 (1H, dt, J=3.29, 13.59Hz), 3.09 (1H, dd, J=3.73, 12.06Hz),
3.23 (1H, dt, J=2.85, 13.59Hz), 3.69 (1H, t, J=7.89Hz), 3.83 (1H, d, J=12.72Hz), 3.92 (1H, d,
J=13.81Hz), 4.01 (1H, d, J=12.90Hz), 4.27 (1H, t, J=6.14Hz), 4.31 (1H, brs), 5.01 (1H, t,
J=7.24Hz), 7.30 (1H, d, J=1.97Hz), 7.95 (1H, s). LC/MS (M+1): m/z = 396.
(S){5-Fluoro[(S)methylpiperazinyl]pyridinyl}ethane-1,2-diol (117)
To a solution of 116 (1.71g, 4.33 mmol) in DCM (9.60 mL) and MeOH (1.50 mL) was added
4N HCl in dioxane (6.49 mL) to form a reaction mixture. The reaction mixture was stirred at a
temperature of about 25°C in a closed vessel for 16h. Thereafter, the resulting suspension was
stirred with diethyl ether. The solid precipitate was collected on filter paper and washed
several times with diethyl ether to provide 1.25g of 117 as a tan solid (88% yield) which, being
>99% pure as analyzed by LC/MS, was used directly in the next step.
(S){5-[(S)-1,2-Dihydroxyethyl]fluoropyridinyl}-N-(5-fluorobenzo[d]thiazolyl)-
2-methylpiperazinecarboxamide (Compound A155(a))
A suspension of 117 (0.18 g, 0.40 mmol) and N-(5-fluorobenzo[d]thiazolyl)-1H-imidazole-
1-carboxamide (118, 0.105 g, 0.40 mmol) in DCM (5 mL) was cooled with an ice bath. DIEA
(1.0 mL) was added to form a reaction mixture. The reaction mixture was stirred at a
temperature of about 25°C for about 16h. The mixture was diluted with DCM (100 mL),
washed with saturated aqueous NaHCO , washed twice with brine, dried, and concentrated.
The obtained residue was chromatographed on a silica gel column eluted with a gradient of
from 100% DCM to 10:90 MeOH:DCM to provide 0.095 g of Compound A155(a) as a white
foam (53% yield). H NMR (DMSO-d ) δ: 1.24 (3H, d, J=6.80Hz), 2.86 (1H, dt, J=3.51,
12.50Hz), 3.05 (1H, dd, J=3.29, 12.24Hz), 3.30 (1H, t, J=12.28Hz), 3.41 (1H, m, J=6.14Hz),
3.48 (1H, m, J=5.26Hz), 3.77 (1H, d, J=12.94Hz), 3.93 (1H, d, J=11.62Hz), 4.19 (1H, d,
J=12.28Hz), 4.52 (1H, qt, J=5.48Hz), 4.61 (1H, brs), 4.77 (1H, t, J=6.14Hz), 5.36 (1H, d,
J=4.60Hz), 7.09 (1H, t, J=9.21Hz), 7.36 (1H, brs), 7.47 (1H, d, J=14.25Hz), 7.88 (1H, m), 7.97
(1H, s), 11.67 (1H, brs). LC/MS (M+1): m/z = 450.
Compound 118, N-(5-fluorobenzo[d]thiazolyl)-1H-imidazolecarboxamide, was prepared
similarly to compound 108 except 5-fluorobenzo[d]thiazolamine (Sigma-Aldrich) was used
in place of 6-methylbenzo[d]thiazolamine.
.5 Example 5: Preparation of Compound A122(a)
2-Chlorofluorovinylpyridine (112)
To a solution of 101 (5.00g, 23.8 mmol) and 4,4,5,5-tetramethylvinyl-1,3,2-dioxaborolane
(119, 21.39 mmol, Sigma-Aldrich) in a mixture of EtOH (30.0 mL) and THF (64.0 mL) under
an argon atmosphere was added Pd(PPh ) Cl (1.33 g, 1.90 mmol) and K CO (8.20 g, 59.4
3 2 2 2 3
mmol). The resulting reaction mixture was heated to 60°C and held for 16 hrs in a sealed
bottle. The mixture was cooled to a temperature of about 25°C, diluted with water, and
extracted with EtOAc. The organic layer was separated, washed with brine, and concentrated.
The residue was chromatographed on a silica gel column eluted with EtOAc:hexanes to provide
112 as a colorless oil (85% yield). H NMR (CDCl ) δ: 5.48 (1H, d, J=10.97Hz), 5.83 (1H, d,
J=17.62Hz), 6.68 (1H, dd, J=10.97, 17.62Hz), 7.52 (1H, d, J=1.60Hz), 8.20 (1H, d, J=1.60Hz).
LC/MS (M+1): m/z = 158.
Thereafter, Compound A122(a) was prepared similarly to Compound A155(a) in Example 4
except compound 120 was used in place of compound 118.
A122(a): (S)-N-(benzo[d]thiazolyl)(5-((S)-1,2-dihydroxyethyl)fluoropyridinyl)-
2-methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.24 (3H, d, J=6.6Hz), 2.85 (1H,
t, J=11.0Hz), 3.04 (1H, d, J=12.9Hz), 3.29 (1H, m), 3.41 (1H, m, J=5.5Hz), 3.48 (1H, m,
J=5.5Hz), 3.77 (1H, d, J=12.7Hz), 3.93 (1H, d, J=12.5Hz), 4.21 (1H, br s), 4.52 (1H, q,
J=5.0Hz), 4.61 (1H, br s), 4.76 (1H, t, J=6.1Hz), 5.34 (1H, d, J=4.6Hz), 7.20 (1H, t, J=6.8Hz),
7.36 (1H, t, J=7.5Hz), 7.46 (1H, dd, J=1.8, 14.3Hz), 7.55 (1H, br s), 7.82 (1H, br s), 7.97 (1H,
s), 11.37 (1H, br s). LC/MS (M+1): m/z = 432.
Compound 120, N-(benzo[d]thiazolyl)-1H-imidazolecarboxamide, was prepared similarly
to compound 108 except benzo[d]thiazolamine (Sigma-Aldrich) was used in place of
6-methylbenzo[d]thiazolamine.
.6 Example 6: Preparation of Compounds A122(b), A122(c), A122(e), A123(e),
A125(b), A125(e), A126(a), A126(e), A155(b), A155(d), A155(e), and
A158(a)
Using procedures similar to those described in Examples 4 and 5 above, the following
Compounds of Formula (I) were prepared.
A122(b): (R)-N-(benzo[d]thiazolyl)(5-((S)-1,2-dihydroxyethyl)fluoropyridinyl)-
3-methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.08 (3H, d, J=6.4Hz), 3.11-3.70
(6H, m), 4.35-3.93 (3H, m), 4.51 (1H, q, J=5.3Hz), 4.75 (1H, t, J=5.6Hz), 5.33 (1H, d,
J=4.4Hz), 7.20 (1H, t, J=7.5Hz), 7.35 (1H, t, J=7.8 Hz), 7.44 (1H, d, J=14.3Hz), 7.54 (1H, br
s), 7.81 (1H, br s), 7.98 (1H, s), 11.32 (1H, br s). LC/MS (M+1): m/z = 433.
A122(c): (S)-N-(benzo[d]thiazolyl){5-[(S)-1,2-dihydroxyethyl]fluoropyridinyl}-
3-methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.08 (3H, d, J=6.6Hz), 3.23-3.63
(6H, m), 3.90-4.21 (3H, m), 4.50 (1H, t, J=5.9Hz), 7.19 (1H, t, J=7.5Hz), 7.35 (1H, t,
J=7.5Hz), 7.44 (1H, dd, J=1.8, 14.3Hz), 7.52 (1H, br s), 7.80 (1H, br s), 7.98 (1H, s), 11.26
(1H, br s). LC/MS (M+1): m/z = 433.
A122(e): (R)-N-(benzo[d]thiazolyl)(5-((R)-1,2-dihydroxyethyl)fluoropyridinyl)-
2-methylpiperazinecarboxamide. H NMR (CD OD-d ) δ: 1.36 (3H, d, J=6.4Hz), 2.95 (1H,
m), 3.12 (1H, d, J=13.6Hz), 3.41 (1H, m), 3.63 (2H, m), 3.89 (1H, d, J=12.0Hz), 4.03 (1H, d,
J=11.0Hz), 4.67 (1H, m), 7.23 (1H, m), 7.37 (1H, m), 7.48 (2H, d, J=14.0Hz), 7.69 (1H, br s),
8.00 (1H, s). LC/MS (M+1): m/z = 432.
A123(e): (R)-N-(6-chlorobenzo[d]thiazolyl)(5-((R)-1,2-dihydroxyethyl)-
3-fluoropyridinyl)methylpiperazinecarboxamide. H NMR (CD OD-d ) δ: 1.15 (3H,
d, J=6.8Hz), 2.73 (1H, t, J=10.0Hz), 2.91 (1H, d, J=14.0Hz), 3.22 (1H, m), 3.42 (2H, m), 3.67
(1H, d, J=14.0Hz), 3.81 (1H, d, J=12.0Hz), 4.00 (1H, m), 4.45 (1H, t, J=5.2Hz), 7.13 (1H, dt,
J=2.0, 8.4Hz), 7.25 (2H, dd, J=1.6, 14.0Hz), 7.55 (1H, m), 7.79 (1H, s). LC/MS (M+1): m/z =
466.
A125(b): (R){5-[(S)-1,2-dihydroxyethyl]fluoropyridinyl}-N-(6-fluorobenzo[d]thiazol-
2-yl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.08 (3H, d, J=6.5Hz),
3.14-3.68 (6H, m), 4.02 (1H, d, J=11.9Hz), 4.26-4.10 (2H, m), 4.51 (1H, dd, J=5.6, 10.7Hz),
4.74 (1H, t, J=5.7Hz), 5.32 (1H, d, J=4.5Hz), 7.21 (1H, td, J=2.6, 9.1Hz), 7.39-7.49 (1H, m),
7.51-7.60 (1H, m), 7.78 (1H, dd, J=2.4, 8.8Hz), 7.98 (1H, s), 11.37 (1H, br s). LC/MS (M+1):
m/z = 451.
A125(e): (R)(5-((R)-1,2-dihydroxyethyl)fluoropyridinyl)-N-(6-fluorobenzo[d]thiazol-
2-yl)methylpiperazinecarboxamide. H NMR (CD OD-d ) δ: 1.26 (3H, d, J=6.8Hz),
2.85 (1H, dt, J=3.2, 13.0Hz), 3.02 (1H, dd, J=3.6, 13.0Hz), 3.32 (1H, m), 3.53 (2H, m), 3.78
(1H, d, J=12.0Hz), 3.92 (1H, d, J=12.0Hz), 4.12 (1H, m), 4.56 (1H, t, J=6.0Hz), 7.02 (1H, dt,
J=2.8, 12.0Hz), 7.35 (1H, dd, J=1.6, 14.0Hz), 7.41 (2H, m), 7.89 (1H, s). LC/MS (M+1): m/z
= 450.
A126(a): (S)(5-((S)-1,2-dihydroxyethyl)fluoropyridinyl)methyl-
N-(6-methylbenzo[d]thiazolyl)piperazinecarboxamide. H NMR (DMSO-d ) δ: 1.23
(3H, d, J=6.8Hz), 2.37 (3H, s), 2.84 (1H, t, J=11.0Hz), 3.03 (1H, dd, J=3.5, 12.1Hz), 3.28 (1H,
m), 3.41 (1H, m, J=5.5Hz), 3.48 (1H, m, J=5.5Hz), 3.77 (1H, d, J=12.7Hz), 3.93 (1H, d,
J=11.6Hz), 4.19 (1H, br s), 4.52 (1H, q, J=5.3Hz), 4.59 (1H, br s), 4.75 (1H, t, J=5.3Hz), 5.34
(1H, d, J=4.6Hz), 7.17 (1H, d, J=7.0,Hz), 7.46 (1H, d, J=13.6Hz), 7.61 (2H, br s), 7.97 (1H, s),
11.23 (1H, br s). LC/MS (M+1): m/z = 446.
A126(e): (R)(5-((R)-1,2-dihydroxyethyl)fluoropyridinyl)methyl-
N-(6-methylbenzo[d]thiazolyl)piperazinecarboxamide . H NMR (CD OD-d ) δ: 1.36
(3H, d, J=6.8Hz), 2.43 (3H, s), 2.95 (1H, t, J=13Hz), 3.12 (1H, dd, J=3.6, 13.0Hz), 3.42 (1H,
m), 3.64 (2H, m), 3.88 (1H, d, J=13.0Hz), 4.02 (1H, d, J=13.0Hz), 4.2 (1H, m), 4.67 (1H, t,
J=6.0Hz), 7.19 (1H, d, J=9.2Hz), 7.34 (1H, m), 7.46 (1H, dd, J=2.4, 14.0Hz), 7.50 (1H, m),
8.00 (1H, s). LC/MS (M+1): m/z = 446.
A155(b): (R){5-[(S)-1,2-dihydroxyethyl]fluoropyridinyl}-N-(5-fluorobenzo[d]thiazol-
2-yl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.08 (4H, d, J=6.7Hz),
3.13-3.67 (6H, m), 3.94-4.07 (1H, m), 4.07-4.28 (2H, m), 4.50 (1H, q, J=5.2Hz), 4.75 (1H, t,
J=5.7Hz), 5.33 (1H, d, J=4.4Hz), 7.00-7.15 (1H, m), 7.38-7.50 (2H, m), 7.85-8.02 (2H, m),
11.39 (1H, br s). LC/MS (M+1): m/z = 451.
A155(d): (S){5-[(R)-1,2-dihydroxyethyl]fluoropyridinyl}-N-(5-fluorobenzo[d]thiazol-
2-yl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.25 (3H, d, J=6.6Hz),
2.83-2.93 (1H, m), 3.04 (1H, dd, J=13.0, 3.4Hz), 3.25-3.48 (3H, m), 3.77 (1H, d, J=13.0Hz),
3.92 (1H, d, J=13.0Hz), 4.19 (1H, d, J=13.0Hz), 4.57-4.69 (3H, m), 5.33 (1H, s), 7.08 (1H, td,
J=1.5, 8.5Hz), 7.34 (1H, d, J=8.5Hz), 7.45 (1H, dd, J=1.5, 14.2Hz), 7.86 (1H, dd, J=5.5,
8.5Hz), 7.97 (1H, s), 11.63 (1H, br s). LC/MS (M+1): m/z = 451.
A155(e): (R){5-[(R)-1,2-dihydroxyethyl]fluoropyridinyl}-N-(5-fluorobenzo[d]thiazol-
2-yl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.24 (3H, d, J=6.7Hz), 2.86
(1H, td, J=12.7, 3.3Hz), 3.05 (1H, dd, J=12.7, 3.3Hz), 3.25-3.48 (3H, m), 3.74-3.79 (1H, m),
3.93 (1H, d, J=12.7Hz), 4.19 (1H, d, J=12.7Hz), 4.58-4.70 (3H, m), 5.34 (1H, s), 7.08 (1H, dt,
J=2.3, 9.1Hz), 7.35-7.48 (2H, m), 7.84-7.96 (2H, m), 11.66 (1H, br s). LC/MS (M+1): m/z =
451.
A158(a): (S)-N-(5,6-difluorobenzo[d]thiazolyl)(5-((S)-1,2-dihydroxyethyl)-
3-fluoropyridinyl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.24 (3H,
d, J=6.6Hz), 2.87 (1H, t, J=12.9Hz), 3.06 (1H, d, J=10.1Hz), 3.31 (1H, m), 3.46 (2H, m), 3.76
(1H, d, J=12.9Hz), 3.92 (1H, d, J=12.9Hz), 4.14 (1H, d, J=12.1Hz), 4.54 (2H, m), 4.76 (1H,
m), 5.35 (1H, d, J=4.2Hz), 7.46 (1H, dd, J=1.5, 14.0Hz), 7.71 (1H, t, J=10.5Hz), 7.97 (1H, s),
8.07 (1H, t, J=8.6Hz), 11.40 (1H, br s). LC/MS (M+1): m/z = 468.
.7 Example 7: Preparation of Compound AE
Using procedures similar to those described in Examples 4 and 5 above, the Compound AE was
prepared.
AE: (R)-N-(5,6-difluorobenzo[d]thiazolyl){5-[(S)-1,2-dihydroxyethyl]fluoropyridin-
2-yl}methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.08 (3H, d, J=6.6Hz),
3.12-3.68 (6H, m), 4.00 (1H, d, J=12.4Hz), 4.08-4.30 (2H, m), 4.51 (1H, q, J=5.3Hz), 4.75
(1H, t, J=5.7Hz), 5.33 (1H, d, J=4.6Hz), 7.44 (1H, dd, J=1.8, 14.3Hz), 7.64 (1H, dd, J=7.6,
10.8Hz), 7.94-7.99 (1H, m), 8.04 (1H, dd, J=8.0, 10.3Hz), 11.49 (1H, br s). LC/MS (M+1):
m/z = 469.
.8 Example 8: Preparation of Compound A155(ad)
The following compound, Compound A155(ad), which is a racemic mixture of the
(R)-1,2-dihydroxyethyl- and (S)-1,2-dihydroxyethyl-enantiomers, was prepared in the same
manner as in Example 4 above except for step 2 in which OsO and NMO were used as
oxidative reagents instead of AD-mix alpha.
A155(ad): (2S)(5-(1,2-dihydroxyethyl)fluoropyridinyl)-N-(5-fluorobenzo[d]thiazol-
2-yl)methylpiperazinecarboxamide. H NMR (DMSO-d ) δ: 1.24 (3H, d, J=6.6Hz),
2.84-2.87 (1H, m), 3.03-3.06 (1H, m), 3.25-3.52 (3H, m), 3.76 (1H, d, J=12.8Hz), 3.92 (1H, d,
J=12.8Hz), 4.19 (1H, d, J=12.8Hz), 4.53-4.75 (3H, m), 5.34 (1H, d, J=4.1Hz), 7.08 (1H, t,
J=8.8Hz), 7.24-7.50 (2H, m), 7.86 (1H, br), 7.96 (1H, s), 11.57 (1H, br s). LC/MS (M+1): m/z
= 450.
5.9 Example 9: Determination of the Optical Purity for Compound A155(e)
The % ee was determined for Compound A155(e) as shown below:
Chiral HPLC was used to determine the % ee for Compound A155(e). A CHIRALPAK 1A
column (Daicel Chemical, Tokyo, Japan) was used. The peak areas for the major and minor
enantiomers were determined and 94% ee was calculated using the equation in Section 4.3.
If desired, H NMR can also be used. For a H NMR determination, bis-Mosher's ester
derivatives are prepared for the compound(s) of interest, e.g., Compound A155(e), by a
technique known in the art. The % ee determination is done by adding an excess of Mosher's
acid chloride to a compound of interest (about 0.6 mg) in pyridine-d (about 0.530 mL) at a
temperature of about 25°C in an NMR tube. A H NMR is taken 20 h after the addition of
Mosher's acid chloride. An appropriate peak is chosen for the bis-Mosher's ester with δ in the
range from about 7.00 ppm to about 6.60 ppm. It is important to note whether C satellites are
observed upfield and/or downfield of the chosen peak. The H NMR peaks for the minor and
major enantiomer are integrated, the C satellites are subtracted out, and the % ee is calculated
using the equation cited above.
.10 Example 10: Combining a Compound of Formula (I) and Fumaric Acid
To 20mg of the free base of Compound A155(a) in 0.3 ± 0.1mL of MeOH in a 4mL vial at a
temperature of about 25°C was added 1.1 eq. of fumaric acid (AK Scientific). The resulting
slurry was stirred with a magnetic stirring bar for about 32h. Thereafter, the slurry was
evaporated to dryness using a centrifugal evaporator (HT-8 Series II, Genevac Inc., Gardiner,
1 13 15
NY). The product was analyzed by H NMR, DTA, PXRD, C NMR, and N NMR.
Dissolution of the product followed by H NMR analysis of the resulting solution for each
component demonstrated that the average molar ratio of Compound A155(a) to fumaric acid
was about 1:0.5 ± 0.2, with values from multiple determinations ranging from 1:0.4 to 1:0.7.
DTA, at a rate of 10°C/minute, of the product yielded a melting onset of 176.8°C, as
determined by the temperature at which the extrapolated melting endotherm deviated from the
extrapolated baseline, and a melting point of 182.9°C, as determined by the temperature at the
melting endotherm peak. In contrast, for Compound A155(a) similarly-crystallized to
anhydrate crystals from MeOH but in the absence of fumaric acid, the DTA melting onset was
185.7°C and the DTA melting point was 189.4°C.
Powder x-ray diffraction intensity data were collected on a Bruker D8 Discover apparatus using
CuKα radiation (λ = 1.5418 Å). The scanning range was from 3.0° to 40° 2θ. The reported 2θ
values are ± 0.2° 2θ. Figure 1 provides the PXRD pattern and Table 4 summarizes the peaks
observed for the product prepared with fumaric acid as described above while Table 5
summarizes the peaks observed for crystalline anhydrate (i.e., free base) Compound A155(a).
For each table, peak maximum relative intensity is denoted as follows: VS = very strong, S =
strong, M = medium, and W = weak.
Table 4: Powder X-ray Diffraction Results for Product
Position Relative
[° 2θ] Intensity
.8 W
6.5 S
8.6 M
9.3 W
.8 W
12.5 S
14.0 M
16.8 VS
18.7 M
19.7 W
.4 M
21.3 M
22.0 M
23.2 S
.3 S
26.8 W
28.2 W
28.5 W
.8 W
.0 W
38.5 S
Table 5: Powder X-ray Diffraction Results for Compound A155(a)
Position Relative
[° 2θ] Intensity
13.5 W
.8 W
17.5 W
18.5 W
.3 M
22.6 S
23.2 M
24.7 VS
26.1 M
26.9 S
27.8 M
36.3 W
38.7 M
All solid-state cross polarization magic angle spinning (CP/MAS) NMR determinations were
performed on a Varian NMR System 600MHz NMR spectrometer (Varian NMR, Inc., Palo
Alto, CA) with a 3.2mm rotor-outside-diameter probe at a frequency of 150.8MHz, for C, and
15
60.79MHz, for N. Sample temperature was controlled at 10°C±0.2°C. The N spectra were
measured under the following conditions: spectral width of 24,510Hz, acquisition time of
40ms, recycle delay time of from 5s to 15s, contact time of 2ms, N π/2 pulse lengths of 4.2µs,
13
1H π/2 pulse lengths of 2.2µs. As a reference, N glycine at δ of -347.54 was used. The C
spectra were measured under the following conditions: spectral width of 43,103Hz, acquisition
time of 40ms, recycle delay time of 10s, contact time of 3ms, C π/2 pulse lengths of 2.0µs, 1H
π/2 pulse lengths of 2.2µs. As a reference, the C the methylene peak of adamantane at δ of
13 15
38.52 was used. For the purposes of the C NMR and N NMR analyses, the non-hydrogen
atoms of Compound A155(a) are identified as follows:
N NMR CP/MAS spectra of the product prepared with Compound A155(a) and fumaric acid,
the dihydrochloride-salt of Compound A155(a), and the free base of Compound A155(a) are
shown in Figure 2. Significant differences in the shapes and/or chemical shifts of the N-3 and
N-25 peaks can be noted between the spectrum of the free base of Compound A155(a) and the
dihydrochloride-salt of Compound A155(a), which differences are believed to be attributable to
the ionic nature of the salt formed with each of these nitrogen atoms in the dihydrochloride-salt.
In contrast, the shapes and/or chemical shifts of the N-3 and N-25 peaks in the spectra of the
free base of Compound A155(a) and the product prepared with Compound A155(a) and
fumaric acid are far more similar, the chemical shifts differing by only less than about 12ppm.
It is believed that its co-crystalline nature is demonstrated by the lack of significant ionization
of the N-3 and N-25 nitrogen atoms in the product prepared with Compound A155(a) and
fumaric acid.
A C NMR CP/MAS spectrum of the product prepared with Compound A155(a) and fumaric
acid is shown in Figure 3. The chemical shifts in this spectrum are clearly different from the
chemical shifts of the free base of Compound A155(a) (not shown). Additionally, new peaks
(at about 171.5, 170.3 and/or 135.6ppm) attributable to the presence of fumarate co-crystal are
evident which differ from peaks of fumaric acid in its free form; these new peaks are denoted
by the five-pointed stars in Figure 3 and are believed to be indicative of the co-crystalline
nature of the product.
In one embodiment, the product prepared with Compound A155(a) and fumaric acid has a
melting onset of from about 175°C to about 179°C when measured using DTA at a rate of
°C/min. In another embodiment, the product prepared with Compound A155(a) and fumaric
acid has a melting onset of from about 175.5°C to about 178.5°C when measured using DTA at
a rate of 10°C/min. In another embodiment, the product prepared with Compound A155(a) and
fumaric acid has a melting onset of from about 176°C to about 178°C when measured using
DTA at a rate of 10°C/min. In another embodiment, the product prepared with Compound
A155(a) and fumaric acid has a melting onset of from about 176.4°C to about 177.2°C when
measured using DTA at a rate of 10°C/min. In another embodiment, the product prepared with
Compound A155(a) and fumaric acid has a melting onset of about 176.8 when measured using
DTA at a rate of 10°C/min.
In one embodiment, the product prepared with Compound A155(a) and fumaric acid has a
melting point of from about 181°C to about 185°C when measured using DTA at a rate of
°C/min. In another embodiment, the product prepared with Compound A155(a) and fumaric
acid has a melting point of from about 181.5°C to about 184.5°C when measured using DTA at
a rate of 10°C/min. In another embodiment, the product prepared with Compound A155(a) and
fumaric acid has a melting point of from about 182°C to about 184°C when measured using
DTA at a rate of 10°C/min. In another embodiment, the product prepared with Compound
A155(a) and fumaric acid has a melting point of from about 182.5°C to about 183.3°C when
measured using DTA at a rate of 10°C/min. In another embodiment, the product prepared with
Compound A155(a) and fumaric acid has a melting point of about 182.9°C when measured
using DTA at a rate of 10°C/min.
In one embodiment, the product prepared with Compound A155(a) and fumaric acid has an x-
ray powder diffraction pattern comprising a peak at each of 6.5°, 12.5°, 16.8°, and 25.3° 2θ±
0.2° 2θ when measured using CuKα radiation. In another embodiment, the product prepared
with Compound A155(a) and fumaric acid has an x-ray powder diffraction pattern comprising a
peak at each of 6.5°, 12.5°, 16.8°, 23.2°, 25.3°, and 38.5° 2θ± 0.2° 2θ when measured using
CuKα radiation. In another embodiment, the product prepared with Compound A155(a) and
fumaric acid has an x-ray powder diffraction pattern comprising a peak at each of 6.5°, 8.6°,
12.5°, 14.0°, 16.8°, 18.7°, and 25.3° 2θ± 0.2° 2θ when measured using CuKα radiation. In
another embodiment, the product prepared with Compound A155(a) and fumaric acid has an x-
ray powder diffraction pattern comprising a peak at each of 6.5°, 8.6°, 12.5°, 14.0°, 16.8°,
18.7°, 20.4°, 21.3°, 22.0°, 23.2°, 25.3°, and 38.5° 2θ± 0.2° 2θ when measured using CuKα
radiation.
In one embodiment, the product prepared with Compound A155(a) and fumaric acid has a
CP/MAS C NMR spectrum comprising peaks with a chemical shift of 170.3±0.2ppm,
130.0±0.2ppm, and 72.2±0.2ppm. In another embodiment, the product prepared with
Compound A155(a) and fumaric acid has a CP/MAS C NMR spectrum comprising peaks
with a chemical shift of 171.5±0.2ppm, 170.3±0.2ppm, 130.0±0.2ppm, and 72.2±0.2ppm. In
another embodiment, the product prepared with Compound A155(a) and fumaric acid has a
CP/MAS C NMR spectrum comprising peaks with a chemical shift of 171.5±0.2ppm,
170.3±0.2ppm, 130.0±0.2ppm, 72.2±0.2ppm, and 15.1 ±0.2ppm. In another embodiment, the
product prepared with Compound A155(a) and fumaric acid has a CP/MAS C NMR spectrum
comprising peaks with a chemical shift of 170.3±0.2ppm, 135.6±0.2ppm, and 72.2±0.2ppm. In
another embodiment, the product prepared with Compound A155(a) and fumaric acid has a
CP/MAS C NMR spectrum comprising peaks with a chemical shift of 171.5±0.2ppm,
170.3±0.2ppm, and 135.6±0.2ppm. In another embodiment, the product prepared with
Compound A155(a) and fumaric acid has a CP/MAS C NMR spectrum comprising peaks
with a chemical shift of 171.5±0.2ppm, 170.3±0.2ppm, 135.6±0.2ppm, and 72.2±0.2ppm. In
another embodiment, the product prepared with Compound A155(a) and fumaric acid has a
CP/MAS C NMR spectrum comprising peaks with a chemical shift of 171.5±0.2ppm,
170.3±0.2ppm, 135.6±0.2ppm, 72.2±0.2ppm, and 15.1 ±0.2ppm.
Alternately, 1.0g of the free base of Compound A155(a) in 20mL of MeOH at a temperature of
about 25°C was stirred with a magnetic stirring bar. Then, 1.1 eq. of fumaric acid was added,
the resulting suspension was stirred with a magnetic stirring bar until dissolution appeared
complete, a seed crystal of the product prepared from Compound A155(a) and fumaric acid
was added, and stirring continued while a precipitate formed. Thereafter, the precipitate was
filtrated and dried under reduced pressure to provide a product that, upon PXRD analysis,
yielded substantially the same PXRD results as provided in Figure 1 and Table 4.
.11 Example 11: Combining a Compound of Formula (I) and Hydrochloric Acid
To 0.3 ± 0.1 mL of MeOH in a 4 mL vial also containing molecular sieve drying agent is added
1.1 eq. of concentrated hydrochloric acid. The resulting mixture is stirred with a magnetic
stirring bar for about 1 h. The molecular sieves are filtered off. Thereafter, 20 mg of a
Compound of Formula (I) is added. The resulting slurry is stirred with a magnetic stirring bar
for about 32 h. Thereafter, the slurry is evaporated to dryness using a centrifugal evaporator
(HT-8 Series II, Genevac Inc., Gardiner, NY). The residue product is analyzed by H NMR,
DTA, and PXRD as described in Example 10.
.12 Example 12: Combining a Compound of Formula (I) and Tartaric Acid
To 20 mg of a Compound of Formula (I) in 0.3 ± 0.1 mL of MeOH in a 4 mL vial is added 1.1
eq. of tartaric acid, i.e., 2,3-dihydroxysuccinic acid (Sigma-Aldrich). The resulting slurry is
stirred with a magnetic stirring bar for about 32 h. Thereafter, the slurry is evaporated to
dryness using a centrifugal evaporator (HT-8 Series II, Genevac Inc., Gardiner, NY). The
residue product is analyzed by H NMR, DTA, and PXRD as described in Example 10.
.13 Example 13: Combining a Compound of Formula (I) and Benzenesulfonic
Acid
To 20 mg of a Compound of Formula (I) in 0.3 ± 0.1 mL of MeOH in a 4 mL vial is added 1.1
eq. of benzenesulfonic acid (Sigma-Aldrich). The resulting slurry is stirred with a magnetic
stirring bar for about 32 h. Thereafter, the slurry is evaporated to dryness using a centrifugal
evaporator (HT-8 Series II, Genevac Inc., Gardiner, NY). The residue product is analyzed by
H NMR, DTA, and PXRD as described in Example 10.
.14 Example 14: Combining a Compound of Formula (I) and Toluenesulfonic
Acid
To 20 mg of a Compound of Formula (I) in 0.3 ± 0.1 mL of MeOH in a 4 mL vial is added 1.1
eq. of toluenesulfonic acid, i.e., 4-methylbenzenesulfonic acid (Sigma-Aldrich). The resulting
slurry is stirred with a magnetic stirring bar for about 32 h. Thereafter, the slurry is evaporated
to dryness using a centrifugal evaporator (HT-8 Series II, Genevac Inc., Gardiner, NY). The
residue product is analyzed by H NMR, DTA, and PXRD as described in Example 10.
5.15 Example 15: Binding of Compounds of Formula (I) to TRPV1
Methods for assaying compounds capable of inhibiting TRPV1 are known in the art, for
example, those methods disclosed in U.S. Patent No. 6,239,267 to Duckworth et al., U.S.
Patent No. 6,406,908 to McIntyre et al., or U.S. Patent No. 6,335,180 to Julius et al. The
results of these assays will demonstrate that Compounds of Formula (I) bind to and modulate
the activity of TRPV1.
PROTOCOL 1
Human TRPV1 Cloning:
Human spinal cord RNA (commercially available from Clontech, Palo Alto, CA) is used.
Reverse transcription is conducted on 1.0 μg total RNA using Thermoscript Reverse
Transcriptase (commercially available from Invitrogen, Carlsbad, CA) and oligo dT primers as
detailed in its product description. Reverse transcription reactions are incubated at 55°C for 1
h, heat-inactivated at 85°C for 5 min, and RNase H-treated at 37°C for 20 min.
Human TRPV1 cDNA sequence is obtained by comparison of the human genomic sequence,
prior to annotation, to the published rat sequence. Intron sequences are removed and flanking
exonic sequences are joined to generate the hypothetical human cDNA. Primers flanking the
coding region of human TRPV1 are designed as follows: forward primer
GAAGATCTTCGCTGGTTGCACACTGGGCCACA (SEQ ID NO: 1), and reverse primer
GAAGATCTTCGGGGACAGTGACGGTTGGATGT (SEQ ID NO: 2).
Using these primers, PCR of TRPV1 is performed on one tenth of the Reverse transcription
reaction mixture using Expand Long Template Polymerase and Expand Buffer 2 in a final
volume of 50 µL according to the manufacturer's instructions (Roche Applied Sciences,
Indianapolis, IN). After denaturation at 94°C for 2 min PCR amplification is performed for 25
cycles at 94°C for 15 sec, 58°C for 30 sec, and 68°C for 3 min followed by a final incubation at
72°C for 7 min to complete the amplification. The PCR product of about 2.8 kb is gel-isolated
using a 1.0% agarose, Tris-Acetate gel containing 1.6 μg/mL of crystal violet and purified with
a S.N.A.P. UV-Free Gel Purification Kit (commercially available from Invitrogen). The
TRPV1 PCR product is cloned into the pIND/V5-His-TOPO vector (commercially available
from Invitrogen) according to the manufacturer's instructions to result in the TRPV1-pIND
construct. DNA preparations, restriction enzyme digestions, and preliminary DNA sequencing
are performed according to standard protocols. Full-length sequencing confirms the identity of
the human TRPV1.
Generation of Inducible Cell Lines:
Unless noted otherwise, cell culture reagents are purchased from Life Technologies of
Rockville, MD. HEK293-EcR cells expressing the ecdysone receptor (commercially available
from Invitrogen) are cultured in Growth Medium (Dulbecco's Modified Eagles Medium
containing 10% fetal bovine serum (commercially available from Hyclone, Logan, UT)), lx
penicillin/streptomycin, lx glutamine, 1 mM sodium pyruvate and 400 μg/mL Zeocin
(commercially available from Invitrogen)). The TRPV1-pIND constructs are transfected into
the HEK293-EcR cell line using Fugene transfection reagent (commercially available from
Roche Applied Sciences, Basel, Switzerland). After 48 h, cells are transferred to Selection
Medium (Growth Medium containing 300 μg/mL G418 (commercially available from
Invitrogen)). Approximately 3 weeks later individual Zeocin/G418 resistant colonies are
isolated and expanded. To identify functional clones, multiple colonies are plated into 96-well
plates and expression is induced for 48 h using Selection Medium supplemented with 5 μM
ponasterone A ("PonA") (commercially available from Invitrogen). On the day of assay, cells
are loaded with Fluo-4 (a calcium-sensitive dye that is commercially available from Molecular
Probes, Eugene, OR) and CAP-mediated calcium influx is measured using a Fluorescence
Imaging Plate Reader ("FLIPR") as described below. Functional clones are re-assayed,
expanded, and cryopreserved.
pH-Based Assay:
Two days prior to performing this assay, cells are seeded on poly-D-lysine-coated 96-well
clear-bottom black plates (commercially available from Becton-Dickinson) at 75,000 cells/well
in growth media containing 5 μM PonA (commercially available from Invitrogen) to induce
expression of TRPV1. On the day of the assay, the plates are washed with 0.2 mL 1x Hank's
Balanced Salt Solution (commercially available from Life Technologies) containing 1.6 mM
CaCl and 20 mM HEPES, pH 7.4 ("wash buffer"), and loaded using 0.1 mL of wash buffer
containing Fluo-4 (3 μM final concentration, commercially available from Molecular Probes).
After 1 h, the cells are washed twice with 0.2 mL wash buffer and resuspended in 0.05 mL 1x
Hank's Balanced Salt Solution (commercially available from Life Technologies) containing 3.5
mM CaCl and 10 mM Citrate, pH 7.4 ("assay buffer"). Plates are then transferred to a FLIPR
for assay. The test compound is diluted in assay buffer, and 50 μL of the resultant solution is
added to the cell plates and the solution is monitored for two minutes. The final concentration
of the test compound is adjusted to range from about 50 picoM to about 3 μM. Agonist buffer
(wash buffer titrated with 1N HCl to provide a solution having a pH of 5.5 when mixed 1:1
with assay buffer) (0.1 mL) is then added to each well, and the plates are incubated for 1
additional minute. Data are collected over the entire time course and analyzed using Excel and
Graph Pad Prism to determine the IC .
Capsaicin-Based Assay:
Two days prior to performing this assay, cells are seeded in poly-D-lysine-coated 96-well clear-
bottom black plates (50,000 cells/well) in growth media containing 5 μM PonA (commercially
available from Invitrogen) to induce expression of TRPV1. On the day of the assay, the plates
are washed with 0.2 mL 1x Hank's Balanced Salt Solution (commercially available from Life
Technologies) containing 1 mM CaCl and 20 mM HEPES, pH 7.4, and cells are loaded using
0.1 mL of wash buffer containing Fluo-4 (3 μM final). After one hour, the cells are washed
twice with 0.2 mL of wash buffer and resuspended in 0.1 mL of wash buffer. The plates are
transferred to a FLIPR for assay. 50 µL of test compound diluted with assay buffer (1x Hank's
Balanced Salt Solution containing 1 mM CaCl and 20 mM HEPES, pH 7.4) are added to the
cell plates and incubated for 2 min. The final concentration of the compound is adjusted to
range from about 50 picoM to about 3 μM. Human TRPV1 is activated by the addition of 50
µL of capsaicin (400 nM), and the plates are incubated for an additional 3 min. Data are
collected over the entire time course and analyzed using Excel and GraphPad Prism to
determine the IC .
PROTOCOL 2
For Protocol 2, a Chinese Hamster Ovary cell line (CHO) that has been engineered to
constitutively express human recombinant TRPV1 was used (TRPV1/CHO cells). The
TRPV1/CHO cell line was generated as described below.
Human TRPV1 Cloning:
A cDNA for the human TRPV1 receptor (hTRPV1) was amplified by PCR (KOD-Plus DNA
polymerase, ToYoBo, Japan) from a human brain cDNA library (BioChain) using primers
designed surrounding the complete hTRPV1 open reading frame (forward
'-GGATCCAGCAAGGATGAAGAAATGG (SEQ ID NO: 3) and reverse
5'-TGTCTGCGTGACGTCCTCACTTCT (SEQ ID NO: 4)). The resulting PCR products were
purified from agarose gels using Gel Band Purification Kit (GE Healthcare Bioscience) and
were subcloned into pCR-Blunt vector (Invitrogen). The cloned cDNA was fully sequenced
using a fluorescent dye-terminator reagent (BigDye Terminator ver3.1 Cycle Sequencing Kit,
Applied Biosystems) and ABI Prism 3100 genetic analyzer (Applied Biosystems). The pCR-
Blunt vector containing the hTRPV1 cDNA was subjected to restriction digestion with EcoR1.
The restriction fragment was subcloned into expression vector pcDNA3.1(-) (Invitrogen) and
named pcDNA3.1(-)-hVR1 plasmid. The sequence of the cDNA encoding TRPV1 is available
at GenBank accession number AJ277028.
Generation of the TRPV1/CHO Cell Line:
CHO-K1 cells were maintained in growth medium consisting of -MEM, 10% FBS (Hyclone),
and 100 IU/mL of penicillin - 100 µg/mL of streptomycin mixed solution (Nacalai Tesque,
Japan) at 37 C in an environment of humidified 95% air and 5% CO . The cells were
transfected with the pcDNA3.1(-)-hVR1 plasmid using FuGENE6 (Roche) according to the
manufacturer's protocol. 24 hr after transfection, neomycin-resistant cells were selected using 1
mg/mL G418 (Nacalai Tesque). After 2 weeks, individual colonies were picked, expanded,
and screened for the expression of hTRPV1 in the capsaicin-induced Ca influx assay (see
below) with a FLIPR (Molecular Devices). A clone with the largest Ca response to capsaicin
was selected and re-cloned by the same procedure. The cells expressing hTRPV1 were
cultured in the growth medium supplemented with 1 mg/mL G418. Approximately 1 month
later, stable expression of functional TRPV1 receptors in the selected cell line was confirmed
by validating Ca responses with or without capsazepine (Sigma, at 1 nM-10 µM) in capsaicin
assay.
Capsaicin-Induced Ca Influx Assay For Cell Selection:
The following assay was performed to identify cells with hTRPV1 expression. CHO-K1 cells
transfected with pcDNA3.1(-)-hVR1 plasmid were seeded in 384-well black-wall clear-bottom
plates (Corning) and cultivated in growth medium (see above) for 1 day. On the day of the
experiment, culture medium was exchanged to assay buffer (20 mM HEPES, 137 mM NaCl,
2.7 mM KCl, 0.9 mM MgCl , 5.0 mM CaCl , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.4)
containing 4 µM FluoAM (Dojin, Japan). After the incubation at 37 C for 1 hr, each well
was washed 3 times with assay buffer using an EMBLA 384 plate washer (Molecular Devices)
and refilled with assay buffer. The plates were incubated at a temperature of about 25°C for 10
min. Subsequently, the plates were inserted into a FLIPR, and 1.5 µM capsaicin (Sigma)
solution prepared in assay buffer was added to each well (final concentration was 500 nM).
Cellular responses were monitored for 5 min.
Cell Culture:
1. Cell Culture Media
1. Alpha-MEM (Gibco, CAT: 12561-056, LOT: 1285752): 450 mL.
2. Fetal Bovine Serum (FBS), heat inactivated (Gibco, CAT: 16140-071, LOT: 1276457): 50
3. HEPES Buffer Solution, 1M stock (Gibco, CAT: 15630-080): 10 mL (final 20 mM).
4. Geneticin, 50mg/mL stock (Gibco, CAT: 10135-035): 10 mL (final 1 mg/mL).
5. Antimicotic Antibiotic Mixed Solution, 100× stock (Nacalai Tesque, CAT: 02892-54): 5
Components 1-5 above were combined at the indicated amounts and stored at 4°C. The cell
culture media were brought to about 37°C before use. Optionally, component 5 can be
replaced by penicillin-streptomycin solution (for example, Gibco 15140-122 or Sigma P-0781).
2. Thawing the cells
TRPV1/CHO cells were frozen in CELLBANKER (Juji-Field, Inc., Japan, CAT: BLC-1)
and stored at -80°C. Optimized cryopreservation solution containing dimethyl sulfoxide and
FBS was used.
Vials containing the TRPV1/CHO cells were stored at -80°C. After removal from -80°C, the
vial was immediately transferred to a 37°C water bath to thaw for ca. 1-2 minutes. Once
completely thawed, the contents of the vial (1 mL/vial) was transferred to a sterile 15 mL test
tube and 9 mL warm culture media were slowly added. The test tube was subsequently
centrifuged at 1000 rpm for 4 min at a temperature of about 25°C. The supernatant was
removed and the pellet resuspended in 10 mL of culture media. The cell suspension was
transferred to a sterile 75 cm plastic flask and incubated at humidified 5% CO /95% air at
37°C. To monitor viability, the cells were visually inspected and/or counted, beginning at
approximately 1 hr after incubation.
3. Passaging the Cells
The cells in a flask were close to confluence at the time of passaging. Cell culture media were
removed from the culture flask and 10 mL of sterile PBS(-) added and the flask gently shaken.
The PBS was removed from the flask and 2 mL of trypsin/EDTA solution (0.05% trypsin with
EDTA-4Na; Gibco, CAT: 25300-054) was added and the flask gently shaken. The flask was
incubated at 37°C for about 2 min. 8 mL cell culture media were subsequently added to the
flask and the flask shaken to ensure that all cells were in solution. The cell suspension was
then transferred to a sterile 15 mL or 50 mL plastic tube, centrifuged at 1,000 rpm for 4 min at
a temperature of about 25°C. The supernatant was removed and the pellet resuspended in ca. 5
mL of culture media. The cell count was measured using the Burker-Turk hemocytometer.
The cells were seeded into a sterile 75 cm plastic flask in ca. 0.8 x 10 cells/mL for 72 hr and
incubated in humidified 5% CO /95% air at 37°C.
4. Freezing the cells
The procedure up to the measurement of the cell count was the same as in the Section entitled
"Passaging the Cells" above. Subsequently, the cell suspension was centrifuged at 1,000 rpm
for 4 min at a temperature of about 25°C. The supernatant was removed and the pellet
TM 5
resuspended in CELLBANKER solution to get a final concentration of from 5 x 10 to 5 x
cells/mL. The cell suspension was transferred into appropriately labeled 1 mL cryovials
and then placed into the -80°C freezer.
pH-Based Assay:
The following assay was conducted to determine the concentration of sulfuric acid that would
give rise to a pH that induces a Ca response optimal to test compounds for their effect on
TRPV1.
1. Cells
TRPV1/CHO cells were seeded in the 96-well clear-bottom black-wall plate (Nunc) at densities
of 1-2 x 10 cells/well and grown in 100 µL of culture medium (alpha-MEM supplemented
with 10 % FBS, 20 mM HEPES, 1 mg/mL geneticin and 1 % antibiotic-antimycotic mixed
stock solution) for 1-2 days before the experiment.
2. Determination of pH Sensitivity and Agonist Dose
2.1. Agonist Solution
Seven different agonist solutions with sulfuric acid concentrations of 15.0, 15.5, 16.0, 16.5,
17.0, 17.5, and 18.0 mM were prepared by diluting 1M sulfuric acid with measuring buffer
(see, e.g., Figure 1 of U.S. Patent Application Publication No. US 2009/0170868 A1). The
different sulfuric acid concentrations in the agonist solutions were selected such that a 1:4
dilution would result in a final sulfuric acid concentration of 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, and
3.6 mM, denoted "B" through "H" respectively. Buffer without sulfuric acid, denoted "A", was
also used.
2.2. Assay
pH dependent Ca responses in TRPV1/CHO cells cultured in a 96-well plate were determined
(see, e.g., Figure 2 of U.S. Patent Application Publication No. US 2009/0170868 A1). In
particular, Ca influx into TRPV1/CHO cells in response to low pH as measured by Fura-2
AM fluorescence was determined. The cells were stimulated using 3.0 mM (well numbers B1-
B6), 3.1 mM (C1-C6), 3.2 mM (D1-D6), 3.3 mM (E1-E6), 3.4 mM (F1-F6), 3.5 mM (G1-
G6), or 3.6 mM (H1-H6) H SO or pH 7.2 measuring buffer without H SO (A1-A6).
2 4 2 4
(1) Culture medium was removed using an 8-channel-pipette (Rainin, USA) from the 96-well
plate and the wells were refilled with 100 µL of loading buffer (20 mM HEPES, 115 mM NaCl,
.4 mM KCl, 0.8 mM MgCl , 1.8 mM CaCl , 13.8 mM D-glucose, 2.5mM probenecid, pH 7.4)
containing 5 µM Fura-2 AM (Dojin, Japan).
(2) The 96-well plate was incubated at 37°C for 45 min.
(3) The loading buffer was removed from each well. The cells were subsequently washed
twice with 150 µL of measuring buffer (20 mM HEPES, 115 mM NaCl, 5.4 mM KCl, 0.8 mM
MgCl , 5.0 mM CaCl , 13.8 mM D-glucose, 0.1 % BSA, pH 7.4) (no probenecid). The wells
were then refilled with 80 µL of measuring buffer.
(4) After an incubation at 4°C for 15 min, the 96-well plate was transferred to a model FDSS-
3000 plate reader apparatus (Hamamatsu Photonics K.K., Japan).
(5) The Fura-2 fluorescent intensity was monitored at a wavelength of 340 nm and at 380 nm,
respectively, at a rate of 0.5Hz for a total of 240 seconds. After 16 time points (32 sec) of
baseline detection, 20 µL of agonist solution was added to each well. The final volume was
100 µL/well.
(6) Fluorescence intensity ratio refers to the fluorescence intensity at 340 nm over the
fluorescence intensity at 380 nm at a particular time point. The baseline was set as the average
of the fluorescent intensity ratios for the first 16 time points before the addition of agonist
solution. The maximum response was the highest fluorescent intensity ratio during the 60 time
points following addition of agonist solution.
(7) Maximal signal ratios from each well were calculated as output data using the FDSS-3000
analysis program. Data were analyzed using Excel (Microsoft) and XLfit (idbs) software.
2.3. pH Determination
After the observation of Ca responses, the buffer of each lane of the 96-well plate (50
µL/well, 8-20 wells/plate) was collected well by well and the pH values were measured using a
portable pH meter (Shindengen, Japan).
The Ca responses in lanes D and E were intermediate and therefore optimal for testing the
effects of compounds on the TRPV1 calcium channel (see, e.g., Figure 2 of U.S. Patent
Application Publication No. US 2009/0170868 A1). The final sulfuric acid concentrations in
the wells of these lanes were 3.2 mM and 3.3 mM, respectively. These final sulfuric acid
concentrations were obtained using agonist solutions with 16.0 mM and 16.5 mM sulfuric acid
concentrations, respectively (lanes D and E). The pH obtained using these sulfuric acid
concentrations was from about 5.0 to about 5.1.
Thus, agonist solutions with 16.0 mM and 16.5 mM sulfuric acid concentrations, respectively
(lanes D and E), were selected for the experiments described below in Section 3.
3. pH Assay
3.1. Agonist
In an "agonist plate," two different agonist solutions with different H SO concentrations were
used for the pH assay (see, e.g., Figure 3A of U.S. Patent Application Publication No. US
2009/0170868 A1). For the first half of a 96-well plate one agonist solution was used; for the
second half the other agonist solution was used. The agonist solutions were obtained by
diluting sulfuric acid (1M H SO ) with measuring buffer. The concentrations for the two
agonist solutions were determined as described above in Section 2 of Protocol 2.
The sulfuric acid concentrations between the two agonist solutions differed by 0.5 mM. In the
experiment described in Section 2 of Protocol 2, the sulfuric acid concentrations in the agonist
solutions were determined to be 16 mM and 16.5 mM, respectively. After 1:4 dilution of the
agonist solutions, the final sulfuric acid concentration was 3.2 mM and 3.3 mM, respectively.
The resulting pH value for the pH assay was 5.0 to 5.1.
3.2. Test Compounds
Test compounds were dissolved in DMSO to yield 1 mM stock solutions. The stock solutions
were further diluted using DMSO in 1:3 serial dilution steps with 6 points (1000, 250, 62.5,
.625, 3.9062, and 0.977 µM). The thereby-obtained solutions were further diluted in
measuring buffer (1:100) as 10× stock serial dilutions with a DMSO concentration of 1%. 10
µL of a 10x stock was added into each well of an "antagonist plate" (see step 3.3.(4) below).
Thus, the final concentrations of antagonists was as follows: 0.977, 3.906, 15.63, 62.5, 250,
and 1000 nM containing 0.1% DMSO (see, e.g., Figure 3B of U.S. Patent Application
Publication No. US 2009/0170868 A1).
3.3. Assay
Steps (1) and (2) of this Assay were the same as steps 2.2.(1) and 2.2.(2), respectively, of
Protocol 2.
(3) The cells were washed twice with 150 µL of measuring buffer (mentioned in step 2.2.(3) of
Protocol 2, no probenecid). The wells were subsequently refilled with 70 µL of measuring
buffer.
(4) Either 10 µL of measuring buffer or 10 µL of 10× stock serial dilution of test compound
(described in step 3.2. above) were applied to each well. Usually, only one test compound was
tested per 96-well plate. The number of replicates per 96-well plate for a particular antagonist
at a particular concentration was 2 x 7 since, as described for the "agonist plate," two different
sulfuric acid concentrations were used per 96-well plate and seven lanes (A-C, E-H) per 96-
well plate were used (N = 2 × 7).
Step (5) was the same as step 2.2.(4) above.
(6) Fura-2 fluorescent intensity was monitored as described in step 2.2.(5) above. After 16 time
points of baseline detection, 20 µL of agonist solution (measuring buffer titrated with H SO to
yield a pH in the range of from about 5.0 to about 5.1 when mixed 1:4 with the measuring
buffer containing test compound) was added to each well (final volume 100 µL/well).
Steps (7) and (8) were as described in steps 2.2.(6) and 2.2.(7) above, respectively.
3.4. pH check
(1) The pH values of the buffer in the wells of A1 through H1 and A7 through H7 were
measured one by one using a portable pH meter.
(2) When a well was confirmed as having a pH of from about 5.0 to about 5.1, the next
five wells to its right (e.g., for well B1, wells B2 through B6) were checked one after another.
(3) For IC calculation, only the data from wells with pH values of 5.0-5.1 were used.
The number of wells tested for their pH varied among plates (from about 16 to 60
wells/plate). The number depended on the results of step 3.4.(1) above and the Ca responses.
Capsaicin-Based Assay:
One day prior to assay, TRPV1/CHO cells were seeded in 96-well clear-bottom black plates
(20,000 cells/well) in growth media. On the day of the experiment, the cells were washed with
0.2 mL 1x Hank's Balanced Salt Solution (Life Technologies) containing 1.6 mM CaCl and 20
mM HEPES, pH 7.4 ("wash buffer"). Subsequently, the cells were loaded by incubation in 0.1
mL of wash buffer containing Fluo-4 at 3 µM final concentration. After 1 hour, the cells were
washed twice with 0.2 mL wash buffer and resuspended in 0.1 mL wash buffer. The plates
were then transferred to a Fluorescence Imaging Plate Reader (Molecular Devices).
Fluorescence intensity was monitored for 15 seconds to establish a baseline. Subsequently, test
compounds diluted in assay buffer (1x Hank's Balanced Salt Solution containing 1 mM CaCl
and 20 mM HEPES, pH 7.4) containing 1% DMSO were added to the cell plate and
fluorescence was monitored for 2 minutes. The final concentration of the compound was
adjusted to range from 100 µM to 1.5625 µM. If the test compound was an especially potent
antagonist, the final concentration of the compound was adjusted to range from 10 µM to
1.5625 nM. Human TRPV1 was then activated by the addition of 50 µL capsaicin (100 nM
final concentration) and plates incubated for an additional 3 min. Data were collected over the
entire time course and analyzed using Excel and the curve-fitting formula GraphPad Prism.
The results of the assays of Protocol 2 are shown in Table 6.
Human TRPV1 Heat-Based Assay:
CHO cells stably expressing human TRPV1 (hTRPV1) were used. Functional assessment of
heat-induced activation of hTRPV1 was carried out in a cell-based Ca flux assay using
ABI7500 Fast Real-Time PCR System as described in Reubish et al., "Functional assessment
of temperature-gated ion-channel activity using a real-time PCR machine,"
www.BioTechniques.com 47(3):iii-ix (2009), which is hereby incorporated by reference.
Briefly, hTRPV1/CHO cells were cultured in growth media in a tissue culture dish at 37°C in a
CO incubator. On the day of the assay, culture media were removed and the cells were then
detached using 0.05% trypsin at 37°C with 5% CO , for 90 s. The detached cells were
centrifuged (1000 rpm, 4 min) to remove trypsin-containing supernatant and resuspended in
assay buffer (115 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl ・6H O, 1.8 mM CaCl ・2H O, 13.8
2 2 2 2
mM D-glucose, and 20 mM HEPES). Then, the cells were loaded with 5 M Fluo-4, a Ca
reporter dye, in the presence of 2.5 mM probenecid at 37°C with 5% CO , for 45 min.
Thereafter, the cells were washed twice with measuring buffer (assay buffer supplemented with
0.1% BSA and 3.2 mM CaCl ) then transferred to a Fast 96-well Reaction Plate (0.1 mL) (Part
no. 4346907, MICROAMP, Applied Biosystems, Foster City, CA). The cell density was
100,000 cells/24 µL/well. A solution of the compound under test (6 μL/well) was added into
each well of the 96-well plate. Thus, the reaction volume per well was 30 µL.
The plates were then placed inside an ABI7500 Fast Real-Time PCR instrument (Applied
Biosystems) to read fluorescence at different temperatures using 7500 software, version 2.0.2
(Applied Biosystems). The initial temperature was set at 25°C for 1 min. followed by a
temperature ramp to 45°C in 100 s to deliver heat to cells. [Ca ] response of hTRPV1/CHO
cells to heat was determined as:
[fluorescence read at 45°C - fluorescence read at 25°C].
Compound concentration response curves and IC values were analyzed using GraphPad Prism
4 software (GraphPad Software, La Jolla, CA).
The IC data provided in Table 6 are shown as mean ± standard error of the mean; the number
of trials conducted for each assay is shown in parentheses except for only a single trial where
no number of trials is shown in parentheses. The results in Table 6 demonstrate that many
Compounds of Formulae (I) and/or (II) are potent TRPV1 antagonists.
Table 6: TRPV1 IC Potency
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
A122(a) 177 ± 69 (3) 98 ± 27 (2)
A122(b) 444 ± 79 (3) 670 ± 94 (2)
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
A122(c) 178 ± 29 (3) 553 ± 12 (2)
A122(e) 80.6 ± 7.5 (3) 5.8 ± 0.7 (2) 96.0 ± 2.4 (2)
A123(e) 11.5 ± 1.4 (3) 0.4 ± 0.0 (2)
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
A125(b) 112 ± 32 (3) 81 ± 13 (3) 389 ± 83 (3)
A125(e) 23.9 ± 3.8 (3) 0.6 ± 0.2 (2) 18.4 ± 0.8 (2)
A126(a) 40.2 ± 11.0 (4) 12.2 ± 5.9 (2)
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
A126(e) 18.2 ± 2.9 (3) 0.4 ± 0.0 (3)
A155(a) 96 ± 18 (4) 700 (2)
A155(b) 216 ± 57 (3) 134 ± 16 (4)
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
A155(d) 168 ± 42 (3)
A155(e) 16.5 ± 4.2 (4)
A158(a) 62.4 ± 13.8 (3) 17.1
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
B122(j) 586 ± 78 (3) 1723
B122(k) 502 ± 128 (3) 2045 ± 245 (2)
B122(o) 199 ± 38 (3) 6881
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
B122(p) 506 ± 155 (3) 1016
B125(j) 194 ± 49 (3) 303
B125(k) 186 ± 16 (3) 415
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
B125(o) 309 ± 105 (3) 398 ± 152 (2)
B125(p) 171 ± 1 (3) 211 ± 50 (2)
B155(h) 107 ± 20 (4)
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
B155(j) 344 ± 116 (3) 439 ± 71 (2)
B155(o) 249 ± 34 (3) 1233 ± 595 (2)
B158(j) 49 ± 10 (3) 136 ± 20 (3)
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
B158(o) 146 ± 52 (3) 171 ± 29 (2)
C4(r) 42.8 ± 2.0 (3) 17.4 ± 1.2 (2) 87 ± 13 (2)
C123(r) 26.9 ± 3.6 (3) 20.6 ± 2.6 (4) 96 ± 14 (2)
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
C125(r) 99 ± 24 (3) 69 ± 3 (2) 335 ± 40 (2)
C126(r) 71 ± 20 (3) 67 ± 12 (2) 155 ± 25 (2)
C170(r) 89 ± 34 (3) 32.8 ± 8.1 (3) 170 ± 20 (2)
Human Heat
Human Capsaicin Human pH CHO
Compound # CHO (hpH-CHO) Structure
(hHeat-CHO)
(hCAP-CHO) (nM) (nM)
(nM)
AE 68 ± 17 (4) 40.8 ± 3.2 (3) 101.5 ± 0.8 (2)
BB 63.7 ± 13.4 (3) 490
.16 Example 16: In Vivo Assays for Prevention or Treatment of Pain
Test Animals: Each experiment uses rats weighing between 200-260g at the start of the
experiment. The rats are group-housed and have free access to food and water at all times,
except prior to oral administration of a Compound of Formula (I) when food is removed for 16
hours before dosing. A control group acts as a comparison to rats treated with a Compound of
Formula (I). The control group is administered the vehicle for the Compound of Formula (I).
The volume of vehicle administered to the control group is the same as the volume of carrier
and Compound of Formula (I) administered to the test group.
Acute Pain: To assess the actions of a Compound of Formula (I) for the treatment or
prevention of acute pain, the rat tail flick test can be used. Rats are gently restrained by hand
and the tail exposed to a focused beam of radiant heat at a point 5 cm from the tip using a tail
flick unit (Model 7360, commercially available from Ugo Basile of Italy). Tail flick latencies
are defined as the interval between the onset of the thermal stimulus and the flick of the tail.
Animals not responding within 20 seconds are removed from the tail flick unit and assigned a
withdrawal latency of 20 seconds. Tail flick latencies are measured immediately before (pre-
treatment) and 1, 3, and 5 hours following administration of a Compound of Formula (I). Data
are expressed as tail flick latency(s) and the percentage of the maximal possible effect (%
MPE), i.e., 20 seconds, is calculated as follows:
[ (post-administration latency) - (pre-administration latency) ]
% MPE = x 100
(20 s pre-administration latency)
The rat tail flick test is described in D'Amour et al., "A Method for Determining Loss of Pain
Sensation," J. Pharmacol. Exp. Ther. 72:74-79 (1941).
Inflammatory Pain: To assess the actions of a Compound of Formula (I) for the treatment or
prevention of inflammatory pain, the Freund's complete adjuvant ("FCA") model of
inflammatory pain was used. FCA-induced inflammation of the rat hind paw is associated with
the development of persistent inflammatory mechanical hyperalgesia and provides reliable
prediction of the anti-hyperalgesic action of clinically useful analgesic drugs (Bartho et al.,
"Involvement of capsaicin-sensitive neurons in hyperalgesia and enhanced opioid
antinociception in inflammation," Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-
670 (1990)). The right hind paw of each male, 6-week old Jcl:SD rat was administered a 50 μL
intraplantar injection of 50% FCA (Sigma-Aldrich). 24 hour post-injection, the animal was
assessed for response to noxious mechanical stimuli by determining the PWT, as described
below. Rats were then administered a single injection of 0.1, 0.3, 1, 3, or 10 mg/kg of either
the product prepared with Compound A155(a) and fumaric acid as described in Example 10, 20
mg/kg of an ibuprofen control (EMD Millipore Chemicals, Inc.), or vehicle as a control (0.5%
weight/volume methylcellulose (400cP, Wako Pure Chemical Industries, Ltd., Osaka,
Japan)/aqueous solution). An amount of fumaric acid (AK Scientific) comparable to that
present with the product prepared with Compound A155(a) and fumaric acid as described in
Example 10 was also present in each control. Responses to noxious mechanical stimuli were
then determined 1, 3, 5, and 7 hours post-administration. Percentage reversal of hyperalgesia
for each animal was defined as:
[ (post-administration PWT) - (pre-administration PWT) ]
% Reversal = x 100
[ (baseline PWT) - (pre-administration PWT) ]
With the exception of the controls (i.e., ibuprofen, vehicle) where the student's t-test was used,
Dunnett's test was conducted for the % reversal. In either instance, values with p < 0.05 were
considered to be statistically significant. The % reversal results for administration of the
product prepared with Compound A155(a) and fumaric acid as described in Example 10 and
the respective controls are presented in Table 7.
Table 7: Inflammatory Pain Relief after Administration of the Product Prepared with
Compound A155(a) and Fumaric Acid as Described in Example 10
% Reversal [mean]
Example 10 Product Comprising Compound A155(a) Ibuprofen Vehicle
Time after
Adminis-
0.1mg/kg 0.3mg/kg 1mg/kg 3mg/kg 10mg/kg 20mg/kg 2mL/kg
tration
(hours)
Pre-
adminis- 0 0 0 0 0 0 0
tration
1 31.9** 65.0** 79.4** 80.3** 102.5** 28.6 -2.0
3 37.8** 60.2** 84.1** 87.9** 94.1** 41.5 -2.2
31.3** 54.1** 78.2** 86.6** 97.3** 39.2 2.3
7 23.6** 39.4** 70.5** 97.3** 93.1** 32.5 1.1
** indicates p < 0.01 (Dunnett's test), indicates p < 0.01 (student's t-test).
As demonstrated by the results in Table 7, assessments of the actions of the Compounds of
Formula (I) revealed that these compounds were efficacious, e.g., the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 significantly reduced FCA-
induced inflammation, with ED values of from about 0.2 mg/kg to about 0.4 mg/kg and
maximum % reversal values of from about 24% to about 100%. For example, the % reversal of
FCA-induced inflammation after administration of a 3mg/kg dose of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 was about 80% or above, i.e.,
80.3% at 1 hour after administration, 87.9% at 3 hours after administration, 86.6% at 5 hours
after administration, and 97.3% at 7 hours after administration of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10.
Even at the minimal effective dose of 0.1mg/kg of the product prepared with Compound
A155(a) and fumaric acid as described in Example 10, the % reversal of FCA-induced
inflammation was about 24% or above, i.e., 31.9% at 1 hour after administration, 37.8% at 3
hours after administration, 31.3% at 5 hours after administration, and 23.6% at 7 hours after
administration of the product prepared with Compound A155(a) and fumaric acid as described
in Example 10. In contrast, a 20mg/kg dose of ibuprofen was far less effective than a 0.3mg/kg
dose of the product prepared with Compound A155(a) and fumaric acid as described in
Example 10 at each time-point tested, i.e., 28.6% versus 65.0% respectively at 1 hour after
administration, 41.5% versus 60.2% respectively at 3 hours after administration, 39.2% versus
54.1% respectively at 5 hours after administration, and 32.5% versus 39.4% respectively at 7
hours after administration. In making this comparison, it should be noted that the dose of
ibuprofen administered, 20mg/kg, was over 66 times greater than the dose of the product
prepared with Compound A155(a) and fumaric acid as described in Example 10, 0.3mg/kg.
Osteoarthritis Pain: To assess the actions of a Compound of Formula (I) for the treatment or
prevention of osteoarthritis pain, the rat monosodium iodo-acetate (MIA, i.e., sodium 2-
iodoacetate) induced osteoarthritis model was used. Intra-articular injection of MIA causes
joint degeneration characterized by osteolysis and swelling, with displacement of the patella,
and reductions in bone mineral content and bone mineral density (Pomonis et al.,
"Development and pharmacological characterization of a rat model of osteoarthritis pain," Pain
114: 339-346 (2005)). Under isoflurane anaesthesia, an intra-articular injection of 2mg of MIA
(Sigma-Aldrich) in 50μl of saline was administered through the infrapatellar ligament of the
knee joint of the right hind leg of the male, 6 week old Crl:CD(SD) rats. Control rats received
an intra-articular injection of 50μl of saline into the knee joint of the right hind leg. The left
knee joint of all rats was untreated. Two weeks after MIA injection, rats were assessed for
osteoarthritis pain related-behaviors immediately prior to and 1, 3, 5, 7, and 24 hours after oral
drug-in-vehicle administration (for day 1) by determining their weight-bearing capabilities, via
the weight bearing difference (WBD) test, and their gripping capabilites, via the grip force test,
each as described below. Thus, in the assessment for osteoarthritis pain relief through gripping
capability determinations, the 24 hour time point was the start of the next day when drug-in-
vehicle was again orally administered (24 hours after the prior adminsitration) for certain
dosages. On days 2, 3, and 4, gripping capability response was determined 3 and 24 hours
thereafter.
Additionally, 3mg/kg of celecoxib (BioVision Inc., Milpitas, CA), a highly selective COX-2
inhibitor accepted for relief of inflammation and pain, in vehicle and the vehicle alone (0.5%
weight/volume methylcellulose (400cP, Wako Pure Chemical Industries, Ltd.)/aqueous
solution) were orally administered as controls. An amount of fumaric acid comparable to that
present with the product prepared with Compound A155(a) and fumaric acid as described in
Example 10 was also present in each control.
Weight Bearing Difference Test as an Assessment of Osteoarthritis Related Pain: The weight
bearing difference test provides an accepted assessment of the efficacy of clinically useful
analgesic drugs with respect of osteoarthritis related pain (see Pomonis et al. (2005)). WBD
was assessed using a Linton Incapacitance Tester (Linton Instrumentation, Norfolk, UK). Rats
were placed on the apparatus so that they were standing on their hind legs, and allowed to
acclimate to the apparatus. When stationary, the weight born on each leg was measured over a
3s period. Three readings were taken for each rat at each time point; the average of the three
readings was used for data analysis. WBD was expressed as "%WR", i.e., the percentage of
weight born on the MIA-injected right hind leg, using the following formula:
%WR = x 100
(WR + WL)
where WR is the weight on the right hind leg and WL is the weight on the left (untreated) hind
leg. The 50% value of %WR corresponds to an equal weight distribution across both hind legs.
The "%WRR", i.e., the percentage reversal of the %WR impediment occurring post-MIA
injection, was determined for each dosage at each time point using the following formula:
[ (%WR) - (%WR) ]
Post-Drug Pre-Drug
%WRR = x 100
[ (%WR) - (%WR) ]
Control Rat Pre-Drug
where (%WR) is the %WR determined at each post-oral-administration time-point for
Post-Drug
each dose of each administered substance, (%WR) is the %WR determined pre-oral-
Pre-Drug
administration of each administered substance, and (%WR) is the %WR determined for
Control Rat
control rats (receiving the saline injection into the right hind leg knee joint). With the
exception of the controls (i.e., celecoxib, vehicle) where the student's t-test was used, Dunnett's
test was conducted for the %WRR. In either instance, values with p < 0.05 were considered to
be statistically significant. The %WRR results for administration of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 are presented in Table 8.
Table 8: Osteoarthritis Pain Relief after Administration of the Product Prepared with
Compound A155(a) and Fumaric Acid as Described in Example 10
as Assessed by the Weight Bearing Difference Test
%WRR [mean]
Example 10 Product Comprising Compound A155(a) Celecoxib Vehicle
Time after
Adminis-
0.3mg/kg 1mg/kg 3mg/kg 10mg/kg 20mg/kg 3mg/kg 2mL/kg
tration
(hours)
Pre-
adminis- 0 0 0 0 0 0 0
tration
1 4.3 15.2 20.9** 33.3** 41.9** 10.2 3.4
3 12.5 28.8** 34.5** 44.1** 56.9** 27.8 -0.2
7.1 16.1** 23.4** 35.0** 46.9** 14.1 -2.7
7 5.0 8.8* 9.5* 22.8** 35.6** 6.0 -4.4
24 0 2.1 3.7 9.8 19.8** 2.0 -1.2
* indicates p < 0.05 (Dunnett's test), ** indicates p < 0.01 (Dunnett's test),
† ††
indicates p < 0.05 (student's t-test), indicates p < 0.01 (student's t-test).
As demonstrated by the results in Table 8, assessments of the actions of the Compounds of
Formula (I) revealed that these compounds were efficacious, e.g., the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 significantly reduced
osteoarthritis pain, as determined by WBD, with maximum % reversal values of from about
8.8% to about 56.9%. For example, the % reversal of osteoarthritis pain after administration of
a 20mg/kg dose of the product prepared with Compound A155(a) and fumaric acid as described
in Example 10 was about 20% or above, i.e., 41.9% at 1 hour after administration, 56.9% at 3
hours after administration, 46.9% at 5 hours after administration, 35.6% at 7 hours after
administration, and even 19.8% at 24 hours after administration of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10.
Even at the minimal effective dose of 1mg/kg of the product prepared with Compound A155(a)
and fumaric acid as described in Example 10, the %WR was about 9% or above, i.e., 15.2% at
1 hour after administration, 28.8% at 3 hours after administration, 16.1% at 5 hours after
administration, and 8.8% at 7 hours after administration of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10. In contrast, a 3mg/kg dose
of celecoxib was less effective than a 1mg/kg dose of the product prepared with Compound
A155(a) and fumaric acid as described in Example 10 at each less-than-24 hour time-point
tested, i.e., 10.2% versus 15.2% respectively at 1 hour after administration, 27.8% versus
28.8% respectively at 3 hours after administration, 14.1% versus 16.1% respectively at 5 hours
after administration, and 6.0% versus 8.8% respectively at 7 hours after administration. In
making this comparison, it should be noted that the dose of celecoxib administered, 3mg/kg,
was 3 times greater than the dose of the product prepared with Compound A155(a) and fumaric
acid as described in Example 10, 1mg/kg.
Grip Force Test as an Assessment of Osteoarthritis Related Pain: The grip force test provides
an accepted assessment of the efficacy of clinically useful analgesic drugs with respect of
osteoarthritis related pain (Chandran et al., "Pharmacological modulation of movement-evoked
pain in a rat model of osteoarthritis," Eur. J. Pharmacol. 613:39-45 (2009); Chu et al.,
"TRPV1-related modulation of spinal neuronal activity and behavior in a rat model of
osteoarthritic pain," Brain Res. 1369:158-166 (2011)). The grip force (GF) of the hind legs was
assessed using a Animal Grip Strength System (San Diego Instruments, San Diego, CA). Rats
were gently restrained and allowed to grasp the wire mesh strain gauge with their hind legs.
The animals were then moved in a rostral-caudal direction until they let go of the gauge. The
force (in g) at which the rat let go was recorded. Each animal was tested twice at
approximately 3-10 minute intervals at each time point and the average of the two readings was
used for the GF in data analysis.
Grip force, normalized to account for the weight of each animal, was expressed as "GF/B", i.e.,
the ratio of GF to body wieght, where GF is the grip force in grams and B is the body weight of
the animal in kg. The "%GFR", i.e., the percentage reversal of the (normalized) grip force
impediment occurring post-MIA injection, was determined for each dosage at each time point
using the following formula:
[ (GF/B) - (GF/B) ]
Drug Vehicle
%GFR = x 100
[ (GF/B) - (GF/B) ]
Control Rat Vehicle
where (GF/B) is the GF/B determined at each post-oral-administration time-point for each
Drug
dose of each substance administered to MIA-injected animals, (GF/B) is the GF/B
Vehicle
determined at each post-oral-administration time-point for the vehicle control administered to
MIA-injected animals, and (GF/B) is the GF/B determined for control rats (saline-
Control Rat
injected animals receiving orally-administered vehicle only). With the exception of the
controls (i.e., celecoxib, vehicle) where the student's t-test was used, Dunnett's test was
conducted for the %GFR. In either instance, values with p < 0.05 were considered to be
statistically significant. The %GFR results for administration of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 are presented in Table 9.
Table 9: Osteoarthritis Pain Relief after Administration of the Product Prepared with
Compound A155(a) and Fumaric Acid as Described in Example 10
as Assessed by the Grip Force Test
%GFR [mean]
Example 10 Product Comprising Compound A155(a) Celecoxib Vehicle
Time after
Administration 0.3mg/kg 1mg/kg 3mg/kg 10mg/kg 20mg/kg 3mg/kg 2mL/kg
(hours)
Pre-
2.2 1.0 0 -2.6 2.3 -3.7 0
administration
1 (day 1) 12.8 29.7** 36.5** 35.9** 49.0** 22.6 1.2
3 (day 1) 21.1* 45.2** 53.6** 55.6** 65.1** 30.0 2.4
(day 1) 17.3* 37.6** 44.3** 45.9** 50.3** 20.9 0.8
7 (day 1) 3.7 16.5* 19.9** 22.8** 29.3** 3.6 -2.1
24 (0 hrs day 2) 4.0 3.1 -2.2 -5.7 -1.3 -3.6 -4.3
3 (day 2) 43.1** 50.5** 57.5** 2.9
24 (0 hrs day 3) 15.4** 22.0** 32.7** -4.7
3 (day 3) 38.0** 45.0** 51.6** -0.7
24 (0 hrs day 4) 26.1** 32.0** 33.4** -5.4
3 (day 4) 40.1** 45.6** 52.2** -5.5
24 (0 hrs day 5) 26.4** 28.9** 32.0** -5.7
* indicates p < 0.05 (Dunnett's test), ** indicates p < 0.01 (Dunnett's test),
indicates p < 0.01 (student's t-test).
As demonstrated by the results in Table 9, one-time administration of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 (0.3, 1, 3, 10, or 20 mg/kg)
and once daily administration of the product prepared with Compound A155(a) and fumaric
acid as described in Example 10 (1, 3, or 10 mg/kg) for four days showed statistically
significant effects against MIA-induced osteoarthritis pain in rats. Following a single
administration, the maximum analgesic effect of the product prepared with Compound A155(a)
and fumaric acid as described in Example 10 at 1 and 3 mg/kg (and 10 and 20 mg/kg) was
greater than the effect of celecoxib at 3 mg/kg. Thus, Compounds of Formula (I) are effective
in relieving osteoarthritis pain in vivo.
In particular, a single administration of the product prepared with Compound A155(a) and
fumaric acid as described in Example 10 demonstrated analgesic effects in the MIA-induced
osteoarthritis pain model. Following dosing at 20 mg/kg, the product prepared with Compound
A155(a) and fumaric acid as described in Example 10 evidenced significant analgesic effects at
1, 3, 5, and 7 hours post-administration. The maximum analgesic efficacy observed with the
product prepared with Compound A155(a) and fumaric acid as described in Example 10 was
65.1% reversal achieved 3 hours after administration. Similarly, following dosing at 1, 3, and
10 mg/kg, the product prepared with Compound A155(a) and fumaric acid as described in
Example 10 evidenced significant analgesic effects at 1, 3, 5, and 7 hours after administration.
Further, even following dosing at 0.3 mg/kg, the product prepared with Compound A155(a)
and fumaric acid as described in Example 10 evidenced significant analgesic effects at 3 and 5
hours after administration. The maximum analgesic efficacy at 0.3, 1, 3, and 10 mg/kg of the
product prepared with Compound A155(a) and fumaric acid as described in Example 10 was
21.1%, 45.2%, 53.6%, and 55.6% reversal, respectively, each at 3 hours post-administration.
These results demonstrate that a dose-dependent significant analgesic effect was achieved.
The results of repeated administration for 4 days of the product prepared with Compound
A155(a) and fumaric acid as described in Example 10 also demonstrate a dose-dependent
significant analgesic effect. On day 2 of dosing, the product prepared with Compound A155(a)
and fumaric acid as described in Example 10 demonstrated a dose-dependent significant
analgesic effect at 3 hours after administration. The analgesic efficacy following dosing at 1, 3,
and 10 mg/kg of the product prepared with Compound A155(a) and fumaric acid as described
in Example 10 was 43.1%, 50.5%, and 57.5% reversal, respectively. On day 3 of dosing, 1, 3,
and 10 mg/kg of the product prepared with Compound A155(a) and fumaric acid as described
in Example 10 demonstrated dose-dependent significant analgesic effects with 38.0%, 45.0%,
and 51.6% reversal, respectively. On day 4 of dosing, 1, 3, and 10 mg/kg of the product
prepared with Compound A155(a) and fumaric acid as described in Example 10 demonstrated
dose-dependent significant analgesic effects with 40.1%, 45.6%, and 52.2% reversal,
respectively.
Moreover, these results demonstrate that there is, desirably, a lack of tolerance development
with repeated administration. For example, dosing at 10 mg/kg of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 evidenced roughly
comparable maximum analgesic efficacy 3 hours after each adminsitration, 55.6%, 57.5%,
51.6%, and 52.2% reversal, respectively, after day 1, 2, 3, and 4 administration.
Oral single dosing of celecoxib, the positive control, also produced analgesic effects in the
MIA-induced osteoarthritis pain model. Following dosing at 3 mg/kg, celecoxib showed
significant analgesic effects at 1, 3, and 5 hours post-administration. However, the maximum
analgesic efficacy observed with celecoxib, 30.0% reversal 3 hours after day 1 administration
of the 3 mg/kg dose, was only about 66.4% and 56.0%, respectively, of the 45.2 % reversal at 1
mg/kg (i.e., one third the celecoxib dose) and 53.6% reversal at 3 mg/kg, each achieved 3 hours
after day 1 administration of the product prepared with Compound A155(a) and fumaric acid as
described in Example 10.
Neuropathic Pain: To assess the actions of a Compound of Formula (I) for the treatment or
prevention of neuropathic pain, either the Seltzer model or the Chung model can be used.
In the Seltzer model, the partial sciatic nerve ligation model of neuropathic pain was used to
produce neuropathic hyperalgesia in rats (Seltzer et al., "A Novel Behavioral Model of
Neuropathic Pain Disorders Produced in Rats by Partial Sciatic Nerve Injury," Pain 43:205-218
(1990)). Partial ligation of the left sciatic nerve was performed under isoflurane/O inhalation
anaesthesia. Following induction of anesthesia, the left thigh of the male, 6-7 week old Jcl:SD
rat was shaved. The sciatic nerve was exposed at high thigh level through a small incision and
was carefully cleared of surrounding connective tissues at a site near the trocanther just distal to
the point at which the posterior biceps semitendinosus nerve branches off of the common
sciatic nerve. A 7-0 silk suture was inserted into the nerve with a 3/8 curved, reversed-cutting
mini-needle and tightly ligated so that the dorsal 1/3 to ½ of the nerve thickness was held
within the ligature. The wound was closed with a single muscle suture (4-0 nylon (Vicryl)) and
vetbond tissue glue. The wound area was then dusted with antibiotic powder. Sham treatment
involved an identical surgical procedure except that the sciatic nerve was not manipulated or
ligated.
Following surgery, animals were weighed and placed on a warm pad until they recoverd from
anesthesia. Animals were then returned to their home cages until behavioral testing began.
The animal was assessed for response to noxious mechanical stimuli by determining PWT for
the rear paw of the animal, as described below, prior to surgery (baseline), then immediately
prior to and 1, 3, 5, 7, and 24 hours after oral drug-in-vehicle administration (for day 1). Thus,
the 24 hour time point was the start of the next day when drug-in-vehicle was again orally
administered (24 hours after the prior adminsitration). On days 2 and 3, PWT response was
determined 1, 3, and 24 hours thereafter. Percentage reversal of neuropathic hyperalgesia at
each of the specified times after administration was defined as:
[ (post-administration PWT) - (pre-administration PWT) ]
% Reversal = x 100
[ (baseline PWT) - (pre-administration PWT) ]
Additionally, 10mg/kg of pregabalin (Kemprotec, Ltd., Middlesbrough, UK), an anticonvulsant
accepted for relief of particular neuropathic pain, in vehicle and the vehicle alone (0.5%
weight/volume methylcellulose (400cP, Wako Pure Chemical Industries, Ltd.)/aqueous
solution) were orally administered as controls. An amount of fumaric acid comparable to that
present with Compound A155(a) was also present in each control. Ten rats that underwent
partial ligation of the left sciatic nerve were used for each treatment group. Dunnett's test was
conducted for the % reversal; values with p < 0.05 were considered to be statistically
significant. The results for administration of the product prepared with Compound A155(a)
and fumaric acid as described in Example 10 are provided in Table 10.
Table 10: Neuropathic Pain Relief after Administration of the Product Prepared with
Compound A155(a) and Fumaric Acid as Described in Example 10
% Reversal [mean ± SEM]
Example 10 Product Comprising Compound
Pregabalin Vehicle
A155(a)
Time after
Administration 1mg/kg 3mg/kg 10mg/kg 10mg/kg 2mL/kg
(hours)
Pre-
0 0 0 0 0
administration
1 (day 1) 14.60±4.26 15.69±4.62 32.51±5.00** 24.05±6.46**
0.75±1.50
3 (day 1) 17.04±4.91** 18.39±1.67** 34.17±5.60** 24.73±4.12**
4.39±1.80
(day 1) 11.39±3.13* 12.22±1.89** 19.59±3.04** 19.97±4.79**
2.98±2.54
7 (day 1) 3.04±4.49 7.65±2.79 17.06±2.95** 11.89±3.16**
3.64±2.99
24 (0 hrs day 2) 0.71±2.46 -5.34±4.20 3.38±3.97 -2.84±4.74
6.84±3.04
1 (day 2) 12.04±4.92* 12.57±2.38* 27.41±4.56** 16.74±4.23**
3.82±1.90
3 (day 2) 12.84±4.12* 17.14±5.38** 29.12±5.44** 23.21±2.30**
4.81±1.61
24 (0 hrs day 3) 4.89±2.68 -3.85±4.61 2.87±4.62 1.70±4.29
0.58±4.19
1 (day 3) 6.44±6.50 11.80±3.29 23.36±4.69** 17.16±6.64*
2.20±2.37
3 (day 3) 9.58±5.23 17.34±3.91* 28.91±5.72** 26.56±4.95** 1.32±2.14
24 (0 hrs day 4) 0.51±3.15 -1.95±2.97 11.09±3.45 -3.67±2.66 1.02±2.19
* indicates p < 0.05 (Dunnett's test), ** indicates p < 0.01 (Dunnett's test).
Additionally, as a control the rats underwent sham surgery in which an identical surgical
procedure was followed with regard to the right thigh but the sciatic nerve was neither
manipulated nor ligated.
As demonstrated by the results in Table 10, once daily administration of the product prepared
with Compound A155(a) and fumaric acid as described in Example 10 (1, 3, or 10 mg/kg) for
three days showed statistically significant effects against mechanical hyperalgesia in rats
subjected to partial sciatic nerve ligation in the Seltzer model of neuropathic pain. Following
either a single administration or repeated administration for 3 days, the maximum analgesic
effect of the product prepared with Compound A155(a) and fumaric acid as described in
Example 10 at 10 mg/kg was greater than the effect of pregabalin at 10 mg/kg. Thus,
Compounds of Formula (I) are effective in relieving neuropathic pain in vivo.
In particular, a single administration of the product prepared with Compound A155(a) and
fumaric acid as described in Example 10 demonstrated analgesic effects in the Selzer model.
Following dosing at 10 mg/kg, the product prepared with Compound A155(a) and fumaric acid
as described in Example 10 evidenced significant analgesic effects at 1, 3, 5, and 7 hours post-
administration. The maximum analgesic efficacy observed with the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 was 34.17% reversal
achieved 3 hours after administration. Similarly, following dosing at 1 and 3 mg/kg, the
product prepared with Compound A155(a) and fumaric acid as described in Example 10
evidenced significant analgesic effects at 3 and 5 hours after administration. The maximum
analgesic efficacy at 1 and 3 mg/kg of the product prepared with Compound A155(a) and
fumaric acid as described in Example 10 was 17.04% and 18.39% reversal, respectively. These
results demonstrate that a dose-dependent significant analgesic effect was achieved.
The results of repeated administration for 3 days of the product prepared with Compound
A155(a) and fumaric acid as described in Example 10 also demonstrate a dose-dependent
significant analgesic effect. On day 2 of dosing, the product prepared with Compound A155(a)
and fumaric acid as described in Example 10 demonstrated a dose-dependent significant
analgesic effect at 1 and 3 hours after administration. The maximum analgesic efficacy
following dosing at 1, 3, and 10 mg/kg of the product prepared with Compound A155(a) and
fumaric acid as described in Example 10 was 12.84%, 17.14%, and 29.12% reversal,
respectively, each at the 3 hour time point. On day 3 of dosing, 3 and 10 mg/kg of the product
prepared with Compound A155(a) and fumaric acid as described in Example 10 demonstrated
dose-dependent significant analgesic effects with maxima of 17.34% reversal at 3 mg/kg and
28.91% reversal at 10 mg/kg, each at the 3 hour time point.
Moreover, these results demonstrate that there is, desirably, a lack of tolerance development
with repeated administration. For example, dosing at 3 mg/kg of the product prepared with
Compound A155(a) and fumaric acid as described in Example 10 evidenced roughly
comparable maximum analgesic efficacy 3 hours after each adminsitration, 18.39%, 17.14%,
and 17.34% reversal, respectively, after day 1, 2, and 3 administration.
Oral single dosing of pregabalin, the positive control, also produced analgesic effects in the
Selzer model. Following dosing at 10 mg/kg, pregabalin showed significant analgesic effects
at 1, 3, 5, and 7 hours post-administration. However, the maximum analgesic efficacy
observed with pregabalin, 24.73% reversal 3 hours after day 1 administration of the 10 mg/kg
dose, was only about 72% of the 34.17% reversal achieved 3 hours after day 1 administration
of the 10 mg/kg dose of the product prepared with Compound A155(a) and fumaric acid as
described in Example 10.
In the Chung model, the spinal nerve ligation model of neuropathic pain is used to produce
mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia in rats. Surgery is
performed under isoflurane/O inhalation anaesthesia. Following induction of anaesthesia, a 3
cm incision is made and the left paraspinal muscles are separated from the spinous process at
the L -S levels. The L transverse process is carefully removed with a pair of small rongeurs
4 2 6
to identify visually the L -L spinal nerves. The left L (or L and L ) spinal nerve(s) is isolated
4 6 5 5 6
and tightly ligated with silk thread. A complete hemostasis is confirmed and the wound is
sutured using non-absorbable sutures, such as nylon sutures or stainless steel staples. Sham-
treated rats undergo an identical surgical procedure except that the spinal nerve(s) is not
manipulated. Following surgery animals are weighed, administered a subcutaneous (s.c.)
injection of saline or ringers lactate, the wound area is dusted with antibiotic powder and they
are kept on a warm pad until they recover from the anesthesia. Animals are then returned to
their home cages until behavioral testing begins. The animals are assessed for response to
noxious mechanical stimuli by determining PWT, as described below, prior to surgery
(baseline), then immediately prior to and 1, 3, and 5 hours after being administered a
Compound of Formula (I) for the left rear paw of the animal. The animal can also be assessed
for response to noxious thermal stimuli or for tactile allodynia, as described below. The Chung
model for neuropathic pain is described in Kim, "An Experimental Model for Peripheral
Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat," Pain 50(3):355-363
(1992).
Response to Mechanical Stimuli as an Assessment of Mechanical Hyperalgesia: The paw
pressure assay was used to assess mechanical hyperalgesia. For this assay, hind paw
withdrawal thresholds (PWT) to a noxious mechanical stimulus were determined using an
analgesymeter (Model 37215, commercially available from Ugo Basile of Italy) as described in
Stein, "Unilateral Inflammation of the Hindpaw in Rats as a Model of Prolonged Noxious
Stimulation: Alterations in Behavior and Nociceptive Thresholds," Pharmacol. Biochem. and
Behavior 31:451-455 (1988). The maximum weight that could be applied to the hind paw was
set at 250 g and the end point was taken as complete withdrawal of the paw. PWT was
determined once for each rat at each time point and either only the affected (ipsilateral) paw
was tested, or both the ipsilateral and contralateral (non-injured) paw were tested.
Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia: The plantar test can
be used to assess thermal hyperalgesia. For this test, hind paw withdrawal latencies to a
noxious thermal stimulus are determined using a plantar test apparatus (commercially available
from Ugo Basile of Italy) following the technique described by Hargreaves et al., "A New and
Sensitive Method for Measuring Thermal Nociception in Cutaneous Hyperalgesia," Pain
32(1):77-88 (1988). The maximum exposure time is set at 32 seconds to avoid tissue damage
and any directed paw withdrawal from the heat source is taken as the end point. Three
latencies are determined at each time point and averaged. Either only the affected (ipsilateral)
paw is tested, or both the ipsilateral and contralateral (non-injured) paw are tested.
Assessment of Tactile Allodynia: To assess tactile allodynia, rats are placed in clear, plexiglass
compartments with a wire mesh floor and allowed to habituate for a period of at least
15minutes. After habituation, a series of von Frey monofilaments are presented to the plantar
surface of the left (operated) foot of each rat. The series of von Frey monofilaments consists of
six monofilaments of increasing diameter, with the smallest diameter fiber presented first. Five
trials are conducted with each filament with each trial separated by approximately 2 minutes.
Each presentation lasts for a period of 4-8 seconds or until a nociceptive withdrawal behavior is
observed. Flinching, paw withdrawal or licking of the paw are considered nociceptive
behavioral responses.
Capsaicin-Induced Eye Wipe Test: To assess the effect of Compounds of Formula (I) on
TRPV1 receptor-mediated pain, the capsaicin-induced eye wipe test is used (Gavva et al.,
"AMG 9810 [(E)(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxinyl)acrylamide], a
Novel Vanilloid Receptor 1 (TRPV1) Antagonist with Antihyperalgesic Properties", J.
Pharmacol. Exp. Ther. 313:474-484 (2005)). The eye wipe test is a reliable high-throughput
test of the effect of TRPV1 antagonists. Rats are given a single injection of 1, 3, 10, or 30
mg/kg of either a Compound of Formula (I), 30 mg/kg of a control selected from Celebrex,
indomethacin, ibuprofen, or naproxen, or a vehicle. At 1, 3, or 5 hours after drug
administration, 3 µL of a 100 μM capsaicin solution (in 10% EtOH/PBS) is instilled in one eye
of each animal with a pipette. The number of forelimb movements (touching or wiping of the
capsaicin-treated eye) are counted during a 2 minute period following instillation of capsaicin
into the eye.
.17 Example 17: In Vivo Assay of Body Temperature Increase
Hyperthermial or undesirable elevation in animal body temperature is known to be an
undesirable side-effect accompanying the administration of certain TRPV1 antagonists (Gavva,
"Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1,"
Trends Pharmacol. Sci. 29(11):550-557 (2008)). Compounds of Formulae (I) and/or (II) are
capable of ameliorating the undesirable side effect of increased body temperature that can occur
upon in vivo administration, as demonstrated in this example.
Test Animals: Selection of rats (Crl/SD rats, 7 weeks, male) was based on rectal body
temperature measured during the morning of the day of dosing as described below. In addition,
to minimize spontaneous, stress-induced increases in body temperature, rats were acclimated in
advance to both the rectal measurement procedure and to being handled and dosed. All lodging
and testing took place in animal care laboratories with constant room temperature and
humidity. The rats were free to move and ingest food and water throughout. Each rat was
coded with a colored line on the tail, housed in a separate cage, and permitted the normal range
of movement. Immediately before each body temperature measurement, a rat was transferred
to a measurement cage. To reduce stress which could influence its body temperature, each rat
was covered with towels during the measurement. A thermistor probe was then carefully
inserted into the rectum of each rat and left in place until the temperature reading on the digital
display had stabilized; this value was recorded.
Assay: On the day before dosing, rectal body temperature was measured at 9:00, 10:00, 11:00,
12:30, 13:30, 14:30, and 15:30 o'clock to familiarize the rats with the measurement procedure
prior to administration of the test or control treatments. The rats were also dosed by oral
gavage without vehicle at 12:30 o'clock to acclimate and familiarize them with the handling
and dosing procedure.
On the day of dosing, only rats with rectal body temperatures within the range of from 37.0°C
to 37.7°C were selected for study. Rectal body temperatures were measured at 9:00, 10:00, and
11:00 o'clock. Rats were excluded from the study if either their rectal body temperature was
over 37.9°C at 10:00 o'clock or was outside the range of from 37.0°C to 37.7°C at 11:00
o'clock. The selected rats were divided into several groups based on their rectal body
temperatures at 11:00 o'clock. Rectal body temperatures of the selected rats were measured
again at 12:30 o'clock and any rat with a rectal body temperature of 38.0°C or greater was also
excluded from the study.
Following assignment to either a test or control group, a test compound or a control was
administered to the rats. Each test compound was dissolved in a vehicle of 0.5% aqueous
methylcellulose solution and the final concentration of the test compound was adjusted to 1
mg/mL. Each test compound was orally administered once at a dose of 10 mL/kg. The same
volume of the control (vehicle only) was administered once to the control group. Rectal body
temperatures were measured at the following time points: 0.5, 1, and 2 hrs after administration.
The body temperature increase (ΔTb) for each test compound was calculated by subtracting, at
each time point, the average temperature of the control group from the average temperature of
the group administered that test compound. The greatest ΔTb obtained for each test compound
at any of the time points is shown in Table 11 below, along with the ΔTb of the control.
Table 11: Body Temperature Increase
Compound ΔTb (°C) Structure
Control 0.0 --
A122(a) 0.4
A125(b) 0.1
A126(a) 0.2
A155(a) 0.2
A155(d) 0.1
A155(e) 0.1
A158(a) 0.4
B158(j) 0.1
Compound ΔTb (°C) Structure
C4(r) 0.3
C125(r) 0.3
C126(r) 0.4
C170(r) 0.2
AA 0.8
AB 0.6
Compound ΔTb (°C) Structure
AC 0.7
AD 0.6
AE 0.5
Compound ΔTb (°C) Structure
BA 0.9
BB 0.5
BC 0.7
Compound ΔTb (°C) Structure
DA 0.9
DB 1.1
DC 1.0
Compound ΔTb (°C) Structure
DD 1.0
DE 1.3
DF 0.5
Compound ΔTb (°C) Structure
DG 1.0
DH 0.9
DI 0.8
Compound ΔTb (°C) Structure
DJ 0.9
DK 0.7
DL 0.9
Compound ΔTb (°C) Structure
DM 0.9
DN 0.8
DO 1.1
Compound ΔTb (°C) Structure
DP 1.2
As demonstrated by the data above, Compounds of Formulae (I) and/or (II) are capable of
ameliorating the undesirable side effect of an increase in body temperature that can occur upon
in vivo administration of a compound which modulates the TRPV1 receptor. For example, the
body temperature increase after administration of Compounds of Formulae (I) and/or (II) is less
than 0.7°C in one embodiment, 0.6°C or less in another embodiment, less than 0.6°C in another
embodiment, 0.5°C or less in another embodiment, less than 0.5°C in another embodiment,
0.4°C or less in another embodiment, less than 0.4°C in another embodiment, 0.3°C or less in
another embodiment, less than 0.3°C in another embodiment, or 0.2°C or less in another
embodiment.
In particular, the body temperature increase after administration of Compounds of Formulae (I)
and/or (II) was determined to be less than 0.5°C, in some cases much less than 0.5°C, e.g.,
0.1°C for Compounds A125(b), A155(d), A155(e), and B158(j); 0.2°C for Compounds
A126(a), A155(a), and C170(r); and 0.3°C for Compounds C4(r) and C125(r). In addition,
Compounds of Formulae (I) and/or (II), e.g., Compound A155(a), showed a significant
separation between doses effective in pain models and doses at which an increase in body
temperature was observed in both rats and monkeys. Doses that increased body temperature
were more than 100 times greater than the ED in the FCA model of inflammatory pain some
instances.
In contrast, the body temperature increase after administration of other compounds was
determined to be greater than 0.5°C, in some cases much greater than 0.5°C, e.g., 0.8°C for
Compounds DI, DN, and AA; 0.9°C for Compounds DA, DH, DJ, DL, DM, and BA; 1.0°C for
Compounds DC, DD, and DG; 1.1°C for Compounds DB and DO; 1.2°C for Compound DP;
and 1.3°C for Compound DE; in some instances, these compounds induced hyperthermia at
doses that were less than those necessary for efficacy in pain models, showing a lack of
separation between efficacy and the side effect of hyperthermia.
The invention is not to be limited in scope by the specific embodiments disclosed in the
examples that are intended as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope of this invention. Indeed,
various modifications of the invention in addition to those shown and described herein will
become apparent to those skilled in the art and are intended to fall within the scope of the
appended claims. A number of references have been cited, the entire disclosures of which are
incorporated herein by reference for all purposes.
Claims (41)
1. A compound of formula (I): 5 (I) or a pharmaceutically acceptable derivative thereof, wherein: R is -halo or -CF ; R is -H or -CH ; each R and R is independently -H, -halo, -CH , -CF , -OCH , -OCF , -OCH CH , - 8 9 3 3 3 3 2 3 10 CH OCH , or -C(O)OR ; 2 3 10 R is -(C -C )alkyl; 10 1 4 each halo is independently -F, -Cl, -Br, or -I; and m is the integer 0 or 1; (1) provided that if R is -H then m is 1; and 15 (2) provided that if R is -H and the carbon atom at the a position of the a-b bond is in the (S) configuration, then the methyl group bonded to the piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group, and wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph, solvate, co-crystal, radiolabeled form, and/or tautomer.
2. The compound of claim 1 or a pharmaceutically acceptable derivative thereof, wherein it is further provided that: 5 (3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl group; (4) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is -F, and R is -F, then the methyl group bonded to the piperazine 10 ring is a (S)methyl group or a (S)methyl group; and (5) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (S) configuration, R is -H, R is -halo, and m is 1, then the methyl group bonded to the piperazine ring is a (S)methyl group or a (R)methyl group. 15
3. The compound of claims 1 or 2 or a pharmaceutically acceptable derivative thereof, wherein R is -F, -Cl, or -CF .
4. The compound of claim 3 or a pharmaceutically acceptable derivative thereof, wherein R is –F.
5. The compound of any one of claims 1-4 or a pharmaceutically acceptable 20 derivative thereof, wherein R is -CH or -CH CH . 10 3 2 3
6. The compound of any one of claims 1-5 or a pharmaceutically acceptable derivative thereof, wherein R is -CH CH . 10 2 3
7. The compound of any one of claims 1-6 or a pharmaceutically acceptable derivative thereof, wherein R is -H, -F, -Cl, -Br, -CH , -CF , -OCH , - 9 3 3 3 25 OCF , -OCH CH , -CH OCH , or -C(O)OCH CH . 3 2 3 2 3 2 3
8. The compound of any one of claims 1-7 or a pharmaceutically acceptable derivative thereof, wherein R is –H.
9. The compound of any one of claims 1-8 or a pharmaceutically acceptable derivative thereof, wherein R is -H, -F, or -CH . 30
10. The compound of any one of claims 1-9 or a pharmaceutically acceptable derivative thereof, wherein R is -F or -CH .
11. The compound of any one of claims 1-10 or a pharmaceutically acceptable derivative thereof, wherein (i) R is -CH and the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (S) configuration; or 5 (ii) R is -CH and the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (R) configuration; or (iii) R is -H and the carbon atom at the a position of the a-b bond is in the (S) configuration or (iv) R is -H and the carbon atom at the a position of the a-b bond is in the (R) 10 configuration.
12. The compound of any one of claims 1-11 or a pharmaceutically acceptable derivative thereof, wherein m is 1 and the methyl group bonded to the piperazine ring is a (S)methyl group.
13. The compound of any one of claims 1-12, wherein the pharmaceutically 15 acceptable derivative is a pharmaceutically acceptable salt, radiolabeled form, a co- crystal, or a combination thereof.
14. The compound of claim 13 or a pharmaceutically acceptable derivative thereof, wherein (i) the pharmaceutically acceptable derivative is a pharmaceutically acceptable 20 salt, radiolabeled form, or a hydrochloric acid, tartaric acid, benzenesulfonic acid, p- toluenesulfonic acid or fumaric acid co-crystal ; or (ii) the pharmaceutically acceptable derivative is a fumaric acid-salt, a fumaric acid co-crystal, or a combination thereof.
15. The compound of claim 14 option (i) or a pharmaceutically acceptable 25 derivative thereof, wherein the pharmaceutically acceptable derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-toluenesulfonic acid salt, a fumaric acid-salt, or a fumaric acid co-crystal.
16. The compound of claim 11 option (i) or (ii) or a pharmaceutically acceptable derivative thereof, wherein m is 0. 30
17. The compound of claim 16 wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, radiolabeled form, or a hydrochloric acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid or fumaric acid co-crystal, or a combination thereof.
18. The compound of claim 17 wherein the pharmaceutically acceptable derivative is a fumaric acid-salt, a fumaric acid co-crystal, or a combination thereof. 5 19. The compound of claim 16 or a pharmaceutically acceptable derivative thereof, which is , or
10 .
20. A compound of claim 1 having formula (II): (II) or a pharmaceutically acceptable derivative thereof, wherein: 5 R is -H or -CH ; R is -H, -F, or -CH ; R is -H, -halo, -CH , -CF , -OCH , -OCF , -OCH CH , -CH OCH , or - 9 3 3 3 3 2 3 2 3 C(O)OCH CH ; and each halo is independently -F, -Cl, -Br, or -I; 10 (1) provided that if R is -H and the carbon atom at the a position of the a-b bond is in the (S) configuration, then the methyl group bonded to the piperazine ring is a (S)methyl group, a (S)methyl group, or a (R)methyl group, and wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph, solvate, co-crystal, radiolabeled form, and/or tautomer. 15
21. The compound of claim 20 or a pharmaceutically acceptable derivative thereof, wherein it is further provided that: (2) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the piperazine ring is a (R)methyl group; (3) if R is -H, the carbon atom at the a position of the a-b bond is in the (S) 5 configuration, R is -F, and R is -F, then the methyl group bonded to the piperazine ring is a (S)methyl group or a (S)methyl group; and (4) if R is -CH , the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (S) configuration, R is -H, and R is -halo, then the methyl group bonded to the piperazine ring is a (S)methyl group or a (R)methyl group. 10
22. The compound of claim 20 or a pharmaceutically acceptable derivative thereof, wherein (i) R is -CH and the carbon atoms at the a and c positions of the a-b bond and the c-d bond are each in the (S) configuration or (ii) R is -CH and the carbon atoms at the a and c positions of the a-b bond and 15 the c-d bond are each in the (R) configuration.
23. The compound of claim 22 or claim 23 or a pharmaceutically acceptable derivative thereof, wherein R is -H and the carbon atom at the a position of the a-b bond is in the (S) configuration.
24. The compound of claim 22 or a pharmaceutically acceptable derivative thereof, 20 wherein R is -H and the carbon atom at the a position of the a-b bond is in the (R) configuration.
25. The compound of any one of claims 20-24 or a pharmaceutically acceptable derivative thereof, wherein the methyl group bonded to the piperazine ring is (i) a (S)methyl group, 25 (ii) a (S)methyl group, or (iii) a (R)methyl group.
26. The compound of any one of claims 20-25 or a pharmaceutically acceptable derivative thereof, wherein R is –H and/or R is -F.
27. The compound of any one of claims 20-26, wherein the pharmaceutically 30 acceptable derivative is (i) a pharmaceutically acceptable salt, or a fumaric acid co-crystal; or (ii) a fumaric acid-salt, a fumaric acid co-crystal, or a combination thereof.
28. The compound of claim 27 according to option (i), wherein the pharmaceutically acceptable derivative is a hydrochloride salt, a sodium salt, a potassium salt, a p-toluenesulfonic acid salt, a fumaric acid-salt, or a fumaric acid co- 5 crystal.
29. The compound of claim 20 or a pharmaceutically acceptable derivative thereof, which is 10 , , or
30. The compound of any one of claims 16, 19 or 29, which is (i) a fumaric acid-salt, a fumaric acid co-crystal, or a combination thereof, or 5 (ii) a free base.
31. A compound of claim 1 which is or a pharmaceutically acceptable derivative thereof. 10
32. A composition comprising the compound of any one of claims 1-31 or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient, wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph, solvate, co-crystal, radiolabeled form, and/or tautomer. 15
33. Use of a compound of any one of claims 1-31 or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, or IBS, and wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph, solvate, co-crystal, radiolabeled form, and/or tautomer. 20
34. An in vitro method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of the compound of any one of claims 1-31 or a pharmaceutically acceptable derivative thereof and wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph, solvate, co-crystal, radiolabeled form, and/or tautomer.
35. Aproduct of combining the compound of a) any one of claims 1-24, 5 b) claim 25 option (i), c) claim 25 option (iii), or d) any one of claims 26-29 with fumaric acid, wherein the molar ratio in the product is about 1:0.5 of (the Compound of Formula (I) or (II)):(fumaric acid). 10
36. A composition comprising the product of claim 35 and a pharmaceutically acceptable carrier or excipient.
37. Use of a product of claim 35 or a composition of claim 36 or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, or IBS and 15 wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt, polymorph, solvate, co-crystal, radiolabeled form, and/or tautomer.
38. An in vitro method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of the product of claim 35. 20
39. The compound, product, method or composition of any one of claims 1-38 or a pharmaceutically acceptable derivative thereof, wherein the % ee of the compound is at least about 90%.
40. The compound, product, method or composition of claim 39, wherein the % ee of the compound is at least about 93%. 25
41. A compound of Formula (I) substantially as hereinbefore described with reference to any one of the foregoing examples.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161499989P | 2011-06-22 | 2011-06-22 | |
US61/499,989 | 2011-06-22 | ||
PCT/IB2012/001252 WO2012176061A1 (en) | 2011-06-22 | 2012-06-21 | Trpv1 antagonists including dihydroxy substituent and uses thereof |
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NZ618912A NZ618912A (en) | 2015-07-31 |
NZ618912B2 true NZ618912B2 (en) | 2015-11-03 |
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