U.S. patent application number 11/773106 was filed with the patent office on 2008-02-14 for bicycloheteroaryl compounds as p2x7 modulators and uses thereof.
This patent application is currently assigned to Renovis, Inc.. Invention is credited to MichaelG Kelly, John Kincaid.
Application Number | 20080039478 11/773106 |
Document ID | / |
Family ID | 37024169 |
Filed Date | 2008-02-14 |
United States Patent
Application |
20080039478 |
Kind Code |
A1 |
Kelly; MichaelG ; et
al. |
February 14, 2008 |
Bicycloheteroaryl Compounds as P2X7 Modulators and Uses Thereof
Abstract
Bicycloheteroaryl compounds are disclosed that have a formula
represented by the following: ##STR1## The compounds may be
prepared as pharmaceutical compositions, and may be used for the
prevention and treatment of a variety of conditions in mammals
including humans, including by way of non-limiting example, pain,
inflammation, traumatic injury, and others.
Inventors: |
Kelly; MichaelG; (Thousand
Oaks, CA) ; Kincaid; John; (San Mateo, CA) |
Correspondence
Address: |
KLAUBER & JACKSON
411 HACKENSACK AVENUE
HACKENSACK
NJ
07601
US
|
Assignee: |
Renovis, Inc.
|
Family ID: |
37024169 |
Appl. No.: |
11/773106 |
Filed: |
July 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
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Patent Number |
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11384045 |
Mar 17, 2006 |
7297700 |
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11773106 |
Jul 3, 2007 |
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60664903 |
Mar 24, 2005 |
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60709186 |
Aug 18, 2005 |
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60710077 |
Aug 22, 2005 |
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60712778 |
Aug 31, 2005 |
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60721390 |
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60753194 |
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Current U.S.
Class: |
514/264.11 ;
514/264.1 |
Current CPC
Class: |
A61P 17/04 20180101;
A61P 3/00 20180101; A61P 19/00 20180101; A61P 17/06 20180101; A61P
35/00 20180101; A61P 9/00 20180101; A61P 13/02 20180101; A61P 17/00
20180101; A61P 25/06 20180101; C07D 401/06 20130101; A61P 11/00
20180101; C07D 471/04 20130101; A61P 25/08 20180101; A61P 37/08
20180101; A61P 43/00 20180101; C07D 405/06 20130101; A61P 17/02
20180101; A61P 25/16 20180101; A61P 29/00 20180101; A61P 25/00
20180101; A61P 25/02 20180101; A61P 25/04 20180101; A61P 25/24
20180101; A61P 37/02 20180101; A61P 13/12 20180101; A61P 3/10
20180101; A61P 25/22 20180101; C07D 487/04 20130101; A61P 11/02
20180101; A61P 37/00 20180101; A61P 25/20 20180101; A61P 11/08
20180101; A61P 19/02 20180101; A61P 27/02 20180101; C07D 413/06
20130101; C07D 417/06 20130101; A61P 1/00 20180101; A61P 1/12
20180101; A61P 27/16 20180101; A61P 9/10 20180101; A61P 11/06
20180101; C07D 217/24 20130101; A61P 25/18 20180101; A61P 9/12
20180101; A61P 1/02 20180101; A61P 13/10 20180101; A61P 3/06
20180101; A61P 1/14 20180101; A61P 39/02 20180101; A61P 3/04
20180101; A61P 13/08 20180101; A61P 17/16 20180101; A61P 7/00
20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/264.11 ;
514/264.1 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61P 11/00 20060101 A61P011/00; A61P 19/00 20060101
A61P019/00; A61P 25/00 20060101 A61P025/00; A61P 29/00 20060101
A61P029/00; A61P 3/00 20060101 A61P003/00; A61P 35/00 20060101
A61P035/00; A61P 37/00 20060101 A61P037/00; A61P 7/00 20060101
A61P007/00; A61P 9/00 20060101 A61P009/00 |
Claims
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. (canceled)
17. (canceled)
18. (canceled)
19. (canceled)
20. (canceled)
21. (canceled)
22. (canceled)
23. (canceled)
24. (canceled)
25. (canceled)
26. (canceled)
27. (canceled)
28. (canceled)
29. (canceled)
30. (canceled)
31. (canceled)
32. (canceled)
33. (canceled)
34. (canceled)
35. (canceled)
36. (canceled)
37. (canceled)
38. (canceled)
39. (canceled)
40. (canceled)
41. (canceled)
42. (canceled)
43. (canceled)
44. (canceled)
45. (canceled)
46. (canceled)
47. (canceled)
48. (canceled)
49. A method for preventing, treating or ameliorating in a mammal a
disease or condition that is causally related to the aberrant
activity of the P2X.sub.7 receptor in vivo, which comprises
administering to the mammal an effective disease-treating or
condition-treating amount of a pharmaceutical composition, said
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a pharmaceutically effective amount of a compound
having a formula: ##STR76## wherein A is selected from
CR.sup.2aR.sup.2b; B and Y are independently selected from
CR.sup.2a and CR.sup.2aR.sup.2b; Z is CR.sup.4: L.sup.1 is a bond,
--CO-- --SO.sub.2-- or a C.sub.1-C.sub.5 alkylene group which can
be optionally substituted by a substituent selected from alkyl
hydroxy hydroxyalkylaminoalkyl alkylaminoalkyl dialkylaminoalkyl
halogen, carbamoyl and C.sub.1-C.sub.6 alkoxy; n is 0, 1, 2 or 3,
R.sup.1 is selected from a 3-13 membered cycloalkyl which can be
optionally substituted with one or more substituents independently
selected from halo hydroxylamino cyano sulfo sulfanyl, sulfinyl
amido, carboxy, ester, alkyl substituted alkyl alkenyl substituted
alkenyl alkynyl substituted alkynyl and sulfonamido: each of
R.sup.2a, R.sup.2bR.sup.2' and R.sup.2'' is independently selected
from hydrogen, substituted or unsubstituted C.sub.1-C.sub.6 alkyl;
or any of R.sup.2' and R.sup.2'' can join together to form a
cycloalkyl or cycloheteroalkyl ring of 3-7 atoms; R.sup.3 is
selected from hydrogen substituted or unsubstituted alkyl
substituted or unsubstituted cycloalkyl substituted or
unsubstituted heterocycloalkyl substituted or unsubstituted aryl
substituted or unsubstituted heteroaryl, substituted or
unsubstituted bicycloaryl, and substituted or unsubstituted
bicycloheteroaryl; provided when R.sup.3 is hydrogen L.sup.1 is a
bond or a C.sub.1-C.sub.5 alkylene group, R.sup.4 is selected from
H, alkyl substituted alkyl acyl substituted acyl substituted or
unsubstituted acylamino substituted or unsubstituted alkylamino
substituted or unsubstituted alkylthio, substituted or
unsubstituted alkoxy, alkoxycarbonyl substituted alkoxycarbonyl
substituted or unsubstituted alkylarylamino arylalkyloxy
substituted arylalkyloxy amino aryl, substituted aryl, arylalkyl
substituted or unsubstituted sulfoxide, substituted or
unsubstituted sulfone substituted or unsubstituted sulfanyl
substituted or unsubstituted aminosulfonyl substituted or
unsubstituted arylsulfonyl sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl substituted or
unsubstituted aminodihydroxyphosphoryl azido, carboxy, substituted
or unsubstituted carbamoyl cyano, substituted or unsubstituted
cycloalkyl substituted or unsubstituted cycloheteroalkyl
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; and the dotted
bond is a single or a double bond, or a pharmaceutically acceptable
salt thereof, and stereoisomers and tautomers thereof.
50. The method of claim 49, wherein the disease or condition is a
pain condition.
51. The method of claim 49, wherein the disease or condition is an
autoimmune disease.
52. The method of claim 49, wherein the disease or condition is an
inflammatory disease or condition.
53. The method of claim 49, wherein the disease or condition is a
neurological or neurodegenerative disease or condition.
54. A method for preventing, treating or ameliorating in a mammal a
disease or condition selected from: pain including acute,
inflammatory and neuropathic pain, chronic pain, dental pain and
headache including migraine, cluster headache and tension headache,
Parkinson's disease, multiple sclerosis; diseases and disorders
which are mediated by or result in neuroinflammation, traumatic
brain injury and encephalitis; centrally-mediated neuropsychiatric
diseases and disorders, depression mania, bipolar disease, anxiety,
schizophrenia, eating disorders, sleep disorders and cognition
disorders; epilepsy and seizure disorders; prostate, bladder and
bowel dysfunction, urinary incontinence, urinary hesitancy, rectal
hypersensitivity, fecal incontinence, benign prostatic hypertrophy
and inflammatory bowel disease; respiratory and airway disease and
disorders, allergic rhinitis, asthma and reactive airway disease
and chronic obstructive pulmonary disease; diseases and disorders
which are mediated by or result in inflammation, arthritis,
rheumatoid arthritis and osteoarthritis, myocardial infarction,
various autoimmune diseases and disorders, uveitis and
atherosclerosis; itch/pruritus, psoriasis; obesity; lipid
disorders; cancer; blood pressure; spinal cord injury; and renal
disorders which comprises administering to the mammal an effective
disease-treating or condition-treating amount of a pharmaceutical
composition, said pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a pharmaceutically
effective amount of a compound having a formula: ##STR77## wherein
A is selected from CR.sup.2aR.sup.2b; B and Y are independently
selected from CR.sup.2a and CR.sup.2aR.sup.2b; Z is CR.sup.4:
L.sup.1 is a bond, --CO-- --SO.sub.2-- or a C.sub.1-C.sub.5
alkylene group which can be optionally substituted by a substituent
selected from alkyl, hydroxy, hydroxyalkyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl halogen, carbamoyl and
C.sub.1-C.sub.6 alkoxy; n is 0, 1, 2 or 3, R.sup.1 is selected from
a 3-13 membered cycloalkyl which can be optionally substituted with
one or more substituents independently selected from halo,
hydroxyl, amino, cyano, sulfo, sulfanyl, sulfinyl amido, carboxy,
ester, alkyl substituted alkyl alkenyl substituted alkenyl alkynyl
substituted alkynyl and sulfonamido: each of R.sup.2a, R.sup.2b,
R.sup.2' and R.sup.2'' is independently selected from hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6 alkyl: or any of
R.sup.2' and R.sup.2'' can join together to form a cycloalkyl or
cycloheteroalkyl ring of 3-7 atoms; R.sup.3 is selected from
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted cycloalkyl substituted or unsubstituted
heterocycloalkyl substituted or unsubstituted aryl substituted or
unsubstituted heteroaryl substituted or unsubstituted bicycloaryl
and substituted or unsubstituted bicycloheteroaryl; provided when
R.sup.3 is hydrogen L.sup.1 is a bond or a C.sub.1-C.sub.5 alkylene
group, R.sup.4 is selected from H, alkyl substituted alkyl acyl
substituted acyl substituted or unsubstituted acylamino,
substituted or unsubstituted alkylamino, substituted or
unsubstituted alkylthio, substituted or unsubstituted alkoxy,
alkoxycarbonyl substituted alkoxycarbonyl substituted or
unsubstituted alkylarylamino arylalkyloxy, substituted
arylalkyloxy, amino, aryl, substituted aryl, arylalkyl substituted
or unsubstituted sulfoxide, substituted or unsubstituted sulfone,
substituted or unsubstituted sulfanyl substituted or unsubstituted
aminosulfonyl substituted or unsubstituted arylsulfonyl sulfuric
acid sulfuric acid ester substituted or unsubstituted
dihydroxyphosphoryl substituted or unsubstituted
aminodihydroxyphosphoryl azido carboxy substituted or unsubstituted
carbamoyl cyano, substituted or unsubstituted cycloalkyl
substituted or unsubstituted cycloheteroalkyl, substituted or
unsubstituted dialkylamino halo heteroaryloxy substituted or
unsubstituted heteroaryl substituted or unsubstituted heteroalkyl
hydroxy, nitro, and thio; and the dotted bond is a single or a
double bond, or a pharmaceutically acceptable salt thereof, and
stereoisomers and tautomers thereof.
55. The method of claim 54, wherein the disease or condition is
Parkinson's disease.
56. The method of claim 54, wherein the disease or condition is
rheumatoid arthritis.
57. The method of claim 54, wherein the disease or condition is
traumatic brain injury.
58. The method of claim 54, wherein the disease or condition is
osteoarthritis.
59. The method of claim 54, wherein the disease or condition is
pain.
60. The method of claim 54, wherein the disease or condition is
neuropathic pain.
61. A method of treating a mammal suffering from at least one
symptom selected from the group consisting of symptoms of exposure
to capsaicin, symptoms of burns or irritation due to exposure to
heat, symptoms of burns or irritation due to exposure to light,
symptoms of burns, bronchoconstriction or irritation due to
exposure to tear gas, and symptoms of burns or irritation due to
exposure to acid, which comprises administering to the mammal an
effective disease-treating or condition-treating amount of a
pharmaceutical composition, said pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a
pharmaceutically effective amount of a compound having a formula:
##STR78## wherein A is selected from CR.sup.2aR.sup.2b; B and Y are
independently selected from CR.sup.2a and CR.sup.2aR.sup.2b; Z is
CR.sup.4: L.sup.1 is a bond, --CO-- --SO.sub.2-- or a
C.sub.1-C.sub.5 alkylene group which can be optionally substituted
by a substituent selected from alkyl hydroxy hydroxyalkylaminoalkyl
alkylaminoalkyl dialkylaminoalkyl halogen, carbamoyl and
C.sub.1-C.sub.6 alkoxy; n is 0, 1, 2 or 3, R.sup.1 is selected from
a 3-13 membered cycloalkyl which can be optionally substituted with
one or more substituents independently selected from halo
hydroxylamino cyano sulfo sulfanyl, sulfinyl amido, carboxy, ester,
alkyl substituted alkyl alkenyl substituted alkenyl alkynyl
substituted alkynyl and sulfonamido: each of R.sup.2a,
R.sup.2bR.sup.2' and R.sup.2'' is independently selected from
hydrogen, substituted or unsubstituted C.sub.1-C.sub.6 alkyl: or
any of R.sup.2 and R.sup.2 can join together to form a cycloalkyl
or cycloheteroalkyl ring of 3-7 atoms; R.sup.3 is selected from
hydrogen substituted or unsubstituted alkyl substituted or
unsubstituted cycloalkyl substituted or unsubstituted
heterocycloalkyl substituted or unsubstituted aryl substituted or
unsubstituted heteroaryl, substituted or unsubstituted bicycloaryl,
and substituted or unsubstituted bicycloheteroaryl; provided when
R.sup.3 is hydrogen L.sup.1 is a bond or a C.sub.1-C.sub.5 alkylene
group, R.sup.4 is selected from H, alkyl substituted alkyl acyl
substituted acyl substituted or unsubstituted acylamino substituted
or unsubstituted alkylamino substituted or unsubstituted alkylthio,
substituted or unsubstituted alkoxy, alkoxycarbonyl substituted
alkoxycarbonyl substituted or unsubstituted alkylarylamino
arylalkyloxy substituted arylalkyloxy amino aryl, substituted aryl,
arylalkyl substituted or unsubstituted sulfoxide, substituted or
unsubstituted sulfone substituted or unsubstituted sulfanyl
substituted or unsubstituted aminosulfonyl substituted or
unsubstituted arylsulfonyl sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl substituted or
unsubstituted aminodihydroxyphosphoryl azido, carboxy, substituted
or unsubstituted carbamoyl cyano, substituted or unsubstituted
cycloalkyl substituted or unsubstituted cycloheteroalkyl
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; and the dotted
bond is a single or a double bond; or a pharmaceutically acceptable
salt thereof; and stereoisomers and tautomers thereof.
62. The method of claim 61, wherein the pain is associated with a
condition selected from the group consisting of postmastectomy pain
syndrome, stump pain, phantom limb pain, oral neuropathic pain,
Charcot's pain, toothache, venomous snake bite, spider bite, insect
sting, postherpetic neuralgia, diabetic neuropathy, reflex
sympathetic dystrophy, trigeminal neuralgia, osteoarthritis,
rheumatoid arthritis, fibromyalgis, Guillain-Barre syndrome,
meralgia paresthetica, burning-mouth syndrome, bilateral peripheral
neuropathy, causalgia, sciatic neuritis, peripheral neuritis,
polyneuritis, segmental neuritis, Gombault's neuritis, neuronitis,
cervicobrachial neuralgia, cranial neuralgia, egniculate neuralgia,
glossopharyngial neuralgia, migranous neuralgia, idiopathic
neuralgia, intercostals neuralgia, mammary neuralgia, mandibular
joint neuralgia, Morton's neuralgia, nasociliary neuralgia,
occipital neuralgia, red neuralgia, Sluder's neuralgia
splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia,
sinus headache, tension headache, labor, childbirth, intestinal
gas, menstruation, cancer, and trauma.
63. (canceled)
64. (canceled)
65. (canceled)
66. A method according to any of claims 49, 54 or 61, wherein said
compound is selected from TABLE-US-00008 Name STRUCTURE
5,6,7,8-Tetrahydro-pyrido[3,4- d]pyrimidine-4-carboxylic acid
cyclohexylmethyl-amide; ##STR79##
7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidine-4-carboxylic
acid cyclohexylmethyl-amide; ##STR80##
7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidine-4-carboxylic
acid (adamantan-1-ylmethyl)-amide; ##STR81##
7-Pyridin-3-ylmethyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidine-4-
carboxylic acid cyclohexylmethyl- amide; ##STR82##
7-Pyridin-4-ylmethyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidine-4-
carboxylic acid cyclohexylmethyl- amide; ##STR83##
7-(2-Chloro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid cyclohexylmethyl-amide;
##STR84## 7-(4-Chloro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid cyclohexylmethyl-amide;
##STR85## 7-Pyridin-2-ylmethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidine-4- carboxylic acid
cyclohexylmethyl- amide; ##STR86##
7-(3-Chloro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid cyclohexylmethyl-amide;
##STR87## 7-(4-Methoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidine-4- carboxylic acid
cyclohexylmethyl- amide; ##STR88##
7-(4-Methyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid cyclohexylmethyl-amide;
##STR89## 7-(4-Methanesulfonyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidine-4- carboxylic acid
cyclohexylmethyl- amide; ##STR90##
7-(4-Acetylamino-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidine-4- carboxylic acid
cyclohexylmethyl- amide; ##STR91##
7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidine-4-carboxylic
acid (1- hydroxy-cycloheptylmethyl)-amide; ##STR92##
7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidine-4-carboxylic
acid (1- hydroxy-3,3-dimethyl- cyclohexylmethyl)-amide; ##STR93##
7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidine-4-carboxylic
acid (1-p- tolyl-cyclohexylmethyl)-amide; ##STR94##
7-(2,4-Difluoro-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidine-4- carboxylic acid (adamantan-1-
ylmethyl)-amide; ##STR95## 7-(2,3-Dihydro-benzo[1,4]dioxin-6-
ylmethyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidine-4-carboxylic
acid (adamantan-1-ylmethyl)-amide; ##STR96##
7-(2-Fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid
(adamantan-1-ylmethyl)-amide; ##STR97##
7-(3-Fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid
(aclamantan-1-ytmetnyt)-amide; ##STR98##
7-(3-Methoxy-benzyl)-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidine-4-
carboxylic acid (adamantan-1- ylmethyl)-amide; ##STR99##
7-(2-Methyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid
(adamantan-1-ylmethyl)-amide; ##STR100##
7-(2-Chloro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid
(adamantan-1-ylmethyl)-amide; ##STR101##
7-(4-Fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidine-4-carboxylic acid
(adamantan-1-ylmethyl)-amide; ##STR102##
7-Benzo[1,3]dioxol-5-ylmethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidine-4- carboxylic acid (adamantan-1-
ylmethyl)-amide; ##STR103## 2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR104##
2-Adamantan-1-yl-N-(5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl)-acetamide; ##STR105## 2-Adamantan-1-yl-N-(7-methyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR106##
2-Adamantan-1-yl-N-(7-ethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR107##
N-(7-Benzyl-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl)-2-
cyclohexyl-acetamide; ##STR108## N-(7-Benzyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-2- cycloheptyl-acetamide; ##STR109##
2-Cyclohexyl-N-(5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-acetamide; ##STR110##
2-Cycloheptyl-N-(5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-acetamide; ##STR111##
2-Adamantan-1-yl-N-[7-(2-hydroxy-3-
methoxy-propyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR112##
2-Adamantan-1-yl-N-(7-phenethyl- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl)-acetamide; ##STR113## 2-Adamantan-1-yl-N-[7-(4-
methanesulfonyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR114##
2-Adamantan-1-yl-N-(7-pyridin-3-
ylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl)-acetamide; ##STR115##
2-Adamantan-1-yl-N-[7-(2-hydroxy-
ethyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamlue;
##STR116## 2-Adamantan-1-yl-N-[7-(3-hydroxy-
propyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR117## 2-Cyclohexyl-N-(7-ethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR118##
2-Cyclohexyl-N-[7-(3-hydroxy-propyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR119## 2-Cyclohexyl-N-[7-(2-hydroxy-ethyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR120## 2-Adamantan-1-yl-N-[7-(2,3-dihydroxy-
propyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR121## 2-Cyclohexyl-N-(7-methyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR122##
2-Adamantan-1-yl-N-[7-(2-chloro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR123## 2-Adamantan-1-yl-N-[7-(2-fluoro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR124## 2-Adamantan-1-yl-N-[7-(2-methoxy-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR125## 2-Adamantan-1-yl-N-[7-(2,4-
dimethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR126##
2-Adamantan-1-yl-N-[7-(2-methyl-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR127## 2-Adamantan-1-yl-N-[7-(2,5-dimethyl-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR128## 2-Adamantan-1-yl-N-[7-(3-fluoro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR129## 2-Adamantan-1-yl-N-[7-(3-chioro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR130## 2-Adamantan-1-yl-N-[7-(3-methoxy-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR131## 2-Adamantan-1-yl-N-[7-(3,4-
dimethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR132##
2-Adamantan-1-yl-N-[7-(3,5- dimethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-u]pyrimidin-4-yl]-acetamide; ##STR133##
2-Adamantan-1-yl-N-[7-(3-methyl-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR134## 2-Adamantan-1-yl-N-[7-(4-methoxy-3-
methyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR135##
2-Adamantan-1-yl-N-[7-(4-methoxy-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR136## 2-Adamantan-1-yl-N-[7-(4-chloro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR137## 2-Adamantan-1-yl-N-[7-(4-cyano-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR138## 2-Adamantan-1-yl-N-(7-pyridin-4-
ylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl)-acetamide; ##STR139##
2-Adamantan-1-yl-N-[7-(4-methyl-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR140## 2-Adamantan-1-yl-N-[7-(4-ethyl-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR141## 2-Adamantan-1-yl-N-[7-(2,3-dihydro-
benzo[1,4]dioxin-6-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR142##
2-Adamantan-1-yl-N-[7-(2,4-difluoro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR143## 2-Adamantan-1-yl-N-(7-pyridin-2-
ylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl)-acetamide; ##STR144##
N-[7-(4-Acetylamino-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-2-adamantan-1-yl-acetamide; ##STR145##
2-Adamantan-1-yl-N-[7-(3-phenyl-
propyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR146## 2-Adamantan-1-yl-N-[7-(1H-indol-5-
ylmethyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR147##
2-Adamantan-1-yl-N-[7-(4-pyridin-2-yl-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR148## 2-Adamantan-1-yl-N-[7-(5-methyl-
thiophen-2-ylmethyl)-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-acetamide; ##STR149## 2-Adamantan-1-yl-N-[7-(1-methyl-1H-
imidazol-2-ylmethyl)-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-acetamide; ##STR150## 2-Adamantan-1-yl-N-[7-(3-phenoxy-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR151## 2-Adamantan-1-yl-N-(7-quinolin-4-
ylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl)-acetamide; ##STR152## 2-Adamantan-1-yl-N-[7-(3-
trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR153##
2-Adamantan-1-yl-N-[7-(4-tert-butyl-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide;
##STR154## 2-Adamantan-1-yl-N-[7-(4-
trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR155##
2-Adamantan-1-yl-N-(7-quinolin-2-
ylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl)-acetamide; ##STR156## 2-Adamantan-1-yl-N-[7-(4-
trifluoromethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR157##
2-Adamantan-1-yl-N-[7-(4-phenoxy-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR158## 2-Adamantan-1-yl-N-[7-(2-
trifluoromethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR159##
2-Adamantan-1-yl-N-[7-(2- difluoromethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR160##
2-Adamantan-1-yl-N-[7-(4- difluoromethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR161##
2-Adamantan-1-yl-N-[7-(5-phenyl- thiophen-2-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR162##
2-Adamantan-1-yl-N-[7-(2-butyl-1H- imidazol-4-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR163##
2-Adamantan-1-yl-N-[7-(5-methyl-3H- imidazol-4-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR164##
2-Adamantan-1-yl-N-[7-(1H-imidazol- 4-ylmethyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR165##
2-Adamantan-1-yl-N-[7-(5-chloro- thiophen-2-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR166##
2-Adamantan-1-yl-N-[7-(3-cyano-4-
fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR167##
2-Adamantan-1-yl-N-[7-(3-fluoro-4-
methyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR168##
2-Adamantan-1-yl-N-[7-(4-fluoro-3-
methyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR169##
2-Adamantan-1-yl-N-[7-(6-chloro-2- fluoro-3-methyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR170##
2-Adamantan-1-yl-N-[7-(2-chloro-6- fluoro-3-methyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR171##
2-Adamantan-1-yl-N-(7-{4-[(2- hydroxy-ethyl)-methyl-amino]-benzyl}-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR172## 2-Adamantan-1-yl-N-[7-(2,2-difluoro-
benzo[1,3]dioxol-4-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR173##
2-{4-[4-(2-Adamantan-1-yl- acetylamino)-5,8-dihydro-6H-
pyrido[3,4-d]pyrimidin-7-ylmethyl]- phenoxy}-acetamide; ##STR174##
2-{2-[4-(2-Adamantan-1-yl- acetylamino)-5,8-dihydro-6H-
pyrido[3,4-d]pyrimidin-7-ylmethyl]- phenoxy}-acetamide; ##STR175##
2-Cycloheptyl-N-(7-pyridin-3-ylmethyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR176## 2-Cycloheptyl-N-(7-pyridin-2-ylmethyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR177## 2-Adamantan-1-yl-N-[7-(2-fluoro-4-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR178##
2-Adamantan-1-yl-N-[7-(5-fluoro-2- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR179##
2-Adamantan-1-yl-N-[7-(3-fluoro-4- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR180##
2-Adamantan-1-yl-N-[7-(4-imidazol-1- yl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR181##
2-Adamantan-1-yl-N-{7-[4-(2-hydroxy-
ethoxy)-benzyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR182## 2-Adamantan-1-yl-N-{7-[2-(2-hydroxy-
ethoxy)-benzyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR183## 2-Adamantan-1-yl-N-{7-[3-(2-hydroxy-
ethoxy)-benzyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR184## 2-Adamantan-1-yl-N-[7-(5-fluoro-2-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR185##
2-Adamantan-1-yl-N-[7-(4-fluoro-3-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR186##
2-Adamantan-1-yl-N-[7-(2-fluoro-5-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR187##
2-Adamantan-1-yl-N-[7-(2,3-dihydro- benzofuran-5-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR188##
2-Adamantan-1-yl-N-[7-(4-fluoro-3- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR189##
2-Adamantan-1-yl-N-[7-(4-fluoro-2- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR190##
2-Adamantan-1-yl-N-[7-(3-fluoro-5- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR191##
2-Adamantan-1-yl-N-[7-(2-fluoro-5- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR192##
2-Adamantan-1-yl-N-[7-(2-fluoro-4- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR193##
2-Adamantan-1-yl-N-[7-(2-fluoro-6- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR194##
2-Adamantan-1-yl-N-[7-(4-methyl- naphthalen-1-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR195##
2-Adamantan-1-yl-N-[7-(4-isopropoxy-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR196## 2-Adamantan-1-yl-N-[7-(3-
trifluoromethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR197##
(E)-3-{4-[4-(2-Adamantan-1-yl- acetylamino)-5,8-dihydro-6H-
pyrido[3,4-d]pyrimidin-7-ylmethyl]- phenyl}-acrylic acid;
##STR198## 2-Adamantan-1-yl-N-[7-(4-
methylsulfanyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR199##
2-Adamantan-1-yl-N-[7-(4-hydroxy-3-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR200##
2-Adamantan-1-yl-N-[7-(6-methyl-
pyridin-2-ylmethyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR201##
2-Adamantan-1-yl-N-[7-(3-fluoro-4-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR202##
2-Adamantan-1-yl-N-[7-(2- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR203##
2-Adamantan-1-yl-N-(7- cyclopentylmethyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-acetamide; ##STR204##
2-Adamantan-1-yl-N-(7- cyclohexylmethyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-acetamide; ##STR205##
2-Adamantan-1-yl-N-[7-(4-fluoro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR206## 2-Cycloheptyl-N-[7-(3-phenyl-propyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR207## 2-Cycloheptyl-N-[7-(5-methyl-
thiophen-2-ylmethyl)-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-acetamide; ##STR208## 2-Cycloheptyl-N-[7-( 1H-imidazol-4-
ylmethyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR209##
2-Cycloheptyl-N-(7-cyclohexylmethyl- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl)-acetamide; ##STR210##
2-Cycloheptyl-N-(7-cyclopentylmethyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR211## 2-Cycloheptyl-N-(7-phenethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR212##
2-Cycloheptyl-N-[7-(4-fluoro-benzyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR213## 2-Adamantan-1-yl-N-[7-(2-fluoro-3-
trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR214##
{4-[4-(2-Adamantan-1-yl-acetylamino)-
5,8-dihydro-6H-pyrido[3,4-d]pyrimidin- 7-ylmethyl]-phenoxy}-acetic
acid; ##STR215## {2-[4-(2-Adamantan-1-yl-acetylamino)-
5,8-dihydro-6H-pyrido[3,4-d]pyrimidin- 7-ylmethyl]-phenoxy}-acetic
acid; ##STR216## 2-Adamantan-1-yl-N-(7-
methanesulfonyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-acetamide; ##STR217##
2-Adamantan-1-yl-N-(7- benzenesulfonyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-acetamide; ##STR218##
2-Adamantan-1-yl-N-[7-(toluene-4-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR219##
2-Adamantan-1-yl-N-[7-(naphthalene-2-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR220##
2-Adamantan-1-yl-N-[7-(quinoline-8-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR221##
2-Adamantan-1-yl-N-[7-(propane-1-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR222##
2-Adamantan-1-yl-N-(7-ethanesulfonyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR223## 2-Adamantan-1-yl-N-[7-(4-methoxy-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR224##
2-Adamantan-1-yl-N-[7-(4-chloro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR225##
2-Adamantan-1-yl-N-[7-(3,4- dimethoxy-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR226##
2-Adamantan-1-yl-N-[7-(4-fluoro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR227##
2-Adamantan-1-yl-N-(7- phenylmethanesulfonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR228##
2-Adamantan-1-yl-N-[7-(3- trifluoromethyl-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR229## 2-Adamantan-1-yl-N-[7-(3,4-dichloro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR230##
2-Adamantan-1-yl-N-[7-(4- trifluoromethoxy-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR231## 2-Adamantan-1-yl-N-[7-(4-methyl-3,4-
dihydro-2H-benzo[1,4]oxazine-7-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR232##
2-Adamantan-1-yl-N-[7-(5-chloro-1,3-
dimethyl-1H-pyrazole-4-sulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR233##
2-Adamantan-1-yl-N-[7-(5-methyl-2-
trifluoromethyl-furan-3-sulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR234##
2-Adamantan-1-yl-N-[7-(5-methyl-1-
phenyl-1H-pyrazole-4-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR235##
2-Adamantan-1-yl-N-[7-(3- trifluoromethoxy-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR236## 2-Adamantan-1-yl-N-[7-(3-methoxy-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR237##
2-Adamantan-1-yl-N-[7-(1-methyl-1H- imidazole-4-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR238##
2-Adamantan-1-yl-N-[7-(1,2-dimethyl-
1H-imidazole-4-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR239##
2-Adamantan-1-yl-N-[7-(2-chloro-4- cyano-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR240##
2-Adamantan-1-yl-N-[7-(2-fluoro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR241##
2-Adamantan-1-yl-N-[7-(4-cyano-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR242##
2-Adamantan-1-yl-N-[7-(3-chioro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR243##
2-Adamantan-1-yl-N-[7-(3,5-dimethyl- isoxazole-4-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR244##
2-Adamantan-1-yl-N-(7- methanesulfonylmethanesulfonyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR245## 2-Adamantan-1-yl-N-[7-(2-oxo-2H-
chromene-6-sulfonyl)-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-acetamide; ##STR246## 2-Adamantan-1-yl-N-{7-[4-(pyridin-2-
yloxy)-benzenesulfonyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-acetamide; ##STR247##
2-Adamantan-1-yl-N-{7-[4-(pyridin-3-
yloxy)-benzenesulfonyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-acetamide; ##STR248##
2-Adamantan-1-yl-N-{7-[4-(pyridin-4-
yloxy)-benzenesulfonyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-acetamide; ##STR249##
2-Adamantan-1-yl-N-{7-[4-(4-methoxy-
phenoxy)-benzenesulfonyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-acetamide; ##STR250##
2-Adamantan-1-yl-N-{7-[4-(3,4- dichloro-phenoxy)-benzenesulfonyl]-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl}-acetamide;
##STR251## 2-Adamantan-1-yl-N-{7-[4-(4- trifluoromethyl-phenoxy)-
benzenesulfonyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR252## 2-Adamantan-1-yl-N-{7-[3-(3,4-
dichloro-phenoxy)-benzenesulfonyl]- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl}-acetamide; ##STR253##
2-Adamantan-1-yl-N-[7-(4'-methoxy-
biphenyl-4-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR254##
2-Adamantan-1-yl-N-[7-(pyridine-3-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR255##
2-Adamantan-1-yl-N-[7-(2-chloro-5-
trifluoromethyl-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR256##
2-Adamantan-1-yl-N-[7-(3,5-bis- trifluoromethyl-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR257##
2-Adamantan-1-yl-N-[7-(4- trifluoromethyl-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR258##
2-Adamantan-1-yl-N-[7-(4-fluoro- phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR259##
2-Adamantan-1-yl-N-[7-(3,4-dichloro-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR260##
2-Adamantan-1-yl-N-[7-(3,5-dichloro-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR261##
2-Adamantan-1-yl-N-[7-(3- trifluoromethyl-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR262##
2-Adamantan-1-yl-N-(7-p- tolylmethanesulfonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR263##
2-Adamantan-1-yl-N-[7-(4-chloro- phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR264##
2-Adamantan-1-yl-N-[7-(4- difluoromethoxy-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR265## 2-Adamantan-1-yl-N-[7-(4-phenoxy-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR266##
2-Adamantan-1-yl-N-[7-(2-chloro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR267##
2-Adamantan-1-yl-N-[7-(3-chloro-4- fluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR268##
2-Adamantan-1-yl-N-[7-(biphenyl-2-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR269## 2-Adamantan-1-yl-N-[7-(2-
trifluoromethyl-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR270##
2-Adamantan-1-yl-N-[7-(4-pyrazol-1-
yl-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR271##
2-Adamantan-1-yl-N-[7-(2,4- dimethoxy-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR272##
2-Adamantan-1-yl-N-[7-(1,3,5- trimethyl-1H-pyrazole-4-sulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR273## 2-Adamantan-1-yl-N-[7-(toluene-2-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR274##
2-Adamantan-1-yl-N-[7-(2,3-dihydro-
benzo[1,4]dioxine-6-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR275##
2-Adamantan-1-yl-N-[7-(4- trifluoromethyl-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR276## 2-Adamantan-1-yl-N-[7-(4-chloro-2-
fluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR277##
2-Adamantan-1-yl-N-[7-(2,5-difluoro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR278##
2-Adamantan-1-yl-N-[7-(2,5-dichloro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR279##
2-Adamantan-1-yl-N-[7-(5-chloro-2- fluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR280##
2-Adamantan-1-yl-N-[7-(2,6-difluoro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR281##
2-Adamantan-1-yl-N-[7-(3-chloro-4- methyl-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR282##
2-Adamantan-1-yl-N-[7-(3,5-dichloro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR283##
2-Adamantan-1-yl-N-[7-(2,4-difluoro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR284##
2-Adamantan-1-yl-N-[7-(2,6-dichloro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR285##
2-Adamantan-1-yl-N-[7-(2-chloro-4- fluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR286##
2-Adamantan-1-yl-N-[7-(5-fluoro-2- methyl-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR287##
2-Adamantan-1-yl-N-[7-(propane-2-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR288##
2-Adamantan-1-yl-N-[7-(2-methoxy-5-
methyl-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR289##
2-Adamantan-1-yl-N-[7-(3-fluoro-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR290##
2-Adamantan-1-yl-N-[7-(2,5- dimethoxy-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR291##
2-Adamantan-1-yl-N-[7-(3,5-dimethyl-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR292##
2-Adamantan-1-yl-N-[7-(2,6-dichloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR293##
N-(7-Acetyl-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl)-2-
adamantan-1-yl-acetamide; ##STR294## 2-Adamantan-1-yl-N-(7-benzoyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR295## 2-Adamantan-1-yl-N-[7-(biphenyl-4-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR296##
2-Adamantan--yl-N-[7-(2-chloro-
pyridine-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR297##
2-Adamantan-1-yl-N-(7-propionyl- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl)-acetamide; ##STR298##
2-Adamantan-1-yl-N-{7-[2-(4-methoxy-
phenyl)-acetyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR299## 2-Adamantan-1-yl-N-(7-phenylacetyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR300## 2-Adamantan-1-yl-N-[7-(4-chloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR301##
2-Adamantan-1-yl-N-[7-(3-fluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR302## 2-Adamantan-1-yl-N-[7-(4-
trifluoromethoxy-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR303##
2-Adamantan-1-yl-N-[7-(4-ethyl-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR304##
2-Adamantan-1-yl-N-[7-(3-methyl-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR305##
2-Adamantan-1-yl-N-[7-(3-cyclopentyl-
propionyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR306##
2-Adamantan-1-yl-N-[7-(3,4-difluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR307## 2-Adamantan-1-yl-N-[7-(3-
trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR308##
2-Adamantan-1-yl-N-[7-(4-methoxy-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR309##
2-Adamantan-1-yl-N-[7-(3,5,5-
trimethyl-hexanoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR310##
2-Adamantan-1-yl-N-(7-diphenylacetyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-acetamide;
##STR311## 2-Adamantan-1-yl-N-[7-(pyridine-3-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR312## 2-Adamantan-1-yl-N-(7-
cyclopentanecarbonyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl)-acetamide; ##STR313## 2-Adamantan-1-yl-N-{7-[2-(2,5-
dimethoxy-phenyl)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-acetamide; ##STR314##
2-Adamantan-1-yl-N-[7-(2-methoxy-
acetyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR315##
2-Adamantan-1-yl-N-{7-[2-(4-fluoro-
phenyl)-acetyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR316## 2-Adamantan-1-yl-N-[7-(3-cyano-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR317## 2-Adamantan-1-yl-N-[7-(4-
trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR318##
2-Adamantan-1-yl-N-(7- cyclohexanecarbonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR319##
2-Adamantan-1-yl-N-[7-(3,4-dichloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR320## 2-Adamantan-1-yl-N-[7-(3,5-
dimethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR321##
2-Adamantan-1-yl-N-[7-(2,6-difluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR322##
2-Adamantan-1-yl-N-[7-(3-phenyl- propionyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR323##
2-Adamantan-1-yl-N-[7-(2-phenoxy-
acetyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR324## 2-Adamantan-1-yl-N-[7-(3-methoxy-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR325##
2-Adamantan-1-yl-N-[7-(4-fluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR326##
2-Adamantan-1-yl-N-[7-(2,2-dimethyl- propionyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR327##
2-Adamantan-1-yl-N-[7-(3-chloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR328##
2-Adamantan-1-yl-N-{7-[2-(3,4- dimethoxy-phenyl)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-acetamide; ##STR329##
2-Adamantan-1-yl-N-[7-(3-methyl-
butyryl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR330##
2-Adamantan-1-yl-N-[7-(2-benzyloxy-
acetyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR331## 2-Adamantan-1-yl-N-[7-(4-cyano-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR332##
2-Adamantan-1-yl-N-[7-(2,4-dichloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR333##
2-Adamantan-1-yl-N-[7-(quinoxaline-2-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR334## 2-Adamantan-1-yl-N-(7-
cyclopropanecarbonyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl)-acetamide; ##STR335## 2-Adamantan-1-yl-N-{7-[2-(3-methoxy-
phenyl)-acetyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR336## 2-Adamantan-1-yl-N-[7-(3,3-dimethyl-
butyryl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR337##
2-Adamantan-1-yl-N-[7-(2-cyclopentyl-
acetyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR338## 2-Adamantan-1-yl-N-{7-[2-(4-chloro-
phenoxy)-acetyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR339## 2-Adamantan-1-yl-N-{7-[2-(4-chloro-
phenyl)-acetyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR340## 2-Adamantan-1-yl-N-[7-(2-fluoro-4-
trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR341##
2-Adamantan-1-yl-N-[7-(3-fluoro-5-
trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR342##
2-Adamantan-1-yl-N-[7-(2- trifluoromethoxy-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR343##
2-Adamantan-1-yl-N-[7-(3- trifluoromethoxy-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR344##
2-Adamantan-1-yl-N-[7-(2- trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR345##
2-Adamantan-1-yl-N-[7-(2-chloro-5-
trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR346##
2-Adamantan-1-yl-N-[7-(2-chloro-6-
fluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR347##
2-Adamantan-1-yl-N-[7-(5-methyl-2-
phenyl-2H-[1,2,3]triazole-4-carbonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR348## 2-Adamantan-1-yl-N-[7-(2-phenoxy-
pyridine-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR349##
2-Adamantan-1-yl-N-[7-(2,4- dimethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR350##
2-Adamantan-1-yl-N-[7-(2,3-dihydro-
benzo[1,4]dioxine-2-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR351##
2-Adamantan-1-yl-N-[7-(2,4-difluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR352##
2-Adamantan-1-yl-N-[7-(2-methyl-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR353##
2-Adamantan-1-yl-N-[7-(2,5-difluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR354##
2-Adamantan-1-yl-N-[7-(2-fluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR355##
2-Adamantan-1-yl-N-[7-(6-chloro-
pyridine-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pynmidin-4-yl]-acetamide; ##STR356##
2-Adamantan-1-yl-N-[7-(2,3-dichloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR357##
2-Adamantan-1-yl-N-[7-(5-methyl- isoxazole-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR358##
2-Adamantan-1-yl-N-[7-(1,5-dimethyl-
1H-pyrazole-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR359##
2-Adamantan-1-yl-N-[7-(2,5-dimethyl-
2H-pyrazole-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR360##
2-Adamantan-1-yl-N-[7-(1-phenyl-5- trifluoromethyl-1H-pyrazole-4-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR361##
2-Adamantan-1-yl-N-[7-(2-methyl-5-
phenyl-furan-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR362##
2-Adamantan-1-yl-N-[7-(5-methyl-1- phenyl-1H-pyrazole-4-carbonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR363## 2-Adamantan-1-yl-N-{7-[5-(4-chloro-
phenyl)-2-methyl-furan-3-carbonyl]- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl}-acetamide; ##STR364##
2-Adamantan-1-yl-N-[7-(naphthalene-2-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR365##
2-Adamantan-1-yl-N-[7-(4-methyl-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR366##
2-Adamantan-1-yl-N-[7-(2-methoxy-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR367##
2-Adamantan-1-yl-N-[7-(2,5-dimethyl-
furan-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR368##
2-Adamantan-1-yl-N-[7-(2-chloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR369##
N-[7-(1-Acetyl-piperidine-4-carbonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-2-adamantan-1-yl-
acetamide; ##STR370## 2-Adamantan-1-yl-N-[7-(isoxazole-5-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR371##
2-Adamantan-1-yl-N-[7-(3,5-dimethyl- isoxazole-4-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR372##
2-Adamantan-1-yl-N-[7-(2-chloro-
pyridine-4-carbonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR373##
2-Adamantan-1-yl-N-[7-(5-methyl- isoxazole-4-carbonyl)-5,6,7,8-
tetrahydro-pyndo[3,4-d]pyrimidin-4- yl]-acetamide; ##STR374##
2-Adamantan-1-yl-N-[7-(2-tert-butyl-5-
methyl-2H-pyrazole-3-carbonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR375##
2-Adamantan-1-yl-N-[7-(4-tert-butyl-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR376##
2-Adamantan-1-yl-N-{7-[2-(2-bromo-
phenyl)-acetyl]-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl}-
acetamide; ##STR377## 2-Adamantan-1-yl-N-[7-(quinoline-2-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR378##
2-Adamantan-1-yl-N-[7-(pyridine-4-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR379##
2-Adamantan-1-yl-N-[7-(pyridine-2-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR380##
2-Adamantan-1-yl-N-{7-[1-(2,2,2- trifluoro-acetyl)-pyrrolidine-2-
carbonyl]-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl}-acetamide; ##STR381##
2-Adamantan-1-yl-N-[7-(3-methoxy- propionyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR382##
2-Adamantan-1-yl-N-[7-(pyrazine-2-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR383##
2-Adamantan-1-yl-N-[7-(2,3-dihydro- benzofuran-5-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR384##
2-Adamantan-1-yl-N-[7-(3-fluoro-4-
methoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR385##
2-Adamantan-1-yl-N-[7-(quinoxaline-6-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR386## 2-Adamantan-1-yl-N-[7-(3,4-
dimethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR387##
2-Adamantan-1-yl-N-[7-(chroman-3-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR388##
2-Adamantan-1-yl-N-[7-(2-chloro-5-
fluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pynmidin-4-yl]-acetamide; ##STR389##
2-Adamantan-1-yl-N-[7-(3,5-dichloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR390##
2-Adamantan-1-yl-N-{7-[1-(2,3-
dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl}-acetamide;
##STR391## 2-Adamantan-1-yl-N-[7-(9H-fluoren-2-
ylmethyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR392##
2-Adamantan-1-yl-N-[7-(2,4-dichloro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR393## 2-Adamantan-1-yl-N-[7-(2,4-dimethyl-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR394## 2-Adamantan-1-yl-N-(7-
benzo[1,3]dioxol-5-ylmethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-acetamide; ##STR395##
2-Adamantan-1-yl-N-[7-(3,4-difluoro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR396## 2-Adamantan-1-yl-N-[7-(3-chloro-4-
fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR397##
2-Adamantan-1-yl-N-[7-(3-chloro-4-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pynmlcun-4-yl]-acetamide; ##STR398##
2-Adamantan-1-yl-N-[7-(4-chloro-3- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR399##
2-Adamantan-1-yl-N-[7-(2-chloro-4-
fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR400##
2-Adamantan-1-yl-N-[7-(2,4-bis- trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR401##
2-Adamantan-1-yl-N-[7-(4-chloro-2-
fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR402##
2-Adamantan-1-yl-N-[7-(4-chloro-3-
fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR403##
2-Adamantan-1-yl-N-[7-(4-benzyloxy-
2-methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR404##
4-{4-[4-(2-Adamantan-1-yl- acetylamino)-5,8-dihydro-6H-
pyrido[3,4-d]pyrimidin-7-ylmethyl]-3- methoxy-phenoxy}-butyric
acid; ##STR405## 2-Adamantan-1-yl-N-[7-(1H-indol-6-
ylmethyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-acetamide; ##STR406##
2-Adamantan-1-yl-N-[7-(3,4-dihydro-
2H-benzo[b][1,4]dioxepin-7-ylmethyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-acetamide;
##STR407## Adamantane-1-carboxylic acid (7-
benzyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide;
##STR408## 2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-isobutyramide; ##STR409##
N-(7-Benzyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-2-(3,5-
dimethyl-adamantan-1-yl)-acetamide; ##STR410##
N-(7-Benzyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-2-(3,5- dimethyl-adamantan-1-yl)-
isobutyramide; ##STR411## N-(7-Benzyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-2-(3,5,7-
trimethyl-adamantan-1-yl)-acetamide; ##STR412##
N-(7-Benzyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-2-(3,5,7- trimethyl-adamantan-1-yl)-
isobutyramide; ##STR413## 3,5,7-Trimethyl-adamantane-1- carboxylic
acid (7-benzyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl)-amide; ##STR414## 2-Adamantan-1-yl-N-[7-(2,4-difluoro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR415##
2-Adamantan-1-yl-N-[7-(2-chloro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR416##
2-Adamantan-1-yl-N-[7-(2-methyl-
benzyl)-5,6,7,o-tetraflyuro-pyrluo[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR417##
2-Adamantan-1-yl-N-[7-(2,3-dihydro-
benzo[1,4]dioxin-6-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-isobutyramide; ##STR418##
2-Adamantan-1-yl-N-[7-(1H-indol-6-
ylmethyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR419##
2-Adamantan-1-yl-N-[7-(4-fluoro-
benzyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR420## 2-Adamantan-1-yl-N-(7-
phenylmethanesulfonyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-
yl)-isobutyramide; ##STR421## 2-Adamantan-1-yl-N-[7-(3-chloro-
benzenesulfonyl)-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl]-
isobutyramide; ##STR422## 2-Adamantan-1-yl-N-[7-(3,4-difluoro-
benzenesulfonyl)-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl]-
isobutyramide; ##STR423## 2-Adamantan-1-yl-N-[7-(3,4-dichloro-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-isobutyramide; ##STR424##
2-Adamantan-1-yl-N-[7-(4-chloro- phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-a]pyrimiain-4- yl]-isobutyramide; ##STR425##
2-Adamantan-1-yl-N-[7-(3-methyl-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR426##
2-Adamantan-1-yl-N-[7-(3- trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-isobutyramide; ##STR427##
2-Adamantan-1-yl-N-[7-(3,4-dichloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR428##
2-Adamantan-1-yl-N-[7-(2,6-difluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR429##
2-Adamantan-1-yl-N-[7-(2-chloro-6-
fluoro-benzoyl)-5,6,7,8-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl]-
isobutyramide; ##STR430## 2-Adamantan-1-yl-N-[7-(2,5-difluoro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR431##
2-Adamantan-1-yl-N-[7-(2,3-dichloro-
benzoyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR432##
2-Adamantan-1-yl-N-[7-(2-cyclopentyl-
acetyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR433## 2-Adamantan-1-yl-N-(7-
cyclohexanecarbonyl-5,6,7,8- tetrahydro-pyrido[3,4-]pyrimidin-4-
yl)-isobutyramide; ##STR434## 2-Adamantan-1-yl-N-[7-(3,3-dimethyl-
butyryl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR435##
2-Adamantan-1-yl-N-[7-(2-fluoro-
benzyl)-5,6,7,8-tetrahydro-pyridol[3,4-
d]pyrimidin-4-yl]-isobutyramide; ##STR436##
N-[7-(2-Chloro-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-ci]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR437##
2-(3,5-Dimethyl-adamantan-1-yl)-N-[7-
(2-fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR438##
2-(3,5-Dimethyl-adamantan-1-yl)-N-[7-
(2-methyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR439##
N-[7-(2,3-Dihydro-benzo[1,4]dioxin-6-
ylmethyl)-5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-2-(3,5-dimethyl- adamantan-1-yl)-acetamide;
##STR440## N-[7-(2,4-Difluoro-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-ci]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR441##
2-(3,5-Dimethyl-adamantan-1-yl)-N-[7-
(1H-indol-6-ylmethyl)-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-acetamide; ##STR442## 2-(3,5-Dimethyl-adamantan-1-yl)-N-[7-
(4-fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR443##
2-(3,5-Dimethyl-adamantan-1-yl)-N-(7-
phenylmethanesulfonyl-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl)-acetamide; ##STR444## N-[7-(3,4-Dichloro-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR445##
N-[7-(4-Chloro- phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR446##
N-[7-(3-Chloro-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
adamantan-1-yl)-acetamide; ##STR447##
N-[7-(2,3-Difluoro-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
adamantan-1-yl)-acetamide; ##STR448##
2-(3,5-Dimethyl-adamantan-1-yl)-N-[7-
(3-methyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-acetamide; ##STR449##
2-(3,5-Dimethyl-adamantan-1-yl)-N-[7-
(3-trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR450##
N-[7-(2-Cyclopentyl-acetyl)-5,6,7,8-
tetrahydro-pyrido[3,4-ci]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR451##
N-[7-(3,4-Dichloro-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-ci]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR452##
N-(7-Cyclohexanecarbonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl)-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR453##
N-[7-(2,6-Difluoro-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR454##
2-(3,5-Dimethyl-adamantan-1-yl)-N-[7-
(3,3-dimethyl-butyryl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-acetamide; ##STR455##
N-[7-(2-Chloro-6-fluoro-benzoyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-z-y,5-dimethyl- adamantan-1-yl)-acetamide;
##STR456## N-[7-(2,5-Difluoro-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-ci]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR457##
N-[7-(2,3-Dichloro-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-u]pyrimidin-4-
yl]-2-(3,5-dimethyl-adamantan-1-yl)- acetamide; ##STR458##
Adamantane-1-carboxylic acid [7-(2,6-
dichloro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR459##
Adamantane-1-carboxylic acid (7-
acetyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide;
##STR460## Adamantane-1-carboxylic acid (7-
benzoyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide;
##STR461## Adamantane-1-carboxylic acid [7-(2-
chloro-pyridine-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR462##
Adamantane-1-carboxylic acid (7-
propionyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide;
##STR463## Adamantane-1-carboxylic acid {7-[2-(4-
methoxy-phenyl)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-amide; ##STR464##
Adamantane-1-carboxylic acid (7- phenylacetyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR465##
Adamantane-1-carboxylic acid [7-(4-
chloro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR466##
Adamantane-1-carboxylic acid [7(3-
fluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR467##
Adamantane-1-carboxylic acid [7-(4-
trifluoromethoxy-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR468##
Adamantane-1-carboxylic acid [7-(4-
ethyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR469##
Adamantane-1-carboxylic acid [7(3-
methyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR470##
Adamantane-1-carboxylic acid [7-(3- cyclopentyl-propionyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR471##
Adamantane-1-carboxylic acid [7-(3,4-
difluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR472##
Adamantane-1-carboxylic acid [7-(3-
trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR473##
Adamantane-1-carboxylic acid [7-(4-
methoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR474##
Adamantane-1-carboxylic acid [7-
(3,5,5-trimethyl-hexanoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR475##
Adamantane-1-carboxylic acid (7- diphenylacetyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR476##
Adamantane-1-carboxylic acid (7- cyclopentanecarbonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-amide; ##STR477##
Adamantane-1-carboxylic acid {7-[2-
(2,5-dimethoxy-phenyl)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-amide; ##STR478##
Adamantane-1-carboxylic acid [7-(2-
methoxy-acetyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR479##
Adamantane-1-carboxylic acid {7-[2-(4-
fluoro-phenyl)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-amide; ##STR480##
Adamantane-1-carboxylic acid [7-(3-
cyano-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR481##
Adamantane-1-carboxylic acid [7-(4-
trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR482##
Adamantane-1-carboxylic acid (7- cyclohexanecarbonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-amide; ##STR483##
Adamantane-1-carboxylic acid [7-(3,4-
dichloro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR484##
Adamantane-1-carboxylic acid [7-(3,5-
dimethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR485##
Adamantane-1-carboxylic acid [7-(2,6-
difluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR486##
Adamantane-1-carboxylic acid [7-(3-
phenyl-propionyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR487##
Adamantane-1-carboxylic acid [7-(2-
phenoxy-acetyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR488##
Adamantane-1-carboxylic acid [7-(3-
methoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR489##
Adamantane-1-carboxylic acid [7-(4-
fluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR490##
Adamantane-1-carboxylic acid [7-(2,2-
dimethyl-propionyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR491##
Adamantane-1-carboxylic acid [7-(3-
chloro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR492##
Adamantane-1-carboxylic acid {7-[2-
(3,4-dimethoxy-phenyl)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-amide; ##STR493##
Adamantane-1-carboxylic acid [7-(3-
methyl-butyryl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR494##
Adamantane-1-carboxylic acid [7-(2-
benzyloxy-acetyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR495##
Adamantane-1-carboxylic acid [7-(4-
cyano-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR496##
Adamantane-1-carboxylic acid [7-(2,4-
dichloro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR497##
Adamantane-1-carboxylic acid [7- (quinoxaline-2-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR498##
Adamantane-1-carboxylic acid (7- cyclopropanecarbonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-amide; ##STR499##
Adamantane-1-carboxylic acid {7-[2-(3-
methoxy-phenyl)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-amide; ##STR500##
Adamantane-1-carboxylic acid [7(3,3-
dimethyl-butyryl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR501##
Adamantane-1-carboxylic acid [7-(2-
cyclopentyl-acetyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR502##
Adamantane-1-carboxylic acid {7-[2-(4-
chloro-phenoxy)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-amide; ##STR503##
Adamantane-1-carboxylic acid {7-[2-(4-
chloro-phenyl)-acetyl]-5,6,7,8-
tetrahydro-pyrido[3,4-ci]pyrimidin-4- yl}-amide; ##STR504##
Adamantane-1-carboxylic acid [7-(2-
fluoro-4-trifluoromethyl-benzoyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR505## Adamantane-1-carboxylic acid
[7-(3- fluoro-5-trifluoromethyl-benzoyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR506##
Adamantane-1-carboxylic acid [7-(2-
trifluoromethoxy-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR507##
Adamantane-1-carboxylic acid [7-(3-
trifluoromethoxy-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR508##
Adamantane-1-carboxylic acid [7-(2-
trifluoromethyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR509##
Adamantane-1-carboxylic acid [7-(2-
chloro-5-trifluoromethyl-benzoyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR510## Adamantane-1-carboxylic acid
[7-(2- chloro-6-fluoro-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR511##
Adamantane-1-carboxylic acid [7-(5-
methyl-2-phenyl-2H-[1,2,3]triazole-4-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide;
##STR512## Adamantane-1-carboxylic acid [7-(2-
phenoxy-pyridine-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR513##
Adamantane-1-carboxylic acid [7-(2,4-
dimethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR514##
Adamantane-1-carboxylic acid [7-(2,3-
dihydro-benzo[1,4]dioxine-2-carbonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR515##
Adamantane-1-carboxylic acid [7-(2,4-
difluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR516##
Adamantane-1-carboxylic acid [7-(2-
methyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR517##
Adamantane-1-carboxylic acid [7-(2,5-
difluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR518##
Adamantane-1-carboxylic acid [7-(2-
fluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR519##
Adamantane-1-carboxylic acid [7-(6-
chloro-pyridine-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR520##
Adamantane-1-carboxylic acid [7-(2,3-
dichloro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR521##
Adamantane-1-carboxylic acid [7-(5-
methyl-isoxazole-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR522##
Adamantane-1-carboxylic acid [7-(1,5-
dimethyl-1H-pyrazole-3-carbonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR523## Adamantane-1-carboxylic acid
[7-(2- methyl-5-phenyl-ftiran-3-carbonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR524##
Adamantane-1-carboxylic acid [7-(5- methyl-1-phenyl-1H-pyrazole-4-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide;
##STR525## Adamantane-1-carboxylic acid {7-[5-(4-
chloro-phenyl)-2-methyl-furan-3-
carbonyl]-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl}-amide;
##STR526## Adamantane-1-carboxylic acid [7-
(naphthalene-2-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR527##
Adamantane-1-carboxylic acid [7-(4-
methyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR528##
Adamantane-1-carboxylic acid [7-(2-
methoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR529##
Adamantane-1-carboxylic acid [7-(2,5-
dimethyl-thran-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR530##
Adamantane-1-carboxylic acid [7-(2-
chloro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR531##
Adamantane-1-carboxylic acid [7-(1-
acetyl-piperidine-4-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR532##
Adamantane-1-carboxylic acid [7- (isoxazole-5-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR533##
Adamantane-1-carboxylic acid [7-(2-
chloro-pyridine-4-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR534##
Adamantane-1-carboxylic acid [7-(2-
tert-butyl-5-methyl-2H-pyrazole-3-
carbonyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide;
##STR535## Adamantane-1-carboxylic acid [7-(4-
tert-butyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR536##
Adamantane-1-carboxylic acid {7-[2-(2-
bromo-phenyl)-acetyl]-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl}-amide; ##STR537## Adamantane-1-carboxylic acid [7-
(quinoline-2-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR538##
Adamantane-1-carboxylic acid {7-[1-
(2,2,2-trifluoro-acetyl)-pyrrolidine-2-
carbonyl]-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl}-amide;
##STR539## Adamantane-1-carboxylic acid [7-
(pyrazine-2-carbonyl)-5,6,7,8- tetrahydro-pyrido[3,4-d]pyrimidin-4-
yl]-amide; ##STR540## Adamantane-1-carboxylic acid [7-(2,3-
dihydro-benzoftiran-5-carbonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR541## Adamantane-1-carboxylic acid
[7-(3- fluoro-4-methoxy-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR542##
Adamantane-1-carboxylic acid [7-(3,4-
dimethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR543##
Adamantane-1-carboxylic acid [7- (chroman-3-carbonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR544##
Adamantane-1-carboxylic acid [7-(2-
chloro-5-fluoro-benzoyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR545##
Adamantane-1-carboxylic acid [7-(3,5-
dichloro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR546##
Adamantane-1-carboxylic acid (7-
methanesulfonyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR547##
Adamantane-1-carboxylic acid (7- benzenesulfonyl-5,6,7,8
-tetrahydro- pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR548##
Adamantane-1-carboxylic acid [7-
(toluene-4-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR549##
Adamantane-1-carboxylic acid [7- (naphthalene-2-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR550##
Adamantane-1-carboxylic acid [7- (quinoline-8-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR551##
Adamantane-1-carboxylic acid [7-
(propane-1-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR552##
Adamantane-1-carboxylic acid (7- ethanesulfonyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR553##
Adamantane-1-carboxylic acid [7-(4-
methoxy-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR554##
Adamantane-1-carboxylic acid [7-(4- chloro-benzenesulfonyl)-5,6,7,8
- tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR555##
Adamantane-1-carboxylic acid [7-(3,4-
dimethoxy-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR556##
Adamantane-1-carboxylic acid [7-(4-
fluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR557##
Adamantane-1-carboxylic acid (7- phenylmethanesulfonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-amide; ##STR558##
Adamantane-1-carboxylic acid [7-(3-
trifluoromethyl-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR559## Adamantane-1-carboxylic acid
[7-(4- trifluoromethoxy-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR560##
Adamantane-1-carboxylic acid [7-(4- methyl-3,4-dihydro-2H-
benzo[1,4]oxazine-7-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR561##
Adamantane-1-carboxylic acid [7-(5-
chloro-1,3-dimethyl-1H-pyrazole-4-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide;
##STR562## Adamantane-1-carboxylic acid [7-(5-
methyl-1-phenyl-1H-pyrazole-4-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide;
##STR563## Adamantane-1-carboxylic acid [7-(3-
trifluoromethoxy-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR564## Adamantane-1-carboxylic acid
[7-(3- methoxy-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR565##
Adamantane-1-carboxylic acid [7-(1,2-
dimethyl-1H-imidazole-4-sulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR566## Adamantane-1-carboxylic acid
[7-(2- chloro-4-cyano-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR567##
Adamantane-1-carboxylic acid [7-(2-
fluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR568##
Adamantane-1-carboxylic acid [7-(4- cyano-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR569##
Adamantane-1-carboxylic acid [7-(3,5-
dimethyl-isoxazole-4-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR570##
Adamantane-1-carboxylic acid (7- methanesulfonylmethanesulfonyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide; ##STR571##
Adamantane-1-carboxylic acid [7-(2-
oxo-2H-chromene-6-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR572##
Adamantane-1-carboxylic acid {7-[4-
(pyridin-2-yloxy)-benzenesulfonyl]- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl}-amide; ##STR573## Adamantane-1-carboxylic acid
{7-[4- (pyridin-3-yloxy)-benzenesulfonyl]-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl}-amide; ##STR574##
Adamantane-1-carboxylic acid {7-[4-
(pyridin-4-yloxy)-benzenesulfonyl]- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl}-amide; ##STR575## Adamantane-1-carboxylic acid
{7-[4-(4- methoxy-phenoxy)-benzenesulfonyl]-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl}-amide; ##STR576##
Adamantane-1-carboxylic acid {7-[4-(4- trifluoromethyl-phenoxy)-
benzenesulfonyl]-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl}-amide; ##STR577##
Adamantane-1-carboxylic acid {7-[3- (3,4-dichloro-phenoxy)-
benzenesulfonyl]-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl}-amide; ##STR578##
Adamantane-1-carboxylic acid [7-(4'-
methoxy-biphenyl-4-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR579##
Adamantane-1-carboxylic acid [7- (pyridine-3-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR580##
Adamantane-1-carboxylic acid [7-(2- chloro-5-trifluoromethyl-
benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR581##
Adamantane-1-carboxylic acid [7(3,5- bis-trifluoromethyl-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR582##
Adamantane-1-carboxylic acid [7-(4- trifluoromethyl-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR583##
Adamantane-1-carboxylic acid [7-(4-
fluoro-phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR584##
Adamantane-1-carboxylic acid [7-(3,4-
dichloro-phenylmethanesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR585## Adamantane-1-carboxylic acid
[7-(3,4- dichloro-phenylmethanesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR586##
Adamantane-1-carboxylic acid [7-(3- trifluoromethyl-
phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR587##
Adamantane-1-carboxylic acid (7-p- tolylmethanesulfonyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin- yl)-amide; ##STR588##
Adamantane-1-carboxylic acid [7-(4-
chloro-phenylmethanesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR589##
Adamantane-1-carboxylic acid [7-(4-
difluoromethoxy-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR590## Adamantane-1-carboxylic acid
[7-(4- phenoxy-benzenesulfonyl)-5,6,7,8 -
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR591##
Adamantane-1-carboxylic acid [7-(2- chloro-benzenesulfonyl)-5,6,7,8
- tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR592##
Adamantane-1-carboxylic acid [7-(3-
chloro-4-fluoro-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR593## Adamantane-1-carboxylic acid
[7- (biphenyl-2-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR594##
Adamantane-1-carboxylic acid [7-(2-
trifluoromethyl-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR595## Adamantane-1-carboxylic acid
[7-(4- pyrazol-1-yl-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR596##
Adamantane-1-carboxylic acid [7-(2,4-
dimethoxy-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR597##
Adamantane-1-carboxylic acid [7- (1,3,5-trimethyl-1H-pyrazole-4-
sulfonyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide;
##STR598## Adamantane-1-carboxylic acid [7-(2-
trifluoromethoxy-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR599## Adamantane-1-carboxylic acid
[7- (toluene-2-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR600##
Adamantane-1-carboxylic acid [7-(2,3-
dihydro-benzo[1,4]dioxine-6-sulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR601##
Adamantane-1-carboxylic acid [7-(4-
trifluoromethyl-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR602## Adamantane-1-carboxylic acid
[7-(4- chloro-2-fluoro-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR603##
Adamantane-1-carboxylic acid [7-(2,5-
difluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR604##
Adamantane-1-carboxylic acid [7-(2,5-
dichloro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR605##
Adamantane-1-carboxylic acid [7-(5-
chloro-2-fluoro-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR606## Adamantane-1-carboxylic acid
[7-(2,6- difluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR607##
Adamantane-1-carboxylic acid [7-(3-
chloro-4-methyl-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR608## Adamantane-1-carboxylic acid
[7-(3,5- dichloro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR609##
Adamantane-1-carboxylic acid [7-(2,4-
difluoro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR610##
Adamantane-1-carboxylic acid [7-(2,6-
dichloro-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR611##
Adamantane-1-carboxylic acid [7-(2-
chloro-4-fluoro-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR612## Adamantane-1-carboxylic acid
[7-(5- fluoro-2 -methyl-benzenesulfonyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR613##
Adamantane-1-carboxylic acid [7-
(propane-2-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR614##
Adamantane-1-carboxylic acid [7-(2-
methoxy-5-methyl-benzenesulfonyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR615## Adamantane-1-carboxylic acid
[7-(2,5- dimethoxy-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR616##
Adamantane-1-carboxylic acid [7-(3,5-
dimethyl-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR617##
Adamantane-1-carboxylic acid [7-(2- cyano-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR618##
Adamantane-1-carboxylic acid [7- (3,5,5-trimethyl-hexyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR619##
Adamantane-1-carboxylic acid [7-(2,2-
diphenyl-ethyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR620##
Adamantane-1-carboxylic acid [7-(2-
phenyl-propyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR621##
Adamantane-1-carboxylic acid (7-
propyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide;
##STR622## Adamantane-1-carboxylic acid (7-
cyclohexylmethyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR623##
Adamantane-1-carboxylic acid (7-
cyclopropylmethyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR624##
Adamantane-1-carboxylic acid (7-
pentyl-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide;
##STR625## Adamantane-1-carboxylic acid [7-(3-
phenyl-propyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR626##
Adamantane-1-carboxylic acid (7-
pyridin-3-ylmethyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR627##
Adamantane-1-carboxylic acid [7-(1-
methyl-1H-pyrrol-2-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR628##
Adamantane-1-carboxylic acid [7-(4-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR629##
Adamantane-1-carboxylic acid [7-(1H-
indol-3-ylmethyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR630##
Adamantane-1-carboxylic acid (7-
benzo[1,3]dioxol-5-ylmethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-amide; ##STR631##
Adamantane-1-carboxylic acid (7- naphthalen-2-ylmethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-amide; ##STR632##
Adamantane-1-carboxylic acid [7-(3,4-
dimethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR633##
Adamantane-1-carboxylic acid [7-(6-
methyl-4-oxo-4H-cbromen-3-ylmethyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR634## Adamantane-1-carboxylic acid
[7-(3- phenoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR635##
Adamantane-1-carboxylic acid [7-(5-
bromo-2-methoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR636##
Adamantane-1-carboxylic acid [7-(2,4-
dichloro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR637##
Adamantane-1-carboxylic acid [7-(3-
cyano-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR638##
Adamantane-1-carboxylic acid [7-(4-
tert-butyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR639##
Adamantane-1-carboxylic acid [7-(6,6-
dimethyl-bicyclo[3.1.1]hept-2-en-2-
ylmethyl)-5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide;
##STR640## Adamantane-1-carboxylic acid [7-(3-
trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR641##
Adamantane-1-carboxylic acid [7-(4- dimethylamino-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR642##
Adamantane-1-carboxylic acid [7-(4-
phenoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR643##
Adamantane-1-carboxylic acid [7-(2-
chloro-6-fluoro-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR644##
Adamantane-1-carboxylic acid (7-butyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide; ##STR645##
Adamantane-1-carboxylic acid (7-ethyl-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl)-amide; ##STR646##
Adamantane-1-carboxylic acid [7-(1-
methyl-1H-indol-3-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR647##
Adamantane-1-carboxylic acid [7-(2-
ethyl-butyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR648##
Adamantane-1-carboxylic acid [7-(2-
methyl-pentyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR649##
Adamantane-1-carboxylic acid [7-(3-
methyl-butyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR650##
Adamantane-1-carboxylic acid [7-(3-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR651##
Adamantane-1-carboxylic acid [7-(3,4-
dimethyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR652##
Adamantane-1-carboxylic acid [7-(2-
chloro-3,4-dimethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR653##
Adamantane-1-carboxylic acid [7-(6-
bromo-benzo[1,3]dioxol-5-ylmethyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR654## Adamantane-1-carboxylic acid
[7-(4- benzyloxy-3-methoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR655##
Adamantane-1-carboxylic acid [7-(2,3-
dihydro-benzo[1,4]dioxin-6-ylmethyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR656##
Adamantane-1-carboxylic acid [7-(3,4-
dichloro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR657##
Adamantane-1-carboxylic acid [7-(2,3-
dimethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR658##
Adamantane-1-carboxylic acid [7-(3-
benzyloxy-4-methoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR659##
Adamantane-1-carboxylic acid [7-(3-
hydroxy-4-methoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR660##
Adamantane-1-carboxylic acid [7-(3-
bromo-4,5-dimethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR661##
Adamantane-1-carboxylic acid [7-(3- cyano-4-fluoro-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR662##
Adamantane-1-carboxylic acid (7-
benzo[1,3]dioxol-4-ylmethyl-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl)-amide; ##STR663##
Adamantane-1-carboxylic acid [7-(4-
bromo-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR664##
Adamantane-1-carboxylic acid [7-(3-
chloro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR665##
Adamantane-1-carboxylic acid [7-(6-
chloro-benzo[1,3]dioxol-5-ylmethyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR666## Adamantane-1-carboxylic acid
[7-(2,2- dimethyl-propyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR667##
Adamantane-1-carboxylic acid [7-(4-
chloro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR668##
Adamantane-1-carboxylic acid [7-(4-
methyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR669##
Adamantane-1-carboxylic acid [7-(4-
cyano-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR670##
Adamantane-1-carboxylic acid [7-(4-
trifluoromethyl-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR671##
Adamantane-1-carboxylic acid [7-(3-
fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR672##
Adamantane-1-carboxylic acid [7-(3-
methyl-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR673##
Adamantane-1-carboxylic acid [7-(4-
fluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR674##
Adamantane-1-carboxylic acid [7-(2,4-
dimethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR675##
Adamantane-1-carboxylic acid [7-(2,4-
difluoro-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR676##
Adamantane-1-carboxylic acid (7-
pyridin-4-ylmethyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR677##
Adamantane-1-carboxylic acid [7-(4-
chloro-3-fluoro-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR678##
Adamantane-1-carboxylic acid [7-(2-
fluoro-4-trifluoromethyl-benzyl)- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl]-amide; ##STR679## Adamantane-1-carboxylic acid
[7-(6- bromo-pyridin-3-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR680##
Adamantane-1-carboxylic acid [7-(3-
bromo-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR681##
Adamantane-1-carboxylic acid [7-(2-
methoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR682##
Adamantane-1-carboxylic acid [7-(4-
acetylamino-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR683##
Adamantane-1-carboxylic acid [7-(2-
bromo-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR684##
Adamantane-1-carboxylic acid [7-(5- bromo-2-fluoro-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR685##
Adamantane-1-carboxylic acid (7-
cyclopentylmethyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl)-amide; ##STR686##
Adamantane-1-carboxylic acid [7-(4-
trifluoromethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR687##
Adamantane-1-carboxylic acid [7-(4-
difluoromethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR688##
Adamantane-1-carboxylic acid {7-[4-(4-
fluoro-benzyloxy)-benzyl]-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl}-amide; ##STR689##
Adamantane-1-carboxylic acid [7-(2-
fluoro-4,5-dimethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR690##
Adamantane-1-carboxylic acid [7-(2,6-
difluoro-4-methoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR691##
Adamantane-1-carboxylic acid [7-(3-
ethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR692##
Adamantane-1-carboxylic acid {7-[3-(3-
trifluoromethyl-phenoxy)-benzyl]- 5,6,7,8-tetrahydro-pyrido[3,4-
d]pyrimidin-4-yl}-amide; ##STR693## Adamantane-1-carboxylic acid
[7-(2,2- difluoro-benzo[1,3]dioxol-5-ylmethyl)-
5,6,7,8-tetrahydro-pyrido[3,4- d]pyrimidin-4-yl]-amide; ##STR694##
Adamantane-1-carboxylic acid [7-(2-
fluoro-5-methoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR695##
Adamantane-1-carboxylic acid [7-(4-
fluoro-3-methoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR696##
Adamantane-1-carboxylic acid [7-(4-
ethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR697##
Adamantane-1-carboxylic acid [7-(2,5-
dimethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR698##
Adamantane-1-carboxylic acid [7-(3-
trifluoromethoxy-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; ##STR699##
Adamantane-1-carboxylic acid [7-(3,5-
dimethoxy-benzyl)-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidin-4-yl]-amide; ##STR700##
Adamantane-1-carboxylic acid [7-(6-
chloro-pyridin-3-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide; and ##STR701##
Adamantane-1-carboxylic acid [7-(4-
chloro-2-fluoro-benzyl)-5,6,7,8-
tetrahydro-pyrido[3,4-d]pyrimidin-4- yl]-amide. ##STR702##
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the priority of co-pending
provisional applications U.S. Ser. No. 60/664,903, filed on Mar.
24, 2005; U.S. Ser. No. 60/709,186 filed on Aug. 18, 2005; U.S.
Ser. No. 60/710,077 filed on Aug. 22, 2005; U.S. Ser. No.
60/712,778 filed on Aug. 31, 2005; U.S. Ser. No. 60/721,390 filed
on Sep. 28, 2005; and U.S. Ser. No. 60/753,194 filed on Dec. 22,
2005. The disclosures of all of the aforementioned applications are
incorporated by reference herein in their entireties. Applicants
claim the benefits of these applications under 35 U.S.C. .sctn.
119(e).
FIELD OF THE INVENTION
[0002] This invention relates to novel compounds of the class
bicycloheteroaryls that are capable of modulating P2X.sub.7
receptor activity, and to pharmaceutical compositions containing
such compounds. This invention also relates to methods for
preventing and/or treating conditions that are causally related to
aberrant P2X.sub.7 activity, such as inflammation-related
conditions in mammals, comprising (but not limited to) rheumatoid
arthritis, osteoarthritis, Parkinson's disease, uveitis, asthma,
cardiovascular conditions including myocardial infarction, the
treatment and prophylaxis of pain syndromes (acute and chronic or
neuropathic), traumatic brain injury, acute spinal cord injury,
neurodegenerative disorders, inflammatory bowel disease and
autoimmune disorders, using the compounds and pharmaceutical
compositions of the invention.
BACKGROUND OF THE INVENTION
[0003] Cell surface receptors for ATP can be divided into
metabotropic (P2Y/P2U) and ionotropic (P2X) classes. The
metabotropic class belongs to the superfamily of G protein-coupled
receptors, with seven transmembrane segments. The ionotropic class
members (P2X.sub.1-P2X.sub.6) are ligand-gated ion channels,
currently thought to be multisubunit proteins with two
transmembrane domains per subunit (Buell et al, Europ. J. Neurosci.
8:2221 (1996)). P2Z receptors have been distinguished from other P2
receptors in three primary ways (Buisman et al, Proc. Natl. Acad.
Sci. USA 85:7988 (1988); Cockcroft et al, Nature 279:541 (1979);
Steinberg et al, J. Biol. Chem. 262:3118 (1987)). First, activation
of P2Z receptors leads not only to an inward ionic current, but
also to cell permeabilization. Second, 3'-O-(4-benzoyl)benzoyl ATP
(BZATP) is the most effective agonist, and ATP itself is of rather
low potency. Third, responses are strongly inhibited by
extracellular magnesium ions, which has been interpreted to
indicate that ATP.sup.4- is the active agonist (DiVirgilio,
Immunol. Today 16:524 (1995)).
[0004] A seventh member of the P2X receptor family has been
isolated from a rat cDNA library and, when expressed in human
embryonic kidney (HEK293) cells, exhibits the above three
properties (Surprenant et al, Science 272:735 (1996)). This
receptor (rP2X.sub.7) thus corresponds to the P2Z receptor.
rP2X.sub.7 is structurally related to other members of the P2X
family but it has a longer cytoplasmic C-terminus domain (there is
35-40% amino acid identity in the corresponding region of homology,
but the C-terminus is 239 amino acids long in the rP2X.sub.7
receptor compared with 27-20 amino acids in the others). The
rP2X.sub.7 receptor functions both as a channel permeable to small
cations and as a cytolytic pore. Brief applications of ATP (1-2s)
transiently open the channel, as is the case of other P2X
receptors. Repeated or prolonged applications of agonist cause cell
permeabilization reducing the extracellular magnesium concentration
potentiates this effect. The unique C-terminal domain of rP2X.sub.7
is required for cell permeabilization and the lytic actions of ATP
(Suprenant et al, Science 272:735 (1996)).
[0005] The P2Z/rP2X.sub.7 receptor has been implicated in lysis of
antigen-presenting cells by cytotoxic T lymphocytes, in the
mitogenic stimulation of human T lymphocytes, as well as in the
formation of multinucleated giant cells (Blanchard et al, Blood
85:3173 (1995); Falzoni et al, J. Clin. Invest. 95:1207 (1995);
Baricolrdi et al, Blood 87:682 (1996)). Certain functional
differences exist between rodent and man (Hickman et al, Blood
84:2452 (1994)). The human macrophage P2X.sub.7 receptor
(P2X.sub.7) has now been cloned and its functional properties
determined (Rassendren et al, J. Biol. Chem. 272:5482 (1997). When
compared with the rat P2X.sub.7 receptor, elicited cation-selective
currents in the human P2X.sub.7 receptor required higher
concentrations of agonists, were more potentiated by removal of
extracellular magnesium ions, and revised more rapidly on agonist
removal. Expression of chimeric molecules indicated that some of
the differences between rat and human P2X.sub.7 receptors could be
revised by exchanging the respective C-terminal domains of the
receptor proteins.
[0006] It has been reported that certain compounds act as P2X.sub.7
antagonists. For example, WO99/29660 and WO99/29661 disclose that
certain adamantane derivatives exhibit P2X.sub.7 antagonistic
activity having therapeutic efficacy in the treatment of rheumatoid
arthritis and psoriasis. Similarly, WO99/29686 discloses that
certain heterocyclic derivatives are P2X.sub.7 receptor antagonists
and are useful as immunosuppressive agents and treating rheumatoid
arthritis, asthma, septic shock and atherosclerosis. Finally,
WO00/71529 discloses certain substituted phenyl compounds
exhibiting immunosuppressing activity. All of the references
described herein are incorporated herein by reference in their
entirety.
[0007] A need therefore exists for therapeutic agents, and
corresponding pharmaceutical compositions and related methods of
treatment, that address the conditions causally related to aberrant
P2X.sub.7 activity, and it is toward the fulfillment and
satisfaction of that need, that the present invention is
directed.
SUMMARY OF THE INVENTION
[0008] Bicycloaryl derivatives of formulas I-VIa, and their
pharmaceutical compositions are disclosed as therapeutic agents
useful for the treatment of conditions in mammals associated with
abnormal or aberrant activity of the P2X.sub.7 receptor, including
inflammatory-mediated conditions such as (but not limited to)
arthritis, myocardial infarction, the treatment and prophylaxis of
pain syndromes (acute and chronic [neuropathic]), traumatic brain
injury, acute spinal cord injury, neurodegenerative disorders,
inflammatory bowel disease and immune dysfunctions such as
autoimmune disorders.
[0009] It has now been found that the present bicycloheteroaryl
compounds are capable of mediating the activity of the P2X.sub.7
receptor. This finding leads to novel compounds having therapeutic
value. It also leads to pharmaceutical compositions having the
compounds of the present invention as active ingredients and to
their use to treat, prevent or ameliorate a range of conditions in
mammals such as but not limited to inflammation of various genesis
or etiology, for example rheumatoid arthritis, cardiovascular
disease, inflammatory bowel disease, acute, chronic, inflammatory
and neuropathic pain, dental pain and headache (such as migraine,
cluster headache and tension headache) and other conditions
causally related to inflammation or immune dysfunction.
[0010] The compounds of the present invention are also useful for
the treatment of inflammatory pain and associated hyperalgesia and
allodynia. They are also useful for the treatment of neuropathic
pain and associated hyperalgesis and allodynia (e.g. trigeminal or
herpetic neuralgia, diabetic neuropathy, causalgia, sympathetically
maintained pain and deafferentation syndromes such as brachial
plexus avulsion). The compounds of the present invention are also
useful as anti-inflammatory agents for the treatment of arthritis,
and as agents to treat Parkinson's Disease, uveitis, asthma,
myocardial infarction, traumatic brain injury, spinal cord injury,
neurodegenerative disorders, inflammatory bowel disease and
autoimmune disorders, renal disorders, obesity, eating disorders,
cancer, schizophrenia, epilepsy, sleeping disorders, cognition,
depression, anxiety, blood pressure, lipid disorders, and
atherosclerosis.
[0011] In one aspect, this invention provides bicycloheteroaryl
compounds which are capable of modulating the activity of the
P2X.sub.7 receptor, in vivo. In a further aspect, the compounds of
the invention are capable of antagonizing (suppressing or
inhibiting) the activity of the P2X.sub.7 receptor, and thereby
treating those conditions, representative ones of which are
causally related to aberrant P2X.sub.7 activity.
[0012] Accordingly, in a first aspect of the invention,
bicycloheteroaryl compounds are disclosed that are capable of
modulating the activity of the P2X.sub.7 receptor in vivo, having a
formula (I): ##STR2## [0013] wherein [0014] A is selected from
CR.sup.2'R.sup.2'', CO, and CS; [0015] B is selected from
CR.sup.2', CR.sup.2'R.sup.2'', CO, and CS; [0016] Y is
independently selected from CR.sup.2' and CR.sup.2'R.sup.2'';
[0017] W, W' and Z are independently selected from CR.sup.4 and N,
provided that all three of W, W' and Z can not be N at the same
time; [0018] L is a C.sub.1-C.sub.5 alkylene group, heteroalkyl, 3
to 8 membered cycloalkyl or heterocycloalkyl, alkylcycloalkyl,
alkylheterocycloalkyl, cycloalkylalkyl, or heterocycloalkylalkyl
group, which can be optionally substituted by a substituent
selected from hydroxyl, halogen and C.sub.1-C.sub.6 alkoxy; [0019]
n is 1, 2 or 3; [0020] R.sup.1 is selected from a 3-13 membered
cycloalkyl, heterocycloalkyl, aryl and heteroaryl ring system,
which can be optionally substituted with one or more substituents
independently selected from halo, hydroxyl, amino, cyano, sulfo,
sulfanyl, sulfinyl, amido, carboxy, ester, alkyl, substituted
alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,
and sulfonamido; [0021] each of R.sup.2, R.sup.2' and R.sup.2'' is
independently selected from hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6 alkyl; or any of R.sup.2' and R.sup.2'' can join
together to form a cycloalkyl or cycloheteroalkyl ring of 3-7
atoms; [0022] R.sup.3 is hydrogen or a functional group selected
from acyl, substituted acyl, substituted or unsubstituted
acylamino, substituted or unsubstituted alkylamino, substituted or
unsubstituted alkylthio, substituted or unsubstituted alkoxy,
alkoxycarbonyl, substituted alkoxycarbonyl, substituted or
unsubstituted alkylarylamino, arylalkyloxy, substituted
arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted
or unsubstituted sulfoxide, substituted or unsubstituted sulfone,
substituted or unsubstituted sulfanyl, substituted or unsubstituted
aminosulfonyl, substituted or unsubstituted arylsulfonyl, sulfuric
acid, sulfuric acid ester, substituted or unsubstituted
dihydroxyphosphoryl, substituted or unsubstituted
aminodihydroxyphosphoryl, azido, carboxy, substituted or
unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; or R.sup.3 is
a 4-9 membered carbocyclic or heterocyclic ring which can be
optionally substituted with at least one substituent selected from
a R.sup.4 group; or the group "R.sup.3-L" is H; [0023] R.sup.4 is
selected from H, alkyl, substituted alkyl, acyl, substituted acyl,
substituted or unsubstituted acylamino, substituted or
unsubstituted alkylamino, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted
alkoxycarbonyl, substituted or unsubstituted alkylarylamino,
arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted
aryl, arylalkyl, substituted or unsubstituted sulfoxide,
substituted or unsubstituted sulfone, substituted or unsubstituted
sulfanyl, substituted or unsubstituted aminosulfonyl, substituted
or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl, substituted or
unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted
or unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; [0024] and the
dotted bond is a single or a double bond; [0025] or a
pharmaceutically acceptable salt, solvate or prodrug thereof,
[0026] and stereoisomers and tautomers thereof.
[0027] In a second aspect of the invention, bicycloheteroaryl
compounds are disclosed that are capable of modulating the activity
of the P2X.sub.7 receptor in vivo, having a formula (Ia): ##STR3##
[0028] wherein [0029] A is selected from CR.sup.2'R.sup.2'', CO,
and CS; B is selected from CR.sup.2', CR.sup.2'R.sup.2'', CO, and
CS; [0030] Y is independently selected from CR.sup.2' and
CR.sup.2'R.sup.2''; [0031] W, W' and Z are independently selected
from CR.sup.4 and N, provided that all three of W, W' and Z can not
be N at the same time; [0032] L is a C.sub.1-C.sub.5 alkylene
group, heteroalkyl, 3 to 8 membered cycloalkyl or heterocycloalkyl,
alkylcycloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl which can be optionally substituted by a
substituent selected from hydroxyl, halogen and C.sub.1-C.sub.6
alkoxy; [0033] n is 1, 2 or 3; [0034] R.sup.1 is selected from a
3-13 membered cycloalkyl, heterocycloalkyl, aryl and heteroaryl
ring system, which can be optionally substituted with one or more
substituents independently selected from halo, hydroxyl, amino,
cyano, sulfo, sulfanyl, sulfinyl, amido, carboxy, ester, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, and sulfonamido; [0035] each of R.sup.2,
R.sup.2' and R.sup.2'' is independently selected from hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6 alkyl; or any of
R.sup.2 ' and R.sup.2'' can join together to form a cycloalkyl or
cycloheteroalkyl ring of 3-7 atoms; [0036] R.sup.3 is hydrogen or a
functional group selected from acyl, substituted acyl, substituted
or unsubstituted acylamino, substituted or unsubstituted
alkylamino, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl,
substituted or unsubstituted alkylarylamino, arylalkyloxy,
substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,
substituted or unsubstituted sulfoxide, substituted or
unsubstituted sulfone, substituted or unsubstituted sulfanyl,
substituted or unsubstituted aminosulfonyl, substituted or
unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl, substituted or
unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted
or unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; or R.sup.3 is
a 4-9 membered carbocyclic or heterocyclic ring which can be
optionally substituted with at least one substituent selected from
a R.sup.4 group; or the group "R.sup.3-L" is H; [0037] R.sup.4 is
selected from H, alkyl, substituted alkyl, acyl, substituted acyl,
substituted or unsubstituted acylamino, substituted or
unsubstituted alkylamino, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted
alkoxycarbonyl, substituted or unsubstituted alkylarylamino,
arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted
aryl, arylalkyl, substituted or unsubstituted sulfoxide,
substituted or unsubstituted sulfone, substituted or unsubstituted
sulfanyl, substituted or unsubstituted aminosulfonyl, substituted
or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl, substituted or
unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted
or unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; [0038] and the
dotted bond is a single or a double bond; [0039] or a
pharmaceutically acceptable salt, solvate or prodrug thereof,
[0040] and stereoisomers and tautomers thereof.
[0041] In a further embodiment, with respect to compounds of
formula I and Ia, n is 0.
[0042] In a further embodiment, with respect to compounds of
formula I and Ia, L may be a bond and R.sup.3 is selected from H,
acyl, substituted acyl, substituted or unsubstituted aminocarbonyl,
alkoxycarbonyl, substituted alkoxycarbonyl, substituted or
unsubstituted sulfoxide, substituted or unsubstituted sulfone,
substituted or unsubstituted aminosulfonyl, substituted or
unsubstituted arylsulfonyl, aryloxycarbonyl, substituted
aryloxycarbonyl, heteroaryloxycarbonyl, and substituted
heteroaryloxycarbonyl.
[0043] In a further embodiment, with respect to compounds of
formula I and Ia, L is L.sup.1; and wherein L.sup.1 is a bond,
--CO--, --SO.sub.2-- or a C.sub.1-C.sub.5 alkylene group which can
be optionally substituted by a substituent selected from alkyl,
hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, halogen, carbamoyl, and C.sub.1-C.sub.6 alkoxy.
In one particular embodiment, when A is CO or CS, L.sup.1 is a bond
or C.sub.1-C.sub.5 alkylene group.
[0044] In a further embodiment, with respect to compounds of
formula I and Ia, L is L.sup.1; and wherein L.sup.1 is a bond,
--CO--, --SO.sub.2-- or a C.sub.1-C.sub.5 alkylene group; and
R.sup.3 is selected from hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted bicycloaryl, and substituted or unsubstituted
bicycloheteroaryl. In one particular embodiment, when R.sup.3 is
hydrogen L.sup.1 is a bond or a C.sub.1-C.sub.5 alkylene group.
[0045] In a further embodiment, with respect to compounds of
formula I and Ia, A, B and Y may all represent CR.sup.2aR.sup.2b.
In another embodiment, A is CR.sup.2aR.sup.2b; and B and Y are
independently selected from CR.sup.2a and CR.sup.2aR.sup.2b.
[0046] In a further embodiment, with respect to compounds of
formula I and Ia, A, B and Y may all represent CH.sub.2 and R.sup.2
represents hydrogen.
[0047] In a further aspect, the present invention provides
pharmaceutical compositions comprising a bicycloheteroaryl compound
of the invention, and a pharmaceutical carrier, excipient or
diluent. In this aspect of the invention, the pharmaceutical
composition can comprise one or more of the compounds described
herein. Moreover, the compounds of the present invention useful in
the pharmaceutical compositions and treatment methods disclosed
herein, are all pharmaceutically acceptable as prepared and
used.
[0048] In a further aspect of the invention, this invention
provides a method of treating a mammal susceptible to or afflicted
with a condition from among those listed herein, and particularly,
such condition as may be associated with e.g. inflammation, such as
rheumatoid arthritis, osteoarthritis, uveitis, asthma, myocardial
infarction, traumatic brain injury; septic shock, atherosclerosis,
chronic pulmonary obstructive disease (COPD), acute spinal cord
injury, inflammatory bowel disease and immune dysfunction,
including autoimmune disorders, which method comprises
administering an effective amount of one or more of the
pharmaceutical compositions just described.
[0049] In yet another method of treatment aspect, this invention
provides a method of treating a mammal susceptible to or afflicted
with a condition that is causally related to aberrant P2X.sub.7
receptor activity, and that for example, gives rise to pain
responses or that relates to imbalances in the maintenance of basal
activity of sensory nerves. The amine compounds of the invention
have use as analgesics for the treatment of pain of various geneses
or etiology, for example acute, inflammatory pain (such as pain
associated with osteoarthritis and rheumatoid arthritis); various
neuropathic pain syndromes (such as post-herpetic neuralgia,
trigeminal neuralgia, reflex sympathetic dystrophy, diabetic
neuropathy, Guillian Barre syndrome, fibromyalgia, phantom limb
pain, post-masectomy pain, peripheral neuropathy, HIV neuropathy,
and chemotherapy-induced and other iatrogenic neuropathies);
visceral pain, (such as that associated with gastroesophageal
reflex disease, irritable bowel syndrome, inflammatory bowel
disease, pancreatitis, and various gynecological and urological
disorders), dental pain and headache (such as migraine, cluster
headache and tension headache).
[0050] In additional method of treatment aspects, this invention
provides methods of treating a mammal susceptible to or afflicted
with conditions that are causally related to abnormal activity of
the P2X.sub.7 receptor, such as neurodegenerative diseases and
disorders including, for example, Parkinson's disease, multiple
sclerosis; diseases and disorders which are mediated by or result
in neuroinflammation such as, for example traumatic brain injury
and encephalitis; centrally-mediated neuropsychiatric diseases and
disorders such as, for example depression mania, bipolar disease,
anxiety, schizophrenia, eating disorders, sleep disorders and
cognition disorders; epilepsy and seizure disorders; prostate,
bladder and bowel dysfunction such as, for example urinary
incontinence, urinary hesitancy, rectal hypersensitivity, fecal
incontinence, benign prostatic hypertrophy and inflammatory bowel
disease; respiratory and airway disease and disorders such as, for
example, allergic rhinitis, asthma and reactive airway disease and
chronic obstructive pulmonary disease; diseases and disorders which
are mediated by or result in inflammation such as, for example
rheumatoid arthritis and osteoarthritis, myocardial infarction,
various autoimmune diseases and disorders, uveitis and
atherosclerosis; itch/pruritus such as, for example psoriasis;
obesity; lipid disorders; cancer; blood pressure; spinal cord
injury; and cardiovascular and renal disorders method comprises
administering an effective condition-treating or
condition-preventing amount of one or more of the pharmaceutical
compositions just described.
[0051] In additional aspects, this invention provides methods for
synthesizing the compounds of the invention, with representative
synthetic protocols and pathways disclosed later on herein.
[0052] Accordingly, it is a principal object of this invention to
provide a novel series of compounds, which can modify the activity
of the P2X.sub.7 receptor and thus avert or treat any maladies that
may be causally related thereto.
[0053] It is further an object of this invention to provide a
series of compounds that can treat or alleviate maladies or
symptoms of same, such as pain and inflammation, that may be
causally related to the activation of the P2X.sub.7 receptor.
[0054] A still further object of this invention is to provide
pharmaceutical compositions that are effective in the treatment or
prevention of a variety of disease states, including the diseases
associated with the central nervous system, cardiovascular
conditions, chronic pulmonary obstructive disease COPD),
inflammatory bowel disease, rheumatoid arthritis, osteoarthritis,
and other diseases where an inflammatory component is present.
[0055] Other objects and advantages will become apparent to those
skilled in the art from a consideration of the ensuing detailed
description.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0056] When describing the compounds, pharmaceutical compositions
containing such compounds and methods of using such compounds and
compositions, the following terms have the following meanings
unless otherwise indicated. It should also be understood that,
consistent with the scope of the present invention, any of the
moieties defined herein and/or set forth below may be substituted
with a variety of substituents, and that the respective definitions
are intended to include such substituted moieties within their
scope. By way of non-limiting example, such substituents may
include e.g. halo (such as fluoro, chloro, bromo), --CN,
--CF.sub.3, --OH, --OCF.sub.3, C.sub.2-C.sub.6 alkenyl,
C.sub.3-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, aryl and
di-C.sub.1-C.sub.6 alkylamino.
[0057] "Acyl" refers to a radical --C(O)R, where R is hydrogen,
alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl, heteroarylalkyl as defined herein. Representative
examples include, but are not limited to, formyl, acetyl,
cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,
benzylcarbonyl and the like.
[0058] "Acylamino" refers to a radical --NR'C(O)R, where R' is
hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,
heteroalkyl, heteroaryl, heteroarylalkyl and R is hydrogen, alkyl,
alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,
heteroaryl or heteroarylalkyl, as defined herein. Representative
examples include, but are not limited to, formylamino, acetylamino,
cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino,
benzoylamino, benzylcarbonylamino and the like.
[0059] "Acyloxy" refers to the group --OC(O)R where R is hydrogen,
alkyl, aryl or cycloalkyl.
[0060] "Substituted alkenyl" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkenyl group having 1 or more substituents, for instance from 1 to
5 substituents, and particularly from 1 to 3 substituents, selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--
[0061] "Alkoxy" refers to the group --OR where R is alkyl.
Particular alkoxy groups include, by way of example, methoxy,
ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
[0062] "Substituted alkoxy" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkoxy group having 1 or more substituents, for instance from 1 to
5 substituents, and particularly from 1 to 3 substituents, selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, heteroaryl, hydroxyl,
keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,
thioketo, thiol, alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--.
[0063] "Alkoxycarbonylamino" refers to the group --NRC(O)OR' where
R is hydrogen, alkyl, aryl or cycloalkyl, and R' is alkyl or
cycloalkyl.
[0064] "Aliphatic" refers to hydrocarbyl organic compounds or
groups characterized by a straight, branched or cyclic arrangement
of the constituent carbon atoms and an absence of aromatic
unsaturation. Aliphatics include, without limitation, alkyl,
alkylene, alkenyl, alkenylene, alkynyl and alkynylene. Aliphatic
groups typically have from 1 or 2 to about 12 carbon atoms.
[0065] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl
groups particularly having up to about 11 carbon atoms, more
particularly as a lower alkyl, from 1 to 8 carbon atoms and still
more particularly, from 1 to 6 carbon atoms. The hydrocarbon chain
may be either straight-chained or branched. This term is
exemplified by groups such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, iso-butyl, tert-butyl, n-hexyl, n-octyl, tert-octyl and
the like. The term "lower alkyl" refers to alkyl groups having 1 to
6 carbon atoms. The term "alkyl" also includes "cycloalkyl" as
defined below.
[0066] "Substituted alkyl" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkyl group having 1 or more substituents, for instance from 1 to 5
substituents, and particularly from 1 to 3 substituents, selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, heteroaryl,
keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,
thioketo, thiol, alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2--, and
aryl-S(O).sub.2--.
[0067] "Alkylene" refers to divalent saturated aliphatic
hydrocarbyl groups particularly having up to about 11 carbon atoms
and more particularly 1 to 6 carbon atoms which can be
straight-chained or branched. This term is exemplified by groups
such as methylene (--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--),
the propylene isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2--) and the like.
[0068] "Substituted alkylene" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkylene group having 1 or more substituents, for instance from 1
to 5 substituents, and particularly from 1 to 3 substituents,
selected from the group consisting of acyl, acylamino, acyloxy,
alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino,
amino, substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen,
hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thioketo, thiol, alkyl-S(O)--, aryl-S(O)--,
alkyl-S(O).sub.2-- and aryl-S(O).sub.2--
[0069] "Alkenyl" refers to monovalent olefinically unsaturated
hydrocarbyl groups preferably having up to about 11 carbon atoms,
particularly, from 2 to 8 carbon atoms, and more particularly, from
2 to 6 carbon atoms, which can be straight-chained or branched and
having at least 1 and particularly from 1 to 2 sites of olefinic
unsaturation. Particular alkenyl groups include ethenyl
(--CH.dbd.CH.sub.2), n-propenyl (--CH.sub.2CH.dbd.CH.sub.2),
isopropenyl (--C(CH.sub.3).dbd.CH.sub.2), vinyl and substituted
vinyl, and the like.
[0070] "Alkenylene" refers to divalent olefinically unsaturated
hydrocarbyl groups particularly having up to about 11 carbon atoms
and more particularly 2 to 6 carbon atoms which can be
straight-chained or branched and having at least 1 and particularly
from 1 to 2 sites of olefinic unsaturation. This term is
exemplified by groups such as ethenylene (--CH.dbd.CH--), the
propenylene isomers (e.g., --CH.dbd.CHCH.sub.2-- and
--C(CH.sub.3).dbd.CH-- and --CH.dbd.C(CH.sub.3)--) and the
like.
[0071] "Alkynyl" refers to acetylenically unsaturated hydrocarbyl
groups particularly having up to about 11 carbon atoms and more
particularly 2 to 6 carbon atoms which can be straight-chained or
branched and having at least 1 and particularly from 1 to 2 sites
of alkynyl unsaturation. Particular non-limiting examples of
alkynyl groups include acetylenic, ethynyl (--C.ident.CH),
propargyl (--CH.sub.2C.ident.CH), and the like.
[0072] "Substituted alkynyl" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
alkynyl group having 1 or more substituents, for instance from 1 to
5 substituents, and particularly from 1 to 3 substituents, selected
from the group consisting of acyl, acylamino, acyloxy, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino,
substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--
[0073] "Alkanoyl" as used herein, which can include "acyl", refers
to the group R--C(O)--, where R is hydrogen or alkyl as defined
above.
[0074] "Aryl" refers to a monovalent aromatic hydrocarbon group
derived by the removal of one hydrogen atom from a single carbon
atom of a parent aromatic ring system. Typical aryl groups include,
but are not limited to, groups derived from aceanthrylene,
acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,
chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene,
hexylene, as-indacene, s-indacene, indane, indene, naphthalene,
octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene,
pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
pleiadene, pyrene, pyranthrene, rubicene, triphenylene,
trinaphthalene and the like. Particularly, an aryl group comprises
from 6 to 14 carbon atoms.
[0075] "Substituted Aryl" includes those groups recited in the
definition of "substituted" herein, and particularly refers to an
aryl group that may optionally be substituted with 1 or more
substituents, for instance from 1 to 5 substituents, particularly 1
to 3 substituents, selected from the group consisting of acyl,
acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy,
substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl,
alkynyl, substituted alkynyl, amino, substituted amino,
aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,
azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl,
halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thiol, alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2--
and aryl-S(O).sub.2--.
[0076] "Fused Aryl" refers to an aryl having two of its ring carbon
in common with a second aryl ring or with an aliphatic ring.
[0077] "Alkaryl" refers to an aryl group, as defined above,
substituted with one or more alkyl groups, as defined above.
[0078] "Aralkyl" or "arylalkyl" refers to an alkyl group, as
defined above, substituted with one or more aryl groups, as defined
above.
[0079] "Aryloxy" refers to --O-aryl groups wherein "aryl" is as
defined above.
[0080] "Alkylamino" refers to the group alkyl-NR'--, wherein R' is
selected from hydrogen and alkyl.
[0081] "Arylamino" refers to the group aryl-NR'--, wherein R' is
selected from hydrogen, aryl and heteroaryl.
[0082] "Alkoxyamino" refers to a radical --N(H)OR where R
represents an alkyl or cycloalkyl group as defined herein.
[0083] "Alkoxycarbonyl" refers to a radical --C(O)-alkoxy where
alkoxy is as defined herein.
[0084] "Alkylarylamino" refers to a radical --NRR' where R
represents an alkyl or cycloalkyl group and R' is an aryl as
defined herein.
[0085] "Alkylsulfonyl" refers to a radical --S(O).sub.2R where R is
an alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methylsulfonyl,
ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
[0086] "Alkylsulfinyl" refers to a radical --S(O)R where R is an
alkyl or cycloalkyl group as defined herein. Representative
examples include, but are not limited to, methylsulfinyl,
ethylsulfinyl, propylsulfinyl, butylsulfinyl and the like.
[0087] "Alkylthio" refers to a radical --SR where R is an alkyl or
cycloalkyl group as defined herein that may be optionally
substituted as defined herein. Representative examples include, but
are not limited to, methylthio, ethylthio, propylthio, butylthio,
and the like.
[0088] "Amino" refers to the radical --NH.sub.2.
[0089] "Substituted amino" includes those groups recited in the
definition of "substituted" herein, and particularly refers to the
group --N(R).sub.2 where each R is independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,
substituted alkenyl, alkynyl, substituted alkynyl, aryl,
cycloalkyl, substituted cycloalkyl, and where both R groups are
joined to form an alkylene group. When both R groups are hydrogen,
--N(R).sub.2 is an amino group.
[0090] "Aminocarbonyl" or "amido" refers to the group --C(O)NRR
where each R is independently hydrogen, alkyl, aryl and cycloalkyl,
or where the R groups are joined to form an alkylene group.
[0091] "Aminocarbonylamino" refers to the group --NRC(O)NRR where
each R is independently hydrogen, alkyl, aryl or cycloalkyl, or
where two R groups are joined to form an alkylene group.
[0092] "Aminocarbonyloxy" refers to the group --OC(O)NRR where each
R is independently hydrogen, alkyl, aryl or cycloalkyl, or where
the R groups are joined to form an alkylene group.
[0093] "Arylalkyloxy" refers to an --O-arylalkyl radical where
arylalkyl is as defined herein.
[0094] "Arylamino" means a radical --NHR where R represents an aryl
group as defined herein.
[0095] "Aryloxycarbonyl" refers to a radical --C(O)--O-aryl where
aryl is as defined herein.
[0096] "Arylsulfonyl" refers to a radical --S(O).sub.2R where R is
an aryl or heteroaryl group as defined herein.
[0097] "Azido" refers to the radical --N.sub.3
[0098] "Bicycloaryl" refers to a monovalent aromatic hydrocarbon
group derived by the removal of one hydrogen atom from a single
carbon atom of a parent bicycloaromatic ring system. Typical
bicycloaryl groups include, but are not limited to, groups derived
from indane, indene, naphthalene, tetrahydronaphthalene, and the
like. Particularly, an aryl group comprises from 8 to 11 carbon
atoms.
[0099] "Bicycloheteroaryl" refers to a monovalent
bicycloheteroaromatic group derived by the removal of one hydrogen
atom from a single atom of a parent bicycloheteroaromatic ring
system. Typical bicycloheteroaryl groups include, but are not
limited to, groups derived from benzofuran, benzimidazole,
benzindazole, benzdioxane, chromene, chromane, cinnoline,
phthalazine, indole, indoline, indolizine, isobenzofuran,
isochromene, isoindole, isoindoline, isoquinoline, benzothiazole,
benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine,
benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline,
quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline,
tetrahydroquinoline, and the like. Preferably, the
bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl,
with 5-10 membered heteroaryl being particularly preferred.
Particular bicycloheteroaryl groups are those derived from
benzothiophene, benzofuran, benzothiazole, indole, quinoline,
isoquinoline, benzimidazole, benzoxazole and benzdioxane.
[0100] "Carbamoyl" refers to the radical --C(O)N(R).sub.2 where
each R group is independently hydrogen, alkyl, cycloalkyl or aryl,
as defined herein, which may be optionally substituted as defined
herein.
[0101] "Carboxy" refers to the radical --C(O)OH.
[0102] "Carboxyamino" refers to the radical --N(H)C(O)OH.
[0103] "Cycloalkyl" refers to cyclic hydrocarbyl groups having from
3 to about 10 carbon atoms and having a single cyclic ring or
multiple condensed rings, including fused and bridged ring systems,
which optionally can be substituted with from 1 to 3 alkyl groups.
Such cycloalkyl groups include, by way of example, single ring
structures such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl,
2-methylcyclooctyl, and the like, and multiple ring structures such
as adamantanyl, and the like.
[0104] "Substituted cycloalkyl" includes those groups recited in
the definition of "substituted" herein, and particularly refers to
a cycloalkyl group having 1 or more substituents, for instance from
1 to 5 substituents, and particularly from 1 to 3 substituents,
selected from the group consisting of acyl, acylamino, acyloxy,
alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino,
amino, substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--
[0105] "Cycloalkoxy" refers to the group --OR where R is
cycloalkyl. Such cycloalkoxy groups include, by way of example,
cyclopentoxy, cyclohexoxy and the like.
[0106] "Cycloalkenyl" refers to cyclic hydrocarbyl groups having
from 3 to 10 carbon atoms and having a single cyclic ring or
multiple condensed rings, including fused and bridged ring systems
and having at least one and particularly from 1 to 2 sites of
olefinic unsaturation. Such cycloalkenyl groups include, by way of
example, single ring structures such as cyclohexenyl,
cyclopentenyl, cyclopropenyl, and the like.
[0107] "Substituted cycloalkenyl" includes those groups recited in
the definition of "substituted" herein, and particularly refers to
a cycloalkenyl group having 1 or more substituents, for instance
from 1 to 5 substituents, and particularly from 1 to 3
substituents, selected from the group consisting of acyl,
acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,
alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,
aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido,
carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,
hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thioketo, thiol, alkyl-S(O)--, aryl-S(O)--,
alkyl-S(O).sub.2-- and aryl-S(O).sub.2--
[0108] "Fused Cycloalkenyl" refers to a cycloalkenyl having two of
its ring carbon atoms in common with a second aliphatic or aromatic
ring and having its olefinic unsaturation located to impart
aromaticity to the cycloalkenyl ring.
[0109] "Cyanato" refers to the radical --OCN.
[0110] "Cyano" refers to the radical --CN.
[0111] "Dialkylamino" means a radical --NRR' where R and R'
independently represent an alkyl, substituted alkyl, aryl,
substituted aryl, cycloalkyl, substituted cycloalkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or
substituted heteroaryl group as defined herein.
[0112] "Ethenyl" refers to substituted or unsubstituted
--(C.dbd.C)--.
[0113] "Ethylene" refers to substituted or unsubstituted
--(C--C)--.
[0114] "Ethynyl" refers to --(C.ident.C)--.
[0115] "Halo" or "halogen" refers to fluoro, chloro, bromo and
iodo. Preferred halo groups are either fluoro or chloro.
[0116] "Hydroxy" refers to the radical --OH.
[0117] "Nitro" refers to the radical --NO.sub.2
[0118] "Substituted" refers to a group in which one or more
hydrogen atoms are each independently replaced with the same or
different substituent(s). Typical substituents include, but are not
limited to, --X, --R.sup.14, --O--, .dbd.O, --OR.sup.14,
--SR.sup.14--S.sup.-, .dbd.S, --NR.sup.14R.sup.15, .dbd.NR.sup.14,
--CX.sub.3, --CF.sub.3, --CN, --OCN, --SCN, --NO, --NO.sub.2,
.dbd.N.sub.2, --N.sub.3, --S(O).sub.2O--, --S(O).sub.2OH,
--S(O).sub.2R.sup.14, --OS(O.sub.2)O--, --OS(O).sub.2R.sup.14,
--P(O)(O--).sub.2, --P(O)(OR.sup.14)(O.sup.-),
--OP(O)(OR.sup.14)(OR.sup.15), --C(O)R.sup.14, --C(S)R.sup.14,
--C(O)OR.sup.14, --C(O)NR.sup.14R.sup.15, --C(O)O.sup.-,
--C(S)OR.sup.14, --NR.sup.16C(O)NR.sup.14R.sup.15,
--NR.sup.16C(S)NR.sup.14R.sup.15,
--NR.sup.17C(NR.sup.16)NR.sup.14R.sup.15 and
--C(NR.sup.16)NR.sup.14R.sup.15, where each X is independently a
halogen; each R.sup.14, R.sup.15, R.sup.16 and R.sup.17 are
independently hydrogen, alkyl, substituted alkyl, aryl, substituted
alkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl,
cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,
substituted heteroalkyl, heteroaryl, substituted heteroaryl,
heteroarylalkyl, substituted heteroarylalkyl, --NR.sup.18R.sup.19,
--C(O)R.sup.18 or --S(O).sub.2R.sup.18 or optionally R.sup.18 and
R.sup.19 together with the atom to which they are both attached
form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and
R.sup.18 and R.sup.19 are independently hydrogen, alkyl,
substituted alkyl, aryl, substituted alkyl, arylalkyl, substituted
alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl, substituted
cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,
substituted heteroaryl, heteroarylalkyl or substituted
heteroarylalkyl.
[0119] Examples of representative substituted aryls include the
following ##STR4##
[0120] In these formulae one of R.sup.6' and R.sup.7' may be
hydrogen and at least one of R.sup.6' and R.sup.7' is each
independently selected from alkyl, alkenyl, alkynyl,
cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy,
alkylamino, arylamino, heteroarylamino, NR.sup.10COR.sup.11,
NR.sup.10SOR.sup.11, NR.sup.10SO.sub.2R.sup.14, COOalkyl, COOaryl,
CONR.sup.10R.sup.11, CONR.sup.10R.sup.11, NR.sup.10R.sup.11,
SO.sub.2NR.sup.10R.sup.11, S-alkyl, S-alkyl, SOalkyl,
SO.sub.2alkyl, Saryl, SOaryl, SO.sub.2aryl; or R.sup.6' and
R.sup.7' may be joined to form a cyclic ring (saturated or
unsaturated) from 5 to 8 atoms, optionally containing one or more
heteroatoms selected from the group N, O or S. R.sup.10, R.sup.11,
and R.sup.12 are independently hydrogen, alkyl, alkenyl, alkynyl,
perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substituted
aryl, heteroaryl, substituted or hetero alkyl or the like.
[0121] "Hetero" when used to describe a compound or a group present
on a compound means that one or more carbon atoms in the compound
or group have been replaced by a nitrogen, oxygen, or sulfur
heteroatom. Hetero may be applied to any of the hydrocarbyl groups
described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g.
cycloheteroalkyl, aryl, e.g. heteroaryl, cycloalkenyl,
cycloheteroalkenyl, and the like having from 1 to 5, and especially
from 1 to 3 heteroatoms.
[0122] "Heteroaryl" refers to a monovalent heteroaromatic group
derived by the removal of one hydrogen atom from a single atom of a
parent heteroaromatic ring system. Typical heteroaryl groups
include, but are not limited to, groups derived from acridine,
arsindole, carbazole, .beta.-carboline, chromane, chromene,
cinnoline, furan, imidazole, indazole, indole, indoline,
indolizine, isobenzofuran, isochromene, isoindole, isoindoline,
isoquinoline, tetrahydroisoquinoline, isothiazole, isoxazole,
naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,
phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
pyrrolizine, quinazoline, quinoline, tetrahydroquinoline,
quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,
thiophene, triazole, xanthene, and the like. Particularly,
heteroaryl can include other saturated ring systems, and can
therefore be derived from indoline, indolizine,
tetrahydroquinoline, and tetrahydroisoquinoline. Preferably, the
heteroaryl group is between 5-20 membered heteroaryl, with 5-10
membered heteroaryl being particularly preferred. Particular
heteroaryl groups are those derived from thiophene, pyrrole,
benzothiophene, benzofuran, indole, pyridine, pyrimidine,
quinoline, tetrahydroquinoline, isoquinoline,
tetrahydroisoquinoline, imidazole, oxazole and pyrazine.
[0123] Examples of representative heteroaryls include the
following: ##STR5## wherein each Y is selected from carbonyl. N,
NR.sup.4, O and S, and where R.sup.4 is defined herein.
[0124] Examples of representative cycloheteroalkyls include the
following ##STR6## wherein each X is selected from CR.sup.4.sub.2,
NR.sup.4, O and S; and each Y is selected from NR.sup.4, O and S,
and where R.sup.6' is R.sup.2, R.sup.2 and R.sup.4 being as defined
herein.
[0125] Examples of representative cycloheteroalkenyls include the
following: ##STR7## wherein each X is selected from CR.sup.4,
NR.sup.4, O and S; and each Y is selected from carbonyl, N,
NR.sup.4, O and S, where R.sup.4 is as defined herein.
[0126] Examples of representative aryl having hetero atoms
containing substitution include the following: ##STR8## wherein
each X is selected from C--R.sup.4, CR.sup.4.sub.2, NR.sup.4, O and
S; and each Y is selected from carbonyl, NR.sup.4, O and S, where
R.sup.4 is as defined herein.
[0127] "Hetero substituent" refers to a halo, O, S or N
atom-containing functionality that may be present as an R.sup.4 in
a CR.sup.4 group present as substituents directly on W or Z of the
compounds of this invention or may be present as a substituent in
the "substituted" aryl, heteroaryl and aliphatic groups present in
the compounds.
[0128] Examples of hetero substituents include:
[0129] -halo,
[0130] --NO.sub.2, --NH.sub.2, --NHR.sup.4, --N(R).sub.2,
[0131] --NRCOR, --NRSOR, --NRSO.sub.2R, OH, CN, CO.sub.2R,
[0132] --CO.sub.2H,
[0133] --O--R,
[0134] --CON(R).sub.2, --CONROR,
[0135] --SO.sub.3H, --S--R, --SO.sub.2N(R).sub.2,
[0136] --S(O)R, and --S(O).sub.2R,
[0137] wherein each R is independently an aryl or aliphatic,
optionally with substitution. Among hetero substituents containing
R groups, preference is given to those materials having aryl and
alkyl R groups as defined herein. Where feasible, each R may
include hydrogen. Also, where feasible, two R groups when on same
atom may join to form a heterocyclic ring of 3-8 atoms. For
example, two R groups of NR.sup.2, SO.sub.2NR.sup.2, and CONR.sup.2
may join, together with the N atom, to form a N-morpholino,
N-pyrrolo, N-piperidino, and N-pyrazolylo ring. Preferred hetero
substituents are those listed above.
[0138] As used herein, the term "cycloheteroalkyl" refers to a
stable heterocyclic non-aromatic ring and fused rings containing
one or more heteroatoms independently selected from N, O and S. A
fused heterocyclic ring system may include carbocyclic rings and
need only include one heterocyclic ring. Examples of heterocyclic
rings include, but are not limited to, piperazinyl,
homopiperazinyl, piperidinyl and morpholinyl, and are shown in the
following illustrative examples: ##STR9## optionally substituted
with one or more groups selected from the group consisting of acyl,
acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,
alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,
aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido,
carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,
hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thioketo, thiol, alkyl-S(O)--, aryl-S(O)--,
alkyl-S(O).sub.2-- and aryl-S(O).sub.2--Substituting groups include
carbonyl or thiocarbonyl which provide, for example, lactam and
urea derivatives. In the examples, M is CR.sup.7, NR.sup.2, O, or
S; Q is O, NR.sup.2 or S, where R.sup.2 is as defined herein.
R.sup.7 and R.sup.8 are independently selected from the group
consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,
alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,
aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,
azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl,
halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,
thioaryloxy, thioketo, thiol, alkyl-S(O)--, aryl-S(O)--,
alkyl-S(O).sub.2-- and aryl-S(O).sub.2--
[0139] "Dihydroxyphosphoryl" refers to the radical
--PO(OH).sub.2.
[0140] "Substituted dihydroxyphosphoryl" includes those groups
recited in the definition of "substituted" herein, and particularly
refers to a dihydroxyphosphoryl radical wherein one or both of the
hydroxyl groups are substituted. Suitable substituents are
described in detail below.
[0141] "Aminohydroxyphosphoryl" refers to the radical
--PO(OH)NH.sub.2
[0142] "Substituted aminohydroxyphosphoryl" includes those groups
recited in the definition of "substituted" herein, and particularly
refers to an aminohydroxyphosphoryl wherein the amino group is
substituted with one or two substituents. Suitable substituents are
described in detail below. In certain embodiments, the hydroxyl
group can also be substituted.
[0143] "Thioalkoxy" refers to the group --SR where R is alkyl.
[0144] "Substituted thioalkoxy" includes those groups recited in
the definition of "substituted" herein, and particularly refers to
a thioalkoxy group having 1 or more substituents, for instance from
1 to 5 substituents, and particularly from 1 to 3 substituents,
selected from the group consisting of acyl, acylamino, acyloxy,
alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino,
amino, substituted amino, aminocarbonyl, aminocarbonylamino,
aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano,
cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro,
thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,
alkyl-S(O)--, aryl-S(O)--, alkyl-S(O).sub.2-- and
aryl-S(O).sub.2--
[0145] "Sulfanyl" refers to the radical HS--. "Substituted
sulfanyl" refers to a radical such as RS-wherein R is any
substituent described herein.
[0146] "Sulfonyl" refers to the divalent radical
--S(O.sub.2)--"Substituted sulfonyl" refers to a radical such as
S(O.sub.2)--R wherein R is any substituent described herein.
"Aminosulfonyl" or "Sulfonamide" refers to the radical
H.sub.2N(O.sub.2)S--, and "substituted aminosulfonyl" "substituted
sulfonamide" refers to a radical such as R.sub.2N(O.sub.2)S--
wherein each R is independently any substituent described
herein.
[0147] "Sulfoxide" refers to the divalent radical --S(O)--.
"Substituted sulfoxide" refers to a radical such as S(O)--R,
wherein R is any substituent described herein.
[0148] "Sulfone" refers to the group --SO.sub.2R. In particular
embodiments, R is selected from H, lower alkyl, alkyl, aryl and
heteroaryl.
[0149] "Thioaryloxy" refers to the group --SR where R is aryl.
[0150] "Thioketo" refers to the group .dbd.S.
[0151] "Thiol" refers to the group --SH.
[0152] One having ordinary skill in the art of organic synthesis
will recognize that the maximum number of heteroatoms in a stable,
chemically feasible heterocyclic ring, whether it is aromatic or
non aromatic, is determined by the size of the ring, the degree of
unsaturation and the valence of the heteroatoms. In general, a
heterocyclic ring may have one to four heteroatoms so long as the
heteroaromatic ring is chemically feasible and stable.
[0153] "Pharmaceutically acceptable" means approved by a regulatory
agency of the Federal or a state government or listed in the U.S.
Pharmacopoeia or other generally recognized pharmacopoeia for use
in animals, and more particularly in humans.
[0154] "Pharmaceutically acceptable salt" refers to a salt of a
compound of the invention that is pharmaceutically acceptable and
that possesses the desired pharmacological activity of the parent
compound. Such salts include: (1) acid addition salts, formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; or (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine and the like.
Salts further include, by way of example only, sodium, potassium,
calcium, magnesium, ammonium, tetraalkylammonium, and the like; and
when the compound contains a basic functionality, salts of non
toxic organic or inorganic acids, such as hydrochloride,
hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the
like. The term "pharmaceutically acceptable cation" refers to a non
toxic, acceptable cationic counter-ion of an acidic functional
group. Such cations are exemplified by sodium, potassium, calcium,
magnesium, ammonium, tetraalkylammonium cations, and the like.
[0155] "Pharmaceutically acceptable vehicle" refers to a diluent,
adjuvant, excipient or carrier with which a compound of the
invention is administered.
[0156] "Preventing" or "prevention" refers to a reduction in risk
of acquiring a disease or disorder (i.e., causing at least one of
the clinical symptoms of the disease not to develop in a subject
that may be exposed to or predisposed to the disease but does not
yet experience or display symptoms of the disease).
[0157] "Prodrugs" refers to compounds, including derivatives of the
compounds of the invention, which have cleavable groups and become
by solvolysis or under physiological conditions the compounds of
the invention which are pharmaceutically active in vivo. Such
examples include, but are not limited to, choline ester derivatives
and the like, N-alkylmorpholine esters and the like.
[0158] "Solvate" refers to forms of the compound that are
associated with a solvent, usually by a solvolysis reaction.
Conventional solvents include water, ethanol, acetic acid and the
like. The compounds of the invention may be prepared e.g. in
crystalline form and may be solvated or hydrated. Suitable solvates
include pharmaceutically acceptable solvates, such as hydrates, and
further include both stoichiometric solvates and non-stoichiometric
solvates.
[0159] "Subject" includes humans. The terms "human," "patient" and
"subject" are used interchangeably herein.
[0160] "Therapeutically effective amount" means the amount of a
compound that, when administered to a subject for treating a
disease, is sufficient to effect such treatment for the disease.
The "therapeutically effective amount" can vary depending on the
compound, the disease and its severity, and the age, weight, etc.,
of the subject to be treated.
[0161] "Treating" or "treatment" of any disease or disorder refers,
in one embodiment, to ameliorating the disease or disorder (i.e.,
arresting or reducing the development of the disease or at least
one of the clinical symptoms thereof). In another embodiment
"treating" or "treatment" refers to ameliorating at least one
physical parameter, which may not be discernible by the subject. In
yet another embodiment, "treating" or "treatment" refers to
modulating the disease or disorder, either physically, (e.g.,
stabilization of a discernible symptom), physiologically, (e.g.,
stabilization of a physical parameter), or both. In yet another
embodiment, "treating" or "treatment" refers to delaying the onset
of the disease or disorder, or even preventing the same.
[0162] It is also to be understood that compounds that have the
same molecular formula but differ in the nature or sequence of
bonding of their atoms or the arrangement of their atoms in space
are termed "isomers". Isomers that differ in the arrangement of
their atoms in space are termed "stereoisomers".
[0163] Stereoisomers that are not mirror images of one another are
termed "diastereomers" and those that are non-superimposable mirror
images of each other are termed "enantiomers". When a compound has
an asymmetric center, for example, it is bonded to four different
groups, a pair of enantiomers is possible. An enantiomer can be
characterized by the absolute configuration of its asymmetric
center and is described by the R- and S-sequencing rules of Cahn
and Prelog, or by the manner in which the molecule rotates the
plane of polarized light and designated as dextrorotatory or
levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral
compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers
is called a "racemic mixture".
[0164] "Tautomers" refer to compounds that are interchangeable
forms of a particular compound structure, and that vary in the
displacement of hydrogen atoms and electrons. Thus, two structures
may be in equilibrium through the movement of 71 electrons and an
atom (usually H). For example, enols and ketones are tautomers
because they are rapidly interconverted by treatment with either
acid or base. Another example of tautomerism is the aci- and
nitro-forms of phenylnitromethane, that are likewise formed by
treatment with acid or base. Representative enol-keto structures
and equilibrium are illustrated below: ##STR10##
[0165] Tautomeric forms may be relevant to the attainment of the
optimal chemical reactivity and biological activity of a compound
of interest.
[0166] The compounds of this invention may possess one or more
asymmetric centers; such compounds can therefore be produced as
individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless
indicated otherwise, the description or naming of a particular
compound in the specification and claims is intended to include
both individual enantiomers and mixtures, racemic or otherwise,
thereof. The methods for the determination of stereochemistry and
the separation of stereoisomers are well-known in the art.
The Compounds
[0167] The present invention provides bicycloheteroaryl compounds
useful for preventing and/or treating a broad range of conditions,
associated with abnormalities in the activity of the P2X.sub.7
receptor, among them, rheumatoid arthritis, Parkinson's disease,
uveitis, asthma, cardiovascular conditions such as myocardial
infarction, the treatment and prophylaxis of pain syndromes (acute
and chronic or neuropathic), traumatic brain injury, acute spinal
cord injury, neurodegenerative disorders, inflammatory bowel
disease and immune dysfunctions such as autoimmune disorders or
conditions, in mammals.
[0168] In a first aspect of the invention, bicycloheteroaryl
compounds are disclosed that are capable of modulating the activity
of the P2X.sub.7 receptor in vivo, having a formula (I): ##STR11##
[0169] wherein [0170] A is selected from CR.sup.2'R.sup.2'', CO,
and CS; [0171] B is selected from CR.sup.2', CR.sup.2'R.sup.2'',
CO, and CS; [0172] Y is independently selected from CR.sup.2' and
CR.sup.2', R.sup.2''; [0173] W, W' and Z are independently selected
from CR.sup.4 and N, provided that all three of W, W' and Z can not
be N at the same time; [0174] L is a C.sub.1-C.sub.5 alkylene
group, heteroalkyl, 3 to 8 membered cycloalkyl or heterocycloalkyl,
alkylcycloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl group, which can be optionally substituted by
a substituent selected from hydroxyl, halogen and C.sub.1-C.sub.6
alkoxy; [0175] n is 1, 2 or 3; [0176] R.sup.1 is selected from a
3-13 membered cycloalkyl, heterocycloalkyl, aryl and heteroaryl
ring system, which can be optionally substituted with one or more
substituents independently selected from halo, hydroxyl, amino,
cyano, sulfo, sulfanyl, sulfinyl, amido, carboxy, ester, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, and sulfonamido; [0177] each of R.sup.2,
R.sup.2' and R.sup.2'' is independently selected from hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6 alkyl; or any of
R.sup.2' and R.sup.2'' can join together to form a cycloalkyl or
cycloheteroalkyl ring of 3-7 atoms; [0178] R.sup.3 is hydrogen or a
functional group selected from acyl, substituted acyl, substituted
or unsubstituted acylamino, substituted or unsubstituted
alkylamino, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl,
substituted or unsubstituted alkylarylamino, arylalkyloxy,
substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,
substituted or unsubstituted sulfoxide, substituted or
unsubstituted sulfone, substituted or unsubstituted sulfanyl,
substituted or unsubstituted aminosulfonyl, substituted or
unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl, substituted or
unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted
or unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; or R.sup.3 is
a 4-9 membered carbocyclic or heterocyclic ring which can be
optionally substituted with at least one substituent selected from
a R.sup.4 group; or the group "R.sup.3-L" is H; [0179] R.sup.4 is
selected from H, alkyl, substituted alkyl, acyl, substituted acyl,
substituted or unsubstituted acylamino, substituted or
unsubstituted alkylamino, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted
alkoxycarbonyl, substituted or unsubstituted alkylarylamino,
arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted
aryl, arylalkyl, substituted or unsubstituted sulfoxide,
substituted or unsubstituted sulfone, substituted or unsubstituted
sulfanyl, substituted or unsubstituted aminosulfonyl, substituted
or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl, substituted or
unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted
or unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; and the dotted
bond is a single or a double bond; [0180] or a pharmaceutically
acceptable salt, solvate or prodrug thereof, [0181] and
stereoisomers and tautomers thereof.
[0182] In another aspect the present invention provides
bicycloheteroaryl compounds bicycloheteroaryl compounds are
disclosed that are capable of modulating the activity of the
P2X.sub.7 receptor in vivo, having a formula (Ia): ##STR12## [0183]
wherein [0184] A is selected from CR.sup.2'R.sup.2'', CO, and CS;
[0185] B is selected from CR.sup.2', CR.sup.2'R.sup.2'', CO, and
CS; [0186] Y is independently selected from CR.sup.2' and
CR.sup.2', R.sup.2''; [0187] W, W' and Z are independently selected
from CR.sup.4 and N, provided that all three of W, W' and Z can not
be N at the same time; [0188] L is a C.sub.1-C.sub.5 alkylene
group, heteroalkyl, 3 to 8 membered cycloalkyl or heterocycloalkyl,
alkylcycloalkyl, alkylheterocycloalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl group, which can be optionally substituted by
a substituent selected from hydroxyl, halogen and C.sub.1-C.sub.6
alkoxy; [0189] n is 1, 2 or 3; [0190] R.sup.1 is selected from a
3-13 membered cycloalkyl, heterocycloalkyl, aryl and heteroaryl
ring system, which can be optionally substituted with one or more
substituents independently selected from halo, hydroxyl, amino,
cyano, sulfo, sulfanyl, sulfinyl, amido, carboxy, ester, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, and sulfonamido; [0191] each of R.sup.2,
R.sup.2' and R.sup.2'' is independently selected from hydrogen,
substituted or unsubstituted C.sub.1-C.sub.6 alkyl; or any of
R.sup.2 and R.sup.2 can join together to form a cycloalkyl or
cycloheteroalkyl ring of 3-7 atoms; [0192] R.sup.3 is hydrogen or a
functional group selected from acyl, substituted acyl, substituted
or unsubstituted acylamino, substituted or unsubstituted
alkylamino, substituted or unsubstituted alkylthio, substituted or
unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl,
substituted or unsubstituted alkylarylamino, arylalkyloxy,
substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,
substituted or unsubstituted sulfoxide, substituted or
unsubstituted sulfone, substituted or unsubstituted sulfanyl,
substituted or unsubstituted aminosulfonyl, substituted or
unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl, substituted or
unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted
or unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; or R.sup.3 is
a 4-9 membered carbocyclic or heterocyclic ring which can be
optionally substituted with at least one substituent selected from
a R.sup.4 group; or the group "R.sup.3-L" is H; [0193] R.sup.4 is
selected from H, alkyl, substituted alkyl, acyl, substituted acyl,
substituted or unsubstituted acylamino, substituted or
unsubstituted alkylamino, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkoxy, alkoxycarbonyl, substituted
alkoxycarbonyl, substituted or unsubstituted alkylarylamino,
arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted
aryl, arylalkyl, substituted or unsubstituted sulfoxide,
substituted or unsubstituted sulfone, substituted or unsubstituted
sulfanyl, substituted or unsubstituted aminosulfonyl, substituted
or unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl, substituted or
unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted
or unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; and the dotted
bond is a single or a double bond; or a pharmaceutically acceptable
salt, solvate or prodrug thereof, and stereoisomers and tautomers
thereof.
[0194] In a further embodiment as to compounds of formula I and Ia,
n may be 0.
[0195] In a further embodiment, with respect to compounds of
formula I and Ia, L may be a bond and R.sup.3 is selected from H,
acyl, substituted acyl, substituted or unsubstituted aminocarbonyl,
alkoxycarbonyl, substituted alkoxycarbonyl, substituted or
unsubstituted sulfoxide, substituted or unsubstituted sulfone,
substituted or unsubstituted aminosulfonyl, substituted or
unsubstituted arylsulfonyl, aryloxycarbonyl, substituted
aryloxycarbonyl, heteroaryloxycarbonyl, and substituted
heteroaryloxycarbonyl.
[0196] In a further embodiment, with respect to compounds of
formula I and Ia, L is L.sup.1; and wherein L.sup.1 is a bond,
--CO--, --SO.sub.2-- or a C.sub.1-C.sub.5 alkylene group which can
be optionally substituted by a substituent selected from alkyl,
hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, halogen, carbamoyl, and C.sub.1-C.sub.6 alkoxy.
In one particular embodiment, when A is CO or CS, L.sup.1 is a bond
or C.sub.1-C.sub.5 alkylene group.
[0197] In a further embodiment, with respect to compound of formula
I and Ia, L is L.sup.1; and wherein L.sup.1 is a bond, --CO--,
--SO.sub.2-- or a C.sub.1-C.sub.5 alkylene group; and R.sup.3 is
selected from hydrogen, substituted or unsubstituted alkyl,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted heterocycloalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted bicycloaryl, and substituted or unsubstituted
bicycloheteroaryl. In one particular embodiment, when R.sup.3 is
hydrogen, L.sup.1 is a bond or a C.sub.1-C.sub.5 alkylene
group.
[0198] In a further embodiment, with respect to compound of formula
I and Ia, A, B and Y may all represent CR.sup.2aR.sup.2b. In
another embodiment, A is CR.sup.2aR.sup.2b; and B and Y are
independently selected from CR.sup.2a and CR.sup.2aR.sup.2b.
[0199] In another aspect the present invention provides
bicycloheteroaryl compounds bicycloheteroaryl compounds are
disclosed that are capable of modulating the activity of the
P2X.sub.7 receptor in vivo, having a formula (II or IIa): ##STR13##
[0200] wherein [0201] A is selected from CR.sup.2aR.sup.2b; [0202]
B and Y are independently selected from CR.sup.2a and
C.sup.2aR.sup.2b; [0203] W, W' and Z are independently selected
from CR.sup.4 and N, provided that all three of W, W' and Z can not
be N at the same time; [0204] L.sup.1 is a bond, --CO--,
--SO.sub.2-- or a C.sub.1-C.sub.5 alkylene group which can be
optionally substituted by a substituent selected from alkyl,
hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, halogen, carbamoyl, and C.sub.1-C.sub.6 alkoxy;
[0205] n is 0, 1, 2 or 3; [0206] R.sup.1 is selected from a 3-13
membered cycloalkyl, heterocycloalkyl, aryl and heteroaryl ring
system, which can be optionally substituted with one or more
substituents independently selected from halo, hydroxyl, amino,
cyano, sulfo, sulfanyl, sulfinyl, amido, carboxy, ester, alkyl,
substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, and sulfonamido; [0207] each of R.sup.2,
R.sup.2a, R.sup.2b, R.sup.2' and R.sup.2'' is independently
selected from hydrogen, substituted or unsubstituted
C.sub.1-C.sub.6 alkyl; or any of R.sup.2 and R.sup.2 can join
together to form a cycloalkyl or cycloheteroalkyl ring of 3-7
atoms; [0208] R.sup.3 is selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
substituted or unsubstituted heterocycloalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
substituted or unsubstituted bicycloaryl, and substituted or
unsubstituted bicycloheteroaryl; [0209] R.sup.4 is selected from H,
alkyl, substituted alkyl, acyl, substituted acyl, substituted or
unsubstituted acylamino, substituted or unsubstituted alkylamino,
substituted or unsubstituted alkylthio, substituted or
unsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl,
substituted or unsubstituted alkylarylamino, arylalkyloxy,
substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,
substituted or unsubstituted sulfoxide, substituted or
unsubstituted sulfone, substituted or unsubstituted sulfanyl,
substituted or unsubstituted aminosulfonyl, substituted or
unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,
substituted or unsubstituted dihydroxyphosphoryl, substituted or
unsubstituted aminodihydroxyphosphoryl, azido, carboxy, substituted
or unsubstituted carbamoyl, cyano, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloheteroalkyl,
substituted or unsubstituted dialkylamino, halo, heteroaryloxy,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroalkyl, hydroxy, nitro, and thio; and the dotted
bond is a single or a double bond; [0210] or a pharmaceutically
acceptable salt, solvate or prodrug thereof, [0211] and
stereoisomers and tautomers thereof.
[0212] In one particular embodiment, with respect to compounds of
formula II and IIa, when R.sup.3 is hydrogen, L.sup.1 is a bond or
a C.sub.1-C.sub.5 alkylene group.
[0213] In a further embodiment, with respect to compounds of
formula II and IIa, A, B and Y may all represent CR.sup.2aR.sup.2b
and the dotted bond is a single bond.
[0214] In a further embodiment, with respect to compounds of
formula II and IIa, A is CR.sup.2aR.sup.2b; and B and Y each
represent CR.sup.2' and the dotted bond is a double bond.
[0215] In a further embodiment, with respect to compounds of
formula II and IIa, A, B and Y may all represent CH.sub.2 and the
dotted bond is a single bond.
[0216] In a further embodiment, with respect to compounds of
formula II and IIa, A is CH.sub.2; and B and Y each represent CH
and the dotted bond is a double bond.
[0217] In one embodiment, with respect to compounds of formula II
and IIa, W' is N.
[0218] In another embodiment, with respect to compounds of formula
II and IIa, W' is CR.sup.4.
[0219] In another embodiment, with respect to compounds of formula
II and IIa, W' is CR.sup.4' and R.sup.4' is selected from hydrogen,
halo, alkoxy, alkyl, and dialkylamino.
[0220] In another embodiment, with respect to compounds of formula
II and IIa, each of R.sup.2' and R.sup.2'' of the ##STR14## group
is H.
[0221] In another embodiment, with respect to compound of formula
II and IIa, wherein one of R.sup.2' and R.sup.2'' of the ##STR15##
group is Me and the other is H.
[0222] In another embodiment, with respect to compounds of formula
II and IIa, each of R.sup.2' and R.sup.2'' of the ##STR16## group
is Me.
[0223] In another embodiment, with respect to compounds of formula
II and IIa, n is 0 or 1. In one particular embodiment, n is 0. In
yet another particular embodiment, n is 1.
[0224] In another embodiment, with respect to compounds of formula
II and IIa, wherein the ##STR17## group is selected from
substituted or unsubstituted ##STR18##
[0225] In another embodiment, with respect to compound of formula
II and IIa, wherein the ##STR19## group is ##STR20## and wherein
R.sup.a, R.sup.b and R.sup.c are independently selected from H,
halo, hydroxyl, substituted hydroxyl, alkyl, substituted alkyl,
amino, substituted amino, aryl and substituted aryl.
[0226] In another embodiment, with respect to compounds of formula
II and IIa, the ##STR21## group is as described in the preceding
paragraph, and R.sup.a, R.sup.b and R.sup.c are independently
selected from H, Br, Cl, OH, Me, NHAc, Ph and F. In one particular
embodiment, each of R.sup.a, R.sup.b and R.sup.c is H.
[0227] In another aspect the present invention provides
bicycloheteroaryl compounds and bicycloheteroaryl compounds are
disclosed that are capable of modulating the activity of the
P2X.sub.7 receptor in vivo, and that have a formula (III, IIIa, IV
or IVa): ##STR22## wherein L.sup.1, R.sup.3, W. Z. W' and n are as
described for formula II or IIa; and wherein R.sup.a, R.sup.b and
R.sup.c are independently selected from H, halo, hydroxyl,
substituted hydroxyl, alkyl, substituted alkyl, amino, substituted
amino, aryl and substituted aryl.
[0228] In one embodiment, with respect to compounds of formulae
II-IVa, each of W. W' and Z is independently CR.sup.4.
[0229] In one embodiment, with respect to compounds of formulae
II-IVa, each of W. W' and Z is independently CH.
[0230] In one embodiment, with respect to compounds of formulae
II-IVa, W' is C-Me and W and Z both are CHs.
[0231] In one embodiment, with respect to compounds of formulae
II-IVa, W' is N and W and Z both are CR.sup.4s.
[0232] In one embodiment, with respect to compounds of formulae
II-IVa, W' is N and W and Z both are CHs.
[0233] In one embodiment, with respect to compounds of formulae
II-IVa, Z is CR.sup.4 and W and W' both are Ns.
[0234] In one embodiment, with respect to compounds of formulae
II-IVa, Z is CH and W and W' both are Ns.
[0235] In one embodiment, with respect to compounds of formulae
II-IVa, Z is N and W and W' both are CR.sup.4s.
[0236] In another aspect the present invention provides
bicycloheteroaryl compounds and bicycloheteroaryl compounds are
disclosed, that are capable of modulating the activity of the
P2X.sub.7 receptor in vivo, having a formula (V, Va, VI or VIa):
##STR23## and wherein L.sup.1, R.sup.3, Z, and n are as described
for formula II or IIa; and wherein R.sup.a, R.sup.b and R.sup.c are
independently selected from H, halo, hydroxyl, substituted
hydroxyl, alkyl, substituted alkyl, amino, substituted amino, aryl
and substituted aryl.
[0237] In one embodiment, with respect to compounds of formulae
II-VIa, n is 0.
[0238] In another embodiment, with respect to compounds of formulae
II-VIa, n is 1.
[0239] In one embodiment, with respect to compounds of formulae
II-VIa, each of R.sup.a, R.sup.b and R.sup.c is H.
[0240] In one embodiment, with respect to compounds of formulae
II-VIa, each of R.sup.a, R.sup.b and R.sup.c is Me.
[0241] In another embodiment, with respect to compounds of formulae
II-VIa, two of R.sup.a, R.sup.b and R.sup.c is Me.
[0242] In another embodiment, with respect to compounds of formulae
II-VIa, one of R.sup.a, R.sup.b and R.sup.c is OH.
[0243] In another embodiment, with respect to compounds of formulae
II-VIa, Z is CR.sup.4' and R.sup.4' is selected from hydrogen,
halo, alkoxy, alkyl, and dialkylamino,
[0244] In one embodiment, with respect to compounds of formulae
II-VIa, Ln is a bond and R.sup.3 is H.
[0245] In another embodiment, with respect to compounds of formulae
II-VIa, Ln is a C.sub.1-C.sub.5 alkylene group which can be
optionally substituted by a substituent selected from alkyl,
hydroxy, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, halogen, carbamoyl, and C.sub.1-C.sub.6 alkoxy;
and R.sup.3 is H.
[0246] In another embodiment, with respect to compounds of formulae
II-VIa, L.sup.1 is --CO--, or --SO.sub.2--.
[0247] In another embodiment, with respect to compounds of formulae
II-VIa, L.sup.1 is C.sub.1-C.sub.5 alkylene group which can be
optionally substituted by a substituent selected from alkyl,
hydroxy, hydroxyalkyl, amino alkyl, alkylaminoalkyl,
dialkylaminoalkyl, halogen, carbamoyl, and C.sub.1-6 alkoxy.
[0248] Further in accordance with compounds of formulae II-VIa,
L.sup.1 may be a substituted or unsubstituted C.sub.1-C.sub.6
alkylene group, and particularly, may be CH.sub.2,
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, or
--(CH.sub.2).sub.4--.
[0249] In one embodiment, with respect to compounds of formulae
II-VIa, R.sup.3 is substituted or unsubstituted alkyl.
[0250] In one particular embodiment, with respect to compounds of
formulae II-VIa, R.sup.3 is substituted alkyl; and the substitution
on alkyl is selected from aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, halo, alkoxy, hydroxy, cyano, and aryloxy. In
another particular embodiment, the substitution on alkyl is
selected from Ph, Cl, F, Br, CN, OH, OMe, OPh, CF.sub.3, CHF.sub.2,
OCF.sub.3, t-Bu, SMe, SOMe, SO.sub.2Me, SO.sub.3H, SO.sub.3Me,
pyridyl, cyclopropyl, cyclopentyl and cyclohexyl.
[0251] Still further in accordance with the invention, and with
respect to the compounds of formulae II-VIa, where present,
-L.sup.1-R.sup.3 may be selected from H, Me, Et, benzyl,
--(CH.sub.2).sub.3--OH, --(CH.sub.2).sub.4--NHMe,
--(CH.sub.2).sub.4--OH, --(CH.sub.2).sub.2--CH(OH)--CH.sub.2OH,
--(CH.sub.2).sub.4--CO.sub.2H, --(CH.sub.2).sub.4--NHEt,
--(CH.sub.2).sub.3--NHEt,
--(CH.sub.2).sub.2--NH--(CH.sub.2).sub.2OH,
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.3OH,
--(CH.sub.2).sub.4--NH.sub.2, --(CH.sub.2).sub.3--NHCONHSO.sub.2Me,
--(CH.sub.2).sub.3--NH--(CH.sub.2).sub.2--Me, or
--(CH.sub.2).sub.2CO.sub.2H.
[0252] In one embodiment, with respect to compounds of formulae
II-VIa, L.sup.1 is a --CO--, --SO.sub.2-- or a C.sub.1-C.sub.5
alkylene group and R.sup.3 is substituted or unsubstituted
aryl.
[0253] In one particular embodiment, with respect to compounds of
formulae II-VIa, L.sup.1 is a --CO--, --SO.sub.2-- or a
C.sub.1-C.sub.5 alkylene group and R.sup.3 is ##STR24## and wherein
n' is selected from 1-5 and each of R.sup.4' is independently
selected from hydrogen, alkyl, substituted alkyl, acyl, substituted
acyl, substituted or unsubstituted acylamino, substituted or
unsubstituted alkylamino, substituted or unsubstituted alkylthio,
substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl,
substituted alkoxycarbonyl, substituted or unsubstituted
alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino,
aryl, substituted aryl, arylalkyl, substituted or unsubstituted
sulfoxide, substituted or unsubstituted sulfone, substituted or
unsubstituted sulfanyl, substituted or unsubstituted aminosulfonyl,
substituted or unsubstituted arylsulfonyl, sulfuric acid, sulfuric
acid ester, substituted or unsubstituted dihydroxyphosphoryl,
substituted or unsubstituted aminodihydroxyphosphoryl, azido,
carboxy, substituted or unsubstituted carbamoyl, cyano, substituted
or unsubstituted cycloalkyl, substituted or unsubstituted
cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo,
heteroaryloxy, substituted or unsubstituted heteroaryl, substituted
or unsubstituted heteroalkyl, hydroxy, nitro, and thio.
[0254] In one particular embodiment, n' is 1, 2 or 3. In another
particular embodiment, n' is 1, or 2. In yet another particular
embodiment, n' is 1.
[0255] In one particular embodiment, each R.sup.4' is independently
selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OPh, COPh,
CF.sub.3, CHF.sub.2, OCF.sub.3, t-Bu, SMe, CH.dbd.CH--CO.sub.2H,
SOMe, SO.sub.2Me, SO.sub.3H, SO.sub.3Me, and pyridyl.
[0256] In one particular embodiment, with respect to compound of
formulae II-VIa, L.sup.1 is a --CO--, --SO.sub.2-- or a
C.sub.1-C.sub.5 alkylene group and R.sup.3 is substituted or
unsubstituted cycloalkyl, heterocycloalkyl, heteroaryl, bicycloaryl
or bicycloheteroaryl. In another particular embodiment, the
substitution is selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe,
OPh, COPh, CF.sub.3, CHF.sub.2, OCF.sub.3, t-Bu, SMe,
CH.dbd.CH--CO.sub.2H, SOMe, SO.sub.2Me, SO.sub.3H, and
SO.sub.3Me.
[0257] In one particular embodiment, with respect to compound of
formulae II-VIa, L.sup.1 is a --CO--, --SO.sub.2-- or a
C.sub.1-C.sub.5 alkylene group and R.sup.3 is substituted or
unsubstituted naphthalene, furanyl, thiophenyl, pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, quinoline,
isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
indolyl, benzopyranyl, benzofuranyl, benzoxazinyl, or
benzodioxanyl. In another particular embodiment, the substitution
is selected from Me, Et, Ph, Cl, F, Br, CN, OH, OMe, OPh, COPh,
CF.sub.3, CHF.sub.2, OCF.sub.3, t-Bu, SMe, CH.dbd.CH--CO.sub.2H,
SOMe, SO.sub.2Me, SO.sub.3H, and SO.sub.3Me.
[0258] In certain aspects, the present invention provides prodrugs
and derivatives of the compounds according to the formulae above.
Prodrugs are derivatives of the compounds of the invention, which
have metabolically cleavable groups and become by solvolysis or
under physiological conditions the compounds of the invention,
which are pharmaceutically active, in vivo. Such examples include,
but are not limited to, choline ester derivatives and the like,
N-alkylmorpholine esters and the like.
[0259] Other derivatives of the compounds of this invention have
activity in both their acid and acid derivative forms, but the acid
sensitive form often offers advantages of solubility, tissue
compatibility, or delayed release in the mammalian organism (see,
Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives well know to
practitioners of the art, such as, for example, esters prepared by
reaction of the parent acid with a suitable alcohol, or amides
prepared by reaction of the parent acid compound with a substituted
or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
Simple aliphatic or aromatic esters, amides and anhydrides derived
from acidic groups pendant on the compounds of this invention are
preferred prodrugs. In some cases it is desirable to prepare double
ester type prodrugs such as (acyloxy)alkyl esters or
((alkoxycarbonyl)oxy)alkylesters. Preferred are the C.sub.1 to
C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, aryl, C.sub.7-C.sub.12
substituted aryl, and C.sub.7-C.sub.12 arylalkyl esters of the
compounds of the invention.
Pharmaceutical Compositions
[0260] When employed as pharmaceuticals, the compounds of this
invention are typically administered in the form of a
pharmaceutical composition. Such compositions can be prepared in a
manner well known in the pharmaceutical art and comprise at least
one active compound.
[0261] Generally, the compounds of this invention are administered
in a pharmaceutically effective amount. The amount of the compound
actually administered will typically be determined by a physician,
in the light of the relevant circumstances, including the condition
to be treated, the chosen route of administration, the actual
compound-administered, the age, weight, and response of the
individual patient, the severity of the patient's symptoms, and the
like.
[0262] The pharmaceutical compositions of this invention can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular, and
intranasal. Depending on the intended route of delivery, the
compounds of this invention are preferably formulated as either
injectable or oral compositions or as salves, as lotions or as
patches all for transdermal administration.
[0263] The compositions for oral administration can take the form
of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the furansulfonic acid
compound is usually a minor component (from about 0.1 to about 50%
by weight or preferably from about 1 to about 40% by weight) with
the remainder being various vehicles or carriers and processing
aids helpful for forming the desired dosing form.
[0264] Liquid forms suitable for oral administration may include a
suitable aqueous or nonaqueous vehicle with buffers, suspending and
dispensing agents, colorants, flavors and the like. Solid forms may
include, for example, any of the following ingredients, or
compounds of a similar nature: a binder such as microcrystalline
cellulose, gum tragacanth or gelatin; an excipient such as starch
or lactose, a disintegrating agent such as alginic acid, Primogel,
or corn starch; a lubricant such as magnesium stearate; a glidant
such as colloidal silicon dioxide; a sweetening agent such as
sucrose or saccharin; or a flavoring agent such as peppermint,
methyl salicylate, or orange flavoring.
[0265] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As before, the active compound in such
compositions is typically a minor component, often being from about
0.05 to 10% by weight with the remainder being the injectable
carrier and the like.
[0266] Transdermal compositions are typically formulated as a
topical ointment or cream containing the active ingredient(s),
generally in an amount ranging from about 0.01 to about 20% by
weight, preferably from about 0.1 to about 20% by weight,
preferably from about 0.1 to about 10% by weight, and more
preferably from about 0.5 to about 15% by weight. When formulated
as a ointment, the active ingredients will typically be combined
with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream
with, for example an oil-in-water cream base. Such transdermal
formulations are well-known in the art and generally include
additional ingredients to enhance the dermal penetration of
stability of the active ingredients or the formulation. All such
known transdermal formulations and ingredients are included within
the scope of this invention.
[0267] The compounds of this invention can also be administered by
a transdermal device. Accordingly, transdermal administration can
be accomplished using a patch either of the reservoir or porous
membrane type, or of a solid matrix variety.
[0268] The above-described components for orally administrable,
injectable or topically administrable compositions are merely
representative. Other materials as well as processing techniques
and the like are set forth in Part 8 of Remington's Pharmaceutical
Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,
which is incorporated herein by reference.
[0269] The compounds of this invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can be found in Remington's Pharmaceutical Sciences.
[0270] The following formulation examples illustrate representative
pharmaceutical compositions of this invention. The present
invention, however, is not limited to the following pharmaceutical
compositions.
Formulation 1
Tablets
[0271] A compound of the invention is admixed as a dry powder with
a dry gelatin binder in an approximate 1:2 weight ratio. A minor
amount of magnesium stearate is added as a lubricant. The mixture
is formed into 240-270 mg tablets (80-90 mg of active amide
compound per tablet) in a tablet press.
Formulation 2
Capsules
[0272] A compound of the invention is admixed as a dry powder with
a starch diluent in an approximate 1:1 weight ratio. The mixture is
filled into 250 mg capsules (125 mg of active amide compound per
capsule).
Formulation 3
Liquid
[0273] A compound of the invention (125 mg), sucrose (1.75 g) and
xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S.
sieve, and then mixed with a previously made solution of
microcrystalline cellulose and sodium carboxymethyl cellulose
(11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color
are diluted with water and added with stirring. Sufficient water is
then added to produce a total volume of 5 mL.
Formulation 4
Tablets
[0274] A compound of the invention is admixed as a dry powder with
a dry gelatin binder in an approximate 1:2 weight ratio. A minor
amount of magnesium stearate is added as a lubricant. The mixture
is formed into 450-900 mg tablets (150-300 mg of active amide
compound) in a tablet press.
Formulation 5
Injection
[0275] A compound of the invention is dissolved or suspended in a
buffered sterile saline injectable aqueous medium to a
concentration of approximately 5 mg/ml.
Formulation 6
Topical
[0276] Stearyl alcohol (250 g) and a white petrolatum (250 g) are
melted at about 75.degree. C. and then a mixture of a compound of
the invention (50 g) methylparaben (0.25 g), propylparaben (0.15
g), sodium lauryl sulfate (10 g), and propylene glycol (120 g)
dissolved in water (about 370 g) is added and the resulting mixture
is stirred until it congeals.
Methods of Treatment
[0277] The present compounds are used as therapeutic agents for the
treatment of conditions in mammals that are causally related or
attributable to aberrant activity of the P2X.sub.7 receptor.
Accordingly, the compounds and pharmaceutical compositions of this
invention find use as therapeutics for preventing and/or treating
autoimmune, inflammatory and cardiovascular conditions in mammals
including humans.
[0278] In a method of treatment aspect, this invention provides a
method of treating a mammal susceptible to or afflicted with a
condition associated with arthritis, uveitis, asthma, myocardial
infarction, traumatic brain injury, acute spinal cord injury,
inflammatory bowel disease and autoimmune disorders, which method
comprises administering an effective amount of one or more of the
pharmaceutical compositions just described.
[0279] In yet another method of treatment aspect, this invention
provides a method of treating a mammal susceptible to or afflicted
with a condition that gives rise to pain responses or that relates
to imbalances in the maintenance of basal activity of sensory
nerves. The present amines have use as analgesics for the treatment
of pain of various geneses or etiology, for example acute,
inflammatory pain (such as pain associated with osteoarthritis and
rheumatoid arthritis); various neuropathic pain syndromes (such as
post-herpetic neuralgia, trigeminal neuralgia, reflex sympathetic
dystrophy, diabetic neuropathy, Guillian Barre syndrome,
fibromyalgia, phantom limb pain, post-masectomy pain, peripheral
neuropathy, HIV neuropathy, and chemotherapy-induced and other
iatrogenic neuropathies); visceral pain, (such as that associated
with gastroesophageal reflex disease, irritable bowel syndrome,
inflammatory bowel disease, pancreatitis, and various gynecological
and urological disorders), dental pain and headache (such as
migraine, cluster headache and tension headache).
[0280] In additional method of treatment aspects, this invention
provides methods of treating a mammal susceptible to or afflicted
with neurodegenerative diseases and disorders such as, for example
Parkinson's disease, multiple sclerosis; diseases and disorders
which are mediated by or result in neuroinflammation such as, for
example traumatic brain injury, and encephalitis;
centrally-mediated neuropsychiatric diseases and disorders such as,
for example depression mania, bipolar disease, anxiety,
schizophrenia, eating disorders, sleep disorders and cognition
disorders; epilepsy and seizure disorders; prostate, bladder and
bowel dysfunction such as, for example urinary incontinence,
urinary hesitancy, rectal hypersensitivity, fecal incontinence,
benign prostatic hypertrophy and inflammatory bowel disease;
respiratory and airway disease and disorders such as, for example,
allergic rhinitis, asthma and reactive airway disease and chronic
obstructive pulmonary disease; diseases and disorders which are
mediated by or result in inflammation such as, for example
rheumatoid arthritis and osteoarthritis, myocardial infarction,
various autoimmune diseases and disorders, uveitis and
atherosclerosis; itch/pruritus such as, for example psoriasis;
obesity; lipid disorders; cancer; blood pressure; spinal cord
injury; and renal disorders method comprises administering an
effective condition-treating or condition-preventing amount of one
or more of the pharmaceutical compositions just described.
[0281] As a further aspect of the invention there is provided the
present amine compounds for use as a pharmaceutical especially in
the treatment or prevention of the aforementioned conditions and
diseases. We also provide use of a present amine compound in the
manufacture of a medicament for the treatment or prevention of one
of the aforementioned conditions and diseases.
[0282] Injection dose levels range from about 0.1 mg/kg/hour to at
least 10 mg/kg/hour, all for from about 1 to about 120 hours and
especially 24 to 96 hours. A preloading bolus of from about 0.1
mg/kg to about 10 mg/kg or more may also be administered to achieve
adequate steady state levels. The maximum total dose is not
expected to exceed about 2 g/day for a 40 to 80 kg human
patient.
[0283] For the prevention and/or treatment of long-term conditions,
such as neurodegenerative and autoimmune conditions, the regimen
for treatment usually stretches over many months or years so oral
dosing is preferred for patient convenience and tolerance. With
oral dosing, one to five and especially two to four and typically
three oral doses per day are representative regimens. Using these
dosing patterns, each dose provides from about 0.01 to about 20
mg/kg of the compound of the invention, with preferred doses each
providing from about 0.1 to about 10 mg/kg and especially about 1
to about 5 mg/kg.
[0284] Transdermal doses are generally selected to provide similar
or lower blood levels than are achieved using injection doses.
[0285] When used to prevent the onset of a neurodegenerative,
autoimmune or inflammatory condition, the compounds of this
invention will be administered to a patient at risk for developing
the condition, typically on the advice and under the supervision of
a physician, at the dosage levels described above. Patients at risk
for developing a particular condition generally include those that
have a family history of the condition, or those who have been
identified by genetic testing or screening to be particularly
susceptible to developing the condition.
[0286] The compounds of this invention can be administered as the
sole active agent or they can be administered in combination with
other agents, including other compounds that demonstrate the same
or a similar therapeutic activity, and that are determined to safe
and efficacious for such combined administration.
General Synthetic Procedures
[0287] The bicycloheteroaryl compounds of this invention can be
prepared from readily available starting materials using the
following general methods and procedures. It will be appreciated
that where typical or preferred process conditions (i.e., reaction
temperatures, times, mole ratios of reactants, solvents, pressures,
etc.) are given, other process conditions can also be used unless
otherwise stated. Optimum reaction conditions may vary with the
particular reactants or solvent used, but such conditions can be
determined by one skilled in the art by routine optimization
procedures.
[0288] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art. For example, numerous
protecting groups, and their introduction and removal, are
described in T. W. Greene and P. G. M. Wuts, Protecting Groups in
Organic Synthesis, Second Edition, Wiley, New York, 1991, and
references cited therein.
[0289] The following schemes are presented with details as to the
preparation of representative bicycloheteroaryls that have been
listed hereinabove. The compounds of the invention may be prepared
from known or commercially available starting materials and
reagents by one skilled in the art of organic synthesis.
[0290] The intermediate heteroaryl amines, heteroaryl acids, acid
chlorides (Intermediate 1-16) can be obtained using synthetic
methods given below.
Intermediate 1
Preparation of
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine a)
7-Benzyl-5,6,7,8-tetrahydropyrido[3,4d]pyrimidin-4(3H)-one
hydrochloride
[0291] ##STR25##
[0292] Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (30 g, 101
mmol) was combined with formamidine aceate (10.5 g, 101 mmol) and
EtOH (450 mL) in a 2-liter flask. The resulting mixture was stirred
at 0.degree. C. and treated with NaOEt (21% in EtOH) (112.6 mL, 299
mmol). The reaction was heated at 60.degree. C. overnight and
monitored for completion via lcms and TLC (DCM:MeOH:: 95:5).
Additional ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (2 g, 6.6
mmol) was added after 12 h with continued heating at 60.degree. C.
The reaction was complete after 4 h as indicated by LCMS. The
cooled reaction was reduced in vacuo and the residue was treated
concentrated HCl (300 mL) and stirred overnight at room
temperature. The solvents were removed under vacuum and the
resulting solids treated with EtOH (300 mL), stirred for 15
minutes, and then filtered. The mother liquor was discarded and the
precipitate dried in a vacuum oven affording
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol (44 g) as
the tri-HCl salt which was used directly in the next step.
[0293] LCMS (ESI.sup.+) m/z 242.2 [M+H].sup.+
[0294] .sup.1H NMR (300 MHz CD.sub.3OD) .delta. 7.98 (s, 1H),
7.35-7.32 (m, 5H), 3.72 (s, 2H), 3.41-3.40 (m, 2H), 2.75 (t 2H),
2.57 (m, 2H).
b) 7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
[0295] ##STR26##
[0296] 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol.HCl
(35.5 g, 0.101 mol) was added in a 250 ml round bottom flask,
equipped with a reflux condenser, followed by the addition of
POCl.sub.3 (100.5 g, 0.655 mol). The resulting mixture was refluxed
for 4 h under argon, cooled to room temperature, and diluted with
DCM (200 mL). The crude reaction was then poured into ice-cold
water (200 mL) and stirred overnight at 0.degree. C. The layers
were separated and the pH of aqueous layer was carefully adjusted
to 7 via the addition of satd. NaHCO.sub.3. The aqueous layer was
extracted with DCM (3.times.100 mL) and the combined organics
washed with satd. NaHCO.sub.3 (50 mL), dried over anhyd.
Na.sub.2SO.sub.4, and reduced in vacuo to yield
7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine as a
viscous dark brown oil (21 g, 80%).
[0297] LCMS (ESI.sup.+) m/z 260.1 [M+H].sup.+
[0298] .sup.1H NMR (300 MHz CD.sub.3OD) .delta. 8.68 (s, 1H),
7.36-7.29 (m, 5H), 3.75 (s, 2H), 3.65 (s, 2H), 2.86 (s, 4H).
c) 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine
[0299] ##STR27##
[0300] 7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
(9.83 g, 38 mmol) was dissolved in solution of NH.sub.3 in MeOH
(7N, 60 mL) in a re-sealable tube. The sealed tube was heated at
100.degree. C. for 21 h. The reaction was cooled to room
temperature and kept standing at room temperature for 48 h which
led to the precipitation of the desired product
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine.(5.1 g,
56%). The mother liquor was evaporated and dried under vacuum to
yield a mixture of 4.12 g of desired product together with the side
product
7-benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.
[0301] LCMS (ESI.sup.+) m/z 241.3 [M+H].sup.+
[0302] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.33 (s, 1H), 7.28
(m, 5H), 4.86 (br `s`, 2H), 3.69 (s, 2H), 3.55 (s, 2H), 2.79 (t,
2H), 2.48 (t, 2H).
[0303] .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 161.2, 161.1,
155.8, 137.6, 129.3, 128.6, 127.5, 110.2, 62.6, 57.6, 49.5,
23.2.
Intermediate 2
Preparation of
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-aceta-
mide Method A
Representative Synthesis of Compound 5
a)
2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin--
4-yl)-acetamide
[0304] ##STR28##
[0305] To a solution of
7-benzyl-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine and
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (1.2 g, 5
mmol (based on 5)) in THF (15 mL) was added NaH (60% in mineral
oil) (0.04 g, 1.67 mmol) and the resulting mixture was stirred for
1 h. 1-adamant-1-yl-acetyl chloride (1.11 g, 0.86 mmol) was then
added to the reaction mixture and the reaction stirred at room
temperature for 18 h. The reaction was monitored by LCMS and
treated with an additional amount each of NaH (0.3 g) and
1-adamant-1-yl-acetyl chloride (0.3 g). Upon completion the
reaction mixture was treated with saturated. NaHCO.sub.3 (50 mL)
and extracted with EtOAc (2.times.50 ml). The combined organics
were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated to yield
2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimi-
din-4-yl)-acetamide (2.06 g)
[0306] LCMS (ESI.sup.+) m/z 417.5 [M+H].sup.+
[0307] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.68 (s, 1H), 7.50
(s, 1H), 7.30 (m, 5H), 3.70 (s, 4H), 2.74 (s, 4H), 2.30 (s, 2H),
1.98 (br `s`, 3H), 1.65 (m, 12H).
b) Representative Synthesis of Compound 6
2-Adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-acetam-
ide
[0308] ##STR29##
[0309] To a solution of
2-adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4--
yl)-acetamide in glacial acetic acid (15 mL) in a 250 ml round
bottom flask was added 10% Pd/C (0.45 g). The resulting mixture was
stirred for 15 h under an atmosphere of hydrogen (via a balloon),
which was introduced after evacuation of air from the reaction
vessel. The reaction was then filtered over celite, washed with
EtOAc (20 mL) and the filtrate concentrated under reduced pressure.
The residue was re-dissolved on EtOAc (50 mL) and stirred with aq.
10% NaOH solution (50 mL) for 1 h. The layers were separated and
the aqueous layer washed with EtOAc (5.times.50 mL). The combined
organics were dried over anhyd. Na.sub.2SO.sub.4, filtered and
concentrated to yield
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-aceta-
mide (0.68 g, 2.1 mmol, 87%) as a tan colored solid.
[0310] LCMS (ESI.sup.+) m/z 327.3 [M+H].sup.+
[0311] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 8.70 (s, 1H), 7.73
(s, 1H), 4.06 (s, 2H), 3.13 (t, J=5.7 Hz, 2H), 2.66 (t, 2H), 2.29
(s, 2H), 1.99 (br s, 3H), 1.71 (m, 12H).
Intermediate 3
Preparation of (3,5-Dimethyl-adamantan-1-yl)-acetyl chloride
[0312] ##STR30##
(3,5-Dimethyl-adamantan-1-yl)-acetic acid
[0313] The bromide (24.32 g, 100 mmol) in dichloroethane was added
into 90% H.sub.2SO.sub.4 solution at 10.degree. C. (cold water
bath). The reaction mixture was stirred at 10.degree. C. for 1 hr.
Then BF.sub.3 etherate (2.84 g, 20 mmol) was added dropwise in 30
minutes via a syringe. The reaction mixture was stirred at
10-15.degree. C. for 2 more hours with additional BF.sub.3 etherate
was added until complete consumption of the starting bromide before
pouring onto ice. The water was adjusted to pH=9 followed by
extraction with ether. The aqueous layer was acidified with HCl to
pH=3 followed by extraction with ether, dried, removal of organic
solvent to give solid product, which was taken on directly to the
next step.
[0314] .sup.1HNMR (300 MHz, CD.sub.3Cl.sub.3), 2.13 (s, 2H), 1.74
(s, 1H), 1.02-1.38 (m, 12H), .delta. 0.82(s, 6H), ##STR31##
(3,5-Dimethyl-adamantan-1-yl)-acetyl chloride
[0315] Into a flask containing 3,5-dimethyl-adamantan-1-yl)-acetic
acid in toluene (50 ml) was added SOCl.sub.2 and 1 drop of DMF.
Reaction was then heated to 60.degree. C. for 1 hour. After removal
of solvent and co-evaporation with toluene (2 ml), the crude
product was used without further purification.
Intermediate 4
Preparation of (3,5,7-Trimethyl-adamantan-1-yl)-acetyl chloride
[0316] ##STR32##
[0317] 3,5,7-trimethyl adamantane-1-carboxylic acid was converted
to it's acid chloride per the procedure described for
3,5-dimethyl-adamantan-1-yl)-acetic acid. It was then homologated
to the corresponding benzyl ester via the procedure described in
Tetrahedron Letters, 1980, 21, 4461-4462. The benzyl ester was
converted to the acid by standard hydrogenation conditions of 10%
Pd/C in MeOH/EtOAc::1:1. The acid was then converted to the acid
chloride via standard treatment with thionyl chloride at reflux for
1 to 2 hours. Excess reagent was azeotropically removed with
hexanes and the resulting acid chloride was used without further
purification.
Intermediate 5
Preparation of 2-Adamantan-1-yl-2-methyl-propionyl chloride
[0318] ##STR33##
2-Adamantan-1-yl-2-methyl-propionic acid methyl ester
[0319] The methyl ester was prepared via the route described in
Tetrahedron Letters, 1978, 17, 1455-1458. Thus 1-bromoadamantane
(6.17 g, 28.7 mmol),
(1-methoxy-2-methylprop-1-enyloxy)-trimethylsilane (5.5 g, 31.6
mmol), and ZnCl.sub.2 (300 mg) in DCM (40 ml) was stirred at rt for
3 days. The reaction was monitored for the disappearance of the
bromide by LCMS and worked up according to the literature
reference.
2-Adamantan-1-yl-2-methyl-propionic acid
[0320] The methyl ester was dissolved in DMSO (15 ml) and treated
with NaSMe (6.654 g, 9.3 mmol, 2 equiv.) and heated at 80.degree.
C. for 3 h. The reaction was cooled to room temperature and treated
with 100 ml of water, extracted with Et.sub.2O and the layers were
then separated. The aqueous layer was acidified to ph 3 to give
1.07 g of 2-Adamantan-1-yl-2-methyl-propionic acid as a white
solid.
2-Adamantan-1-yl-2-methyl-propionyl chloride
[0321] 2-Adamantan-1-yl-2-methyl-propionyl chloride was prepared
via treatment with SOCl.sub.2 at reflux for 1 to 2 h. Excess
reagent was removed under reduced pressure and the mixture
azeotroped with hexanes and the resulting acid chloride was used
without further purification in the next step.
Intermediate 6 and 7
Preparation of
2-Methyl-2-(3,5,7-trimethyl-adamantan-1-yl)-propionyl chloride and
2-(3,5-dimethyl-adamantan-1-yl)-2-methyl-propionyl chloride
[0322] ##STR34##
[0323] Prepared in an analogous manner to that for
2-Adamantan-1-yl-2-methyl-propionyl chloride, Intermediate 5.
Method B
Representative synthesis of Compound 341
N-(7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-2-(3,5-dimethy-
l-adamantan-1-yl)-acetamide
[0324] ##STR35##
[0325] The reaction was performed in DMF under an inert atmosphere
as follows:
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (30 mg,
0.012 mmol) in 1 ml of DMF was treated with 15 mg of NaH and the
result stirred at rt for 10 minutes. 40 uL intermediate 3 was added
and stirring continued for 1 h at rt. After quenching with water (8
ml) and Satd. NaHCO.sub.3 (10 ml) the resulting mixture was
extracted with Et.sub.2O. The combined organics were concentrated
under reduced pressure to give the crude product, which was
purified by HPLC to give the pure product (19 mg, 0.042 mmol) in a
35% yield.
Representative Synthesis of Compound 334
Adamantane-1-carboxylic acid
(7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide
[0326] ##STR36##
[0327] In a 20 ml microwave vessel was added
7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-ylamine (1.5
g, 6.3 mmole) in 7.0 ml of chloroform, diisopropylethylamine (2.2
ml, 12.6 mmole) and 1-adamantane carbonylchloride (2.51 g, 12.6
mmole). The reaction was heated at 160.degree. C. for 7.0 minutes
in a microwave. After completion the solvent was evaporated and the
residue was dissolved in EtOAc and washed with sat. NaHCO.sub.3,
washed with brine and dried over sodium sulphate. The solvents were
removed under reduced pressure and the residue was chromatographed
using chloroform (100%) to give the desired product as a white
solid (1.06 g).
[0328] ESI-MS m/z 403 [M+H].sup.+.
[0329] The following examples were prepared in a manner analogous
to that given for Method A or Method B using
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine and the
appropriate intermediate acid or acid chloride as listed in the
table below.
Compound 9
[0330] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
cyclohexylacetyl chloride.
Compound 10
[0331] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
cycloheptylacetyl chloride.
Compound 24
[0332] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
3-(3-methoxyphenyl)propanoyl chloride.
Compound 339
[0333] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
Intermediate 5.
Compound 341
[0334] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
Intermediate 3.
Compound 343
[0335] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
Intermediate 7.
Compound 344
[0336] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
Intermediate 4.
Compound 345
[0337] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
Intermediate 6.
Compound 346
[0338] Prepared by reacting
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with
3,5,7-trimethyl-adamantane-1-carbonyl chloride.
[0339] The following examples were prepared by debezylation of the
corresponding N-benzyl derivatives and in a manner analogous to
that given for the preparation of
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-aceta-
mide (Compound 6).
Compound 11
[0340] Prepared by debenzylation of Compound 9.
Compound 12
[0341] Prepared by debenzylation of Compound 10.
Compound 25
[0342] Prepared by debenzylation of Compound 24.
Intermediate 8
2-Adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-isobut-
yramide
[0343] Prepared by debenzylation of Compound 339.
Intermediate 9
2-(3,5-Dimethyl-adamantan-1-yl)-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimid-
in-4-yl)-acetamide
[0344] Prepared by debenzylation of Compound 341
Intermediate 10
Preparation of Adamantane-1-carboxylic acid
(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide
[0345] ##STR37##
[0346] Adamantane-1-carboxylic acid
(7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide
(1.1 g, 2.64 mmole) was suspended in 30 ml of methanol. To the
mixture was added palladium hydroxide on carbon (20% wt, 0.41 g)
and the reaction was shaken under 60 PSI of hydrogen gas for 16
hrs. The mixture was filtered through celite and the filtrate was
concentrated to give the desired product as an off white solid (0.8
g).
[0347] ESI-MS m/z 313 [M+H].sup.+.
General methods for the preparation of substituted
5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl acetamides
Method C
[0348] Representative Synthesis of Compound 46 ##STR38##
[0349]
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl-
)-acetamide (0.05 g, 0.153 mmol) and
2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (0.0504 g, 0.306
mmol) in DCE (1 mL) was treated with NaBH(OAc).sub.3 (0.065 g,
0.306 mmol) and the resulting mixture agitated overnight at room
temperature. The crude reaction was purified by HPLC affording the
desired compound.
[0350] LCMS (ESI.sup.+) m/z 474.9 [M+H].sup.+
[0351] NMR (300 MHz, CD.sub.3OD): .delta. 8.65 (s, 1H), 6.86-6.79
(m, 3H), 4.21 (s, 4H), 3.62 (m, 4H), 2.76 (s, 4H), 2.22 (s, 2H),
1.97 (br s, 3H), 1.74-1.64 (m, 12H).
[0352] The reductive alkylation products with other aldehydes and
ketones to obtain specified examples in Table 1A-1E were obtained
in an analogous manner by using
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-aceta-
mide, or the appropriate corresponding amine (0.05 g, 0.153 mmol)
and 2 mmol of the corresponding aldehyde or ketone and reducing
agent.
Method D
Representative Example
Compound 361
[0353] ##STR39##
[0354] To a solution of
1,1-dimethyl-2-adamantyl-N-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-
)acetamide (29 mg, 0.082 mmol) in anhydrous dichloroethane (2 mL)
was added diisopropylethylamine (0.04 mL, 0.24 mmol) and
2,6-difluorobenzoyl chloride (21.7 mg, 0.12 mmol) at room
temperature. After stirring at room temperature for 5 h, the
reaction was quenched with water (0.5 mL) and evaporated to
dryness. The dry residue was purified by prep-HPLC directly and
afforded desired product.
[0355] LCMS (ESI.sup.+) m/z 495.3 [M+H].sup.+
[0356] NMR (300 MHz, CDCl.sub.3): .delta. 8.80 (s, 0.5H), 8.72 (s,
0.5H), 7.64 (m, 1H), 7.37 (m, 1H), 6.97 (m, 2H), 5.01 (s, 1H), 4.56
(s, 1H), 4.04 (t, 1H), 3.57 (t, 1H), 2.85 (t, 1H), 2.75 (t, 1H),
2.03 (br m, 3H), 1.57-1.73 (m, 12H), 1.27 (s, 3H), 1.24 (s,
3H).
[0357] Specific representative examples of N-benzoyl and N-sulfonyl
derivatives of
1,1-dimethyl-2-adamantyl-N-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-
)acetamide given in Table 1A-1E can be or were prepared in an
analogous manner by using either
1,1-dimethyl-2-adamantyl-N-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl-
)acetamide (29 mg, 0.082 mmol) or
2-(3,5-dimethyl)adamantyl-N-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-y-
l)acetamide (26 mg, 0.073 mmol), and 0.12 mmol of the corresponding
acyl chlorides and sulfonyl chlorides.
Method E
A parallel synthetic method for N-benzoylation of
2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-y-
l)acetamide
[0358] Representative synthesis of Compound 220 ##STR40##
[0359] In one well of a 96-well polypropylene reaction plate was
added
2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-y-
l)acetamide (3.27 mg, 10 .mu.mol) in 100 .mu.l of anhydrous
chloroform. To the reaction was added benzoyl chloride (2.1 mg, 15
.mu.mol), followed by diisopropylethylamine (5.2 mg, 40 .mu.mol).
The reaction plate was heated at 50.degree. C. for 15 minutes and
the solvent was evaporated. The residue was dissolved in DMSO and
purified using LC-MS based purification.
[0360] ESI-MS m/z 431 [M+H].sup.+.
[0361] Specified examples of Table 1A-1E compounds were prepared in
an analogous manner using the appropriate acyl chloride
Method F
A parallel synthetic method for N-Sulphonylation of
2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8tetrahydropyrido[3,4-d]pyrimidin-4-yl-
)acetamide
Representative Example
Compound 143
[0362] ##STR41##
[0363] In one well of a 96-well polypropylene reaction plate was
added
2-2-Adamantan-1-yl-N-(7-benzenesulfonyl-5,6,7,8-tetrahydropyrido[3,4-d]py-
rimidin-4-yl)acetamide (3.27 mg, 10 .mu.mol) in 100 .mu.l of
anhydrous chloroform. To the reaction was added benzenesulphonyl
chloride (2.64 mg, 15 .mu.mol), followed by diisopropylethylamine
(5.2 mg, 40 .mu.mol). The reaction plate was heated at 50.degree.
C. for 15 minutes and the solvent was evaporated. The residue was
dissolved in DMSO and purified using LC-MS based purification
[0364] ESI-MS m/z 467 [M+H].sup.+.
[0365] Specified examples of Table 1A-1E compounds were prepared in
an analogous manner using the appropriate sulphonyl chloride.
Method G
A parallel synthetic method for N-benzylation of
2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-y-
l)acetamide
Representative Example
Compound 5
[0366] ##STR42##
[0367] In a 2.0 ml-wave vessel was added
2-Adamantan-1-yl-N-(7-benzenesulfonyl-5,6,7,8-tetrahydropyrido[3,4-d]pyri-
midin-4-yl)acetamide (3.27 mg, 10 mol) in 600 .mu.l of absolute
ethanol. To the reaction was added benzaldehyde (2.1 mg, 15 mol),
followed by acetic acid (60 l) and silica bound sodium
cyanoborohydride (15 mg, 15 mol). The reaction was heated at
120.degree. C. for 5 minutes and the solvent was evaporated. The
residue was dissolved in DMSO and purified using LC-MS based
purification.
[0368] ESI-MS m/z 417 [M+H].sup.+.
[0369] Specified examples of Table 1A-1E compounds were prepared in
an analogous manner using the appropriate aldehyde
Method H
A parallel synthetic method for N-benzoylation of
Adamantane-1-carboxylic acid
(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide
Representatitive Example
Compound 394
[0370] ##STR43##
[0371] In one well of a 96-well polypropylene reaction plate was
added adamantane-1-carboxylic acid
(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide (3.12 mg, 10
.mu.mol) in 100 .mu.l of anhydrous chloroform. To the reaction was
added benzoyl chloride (2.1 mg, 15 .mu.mol), followed by
diisopropylethylamine (5.2 mg, 40 .mu.mol). The reaction plate was
heated at 50.degree. C. for 15 minutes and the solvent was
evaporated. The residue was dissolved in DMSO and purified using
LC-MS based purification.
[0372] ESI-MS m/z 417 [M+H].sup.+.
[0373] Specified examples of Table 1A-1E compounds were prepared in
an analogous manner using the appropriate acyl chloride
Method I
A parallel synthetic method for N-Sulphonylation of
Adamantane-1-carboxylic acid
(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide
Representative Example
Compound 481
[0374] ##STR44##
[0375] In one well of a 96-well polypropylene reaction plate was
added 2-adamantane-1-carboxylic acid
(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide (3.12 mg, 10
.mu.mol) in 100 .mu.l of anhydrous chloroform. To the reaction was
added benzenesulphonyl chloride (2.64 mg, 15 .mu.mol), followed by
diisopropylethylamine (5.2 mg, 40 .mu.mol). The reaction plate was
heated at 50.degree. C. for 15 minutes and the solvent was
evaporated. The residue was dissolved in DMSO and purified using
LC-MS based purification.
[0376] ESI-MS m/z 453 [M+H].sup.+.
[0377] Specified examples of Table 1A-1E compounds were prepared in
an analogous manner using the appropriate sulphonyl chloride.
Method J
A parallel synthetic method for N-benzylation of
Adamantane-1-carboxylic acid
(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide
Representative Example
Compound 334
[0378] ##STR45##
[0379] In a 2.0 ml microwave vessel was added
adamantane-1-carboxylic acid
(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amide (3.12 mg, 10
.mu.mol) in 600 .mu.l of absolute ethanol. To the reaction was
added benzaldehyde (2.1 mg, 15 .mu.mol), followed by acetic acid
(60 .mu.l) and silica bound sodium cyanoborohydride (15 mg, 15
.mu.mol). The reaction was heated at 120.degree. C. for 5 minutes
and the solvent was evaporated. The residue was dissolved in DMSO
and purified using LC-MS based purification
[0380] ESI-MS m/z 403 [M+H].sup.+.
[0381] Specified examples of Table 1A-1E compounds were prepared in
an analogous manner using the appropriate aldehyde.
Intermediate 11
Preparation of
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylic
acid
a)
7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carbonitrile
[0382] ##STR46##
[0383] Four 10-20 mL microwave vials were each charged with
7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (1 g, 4
mmol), Pd((PPh.sub.3).sub.4 (500 mg, 0.4 mmol) and Zn(CN).sub.2
(300 mg, 2 mmol) were suspended in dry DMF (7 mL). These sealed
suspensions were then heated at 160.degree. C. for 50 min in a
microwave reactor. After cooling the reaction mixture an aliquot
was taken and the sample tested by LCMS. The reaction showed 100%
conversion of
7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine to
desired product. The crude reaction mixtures were poured into water
(200 mL), resulting in the precipitation of a brown solid, which
was filtered and dried. The aqueous filtrate was extracted with DCM
(2.times.100 mL). The organic layer was filtered through a Horizon
Technology DryDisk and concentrated. The crude solids and oil were
purified via column chromatography first with DCM/MeOH (20:1) of
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carbonitrile.
(2.1 g, 55%)
[0384] ESI-MS m/z 251.3 [M+H].sup.+.
[0385] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.99 (s, 1H),
7.4-7.3 (m, 5H), 3.79 (s, 2H), 3.73 (s, 2H), 3.05 (t, 2H), 2.91 (t,
2H).
b) Methyl
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylate
[0386] ##STR47##
[0387]
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carbonitrile
(2.1 g, 8.38 mmol) was dissolved in satd. solution of HCl MeOH (15
mL) in a microwave tube. The vial was heated in a microwave reactor
at 70.degree. C. for 1 h. The reaction was cooled and depressurized
and concentrated under reduced pressure. The crude oil was
dissolved in MeOH followed by removal of MeOH under reduced
pressure to assist with the remove of excess HCl. The red-brown oil
was dissolved in minimal amount of water (10 mL) and added to an
ice cold sat. NaHCO.sub.3 solution (200 mL). The aqueous layer was
extracted with DCM (3.times.100 mL). The combined organic layers
were then filtered through a Horizon Technologies DryDisk and
concentrated. The resulting red-brown oil was purified by flash
chromatographed using DCM/MeOH (20:1) as elutant. The pure
fractions were combined, treated with norite, filtered through a
pad of celite and the filtrate concentrated to afford methyl
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylate
(1.01 g, 42.3%.)
[0388] ESI-MS m/z 284.3 [M+H].sup.+.
[0389] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.94 (s, 1H),
7.4-7.3 (m, 5H), 3.96 (s, 3H), 3.76 (s, 2H), 3.73 (s, 2H), 3.15 (t,
2H), 2.82 (t, 2H),
c) 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylic
acid
[0390] ##STR48##
[0391] Methyl
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylate
(0.2 g, 0.705 mmol) was dissolved in MeOH (10 mL). 10% NaOH
solution (1.5 mL) was added. The solution was heated at 85.degree.
C. for 1 h. Solvent was removed under reduced pressure. The
aqueous. layer was acidified to ca. pH 4. The aqueous layer was
then extracted with DCM (2.times.50 mL) to remove organic
impurities. The acidic aqueous layer was dried on the lyophilizer.
The resulting solids were washed with MeOH (10 mL) and filtrate
concentrated to give
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-carboxylic
acid (0.173 g, 0.642 mmol, 91%) as a brown oil. The resulting
product was used without further purification.
[0392] ESI-MS m/z 270.3 [M+H].sup.+.
[0393] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.75 (s, 1H),
7.4-7.3 (m, 5H), 3.74 (s, 2H), 3.65 (s, 2H), 3.00 (t, 2H), 2.82 (t,
2H).
Preparation of Compound 17
7-Benzyl-N-adamantylmethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-car-
boxamide
[0394] ##STR49##
[0395] In a 2-dram vial, intermediate 11 (0.5 g, 1.85 mmol) was
dissolved in DMF (1 mL) with 1-adamantyl methylamine (0.37 g, 2.24
mmol) and HATU (1.2 g, 2.8 mmol) followed by DIEA (300 .mu.L, 2.79
mmol) was added to the mixture. The vial was sealed and placed on
an orbital shaker for 16 h. The reaction mixture was diluted with
DCM (50 mL). The organic layer was washed with sat. NaHCO.sub.3
solution (1.times.25 mL) and water (1.times.25 mL). The organic
layer was filtered through a Horizon Technologies DryDisk and
concentrated. The crude product was purified by column
chromatography to afford
7-benzyl-N-adamantylmethyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4-ca-
rboxamide (0.048 g 6.2%) which was taken on to the next step
without further purification.
[0396] ESI-MS m/z 417.1 [M+H].sup.+.
[0397] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.91 (s, 1H),
7.4-7.3 (m, 5H), 3.75 (s, 2H), 3.7 (s, 2H), 3.25 (t, 2H), 3.08 (s,
2H), 2.81 (t, 2H), 1.98 (s, 3H), 1.78-1.6 (m, 12H).
Intermediate 12
Preparation of 1-(aminomethyl)-3,3-dimethylcyclohexanol
hydrochloride
[0398] ##STR50##
[0399] Prepared by standard LAH reduction in THF at 0.degree. C.
using 1.49 g (9.74 mmol) of
1-hydroxy-3,3-dimethylcyclohexanecarbonitrile and 740 mg (19.48
mmol) of LAH. The mixture was stirred at room temperature
overnight. The mixture was quenched with 740 ul of water and 740 ul
of 15% methanol in water, stirred for 2 hours and then filterered.
The filtrate was washed with EtOAc, concentrated under reduced
pressure and dried under high vacuum. The dark viscous oil was
taken up in 50 ml of EtOAc and was treated with 20 ml of 4M HCl
solution in 1,4-dioxane followed by 10% MeOH and then heated to
ensure dissolution. Upon cooling to room temperature followed by
further cooling to -78.degree. C. 1 g (73%) of the recrystallized
HCl salt of 1-(aminomethyl)-3,3-dimethylcyclohexanol was
obtained.
Intermediates 13, 14 and 15
Preparation of 1-(aminomethyl)cycloheptanol,
(1-p-tolylcyclohexyl)methanamine and cycloheptylmethanamine
[0400] ##STR51##
[0401] The title intermediates were prepared in an analogous manner
to that for 1-(aminomethyl)-3,3-dimethylcyclohexanol using the
appropriate nitrile.
Preparation of Compounds 1, 4, 58, 59 and 60 and 1:
[0402] The title compounds were prepared in a manner analogous to
that given for Compound 17 using the Intermediate 11 and the
appropriate amine.
Intermediate 16
Preparation of
5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-4-carboxylic acid
(adamantan-1-ylmethyl)-amide
[0403] ##STR52##
[0404] In a round bottom flask,
7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-4-carboxylic
acid(adamantan-1-ylmethyl)-amide (1.15 g, 2.74 mmol) was dissolved
in glacial acetic acid (10 mL) with stirring and 10% Pd/C (417 mg)
was added. The suspension was stirred under an atmosphere of
H.sub.2 for 16 h. By LCMS and TLC (DCM:MeOH::20:1), no starting
material appeared to be present. The desired m/z was observed at
327.3 (M+H). The reaction mixture was then filtered through a pad
of celite. The filtrate was concentrated. The resulting oil was
re-dissolved in EtOAc (50 mL) with stirring. A 10% NaOH solution
(50 mL) was added. The mixture was stirred at RT for 1 h. The
layers were separated and the aqueous layer was extracted with
EtOAc (3.times.50 mL). The combined organic layers were filtered
through a Horizon Technologies DryDisk and concentrated. The crude
oil was chromatographed using DCM/MeOH (0-30% gradient) as elutant
affording 0.133 g of the title compound.
[0405] ESI-MS m/z 327.3 [M+H].sup.+.
[0406] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.96 (s, 1H), 4.13
(s, 2H), 3.3-3.2 (m, 4H), 3.07 (s, 2H), 1.98 (s, 3H), 1.79-1.6 (m,
12H).
Preparation of Compounds 2 and 3
[0407] The title compounds were prepared in a manner analogous to
that given for intermediate 16 using Compounds 4 and 1 as starting
materials, respectively.
Method K
[0408] General procedure for the N-benzylation of
5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidine-4-carboxylic acid
(adamantan-1-ylmethyl)-amide
Preparation of a representative example Compound 137
[0409] ##STR53##
[0410] In a 2-dram vial, a solution of
5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidine-4-carboxylic acid
(adamantan-1-ylmethyl)-amide (0.44 g, 0.134 mmol) in DCE was added
followed by 2,4-difluorbenzaldehyde (0.26 g, 0.18 mmol). The
solution was placed on an orbital shaker at room temperature for 1
h. Sodium triacetoxyborohydride (0.43 g, 0.2 mmol) was added. The
mixture was agitated for an additional 16 h at room temperature.
LCMS and TLC (DCM:MeOH::20:1), indicated that no starting material
remained. The reaction was quenched by the addition of MeOH (0.5
mL). The mixture was then filtered through a pad of celite. The pad
was subsequently washed with MeOH (2 mL). The filtrate was
concentrated and the crude solid was purified via HPLC to yield the
title compound (0.0166 g) as a yellow oil.
[0411] ESI-MS m/z 453.3 [M+H].sup.+.
[0412] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.92 (s, 1H), 7.51
(q, 2H), 6.97, (t, 1H), 3.81 (s, 2H), 3.38 (s, 2H), 3.25 (t, 2H),
3.23 (s, 2H), 2.84 (t, 2H), 1.98 (s, 3H), 1.79-1.6 (m, 12H).
[0413] Specified examples of Table 1A-1E compounds were prepared
from 5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-4-carboxylic acid
(adamantan-1-ylmethyl)-amide, and Compound 2 in an analogous manner
using the appropriate aldehyde. Preparation of a Representative
Example Compound 13 ##STR54##
[0414] A solution of
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-aceta-
mide (0.1 g, 0.306 mmol) and 2-Methoxymethyl-oxirane (0.035 g,
0.398 mmol) in i-PrOH (5 mL) was stirred at 60.degree. C. for 20 h.
The reaction vessel was allowed to cool to room temperature,
opened, and the volatiles were removed under reduced vacuum. The
crude product was purified by HPLC to afford
2-adamantan-1-yl-N-[7-(2-hydroxy-3-methoxy-propyl)-5,6,7,8-tetr-
ahydro-pyrido[3,4-d]pyrimidin-4-yl]-acetamide (Compound 13) (0.0134
g, 0.032 mmol, 100%) in 100% purity as determined by LCMS. ESI-MS
m/z 415.5 [M+H].sup.+.
[0415] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.71 (s, 1H),
7.88 (s, 1H), 3.99 (m, 1H), 3.86 (d, 1H), 3.71 (d, 1H), 3.46 (m,
2H), 3.40 (s, 3H), 2.94 (m, 1H), 2.76 (m, 3H), 2.70-2.55 (m, 2H),
2.28 (s, 2H), 1.99 (br s, 3H), 1.74-1.65 (m, 12H). Preparation of a
Representative Example Compound 23 ##STR55##
[0416]
2-Adamantan-1-yl-N-[7-(2,3-dihydroxy-propyl)-5,6,7,8-tetrahydro-py-
rido[3,4-d]pyrimidin-4-yl]-acetamide was synthesized from
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-aceta-
mide (0.05 g, 0.153 mmol) and glycidol (0.015 g, 0.2 mmol) in
i-PrOH (3 mL) in a manner analogous to the preparation of Compound
13. Preparative TLC purification using DCM/MeOH/TEA (10:1:1))
afforded the desired product (0.0074 mg, 12%).
[0417] ESI-MS m/z 401.3 [M+H].sup.+. Preparation of a
Representative Example Compound 19 ##STR56##
[0418] A solution of
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-aceta-
mide (0.05 g, 0.153 mmol), 3-bromo-1-propanol (0.021 g, 0.15 mmol)
and DIPEA (0.045 g, 0.35 mmol) in EtOH (4 mL) was stirred at
75.degree. C. for 17 h. The reaction vessel was allowed to cool to
room temperature, opened, and the volatiles were removed on a
rotary evaporator. The residue was redissolved in THF (3 mL).
PL-NCO resin (300 mg) was added, and the resulting suspension was
stirred at room temperature for 16 h. The resin was filtered and
the volatiles were removed under vacuum. The crude product was
purified by HPLC to afford
2-adamantan-1-yl-N-[7-(3-hydroxy-propyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]-
pyrimidin-4-yl]-acetamide (0.0098 g, 17%).
[0419] ESI-MS m/z 385.5 [M+H].sup.+.
[0420] .sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.71 (s, 1H),
7.65 (s, 1H), 3.82 (t, 2H), 3.75 (s, 2H), 2.86-2.75 (m, 6H), 2.30
(s, 2H), 1.99 (br's', 3H), 1.83 (m, 2H), 1.74-1.60 (m, 12H).
[0421] The title compound was prepared in a manner analogous to
that given for Compound 21 using the appropriate starting material.
Preparation of a Representative Example Compound 18 ##STR57##
[0422]
2-Adamantan-1-yl-N-[7-(2-hydroxy-ethyl)-5,6,7,8-tetrahydro-pyrido[-
3,4-d]pyrimidin-4-yl]-acetamide was synthesized from
2-adamantan-1-yl-N-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-aceta-
mide (0.05 g, 0.153 mmol), 2-bromoethanol (0.019 g, 0.15 mmol) and
DIPEA (0.052 g, 0.4 mmol) in EtOH (4 mL) in a manner analogous to
compound 21 The crude reaction was purified by HPLC affording the
desired product (0.0064 g, 0.017 mmol, 12%).
[0423] ESI-MS m/z 371.3 [M+H].sup.+.
Preparation of a Representative Example Compound 22
[0424] The title compound was prepared in a manner analogous to
that given for Compound 21 using the appropriate starting
materials.
Preparation of
7-Benzyl-3-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic
acid (adamantan-1-ylmethyl)-amide (Compound 368)
[0425] ##STR58##
[0426] A solution of O-aminocrotononitrile (12 g, 147 mmol) and
NEt.sub.3 (37 mL, 266 mmol) in CH.sub.2Cl.sub.2 (150 mL) was cooled
with an ice bath to 0.degree.. TiCl.sub.4 (7.9 mL, 72 mmol) in
CH.sub.2Cl.sub.2 (100 mL) was added slowly with stirring followed
by N-benzyl-4-piperidone (21.4 mL, 120 mmol) in one portion. The
mixture was stirred for 24 h at ambient temperature and the
volatiles were removed under reduced pressure. Ethyl ether (400 mL)
was added, and the resulting mixture was stirred vigorously until
the residue was ground to a fine powder. The powder was filtered
off and washed with ethyl ether (400 mL) and evaporation of the
solvent afforded
(E)-3-amino-2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-but-2-enenitrile
as an oil (20 g, 70%), which was used without further
purification.
[0427] To a solution of
(E)-3-amino-2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-but-2-enenitrile
(15 g, 0.056 mole) in dichloromethane (200 mL), freshly prepared
benzotriazol-1-ylmethylene-dimethyl-ammonium chloride (12 g, 0.068
mole) was added in one portion. The mixture was stirred for 24 h at
ambient temperature. NaOH (2N, 200 mL) was added, and the resulting
mixture was stirred vigorously for 5 min. The phases were separated
and the aqueous phase was extracted with dichloromethane (100 mL).
The combined organic phases were dried over magnesium sulfate, and
the solvent was removed in vacuo. The crude product was purified by
column chromatography to give
7-benzyl-3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile
as a colorless oil (8.9 g, 53% yield).
[0428] .sup.1H NMR (CDCl.sub.3) .delta. 8.28 (s, 1H), 7.36-7.31 (m,
5H), 3.72 (s, 2H), 3.59 (s, 2H), 3.01 (t, 2H), 2.80 (t, 2H), 2.71
(s, 3H)
Preparation of
7-benzyl-3-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic
acid amide
[0429] ##STR59##
[0430] NaOH (9.1 mg, 2.24 mmol) was added to 0.5 ml of EtOH, which
contained 30 mg (0.114 mmol) of the nitrile and the resulting
mixture was heated at 100.degree. C. overnight. The mixture was
acidified by concentrated HCl to pH>2 and extracted with
dichloromethane. The pH of the aqueous layer was then adjusted to 7
and extracted with dichlormethane. The combined DCM layers were
washed with brine, dried, and concentrated under reduced pressure
to afford the crude product, which was purified by column
chromatography using MeOH:DCM (3-25%) to afford the pure product
(22 mg, 0.078 mmol) in a 69% yield.
Preparation of
7-benzyl-3-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carboxylic
acid (adamantan-1-ylmethyl)-amide
[0431] ##STR60##
[0432]
7-benzyl-5,6,7,8-tetrahydro-3-methyl-2,7-naphthyridine-4-carboxami-
de (40 mg, 0.142 mmol) was taken up in anhydrous DMF (0.5 ml) under
an inert atmosphere. NaH (60% in mineral oil) (6.8 mg, 0.17 mmol)
was added to the reaction vessel and the mixture stirred for 30
minutes until the evolution of hydrogen gas ceased. To this mixture
was added 1-adamantylmethylbromide in DMF (0.5 ml) and reaction was
stirred at room temperature for 4 hr. The reaction was monitored by
TLC and LCMS. Excess NaH and I-adamantylmethylbromide and heated
from 40 to 75.degree. C. for 3 days. The mixture was cooled to room
temperature, and added to ice water. The aqueous layer was
extracted with EtOAc, washed with water, brine, dried over sodium
sulfate, and reduced in vacuo. The crude was purified by flash
chromatography followed by prep. TLC using MeOH:DCM (5-10%) to
afford the title compound. (5 mg, 8%).
Preparation of
2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro-[1,7]
naphthyridin-4-yl)-acetamide (Compound 342)
[0433] ##STR61##
Preparation of
5-amino-1-benzyl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid
ethyl ester
[0434] Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (25 g, 83.96
mM) and ammonium acetate (32.36 g, 419.79 mM) in MeOH (250 mL) were
agitated overnight. The mixture was concentrated, the crude product
was dissolved in methylene chloride and washed sequentially with
aqueous saturated potassium carbonate solution and water. The
organic was dried and reduced in vacuo to yield the title compound
(24.0 g, 110%, higher yield possibly due to accluded solvents) as
an oil which solidified on standing.
Preparation of
7-benzyl-4-hydroxy-5,6,7,8-tetrahydro-[1,7]naphthyridine-3-carboxylic
acid methyl ester
[0435] ##STR62##
[0436] To a suspension of NaOtBu (4.23 g, 34.57 mM) in THF (50 mL)
was added a mixture of ethyl
3-amino-1-benzyl-1,2,5,6-tetrahydropyridine-4-carboxylate (3.0 g,
11.52 mM) and methyl 3,3-dimethoxypropanoate (5.12 g, 34.57 mM) in
THF (20 mL) in one portion and the mixture was agitated at ambient
temperature overnight. The mixture was concentrated to half the
volume before being quenched with ice-cold water. The homogeneous
solution was extracted ethyl ether and the aqueous layer was
carefully acidified with HCl until acidic. The precipitate was
filtered, washed with water, and dried under vacuum to obtain the
title compound as an off-white solid (1.6 g, 47%).
Preparation of 7-benzyl-4-hydroxy-5,6,7,8-tetrahydro-[1,7]
naphthyridine-3-carboxylic acid
[0437] ##STR63##
[0438] In a round bottom flask,
7-Benzyl-4-hydroxy-5,6,7,8-tetrahydro-[1,7]naphthyridine-3-carboxylic
acid methyl ester (56 mg) was dissolved in methanol (15 mL) and a
10% NaOH solution in water (5 mL) was added with stirring. The
mixture was heated at reflux for 2 hours, reduced in vacuo, and the
aqueous remainder was acidified with 1N HCl. The aqueous layer was
extracted with dichloromethane. The aqueous layer was concentrated
to give 0.06 grams of the product as its hydrochloride salt after
drying.
d) 7-Benzyl-5,6,7,8-tetrahydro-[1,7] naphthyridin-4-ol
[0439] ##STR64##
[0440]
7-Benzyl-4-hydroxy-5,6,7,8-tetrahydro-[1,7]naphthyridine-3-carboxy-
lic acid (0.025 g, 0.089 mmol) in 2 ml of 1-PrOH and column packed
with Cu(0) was heated to 270.degree. C. under 1000 psi in a
continuous flow reactor. The flow rate was adjusted to 1.5
.mu.l/min. After cooling, filtering, and washing with methanol the
filtrate was concentrated to afford 50 mg (0.208 mmol) of the
desired product.
[0441] ESI-MS m/z 241.1 [M+H].sup.+.
Preparation of
7-benzyl-4-chloro-5,6,7,8-tetrahydro-[1,7]naphthyridine
[0442] ##STR65##
[0443] 7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-4-ol (0.1 g,
0.417 mmol) in 3 ml of POCl.sub.3 was refluxed for 40 minutes. LCMS
indicated complete coversion to the desired product. The excess
POCl.sub.3 was removed under reduced pressure and taken on to the
next step without further purification.
[0444] ESI-MS m/z 259.5 [M+H].sup.+.
Preparation of 4-Azido-7-benzyl-5,6,7,8-tetrahydro-[1,7]
naphthyridine
[0445] ##STR66##
[0446] 7-Benzyl-4-chloro-5,6,7,8-tetrahydro-[1,7]naphthyridine
(0.417 mmol) was treated with 5 equiv. of NaN.sub.3 (135 mg) in DMF
(0.5 ml) and heated to 70.degree. C. for 4 h. The residue was
dissolved on 50 ml of DCM and washed with brine. The organic layer
was concentrated to afford a black oil, which was purified by
column chromatography to afford the desired azide (61 mg), which
was used directly in the next step.
[0447] ESI-MS m/z 266.5 [M+H]
7-Benzyl-5,6,7,8-tetrahydro-[1,7] naphthyridin-4-ylamine
[0448] ##STR67##
[0449] 4-azido-7-benzyl-5,6,7,8-tetrahydro-1,7-naphthyridine (0.06
g, 0.226 mmol) was treated with 0.5 g of PS--PPh.sub.3 resin in a 8
ml mixture THF:H.sub.2O (18:1) at 32.degree. C. ON. *The reaction
was monitored by LCMS and TLC. The reaction mixture was filtered
and washed with THF and methanol. The combined filtrate was
concentrated and used directly in the next step. ESI-MS m/z 240.3
[M+H].sup.+.
Preparation of
2-Adamantan-1-yl-N-(7-benzyl-5,6,7,8-tetrahydro-[1,7]
naphthyridin-4-yl)-acetamide (Compound 342)
[0450] ##STR68##
[0451] 7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-4-ylamine (48
mg, 0.202 mmol) in 6 ml of dioxane was treated with NMM (22 .mu.l,
0.202 mmol) followed by adamantan-1-yl-acetyl chloride (0.043 g,
0.202 mmol) and stirred at rt under argon. The reaction was
monitored by TLC and LCMS. Excess acid chloride was added and the
reaction was stirred. The contents were concentrated and purified
by HPLC to afford the desired product (3.3 mg, 4%).
[0452] ESI-MS m/z 416.7 [M+H].sup.+.
Exemplary Compounds of the Invention
[0453] In addition to the compounds exemplified above, the
following compounds recited below in Tables 1A-1E, which comprise
various substituted amides of this invention, are prepared or can
be prepared using the procedure and synthetic schemes described
above, or some modification thereof, and the corresponding starting
materials, appropriate reagents, and purification methods known to
those skilled in the art. Modifications of the methods described
herein are within the scope of the invention and will be obvious to
one of skill in the art. TABLE-US-00001 TABLE 1A Adamantane
Substituted Amide Compounds ##STR69## ID L.sup.1 R.sup.3a R.sup.3b
R.sup.3c R.sup.3d R.sup.3e n R.sup.2' R.sup.2'' RR.sup.a R.sup.b
R.sup.c 5 CH.sub.2 H H H H H 1 H H H H H 15 CH.sub.2 H H MeO.sub.2S
H H 1 H H H H H 27 CH.sub.2 Cl H H H H 1 H H H H H 28 CH.sub.2 F H
H H H 1 H H H H H 29 CH.sub.2 MeO H H H H 1 H H H H H 30 CH.sub.2
MeO H MeO H H 1 H H H H H 31 CH.sub.2 Me H H H H 1 H H H H H 32
CH.sub.2 Me H H Me H 1 H H H H H 33 CH.sub.2 H F H H H 1 H H H H H
34 CH.sub.2 H Cl H H H 1 H H H H H 35 CH.sub.2 H MeO H H H 1 H H H
H H 36 CH.sub.2 H MeO MeO H H 1 H H H H H 37 CH.sub.2 H MeO H MeO H
1 H H H H H 38 CH.sub.2 H Me H H H 1 H H H H H 39 CH.sub.2 H Me MeO
H H 1 H H H H H 40 CH.sub.2 H H MeO H H 1 H H H H H 41 CH.sub.2 H H
Cl H H 1 H H H H H 42 CH.sub.2 H H CN H H 1 H H H H H 44 CH.sub.2 H
H Me H H 1 H H H H H 45 CH.sub.2 H H C.sub.2H.sub.5 H H 1 H H H H H
47 CH.sub.2 F H F H H 1 H H H H H 62 CH.sub.2 H H AcNH H H 1 H H H
H H 65 CH.sub.2 H H 2-Pyridyl H H 1 H H H H H 68 CH.sub.2 H PhO H H
H 1 H H H H H 70 CH.sub.2 H CF.sub.3 H H H 1 H H H H H 71 CH.sub.2
H H t-Bu H H 1 H H H H H 72 CH.sub.2 H H CF.sub.3 H H 1 H H H H H
74 CH.sub.2 H H CF.sub.3O H H 1 H H H H H 75 CH.sub.2 H H PhO H H 1
H H H H H 76 CH.sub.2 CF.sub.3O H H H H 1 H H H H H 77 CH.sub.2
OCHF.sub.2 H H H H 1 H H H H H 78 CH.sub.2 H H OCHF.sub.2 H H 1 H H
H H H 84 CH.sub.2 H CN F H H 1 H H H H H 85 CH.sub.2 H F Me H H 1 H
H H H H 86 CH.sub.2 H Me F H H 1 H H H H H 87 CH.sub.2 F Me H H Cl
1 H H H H H 88 CH.sub.2 Cl Me H H F 1 H H H H H 89 CH.sub.2 H H
N(Me)- H H 1 H H H H H CH.sub.2CH.sub.2OH 91 CH.sub.2 H H
OCH.sub.2CONH.sub.2 H H 1 H H H H H 92 CH.sub.2 H H H H
C.sub.2H.sub.4NO.sub.2 1 H H H H H 95 CH.sub.2 F H MeO H H 1 H H H
H H 96 CH.sub.2 CF.sub.3 H H F H 1 H H H H H 97 CH.sub.2 H F
CF.sub.3 H H 1 H H H H H 98 CH.sub.2 H H 1-imidazolyl H H 1 H H H H
H 99 CH.sub.2 H H OCH.sub.2CH.sub.2OH H H 1 H H H H H 100 CH.sub.2
OCH.sub.2CH.sub.2OH H H H H 1 H H H H H 101 CH.sub.2 H
OCH.sub.2CH.sub.2OH H H H 1 H H H H H 102 CH.sub.2 MeO H H F H 1 H
H H H H 103 CH.sub.2 H MeO F H H 1 H H H H H 104 CH.sub.2 F H H MeO
H 1 H H H H H 106 CH.sub.2 H CF.sub.3 F H H 1 H H H H H 107
CH.sub.2 CF.sub.3 H F H H 1 H H H H H 108 CH.sub.2 H CF.sub.3 H F H
1 H H H H H 109 CH.sub.2 H CF.sub.3 H H F 1 H H H H H 110 CH.sub.2
F H CF.sub.3 H H 1 H H H H H 111 CH.sub.2 CF.sub.3 H H H F 1 H H H
H H 113 CH.sub.2 H H O-isoPr H H 1 H H H H H 114 CH.sub.2 H
CF.sub.3O H H H 1 H H H H H 115 CH.sub.2 H H CH.dbd.CHCO.sub.2H H H
1 H H H H H 116 CH.sub.2 H H MeS H H 1 H H H H H 117 CH.sub.2 H MeO
HO H H 1 H H H H H 119 CH.sub.2 H F MeO H H 1 H H H H H 120
CH.sub.2 CF.sub.3 H H H H 1 H H H H H 123 CH.sub.2 H H F H H 1 H H
H H H 131 CH.sub.2 F CF.sub.3 H H H 1 H H H H H 140 CH.sub.2 H H
OCH.sub.2CO.sub.2H H H 1 H H H H H 141 CH.sub.2 H H H H OCH.sub.2 1
H H H H H CO.sub.2H 143 SO.sub.2 H H H H H 1 H H H H H 144 SO.sub.2
H H Me H H 1 H H H H H 149 SO.sub.2 H H MeO H H 1 H H H H H 150
SO.sub.2 H H Cl H H 1 H H H H H 151 SO.sub.2 H H MeO MeO H 1 H H H
H H 152 SO.sub.2 H H F H H 1 H H H H H 154 SO.sub.2 H H H CF.sub.3
H 1 H H H H H 155 SO.sub.2 H H Cl Cl H 1 H H H H H 156 SO.sub.2 H H
CF.sub.3O H H 1 H H H H H 161 SO.sub.2 H H H CF.sub.3O H 1 H H H H
H 162 SO.sub.2 H H H MeO H 1 H H H H H 165 SO.sub.2 H H CN H Cl 1 H
H H H H 166 SO.sub.2 H H H H F 1 H H H H H 167 SO.sub.2 H H CN H H
1 H H H H H 168 SO.sub.2 H H H Cl H 1 H H H H H 172 SO.sub.2 H H
O-2-pyridyl H H 1 H H H H H 173 SO.sub.2 H H O-3-pyridyl H H 1 H H
H H H 174 SO.sub.2 H H O-3-pyridyl H H 1 H H H H H 175 SO.sub.2 H H
O-(4-MeOPh) H H 1 H H H H H 176 SO.sub.2 H H O-(3,4-diClPh) H H 1 H
H H H H 177 SO.sub.2 H H O-(4-CF.sub.3Ph) H H 1 H H H H H 178
SO.sub.2 H H H (3,4-di H 1 H H H H H ClPh)O 179 SO.sub.2 H H
4-MeOPh H H 1 H H H H H 181 SO.sub.2 Cl H H CF.sub.3 H 1 H H H H H
190 SO.sub.2 H H OCHF.sub.2 H H 1 H H H H H 191 SO.sub.2 H H PhO H
H 1 H H H H H 192 SO.sub.2 H H H H Cl 1 H H H H H 193 SO.sub.2 H H
F Cl H 1 H H H H H 194 SO.sub.2 H H H H C.sub.6H.sub.5 1 H H H H H
195 SO.sub.2 H H H H CF.sub.3 1 H H H H H 196 SO.sub.2 H H
1-pyrazolyl H H 1 H H H H H 197 SO.sub.2 H H MeO H MeO 1 H H H H H
199 SO.sub.2 H H H H Me 1 H H H H H 201 SO.sub.2 H H CF.sub.3 H H 1
H H H H H 202 SO.sub.2 H H Cl H F 1 H H H H H 203 SO.sub.2 F H H F
H 1 H H H H H 204 SO.sub.2 Cl H H Cl H 1 H H H H H 205 SO.sub.2 F H
H Cl H 1 H H H H H 206 SO.sub.2 F H H H F 1 H H H H H 207 SO.sub.2
H H Me Cl H 1 H H H H H 208 SO.sub.2 H Cl H Cl H 1 H H H H H 209
SO.sub.2 H H F H F 1 H H H H H 210 SO.sub.2 Cl H H H Cl 1 H H H H H
211 SO.sub.2 H H F H Cl 1 H H H H H 212 SO.sub.2 Me H H F H 1 H H H
H H 214 SO.sub.2 H Me H H MeO 1 H H H H H 215 SO.sub.2 H H H F H 1
H H H H H 216 SO.sub.2 MeO H H MeO H 1 H H H H H 217 SO.sub.2 H Me
H Me H 1 H H H H H 218 CO Cl H H H Cl 1 H H H H H 220 CO H H H H H
1 H H H H H 221 CO H H C.sub.6H.sub.5 H H 1 H H H H H 226 CO H H Cl
H H 1 H H H H H 227 CO H F H H H 1 H H H H H 228 CO H H CF.sub.3O H
H 1 H H H H H 229 CO H H C.sub.2H.sub.5 H H 1 H H H H H 230 CO H Me
H H H 1 H H H H H 232 CO H F F H H 1 H H H H H 233 CO H CF.sub.3 H
H H 1 H H H H H 234 CO H H MeO H H 1 H H H H H 242 CO H CN H H H 1
H H H H H 243 CO H H CF.sub.3 H H 1 H H H H H 245 CO H Cl Cl H H 1
H H H H H 246 CO H MeO H MeO H 1 H H H H H 247 CO F H H H F 1 H H H
H H 250 CO H MeO H H H 1 H H H H H 251 CO H H F H H 1 H H H H H 253
CO H Cl H H H 1 H H H H H 257 CO H H CN H H 1 H H H H H 258 CO Cl H
Cl H H 1 H H H H H 266 CO F H CF.sub.3 H H 1 H H H H H 267 CO H
CF.sub.3 H F H 1 H H H H H 268 CO CF.sub.3O H H H H 1 H H H H H 269
CO H CF.sub.3O H H H 1 H H H H H 270 CO CF.sub.3 H H H H 1 H H H H
H 271 CO H CF.sub.3 H H Cl 1 H H H H H 272 CO F H H H Cl 1 H H H H
H 275 CO MeO H MeO H H 1 H H H H H 277 CO F H F H H 1 H H H H H 278
CO Me H H H H 1 H H H H H 279 CO F H H F H 1 H H H H H 280 CO F H H
H H 1 H H H H H 282 CO Cl Cl H H H 1 H H H H H 291 CO H H Me H H 1
H H H H H 292 CO MeO H H H H 1 H H H H H 294 CO Cl H H H H 1 H H H
H H 301 CO H H t-Bu H H 1 H H H H H 310 CO H F MeO H H 1 H H H H H
312 CO H MeO MeO H H 1 H H H H H 314 CO Cl H H F H 1 H H H H H 315
CO H Cl H Cl H 1 H H H H H 319 CH.sub.2 H H Cl H Cl 1 H H H H H 320
CH.sub.2 H H Me H Me 1 H H H H H 322 CH.sub.2 H H F F H 1 H H H H H
323 CH.sub.2 H H F Cl H 1 H H H H H 324 CH.sub.2 H H MeO Cl H 1 H H
H H H 325 CH.sub.2 H H Cl CF.sub.3 H 1 H H H H H 326 CH.sub.2 H H F
H Cl 1 H H H H H 327 CH.sub.2 H H CF.sub.3 H CF.sub.3 1 H H H H H
328 CH.sub.2 H H Cl H F 1 H H H H H 329 CH.sub.2 H H Cl F H 1 H H H
H H 330 CH.sub.2 H H OCH.sub.2Ph H MeO 1 H H H H H 331 CH.sub.2 H H
OCH.sub.2CH.sub.2CO.sub.2H H MeO 1 H H H H H 334 CH.sub.2 H H H H H
0 - - H H H 339 CH.sub.2 H H H H H 1 Me Me H H H 341 CH.sub.2 H H H
H H 1 H H Me Me H 343 CH.sub.2 H H H H H 1 Me Me Me Me H 344
CH.sub.2 H H H H H 1 H H Me Me Me 345 CH.sub.2 H H H H H 1 Me Me Me
Me Me 346 CH.sub.2 H H H H H 0 - - Me Me Me 347 CH.sub.2 F H F H H
1 Me Me H H H 348 CH.sub.2 Cl H H H H 1 Me Me H H H 349 CH.sub.2 Me
H H H H 1 Me Me H H H 352 CH.sub.2 H H F H H 1 Me Me H H H 354
SO.sub.2 H Cl H H H 1 Me Me H H H 355 SO.sub.2 H H F F H 1 Me Me H
H H 358 CO H Me H H H 1 Me Me H H H 359 CO H H H CF.sub.3 H 1 Me Me
H H H 360 CO H H Cl Cl H 1 Me Me H H H 361 CO F H H H F 1 Me Me H H
H 362 CO F H H H Cl 1 Me Me H H H 363 CO F H H F H 1 Me Me H H H
364 CO Cl Cl H H H 1 Me Me H H H 369 CH.sub.2 F H H H H 1 Me Me H H
H 370 CH.sub.2 H H H H Cl 1 H H H Me Me 371 CH.sub.2 H H H H F 1 H
H H Me Me 372 CH.sub.2 H H H H Me 1 H H H Me Me 374 CH.sub.2 H H F
H F 1 H H H Me Me 376 CH.sub.2 H H F H H 1 H H H Me Me 380 SO.sub.2
H H H Cl H 1 H H H Me Me 381 SO.sub.2 H H H F F 1 H H H Me Me 382
CO H H H Me H 1 H H Me H Me 383 CO H CF.sub.3 H H H 1 H H Me H Me
385 CO H Cl Cl H H 1 H H Me H Me 387 CO F H H H F 1 H H Me H Me 389
CO F H H H Cl 1 H H Me H Me 390 CO F H H F H 1 H H Me H Me 391 CO
Cl Cl H H H 1 H H Me H Me 392 CO Cl H H H Cl 0 - - H H H 394 CO H H
H H H 0 - - H H H 399 CO H H Cl H H 0 - - H H H 400 CO H H H F H 0
- - H H H 401 CO H H CF.sub.3O H H 0 - - H H H 402 CO H H
C.sub.2H.sub.5 H H 0 - - H H H 403 CO H H H Me H 0 - - H H H 405 CO
H H F F H 0 - - H H H 406 CO H H H CF.sub.3 H 0 - - H H H 407 CO H
H MeO H H 0 - - H H H 414 CO H H H CN H 0 - - H H H 415 CO H H
CF.sub.3 H H 0 - - H H H 417 CO H H Cl Cl H 0 - - H H H 418 CO H
MeO H MeO H 0 - - H H H 419 CO F H H H F 0 - - H H H 422 CO H H H
MeO H 0 - - H H H 423 CO H H F H H 0 - - H H H 425 CO H H H Cl H 0
- - H H H 429 CO H H CN H H 0 - - H H H 430 CO H H Cl H Cl 0 - - H
H H 438 CO H H CF.sub.3 H F 0 - - H H H 439 CO H F H CF.sub.3 H 0 -
- H H H 440 CO H H H H CF.sub.3O 0 - - H H H 441 CO H H H CF.sub.3O
H 0 - - H H H 442 CO H H H H CF.sub.3 0 - - H H H
443 CO Cl H H CF.sub.3 H 0 - - H H H 444 CO Cl H H H F 0 - - H H H
447 CO H H MeO H MeO 0 - - H H H 449 CO H H F H F 0 - - H H H 450
CO H H H H Me 0 - - H H H 451 CO H F H H F 0 - - H H H 452 CO H H H
H F 0 - - H H H 454 CO H H H Cl Cl 0 - - H H H 461 CO H H Me H H 0
- - H H H 462 CO H H H H MeO 0 - - H H H 464 CO H H H H Cl 0 - - H
H H 469 CO H H t-Bu H H 0 - - H H H 475 CO H H MeO F H 0 - - H H H
476 CO H H MeO MeO H 0 - - H H H 478 CO H F H H Cl 0 - - H H H 479
CO H Cl H Cl H 0 - - H H H 481 SO.sub.2 H H H H H 0 - - H H H 482
SO.sub.2 H H Me H H 0 - - H H H 487 SO.sub.2 H H MeO H H 0 - - H H
H 488 SO.sub.2 H H Cl H H 0 - - H H H 489 SO.sub.2 H MeO MeO H H 0
- - H H H 490 SO.sub.2 H H F H H 0 - - H H H 492 SO.sub.2 H
CF.sub.3 H H H 0 - - H H H 493 SO.sub.2 H H CF.sub.3O H H 0 - - H H
H 497 SO.sub.2 H CF.sub.3O H H H 0 - - H H H 498 SO.sub.2 H MeO H H
H 0 - - H H H 500 SO.sub.2 Cl H CN H H 0 - - H H H 501 SO.sub.2 F H
H H H 0 - - H H H 502 SO.sub.2 H H CN H H 0 - - H H H 506 SO.sub.2
H H O-2-pyridyl H H 0 - - H H H 507 SO.sub.2 H H O-3-pyridyl H H 0
- - H H H 508 SO.sub.2 H H O-4-pyridyl H H 0 - - H H H 509 SO.sub.2
H H O-(4-MeOPh) H H 0 - - H H H 510 SO.sub.2 H H O-(4-CF.sub.3Ph) H
H 0 - - H H H 511 SO.sub.2 H O-(3,4-di H H H 0 - - H H H ClPh) 512
SO.sub.2 H H 4-MeOPh H H 0 - - H H H 514 SO.sub.2 H CF.sub.3 H H Cl
0 - - H H H 523 SO.sub.2 H H CHF.sub.2O H H 0 - - H H H 524
SO.sub.2 H H C.sub.6H.sub.5O H H 0 - - H H H 525 SO.sub.2 Cl H H H
H 0 - - H H H 526 SO.sub.2 H Cl F H H 0 - - H H H 527 SO.sub.2
C.sub.6H.sub.5 H H H H 0 - - H H H 528 SO.sub.2 CF.sub.3 H H H H 0
- - H H H 529 SO.sub.2 H H 1-pyrazolyl H H 0 - - H H H 530 SO.sub.2
MeO H MeO H H 0 - - H H H 532 SO.sub.2 CF.sub.3O H H H H 0 - - H H
H 533 SO.sub.2 Me H H H H 0 - - H H H 535 SO.sub.2 H H CF.sub.3 H H
0 - - H H H 536 SO.sub.2 F H Cl H H 0 - - H H H 537 SO.sub.2 H F H
H F 0 - - H H H 538 SO.sub.2 H Cl H H Cl 0 - - H H H 539 SO.sub.2 H
Cl H H F 0 - - H H H 540 SO.sub.2 F H H H F 0 - - H H H 541
SO.sub.2 H Cl Me H H 0 - - H H H 542 SO.sub.2 H Cl H Cl H 0 - - H H
H 543 SO.sub.2 F H F H H 0 - - H H H 544 SO.sub.2 Cl H H H Cl 0 - -
H H H 545 SO.sub.2 Cl H F H H 0 - - H H H 546 SO.sub.2 H F H H Me 0
- - H H H 548 SO.sub.2 MeO H H Me H 0 - - H H H 549 SO.sub.2 H MeO
H H MeO 0 - - H H H 550 SO.sub.2 H Me H Me H 0 - - H H H 551
SO.sub.2 CN H H H H 0 - - H H H 562 CH.sub.2 H H MeO H H 0 - - H H
H 566 CH.sub.2 H H MeO MeO H 0 - - H H H 568 CH.sub.2 H H H
C.sub.6H.sub.5O H 0 - - H H H 569 CH.sub.2 H Br H H MeO 0 - - H H H
570 CH.sub.2 H H Cl H Cl 0 - - H H H 571 CH.sub.2 H H H CN H 0 - -
H H H 572 CH.sub.2 H H t-Bu H H 0 - - H H H 574 CH.sub.2 H H H
CF.sub.3 H 0 - - H H H 575 CH.sub.2 H H NMe.sub.2 H H 0 - - H H H
576 CH.sub.2 H H C.sub.6H.sub.5O H H 0 - - H H H 577 CH.sub.2 Cl H
H H F 0 - - H H H 584 CH.sub.2 H H H MeO H 0 - - H H H 585 CH.sub.2
H H Me Me H 0 - - H H H 586 CH.sub.2 H H MeO MeO Cl 0 - - H H H 588
CH.sub.2 H H OCH.sub.2Ph MeO H 0 - - H H H 590 CH.sub.2 H H Cl Cl H
0 - - H H H 591 CH.sub.2 H H H MeO MeO 0 - - H H H 592 CH.sub.2 H H
MeO OCH.sub.2Ph H 0 - - H H H 593 CH.sub.2 H H MeO HO H 0 - - H H H
594 CH.sub.2 H MeO MeO Br H 0 - - H H H 595 CH.sub.2 H H F CN H 0 -
- H H H 597 CH.sub.2 H H Br H H 0 - - H H H 598 CH.sub.2 H H H Cl H
0 - - H H H 601 CH.sub.2 H H Cl H H 0 - - H H H 602 CH.sub.2 H H Me
H H 0 - - H H H 603 CH.sub.2 H H CN H H 0 - - H H H 604 CH.sub.2 H
H CF.sub.3 H H 0 - - H H H 605 CH.sub.2 H H H F H 0 - - H H H 606
CH.sub.2 H H H Me H 0 - - H H H 607 CH.sub.2 H H F H H 0 - - H H H
608 CH.sub.2 H H MeO H MeO 0 - - H H H 609 CH.sub.2 H H F H F 0 - -
H H H 611 CH.sub.2 H H Cl F H 0 - - H H H 612 CH.sub.2 H H CF.sub.3
H F 0 - - H H H 614 CH.sub.2 H H H Br H 0 - - H H H 615 CH.sub.2 H
H H H MeO 0 - - H H H 616 CH.sub.2 H H NHAc H H 0 - - H H H 617
CH.sub.2 H H H H Br 0 - - H H H 618 CH.sub.2 H Br H H F 0 - - H H H
620 CH.sub.2 H H CF.sub.3O H H 0 - - H H H 621 CH.sub.2 H H
CHF.sub.2O H H 0 - - H H H 622 CH.sub.2 H H OCH.sub.2-(4-F-Ph) H H
0 - - H H H 623 CH.sub.2 H MeO MeO H F 0 - - H H H 624 CH.sub.2 F H
MeO H F 0 - - H H H 625 CH.sub.2 H H H C2H5O H 0 - - H H H 626
CH.sub.2 H H H (3-CF.sub.3Ph)O) H 0 - - H H H 628 CH.sub.2 H MeO H
H F 0 - - H H H 629 CH.sub.2 H H F MeO H 0 - - H H H 630 CH.sub.2 H
H C.sub.2H.sub.5O H H 0 - - H H H 631 CH.sub.2 H MeO H H MeO 0 - -
H H H 632 CH.sub.2 H H H CF.sub.3O H 0 - - H H H 633 CH.sub.2 H MeO
H MeO H 0 - - H H H 635 CH.sub.2 H H Cl H F 0 - - H H H
[0454] TABLE-US-00002 TABLE 1B Adamantane Substituted Amide
Compounds ##STR70## ID L.sup.1-R.sup.3 n R.sup.2' R.sup.2'' R.sup.a
R.sup.b R.sup.c 6 H 1 H H H H H 7 methyl 1 H H H H H 8 ethyl 1 H H
H H H 13 2-hydroxy-3-methoxy-propyl 1 H H H H H 14 phenethyl 1 H H
H H H 16 3-pyridylmethyl 1 H H H H H 18 2-hydroxyethyl 1 H H H H H
19 3-hydroxypropyl 1 H H H H H 23 2,3-dihydroxypropyl 1 H H H H H
43 4-pyridylmethyl 1 H H H H H 46
2,5-dioxabicyclo[4.4.Odeca-6,8,10-trien-9- 1 H H H H H ylmethyl 61
2-pyridylmethyl 1 H H H H H 63 3-phenylpropyl 1 H H H H H 64
1H-indol-5-ylmethyl 1 H H H H H 66 [(5-methyl-2-thienyl)methyl 1 H
H H H H 67 (1-methylimidazol-2-yl)methyl 1 H H H H H 69
4-quinolylmethyl 1 H H H H H 73 2-quinolylmethyl 1 H H H H H 79
(5-phenyl-2-thienyl)methyl 1 H H H H H 80
(2-butyl-1H-imidazol-4-yl)methyl 1 H H H H H 81
(5-methyl-3H-imidazol-4-yl)methyl 1 H H H H H 82
1H-imidazol-4-ylmethyl 1 H H H H H 83 (5-chloro-2-thienyl)methyl 1
H H H H H 90 (2,2-difluorobenzo[1,3dioxol-4-yl)methyl 1 H H H H H
105 2,3-dihydrobenzofuran-5-ylmethyl 1 H H H H H 112
(4-methyl-1-naphthyl)methyl 1 H H H H H 118
(6-methyl-2-pyridyl)methyl 1 H H H H H 121 cyclopentylmethyl 1 H H
H H H 122 cyclohexylmethyl 1 H H H H H 142 methylsulfonyl 1 H H H H
H 145 2-naphthylsulfonyl 1 H H H H H 146 8-quinolylsulfonyl 1 H H H
H H 147 propylsulfonyl 1 H H H H H 148 ethylsulfonyl 1 H H H H H
153 benzylsulfonyl 1 H H H H H 157 trien-9-yl)sulfonyl 1 H H H H H
158 5-chloro-1,3-dimethyl-pyrazol-4-yl)sulfonyl 1 H H H H H 159
[5-methyl-2-(trifluoromethyl)-3-furylsulfonyl 1 H H H H H 160
5-methyl-1-phenyl-pyrazol-4-yl)sulfonyl 1 H H H H H 163 1 H H H H H
164 1,2-dimethylimidazol-4-yl)sulfonyl 1 H H H H H 169
3,5-dimethylisoxazol-4-yl)sulfonyl 1 H H H H H 170
methylsulfonylmethylsulfonyl 1 H H H H H 171
(2-oxocbromen-6-yl)sulfonyl 1 H H H H H 180 3-pyridylsulfonyl 1 H H
H H H 182 [3,5-bis(trifluoromethyl)phenylmethylsulfonyl 1 H H H H H
183 [4-(trifluoromethyl)phenylmethylsulfonyl 1 H H H H H 184
(4-fluorophenyl)methylsulfonyl 1 H H H H H 185
(3,4-dichlorophenyl)methylsulfonyl 1 H H H H H 186
(3,5-dichlorophenyl)methylsulfonyl 1 H H H H H 187
[3-(trifluoromethyl)phenylmethylsulfonyl 1 H H H H H 188 1 H H H H
H 189 (4-chlorophenyl)methylsulfonyl 1 H H H H H 198
1,3,5-trimethylpyrazol-4-yl)sulfonyl 1 H H H H H 200
2,5-dioxabicyclo[4.4.Odeca-7,9,11-trien-9- 1 H H H H H ylsulfonyl)
213 isopropylsulfonyl 1 H H H H H 219 acetyl 1 H H H H H 222
2-chloropyridine-3-carbonyl 1 H H H H H 223 propanoyl 1 H H H H H
224 2-(4-methoxyphenyl)acetyl 1 H H H H H 225 2-phenylacetyl 1 H H
H H H 231 3-cyclopentylpropanoyl 1 H H H H H 235
3,5,5-trimethylhexanoyl 1 H H H H H 236 2,2-diphenylacetyl 1 H H H
H H 237 pyridine-3-carbonyl 1 H H H H H 238 cyclopentanecarbonyl 1
H H H H H 239 2-(2,5-dimethoxyphenyl)acetyl 1 H H H H H 240
2-methoxyacetyl 1 H H H H H 241 2-(4-fluorophenyl)acetyl 1 H H H H
H 244 cyclohexanecarbonyl 1 H H H H H 248 3-phenylpropanoyl 1 H H H
H H 249 2-phenoxyacetyl 1 H H H H H 252 2,2-dimethylpropanoyl 1 H H
H H H 254 2-(3,4-dimethoxyphenyl)acetyl 1 H H H H H 255
3-methylbutanoyl 1 H H H H H 256 2-benzyloxyacetyl 1 H H H H H 259
quinoxaline-2-carbonyl 1 H H H H H 260 cyclopropanecarbonyl 1 H H H
H H 261 2-(3-methoxyphenyl)acetyl 1 H H H H H 262
3,3-dimethylbutanoyl 1 H H H H H 263 2-cyclopentylacetyl 1 H H H H
H 264 2-(4-chlorophenoxy)acetyl 1 H H H H H 265
2-(4-chlorophenyl)acetyl 1 H H H H H 273
5-methyl-2-phenyl-triazole-4-carbonyl 1 H H H H H 274
2-phenoxypyridine-3-carbonyl 1 H H H H H 276
7,10-dioxabicyclo[4.4.Odeca-2,4,11-triene-9- 1 H H H H H carbonyl)
281 6-chloropyridine-3-carbonyl 1 H H H H H 283
5-methylisoxazole-3-carbonyl 1 H H H H H 284
1,5-dimethylpyrazole-3-carbonyl 1 H H H H H 285
2,5-dimethylpyrazole-3-carbonyl 1 H H H H H 286
1-phenyl-5-(trifluoromethyl)pyrazole-4- 1 H H H H H carbonyl 287 1
H H H H H 288 5-methyl-1-phenyl-pyrazole-4-carbonyl 1 H H H H H 289
5-(4-chlorophenyl)-2-methyl-furan-3-carbonyl 1 H H H H H 290
naphthalene-2-carbonyl 1 H H H H H 293 2,5-dimethylfuran-3-carbonyl
1 H H H H H 295 1-acetylpiperidine-4-carbonyl 1 H H H H H 296
isoxazole-5-carbonyl 1 H H H H H 297
3,5-dimethylisoxazole-4-carbonyl 1 H H H H H 298
2-chloropyridine-4-carbonyl 1 H H H H H 299
5-methylisoxazole-4-carbonyl 1 H H H H H 300
5-methyl-2-tert-butyl-pyrazole-3-carbonyl 1 H H H H H 302
2-(2-bromophenyl)acetyl 1 H H H H H 303 quinoline-2-carbonyl 1 H H
H H H 304 pyridine-4-carbonyl 1 H H H H H 305 pyridine-2-carbonyl 1
H H H H H 306 1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carbonyl 1 H H
H H H 307 3-methoxypropanoyl 1 H H H H H 308 pyrazine-2-carbonyl 1
H H H H H 309 2,3-dihydrobenzothran-5-carbonyl 1 H H H H H 311
quinoxaline-6-carbonyl 1 H H H H H 313 cbroman-3-carbonyl 1 H H H H
H 317 1-(2,5-dioxabicyclo[4.4.Odeca-6,8,10-trien-9- 1 H H H H H
yl)ethyl 318 9H-fluoren-2-ylmethyl 1 H H H H H 321
benzo[1,3dioxol-5-ylmethyl 1 H H H H H 332 1H-indol-6-ylmethyl 1 H
H H H H 333 2,6-dioxabicyclo[5.4.Oundeca-7,9,11-trien-9- 1 H H H H
H ylmethyl 350 (7,10-dioxabicyclo[4.4.Odeca-1,3,5-trien-4- 1
CH.sub.3 CH.sub.3 H H H ylmethyl) 351 (1H-indol-6-ylmethyl) 1
CH.sub.3 CH.sub.3 H H H 353 benzylsulfonyl 1 CH.sub.3 CH.sub.3 H H
H 356 (3,4-dichlorophenyl)methylsulfonyl 1 CH.sub.3 CH.sub.3 H H H
357 (4-chlorophenyl)methylsulfonyl 1 CH.sub.3 CH.sub.3 H H H 365
(2-cyclopentylacetyl) 1 CH.sub.3 CH.sub.3 H H H 366
(cyclohexanecarbonyl) 1 CH.sub.3 CH.sub.3 H H H 367
(3,3-dimethylbutanoyl) 1 CH.sub.3 CH.sub.3 H H H 373
7,10-dioxabicyclo[4.4.Odeca-1,3,5-trien-4- 1 H H CH.sub.3 CH.sub.3
H ylmethyl) 375 2-(3,5-dimethyl-1-adamantyl)-1H-indol-6- 1 H H
CH.sub.3 CH.sub.3 H ylmethyl) 377 benzylsulfonyl 1 H H H CH.sub.3
CH.sub.3 378 (3,4-dichlorophenyl)methylsulfonyl 1 H H H CH.sub.3
CH.sub.3 379 (4-chlorophenyl)methylsulfonyl 1 H H H CH.sub.3
CH.sub.3 384 (2-cyclopentylacetyl) 1 H H H CH.sub.3 CH.sub.3 386
(cyclohexanecarbonyl) 1 H H H CH.sub.3 CH.sub.3 388
(3,3-dimethylbutanoyl) 1 H H H CH.sub.3 CH.sub.3 393 acetyl 0 - - H
H H 397 [2-(4-methoxyphenyl)acetyl] 0 - - H H H 398
(2-phenylacetyl) 0 - - H H H 409 (2,2-diphenylacetyl) 0 - - H H H
411 [2-(2,5-dimethoxyphenyl)acetyl] 0 - - H H H 412
(2-methoxyacetyl) 0 - - H H H 413 [2-(4-fluorophenyl)acetyl] 0 - -
H H H 420 (3-phenylpropanoyl) 0 - - H H H 421 (2-phenoxyacetyl) 0 -
- H H H 424 (2,2-dimethylpropanoyl) 0 - - H H H 428
(2-benzyloxyacetyl) 0 - - H H H 431 (quinoxaline-2-carbonyl) 0 - -
H H H 432 (cyclopropanecarbonyl) 0 - - H H H 433
[2-(3-methoxyphenyl)acetyl] 0 - - H H H 436
[2-(4-chlorophenoxy)acetyl] 0 - - H H H 437
[2-(4-chlorophenyl)acetyl] 0 - - H H H 445
(5-methyl-2-phenyl-triazole-4-carbonyl) 0 - - H H H 446
(2-phenoxypyridine-3-carbonyl) 0 - - H H H 453
(6-chloropyridine-3-carbonyl) 0 - - H H H 455
(5-methylisoxazole-3-carbonyl) 0 - - H H H 456
(1,5-dimethylpyrazole-3-carbonyl) 0 - - H H H 458
(5-methyl-1-phenyl-pyrazole-4-carbonyl) 0 - - H H H 459
[5-(4-chlorophenyl)-2-methyl-furan-3-carbonyl] 0 - - H H H 460
(naphthalene-2-carbonyl) 0 - - H H H 463
(2,5-dimethylfuran-3-carbonyl) 0 - - H H H 465
(1-acetylpiperidine-4-carbonyl) 0 - - H H H 466
(isoxazole-5-carbonyl) 0 - - H H H 468
(5-methyl-2-tert-butyl-pyrazole-3-carbonyl) 0 - - H H H 470
[2-(2-bromophenyl)acetyl] 0 - - H H H 471 (quinoline-2-carbonyl) 0
- - H H H 472 [1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carbonyl] 0 -
- H H H 474 (2,3-dihydrobenzofuran-5-carbonyl) 0 - - H H H 477
(cbroman-3-carbonyl) 0 - - H H H 480 methylsulfonyl 0 - - H H H 483
(2-naphthylsulfonyl) 0 - - H H H 484 (8-quinolylsulfonyl) 0 - - H H
H 485 propylsulfonyl 0 - - H H H 486 ethylsulfonyl 0 - - H H H 491
benzylsulfonyl 0 - - H H H 494
[(5-methyl-2-oxa-5-azabicyclo[4.4.0]deca- 0 - - H H H
7,9,11-trien-9-yl)sulfonyl] 495
(5-chioro-1,3-dimethyl-pyrazol-4-yl)sulfonyl 0 - - H H H 496
(5-methyl-1-phenyl-pyrazol-4-yl)sulfonyl 0 - - H H H 499
(1,2-dimethylimidazol-4-yl)sulfonyl 0 - - H H H 503
(3,5-dimethylisoxazol-4-yl)sulfonyl 0 - - H H H 505
(2-oxocbromen-6-yl)sulfonyl 0 - - H H H 515 [[3,5- 0 - - H H H
bis(trifluoromethyl)phenyl]methylsulfonyl] 516
[[4-(trifluoromethyl)phenyl]methylsulfonyl] 0 - - H H H 517
[(4-fluorophenyl)methylsulfonyl] 0 - - H H H 518
[(3,4-dichlorophenyl)methylsulfonyl] 0 - - H H H 519
[(3,5-dichlorophenyl)methylsulfonyl] 0 - - H H H 520
[[3-(trifluoromethyl)phenyl]methylsulfonyl] 0 - - H H H 522
[(4-chlorophenyl)methylsulfonyl] 0 - - H H H 531
(1,3,5-trimethylpyrazol-4-yl)sulfonyl 0 - - H H H 534
(2,5-dioxabicyclo[4.4.0]deca-7,9,11-trien-9- 0 -- -- H H H
ylsulfonyl) 547 isopropylsulfonyl 0 - - H H H 552
(3,5,5-trimethylhexyl) 0 - - H H H 553 (2,2-diphenylethyl) 0 - - H
H H 554 (2-phenylpropyl) 0 - - H H H 555 propyl 0 - - H H H 556
(cyclohexylmethyl) 0 - - H H H 557 (cyclopropylmethyl) 0 - - H H H
558 pentyl 0 - - H H H 559 (3-phenylpropyl) 0 - - H H H 560
(3-pyridylmethyl) 0 - - H H H 564 (benzo[1,3]dioxol-5-ylmethyl) 0 -
- H H H 565 (2-naphthylmethyl) 0 - - H H H 567
[(6-methyl-4-oxo-cbromen-3-yl)methyl] 0 - - H H H 580
[(1-methylindol-3-yl)methyl] 0 - - H H H 581 (2-ethylbutyl) 0 - - H
H H 582 (2-methylpentyl) 0 - - H H H 583 isopentyl 0 - - H H H 589
(2,5-dioxabicyclo[4.4.0]deca-6,8,10-trien-9- 0 - - H H H ylmethyl)
596 (benzo[1,3]dioxol-4-ylmethyl) 0 - - H H H 599
[(6-chlorobenzo[1,3]dioxol-5-yl)methyl] 0 - - H H H 600 neopentyl 0
- - H H H 610 (4-pyridylmethyl) 0 - - H H H 613
[(6-bromo-3-pyridyl)methyl] 0 - - H H H 619 (cyclopentylmethyl) 0 -
- H H H 627 [(2,2-difluorobenzo[1,3]dioxol-5-yl)methyl] 0 - - H H H
634 [(6-chloro-3-pyridyl)methyl] 0 - - H H H
[0455] TABLE-US-00003 TABLE 1C Substituted Amide Compounds
##STR71## ID L.sup.1-R.sup.3 R.sup.1a 9 4-benzyl cyclohexylmethyl
10 4-benzyl cycloheptylmethyl 11 H cyclohexylmethyl 12 H
cycloheptylmethyl 20 ethyl cyclohexylmethyl 21 (3-hydroxypropyl)
cyclohexylmethyl 22 (2-hydroxyethyl) cyclohexylmethyl 24 benzyl
(2-methoxyphenyl)ethyl 25 H (2-methoxyphenyl)ethyl 26 methyl
cyclohexylmethyl 93 (3-pyridylmethyl) cycloheptylmethyl 94
(2-pyridylmethyl) cycloheptylmethyl 124 (3-phenylpropyl)
(3-phenylpropyl) 125 (5-methyl-2-thienyl)methyl cycloheptylmethyl
126 (1H-imidazol-4-ylmethyl) cycloheptylmethyl 127
(cyclohexylmethyl) cycloheptylmethyl 128 (cyclopentylmethyl)
cycloheptylmethyl 129 phenethyl cycloheptylmethyl 130
(4-fluorophenyl)methyl cycloheptylmethyl 132 (3-pyridylmethyl)
(2-methoxyphenyl)ethyl 133 (4-pyridyl)methyl (2-methoxyphenyl)ethyl
134 (2-pyridylmethyl) (2-methoxyphenyl)ethyl 135
(1H-imidazol-4-ylmethyl) (2-methoxyphenyl)ethyl 136
(cyclohexylmethyl) (2-methoxyphenyl)ethyl
[0456] TABLE-US-00004 TABLE 1D Substituted Amide Compounds
##STR72## ID L.sup.1-R.sup.3 R.sup.1a 1 benzyl
2-(2-chlorophenyl)ethyl] 2 H (cyclohexylmethyl) 3 H phenethyl 4
benzyl (cyclohexylmethyl) 17 benzyl (1-adamantylmethyl) 48
(3-pyridylmethyl) (cyclohexylmethyl) 49 (4-pyridylmethyl)
(cyclohexylmethyl) 50 (2-chlorophenyl)methyl (cyclohexylmethyl) 51
(4-chlorophenyl)methyl (cyclohexylmethyl) 52 (2-pyridylmethyl)
(cyclohexylmethyl) 53 (3-chlorophenyl)methyl (cyclohexylmethyl) 54
(4-methoxyphenyl)methyl (cyclohexylmethyl) 55 (p-tolylmethyl)
(cyclohexylmethyl) 56 (4-methylsulfonylphenyl)methyl
(cyclohexylmethyl) 57 (4-acetamidophenyl)methyl
4-[(4-acetamidophenyl)methyl]-(cyclohexyl- methyl) 58 benzyl
[(1-hydroxycycloheptyl)methyl] 59 benzyl [(1-hydroxy-3,3-dimethyl-
cyclohexyl)methyl] 60 benzyl [[1-(p-tolyl)cyclohexyl]methyl] 137
(2,4-difluorophenyl)methyl (1-adamantylmethyl) 138
(7,10-dioxabicyclo[4.4.0]deca-1,3,5- (1-adamantylmethyl)
trien-4-ylmethyl) 139 [(2-fluorophenyl)methyl] (1-adamantylmethyl)
316 [(3-fluorophenyl)methyl] (1-adamantylmethyl) 335
[(3-methoxyphenyl)methyl] (1-adamantylmethyl) 336 (o-tolylmethyl)
(1-adamantylmethyl) 337 [(2-chlorophenyl)methyl]
(1-adamantylmethyl) 338 (4-fluorophenyl)methyl (1-adamantylmethyl)
340 benzo[1,3]dioxol-5-ylmethyl (1-adamantylmethyl)
[0457] TABLE-US-00005 TABLE 1E Misc. Amide Compounds ID STRUCTURE
368 ##STR73## 342 ##STR74## 636 ##STR75##
[0458] TABLE-US-00006 TABLE 2 NMR Data for Exemplary Compounds of
the Invention. ID NMR Data 5 (CDCl.sub.3) `.delta.` 8.68 (s, 1H),
7.50 (s, 1H), 7.30 (m, 5H), 3.70 (s, 4H), 2.74 (s, 4H), 2.30 (s,
2H), 1.98 (br `s`, 3H), 1.65 (m, 12H). 6 (CDCl.sub.3) `.delta.`
8.70 (s, 1H), 7.73 (s, 1H), 4.06 (s, 2H), 3.13 (t, J = 5.7Hz, 2H),
2.66 (t, J = 5.7Hz, 2H), 2.29 (s, 2H), 1.99 (br`s`, 3H), 1. 7
(CDCl3) .delta. 8.71 (s, 1H), 7.60 (s, 1H), 3.63 (s, 3H), 2.91-2.83
(m, 6H), 2.48 (s, 2H), 2.33 (s, 2H), 2.04-1.55 (m, 1H). 8 (CDCl3)
.delta. 8.71 (s, 1H), 7.60 (s, 1H), 3.68 (s, 2H), 2.76 (brs, 4H),
2.62 (q, 2H), 2.34 (brs, 2H), 1.99 (brs, 3H), 1.80-1.48 (m, 12H),
1.18 (t, 3H). 9 (CD3OD) .delta. 8.64 (s, 1H), 7.42-7.21 (m, 5H),
3.73 (s, 2H), 3.64 (s, 2H), 2.83-2.65 (m, 4H), 2.36 (d, 2H),
1.95-1.50 (m, 6H), 1.40-0.95 (m, 5H). 10 (CD3OD) .delta. 8.64 (s,
1H), 7.40-7.20 (m, 5H), 3.73 (s, 2H), 3.64 (s, 2H), 2.75-2.66 (m,
4H), 2.40 (d, 2H), 2.10-2.0 (m, 1H), 1.94-1.90 (m, 12H). 11 (CD3OD)
.delta. 8.66 (s, 1H), 3.95 (brs, 2H), 3.09 (t, 2H), 2.67 (t, 2H),
2.36 (d, 2H), 1.95-0.98 (m, 11H). 13 (CDCl3) .delta. 8.71 (s, 1H),
7.89 (s, 1H), 4.05-3.66 (m, 3H), 3.55-3.39 (m, 5H), 2.98-2.55 (m,
5H), 2.28 (brs, 2H), 1.99 (brs, 4H), 1.75-1.60 (m, 14H). 17
CD.sub.3OD) `.delta.` 8.91 (s, 1H), 7.4-7.3 (m, 5H), 3.75 (s, 2H),
3.7 (s, 2H), 3.25 (t, J = 5.8, 2H), 3.08 (s, 2H), 2.81 (t, J = 5.8,
2H), 1.98(s, 4H), 1.78-1.6 (m, 16H). 26 (CD3OD) .delta. 8.67 (s,
1H), 2.83 (s, 2H), 2.72 (s, 3H), 2.47 (brs, 4H), 2.36 (d, 2H),
1.98-1.59 (m, 6H), 1.40-0.95 (m, 5H). 27 (CD3OD) .delta. 8.65 (s,
1H), 7.54-7.24 (m, 4H), 3.86 (s, 2H), 3.57 (s, 2H), 2.84 (t, 2H),
2.76 (t, 2H), 2.22 (s, 2H), 2.0-1.60 (m, 15H). 28 (DMSO-d6) .delta.
10.16 (s, 1H), 8.70 (s, 1H), 7.32-7.27 (m, 1H), 7.48 (dt, 1H)
7.39-7.32 (m, 1H), 7.24-7.17 (m, 2H) 3.76 (s, 2H), 3.61 (s, 2H),
2.70 (t, 2H), 2.62 (t, 2H), 2.15 (s, 2H) 1.93 (br s, 3H) 1.70-1.53
(m, 12H) 30 (CD3OD) .delta. 8.64 (s, 1H), 7.22 (d, 1H), 6.59-6.44
(m, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 3.72 (s, 2H), 3.66 (s, 2H),
2.81 (t, 2H), 2.76 (t, 2H), 2.20 (s, 2H), 2.05-1.60 (m, 15H). 31
(DMSO-d6) .delta. 10.16 (s, 1H), 8.70 (s, 1H), 7.32-7.27 (m, 1H),
7.21-7.15 (m, 3H), 3.65 (s, 2H), 3.58 (s, 2H), 2.68 (t, 2H), 2.60
(t, 2H), 2.34 (s, 3H), 2.15 (s, 2H) 1.93 (br s, 3H) 1.70-1.53 (m,
12H) 39 (CD3OD) .delta. 8.64 (s, 1H), 7.14-7.12 (m, 2H), 6.85 (d,
1H), 3.81 (s, 3H), 3.64 (s, 2H), 3.62 (s, 2H), 2.77 (brs, 4H), 2.22
(s, 2H), 2.17 (s, 3H), 2.0-1.56 (m, 15H). 41 (CD3OD) .delta. 8.65
(s, 1H), 7.37 (d, 2H), 7.33 (d, 2H), 3.72 (s, 2H), 3.64 (s, 2H),
2.77 (brs, 4H), 2.22 (s, 2H), 2.0-1.48 (m, 15H). 46 (CD3OD) .delta.
8.65 (s, 1H), 6.84-6.65 (m, 3H), 4.21 (brs, 4H), 3.63 (brs, 4H),
2.78 (brs, 4H), 2.22 (s, 2H), 2.04-1.60 (m, 15H). 47 (CD3OD)
.delta. 8.65 (s, 1H), 7.29-7.21 (m, 1H), 7.0-6.84 (m, 2H), 3.79 (s,
2H), 3.68 (s, 2H), 2.82-2.65 (m, 4H), 2.21 (s, 2H), 2.05-1.60 (m,
15H). 58 (CD3OD) .delta. 8.92 (s, 1H), 7.41-7.25 (m, 5H), 3.75 (s,
2H), 3.71 (s, 2H), 3.38-3.30 (m, 3H), 2.81 (t, 2H), 1.70-1.45 (m,
13H). 60 (CD3OD) .delta. 8.82 (s, 1H), 8.53 (s, 1H), 7.20-7.05 (m,
9H), 3.89-3.19 (m, 8H), 3.05 (t, 2H), 2.74 (t, 2H), 2.20-2.05 (m,
5H), 1.85-1.10 (m, 7H). 71 (CD3OD) .delta. 8.65 (s, 1H), 7.38 (d,
2H), 7.29 (d, 2H), 3.71 (s, 2H), 3.64 (s, 2H), 2.79 (brs, 4H), 2.22
(s, 2H), 2.0-1.60 (m, 15H), 1.32 (s, 9H). 90 (CD3OD) .delta. 8.65
(s, 1H), 7.23-7.10 (m, 3H), 3.85 (s, 2H), 3.70 (s, 2H), 2.83-2.65
(m, 4H), 2.22 (s, 2H), 2.01-1.60 (m, 15H). 107 (CD3OD) .delta. 8.65
(s, 1H), 7.86 (dd, 1H), 7.43-7.25 (m, 2H), 3.86 (s, 2H), 3.69 (s,
2H), 2.77 (brs, 4H), 2.22 (s, 2H), 2.10-1.58 (m, 15H). 137 (CD3OD)
.delta. 8.65 (s, 1H), 7.60-7.41 (m, 1H), 7.02-6.95 (m, 2H), 3.81
(s, 2H), 3.70 (s, 2H), 3.03 (s, 2H), 2.80 (brt, 4H), 2.06-1.56 (m,
15H). 140 (CD3OD) .delta. 8.66 (s, 1H), 7.30 (d, 2H), 6.90 (d, 2H),
4.45 (s, 2H), 3.79 (s, 2H), 3.76 (s, 2H), 2.96-2.70 (m, 4H), 2.21
(s, 2H), 2.0-1.60 (m, 15H). 168 (DMSO-d6) .delta. 10.28 (s, 1H),
8.76 (s, 1H) 7.90 (t, 1H), 7.86-7.78 (m, 2H), 7.67 (t, 1H), 4.27
(s, 2H), 3.39 (t, 2H), 2.66 (t, 2H), 2.16 (s, 2H), 1.94 (br s, 3H)
1.71-1.56 (m, 12H) 316 (CD3OD) .delta. 8.92 (s, 1H), 7.36-6.90 (m,
4H), 3.79 (s, 2H), 3.75 (s, 2H), 3.03 (brs, 2H), 2.80 (brs, 2H),
2.62 (s, 2H), 2.10-1.56 (m, 15H). 321 (DMSO-d6) .delta. 10.15 (s,
1H), 8.70 (s, 1H), 6.93-6.79 (m, 3H), 6.0 (s, 2H), 3.59 (s, 2H),
3.55 (s, 2H), 2.68-2.58 (m, 4H), 2.15 (s, 2H) 1.93 (br s, 3H),
1.71-1.52 (m, 12H) 334 (d6-DMSO) .delta. 9.77 (s, 1H), 8.72 (s,
1H), 7.20-7.10 (m, 5H), 3.68 (s, 2H), 3.59 (s, 2H), 2.64 (brs, 4H),
2.05-1.80 (m, 15H). 338 (CDCl3) .delta. 8.89 (s, 1H), 7.39-7.28 (m,
2H), 7.20-6.90 (m, 2H), 3.68 (d, 2H), 3.46 (t, 2H), 3.10 (d, 2H),
2.76 (t, 2H), 2.15 (s, 2H), 2.0-1.20 (m, 15H). 339 (CDCl3) .delta.
8.66 (s, 1H), 7.39-7.24 (m, 5H), 3.71 (brs, 4H), 2.74 (brs, 4H),
2.01 (brs, 2H), 1.78-1.46 (m, 13H), 1.25 (s, 6H). 368 (CDCl3)
.delta. 8.13 (s, 1H), 7.40-7.20 (m, 5H), 3.68 (s, 2H), 3.58 (s,
2H), 3.14 (d, 2H), 2.88 (t, 2H), 2.74 (t, 2H), 2.51 (s, 3H), 2.0
(brs, 3H), 1.80-1.52 (m, 12H). 535 (CDCl.sub.3) .delta. 8.33 (d,
1H), 7.97 (d, 1H), 7.49 (t, 1H), 7.33-7.28 (m, 2H), 7.13-7.08 (m,
2H), 7.02 (t, 2H), 6.45 (d, 1H), 5.18 (s, 2H), 2.20 (s, 2H), 2.02
(brs, 3H), 1.75-1.54 (m, 12H)
[0459] The following biological examples, Examples 1-9, are offered
to illustrate the present invention and are not to be construed in
any way as limiting its scope. In the examples below, all
temperatures are in degrees Celsius (unless otherwise
indicated).
EXAMPLE 1
[0460] The P2X.sub.7 receptor is strongly expressed in
macrophage-derived cell lines, including, but not limited to, J774
(mouse macrophage line, American Type Culture Collection (ATCC),
Rockville, Md., ATCC TIB-67), P388 (mouse cell line, ATCC CCL-46),
P815 (mouse mast cell mastocytoma-derived line, ATCC TIB-64), THP-1
(Human monocyte-derived cell line, ATCC TIB202) and U937 (human
cell line derived from histiocytic lymphoma, induceable to monocyte
differentiation, ATCC CRL-1593.2) and in isolated macrophage
cultures. Human or non-human animal macrophages are isolated using
the procedure noted below.
[0461] The P2Z/P2X.sub.7 receptor can be characterized by measuring
channel opening, for instance ion flux, and/or by assessing pore
formation, including by monitoring dye uptake or cell lysis in
cells naturally expressing this receptor. Compounds such as ATP, 2'
and 3'-(O)-(4-benzoyl benzoyl) ATP (BzATP) effect the formation of
pores in the plasma membrane of these cells, particularly at low
extracellular divalent ion concentrations (Buisman et al, Proc.
Natl. Acad. Sci. USA 85:7988 (1988); Zambon et al, Cell. Immunol
156:458 (1994); Hickman et al Blood 84:2452 (1994)). Large
molecular size dyes, including propidium dye YO-PRO-1, can be seen
entering macrophage-derived cell lines during cell recordings
(Hickman et al, Blood 84:2452 (1994); Wiley et al, Br J Pharmacol
112:946 (1994); Steinberg et al, J Biol Chem 262:8884 (1987)).
Ethidium bromide (a fluorescent DNA probe) can also be monitored,
where an increase in the fluorescence of intracellular DNA-bound
ethidium bromide is observed. Expression of recombinant rat or
human rP2X.sub.7 in cells, including HEK293 cells, and in Xenopus
oocytes demonstrates influx and pore formation by whole cell
recordings and YO-PRO-1 fluorescence (Suprenant et al, Science
272:735 (1996); Rassendren et al, J Biol Chem 272:5482 (1997)).
[0462] The compounds of the invention may be tested for antagonist
activity at the P2X.sub.7 receptor. Tests that may be performed
include and are selected from: (i) electrophysiological
experiments; (ii) YO-PRO1 fluorescence; (iii) ethidium bromide
fluorescence; and (iv) IL-10 release from stimulated macrophages,
including as described below. Compounds can be tested in vivo in
animal models including for inflammation models (e.g. paw edema
model, collagen-induced arthritis, EAE model of MS).
Isolation of Human Macrophages
[0463] Monocyte-derived human or non-human animal macrophage
cultures are prepared as described by Blanchard et al (Blanchard et
al, J Cell Biochem 57:452 (1995); Blanchard et al, J Immunol
147:2579 (1991)). Briefly, monocytes are isolated from leukocyte
concentrates obtained from a healthy volunteer. Leukocytes are
suspended in RPMI 1460 medium (Life Techologies, Inc.) with 20%
serum (human for human cells), 2 mM glutamine, 5 mM HEPES, and 100
.mu.g/ml streptomycin. Cells are allowed to adhere to culture
flasks for 1-2 h, after which nonadherent cells are washed away.
Adherent cells are cultured for 7-14d in this medium plus
interferon-.gamma. (human for human cells) (1000 units/ml).
Macrophages are recovered from the culture flask by pipetting with
cold phosphate-buffered saline and plated onto glass coverslips for
electrophysiological or other experiments carried out 12-24 h
later.
EXAMPLE 2
Electrophysiological Experiments
[0464] Whole cell recordings are made using the EPC9 patch-clamp
amplifier and Pulse acquisition programs (HEKA, Lambrecht,
Germany). Whole-cell recordings are obtained from cells, e.g.
J774A.1 cells (American Type Culture Collection, Rockville, Md.,
ATCC TIB-67)); agonists are applied for periods of 1 to 3 s by a
fast-flow U-tube delivery system [E. M. Fenwick, A. Marty, E.
Neher, J. Physiol, (London) 331, 577 (1982)]. The internal pipette
solution is 140 mM cesium-aspartate or potassium-aspartate, 20 mM
NaCl, 10 mM EGTA, and 5 mM Hepes; normal external solution is 145
mM NaCl, 2 mM KCl, 2 mM CaCl.sub.2, 1 mM MgCl.sub.2, 10 mM Hepes,
and 12 mM glucose. Low divalent external solution is nominally
magnesium-free with 0.3 mM CaCl.sub.2-Concentration-response curves
are constructed in low divalent solution by recording currents in
response to 1 s applications of agonist at 8 min intervals with
normal external solution present for 6 min before each application.
This protocol is necessary to prevent the development of sustained
inward currents.
[0465] Reversal potentials (E.sub.rev) are obtained by application
of ATP (300 .mu.M) or BzATP (30 .mu.M)(controls), or the compound
being tested, while the membrane is held at various potentials or
by application of voltage ramps from -120 to 30 or 50 mV.
Permeability ratios are calculated from E.sub.rev by first
computing .alpha.(=P.sub.Na/P.sub.K' where P is permeability) for
internal (i) and external (O) concentrations [Na].sub.1=20 mM,
[Na].sub.o=145 mM, [K].sub.o=0 mM, and [K].sub.1=140 mM from
.alpha.=([145/exp(E.sub.revFIRT)]-20)/140 (where F is the Faraday,
R is the gas constant, and T is the absolute temperature). Other
P.sub.x/P.sub.Na values, when [X].sub.o=145 mM, [Na].sub.1=20 mM,
[K].sub.1=140 mM, and [Na].sub.o=[K].sub.o=[X].sub.1=0 mM, are
computed from P.sub.x/P.sub.Na=[(exp)E.sub.revF/RT)]
(20+140.alpha.))/145. In order of size, X is cesium, methylamine,
tris(hydroxymethyl)-aminomethane, tetraethylammonium, and
N-methyl-D-glucamine. The internal solution also contains 10 mM
EGTA and 5 mM Hepes. External solutions also contain 10 mM glucose
and normal or low concentrations of divalent cations; pH is
maintained at 7.3 with HCl, histidine, or Hepes as required, and
the osmolarity of all solutions is 295 to 315.
EXAMPLE 3
YO-PRO1 Fluorescence
[0466] The Photonics Imaging (IDEA) system for microscopic
fluorescence measurements (Photonics, Planegg, Germany) is used.
Coverslips are placed at the stage of a Zeiss Axiovert 100 or
equivalent inverted microscope and viewed under oil immersion with
a 40.times. Fluor objective. YO-PRO-1 (10 .mu.M; Molecular Probes,
Eugene, Oreg.) is added to the superfusion fluid during
electrophysiological recordings 3 to 6 min before switching to low
divalent solution and washed out upon switching back to normal
divalent solution, after which the fluorescent lamp is turned on
and cells are examined with a fluorescein isothiocyanate filter.
YO-PRO1 fluorescence is measured using 491/509 nm
excitation/emission wavelengths. Images are obtained at 5-20s
intervals during continuous superfusion (2 ml/min) with YO-PRO1 and
varying concentrations of control ATP, BzATP or compound to be
tested. For each experiment, the time course of YO-PRO1
fluorescence is obtained for 10-20 individual cells and then
averaged to obtain the mean fluorescence signal. Results are
expressed as mean signal at 3 min for rP2X.sub.7, and the signal at
10 min is used for P2X.sub.7 and human macrophage cells. All
experiments are carried out at room temperature.
EXAMPLE 4
Ethidium Bromide
[0467] Compounds of the invention are tested for antagonist
activity at the P2X.sub.7 receptor by monitoring Ethidium Bromide
entering P2X.sub.7 receptor-expressing cells on pore formation. The
test is performed in 96-well flat bottomed microtitre plates, the
wells being filled with 250 .mu.l of test solution comprising 200
.mu.l of a suspension of P2X.sub.7-expressing cells (e.g. THP-1
cells, J774 cells, etc.)(2.5.times.10.sup.6 cells/ml) containing
10.sup.-4M ethidium bromide, 25 .mu.L of a high potassium buffer
solution containing 10.sup.-5M BzATP, and 25 .mu.L of a high
potassium buffer solution containing test compound. The plate is
covered with a plastic sheet and incubated at 37.degree. C. for one
hour. The plate is then read in a Perkin-Elmer fluorescent plate
reader, excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm,
EM 20 nm. For the purposes of comparison, BzATP (a P2X.sub.7
receptor agonist) and pyridoxal 5-phosphate (a P2X.sub.7 receptor
agonist) are used separately in the test as controls. From the
readings obtained, a pIC.sub.50 figure is calculated for each test
compound. This figure is the negative logarithm of the
concentration of test compound necessary to reduce the BzATP
agonist activity by 50%.
EXAMPLE 5
[0468] IL-1.beta. Release
[0469] This Example demonstrates the testing of the compounds of
this invention for efficacy as inhibitors of P2X.sub.7-mediated
release of IL-1 B from human macrophages activated by the
Alzheimer's beta amyloid peptide 1-42.
Cell Isolation
[0470] Monocytes are isolated from peripheral blood mononuclear
cells (PBMCs) as follows. Whole blood is layered directly onto
Histopak 1077-1 columns (Sigma Biochemicals) and centrifuged at
800.times.g for 15 minutes. The PBMC band of cells is removed to a
fresh 50 ml culture tube and diluted 1:1 with wash buffer
(Phosphate buffered saline, pH 7.4 containing 2 mM EDTA and 5 mg/ml
BSA) followed by centrifugation at 800.times.g for 5 minutes. Cells
are then washed by sequential resuspension of the cell pellet in
wash buffer and centrifugation at 600.times.g for 5 minutes. The
wash process is repeated until the supernatent is clear of
contaminating platelets (generally, 5 to 6 washes). Monocytes are
then purified from the PBMCs by negative selection using a monocyte
isolation kit (Miltenyi Biotec, Inc.) that contains antibodies to
non-monocytic cells, running the cells over a magnetic column to
remove antibody-bound cells, and collecting the flow through volume
of monocytes. Monocytes are washed once with wash buffer and seeded
at 10E5 cells per well in 100 .mu.l serum-free RPMI 1640 in 96-well
plates and incubated for 1 hour at 37.degree. C. in a 5%
CO.sub.2/95% humidified tissue culture incubator. After 1 hour, the
medium is replaced with 100 .mu.L complete culture medium (RPMI
1640, 10% human serum-type AB (heat inactivated), 25 mM HEPES, 2 mM
glutamine, 50 U/ml each of penicillin and streptomycin) and
incubated overnight (16 hours).
Dosing Regimen
[0471] The next day, the culture medium is replaced with 100 .mu.L
fresh complete culture medium in the absence or presence of human
beta amyloid 1-42 peptide (5 .mu.M) and incubated at 37.degree. C.
in a 5% CO.sub.2/95% humidified tissue culture incubator for 5
hours. Medium is then removed and discarded. Each well is washed
once with Hanks buffered saline (HBSS) containing 1 mM CaCl.sub.2
followed by the addition of 80 .mu.L of HBSS/CaCl.sub.2-inhibiting
compound of the present invention (10.times. stock in
HBSS/CaCl.sub.2 for a final concentration of 23 nM and 206 nM) and
incubated 15 minutes in the tissue culture incubator followed by
the addition of either 10 .mu.L of HBSS/CaCl.sub.2 or 10 .mu.L of
benzoyl ATP (BzATP; 3 mM stock in HBSS/CaCl.sub.2 for a 300 .mu.M
final concentration) and incubated for a further 30 minutes in the
tissue culture incubator. Medium is then removed to new 96-well
plates for storage at -70.degree. C. until the IL-1 B content is
quantitated by ELISA (from R&D Systems). The cells are washed
once with HBSS/CaCl.sub.2 followed by lysing the cells with 100
.mu.l ice cold lysis buffer (100 mM Tris, pH 7.6, 1% Triton X-100,
and 1 tablet per 30 ml Complete TM protease inhibitor from Roche
Biochemicals, Inc). Cell lysates are stored at -70.degree. C. until
the IL-1.beta. is quantitated by ELISA.
EXAMPLE 6
In Vivo Animal Models
[0472] A. This example illustrates the efficacy of the compounds of
this invention in the treatment of multiple sclerosis. As described
herein, an experimental autoimmune encephalomyelitis (EAE) model is
used to show such efficacy. The following procedures are employed
in this model.
Animals
[0473] SJL/J female mice, 8 wks. old, are obtained from Jackson
Laboratories.
Antigens
[0474] Myelin Proteolipid Protein (PLP 139-151) (HSLGKWLGHPDKF)
(Cat # H-2478) is obtained from BACHEM, Bioscience, Inc., King of
Prussia, Pa.
[0475] Complete Freund's Adjuvant H37 Ra [1 mg/ml Mycobacterium
Tuberculosis H37 R.sup.a] is obtained from Difco (Cat # 3114-60-5,
6X10 ml).
[0476] Mycobacterium Tuberculosis is also obtained from Difco, (Cat
# 3114-33-8, 6.times.100 mg).
Pertussis Toxin
[0477] Bordetella Pertussis, (Lyophilized powder containing PBS and
lactose) is obtained from List Biological Laboratories, (Product
#180, 50 ug).
Induction of EAE in Mice
[0478] PLP139-151 peptide is dissolved in H.sub.2O:PBS (1:1)
solution to a concentration 7.5 mg/10 ml (for 75 .mu.g PLP per
group) and emulsified with an equal volume of CFA supplemented with
40 mg/10 ml heated-killed mycobacterium tuberculosis H37R.sup.a.
Mice are injected s.c. with 0.2 ml of peptide emulsion in the
abdominal flank (0.1 ml on each side). On the same day and 72 hours
later, mice are injected i.v. with 100% of 35 ng and 50 ng of
Bordetella Pertussis toxin in saline respectively.
Clinical Assessment
STAGE 0: Normal
STAGE 0.5: Partial limp tail
STAGE 1: Complete Limp Tail
STAGE 2: Impaired righting reflex
STAGE 2.5: Righting reflex is delayed (ot weak enough to be stage
3).
STAGE 3: Partial hind limb paralysis
STAGE 3.5: One leg is completely paralyzed, and one leg is
partially paralyzed,
STAGE 4: Complete hind limb paralysis
STAGE 4.5: Legs are completely paralyzed and Moribund
STAGE 5: Death due to EAE
[0479] Clinical Courses of EAE
Acute phase: First clinical episode (Day 10-18)
Remission: Phase of clinical improvement following a clinical
episode; characterized by a reduction (>=one grade) in clinical
score for at least two days after the peak score of acute phase or
a disease relapse.
[0480] Relapse: Increase of at least one grade in clinical score
for at least two days after remission has been attained.
[0481] The animals treated with the compounds of this invention
generally would be expected to show improvements in clinical
scores.
[0482] B. This Example illustrates a protocol for determining the
efficacy of the compounds of the present invention for the
treatment of stroke using an animal model.
[0483] Male Sprague Dawley rats (Charles River) weighing 280-320 g
are given free access to food and water and acclimatized for a
minimum of 4 days before use in experiments. All rats for use in
studies are to be fasted beginning at 3:00 pm the day prior to
surgery but given free access to water. Prior to surgery each rat
is weighed. The rat is initially induced with 5% isoflurane
(Aerrane, Fort Dodge), combined with 30% O.sub.2, 70% N.sub.2O for
2-5 minutes. The rat is then placed on a circulating water-heating
pad and into a nose cone for spontaneous respiration of anesthetic
gases. The isoflurane is reduced to 2%. A rectal probe is inserted
and body temperature maintained at 36.5-37.5.degree. C. The hair is
clipped at all surgical sites and these regions will then be
scrubbed with Betadine.
Surgical Procedure
[0484] A temporalis muscle probe is placed into the right
temporalis muscle and "brain" temperature" is monitored. A midline
neck incision is made in the upper thorax of the rat. Careful
dissection, isolation and retraction of the sternomastoideus,
digastricus, and sternohyoideus muscles is made to expose the right
common, internal and external carotid arteries. The right common
carotid artery is isolated with a 5-0 silk suture. During surgery
the suture is released allowing reperfusion every 2-4 minutes. The
right external carotid and superior thyroid arteries are also
isolated and the superior thyroid is cauterized, while the external
carotid is ligated distally with a 5-0 silk suture. Another 5-0
silk suture is loosely tied around the external carotid artery. The
occipital artery is isolated, ligated and incised. The internal
carotid is isolated.
[0485] With the common and external carotid arteries immobilized,
an aneurysm clip is placed onto the internal carotid artery. A
small incision is made at the distal end of the external carotid. A
3-0 nylon suture coated with poly-L-lysine is then inserted into
the external carotid and up into the common carotid artery. The
loosely tied 5-0 silk suture around the external carotid is now
gently tightened around the filament. The external carotid artery
is then incised and the remaining piece of the external carotid
artery with the filament is rotated so that the filament may be
inserted into the internal carotid artery the length of insertion
depending on the weight and rat strain. In Sprague Dawley rats the
monofilament is inserted 18-19 mm (18 mm for rats weighing <300
gm, 19 mm for rats weighing .gtoreq.300 gm) effectively blocking
blood flow to the middle cerebral artery.
[0486] The external jugular vein will be cannulated with PE 50
tubing for I.V. administration of compounds. The cannula will be
exteriorized at the previously shaven, scruff of the neck and
sutured in place. The wound will be closed by means of suture. The
right femoral artery is catheterized for blood gas and glucose
determination during surgery.
[0487] Two hours after the insertion of the monofilament suture the
rats are re-anesthetized with the same anesthetic combination used
initially and placed back into the nose cone with the reduction of
isoflurane concentration to 2%. The neck incision is reopened to
expose the external carotid artery. The restoration of blood flow
is accomplished by completely withdrawing the intraluminal suture
from the carotid arteries. The incision is then closed with 3-0
silk in an interrupted stitch.
Compound Administration
[0488] Five groups of 15 animals are subjected to the above
methodology. Compounds are infused (I.V.) at various doses (dose
response) over different time periods post MCAo. A pre-determined
concentration is infused over a pre-selected time period beginning
at various intervals post MCAo. Vehicle-treated controls receive an
infusion of normally 0.9 ml/hr. A positive control compound is run
at the same time.
Neurological Tests
[0489] Prior to surgery, 2 hours following the onset of ischaemia
and 24 hours after ischaemia, a battery of neurological tests are
performed. The postural reflex test, which is designed to examine
upper body posture, when the rat is suspended by the tail above a
flat surface. A normal rat will extend the entire body and both
forelimbs towards the surface. Rats with an infarction will
consistently flex the contralateral limb and show signs of body
rotation.
[0490] The rats' response to a gentle lateral push with a finger
behind the shoulders is observed and noted. A normal rat would
resist such a push, whereas a rat with an infarction will not. The
elicited forelimb placing in response to visual and tactile
stimuli. The animal is held by the body so that the lateral or
dorsal forepaw surface is placed against a bench. This test is
repeated but on this occasion obstructing the view of the rat.
[0491] Upon completion of each experiment, all animals are deeply
anaesthetized with isoflurane (5%), euthanized by decapitation, and
the brains removed, the extent and location of the ischaemic damage
is verified histologically by means of tetrazolium chloride.
[0492] C. This Example illustrates the anti-inflammatory activity
of the compounds of this invention using a model of
2,4-dinitrobenzenesulfonic acid (DNBS) induced distal colitis (a
model of inflammatory bowel disease).
Test Substance and Dosing Pattern
[0493] A compound of this invention is dissolved in vehicle of 2%
Tween 80 in distilled water for oral administration at a dose of 50
mg/kg or dissolved in vehicle of 2% Tween 80 and 0.9% NaCl for
intraperitoneal injection at 30 mg/kg. The dose is given once daily
for 7 consecutive days. Dosing volume was 10 ml kg. DNBS is
challenged 2 hours after dosing on the second day.
Animals
[0494] In these studies, male Wistar, Long Evans rats provided by
the animal breeding center of MDS Panlabs Taiwan, Ltd. and
Balb/cByJ derived male mice (weighing 20.+-.2 gms), provided by
National Laboratory Animals Breeding Research center (ALBRC,
Taiwan), may be used. Space allocation of 6 animals may be
45.times.23.times.15 cm. Animals are housed in APEC.RTM. cages
(Allentown Caging, Allentown, N.J. 08501, USA) in a positive
pressure isolator (NuAire.RTM., Mode: Nu-605, airflow velocity
50.+-.5 ft/min, HEPA Filter) and maintained in a controlled
temperature (22.degree. C.-24.degree. C.) and humidity (60%-80%)
environment with 12 hours light dark cycles for at least one week
in MDS Panlabs Taiwan laboratory prior to being used. Free access
to standard lab chow for rats (Fwusow Industry Co., Limited,
Taiwan) and tap water is granted. All aspects of this work
including housing, experimentation and disposal of animals would be
performed in general accordance with the International Guiding
Principles for Biomedical Research Involving Animals (CIOMS
Publication No. ISBN 92 90360194, 1985).
Chemicals
[0495] DNBS is obtained from TCI, Tokyo, Japan, ethanol is from
Merck, Germany and Sulfasalazine is purchased from Sigma, USA.
Equipment
[0496] Electriconic scale (Tanita, Model 1140, Japan), Electriconic
scale (Sartorius, R160P, Germany), Glass syringe (2 ml, Mitsuba,
Japan), Rat oral needle, Hypodermic needle (25GxI'' TOP
Corporation, Japan), Stainless Scissors (Klappenclear, Germany),
Stainless Forceps (Klappenclear, Germany).
Method
[0497] Groups of 3 Wistar derived male rats weighing 180.+-.20 gms
are used. Distal colitis is induced by intra-colonic instillation
of DNBS (2,4-dinitrobenzene sulfonic acid, 30 mg in 0.5 ml ethanol
30%) after which, 2 ml of air is gently injected through the
cannula to ensure that the solution remains in the colon. Test
substance is administered orally (PO) at a dose of 50 mg/kg or
intraperitoneally (IP) at 30 mg/kg once daily for 7 consecutive
days. DNBS is instillated into the distal colon of each animal 2
hours after dosing on the second day. The control group is
similarly treated with vehicle alone and sulfasalazine (300 mg/kg,
PO) is used as reference agent. Animals are fasted 24 hours before
DNBS challenge and 24 hours after the final treatment when they are
sacrificed and each colon is removed and weighed. During the
experiments, presence of diarrhea is recorded daily. When the
abdominal cavity is opened before removal of the colon, adhesions
between the colon and other organs are noted. After weighing the
colon, the extent of colonic ulceration is observed and noted as
well. Colon-to-body weight ratio is then calculated for each animal
according to the formula: Colon (g)/BW.times.100%. The "Net"
increase in ratio of Vehicle-control+DNBS group relative to
Vehicle-control group is used as a base value for comparison with
test substance treated groups and expressed as % decrease in
inflammation. A 30 percent or more (30%) decrease in "Net"
colon-to-body weight ratio for each test substance treated group
relative to the "Net" vehicle+DNBS treated group is considered
significant.
[0498] D. This Example illustrates the anti-inflammatory activity
of the present compounds using a model of carrageenan induced paw
edema (a model of inflammation, carrageenan).
Test Substance and Dosing Pattern
[0499] A compound of this invention is dissolved in vehicle of 2%
Tween 80/0.9% NaCl and administered intraperitoneally at a dose of
30 mg/kg 30 minutes before carrageenan (1% 0.1 ml/paw) challenge.
Dosing volume is 10 ml/kg.
Animals
[0500] Animals are conditioned in accordance with the procedures
set forth in the previous Example.
Chemicals
[0501] Carrageenan is obtained from TCI, Japan; Pyrogen free saline
is from Astar, Taiwan; and Aspirin is purchased from ICN
BioMedicals, USA.
Equipment
[0502] Glass syringe (1 ml and 2 ml Mitsuba, Japan), Hypodermic
needle 24G.times.1'' (Top Corporation, Japan), Plethysmometer #7150
(Ugo Basile, Italy), and Water cell 25 mm Diameter, #7157 (UGO
Basile, Italy).
Method
[0503] Test substance (Example) is administered IP (30 mg/kg) to
groups of 3 Long Evans derived male overnight fasted rats weighing
150.+-.20 gms 30 minutes before right hind paw injection of
carrageenan (0.1 ml of 1% suspension intraplantar). Hind paw edema,
as a measure of inflammation, is recorded 3 hours after carrageenan
administration using a plethysmometer (Ugo Basile Cat. #7150) with
water cell (25 mm diameter, Cat. #7157). Reduction of hind paw
edema by 30 percent or more (.gtoreq.30%) indicated significant
acute anti-inflammatory activity.
[0504] E. This Example illustrates the anti-inflammatory activity
of the present compounds using a model of Balb/c mice subjected to
monoclonal antibody (mAb) type II collagen induced arthritis.
Test Substance and Dosing Pattern
[0505] A compound of this invention is dissolved in vehicle of 2%
Tween 80/0.9% NaCl, at doses of 50 or 30 and administered orally
(50 mg/kg) or intraperitoneally at 30 mg/kg once daily for 3
consecutive days after monoclonal antibody of collagen is injected.
Dosing volume is 20 ml kg.
Animals
[0506] Animals are conditioned in accordance with the procedures
set forth in the previous Example.
Chemicals
[0507] Lipopolysaccharide is obtained from Sigma, USA; Indomethacin
is from Sigma, USA; Arthrogen-CIA.TM. Monoclonal Antibodies D8,
F10, DI-2G and A2 are obtained from IBL, Japan; Phosphated-Buffer
Saline is purchased from Sigma, USA; and Tween 80 is from Wako,
Japan.
Equipment
[0508] Plethysmometer (Ugo Basile, Italy) and Water Cell (Ugo
Basile, Italy).
Method
[0509] Groups of 5 Balb/cByJ mice strain, 6-8 weeks of age, are
used for the induction of arthritis by monoclonal antibodies (mAbs)
responding to type II collagen, plus lipopolysaccharide (LPS). The
animals are administered intravenously with a combination of 4
different mAbs in a total of 4 mg/mouse at day 0, and followed by
intravenous 25 .mu.g of LPS 72 hours later (day 3). From day 3, one
hour after LPS administration, ML-659 at 50 mg/kg (PO) or 30 mg/kg
(IP) and vehicle (2% Tween 80/0.9% NaCl, PO) as well as the
positive control indomethacin, 3 mg/kg (PO) are administrated once
daily for 3 consecutive days. A plethysmometer (Ugo Basile Cat
#7150) with water cell (12 mm diameter) is used for the measurement
of increase in volume of the two hind paws at day 0, 5, 7, 10, 14,
and 17. The percent inhibition of increase in volume is calculated
by the following formula: Inhibition (%):
[1-(Tn-To)/(Cn-Co)].times.100 Where: Co (Cn): volume of day 0 (day
n) in vehicle control To (Tn): volume of day 0 (day n) in test
compound-treated group The reduction of both of two hind paws edema
by more than 30% is considered significant.
EXAMPLE 7
Neuropathic Pain Model
[0510] This example illustrates the analgesic activity of the
compounds of this invention using a Sciatic Nerve ligation model of
mononeuropathic pain.
Test System
[0511] Adult male Sprague Dawley (SD) rats weighing 250-300 gm
(Charles River Laboratories, San Diego, Calif.) are used. The
animal room is lighted artificially at a 12-hr light-dark cycle
(e.g. from 7:00 A.M. to 7:00 P.M.) with water and food supply ad
libitum. Animals are allocated randomly into groups.
Model Induction
[0512] Sciatic nerve ligation (SNL, Seltzer's model): Under
anesthesia with pentobarbital (50 mg/kg, i.p.) and aseptic
techniques, the selective nerve injury is created by tightly
ligating the selective portion of the common sciatic nerve
according to the method of Seltzer (1990). Briefly, the high-thigh
level of the left sciatic nerve is exposed after skin incision and
blunt separation of muscles at a site near the trochanter just
distal to the point at which the posterior biceps semitendious
nerve nerve branches from the common sciatic nerve. The nerve is
then fixed in this position with fine forceps by pinching the
epineurium on its dorsal aspect, taking care not to press the nerve
against underlying structures. An 8-0 silicon-treated silk suture
is inserted into the nerve with a 3/8 curved, reversed-cutting
mini-needle, and tightly ligated so that the dorsal 1/3-1/2 of the
nerve is trapped in the ligature. The muscles are sutured in
layers, and the skin closed with wound clips. Animals are then
returned to their home cages. Rats exhibiting postoperative
neurological deficits or poor grooming are excluded from the
experiments.
Equipment
[0513] The following equipment is used in the current studies: von
Frey filament set (Touch-test Sensory Evaluator, North Coast
Medical Inc., Morgan Hill, Calif.).
Statistical Methods:
[0514] Within each experiment mean, standard error of the mean
(SEM) and statistical significance are calculated using the
average, standard error of the mean and unpaired, two-tailed t-Test
functions, respectively, using Microsoft Excel.RTM.. Statistical
significance of effects observed between individual experiments is
determined, using Prism (GraphPad Software Inc., San Diego,
Calif.). for the one-way or two-way analysis of variance (ANOVA)
function. Statistical analyses are performed with a confidence
limit of 0.95 and a significance level of 0.05.
EXAMPLE 8
Pore Formation
[0515] THP-1 cells (ATCC Cat # 285-IF-100) are plated in 96 well
plates at a concentration of 200,000 cells per well and allowed to
differentiate in RPMI-1640 media (ATCC Cat # 30-2001) containing
10% FBS, 100 IU/mL penicillin, 100 ug/mL streptomycin, 100 ng/mL
LPS and 100 ng/mL IFN-.gamma. for 16 hours. Following
differentiation, the cells are pretreated with the compound of
interest at the appropriate concentration for 30 minutes in
RPMI-1640 media containing 100 IU/mL penicillin, 100 ug/mL
streptomycin. The pretreatment media is then replaced with assay
buffer (20 mM HEPES, 10 mM D-glucose, 118 mM NMDG, 5 mM KCl, 0.4 mM
CaCl.sub.2) containing 5 uM Yo-Pro 1 (Molecular Probes Cat # Y3603)
and the compound of interest at the appropriate concentration and
the cells are incubated for an additional 10 minutes.
2',3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (Sigma Aldrich
Cat# B6396) is then added to a final concentration of 40 uM and
fluoroscence readings measured at 491/509 excitation/emission every
minute for 50 minutes using a Tecan Safire plate reader. During
this time temperature is maintained at of 37.degree. C. Background
adjusted fluorescence levels between drug treated and non-treated
cells are used to calculate the percent inhibition.
EXAMPLE 9
IL-1.beta. Release Assay (Alternate Method)
[0516] THP-1 cells (ATCC Cat # 285-IF-100) are plated in 96 well
plates at a concentration of 200,000 cells per well and allowed to
differentiate in RPMI-1640 media (ATCC Cat # 30-2001) containing
10% FBS, 100 IU/mL penicillin, 100 ug/mL streptomycin, 100 ng/mL
LPS and 100 ng/mL IFN-.gamma. for 16 hours. Following
differentiation, the cells are treated for an additional 2 hours in
RPMI-1640 media containing 100 IU/mL penicillin, 100 ug/mL
streptomycin and fresh LPS at 100 ng/mL. The cells are then
pretreated for 30 minutes with the compound of interest at the
appropriate concentration in RPMI media containing 100 IU/mL
penicillin, 100 ug/mL streptomycin. Following the pretreatment
2',3'-O-(4-benzoylbenzoyl)-adenosine 5'-triphosphate (Sigma Aldrich
Cat# B6396) is added to a final concentration of 250 uM and the
cells incubated for an additional 45 minutes. 30 uL of cell
supernatant is then collected and IL-1B levels determined via ELISA
(R&D systems Cat. # HSLB50) according to manufacturer's
recommendations using the Tecan Safire plate reader. Background
adjusted IL-1.beta. levels of drug treated and non-treated cells
are used to calculate the percent inhibition.
[0517] The synthetic and biological examples described in this
application are offered to illustrate this invention and are not to
be construed in any way as limiting the scope of this invention. In
the examples, all temperatures are in degrees Celsius (unless
otherwise indicated). The compounds that have been prepared in
accordance with the invention along with their biological activity
data are presented in the following Table (Table 3). The syntheses
of compounds of this invention are carried out in accordance with
the methods set forth above.
Activity of Compounds of the Invention
[0518] The % Inhibition data for the representative compounds of
the inventions are given in Table 3 below. For purpose of Table 3,
activity of each compound is expressed as follows:
"+" compound exhibited 0-25% inhibition at 0.3 .mu.M
"++" compound exhibited 25-50% inhibition at 0.3 .mu.M
"+++" compound exhibited 50-75% inhibition at 0.3 .mu.M
"++++" compound exhibited 75% or greater inhibition at 0.3.mu.M
[0519] Compounds with a percent inhibition represented by "++++"
are of particular interest. TABLE-US-00007 TABLE 3 Amide Compounds
Method of MW MS IL-1.beta. ID Synthesis (calcd) (obs) % inhibition
1 .DELTA. 406.91 + 2 .DELTA. 274.37 + 3 .DELTA. 282.35 + 4 .DELTA.
364.49 + 5 .DELTA. 416.57 417.78 ++ 6 .DELTA. 326.44 327.58 + 7 C
340.47 341.40 + 8 C 354.50 355.72 + 9 A 364.49 365.72 + 10 A 378.52
379.69 + 11 .DELTA. 274.37 275.22 + 12 .DELTA. 288.39 289.56 + 13
414.55 415.66 + 14 C 430.59 431.84 + 15 C 494.66 495.77 + 16 C
417.55 418.71 + 17 .DELTA. 416.57 417.82 ++++ 18 C 370.49 371.59 +
19 .DELTA. 384.52 385.60 + 20 C 302.42 303.73 + 21 .DELTA. 332.45
333.72 + 22 .DELTA. 318.42 319.53 + 23 .DELTA. 400.52 401.64 + 24 A
402.50 403.75 + 25 .DELTA. 312.37 -- + 26 C 288.39 289.50 +++ 27 C
451.01 452.29 +++ 28 C 434.56 435.77 ++++ 29 C 446.59 447.40 + 30 C
476.62 477.43 ++++ 31 C 430.59 431.90 +++ 32 C 444.62 445.63 + 33 C
434.56 435.25 + 34 C 451.01 451.31 + 35 C 446.59 447.69 +++ 36 C
476.62 477.44 + 37 C 476.62 477.43 + 38 C 430.59 431.82 + 39 C
460.62 461.77 + 40 C 446.59 447.73 + 41 C 451.01 451.40 + 42 C
441.58 442.62 + 43 C 417.55 418.67 + 44 C 430.59 431.69 + 45 C
444.62 445.63 + 46 C 474.60 475.45 ++++ 47 C 452.55 453.26 ++++ 48
K 365.48 366.60 + 49 K 365.48 366.63 + 50 K 398.94 399.32 + 51 K
398.94 399.32 + 52 K 365.48 366.66 + 53 K 398.94 399.34 + 54 K
394.52 395.60 + 55 K 378.52 379.73 + 56 K 442.58 443.64 + 57 K
421.54 422.67 + 58 .DELTA. 394.52 395.10 + 59 .DELTA. 408.54 409.41
+ 60 .DELTA. 454.61 455.49 + 61 C 417.55 418.74 + 62 C 473.62
474.72 +++ 63 C 444.62 445.88 + 64 C 455.60 456.71 + 65 C 493.65
494.87 + 66 C 436.62 437.43 + 67 C 420.56 421.70 ++ 68 C 508.66
509.74 + 69 C 467.61 468.86 + 70 C 484.56 485.78 + 71 C 472.67
473.75 + 72 C 484.56 485.77 + 73 C 467.61 468.86 + 74 C 500.56
501.76 + 75 C 508.66 509.76 + 76 C 500.56 501.82 + 77 C 482.57
483.69 + 78 C 482.57 483.70 + 79 C 498.69 499.85 + 80 C 462.64
463.81 ++ 81 C 420.56 421.67 +++ 82 C 406.53 407.71 +++ 83 C 457.04
457.37 ++++ 84 C 459.57 460.72 + 85 C 448.58 449.68 + 86 C 448.58
449.67 ++ 87 C 483.03 483.37 ++ 88 C 483.03 483.38 +++ 89 C 489.66
490.73 + 90 C 496.56 497.98 + 91 C 489.62 490.72 + 92 C 489.62
490.78 +++ 93 C 379.51 380.67 + 94 C 379.51 380.74 + 95 C 464.58
465.80 ++++ 96 C 502.55 503.68 + 97 C 502.55 503.67 ++ 98 C 482.63
483.72 ++ 99 C 476.62 477.63 + 100 C 476.62 477.65 ++ 101 C 476.62
477.63 ++ 102 C 464.58 465.83 + 103 C 464.58 465.79 + 104 C 464.58
465.81 +++ 105 C 458.60 459.75 + 106 C 502.55 503.70 + 107 C 502.55
503.68 + 108 C 502.55 503.68 + 109 C 502.55 503.75 ++ 110 C 502.55
503.70 + 111 C 502.55 503.76 ++ 112 C 480.65 481.61 + 113 C 474.65
475.72 + 114 C 500.56 501.80 + 115 C 486.61 487.73 + 116 C 462.66
463.75 + 117 C 462.59 463.68 + 118 C 431.58 432.87 + 119 C 464.58
465.80 ++ 120 C 484.56 485.78 + 121 C 408.59 409.80 + 122 C 422.61
423.72 + 123 C 434.56 435.69 + 124 C 406.57 407.78 + 125 C 398.57
399.68 + 126 C 368.48 369.61 + 127 C 384.56 385.67 + 128 C 370.54
371.71 + 129 C 392.54 393.76 + 130 C 396.51 397.70 + 131 C 502.55
503.73 + 133 C 403.48 404.68 + 134 C 403.48 404.68 + 135 C 392.46
393.40 + 136 C 408.54 409.70 + 137 K 452.55 451.46 +++ 138 K 474.60
475.66 ++++ 139 K 434.56 435.90 ++ 140 C 490.60 491.78 + 141 C
490.60 491.82 + 142 F 404.53 405.38 +++ 143 F 466.60 467.26 + 144 F
480.63 481.24 +++ 147 F 432.59 433.30 ++++ 148 F 418.56 419.26 +
149 F 496.63 497.39 +++ 150 F 501.05 501.20 + 151 F 526.65 527.26 +
152 F 484.59 485.33 + 153 F 480.63 481.24 ++++ 154 F 534.60 535.18
++++ 155 F 535.49 535.03 + 157 F 537.68 538.42 + 158 F 519.07
519.30 + 159 F 538.59 539.32 + 160 F 546.69 547.31 ++++ 161 F
550.60 551.34 ++ 162 F 496.63 497.40 + 164 F 484.62 485.35 + 165 F
526.06 526.20 +++ 166 F 484.59 485.33 ++ 167 F 491.61 492.23 ++ 168
F 501.05 501.20 ++++ 169 F 485.61 486.30 ++ 172 F 559.69 560.15 +++
173 F 559.69 560.16 174 F 559.69 560.15 ++++ 175 F 588.73 589.31
+++ 177 F 626.70 627.38 ++ 181 F 569.05 569.20 ++ 182 F 616.62
617.35 +++ 183 F 548.63 549.32 ++ 184 F 498.62 499.25 ++++ 185 F
549.52 549.26 ++ 186 F 549.52 549.27 ++++ 187 F 548.63 549.33 ++++
189 F 515.07 515.29 ++++ 190 F 532.61 533.16 +++ 191 F 558.70
559.21 + 192 F 501.05 501.21 +++ 193 F 519.04 519.29 + 194 F 542.70
543.28 ++++ 195 F 534.60 535.20 + 197 F 526.65 527.28 ++++ 198 F
498.65 499.31 + 199 F 480.63 481.26 ++++ 200 F 524.64 525.34 + 202
F 519.04 519.28 ++ 203 F 502.58 503.25 + 204 F 535.49 535.07 + 205
F 519.04 519.27 + 206 F 502.58 503.26 + 207 F 515.07 515.29 +++ 208
F 535.49 535.08 +++ 209 F 502.58 503.26 ++++ 210 F 535.49 535.08 +
211 F 519.04 519.27 + 212 F 498.62 499.28 +++ 214 F 510.66 511.41 +
215 F 484.59 485.34 +++ 216 F 526.65 527.28 +++ 217 F 494.66 495.35
+ 218 E 499.44 499.16 ++++ 219 E 368.48 369.24 + 220 E 430.55
431.50 ++++ 222 E 465.98 466.32 +++ 223 E 382.51 383.30 + 224 E
474.60 475.26 + 225 E 444.58 445.36 ++ 227 E 448.54 449.15 + 228 E
514.55 515.31 + 229 E 458.60 459.39 +++ 230 E 444.58 445.36 ++++
231 E 450.62 451.27 ++ 232 E 466.53 467.27 +++ 233 E 498.55 499.29
++++ 234 E 460.57 461.28 ++ 235 E 466.67 467.33 ++++ 236 E 520.67
521.33 +++ 237 E 431.54 432.39 + 238 E 422.57 423.26 ++++ 239 E
504.63 505.27 ++ 240 E 398.50 399.25 + 241 E 462.57 463.29 +++ 242
E 455.56 456.28 +++ 243 E 498.55 499.29 +++ 244 E 436.60 437.27 ++
245 E 499.44 499.17 +++ 246 E 490.60 491.29 ++ 247 E 466.53 467.27
++++ 248 E 458.60 459.38 + 249 E 460.57 461.29 + 250 E 460.57
461.29 +++ 251 E 448.54 449.15 + 252 E 410.56 411.30 ++ 253 E
464.99 465.22 +++ 254 E 504.63 505.27 + 255 E 410.56 411.30 ++ 256
E 474.60 475.26 +++ 257 E 455.56 456.31 + 258 E 499.44 499.18 ++++
260 E 394.52 395.18 +++
261 E 474.60 475.27 + 262 E 424.59 425.28 + 263 E 436.60 437.28
++++ 264 E 495.02 495.34 +++ 265 E 479.02 479.13 ++ 266 E 516.54
517.29 + 267 E 516.54 517.28 ++ 269 E 514.55 515.31 ++ 270 E 498.55
499.30 + 271 E 532.99 533.17 ++++ 272 E 482.98 483.30 ++++ 273 E
511.63 512.46 ++++ 274 E 523.63 524.50 + 275 E 490.60 491.29 +++
276 E 488.58 489.33 ++++ 277 E 466.53 467.27 +++ 278 E 444.58
445.37 +++ 279 E 466.53 467.27 ++++ 280 E 448.54 449.19 +++ 281 E
465.98 466.32 + 282 E 499.44 499.19 ++++ 283 E 435.53 436.32 +++
284 E 448.57 449.22 ++ 285 E 448.57 449.22 + 286 E 564.61 565.37
+++ 288 E 510.64 511.45 + 290 E 480.61 481.29 ++++ 291 E 444.58
445.37 ++++ 292 E 460.57 461.28 +++ 293 E 448.56 449.20 +++ 294 E
464.99 465.23 +++ 295 E 479.62 480.21 + 296 E 421.50 422.09 +++ 297
E 449.55 450.19 + 298 E 465.98 466.32 ++++ 299 E 435.53 436.32 +
300 E 490.65 491.32 + 301 E 486.66 487.36 ++++ 302 E 523.47 523.35
+++ 303 E 481.60 482.22 +++ 304 E 431.54 432.38 + 306 E 519.56
520.28 + 307 E 412.53 413.33 ++ 308 E 432.53 433.33 309 E 472.59
473.26 ++++ 310 E 478.56 479.13 +++ 311 E 482.59 483.31 312 E
490.60 491.29 + 313 E 486.61 487.33 ++++ 316 K 434.56 435.41 + 317
C 488.63 489.69 + 318 C 504.67 505.72 + 319 C 485.46 485.45 + 320 C
444.62 445.88 + 321 C 460.57 461.74 ++++ 322 C 452.55 453.60 + 323
C 469.00 469.60 + 324 C 481.04 481.39 + 325 C 519.01 519.44 + 326 C
469.00 469.61 ++ 327 C 552.56 553.75 + 328 C 469.00 469.60 +++ 329
C 469.00 469.61 +++ 330 C 552.72 553.96 +++ 331 C 548.68 549.84 +
332 C 455.60 456.75 +++ 333 C 488.63 489.78 +++ 334 B 402.54 403.72
+++ 335 K 446.59 447.72 ++ 336 K 430.59 431.84 ++++ 337 K 451.01
451.37 ++ 338 K, B 434.56 435.75 ++++ 339 .DELTA. 444.62 445.89 +
340 k 460.57 461.72 +++ 341 B 444.62 445.92 ++ 342 .DELTA. 415.58
416.81 + 343 B 472.67 473.86 + 344 B 458.65 459.60 + 345 B 486.70
487.64 + 346 B 444.62 445.68 + 347 C 480.60 481.32 + 348 C 479.06
479.41 + 349 C 458.65 459.61 + 350 C 502.66 503.48 + 351 C 483.66
484.42 + 352 C 462.61 463.48 + 353 D 508.68 509.78 + 354 D 529.10
529.37 + 355 D 530.64 531.58 + 356 D 577.57 577.60 + 357 D 543.13
543.54 + 358 D 472.63 473.79 + 359 D 526.60 527.74 + 360 D 527.49
527.55 + 361 D 494.58 495.77 + 362 D 511.04 511.57 + 363 D 494.58
495.82 + 364 D 527.49 527.50 + 365 D 464.65 465.74 + 366 D 464.65
465.81 + 367 D 452.64 453.70 + 368 .DELTA. 429.60 430.78 + 369 C
462.61 463.49 + 370 C 479.06 479.01 ++ 371 C 462.61 463.49 +++ 372
C 458.65 459.50 +++ 373 C 502.66 503.34 ++++ 374 C 480.60 481.34 ++
375 C 483.66 484.34 ++ 376 C 462.61 463.47 ++ 377 D 508.68 509.31
++++ 378 D 577.57 577.18 +++ 379 D 543.13 543.50 +++ 380 D 529.10
529.26 + 381 D 530.64 531.21 + 382 D 472.63 473.40 ++ 383 D 526.60
527.41 + 384 D 464.65 465.50 ++ 385 D 527.49 527.34 + 386 D 464.65
465.50 ++ 387 D 494.58 495.26 + 388 D 452.64 453.34 + 389 D 511.04
511.25 ++ 390 D 494.58 495.26 + 391 D 527.49 527.33 + 394 H 416.52
417.34 ++ 398 H 430.55 431.33 +++ 399 H 450.97 451.08 + 400 H
434.51 435.30 + 401 H 500.52 501.23 + 402 H 444.58 445.32 + 403 H
430.55 431.33 ++ 405 H 452.50 453.02 ++ 406 H 484.52 485.32 ++ 407
H 446.55 447.19 + 409 H 506.65 507.30 + 413 H 448.54 449.02 ++ 414
H 441.53 442.31 ++ 415 H 484.52 485.32 + 417 H 485.41 485.29 + 418
H 476.57 477.23 ++ 419 H 452.50 453.03 + 421 H 446.55 447.19 + 422
H 446.55 447.19 ++ 423 H 434.51 435.30 ++ 424 H 396.53 397.24 + 425
H 450.97 451.09 + 428 H 460.57 461.28 + 430 H 485.41 485.28 ++ 433
H 460.57 461.27 ++ 436 H 480.99 481.16 ++ 437 H 464.99 465.13 + 438
H 502.51 503.26 ++ 439 H 502.51 503.27 ++ 442 H 484.52 485.32 ++
443 H 518.96 519.28 ++ 444 H 468.96 469.29 + 446 H 509.61 510.36 ++
449 H 452.50 453.03 ++ 450 H 430.55 431.33 + 451 H 452.50 453.02 +
452 H 434.51 435.31 ++ 453 H 451.96 452.10 + 454 H 485.41 485.29 ++
455 H 421.50 422.02 459 H 531.05 531.09 460 H 466.58 467.26 + 461 H
430.55 431.33 + 463 H 434.54 435.32 ++ 464 H 450.97 451.09 ++ 466 H
407.47 408.19 + 470 H 509.45 509.21 + 471 H 467.57 468.20 ++ 475 H
464.54 465.18 ++ 476 H 476.57 477.23 ++ 477 H 472.59 473.25 ++ 479
H 485.41 485.29 + 480 H 390.51 391.30 + 481 H 452.58 453.02 ++ 482
H 466.60 467.24 ++ 483 H 502.64 503.26 +++ 485 I 418.56 419.24 +
486 I 404.53 405.33 + 487 I 482.60 483.29 ++ 488 I 487.02 487.25 +
489 I 512.63 513.33 +++ 490 I 470.57 471.35 +++ 491 I 466.60 467.25
+ 492 I 520.57 521.23 +++ 493 I 536.57 537.30 ++ 494 I 523.65
524.45 +++ 495 I 505.04 505.09 ++ 497 I 536.57 537.30 + 498 I
482.60 483.30 + 499 I 470.60 471.38 + 500 I 512.03 512.29 +++ 501 I
470.57 471.35 ++ 503 I 471.58 472.28 + 505 I 520.61 521.23 + 506 I
545.66 546.17 ++++ 509 I 574.70 575.32 +++ 510 I 612.67 613.09 ++++
512 I 558.70 559.19 ++ 514 I 555.02 555.07 + 515 I 602.60 603.35
+++ 516 I 534.60 535.14 ++ 517 I 484.59 485.32 ++ 518 I 535.49
535.04 ++++ 519 I 535.49 535.03 +++ 520 I 534.60 535.14 ++ 522 I
501.05 501.20 +++ 523 I 518.58 519.29 + 524 I 544.67 545.25 ++++
525 I 487.02 487.24 + 526 I 505.01 505.07 ++ 527 I 528.67 529.17
+++ 528 I 520.57 521.23 ++ 531 I 484.62 485.34 ++ 532 I 536.57
537.30 + 533 I 466.60 467.25 +++ 534 I 510.61 511.35 +++ 535 I
520.57 521.23 ++ 536 I 505.01 505.06 ++ 537 I 488.56 489.26 ++ 538
I 521.47 521.11 ++ 539 I 505.01 505.05 ++ 540 I 488.56 489.25 + 541
I 501.05 501.19 ++++ 542 I 521.47 521.10 + 543 I 488.56 489.26 ++
545 I 505.01 505.03 ++ 546 I 484.59 485.32 + 548 I 496.63 497.36 +
549 I 512.63 513.33 ++ 550 I 480.63 481.21 + 552 J 438.66 439.43
++++ 553 J 492.66 493.37 ++ 554 J 430.59 431.35 ++++ 555 J 354.50
355.27 + 556 J 408.59 409.36 + 557 J 366.51 367.23 + 558 J 382.55
383.31 ++ 559 J 430.59 431.35 ++ 560 J 403.53 404.45 ++ 562 J
432.56 433.30 + 564 J 446.55 447.20 ++++ 565 J 452.60 453.09 ++++
566 J 462.59 463.29 + 567 J 484.60 485.34 ++ 568 J 494.64 495.34 +
570 J 471.43 471.34 ++
571 J 427.55 428.17 ++++ 572 J 458.65 459.35 ++++ 576 J 494.64
495.35 +++ 583 J 382.55 383.31 + 584 J 432.56 433.30 + 585 J 430.59
431.35 ++ 586 J 497.04 497.38 + 588 J 538.69 539.37 ++ 589 J 460.57
461.27 +++ 590 J 471.43 471.33 + 591 J 462.59 463.29 + 592 J 538.69
539.37 ++++ 593 J 448.56 449.09 + 594 J 541.49 541.24 + 595 J
445.54 446.17 + 596 J 446.55 447.20 +++ 597 J 481.44 481.05 +++ 598
J 436.98 437.12 + 599 J 480.99 481.17 + 601 J 436.98 437.12 +++ 602
J 416.57 417.37 ++ 603 J 427.55 428.16 + 604 J 470.54 471.38 ++++
605 J 420.53 421.21 + 606 J 416.57 417.37 + 607 J 420.53 421.21
++++ 608 J 462.59 463.30 + 610 J 403.53 404.46 + 611 J 454.97
455.21 +++ 612 J 488.53 489.30 ++++ 613 J 482.42 482.13 + 614 J
481.44 481.04 + 615 J 432.56 433.30 +++ 618 J 499.43 499.13 + 619 J
394.56 395.19 + 620 J 486.54 487.29 ++ 621 JJ 468.55 469.31 +++ 622
J 526.65 527.31 ++ 623 J 480.58 481.25 + 624 J 468.55 469.32 + 625
J 446.59 447.23 + 626 J 562.63 563.31 ++ 627 J 482.53 483.31 ++++
628 J 450.55 451.20 + 629 J 450.55 451.20 + 630 J 446.59 447.22
++++ 631 J 462.59 463.29 + 632 J 486.54 487.29 ++ 633 J 462.59
463.29 + 634 J 437.97 438.15 + 635 J 454.97 455.22 + 636 J 430.56 +
.DELTA. - Method of synthesis described in "Synthetic Methods"
section
[0520] At least some of the chemical names of compounds of the
invention as given and set forth in this application, may have been
generated on an automated basis by use of a commercially available
chemical naming software program, and have not been independently
verified. Representative programs performing this function include
the Lexichem naming tool sold by Open Eye Software, Inc. and the
Autonom Software tool sold by MDL, Inc. Also, the various groups as
recited in Tables 1A-1D may be attached to the core structure in a
conventional manner which should occur to those skilled in the
art.
[0521] From the foregoing description, various modifications and
changes in the compositions and methods of this invention will
occur to those skilled in the art. All such modifications coming
within the scope of the appended claims are intended to be included
therein.
[0522] All publications, including but not limited to patents and
patent applications, cited in this specification are herein
incorporated by reference as if each individual publication were
specifically and individually indicated to be incorporated by
reference herein as though fully set forth.
* * * * *