U.S. patent application number 17/223426 was filed with the patent office on 2021-07-22 for compounds acting at multiple prostaglandin receptors giving a general anti-inflammatory response.
The applicant listed for this patent is ALLERGAN, INC.. Invention is credited to William R. Carling, Jussi J. Kangasmetsa, Jose L. Martos, Jenny W. Wang, David F. Woodward.
Application Number | 20210221810 17/223426 |
Document ID | / |
Family ID | 1000005504777 |
Filed Date | 2021-07-22 |
United States Patent
Application |
20210221810 |
Kind Code |
A1 |
Carling; William R. ; et
al. |
July 22, 2021 |
COMPOUNDS ACTING AT MULTIPLE PROSTAGLANDIN RECEPTORS GIVING A
GENERAL ANTI-INFLAMMATORY RESPONSE
Abstract
The present invention provides a compound, that is a
1-({halo-2-[(2-hydrocarbyl or substituted
hydrocarbyl)oxy]phenyl}methyl)-(fused bicyclic nitrogen heteroaryl)
carboxylic acid or an ester or sulfonamide thereof. The compound
may be represented by the following formula ##STR00001## Wherein
R.sub.1, R.sub.2, R.sub.3, R.sub.4 A, X, W, Z and Y are as defined
in the specification. The compounds may be administered to treat
DP, FP, EP1, TP and/or EP4 receptor-mediated diseases or
conditions.
Inventors: |
Carling; William R.;
(Bishop's Stortford, GB) ; Martos; Jose L.;
(Basildon Essex, GB) ; Kangasmetsa; Jussi J.;
(Essex, GB) ; Wang; Jenny W.; (Irvine, CA)
; Woodward; David F.; (Lake Forest, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ALLERGAN, INC. |
Irvine |
CA |
US |
|
|
Family ID: |
1000005504777 |
Appl. No.: |
17/223426 |
Filed: |
April 6, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16539835 |
Aug 13, 2019 |
10988474 |
|
|
17223426 |
|
|
|
|
15406295 |
Jan 13, 2017 |
10392382 |
|
|
16539835 |
|
|
|
|
13720520 |
Dec 19, 2012 |
9567328 |
|
|
15406295 |
|
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|
61578640 |
Dec 21, 2011 |
|
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 235/08 20130101; C07D 209/08 20130101; C07D 231/56 20130101;
C07D 401/06 20130101; C07D 235/06 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 231/56 20060101 C07D231/56; C07D 235/08 20060101
C07D235/08; C07D 401/06 20060101 C07D401/06; C07D 209/08 20060101
C07D209/08; C07D 235/06 20060101 C07D235/06 |
Claims
1. A compound represented by the Formula IV: ##STR00191## or a
pharmaceutically acceptable salt thereof, wherein: Y is
(CH.sub.2).sub.m, wherein m is 0; Z is O; W is selected from the
group consisting of ##STR00192## R.sup.1 is OH; R.sup.3 is H; and
R.sup.4 is selected from the group consisting of Cl and Br.
2. The compound according to claim 7, wherein the compound is:
2-(5-Chloro-2-Isobutoxy-Benzyl)-2H-Indazole-5-Carboxylic Acid;
2-(5-Bromo-2-Isobutoxy-Benzyl)-2H-Indazole-5-Carboxylic Acid;
2-(5-Chloro-2-Cyclopropylmethoxy-Benzyl)-2H-Indazole-4-Carboxylic
Acid; 2-(5-Chloro-2-Isobutoxy-Benzyl)-2H-Indazole-4-Carboxylic
Acid;
2-[5-Chloro-2-(2-Ethyl-Butoxy)-Benzyl]-2H-Indazole-4-Carboxylic
Acid;
2-[5-Chloro-2-(4-Chloro-Benzyloxy)-Benzyl]-2H-Indazole-4-Carboxylic
Acid; 2-(5-Bromo-2-Isobutoxy-Benzyl)-2H-Indazole-6-Carboxylic Acid;
2-(5-Bromo-2-Cyclopentylmethoxy-Benzyl)-2H-Indazole-6-Carboxylic
Acid; or a pharmaceutically acceptable salt thereof.
3. A compound selected from the group consisting of:
1-(3-Isobutoxy-6-Methyl-Pyridin-2-Ylmethyl)-1H-Indazole-5-Carboxylic
Acid;
1-(5-Bromo-2-Isobutoxy-Benzyl)-1H-Pyrrolo[3,2-B]Pyridine-5-Carboxyl-
ic Acid; or a pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/539,835, filed Aug. 13, 2019, which is a
continuation of U.S. patent application Ser. No. 15/406,295, filed
Jan. 13, 2017, now U.S. Pat. No. 10,392,382, issued Aug. 27, 2019,
which is a continuation of U.S. patent application Ser. No.
13/720,520, filed Dec. 19, 2012, now U.S. Pat. No. 9,567,328,
issued Feb. 14, 2017, which claims the benefit of U.S. Provisional
Application Serial No. 61,578,640, filed Dec. 21, 2011, the
disclosures of which are hereby incorporated by reference in their
entireties and serve as the basis of a priority and/or benefit
claim for the present application.
BACKGROUND OF THE INVENTION
1. Field of the Invention
[0002] This invention relates to compounds, to processes for their
preparation, to pharmaceutical compositions containing them and to
their use in medicine, in particular their use in the treatment of
conditions mediated by the action of ligands for the DP.sub.1, FP,
TP, EP.sub.1 and EP.sub.4 prostaglandin (PG) receptors. The present
compounds have the general structure shown below and act at
different prostaglandin receptors to thereby provide a general
anti-inflammatory response.
2. Summary of the Related Art
[0003] The EP.sub.1 receptor is a 7-transmembrane receptor and its
natural ligand is the prostaglandin PGE.sub.2. PGE.sub.2 also has
affinity for the other EP receptors (types EP.sub.2, EP.sub.3 and
EP.sub.4). The EP.sub.1 receptor is associated with smooth muscle
contraction, pain (in particular inflammatory, neuropathic and
visceral), inflammation, allergic activities, renal regulation and
gastric or enteric mucus secretion.
[0004] Prostaglandin E.sub.2 (PGE.sub.2) exerts allodynia through
the EP.sub.1 receptor subtype and hyperalgesia through EP.sub.2 and
EP.sub.3 receptors in the mouse spinal cord. Furthermore, it has
been shown that in the EP.sub.1 knock-out mouse pain-sensitivity
responses are reduced by approximately 50%. EP.sub.1 receptor
antagonist (ONO-8711) reduces hyperalgesia and allodynia in a rat
model of chronic constriction injury and inhibits mechanical
hyperalgesia in a rodent model of post-operative pain. The efficacy
of EP.sub.1 receptor antagonists in the treatment of visceral pain
in a human model of hypersensitivity has been demonstrated. Thus,
selective prostaglandin ligands, agonists or antagonists, depending
on which prostaglandin E receptor subtype is being considered, have
anti-inflammatory, antipyretic and analgesic properties similar to
a conventional non-steroidal anti-inflammatory drug, and in
addition, inhibit hormone-induced uterine contractions and have
anti-cancer effects. These compounds have a diminished ability to
induce some of the mechanism-based side effects of NSAIDs which are
indiscriminate cyclooxygenase inhibitors. In particular, the
compounds have a reduced potential for gastrointestinal toxicity, a
reduced potential for renal side effects, a reduced effect on
bleeding times and a lessened ability to induce asthma attacks in
aspirin-sensitive asthmatic subjects. Moreover, as a result of
sparing potentially beneficial prostaglandin pathways, these agents
may have enhanced efficacy and safety over NSAIDS and/or COX-2
inhibitors. EP.sub.4 receptors have also been implicated in pain,
hyperalgesia, allodynia, and inflammation. (See Pub. No. US
2005/0065200 which is hereby incorporated by reference for other
diseases that may be treated by EP4 receptor antagonists.)
[0005] The TP (also known as TxA.sub.2) receptor is a prostanoid
receptor subtype stimulated by the endogenous mediator thromboxane.
Activation of this receptor results in various physiological
actions primarily incurred by its platelet aggregatory and smooth
muscle constricting effects, thus opposing those of prostacyclin
receptor activation.
[0006] TP receptors have been identified in human kidneys in the
glomerulus and extraglomerular vascular tissue. Activation of TP
receptors constricts glomerular capillaries and suppresses
glomerular filtration rates indicating that TP receptor antagonists
could be useful for renal dysfunction in glomerulonephritis,
diabetes mellitus and sepsis.
[0007] Activation of TP receptors induces bronchoconstriction, an
increase in microvascular permeability, formation of mucosal edema
and mucus secretion, which are typical characteristic features of
bronchial asthma. TP antagonists have been investigated as
potential asthma treatments resulting in, for example, orally
active Seratrodast (AA-2414). Ramatroban is another TP receptor
antagonist currently undergoing phase III clinical trials as an
anti-asthmatic compound.
[0008] Since DP.sub.1 receptor stimulation may trigger an asthmatic
response in certain individuals, compounds that have DP.sub.1
antagonist properties may be useful as anti-asthmatic drugs. (See
Pub. No. 2004/0162323 which is hereby incorporated by reference in
its entirety for the disclosure of other diseases and conditions
that may be treated with DP antagonists.)
[0009] Finally, the FP receptor modulates intraocular pressure and
mediates smooth muscle contraction of the sphincter muscles in the
gastrointestinal tract and the uterus. Thus, antagonists of the FP
receptor are useful for treating reproductive disorders. (See U.S.
Pat. No. 6,511,999 which is hereby incorporated by reference in its
entirety for other diseases and conditions that may be treated with
FP receptor antagonists.)
[0010] As further background for the present invention, see US
Published Patent Application 2007/0060596 which is hereby
incorporated by reference in its entirety.
BRIEF SUMMARY OF THE INVENTION
[0011] This invention provides compounds, that are
1-({halo-2-[(2-hydrocarbyl or substituted
hydrocarbyl)oxy]phenyl}methyl)-(fused bicyclic nitrogen
heteroaryl)carboxylic acids, or esters and sulfonamides thereof,
such as 1-({halo-2-[(2-hydrocarbyl or substituted
hydrocarbyl)oxy]phenyl}methyl)-(2,3 benzopyrrole or 2,3
benzo-1,2-diazole)carboxylic acids, or esters and sulfonamides
thereof e.g. 1-({5-halo-2-[(2-alkyl)oxy]phenyl}methyl)-(2,3
benzopyrrole or 2,3 benzo-1,2-diazole)-5-carboxylic acids or esters
or sulfonamides thereof. Said fused bicyclic nitrogen heteroaryl
may be indole, isoindole, indolizine, benzotriazole, or purine.
Preferably the ester or sulfonamide is an alkyl ester or
sulfonamide. Preferably said halo is chloro or bromo and said alkyl
is a branched chain alkyl having from 4 to 7 carbons, e.g.
3-ethylbutyl or 2-methylpropyl.
[0012] The invention further relates to pharmaceutical compositions
containing the above compounds in combination with a
pharmaceutically-acceptable excipient and to their use in medicine,
in particular their use in the treatment of conditions mediated by
the action of ligands for the DP.sub.1, FP, EP.sub.1 and EP.sub.4
prostaglandin (PG) receptors. The compounds of this invention are
also useful for treating conditions mediated by the action of
ligands for the thromboxane (TP) receptor.
Some embodiments of the present invention include: 1. A compound,
that is a 1-({halo-2-[(2-hydrocarbyl or substituted
hydrocarbyl)oxy]phenyl}methyl)-(fused bicyclic nitrogen
heteroaryl)carboxylic acid, or ester or sulfonamide thereof, and
said hydrocarbyl may be a branched chain alkyl having from 4 to 7
carbons, e.g. 3-ethylbutyl or 2-methylpropyl. 2. A compound
according to paragraph 1 wherein said compound is a
1-({5-halo-2-[(2-alkyl)oxy]phenyl}methyl)-(2,3 benzopyrrole or 2,3
benzo-1,2-diazole)-5-carboxylic acid or ester or sulfonamide
thereof. 3. A compound according to paragraph 2 wherein said ester
or sulfonamide is an alkyl ester or sulfonamide. 4. A compound
according to paragraph 3, wherein said halo is selected from the
group consisting of chloro and bromo. 5. A compound according to
paragraph 3 wherein said alkyl is a branched chain alkyl having
from 4 to 7 carbons. 6. A compound according to paragraph 3 wherein
said alkyl is selected from the group consisting of 2-ethylbutyl
and 2-methylpropyl. 7. A compound represented by the following
formula
##STR00002##
wherein X is N or CR.sub.7; A is N or CR.sub.7 with the proviso
that at least one A is N and when each A is N, R.sub.2 is absent; Y
is (CH.sub.2).sub.m wherein m is 0 or an integer of from 1 to 3; Z
is selected from the group consisting of O, S, SO, SO.sub.2 and
(CH.sub.2).sub.p, wherein p is 0 or an integer of from 1 to 3; W is
hydrocarbyl or substituted hydrocarbyl; R.sub.1 is selected from
the group consisting of OR.sub.7, NH.sub.2, N(R.sub.7).sub.2, and
N(R.sub.7)SO.sub.2R.sub.7; R.sub.2 is selected from the group
consisting of H, hydroxyl, alkyl, aryl, alkoxy, aryloxy, halogen,
nitro, amino, cyano and hydroxyl halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy; R.sub.3 is
selected from the group consisting of H, hydroxyl, alkyl, aryl,
alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,
nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R.sub.4 is selected from the group consisting of H, hydroxyl,
alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and
hydroxy, halogen, nitro, amino and cyano-substituted alkyl, aryl,
alkoxy or aryloxy; and, R.sub.7 is selected from the group
consisting of H, hydrocarbyl and substituted hydrocarbyl. 8. The
compound of paragraph 7 wherein R.sub.7 is selected from the group
consisting of carbocyclic aryl and alkyl. 9. The compound of
paragraph 7 wherein said compound is represented by the formula
II:
##STR00003##
10. The compound of paragraph 9 wherein R.sub.1 is OH. 11. The
compound of paragraph 9 wherein R.sub.2 is selected from the group
consisting of H, alkyl and halogen substituted alkyl. 12. The
compound of paragraph 11 wherein R.sub.2 is selected from the group
consisting of fluoro-substituted alkyl. 13. The compound of
paragraph 10 wherein X is N or CH. 14. The compound of paragraph 7
wherein said compound is represented by formula III.
##STR00004##
15. The compound of paragraph 10 wherein R.sub.3 is selected from
the group consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy,
halogen, nitro, amino, cyano and hydroxy, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy. 16. The compound
of paragraph 10 wherein R.sub.3 is chloro or bromo. 17. The
compound of paragraph 10 wherein R.sub.4 is selected from the group
consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen,
nitro, amino, cyano and hydroxy, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy. 18. The compound
of paragraph 10 wherein R.sub.4 is H. 19. The compound of paragraph
10 wherein Y is absent, i.e. n is 0. 20. The compound of paragraph
10 wherein Z is 0. 21. The compound of paragraph 10 wherein W is
selected from the group consisting of alkyl, aryl, alkoxy, aryloxy
and hydroxy, halogen, nitro, amino and cyano-substituted alkyl,
aryl, alkoxy or aryloxy. 22. The compound of paragraph 10 wherein W
is alkyl. 23. The compound of paragraph 10 wherein W is a branched
chain alkyl. 24. The compound of paragraph 10 wherein W is
2-ethylbutyl or 2-methylpropyl. 25. The compound of paragraph 10
that is selected from the group consisting of: [0013]
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid,
[0014]
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid, [0015]
1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid,
[0016] 1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid, [0017]
1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid, [0018]
1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic
acid, [0019]
1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid,
[0020] 1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic
acid, [0021]
1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic
acid, [0022]
1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, [0023]
1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, [0024]
1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid,
[0025]
1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxyli-
c acid, [0026]
1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, [0027]
1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, [0028]
2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid and
[0029] 2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic
acid. [0030]
1-(2-(Trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid, [0031]
1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-car-
boxylic acid, [0032]
1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic
acid, [0033]
1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylic
acid, [0034]
1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic
acid, and, [0035]
1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxy-
lic acid. 26. A method comprising administering a compound having
the following formula
##STR00005##
[0035] X is N or CR.sub.7;
[0036] A is N or CR.sub.7 with the proviso that at least one A is N
and when each A is N, R.sub.2 is absent; Y is (CH.sub.2).sub.m
wherein m is 0 or an integer of from 1 to 3; Z is selected from the
group consisting of O, S, SO, SO.sub.2 and (CH.sub.2).sub.p,
wherein p is 0 or an integer of from 1 to 3; W is hydrocarbyl or
substituted hydrocarbyl; R.sub.1 is selected from the group
consisting of OR.sub.7, N(R.sub.7).sub.2, and
N(R.sub.7)SO.sub.2R.sub.7; R.sub.2 is selected from the group
consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen,
nitro, amino, cyano and hydroxy, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy; R.sub.3 is
selected from the group consisting of H, hydroxy, alkyl, aryl,
alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,
nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R.sub.4 is selected from the group consisting of H, hydroxy, alkyl,
aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy,
halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or
aryloxy; and, R.sub.7 is selected from the group consisting of H,
hydrocarbyl and substituted hydrocarbyl, e.g. carbocyclic aryl and
alkyl. 27. The method of paragraph 26 wherein said compound is
administered to treat DP1, FP, EP.sub.1, TP and/or EP.sub.4
receptor mediated diseases or conditions. 28. The method of
paragraph 27 wherein said condition or disease is related to
inflammation. 29. The method of paragraph 27 wherein said DP1, FP,
EP.sub.1, TP and/or EP.sub.4 receptor mediated condition or disease
is selected from the group consisting of allergic conditions,
asthma, allergic asthma, allergic rhinitis, uveitis and related
disorders, atherosclerosis, blood coagulation disorders, bone
disorders, cancer, cellular neoplastic transformations, chronic
obstructive pulmonary diseases and other forms of lung
inflammation, congestive heart failure, diabetic retinopathy,
diseases or conditions requiring a treatment of anti-coagulation,
diseases requiring control of bone formation and resorption,
endometriosis, fertility disorders, gangrene, glaucoma,
hyperpyrexia, immune and autoimmune diseases, inflammatory
conditions, metastic tumor growth, migraine, mucus secretion
disorders, nasal congestion, nasal inflammation, occlusive vascular
diseases, ocular hypertension, ocular hypotension, osteoporosis,
pre-term labor rheumatoid arthritis, pain, perennial rhinitis,
pulmonary congestion, pulmonary hypotension, Raynaud's disease,
rejection in organ transplant and by-pass surgery, respiratory
conditions, hirsutism, rhinorrhea, shock, sleep disorders, and
sleep-wake cycle disorders. 30. The method of paragraph 27 wherein
said compound is administered as a surgical adjunct in
ophthalmology for cataract removal and artificial lens insertion,
ocular implant procedures, photorefractive radial keratotomy and
other ophthamological laser procedures. 31. The method of paragraph
27 wherein said compound is administered as a surgical adjunct in a
procedure involving skin incisions, relief of pain and inflammation
and scar formation/keloids post-surgery, for treating sports
injuries and general aches and pains in muscles and joints. 32. The
method of paragraph 27 wherein said DP.sub.1, FP, EP.sub.1, TP,
and/or EP.sub.4 receptor mediated condition or disease is an
EP.sub.1 and/or EP.sub.4 receptor mediated condition or disease.
33. The method of paragraph 27 wherein said DP.sub.1, FP, EP.sub.1,
TP and/or EP.sub.4 receptor mediated condition or disease is an
allergic condition. 34. The method of paragraph 33 wherein said
condition is dermatological allergy. 35. The method of paragraph 27
wherein said condition is an ocular allergy. 36. The method of
paragraph 27 wherein said condition is a respiratory allergy. 37.
The method of paragraph 27 wherein said condition or disease is
selected from the group consisting of nasal congestion, rhinitis,
and asthma. 38. The method of paragraph 27 wherein said condition
or disease is related to pain. 39. The method of paragraph 27
wherein said condition or disease is selected from the group
consisting of arthritis, migraine, and headache. 40. The method of
paragraph 27 wherein said condition or disease is associated with
the gastrointestinal tract. 41. The method of paragraph 27 wherein
said condition or disease is selected from the group consisting of
peptic ulcer, heartburn, reflux esophagitis, erosive esophagitis,
non-ulcer dyspepsia, infection by Helicobacter pylori, alrynitis,
and irritable bowel syndrome. 42. The method of paragraph 27
wherein said condition or disease is selected from the group
consisting of hyperalgesia and allodynia. 43. The method of
paragraph 27 wherein said condition or disease is related to mucus
secretion. 44. The method of paragraph 27 wherein said mucus
secretion is gastrointestinal. 45. The method of paragraph 27
wherein said mucus secretion occurs in the nose, sinuses, throat,
or lungs. 46. The method of paragraph 27 wherein said condition or
disease is related to abdominal cramping. 47. The method of
paragraph 27 wherein said condition or disease is irritable bowel
syndrome. 48. The method of paragraph 27 wherein said condition or
disease is a bleeding disorder. 49. The method of paragraph 27
wherein said condition or disease is a sleep disorder. 50. The
method of paragraph 27 wherein said condition or disease is
mastocytosis. 51. The method of paragraph 27 wherein said condition
or disease is associated with elevated body temperature. 52. The
method of paragraph 27 wherein said condition or disease is
associated with ocular hypertension and glaucoma. 53. The method of
paragraph 27 wherein said condition or disease is associated with
ocular hypotension. 54. The method of paragraph 27 wherein said
condition relates to surgical procedures to treat pain,
inflammation and other unwanted sequelae wherein said surgical
procedure includes incision, laser surgery or implantation. 55. The
method of paragraph 27 where said condition is related to pain and
inflammation and post-surgical scar and keloid formation. 56. The
method of paragraph where said condition is related to diseases of
female reproduction, associated with menstrual cramping,
endometriosis, and pre-term labor
[0037] A pharmaceutical product comprising a compound having the
following formula
##STR00006##
wherein X is N or CR.sub.7; A is N or CR.sub.7 with the proviso
that at least one A is N and when each A is N, R.sub.2 is absent; Y
is (CH.sub.2).sub.m wherein m is 0 or an integer of from 1 to 3; Z
is selected from the group consisting of O, S, SO, SO.sub.2 and
(CH.sub.2).sub.p, wherein p is 0 or an integer of from 1 to 3; W is
hydrocarbyl or substituted hydrocarbyl: R.sub.1 is selected from
the group consisting of OR.sub.7, N(R.sub.7).sub.2, and
N(R.sub.7)SO.sub.2R.sub.7; R.sub.2 is selected from the group
consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen,
nitro, amino, cyano and hydroxy, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy; R.sub.3 is
selected from the group consisting of H, hydroxy, alkyl, aryl,
alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,
nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R.sub.4 is selected from the group consisting of H, hydroxy, alkyl,
aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy,
halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or
aryloxy; and, R.sub.7 is selected from the group consisting of H,
hydrocarbyl and substituted hydrocarbyl, e.g. carbocyclic aryl and
alkyl or a pharmaceutically acceptable salt or a prodrug thereof.
59. The compound of paragraphs 1-58 wherein the compounds are PG
antagonists. 60. The compounds of paragraphs 1-58 wherein the
compounds are useful for treating or reducing the symptoms of a
DP.sub.1, FP, EP.sub.1, TP EP.sub.1 or EP.sub.4 receptor mediated
condition or disease and wherein said compound is packaged and
labeled for the treatment or prevention of a disease or condition
selected from the group consisting of uveitis, allergic conditions,
asthma, allergic asthma, allergic rhinitis, atherosclerosis, blood
coagulation disorders, bone disorders, cancer, cellular neoplastic
transformations, chronic obstructive pulmonary diseases and other
forms of lung inflammation, congestive heart failure, diabetic
retinopathy, diseases or conditions requiring a treatment of
anti-coagulation, diseases requiring control of bone formation and
resorption, endometriosis fertility disorders, hyperpyrexia,
gangrene, glaucoma, hypothermia, immune and autoimmune diseases,
inflammatory conditions, menstrual cramping, metastic tumor growth,
migraine, mucus secretion disorders, nasal congestion, nasal
inflammation, occlusive vascular diseases, ocular hypertension,
ocular hypotension, osteoporosis, pain, perennial rhinitis,
pre-term labor pulmonary congestion, pulmonary hypotension,
Raynaud's disease, rejection in organ transplant and by-pass
surgery, respiratory conditions, rheumatoid arthritis, rhinorrhea,
shock, sleep disorders, sleep-wake cycle disorders, sports
injuries, muscle aches and pains, and surgical adjunct for
minimizing pain, inflammation and scar/keloid formation. 58. A
pharmaceutical composition comprising a compound having the
following formula
##STR00007##
Wherein X is N or CR.sub.7;
[0038] A is N or CR.sub.7 with the proviso that at least one A is N
and when each A is N, R.sub.2 is absent; Y is (CH.sub.2).sub.m
wherein m is 0 or an integer of from 1 to 3; Z is selected from the
group consisting of O, S, SO, SO.sub.2 and (CH.sub.2).sub.p,
wherein p is 0 or an integer of from 1 to 3; W is hydrocarbyl or
substituted hydrocarbyl: R.sub.1 is selected from the group
consisting of OR.sub.7, N(R.sub.7).sub.2, and
N(R.sub.7)SO.sub.2R.sub.7; R.sub.2 is selected from the group
consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen,
nitro, amino, cyano and hydroxy, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy; R.sub.3 is
selected from the group consisting of H, hydroxy, alkyl, aryl,
alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,
nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R.sub.4 is selected from the group consisting of H, hydroxy, alkyl,
aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy,
halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or
aryloxy; and, R.sub.7 is selected from the group consisting of H,
hydrocarbyl and substituted hydrocarbyl, e.g. carbocyclic aryl and
alkyl or a pharmaceutically acceptable salt or a prodrug thereof,
and a pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0039] FIGS. 1, 2, 3 and 4 show reaction schemes for the
preparation of the compounds of this invention.
DETAILED DESCRIPTION OF THE INVENTION
[0040] The following terms are used to define the disclosed
invention.
"Hydrocarbyl" refers to a hydrocarbon radical having only carbon
and hydrogen atoms. Preferably, the hydrocarbyl radical has from 1
to 20 carbon atoms, more preferably from 1 to 12 carbon atoms and
most preferably from 1 to 7 carbon atoms.
[0041] "Substituted hydrocarbyl" refers to a hydrocarbyl radical
wherein one or more, but not all, of the hydrogen and/or the carbon
atoms are replaced by a halogen, nitrogen, oxygen, sulfur or
phosphorus atom or a radical including a halogen, nitrogen, oxygen,
sulfur or phosphorus atom, e.g. fluoro, chloro, cyano, nitro,
hydroxyl, phosphate, thiol, etc.
[0042] "Alkyl" refers to a straight-chain, branched or cyclic
saturated aliphatic hydrocarbon. Preferably, the alkyl group has 1
to 12 carbons. More preferably, it is an alkyl of from 4 to 10
carbons, most preferably 4 to 8 carbons. Typical alkyl groups
include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary
butyl, pentyl, hexyl and the like. The alkyl group may be
optionally substituted with one or more substituents selected from
the group consisting of hydroxyl, cyano, alkoxy, .dbd.O, .dbd.S,
NO.sub.2, halogen, dimethyl amino, and SH.
[0043] "Cycloalkyl" refers to a cyclic saturated aliphatic
hydrocarbon group. Preferably, the cycloalkyl group has 3 to 12
carbons. More preferably, it has from 4 to 7 carbons, most
preferably 5 or 6 carbons.
[0044] "Aryl" refers to an aromatic group which has at least one
ring having a conjugated pi electron system and includes
carbocyclic aryl, heterocyclic aryl and biaryl groups. The aryl
group may be optionally substituted with one or more substituents
selected from the group consisting of alkyl, hydroxyl, halogen,
COOR.sup.6, NO.sub.2, CF.sub.3, N(R.sup.6).sub.2,
CON(R.sup.6).sub.2, SR.sup.6, sulfoxy, sulfone, CN and OR.sup.6,
wherein R.sup.6 is alkyl.
[0045] "Carbocyclic aryl" refers to an aryl group wherein the ring
atoms are carbon.
[0046] "Heteroaryl or heterocyclic aryl" refers to an aryl group
having from 1 to 3 heteroatoms as ring atoms, the remainder of the
ring atoms being carbon. Heteroatoms include oxygen, sulfur, and
nitrogen. Thus, heterocyclic aryl groups include furanyl, thienyl,
pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl,
imidazolyl and the like. Preferably, the heteroaryl group has from
2 to 10 carbons. More preferably, it has from 3 to 10 carbons, most
preferably 3 carbons.
[0047] Pharmaceutical compositions contemplated herein include
compositions wherein the active ingredient is contained in an
effective amount, i.e., in an amount effective to achieve its
intended purpose. An "effective amount" is an amount sufficient to
accomplish a stated purpose (e.g., achieve the effect for which it
is administered, treat a disease, reduce one or more symptoms of a
disease or condition). An example of an "effective amount" is an
amount sufficient to contribute to the treatment, prevention, or
reduction of a symptom or symptoms of a disease, which can be
referred to as a "therapeutically effective amount." A "reduction"
of a symptom or symptoms (and grammatical equivalents of this
phrase) means decreasing of the severity or frequency of the
symptom(s), or elimination of the symptom(s). The actual amount
effective for a particular application will depend, inter alia, on
the condition being treated.
"Treatment", "treat" or "treating" can refer to curing any disease
or condition or reducing or alleviating the symptoms of the disease
or condition. The present invention provides compounds having the
general formula I:
##STR00008##
wherein X is N or CR.sub.7 independently; A is N or CR.sub.7 with
the proviso that at least one A is N and when each A is N, R.sub.2
is absent; Y is (CH.sub.2).sub.m wherein m is 0 or an integer of
from 1 to 3; Z is selected from the group consisting of O, S, SO,
SO.sub.2 and (CH.sub.2).sub.p, wherein p is 0 or an integer of from
1 to 3; W is hydrocarbyl or substituted hydrocarbyl: R.sub.1 is
selected from the group consisting of OR.sub.7, N(R.sub.7).sub.2,
and N(R.sub.7)SO.sub.2R.sub.7; R.sub.2 is selected from the group
consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen,
nitro, amino, cyano and hydroxy, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy; R.sub.3 is
selected from the group consisting of H, hydroxy, alkyl, aryl,
alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,
nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R.sub.4 is selected from the group consisting of H, hydroxy, alkyl,
aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy,
halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or
aryloxy; and R.sub.7 is selected from the group consisting of H,
hydrocarbyl and substituted hydrocarbyl, e.g. carbocyclic aryl and
alkyl.
[0048] More preferably, the compound of the invention is
represented by the formula II:
##STR00009##
[0049] Most preferably, the compound of the invention is
represented by the formula III:
##STR00010##
Preferably, R.sub.1 is OH;
[0050] Preferably, R.sub.2 is selected from the group consisting of
H, alkyl and halogen substituted alkyl, e.g. fluoro-substituted
alkyl;
Preferably, X is N or CH;
[0051] Preferably, R.sub.3 is selected from the group consisting of
H, hydroxyl, alkyl, aryl, alkoxy, aryloxy, halogen, nitro, amino,
cyano and hydroxyl, halogen, nitro, amino and cyano-substituted
alkyl, aryl, alkoxy or aryloxy. More preferably R.sub.3 is chloro
or bromo; Preferably, R.sub.4 is selected from the group consisting
of H, hydroxyl, alkyl, aryl, alkoxy, aryloxy, halogen, nitro,
amino, cyano and hydroxyl, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy. More preferably
R.sub.4 is H; Preferably, Y is absent, i.e. n is 0; Preferably, Z
is O; Preferably, W is selected from the group consisting of alkyl,
aryl, alkoxy, aryloxy and hydroxyl, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy; More preferably W
is selected from the group consisting of alkyl, e.g. branched chain
alkyl such as 2-ethylbutyl, 2-methylpropyl, etc. The most preferred
compounds of the present invention are selected from the group
consisting of: [0052]
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid;
[0053]
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid; [0054]
1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;
[0055] 1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0056]
1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid; [0057]
1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic
acid; [0058]
1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;
[0059] 1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic
acid; [0060] 1-[5-Chloro-2-(4-chloro-benzyl
oxy)-benzyl]-1H-indazole-5-carboxylic acid; [0061]
1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0062]
1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0063]
1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid;
[0064] 1-[5-Bromo-2-(4-chloro-benzyl
oxy)-benzyl]-1H-indazole-5-carboxylic acid; [0065]
1-(5-Bromo-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0066]
1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0067]
2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;
[0068] 2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic
acid; [0069]
1-(2-(Trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0070]
1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-car-
boxylic acid; [0071]
1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0072]
1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylic
acid; [0073]
1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-3-methyl-1h-indazole-5-carboxyl-
ic acid; [0074]
1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1h-indazole-5-carboxylic
acid; [0075]
1-(5-chloro-2-isobutoxy-benzyl)-3-methyl-1h-indazole-5-carboxylic
acid; [0076]
1-(2-isobutoxy-5-trifluoromethyl-benzyl)-3-methyl-1h-indazole-5-ca-
rboxylic acid; [0077]
1-[2-(2-ethyl-butoxy)-5-trifluoromethyl-benzyl]-3-methyl-1h-indazole-5-ca-
rboxylic acid; [0078]
1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1h-indazole-5-carboxylic
acid; [0079]
1-[5-bromo-2-(1-methyl-cyclopropylmethoxy)-benzyl]-3-methyl-1h-indazole-5-
-carboxylic acid; [0080]
1-[5-chloro-2-(1-methyl-cyclopropylmethoxy)-benzyl]-3-methyl-1h-indazole--
5-carboxylic acid; [0081]
1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic
acid; [0082]
1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxy-
lic acid; [0083]
1-[2-(4-Chloro-benzyloxy)-5-trifluoromethyl-benzyl]-1H-indazole-5-carboxy-
lic acid; [0084]
1-(2-Cyclopentylmethoxy-5-trifluoromethyl-benzyl)-1H-indazole-5-carboxyli-
c acid; [0085]
1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-4-carboxylic
acid; [0086]
2-(5-Chloro-2-cyclopropylmethoxy-benzyl)-2H-indazole-4-carboxylic
acid; [0087]
1-(5-Chloro-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;
[0088] 2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-4-carboxylic
acid; [0089]
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-4-carboxylic
acid; [0090]
2-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-2H-indazole-4-carboxylic
acid; [0091]
1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-4-carboxylic
acid; [0092]
2-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-2H-indazole-4-carboxyli-
c acid; [0093]
1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-6-carboxylic acid;
[0094] 2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-6-carboxylic
acid; [0095]
1-(5-Bromo-2-cyclopentylmethoxy-benzyl)-1H-indazole-6-carboxylic
acid; [0096]
2-(5-Bromo-2-cyclopentylmethoxy-benzyl)-2H-indazole-6-carboxylic
acid; [0097]
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic
acid; [0098]
1-(5-Chloro-3-fluoro-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0099]
1-(2-Isobutoxy-5-methanesulfonyl-benzyl)-1H-indazole-5-carboxylic
acid; [0100]
1-(4,5-Dichloro-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;
[0101]
1-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxyl-
ic acid; [0102]
1-[5-Bromo-2-(1-ethyl-propoxy)-benzyl]-1H-indazole-5-carboxylic
acid; [0103]
1-[5-Bromo-2-(2,2-dimethyl-propoxy)-benzyl]-1H-indazole-5-carboxyl-
ic acid; [0104]
1-[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1H-indazole-5-carboxyli-
c acid; [0105]
1-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;
[0106]
1-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylic
acid; [0107]
1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0108]
1-(5-Chloro-2-isobutoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-carbo-
xylic acid; [0109]
1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-pyrazolo[3,4-b]pyridine-5-ca-
rboxylic acid; [0110]
1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-
-5-carboxylic acid; [0111]
1-[5-CHLORO-2-(2-ethyl-butoxy)-benzyl]-3-methyl-1H-pyrazolo[3,4-b]pyridin-
e-5-carboxylic acid; [0112]
1-(5-Chloro-2-isobutoxy-benzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-car-
boxylic acid; [0113]
1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-c]pyridine-5-carbo-
xylic acid amide; [0114]
1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-c]pyridine-5-carbo-
xylic acid; [0115]
1-(5-bromo-2-isobutoxy-benzyl)-3-ethyl-1h-indazole-5-carboxylic
acid; [0116]
1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-3-ethyl-1h-indazole-5-carbox-
ylic acid; [0117]
1-(5-bromo-2-isobutoxy-benzyl)-2-methyl-1h-indole-5-carboxylic
acid; [0118] 1-(5-bromo-2-isobutoxy-benzyl)-1h-indole-5-carboxylic
acid; [0119]
1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-2-methyl-1h-indole-5-carboxylic
acid; [0120]
1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-indole-5-carboxylic acid;
[0121] 1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-indole-6-carboxylic
acid; [0122]
1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-1h-indole-5-carboxylic
acid; [0123]
1-(5-bromo-2-isobutoxy-benzyl)-1h-pyrrolo[2,3-b]pyridine-5-carboxy-
lic acid; [0124]
1-(5-bromo-2-isobutoxy-benzyl)-1h-pyrrolo[3,2-b]pyridine-5-carboxylic
acid; [0125]
1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-1h-pyrrolo[2,3-b]pyridine-5-car-
boxylic acid; [0126]
1-(2-isobutoxy-5-trifluoromethoxy-benzyl)-3-methyl-1h-indole-5-carboxylic
acid; [0127]
1-[2-(2-ethyl-butoxy)-5-trifluoromethoxy-benzyl]-1h-pyrrolo[2,3-b]pyridin-
e-5-carboxylic acid; [0128]
1-[2-(2-ethyl-butoxy)-5-trifluoromethoxy-benzyl]-3-methyl-1h-indole-5-car-
boxylic acid; [0129]
1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-benzoimidazole-5-carboxylic
acid; [0130]
1-(5-bromo-2-isobutoxy-benzyl)-1h-benzoimidazole-5-carboxylic acid;
[0131]
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid; [0132]
1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid;
[0133] 1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0134]
1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid; [0135]
1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic
acid; [0136]
1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid;
[0137] 1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic
acid; [0138]
1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic
acid; [0139]
1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0140]
1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0141]
1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid;
[0142]
1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxyli-
c acid; [0143]
1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0144]
1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0145]
2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid;
[0146] 2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic
acid; [0147]
1-(2-(Trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0148]
1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-car-
boxylic acid; [0149]
1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic
acid; [0150]
1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylic
acid; [0151]
1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic
acid; and, [0152]
1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxy-
lic acid.
[0153] As shown in FIGS. 1, 2, 3 and 4, the compounds of the
present invention may be prepared by the methods disclosed in the
Examples.
The following examples are intended to illustrate the present
invention. The reagents and conditions used in FIGS. 1, 2, 3 and 4
and the examples may be abbreviated as follows: Ac is acetyl; DCM
is dichloromethane; DTAD is Di-tert-butyl azodicarboxylate; TFA is
trifluoroacetic acid; RT is room temperature; Ph is phenyl; DiBAL-H
is diisobutylaluminumhydride; DMF is dimethylformamide; Et is
ethyl; THF is tetrahydrofuran; DMAP is 4-dimethylaminopyridine;
HEPES is 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid).
EXAMPLE 1
1-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-INDOLE-5-CARBOXYLIC ACID
3
##STR00011##
[0154] STEP 1
2-Bromomethyl-1-chloro-4-(2-ethyl-butoxy)-benzene 1
##STR00012##
[0156] To a solution of 4-chloro-2-methylphenol 5 g (35 mmol) in
DMF (75 mL) were added potassium carbonate 10 g (70 mmol),
tetrabutylammonium iodide 0.5 g (1.4 mmol) and
3-chloromethylpentane 7.7 ml (52.6 mmol). The resulting mixture was
refluxed for 20 hours. The mixture was poured into 2M NaOH solution
and extracted with EtOAC. The organic layers were combined, washed
with aqueous HCl and with brine, dried (MgSO.sub.4) and the
volatiles were removed in vacuo. The crude product (5.1 g) was used
without further purification. LC-MS: m/z 227 M+H.sup.+.
[0157] A solution of 1-chloro-4-(2-ethyl-butoxy)-2-methyl-benzene
(5.1 g, 22.5 mmol), N-bromosuccinimide (4.8 g, 27 mmol) and
benzoylperoxide (0.27 g, 1.1 mmol) in CCl.sub.4 (50 mL) was
refluxed under illumination from a high energy lamp for 3 hours.
The reaction mixture was cooled to room temperature and partitioned
between water (50 mL) and CH.sub.2Cl.sub.2 (25 mL). The aqueous
layer was extracted with CH.sub.2Cl.sub.2 (25 mL). The combined
organic layers were washed with water (2.times.75 mL), dried
(Na.sub.2SO.sub.4) and evaporated to dryness to give bromide 1 as a
light brown oil, 3.9 g (57%).
[0158] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.25
.quadrature..quadrature. (m.quadrature..quadrature.,
2H.quadrature..quadrature..quadrature., ArH),
.quadrature..quadrature..quadrature.6.80 (dd, 1H, ArH), 4.50 (s,
2H, ArCH), 3.93 (dd, 2H, CH.sub.2), 1.73 (m, 1H, --CH), 1.54 (m,
4H, --CH.sub.2), 0.94 (m, 6H, --CH.sub.3). LC-MS: m/z 306
M+H.sup.+
STEP 2
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1h-indole-5-carboxylic acid
methyl ester 2
##STR00013##
[0160] To a solution of
2-bromomethyl-1-chloro-4-(2-ethyl-butoxy)-benzene 1 0.11 g (0.63
mmol) in DMF (2.5 mL) were added potassium carbonate 0.24 g (1.74
mmol), tetrabutylammonium iodide 0.02 g and methyl
indole-5-carboxylate 0.22 g (1.26 mmol). The resulting mixture was
heated at 150.degree. C. in an Emrys microwave reactor for 20
minutes. The mixture was poured into water and extracted with
EtOAc. The organic layers were combined, washed with aqueous HCl
(20 ml, 2M) and with brine (20 mL), dried (MgSO.sub.4) and the
volatiles were removed in vacuo. The crude product was purified on
silica to yield
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid
methyl ester 2 0.04 g as a white solid (16%).
[0161] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.43 (d, 1H, ArH),
7.91 (dd, 1H, ArH), 7.32 (d, 1H, ArH), 7.19 (dd, 2H, ArH),
.quadrature.6.85 (d, 1H, ArH), 6.70 (dd, 1H, ArH), 6.66 (dd, 1H,
ArH), 5.31 (s, 2H, ArCH.sub.2), 3.95 (s, 2H, CH.sub.3), 3.94 (dd,
2H, CH.sub.2) 1.70 (m, 1H, CII), 1.47 (m, 4H, CH.sub.2), 0.95 (m,
6H, CH.sub.3).
[0162] LC-MS: m/z 400 M+H.sup.+
STEP 3
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid
3
##STR00014##
[0164] To a solution of
1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid
methyl ester 2 0.04 g (0.1 mmol) in a mixture of THF (2 mL) and
methanol (1 ml) was added a solution of LiOH (0.12 g in 0.7 ml
H.sub.2O). The resulting mixture was heated at 100.degree. C. in an
Emrys microwave reactor for 10 minutes. The mixture was poured into
water (20 mL) and extracted with EtOAc (3.times.15 mL). The organic
layers were combined, washed with brine (30 mL), dried (MgSO.sub.4)
and the volatiles were removed in vacuo. The crude product was
purified on silica to yield 21.9 mg (57%) of
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indole-5-carboxylic acid
3 as a white solid.
[0165] .sup.1H-NMR (CDCl.sub.3, .quadrature.8.54 (s, 1H, ArH), 7.99
(dd, 1H, ArH), 7.37 (dd, 1H, ArH), 7.20 (dd, 2H, ArH),
.quadrature.6.86 (d, 1H, ArH), 6.74 (dd, 1H, ArH), 6.70 (dd, 1H,
ArH), 5.33 (s, 2H, ArCH.sub.2), 3.92 (dd, 2H, CH.sub.2) 1.70 (m,
1H, CH), 1.47 (m, 4H, CH.sub.2), 0.95 (m, 6H, CH.sub.3).
[0166] LC-MS: m/z 386 M+H.sup.+.
EXAMPLE 2
1-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-INDAZOLE-5-CARBOXYLIC
ACID 6
##STR00015##
[0167] STEP 1
1H-Indazole-5-carboxylic acid methyl ester 4
##STR00016##
[0169] A solution of 1H-indazole-5-carboxylic acid 0.25 g (1.54
mmol) in methanol (2.5 mL) and conc. H.sub.2SO.sub.4 (0.1 ml) was
heated at 100.degree. C. in an Emrys microwave reactor for 5
minutes. The mixture was poured into water (20 mL) and extracted
with EtOAc (3.times.15 mL). The organic layers were combined,
washed with saturated NaHCO.sub.3 and brine (30 mL), dried
(MgSO.sub.4) and the volatiles were removed in vacuo to yield of
1H-indazole-5-carboxylic acid methyl ester 0.086 g (32%) 4 as a
pale yellow solid.
[0170] .sup.1H-NMR (CDCl.sub.3, .delta. 8.58 (dd, 1H, ArH), 8.21
(d, 1H, ArH), 8.11 (dd, 1H, ArH), 7.54 (d, 2H, ArH),
.quadrature.3.98 (s, 3H, CH.sub.3).
[0171] LC-MS: m/z 177 M+H.sup.+
STEP 2
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid methyl ester, 5
##STR00017##
[0173] The title compound was prepared following the method in
Example 1, Step 2.
[0174] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.55
(dd, 1H, ArH), 8.18 (d, 1H, ArH), 8.05 (dd, 1H, ArH), 7.40 (d, 1H,
ArH), .quadrature.7.20 (dd, 1H, ArH), 6.84 (d, 1H, ArH), 6.80 (dd,
1H, ArH), 5.60 (s, 2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.91
(dd, 2H, CH.sub.2) 1.70 (m, 1H, CH), 1.47 (m, 4H, CH.sub.2), 0.94
(m, 6H, CH.sub.3). LC-MS: m/z 401 M+H.sup.+.
STEP 3
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid, 6
##STR00018##
[0176] The title compound was prepared following the method in
Example 1, Step 3.
[0177] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.66 (dd, 1H,
ArH), 8.22 (d, 1H, ArH), 8.11 (dd, 1H, ArH), 7.45 (d, 1H, ArH),
.quadrature.7.21 (dd, 1H, ArH), 6.85 (dd, 1H, ArH), 6.83 (d, 1H,
ArH), 5.62 (s, 2H, ArCH.sub.2), 3.91 (d, 2H, CH.sub.2) 1.70 (m, 1H,
CH), 1.47 (m, 4H, CH.sub.2), 0.95 (m, 6H, CH.sub.3).
[0178] LC-MS: m/z 387 M+H.sup.+.
EXAMPLE 3
1-(2-CHLORO-5-ISOBUTOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC ACID,
10
##STR00019##
[0179] STEP 1
1-(5-Chloro-2-methoxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 7
##STR00020##
[0181] A solution of 1H-indazole-5-carboxylic acid methyl ester, 4,
(0.05 g 0.28 mmol), triphenylphosphine (0.11 g, 0.43 mmol),
di-tert-butylazodicarboxylate (0.1 g, 0.43 mmol) and
(5-chloro-2-methoxy-phenyl)-methanol, (0.075 g, 0.43 mmol) in a
mixture of THF (1 mL) and toluene (1 ml) was heated at 120.degree.
C. in an Emrys microwave reactor for 20 min. The volatiles were
removed in vacuo. The crude product was purified on silica to yield
1-(5-chloro-2-methoxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 7. 0.035 g (38%).
[0182] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.54 (s, 1H, ArH),
8.17 (s, 1H, ArH), 8.07 (dd, 1H, ArH), 7.47 (dd, 1H, ArH), 7.22
(dd, 1H, ArH), 6.90 (d, 1H, ArH), 6.83 (dd, 1H, ArH), 5.59 (s, 2H,
ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.86 (s, 3H, CH.sub.3).
STEP 2
1-(2-Chloro-5-hydroxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 8
##STR00021##
[0184] To a solution of
1-(5-chloro-2-methoxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 8, 0.09 g (0.27 mmol) in dry DCM (10 ml) under N.sub.2 atm
at 0.degree. C., 2.0 ml of boron tribromide (1M in DCM) was added.
and the solution was allowed to warm to room temperature. The
mixture was stirred for 24 hours, quenched with MeOH and refluxed
for 3 hours. After cooling to room temperature, water was added and
the mixture was extracted with EtOAc and washed with brine. After
drying over MgSO.sub.4, the solvents were removed in vacuo to yield
0.05 g of 1-(2-chloro-5-hydroxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 8.
[0185] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.36 (s, 1H, ArH),
8.13 (s, 1H, ArH), 7.84 (m, 2H, ArH), 7.28 (d, 1H, ArH),
.quadrature.7.19 (dd, 1H, ArH), 6.93 (d, 1H, ArH), 5.52 (s, 2H,
ArCH.sub.2), 4.03 (s, 3H, CH.sub.3). LC-MS: m/z 317 M+H.sup.+
STEP 3
1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid
methyl ester, 9
##STR00022##
[0187] A solution of
1-(2-Chloro-5-hydroxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester 8 (0.1 g g 0.33 mmol), triphenylphosphine (0.173 g, 0.66
mmol), di-tert-butylazodicarboxylate (0.15 g, 0.66 mmol) and
2-methyl-1-propanol (0.061 mL, 0.66 mmol) in THF (3 mL) was at
120.degree. C. on microwave for 20 min. The volatiles were removed
in vacuo. The crude product was purified on silica to yield
1-(2-chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid
methyl ester, 9.
0.09 g (73%).
[0188] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature.8.55
(s, 1H, ArH), 8.18 (s, 1H, ArH), 8.05 (dd, 1H, ArH), 7.43 (d, 1H,
ArH), .quadrature.7.20 (dd, 1H, ArH), 6.83 (s, 1H, ArH), 6.81 (d,
1H, ArH), 5.62 (s, 2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.77
(d, 2H, CH.sub.2). 2.11 (m, 1H, CH), 1.04 (d, 6H, CH.sub.3).
[0189] LC-MS: m/z 373 M+H.sup.+.
STEP 4
1-(2-Chloro-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid,
10
##STR00023##
[0191] The title compound was prepared following the method in
Example 1, Step 3.
[0192] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.64 (s, 1H, ArH),
8.22 (s, 1H, ArH), 8.11 (dd, 1H, ArH), 7.47 (d, 1H, ArH),
.quadrature.7.21 (dd, 1H, ArH), 6.86 (d, 1H, ArH), 6.82 (d, 1H,
ArH), 5.63 (s, 2H, ArCH.sub.2), 3.78 (d, 2H, CH.sub.2). 2.10 (m,
1H, CH), 1.04 (d, 6H, CH.sub.3).
[0193] LC-MS: m/z 359 M+H.sup.+.
EXAMPLE 4
1-(2-BROMO-5-ISOBUTOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC ACID,
14
##STR00024##
[0194] STEP 1
1-(5-Bromo-2-methoxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 11
##STR00025##
[0196] The title compound was prepared following the method in
Example 3, Step 1. But using (5-bromo-2-methoxy-phenyl)-methanol,
instead of (5-chloro-2-methoxy-phenyl)-methanol,
[0197] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.54 (s, 1H, ArH),
8.17 (s, 1H, ArH), 8.07 (dd, 1H, ArH), 7.47 (dd, 1H, ArH),
.quadrature.7.22 (dd, 1H, ArH), 6.90 (d, 1H, ArH), 6.83 (dd, 1H,
ArH), 5.59 (s, 2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.86 (s,
3H, CH.sub.3).
[0198] LC-MS: m/z 376 M+H.sup.+
STEP 2
1-(2-Bromo-5-hydroxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 12
##STR00026##
[0200] The title compound was prepared following the method in
Example 3, Step 2.
[0201] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.56
(s, 1H, ArH), 8.18 (dd, 1H, ArH), 8.16 (dd, 1H, ArH),
.quadrature.7.58 (d, 1H, ArH), 7.42 (d, 1H, ArH), 7.35 (dd, 1H,
ArH), 6.90 (d, 1H, ArH), 5.47 (s, 2H, ArCH.sub.2), 3.97 (s, 3H,
CH.sub.3).
[0202] LC-MS: m/z 362 M+H.sup.+
STEP 3
1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 13
##STR00027##
[0204] The title compound was prepared following the method in
Example 3, Step 3.
[0205] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.55
(s, 1H, ArH), 8.17 (s, 1H, ArH), 8.06 (dd, 1H, ArH), 7.43 (d, 1H,
ArH), .quadrature.7.35 (dd, 1H, ArH), 6.99 (d, 1H, ArH), 6.76 (d,
1H, ArH), 5.61 (s, 2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.76
(d, 2H, CH.sub.2). 2.11 (m, 1H, CH), 1.03 (d, 6H, CH.sub.3).
[0206] LC-MS: m/z 418 M+H.sup.+
STEP 4
1-(2-Bromo-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid,
14
##STR00028##
[0208] The title compound was prepared following the method in
Example 1, Step 3.
[0209] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.65 (s, 1H, ArH),
8.21 (s, 1H, ArH), 8.11 (dd, 1H, ArH), 7.48 (d, 1H, ArH),
.quadrature.7.36 (dd, 1H, ArH), 7.02 (d, 1H, ArH), 6.77 (d, 1H,
ArH), 5.63 (s, 2H, ArCH.sub.2), 3.77 (d, 2H, CH.sub.2). 2.11 (m,
1H, CII), 1.03 (d, 6H, CH.sub.3), LC-MS: m/z 404 M+H.sup.+.
EXAMPLE 5
1-[2-BROMO-5-(2-ETHYL-BUTOXY)-BENZYL]-1H-INDAZOLE-5-CARBOXYLIC
ACID, 16
##STR00029##
[0210] STEP 1
1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic acid
methyl ester, 15
##STR00030##
[0212] The title compound was prepared following the method in
Example 3, Step 3.
[0213] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH),
8.18 (s, 1H, ArH), 8.05 (dd, 1H, ArH), 7.41 (d, 1H, ArH),
.quadrature.7.35 (dd, 1H, ArH), 6.95 (d, 1H, ArH), 6.80 (d, 1H,
ArH), 5.60 (s, 2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.90 (d,
2H, CH.sub.2). 1.69 (m, 1H, CH), 1.46 (m, 4H, CH.sub.2), 0.94 (t,
6H, CH.sub.3). LC-MS: m/z 446 M+H.sup.+
STEP 2
1-[2-Bromo-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-5-carboxylic
acid, 16
##STR00031##
[0215] The title compound was prepared following the method in
Example 1, Step 3.
[0216] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.65 (s, 1H, ArH),
8.22 (s, 1H, ArH), 8.11 (dd, 1H, ArH), 7.45 (d, 1H, ArH),
.quadrature.7.36 (dd, 1H, ArH), 6.99 (d, 1H, ArH), 6.80 (d, 1H,
ArH), 5.62 (s, 2H, ArCH.sub.2), 3.92 (s, 3H, CH.sub.3), 3.90 (d,
2H, CH.sub.2). 1.69 (m, 1H, CH), 1.46 (m, 4H, CH.sub.2), 0.94 (t,
6H, CH.sub.3). LC-MS: m/z 446 M+H.sup.+.
EXAMPLE 6
1-[2-CHLORO-5-(2-ETHYL-BUTOXY)-BENZYL]-1H-INDAZOLE-6-CARBOXYLIC
ACID, 21
##STR00032##
[0217] STEP 1
1H-Indazole-6-carboxylic acid methyl ester 17
##STR00033##
[0219] The title compound was prepared following the method in
Example 2, Step 1.
[0220] .sup.1H-NMR (CDCl.sub.3, .delta. 10.37 (broad s, 1H, --NH),
8.29 (s, 1H, ArH), 8.17 (s, 1H, ArH), 8.11 (dd, 1H, ArH), 7.85 (dd,
2H, ArH), .quadrature.3.99 (s, 3H, CH.sub.3).
[0221] LC-MS: m/z 177 M+H.sup.+
STEP 2
1-(2-Chloro-5-methoxy-benzyl)-1H-indazole-6-carboxylic acid methyl
ester, 18
##STR00034##
[0223] The title compound was prepared following the method in
Example 3, Step 1.
[0224] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.27 (s, 1H, ArH),
8.11 (s, 1H, ArH), 7.80 (m, 2H, ArH), 7.20 (dd, 1H, ArH), 6.89 (dd,
1H, ArH), 6.82 (d, 1H, ArH), 5.63 (s, 2H, ArCH.sub.2), 3.96 (s, 3H,
CH.sub.3), 3.89 (s, 3H, CH.sub.3).
[0225] LC-MS: m/z 331 M+H.sup.+
STEP 3
1-(2-Chloro-5-hydroxy-benzyl)-1H-indazole-6-carboxylic methyl
ester, 19
##STR00035##
[0227] The title compound was prepared following the method in
Example 3, Step 2.
[0228] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.33 (s, 1H, ArH),
8.13 (s, 1H, ArH), 7.84 (m, 2H, ArH), 7.29 (d, 1H, ArH), 7.19 (dd,
1H, ArH), 6.94 (d, 1H, ArH), 5.52 (s, 2H, ArCH.sub.2), 4.03 (s, 3H,
CH.sub.3).
[0229] LC-MS: m/z 331 M+H.sup.+
STEP 4
1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic
acid methyl ester 20
##STR00036##
[0231] The title compound was prepared following the method in
Example 3, Step 3.
[0232] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.18
(s, 1H, ArH), 8.13 (s, 1H, ArH), 7.83 (m, 2H, ArH), 7.20 (dd, 1H,
ArH), 6.84 (d, 1H, ArH), 6.72 (d, 1H, ArH), 5.65 (s, 2H,
ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.92 (d, 2H, CH.sub.2). 1.73
(m, 1H, CH), 1.48 (m, 4H, CH.sub.2), 0.95 (t, 6H, CH.sub.3).
[0233] LC-MS: m/z 401 M+H.sup.+
STEP 5
1-[2-Chloro-5-(2-ethyl-butoxy)-benzyl]-1H-indazole-6-carboxylic
acid, 21
##STR00037##
[0235] The title compound was prepared following the method in
Example 1, Step 3.
[0236] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.29
(s, 1H, ArH), 8.16 (s, 1H, ArH), 7.88 (m, 2H, ArH), 7.21 (dd, 1H,
ArH), .quadrature.6.85 (d, 1H, ArH), 6.82 (d, 1H, ArH), 5.68 (s,
2H, ArCH.sub.2), 3.93 (d, 2H, CH.sub.2). 1.76 (m, 1H, CH), 1.48 (m,
4H, CH.sub.2), 0.95 (t, 6H, CH.sub.3).
[0237] LC-MS: m/z 387 M+H.sup.+.
EXAMPLE 7
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-1H-INDAZOLE-4-CARBOXYLIC ACID,
25
##STR00038##
[0238] STEP 1
1-(5-Bromo-2-methoxy-benzyl)-1H-indazole-4-carboxylic acid methyl
ester, 22
##STR00039##
[0240] The title compound was prepared following the method in
Example 3, Step 1.
[0241] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.56 (s, 1H, ArH),
7.94 (d, 1H, ArH), 7.65 (d, 1H, ArH), 7.44 (dd, 1H, ArH),
.quadrature.6.98 (d, 1H, ArH), 6.76 (m, 2H, ArH), 5.61 (s, 2H,
ArCH.sub.2), 4.04 (s, 3H, CH.sub.3), 3.85 (s, 3H, CH.sub.3).
[0242] LC-MS: m/z 376 M+H.sup.+
STEP 2
1-(5-Bromo-2-hydroxy-benzyl)-1H-indazole-4-carboxylic acid methyl
ester, 23
##STR00040##
[0244] The title compound was prepared following the method in
Example 3, Step 2.
[0245] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 9.48
(s, 1H, ArOH), 8.59 (s, 1H, ArH), 7.98 (d, 1H, ArH), 7.78 (d, 1H,
ArH), 7.56 (dd, 1H, ArH), .quadrature.7.39 (d, 1H, ArH),
.quadrature.7.33 (dd, 1H, ArH), 6.89 (d, 1H, ArH), 5.49 (s, 2H,
ArCH.sub.2), 4.03 (s, 3H, CH.sub.3).
[0246] LC-MS: m/z 362 M+H.sup.+.
STEP 3
1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid methyl
ester, 24
##STR00041##
[0248] The title compound was prepared following the method in
Example 3, Step 3.
[0249] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.58 (s, 1H, ArH),
7.96 (d, 1H, ArH), 7.63 (d, 1H, ArH), 7.43 (dd, 1H, ArH),
.quadrature.7.33 (dd, 1H, ArH), .quadrature.6.91 (d, 1H, ArH), 6.76
(d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2), 4.05 (s, 3H, CH.sub.3),
3.76 (d, 2H, CH.sub.2). 2.12 (m, 1H, CH), 1.05 (d, 6H, CH.sub.3).
LC-MS: m/z 418 M+H.sup.+
STEP 4
1-(5-Bromo-2-isobutoxy-benzyl)-1H-indazole-4-carboxylic acid,
25
##STR00042##
[0251] The title compound was prepared following the method in
Example 1, Step 3.
[0252] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.67
(s, 1H, ArH), 8.07 (d, 1H, ArH), 7.71 (d, 1H, ArH), 7.48 (dd, 1H,
ArH), .quadrature.7.34 (dd, 1H, ArH), .quadrature.6.97 (d, 1H,
ArH), 6.77 (d, 1H, ArH), 5.68 (s, 2H, ArCH.sub.2), 3.78 (d, 2H,
CH.sub.2). 2.12 (m, 1H, CH), 1.05 (d, 6H, CH.sub.3).
[0253] LC-MS: m/z 404 M+H.sup.+.
EXAMPLE 8
1-(2-BENZYLOXY-5-CHLORO-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC ACID,
27
##STR00043##
[0254] STEP 1
1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid
methyl ester, 26
##STR00044##
[0256] To a solution of
1-(5-Chloro-2-hydroxy-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 8, 0.04 g (0.13 mmol) in acetonitrile (10 ml), benzyl
bromide (0.026 g, 0.15 mmol) and K.sub.2CO.sub.3 (0.026 g, 0.19
mmol) was added. The mixture was stirred under reflux for 2 hours,
then the solids were filtered off and the solvents were removed in
vacuo. The crude product was purified on silica to yield 0.05 g of
1-(2-benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid
methyl ester, 28 as a white solid.
[0257] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.52 (s, 1H, ArH), 8.16
(s, 1H, ArH), 7.92 (dd, 1H, ArH), 7.44-7.25 (m, 6H, ArH),
.quadrature.7.21 (dd, 1H, ArH), 6.96 (d, 1H, ArH), 6.89 (d, 1H,
ArH), 5.61 (s, 2H, ArCH.sub.2), 5.09 (s, 2H, ArCH.sub.2), 3.97 (s,
3H, CH.sub.3).
[0258] LC-MS: m/z 407 M+H.sup.+
STEP 2
1-(2-Benzyloxy-5-chloro-benzyl)-1H-indazole-5-carboxylic acid,
27
##STR00045##
[0260] The title compound was prepared following the method in
Example 1, Step 3.
[0261] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.62 (s, 1H, ArH), 8.20
(s, 1H, ArH), 7.96 (dd, 1H, ArH), 7.45-7.30 (m, 6H, ArH),
.quadrature.7.22 (dd, 1H, ArH), 7.01 (d, 1H, ArH), 6.91 (d, 1H,
ArH), 5.62 (s, 2H, ArCH.sub.2), 5.08 (s, 2H, ArCH.sub.2), 3.97 (s,
3H, CH.sub.3).
[0262] LC-MS: m/z 407 M+H.sup.+.
EXAMPLE 9
1-[5-CHLORO-2-(4-CHLORO-BENZYLOXY)-BENZYL]-1H-INDAZOLE-5-CARBOXYLIC
ACID, 29
##STR00046##
[0263] STEP 1
1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic
acid methyl ester, 28
##STR00047##
[0265] The title compound was prepared following the method in
Example 8, Step 1.
[0266] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.52 (s, 1H, ArH), 8.15
(s, 1H, ArH), 7.93 (dd, 1H, ArH), 7.38-7.17 (m, 6H, ArH), 6.98 (d,
1H, ArH), 6.85 (d, 1H, ArH), 5.58 (s, 2H, ArCH.sub.2), 5.01 (s, 2H,
ArCH.sub.2), 3.97 (s, 3H, CH.sub.3).
[0267] LC-MS: m/z 442 M+H.sup.+.
STEP 2
1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic
acid, 29
##STR00048##
[0269] The title compound was prepared following the method in
Example 1, Step 3.
[0270] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.63 (s, 1H, ArH), 8.20
(s, 1H, ArH), 8.00 (dd, 1H, ArH), 7.40-7.31 (m, 3H, ArH), 7.30-7.18
(m, 3H, ArH), 7.01 (d, 1H, ArH), 6.87 (d, 1H, ArH), 5.61 (s, 2H,
ArCH.sub.2), 5.04 (s, 2H, ArCH.sub.2).
[0271] LC-MS: m/z 428 M+H.sup.+.
EXAMPLE 10
1-(5-CHLORO-2-CYCLOPENTYLMETHOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 31
##STR00049##
[0272] STEP 1
1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 30
##STR00050##
[0274] The title compound was prepared following the method in
Example 3, Step 3.
[0275] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH), 8.17
(s, 1H, ArH), 8.06 (dd, 1H, ArH), 7.45 (dd, 1H, ArH), 7.19 (dd, 1H,
ArH), 6.86 (d, 1H, ArH), 6.81 (d, 1H, ArH), 5.30 (s, 2H,
ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.87 (d, 2H, CH.sub.2), 2.37
(m, 1H, CH), 1.92-0.81 (m, 8H, CH.sub.2). LC-MS: m/z 399
M+H.sup.+.
STEP 2
1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, 31
##STR00051##
[0277] The title compound was prepared following the method in
Example 1, Step 3.
[0278] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.66 (s, 1H, ArH), 8.22
(s, 1H, ArH), 8.12 (dd, 1H, ArH), 7.50 (d, 1H, ArH), 7.21 (d, 1H,
ArH), 6.91 (d, 1H, ArH), 6.82 (d, 1H, ArH), 5.62 (s, 2H,
ArCH.sub.2), 3.88 (d, 2H, CH.sub.2), 2.37 (m, 1H, CH), 1.83 (m, 2H,
CH.sub.2), 1.64 (m, 4H, CH.sub.2), 1.45-1.21 (m, 2H, CH.sub.2).
LC-MS: m/z 385 M+H.sup.+.
EXAMPLE 11
1-(5-CHLORO-2-CYCLOPROPYLMETHOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 33
##STR00052##
[0279] STEP 1
1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 32
##STR00053##
[0281] The title compound was prepared following the method in
Example 3, Step 3 and was used without purification in subsequent
step.
[0282] LC-MS: m/z 371 M+H.sup.+
STEP 2
1-(5-Chloro-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, 33
##STR00054##
[0284] The title compound was prepared following the method in
Example 1, Step 3.
[0285] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.63 (s, 1H,
ArH), 8.20 (s, 1H, ArH), 8.11 (dd, 1H, ArH), 7.63 (d, 1H, ArH),
7.20 (d, 1H, ArH), 7.06 (d, 1H, ArH), 6.77 (d, 1H, ArH), 5.64 (s,
2H, ArCH.sub.2), 3.82 (d, 2H, CH.sub.2), 1.24 (m, 1H, CH), 0.65 (m,
2H, CH.sub.2), 0.33 (m, 2H, CH.sub.2).
[0286] LC-MS: m/z 357 M+H.sup.+.
EXAMPLE 12
1-(2-BENZYLOXY-5-BROMO-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC ACID,
35
##STR00055##
[0287] STEP 1
1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid methyl
ester, 34
##STR00056##
[0289] The title compound was prepared following the method in
Example 8, Step 1.
[0290] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.52 (s, 1H, ArH), 8.16
(s, 1H, ArH), 7.91 (dd, 1H, ArH), 7.44-7.25 (m, 7H, ArH),
.quadrature.7.12 (dd, 1H, ArH), 6.84 (d, 1H, ArH), 5.60 (s, 2H,
ArCH.sub.2), 5.08 (s, 2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3).
[0291] LC-MS: m/z 452 M+H.sup.+
STEP 2
1-(2-Benzyloxy-5-bromo-benzyl)-1H-indazole-5-carboxylic acid,
35
##STR00057##
[0293] The title compound was prepared following the method in
Example 1, Step 3.
[0294] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.60 (s, 1H, ArH), 8.19
(s, 1H, ArH), 7.95 (dd, 1H, ArH), 7.43-7.29 (m, 7H, ArH),
.quadrature.7.17 (dd, 1H, ArH), 6.85 (d, 1H, ArH), 5.61 (s, 2H,
ArCH.sub.2), 5.08 (s, 2H, ArCH.sub.2).
[0295] LC-MS: m/z 438 M+H.sup.+.
EXAMPLE 13
1-[5-BROMO-2-(4-CHLORO-BENZYLOXY)-BENZYL]-1H-INDAZOLE-5-CARBOXYLIC
ACID, 37
##STR00058##
[0296] STEP 1
1-[5-Bromo-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic
acid methyl ester, 36
##STR00059##
[0298] The title compound was prepared following the method in
Example 8, Step 1.
[0299] H-NMR (CDCl.sub.3, 300 MHz) 8.52 (s, 1H, ArH), 8.15 (s, 1H,
ArH), 7.93 (dd, 1H, ArH), 7.42-7.17 (m, 6H, ArH), 7.14 (d, 1H,
ArH), 6.80 (d, 1H, ArH), 5.58 (s, 2H, ArCH.sub.2), 5.02 (s, 2H,
ArCH.sub.2), 3.97 (s, 3H, CH.sub.3).
[0300] LC-MS: m/z 486 M+H.sup.+
STEP 2
1-[5-Chloro-2-(4-chloro-benzyloxy)-benzyl]-1H-indazole-5-carboxylic
acid, 37
##STR00060##
[0302] The title compound was prepared following the method in
Example 1, Step 3.
[0303] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.63 (s, 1H,
ArH), 8.20 (s, 1H, ArH), 8.00 (dd, 1H, ArH), 7.43-7.17 (m, 6H,
ArH), 7.17 (d, 1H, ArH), 6.82 (d, 1H, ArH), 5.60 (s, 2H,
ArCH.sub.2), 5.03 (s, 2H, ArCH.sub.2).
[0304] LC-MS: m/z 428 M+H.sup.+.
EXAMPLE 14
1-(5-BROMO-2-CYCLOPENTYLMETHOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 39
##STR00061##
[0305] STEP 1
1-(5-Bromo-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 38
##STR00062##
[0307] The title compound was prepared following the method in
Example 3, Step 3.
[0308] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH), 8.17
(s, 1H, ArH), 8.05 (dd, 1H, ArH), 7.46 (dd, 1H, ArH), 7.34 (dd, 1H,
ArH), 7.02 (d, 1H, ArH), 6.77 (d, 1H, ArH), 5.59 (s, 2H,
ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.87 (d, 2H, CH.sub.2), 2.36
(m, 1H, CH), 1.91-0.81 (m, 8H, CH.sub.2).
[0309] LC-MS: m/z 444 M+H.sup.+
STEP 2
1-(5-Chloro-2-cyclopentylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, 39
##STR00063##
[0311] The title compound was prepared following the method in
Example 1, Step 3.
[0312] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.65 (s, 1H, ArH), 8.21
(s, 1H, ArH), 8.11 (dd, 1H, ArH), 7.50 (d, 1H, ArH), 7.35 (d, 1H,
ArH), 7.06 (d, 1H, ArH), 6.78 (d, 1H, ArH), 5.61 (s, 2H,
ArCH.sub.2), 3.87 (d, 2H, CH.sub.2), 2.36 (m, 1H, CH), 1.83 (m, 2H,
CH.sub.2), 1.91-1.17 (m, 8H, CH.sub.2).
[0313] LC-MS: m/z 430 M+H.sup.+.
EXAMPLE 15
1-(5-BROMO-2-CYCLOPROPYLMETHOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 41
##STR00064##
[0314] STEP 1
1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 40
##STR00065##
[0316] The title compound was prepared following the method in
Example 3, Step 3.
[0317] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.53 (s, 1H,
ArH), 8.16 (s, 1H, ArH), 8.05 (dd, 1H, ArH), 7.59 (d, 1H, ArH),
7.34 (dd, 1H, ArH), 7.18 (d, 1H, ArH), 6.71 (d, 1H, ArH), 5.61 (s,
2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.81 (d, 2H, CH.sub.2),
1.23 (m, 1H, CH), 0.92 (m, 2H, CH.sub.2), 0.63 (m, 2H,
CH.sub.2).
[0318] LC-MS: m/z 416 M+H.sup.+
STEP 2
1-(5-Bromo-2-cyclopropylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, 41
##STR00066##
[0320] The title compound was prepared following the method in
Example 1, Step 3.
[0321] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.61 (s, 1H, ArH), 8.19
(s, 1H, ArH), 8.09 (dd, 1H, ArH), 7.63 (d, 1H, ArH), 7.35 (dd, 1H,
ArH), 7.21 (d, 1H, ArH), 6.72 (d, 1H, ArH), 5.63 (s, 2H,
ArCH.sub.2), 3.81 (d, 2H, CH.sub.2), 1.26 (m, 1H, CH), 0.64 (m, 2H,
CH.sub.2), 0.32 (m, 2H, CH.sub.2).
[0322] LC-MS: m/z 402 M+H.sup.+.
EXAMPLE 16
2-(5-CHLORO-2-ISOBUTOXY-BENZYL)-2H-INDAZOLE-5-CARBOXYLIC ACID,
45
##STR00067##
[0323] STEP 1
2-(5-Chloro-2-methoxy-benzyl)-2H-indazole-5-carboxylic acid methyl
ester 42
##STR00068##
[0325] The title compound was prepared following the method in
Example 3, Step 1.
[0326] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.51
(s, 1H, ArH), 8.11 (s, 1H, ArH), 7.91 (dd, 1H, ArH), 7.73 (d, 1H,
ArH), 7.30 (dd, 1H, ArH), 7.16 (d, 1H, ArH), 6.87 (d, 1H, ArH),
5.60 (s, 2H, ArCH.sub.2), 3.95 (s, 3H, CH.sub.3), 3.88 (s, 3H,
CH.sub.3).
[0327] LC-MS: m/z 331 M+H.sup.+
STEP 2
2-(5-Chloro-2-hydroxy-benzyl)-2H-indazole-5-carboxylic acid methyl
ester 43
##STR00069##
[0329] The title compound was prepared following the method in
Example 3, Step 2.
[0330] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 10.53
(s, 1H, ArOH), 8.52 (s, 1H, ArH), 8.21 (s, 1H, ArH), 7.99 (dd, 1H,
ArH), 7.70 (d, 1H, ArH), 7.33-7.21 (m, 2H, ArH), 6.99 (d, 1H, ArH),
5.50 (s, 2H, ArCH.sub.2), 3.96 (s, 3H, CH.sub.3.
[0331] LC-MS: m/z 317 M+H.sup.+
STEP 3
2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid
methyl ester, 44
##STR00070##
[0333] The title compound was prepared following the method in
Example 3, Step 3.
[0334] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.49
(s, 1H, ArH), 8.09 (s, 1H, ArH), 7.91 (dd, 1H, ArH), 7.73 (d, 1H,
ArH), .quadrature.7.27 (dd, 1H, ArH), 7.14 (d, 1H, ArH), 6.83 (d,
1H, ArH), 5.62 (s, 2H, ArCH.sub.2), 3.94 (s, 3H, CH.sub.3), 3.76
(d, 2H, CH.sub.2). 2.10 (m, 1H, CH), 1.00 (d, 6H, CH.sub.3).
[0335] LC-MS: m/z 373 M+H.sup.+.
STEP 4
2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid,
45
##STR00071##
[0337] The title compound was prepared following the method in
Example 1, Step 3.
[0338] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.57 (s, 1H, ArH),
8.12 (s, 1H, ArH), 7.95 (dd, 1H, ArH), 7.76 (d, 1H, ArH),
.quadrature.7.28 (dd, 1H, ArH), 7.16 (d, 1H, ArH), 6.85 (d, 1H,
ArH), 5.63 (s, 2H, ArCH.sub.2), 3.77 (d, 2H, CH.sub.2). 2.11 (m,
1H, CII), 1.01 (d, 6H, CH.sub.3).
[0339] LC-MS: m/z 359 M+H.sup.+.
EXAMPLE 17
2-(5-BROMO-2-ISOBUTOXY-BENZYL)-2H-INDAZOLE-5-CARBOXYLIC ACID,
49
##STR00072##
[0340] STEP 1
2-(5-Bromo-2-methoxy-benzyl)-2H-indazole-5-carboxylic acid methyl
ester 46
##STR00073##
[0342] The title compound was prepared following the method in
Example 3, Step 1.
[0343] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.50 (s, 1H, ArH),
8.11 (s, 1H, ArH), 7.92 (dd, 1H, ArH), 7.73 (d, 1H, ArH), 7.45 (dd,
1H, ArH), 7.30 (d, 1H, ArH), 6.82 (d, 1H, ArH), 5.60 (s, 2H,
ArCH.sub.2), 3.95 (s, 3H, CH.sub.3), 3.87 (s, 3H, CH.sub.3).
[0344] LC-MS: m/z 376 M+H.sup.+.
STEP 2
2-(5-Bromo-2-hydroxy-benzyl)-2H-indazole-5-carboxylic acid methyl
ester 47
##STR00074##
[0346] The title compound was prepared following the method in
Example 3, Step 2.
[0347] .sup.1H-NMR (CDCl.sub.3, 300 MHz) 10.59 (broad s, 1H, ArOH),
8.52 (s, 1H, ArH), 8.21 (s, 1H, ArH), 7.99 (dd, 1H, ArH), 7.70 (d,
1H, ArH), 7.45-7.36 (m, 2H, ArH), 6.94 (d, 1H, ArH), 5.49 (s, 2H,
ArCH.sub.2), 3.96 (s, 3H, CH.sub.3.
[0348] LC-MS: m/z 362 M+H.sup.+.
STEP 3
2-(5-Chloro-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid
methyl ester, 48
##STR00075##
[0350] The title compound was prepared following the method in
Example 3, Step 3.
[0351] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. .quadrature.8.50
(s, 1H, ArH), 8.09 (s, 1H, ArH), 7.92 (dd, 1H, ArH), 7.73 (d, 1H,
ArH), .quadrature.7.43 (dd, 1H, ArH), 7.29 (d, 1H, ArH), 6.80 (d,
1H, ArH), 5.62 (s, 2H, ArCH.sub.2), 3.95 (s, 3H, CH.sub.3), 3.76
(d, 2H, CH.sub.2). 2.10 (m, 1H, CII), 1.00 (d, 6H, CH.sub.3).
[0352] LC-MS: m/z 417M+H.sup.+
STEP 4
2-(5-Bromo-2-isobutoxy-benzyl)-2H-indazole-5-carboxylic acid,
49
##STR00076##
[0354] The title compound was prepared following the method in
Example 1, Step 3.
[0355] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.60 (s, 1H, ArH),
8.12 (s, 1H, ArH), 7.96 (dd, 1H, ArH), 7.77 (d, 1H, ArH),
.quadrature.7.43 (dd, 1H, ArH), 7.32 (d, 1H, ArH), 6.80 (d, 1H,
ArH), 5.64 (s, 2H, ArCH.sub.2), 3.77 (d, 2H, CH.sub.2). 2.11 (m,
1H, CH), 1.01 (d, 6H, CH.sub.3).
EXAMPLE 18
1-(2-(TRIFLUOROMETHYL)-5-ISOBUTOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 53
##STR00077##
[0356] STEP 1
1-(5-(Trifluoromethyl)-2-methoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 50
##STR00078##
[0358] The title compound was prepared following the method in
Example 3, Step 1. But using
(5-(trifluoromethyl)-2-methoxy-phenyl)-methanol, instead of
(5-chloro-2-methoxy-phenyl)-methanol.
[0359] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.54 (s, 1H, ArH),
8.16 (s, 1H, ArH), 8.07 (dd, 1H, ArH), 7.53 (d, 1H, ArH), 7.45 (dd,
1H, ArH), .quadrature.7.23 (m, 1H, ArH), 6.94 (d, 1H, ArH), 5.62
(s, 2H, ArCH.sub.2), 3.91 (s, 3H, CH.sub.3), 3.90 (s, 3H,
CH.sub.3).
STEP 2
1-(2-(trifluoromethyl)-5-hydroxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 51
##STR00079##
[0361] The title compound was prepared following the method in
Example 3, Step 2
[0362] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.54 (s, 1H, ArH),
8.16 (s, 1H, ArH), 8.07 (dd, 1H, ArH), 7.53 (d, 1H, ArH), 7.45 (dd,
1H, ArH), .quadrature.7.23 (m, 1H, ArH), 6.94 (d, 1H, ArH), 5.54
(s, 2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3).
[0363] LC-MS: m/z 351 M+H.sup.+
STEP 3
1-(2-(trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 52
##STR00080##
[0365] The title compound was prepared following the method in
Example 3, Step 3.
[0366] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH),
8.17 (s, 1H, ArH), 8.05 (dd, 1H, ArH), 7.52 (dd, 1H, ArH), 7.43 (d,
1H, ArH), .quadrature.7.17 (m, 1H, ArH), 6.95 (d, 1H, ArH), 5.65
(s, 2H, ArCH.sub.2), 3.96 (s, 3H, CH.sub.3), 3.82 (d, 2H,
--OCH.sub.2CH(CH.sub.3).sub.2), 2.11 (m, 1H,
--OCH.sub.2CH(CH.sub.3).sub.2), 1.02 (d, 3H,
--OCH.sub.2CH(CH.sub.3).sub.2), 0.87 (d, 3H,
--OCH.sub.2CH(CH.sub.3).sub.2).
STEP 4
1-(2-(trifluoromethyl)-5-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid, 53
##STR00081##
[0368] The title compound was prepared following the method in
Example 1, Step 3.
[0369] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.66 (s, 1H, ArH),
8.22 (s, 1H, ArH), 8.12 (dd, 1H, ArH), 7.53 (dd, 1H, ArH), 7.47 (d,
1H, ArH), .quadrature.7.22 (m, 1H, ArH), 6.95 (d, 1H, ArH), 5.68
(s, 2H, ArCH.sub.2), 3.83 (d, 2H, --OCH.sub.2CH(CH.sub.3).sub.2),
2.14 (m, 1H, --OCH.sub.2CH(CH.sub.3).sub.2), 1.02 (d, 6H,
--OCH.sub.2CH(CH.sub.3).sub.2).
[0370] LC-MS: m/z 393 M+H.sup.+.
EXAMPLE 19
1-(5-BROMO-2-CYCLOPROPYL-2-METHYLMETHOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 55
##STR00082##
[0371] STEP 1
1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 54
##STR00083##
[0373] The title compound was prepared following the method in
Example 3, Step 3.
[0374] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.55 (s, 1H,
ArH), 8.15 (s, 1H, ArH), 8.05 (dd, 1H, ArH), 7.55 (d, 1H, ArH),
7.34 (dd, 1H, ArH), 7.10 (d, 1H, ArH), 6.70 (d, 1H, ArH), 5.65 (s,
2H, ArCH.sub.2), 3.97 (s, 3H, CH.sub.3), 3.75 (s, 2H, CH.sub.2),
1.20 (s, 3H, CH.sub.3), 0.55 (m, 2H, CH.sub.2), 0.45 (m, 2H,
CH.sub.2).
[0375] LC-MS: m/z 430 M+H.sup.+
STEP 2
1-(5-Bromo-2-cyclopropyl-2-methylmethoxy-benzyl)-1H-indazole-5-carboxylic
acid, 55
##STR00084##
[0377] The title compound was prepared following the method in
Example 1, Step 3.
[0378] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.65 (s, 1H,
ArH), 8.20 (s, 1H, ArH), 8.10 (dd, 1H, ArH), 7.60 (d, 1H, ArH),
7.34 (dd, 1H, ArH), 7.10 (d, 1H, ArH), 6.70 (d, 1H, ArH), 5.65 (s,
2H, ArCH.sub.2), 3.75 (s, 2H, CH.sub.2), 1.20 (s, 3H, CH.sub.3),
0.55 (m, 2H, CH.sub.2), 0.45 (m, 2H, CH.sub.2).
[0379] LC-MS: m/z 416 M+H.sup.+.
EXAMPLE 20
1-(2-ISOBUTOXY-5-TRIFLUOROMETHOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 60
##STR00085##
[0380] STEP 1
2-Isobutoxy-5-trifluoromethoxy-benzaldehyde, 56
##STR00086##
[0382] A solution of 2-Hydroxy-5-trifluoromethoxy-benzaldehyde (1.0
g, 4.9 mmole) in DMF (10 ml) was treated with potassium carbonate
(1.5 g, 10.9 mmole) and tetrabutylammonium iodide (0.01 g) and
1-chloro-2-methylpropane (1.05 ml, 10 mmole). The mixture was
stirred at 110.degree. C. under a nitrogen atmosphere for 18h. The
mixture was then evaporated to dryness and the residue partitioned
between ethyl acetate (50 ml) and water (50 ml). The organic
extract was separated then washed with saturated brine then dried
over sodium sulphate, filtered and evaporated to dryness. The
residue was chromatographed on silica gel eluting with a gradient
of 5-15% ethyl acetate/isohexane. This gave the title compound as a
pale yellow oil (1.02 g, 80%).
[0383] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 10.49 (s,
1H, CHO), 7.71 (d, 1H, ArH), 7.38 (dd, 1H, ArH), 6.95 (d, 1H, ArH),
3.89 (d, 2H, CH.sub.2), 2.15-2.28 (m, 1H, CH), 1.05 (d, 6H,
2.times.CH.sub.3).
STEP 2
(2-Isobutoxy-5-trifluoromethoxy-phenyl)-methanol, 57
##STR00087##
[0385] A solution of 2-Isobutoxy-5-trifluoromethoxy-benzaldehyde
(1.02 g, 3.9 mmole) in methanol (20 ml) was treated with sodium
borohydride (0.22 g, 5.8 mmole) then stirred at ambient temperature
under a nitrogen atmosphere for 2h. The mixture was evaporated to
dryness and the residue partitioned between water (50 ml) and
dichloromethane (2.times.50 ml). The combined organic extracts were
dried over sodium sulphate, filtered and evaporated to dryness. The
residue was chromatographed on silica gel eluting with a gradient
of 10-20% ethyl acetate/isohexane. This gave the title compound as
a colorless oil (1.0 g, 97%).
[0386] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 7.22
.quadrature..quadrature.s, 1H, ArH), 7.09 (dd, 1H, ArH), 6.41 (d,
1H, ArH), 4.71 (d, 2H, CH.sub.2), 3.81 (d, 2H, CH.sub.2), 2.23 (t,
1H, OH), 2.07-2.19 (m, 1H, CH), 1.07 (d, 6H, 2.times.CH.sub.3).
STEP 3
Methanesulfonic acid 2-isobutoxy-5-trifluoromethoxy-benzyl ester,
58
##STR00088##
[0388] A solution of
(2-Isobutoxy-5-trifluoromethoxy-phenyl)-methanol (1.0 g, 3.8 mmole)
in dichloromethane (50 ml) was treated with diisopropylethylamine
(0.73 ml, 4.2 mmole) and methanesulphonic anhydride (0.73 g, 4.2
mmole) then stirred at ambient temperature under a nitrogen
atmosphere for 1.5h. The mixture was then washed with water (50 ml)
and saturated brine (50 ml). The organic layer was dried over
sodium sulphate, filtered and evaporated to dryness to give the
title compound as a colorless oil (1.2 g, 92%).
[0389] H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.27.quadrature.(s, 1H,
ArH), 7.19 (dd, 1H, ArH), 6.92 (d, 1H, ArH), 5.29 (s, 2H,
CH.sub.2), 3.79 (d, 2H, CH.sub.2), 2.99 (s, 3H, CH.sub.3),
2.07-2.19 (m, 1H, CH), 1.05 (d, 6H, 2.times.CH.sub.3).
STEP 4
1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 59
##STR00089##
[0391] A solution of 1H-Indazole-5-carboxylic acid methyl ester
(0.154 g, 0.88 mmole) in DMF (5 ml) was treated with sodium hydride
(60% dispersion in oil) (0.042 g, 1 mmole) then stirred at ambient
temperature under a nitrogen atmosphere for 1h. A solution of
methanesulfonic acid 2-isobutoxy-5-trifluoromethoxy-benzyl ester
(0.3 g, 0.88 mmole) in DMF (5 ml) was then added and the mixture
stirred at ambient temperature for 18h. The mixture was evaporated
to dryness and the residue partitioned between water (20 ml) and
dichloromethane (2.times.20 ml). The combined organics were dried
over sodium sulphate, filtered and evaporated to dryness. The
residue was chromatographed using silica gel eluting with a
gradient of 5-20% ethyl acetate/isohexane to give in the early
fractions the title compound (0.217 g, 59%) as a white solid. The
corresponding 2-yl-indazole isomer eluted in the later column
fractions.
[0392] H-NMR (CDCl.sub.3, 300 MHz)
.delta..quadrature..quadrature.8.55 (s, 1H, ArH), 8.15 (s, 1H,
ArH), 8.01 (dd, 1H, ArH), 7.41 (d, 1H, ArH), 7.11 (dd, 1H, ArH),
6.88 (d, 1H, ArH), 6.71 (s, 1H, ArH), 5.61 (s, 2H, CH.sub.2), 3.99
(s, 3H, CH.sub.3), 3.78 (d, 2H, CH.sub.2), 2.05-2.19 (m, 1H, CH),
1.04 (d, 6H, 2.times.CH.sub.3).
STEP 5
1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylic
acid, 60
##STR00090##
[0394] A solution of
1-(2-Isobutoxy-5-trifluoromethoxy-benzyl)-1H-indazole-5-carboxylicacidmet-
hyl ester (0.217 g, 0.51 mmole) in 1,4-dioxane (20 ml) was treated
with 2M sodium hydroxide (20 ml) and the mixture stirred at
60.degree. C. for 18h. The mixture was evaporated to dryness and
the residue dissolved in water (20 ml) then acidified to pH1 with
2M hydrochloric acid. The resulting precipitate was extracted into
ethyl acetate (2.times.50 ml). The combined organics were dried
over sodium sulphate, filtered and evaporated to dryness. The
residue was chromatographed on silica gel eluting with a gradient
of 0.75-2% methanol/dichloromethane to give the title compound as a
white solid (0.154 g, 73%).
[0395] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.68 (s, 1H,
ArH), 8.21 (s, 1H, ArH), 8.11 (dd, 1H, ArH), 7.48 (d, 1H, ArH),
7.11 (dd, 1H, ArH), 6.88 (d, 1H, ArH), 6.72 (s, 1H, ArH), 5.67 (s,
2H, CH.sub.2), 3.79 (d, 2H, CH.sub.2), 2.05-2.19 (m, 1H, CH), 1.03
(d, 6H, 2.times.CH.sub.3).
[0396] LC-MS m/z 409 M+H.sup.+.
EXAMPLE 21
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-3-METHYL-1H-INDAZOLE-5-CARBOXYLIC
ACID, 65
##STR00091##
[0397] STEP 1
5-Bromo-2-isobutoxy-benzaldehyde, 61
##STR00092##
[0399] The title compound was prepared following the method in
Example 20, Step 1.
[0400] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 10.52 (s,
1H, CHO), 7.95 (d, 1H, ArH), 7.61 (dd, 1H, ArH), 6.93 (s, 1H, ArH),
3.85 (d, 2H, CH.sub.2), 2.12-2.24 (m, 1H, CH), 1.09 (d, 6H,
2.times.CH.sub.3).
STEP 2
(5-Bromo-2-isobutoxy-phenyl)-methanol, 62
##STR00093##
[0402] The title compound was prepared following the method in
Example 20, Step 2.
[0403] H-NMR (CDCl.sub.3, 300 MHz) .delta. 7.45 (d, 1H, ArH), 7.36
(dd, 1H, ArH), 6.77 (d, 1H, ArH), 4.69 (d, 2H, CH.sub.2), 3.78 (d,
2H, CH.sub.2), 2.27 (t, 1H, OH), 2.07-2.21 (m, 1H, CH), 1.07 (d,
6H, 2.times.CH.sub.3).
STEP 3
Methanesulfonic acid 5-bromo-2-isobutoxy-benzyl ester, 63
##STR00094##
[0405] The title compound was prepared following the method in
Example 20, Step 3.
[0406] H-NMR (CDCl.sub.3, 300 MHz) .delta. .quadrature.7.49 (d, 1H,
ArH), 7.45 (dd, 1H, ArH), 6.79 (d, 1H, ArH), 5.27 (s, 2H,
CH.sub.2), 3.77 (d, 2H, CH.sub.2), 3.01 (s, 3H, CH.sub.3),
2.07-2.20 (m, 1H, CH), 1.06 (d, 6H, 2.times.CH.sub.3).
STEP 4
1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylic
acid methyl ester, 64
##STR00095##
[0408] To a mixture of methanesulfonic acid
5-bromo-2-isobutoxy-benzyl ester (0.044 g, 0.1 mmole) and
3-Methyl-1H-indazole-5-carboxylic acid methyl ester (0.02 g, 0.1
mmole) in DMF was added cesium carbonate (0.051 g, 0.15 mmole) and
the mixture stirred at ambient temperature for 18h under a nitrogen
atmosphere. The mixture was evaporated to dryness and the residue
partitioned between water (10 ml) and dichloromethane (2.times.20
ml). The combined organics were dried over sodium sulphate,
filtered and evaporated to dryness. The residue was chromatographed
on silica gel eluting with a gradient of 5-20% ethyl
acetate/isohexane to give the title compound (0.04 g) as a
colorless oil.
[0409] H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.48 (s, 1H,
ArH), 8.02 (d, 1H, ArH), 7.30-7.37 (m, 2H, 2.times.ArH), 6.96 (d,
1H, ArH), 6.76 (d, 1H, ArH), 5.52 (s, 2H, CH.sub.2), 3.99 (s, 3H,
CH.sub.3), 3.77 (d, 2H, CH.sub.2), 2.65 (s, 3H, CH.sub.3),
2.05-2.19 (m, 1H, CH), 1.04 (d, 6H, 2.times.CH.sub.3).
STEP 5
1-(5-Bromo-2-isobutoxy-benzyl)-3-methyl-1H-indazole-5-carboxylic
acid, 65
##STR00096##
[0411] The title compound was prepared following the method in
Example 20, Step 5.
[0412] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.59 (s,
1H, ArH), 8.09 (d, 1H, ArH), 7.33-7.41 (m, 2H, 2.times.ArH), 6.98
(d, 1H, ArH), 6.77 (d, 1H, ArH), 5.59 (s, 2H, CH.sub.2), 3.78 (d,
2H, CH.sub.2), 2.68 (s, 3H, CH.sub.3), 2.07-2.20 (m, 1H, CH), 1.06
(d, 6H, 2.times.CH.sub.3).
[0413] LC-MS m/z 417 and 419 M+H.sup.+.
EXAMPLE 22
1-(2-ISOBUTOXY-5-TRIFLUOROMETHOXY-BENZYL)-3-METHYL-1H-INDAZOLE-5-CARBOXYLI-
C ACID, 66
##STR00097##
[0415] The title compound was prepared following the methods
described on Example 21 but using compound 58 as the starting
material.
[0416] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH), 8.08
(dd, 1H, ArH), 7.35 (d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.95 (d, 1H,
ArH), 6.71 (d, 1H, ArH), 5.58 (s, 2H, CH.sub.2), 3.79 (d, 2H,
CH.sub.2), 2.66 (s, 3H, CH.sub.3), 2.07-2.21 (m, 1H, CH), 1.05 (d,
6H, 2.times.CH.sub.3).
EXAMPLE 23
1-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-3-METHYL-1H-INDAZOLE-5-CARBOXYLIC
ACID, 67
##STR00098##
[0418] The title compound was prepared following the methods
described on Example 21 but using 2-Hydroxy-5-chloro-benzaldehyde
as starting material.
[0419] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.58 (s, 1H, ArH), 8.07
(dd, 1H, ArH), 7.34 (d, 1H, ArH), 7.18 (dd, 1H, ArH), 6.85 (d, 1H,
ArH), 6.76 (d, 1H, ArH), 5.56 (s, 2H, CH.sub.2), 3.91 (d, 2H,
CH.sub.2), 2.66 (s, 3H, CH.sub.3), 1.63-1.78 (m, 1H, CH), 1.41-1.53
(m, 4H, 2.times.CH.sub.2), 0.94 (t, 6H, 2.times.CH.sub.3).
EXAMPLE 24
1-(5-CHLORO-2-ISOBUTOXY-BENZYL)-3-METHYL-1H-INDAZOLE-5-CARBOXYLIC
ACID, 68
##STR00099##
[0421] The title compound was prepared following the methods
described on Example 21 but using 2-Hydroxy-5-chloro-benzaldehyde
as starting material.
[0422] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.59 (s, 1H, ArH), 8.09
(dd, 1H, ArH), 7.37 (d, 1H, ArH), 7.18 (dd, 1H, ArH), 6.79 (s, 1H,
ArH), 6.77 (d, 1H, ArH), 5.55 (s, 2H, CH.sub.2), 3.78 (d, 2H,
CH.sub.2), 2.67 (s, 3H, CH.sub.3), 2.04-2.29 (m, 1H, CH), 1.03 (d,
6H, 2.times.CH.sub.3).
EXAMPLE 25
1-(2-ISOBUTOXY-5-TRIFLUOROMETHYL-BENZYL)-3-METHYL-1H-INDAZOLE-5-CARBOXYLIC
ACID, 69
##STR00100##
[0424] The title compound was prepared following the methods
described on Example 21 but using
2-Hydroxy-5-(trifluoromethyl)-benzaldehyde as starting
material.
[0425] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.59 (s, 1H, ArH), 8.11
(dd, 1H, ArH), 7.55 (dd, 1H, ArH), 7.39 (d, 1H, ArH), 7.19 (d, 1H,
ArH), 6.97 (d, 1H, ArH), 5.61 (s, 2H, CH.sub.2), 3.85 (d, 2H,
CH.sub.2), 2.69 (s, 3H, CH.sub.3), 2.05-2.21 (m, 1H, CH), 1.03 (d,
6H, 2.times.CH.sub.3).
EXAMPLE 26
1-[2-(2-ETHYL-BUTOXY)-5-TRIFLUOROMETHYL-BENZYL]-3-METHYL-1H-INDAZOLE-5-CAR-
BOXYLIC ACID, 70
##STR00101##
[0427] The title compound was prepared following the methods
described on Example 21 but using
2-Hydroxy-5-(trifluoromethyl)-benzaldehyde as starting
material.
[0428] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.59 (s, 1H, ArH), 8.09
(dd, 1H, ArH), 7.56 (dd, 1H, ArH), 7.38 (d, 1H, ArH), 7.16 (d, 1H,
ArH), 6.99 (d, 1H, ArH), 5.61 (s, 2H, CH.sub.2), 3.97 (d, 2H,
CH.sub.2), 2.66 (s, 3H, CH.sub.3), 1.68-1.79 (m, 1H, CH), 1.45-1.54
(m, 4H, 2.times.CH.sub.2), 0.97 (t, 6H, 2.times.CH.sub.3).
EXAMPLE 27
1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-3-METHYL-1H-INDAZOLE-5-CARBOXYLIC
ACID, 71
##STR00102##
[0430] The title compound was prepared following the methods
described on Example 21 but using 2-Hydroxy-5-bromo-benzaldehyde as
starting material.
[0431] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.59 (s, 1H, ArH), 8.09
(dd, 1H, ArH), 7.31-7.39 (m, 2H, 2.times.ArH), 6.96 (d, 1H, ArH),
6.79 (d, 1H, ArH), 5.55 (s, 2H, CH.sub.2), 3.92 (d, 2H, CH.sub.2),
2.69 (s, 3H, CH.sub.3), 1.66-1.76 (m, 1H, CH), 1.42-1.54 (m, 4H,
2.times.CH.sub.2), 0.95 (t, 6H, 2.times.CH.sub.3).
EXAMPLE 28
1-[5-BROMO-2-(1-METHYL-CYCLOPROPYLMETHOXY)-BENZYL]-3-METHYL-1H-INDAZOLE-5--
CARBOXYLIC ACID, 72
##STR00103##
[0433] The title compound was prepared following the methods
described on Example 21 but using 2-Hydroxy-5-bromo-benzaldehyde as
starting material.
[0434] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.59 (s, 1H, ArH), 8.12
(dd, 1H, ArH), 7.48 (d, 1H, ArH), 7.34 (dd, 1H, ArH), 7.09 (d, 1H,
ArH), 6.71 (d, 1H, ArH), 5.58 (s, 2H, CH.sub.2), 3.77 (s, 2H,
CH.sub.2), 2.67 (s, 3H, CH.sub.3), 1.23 (s, 3H, CH.sub.3),
0.42-0.59 (m, 4H, 2.times.CH.sub.2).
EXAMPLE 29
1-[5-CHLORO-2-(1-METHYL-CYCLOPROPYLMETHOXY)-BENZYL]-3-METHYL-1H-INDAZOLE-5-
-CARBOXYLIC ACID, 73
##STR00104##
[0436] The title compound was prepared following the methods
described on Example 21 but using 2-Hydroxy-5-chloro-benzaldehyde
as starting material.
[0437] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.58 (s, 1H, ArH), 8.08
(d, 1H, ArH), 7.47 (d, 1H, ArH), 7.19 (dd, 1H, ArH), 6.95 (d, 1H,
ArH), 6.74 (d, 1H, ArH), 5.58 (s, 2H, CH.sub.2), 3.78 (s, 2H,
CH.sub.2), 2.69 (s, 3H, CH.sub.3), 1.22 (s, 3H, CH.sub.3),
0.43-0.57 (m, 4H, 2.times.CH.sub.2).
EXAMPLE 30
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-1H-PYRROLO[2,3-B]PYRIDINE-5-CARBOXYLIC
ACID, 77
##STR00105##
[0438] STEP 1
5-bromo-1H-pyrrolo[2,3-B]pyridine, 74
##STR00106##
[0440] Following the preparation procedure described in
WO2006015124, which is hereby incorporated by reference in its
entirety, 5-bromo-1H-pyrrolo[2,3-b]pyridine was isolated after
column chromatography on silica as a light brown solid (30% over 3
steps). LC-MS: m/z 198, 200 M+H.sup.+.
STEP 2
1h-pyrrolo[2,3-B]pyridine-5-carboxylic acid methyl ester, 75
##STR00107##
[0442] To a mixture of 5-Bromo-1H-pyrrolo[2,3-b]pyridine 0.6 g (3
mmol), molybdenum hexacarbonate 0.4 g (1.5 mmol), Herrmann's
catalyst 0.28 g, 4,4-bis(diphenylphosphino)-9,9-dimethylxanthane
and triethylamine 0.85 ml (6 mmol) in a 20 ml microwave reactor THF
(10 ml) and methanol (2 ml) was added. The resulting suspension was
heated at 150.degree. C. on microwave for 10 minutes. The mixture
was poured into sat NH.sub.4Cl (aq.) and extracted twice with
EtOAC. The organic layers were combined, washed with sat NH.sub.4Cl
(aq.), dried (MgSO.sub.4) and the volatiles were removed in vacuo.
The crude product was purified on silica to yield
1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester 2 0.16 g
as a brown solid (30%).
[0443] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.28 (d, 1H, ArH),
8.86 (d, 1H, ArH), 8.25 (s, 1H, ArH), 4.02 (s, 3H, CH.sub.3) LC-MS:
m/z 178 M+H.sup.+
STEP 3
1-(5-Bromo-2-isobutoxy-benzyl)-1H-pyrazolo[3,4-13]pyridine-5-carboxylic
acid methyl ester, 76
##STR00108##
[0445] The title compound was prepared following the method in
Example 21, Step 4.
[0446] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.22 (d, 1H, ArH),
8.79 (d, 1H, ArH), 8.19 (s, 1H, ArH), 7.34 (dd, 1H, ArH), 6.98 (d,
1H, ArH), 6.74 (d, 1H, ArH), 5.77 (s, 2H, ArCH.sub.2), 4.01 (s, 3H,
CH.sub.3), 3.72 (d, 2H, CH.sub.2). 2.01 (m, 1H, CH), 0.97 (d, 6H,
CH.sub.3).
[0447] LC-MS: m/z 374, 376 M+H.sup.+
STEP 4
1-(5-bromo-2-isobutoxy-benzyl)-1h-pyrazolo[3,4-13]pyridine-5-carboxylic
acid, 77
##STR00109##
[0449] The title compound was prepared following the method in
Example 20, Step 5.
[0450] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.28 (s, 1H, ArH),
8.85 (s, 1H, ArH), 8.18 (s, 1H, ArH), 7.33 (d, 1H, ArH), 6.99 (s,
1H, ArH), 6.74 (d, 1H, ArH), 5.76 (s, 2H, ArCH.sub.2), 3.71 (d, 2H,
CH.sub.2). 2.01 (m, 1H, CH), 0.96 (d, 6H, CH.sub.3).
[0451] LC-MS: m/z 405 M+H.sup.+.
EXAMPLE 31
1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-PYRROLO[2,3-B]PYRIDINE-5-CARBOXYL-
IC ACID, 82
##STR00110##
[0452] STEP 1
5-Bromo-2-(2-ethyl-butoxy)-benzaldehyde 78
##STR00111##
[0454] A solution of 5-bromosalicaldehyde (2.0 g, 10 mmole) in DMF
(50 ml) was treated with potassium carbonate (3 g, 22 mmole) and
tetrabutylammonium iodide (0.22 g) and 3-chloromethylpentane (1.65
ml, 12.2 mmole). The mixture was stirred at 110.degree. C. under a
nitrogen atmosphere for 18h. The mixture was then evaporated to
dryness and the residue partitioned between ethyl acetate (50 ml)
and water (50 ml). The organic extract was separated then washed
with saturated brine then dried over sodium sulphate, filtered and
evaporated to dryness. The residue was chromatographed on silica
gel eluting with a gradient of 5-15% ethyl acetate/isohexane. This
gave the title compound as a pale yellow oil (2.24 g, 78%).
[0455] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 010.49 (s, 1H,
CHO), 7.95 (d, 1H, ArH), 7.63 (dd, 1H, ArH), 6.90 (d, 1H, ArH),
4.00 (d, 2H, CH.sub.2), 1.80 (m, 1H, CH), 1.55 (s, 4H,
2.times.CH.sub.2--CH.sub.3), 1.00 (q, 6H,
2.times.CH.sub.2--CH.sub.3)
STEP 2
[5-Bromo-2-(2-ethyl-butoxy)-phenyl]-methanol, 79
##STR00112##
[0457] The title compound was prepared following the method in
Example 20, Step 2.
[0458] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 7.45
(d, 1H, ArH), 7.37 (dd, 1H, ArH), 6.80 (d, 1H, ArH), 4.70 (d, 2H,
--CH.sub.2OH), 3.90 (d, 2H, CH.sub.2), 1.80 (m, 1H, CH), 1.55 (s,
4H, 2.times.CH.sub.2--CH.sub.3), 1.00 (q, 6H,
2.times.CH.sub.2--CH.sub.3).
STEP 3
Methanesulfonic acid 5-bromo-2-(2-ethyl-butoxy)-benzyl ester,
80
##STR00113##
[0460] The title compound was prepared following the method in
Example 20, Step 3.
[0461] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 7.55
(d, 1H, ArH), 7.45 (dd, 1H, ArH), 6.80 (d, 1H, ArH), 5.75 (d, 2H,
--CH.sub.2OSO2CH.sub.3), 3.90 (d, 2H, CH.sub.2), 3.00 (s, 3H,
CH.sub.2OSO2CH.sub.3), 1.80 (m, 1H, CH), 1.55 (s, 4H,
2.times.CH.sub.2--CH.sub.3), 1.00 (q, 6H,
2.times.CH.sub.2--CH.sub.3)
STEP 4
1-[5-Bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxy-
lic acid methyl ester, 81
##STR00114##
[0463] The title compound was prepared following the method in
Example 21, Step 4.
[0464] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.21 (d, 1H, ArH),
8.80 (d, 1H, ArH), 8.19 (s, 1H, ArH), 7.34 (dd, 1H, ArH), 6.95 (d,
1H, ArH), 6.77 (d, 1H, ArH), 5.76 (s, 2H, ArCH.sub.2), 4.01 (s, 3H,
CH.sub.3), 3.85 (d, 2H, CH.sub.2). 1.60 (m, 1H, CH), 1.39 (m, 4H,
CH.sub.2), 0.88 (m, 6H, CH.sub.3).
[0465] LC-MS: m/z 446, 448 M+H.sup.+
STEP 5
1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-13]pyridine-5-carbox-
ylic acid, 82
##STR00115##
[0467] The title compound was prepared following the method in
Example 20, Step 5.
[0468] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.30 (d, 1H, ArH),
8.87 (d, 1H, ArH), 8.24 (s, 1H, ArH), 7.36 (dd, 1H, ArH), 7.00 (d,
1H, ArH), 6.78 (d, 1H, ArH), 5.78 (s, 2H, ArCH.sub.2), 3.86 (d, 2H,
CH.sub.2). 1.60 (m, 1H, CH), 1.39 (m, 4H, CH.sub.2), 0.89 (m, 6H,
CH.sub.3).
[0469] LC-MS: m/z 432,434 M+H.sup.+.
EXAMPLE 32
1-[2-(4-CHLORO-BENZYLOXY)-5-TRIFLUOROMETHYL-BENZYL]-1H-INDAZOLE-5-CARBOXYL-
IC ACID, 83
##STR00116##
[0471] The title compound was prepared starting from compound 51
and following the methods in Example 8, Step 1 and Example 1, step
3.
[0472] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.65 (s, 1H, ArH),
8.20 (s, 1H, ArH), 8.00 (d, 1H, ArH), 7.55 (d, 1H, ArH), 7.40-7.20
(m, 6H, ArH), 7.00 (d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2O), 5.05
(s, 2H, ArCH.sub.2Het).
[0473] LC-MS: m/z 461 M+H.sup.+.
EXAMPLE 33
1-(2-CYCLOPENTYLMETHOXY-5-TRIFLUOROMETHYL-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 84
##STR00117##
[0475] The title compound was prepared starting from compound 51
and following the methods in Example 3, Step 3 and Example 1, step
3.
[0476] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH),
8.20 (s, 1H, ArH), 8.10 (d, 1H, ArH), 7.65 (d, 1H, ArH), 7.53 (d,
1H, ArH), 7.42 (s, 1H, ArH), 6.87 (d, 1H, ArH), 5.65 (s, 2H,
ArCH.sub.2Het), 4.85 (d, 2H, --CH.sub.2O--), 1.7 (m, 1H, CH),
1.4-0.6 (m, 8H, --CH.sub.2--). LC-MS: m/z 391 M+H.sup.+.
EXAMPLE 34
1-(5-CHLORO-2-CYCLOPROPYLMETHOXY-BENZYL)-1H-INDAZOLE-4-CARBOXYLIC
ACID, 85
##STR00118##
[0478] The title compound was prepared following the same method as
Example 7.
[0479] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.62 (s, 1H, ArH),
8.05 (d, 1H, ArH), 7.82 (d, 1H, ArH), 7.45 (m, 1H, ArH), 7.20 (m,
1H, ArH), 7.00 (s, 1H, ArH), 6.75 (m, 1H, ArH), 5.65 (s, 2H,
ArCH.sub.2Het), 3.80 (d, 2H, --CH.sub.2O--), 1.55 (m, 1H, CH), 0.7
(m, 2H, --CH.sub.2--), 0.4 (m, 2H, --CH.sub.2--). LC-MS: m/z 357
M+H.sup.+.
EXAMPLE 35
2-(5-CHLORO-2-CYCLOPROPYLMETHOXY-BENZYL)-2H-INDAZOLE-4-CARBOXYLIC
ACID, 86
##STR00119##
[0481] The title compound was prepared following the same method as
Example 7.
[0482] .sup.1H-NMR (DMSO, 300 MHz) .delta. 8.70 (s, 1H, ArH), 8.05
(d, 1H, ArH), 7.85 (d, 1H, ArH), 7.75 (d, 1H, ArH), 7.32 (m, 2H,
ArH), 7.20 (s, 1H, ArH), 7.00 (d, 1H, ArH), 5.65 (s, 2H,
ArCH.sub.2Het), 3.85 (d, 2H, --CH.sub.2O--), 1.70 (m, 1H, CH), 0.55
(m, 2H, --CH.sub.2--), 0.3 (m, 2H, --CH.sub.2--). LC-MS: m/z
357M+W.
EXAMPLE 36
1-(5-CHLORO-2-ISOBUTOXY-BENZYL)-1H-INDAZOLE-4-CARBOXYLIC ACID,
87
##STR00120##
[0484] The title compound was prepared following the same method as
Example 7.
[0485] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.62 (s, 1H, ArH),
8.05 (d, 1H, ArH), 7.70 (d, 1H, ArH), 7.45 (m, 1H, ArH), 7.15 (m,
1H, ArH), 6.80 (m, 2H, ArH), 5.65 (s, 2H, ArCH.sub.2Het), 3.75 (d,
2H, --CH.sub.2O--), 2.10 (m, 1H, CH), 1.05 (d, 6H, --CH.sub.3).
[0486] LC-MS: m/z 359 M+H.sup.+.
EXAMPLE 37
2-(5-CHLORO-2-ISOBUTOXY-BENZYL)-2H-INDAZOLE-4-CARBOXYLIC ACID,
88
##STR00121##
[0488] The title compound was prepared following the same method as
Example 7.
[0489] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH),
8.15 (m, 2H, ArH), 7.40 (t, 1H, ArH), 7.25 (m, 1H, ArH), 7.10 (s,
1H, ArH), 6.80 (d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2Het), 3.75 (d,
2H, --CH.sub.2O--), 2.15 (m, 1H, CH), 1.05 (d, 6H, --CH.sub.3).
[0490] LC-MS: m/z 359 M+H.sup.+.
EXAMPLE 38
1-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-INDAZOLE-4-CARBOXYLIC
ACID, 89
##STR00122##
[0492] The title compound was prepared following the same method as
Example 7.
[0493] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.65 (s, 1H, ArH),
8.05 (d, 1H, ArH), 7.65 (d, 1H, ArH), 7.52 (t, 1H, ArH), 7.18 (m,
1H, ArH), 6.85 (d, 1H, ArH), 6.75 (m, 1H, ArH), 5.65 (s, 2H,
ArCH.sub.2Het), 3.90 (d, 2H, --CH.sub.2O--), 1.50 (m, 1H, CH), 1.45
(t, 4H, --CH.sub.2CH.sub.3), 0.95 (t, 6H, --CH.sub.2CH.sub.3).
LC-MS: m/z 387 M+H.sup.+.
EXAMPLE 39
2-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-2H-INDAZOLE-4-CARBOXYLIC
ACID, 90
##STR00123##
[0495] The title compound was prepared following the same method as
Example 7.
[0496] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.50 (s, 1H, ArH),
8.02 (m, 2H, ArH), 7.40 (t, 1H, ArH), 7.25 (m, 1H, ArH), 7.15 (s,
1H, ArH), 6.82 (d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2Het), 3.90 (d,
2H, --CH.sub.2O--), 1.70 (m, 1H, CH), 1.45 (t, 4H,
--CH.sub.2CH.sub.3), 0.85 (t, 6H, --CH.sub.2CH.sub.3).
[0497] LC-MS: m/z 387 M+H.sup.+.
EXAMPLE 40
1-[5-CHLORO-2-(4-CHLORO-BENZYLOXY)-BENZYL]-1H-INDAZOLE-4-CARBOXYLIC
ACID, 91
##STR00124##
[0499] The title compound was prepared following the same method as
Example 7.
[0500] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.52 (s, 1H, ArH),
8.02 (d, 1H, ArH), 7.55 (d, 1H, ArH), 7.40-7.20 (m, 6H, ArH), 7.00
(s, 1H, ArH), 6.85 (d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2Het), 5.05
(s, 2H, ArCH.sub.2O--). LC-MS: m/z 427 M+H.sup.+.
EXAMPLE 41
2-[5-CHLORO-2-(4-CHLORO-BENZYLOXY)-BENZYL]-2H-INDAZOLE-4-CARBOXYLIC
ACID, 92
##STR00125##
[0502] The title compound was prepared following the same method as
Example 7.
[0503] .sup.1H-NMR (DMSO, 300 MHz) .delta. 13.00 (s, 1H, COOH),
8.65 (s, 1H, ArH), 7.90 (m, 1H, ArH), 7.80 (d, 1H, ArH), 7.40 (m,
6H, ArH), 7.25 (s, 1H, ArH), 7.10 (d, 1H, ArH), 5.70 (s, 2H,
ArCH.sub.2Het), 5.15 (s, 2H, ArCH.sub.2O--). LC-MS: m/z 427
M+H.sup.+.
EXAMPLE 42
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-1H-INDAZOLE-6-CARBOXYLIC ACID,
93
##STR00126##
[0505] The title compound was prepared following the same method as
Example 7.
[0506] .sup.1H-NMR (DMSO, 300 MHz) .delta. 13.00 (s, 1H, COOH),
8.30 (s, 1H, ArH), 8.20 (s, 1H, ArH), 7.85 (d, 1H, ArH), 7.70 (d,
1H, ArH), 7.40 (m, 1H, ArH), 7.15 (s, 1H, ArH), 6.95 (d, 1H, ArH),
5.65 (s, 2H, ArCH.sub.2Het), 3.70 (d, 2H, --CH.sub.2O--), 1.95 (m,
1H, CH), 0.85 (d, 6H, --CH.sub.3). LC-MS: m/z 404 M+H.sup.+.
EXAMPLE 43
2-(5-BROMO-2-ISOBUTOXY-BENZYL)-2H-INDAZOLE-6-CARBOXYLIC ACID,
94
##STR00127##
[0508] The title compound was prepared following the same method as
Example 7.
[0509] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.60 (s, 1H, ArH),
8.00 (s, 1H, ArH), 7.70 (m, 2H, ArH), 7.40 (m, 1H, ArH), 7.25 (m,
1H, ArH), 6.75 (d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2Het), 3.75 (d,
2H, --CH.sub.2O--), 2.10 (m, 1H, CH), 1.00 (d, 6H, --CH.sub.3).
LC-MS: m/z 404 M+H.sup.+.
EXAMPLE 44
1-(5-BROMO-2-CYCLOPENTYLMETHOXY-BENZYL)-1H-INDAZOLE-6-CARBOXYLIC
ACID, 95
##STR00128##
[0511] The title compound was prepared following the same method as
Example 7.
[0512] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.30 (s, 1H, ArH),
8.15 (s, 1H, ArH), 7.85 (q, 2H, ArH), 7.30 (m, 1H, ArH), 7.05 (s,
1H, ArH), 6.75 (d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2Het), 3.87 (d,
2H, --CH.sub.2O--), 2.45 (m, 1H, CH), 1.85 (m, 2H,
--CH.sub.2--CH.sub.2--), 1.65 (m, 4H, --CH.sub.2--CH.sub.2--), 1.30
(m, 2H, --CH.sub.2--CH.sub.2--). LC-MS: m/z 430 M+H.sup.+.
EXAMPLE 45
2-(5-BROMO-2-CYCLOPENTYLMETHOXY-BENZYL)-2H-INDAZOLE-6-CARBOXYLIC
ACID, 96
##STR00129##
[0514] The title compound was prepared following the same method as
Example 7.
[0515] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.65 (s, 1H, ArH),
8.00 (s, 1H, ArH), 7.70 (q, 2H, ArH), 7.37 (m, 1H, ArH), 7.25 (m,
1H, ArH), 6.75 (d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2Het), 3.85 (d,
2H, --CH.sub.2O--), 2.35 (m, 1H, CH), 1.80 (m, 2H,
--CH.sub.2--CH.sub.2--), 1.55 (m, 4H, --CH.sub.2--CH.sub.2--), 1.30
(m, 2H, --CH.sub.2--CH.sub.2--). LC-MS: m/z 430 M+H.sup.+.
EXAMPLE 46
1-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-INDAZOLE-6-CARBOXYLIC
ACID, 97
##STR00130##
[0517] The title compound was prepared following the same method as
Example 7.
[0518] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.25 (s, 1H, ArH),
8.15 (s, 1H, ArH), 7.85 (q, 2H, ArH), 7.15 (m, 1H, ArH), 6.80 (m,
2H, ArH), 5.65 (s, 2H, ArCH.sub.2Het), 3.90 (d, 2H, --CH.sub.2O--),
1.75 (m, 1H, CH), 1.45 (q, 4H, --CH.sub.2--CH.sub.3), 0.95 (t, 6H,
--CH.sub.2--CH.sub.3). LC-MS: m/z 387 M+H.sup.+.
EXAMPLE 47
1-(5-CHLORO-3-FLUORO-2-ISOBUTOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 98
##STR00131##
[0520] The title compound was prepared following the same method as
Example 3 but using (5-chloro-3-fluoro-2-methoxy-phenyl)-methanol
as the starting material.
[0521] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.60 (s, 1H, ArH),
8.17 (m, 2H, ArH), 7.62 (d, 1H, ArH), 7.14 (m, 1H, ArH), 6.90 (t,
1H, ArH), 5.74 (s, 2H, ArCH.sub.2Het), 3.76 (d, 2H, --CH.sub.2O--),
2.11 (m, 1H, CH), 1.03 (d, 6H, --CH.sub.3). LC-MS: m/z 377
M+H.sup.+.
EXAMPLE 48
1-(2-ISOBUTOXY-5-METHANESULFONYL-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 99
##STR00132##
[0523] The title compound was prepared following the same method as
Example 3 but using (5-methyl sulphone-2-methoxy-phenyl)-methanol
as the starting material.
[0524] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.53 (s, 1H, ArH),
8.14 (s, 1H, ArH), 8.03 (m, 1H, ArH), 7.81 (m, 1H, ArH), 7.45 (m,
1H, ArH), 7.40 (d, 1H, ArH), 6.97 (d, 1H, ArH), 5.61 (s, 2H,
ArCH.sub.2Het), 3.81 (d, 2H, --CH.sub.2O--), 2.92 (s, 3H,
SO.sub.2CH.sub.3), 2.05 (m, 1H, CH), 0.95 (d, 6H, --CH.sub.3).
[0525] LC-MS: m/z 402 M+H.sup.+.
EXAMPLE 49
1-(4,5-DICHLORO-2-ISOBUTOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC ACID,
100
##STR00133##
[0527] The title compound was prepared following the same method as
Example 3 but using (4,5-dichloro-2-methoxy-phenyl)-methanol as the
starting material.
[0528] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.45 (s, 1H, ArH),
8.05 (m, 1H, ArH), 7.95 (d, 1H, ArH), 7.31 (d, 1H, ArH), 6.83 (d,
2H, ArH), 5.45 (s, 2H, ArCH.sub.2Het), 3.65 (d, 2H, --CH.sub.2O--),
1.98 (m, 1H, CH), 0.89 (d, 6H, --CH.sub.3). LC-MS: m/z 393
M+H.sup.+.
EXAMPLE 50
1-(3-ISOBUTOXY-6-METHYL-PYRIDIN-2-YLMETHYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 104
##STR00134##
[0529] STEP 1
(3-Isobutoxy-6-methyl-pyridin-2-yl)-methanol, 101
##STR00135##
[0531] A solution of 3-Hydroxy-2-(hydroxymethyl)-5-methyl-pyridine
(1.0 g, 7.19 mmole) in DMF (10 ml) was treated with potassium
carbonate (5 g, 35.9 mmole) and 1-iodo-2-methylpropane (1.65 ml,
14.4 mmole). The mixture was stirred at room temperature under a
nitrogen atmosphere for 18h. The mixture was then evaporated to
dryness and the residue partitioned between ethyl acetate (50 ml)
and water (50 ml). The organic extract was separated then washed
with saturated brine then dried over sodium sulphate, filtered and
evaporated to dryness. The residue was chromatographed on silica
gel eluting with a 1:2 mixture of ethyl acetate/isohexane. This
gave the title compound as a pale yellow oil (0.62 g, 45%).
[0532] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 7.02 (m,
2H, ArH), 4.73 (s, 2H, CH.sub.2OH), 3.73 (d, 2H, --OCH.sub.2--),
2.50 (s, 3H, ArCH.sub.3), 2.10 (m, 1H, CH), 1.03 (d, 6H,
2.times.CH.sub.3).
STEP 2
Methanesulfonic acid 3-isobutoxy-6-methyl-pyridin-2-ylmethyl ester,
102
##STR00136##
[0534] A solution of (3-Isobutoxy-6-methyl-pyridin-2-yl)-methanol
(0.3 g, 1.54 mmole) in dichloromethane (10 ml) was treated with
diisopropylethylamine (0.3 ml, 1.69 mmole) and methanesulphonic
anhydride (0.3 g, 1.69 mmole) then stirred at ambient temperature
under a nitrogen atmosphere for 1.5h. The mixture was then washed
with water (50 ml) and saturated brine (50 ml). The organic layer
was dried over sodium sulphate, filtered and evaporated to dryness
to give the title compound as a colorless oil.
[0535] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 7.15 (m,
2H, ArH), 5.41 (s, 2H, CH.sub.2OMs), 3.77 (d, 2H, --OCH.sub.2--),
3.11 (s, 3H, --OSOCH.sub.3), 2.51 (s, 3H, ArCH.sub.3), 2.15 (m, 1H,
CH), 1.06 (d, 6H, 2.times.CH.sub.3).
STEP 3
1-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxylic
acid methyl ester, 103
##STR00137##
[0537] To a solution of Methanesulfonic acid
3-isobutoxy-6-methyl-pyridin-2-ylmethyl ester (1.54 mmole) and
1H-Indazole-5-carboxylic acid methyl ester (0.247 g, 1.4 mmole) in
DMF (8 ml) was added cesium carbonate (0.548 g, 1.68 mmole) and the
mixture stirred at ambient temperature for 18h. The mixture was
evaporated to dryness and the residue partitioned between water (20
ml) and ethyl acetate (2.times.20 ml). The combined organics were
dried over sodium sulphate, filtered and evaporated to dryness. The
residue was chromatographed using silica gel eluting with a 1:2
mixture of ethyl acetate/isohexane to give in the early fractions
the title compound (0.240 g, 48%) as a white solid. The
corresponding 2-yl-indazole isomer eluted in the later column
fractions.
[0538] 1H-NMR (CDCl.sub.3, 300 MHz)
.delta..quadrature..quadrature.8.49 (s, 1H, ArH), 8.09 (s, 1H,
ArH), 8.01 (dd, 1H, ArH), 7.56 (d, 1H, ArH), 7.03 (s, 2H, ArH),
5.73 (s, 2H, CH.sub.2), 3.94 (s, 3H, CH.sub.3), 3.62 (d, 2H,
CH.sub.2), 2.49 (s, 3H, CH.sub.3), 1.94 (m, 1H, CH), 0.89 (d, 6H,
2.times.CH.sub.3). LC-MS: m/z 354 M+H.sup.+
STEP 4
1-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxylic
acid, 104
##STR00138##
[0540] A solution of
1-(3-Isobutoxy-6-methyl-pyridin-2-ylmethyl)-1H-indazole-5-carboxylic
acid methyl ester (0.240 g, 0.68 mmole) in 1,4-dioxane (10 ml) was
treated with 2M sodium hydroxide (10 ml) and the mixture stirred at
60.degree. C. for 18h. The mixture was evaporated to dryness and
the residue dissolved in water (20 ml) then acidified to pH1 with
2M hydrochloric acid. The resulting precipitate was extracted into
ethyl acetate (2.times.50 ml). The combined organics were dried
over sodium sulphate, filtered and evaporated to dryness. The
residue was chromatographed on silica gel eluting a mixture 1:1 of
isohexane/ethyl acetate to give the title compound as a white solid
(0.2 g, 87%).
[0541] 1H-NMR (CDCl.sub.3, 300 MHz)
.delta..quadrature..quadrature.8.55 (s, 1H, ArH), 8.13 (s, 1H,
ArH), 8.02 (dd, 1H, ArH), 7.59 (d, 1H, ArH), 7.07 (s, 2H, ArH),
5.79 (s, 2H, CH.sub.2), 3.64 (d, 2H, CH.sub.2), 2.49 (s, 3H,
CH.sub.3), 1.96 (m, 1H, CH), 0.90 (d, 6H, 2.times.CH.sub.3). LC-MS
m/z 340 M+H.sup.+.
EXAMPLE 51
1-[5-BROMO-2-(1-ETHYL-PROPOXY)-BENZYL]-1H-INDAZOLE-5-CARBOXYLIC
ACID, 105
##STR00139##
[0543] The title compound was prepared following the same method as
Example 4.
[0544] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH),
8.20 (s, 1H, ArH), 8.10 (d, 1H, ArH), 7.50 (d, 1H, ArH), 7.30 (m,
1H, ArH), 7.10 (s, 1H, ArH), 6.75 (d, 1H, ArH), 5.55 (s, 2H,
ArCH.sub.2Het), 4.15 (m, 1H, --CHO--), 1.60 (q, 4H, CH.sub.2), 0.80
(d, 6H, --CH.sub.3).
[0545] LC-MS: m/z 418 M+H.sup.+.
EXAMPLE 52
1-[5-BROMO-2-(2,2-DIMETHYL-PROPOXY)-BENZYL]-1H-INDAZOLE-5-CARBOXYLIC
ACID, 106
##STR00140##
[0547] The title compound was prepared following the same method as
Example 4.
[0548] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.57 (s, 1H, ArH),
8.20 (s, 1H, ArH), 8.10 (d, 1H, ArH), 7.40 (d, 1H, ArH), 7.33 (m,
1H, ArH), 6.87 (s, 1H, ArH), 6.80 (d, 1H, ArH), 5.65 (s, 2H,
ArCH.sub.2Het), 3.68 (s, 2H, CH.sub.2), 1.05 (s, 9H,
3.times.CH.sub.3). LC-MS: m/z 418 M+H.sup.+.
EXAMPLE 53
1-[5-BROMO-2-(2-HYDROXY-2-METHYL-PROPDXY)-BENZYL]-1H-INDAZOLE-5-CARBOXYLIC
ACID, 108
##STR00141##
[0549] STEP 1
1-[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1H-indazole-5-carboxylic
acid methyl ester, 107
##STR00142##
[0551] A mixture of compound 12 (0.037 g, 0.1 mmole),
1.2-epoxy-2-methylpropane (0.1 mL, 1.1 mmol) and tetrabutylammonium
fluoride 1M (0.1 mL, 0.1 mmol) in THF (3 ml) was treated under
microwave conditions at 120.degree. C. for 20 min. Then methyl
iodide (0.1 mL) and N-methylmorpholine (0.1 mL) were added to the
solution and the mixture was treated under microwave conditions at
120.degree. C. for 10 minutes.
[0552] The mixture was diluted with methanol and ethyl acetate.
Washed with water and Brine. The organic extract was separated then
dried over sodium sulphate, filtered and evaporated to dryness. The
residue was chromatographed on silica gel eluting with a gradient
from 1:4 to 2:3 mixture of ethyl acetate/isohexane. This gave the
title compound as a pale yellow oil (0.03 g, 70%).
[0553] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH),
8.15 (s, 1H, ArH), 8.10 (m, 1H, ArH), 7.55 (d, 1H, ArH), 7.40 (m,
2H, ArH), 6.75 (d, 1H, ArH), 5.55 (s, 2H, ArCH.sub.2Het), 3.97 (s,
3H, CH.sub.3), 3.80 (s, 2H, --CH.sub.2O--), 1.40 (s, 6H,
--CH.sub.3).
STEP 2
1-[5-bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1h-indazole-5-carboxylic
acid, 108
##STR00143##
[0555] A solution of
1-[5-Bromo-2-(2-hydroxy-2-methyl-propoxy)-benzyl]-1H-indazole-5-carboxyli-
c acid methyl ester (0.03 g, 0.7 mmole) in a mixture of THF (5 ml),
methanol (5 mL) and water (1 mL) was treated with lithium hydroxide
(0.1 g, 2.4 mmole) then stirred at ambient temperature under a
nitrogen atmosphere for 20h. The mixture was diluted with more
water and extracted with isohexane. The aqueous layer was acidified
with a 2M HCl solution and extracted with ethyl acetate. The
organic layer was washed with saturated brine (50 ml). The organic
layer was dried over sodium sulphate, filtered and evaporated to
dryness to give the title compound as a colorless oil.
[0556] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (s, 1H, ArH),
8.15 (s, 1H, ArH), 8.10 (m, 1H, ArH), 7.55 (d, 1H, ArH), 7.40 (m,
2H, ArH), 6.75 (d, 1H, ArH), 5.55 (s, 2H, ArCH.sub.2Het), 3.80 (s,
2H, --CH.sub.2O--), 1.40 (s, 6H, --CH.sub.3). LC-MS: m/z 420
M+H.sup.+.
##STR00144##
STEP 1
5-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-benzoic acid methyl
ester, 109
##STR00145##
[0558] To a solution of methyl-2,5-dihydroxybenzoate (7.0 g, 41.7
mmole) and imidazole (4.24 g, 62.4 mmole), at 0.degree. C. and
under nitrogen, in DCM (300 mL) was added a solution of
tert-butyldimethylsilyl chloride (6.6 g, 43.8 mmole) in DCM (60 mL)
drop wise over 30 minutes. After 3h, the ice-bath was removed and
the mixture was stirred at room temperature for 16h. Then the
mixture was washed with 2M HCl solution and saturated brine then
dried over sodium sulphate, filtered and evaporated to dryness.
This gave the title compound as colorless oil (11.1 g, 95%).
[0559] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 10.3 (s,
1H, ArOH), 7.25 (m, 1H, ArH), 7.00 (m, 1H, ArH), 6.85 (m, 1H, ArH),
3.95 (s, 3H, --OCH.sub.3), 1.00 (s, 9H, SiC(CH.sub.3).sub.3), 0.2
(s, 6H, 2.times.SiCH.sub.3).
STEP 2
5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-benzoic acid methyl
ester, 110
##STR00146##
[0561] A solution of
5-(tert-Butyl-dimethyl-silanyloxy)-2-hydroxy-benzoic acid methyl
ester (5 g, 17.7 mmole) in anhydrous THF (150 ml) was treated with
2-methyl-1-propanol (1.8 ml, 19.5 mmole), triphenylphosphine (5.1
g, 19.5 mmole) and DIAD (3.8 mL, 19.5 mmole) then stirred at
0.degree. C. for 2h, at room temperature for 1h and at reflux for
24h. The mixture was then evaporated to dryness and the residue was
purified by column chromatography using 95:5 mixture of
isohexane/ethyl acetate to give the title compound as a colorless
oil. (1.8 g, 30%).
[0562] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 7.25 (m,
1H, ArH), 7.00 (m, 1H, ArH), 6.85 (m, 1H, ArH), 3.85 (s, 3H,
--OCH.sub.3), 3.75 (d, 2H, OCH.sub.2--), 2.10 (m, 1H, CH), 1.05 (d,
6H, 2.times.CH.sub.3), 1.00 (s, 9H, SiC(CH.sub.3).sub.3), 0.2 (s,
6H, 2.times.SiCH.sub.3).
STEP 3
[5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-phenyl]-methanol,
111
##STR00147##
[0564] To a solution
5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-benzoic acid methyl
ester (1.8 g, 5.32 mmole) in anhydrous toluene (50 ml) was added a
1M solution in toluene of DIBAL (21 mL, 21 mmole) and the mixture
stirred under nitrogen atmosphere at ambient temperature for 2h.
Then a 10% Rochelle's salt solution was added and the mixture
stirred for 30 min more. 2M HCl solution (20 mL) was added and the
mixture was extracted with ethyl acetate. The combined organics
were dried over sodium sulphate, filtered and evaporated to
dryness. The residue was chromatographed using silica gel eluting
with a 1:2 mixture of ethyl acetate/isohexane to give in the early
fractions the title compound (0.91 g, 55%) as a colorless oil.
[0565] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 6.75 (s,
1H, ArH), 6.55 (s, 2H, ArH), 4.52 (d, 2H, --CH.sub.2OH), 3.62 (d,
2H, OCH.sub.2--), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2.times.CH.sub.3),
1.00 (s, 9H, SiC(CH.sub.3).sub.3), 0.2 (s, 6H, 2.times.SiCH.sub.3).
LC-MS: m/z 293 [M+H.sub.2O].sup.+.
STEP 4
1-[5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-benzyl]-1H-indazole-5-ca-
rboxylic acid methyl ester, 112
##STR00148##
[0567] A solution of 1H-indazole-5-carboxylic acid methyl ester, 4,
(0.6 g, 3.5 mmole), triphenylphosphine (1.2 g, 4.4 mmole),
[5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-phenyl]-methanol
(0.9 g, 2.9 mmole) and di-isopropylazodicarboxylate (0.9 mL, 4.4
mmol) in anhydrous THF (50 mL) was heated at reflux for 16h. Then
the volatiles were removed in vacuo and the crude product was
purified on silica using a gradient from 95:5 to 90:10
isohexane/ethyl acetate. This gave the title compound as colorless
oil (0.3 g, 20%).
[0568] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.55 (s,
1H, ArH), 8.15 (s, 1H, ArH), 8.00 (d, 1H, ArH), 7.40 (d, 1H, ArH),
6.70 (m, 2H, ArH), 6.25 (s, 1H, ArH), 5.52 (s, 2H, -CH.sub.2Het),
3.95 (s, 3H, OCH.sub.3), 3.72 (d, 2H, OCH.sub.2--), 2.10 (m, 1H,
CH), 1.05 (d, 6H, 2.times.CH.sub.3), 0.85 (s, 9H,
SiC(CH.sub.3).sub.3), 0.05 (s, 6H, 2.times.SiCH.sub.3).
STEP 5
1-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid
methyl ester, 113
##STR00149##
[0570] A solution of
1-[5-(tert-Butyl-dimethyl-silanyloxy)-2-isobutoxy-benzyl]-1H-indazole-5-c-
arboxylic acid methyl ester (0.3 g, 0.64 mmole) in anhydrous THF
(10 mL) was treated with a 1M TBAF solution in THF (1 mL, 1 mmole)
and the mixture was stirred at room temperature for 1 h. Then the
volatiles were removed in vacuo and the crude product was purified
on silica using a gradient from 4:1 to 3:1 isohexane/ethyl acetate.
This gave the title compound as colorless oil (0.135 g, 60%).
[0571] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.50 (s,
1H, ArH), 8.02 (d, 1H, ArH), 7.90 (s, 1H, ArH), 7.40 (d, 1H, ArH),
6.70 (m, 2H, ArH), 6.20 (s, 1H, ArH), 6.10 (s, 1H, ArOH), 5.60 (s,
2H, -CH.sub.2Het), 3.97 (s, 3H, OCH.sub.3), 3.75 (d, 2H,
OCH.sub.2--), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2.times.CH.sub.3).
STEP 6
1-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid,
114
##STR00150##
[0573] A solution of
11-(5-Hydroxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic acid
methyl ester (0.03 g, 0.08 mmole) in a mixture of THF (2 ml),
methanol (1 mL) and water (1 mL) was treated with lithium hydroxide
(0.09 g, 2.14 mmole) then stirred under microwave conditions at
120.degree. C. for 5 min. The mixture was diluted with more water
and extracted with isohexane. The aqueous layer was acidified with
a 2M HCl solution and extracted with ethyl acetate. The organic
layer was washed with saturated brine (50 ml). The organic layer
was dried over sodium sulphate, filtered and evaporated to dryness
to give the crude residue that was purified by column in silica
using 1:1 mixture ethyl acetate/isohexane as eluent to give the
title compound as a colorless oil. (12.3 mg, 50%).
[0574] 1H-NMR (MeOD, 300 MHz) .delta..quadrature. 8.55 (s, 1H,
ArH), 8.20 (s, 1H, ArH), 8.12 (d, 1H, ArH), 7.55 (d, 1H, ArH), 6.80
(m, 1H, ArH), 6.75 (m, 1H, ArH), 6.25 (s, 1H, ArH), 5.60 (s, 2H,
-CH.sub.2Het), 3.70 (d, 2H, OCH.sub.2--), 2.10 (m, 1H, CH), 1.00
(d, 6H, 2.times.CH.sub.3). LC-MS: m/z 341 M+H.sup.+.
EXAMPLE 55
1-[5-(2,2-DIFLUORO-ETHOXY)-2-ISOBUTOXY-BENZYL]-1H-INDAZOLE-5-CARBOXYLIC
ACID, 116
##STR00151##
[0575] STEP 1
1-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylic
acid methyl ester
##STR00152##
[0577] A solution of compound 104 (0.03 g, 0.08 mmole) in a mixture
of anhydrous THF (2 ml) and anhydrous toluene (1 mL) was treated
with 2,2-difluoroethanol (0.04 ml, 0.27 mmole), triphenylphosphine
(0.07 g, 0.27 mmole) and DTAD (0.055 g, 0.27 mmole) then stirred
under microwave conditions at 140.degree. C. for 20 min. The
mixture was then evaporated to dryness and the residue was purified
by column chromatography using a gradient from 90:10 to 80:20
mixture of isohexane/ethyl acetate to give the title compound as a
colorless oil. (0.02 g, 60%).
[0578] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.55 (s,
1H, ArH), 8.15 (s, 1H, ArH), 8.02 (d, 1H, ArH), 7.45 (d, 1H, ArH),
6.75 (m, 2H, ArH), 6.45 (s, 1H, ArH), 5.97 (tt, 1H, F.sub.2CH),
5.65 (s, 2H, -CH.sub.2Het), 4.00 (m, 2H, CH.sub.2CHF.sub.2), 3.95
(s, 3H, OCH.sub.3), 3.75 (d, 2H, OCH.sub.2--), 2.10 (m, 1H, CH),
1.05 (d, 6H, 2.times.CH.sub.3).
STEP 2
1-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylic
acid, 116
##STR00153##
[0580] A solution of
1-[5-(2,2-Difluoro-ethoxy)-2-isobutoxy-benzyl]-1H-indazole-5-carboxylic
acid methyl ester (0.02 g, 0.05 mmole) in a mixture of THF (3 ml),
methanol (4 mL) and water (1 mL) was treated with lithium hydroxide
(0.1 g, 2.4 mmole) then stirred at room temperature for 16h. The
mixture was diluted with more water and extracted with isohexane.
The aqueous layer was acidified with a 2M HCl solution and
extracted with ethyl acetate. The organic layer was washed with
saturated brine (50 ml). The organic layer was dried over sodium
sulphate, filtered and evaporated to dryness to give the title
compound as a colorless oil. (19.2 mg, 95%).
[0581] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.60 (s,
1H, ArH), 8.17 (s, 1H, ArH), 8.05 (d, 1H, ArH), 7.45 (d, 1H, ArH),
6.77 (m, 2H, ArH), 6.50 (s, 1H, ArH), 5.97 (tt, 1H, F.sub.2CH),
5.65 (s, 2H, -CH.sub.2Het), 4.00 (td, 2H, CH.sub.2CHF.sub.2), 3.75
(d, 2H, OCH.sub.2--), 2.10 (m, 1H, CH), 1.05 (d, 6H,
2.times.CH.sub.3). LC-MS: m/z 405 M+H.sup.+.
EXAMPLE 56
1-(5-DIFLUOROMETHOXY-2-ISOBUTOXY-BENZYL)-1H-INDAZOLE-5-CARBOXYLIC
ACID, 118
##STR00154##
[0582] STEP 1
1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester, 117
##STR00155##
[0584] To a solution of compound 104 (0.07 g, 0.2 mmole) in
acetonitrile (1.5 ml) was added an aqueous solution of KOH in water
(4 mmole in 1.5 mL). Nitrogen was bubbled through the mixture for 5
min. and then cold down to -78.degree. C. under nitrogen
atmosphere. Then the mixture was treated with a solution of
diethyl(bromodifluoromethyl)phosphonate (0.074 ml, 0.4 mmole) in
acetonitrile (0.3 mL), allowed to warm to room temperature slowly
(20 min) and stirred for 1.5h. Then, the same process was repeated
again but this time the reaction was stirred overnight.
[0585] To the reaction mixture was added ethyl acetate and 2M HCl
solution. The organic layer was separated, washed with Brine, dried
and then evaporated to dryness. The residue was purified by column
chromatography using a gradient from 100:0 to 90:10 mixture of
isohexane/ethyl acetate to give the title compound as a colorless
oil. (0.014 g, 17%).
[0586] 1H-NMR (CDCl.sub.3, 300 MHz) 8.65 (s, 1H, ArH), 8.20 (s, 1H,
ArH), 8.08 (d, 1H, ArH), 7.45 (d, 1H, ArH), 7.00 (m, 1H, ArH), 6.85
(d, 1H, ArH), 6.55 (s, 1H, ArH), 6.3 (t, 1H, F.sub.2CH), 5.65 (s,
2H, -CH.sub.2Het), 3.95 (s, 3H, OCH.sub.3), 3.78 (d, 2H,
OCH.sub.2--), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2.times.CH.sub.3).
STEP 2
1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid, 118
##STR00156##
[0588] A solution of
1-(5-Difluoromethoxy-2-isobutoxy-benzyl)-1H-indazole-5-carboxylic
acid methyl ester (0.014 g, 0.035 mmole) in a mixture of THF (1
ml), methanol (1 mL) and water (1 mL) was treated with lithium
hydroxide (0.05 g, 1.2 mmole) then stirred at room temperature for
16h. The mixture was diluted with more water and extracted with
isohexane. The aqueous layer was acidified with a 2M HCl solution
and extracted with ethyl acetate. The organic layer was washed with
saturated brine (50 ml). The organic layer was dried over sodium
sulphate, filtered and evaporated to dryness to give the title
compound as a colorless oil. (8.7 mg, 63%).
[0589] 1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 8.65 (s,
1H, ArH), 8.20 (s, 1H, ArH), 8.08 (d, 1H, ArH), 7.45 (d, 1H, ArH),
7.00 (m, 1H, ArH), 6.85 (d, 1H, ArH), 6.55 (s, 1H, ArH), 6.3 (t,
1H, F.sub.2CH), 5.65 (s, 2H, -CH.sub.2Het), 3.78 (d, 2H,
OCH.sub.2--), 2.10 (m, 1H, CH), 1.05 (d, 6H, 2.times.CH.sub.3).
LC-MS: m/z 391 M+H.sup.+.
EXAMPLE 57
1-(5-CHLORO-2-ISOBUTOXY-BENZYL)-1H-PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXYLIC
ACID, 119
##STR00157##
[0591] The title compound was prepared following the same method as
Example 30.
[0592] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.25 (s, 1H, ArH),
8.80 (s, 1H, ArH), 8.20 (s, 1H, ArH), 7.33 (m, 2H, ArH), 6.74 (d,
1H, ArH), 5.65 (s, 2H, ArCH.sub.2), 3.75 (d, 2H, OCH.sub.2). 2.01
(m, 1H, CH), 0.96 (d, 6H, CH.sub.3). LC-MS: m/z 360 M
EXAMPLE 58
1-(2-ISOBUTOXY-5-TRIFLUOROMETHOXY-BENZYL)-1H-PYRAZOLO[3,4-B]PYRIDINE-5-CAR-
BOXYLIC ACID, 120
##STR00158##
[0594] The title compound was prepared following the same method as
Example 30.
[0595] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.25 (s, 1H, ArH),
8.70 (s, 1H, ArH), 8.00 (s, 1H, ArH), 7.05 (m, 1H, ArH), 6.75 (d,
1H, ArH), 6.65 (s, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2), 3.65 (d, 2H,
OCH.sub.2). 2.01 (m, 1H, CH), 0.96 (d, 6H, CH.sub.3). LC-MS: m/z
410 M+H.sup.+.
EXAMPLE 59
1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDINE--
5-CARBOXYLIC ACID, 121
##STR00159##
[0597] The title compound was prepared following the same method as
Example 30.
[0598] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.22 (s, 1H, ArH),
8.80 (s, 1H, ArH), 7.32 (s, 1H, ArH), 6.85 (m, 1H, ArH), 6.75 (d,
1H, ArH), 5.70 (s, 2H, ArCH.sub.2), 3.88 (d, 2H, OCH.sub.2). 2.65
(s, 3H, ArCH.sub.3), 2.01 (m, 1H, CH), 1.45 (q, 4H,
2.times.CH.sub.2), 0.96 (t, 6H, 2.times.CH.sub.3).
[0599] LC-MS: m/z 448 M+H.sup.+.
EXAMPLE 60
1-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDINE-
-5-CARBOXYLIC ACID, 122
##STR00160##
[0601] The title compound was prepared following the same method as
Example 30.
[0602] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.22 (s, 1H, ArH),
8.80 (s, 1H, ArH), 7.15 (m, 1H, ArH), 6.80 (d, 1H, ArH), 6.70 (d,
1H, ArH), 5.65 (s, 2H, ArCH.sub.2), 3.88 (d, 2H, OCH.sub.2). 2.65
(s, 3H, ArCH.sub.3), 2.01 (m, 1H, CH), 1.45 (q, 4H,
2.times.CH.sub.2), 0.96 (t, 6H, 2.times.CH.sub.3).
[0603] LC-MS: m/z 402 M+H.sup.+.
EXAMPLE 61
1-(5-CHLORO-2-ISOBUTOXY-BENZYL)-3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDINE-5-CARB-
OXYLIC ACID, 123
##STR00161##
[0605] The title compound was prepared following the same method as
Example 30.
[0606] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.25 (s, 1H, ArH),
8.70 (s, 1H, ArH), 7.15 (d, 1H, ArH), 6.75 (d, 1H, ArH), 6.15 (d,
1H, ArH), 5.65 (s, 2H, ArCH.sub.2), 3.70 (d, 2H, OCH.sub.2). 2.65
(s, 3H, ArCH.sub.3), 2.01 (m, 1H, CH), 0.90 (d, 6H,
2.times.CH.sub.3).
[0607] LC-MS: m/z 374 M+H.sup.+.
EXAMPLE 62
1-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-PYRAZOLO[3,4-C]PYRIDINE-5-CARBOX-
YLIC ACID AMIDE, 129
##STR00162##
[0608] STEP 1
1H-Pyrazolo[3,4-c]pyridine-5-carbonitrile, 124
##STR00163##
[0610] A mixture of 5-Bromo-1,4-pyrazolo[3,4,c]pyridine (0.15 g,
0.76 mmole), Zn(CN).sub.2 (0.092 g, 0.76 mmole) and
Pd(PPh.sub.3).sub.4 (0.026 g, 0.02 mmole) in DMF (2 ml) heated at
180.degree. C. in a microwave reactor under a N.sub.2 atmosphere
for 30 min. The mixture was partitioned between water and EtOAc.
The organic layer was washed with brine, dried (MgSO.sub.4) and
evaporated to dryness to give the title compound as a brown
solid.
[0611] 1H-NMR (MeOD, 300 MHz) .delta..quadrature. 8.35 (s, 1H,
ArH), 7.38 (s, 1H, ArH), 7.28 (s, 1H, ArH).
STEP 2
5-chloro-2-(2-ethyl-butoxy)-benzaldehyde, 125
##STR00164##
[0613] A solution of 5-chloroalicaldehyde (2.0 g, 12.8 mmole) in
DMF (50 ml) was treated with potassium carbonate (3 g, 22 mmole)
and tetrabutylammonium iodide (0.22 g) and 3-chloromethylpentane
(1.65 ml, 12.2 mmole). The mixture was stirred at 110.degree. C.
under a nitrogen atmosphere for 18h. The mixture was then
evaporated to dryness and the residue partitioned between ethyl
acetate (50 ml) and water (50 ml). The organic extract was
separated then washed with saturated brine then dried over sodium
sulphate, filtered and evaporated to dryness. The residue was
chromatographed on silica gel eluting with a gradient of 5-15%
ethyl acetate/isohexane. This gave the title compound as a pale
yellow oil (2.97 g, 78%).
[0614] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta..quadrature. 10.49
(s, 1H, CHO), 7.95 (d, 1H, ArH), 7.63 (dd, 1H, ArH), 6.90 (d, 1H,
ArH), 4.00 (d, 2H, CH.sub.2), 1.80 (m, 1H, CH), 1.55 (s, 4H,
2.times.CH.sub.2--CH.sub.3), 1.00 (q, 6H,
2.times.CH.sub.2--CH.sub.3).
STEP 3
[5-Chloro-2-(2-ethyl-butoxy)-phenyl]-methanol, 126
##STR00165##
[0616] The title compound was prepared following the method in
Example 20, Step 2.
[0617] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. .quadrature.7.45
(d, 1H, ArH), 7.37 (dd, 1H, ArH), 6.80 (d, 1H, ArH), 4.70 (d, 2H,
--CH.sub.2OH), 3.90 (d, 2H, CH.sub.2), 1.80 (m, 1H, CH), 1.55 (s,
4H, 2.times.CH.sub.2--CH.sub.3), 1.00 (q, 6H,
2.times.CH.sub.2--CH.sub.3).
STEP 4
Methanesulfonic acid 5-chloro-2-(2-ethyl-butoxy)-benzyl ester,
127
##STR00166##
[0619] The title compound was prepared following the method in
Example 20, Step 3.
[0620] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. .quadrature.7.55
(d, 1H, ArH), 7.45 (dd, 1H, ArH), 6.80 (d, 1H, ArH), 5.75 (d, 2H,
--CH.sub.2OSO2CH.sub.3), 3.90 (d, 2H, CH.sub.2), 3.00 (s, 3H,
CH.sub.2OSO2CH.sub.3), 1.80 (m, 1H, CH), 1.55 (s, 4H,
2.times.CH.sub.2--CH.sub.3), 1.00 (q, 6H,
2.times.CH.sub.2--CH.sub.3).
STEP 5
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazolo[3,4-c]pyridine-5-carbon-
itrile, 128
##STR00167##
[0622] The title compound was prepared following the method in
Example 21, Step 4.
[0623] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.95 (s, 1H, ArH),
8.20 (s, 1H, ArH), 8.10 (s, 1H, ArH), 7.25 (m, 1H, ArH), 7.05 (s,
1H, ArH), 6.85 (s, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2), 3.85 (d, 2H,
CH.sub.2). 1.65 (m, 1H, CH), 1.35 (q, 4H, 2.times.CH.sub.2), 0.85
(t, 6H, 2.times.CH.sub.3).
[0624] LC-MS: m/z 369 M+H.sup.+
STEP 6
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazolo[3,4-c]pyridine-5-carbox-
ylic acid amide, 129
##STR00168##
[0626] A mixture of
1-[5-Chloro-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazolo[3,4-c]pyridine-5-carbo-
nitrile (0.048 g, 0.13 mmole), 5M aqueous solution of KOH (1 mL),
PEG-400 (0.5 mL) and dioxane (0.5 mL) was heated at 180.degree. C.
under microwave conditions for 30 min. The mixture was diluted with
ethyl acetate (6 mL) and 2M HCl solution (6 mL) and the reaction
mixture was extracted. The organic layer was separated, washed with
Brine, dried (MgSO.sub.4), filtered and the solvent evaporated
under vacuum. The residue was purified in silica using 3:2 mixture
of isohexane/ethyl acetate to give the title compound as a
colorless oil. (0.024 mg, 48%).
[0627] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.12 (s, 1H, ArH),
8.50 (s, 1H, ArH), 8.07 (s, 1H, ArH), 7.30 (m, 1H, ArH), 7.22 (s,
1H, ArH), 6.85 (d, 1H, ArH), 5.75 (s, 2H, ArCH.sub.2), 3.80 (d, 2H,
CH.sub.2). 1.50 (m, 1H, CH), 1.25 (q, 4H, 2.times.CH.sub.2), 0.80
(t, 6H, 2.times.CH.sub.3).
[0628] LC-MS: m/z 387 M+H.sup.+.
EXAMPLE 63
1-[5-CHLORO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-PYRAZOLO[3,4-C]PYRIDINE-5-CARBOX-
YLIC ACID, 130
##STR00169##
[0630] A mixture of
1-[5-chloro-2-(2-ethyl-butoxy)-benzyl]-1h-pyrazolo[3,4-c]pyridine-5-carbo-
xylic acid amide (0.019 g, 0.05 mmole), concentrated solution of
HCl (1 mL) and dioxane (0.5 mL) was heated at 150.degree. C. under
microwave conditions for 30 min. The mixture was diluted with ethyl
acetate (6 mL) and 2M HCl solution (6 mL) and the reaction mixture
was extracted. The aqueous phase was basified to PH 5-6 with 2M
solution of NaOH and extracted again with ethyl acetate. The
combined organic layers were washed with Brine, dried (MgSO.sub.4),
filtered and the solvent evaporated under vacuum. The residue was
purified in a RP-HPLC to give the title compound as a colorless
oil. (0.011 mg, 58%).
[0631] .sup.1H-NMR (MeOD, 300 MHz) .delta. 9.05 (s, 1H, ArH), 8.52
(s, 1H, ArH), 8.30 (s, 1H, ArH), 7.30 (m, 1H, ArH), 7.25 (s, 1H,
ArH), 6.95 (d, 1H, ArH), 5.65 (s, 2H, ArCH.sub.2), 3.85 (d, 2H,
CH.sub.2). 1.52 (m, 1H, CH), 1.35 (q, 4H, 2.times.CH.sub.2), 0.85
(t, 6H, 2.times.CH.sub.3).
[0632] LC-MS: m/z 388 M+H.sup.+.
EXAMPLE 64
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-3-ETHYL-1H-INDAZOLE-5-CARBOXYLIC
ACID, 134
##STR00170##
[0633] STEP 1
3-Vinyl-1H-indazole-5-carboxylic acid methyl ester, 131
##STR00171##
[0635] 3-Iodo-1H-indazole-5-carboxylic acid methyl ester (0.5 g,
1.65 mmole) in dimethoxyethane (12.5 ml) was placed in a microwave
vial and treated with sodium carbonate (0.55 g, 5.1 mmole),
tetrakis(triphenylphosphine)palladium(0) (0.09 g, 5 mol %) and
vinylboronicanhydride pyridine complex (0.96 g, 4 mmole). The
mixture was heated in a microwave at 160.degree. C. (very high
absorbance setting) for 1 hour. After cooling the mixture was
partitioned between water (50 ml) and ethyl acetate (3.times.50
ml). The combined organic extracts were then washed with saturated
brine (50 ml), separated and dried over sodium sulphate, filtered
and evaporated to dryness. The residue was chromatographed on
silica eluting with a gradient of 20-60% ethyl acetate/isohexane to
give the title compound as a white solid (0.134 g).
[0636] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 10.45-11.05 (brs, 1H,
NH), 8.71 (s, 1H, ArH), 8.12 (d, 1H, ArH), 7.47 (d, 1H, ArH), 7.12
(dd, 1H, CH), 6.25 (d, 1H, CH), 5.67 (d, 1H, CH), 3.97 (s, 3H,
CH.sub.3)
STEP 2
3-Ethyl-1H-indazole-5-carboxylic acid methyl ester, 132
##STR00172##
[0638] 3-Vinyl-1H-indazole-5-carboxylic acid methyl ester (0.134 g,
0.66 mmole) in ethanol (10 ml) was hydrogenated at atmospheric
pressure over 10% palladium on charcoal at ambient temperature for
20 hours. The mixture was then filtered through celite washing with
ethanol. The combined filtrates were evaporated to dryness to give
the title compound as a pale yellow oil (0.118 g).
[0639] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 10.71-11.02 (brs, 1H,
NH), 8.51 (s, 1H, ArH), 8.05 (d, 1H, ArH), 7.45 (d, 1H, ArH), 3.97
(s, 3H, CH.sub.3), 3.03 (q, 2H, CH.sub.2), 1.45 (t, 3H,
CH.sub.3).
STEP 3
1-(5-bromo-2-isobutoxy-benzyl)-3-ethyl-1h-indazole-5-carboxylic
acid methyl ester, 133
##STR00173##
[0641] The titled compound was prepared following the method
described in Example 21, step 4.
[0642] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.62 (s, 1H, ArH), 8.09
(dd, 1H, ArH), 7.39 (d, 1H, ArH), 7.34 (dd, 1H, ArH), 6.95 (d, 1H,
ArH), 6.77 (d, 1H, ArH), 5.57 (s, 2H, CH.sub.2), 3.97 (s, 3H,
OCH.sub.3), 3.77 (d, 2H, CH.sub.2), 3.08 (q, 2H, CH.sub.2),
2.07-2.18 (m, 1H, CH), 1.48 (t, 3H, CH.sub.3), 1.05 (d, 6H,
2.times.CH.sub.3).
STEP 4
1-(5-bromo-2-isobutoxy-benzyl)-3-ethyl-1h-indazole-5-carboxylic
acid, 134
##STR00174##
[0644] The titled compound was prepared following the method
described in Example 20, step 5.
[0645] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.62 (s, 1H, ArH), 8.09
(dd, 1H, ArH), 7.39 (d, 1H, ArH), 7.34 (dd, 1H, ArH), 6.95 (d, 1H,
ArH), 6.77 (d, 1H, ArH), 5.57 (s, 2H, CH.sub.2), 3.77 (d, 2H,
CH.sub.2), 3.08 (q, 2H, CH.sub.2), 2.07-2.18 (m, 1H, CH), 1.48 (t,
3H, CH.sub.3), 1.05 (d, 6H, 2.times.CH.sub.3).
EXAMPLE 65
1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-3-ETHYL-1H-INDAZOLE-5-CARBOXYLIC
ACID, 135
##STR00175##
[0647] The title compound was prepared following the same method as
Example 64 but using Compound 80 as the starting material.
[0648] H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.61 (s, 1H, ArH), 8.09
(d, 1H, ArH), 7.32-7.39 (m, 2H, 2.times.ArH), 6.92 (d, 1H, ArH),
6.77 (d, 1H, ArH), 5.58 (s, 2H, CH.sub.2), 3.88 (d, 2H, CH.sub.2),
3.08 (q, 2H, CH.sub.2), 1.65-1.77 (m, 1H, CH), 1.41-1.53 (m, 7H,
2.times.CH.sub.2+CH.sub.3), 0.95 (t, 6H, 2.times.CH.sub.3).
EXAMPLE 66
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-2-METHYL-1H-INDOLE-5-CARBOXYLIC
ACID, 136
##STR00176##
[0650] The title compound was prepared following the same method as
Example 21.
[0651] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.41 (s, 1H, ArH), 7.92
(s, 1H, ArH), 7.28 (dd, 1H, ArH), 7.21 (d, 1H, ArH), 6.78 (d, 1H,
ArH), 6.49 (s, 1H, ArH), 6.41 (d, 1H, ArH), 5.31 (s, 2H, CH.sub.2),
3.81 (d, 2H, CH.sub.2), 2.38 (s, 3H, CH.sub.3), 2.15-2.25 (m, 1H,
CH), 1.11 (d, 6H, 2.times.CH.sub.3).
EXAMPLE 67
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-1H-INDOLE-5-CARBOXYLIC ACID, 137
##STR00177##
[0653] The title compound was prepared following the same method as
Example 21.
[0654] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.51 (s, 1H, ArH), 7.99
(d, 1H, ArH), 7.35 (d, 1H, ArH), 7.31 (dd, 1H, ArH), 7.21 (d, 1H,
ArH), 6.97 (d, 1H, ArH), 6.75 (d, 1H, ArH), 6.65 (d, 1H, ArH), 5.31
(s, 2H, CH.sub.2), 3.77 (d, 2H, CH.sub.2), 2.08-2.31 (m, 1H, CH),
1.04 (d, 6H, 2.times.CH.sub.3).
EXAMPLE 68
1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-2-METHYL-1H-INDOLE-5-CARBOXYLIC
ACID, 138
##STR00178##
[0656] The title compound was prepared following the same method as
Example 21.
[0657] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.45 (s, 1H, ArH), 7.91
(d, 1H, ArH), 7.29 (dd, 1H, ArH), 7.19 (d, 1H, ArH), 6.81 (d, 1H,
ArH), 6.47 (s, 1H, ArH), 6.38 (s, 1H, ArH), 5.29 (s, 2H, CH.sub.2),
3.95 (d, 2H, CH.sub.2), 2.38 (s, 3H, CH.sub.3), 1.81-1.92 (m, 1H,
CH), 1.48-1.62 (m, 4H, 2.times.CH.sub.2), 0.97 (t, 6H,
2.times.CH.sub.3).
EXAMPLE 69
1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-INDOLE-5-CARBOXYLIC ACID,
139
##STR00179##
[0659] The title compound was prepared following the same method as
Example 21.
[0660] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.52 (s, 1H, ArH), 7.99
(d, 1H, ArH), 7.35 (d, 1H, ArH), 7.31 (d, 1H, ArH), 7.19 (d, 1H,
ArH), 6.91 (d, 1H, ArH), 6.82 (d, 1H, ArH), 6.69 (d, 1H, ArH), 5.32
(s, 2H, CH.sub.2), 3.91 (d, 2H, CH.sub.2), 1.62-1.74 (m, 1H, CH),
1.39-1.51 (m, 4H, 2.times.CH.sub.2), 0.93 (t, 6H,
2.times.CH.sub.3).
EXAMPLE 70
1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-INDOLE-6-CARBOXYLIC ACID,
140
##STR00180##
[0662] The title compound was prepared following the same method as
Example 21.
[0663] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.22 (s, 1H, ArH), 7.91
(d, 1H, ArH), 7.71 (d, 1H, ArH), 7.35 (dd, 1H, ArH), 7.27 (d, 1H,
ArH), 6.85 (d, 1H, ArH), 6.81 (d, 1H, ArH), 6.63 (d, 1H, ArH), 5.37
(s, 2H, CH.sub.2), 3.93 (d, 2H, CH.sub.2), 1.65-1.78 (m, 1H, CH),
1.41-1.52 (m, 4H, 2.times.CH.sub.2), 0.94 (t, 6H,
2.times.CH.sub.3)
EXAMPLE 71
1-(2-ISOBUTOXY-5-TRIFLUOROMETHOXY-BENZYL)-1H-INDOLE-5-CARBOXYLIC
ACID, 141
##STR00181##
[0665] The title compound was prepared following the same method as
Example 21.
[0666] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.53 (s, 1H, ArH), 7.97
(d, 1H, ArH), 7.35 (d, 1H, ArH), 7.22 (d, 1H, ArH), 7.13 (dd, 1H,
ArH), 6.96 (d, 1H, ArH), 6.68 (d, 1H, ArH), 6.61 (s, 1H, ArH), 5.35
(s, 2H, CH.sub.2), 3.79 (d, 2H, CH.sub.2), 2.07-2.21 (m, 1H, CH),
0.94 (d, 6H, 2.times.CH.sub.3).
EXAMPLE 72
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-1H-PYRROLO[2,3-B]PYRIDINE-5-CARBOXYLIC
ACID, 142
##STR00182##
[0668] The title compound was prepared following the same method as
Example 21.
[0669] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.13 (s, 1H, ArH), 8.65
(s, 1H, ArH), 7.36 (dd, 1H, ArH), 7.29 (d, 1H, ArH), 7.13 (d, 1H,
ArH), 6.75 (d, 1H, ArH), 6.61 (d, 1H, ArH), 5.53 (s, 2H, CH.sub.2),
3.75 (d, 2H, CH.sub.2), 2.01-2.18 (m, 1H, CH), 1.02 (d, 6H,
2.times.CH.sub.3).
EXAMPLE 73
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-1H-PYRROLO[3,2-B]PYRIDINE-5-CARBOXYLIC
ACID, 143
##STR00183##
[0671] The title compound was prepared following the same method as
Example 21.
[0672] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.09 (d, 1H, ArH), 7.81
(d, 1H, ArH), 7.55 (d, 1H, ArH), 7.39 (dd, 1H, ArH), 6.99 (d, 1H,
ArH), 6.81 (s, 1H, ArH), 6.78 (d, 1H, ArH), 5.33 (s, 2H, CH.sub.2),
3.74 (d, 2H, CH.sub.2), 1.98-2.12 (m, 1H, CH), 0.99 (d, 6H,
2.times.CH.sub.3).
EXAMPLE 74
1-(2-ISOBUTOXY-5-TRIFLUOROMETHOXY-BENZYL)-1H-PYRROLO[2,3-B]PYRIDINE-5-CARB-
OXYLIC ACID, 144
##STR00184##
[0674] The title compound was prepared following the same method as
Example 21.
[0675] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.99 (s, 1H, ArH), 8.61
(s, 1H, ArH), 7.23 (d, 1H, ArH), 7.05 (dd, 1H, ArH), 6.81 (d, 1H,
ArH), 6.78 (s, 1H, ArH), 6.54 (d, 1H, ArH), 5.47 (s, 2H, CH.sub.2),
3.75 (d, 2H, CH.sub.2), 1.98-2.12 (m, 1H, CH), 0.97 (d, 6H,
2.times.CH.sub.3).
EXAMPLE 75
1-(2-ISOBUTOXY-5-TRIFLUOROMETHOXY-BENZYL)-3-METHYL-1H-INDOLE-5-CARBOXYLIC
ACID, 145
##STR00185##
[0677] The title compound was prepared following the same method as
Example 21.
[0678] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.48 (s, 1H, ArH), 7.97
(dd, 1H, ArH), 7.31 (d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.95 (s, 1H,
ArH), 6.85 (d, 1H, ArH), 6.61 (d, 1H, ArH), 5.28 (s, 2H, CH.sub.2),
3.75 (d, 2H, CH.sub.2), 2.48 (s, 3H, CH.sub.3), 2.06-2.21 (m, 1H,
CH), 1.05 (d, 6H, 2.times.CH.sub.3).
EXAMPLE 76
1-[2-(2-ETHYL-BUTOXY)-5-TRIFLUOROMETHOXY-BENZYL]-1H-PYRROLO[2,3-B]PYRIDINE-
-5-CARBOXYLIC ACID, 146
##STR00186##
[0680] The title compound was prepared following the same method as
Example 21.
[0681] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.11 (d, 1H, ArH), 8.71
(d, 1H, ArH), 7.29 (d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.85-6.91 (m,
2H, 2.times.ArH), 6.61 (d, 1H, ArH), 5.55 (s, 2H, CH.sub.2), 3.92
(d, 2H, CH.sub.2), 1.59-1.71 (m, 1H, CH), 1.37-1.48 (m, 4H,
2.times.CH.sub.2), 0.89 (t, 6H, 2.times.CH.sub.3).
EXAMPLE 77
1-[2-(2-ETHYL-BUTOXY)-5-TRIFLUOROMETHOXY-BENZYL]-3-METHYL-1H-INDOLE-5-CARB-
OXYLIC ACID, 147
##STR00187##
[0683] The title compound was prepared following the same method as
Example 21.
[0684] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.45 (s, 1H, ArH), 7.95
(d, 1H, ArH), 7.28 (d, 1H, ArH), 7.11 (dd, 1H, ArH), 6.93 (s, 1H,
ArH), 6.88 (d, 1H, ArH), 6.65 (d, 1H, ArH), 5.25 (s, 2H, CH.sub.2),
3.93 (d, 2H, CH.sub.2), 2.41 (s, 3H, CH.sub.3), 1.62-1.75 (m, 1H,
CH), 1.41-1.53 (m, 4H, 2.times.CH.sub.2), 0.93 (t, 6H,
2.times.CH.sub.3).
EXAMPLE 78
1-[5-BROMO-2-(2-ETHYL-BUTOXY)-BENZYL]-1H-BENZOIMIDAZOLE-5-CARBOXYLIC
ACID, 148
##STR00188##
[0686] The title compound was prepared following the same method as
Example 21.
[0687] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.59 (s, 1H, ArH), 8.07
(dd, 1H, ArH), 8.02 (s, 1H, ArH), 7.39-7.47 (m, 2H, 2.times.ArH),
7.19 (d, 1H, ArH), 6.82 (d, 1H, ArH), 5.31 (s, 2H, CH.sub.2), 3.87
(d, 2H, CH.sub.2), 1.59-1.69 (m, 1H, CH), 1.33-1.45 (m, 4H,
2.times.CH.sub.2), 0.88 (t, 6H, 2.times.CH.sub.3).
EXAMPLE 79
1-(5-BROMO-2-ISOBUTOXY-BENZYL)-1H-BENZOIMIDAZOLE-5-CARBOXYLIC ACID,
149
##STR00189##
[0689] The title compound was prepared following the same method as
Example 21.
[0690] 1H-NMR (CDCl.sub.3, 300 MHz) .delta. 8.51 (s, 1H, ArH), 8.03
(s, 1H, ArH), 8.01 (dd, 1H, ArH), 7.37-7.46 (m, 2H, 2.times.ArH),
7.19 (d, 1H, ArH), 6.78 (d, 1H, ArH), 5.31 (s, 2H, CH.sub.2), 3.71
(d, 2H, CH.sub.2), 1.97-2.09 (m, 1H, CH), 0.88 (d, 6H,
2.times.CH.sub.3).
[0691] While the Examples, above, demonstrate the preparation of
certain indole and indazole compounds, isoindoles, as well as other
aza compounds may also be prepared by analogous methods as those
shown in the Examples.
[0692] The above compounds were tested for PG antagonist activity
as follows using human recombinant prostanoid receptor (DP.sub.1,
EP.sub.1-4, FP, IP and TP) stable cell lines: In order to measure
the response of G.sub.s and G.sub.i coupled prostanoid receptors as
a Ca.sup.2+ signal, chimeric G protein cDNAs were used. Stable cell
lines over-expressing human prostanoid DP.sub.1, EP.sub.1-4, FP,
IP, and TP receptors were established as follows:
[0693] Briefly, human prostanoid DP.sub.1, EP.sub.2, and EP.sub.4
receptor cDNAs were co-transfected with chimeric G.sub.qs cDNA
containing a haemagglutanin (HA) epitope; human prostanoid EP.sub.3
receptors were co-transfected with chimeric G.sub.qi-HA; human
EP.sub.1, FP, IP, and TP receptor cDNAs were expressed with no
exogenous G-proteins. G.sub.qs and G.sub.qi chimeric cDNAs
(Molecular Devices, Sunnyvale, Calif., U.S.A.), as well as cDNAs of
prostanoid receptors, were cloned into a pCEP4 vector with a
hygromycin B selection marker. Transfection into HEK-293 EBNA
(Epstein-Barr virus nuclear antigen) cells was achieved by the
FuGENE 6 transfection Reagent (Roche Applied Science, Indianapolis,
Ind., USA). Stable transfectants were selected according to
hygromycin resistance. Because G.sub.qs and G.sub.qi contained an
HA epitope, G-protein expression was detected by Western blotting
analysis using anti-mouse HA monoclonal antibody and horseradish
peroxidase (HRP)-conjugated secondary antibody, while functional
expression of prostanoid receptors was detected by FLIPR screening
(Matias et al., 2004). These stable cell lines were validated using
previously published antagonists at 10 .mu.M against serial
dilutions of standard agonists by FLIPR functional assays for
Ca.sup.2+ Signaling (as described below).
[0694] Ca.sup.2+ signaling studies were performed using a FLIPR
TETRA system (Molecular Devices, Sunnyvale, Calif., USA) in the
384-format. This is a high-throughput instrument for cell-based
assays to monitor Ca.sup.2+ signaling associated with GPCRs and ion
channels. Cells were seeded at a density of 5.times.10.sup.4
cells/well in BioCoat poly-D-lysine coated, black wall, clear
bottom 384-well plates (BD Biosciences, Franklin lakes, NJ, USA)
and allowed to attach overnight in an incubator at 37.degree. C.
The cells were then washed twice with HBSS-HEPES buffer (Hanks'
balanced salt solution without bicarbonate and phenol red, 20 mM
HEPES, pH 7.4) using an ELx405 Select CW Microplate Washer (BioTek,
Winooski, Vt., USA). After 60 min of dye-loading in the dark using
the Ca.sup.2+-sensitive dye Fluo-4AM (Invitrogen, Carlsbad, Calif.,
USA), at a final concentration of 2.times.10.sup.-6M, the plates
were washed 4 times with HBSS-HEPES buffer to remove excess dye and
leaving 50 .mu.l of buffer in each well. The plates were then
placed in the FLIPR TETRA instrument and allowed to equilibrate at
37.degree. C. Compounds were added in a 25 .mu.l volume to each
well to give final concentrations of 0.1 .mu.M, 0.3 .mu.M, 1 .mu.M,
3 .mu.M, 10 .mu.M, and 30 .mu.M; or 0.067 .mu.M, 0.1 .mu.M, 0.2
.mu.M, 0.304, 0.67 .mu.M, and 1 .mu.M for cells over-expressing TP
receptors. After 4.5 minutes, a 7-point serial dilution of the
standard agonist for the corresponding receptor, in a 25 .mu.l
volume was injected at the final concentrations from 10.sup.-11M to
10.sup.-5M in 10-fold serial dilution increments for cells
expressing human recombinant DP1, EP.sub.1, EP.sub.2, EP.sub.3,
EP.sub.4, FP, and IP receptors. The dose range for the standard
agonist for human recombinant TP receptors was from 10.sup.-12M to
10.sup.-6M. HBSS-HEPES buffer was used as the negative control for
the standard agonists. Cells were excited with LED (light emitting
diode) excitation at 470-495 nm and emission was measured through
an emission filter at 515-575 nm. Assay plates were read for 3.5
minutes using the FLIPR.sup.TETRA. The peak increase in
fluorescence intensity was recorded for each well. On each plate,
negative controls, dose response of positive controls, and
co-treatments of antagonist-agonist for each dose were in
triplicates. Standard agonists were as follows: DP=BW 245C,
EP.sub.1-EP.sub.4=PGE.sub.2, FP=17-phenyl-PGF.sub.2.alpha.,
IP=Cicaprost, and TP=U-46619. The peak fluorescence change in each
well containing drug was expressed relative to vehicle controls
with the standard agonist at 10.sup.-6M (the positive control). To
obtain concentration-response curves, compounds were tested in
triplicate in each plate over the desired concentration range.
Data Processing
[0695] All plates were subjected to appropriate baseline
corrections. Maximum fluorescence values were exported. The raw
data of n=1 was first processed by Activity Base using nonlinear
regression curve fit to calculate the percentage activity of each
data point relative to the positive control (=10.sup.-6M of the
standard agonist). Then n=3 of this data were exported to GraphPad
Prism 4 to calculate the average EC.sub.50 of the standard agonist,
and the IC.sub.50 (the concentration of the antagonist required to
inhibit half the standard agonist activity) were calculated using
nonlinear regression curve fit, with constraints of bottom constant
equal to 0 and top constant equal to 100. Calculation of
Kb=[Antagonist Concentration]/(IC.sub.50/EC.sub.50-1). When no
antagonism was detected or when Kb.gtoreq.10,000 nM, the antagonist
is defined as not active (NA).
[0696] The results of the above testing are reported in TABLE 1,
below.
TABLE-US-00001 Example FP DP EP.sub.1 EP.sub.2 EP.sub.3 EP.sub.4 IP
TP 1 560 2100 180 8700 5200 70 2200 150 2 160 1300 140 2900 1100 20
1100 110 3 50 1200 16 3400 3000 60 1200 4 4 20 700 6 1800 1500 25
800 2 5 340 2100 130 NA NA 50 5200 40 6 2400 7100 NA NA NA NA NA
150 7 300 1900 45 4400 NA 1800 1300 20 8 200 2600 220 5000 NA 1300
2800 2100 9 20 1200 90 3200 4900 3000 1350 PAgonist 10 30 440 50
500 1100 20 400 20 11 120 900 120 2000 6500 110 5500 120 12 120
1600 360 7900 NA 1150 5000 44 13 20 1200 50 1900 8500 2700 600 900
14 30 600 20 400 1500 15 340 600 15 130 1800 190 3300 8400 200 1800
20 16 3000 1500 90 NA 4000 600 6600 400 17 2300 3500 40 NA NA 600
NA 3300 18 20 1400 40 NA 4000 60 6500 4 19 16 1200 12 8800 3600 14
4600 50 20 13 500 30 NA NA 30 2700 50 21 30 100 14 3500 2200 70 900
13 22 140 1700 16 NA NA 350 6000 5 23 170 900 30 7100 1200 50 500 1
24 40 160 20 4500 2440 150 1430 80 25 180 220 27 9300 4500 160 1030
50 26 500 1700 80 NA 3300 70 1800 18 27 200 1600 110 3640 2600 53
440 20 28 70 730 43 9200 2220 40 1530 7 29 30 140 1700 16 NA NA 350
6000 5 31 170 900 30 7100 1200 50 520 1 32 50 1700 210 NA NA 5000
7400 50 33 70 350 70 2600 1400 30 400 1 34 3200 5400 70 NA NA NA NA
100 35 4300 1900 4200 NA NA 670 NA 1200 36 580 1100 60 2900 4000
1200 200 3 37 NA 1300 480 NA 3400 700 NA 200 38 1100 630 70 2100
1700 400 60 3 39 NA 1000 1200 NA 5500 1600 4900 110 40 270 1000 60
900 12000 2500 PAg Ag 41 NA 4700 NA NA NA NA 9800 7400 42 900 160
24 NA 1900 1800 3400 20 43 2200 2000 1200 NA 5500 1600 4900 110 44
1400 PAg 240 NA 1600 3200 PAg 1 45 1400 2800 23 NA NA 2000 7000 80
46 NA 2500 7100 NA NA NA NA 150 47 4700 700 2000 NA NA NA 4800 NA
48 NA NA 260 NA NA NA NA 500 49 70 3500 540 NA NA 50 3200 6 50 4900
2400 90 NA 7100 1800 NA 5700 51 110 600 70 NA 2600 270 1100 50 52
11 2300 24 3800 2100 10 NA 2 53 230 NA 1500 NA NA NA NA 1200 54
1100 9900 1300 NA NA 2700 NA 640 55 40 1200 40 NA NA 2100 NA 300 56
24 1800 24 NA 8800 150 4100 5 57 190 5500 27 NA NA 1300 NA 150 58
60 1800 30 NA 9800 380 NA 70 59 1300 520 280 NA 5400 190 540 320 60
2500 580 410 7500 5100 150 630 410 61 1500 740 180 NA NA 760 1750
300 62 NA 5800 NA NA NA NA NA NA 63 2400 NA 1200 NA 7400 2500 5000
180 64 190 260 5 3100 2900 50 700 8 65 PAg 1500 40 6500 4700 55 880
52 66 23 NA 50 NA NA 1400 4600 320 67 100 NA 60 NA NA 340 NA 160 68
NA NA NA NA NA 9700 6600 NA 69 800 3700 250 NA 7900 130 3000 550 70
NA 2200 200 NA NA 6000 NA 320 71 120 NA 100 NA NA 280 NA 600 72 25
1500 10 NA NA 220 2000 3 73 430 NA 80 NA NA NA 9000 8 74 660 290 60
NA 2800 440 1400 20 75 330 1300 20 6400 NA 280 4400 300 76 660 290
60 NA 2800 440 1400 20 77 9600 3600 900 9200 NA 1500 NA 1100 78 800
3800 145 NA NA 35 3000 16 79 80 2000 11 NA 8700 80 7000 8
[0697] As shown in TABLE 1, the preferred compounds of this
invention are pan antagonists having activity at the FP, DP.sub.1,
EP.sub.1, EP.sub.4 and TP receptors, but are inactive at the IP,
EP.sub.2 and EP.sub.3 receptors. Thus, these compounds have a
biological selectivity profile making them useful in treating
diseases and conditions which are ameliorated by the IP/EP.sub.2
and/or EP.sub.3 receptor stimulation, without the symptoms side
effects mediated by the FP, DP, EP.sub.1, EP.sub.4 and TP
receptors. Also, based on the data generated for this TABLE 1, it
appears that the 5-carboxylic acid compounds are more active at the
EP.sub.1 and EP.sub.4 receptors than the 4 or 6-carboxylic acid
compounds. Therefore, the 5-carboxylic acid compounds are
preferred.
[0698] Thus, the compounds of this invention compound may be
administered to treat DP1, FP, EP.sub.1, TP and/or EP.sub.4
receptor mediated diseases or conditions.
[0699] For example, said condition or disease may be related to
inflammation, or said, FP, EP.sub.1, TP and/or EP.sub.4 receptor
mediated condition or disease may be selected from the group
consisting of allergic conditions, asthma, allergic asthma,
allergic rhinitis, uveitis and related disorders, atherosclerosis,
blood coagulation disorders, bone disorders, cancer, cellular
neoplastic transformations, chronic obstructive pulmonary diseases
and other forms of lung inflammation, congestive heart failure,
diabetic retinopathy, diseases or conditions requiring a treatment
of anti-coagulation, diseases requiring control of bone formation
and resorption, endometriosis, fertility disorders, gangrene,
glaucoma, hyperpyrexia, immune and autoimmune diseases,
inflammatory conditions, metastic tumor growth, migraine, mucus
secretion disorders, nasal congestion, nasal inflammation,
occlusive vascular diseases, ocular hypertension, ocular
hypotension, osteoporosis, rheumatoid arthritis, pain, perennial
rhinitis, pre-term labor, pulmonary congestion, pulmonary
hypotension, Raynaud's disease, rejection in organ transplant and
by-pass surgery, respiratory conditions, hirsutism, rhinorrhea,
shock, sleep disorders, and sleep-wake cycle disorders.
[0700] The compounds of the present invention may be administered
as a surgical adjunct in ophthalmology for cataract removal and
artificial lens insertion, ocular implant procedures,
photorefractive radial keratotomy and other ophthalmogical laser
procedures or as a surgical adjunct in a procedure involving skin
incisions, relief of pain and inflammation and scar
formation/keloids post-surgery, for treating sports injuries and
general aches and pains in muscles and joints.
[0701] Preferably, said DP.sub.1, FP, EP.sub.1, TP, and/or EP.sub.4
receptor mediated condition or disease is an EP.sub.1 and/or
EP.sub.4 receptor mediated condition or disease. Preferably, said
DP.sub.1, FP, EP.sub.1, TP and/or EP.sub.4 receptor mediated
condition or disease is an allergic condition, e.g. an
dermatological allergy, or an ocular allergy, or a respiratory
allergy, e.g. nasal congestion, rhinitis, and asthma.
[0702] The condition or disease may be related to pain. The
condition or disease may be selected from the group consisting of
arthritis, migraine, and headache. The condition or disease may be
associated with the gastrointestinal tract, wherein said condition
or disease may be peptic ulcer, heartburn, reflux esophagitis,
erosive esophagitis, non-ulcer dyspepsia, infection by Helicobacter
pylori, alrynitis, and irritable bowel syndrome.
[0703] The condition or disease may be selected from the group
consisting of hyperalgesia and allodynia, or said condition or
disease may be related to mucus secretion, wherein said mucus
secretion is gastrointestinal, or occurs in the nose, sinuses,
throat, or lungs.
[0704] The condition or disease is related to abdominal cramping,
e.g. said condition, menstrual cramping or disease may be irritable
bowel syndrome. The condition or disease may be a bleeding
disorder, or a sleep disorder, or mastocytosis.
[0705] The condition or disease may be associated with elevated
body temperature, or ocular hypertension and glaucoma, or ocular
hypotension. The condition may relate to surgical procedures to
treat pain, inflammation and other unwanted sequelae wherein said
surgical procedure includes incision, laser surgery or
implantation.
[0706] The present invention also relates to a method of treating
inflammation resulting from inflammatory diseases characterized by
monocytic infiltration caused by the secretion of cytokines and/or
chemokines by administration, to a patient in need of said
treatment, of a pharmaceutical composition comprising a compound of
the present invention
[0707] The current finding that the compounds of this invention are
effective in attenuating the production of TNF family cytokines
(TNF.alpha.), and the classical interleukin-1 (IL-1) family
cytokines is especially important. These cytokines exert a broad
spectrum of biological and pathological effects. They play key
roles in inflammation and RA pathogenesis by stimulating the
release of multiple proinflammatory cytokines, including
themselves, through the NF.kappa.B signaling pathway. Although
alleviating the symptoms of RA in 50-65% of patients, a TNF.alpha.
antibody is very expensive to use compared to chemically
synthesized small molecules, inconvenient to administer usually
requiring injections, and has been linked to tuberculosis,
lymphoma, and other adverse effects. Unlike a TNF.alpha. antibody
that totally eliminates all circulating TNF.alpha. in the system;
the compounds of this invention only attenuate the production of
TNF.alpha. by inhibiting proinflammatory PG receptors. Therefore,
the adverse effects associated with a TNF.alpha. antibody in
elevating infectious and cancerous tendency is less likely.
[0708] Proinflammatory elements TNF, RANTES, and MCP-1 are involved
in the cascade of events in the early and late stages of
atherosclerosis. Plasma MCP-1 levels have been linked to
cardiovascular disease risk factors in clinical studies. Platelet
activation leads to the release of MIP-1.alpha., RANTES, and IL-8,
which attract leukocytes and further activate other platelets.
These evidences provide a direct linkage between homeostasis,
infection, and inflammation and the development of atherosclerosis.
The compounds of this invention are able to target multiple
biomarkers of inflammation, thrombosis, and atherothrombosis
simultaneously, which may confer pharmaceutical potential on the
compounds of this invention in treating atherosclerosis and
atherothrombosis. As a result, the compounds of this invention are
unlikely to be associated with cardiovascular liability as in the
case of the COXIBs, conversely it may even have a beneficial effect
on cardiovascular function.
[0709] In summary, because of their ability to suppress the
synthesis of some key proinflammatory cytokines/chemokines IL-8,
MCP-1, MDC, RANTES, and TNF.alpha., the compounds of the present
invention are believed to be, not only at least as effective as
COXIBs and NSAIDs in RA treatment, but also are a safer therapy in
RA treatment. They are also a potential therapy for cardiovascular
diseases.
[0710] The compounds of this invention are believed to treat or
prevent inflammation at least in part by the decreasing the amount
of the secretion of certain cytokines and/or chemokines that result
from the exposure of the patient to a stimulant. In particular, the
secretion of VEGF, MIP-10, IL-8, MCP-1, MDC, and RANTES may be
reduced in those instances where said secretions are triggered by
lipopolysaccharides (LPS) and or TNF.alpha..
[0711] Interleukin-8 (IL-8): functions as a potent chemoattractant
and activator of neutrophils, IL-8 is produced in response to
stimulation with either IL-1 or TNF.alpha.. IL-8 not only accounts
for a significant proportion of the chemotactic activity for
neutrophils in rheumatoid arthritis (RA) synovial fluids, but also
is a potent angiogenic factor in the RA synovium. Monocyte
chemoattractant protein-1 (MCP-1, or CCL-2): is not only believed
to play a role in inflammatory diseases characterized by monocytic
infiltration, such as rheumatoid arthritis ("RA"), psoriasis, and
atherosclerosis, but is also implicated in other diseases, such as
atopic dermatitis, renal disease, pleurisy, allergy and asthma,
colitis, endometriosis, polymyositis and dermatomyositis, uveitis,
restenosis, brain inflammation and obesity. MCP-1 also controls
leukocyte trafficking in vascular cells involved in diabetes and
diabetes-induced atherosclerosis. MCP-1 antibodies are potential
therapeutic agents for treating MCP-1/CCR2-mediated multiple
inflammatory diseases.
[0712] Tumor necrosis factor .alpha. (TNF.alpha.): mainly secreted
by macrophages and recognized for its importance in activating the
cytokine cascade. TNF.alpha. stimulates the production of
proinflammatory cytokines/chemokines, collagenases,
metalloproteinases, and other inflammatory mediators; activates
endothelial cells and neutrophils; promotes T- and B-cell growth,
as well as stimulating bone resorption. The TNF.alpha. antibody
infliximab not only decreases the production of local and systemic
proinflammatory cytokines/chemokines, but also reduces serum MMP-3
production, nitric oxide synthase activity, VEGF release, and
angiogenesis in inflamed joints.
[0713] Macrophage-derived chemokine (MDC) induces chemotaxis for
monocyte-derived dendritic cells, activated T cells and natural
killer (NK) cells (Ho et al., 2003). Highly expressed by the three
major cell types involved in allergic inflammation: eosinophils,
basophils, and Th2 lymphocytes (Garcia et al., 2005), as well as
highly expressed in atopic dermatitis (Pivarcsi et al., 2005), MDC
plays a role in inflammatory diseases such as allergic asthma and
atopic dermatitis (Ho et al., 2003). Significantly enhanced in
keratinocytes of patients with atopic dermatitis, MDC could be a
candidate therapeutic target for inflammatory skin disease such as
atopic dermatitis (Qi et al., 2009). MDC is also implicated in
disease activity of RA. After combination treatment with the
disease-modifying anti-rheumatic drugs leflunomide and methotrexate
in RA patients, plasma MCP-1 and MDC concentrations were
significantly lower, and so was the recruitment of inflammatory
cells into the sites of inflammation (Ho et al., 2003). Moreover,
MDC also amplify platelet activation and has been associated with
the pathogenesis of atherosclerotic disease including thrombosis
(Gleissner et al., 2008).
[0714] Regulated on Activation, Normal T Cell Expressed and
Secreted (RANTES) is a chemoattractant for blood monocytes, memory
T-helper cells and eosinophils, and plays an active role in
recruiting leukocytes into inflammatory sites. It also stimulates
the release of histamine from basophils, activates eosinophils and
causes hypodense eosinophils, which are associated with diseases
such as asthma and allergic rhinitis. RANTES receptor CCR5 is also
expressed on cells involved in atherosclerosis (e.g.
monocytes/macrophages, T lymphocytes, or Th1-type cells), and is
specialized in mediating RANTES-triggered atherosclerotic plaque
formation (Zernecke et al., 2008). Like MCP-1, stimulation with
RANTES enhances production of IL-6 and IL-8 in RA fibroblast-like
synovial cells; elevated MMP-3 production by chondrocytes, and
inhibited proteoglycan synthesis and enhanced proteoglycan release
from the chondrocytes (Iwamoto et al., 2008). Both MCP-1 and RANTES
were found to play an important role in allergic lung inflammation,
lung leukocyte infiltration, bronchial hyper-responsiveness, and
the recruitment of eosinophils in the pathogenesis of asthma (Conti
et al., 2001). Similar to MCP-1, RANTES also enhances the
inflammatory response within the nervous system, which plays an
apparent role in the pathogenesis of multiple sclerosis (Conti et
al., 2001). Inhibitors for RANTES may provide clinical benefits in
treating inflammation, CNS disorders, parasitic disease, cancer,
autoimmune and heart diseases (Castellani et al., 2007). Thus the
compounds of the present invention, given locally or systemically,
may be useful for treatment or alleviating symptoms of T cell
mediated autoimmune disorders such as RA and multiple
sclerosis.
[0715] While the use of the compounds of this invention are
believed to decrease the secretion of the above cytokines, it is
also believed that the compounds of this invention are effective to
decrease the secretion of ENA-7, PAI-1, CD-10, G-CSF, GM-CSF,
IL-1{acute over (.alpha.)} and IL-18, as well.
[0716] The compounds of this invention may be also tested for
efficacy in treating uveitis as described below.
Arachidonate Induced Uveitis
[0717] The rational for this protocol is to use arachidonate to
directly produce ocular anterior segment uveitis, as opposed to
using lipopolysaccharide (LPS) to indirectly release arachidonic
acid.
Induction of Uveitis:
[0718] Conscious male or female Dutch-belted pigmented rabbits
weighing 2.5-3 kg are used for all in vivo slit lamp studies. Four
animals are employed per test group. The right eye of each animal
receiving 35 .mu.l of topically administered test and the
contralateral left eye of each animal receiving 35 .mu.l of
topically administered vehicle (t=0 minutes), followed 30 minutes
later by treatment with 35 .mu.l of 0.5% sodium arachidonate onto
the surface of both eyes (t=30 minutes). Both eyes are examined by
slit lamp 60 minutes following sodium arachdionate challenge (t=90
minutes) at 16.times. magnification under both white light and blue
light illumination at an approximate angle of 45.degree. through 1
mm and 5 mm slit widths.
Measurement of anterior chamber leukocyte infiltration:
[0719] Anterior chamber leukocyte infiltration is measured using a
numerical scoring system to estimate cell number per field defined
by a 5 mm slit width: 0=no cells per field (no response); 1=1-10
cells per field (mild); 2=11-20 cells per field (moderate); 3=26-50
cells per field (severe); 4=>50 cells per filed (florid).
Results are reported as the mean score value.+-.S.E.M.
[0720] The compounds of this invention may be tested according to
the method described in "Characterization of Receptor Subtypes
Involved in Prostanoid-Induced Conjunctival Pruritis and Their Role
in Mediating Conjunctival Itching", Vol. 279, No. 1, (JPET) 279,
137-142' 1996 for their efficacy in alleviating itch to thereby
indicate that the compounds of this invention are useful in
treating allergic conjunctivitis. This reference is hereby
incorporated by reference.
[0721] While the use of the compounds of this invention are
believed to decrease the secretion of the above cytokines, it also
is believed that the compounds of this invention are effective to
decrease the secretion of ENA-7, PAI-1, CD-10, G-CSF, GM-CSF,
IL-1{acute over (.alpha.)} and IL-18, as well.
[0722] Finally, said condition that may be treated with the
compounds of this invention may be related to pain and inflammation
and post-surgical scar and keloid formation.
[0723] In view of the various diseases and conditions that may be
treated with the compositions of this invention there is provided a
pharmaceutical product comprising a compound having the following
formula:
##STR00190##
Wherein:
X is N or CR.sub.7;
[0724] A is N or CR.sub.7 with the proviso that at least one A is N
and when each A is N, R.sub.2 is absent; Y is (CH.sub.2).sub.m
wherein m is 0 or an integer of from 1 to 3; Z is selected from the
group consisting of O, S, SO, SO.sub.2 and (CH.sub.2).sub.p,
wherein p is 0 or an integer of from 1 to 3; W is hydrocarbyl or
substituted hydrocarbyl; R.sub.1 is selected from the group
consisting of OR.sub.7, NH.sub.2, N(R.sub.7).sub.2, and
N(R.sub.7)SO.sub.2R.sub.7; R.sub.2 is selected from the group
consisting of H, hydroxy, alkyl, aryl, alkoxy, aryloxy, halogen,
nitro, amino, cyano and hydroxy, halogen, nitro, amino and
cyano-substituted alkyl, aryl, alkoxy or aryloxy; R.sub.3 is
selected from the group consisting of H, hydroxy, alkyl, aryl,
alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy, halogen,
nitro, amino and cyano-substituted alkyl, aryl, alkoxy or aryloxy;
R.sub.4 is selected from the group consisting of H, hydroxy, alkyl,
aryl, alkoxy, aryloxy, halogen, nitro, amino, cyano and hydroxy,
halogen, nitro, amino and cyano-substituted alkyl, aryl, alkoxy or
aryloxy; and/or a pharmaceutically acceptable salt or a prodrug
thereof.
[0725] The compounds of the present invention may be formulated,
packaged and labeled for the treatment or prevention of a disease
or condition selected from the group consisting of uveitis,
allergic conditions, asthma, allergic asthma, allergic rhinitis,
atherosclerosis, blood coagulation disorders, bone disorders,
cancer, cellular neoplastic transformations, chronic obstructive
pulmonary diseases and other forms of lung inflammation, congestive
heart failure, diabetic retinopathy, diseases or conditions
requiring a treatment of anti-coagulation, diseases requiring
control of bone formation and resorption, fertility disorders,
hyperpyrexia, endometriosis gangrene, glaucoma, hypothermia, immune
and autoimmune diseases, inflammatory conditions, metastic tumor
growth, migraine, mucus secretion disorders, nasal congestion,
nasal inflammation, occlusive vascular diseases, ocular
hypertension, ocular hypotension, osteoporosis, pain, perennial
rhinitis, pre-term labor pulmonary congestion, pulmonary
hypotension, Raynaud's disease, rejection in organ transplant and
by-pass surgery, respiratory conditions, rheumatoid arthritis,
rhinorrhea, shock, sleep disorders, sleep-wake cycle disorders,
sports injuries, muscle aches and pains, and surgical adjunct for
minimizing pain, inflammation and scar/keloid formation.
[0726] Those skilled in the art will readily understand that for
administration the compounds disclosed herein can be admixed with
pharmaceutically acceptable excipients which, per se, are well
known in the art. Specifically, a drug to be administered
systemically, it may be formulated as a powder, pill, tablet or the
like, or as a solution, emulsion, suspension, aerosol, syrup or
elixir suitable for oral or parenteral administration or
inhalation.
[0727] For solid dosage forms, non-toxic solid carriers include,
but are not limited to, pharmaceutical grades of mannitol, lactose,
starch, magnesium stearate, sodium saccharin, the polyalkylene
glycols, talcum, cellulose, glucose, sucrose and magnesium
carbonate. The solid dosage forms may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distcarate may be
employed. They may also be coated by the technique described in the
U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 which are hereby
incorporated by reference to form osmotic therapeutic tablets for
control release. Liquid pharmaceutically administrable dosage forms
can, for example, comprise a solution or suspension of one or more
of the compounds of the present invention and optional
pharmaceutical adjutants in a carrier, such as for example, water,
saline, aqueous dextrose, glycerol, ethanol and the like, to
thereby form a solution or suspension. If desired, the
pharmaceutical composition to be administered may also contain
minor amounts of nontoxic auxiliary substances such as wetting or
emulsifying agents, pH buffering agents and the like. Typical
examples of such auxiliary agents are sodium acetate, sorbitan
monolaurate, triethanolamine, sodium acetate, triethanolamine
oleate, etc. Actual methods of preparing such dosage forms are
known, or will be apparent, to those skilled in this art; for
example, see Remington's Pharmaceutical Sciences, Mack Publishing
Company, Easton, Pa., 16th Edition, 1980. The composition of the
formulation to be administered, in any event, contains a quantity
of one or more of the presently useful compounds in an amount
effective to provide the desired therapeutic effect.
[0728] Parenteral administration is generally characterized by
injection, either subcutaneously, intramuscularly or intravenously.
Injectable formulations can be prepared in conventional forms,
either as liquid solutions or suspensions, solid forms suitable for
solution or suspension in liquid prior to injection, or as
emulsions. Suitable excipients are, for example, water, saline,
dextrose, glycerol, ethanol and the like. In addition, if desired,
the injectable pharmaceutical compositions to be administered may
also contain minor amounts of non-toxic auxiliary substances such
as wetting or emulsifying agents, pH buffering agents and the
like.
[0729] The amount of the presently useful compound or compounds of
the present invention administered is, of course, dependent on the
therapeutic effect or effects desired, on the specific mammal being
treated, on the severity and nature of the mammal's condition, on
the manner of administration, on the potency and pharmacodynamics
of the particular compound or compounds employed, and on the
judgment of the prescribing physician. The therapeutically
effective dosage of the presently useful compound or compounds is
preferably in the range of about 0.5 ng/kg/day or about 1 ng/kg/day
to about 100 mg/kg/day.
[0730] For ophthalmic application, solutions are often prepared
using a physiological saline solution as a major vehicle.
Ophthalmic solutions should preferably be maintained at a
comfortable pH with an appropriate buffer system. The formulations
may also contain conventional, pharmaceutically acceptable
preservatives, stabilizers and surfactants.
[0731] Preservatives that may be used in the pharmaceutical
compositions of the present invention include, but are not limited
to, benzalkonium chloride, chlorobutanol, thimerosal,
phenylmercuric acetate and phenylmercuric nitrate. A useful
surfactant is, for example, Tween 80. Likewise, various useful
vehicles may be used in the ophthalmic preparations of the present
invention. These vehicles include, but are not limited to,
polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,
poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and
purified water.
[0732] Tonicity adjustors may be added as needed or convenient.
They include, but are not limited to, salts, particularly sodium
chloride, potassium chloride, mannitol and glycerin, or any other
suitable ophthalmically acceptable tonicity adjustor.
[0733] Various buffers and means for adjusting pH may be used so
long as the resulting preparation is ophthalmically acceptable.
Accordingly, buffers include acetate buffers, citrate buffers,
phosphate buffers and borate buffers. Acids or bases may be used to
adjust the pH of these formulations as needed.
[0734] Similarly, an ophthalmically acceptable antioxidant for use
in the present invention includes, but is not limited to, sodium
metabisulfite, sodium thiosulfate, acetylcysteine, butylated
hydroxyanisole and butylated hydroxytoluene.
[0735] Other excipient components which may be included in the
ophthalmic preparations are chelating agents. A useful chelating
agent is edentate disodium, although other chelating agents may
also be used in place or in conjunction with it.
[0736] For topical use, creams, ointments, gels, solutions or
suspensions, etc., containing the compound of the present invention
are employed. Topical formulations may generally be comprised of a
pharmaceutical carrier, cosolvent, emulsifier, penetration
enhancer, preservative system, and emollient.
[0737] The actual dose of the compounds of the present invention
depends on the specific compound, and on the condition to be
treated; the selection of the appropriate dose is well within the
knowledge of the skilled artisan.
[0738] The present invention is not to be limited in scope by the
exemplified embodiments, which are only intended as illustrations
of specific aspects of the invention. Various modifications of the
invention, in addition to those disclosed herein, will be apparent
to those skilled in the art by a careful reading of the
specification, including the claims, as originally filed. It is
intended that all such modifications will fall within the scope of
the appended claims.
* * * * *