U.S. patent application number 09/922729 was filed with the patent office on 2003-04-17 for amino-phthalazinone derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions containing them.
This patent application is currently assigned to PHARMACIA & UPJOHN S.p.A.. Invention is credited to Pulici, Maurizio.
Application Number | 20030073692 09/922729 |
Document ID | / |
Family ID | 25447517 |
Filed Date | 2003-04-17 |
United States Patent
Application |
20030073692 |
Kind Code |
A1 |
Pulici, Maurizio |
April 17, 2003 |
Amino-phthalazinone derivatives active as kinase inhibitors,
process for their preparation and pharmaceutical compositions
containing them
Abstract
Compounds which are amino-phthalazinone derivatives and
pharmaceutically acceptable salts thereof, together with
pharmaceutical compositions comprising them are disclosed; these
compounds or compositions are useful in the treatment of diseases
caused by and/or associated with an altered protein kinase activity
such as cancer, cell proliferative disorders, Alzheimer's disease,
viral infections, auto-immune diseases and neurodegenerative
disorders.
Inventors: |
Pulici, Maurizio; (Caponago,
IT) |
Correspondence
Address: |
OBLON SPIVAK MCCLELLAND MAIER & NEUSTADT PC
FOURTH FLOOR
1755 JEFFERSON DAVIS HIGHWAY
ARLINGTON
VA
22202
US
|
Assignee: |
PHARMACIA & UPJOHN
S.p.A.
Via Robert Koch 1.2
Milan
IT
20152
|
Family ID: |
25447517 |
Appl. No.: |
09/922729 |
Filed: |
August 7, 2001 |
Current U.S.
Class: |
514/249 ;
544/237 |
Current CPC
Class: |
A61P 11/00 20180101;
A61P 19/02 20180101; A61P 35/00 20180101; C07D 401/06 20130101;
A61P 25/00 20180101; A61P 13/12 20180101; A61P 37/04 20180101; A61P
25/28 20180101; C07D 237/34 20130101; A61P 21/00 20180101; A61P
9/10 20180101; A61P 35/04 20180101; C07D 405/12 20130101; A61P
35/02 20180101; A61P 37/06 20180101; C07D 237/32 20130101; A61P
9/08 20180101; A61P 31/12 20180101; C07D 409/06 20130101; A61P
31/18 20180101; C04B 35/632 20130101; C07D 401/04 20130101; C07D
401/12 20130101; A61P 43/00 20180101; A61P 17/06 20180101 |
Class at
Publication: |
514/249 ;
544/237 |
International
Class: |
C07D 237/32; A61K
031/502 |
Claims
1. A method for treating diseases caused by and/or associated with
an altered protein kinase activity which comprises administering to
a mammal in need thereof an effective amount of an
amino-phthalazinone derivative represented by formula (I) 14wherein
Ra and Rb are, each independently, a hydrogen atom or a group,
optionally further substituted, selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
or one of Ra or Rb is hydrogen or an optionally substituted
straight or branched C.sub.1-C.sub.6 alkyl group, and the other is
a group selected from --COR', --CONHR', --COOR' or --SO.sub.2R',
wherein R' is hydrogen or an optionally substituted group selected
from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl, as set forth above; R.sub.1 is a
group of formula --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5
are, each independently, hydrogen or an optionally substituted
group selected from straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl or cycloalkyl C.sub.1-C.sub.6 alkyl,
aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7 membered heterocyclyl or
heterocyclyl C.sub.1-C.sub.6 alkyl with from 1 to 3 heteroatoms
selected among nitrogen, oxygen or sulfur; or R.sub.1 is a group of
formula --NHR', --NR'COR", --NR'CONHR" or --NR'SO.sub.2R", wherein
R' has the above reported meanings other than hydrogen, and R" is
hydrogen or has the meanings set forth above for R'; R.sub.2 is a
hydrogen atom or it is a group, optionally further substituted,
selected from straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl or cycloalkyl C.sub.1-C.sub.6 alkyl,
aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7 membered heterocyclyl or
heterocyclyl C.sub.1-C.sub.6 alkyl with from 1 to 3 heteroatoms
selected among nitrogen, oxygen or sulfur; any R.sub.3, being
placed in one or more of the free positions 5, 6 and 8 of the
phthalazinone ring are, independently from each other, halogen,
nitro, carboxy, cyano or a group optionally further substituted
selected from straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl or cycloalkyl C.sub.1-C.sub.6 alkyl,
aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7 membered heterocyclyl or
heterocyclyl C.sub.1-C.sub.6 alkyl with from 1 to 3 heteroatoms
selected among nitrogen, oxygen or sulfur; or R.sub.3 is a group
selected from --COR', --CONHR', --SO.sub.2R', --NR'R", --NR'COR",
--NR'CONHR' or --NR'S.sub.2R", wherein R' and R" are, the same or
different, hydrogen or a group as set forth above; m is 0 or an
integer from 1 to 3; or a pharmaceutically acceptable salt
thereof.
2. The method of claim 1 wherein the disease caused by and/or
associated with an altered protein kinase activity is a cell
proliferative disorder selected from the group consisting of
cancer, Alzheimer's disease, viral infections, auto-immune diseases
and neurodegenerative disorders.
3. The method of claim 2 wherein the cancer is selected from
carcinoma, squamous cell carcinoma, hematopoietic tumors of
lymphoid or myeloid lineage, tumors of mesenchymal origin, tumors
of the central and peripheral nervous system, melanoma, seminoma,
teratocarcinoma, osteosarcoma, xeroderma pigmentosum,
keratocanthoma, thyroid follicular cancer and Kaposi's sarcoma.
4. The method of claim 1 wherein the cell proliferative disorder is
selected from benign prostate hyperplasia, familial adenomatosis,
polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell
proliferation associated with atherosclerosis, pulmonary fibrosis,
arthritis glomerulonephritis and post-surgical stenosis and
restenosis.
5. The method of claim 1 which provides tumor angiogenesis and
metastasis inhibition.
6. The method of claim 1 further comprising subjecting the mammal
in need thereof to a radiation therapy or chemotherapy regimen in
combination with at least one cytostatic or cytotoxic agent.
7. The method of claim 1 wherein the mammal in need thereof is a
human.
8. The method of claim 1 wherein, within the compounds of formula
(I), one of Ra and Rb is a hydrogen atom and the other is a group
--COR', --CONHR', --COOR' or --SO.sub.2R', wherein R' is as defined
in claim 1.
9. The method of claim 1 wherein, within the compounds of formula
(I), one of Ra and Rb is a hydrogen atom and the other is a group
--COR', --CONHR', --COOR' or --SO.sub.2R', R.sub.2 is hydrogen, m
is 0 and R.sub.1 and R' are as defined in claim 1.
10. A method for inhibiting protein kinase activity which comprises
contacting the said kinase with an effective amount of a compound
as defined in claim 1.
11. An amino-phthalazinone derivative represented by formula (I)
15wherein Ra and Rb are, each independently, a hydrogen atom or a
group, optionally further substituted, selected from straight or
branched C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or
cycloalkyl C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl,
5 to 7 membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl
with from 1 to 3 heteroatoms selected among nitrogen, oxygen or
sulfur; or one of Ra or Rb is hydrogen or an optionally substituted
straight or branched C.sub.1-C.sub.6 alkyl group, and the other is
a group selected from --COR', --CONHR', --COOR' or --SO.sub.2R',
wherein R' is hydrogen or an optionally substituted group selected
from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl, as set forth above; R.sub.1 is a
group of formula --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5
are, each independently, hydrogen or an optionally substituted
group selected from straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl or cycloalkyl C.sub.1-C.sub.6 alkyl,
aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7 membered heterocyclyl or
heterocyclyl C.sub.1-C.sub.6 alkyl with from 1 to 3 heteroatoms
selected among nitrogen, oxygen or sulfur; or R.sub.1 is a group of
formula --NHR', --NR'COR", --NR'CONHR" or --NR'SO.sub.2R", wherein
R' has the above reported meanings other than hydrogen, and R" is
hydrogen or has the meanings set forth above for R'; R.sub.2 is a
hydrogen atom or it is a group, optionally further substituted,
selected from straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl or cycloalkyl C.sub.1-C.sub.6 alkyl,
aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7 membered heterocyclyl or
heterocyclyl C.sub.1-C.sub.6 alkyl with from 1 to 3 heteroatoms
selected among nitrogen, oxygen or sulfur; any R.sub.3, being
placed in one or more of the free positions 5, 6 and 8 of the
phthalazinone ring are, independently from each other, halogen,
nitro, carboxy, cyano or a group optionally further substituted
selected from straight or branched C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl or cycloalkyl C.sub.1-C.sub.6 alkyl,
aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7 membered heterocyclyl or
heterocyclyl C.sub.1-C.sub.6 alkyl with from 1 to 3 heteroatoms
selected among nitrogen, oxygen or sulfur; or R.sub.3 is a group
selected from --COR', --CONHR', --SO.sub.2R', --NR'R", --NR'COR",
--NR'CONHR' or --NR'SO.sub.2R", wherein R' and R" are, the same or
different, hydrogen or a group as set forth above; m is 0 or an
integer from 1 to 3; or a pharmaceutically acceptable salt thereof;
the compounds N- [3,4-dihydro-4-oxo-1- (4-pyridinylmethyl)
-6-phthalazinyl]-acetamide and
N-[3,4-dihydro-4-oxo-1-(4-pyridinylmethyl)-6-phthalazinyl]-2,2,2-trif-
luoro-acetamide, being excluded.
12. A compound of formula (I) according to claim 11 wherein one of
Ra or Rb is a hydrogen atom or an optionally substituted straight
or branched C.sub.1-C.sub.6 alkyl group and the other is a group
--COR' wherein R' is an optionally substituted group selected from
alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl
or heterocyclylalkyl, as defined in claim 11, and R.sub.1, R.sub.2,
R.sub.3 and m are as defined in claim 11.
13. A compound of formula (I) according to claim 12 wherein R.sub.1
is a group --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as
defined in claim 11, R.sub.2 is hydrogen and m is 0.
14. A compound of formula (I) according to claim 11 wherein one of
Ra or Rb is a hydrogen atom or an optionally substituted straight
or branched C.sub.1-C.sub.6 alkyl group and the other is a group
--CONHR' wherein R' is a hydrogen atom or an optionally substituted
group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heterocyclyl or heterocyclylalkyl, as defined in claim
11, and R.sub.1, R.sub.2, R.sub.3 and m are as defined in claim
11.
15. A compound of formula (I) according to claim 14 wherein R.sub.1
is a group --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as
defined in claim 11, R.sub.2 is hydrogen and m is 0.
16. A compound of formula (I) according to claim 11 wherein one of
Ra or Rb is a hydrogen atom or an optionally substituted straight
or branched C.sub.1-C.sub.6 alkyl group and the other is a group
--COOR' wherein R' is a hydrogen atom or an optionally substituted
group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heterocyclyl or heterocyclylalkyl, as defined in claim
11, and R.sub.1, R.sub.2, R.sub.3 and m are as defined in claim
11.
17. A compound of formula (I) according to claim 16 wherein R.sub.1
is a group --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as
defined in claim 11, R.sub.2 is hydrogen and m is 0.
18. A compound of formula (I) according to claim 11 wherein one of
Ra or Rb is a hydrogen atom or an optionally substituted straight
or branched C.sub.1-C.sub.6 alkyl group and the other is a group
--SO.sub.2R' wherein R' is an optionally substituted group selected
from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl, as defined in claim 11, and
R.sub.1, R.sub.2, R.sub.3 and m are as defined in claim 11.
19. A compound of formula (I) according to claim 18 wherein R.sub.1
is a group --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as
defined in claim 11, R.sub.2 is hydrogen and m is 0.
20. A compound of formula (I) according to claim 11 wherein Ra and
Rb are both hydrogen atoms and R.sub.1, R.sub.2, R.sub.3 and m are
as defined in claim 11.
21. A compound of formula (I) according to claim 20 wherein R.sub.1
is a group --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as
defined in claim 11, R.sub.2 is hydrogen and m is 0.
22. A compound of formula (I) according to claim 11 wherein one of
Ra or Rb is a hydrogen atom or an optionally substituted straight
or branched C.sub.1-C.sub.6 alkyl and the other is a group,
optionally further substituted, selected from alkyl,
cycloalkylalkyl, arylalkyl or heterocyclylalkyl as defined in claim
11, and R.sub.1, R.sub.2, R.sub.3 and m are as defined in claim
11.
23. A compound of formula (I) according to claim 22 wherein R.sub.1
is a group --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as
above defined, R.sub.2 is hydrogen and m is 0.
24. A compound of formula (I) as defined in claim 11, optionally in
the form of a pharmaceutically acceptable salt, selected from: 1.
4-(4-Oxo-6-propionylamino-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic
acid methyl ester; 2.
4-[4-Oxo-6-(4-trifluoromethyl-benzoylamino)-3,4-dihydro--
phthalazin-1-ylmethyl]-benzoic acid methyl ester; 3.
4-{6-[(Furan-2-carbonyl)-amino]-4-oxo-3,4-dihydro-phthalazin-1-ylmethyl}--
benzoic acid methyl ester; 4.
4-[6-(3,4-Dimethoxy-benzoylamino)-4-oxo-3,4--
dihydro-phthalazin-1-ylmethyl]-benzoic acid methyl ester; 5.
4-[6-(3-Cyclopentyl-propionylamino)-4-oxo-3,4-dihydro-phthalazin-1-ylmeth-
yl]-benzoic acid methyl ester; 6.
4-[4-Oxo-6-(2-propyl-pentanoylamino)-3,4-
-dihydro-phthalazin-1-ylmethyl]-benzoic acid methyl ester; 7.
4-{4-Oxo-6-[3-(3-trifluoromethyl-phenyl)-ureido]-3,4-dihydro-phthalazin-1-
-ylmethyl}-benzoic acid methyl ester; 8.
4-{6-[3-(3-Methoxy-phenyl)-ureido-
]-4-oxo-3,4-dihydro-phthalazin-1-ylmethyl}-benzoic acid methyl
ester; 9.
4-[4-Oxo-6-(3-p-tolyl-ureido)-3,4-dihydro-phthalazin-1-ylmethyl]-benzoic
acid methyl ester; 10.
4-{6-[3-(2,4-Difluoro-phenyl)-ureido]-4-oxo-3,4-di-
hydro-phthalazin-1-ylmethyl}-benzoic acid methyl ester; 11.
4-{6-[3-(3,4-Dichloro-phenyl)-ureido]-4-oxo-3,4-dihydro-phthalazin-1-ylme-
thyl}-benzoic acid methyl ester; 12.
4-[4-Oxo-6-(3-pyridin-3-yl-ureido)-3,-
4-dihydro-phthalazin-1-ylmethyl]-benzoic acid methyl ester; 13.
4-(6-Amino-4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic acid
methyl ester; 14.
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-
-yl]-propionamide; 15.
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-p-
hthalazin-6-yl]-4-trifluoromethyl-benzamide; 16. Furan-2-carboxylic
acid
[1-(4-chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide;
17.
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3,-
4-dimethoxy-benzamide; 18.
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihyd-
ro-phthalazin-6-yl]-3-cyclopentyl-propionamide; 19.
2-Propyl-pentanoic acid
[1-(4-chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-ami-
de; 20.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-
-3-(3-trifluoromethyl-phenyl)-urea; 21.
1-[1-(4-Chloro-3-fluoro-benzyl)-4--
oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-methoxy-phenyl)-urea; 22.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p-to-
lyl-urea; 23.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-
-6-yl]-3-(2,4-difluoro-phenyl)-urea; 24.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-
-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3,4-dichloro-phenyl)-urea; 25.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-pyri-
din-3-yl-urea; 26.
7-Amino-4-(4-chloro-3-fluoro-benzyl)-2H-phthalazin-1-on- e; 27.
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazin-6--
yl}-propionamide; 28.
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydr-
o-phthalazin-6-yl}-4-trifluoromethyl-benzamide; 29.
Furan-2-carboxylic acid
{1-[(E)-3-(4-nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazin-6-yl}-
-amide; 30.
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalaz-
in-6-yl}-3,4-dimethoxy-benzamide; 31.
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]--
4-oxo-3,4-dihydro-phthalazin-6-yl}-3-cyclopentyl-propionamide; 32.
2-Propyl-pentanoic acid
{1-[(E)-3-(4-nitro-phenyl)-allyl]-4-oxo-3,4-dihyd-
ro-phthalazin-6-yl}-amide; 33.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3-
,4-dihydro-phthalazin-6-yl}-3-(3-trifluoromethyl-phenyl)-urea; 34.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazin-6-yl}-(3-
-methoxy-phenyl)-urea; 35.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-d-
ihydro-phthalazin-6-yl}-3-p-tolyl-urea; 36.
1-{1-[(E)-3-(4-Nitro-phenyl)-a-
llyl]-4-oxo-3,4-dihydro-phthalazin-6-yl}-3-(2,4-difluoro-phenyl)-urea;
37.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazin-6-yl}-3--
(3,4-dichloro-phenyl)-urea; 38.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo--
3,4-dihydro-phthalazin-6-yl}-3-pyridin-3-yl-urea; 39.
7-Amino-4-[(E)-3-(4-nitro-phenyl)-allyl]-2H-phthalazin-1-one; 40.
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-propionamide;
41.
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4-trifluo-
romethyl-benzamide; 42. Furan-2-carboxylic acid
(4-oxo-1-thiophen-3-ylmeth- yl-3,4-dihydro-phthalazin-6-yl)-amide;
43. N-(4-Oxo-1-thiophen-3-ylmethyl--
3,4-dihydro-phthalazin-6-yl)-3,4-dimethoxy-benzamide; 44.
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-cyclopentyl-
-propionamide; 45. 2-Propyl-pentanoic acid
(4-oxo-1-thiophen-3-ylmethyl-3,- 4-dihydro-phthalazin-6-yl)-amide;
46. 1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-d-
ihydro-phthalazin-6-yl)-3-(3-trifluoromethyl-phenyl)-urea; 47.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-(3-methoxy-ph-
enyl)-urea; 48.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl-
)-3-p-tolyl-urea; 49.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazi-
n-6-yl)-3-(2,4-difluoro-phenyl)-urea; 50.
1-(4-Oxo-1-thiophen-3-ylmethyl-3-
,4-dihydro-phthalazin-6-yl)-3-(3,4-dichloro-phenyl)-urea; 51.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-pyridin-3-y-
l-urea; 52. 7-Amino-4-thiophen-3-ylmethyl-2H-phthalazin-1-one; 53.
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propionamide;
54.
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-trifluor-
omethyl-benzamide; 55. Furan-2-carboxylic acid
[1-(3-methoxy-benzyl)-4-oxo- -3,4-dihydro-phthalazin-6-yl]-amide;
56. N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-
-dihydro-phthalazin-6-yl]-3,4-dimethoxy-benzamide; 57.
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cyclopentyl--
propionamide; 58. 2-Propyl-pentanoic acid
[1-(3-methoxy-benzyl)-4-oxo-3,4-- dihydro-phthalazin-6-yl]-amide;
59. 1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihy-
dro-phthalazin-6-yl]-3-(3-trifluoromethyl-phenyl)-urea; 60.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-(3-methoxy-phe-
nyl)-urea; 61.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-p-tolyl-urea; 62.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-
-yl]-3-(2,4-difluoro-phenyl)-urea; 63.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-d-
ihydro-phthalazin-6-yl]-3-(3,4-dichloro-phenyl)-urea; 64.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-pyridin-3-yl-
-urea; 65. 7-Amino-4-(3-methoxy-benzyl)-2H-phthalazin-1-one; 66.
N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-propionamide; 67.
N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-4-trifluoromethyl-benzamid-
e; 68. Furan-2-carboxylic acid
(4-oxo-1-propyl-3,4-dihydro-phthalazin-6-yl- )-amide; 69.
N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3,4-dimethoxy--
benzamide; 70.
N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-cyclopenty-
l-propionamide; 71. 2-Propyl-pentanoic acid
(4-oxo-1-propyl-3,4-dihydro-ph- thalazin-6-yl)-amide; 72.
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-
-(3-trifluoromethyl-phenyl)-urea; 73.
1-(4-Oxo-1-propyl-3,4-dihydro-phthal-
azin-6-yl)-(3-methoxy-phenyl)-urea; 74.
1-(4-Oxo-1-propyl-3,4-dihydro-phth- alazin-6-yl)-3-p-tolyl-urea;
75. 1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin--
6-yl)-3-(2,4-difluoro-phenyl)-urea; 76.
1-(4-Oxo-1-propyl-3,4-dihydro-phth-
alazin-6-yl)-3-(3,4-dichloro-phenyl)-urea; 77.
1-(4-Oxo-1-propyl-3,4-dihyd-
ro-phthalazin-6-yl)-3-pyridin-3-yl-urea; 78.
7-Amino-4-propyl-2H-phthalazi- n-1-one; 79.
N-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
propionamide; 80.
N-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-
-yl]-4-trifluoromethyl-benzamide; 81. Furan-2-carboxylic acid
[1-(3,3-dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide;
82.
N-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3,4-dimethox-
y-benzamide; 83.
N-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-cyclopentyl-propionamide; 84. 2-Propyl-pentanoic acid
[1-(3,3-dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide;
85.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trifluo-
romethyl-phenyl)-urea; 86.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-pht-
halazin-6-yl]-(3-methoxy-phenyl)-urea; 87.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-
-3,4-dihydro-phthalazin-6-yl]-3-p-tolyl-urea; 88.
1-[1-(3,3-Dimethyl-butyl-
)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2,4-difluoro-phenyl)-urea;
89.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3,4-dichl-
oro-phenyl)-urea; 90.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalaz-
in-6-yl]-3-pyridin-3-yl-urea; 91.
7-Amino-4-(3,3-dimethyl-butyl)-2H-phthal- azin-1-one; 92.
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]--
propionamide; 93.
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl-
]-4-trifluoromethyl-benzamide; 94. Furan-2-carboxylic acid
[4-oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-amide; 95.
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3,4-dimethoxy-b-
enzamide; 96.
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3--
cyclopentyl-propionamide; 97. 2-Propyl-pentanoic acid
[4-oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-amide; 98.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-(3-trifluorom-
ethyl-phenyl)-urea; 99.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazi- n-6-yl]-(
3-methoxy-phenyl)-urea; 100. 1-[4-Oxo-1-(3-phenyl-propyl)-3,4-di-
hydro-phthalazin-6-yl]-3-p-tolyl-urea; 101.
1-[4-Oxo-1-(3-phenyl-propyl)-3-
,4-dihydro-phthalazin-6-yl]-3-(2,4-difluoro-phenyl)-urea; 102.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-(3,4-dichloro-
-phenyl)-urea; 103.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6--
yl]-3-pyridin-3-yl-urea; 104.
7-Amino-4-(3-phenyl-propyl)-2H-phthalazin-1-- one; 105.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-propi-
onamide; 106.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4-
-trifluoromethyl-benzamide; 107. Furan-2-carboxylic acid
(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-amide;
108.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-succinamic
acid ethyl ester; 109.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalaz-
in-6-yl)-3-cyclopentyl-propionamide; 110. 2-Propyl-pentanoic acid
(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-amide;
111.
1-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(3-trifluoro-
methyl-phenyl)-urea; 112.
1-(3-Methoxy-phenyl)-3-(4-oxo-1-pyridin-3-ylmeth-
yl-3,4-dihydro-phthalazin-6-yl)-urea; 113.
1-(4-Oxo-1-pyridin-3-ylmethyl-3-
,4-dihydro-phthalazin-6-yl)-3-p-tolyl-urea; 114.
1-(2,4-Difluoro-phenyl)-3-
-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-urea;
115.
1-(3,4-Dichloro-phenyl)-3-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthala-
zin-6-yl)-urea; 116.
1-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin--
6-yl)-3-pyridin-3-yl-urea; 117.
7-Amino-4-pyridin-3-ylmethyl-2H-phthalazin- -1-one 118.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-ben-
zamide; 119.
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-pro-
pionamide; 120.
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
4-trifluoromethyl-benzamide; 121. Furan-2-carboxylic acid
[1-(4-chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; 122.
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succinamic
acid ethyl ester; 123.
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-y-
l]-3-cyclopentyl-propionamide; 124. 2-Propyl-pentanoic acid
[1-(4-chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; 125.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trifluorom-
ethyl-phenyl)-urea; 126.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalaz-
in-6-yl]-3-(3-methoxy-phenyl)-urea; 127.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4--
dihydro-phthalazin-6-yl]-3-p-tolyl-urea; 128.
1-[1-(4-Chloro-benzyl)-4-oxo-
-3,4-dihydro-phthalazin-6-yl]-3-(2,4-difluoro-phenyl)-urea; 129.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3,4-dichloro-
-phenyl)-urea; 130.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-pyridin-3-yl-urea; 131.
7-Amino-4-(4-Chloro-benzyl)-2H-phthalazin-1-- one; 132.
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propion-
amide; 133.
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-tri-
fluoromethyl-benzamide; 134. Furan-2-carboxylic acid
[1-(4-cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; 135.
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succinamic
acid ethyl ester; 136.
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl-
]-3-cyclopentyl-propionamide; 137. 2-Propyl-pentanoic acid
[1-(4-cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; 138.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trifluorome-
thyl-phenyl)-urea; 139.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-
-6-yl]-3-(3-methoxy-phenyl)-urea; 140.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dih-
ydro-phthalazin-6-yl]-3-p-tolyl-urea; 141.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-
-dihydro-phthalazin-6-yl]-3-(2,4-difluoro-phenyl)-urea; 142.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3,4-dichloro--
phenyl)-urea; 143.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl-
]-3-pyridin-3-yl-urea; 144.
7-Amino-4-(4-Cyano-benzyl)-2H-phthalazin-1-one- ; 145.
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propionam-
ide; 146.
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-trif-
luoromethyl-benzamide; 147. Furan-2-carboxylic acid
[1-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; 148.
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succinamic
acid ethyl ester; 149.
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-y-
l]-3-cyclopentyl-propionamide; 150. 2-Propyl-pentanoic acid
[1-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; 151.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trifluorom-
ethyl-phenyl)-urea; 152.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalaz-
in-6-yl]-3-(3-methoxy-phenyl)-urea; 153.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4--
dihydro-phthalazin-6-yl]-3-p-tolyl-urea; 154.
1-[1-(3-Fluoro-benzyl)-4-oxo-
-3,4-dihydro-phthalazin-6-yl]-3-(2,4-difluoro-phenyl)-urea; 155.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3,4-dichloro-
-phenyl)-urea; 156.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-pyridin-3-yl-urea; 157.
7-Amino-4-(3-Fluoro-benzyl)-2H-phthalazin-1-- one; 158.
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propio-
namide; 159.
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-t-
rifluoromethyl-benzamide; 160. Furan-2-carboxylic acid
[1-(3-methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; 161.
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succinamic
acid ethyl ester; 162.
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-y-
l]-3-cyclopentyl-propionamide; 163. 2-Propyl-pentanoic acid
[1-(3-methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide; 164.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trifluorom-
ethyl-phenyl)-urea; 165.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalaz-
in-6-yl]-3-(3-methoxy-phenyl)-urea; 166.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4--
dihydro-phthalazin-6-yl]-3-p-tolyl-urea; 167.
1-[1-(3-Methyl-benzyl)-4-oxo-
-3,4-dihydro-phthalazin-6-yl]-3-(2,4-difluoro-phenyl)-urea; 168.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3,4-dichloro-
-phenyl)-urea; 169.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-pyridin-3-yl-urea; 170.
7-Amino-4-(3-Methyl-benzyl)-2H-phthalazin-1-- one; 171.
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-pr-
opionamide; 172.
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-
-yl]-4-trifluoromethyl-benzamide; 173. Furan-2-carboxylic acid
[1-(2,4-dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide;
174.
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succinamic
acid ethyl ester; 175.
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phtha-
lazin-6-yl]-3-cyclopentyl-propionamide; 176. 2-Propyl-pentanoic
acid
[1-(2,4-dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-amide;
177.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-triflu-
oromethyl-phenyl)-urea; 178.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro--
phthalazin-6-yl]-3-(3-methoxy-phenyl)-urea; 179.
1-[1-(2,4-Dichloro-benzyl-
)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p-tolyl-urea; 180.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2,4-difl-
uoro-phenyl)-urea; 181.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phtha-
lazin-6-yl]-3-(3,4-dichloro-phenyl)-urea; 182.
1-[1-(2,4-Dichloro-benzyl)--
4-oxo-3,4-dihydro-phthalazin-6-yl]-3-pyridin-3-yl-urea; 183.
7-Amino-4-(2,4-dichloro-benzyl)-2H-phthalazin-1-one; 184.
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-propionamide;
185.
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4-triflu-
oromethyl-benzamide; 186. Furan-2-carboxylic acid
(4-oxo-1-quinolin-3-ylme- thyl-3,4-dihydro-phthalazin-6-yl)-amide;
187. N-(4-Oxo-1-quinolin-3-ylmeth-
yl-3,4-dihydro-phthalazin-6-yl)-succinamic acid ethyl ester; 188.
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-cyclopentyl-
-propionamide; 189. 2-Propyl-pentanoic acid
(4-oxo-1-quinolin-3-ylmethyl-3- ,4-dihydro-phthalazin-6-yl)-amide;
190. 1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-
-dihydro-phthalazin-6-yl)-3-(3-trifluoromethyl-phenyl)-urea; 191.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(3-methoxy--
phenyl)-urea; 192.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-
-yl)-3-p-tolyl-urea; 193.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phtha-
lazin-6-yl)-3-(2,4-difluoro-phenyl)-urea; 194.
1-(4-Oxo-1-quinolin-3-ylmet-
hyl-3,4-dihydro-phthalazin-6-yl)-3-(3,4-dichloro-phenyl)-urea; 195.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-pyridin-3-y-
l-urea; 196. 7-Amino-4-quinolin-3-ylmethyl-2H-phthalazin-1-one;
197.
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]-propio-
namide; 198.
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin--
6-yl]-4-trifluoromethyl-benzamide; 199. Furan-2-carboxylic acid
[4-oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]-amide;
200.
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]-s-
uccinamic acid ethyl ester; 201.
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-
-dihydro-phthalazin-6-yl]-3-cyclopentyl-propionamide; 202.
2-Propyl-pentanoic acid
[4-oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-p-
hthalazin-6-yl]-amide; 203.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihy-
dro-phthalazin-6-yl]-3-(3-trifluoromethyl-phenyl)-urea; 204.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]-3-(3-m-
ethoxy-phenyl)-urea; 205.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydr-
o-phthalazin-6-yl]-3-p-tolyl-urea; 206.
1-[4-Oxo-1-(2-trifluoromethyl-benz-
yl)-3,4-dihydro-phthalazin-6-yl]-3-(2,4-difluoro-phenyl)-urea; 207.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]-3-(3,4-
-dichloro-phenyl)-urea; 208.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dih-
ydro-phthalazin-6-yl]-3-pyridin-3-yl-urea; 209.
7-Amino-4-(2-trifluorometh- yl-benzyl)-2H-phthalazin-1-one.
25. A process for preparing the compounds of formula (I) as defined
in claim 11, and the pharmaceutically acceptable salts thereof,
which process comprises: a) reacting a compound of formula (II)
16wherein R.sub.3 and m are as defined in claim 11 and Hal
represents a halogen atom, with a suitable phosphine derivative
(PL.sub.3), under optional reductive conditions, so as to obtain a
compound of formula (III) 17wherein P is a phosphorous atom and L
are the phosphine ligands; b) reacting the compound of formula
(III) with an aldehydic Resin-CHO, in the presence of a suitable
reducing agent, so as to obtain a resin supported compound of
formula (IV) 18wherein R.sub.3, m, P, L, Hal and the Resin are as
above defined; c) reacting the compound of formula (IV) with a
carbonyl derivative of formula (V) or a nitroso derivative of
formula (VI)R.sub.4--CO--R.sub.5 (V)R'--NO (VI)wherein R.sub.4,
R.sub.5 and R' are as defined in claim 11; so as to obtain the
compound of formula (VII) 19wherein A is a group
.dbd.CR.sub.4R.sub.5 or .dbd.NR', respectively; and optionally
reacting the compound of formula (VII) according to any one of the
alternative steps d.1) or d.2) below d.1) with one of the
derivatives of formula (VIII), (IX), (X) or (XI), under optional
basic conditions,R'COZ (VIII),R'NCO (IX),R'OCOZ (X),R'SO.sub.2Z
(XI)wherein Z is a halogen atom or a suitable leaving group and R'
is as defined in claim 11, so as to obtain the compound of formula
(XII) 20wherein Rb is --COR', --CONHR', --COOR' or --SO.sub.2R',
respectively; or d.2) with a compound of formula (XIII)Rb-Z
(XIII)wherein Z is a halogen atom and Rb is alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl
as defined in claim 11, so as to obtain the corresponding compound
of the above formula (XII); e) reacting the thus obtained compounds
of formula (VII) or (XII) with a hydrazine derivative of formula
(XIV)R.sub.2--NH--NH.sub.2 (XIV)wherein R.sub.2 is as defined in
claim 11, so as to obtain the compounds of formula (XV) or (XVI),
respectively 21wherein Rb, R.sub.2, R.sub.3, m and the Resin are as
above defined and R.sub.1 is a group of formula --CHR.sub.4R.sub.5
or --NHR' wherein R.sub.4, R.sub.5 and R' are as above defined; f)
reacting the compounds of formula (XV) or (XVI) under acidic
conditions so as to obtain the compound of formula (I) and,
whenever desired, converting it into another compound of formula
(I) and/or into a pharmaceutically acceptable salt thereof.
26. The process of claim 25 wherein, in step a), the phosphine
derivative is triphenylphosphine PPh.sub.3.
27. The process of claim 25 wherein, in step b), the reducing agent
is selected from pyridine-borane complex, sodium cyanoboron
hydride, sodium triacetate boron hydride or dimethylsufide
borane.
28. The process of claim 25 wherein, in step d.1), it is used a
compound of formula (VIII), (X) or (XI), wherein Z is a chlorine
atom.
29. The process of claim 25 wherein, in step f), acidic conditions
are reached by using trifluoroacetic acid.
30. Any specific compound of formula (I), as defined in claim 11,
which is obtainable, for instance through a combinatorial chemistry
technique according to the process as set forth in claim 25, by
first reacting the compound of formula (IV) 22with each one of the
aldehyde derivatives of formula (V), as set forth in table I; by
reacting any of the resultant compounds of formula (VII) with each
one of the acyl chloride derivatives of formula (VIII), as set
forth in table II; by reacting any of the resultant compounds of
formula (XII) with hydrazine; and by working according to step f)
of the process of claim 25.
31. Any specific compound of formula (I), as defined in claim 11,
which is obtainable, for instance through a combinatorial chemistry
technique according to the process as set forth in claim 25, by
first reacting the compound of formula (IV) 23with each one of the
aldehyde derivatives of formula (V), as set forth in table I; by
reacting any of the resultant compounds of formula (VII) with each
one of the isocyanate derivatives of formula (IX), as set forth in
table III; by reacting any of the resultant compounds of formula
(XII) with hydrazine; and by working according to step f) of the
process of claim 25.
32. A library of two or more amino-phthalazinone derivatives of
formula (I) 24wherein Ra and Rb are, each independently, a hydrogen
atom or a group, optionally further substituted, selected from
straight or branched C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl or cycloalkyl C.sub.1-C.sub.6 alkyl, aryl, aryl
C.sub.1-C.sub.6 alkyl, 5 to 7 membered heterocyclyl or heterocyclyl
C.sub.1-C.sub.6 alkyl with from 1 to 3 heteroatoms selected among
nitrogen, oxygen or sulfur; or one of Ra or Rb is hydrogen or an
optionally substituted straight or branched C.sub.1-C.sub.6 alkyl
group, and the other is a group selected from --COR', --CONHR',
--COOR' or --SO.sub.2R', wherein R' is hydrogen or an optionally
substituted group selected from alkyl, cycloalkyl, cycloalkylalkyl,
aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, as set forth
above; R.sub.1 is a group of formula --CHR.sub.4R.sub.5 wherein
R.sub.4 and R.sub.5 are, each independently, hydrogen or an
optionally substituted group selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
or R.sub.1 is a group of formula --NHR', --NR'COR", --NR'CONHR" or
--NR'SO.sub.2R", wherein R' has the above reported meanings other
than hydrogen, and R" is hydrogen or has the meanings set forth
above for R'; R.sub.2 is a hydrogen atom or it is a group,
optionally further substituted, selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
any R.sub.3, being placed in one or more of the free positions 5, 6
and 8 of the phthalazinone ring are, independently from each other,
halogen, nitro, carboxy, cyano or a group optionally further
substituted selected from straight or branched C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl C.sub.1-C.sub.6
alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7 membered
heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with from 1 to 3
heteroatoms selected among nitrogen, oxygen or sulfur; or R.sub.3
is a group selected from --COR', --CONHR', --SO.sub.2R', --NR'R",
--NR'COR", --NR'CONHR' or --NR'SO.sub.2R", wherein R' and R" are,
the same or different, hydrogen or a group as set forth above; m is
0 or an integer from 1 to 3; or a pharmaceutically acceptable salt
thereof.
33. A pharmaceutical composition comprising an effective amount of
a compound of formula (I) as defined in claim 11 and, at least, one
pharmaceutically acceptable excipient, carrier or diluent.
34. A pharmaceutical composition according to claim 33 further
comprising one or more chemotherapeutic agents, as a combined
preparation for simultaneous, separate or sequential use in
anticancer therapy.
35. A product or kit comprising a compound of claim 11 or a
pharmaceutical composition thereof as defined in claim 33, and one
or more chemotherapeutic agents, as a combined preparation for
simultaneous, separate or sequential use in anticancer therapy.
36. A compound of formula (I) or a pharmaceutically acceptable salt
thereof, as defined in claim 11, for use as a medicament.
37. Use of a compound of formula (I) or a pharmaceutically
acceptable salt thereof, as defined in claim 11, in the manufacture
of a medicament for treating diseases caused by and/or associated
with an altered protein kinase activity.
38. Use according to claim 37 for treating tumors.
Description
[0001] The present invention relates to amino-phthalazinone
derivatives active as kinase inhibitors and, more in particular, it
relates to 7-amino-phthalazin-1-one derivatives, to a process for
their preparation, to pharmaceutical compositions comprising them
and to their use as therapeutic agents, particularly in the
treatment of diseases linked to disregulated protein kinases.
[0002] The malfunctioning of protein kinases (PKs) is the hallmark
of numerous diseases. A large share of the oncogenes and
proto-oncogenes involved in human cancers code for PKs. The
enhanced activities of PKs are also implicated in many
non-malignant diseases, such as benign prostate hyperplasia,
familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis,
vascular smooth cell proliferation associated with atherosclerosis,
pulmonary fibrosis, arthritis glomerulonephritis and post-surgical
stenosis and restenosis. PKs are also implicated in inflammatory
conditions and in the multiplication of viruses and parasites. PKs
may also play a major role in the pathogenesis and development of
neurodegenerative disorders. For a general reference to PKs
malfunctioning or disregulation see, for instance, Current Opinion
in Chemical Biology 1999, 3, 459-465. It is an object of the
invention to provide compounds which are useful in therapy as
agents against a host of diseases caused by and/or associated to a
disregulated protein kinase activity. It is another object to
provide compounds which are endowed with multiple protein kinase
inhibiting activity. The present inventors have now discovered that
some 7-amino-phthalazin-1-one derivatives, hereinafter shortly
referred to as amino-phthalazinone derivatives or
amino-phthalazinones, are endowed with multiple protein kinase
inhibiting activity and are thus useful in therapy in the treatment
of diseases associated with disregulated protein kinases. More
specifically, the amino-phthalazinones of this invention are useful
in the treatment of a variety of cancers including, but not limited
to: carcinoma such as bladder, breast, colon, kidney, liver, lung,
including small cell lung cancer, esophagus, gall-bladder, ovary,
pancreas, stomach, cervix, thyroid, prostate, and skin, including
squamous cell carcinoma; hematopoietic tumors of lymphoid lineage,
including leukemia, acute lymphocitic leukemia, acute lymphoblastic
leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma,
non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma;
hematopoietic tumors of myeloid lineage, including acute and
chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia; tumors of mesenchymal origin, including
fibrosarcoma and rhabdomyosarcoma; tumors of the central and
peripheral nervous system, including astrocytoma, neuroblastoma,
glioma and schwannomas; other tumors, including melanoma, seminoma,
teratocarcinoma, osteosarcoma, xeroderma pigmentosum,
keratocanthoma, thyroid follicular cancer and Kaposi's sarcoma. Due
to the key role of PKs in the regulation of cellular proliferation,
these amino-phthalazinones are also useful in the treatment of a
variety of cell proliferative disorders such as, for instance,
benign prostate hyperplasia, familial adenomatosis, polyposis,
neuro-fibromatosis, psoriasis, vascular smooth cell proliferation
associated with atherosclerosis, pulmonary fibrosis, arthritis
glomerulonephritis and post-surgical stenosis and restenosis. The
compounds of the invention can be useful in the treatment of
Alzheimer's disease, as suggested by the fact that cdk5 is involved
in the phosphorylation of tau protein (J. Biochem., 117, 741-749,
1995). The compounds of this invention, as modulators of apoptosis,
may also be useful in the treatment of cancer, viral infections,
prevention of AIDS development in HIV-infected individuals,
autoimmune diseases and neurodegenerative disorders. The compounds
of this invention may be useful in inhibiting tumor angiogenesis
and metastasis. The compounds of the invention are useful as cyclin
dependent kinase (cdk) inhibitors and also as inhibitors of other
protein kinases such as, for instance, protein kinase C in
different isoforms, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora
1, Aurora 2, Bub-1, PLK, Chk1, Chk2, HER2, raf1, MEK1, MAPK, EGF-R,
PDGF-R, FGF-R, IGF-R, VEGF-R, PI3K, weel kinase, Src, Abl, Akt,
ILK, MK-2, IKK-2, Cdc7, Nek, and thus be effective in the treatment
of diseases associated with other protein kinases.
[0003] Some amino-phthalazinone and amino-phthalazinedione
derivatives are known in the art, as chemical intermediates, as
therapeutic agents and even as protein kinase inhibitors. As an
example, the compounds
N-[3-[2,4-bis(1,1-dimethylpropyl)phenoxy]propyl]-N'-(3,4-dihydro-4-oxo-6--
phthalazinyl)-urea and
2-[2,4-bis(1,1-dimethylpropyl)phenoxy]-N-(3,4-dihyd-
ro-4-oxo-6-phthalazinyl)-butanamide are disclosed as heat
development image forming agents, in JP-A-09061961 by Heisei. The
compound
N-[3,4-dihydro-3-[4-[4-(1-naphthalenyl)-1-piperazinyl]butyl]-4-oxo-6-phth-
alazinyl]-acetamide is disclosed in JP-A-10287658 by Heisei, as a
serotoninergic/dopaminergic agent. The compounds
N-[3,4-dihydro-4-oxo-1-(-
4-pyridinylmethyl)-6-phthalazinyl]-acetamide and
N-[3,4-dihydro-4-oxo-1-(4-
-pyridinylmethyl)-6-phthalazinyl]-2,2,2-trifluoro-acetamide are
disclosed in WO 98/35958 by Novartis, as synthetic intermediates
for the preparation of anilino-phthalazines, as VEGF receptor
tyrosine kinase inhibitors. In addition to the above,
phthalazinedione or phthalazinone derivatives bearing substituted
amino groups in both positions 6 and 7 of the ring such as, for
instance, 7-(cyclohexylamino)-6-phenylamino-1(2H)-p- hthalazinone
and 6,7-bis(phenylamino)-1(2H)-phthalazinone, are disclosed in
EP-A-600831 by Ciba-Geigy as protein kinase inhibitors.
[0004] Accordingly, the present invention provides a method for
treating diseases caused by and/or associated with an altered
protein kinase activity, by administering to a mammal in need
thereof an effective amount of an amino-phthalazinone derivative
represented by formula (I): 1
[0005] wherein
[0006] Ra and Rb are, each independently, a hydrogen atom or a
group, optionally further substituted, selected from straight or
branched C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or
cycloalkyl C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl,
5 to 7 membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl
with from 1 to 3 heteroatoms selected among nitrogen, oxygen or
sulfur; or one of Ra or Rb is hydrogen or an optionally substituted
straight or branched C.sub.1-C.sub.6 alkyl group, and the other is
a group selected from --COR', --CONHR', --COOR' or --SO.sub.2R',
wherein R' is hydrogen or an optionally substituted group selected
from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl, as set forth above;
[0007] R.sub.1 is a group of formula --CHR.sub.4R.sub.5 wherein
R.sub.4 and R.sub.5 are, each independently, hydrogen or an
optionally substituted group selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
or R.sub.1 is a group of formula --NHR', --NR'COR", --NR'CONHR" or
--NR'SO.sub.2R", wherein R' has the above reported meanings other
than hydrogen, and R" is hydrogen or has the meanings set forth
above for R';
[0008] R.sub.2 is a hydrogen atom or it is a group, optionally
further substituted, selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or
sulfur;
[0009] any R.sub.3, being placed in one or more of the free
positions 5, 6 and 8 of the phthalazinone ring are, independently
from each other, halogen, nitro, carboxy, cyano or a group
optionally further substituted selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
or R.sub.3 is a group selected from --COR', --CONHR', --SO.sub.2R',
--NR'R", --NR'COR", --NR'CONHR' or --NR'SO.sub.2R", wherein R' and
R" are, the same or different, hydrogen or a group as set forth
above;
[0010] m is 0 or an integer from 1 to 3;
[0011] or a pharmaceutically acceptable salt thereof.
[0012] In a preferred embodiment of the method described above, the
disease caused by and/or associated with an altered protein kinase
activity is selected from the group consisting of cancer, cell
proliferative disorders, Alzheimer's disease, viral infections,
auto-immune diseases and neurodegenerative disorders. Specific
types of cancer that may be treated include carcinoma, squamous
cell carcinoma, hematopoietic tumors of myeloid or lymphoid
lineage, tumors of mesenchymal origin, tumors of the central and
peripheral nervous system, melanoma, seminoma, teratocarcinoma,
osteosarcoma, xeroderma pigmentosum, keratocanthoma, thyroid
follicular cancer and Kaposi's sarcoma. In another preferred
embodiment of the method described above, the cell proliferative
disorder is selected from the group consisting of benign prostate
hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,
psoriasis, vascular smooth cell proliferation associated with
atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis
and post-surgical stenosis and restenosis. In addition, the method
object of the present invention, also provides tumor angiogenesis
and metastasis inhibition.
[0013] The present invention further provides an
amino-phthalazinone derivative represented by formula (I) 2
[0014] wherein
[0015] Ra and Rb are, each independently, a hydrogen atom or a
group, optionally further substituted, selected from straight or
branched C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or
cycloalkyl C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl,
5 to 7 membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl
with from 1 to 3 heteroatoms selected among nitrogen, oxygen or
sulfur; or one of Ra or Rb is hydrogen or an optionally substituted
straight or branched C.sub.1-C.sub.6 alkyl group, and the other is
a group selected from --COR', --CONHR', --COOR' or --SO.sub.2R',
wherein R' is hydrogen or an optionally substituted group selected
from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl, as set forth above;
[0016] R.sub.1 is a group of formula --CHR.sub.4R.sub.5 wherein
R.sub.4 and R.sub.5 are, each independently, hydrogen or an
optionally substituted group selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
or R.sub.1 is a group of formula --NHR', --NR'COR", --NR'CONHR" or
--NR'SO.sub.2R", wherein R' has the above reported meanings other
than hydrogen, and R" is hydrogen or has the meanings set forth
above for R';
[0017] R.sub.2 is a hydrogen atom or it is a group, optionally
further substituted, selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or
sulfur;
[0018] any R.sub.3, being placed in one or more of the free
positions 5, 6 and 8 of the phthalazinone ring are, independently
from each other, halogen, nitro, carboxy, cyano or a group
optionally further substituted selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
or R.sub.3 is a group selected from --COR', --CONHR', --SO.sub.2R',
--NR'R", --NR'COR", --NR'CONHR' or --NR'SO.sub.2R", wherein R' and
R" are, the same or different, hydrogen or a group as set forth
above;
[0019] m is 0 or an integer from 1 to 3;
[0020] or a pharmaceutically acceptable salt thereof; the compounds
N-[3,4-dihydro-4-oxo-1-(4-pyridinylmethyl)-6-phthalazinyl]-acetamide
and
N-[3,4-dihydro-4-oxo-1-(4-pyridinylmethyl)-6-phthalazinyl]-2,2,2-trifluor-
o-acetamide, being excluded.
[0021] The compounds of formula (I), object of the present
invention, may have asymmetric carbon atoms and may therefore exist
either as racemic admixtures or as individual optical isomers.
Accordingly, all the possible isomers and their admixtures and of
both the metabolites and the pharmaceutically acceptable
bio-precursors (otherwise referred to as pro-drugs) of the
compounds of formula (I), as well as any therapeutic method of
treatment comprising them, are also within the scope of the present
invention.
[0022] As used herein, unless otherwise specified, with the term
halogen atom we intend a chlorine, bromine, fluorine or iodine
atom. With the term straight or branched C.sub.1-C.sub.6 alkyl we
intend a group such as, for instance, methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,
n-hexyl and the like. With the term C.sub.3-C.sub.6 cycloalkyl we
intend a group such as, for instance, cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl. With the term aryl we intend a mono-,
bi- or poly- either carbocyclic as well as heterocyclic hydrocarbon
with from 1 to 4 ring moieties, either fused or linked to each
other by single bonds, wherein at least one of the carbocyclic or
heterocyclic rings is aromatic. Non limiting examples of aryl
groups are, for instance, phenyl, indanyl, biphenyl, .alpha.- or
.beta.-naphthyl, fluorenyl, 9,10-dihydroanthracenyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl,
imidazopyridyl, 1,2-methylenedioxypheny- l, thiazolyl,
isothiazolyl, pyrrolyl, pyrrolyl-phenyl, furyl, phenyl-furyl,
benzotetrahydrofuranyl, oxazolyl, isoxazolyl, pyrazolyl, chromenyl,
thienyl, benzothienyl, isoindolinyl, benzoimidazolyl,
isoindolinyl-phenyl, quinolinyl, isoquinolinyl,
2,6-diphenyl-pyridyl, quinoxalinyl, pyrazinyl, phenyl-quinolinyl,
benzofurazanyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, and the
like. With the term 5 to 7 membered heterocyclyl, hence
encompassing aromatic heterocyclyc groups also referred to as aryl
groups, we further intend a saturated or partially unsaturated 5 to
7 membered carbocycle wherein one or more carbon atoms are replaced
by 1 to 3 heteroatoms such as nitrogen, oxygen and sulfur. Besides
the above heteroaryl groups, additional examples of 5 to 7 membered
heterocyclyl groups, optionally benzocondensed or further
substituted, are 1,3-dioxolane, pyran, pyrrolidine, pyrroline,
imidazolidine, pyrazolidine, pyrazoline, piperidine, piperazine,
morpholine, tetrahydrofuran, azepine, diazepine and the like.
[0023] According to the present formula (I), it is clear to the
skilled man that when m is 0 there are no R.sub.3 groups or, in
other words, the positions 5, 6 and 8 of the phthalazinone ring, as
per the numbering below, are unsubstituted or hydrogen substituted
3
[0024] Likewise, when m is 1 or 2, one or two R.sub.3 substituents,
the same or different from each other, are present in one or two of
the positions 5, 6 or 8; finally, when m is 3, all of the available
5, 6 and 8 positions are occupied by R.sub.3 groups, the same or
different, as above indicated.
[0025] According to the above meanings provided to Ra, Rb, R', R",
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 substituents, any of the
above groups may be further optionally substituted in any of the
free positions by one or more groups, for instance 1 to 6 groups,
selected from: halogen, nitro, oxo groups (.dbd.O), carboxy, cyano,
alkyl, perfluorinated alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
heterocyclyl, amino groups and derivatives thereof such as, for
instance, alkylamino, dialkylamino, arylamino, diarylamino, ureido,
alkylureido or arylureido; carbonylamino groups and derivatives
thereof such as, for instance, formylamino, alkylcarbonylamino,
alkenylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino;
hydroxy groups and derivatives thereof such as, for instance,
alkoxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy
or alkylideneaminooxy; carbonyl groups and derivatives thereof such
as, for instance, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl, cycloalkyloxycarbonyl, aminocarbonyl,
alkylaminocarbonyl, dialkylaminocarbonyl; sulfurated derivatives
such as, for instance, alkylthio, arylthio, alkylsulfonyl,
arylsulfonyl, alkylsulfinyl, arylsulfinyl, arylsulfonyloxy,
aminosulfonyl, alkylaminosulfonyl or dialkylaminosulfonyl. In their
turn, whenever appropriate, each of the above substituents may be
further substituted by one or more of the aforementioned groups.
Among these latter groups and unless otherwise specified in the
present description, with the term perfluorinated alkyl we intend a
straight or branched C.sub.1-C.sub.6 alkyl group as above defined,
wherein more than one hydrogen atom are replaced by fluorine atoms.
Example of perfluorinated alkyl groups are, for instance,
trifluoromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl,
1,1,1,3,3,3-hexafluoropropyl-2-yl and the like. With the term
alkenyl or alkynyl we intend a straight or branched C.sub.2-C.sub.6
alkenyl or alkynyl group such as, for instance, vinyl, allyl,
isopropenyl, 1-, 2- or 3-butenyl, isobutylenyl, hexenyl, ethynyl,
1- or 2-propynyl, butynyl and the like. From all of the above, it
is clear to the skilled man that any group which name has been
identified as a composite name such as, for instance,
cycloalkylalkyl, arylalkyl, heterocyclylalkyl, alkoxy, alkylthio,
aryloxy, arylalkoxy, heterocyclyloxy, heterocyclylalkoxy,
alkylcarbonyloxy and the like, have to be intended as
conventionally construed from the parts to which derive. As an
example, the term heterocyclyl-alkoxy stands for an alkoxy (e.g.
alkyl-oxy) group further substituted by a heterocyclyl group.
[0026] Pharmaceutically acceptable salts of the compounds of
formula (I) are the acid addition salts with inorganic or organic,
e.g. nitric, hydrochloric, hydrobromic, sulfuric, perchloric,
phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic,
oxalic, malonic, malic, maleic, tartaric, citric, benzoic,
cinnamic, mandelic, methanesulfonic, isethionic and salicylic acid,
as well as the salts with inorganic or organic bases, e.g. alkali
or alkaline-earth metals, especially sodium, potassium, calcium or
magnesium hydroxides, carbonates or bicarbonates, acyclic or cyclic
amines, preferably methylamine, ethylamine, diethylamine,
triethylamine or piperidine.
[0027] A first class of preferred compounds of the invention is
represented by the compounds of formula (I) wherein one of Ra or Rb
is a hydrogen atom or an optionally substituted straight or
branched C.sub.1-C.sub.6 alkyl group and the other is a group
--COR' wherein R' is an optionally substituted group selected from
alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl
or heterocyclylalkyl, as set forth above, and R.sub.1, R.sub.2,
R.sub.3 and m are as above defined. More preferred, within this
class, are the compounds of formula (I) wherein R.sub.1 is a group
--CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as above
defined, R.sub.2 is hydrogen and m is 0.
[0028] Another class of preferred compounds of the invention is
represented by the compounds of formula (I) wherein one of Ra or Rb
is a hydrogen atom or an optionally substituted straight or
branched C.sub.1-C.sub.6 alkyl group and the other is a group
--CONHR' wherein R' is a hydrogen atom or an optionally substituted
group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heterocyclyl or heterocyclylalkyl, as set forth above,
and R.sub.1, R.sub.2, R.sub.3 and m are as above defined. More
preferred, within this class, are the compounds of formula (I)
wherein R.sub.1 is a group --CHR.sub.4R.sub.5 wherein R.sub.4 and
R.sub.5 are as above defined, R.sub.2 is hydrogen and m is 0.
[0029] Another class of preferred compounds of the invention is
represented by the compounds of formula (I) wherein one of Ra or Rb
is a hydrogen atom or an optionally substituted straight or
branched C.sub.1-C.sub.6 alkyl group and the other is a group
--COOR' wherein R' is a hydrogen atom or an optionally substituted
group selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl,
arylalkyl, heterocyclyl or heterocyclylalkyl, as set forth above,
and R.sub.1, R.sub.2, R.sub.3 and m are as above defined. More
preferred, within this class, are the compounds of formula (I)
wherein R.sub.1 is a group --CHR.sub.4R.sub.5 wherein R.sub.4 and
R.sub.5 are as above defined, R.sub.2 is hydrogen and m is 0.
[0030] Another class of preferred compounds of the invention is
represented by the compounds of formula (I) wherein one of Ra or Rb
is a hydrogen atom or an optionally substituted straight or
branched C.sub.1-C.sub.6 alkyl group and the other is a group
--SO.sub.2R' wherein R' is an optionally substituted group selected
from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl, as set forth above, and R.sub.1,
R.sub.2, R.sub.3 and m are as above defined. More preferred, within
this class, are the compounds of formula (I) wherein R.sub.1 is a
group --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as above
defined, R.sub.2 is hydrogen and m is 0.
[0031] Another class of preferred compounds of the invention is
represented by the compounds of formula (I) wherein Ra and Rb are
both hydrogen atoms and R.sub.1, R.sub.2, R.sub.3 and m are as
above defined. More preferred, within this class, are the compounds
of formula (I) wherein R.sub.1 is a group --CHR.sub.4R.sub.5
wherein R.sub.4 and R.sub.5 are as above defined, R.sub.2 is
hydrogen and m is 0.
[0032] Another class of preferred compounds of the invention is
represented by the compounds of formula (I) wherein one of Ra or Rb
is a hydrogen atom or an optionally substituted straight or
branched C.sub.1-C.sub.6 alkyl and the other is a group, optionally
further substituted, selected from alkyl, cycloalkylalkyl,
arylalkyl or heterocyclylalkyl as set forth above, and R.sub.1,
R.sub.2, R.sub.3 and m are as above defined. More preferred, within
this class, are the compounds of formula (I) wherein R.sub.1 is a
group --CHR.sub.4R.sub.5 wherein R.sub.4 and R.sub.5 are as above
defined, R.sub.2 is hydrogen and m is 0.
[0033] Specific examples of preferred compounds of formula (I) of
the invention, optionally in the form of pharmaceutically
acceptable salts, are:
[0034] 1.
4-(4-Oxo-6-propionylamino-3,4-dihydro-phthalazin-1-ylmethyl)-ben-
zoic acid methyl ester;
[0035] 2.
4-[4-Oxo-6-(4-trifluoromethyl-benzoylamino)-3,4-dihydro-phthalaz-
in-1-ylmethyl]-benzoic acid methyl ester;
[0036] 3.
4-{6-[(Furan-2-carbonyl)-amino]-4-oxo-3,4-dihydro-phthalazin-1-y-
lmethyl}-benzoic acid methyl ester;
[0037] 4.
4-[6-(3,4-Dimethoxy-benzoylamino)-4-oxo-3,4-dihydro-phthalazin-1-
-ylmethyl]-benzoic acid methyl ester;
[0038] 5.
4-[6-(3-Cyclopentyl-propionylamino)-4-oxo-3,4-dihydro-phthalazin-
-1-ylmethyl]-benzoic acid methyl ester;
[0039] 6.
4-[4-Oxo-6-(2-propyl-pentanoylamino)-3,4-dihydro-phthalazin-1-yl-
methyl]-benzoic acid methyl ester;
[0040] 7.
4-{4-Oxo-6-[3-(3-trifluoromethyl-phenyl)-ureido]-3,4-dihydro-pht-
halazin-1-ylmethyl}-benzoic acid methyl ester;
[0041] 8.
4-{6-[3-(3-Methoxy-phenyl)-ureido]-4-oxo-3,4-dihydro-phthalazin--
1-ylmethyl}-benzoic acid methyl ester;
[0042] 9.
4-[4-Oxo-6-(3-p-tolyl-ureido)-3,4-dihydro-phthalazin-1-ylmethyl]-
-benzoic acid methyl ester;
[0043] 10.
4-{6-[3-(2,4-Difluoro-phenyl)-ureido]-4-oxo-3,4-dihydro-phthala-
zin-1-ylmethyl}-benzoic acid methyl ester;
[0044] 11.
4-{6-[3-(3,4-Dichloro-phenyl)-ureido]-4-oxo-3,4-dihydro-phthala-
zin-1-ylmethyl}-benzoic acid methyl ester;
[0045] 12.
4-[4-Oxo-6-(3-pyridin-3-yl-ureido)-3,4-dihydro-phthalazin-1-ylm-
ethyl]-benzoic acid methyl ester;
[0046] 13.
4-(6-Amino-4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic acid
methyl ester;
[0047] 14.
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-propionamide;
[0048] 15.
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-4-trifluoromethyl-benzamide;
[0049] 16. Furan-2-carboxylic acid
[1-(4-chloro-3-fluoro-benzyl)-4-oxo-3,4-
-dihydro-phthalazin-6-yl]-amide;
[0050] 17.
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3,4-dimethoxy-benzamide;
[0051] 18.
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-cyclopentyl-propionamide;
[0052] 19. 2-Propyl-pentanoic acid
[1-(4-chloro-3-fluoro-benzyl)-4-oxo-3,4-
-dihydro-phthalazin-6-yl]-amide;
[0053] 20.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-(3-trifluoromethyl-phenyl)-urea;
[0054] 21.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-(3-methoxy-phenyl)-urea;
[0055] 22.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-p-tolyl-urea;
[0056] 23.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-(2,4-difluoro-phenyl)-urea;
[0057] 24.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-(3,4-dichloro-phenyl)-urea;
[0058] 25.
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6--
yl]-3-pyridin-3-yl-urea;
[0059] 26.
7-Amino-4-(4-chloro-3-fluoro-benzyl)-2H-phthalazin-1-one;
[0060] 27.
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-propionamide;
[0061] 28.
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-4-trifluoromethyl-benzamide;
[0062] 29. Furan-2-carboxylic acid
{1-[(E)-3-(4-nitro-phenyl)-allyl]-4-oxo-
-3,4-dihydro-phthalazin-6-yl}-amide;
[0063] 30.
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-3,4-dimethoxy-benzamide;
[0064] 31.
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-3-cyclopentyl-propionamide;
[0065] 32. 2-Propyl-pentanoic acid
{1-[(E)-3-(4-nitro-phenyl)-allyl]-4-oxo-
-3,4-dihydro-phthalazin-6-yl}-amide;
[0066] 33.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-3-(3-trifluoromethyl-phenyl)-urea;
[0067] 34.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-(3-methoxy-phenyl)-urea;
[0068] 35.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-3-p-tolyl-urea;
[0069] 36.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-3-(2,4-difluoro-phenyl)-urea;
[0070] 37.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-3-(3,4-dichloro-phenyl)-urea;
[0071] 38.
1-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazi-
n-6-yl}-3-pyridin-3-yl-urea;
[0072] 39.
7-Amino-4-[(E)-3-(4-nitro-phenyl)-allyl]-2H-phthalazin-1-one;
[0073] 40.
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-pro-
pionamide;
[0074] 41.
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4-t-
rifluoromethyl-benzamide;
[0075] 42. Furan-2-carboxylic acid
(4-oxo-1-thiophen-3-ylmethyl-3,4-dihydr-
o-phthalazin-6-yl)-amide;
[0076] 43.
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3,4-
-dimethoxy-benzamide;
[0077] 44.
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-c-
yclopentyl-propionamide;
[0078] 45. 2-Propyl-pentanoic acid
(4-oxo-1-thiophen-3-ylmethyl-3,4-dihydr-
o-phthalazin-6-yl)-amide;
[0079] 46.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(-
3-trifluoromethyl-phenyl)-urea;
[0080] 47.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-(3--
methoxy-phenyl)-urea;
[0081] 48.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-
-tolyl-urea;
[0082] 49.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(-
2,4-difluoro-phenyl)-urea;
[0083] 50.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(-
3,4-dichloro-phenyl)-urea;
[0084] 51.
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-
yridin-3-yl-urea;
[0085] 52. 7-Amino-4-thiophen-3-ylmethyl-2H-phthalazin-1-one;
[0086] 53.
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-prop-
ionamide;
[0087] 54.
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-tr-
ifluoromethyl-benzamide;
[0088] 55. Furan-2-carboxylic acid
[1-(3-methoxy-benzyl)-4-oxo-3,4-dihydro-
-phthalazin-6-yl]-amide;
[0089] 56.
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3,4--
dimethoxy-benzamide;
[0090] 57.
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cy-
clopentyl-propionamide;
[0091] 58. 2-Propyl-pentanoic acid
[1-(3-methoxy-benzyl)-4-oxo-3,4-dihydro-
-phthalazin-6-yl]-amide;
[0092] 59.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
-trifluoromethyl-phenyl)-urea;
[0093] 60.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-(3-m-
ethoxy-phenyl)-urea;
[0094] 61.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p--
tolyl-urea;
[0095] 62.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2-
,4-difluoro-phenyl)-urea;
[0096] 63.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
,4-dichloro-phenyl)-urea;
[0097] 64.
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-py-
ridin-3-yl-urea;
[0098] 65. 7-Amino-4-(3-methoxy-benzyl)-2H-phthalazin-1-one;
[0099] 66.
N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-propionamide;
[0100] 67.
N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-4-trifluoromethy-
l-benzamide;
[0101] 68. Furan-2-carboxylic acid
(4-oxo-1-propyl-3,4-dihydro-phthalazin-- 6-yl)-amide;
[0102] 69.
N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3,4-dimethoxy-be-
nzamide;
[0103] 70.
N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-cyclopentyl-pr-
opionamide;
[0104] 71. 2-Propyl-pentanoic acid
(4-oxo-1-propyl-3,4-dihydro-phthalazin-- 6-yl)-amide;
[0105] 72.
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-(3-trifluorome-
thyl-phenyl)-urea;
[0106] 73.
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-(3-methoxy-pheny-
l)-urea;
[0107] 74.
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-p-tolyl-urea;
[0108] 75.
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-(2,4-difluoro--
phenyl)-urea;
[0109] 76.
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-(3,4-dichloro--
phenyl)-urea;
[0110] 77.
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-pyridin-3-yl-u-
rea;
[0111] 78. 7-Amino-4-propyl-2H-phthalazin-1-one;
[0112] 79.
N-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-pr-
opionamide;
[0113] 80.
N-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4--
trifluoromethyl-benzamide;
[0114] 81. Furan-2-carboxylic acid
[1-(3,3-dimethyl-butyl)-4-oxo-3,4-dihyd-
ro-phthalazin-6-yl]-amide;
[0115] 82.
N-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3,-
4-dimethoxy-benzamide;
[0116] 83.
N-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3--
cyclopentyl-propionamide;
[0117] 84. 2-Propyl-pentanoic acid
[1-(3,3-dimethyl-butyl)-4-oxo-3,4-dihyd-
ro-phthalazin-6-yl]-amide;
[0118] 85.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3--
(3-trifluoromethyl-phenyl)-urea;
[0119] 86.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-(3-
-methoxy-phenyl)-urea;
[0120] 87.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3--
p-tolyl-urea;
[0121] 88.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3--
(2,4-difluoro-phenyl)-urea;
[0122] 89.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3--
(3,4-dichloro-phenyl)-urea;
[0123] 90.
1-[1-(3,3-Dimethyl-butyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3--
pyridin-3-yl-urea;
[0124] 91. 7-Amino-4-(3,3-dimethyl-butyl)-2H-phthalazin-1-one;
[0125] 92.
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-propi-
onamide;
[0126] 93.
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-4-tri-
fluoromethyl-benzamide;
[0127] 94. Furan-2-carboxylic acid
[4-oxo-1-(3-phenyl-propyl)-3,4-dihydro--
phthalazin-6-yl]-amide;
[0128] 95.
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3,4-d-
imethoxy-benzamide;
[0129] 96.
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-cyc-
lopentyl-propionamide;
[0130] 97. 2-Propyl-pentanoic acid
[4-oxo-1-(3-phenyl-propyl)-3,4-dihydro--
phthalazin-6-yl]-amide;
[0131] 98.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-(3--
trifluoromethyl-phenyl)-urea;
[0132] 99.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-(3-me-
thoxy-phenyl)-urea;
[0133] 100.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-p--
tolyl-urea;
[0134] 101.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-(2-
,4-difluoro-phenyl)-urea;
[0135] 102.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-(3-
,4-dichloro-phenyl)-urea;
[0136] 103.
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-py-
ridin-3-yl-urea;
[0137] 104. 7-Amino-4-(3-phenyl-propyl)-2H-phthalazin-1-one;
[0138] 105.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-pro-
pionamide;
[0139] 106.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4-t-
rifluoromethyl-benzamide;
[0140] 107. Furan-2-carboxylic acid
(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydr-
o-phthalazin-6-yl)-amide;
[0141] 108.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-suc-
cinamic acid ethyl ester;
[0142] 109.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-c-
yclopentyl-propionamide;
[0143] 110. 2-Propyl-pentanoic acid
(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydr-
o-phthalazin-6-yl)-amide;
[0144] 111.
1-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(-
3-trifluoromethyl-phenyl)-urea;
[0145] 112.
1-(3-Methoxy-phenyl)-3-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-
-phthalazin-6-yl)-urea;
[0146] 113.
1-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-
-tolyl-urea;
[0147] 114.
1-(2,4-Difluoro-phenyl)-3-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihy-
dro-phthalazin-6-yl)-urea;
[0148] 115.
1-(3,4-Dichloro-phenyl)-3-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihy-
dro-phthalazin-6-yl)-urea;
[0149] 116.
1-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-
yridin-3-yl-urea;
[0150] 117. 7-Amino-4-pyridin-3-ylmethyl-2H-phthalazin-1-one
[0151] 118.
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-ben-
zamide;
[0152] 119.
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-prop-
ionamide;
[0153] 120.
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-tr-
ifluoromethyl-benzamide;
[0154] 121. Furan-2-carboxylic acid
[1-(4-chloro-benzyl)-4-oxo-3,4-dihydro-
-phthalazin-6-yl]-amide;
[0155] 122.
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succ-
inamic acid ethyl ester;
[0156] 123.
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cy-
clopentyl-propionamide;
[0157] 124. 2-Propyl-pentanoic acid
[1-(4-chloro-benzyl)-4-oxo-3,4-dihydro-
-phthalazin-6-yl]-amide;
[0158] 125.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
-trifluoromethyl-phenyl)-urea;
[0159] 126.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
-methoxy-phenyl)-urea;
[0160] 127.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p--
tolyl-urea;
[0161] 128.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2-
,4-difluoro-phenyl)-urea;
[0162] 129.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
,4-dichloro-phenyl)-urea;
[0163] 130.
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-py-
ridin-3-yl-urea;
[0164] 131. 7-Amino-4-(4-Chloro-benzyl)-2H-phthalazin-1-one;
[0165] 132.
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propi-
onamide;
[0166] 133.
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-tri-
fluoromethyl-benzamide;
[0167] 134. Furan-2-carboxylic acid
[1-(4-cyano-benzyl)-4-oxo-3,4-dihydro-- phthalazin-6-yl]-amide;
[0168] 135.
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-suc-
cinamic acid ethyl ester;
[0169] 136.
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cyc-
lopentyl-propionamide;
[0170] 137. 2-Propyl-pentanoic acid
[1-(4-cyano-benzyl)-4-oxo-3,4-dihydro-- phthalazin-6-yl]-amide;
[0171] 138.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3--
trifluoromethyl-phenyl)-urea;
[0172] 139.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3--
methoxy-phenyl)-urea;
[0173] 140.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p-t-
olyl-urea;
[0174] 141.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2,-
4-difluoro-phenyl)-urea;
[0175] 142.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3,-
4-dichloro-phenyl)-urea;
[0176] 143.
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-pyr-
idin-3-yl-urea;
[0177] 144. 7-Amino-4-(4-Cyano-benzyl)-2H-phthalazin-1-one;
[0178] 145.
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-prop-
ionamide;
[0179] 146.
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-tr-
ifluoromethyl-benzamide;
[0180] 147. Furan-2-carboxylic acid
[1-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-
-phthalazin-6-yl]-amide;
[0181] 148.
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succ-
inamic acid ethyl ester;
[0182] 149.
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cy-
clopentyl-propionamide;
[0183] 150. 2-Propyl-pentanoic acid
[1-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-
-phthalazin-6-yl]-amide;
[0184] 151.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
-trifluoromethyl-phenyl)-urea;
[0185] 152.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
-methoxy-phenyl)-urea;
[0186] 153.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p--
tolyl-urea;
[0187] 154.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2-
,4-difluoro-phenyl)-urea;
[0188] 155.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
,4-dichloro-phenyl)-urea;
[0189] 156.
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-py-
ridin-3-yl-urea;
[0190] 157. 7-Amino-4-(3-Fluoro-benzyl)-2H-phthalazin-1-one;
[0191] 158.
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-prop-
ionamide;
[0192] 159.
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-tr-
ifluoromethyl-benzamide;
[0193] 160. Furan-2-carboxylic acid
[1-(3-methyl-benzyl)-4-oxo-3,4-dihydro-
-phthalazin-6-yl]-amide;
[0194] 161.
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succ-
inamic acid ethyl ester;
[0195] 162.
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cy-
clopentyl-propionamide;
[0196] 163. 2-Propyl-pentanoic acid
[1-(3-methyl-benzyl)-4-oxo-3,4-dihydro-
-phthalazin-6-yl]-amide;
[0197] 164.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
-trifluoromethyl-phenyl)-urea;
[0198] 165.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
-methoxy-phenyl)-urea;
[0199] 166.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p--
tolyl-urea;
[0200] 167.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2-
,4-difluoro-phenyl)-urea;
[0201] 168.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-
,4-dichloro-phenyl)-urea;
[0202] 169.
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-py-
ridin-3-yl-urea;
[0203] 170. 7-Amino-4-(3-Methyl-benzyl)-2H-phthalazin-1-one;
[0204] 171.
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
propionamide;
[0205] 172.
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
4-trifluoromethyl-benzamide;
[0206] 173. Furan-2-carboxylic acid
[1-(2,4-dichloro-benzyl)-4-oxo-3,4-dih-
ydro-phthalazin-6-yl]-amide;
[0207] 174.
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
succinamic acid ethyl ester;
[0208] 175.
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-cyclopentyl-propionamide;
[0209] 176. 2-Propyl-pentanoic acid
[1-(2,4-dichloro-benzyl)-4-oxo-3,4-dih-
ydro-phthalazin-6-yl]-amide;
[0210] 177.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-(3-trifluoromethyl-phenyl)-urea;
[0211] 178.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-(3-methoxy-phenyl)-urea;
[0212] 179.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-p-tolyl-urea;
[0213] 180.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-(2,4-difluoro-phenyl)-urea;
[0214] 181.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-(3,4-dichloro-phenyl)-urea;
[0215] 182.
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-pyridin-3-yl-urea;
[0216] 183.
7-Amino-4-(2,4-dichloro-benzyl)-2H-phthalazin-1-one;
[0217] 184.
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-pr-
opionamide;
[0218] 185.
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4--
trifluoromethyl-benzamide;
[0219] 186. Furan-2-carboxylic acid
(4-oxo-1-quinolin-3-ylmethyl-3,4-dihyd-
ro-phthalazin-6-yl)-amide;
[0220] 187.
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-su-
ccinamic acid ethyl ester;
[0221] 188.
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3--
cyclopentyl-propionamide;
[0222] 189. 2-Propyl-pentanoic acid
(4-oxo-1-quinolin-3-ylmethyl-3,4-dihyd-
ro-phthalazin-6-yl)-amide;
[0223] 190.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3--
(3-trifluoromethyl-phenyl)-urea;
[0224] 191.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3--
(3-methoxy-phenyl)-urea;
[0225] 192.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3--
p-tolyl-urea;
[0226] 193.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3--
(2,4-difluoro-phenyl)-urea;
[0227] 194.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3--
(3,4-dichloro-phenyl)-urea;
[0228] 195.
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3--
pyridin-3-yl-urea;
[0229] 196. 7-Amino-4-quinolin-3-ylmethyl-2H-phthalazin-1-one;
[0230] 197.
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-propionamide;
[0231] 198.
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-4-trifluoromethyl-benzamide;
[0232] 199. Furan-2-carboxylic acid
[4-oxo-1-(2-trifluoromethyl-benzyl)-3,-
4-dihydro-phthalazin-6-yl]-amide;
[0233] 200.
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-succinamic acid ethyl ester;
[0234] 201.
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-3-cyclopentyl-propionamide;
[0235] 202. 2-Propyl-pentanoic acid
[4-oxo-1-(2-trifluoromethyl-benzyl)-3,-
4-dihydro-phthalazin-6-yl]-amide;
[0236] 203.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-3-(3-trifluoromethyl-phenyl)-urea;
[0237] 204.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-3-(3-methoxy-phenyl)-urea;
[0238] 205.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-3-p-tolyl-urea;
[0239] 206.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-3-(2,4-difluoro-phenyl)-urea;
[0240] 207.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-3-(3,4-dichloro-phenyl)-urea;
[0241] 208.
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-
-yl]-3-pyridin-3-yl-urea;
[0242] 209.
7-Amino-4-(2-trifluoromethyl-benzyl)-2H-phthalazin-1-one.
[0243] As set forth above, the process for preparing the
amino-phthalazinone derivatives of formula (I) represents a further
object of the present invention. The compounds of formula (I) and
the pharmaceutically acceptable salts thereof, may be thus obtained
by a process comprising:
[0244] a) reacting a compound of formula (II) 4
[0245] wherein R.sub.3 and m have the above reported meanings and
Hal represents a halogen atom, with a suitable phosphine derivative
(PL.sub.3), under optional reductive conditions, so as to obtain a
compound of formula (III) 5
[0246] wherein P is a phosphorous atom and L are the phosphine
ligands;
[0247] b) reacting the compound of formula (III) with an aldehydic
Resin-CHO, in the presence of a suitable reducing agent, so as to
obtain a resin supported compound of formula (IV) 6
[0248] wherein R.sub.3, m, P, L, Hal and the Resin are as above
defined;
[0249] c) reacting the compound of formula (IV) with a carbonyl
derivative of formula (V) or a nitroso derivative of formula
(VI)
R.sub.4--CO--R.sub.5 (V)
R'--NO (VI)
[0250] wherein R.sub.4, R.sub.5 and R' are as above defined; so as
to obtain the compound of formula (VII) 7
[0251] wherein A is a group .dbd.CR.sub.4R.sub.5 or .dbd.NR',
respectively; and optionally reacting the compound of formula (VII)
according to any one of the alternative steps d.1) or d.2)
below
[0252] d.1) with one of the derivatives of formula (VIII), (IX),
(X) or (XI), under optional basic conditions,
R'COZ (VII),
R'NCO (IX),
R'OCOZ (X),
R'SO.sub.2Z (XI)
[0253] wherein Z is a halogen atom or a suitable leaving group and
R' is as above defined, so as to obtain the compound of formula
(XII) 8
[0254] wherein Rb is --COR', --CONHR', --COOR' or --SO.sub.2R',
respectively; or
[0255] d.2) with a compound of formula (XIII)
Rb-Z (XIII)
[0256] wherein Z is a halogen atom and Rb is alkyl, cycloalkyl,
cycloalkylalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl
as above defined, so as to obtain the corresponding compound of the
above formula (XII);
[0257] e) reacting the thus obtained compounds of formula (VII) or
(XII) with a hydrazine derivative of formula (XIV)
R.sub.2--NH--NH.sub.2 (XIV)
[0258] wherein R.sub.2 is as above defined, so as to obtain the
compounds of formula (XV) or (XVI), respectively 9
[0259] wherein Rb, R.sub.2, R.sub.3, m and the Resin are as above
defined and R.sub.1 is a group of formula --CHR.sub.4R.sub.5 or
--NHR' wherein R.sub.4, R.sub.5 and R' are as above defined;
[0260] f) reacting the compounds of formula (XV) or (XVI) under
acidic conditions so as to obtain the compound of formula (I) and,
whenever desired, converting it into another compound of formula
(I) and/or into a pharmaceutically acceptable salt thereof.
[0261] The above process is an analogy process which can be carried
out according to well known methods. It is clear to the person
skilled in the art that if a compound of formula (I), prepared
according to the above process, is obtained as an admixture of
isomers, their separation into the single isomers of formula (I),
carried out according to conventional techniques, is still within
the scope of the present invention. Likewise, the conversion into
the free compound (I) of a corresponding salt thereof, according to
well-known procedures in the art, is still within the scope of the
invention.
[0262] According to step a) of the process, a compound of formula
(II) wherein Hal represents a halogen atom, preferably bromine, is
reacted with a suitable phosphine derivative PL.sub.3 such as, for
instance, triphenylphosphine, tri-n-butylphoshine,
tri-t-butylphosphine or 1,4-bis(diphenylphosphino)butane.
Preferably, the phosphine derivative is triphenylphosphine
PPh.sub.3. The reaction may be carried out in a variety of solvents
for instance comprising ethyl acetate, ethyl propionate and the
like, dimethylformammide, dimethylacetammide and the like,
dichloromethane chloroform and the like, acetone, or acetonitrile;
preferred is the use of ethyl propionate. The temperature may vary
from about 20.degree. C. to about 100.degree. C.
[0263] The reaction may be performed by adding the phosphine to a
solution of the compound of formula (II) or by adding a solution of
(II) to the phosphine. When using triphenylphosphine, the compound
of formula (II) is directly converted into the corresponding
derivative of formula (III) bearing the amino group in place of the
original nitro group. Alternatively, when using PL.sub.3 reagents
other than triphenylphosphine, the compound of formula (II) may be
first converted into an intermediate derivative of formula (IIa)
10
[0264] wherein R.sub.3, m, P and L are as above defined, which has
to be properly reduced to the compound of formula (III). The
reductive conditions to be employed are those conventionally used
for reducing aromatic nitro derivatives to amino derivatives and
comprise, for instance, the use of chemical reducing agents such
as, for instance, tin dichloride, iron and acetic acid, zinc and
hydrochloric acid, or titanium trichloride. Alternatively, the
reductive step may occur under catalytic hydrogenation conditions
in the presence of suitable catalysts, typically platinum,
palladium or palladium on charcoal. Preferably, the compound of
formula (II) is conveniently converted into the compound of formula
(III) by using triphenylphosphine.
[0265] According to step b) of the process, the compound of formula
(III) is reacted, in the presence of a reducing agent such as, for
instance, a pyridine-borane complex, sodium cyanoboron hydride,
sodium triacetoxy boron hydride, dimethylsufide borane and the
like, with a suitable aldehydic RCHO resin, for instance a
polystirene or polyethyleneglycol resin. Preferably, the resin is a
4-(4-formyl-3-methoxyphenoxy)butyryl aminomethylated resin or
4-(4-formyl-3-methoxyphenoxy)butyryl (NOVAGEL.TM.). The reaction is
carried out in the presence of a suitable solvent, preferably
dichloromethane, 2,2,2-trifluoroethanol and acetic acid, by adding
an excess of the reducing agent, optionally dissolved into the same
solvent, directly to the mixture of resin and of the compound of
formula (III), and by stirring at a temperature ranging from about
0.degree. C. to about 40.degree. C. for a suitable time. As an
example, the reaction may be carried at about 20.degree. C. for
about 15 hours.
[0266] According to step c) of the process, the compound of formula
(IV) is then reacted with a compound of formula (V) or,
alternatively, of formula (VI), so as to obtain the corresponding
derivative of formula (VII). The reaction is carried out in the
presence of a suitable base, for instance triethylamine,
diisopropylethylamine, piperidine, sodium carbonate, cesium
carbonate, potassium t-butoxide, sodium methoxide,
diazabicycloundecene, potassium hydroxide and the like, optionally
in the presence of a suitable phase-transfer catalyst. The compound
of formula (V) or, alternatively, of formula (VI), is added to a
suspension of the compound of formula (IV) in a suitable solvent
such as dichloromethane, dimethyl formammide, tetrahydrofuran or
the like. The temperature is then brought to a suitable value, for
instance from about -70.degree. C. to about 40.degree. C. according
to the electrophile (V) or (VI), and the base is added. Stirring is
carried on for a suitable time, for instance from about 2 to about
15 hours.
[0267] The product of formula (VII) thus obtained may be further
reacted according to any one of the alternative steps d.1) or d.2),
or directly processed according to step e). According to step d.1)
of the process, in particular, the compound of formula (VII) is
reacted with a carboxylic acid derivative of formula (VIII), with
an isocyanate of formula (IX), with a chloroformate derivative of
formula (X) or with a sulphonyl derivative of formula (XI), so as
to obtain the corresponding compound of formula (XII) wherein Rb is
a group of formula --COR', --CONHR', --COOR' or --SO.sub.2R',
respectively. When using a compound of formula (VIII), (X) or (XI),
Z is preferably a halogen atom and, even more preferably, a
chlorine atom. In this instance, the compound of formula (VII) is
suspended into a suitable solvent such as dichloromethane,
dimethylformammide, tetrahydrofurane, dioxane or the like, and a
suitable base is then added, for instance triethylamine,
diisopropylethylamine, sodium carbonate or the like. The
electrophile of general formula (VIII), (X), or (XI) is then added
and the mixture stirred for about 2 to about 15 hours, at a
temperature ranging from about 20.degree. C. to about 80.degree. C.
When using an isocyanate of general formula (IX), the reaction
conditions are the same as above reported except that the base may
not be required. In the latter case a catalyst such as
dimethylamino pyridine may be optionally used.
[0268] Substantially analogous considerations apply when
considering step d.2) of the process wherein the compound of
formula (VII) is further converted into the corresponding
functionalized amino derivative of formula (XII), according to well
known methods. As an example, the compound of formula (VII) may be
reacted with a derivative of formula (XIII) wherein Z is halogen,
for instance bromine, and Rb is an arylalkyl group such as, for
instance, the benzyl group, by working according to conventional
methods.
[0269] According to step e) of the process, the compound of formula
(VII) obtained from step c) or, alternatively, the compound of
formula (XII) obtained from any one of steps d.1) or d.2), is
reacted with hydrazine or a hydrazine derivative of formula (XIV)
so as to obtain the corresponding compounds of formula (XV) or
(XVI). The compound of formula (XII) is suspended in a suitable
solvent, preferably dimethylformammide, in the presence of
hydrazine hydrate or another hydrazine of general formula (XIV) and
stirred at a suitable temperature, for instance at 20.degree. C.,
for about 2 to about 20 hours.
[0270] According to step f) of the process, the compounds of
formula (XV) or (XVI) are reacted under acidic conditions,
preferably in the presence of trifluoroacetic acid, so as to yield
the desired compound of formula (I). Compounds of formula (XV) or
(XVI) may be thus suspended in a solution of 5-95% trifluoroacetic
acid in dichloromethane and the mixture stirred at a temperture
ranging from about 20.degree. C. to refluxing temperature, for a
time varying from about 5 minutes to about 3 hours.
[0271] From the above, it is clear to the skilled man that by
carrying out the above resin cleavage from the compound of formula
(XV), the corresponding derivative having both Ra and Rb as
hydrogen atoms will be obtained. Likewise, when starting from the
compound of formula (XVI), the corresponding derivative of formula
(I) having one of Ra or Rb, e.g. Ra, as a hydrogen atom and the
other, e.g. Rb, as a group as defined under steps d.1) or d.2),
will be obtained. In addition, it is clear to the skilled man that,
if desired, any of the above compounds of formula (I) may be
further converted by working according to conventional methods into
other compounds of formula (I), as set forth in step f). As an
example, the compounds of formula (I) wherein both Ra and Rb are
other than hydrogen atoms may be prepared according to well-known
methods by reacting any compound of formula (I) having one of Ra or
Rb as a hydrogen atom, into another compound of formula (I) having
this same hydrogen atom being replaced by a suitable group. When
preparing the compounds of formula (I) according to any variant of
the process, which are all to be intended as within the scope of
the present invention, optional functional groups within both the
starting materials or the intermediates thereof, which could give
rise to unwanted side reactions, need to be properly protected
according to conventional techniques. Likewise, the conversion of
these latter into the free deprotected compounds may be carried out
according to known procedures.
[0272] Pharmaceutically acceptable salts of the compounds of
formula (I) or, alternatively, their free compounds from the salts
thereof, my be all obtained according to conventional methods.
[0273] The compounds of formula (II) are known or easily prepared
according to known methods [see, for a reference, J. Org. Chem.
(1985), 50, 4120-4125; J. Chem. Soc. (1961), 5275-5284].
Alternatively, the compounds of formula (II) wherein Hal represents
a bromine atom, may be prepared as reported in the working
examples, that is by reacting commercially available
6-nitro-phthalide under brominating conditions, for instance with
bromine in the presence of aqueous hydrogen peroxide, in a suitable
solvent such as dichloromethane, dichloromethane/water or
hexane/water admixtures, at a temperature varying from about
20.degree. C. to reflux. The compounds of formula (V), (VI),
(VIII), (IX), (X), (XI), (XIII) and (XIV) are known or easily
prepared according to well-known methods. Likewise, the aldehydic
resin R--CHO, the phosphine derivative PL.sub.3 and any other
suitable reagent of the process, are known compounds which are
commercially available or easily prepared according to known
methods.
[0274] The compounds of formula (I) of the invention were
advantageously prepared according to combinatorial chemistry
techniques widely known in the art, by accomplishing the
aforementioned reactions between the several intermediates in a
serial manner.
[0275] Therefore, all of the preferred compounds of the invention,
whenever appropriate in the form of pharmaceutically acceptable
salts, are herewith conveniently indicated and defined as products
by process, that is as products of formula (I) which are
obtainable, for instance through a defined process.
[0276] Therefore, herewith provided is any specific compound of
formula (I) which is obtainable, for instance through a
combinatorial chemistry technique according to the process of the
invention, by first reacting the compound of formula (IV) 11
[0277] with each one of the aldehyde derivatives of formula (V), as
set forth in table I; by reacting any of the resultant compounds of
formula (VII) with each one of the acyl chloride derivatives of
formula (VIII), as set forth in table II; by reacting any of the
resultant compounds of formula (XII) with hydrazine; and by working
according to step f) of the process.
[0278] Also provided is any specific compound of formula (I) which
is obtainable, for instance through a combinatorial chemistry
technique according to the process of the invention, by first
reacting the compound of formula (IV) 12
[0279] with each one of the aldehyde derivatives of formula (V), as
set forth in table I; by reacting any of the resultant compounds of
formula (VII) with each one of the isocyanate derivatives of
formula (IX), as set forth in table III; by reacting any of the
resultant compounds of formula (XII) with hydrazine; and by working
according to step f) of the process.
1TABLE I Aldehyde derivatives of formula (V) R.sub.4--CO--R.sub.5
(R.sub.5 = H) 1. 3,5-diiodo-4-hydroxybenzaldehyde 2.
3-iodobenzaldehyde 3. 3,5-dibromobenzaldehyde 4.
4-bromothiophene-2-carboxaldehyde 5. 2-naphthaldehyde 6.
n-ethyl-carbazole-3-aldehyde 7.
4-chloro-1-methylpyrazole-3-carboxaldehyde 8.
(3-formyl-1-phenyl-1h-pyrazol-5-yl)methyl acetate 9.
1-acetyl-3-indolecarboxaldehyde 10. methyl 4-formyl-1-methylpyrrol-
e-2-carboxylate 11. 3,5-di-tert-butyl-4-hydroxybenzaldehyde 12.
5-(methylthio)-2-thiophenecarboxaldehyde 13.
4-(methylthio)benzaldehyde 14. 3-nitro-4-(2-pyridylthio)benzaldehy-
de 15. 5-methyl-2-thiophenecarboxaldehyde 16. 3-acetoxybenzaldehyde
17. 3,4-dimethylbenzaldehyde 18. 4-pyridinecarboxaldehyde n-oxide
19. 4-fluoro-3-methylbenzaldehyde 20.
2,6-dichloroisonicotinaldehyde 21.
5-(2,4-difluorophenyl)-2-furaldehyde 22. 2-(4-bromobenzoyl)-1-benz-
ofuran-5-carbaldehyde 23. 2-benzoyl-1-benzofuran-5-carbaldehyde 24.
2-butyl-4-formylimidazole 25. 5-benzyloxy-1h-pyrrolo[2,3-c]-
pyridine-3- carboxaldehyde 26. 6-methyl-2-pyridinecarboxald- ehyde
27. 4-[4-(tert-butyl)thiazol-2-yl]benzaldehyde 28.
5-formyl-2,4-dimethoxy-pyrimidine 29. 2-[(4-chlorobenzyl)thio]pyri-
midine-4- carbaldehyde 30. 3-fluoro-2-hydroxybenzaldehyde 31.
3-hydroxybenzaldehyde 32. 3-carboxybenzaldehyde 33.
4-vinylbenzaldehyde 34. 5-(2,5-dichlorophenyl)-2-furaldehyde 35.
2-fluoro-5-nitrobenzaldehyde 36. 5-(4-nitrophenyl)-2-fura- ldehyde
37. 4-dimethylaminobenzaldehyde 38.
4-[3-(dimethylamino)propoxy]benzaldehyde 39. 4-n-butylbenzaldehyde
40. 4-(4-benzylpiperazino)benzaldehyde 41.
2,2'-bithiophene-5-carboxaldehyde 42. 4-[4-(1-adamantyl)-1,3-thiaz-
ol-2-yl]benzaldehyde 43. 4-formyl-trans-stilbene 44.
6-chloroimidazo[2,1-b] [1,3]thiazole-5- carbaldehyde 45.
4-(phenylethynyl)benzaldehyde 46. 3,3'-(4-formylphenylimino)diprop-
ionitrile 47. 6-formyl-2-(methylthio)nicotinonitrile 48.
4-cyanobenzaldehyde 49. 3-[(4-formylphenoxy)methyl]thiophene-2-
carbonitrile 50. 2-(3-formyl-1h-indol-1-yl)benzonitrile 51.
2-formyl-6-methoxyphenyl 2,6-difluorobenzoate 52. tert-butyl
4-formyl-2-methoxyphenyl carbonate 53. 4-(difluoromethoxy)benzalde-
hyde 54. 2-[1-methyl-5-(trifluoromethyl)pyrazol-3-
yl]thiophene-5-carboxaldehyde 55. 5-(3-trifluoromethylphenyl)furan-
-2- carboxaldehyde 56. 2,3-difluoro-4-methylbenzaldehyde 57.
3-chloro-5-(trifluoromethyl)pyridine-2- carboxaldehyde 58.
4-(trifluoromethoxy)benzaldehyde 59.
3-[(2,4-difluorophenyl)thio]-5- (trifluoromethyl)pyridine-2-carba-
ldehyde 60. 3,5-bis(trifluoromethyl)benzaldehyde 61.
2,3,5,6-tetrafluorobenzaldehyde 62. 4-(methylsulfonyl)benzaldehyde
63. 1-[(4-methylphenyl)sulfonyl]-1h-indole-3- carbaldehyde 64.
4-formyl-2-methoxyphenyl 2,4,5- trichlorobenzenesulfonate 65.
4-formylphenyl 2,3,4,5,6- pentamethylbenzenesulfonate 66.
3-(4-formylphenyl)-2-(pyridin-2- ylsulfonyl)acrylonitrile 67.
4-acetamidobenzaldehyde 68. 4-[[5-chloro-2-oxopyrimidin-1(2h)-
yl]methoxy]benzaldehyde 69.
4-(5-formyl-2-furyl)benzene-1-sulfonamide 70.
3-Benzo[1,3]dioxol-5-yl-2-methyl-propionaldehyde 71.
3-(phenylthio)butyraldehyde 72. 3-chloro-4,4,4-trifluoro-2-phenylb-
utanal 73. 2-cyano-2-phenylacetaldehyde 74.
3-methoxyphenylacetaldehyde 75. pyridine-3-carboxaldehide 76.
4-chlorobenzaldehyde 77. 4-cyanobenzaldehyde 78.
3-fluorobenzaldehyde 79. m-tolualdehyde 80.
2,4-dichlorobenzaldehyde 81. quinoline-3-carboxaldehyde 82.
2-(trifluoromethyl)benzaldehyde 83. methyl 4-formylbenzoate 84.
4-chloro-3-fluorobenzaldehyde 85. 4-nitrocinnamaldehyde 86.
3-thiophenecarboxaldehyde 87. 3-methoxybenzaldehyde 88.
propionaldehyde 89. 3,3-dimethylbutyraldehyde 90.
3-phenylpropionaldehyde
[0280]
2TABLE II Acyl chloride derivatives of formula (VIII) R'COZ (Z =
Cl) 1. 3,5-bis(trifluoromethyl)b- enzoyl chloride 2. benzoyl
chloride 3. 2-bromobenzoyl chloride 4. 2-fluorobenzoyl chloride 5.
2,4-difluorobenzoyl chloride 6. 2,6-difluorobenzoyl chloride 7.
2-chlorobenzoyl chloride 8. 2,4-dichlorobenzoyl chloride 9.
2-methoxybenzoyl chloride 10. 2-(trifluoromethyl)benzoyl chloride
11. o-toluoyl chloride 12. 3-bromobenzoyl chloride 13.
3-fluorobenzoyl chloride 14. 3-chlorobenzoyl chloride 15.
3,4-dichlorobenzoyl chloride 16. m-anisoyl chloride 17.
3,4-dimethoxybenzoyl chloride 18. 3,4,5-trimethoxybenzoyl chloride
19. 3,5-dimethoxybenzoyl chloride 20. 3-(trifluoromethyl)benzoyl
chloride 21. m-toluoyl chloride 22. 4-bromobenzoyl chloride 23.
4-fluorobenzoyl chloride 24. 4-chlorobenzoyl chloride 25. p-anisoyl
chloride 26. 4-ethoxybenzoyl chloride 27. 4-n-butoxybenzoyl
chloride 28. 4-biphenylcarbonyl chloride 29.
4-(trifluoromethyl)benzoyl chloride 30. 4-tert-butylbenzoyl
chloride 31. p-toluoyl chloride 32. 4-ethylbenzoyl chloride 33.
4-n-propylbenzoyl chloride 34. 4-n-butylbenzoyl chloride 35.
pivaloyl chloride 36. isobutyryl chloride 37. 2-ethylhexanoyl
chloride 38. acetyl chloride 39. phenoxyacetyl chloride 40.
4-chlorophenoxyacetyl chloride 41. methoxyacetyl chloride 42.
phenylacetyl chloride 43. tert-butylacetyl chloride 44. isovaleryl
chloride 45. propionyl chloride 46. hydrocinnamoyl chloride 47.
butyryl chloride 48. pentanoyl chloride 49. 4-iodobenzoyl chloride
50. cyclopropanecarbonyl chloride 51. cyclobutanecarbonyl chloride
52. cyclopentanecarbonyl chloride 53. 3-cyclopentylpropionyl
chloride 54. cyclohexanecarbonyl chloride 55. 4-cyanobenzoyl
chloride 56. 2-furoyl chloride 57. 1-naphthoyl chloride 58.
2-naphthoyl chloride 59. thiophene-2-carbonyl chloride 60.
thiophene-2-acetyl chloride 61. (3,4-dimethoxyphenyl)acetyl
chloride 62. 3,5-dichlorobenzoyl chloride 63. 2,5-difluorobenzoyl
chloride 64. 3,4-difluorobenzoyl chloride 65.
9-fluorenone-4-carbonyl chloride 66. 3,5-difluorobenzoyl chloride
67. benzyloxyacetyl chloride 68. 3-cyanobenzoyl chloride 69.
(2,5-dimethoxyphenyl)acetyl chloride 70. 3-methoxyphenylacetyl
chloride 71. nicotinoyl chloride hydrochloride 72. isonicotinoyl
chloride hydrochloride 73. 2,4,6-trimethylbenzoyl chloride 74.
diphenylacetyl chloride 75. 2-methylvaleryl chloride 76.
3,4-methylenedioxybenzoyl chloride 77. 2,4-dimethoxybenzoyl
chloride 78. 2-phenoxypropionyl chloride 79. 2-phenylbutyryl
chloride 80. 2-ethylbutyryl chloride 81. 2,3-dichlorobenzoyl
chloride 82. 4-chlorophenylacetyl chloride 83. d1-2-methylbutyryl
chloride 84. 2,3-difluorobenzoyl chloride 85.
1-(4-chlorophenyl)-1-cyclopentanecarbonyl- chloride 86.
2-ethoxy-1-naphthoyl chloride 87. benzo[b]thiophene-2-carbonyl
chloride 88. 4-(trifluoromethoxy)benz- oyl chloride 89.
2-(trifluoromethoxy)benzoyl chloride 90.
3-chlorobenzo[b]thiophene-2-carbonyl chloride 91.
2-fluoro-3-(trifluoromethyl)benzoyl chloride 92.
2-fluoro-4-(trifluoromethyl)benzoyl chloride 93.
2-fluoro-5-(trifluoromethyl)benzoyl chloride 94.
3-fluoro-5-(trifluoromethyl)benzoyl chloride 95.
4-fluoro-2-(trifluoromethyl)benzoyl chloride 96.
4-fluoro-3-(trifluoromethyl)benzoyl chloride 97.
2-fluoro-6-(trifluoromethyl)benzoyl chloride 98.
2,3,6-trifluorobenzoyl chloride 99. 2,4,5-trifluorobenzoyl chloride
100 3-(trifluoromethoxy)benzoyl chloride 101 isoxazole-5-carbonyl
chloride 102 2,4,6-trifluorobenzoyl chloride 103
2,5-bis(trifluoromethyl)benzoyl chloride 104 2,3,4-trifluorobenzoyl
chloride 105 2,4,6-trichlorobenzoyl chloride 106
2,4-dichloro-5-fluorobenzoyl chloride 107 4-methoxyphenylacetyl
chloride 108 5-fluoro-2-(trifluoromethyl)ben- zoyl chloride 109
2-chloro-6-fluorobenzoyl chloride 110 2-bromo-5-methoxybenzoyl
chloride 111 cyclopentylacetyl chloride 112
3-chloro-4-fluorobenzoyl chloride 113
3-fluoro-4-(trifluoromethyl)benzoyl chloride 114
4-fluorophenylacetyl chloride 115 4-tert-butylphenoxyacetyl
chloride 116 7-Imidazol-1-yl-5,6-dihydro-naphthalene-2- carbonyl
chloride 117 4-Imidazol-1-ylmethyl-benzoyl chloride 118
4-bromo-3-methylbenzoyl chloride
[0281]
3TABLE III Isocyanate derivatives of formula (IX) R'NCO 1. phenyl
isocyanate 2. 2-bromophenyl isocyanate 3. 2-fluorophenyl isocyanate
4. 2,4-difluorophenyl isocyanate 5. 2,6-difluorophenyl isocyanate
6. 2-chlorophenyl isocyanate 7. 2,3-dichlorophenyl isocyanate 8.
2,4-dichlorophenyl isocyanate 9. 2,5-dichlorophenyl isocyanate 10.
2,6-dichlorophenyl isocyanate 11. 2-methoxyphenyl isocyanate 12.
2,4-dimethoxyphenyl isocyanate 13. 2,5-dimethoxyphenyl isocyanate
14. 2-ethoxyphenyl isocyanate 15. 2-(trifluoromethyl)phenyl
isocyanate 16. o-tolyl isocyanate 17. 2,6-dimethylphenyl isocyanate
18. 2-ethylphenyl isocyanate 19. 3-bromophenyl isocyanate 20.
3-fluorophenyl isocyanate 21. 3-chlorophenyl isocyanate 22.
3,4-dichlorophenyl isocyanate 23. 3-methoxyphenyl isocyanate 24.
3-(trifluoromethyl)phenyl isocyanate 25. m-tolyl isocyanate 26.
4-bromophenyl isocyanate 27. 4-fluorophenyl isocyanate 28.
4-chlorophenyl isocyanate 29. 4-methoxyphenyl isocyanate 30.
4-(trifluoromethyl)phenyl isocyanate 31. p-tolyl isocyanate 32.
benzoyl isocyanate 33. 1-naphthyl isocyanate 34. Benzyl isocyanate
35. 3,5-bis(trifluoromethyl)phenyl isocyanate 36.
2,5-difluorophenyl isocyanate 37. 2,4,5-trichlorophenyl isocyanate
38. 2,4,6-trichlorophenyl isocyanate 39. 2-isopropylphenyl
isocyanate 40. 2,3-dimethylphenyl isocyanate 41.
4-methoxy-2-methylphenyl isocyanate 42. 2,4-dimethylphenyl
isocyanate 43. 2,5-dimethylphenyl isocyanate 44.
2-ethyl-6-methylphenyl isocyanate 45. 3-cyanophenyl isocyanate 46.
5-chloro-2,4-dimethoxyphenyl isocyanate 47. 3-chloro-4-methylphenyl
isocyanate 48. 3,5-dichlorophenyl isocyanate 49.
5-chloro-2-methoxyphenyl isocyanate 50. 3,4,5-trimethoxyphenyl
isocyanate 51. 3,5-dimethoxyphenyl isocyanate 52.
3-(methylthio)phenyl isocyanate 53. 3-acetylphenyl isocyanate 54.
3,4-dimethylphenyl isocyanate 55. 3,5-dimethylphenyl isocyanate 56.
2-methoxy-5-methylphenyl isocyanate 57. 3-ethylphenyl isocyanate
58. 4-bromo-2-(trifluoromethyl)phenyl isocyanate 59.
4-chloro-2-(trifluoromethyl)phenyl isocyanate 60.
4-chloro-3-(trifluoromethyl)phenyl isocyanate 61. 4-iodophenyl
isocyanate 62. 4-phenoxyphenyl isocyanate 63. 4-ethoxyphenyl
isocyanate 64. 4-acetylphenyl isocyanate 65. 4-isopropylphenyl
isocyanate 66. 4-ethylphenyl isocyanate 67. 4-n-butylphenyl
isocyanate 68. 2,4,6-trimethylphenyl isocyanate 69.
2-isopropyl-6-methylphenyl isocyanate 70. 2,6-diethylphenyl
isocyanate 71. 5-chloro-2-methylphenyl isocyanate 72.
4-chloro-2-methylphenyl isocyanate 73. 4-(trifluoromethoxy)phenyl
isocyanate 74. 2-chloro-5-(trifluoromet- hyl)phenyl isocyanate 75.
2-chloro-6-methylphenyl isocyanate 76. 2,4,5-trimethylphenyl
isocyanate 77. 3-chloro-2-methoxyphenyl isocyanate 78.
3-chloro-2-methylphenyl isocyanate 79. 3-chloro-4-fluorophenyl
isocyanate 80. 4-bromo-2-methylphenyl isocyanate 81.
4-bromo-2,6-dimethylphenyl isocyanate 82.
2,6-dibromo-4-fluorophenyl isocyanate 83. 4-butoxyphenyl isocyanate
84. 3-fluoro-4-methylphenyl isocyanate 85. 5-fluoro-2-methylphenyl
isocyanate 86. 2-biphenylyl isocyanate 87. 4-biphenylyl isocyanate
88. 2-bromo-4,6-difluorophenyl isocyanate 89. (r)-(+)-1-phenylethyl
isocyanate 90. 1-(1-naphthyl)ethyl isocyanate 91.
(s)-(+)-1-(1-naphthyl)ethyl isocyanate 92. 3,4-difluorophenyl
isocyanate 93. 2-(trifluoromethoxy)phenyl isocyanate 94.
4-benzyloxyphenyl isocyanate 95. 4-bromo-2-chlorophenyl isocyanate
96. 4-bromo-2-fluorophenyl isocyanate 97. 2-fluoro-5-methylphenyl
isocyanate 98. 2,3,4-trifluorophenyl isocyanate 99.
2-(difluoromethoxy)phenyl isocyanate 100. 4-(difluoromethoxy)pheny-
l isocyanate 101. 2-methylbenzyl isocyanate 102. 2-chlorobenzyl
isocyanate 103. 4-fluorobenzyl isocyanate 104. 4-methoxybenzyl
isocyanate 105. 2,6-difluorobenzoyl isocyanate 106. 4-fluorobenzoyl
isocyanate 107. 2-fluoro-3-(trifluoromethyl)phenyl isocyanate 108.
2-fluoro-5-(trifluoromethyl)phenyl isocyanate 109.
2-fluoro-6-(trifluoromethyl)phenyl isocyanate 110.
4-fluoro-2-(trifluoromethyl)phenyl isocyanate 111.
2-(tert-butyl)phenyl isocyanate 112. 3-pyridyl isocyanate
[0282] Accordingly, it is a further object of the present invention
a library of two or more amino-phthalazinone derivatives of formula
(I) 13
[0283] wherein
[0284] Ra and Rb are, each independently, a hydrogen atom or a
group, optionally further substituted, selected from straight or
branched C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or
cycloalkyl C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl,
5 to 7 membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl
with from 1 to 3 heteroatoms selected among nitrogen, oxygen or
sulfur; or one of Ra or Rb is hydrogen or an optionally substituted
straight or branched C.sub.1-C.sub.6 alkyl group, and the other is
a group selected from --COR', --CONHR', --COOR' or --SO.sub.2R',
wherein R' is hydrogen or an optionally substituted group selected
from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,
heterocyclyl or heterocyclylalkyl, as set forth above;
[0285] R.sub.1 is a group of formula --CHR.sub.4R.sub.5 wherein
R.sub.4 and R.sub.5 are, each independently, hydrogen or an
optionally substituted group selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
or R.sub.1 is a group of formula --NHR', --NR'COR", --NR'CONHR" or
--NR'SO.sub.2R", wherein R' has the above reported meanings other
than hydrogen, and R" is hydrogen or has the meanings set forth
above for R';
[0286] R.sub.2 is a hydrogen atom or it is a group, optionally
further substituted, selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or
sulfur;
[0287] any R.sub.3, being placed in one or more of the free
positions 5, 6 and 8 of the phthalazinone ring are, independently
from each other, halogen, nitro, carboxy, cyano or a group
optionally further substituted selected from straight or branched
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or cycloalkyl
C.sub.1-C.sub.6 alkyl, aryl, aryl C.sub.1-C.sub.6 alkyl, 5 to 7
membered heterocyclyl or heterocyclyl C.sub.1-C.sub.6 alkyl with
from 1 to 3 heteroatoms selected among nitrogen, oxygen or sulfur;
or R.sub.3 is a group selected from --COR', --CONHR', --SO.sub.2R',
--NR'R", --NR'COR", --NR'CONHR' or --NR'SO.sub.2R", wherein R' and
R" are, the same or different, hydrogen or a group as set forth
above;
[0288] m is 0 or an integer from 1 to 3;
[0289] or a pharmaceutically acceptable salt thereof.
[0290] Pharmacology
[0291] The compounds of formula (I) are active as protein kinase
inhibitors and are therefore useful, for instance, to restrict the
unregulated proliferation of tumor cells. In therapy, they may be
used in the treatment of various tumors such as, for instance,
carcinomas, e.g. mammary carcinoma, lung carcinoma, bladder
carcinoma, colon carcinoma, ovary and endometrial tumors, sarcomas,
e.g. soft tissue and bone sarcomas, and the hematological
malignancies such as, e.g., leukemias. In addition, the compounds
of formula (I) are also useful in the treatment of other cell
proliferative disorders such as psoriasis, vascular smooth cell
proliferation associated with atherosclerosis and post-surgical
stenosis and restenosis and in the treatment of Alzheimer's
disease. The inhibiting activity of putative protein kinase
inhibitors and the potency of selected compounds was determined
through a method of assay based on the use of the MultiScreen-PH 96
well plate (Millipore), in which a phosphocellulose filter paper
was placed at each well bottom allowing binding of positive charged
substrate after a washing/filtration step. When a radioactivity
labeled phosphate moiety was transferred by the ser/threo kinase to
the filter-bound histone, light emitted was measured in a
scintillation counter.
[0292] Inhibition Assay of cdk2/Cyclin A Activity
[0293] Kinase reaction: 1.5 .mu.M histone H1 substrate, 25 .mu.M
ATP (0.2 uCi P33.gamma.-ATP), 30 ng of baculovirus co-expressed
cdk2/Cyclin A, 10 .mu.M inhibitor in a final volume of 100 .mu.l
buffer (TRIS HCl 10 mM pH 7.5, MgCl.sub.2 10 mM, 7.5 mM DTT) were
added to each well of a 96 U bottom well plate. After 10 min at
37.degree. C. incubation, reaction was stopped by 20 .mu.l EDTA 120
mM. Capture: 100 .mu.l were transferred from each well to
MultiScreen plate, to allow substrate binding to phosphocellulose
filter. Plates were then washed 3 times with 150 .mu.l/well PBS
Ca++/Mg++ free and filtered by MultiScreen filtration system.
Detection: filters were allowed to dry at 37.degree. C., then 100
.mu.l/well scintillant were added and 33P labeled histone H1 was
detected by radioactivity counting in the Top-Count instrument.
Results: data were analyzed and expressed as % inhibition referred
to total activity of enzyme (=100%). All compounds showing
inhibition .gtoreq.50% were further analyzed in order to study and
define potency (IC50) as well as the kinetic-profile of inhibitor
through Ki calculation. IC50 determination: the protocol used was
the same described above, where inhibitors were tested at different
concentrations ranging from 0.0045 to 10 .mu.M. Experimental data
were analyzed by the computer program GraphPad Prizm using the four
parameter logistic equation:
y=bottom+(top-bottom)/(1+10 ((logIC50-x)*slope))
[0294] where x is the logarithm of the inhibitor concentration, y
is the response; y starts at bottom and goes to top with a sigmoid
shape. Ki calculation: either the concentration of ATP and histone
H1 substrate were varied: 4, 8, 12, 24, 48 .mu.M for ATP
(containing proportionally diluted P.sup.33.gamma.-ATP) and 0.4,
0.8, 1.2, 2.4, 4.8 .mu.M for histone were used in absence and
presence of two different, properly chosen inhibitor
concentrations. Experimental data were analyzed by the computer
program "SigmaPlot" for Ki determination, using a random bireactant
system equation: 1 v = V max ( A ) ( B ) aKAKB 1 + ( A ) KA + ( B )
KB + ( A ) ( B ) aKAKB
[0295] where A=ATP and B=histone H1.
[0296] In addition the selected compounds have been characterized
on a panel of ser/threo kinases strictly related to cell cycle
(cdk2/cyclin E, cdk1/cyclin B1, cdk4/Cyclin D1), and also for
specificity on MAPK, PKA, EGFR, IGF1-R, Cdc7/dbf4 and aurora-2.
[0297] Inhibition Assay of cdk2/Cyclin E Activity
[0298] Kinase reaction: 1.5 .mu.M histone H1 (Sigma #H-5505)
substrate, 25 .mu.M ATP (0.2 .mu.Ci P.sup.33.gamma.-ATP), 15 ng of
baculovirus co-expressed cdk2/GST-Cyclin E, suitable concentrations
of inhibitor in a final volume of 100 .mu.l buffer (TRIS HCl 10 mM
pH 7.5, MgCl.sub.2 10 mM, 7.5 mM DTT+0.2 mg/ml BSA) were added to
each well of a 96 U bottom well plate. After 10 min at 37.degree.
C. incubation, reaction was stopped by 20 .mu.l EDTA 120 mM.
Capture: 100 .mu.l were transferred from each well to MultiScreen
plate, to allow substrate binding to phosphocellulose filter.
Plates were then washed 3 times with 150 .mu.l/well PBS
Ca.sup.++/Mg.sup.++ free and filtered by MultiScreen filtration
system. Detection: filters were allowed to dry at 37.degree. C.,
then 100 .mu.l/well scintillant were added and .sup.33P labeled
histone H1 was detected by radioactivity counting in the Top-Count
instrument.
[0299] Inhibition Assay of cdk1/Cyclin B1 Activity
[0300] Kinase reaction: 1.5 .mu.M histone H1 (Sigma #H-5505)
substrate, 25 .mu.M ATP (0.2 .mu.Ci P.sup.33.gamma.-ATP), 30 ng of
baculovirus co-expressed cdk1/Cyclin B1, suitable concentrations of
inhibitor in a final volume of 100 .mu.l buffer (TRIS HCl 10 mM pH
7.5, MgCl.sub.2 10 mM, 7.5 mM DTT+0.2 mg/ml BSA) were added to each
well of a 96 U bottom well plate. After 10 min at 37.degree. C.
incubation, reaction was stopped by 20 .mu.l EDTA 120 mM. Capture:
100 .mu.l were transferred from each well to MultiScreen plate, to
allow substrate binding to phosphocellulose filter. Plates were
then washed 3 times with 150 .mu.l/well PBS Ca.sup.++/Mg.sup.++
free and filtered by MultiScreen filtration system. Detection:
filters were allowed to dry at 37.degree. C., then 100 .mu.l/well
scintillant were added and .sup.33P labeled histone H1 was detected
by radioactivity counting in the Top-Count instrument.
[0301] Inhibition Assay cdk4/Cyclin D1 Activity
[0302] Kinase reaction: 0,4 uM .mu.M mouse GST-Rb(769-921)
(#sc-4112 from Santa Cruz) substrate, 10 .mu.M ATP (0.5 .mu.Ci
P.sup.33.gamma.-ATP), 100 ng of baculovirus expressed
GST-cdk4/GST-Cyclin D1, suitable concentrations of inhibitor in a
final volume of 50 .mu.l buffer (TRIS HCl 10 mM pH 7.5, MgCl.sub.2
10 mM, 7.5 mM DTT+0.2 mg/ml BSA) were added to each well of a 96 U
bottom well plate. After 40 min at 37.degree. C. incubation,
reaction was stopped by 20 .mu.l EDTA 120 mM. Capture: 60 .mu.l
were transferred from each well to MultiScreen plate, to allow
substrate binding to phosphocellulose filter. Plates were then
washed 3 times with 150 .mu.l/well PBS Ca.sup.++/Mg.sup.++ free and
filtered by MultiScreen filtration system. Detection: filters were
allowed to dry at 37.degree. C., then 100 .mu.l/well scintillant
were added and .sup.33P labeled Rb fragment was detected by
radioactivity counting in the Top-Count instrument.
[0303] Inhibition Assay of MAPK Activity
[0304] Kinase reaction: 10 .mu.M MBP (Sigma #M-1891) substrate, 25
.mu.M ATP (0.2 .mu.Ci P.sup.33.gamma.-ATP), 25 ng of bacterially
expressed GST-MAPK (Upstate Biotechnology #14-173), suitable
concentrations of inhibitor in a final volume of 100 .mu.l buffer
(TRIS HCl 10 mM pH 7.5, MgCl.sub.2 10 mM, 7.5 mM DTT+0.1 mg/ml BSA)
were added to each well of a 96 U bottom well plate. After 15 min
at 37.degree. C. incubation, reaction was stopped by 20 .mu.l EDTA
120 mM. Capture: 100 .mu.l were transferred from each well to
MultiScreen plate, to allow substrate binding to phosphocellulose
filter. Plates were then washed 3 times with 150 .mu.l/well PBS
Ca.sup.++/Mg.sup.++ free and filtered by MultiScreen filtration
system. Detection: filters were allowed to dry at 37.degree. C.,
then 100 .mu.l/well scintillant were added and .sup.33P labeled MBP
was detected by radioactivity counting in the Top-Count
instrument.
[0305] Inhibition Assay of PKA Activity
[0306] Kinase reaction: 10 .mu.M histone H1 (Sigma #H-5505)
substrate, 10 .mu.M ATP (0.2 .mu.Ci P.sup.33.gamma.-ATP), 1 U of
bovine heart PKA (Sigma #2645), suitable concentrations of
inhibitor in a final volume of 100 .mu.l buffer (TRIS HCl 10 mM pH
7.5, MgCl.sub.2 10 mM, 7.5 mM DTT+0.2 mg/ml BSA) were added to each
well of a 96 U bottom well plate. After 5 min at 37.degree. C.
incubation, reaction was stopped by 20 .mu.l EDTA 120 mM. Capture:
100 .mu.l were transferred from each well to MultiScreen plate, to
allow substrate binding to phosphocellulose filter. Plates were
then washed 3 times with 150 .mu.l/well PBS Ca.sup.++/Mg.sup.++
free and filtered by MultiScreen filtration system. Detection:
filters were allowed to dry at 37.degree. C., then 100 .mu.l/well
scintillant were added and .sup.33P labeled histone H1 was detected
by radioactivity counting in the Top-Count instrument.
[0307] Inhibition Assay of EGFR Activity
[0308] Kinase reaction: 25 nM in house biotinylated PolyGluTyr
(Sigma #0275) substrate, 2,5 .mu.M ATP (0.3 .mu.Ci
P.sup.33.gamma.-ATP), 80 ng baculovirus expressed GST-EGFR,
suitable concentrations of inhibitor in a final volume of 100 .mu.l
buffer (Hepes 50 mM pH 7,5, MnCl.sub.2-MgCl.sub.2 3 mM, 1 mM DTT+3
.mu.M NaVO3, 0.1 mg/ml BSA) were added to each well of a 96 U
bottom well plate. After 5 min. at 37.degree. C. incubation,
reaction was stopped by 20 .mu.l EDTA 120 mM. Capture: 100 .mu.l
were transferred from each well to streptavidin-Flashplate, to
allow biotinylated-substrate binding to plate. Plates were then
washed 3 times with 150 .mu.l/well PBS Ca.sup.++/Mg.sup.++ free.
Detection: radioactivity counting in the Top-Count instrument.
[0309] Inhibition Assay of IGF1-R Activity
[0310] The inhibition assay of IGF1-R activity was performed
according to the following protocol. Kinase reaction: 10 .mu.M
biotinylated MBP (Sigma cat. #M-1891) substrate, 0-20 .mu.M
inhibitor, 6 .mu.M cold ATP, 2 nM .sup.33P-ATP, and 22.5 ng IGF1-R
(pre-incubated for 30 min at room temperature with cold 60 .mu.M
cold ATP) in a final volume of 30 .mu.l buffer (50 mM HEPES pH 7.9,
3 mM MnCl.sub.2, 1 mM DTT, 3 .mu.M NaVO.sub.3) were added to each
well of a 96 U bottom well plate. After incubation for 35 min at
room temperature, the reaction was stopped by addition of 100 .mu.l
PBS buffer containing 32 mM EDTA, 500 .mu.M cold ATP, 0.1% Triton
X100 and 10 mg/ml streptavidin coated SPA beads. After 15 min
incubation, 110 .mu.L of suspension were withdrawn and transferred
into 96-well OPTIPLATEs containing 100 .mu.l of 5M CsCl. After 4
hours, the plates were read for 2 min in a Packard TOP-Count
radioactivity reader. Results: Experimental data were analyzed with
the program GraphPad Prizm.
[0311] In addition, the inhibiting activity of putative protein
kinase inhibitors and the potency of selected compounds was also
determined through a method of assay based on the use of a SPA
(Scintillation Proximity Assay) 96 well plate assay. The assay is
based on the ability of streptavidin coated SPA beads to capture a
biotinylated peptide derived from a phosphorylation site of
histone. When a radioactivity labeled phosphate moiety was
transferred by the ser/threo kinase to the biotinylated histone
peptide, light emitted was measured in a scintillation counter.
[0312] Inhibition Assay of cdk5/p25 Activity
[0313] The inhibition assay of cdk5/p25 activity was performed
according to the following protocol. Kinase reaction: 1.0 .mu.M
biotinylated histone peptide substrate, 0.25 uCi P33g-ATP, 4 nM
cdk5/p25 complex, 0-100 .mu.M inhibitor in a final volume of 100
.mu.l buffer (Hepes 20 mM pH 7.5, MgCl2 15 mM, 1 mM DTT) were added
to each well of a 96 U bottom well plate. After 20 min at
37.degree. C. incubation, the reaction was stopped by the addition
of 500 ug SPA beads in phosphate-buffered saline containing 0.1%
Triton X-100, 50 uM ATP and 5 mM EDTA. The beads were allowed to
settle, and the radioactivity incorporated in the 33P-labelled
peptide was detected in a Top Count scintillation counter. Results:
Data were analyzed and expressed as % Inhibition using the
formula:
100.times.(1-(Unknown-Bkgd)/(Enz. Control-Bkgd))
[0314] IC50 values were calculated using a variation of the four
parameter logistics equation:
Y=100/[1+10 ((LogEC50-X)*Slope)]
[0315] Where X=log(uM) and Y=% Inhibition.
[0316] Inhibition Assay of Cdc7/dbf4 Activity
[0317] The inhibition assay of Cdc7/dbf4 activity was performed
according to the following protocol. The Biotin-MCM2 substrate is
trans-phosphorylated by the Cdc7/Dbf4 complex in the presence of
ATP traced with .gamma..sup.33-ATP. The phosphorylated Biotin-MCM2
substrate is then captured by Streptavidin-coated SPA beads and the
extent of phosphorylation evaluated by .beta. counting. The
inhibition assay of Cdc7/dbf4 activity was performed in 96 wells
plate according to the following protocol. To each well of the
plate were added:
[0318] 10 .mu.l substrate (biotinylated MCM2, 6 .mu.M final
concentration)
[0319] 10 .mu.l enzyme (Cdc7/Dbf4, 12.5 nM final concentration)
[0320] 10 .mu.l test compound (12 increasing concentrations in the
nM to .mu.M range to generate a dose-response curve)
[0321] 10 .mu.l of a mixture of cold ATP (10 .mu.M final
concentration) and radioactive ATP (1/2500 molar ratio with cold
ATP) was then used to start the reaction which was allowed to take
place at 37.degree. C.
[0322] Substrate, enzyme and ATP were diluted in 50 mM HEPES pH 7.9
containing 15 mM MgCl.sub.2, 2 mM DTT, 3 .mu.M NaVO.sub.3, 2 mM
glycerophosphate and 0.2 mg/ml BSA. The solvent for test compounds
also contained 10% DMSO. After incubation for 20 minutes, the
reaction was stopped by adding to each well 100 .mu.l of PBS pH 7.4
containing 50 mM EDTA, 1 mM cold ATP, 0.1% Triton X100 and 10 mg/ml
streptavidin coated SPA beads. After 15 minutes of incubation at
room temperature to allow the biotinylated MCM2-streptavidin SPA
beads interaction to occur, beads were trapped in a 96 wells filter
plate (Unifilter.RTM. GF/B.TM.) using a Packard Cell Harvester
(Filtermate), washed with distilled water and then counted using a
Top Count (Packard). Counts were blank-subtracted and then the
experimental data (each point in triplicate) were analyzed for IC50
determination using a non-linear regression analysis (Sigma
Plot).
[0323] Inhibition Assay of Aurora-2 Activity
[0324] The inhibiting activity and the potency of selected
compounds was determined through a method of assay based on the use
of the streptavidin scintillation proximity assay beads
(amershampharmacia biotech) run in a 96 well plates. At the end of
the reaction, the biotinylated peptide substrate was captured with
the beads and subsequently allowed to stratify using CsCl.sub.2.
When a radioactivity labeled phosphate moiety was transferred by
the kinase to the beads-bound peptide, light emitted was measured
in a scintillation counter. The inhibition assay of Aurora-2
activity was performed in 96 wells plate according to the following
protocol. Kinase reaction: 8 .mu.M biotinylated peptide (4 repeats
of LRRWSLG), 10 .mu.M ATP (0.5 uCi P.sup.33g-ATP), 10 nM Aurora2,
10 .mu.M inhibitor in a final volume of 60 .mu.l buffer (HEPES 50
mM pH 7.0, MgCl.sub.2 10 mM, 1 mM DTT, 0.125 mg/ml BSA, 3 .mu.M
orthovanadate) were added to each well of a 96 U bottom well plate.
After 30 minutes at room temperature incubation, reaction was
stopped and biotinylated peptide captured by adding 100 .mu.l of
bead suspension. Stratification: 100 .mu.l of CsCl2 7.5 M were
added to each well and let stand one hour before radioactivity was
counted in the Top-Count instrument. Results: data were analyzed
and expressed as % inhibition referred to total activity of enzyme
(=100%). All compounds showing inhibition .gtoreq.60% were further
analyzed in order to study the potency of the inhibitor through
IC50 calculation. The protocol used was the same described above,
except that serial dilution of the inhibitor was used. Experimental
data were fitted by nonlinear regression using the following
equation: 2 v = v 0 + ( v 0 - v b ) 1 + 10 n ( log IC 50 - log [ I
] )
[0325] With v.sub.b as the baseline velocity, v as the observed
reaction velocity, v.sub.o as the velocity in the absence of
inhibitors, and [I] as the inhibitor concentration.
[0326] The compounds of formula (I) of the present invention,
suitable for administration to a mammal, e.g. to humans, can be
administered by the usual routes and the dosage level depends upon
the age, weight, conditions of the patient and the administration
route.
[0327] For example, a suitable dosage adopted for oral
administration of a compound of formula (I) may range from about 10
to about 500 mg pro dose, from 1 to 5 times daily. The compounds of
the invention can be administered in a variety of dosage forms,
e.g. orally, in the form of tablets, capsules, sugar or film coated
tablets, liquid solutions or suspensions; rectally in the form of
suppositories; parenterally, e.g. intramuscularly, or by
intravenous and/or intrathecal and/or intraspinal injection or
infusion.
[0328] In addition, the compounds of the invention can be
administered either as single agents or, alternatively, in
combination with known anticancer treatments such as radiation
therapy or chemotherapy regimen in combination with cytostatic or
cytotoxic agents, antibiotic-type agents, alkylating agents,
antimetabolite agents, hormonal agents, immunological agents,
interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2
inhibitors), metallomatrixprotease inhibitors, telomerase
inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor
agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis
agents, farnesyl transferase inhibitors, ras-raf signal
transduction pathway inhibitors, cell cycle inhibitors, other cdks
inhibitors, tubulin binding agents, topoisomerase I inhibitors,
topoisomerase II inhibitors, and the like. As an example, the
compounds of the invention can be administered in combination with
one or more chemotherapeutic agents such as, for instance,
exemestane, formestane, anastrozole, letrozole, fadrozole, taxane,
taxane derivatives, encapsulated taxanes, CPT-11, camptothecin
derivatives, anthracycline glycosides, e.g., doxorubicin,
idarubicin, epirubicin, etoposide, navelbine, vinblastine,
carboplatin, cisplatin, estramustine, celecoxib, tamoxifen,
raloxifen, Sugen SU-5416, Sugen SU-6668, Herceptin, and the like,
optionally within liposomal formulations thereof. If formulated as
a fixed dose, such combination products employ the compounds of
this invention within the dosage range described above and the
other pharmaceutically active agent within the approved dosage
range. Compounds of formula (I) may be used sequentially with known
anticancer agents when a combination formulation is
inappropriate.
[0329] The present invention also includes pharmaceutical
compositions comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof in association with a
pharmaceutically acceptable excipient (which can be a carrier or a
diluent). The pharmaceutical compositions containing the compounds
of the invention are usually prepared following conventional
methods and are administered in a pharmaceutically suitable form.
For example, the solid oral forms may contain, together with the
active compound, diluents, e.g. lactose, dextrose, saccharose,
sucrose, cellulose, corn starch or potato starch; lubricants, e.g.
silica, talc, stearic, magnesium or calcium stearate, and/or
polyethylene glycols; binding agents, e.g. starches, arabic gum,
gelatin, methylcellulose, carboxymethylcellulose or polyvinyl
pyrrolidone; disaggregating agents, e.g. a starch, alginic,
alginates or sodium starch glycolate; effervescing mixtures;
dyestuffs; sweeteners; wetting agents such as lecithin,
polysorbates, laurylsulfates; and, in general, non-toxic and
pharmacologically inactive substances used in pharmaceutical
formulations. Said pharmaceutical preparations may be manufactured
in known manner, for example, by means of mixing, granulating,
tabletting, sugar-coating, or film-coating processes.
[0330] The liquid dispersions for oral administration may be e.g.
syrups, emulsions and suspensions. The syrups may contain as
carrier, for example, saccharose or saccharose with glycerin and/or
mannitol and/or sorbitol. The suspensions and the emulsions may
contain as carrier, for example, a natural gum, agar, sodium
alginate, pectin, methylcellulose, carboxymethylcellulose, or
polyvinyl alcohol. The suspension or solutions for intramuscular
injections may contain, together with the active compound, a
pharmaceutically acceptable carrier, e.g. sterile water, olive oil,
ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a
suitable amount of lidocaine hydrochloride. The solutions for
intravenous injections or infusions may contain as carrier, for
example, sterile water or preferably they may be in the form of
sterile, aqueous, isotonic saline solutions or they may contain as
a carrier propylene glycol. The suppositories may contain together
with the active compound a pharmaceutically acceptable carrier,
e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan
fatty ester surfactant or lecithin.
[0331] The following examples illustrate but do not limit the
present invention.
[0332] General Methods
[0333] Flash chromatografy was performed on silica gel (Merck grade
9385, 60 .ANG.). HPLC/MS was performed on a Waters X Terra RP 18
(4.6.times.50 mm, 3.5 .mu.m) column using a Waters 2790 HPLC system
equipped with a 996 Waters PDA detector and a Micromass mod. ZQ
single quadrupole mass spectrometer, equipped with an electrospray
(ESI) ion source. Mobile phase A was ammonium acetate 5 mM buffer
(pH 5.5 with acetic acid/acetonitrile 95:5), and Mobile phase B was
H.sub.2O/acetonitrile (5:95). Gradient from 10 to 90% B in 8
minutes, hold 90% B 2 min. UV detection at 220 nm and 254 nm. Flow
rate 1 ml/min. Injection volume 10 .mu.l. Full scan, mass range
from 100 to 800 amu. Capillary voltage was 2.5 KV; Source temp. was
120.degree. C.; Cone was 10 V. Retention Times (HPLC r.t.) are
given in minutes at 220 nm or 254 nm. Mass are given as m/z ratio.
When necessary compounds have been purified by Preparative HPLC on
a Waters Symmetry C18 (19.times.50 mm, 5 um) column using a Waters
preparative HPLC 600 equipped with a 996 Waters PDA detector and a
Micromass mod. ZMD single quadrupole mass spectrometer,
electrospray ionisation, positive mode. Mobile phase A was water
0.01% TFA, and Mobile phase B was acetonitrile. Gradient from 10 to
90%B in 8 min, hold 90%B 2 min. Flow rate 20 ml/m. .sup.1H-NMR
spectroscopy was performed on a Mercury VX 400 operating at 400.45
MHz equipped with a 5 mm double resonance probe (1H {15N-31P}
ID_PFG Varian).
EXAMPLE 1
6-nitro-3-bromo-3H-isobenzofuran-1-one (II)
[0334] To 125 ml of a dichloromethane solution of 6-nitrophtalide
(8.0 g, 0.047 mol), bromine (8.25 g, 0.052 mol, 1.15 eq) and
hydrogen peroxide (5.07 g of a 35% solution in water, equivalent to
1.77 of hydrogen peroxide, 0.052 mol, 1.15 eq) were added. The
mixture was gently refluxed for 11 hours, then cooled down and
concentrated by solvent evaporation. The aqueous layer was
separated, and the organic phase washed with water before drying up
(Na.sub.2SO.sub.4). After evaporation of the solvent the crude
residue was purified by flash chromatography over silica gel
(hexane-ethyl acetate 8-2 to 7-3). 8.18 g of the titled compound
were obtained. [M-1].sup.31 =257; HPLC r.t. 5.37; .sup.1H-NMR
(CDCl.sub.3), diagnostic signals (ppm): 7.47 (s, 1H), 7.86 (d, 1H),
8.67 (dd, 1H), 8.74 (d, 1H).
EXAMPLE 2
(5-Amino-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium
bromide (III)
[0335] A solution of 6-nitro-3-bromo-3H-isobenzofuran-1-one (8.7 g,
0.034 mol) in ethyl propionate (464 ml) was heated to 70-75.degree.
C., and stirred while 313 ml of an ethyl propionate solution of
triphenyl phosphine (36 g, 0.137 mol, 4 eq) were added dropwise
over a time of 7 hours. Heating and stirring were continued
overnight, and then the mixture was cool down to room temperature.
The precipitate was collected, dried up under vacuum and purified
by flash chromatography over silica gel. A gradient of
dichloromethane-methanol-acetic acid, from 97-3-0 to 93-5-2 was
used as the eluant, to yield 6.2 g of the title compound.
[M].sup.+=410; HPLC r.t. 4.72; .sup.1H-NMR (DMSO-d.sub.6),
diagnostic signals (ppm): 6.01 (br. s, 2H exchangeable with
deuterated water), 6.49 (dd, 1H), 6.80 (d, 1H), 6.87 (d, 1H),
7.62-8.00 (m, 15H), 8.17 (s, 1H).
EXAMPLE 3
(5-{2-Methoxy-4-[3-(4-resin-benzylcarbamoyl)-propoxy]-benzylamino}-3-oxo-1-
,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium bromide
[0336] The compound of example 2 (252 mg, 0.514 mmol) was dissolved
in 15.25 ml of a solvent mixture made up of dichloromethane (13.5
ml), trifluoroethanol (1.5 ml) and acetic acid (0.25 ml).
Novabiochem 4-(4-Formyl-3-methoxyphenoxy)butyryl aminomethylated
resin (326 mg, declared substitution 0.94 mmol/g, 0.6 eq.) was
poured into the solution, and the resulting suspension was gently
stirred for 9 hours before adding dropwise the pyridine-borane
complex (250 .mu.l, .about.6 mmol, 10 eq.). After 40 hours the
resin was filtered, washed with dichloromethane, methanol and again
dichloromethane, hence dried under vacuum (518 mg, calculated
loading: 0.78 mmol/g; IR: 1787 cm.sup.-1, lactone stretching
band).
EXAMPLE 4
4-[3-Methoxy-4-({3-oxo-1-[1-pyridin-3-yl-methylidene]-1,3-dihydro-isobenzo-
furan-5-ylamino}-methyl)-phenoxy]-N-(4-resin-benzyl)-butyramide
[0337]
(5-{2-Methoxy-4-[3-(4-resin-benzylcarbamoyl)-propoxy]-benzylamino}--
3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium bromide
of example 3 (100 mg, 0.078 meq) was suspended in dried
dichloromethane (3 ml); pyridine-3-carboxaldehyde (50 .mu.l, about
.about.6 eq.) was added, followed by TEA (50 .mu.l). Stirring at
room temperature was maintained for 20 hours then the resin was
filtered and washed with dichloromethane, methanol, and again
dichloromethane before drying under vacuum (IR: 1776
cm.sup.-1).
EXAMPLE 5
N-{2-Methoxy-4-[3-(4-resin-benzylcarbamoyl)
-propoxy]-benzyl}-N-{3-oxo-1-[-
1-pyridin-3-yl-methylidene]-1,3-dihydro-isobenzofuran-5-yl}-benzamide
[0338]
4-[3-Methoxy-4-({3-oxo-1-[1-pyridin-3-yl-methylidene]-1,3-dihydro-i-
sobenzofuran-5-ylamino}-methyl)-phenoxy]-N-(4-resin-benzyl)-butyramide
of example 4 was suspended in dried dichloromethane (3 ml);
diisopropyl ethylamine (200 .mu.l) and benzoyl chloride (100 .mu.l,
.about.10 eq.) were added in this order. After stirring at room
temperature for 20 hours, the resin was filtered and washed with
dichloromethane, methanol, and again dichloromethane before drying
under vacuum (IR: 1786 cm.sup.-1).
EXAMPLE 6
4-[3-Methoxy-4-(1-{3-oxo-1-[1-pyridin-3-yl-methylidene]-1,3-dihydro-isoben-
zofuran-5-yl}-3-p-tolyl-ureidomethyl)-phenoxy]-N-(4-resin-benzyl)-butyrami-
de
[0339]
4-[3-Methoxy-4-({3-oxo-1-[1-pyridin-3-yl-methylidene]-1,3-dihydro-i-
sobenzofuran-5-ylamino}-methyl)-phenoxy]-N-(4-resin-benzyl)-butyramide
of example 4 was suspended in dried dichloromethane (3 ml) and
p-toluyl isocyanate (100 .mu.l, .about.10 eq.) was added. After
stirring at room temperature for 20 hours, the resin was filtered
and washed with dichloromethane, methanol, and again
dichloromethane before drying under vacuum.
EXAMPLE 7
N-{2-Methoxy-4-[3-(4-resin-benzylcarbamoyl)-propoxy]-benzyl}-N-(4-oxo-1-py-
ridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-benzamide
[0340]
N-{2-Methoxy-4-[3-(4-resin-benzylcarbamoyl)-propoxy]-benzyl}-N-{3-o-
xo-1-[1-pyridin-3-yl-methylidene]-1,3-dihydro-isobenzofuran-5-yl}-benzamid-
e of example 5 was suspended in dimethylformammide (3 ml) and
aqueous hydrazine (approximately 25% solution) was added (400
.mu.l, about 40 eq.). After stirring at room temperature for 20
hours, the resin was filtered, washed with dimethylformammide,
methanol and dichloromethane before drying under vacuum. (IR:
disappearance of lactone stretching band).
EXAMPLE 8
4-{3-Methoxy-4-[1-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-
-3-p-tolyl-ureidomethyl]-phenoxy}-N-(4-methyl-benzyl)-butyramide
[0341]
4-[3-Methoxy-4-(l-{3-oxo-1-[1-pyridin-3-yl-methylidene]-1,3-dihydro-
-isobenzofuran-5-yl}-3-p-tolyl-ureidomethyl)-phenoxy]-N-(4-resin-benzyl)-b-
utyramide of example 6 was suspended in dimethylformammide (3 ml)
and aqueous hydrazine (approximately 25% solution) was added (400
.mu.l, about 40 eq.). After stirring at room temperature for 20
hours, the resin was filtered, washed with dimethylformammide,
methanol and dichloromethane before drying under vacuum.
EXAMPLE 9
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-benzamide
[0342]
N-{2-Methoxy-4-[3-(4-resin-benzylcarbamoyl)-propoxy]-benzyl}-N-(4-o-
xo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-benzamide of
example 6 was suspended in a solution of 20% TFA in DCM (3 ml), and
stirred at room temperature for 2 hours. The resin was filtered and
the solution collected and dried up yielding 15 mg of title
compound. [M+1].sup.+=357; HPLC r.t. 4.02; .sup.1H-NMR (DMSO-d6),
diagnostic signals (ppm): 4.39 (s, 2H), 7.47-7.62 (m, 3H),
7.93-8.05 (m, 3H), 8.26 (dd, 1H), 8.54 (m, 1H), 8.65 (br. S, 1H),
8.76 (d, 1H), 10.73 (s, 1H, exchangeable with water), 12.45 (s, 1H,
exchangeable with water).
EXAMPLE 10
1-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-tolyl-urea
[0343]
4-{3-Methoxy-4-[1-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazi-
n-6-yl)-3-p-tolyl-ureidomethyl]-phenoxy}-N-(4-methyl-benzyl)-butyramide
of example 8 was suspended in a solution of 20% TFA in DCM (3 ml),
and stirred at room temperature for 2 hours. The resin was filtered
and the solution collected and dried up yielding 11 mg of title
compound. [M+1].sup.+=386; HPLC r.t. 4.72; .sup.1H-NMR (DMSO-d6),
diagnostic signals (ppm): 2.24 (s, 3H), 4.39 (s, 2H), 7.08 (d, 2H),
7.55 (d, 2H), 7.62 (m, 1H), 7.85-8.04 (m, 3H), 8.40 (d, 1H), 8.58
(m, 1H), 8.73 (br. S, 1H), 8.78 (s, 1H, exchangeable with water),
9.31 (s, 1H, exchangeable with water), 12.38 (s, 1H, exchangeable
with water). By working in an analogous way and by reacting the
compound of formula (III) with the appropriate aldehyde of formula
(V) and then with the proper acyl chloride derivative of formula
(VIII) or isocyante of formula (IX), the following compounds were
prepared:
[0344] 7-Amino-4-(4-chloro-benzyl)-2H-phthalazin-1-one
[M+1].sup.+=286; HPLC r.t. 4.62; .sup.1H-NMR (DMSO-d6), diagnostic
signals (ppm): 4.11 (s, 2H), 6.97 (dd, 1H), 7.24-7.32 (m, 5H), 7.56
(d, 1H), 12.05 (s, 1H, exchangeable with deuterated water).
[0345] 7-Amino-4-(4-methoxy-benzyl)-2H-phthalazin-1-one
[M+1].sup.+=282; HPLC r.t. 3.83; .sup.1H-NMR (DMSO-d6), diagnostic
signals (ppm): 3.68 (s, 3H) 4.04 (s, 2H), 6.10 (s, 2H, exchangeable
with deuterated water), 6.82 (d, 2H), 6.97 (dd, 1H), 7.17 (d, 2H),
7.23 (d, 1H), 7.57 (d, 1H).
[0346] 7-Amino-4-(4-nitro-benzyl)-2H-phthalazin-1-one
[M+1].sup.+=297; .sup.1H-NMR (DMSO-d6), diagnostic signals (ppm):
4.29 (s, 2H), 6.18 (s, 2H, exchangeable with deuterated water),
7.00 (dd, 1H), 7.26 (d, 1H), 7.57 (m, 3H), 8.14 (d, 2H).
[0347]
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-propiona-
mide; [M+H]+=309; HPLC r.t. 2.88.
[0348]
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4-triflu-
oromethyl-benzamide; [M+H]+=425; HPLC r.t. 5.1.
[0349] Furan-2-carboxylic acid
(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-pht- halazin-6-yl)-amide;
[M+H]+=346; HPLC r.t. 3.37.
[0350]
N-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-cyclop-
entyl-propionamide; [M+H]+=377; HPLC r.t. 4.99.
[0351] 2-Propyl-pentanoic acid
(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-pht- halazin-6-yl)-amide;
[M+H]+=379; HPLC r.t. 5.09.
[0352]
1-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(3-tri-
fluoromethyl-phenyl)-urea; [M+H]+=440; HPLC r.t. 5.29.
[0353]
1-(3-Methoxy-phenyl)-3-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phth-
alazin-6-yl)-urea; [M+H]+=402; HPLC r.t. 4.33.
[0354]
1-(4-Oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-toly-
l-urea; [M+H]+=386; HPLC r.t. 4.62.
[0355]
1-(2,4-Difluoro-phenyl)-3-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-p-
hthalazin-6-yl)-urea; [M+H]+=408; HPLC r.t. 4.58.
[0356]
1-(3,4-Dichloro-phenyl)-3-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-p-
hthalazin-6-yl)-urea; [M+H]+=440; HPLC r.t. 5.59.
[0357]
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propionam-
ide; [M+H]+=342; HPLC r.t. 5.18.
[0358]
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-trifluo-
romethyl-benzamide; [M+H]+=458; HPLC r.t. 7.13.
[0359] Furan-2-carboxylic acid
[1-(4-chloro-benzyl)-4-oxo-3,4-dihydro-phth- alazin-6-yl]-amide;
[M+H]+=380; HPLC r.t. 5.66.
[0360]
N-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cyclope-
ntyl-propionamide; [M+H]+=410; HPLC r.t. 7.22.
[0361] 2-Propyl-pentanoic acid
[1-(4-chloro-benzyl)-4-oxo-3,4-dihydro-phth- alazin-6-yl]-amide;
[M+H]+=412; HPLC r.t. 7.33.
[0362]
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trif-
luoromethyl-phenyl)-urea; [M+H]+=473; HPLC r.t. 7.26.
[0363]
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-meth-
oxy-phenyl)-urea; [M+H]+=435; HPLC r.t. 6.43.
[0364]
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p-tolyl-
-urea; [M+H]+=419; HPLC r.t. 6.74.
[0365]
1-[1-(4-Chloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2,4-di-
fluoro-phenyl)-urea; [M+H]+=441; HPLC r.t. 6.71.
[0366]
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propionami-
de; [M+H]+=333; HPLC r.t. 4.26.
[0367]
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-trifluor-
omethyl-benzamide; [M+H]+=449; HPLC r.t. 6.3.
[0368] Furan-2-carboxylic acid
[1-(4-cyano-benzyl)-4-oxo-3,4-dihydro-phtha- lazin-6-yl]-amide;
[M+H]+=371; HPLC r.t. 4.72.
[0369]
N-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cyclopen-
tyl-propionamide; [M+H]+=401; HPLC r.t. 6.3.
[0370] 2-Propyl-pentanoic acid
[1-(4-cyano-benzyl)-4-oxo-3,4-dihydro-phtha- lazin-6-yl]-amide;
[M+H]+=403; HPLC r.t. 6.42.
[0371]
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trifl-
uoromethyl-phenyl)-urea; [M+H]+=464; HPLC r.t. 6.46.
[0372]
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-metho-
xy-phenyl)-urea; [M+H]+=426; HPLC r.t. 5.59.
[0373]
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p-tolyl--
urea; [M+H]+=410; HPLC r.t. 5.89.
[0374]
1-[1-(4-Cyano-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2,4-dif-
luoro-phenyl)-urea; [M+H]+=432; HPLC r.t. 6.
[0375]
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propionam-
ide; [M+H]+=326; HPLC r.t. 4.69.
[0376]
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-trifluo-
romethyl-benzamide; [M+H]+=442; HPLC r.t. 6.68.
[0377] Furan-2-carboxylic acid
[1-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-phth- alazin-6-yl]-amide;
[M+H]+=364; HPLC r.t. 5.16.
[0378]
N-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cyclope-
ntyl-propionamide; [M+H]+=394; HPLC r.t. 6.73.
[0379] 2-Propyl-pentanoic acid
[1-(3-fluoro-benzyl)-4-oxo-3,4-dihydro-phth- alazin-6-yl]-amide;
[M+H]+=396; HPLC r.t. 6.85.
[0380]
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trif-
luoromethyl-phenyl)-urea; [M+H]+=457; HPLC r.t. 6.86.
[0381]
1-[1-(3-Fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-meth-
oxy-phenyl)-urea; [M+H]+=419; HPLC r.t. 5.98.
[0382]
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propionam-
ide; [M+H]+=322; HPLC r.t. 4.92.
[0383]
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-trifluo-
romethyl-benzamide; [M+H]+=438; HPLC r.t. 6.93.
[0384] Furan-2-carboxylic acid
[1-(3-methyl-benzyl)-4-oxo-3,4-dihydro-phth- alazin-6-yl]-amide;
[M+H]+=360; HPLC r.t. 5.38.
[0385]
N-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cyclope-
ntyl-propionamide; [M+H]+=390; HPLC r.t. 6.95.
[0386] 2-Propyl-pentanoic acid
[1-(3-methyl-benzyl)-4-oxo-3,4-dihydro-phth- alazin-6-yl]-amide;
[M+H]+=392; HPLC r.t. 7.08.
[0387]
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-trif-
luoromethyl-phenyl)-urea; [M+H]+=453; HPLC r.t. 7.04.
[0388]
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-meth-
oxy-phenyl)-urea; [M+H]+=415; HPLC r.t. 6.18.
[0389]
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p-tolyl-
-urea; [M+H]+=399; HPLC r.t. 6.48.
[0390]
1-[1-(3-Methyl-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2,4-di-
fluoro-phenyl)-urea; [M+H]+=421; HPLC r.t. 6.5.
[0391]
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propi-
onamide; [M+H]+=376; HPLC r.t. 5.83.
[0392]
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-tri-
fluoromethyl-benzamide; [M+H]+=492; HPLC r.t. 7.68.
[0393] Furan-2-carboxylic acid
[1-(2,4-dichloro-benzyl)-4-oxo-3,4-dihydro--
phthalazin-6-yl]-amide; [M+H]+=414; HPLC r.t. 6.26.
[0394]
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-succi-
namic acid ethyl ester; [M+H]+=; HPLC r.t. 6.11.
[0395]
N-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cyc-
lopentyl-propionamide; [M+H]+=444; HPLC r.t. 7.82.
[0396] 2-Propyl-pentanoic acid
[1-(2,4-dichloro-benzyl)-4-oxo-3,4-dihydro--
phthalazin-6-yl]-amide; [M+H]+=446; HPLC r.t. 7.94.
[0397]
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3--
trifluoromethyl-phenyl)-urea; [M+H]+=507; HPLC r.t. 7.83.
[0398]
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3--
methoxy-phenyl)-urea; [M+H]+=469; HPLC r.t. 7.02.
[0399]
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p-t-
olyl-urea; [M+H]+=453; HPLC r.t. 7.35.
[0400]
1-[1-(2,4-Dichloro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2,-
4-difluoro-phenyl)-urea; [M+H]+=475; HPLC r.t. 7.38.
[0401]
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-propion-
amide; [M+H]+=359; HPLC r.t. 4.01.
[0402]
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4-trifl-
uoromethyl-benzamide; [M+H]+=475; HPLC r.t. 6.
[0403]
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-succina-
mic acid ethyl ester; [M+H]+=431; HPLC r.t. 4.37.
[0404]
N-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-cyclo-
pentyl-propionamide; [M+H]+=427; HPLC r.t. 5.97.
[0405] 2-Propyl-pentanoic acid
(4-oxo-1-quinolin-3-ylmethyl-3,4-dihydro-ph- thalazin-6-yl)-amide;
[M+H]+=429; HPLC r.t. 6.08.
[0406]
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(3-tr-
ifluoromethyl-phenyl)-urea; [M+H]+=490; HPLC r.t. 6.16.
[0407]
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(3-me-
thoxy-phenyl)-urea; [M+H]+=452; HPLC r.t. 5.27.
[0408]
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-tol-
yl-urea; [M+H]+=436; HPLC r.t. 5.56.
[0409]
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(2,4--
difluoro-phenyl)-urea; [M+H]+=458; HPLC r.t. 5.55.
[0410]
1-(4-Oxo-1-quinolin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(3,4--
dichloro-phenyl)-urea; [M+H]+=491; HPLC r.t. 6.51.
[0411]
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]--
propionamide; [M+H]+=376; HPLC r.t. 5.41.
[0412]
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]--
4-trifluoromethyl-benzamide; [M+H]+=492; HPLC r.t. 7.23.
[0413] Furan-2-carboxylic acid
[4-oxo-1-(2-trifluoromethyl-benzyl)-3,4-dih-
ydro-phthalazin-6-yl]-amide; [M+H]+=414; HPLC r.t. 5.82.
[0414]
N-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]--
3-cyclopentyl-propionamide; [M+H]+=444; HPLC r.t. 7.33.
[0415] 2-Propyl-pentanoic acid
[4-oxo-1-(2-trifluoromethyl-benzyl)-3,4-dih-
ydro-phthalazin-6-yl]-amide; [M+H]+=446; HPLC r.t. 7.43.
[0416]
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]--
3-(3-trifluoromethyl-phenyl)-urea; [M+H]+=507; HPLC r.t. 7.36.
[0417]
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]--
3-p-tolyl-urea; [M+H]+=453; HPLC r.t. 6.88.
[0418]
1-[4-Oxo-1-(2-trifluoromethyl-benzyl)-3,4-dihydro-phthalazin-6-yl]--
3-(2,4-difluoro-phenyl)-urea; [M+H]+=475; HPLC r.t. 6.88.
[0419]
4-(4-Oxo-6-propionylamino-3,4-dihydro-phthalazin-1-ylmethyl)-benzoi-
c acid methyl ester; [M+H]+=366; HPLC r.t. 2.61.
[0420]
4-[4-Oxo-6-(4-trifluoromethyl-benzoylamino)-3,4-dihydro-phthalazin--
1-ylmethyl]-benzoic acid methyl ester; [M+H]+=482; HPLC r.t.
6.47.
[0421]
4-{6-[(Furan-2-carbonyl)-amino]-4-oxo-3,4-dihydro-phthalazin-1-ylme-
thyl}-benzoic acid methyl ester; [M+H]+=404; HPLC r.t. 4.91.
[0422]
4-[6-(3,4-Dimethoxy-benzoylamino)-4-oxo-3,4-dihydro-phthalazin-1-yl-
methyl]-benzoic acid methyl ester; [M+H]+=474; HPLC r.t. 5.27.
[0423]
4-[6-(3-Cyclopentyl-propionylamino)-4-oxo-3,4-dihydro-phthalazin-1--
ylmethyl]-benzoic acid methyl ester; [M+H]+=434; HPLC r.t.
6.48.
[0424]
4-[4-Oxo-6-(2-propyl-pentanoylamino)-3,4-dihydro-phthalazin-1-ylmet-
hyl]-benzoic acid methyl ester; [M+H]+=436; HPLC r.t. 6.61.
[0425]
4-{6-[3-(3-Methoxy-phenyl)-ureido]-4-oxo-3,4-dihydro-phthalazin-1-y-
lmethyl}-benzoic acid methyl ester; [M+H]+=459; HPLC r.t. 5.74.
[0426]
4-[4-Oxo-6-(3-p-tolyl-ureido)-3,4-dihydro-phthalazin-1-ylmethyl]-be-
nzoic acid methyl ester; [M+H]+=443; HPLC r.t. 6.03.
[0427]
4-{6-[3-(2,4-Difluoro-phenyl)-ureido]-4-oxo-3,4-dihydro-phthalazin--
1-ylmethyl}-benzoic acid methyl ester; [M+H]+=465; HPLC r.t.
6.04.
[0428]
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
propionamide; [M+H]+=360; HPLC r.t. 4.04.
[0429]
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
4-trifluoromethyl-benzamide; [M+H]+=476; HPLC r.t. 6.3.
[0430] Furan-2-carboxylic acid
[1-(4-chloro-3-fluoro-benzyl)-4-oxo-3,4-dih-
ydro-phthalazin-6-yl]-amide; [M+H]+398; HPLC r.t. 4.58.
[0431]
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3,4-dimethoxy-benzamide; [M+H]+=468; HPLC r.t. 4.97.
[0432]
N-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-cyclopentyl-propionamide; [M+H]+=428; HPLC r.t. 7.3.
[0433] 2-Propyl-pentanoic acid
[1-(4-chloro-3-fluoro-benzyl)-4-oxo-3,4-dih-
ydro-phthalazin-6-yl]-amide; [M+H]+=430; HPLC r.t. 7.41.
[0434]
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-(3-trifluoromethyl-phenyl)-urea; [M+H]+=491; HPLC r.t. 6.54.
[0435]
1-[1-(4-Chloro-3-fluoro-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]--
3-p-tolyl-urea; [M+H]+=437; HPLC r.t. 5.91.
[0436]
N-{1-[(E)-3-(4-Nitro-phenyl)-allyl]-4-oxo-3,4-dihydro-phthalazin-6--
yl}-3,4-dimethoxy-benzamide; [M+H]+=; HPLC r.t. 4.96.
[0437]
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-propion-
amide; [M+H]+=314; HPLC r.t. 4.26.
[0438]
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-4-trifl-
uoromethyl-benzamide; [M+H]+=430; HPLC r.t. 6.43.
[0439] Furan-2-carboxylic acid
(4-oxo-1-thiophen-3-ylmethyl-3,4-dihydro-ph- thalazin-6-yl)-amide;
[M+H]+=352; HPLC r.t. 4.76.
[0440]
N-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3,4-dim-
ethoxy-benzamide; [M+H]+=422; HPLC r.t. 5.16.
[0441] 2-Propyl-pentanoic acid
(4-oxo-1-thiophen-3-ylmethyl-3,4-dihydro-ph- thalazin-6-yl)-amide;
[M+H]+=384; HPLC r.t. 6.54.
[0442]
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(3-tr-
ifluoromethyl-phenyl)-urea; [M+H]+=445; HPLC r.t. 6.57.
[0443]
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-(3-meth-
oxy-phenyl)-urea; [M+H]+=407; HPLC r.t. 5.66.
[0444]
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-tol-
yl-urea; [M+H]+=391; HPLC r.t. 5.98.
[0445]
1-(4-Oxo-1-thiophen-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-(2,4--
difluoro-phenyl)-urea; [M+H]+=413; HPLC r.t. 5.96.
[0446]
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-propiona-
mide; [M+H]+=338; HPLC r.t. 4.48.
[0447]
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-4-triflu-
oromethyl-benzamide; [M+H]+=454; HPLC r.t. 6.52.
[0448] Furan-2-carboxylic acid
[1-(3-methoxy-benzyl)-4-oxo-3,4-dihydro-pht- halazin-6-yl]-amide;
[M+H]+=376; HPLC r.t. 4.95.
[0449]
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3,4-dime-
thoxy-benzamide; [M+H]+=446; HPLC r.t. 5.32.
[0450]
N-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-cyclop-
entyl-propionamide; [M+H]+=406; HPLC r.t. 6.53.
[0451] 2-Propyl-pentanoic acid
[1-(3-methoxy-benzyl)-4-oxo-3,4-dihydro-pht- halazin-6-yl]-amide;
[M+H]+=408; HPLC r.t. 6.65.
[0452]
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(3-tri-
fluoromethyl-phenyl)-urea; [M+H]+=469; HPLC r.t. 6.67.
[0453]
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-(3-metho-
xy-phenyl)-urea; [M+H]+=431; HPLC r.t. 5.79.
[0454]
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-p-toly-
l-urea; [M+H]+=415; HPLC r.t. 6.08.
[0455]
1-[1-(3-Methoxy-benzyl)-4-oxo-3,4-dihydro-phthalazin-6-yl]-3-(2,4-d-
ifluoro-phenyl)-urea; [M+H]+=437; HPLC r.t. 6.08.
[0456] N-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-propionamide;
[M+H]+=260; HPLC r.t. 3.78.
[0457] Furan-2-carboxylic acid
(4-oxo-1-propyl-3,4-dihydro-phthalazin-6-yl- )-amide; [M+H]+=298;
HPLC r.t. 4.35.
[0458]
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-p-tolyl-urea;
[M+H]+=; HPLC r.t. 5.69.
[0459]
1-(4-Oxo-1-propyl-3,4-dihydro-phthalazin-6-yl)-3-(2,4-difluoro-phen-
yl)-urea; [M+H]+=359; HPLC r.t. 5.68.
[0460]
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-propionam-
ide; [M+H]+=336; HPLC r.t. 5.35.
[0461]
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-4-trifluo-
romethyl-benzamide; [M+H]+=452; HPLC r.t. 7.26.
[0462] Furan-2-carboxylic acid
[4-oxo-1-(3-phenyl-propyl)-3,4-dihydro-phth- alazin-6-yl]-amide;
[M+H]+=374; HPLC r.t. 5.78.
[0463]
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3,4-dimet-
hoxy-benzamide; [M+H]+=444; HPLC r.t. 6.11.
[0464]
N-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-cyclope-
ntyl-propionamide; [M+H]+=404; HPLC r.t. 7.31.
[0465] 2-Propyl-pentanoic acid
[4-oxo-1-(3-phenyl-propyl)-3,4-dihydro-phth- alazin-6-yl]-amide;
[M+H]+=406; HPLC r.t. 7.43.
[0466]
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-(3-trif-
luoromethyl-phenyl)-urea; [M+H]+=467; HPLC r.t. 7.41.
[0467] 1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-(
3-methoxy-phenyl)-urea; [M+H]+=429; HPLC r.t. 6.56.
[0468]
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-p-tolyl-
-urea; [M+H]+=413; HPLC r.t. 6.88.
[0469]
1-[4-Oxo-1-(3-phenyl-propyl)-3,4-dihydro-phthalazin-6-yl]-3-(2,4-di-
fluoro-phenyl)-urea; [M+H]+=435; HPLC r.t. 6.88.
* * * * *