U.S. patent application number 11/504720 was filed with the patent office on 2007-04-26 for substituted azetidine compounds as cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation and use as medicaments.
This patent application is currently assigned to LABORATORIOS DEL DR. ESTEVE S.A. Invention is credited to Rosa Cuberes Altisen, Jordi Frigola Constansa, Ines Alvares Mathieu.
Application Number | 20070093469 11/504720 |
Document ID | / |
Family ID | 34833899 |
Filed Date | 2007-04-26 |
United States Patent
Application |
20070093469 |
Kind Code |
A1 |
Cuberes Altisen; Rosa ; et
al. |
April 26, 2007 |
Substituted azetidine compounds as
cyclooxygenase-1-cyclooxygenase-2 inhibitors, and their preparation
and use as medicaments
Abstract
The present invention relates to substituted Azetidine compounds
of general formula (I), methods for their preparation, medicaments
comprising these compounds as well as their use for the preparation
of a medicament for the treatment of humans and animals.
##STR1##
Inventors: |
Cuberes Altisen; Rosa;
(E-Barcelona, ES) ; Frigola Constansa; Jordi;
(E-Barcelona, ES) ; Mathieu; Ines Alvares;
(Barcelona, ES) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
LABORATORIOS DEL DR. ESTEVE
S.A
Barcelona
ES
|
Family ID: |
34833899 |
Appl. No.: |
11/504720 |
Filed: |
August 16, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/EP05/01657 |
Feb 16, 2005 |
|
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11504720 |
Aug 16, 2006 |
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Current U.S.
Class: |
514/210.17 ;
514/210.18; 548/950; 548/953 |
Current CPC
Class: |
C07D 205/04 20130101;
C07D 405/06 20130101 |
Class at
Publication: |
514/210.17 ;
514/210.18; 548/950; 548/953 |
International
Class: |
A61K 31/397 20060101
A61K031/397; C07D 205/02 20060101 C07D205/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 16, 2004 |
ES |
P2004 00363 |
Claims
1. A substituted azetidine compound of general formula I, ##STR34##
wherein A represents a --C.dbd.O-moiety, a --CH.sub.2-moiety, a
--CH.sub.2--C.dbd.O-moiety bonded to the azetidine ring via its
carbonyl carbon atom, or a --O--C(.dbd.O)-moiety bonded to the
azetidine ring via its carbonyl carbon atom, R.sup.1, R.sup.3,
identical or different, represent a hydrogen atom or a linear or
branched, saturated or unsaturated C.sub.1-4-aliphatic group,
R.sup.2 represents a hydrogen atom, a hydroxyl group or a
C.sub.1-3-alkoxy group, or R.sup.1 and R.sup.2 or R.sup.2 and
R.sup.3 together form an --O--CH.sub.2--CH.sub.2-chain, which is
optionally substituted with one or more methyl groups with the
proviso that R.sup.1, R.sup.2 and R.sup.3 do not identically
represent a hydrogen atom, and if A represents a --CH.sub.2-moiety,
then at least two of the residues R.sup.1, R.sup.2 and R.sup.3 do
not identically represent a hydrogen atom, R.sup.4 represents a
hydrogen atom, an optionally at least mono-substituted aryl group,
or a linear or branched, saturated or unsaturated aliphatic group,
which may be substituted by one or more substituents independently
selected from the group consisting of hydroxy, fluorine, chlorine,
bromine, branched or unbranched C.sub.1-4-alkoxy, branched or
unbranched C.sub.1-4-perfluoroalkoxy and branched or unbranched
C.sub.1-4-perfluoroalkyl, R.sup.5 represents a hydrogen atom, a
halogen atom, a hydroxyl group, a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic group,
an --OR.sup.7-moiety, -an --NH.sub.2-moiety, a
--CO--NH.sub.2-moiety, an --NH--CO--R.sup.3-moiety, an
--N(OH)--CO--NH.sub.2-moiety, an
--O(CH.sub.2).sub.1-4--ONO.sub.2-moiety, an optionally at least
mono-substituted aryl group, or a carboxy-group, R.sup.6 represents
a hydrogen atom, a halogen atom, a hydroxyl group, a linear or
branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic group, an --OR.sup.9-moiety, -an
--NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an
--NH--CO--R.sup.10-moiety, an --N(OH)--CO--NH.sub.2-moiety, an
optionally at least mono-substituted aryl group, or a
carboxy-group, and R.sup.7, R.sup.8, R.sup.9, R.sup.10, independent
from one another, represent a linear or branched, saturated or
unsaturated, optionally at least mono-substituted aliphatic group,
with the provisos that if A represents a --(C.dbd.O)-moiety,
R.sup.4 represents a hydrogen atom and one of the residues R.sup.5
and R.sup.6 represents a hydrogen atom, then the other one of these
residues R.sup.5 and R.sup.6 does not represent an
--NH.sub.2-moiety, a --CONH.sub.2-moiety, or a methyl group, which
is substituted by an --NH.sub.2-moiety or an azaheterocycle, and if
A represents a --C.dbd.O-moiety, a --CH.sub.2--C.dbd.O-moiety
bonded to the azetidine ring via its carbonyl carbon atom, or a
--O--C(.dbd.O)-moiety bonded to the azetidine ring via its carbonyl
carbon atom and one of the residues R.sup.5 and R.sup.6 represents
a hydrogen atom or an optionally at least mono-substituted, linear
or branched, saturated or unsaturated aliphatic group, then the
other one of these residues R.sup.5 and R.sup.6 does not represent
an --NH.sub.2-- or a COOH-moiety, optionally in the form of one of
the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in the form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
2. The compound according to claim 1, wherein R.sup.1 and R.sup.3,
identical or different, represent a hydrogen atom or a linear or
branched C.sub.1-4-alkyl group.
3. The compound according to claim 1 wherein R.sup.1 and R.sup.3
are identical and represent a C.sub.1-4-alkyl group, preferably a
C.sub.3-4 alkyl group, more preferably an iso-propyl group or a
tert.-Butyl group.
4. The compound according to claim 1, wherein R.sup.2 represents a
hydrogen atom, a hydroxyl group or a methoxy group.
5. The compound according to claim 1, wherein R.sup.4 represents a
hydrogen atom, an optionally at least mono-substituted phenyl
group, or a linear or branched, saturated or unsaturated C.sub.1-6
aliphatic group, whereby said aliphatic group may be substituted by
one or more substituents independently selected from the group
consisting of hydroxy, fluorine, chlorine, bromine, branched or
unbranched C.sub.1-4-alkoxy, branched or unbranched
C.sub.1-4-perfluoroalkoxy and branched or unbranched
C.sub.1-4-perfluoroalkyl, preferably a hydrogen atom, a methyl
group or an unsubstituted phenyl group.
6. The compound according to claim 1, wherein R.sup.5 represents a
hydrogen atom, a halogen atom, a hydroxyl group, a linear or
branched, saturated or unsaturated, optionally at least
mono-substituted C.sub.1-6 aliphatic group, an --NH.sub.2-moiety, a
--CO--NH.sub.2-moiety, an --NH--CO--R.sup.8-moiety, an
--N(OH)--CO--NH.sub.2-moiety, an --O(CH.sub.2)4-ONO.sub.2-moiety,
an optionally at least mono-substituted phenyl group, or a
carboxy-group, preferably a hydrogen atom, a bromine atom, a
hydroxyl group, an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an
--NH--CO--R.sup.3-moiety, an --N(OH)--CO--NH.sub.2 H.sub.2-moiety,
an --O(CH.sub.2).sub.4--ONO.sub.2-moiety, an unsubstituted phenyl
group, or a carboxy-group.
7. The compound according to claim 1, wherein R.sup.6 represents a
hydrogen atom, a halogen atom, a hydroxyl group, a linear or
branched, saturated or unsaturated, optionally at least
mono-substituted C.sub.1-6 aliphatic group, an --NH.sub.2-moiety, a
--CO--NH.sub.2-moiety, an --NH--CO--R.sup.8--moiety, an
--N(OH)--CO--NH.sub.2-moiety, an optionally at least
mono-substituted phenyl group, or a carboxy-group, preferably a
hydrogen atom, a hydroxyl group or a methyl group.
8. The compound according to claim 1, wherein R.sup.7, R.sup.8,
R.sup.9, R.sup.10, independent from one another, represent a linear
or branched, saturated or unsaturated, optionally at least
mono-substituted C.sub.1-6 aliphatic group, preferably a linear or
branched, optionally at least mono-substituted C.sub.1-6 alkyl
group, more preferably a methyl group or an ethyl group, which is
optionally perfluorinated.
9. The compound according to claim 1 of general formula I,
##STR35## wherein A represents a --C.dbd.O-moiety, a
--CH.sub.2-moiety, a --CH.sub.2--C.dbd.O-moiety bonded to the
azetidine ring via its carbonyl carbon atom, or a
--O--C(.dbd.O)-moiety bonded to the azetidine ring via its carbonyl
carbon atom, R.sup.1, R.sup.3 both identically represent a linear
or branched C.sub.1-4-alkyl group, preferably an iso-propyl group
or a tert.-butyl group, R.sup.2 represents a hydrogen atom, a
hydroxyl group or a linear or branched C.sub.1-4-alkoxy group, or
R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 together form an
--O--CH.sub.2--C(CH.sub.3).sub.2-chain, whereby the oxygen atom of
said chain is bonded to the 4-position of the phenyl ring, R.sup.4
represents a hydrogen atom, a linear or branched C.sub.1-4 alkyl
group or an unsubstituted phenyl group, R.sup.5 represents a
fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group,
an --NH--CO--CF.sub.3-moiety, an
--N(OH)--CO--NH.sub.2H.sub.2-moiety, an
--O(CH.sub.2).sub.4ONO.sub.2 moiety, or an unsubstituted phenyl
group, and R.sup.6 represents a hydrogen atom, a linear or branched
C.sub.1-4-alkyl group, or a hydroxyl group, optionally in the form
of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in the form of a mixture of at least
two of the stereoisomers, preferably enantiomers and/or
diastereomers, in any mixing ratio, or a corresponding salt
thereof, or a corresponding solvate thereof.
10. The compound according to claim 1 of general formula I
##STR36## wherein A represents a --C.dbd.O-moiety, a
--CH.sub.2-moiety, a --CH.sub.2--C.dbd.O-moiety bonded to the
azetidine ring via its carbonyl carbon atom, or a
--O--C(.dbd.O)-moiety bonded to the azetidine ring via its carbonyl
carbon atom, R.sup.1, R.sup.3 both identically represent an
iso-propyl group or a tert.-butyl group, R.sup.2 represents a
hydrogen atom, a hydroxyl group or a methoxy group, or R.sup.1 and
R.sup.2 or R.sup.2 and R.sup.3 together form an
--O--CH.sub.2H.sub.2--C(CH.sub.3).sub.2-chain, whereby the oxygen
atom of said chain is bonded to the 4-position of the phenyl ring,
R.sup.4 represents a hydrogen atom, a methyl group or an
unsubstituted phenyl group, R.sup.5 represents a bromine atom, a
hydroxyl group, an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an
--NH--CO--CF.sub.3-moiety, an --N(OH)--CO--NH.sub.2-moiety, an
--O(CH.sub.2).sub.4ONO.sub.2-moiety, an unsubstituted phenyl group,
or a carboxy-group, and R.sup.6 represent a hydrogen atom, a methyl
group or a hydroxyl group, optionally in the form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in the form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
11. The compounds according to claim 1 selected from the group
consisting of
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methan-
one;
(3,5-di-tert-butyl-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone;
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-methyl-azetidin-1-yl)-m-
ethanone;
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-2-methyl-azetid-
in-1-yl)-methanone;
(3-Bromo-azetidin-1-yl)-(3,5-di-tert-butyl-4-hydroxy-phenyl)-methanone;
(3,5-di-tert-butyl-4-methoxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone;
(3-hydroxy-azetidin-1-yl)-(4-hydroxy-3,5-diisopropyl-phenyl)-methanone;
(3,5-di-tert-butyl-phenyl)-[3-(4-nitrooxy-butoxy)-azetidin-1-yl]-methanon-
e;
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-2-phenyl-azetidin-1-yl-
)-methanone;
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-phenyl-azetidin-1-yl)-m-
ethanone;
(7-tert-butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-(3-hydr-
oxy-azetidin-1-yl)-methanone;
[1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-yl]-N-hydroxy-urea;
N-[1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-(2S,3R)-2-methyl-azetidin-3-yl-
]-2,2,2-trifluoro-acetamide;
(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-ol;
(3,5-di-tert-butyl-4-hydroxy-phenyl)-1-(3-hydroxy-azetidin-1-yl)-ethanone-
; and (3-hydroxy-azetidine-1-carboxylic
acid)-3,5-di-tert-butyl-phenyl ester. optionally in form of a
corresponding salt or a corresponding solvate.
12. A process for the preparation of a substituted azetidine
compound of general formula I according to claim 1, comprising
reacting at least one compound of general formula II, ##STR37##
wherein R.sup.1-R.sup.3 have the meaning according to claim 1, X
represents a bond or an --(CH.sub.2)-moiety and R represents a
carboxy group or an activated carbonyl group, with at least one
compound of general formula III, ##STR38## optionally in the form
of a corresponding salt, wherein R.sup.4-R6 have the meaning
according to claim 1, to yield a compound of general formula I
according to claim 1, wherein A represents a --(C.dbd.O)-moiety or
an --(CH.sub.2)--CO-moiety, which is optionally purified and/or
optionally isolated, and optionally at least one compound of
general formula I according to claim 1, wherein A represents a
--(C.dbd.O)-moiety is reduced to yield at least one compound of
general formula I according to claim 1, wherein A represents a
--(CH2)-moiety, which is optionally purified and/or isolated, or at
least one compound of general formula IV, ##STR39## wherein
R.sup.1-R.sup.3 have the meaning according to claim 1, is reacted
with at least one compound of general formula III given above, to
yield at least one compound of general formula I according to claim
1, wherein A represents an O--(C.dbd.O)-moiety, and said compound
is optionally purified and/or optionally isolated.
13. A medicament comprising at least one substituted azetidine
compound according to claim 1 and optionally one or more
pharmaceutically acceptable excipients.
14. The medicament according to claim 13 containing an amount of
the compound effective for the inhibition of Cyclooxygenase-1, for
the prophylaxis and/or treatment of Cyclooxygenase-1 related
disorders, for the inhibition of Cyclooxgenase-2 and/or for the
prophylaxis and/or treatment of Cyclooxygenase-2 related
disorders.
15. The medicament according to claim 13 containing an amount of
the compound effective for the prophylaxis and/or treatment of
pain, for the prophylaxis and/or treatment of inflammation and/or
for the prophylaxis and/or treatment of inflammation related
disorders, whereby said inflammation-related disorders may
preferably be selected from the group consisting of arthritis,
rheumatoid arthritis, spondyloarthropathies, gouty arthritis,
osteoarthritis, systemic lupus erythematosus, juvenile arthritis,
rheumatic fever, symptoms associated with influenza or other viral
infections, common cold, lower back pain, neck pain, dysmenorrhea,
headache, toothache, sprains, strains, myositis, neuralgia,
synovitis, gout, ankylosing spondylitis, bursitis, edema,
inflammations following dental procedures, inflammations following
dental procedures, vascular diseases, migraine headaches,
periarteritis nodosa, thyroiditis, plastic anemia, Hodkin's
disease, sclerodoma, type I diabetes, myasthenia gravis,
sarcoidosis, nephrotic syndrome, Behcefs syndrome, polymyositis,
gingivitis, hypersensivity, conjunctivitis, swelling occurring
after injury and myocardia ischemia, for the prophylaxis and/or
treatment of asthma, for the prophylaxis and/or treatment of
bronchitis, for the prophylaxis and/or treatment of tendinitis, for
the prophylaxis and/or treatment of bursitis, for the prophylaxis
and/or treatment of skin related conditions, whereby said skin
related conditions may preferably be selected from the group
consisting of psoriasis, eczema, bums and dermatitis, for the
prophylaxis and/or treatment of gastrointestinal disorders, whereby
said gastrointestinal disorders may preferably be selected from the
group consisting of inflammatory bowel disease, Crohn's disease,
gastritis, irritable bowel syndrome and ulcerative colitis, or for
treatment of fever, or for the prophylaxis and/or treatment of
cancer or a cancer-related disorders, whereby said cancer or
related disorder may preferably be selected from the group
consisting of brain cancer, bone cancer, epithelial cell-derived
neoplasia (epithelial carcinoma), basal cell carcinoma,
adenocarcinoma, gastrointestinal cancer, lip cancer, colon cancer,
liver cancer, bladder cancer, pancreas cancer, ovary cancer,
cervical cancer, lung cancer, breast cancer, skin cancer, squamous
cell cancer, prostate cancer, renal cell carcinoma and other known
cancers that effect epithelial cells throughout the body, for the
prophylaxis and/or treatment of polyps, for the prophylaxis and/or
treatment of angiogenesis mediated disorders, preferably selected
from the group consisting of metastasis, corneal graft rejection,
ocular neovascularization, retinalneovascularisation, diabethic
retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric
ulcer, infantile hemaginomas, angiofibroma of the nasopharynx,
vascular necrosis of the bone and endometriosis.
16. The medicament according to claim 13 containing an amount of
the compound effective for the prophylaxis and/or treatment of
pain.
17. The medicament according to claim 13 containing an amount of
the compound effective for the prophylaxis and/or treatment of
inflammation.
18. The medicament according to claim 13 containing an amount of
the compound effective for the prophylaxis and/or treatment of
inflammation related disorders, whereby said inflammation-related
disorders may preferably be selected from the group consisting of
arthritis, rheumatoid arthritis, spondyloarthropathies, gouty
arthritis, osteoarthritis, systemic lupus erythematosus, juvenile
arthritis, rheumatic fever, symptoms associated with influenza or
other viral infections, common cold, lower back pain, neck pain,
dysmenorrhea, headache, toothache, sprains, strains, myositis,
neuralgia, synovitis, gout, ankylosing spondylitis, bursitis,
edema, inflammations following dental procedures, inflammations
following dental procedures, vascular diseases, migraine headaches,
periarteritis nodosa, thyroiditis, plastic anemia, Hodkin's
disease, sclerodoma, type I diabetes, myasthenia gravis,
sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis,
gingivitis, hypersensivity, conjunctivitis, swelling setting
occurring after injury and myocardia ischemia.
19. A method for the preparation of a medicament for the inhibition
of Cyclooxygenase-1, for the prophylaxis and/or treatment of
Cyclooxygenase-1 related disorders, for the inhibition of
Cyclooxgenase-2 and/or for the prophylaxis and/or treatment of
Cyclooxygenase-2 related disorders, comprising providing an
effective amount of at least one substituted azetidine compound
according to claim 1 and optionally one or more pharmaceutically
acceptable excipients.
20. A method for the prophylaxis and/or treatment of pain, for the
prophylaxis and/or treatment of inflammation and/or for the
prophylaxis and/or treatment of inflammation related disorders,
whereby said inflammation-related disorders may preferably be
selected from the group consisting of arthritis, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,
systemic lupus erythematosus, juvenile arthritis, rheumatic fever,
symptoms associated with influenza or other viral infections,
common cold, lower back pain, neck pain, dysmenorrhea, headache,
toothache, sprains, strains, myositis, neuralgia, synovitis, gout,
ankylosing spondylitis, bursitis, edema, inflammations following
dental procedures, inflammations following dental procedures,
vascular diseases, migraine headaches, periarteritis nodosa,
thyroiditis, plastic anemia, Hodkin's disease, sclerodoma, type I
diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, hypersensivity,
conjunctivitis, swelling occurring after injury and myocardia
ischemia, for the prophylaxis and/or treatment of asthma, for the
prophylaxis and/or treatment of bronchitis, for the prophylaxis
and/or treatment of tendinitis, for the prophylaxis and/or
treatment of bursitis, for the prophylaxis and/or treatment of skin
related conditions, whereby said skin related conditions may
preferably be selected from the group consisting of psoriasis,
eczema, burns and dermatitis, for the prophylaxis and/or treatment
of gastrointestinal disorders, whereby said gastrointestinal
disorders may preferably be selected from the group consisting of
inflammatory bowel disease, Crohn's disease, gastritis, irritable
bowel syndrome and ulcerative colitis, or for treatment of fever,
or for the prophylaxis and/or treatment of cancer or a
cancer-related disorders, whereby said cancer or related disorder
may preferably be selected from the group consisting of brain
cancer, bone cancer, epithelial cell-derived neoplasia (epithelial
carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal
cancer, lip cancer, colon cancer, liver cancer, bladder cancer,
pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast
cancer, skin cancer, squamous cell cancer, prostate cancer, renal
cell carcinoma and other known cancers that effect epithelial cells
throughout the body, for the prophylaxis and/or treatment of
polyps, for the prophylaxis and/or treatment of angiogenesis
mediated disorders, preferably selected from the group consisting
of metastasis, corneal graft rejection, ocular neovascularization,
retinalneovascularisation, diabethic retinopathy, retrolental
fibroplasia, neovascular glaucoma, gastric ulcer, infantile
hemaginomas, angiofibroma of the nasopharynx, vascular necrosis of
the bone and endometriosis, comprising applying to a patient in
need thereof an effective amount of a substituted azetidine
compound according to claim 1 and optionally one or more
pharmaceutically acceptable excipients.
21. A method for the prophylaxis and/or treatment of pain,
comprising applying to a patient in need thereof an effective
amount of a substituted azetidine compound according to claim 1 and
optionally one or more pharmaceutically acceptable excipients.
22. A method for the prophylaxis and/or treatment of inflammation,
comprising applying to a patient in need thereof an effective
amount of a substituted azetidine compound according to claim 1 and
optionally one or more pharmaceutically acceptable excipients.
23. A method for the prophylaxis and/or treatment of inflammation
related disorders, whereby said inflammation-related disorders may
preferably be selected from the group consisting of arthritis,
rheumatoid arthritis, spondyloarthropathies, gouty arthritis,
osteoarthritis, systemic lupus erythematosus, juvenile arthritis,
rheumatic fever, symptoms associated with influenza or other viral
infections, common cold, lower back pain, neck pain, dysmenorrhea,
headache, toothache, sprains, strains, myositis, neuralgia,
synovitis, gout, ankylosing spondylitis, bursitis, edema,
inflammations following dental procedures, inflammations following
dental procedures, vascular diseases, migraine headaches,
periarteritis nodosa, thyroiditis, plastic anemia, Hodkin's
disease, sclerodoma, type I diabetes, myasthenia gravis,
sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis,
gingivitis, hypersensivity, conjunctivitis, swelling occurring
after injury and myocardia ischemia, comprising applying to a
patient in need thereof an effective amount of a substituted
azetidine compound according to claim 1 and optionally one or more
pharmaceutically acceptable excipients.
Description
[0001] The present invention relates to substituted Azetidine
compounds of general formula (I), methods for their preparation,
medicaments comprising these compounds as well as their use for the
preparation of a medicament for the treatment of humans and
animals.
[0002] The metabolites of arachidonic acid, such as prostaglandins,
lipoxygenases and thromboxane products are produced in a wide
variety of tissues and play a key role in many physiological and
pathophysiological processes, such as inflammation, pain and
cancer.
[0003] Prostaglandins, for example, are produced from cell membrane
phospholipids via a cascade of enzymes, involving the conversion of
arachidonic acid to a common prostaglandin precursor, PGH.sub.2, by
the enzyme Cyclooxygenase. Today, two different subtypes of
Cyclooxygenase are known, namely Cyclooxygenase-1 (COX-1) and
Cyclooxygenase-2 (COX-2).
[0004] COX-1, which is not-inducible or modulated by
glucocorticoids, is the constitutive cyclooxygenase isoform and is
mainly responsible for the synthesis of cytoprotective
prostaglandins in the gastrointestinal tract and the synthesis of
thromboxane which triggers platelet aggregation in blood platelets.
COX-2 is inducible and generally short lived except in the case of
certain tumors where it is constitutively activated. COX-2
expression is stimulated in response to endotoxins, cytokines,
hormones, growth factors and mitogens.
[0005] Thus, the object of the present invention was to provide
novel compounds that are particularly suitable as pharmacologically
active substances in medicaments. Preferably these compounds should
be suitable for inhibition of the Cyclooxygenase-1 and/or
Cyclooxygenase-2 and for the prophylaxis and/or treatment of
disorders related to these enzymes.
[0006] It has surprisingly been found that the substituted
compounds of general formula I given below, stereoisomers thereof,
corresponding salts and corresponding solvates show inhibition of
Cyclooxgenase-1 and Cyclooxygenase-2.
[0007] Thus, in one of its aspects the present invention relates to
substituted azetidine compounds of general formula I, ##STR2##
wherein [0008] A represents a --C.dbd.O-moiety, a
--CH.sub.2-moiety, a --CH.sub.2--C.dbd.O-moiety bonded to the
azetidine ring via its carbonyl carbon atom, or a
--O--C(.dbd.O)-moiety bonded to the azetidine ring via its carbonyl
carbon atom, [0009] R.sup.1, R.sup.3, identical or different,
represent a hydrogen atom or a linear or branched, saturated or
unsaturated, optionally at least mono-substituted
C.sub.1-4-aliphatic group, [0010] R.sup.2 represents a hydrogen
atom, a hydroxyl group or a C.sub.1-3-alkoxy group, [0011] or
R.sup.1 and R.sup.2 or R.sup.2 and R.sup.3 together form an
--O--CH.sub.2--CH.sub.2-chain, which is optionally substituted with
one or more methyl groups, [0012] R.sup.4 represents a hydrogen
atom, an optionally at least mono-substituted aryl group, or a
linear or branched, saturated or unsaturated aliphatic group,
whereby said aliphatic group may be substituted by one or more
substituents independently selected from the group consisting of
hydroxy, fluorine, chlorine, bromine, branched or unbranched
C.sub.1-4-alkoxy, branched or unbranched C.sub.1-4-perfluoroalkoxy
and branched or unbranched C.sub.1-4-perfluoroalkyl, [0013] R.sup.5
represents a hydrogen atom, a halogen atom, a hydroxyl group, a
linear or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic group, an --OR.sup.7-moiety, -an
--NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an
--NH--CO--R.sup.8-moiety, an --N(OH)--CO--NH.sub.2-moiety, an
--O(CH.sub.2).sub.1-4ONO.sub.2-moiety, an optionally at least
mono-substituted aryl group, or a carboxy-group, [0014] R.sup.6
represent a hydrogen atom, a halogen atom, a hydroxyl group, a
linear or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic group, an --OR.sup.9-moiety, -an
--NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an
--NH--CO--R.sup.10-moiety, an --N(OH)--CO--NH.sub.2-moiety, an
optionally at least mono-substituted aryl group, or a
carboxy-group, [0015] R.sup.7, R.sup.8, R.sup.9, R.sup.10,
independent from one another, represent a linear or branched,
saturated or unsaturated, optionally at least mono-substituted
aliphatic group, [0016] optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0017] It is highly preferred that for the substituted azetidine
compounds of general formula I given above one or more of the
following provisos (disclaimer) apply, namely [0018] that R.sup.1,
R.sup.2 and R.sup.3 do not identically represent a hydrogen atom,
and if A represents a --CH.sub.2-moiety, then at least two of the
residues R.sup.1, R.sup.2 and R.sup.3 do not identically represent
a hydrogen atom, [0019] that if A represents a --(C.dbd.O)-moiety,
R.sup.4 represents a hydrogen atom and one of the residues R.sup.5
and R.sup.6 represents a hydrogen atom, then the other one of these
residues R.sup.5 and R.sup.6 does not represent an
--NH.sub.2-moiety, a --CONH.sub.2-moiety or a methyl group, which
is substituted by an --NH.sub.2-moiety or an optionally substituted
azaheterocycle, and [0020] that if A represents a
--(C.dbd.O)-moiety, a --CH.sub.2--C.dbd.O-moiety bonded to the
azetidine ring via its carbonyl atom, or a --O--C(.dbd.O)-moiety
bonded to the azetidine ring via its carbonyl carbon atom and one
of the residues R.sup.5 and R.sup.6 represents a hydrogen atom or a
linear or branched, saturated or unsaturated, optionally at least
mono-substituted aliphatic group, then the other one of these
residues R.sup.5 and R.sup.6 does not represent an --NH.sub.2-- or
-carboxy -moiety,
[0021] If any of the afore mentioned substituents represents an
aliphatic group, which is substituted by one or more, e.g. 1, 2, 3,
4 or 5, substituents, these substituents may, independent from one
another, preferably be selected from the group consisting of
hydroxy, fluorine, chlorine, bromine, branched or unbranched
C.sub.1-4-alkoxy, branched or unbranched C.sub.1-4-perfluoroalkoxy,
branched or unbranched C.sub.1-4-perfluoroalkyl, more preferably be
selected from the group consisting of hydroxy, F, Cl, Br, methoxy,
ethoxy and CF.sub.3.
[0022] Preferred linear or branched, saturated or unsaturated
aliphatic groups, which may be substituted by one or more
substituents, may preferably be selected from the group consisting
of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,
sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,
n-nonyl, n-decyl, vinyl, ethinyl, propenyl, propinyl, butenyl and
butinyl.
[0023] If any of the afore mentioned substituents represents an
aryl group, which is substituted by one or more, e.g. 1, 2, 3, 4 or
5, substituents, these substituents may, independent from one
another, preferably be selected from the group consisting of
hydroxy, fluorine, chlorine, bromine, branched or unbranched
C.sub.1-4-alkyl, branched or unbranched C.sub.2-4-alkenyl, branched
or unbranched C.sub.2-4-alkinyl, branched or unbranched
C.sub.1-4-alkoxy, branched or unbranched C.sub.1-4-perfluoroalkoxy,
branched or unbranched C.sub.1-4-perfluoroalkyl, more preferably be
selected from the group consisting of hydroxy, F, Cl, Br, methyl,
ethyl, n-propyl, iso-propyl, tert.-Butyl, n-Butyl, sec-Butyl,
methoxy, ethoxy and CF.sub.3.
[0024] Preferred aryl groups, which may optionally be at least
mono-substituted, are phenyl and naphthyl.
[0025] Preferred are compounds of general formula I given above,
wherein R.sup.1 and R.sup.3, identical or different, represent a
hydrogen atom or a linear or branched C.sub.1-4-alkyl group,
preferably R.sup.1 and R.sup.3 are identical and represent an
unsubstituted C.sub.1-4-alkyl group, more preferably R.sup.1 and
R.sup.3 are identical and represent a C.sub.3-4 alkyl group, most
preferably R.sup.1 and R.sup.3 are identical and represent an
iso-propyl group or a tert.-Butyl group and R.sup.2,
R.sup.4-R.sup.10 and A have the meaning given above, optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0026] Also preferred are compounds of general formula I given
above, wherein R.sup.2 represents a hydrogen atom, a hydroxyl group
or a methoxy group, and R.sup.1, R.sup.3-R.sup.10 and A have the
meaning given above, optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0027] Furthermore, compounds of general formula I are preferred,
in which R.sup.4 represents a hydrogen atom, an optionally at least
mono-substituted phenyl group, or a linear or branched, saturated
or unsaturated C.sub.1-6 aliphatic group, whereby said aliphatic
group may be substituted with one or more substituents
independently selected from the group consisting of hydroxy,
fluorine, chlorine, bromine, branched or unbranched
C.sub.1-4-alkoxy, branched or unbranched C.sub.1-4-perfluoroalkoxy
and branched or unbranched C.sub.1-4-perfluoroalkyl, more
preferably R.sup.4 a hydrogen atom, a methyl group or an
unsubstituted phenyl group and R.sup.1-R.sup.3, R.sup.5-R.sup.10
and A have the meaning given above, optionally in form of one of
the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0028] Preference is also given to compounds of general formula I
given above, in which R.sup.5 represents a hydrogen atom, a halogen
atom, a hydroxyl group, a linear or branched, saturated or
unsaturated, optionally at least mono-substituted C.sub.1-6
aliphatic group, an --NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an
--NH--CO--R.sup.8-moiety, an --N(OH)--CO--NH.sub.2-moiety, an
--O(CH.sub.2).sub.4--ONO.sub.2-moiety, an optionally at least
mono-substituted phenyl group, or a carboxy-group, preferably a
hydrogen atom, a bromine atom, a hydroxyl group, an
--NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an
--NH--CO--R.sup.8-moiety, an --N(OH)--CO--NH.sub.2-moiety,
--O(CH.sub.2).sub.4--ONO.sub.2-moiety, an unsubstituted phenyl
group, or a carboxy-group, and R.sup.1-R.sup.4, R.sup.6-R.sup.10
and A have the meaning given above, optionally in form of one of
the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0029] Also preferred are compounds of general formula I, in which
R.sup.6 represents a hydrogen atom, a halogen atom, a hydroxyl
group, a linear or branched, saturated or unsaturated, optionally
at least mono-substituted C.sub.1-6 aliphatic group, an
--NH.sub.2-moiety, a --CO--NH.sub.2-moiety, an
--NH--CO--R.sup.8-moiety, an --N(OH)--CO--NH.sub.2-moiety, an
optionally at least mono-substituted phenyl group, or a
carboxy-group, preferably a hydrogen atom, a hydroxyl group or a
methyl group, and R.sup.1-R.sup.5, R.sup.7-R.sup.10 and A have the
meaning given above, optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof.
[0030] Preferred are also compounds of general formula I given
above, in which R.sup.7, R.sup.8, R.sup.9, R.sup.10, independent
from one another, represent a linear or branched, saturated or
unsaturated, optionally at least mono-substituted C.sub.1-6
aliphatic group, preferably a linear or branched C.sub.1-6 alkyl
group, more preferably a methyl group or an ethyl group, and
R.sup.1-R.sup.6 and A have the meaning given above, optionally in
form of one of the stereoisomers, preferably enantiomers or
diastereomers, a racemate or in form of a mixture of at least two
of the stereoisomers, preferably enantiomers and/or diastereomers,
in any mixing ratio, or a corresponding salt thereof, or a
corresponding solvate thereof.
[0031] Particularly preferred are substituted azetidine compounds
of general formula I, ##STR3## wherein [0032] A represents a
--C.dbd.O-moiety, a --CH.sub.2-moiety, a --CH.sub.2--C.dbd.O-moiety
bonded to the azetidine ring via its carbonyl carbon atom, or a
--O--C(.dbd.O)-moiety bonded to the azetidine ring via its carbonyl
carbon atom, [0033] R.sup.1, R.sup.3 both represent an iso-propyl
group or a tert.-butyl group, [0034] R.sup.2 represents a hydrogen
atom, a hydroxyl group or a methoxy group, [0035] or R.sup.1 and
R.sup.2 or R.sup.2 and R.sup.3 together form an
--O--CH.sub.2--C(CH.sub.3).sub.2-chain, whereby the oxygen atom of
said chain is bonded to the 4-position of the phenyl ring, [0036]
R.sup.4 represents a hydrogen atom, a methyl group or an
unsubstituted phenyl group, [0037] R.sup.5 represents a bromine
atom, a hydroxyl group, -an --NH.sub.2-moiety, a
--CO--NH.sub.2-moiety, an --NH--CO--CF.sub.3-moiety, an
--N(OH)--CO--NH.sub.2-moiety, an
--O(CH.sub.2).sub.4ONO.sub.2-moiety, an unsubstituted phenyl group,
or a carboxy-group, [0038] R.sup.6 represents hydrogen atom, a
methyl group or a hydroxyl group, [0039] optionally in form of one
of the stereoisomers, preferably enantiomers or diastereomers, a
racemate or in form of a mixture of at least two of the
stereoisomers, preferably enantiomers and/or diastereomers, in any
mixing ratio, or a corresponding salt thereof, or a corresponding
solvate thereof.
[0040] Most particularly preferred are compounds of general formula
I selected from the group consisting of [0041] [1]
(3,5-di-tert-butyl-4-hydroxy-phenyly(3-hydroxy-azetidin-1-yl)-methanone;
[0042] [2]
(3,5-di-tert-butyl-phenyly)-(3-hydroxy-azetidin-1-yl)-methanone;
[0043] [3]
(3,5-di-tert-butyl4-hydroxy-phenyl)-(3-hydroxy-3-methyl-azetidin-1-yl-
)-methanone; [0044] [4]
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-2-methyl-azetidin-1-yl)-m-
ethanone; [0045] [7]
(3-Bromo-azetidin-1-yl)-(3,5-di-tert-butyl-4-hydroxy-phenyl)-methanone;
[0046] [9]
(3,5-di-tert-butyl-4-methoxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone;
[0047] [10]
(3-hydroxy-azetidin-1-yl)-(4-hydroxy-3,5-diisopropyl-phenyl)-methanone;
[0048] [11]
(3,5-di-tert-butyl-phenyl)-[3-(4-nitrooxy-butoxy)-azetidin-1-yl]-methanon-
e; [0049] [12]
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-2-phenyl-azetidin-1-yl)-m-
ethanone; [0050] [13]
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-phenyl-azetidin-1-yl)-m-
ethanone; [0051] [14]
(7-tert-butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-(3-hydroxy-azetid-
in-1-yl)-methanone; [0052] [15]
[1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-yl]-N-hydroxy-urea;
[0053] [16] N-[1-(3,5-di-tert-butyl-4-hydroxy-benzoyly
(2S,3R)-2-methyl-azetidin-3-yl]-2,2,2-trifluoro-acetamide; [0054]
[17] 1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-ol; [0055]
[18]
2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-1-(3-hydroxy-azetidin-1-yl)-ethano-
ne; [0056] [19] (3-hydroxy-azetidine-1-carboxylic
acid)-3,5-di-tert-butyl-phenyl ester optionally in form of a
corresponding salt or a corresponding solvate.
[0057] In another aspect the present invention relates to a process
for the preparation of the inventive substituted azetidine
compounds of general formula I given above, according to which at
least one compound of general formula II, ##STR4## wherein
R.sup.1-R.sup.3 have the meaning given above, X represents a bond
or an --(CH.sub.2)-moiety and R represents a carboxy group or an
activated carbonyl group, is reacted with at least one compound of
general formula III, ##STR5## optionally in the form of a
corresponding salt, wherein R.sup.4-R.sup.6 have the meaning given
above, to yield a compound of general formula I given above,
wherein R.sup.1 to R.sup.6 have the meaning given above and A
represents a --(C.dbd.O)-moiety or a --(CH.sub.2)--CO-moiety, which
is optionally purified and/or optionally isolated, [0058] and
optionally at least one compound of general formula I, wherein A
represents a --(C.dbd.O)-moiety is reduced to yield at least one
compound of general formula I, wherein R.sup.1-R.sup.6 have the
meaning given above and A represents a --(CH.sub.2)-moiety, which
is optionally purified and/or optionally isolated, [0059] or at
least one compound of general formula IV, ##STR6## [0060] wherein
R.sup.1-R.sup.3 have the meaning given above, is reacted with at
least one compound of general formula III given above, to yield at
least one compound of general formula I, wherein R.sup.1-R.sup.6
have the meaning given above and A represents an
O--(C.dbd.O)-moiety, and said compound is optionally purified
and/or optionally isolated.
[0061] Compounds of general formula (II) may be prepared by
conventional methods known to those skilled in the art.
[0062] The reaction of compounds of general formula (II) and
general formula (III) may also be carried out according to
conventional methods well known to those skilled in the art. The
compounds of general formula II may either be used in form of the
free carboxylic acid, i.e. R represents a --COOH group, or in form
of an activated carbonyl group. Suitable activating groups and
methods for activation are well-known to those skilled in the art,
e.g. activation with N,N-Dicyclohexylcarbodiimide or other coupling
reagents.
[0063] The reaction between compounds of of general formula II and
compounds of general formula III is preferably carried out in a
suitable reaction medium such as diethyl ether, tetrahydrofuran,
dioxane, dimethoxyethane and the like. Reaction temperatures and
reaction times may vary over a broad range. The temperature is
preferably kept in the range of ambient temperature, i.e.
approximately 25.degree. C. and the boiling point of the reaction
medium. Suitable reaction times may vary over a broad range, i.e.
from a few minutes to several hours.
[0064] Other compounds of general formula II, wherein R represents
an activated carbonyl group include but are not limited to the
acide chlorides, anhydrides, mixed anhydrides, alkyl esters,
preferably C.sub.1-4 alkyl esters or activated ester, e.g.
p-nitro-phenyl esters.
[0065] If the activated compound of general formula II is an acid
chloride it is preferably prepared by conventional methods well
known to those skilled in the art, e.g. by reaction of the
respective compound of general formula II in form of the free
carboxylic acid with thionyl chloride or oxalyl chloride, whereby
said chlorinating agent may also be used as the reaction medium,
optionally in a mixture with at least one other reaction medium.
Other suitable reaction media include but are not limited thereto
hydrocarbons such as benzene, toluene or xylene, halogenated
hydrocarbons such as methylenechloride, chloroform or carbon
tetrachloride, or ethers such as diethyl ether, dioxane,
tetrahydrofuran or dimethoxyethane or mixtures of two or more of
these afore mentioned compounds. Suitable reaction temperatures and
reaction times may vary over a broad range, for example, from
0.degree. C. to the boling point of the reaction medium and from
several minutes to several hours.
[0066] The reaction of an acid chloride of general formula II with
an azetidine compound of general formula III is preferably carried
out in the presence of inorganic base such as sodium hydroxide,
potassium hydroxide, sodium carbonate, potassium carbonate and the
like and/or in the presence of an organic base such as triethyl
amine, pyridine and the like in a suitable reaction medium such as
a hydrocarbons like benzene, toluene or xylene, halogenated
hydrocarbons like methylenchloride, chloroform or carbon
tetrachloride, or ethers such as diethyl ether, dioxane,
tetrahydrofuran or dimethoxyethane or mixtures of at least two or
more of the afore mentioned compounds. Said reaction may also be
carried out in a reaction medium based on one or more of the afore
mentioned compounds and water in a biphasic system.
[0067] Those skilled in the art understand that if the compound of
general formula II is present in the form of an acid chloride and
compound of general formula III is substituted with one or two
hydroxyl groups in the 3-position of the azetidine ring, then
reaction may also take place between the acid chloride and said
alcohol group(s). In this case, the compound of general formula I
may be obtained via selective hydrolysis of the respective ester by
reaction with a suitable base, preferably lithium hydroxide, in a
water-based reaction medium, whereby the reaction medium may
comprise conventional organic solvents, which are partially or
totally miscible with the aqueous phase, such as methanol, ethanol,
propanol and the like or a suitable ether such as tetrahydrofuran,
dioxane or dimethoxyethane. Reaction temperature and reaction time
may vary over a broad range, preferably from -20.degree. C. to
ambient temperature, i.e. approximately 25.degree. C. and from
several hours to several. days.
[0068] If the activated derivative of general formula is a mixed
anhydride said compound may preferably be prepared by reaction of
the corresponding free acid with an alkyl chloroformiate or an aryl
chloroformiate compound, preferably in the presence of a base such
as triethylamine or pyridine in a suitable reaction medium.
[0069] The compounds of general formula I, wherein A represents a
--(C.dbd.O)-moiety, may be reduced to the corresponding compound of
geneal formula I, wherein A represents a --CH.sub.2)-moiety, using
at least one suitable reducing agent known to those skilled in the
art. A preferred reducing agent is lithium aliuminium hydride.
Those skilled in the art understand that if the respective compound
of general formula I, wherein A represents a --(C.dbd.O)-moiety
contains one or more further groups, which are suceptible to
reduction, these will also be reduced and suitable steps of
protecting these groups may be required.
[0070] The reduction is preferably carried out in a suitable
reaction medium such as ether, preferably diethyl ether,
tetrahydrofurane, dioxane or dimethoxyethane. The reaction
temperature and reaction time may vary over a broad range, e.g.
from ambient temperature, i.e. approximately 25.degree. C. to the
boiling point of the reaction medium and from several minutes to
several hours.
[0071] The compounds of general formula IV may preferably be
prepared from compounds of general formula V, ##STR7## wherein
R.sup.1-R.sup.3 have the meaning given above, by reaction with
diphosgene in an anhydrous solvent such as ether, preferably
diethyl ether, tetrahydrofuran, dioxane, dimethoxyethan and the
like. Reaction temperatures may vary over a broad range, whereby
preferred temperatures range from -20.degree. C. to ambient
temperature, i.e. approximately 25.degree. C. and suitable reaction
times vary from several minutes to several hours.
[0072] The reaction of compounds of general formula IV with
compounds of general formula III may preferably be carried out in
the presence of an organic base such triethylamine, pyridine and
the like in a suitable reaction medium such as hydrocarbons like
benzene, toluene, xylene, halogenated hydrocarbons like methylene
chloride, chloroform, or carbontetrachloride, ethers like diethyl
ether, tetrah.hydrofuran or dimethoxyethan or mixtures of at least
two of these afore mentioned solvents. Reaction temperatures and
reaction times may vary over a broad range, preferably from
0.degree. C. to the boiling point of the reaction medium and from
several minutes to several hours.
[0073] The substituted azetidine compounds of general formula III
may be prepared by conventional methods described in the prior art,
for example in V. R. Gaertner, J. Org. Chem., 1967, 32, 2972; A. G.
Anderson et al., J. Org. Chem., 1972, 37, 3953; N. H. Cromwell et
al., Chem. Rev., 1979, 79, 331-358; D. Nisato et al., J.
Heterocyclic Chem., 1985, 22, 961-963; A. P. Kozikowski et al.,
Synlett, 1991, 783-784; J. Frigola et al., J. Med. Chem., 1993, 36,
801-810; J. Frigola et al., J. Med. Chem., 1994, 37, 4195-4210; J.
Frigola et al., J. Med. Chem., 1995, 38, 1203-1215; M. Poch et al.,
Tetrahedron Letters, 1993, 34 (48), 7781-7784; M. Poch et al.,
Tetrahedron Letters, 1991, 32 (47), 6935-6938; T. Toda et al.,
Heterocycles, 1992, 33, 511-514; R. H. Higgins et al., J. Org.
Chem., 1994, 59, 2172-2178; J. Barluenga et al., J. Org. Chem.,
1997, 62, 5974-5977; U.S. Pat. No. 5,073,646 and references cited
therein. The respective parts of the description are hereby
enclosed by reference and form part of the present disclosure.
[0074] In a further aspect the present invention also provides a
process for the preparation of salts of substituted azetidine
compounds of general formula (I), or stereoisomers thereof, wherein
at least one compound of general formula (I) having at least one
basic group is reacted with at least one inorganic and/or organic
acid, preferably in the presence of a suitable reaction medium.
Suitable reaction media include, for example, any of the ones given
above. Suitable inorganic acids include hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid,
suitable organic acids are e.g. citric acid, maleic acid, fumaric
acid, tartaric acid, or derivatives thereof, p-toluenesulfonic
acid, methanesulfonic acid or camphersulfonic acid.
[0075] In yet a further aspect the present invention also provides
a process for the preparation of salts of substituted azetidine
compounds of general formula (I), or stereoisomers thereof, wherein
at least one compound of general formula (I) having at least one
acidic group is reactecd with one. or more suitable bases,
preferably in the presence of a suitable reaction medium. Suitable
bases are e.g; hydroxides, carbonates or alkoxides, which include
suitable cations, derived e.g. from alkaline metals, alkaline earth
metals or organic cations, e.g. [NH.sub.nR.sub.4-n].sup.+, wherein
n is 0, 1, 2, 3 or 4 and R represents a branched or unbranched
C.sub.1-4-alkyl-radical. Suitable reaction media are, for example,
any of the ones given above.
[0076] Solvates, preferably hydrates, of the substituted azetidine
compounds of general formula (I), of corresponding stereoisomers,
or of corresponding salts thereof may also be obtained by standard
procedures known to those skilled in the art.
[0077] The purification and isolation of the inventive substituted
azetidine compounds of general formula (I), of a corresponding
stereoisomer, or salt, or solvate or any intermediate thereof may,
if required, be carried out by conventional methods known to those
skilled in the art, e.g. chromatographic methods or
recrystallization.
[0078] If the substituted azetidine compounds of general formula
(I) themselves are obtained in form of a mixture of stereoisomers,
particularly enantiomers or diastereomers, said mixtures may be
separated by standard procedures known to those skilled in the art,
e.g. chromatographic methods or fractunalized crystallization with
chiral reagents. It is also possible to obtain pure stereoisomers
via stereoselective synthesis.
[0079] The substituted azetidine compounds of general formula (I),
their stereoisomers, corresponding salts thereof and corresponding
solvates are toxicologically acceptable and are therefore suitable
as pharmaceutical active substances for the preparation of
medicaments.
[0080] It has surprisingly been found that the substituted
compounds of general formula I given above, stereoisomers thereof,
corresponding salts and corresponding solvates show inhibition of
Cyclooxgenase-1 and/or Cyclooxygenase-2.
[0081] Thus, in another aspect the present invention relates to a
medicament comprising at least one substituted azetidine compound
of general formula I given above, optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate thereof
and optionally one or more pharmaceutically acceptable
excipients.
[0082] Preferably the medicament of the present invention is
suitable for the inhibition of Cyclooxygenase-1, for the
prophylaxis and/or treatment of Cyclooxygenase-1 related disorders,
for the inhibition of Cyclooxgenase-2 and/or for the prophylaxis
and/or treatment of Cyclooxygenase-2 related disorders.
[0083] Particularly preferably the medicament of the present
invention is suitable for the prophylaxis and/or treatment of pain,
for the prophylaxis and/or treatment of inflammation and/or for the
prophylaxis and/or treatment of inflammation related disorders,
whereby said inflammation-related disorders may preferably be
selected from the group consisting of arthritis, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,
systemic lupus erythematosus, juvenile arthritis, rheumatic fever,
symptoms associated with influenza or other viral infections,
common cold, lower back pain, neck pain, dysmenorrhea, headache,
toothache, sprains, strains, myositis, neuralgia, synovitis, gout,
ankylosing spondylitis, bursitis, edema, inflammations following
dental procedures, inflammations following dental procedures,
vascular diseases, migraine headaches, periarteritis nodosa,
thyroiditis, aplastic anemia, Hodkin's disease, sclerodoma, type I
diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, hypersensivity,
conjunctivitis, swelling ocurring after injury and myocardia
ischemia, for the prophylaxis and/or treatment of asthma, for the
prophylaxis and/or treatment of bronchitis, for the prophylaxis
and/or treatment of tendinitis, for the prophylaxis and/or
treatment of bursitis, for the prophylaxis and/or treatment of skin
related conditions, whereby said skin related conditions may
preferably be selected from the group consisting of psoriasis,
eczema, burns and dermatitis, for the prophylaxis and/or treatment
of gastrointestinal disorders, whereby said gastrointestinal
disorders may preferably be selected from the group consisting of
inflammatory bowel disease, Crohn's disease, gastritis, irritable
bowel syndrome and ulcerative colitis, or for treatment of fever,
or for the prophylaxis and/or treatment of cancer or a
cancer-related disorders, whereby said cancer or related disorder
may preferably be selected from the group consisting of brain
cancer, bone cancer, epithelial cell-derived neoplasia (epithelial
carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal
cancer, lip cancer, colon cancer, liver cancer, bladder cancer,
pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast
cancer, skin cancer, squamous cell cancer, prostate cancer, renal
cell carcinoma and other known cancers that effect epithelial cells
throughout the body, for the prophylaxis and/or treatment of
polyps, for the prophylaxis and/or treatment of angiogenesis
mediated disorders, preferably selected from the group consisting
of metastasis, corneal graft rejection, ocular neovascularization,
retinal neovascularisation, diabethic retinopathy, retrolental
fibroplasia, neovascular glaucoma, gastric ulcer, infantile
hemaginomas, angiofibroma of the nasopharynx, avascular necrosis of
the bone and endometriosis.
[0084] Most particularly preferred the medicament of the present
invention is suitable for the prophylaxis and/or treatment of pain,
for the prophylaxis and/or treatment of inflammation and/or for the
prophylaxis and/or treatment of inflammation related disorders,
whereby said inflammation-related disorders may preferably be
selected from the group consisting of arthritis, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,
systemic lupus erythematosus, juvenile arthritis, rheumatic fever,
symptoms associated with influenza or other viral infections,
common cold, lower back pain, neck pain, dysmenorrhea, headache,
toothache, sprains, strains, myositis, neuralgia, synovitis, gout,
ankylosing spondylitis, bursitis, edema, inflammations following
dental procedures, inflammations following dental procedures,
vascular diseases, migraine headaches, periarteritis nodosa,
thyroiditis, aplastic anemia, Hodkin's disease, sclerodoma, type I
diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, hypersensivity,
conjunctivitis, swelling ocurring after injury and myocardia
ischemia.
[0085] In yet another aspect the present invention relates to the
use of at least one substituted azetidine of general formula I
given above, optionally in form of one of the stereoisomers,
preferably enantiomers or diastereomers, a racemate or in form of a
mixture of at least two of the stereoisomers, preferably
enantiomers and/or diastereomers, in any mixing ratio, or a
corresponding salt thereof, or a corresponding solvate thereof,
optionally in combination with one or more pharmaceutically
acceptable excipients, for the preparation of a medicament for the
inhibition of Cyclooxygenase-1, for the prophylaxis and/or
treatment of Cyclooxygenase-1 related disorders, for the inhibition
of Cyclooxgenase-2 and/or for the prophylaxis and/or treatment of
Cyclooxygenase-2 related disorders.
[0086] The use of at least one substituted azetidine compound of
general formula I given above, optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof, optionally in combination with one or more
pharmaceutically acceptable excipients, for the preparation of a
medicament for the prophylaxis and/or treatment of pain, for the
prophylaxis and/or treatment of inflammation and/or for the
prophylaxis and/or treatment of inflammation related disorders,
whereby said inflammation-related disorders may preferably be
selected from the group consisting of arthritis, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,
systemic lupus erythematosus, juvenile arthritis, rheumatic fever,
symptoms associated with influenza or other viral infections,
common cold, lower back pain, neck pain, dysmenorrhea, headache,
toothache, sprains, strains, myositis, neuralgia, synovitis, gout,
ankylosing spondylitis, bursitis, edema, inflammations following
dental procedures, inflammations following dental procedures,
vascular diseases, migraine headaches, periarteritis nodosa,
thyroiditis, aplastic anemia, Hodkin's disease, sclerodoma, type I
diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, hypersensivity,
conjunctivitis, swelling ocurring after injury and myocardia
ischemia, for the prophylaxis and/or treatment of asthma, for the
prophylaxis and/or treatment of bronchitis, for the prophylaxis
and/or treatment of tendinitis, for the prophylaxis and/or
treatment of bursitis, for the prophylaxis and/or treatment of skin
related conditions, whereby said skin related conditions may
preferably be selected from the group consisting of psoriasis,
eczema, burns and dermatitis, for the prophylaxis and/or treatment
of gastrointestinal disorders, whereby said gastrointestinal
disorders may preferably be selected from the group consisting of
inflammatory bowel disease, Crohn's disease, gastritis, irritable
bowel syndrome and ulcerative colitis, or for treatment of fever,
or for the prophylaxis and/or treatment of cancer or a
cancer-related disorders, whereby said cancer or related disorder
may preferably be selected from the group consisting of brain
cancer, bone cancer, epithelial cell-derived neoplasia (epithelial
carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal
cancer, lip cancer, colon cancer, liver cancer, bladder cancer,
pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast
cancer, skin cancer, squamous cell cancer, prostate cancer, renal
cell carcinoma and other known cancers that effect epithelial cells
throughout the body, for the prophylaxis and/or treatment of
polyps, for the prophylaxis and/or treatment of angiogenesis
mediated disorders, preferably selected from the group consisting
of metastasis, corneal graft rejection, ocular neovascularization,
retinal neovascularisation, diabethic retinopathy, retrolental
fibroplasia, neovascular glaucoma, gastric ulcer, infantile
hemaginomas, angiofibroma of the nasopharynx, avascular necrosis of
the bone and endometriosis is particularly preffered.
[0087] The use of at least one substituted azetidine compound of
general formula I given above, optionally in form of one of the
stereoisomers, preferably enantiomers or diastereomers, a racemate
or in form of a mixture of at least two of the stereoisomers,
preferably enantiomers and/or diastereomers, in any mixing ratio,
or a corresponding salt thereof, or a corresponding solvate
thereof, optionally in combination with one or more
pharmaceutically acceptable excipients, for the preparation of a
medicament for the prophylaxis and/or treatment of pain, for the
prophylaxis and/or treatment of inflammation and/or for the
prophylaxis and/or treatment of inflammation related disorders,
whereby said inflammation-related disorders may preferably be
selected from the group consisting of arthritis, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,
systemic lupus erythematosus, juvenile arthritis, rheumatic fever,
symptoms associated with influenza or other viral infections,
common cold, lower back pain, neck pain, dysmenorrhea, headache,
toothache, sprains, strains, myositis, neuralgia, synovitis, gout,
ankylosing spondylitis, bursitis, edema, inflammations following
dental procedures, inflammations following dental procedures,
vascular diseases, migraine headaches, periarteritis nodosa,
thyroiditis, aplastic anemia, Hodkin's disease, sclerodoma, type I
diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, hypersensivity,
conjunctivitis, swelling ocurring after injury and myocardia
ischemia is most particularly preferred.
[0088] The medicament according to the present invention may be in
any form suitable for the application to humans and/or animals,
preferably humans including infants, children and adults and can be
produced by standard procedures known to those skilled in the art.
The composition of the medicament may vary depending on the route
of administration.
[0089] The medicament of the present invention may for example be
administered parentally in combination with conventional injectable
liquid carriers, such as water or suitable alcohols. Conventional
pharmaceutical excipients for injection, such as stabilizing
agents, solubilizing agents, and buffers, may be included in such
injectable compositions. These medicaments may for example be
injected intramuscularly, intraperitoneally, or intravenously.
[0090] Medicaments according to the present invention may also be
formulated into orally administrable compositions containing one or
more physiologically compatible carriers or excipients, in solid or
liquid form. These compositions may contain conventional
ingredients such as binding agents, fillers, lubricants, and
acceptable wetting agents. The compositions may take any convenient
form, such as tablets, pellets, granules, capsules, lozenges,
aqueous or oily solutions, suspensions, emulsions, or dry powdered
forms suitable for reconstitution with water or other suitable
liquid medium before use, for immediate or retarded release.
[0091] The liquid oral forms for administration may also contain
suitable additives such as sweeteners, flavoring, preservatives,
and emulsifying agents. Non-aqueous liquid compositions for oral
administration may also be formulated, containing edible oils. Such
liquid compositions may be conveniently encapsulated in e.g.,
gelatin capsules in a unit dosage amount.
[0092] The compositions of the present invention may also be
administered topically or via a suppository.
[0093] The daily dosage for humans and animals may vary depending
on factors that have their basis in the respective species or other
factors, such as age, sex, weight or degree of illness and so
forth. The daily dosage for humans may preferably be in the range
from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000
milligrams of active substance to be administered during one or
several intakes per day.
Pharmacological Methods:
I. Cox-1/Cox-2 Enzyme Assay:
[0094] The Cox-1/Cox-2 enzyme assay for the inventive azetidine
compounds is carried out according to the following
description:
[0095] Approximately 390 units of the Cox-1 or Cox-2 enzyme (Cayman
Chemical, Ann Habor, Mich., U.S.A., catalogue number 60100 and
60120 respectively are suspended in 200-300 .mu.l of Tris HCl (100
mM), hematin (1 mM) and phenol (2 mM) buffer, and 200 ml
epinephrine (5.8 mM) as chromogen. The compounds, which are to be
tested, are solved in dimethylformamide or 0.1 N sodium hydroxide,
at a volume of 60 .mu.l. The total volume of each enzyme reaction
is 0.6 ml. It is taken care that the vehicle concentration in the
reaction mixture does not exceed 5 % (volume/volume). The reaction
medium is incubated for 4 minutes at 37.degree. C., and then 100
.mu.l of 0.5 mM arachidonic acid are added as substrate.
Immediately after the addition of the substrate, the slope
corresponding to the optical density increase at 480 nm is recorded
for 1 minute. The reaction is monitored with a Hewlett-Packard
8452A spectrophotometer.
II. Determination of Cox-1- and Cox-2-Activity in Human Whole
Blood
[0096] The Cox-1- and Cox-2-activity in human whole blood is
determined according to a modification of the method described in
the publication of C. Brideau et al., "A human whole blood assay
for clinical evaluation of biochemical efficacy of cyclooxygenase
inhibitors", Inflamm Res 1996; 45: 68-74. The respective part of
the description is hereby incorporated by reference and forms part
of the present disclosure.
[0097] For Cox-1 activity determination, fresh human blood is
distributed in a volume of 0.5 ml to silicone Eppendorf tubes, into
which 2 .mu.l of the compound to be tested or dimethylsulfoxide
(DMSO) at a final concentration of 0.4% (volume/volume). The tubes
are inverted for homogenization and incubated for 1 hour at
37.degree. C. under slight stirring. Afterwards they are
centrifuged for 15 min at 10500 g and 100 .mu.l of serum is
collected. Proteins are precipitated by the addition of 400 .mu.l
of methanol to each tube, tubes were centrifuged for 10 minutes at
5000 g and 300 .mu.l of supernatant is aspirated and then dried
under nitrogen atmosphere.
[0098] Tromboxane B2 (TXB2) concentration is quantified using an
assay kit (Caymann Chemical, Ann Arbor, Mich., U.S.A., Catalogue
number 519031) after reconstitution into 300 .mu.l assay buffer
supplied in the assay kit.
[0099] For Cox-2 activity determination, tubes are prepared with 2
.mu.l of the compound to be tested or DMSO, 12 .mu.g/ml of
aspirine, 9 .mu.l of 1% (weight/volume) sodium heparine and 0.5 ml
of fresh human blood. Samples are pre-incubated at 37.degree. C.
during 15 minutes and E. coli 0111:B4 LPS (from Sigma Chemical, St.
Louis, Mo. U.S.A., catalogue number L-3012) are added for
incubation during 24 h at 37.degree. C. The samples are centrifuged
for 100 .mu.l of plasma collection. 400 .mu.l of Ethyl acetate and
1% (volume/volume) methanol are added to each sample and the tubes
are stirred and centrifuged for 10 minutes at 5000 g at 4.degree.
C. 300.mu.l of supernatant are aspirated and evaporated under
nitrogen atmosphere. Prostaglandin E2 concentration is quantified
using an assay kit from Cayman Chemical, Ann-Arbor, Mich., U.S.A.
(Catalogue number: 514010 ) after reconstitution into 300 .mu.l
assay buffer supplied in the assay kit.
III: Analgesia Test in Rats
[0100] The inventive compounds are tested for analgesic activity as
described above is carried out as described in the publication of
K. Hargreaves et al., Pain, 32, 77-88, (1988). The respective part
of the description is hereby incorporated by reference and forms
part of the disclosure.
[0101] The rats are transferred to the experimentation laboratory,
where they remain in groups of 5, in makrolon cages with a barred
floor to avoid coprophagy. At the beginning of the experiment,
water and food were removed, and animals were adequately weighed
and marked.
[0102] Each rat receives via subplantar injection 0.1 ml of sterile
saline solution into the left hind paw, followed by 0.1 ml of a 2%
(weight/volume) carrageenan suspension in sterile saline solution
into the right hind paw.
[0103] Two hours after the subplantar injections of carrageenan and
vehicle, each rat receives by oral route the compounds to be
tested, suspended in 5% (weight/volume) gum arabic, administered at
10 ml per kg of body weight. Two hours after the administration of
the compounds to be tested, the values for analgesic activity are
determined. To this purpose, the rats are transferred to the
methacrylate chambers of an analgesimeter provided with a glass
floor. Once the acclimatisation period in the chambers is over
(i.e. after 5 minutes) an infra-red beam lamp capable of producing
a thermal stimulus, is placed below the rat's paws.
[0104] The thermal stimulus, previously calibrated at 10 Amperes,
is applied to each of the hind paws with at least 1 minute
intervals. The response of the rats to pain consists of raising the
paw, thus avoiding contact with the floor. Simultaneously, the
infra-red light is automatically turned down, and the digital
display of the device shows the latency time in seconds. The rats
are tested once only to avoid possible learning behaviour.
IV. Test for Activity Against Edema in Rats
[0105] The test for activity against edema is carried out as
described in the publication of Winter et al., Proc. Soc. Exp.
Biol. Med. 111, 544-547, (1962). The respective part of the
description is hereby incorporated by reference and forms part of
the present disclosure.
[0106] At the beginning of each experimental session the rats are
deprived of food, and kept in cages within groups of 5 animals, the
cages being fitted with a grating on the floor to prevent
coprophagy. After a period of 24 hours without food, the animals
are marked in a suitable way, weighed and hydrated via oral
administration of 30 ml/kg body weight of tap water. Half an hour
after the hydratisation, the compounds to be tested are
administered via oral route, in an amount of 10 ml/kg body weight
as a suspension in gum arabic at 5% (weight/volume). One hour after
administration of the compounds the animals receive 0.1 ml of the
inflammation causing agent (carrageenin 1% weight/volume, in
sterile solution), injected via subplantar route into the right
hind paw of the rats. Immediately after the carrageenin injection
the volume of the injected paw is determined using a
plethysmometer. The readings are expressed in ml. Readings of the
volume of the paw are taken every hour after administration of the
carrageenin for 7 hours.
V: Test for Antiarthritic Activity in Rats
[0107] The test for antiarthritic activity is carried out as
described in the publication of Anderson et al., J. Clin. Invest.
97, 11, 2672-2679, (1996). The respective part of the description
is hereby incorporated by reference and forms part of the present
disclosure.
[0108] On day 0 of the experiment, the volumes of the contralateral
paws to those injected, i.e. left hind paws, are measured by means
of a pletismometer, the readings of which are expressed in ml.
[0109] Next, each rat is injected the adjuvant, consisting of 1 mg
of Mycobacterium butyricum suspended in 0.1 ml of mineral oil, via
subplantar route in the right hind paw.
[0110] Approximately every day, and for 15 days after the injection
of adjuvant, the volumes of non-injected hind paws (contralateral)
are measured again. On day 15, those rats of which the
contralateral paws show an increase of at least 0.42 ml compared to
the day of the adjuyant injection are selected, discarding those
animals with lower volume increases, since their inflammation is
not considered to have the adequate magnitude.
[0111] On day 15 of the experiment, daily administration of the
compounds to be tested via oral route is started, and on each day,
the volumes of non-injected hind paws is recorded.
[0112] On Day 25 of the experiment, the body weights and
non-injected hind paws (contralateral) volumes are measured for the
last time, and these values were used to determine the
activities.
VI: PGE2 Production in Rat Inflammatory Exudate and Gastric
Mucosa
[0113] The PGE2 production in rat inflammatory exudate and gastric
mucosa is carried out as described in the publication of O
Tofanetti et al., "Effect of nimesulide on cyclo-oxygenase activity
in rat gastric mucosa and inflammatory exudate", Med Sci Res 17,
745-746 (1989). The respective part of the description is hereby
incorporated by reference and forms part of the present
disclosure.
[0114] For this text 6 male wistar rats (Interfauna-St Feli de
Codines, Barcelona) of approximately 200 g (each approximately 6
weeks of age) are used. The compounds to be tested are administered
via oral route in gum Arabic at 5% (weight/volume) at a rate of 10
ml/kg.
[0115] One hour after administration of the compounds and under
halothane anaesthesia, each rat is implanted subcutaneously in the
interescapular area a 40.times.15.times.5 mm polyester sponge,
soaked in a 0.5% suspension of carrageenan. Rats are sacrificed 6
hours after the implant, the sponges are removed and squeezed. The
exudates are collected and centrifuged at 6000.times.G for 15
minutes.
[0116] The rats's stomachs are removed and the gastric mucosa is
detached from the underlying layers and by means of a 10 mm
diameter die, mucosa samples from an area between the gastric
corpus and pyloric antrum are taken. The mucosal PGE2 is extracted.
PGE2 concentrations from the inflammatory exudates and the gastric
mucosa are determined by means of inmmunoassay reagents of Cayman
Chemical kit, Ann Arbor, Mich., U.S.A. (Catalogue number: 514010)
according to the manufacturer's instructions.
[0117] The present invention is illustrated below with the aid of
examples. These illustrations are given solely by way of example
and do not limit the general spirit of the present invention.
EXAMPLES
Example 1
Synthesis of
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone
a) 3,5-Di-tert-butyl-4-hydroxy-benzoyl chloride
[0118] ##STR8##
[0119] 3,5-Di-tert-butyl-4-hydroxy-benzoic acid (16.6 g, 66.3
mmoles) was dissolved in chloroform (150 ml) and Thionyl chloride
(10 ml, .apprxeq.139 mmoles) was added. The resulting mixture was
refluxed for 9 hours, cooled to room temperature (approximately
25.degree. C.) and evaporated to dryness under reduced pressure.
17.6 g (99% of theoretical yield) of
3,5-di-tert-butyl-4-hydroxy-benzoyl chloride were obtained in form
of yellow solid, which was used in the following reaction step
without purification.
[0120] IR (KBr, cm.sup.-1): 3555, 2958, 1736, 1125.
b)
(3,5-Di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanon-
e
[0121] ##STR9##
[0122] Azetidin-3-ol hydrochloride (2 g, 18.3 mmoles) was dissolved
in a 5 % weight/weight (45 ml) of an aqueous solution of sodium
hydroxide, the resulting solution cooled to -5.degree. C. and under
vigorous stirring 3,5-di-tert-butyl-4-hydroxy-benzoyl chloride (5.4
g, 20 mmoles) obtained according to step (a) dissolved in 8 ml of
THF was added. Afterwards the cooling bath was removed, the
reaction mixture warmed to room temperature (approximately
25.degree. C.) and stirred for an additional hour under these
conditions. The reaction mixture was then extracted several times
with diethyl ether, the etherical phases combined, washed with
water, dried with sodium sulfate and evaporated to dryness to
obtain 1.9 g of the crude product, which is crystallized from ethyl
acetate-petroleum ether. 1.6 g (30% of theoretical yield) of
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-azetidin-1-yl)-methanone
were obtained in crystalline form.
[0123] Melting point=185-189.degree. C. IR (KBr, cm.sup.-1): 3506,
3262, 2956, 1611, 1572, 1449, 1421, 1406, 1113. .sup.1H-NMR
(CDCl.sub.3, .delta.): 1.43 (s, 18H), 2.8 (bs, 1H), 4.0-4.2 (m,
2H), 4.45 (m, 2H), 4.7 (m, 1H), 5.5 (s, 1H), 7.5 (s, 2H).
Example 3
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-methyl-azetidin-1-yl)-me-
thanone
[0124] ##STR10##
[0125] 3-Methyl-azetidin-3-ol hydrochloride (0.6 g, 4.84 mmoles)
was suspended in tetrahydrofuran (50 ml) and Triethylamine (1.2 ml)
was added. The mixture was stirred at room temperature
(approximately 25.degree. C.) for 30 minutes and
3,5-di-tert-butyl-4-hydroxy benzoic acid (1.26 g, 5.1 mmoles) was
added in one portion, the mixture was cooled to 0.degree. C. and
subsequently a solution of dicyclohexylcarbodiimide (1 g, 4.84
mmoles) in tetrahydrofuran (27 ml) was added. The reaction mixture
was then heated to reflux for 3.5 hours, cooled and the insoluble
solid was filtered off. The filtrate was concentrated using a
rotavapor, the remaining solid dissolved in ethyl acetate, washed
with water, dried over magnesium sulfate, filtered and evaporated
to dryness. The crude residue obtained is crystallized from diethyl
ether to give 1.14 g (73% of theoretical yield) of
(3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-methyl-azetidin-1-yl)-m-
ethanone.
[0126] Melting point=148-153.degree. C. IR (KBr, cm.sup.-1): 3497,
3274, 2963, 1612, 1598, 1415, 1235, 1120. .sup.1H-NMR (CDCl.sub.3,
.delta.): 1.4 (s, 18H), 1.5 (s, 3H), 3.9 (s, 1H), 4.1 (m, 3H), 4.3
(m, 1H), 5.5 (s, 1H), 7.5 (s, 2H).
Example 15
Synthesis of
[1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-yl]-N-hydroxy-urea
(a)
[1-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-yl]-N-hydroxy-carba-
mic acid phenyl ester
[0127] ##STR11##
[0128] 1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-ol (2.,27
g, 7.8 mmols), N,O bis-(phenoxycarbonyl)hydroxylamino (2.36 g, 8.58
mmols) (prepared according to the method described in A. O. Stewart
and D. W. Brooks, J. Org. Chem., 57(18), 1992, 5020-5023. The
respective part of the description is introduced by reference and
forms part of the disclosure), and Triphenylphosphine (2.45 g, 9.36
mmols) were dissolved in 80 ml of anhydrous Tetrahydrofurane. The
reaction mixture was cooled to 0.degree. C. under a nitrogen
atmosphere, a solution of diisopropylazodicarboxylate (1.84 ml,
9.36 mmols) was added dropwise and the mixture was stirred at
0.degree. C. for one hour. Afterwards the mixture was allowed to
warm up to room temperature and stirred overnight. The solvent was
removed under reduced pressure via a rotavapor and the crude
product was purified via column chromatography (silica gel, eluent:
CHCl.sub.3). After crystallization from diethyl ether 1.53 g (46%
of theoretical yield) of the desired product were obtained as a
white solid having asmelting point of 161-163.degree. C.
[0129] IR (KBr, cm.sup.-1): 3540, 3420, 2958, 1720, 1440, 1198, 760
.sup.1H-NMR (CDCl.sub.3, .delta.): 1.4 (s, 18H), 3.5 (t, 2H), 3.6
(m+s, 4H), 4.75 (m, 1H), 5.2 (bs, 1H), 7.05 (m, 3H), 7.25 (d, 1H),
7.3 (m, 3H).
(b)
[1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-yl]-N-hydroxy-urea
[0130] ##STR12##
[0131] The product obtained according to step (a) (1.53 g, 3.6
mmols) was dissolved in 50 ml of Methanol and the solution was
cooled to -78.degree. C. under nitrogen atmosphere. A solution of
5.4 ml of NH.sub.3 condensed in 12.7 ml of Methanol at -78.degree.
C. was added, the mixture was allowed to warm up to room
temperature and stirred at this temperature in a closed reactor,
thereby controlling the progress of the reaction via
Thin-layer-chromatography (TLC) after two hours. If any unreacted
starting product is detected another portion of NH.sub.3 may be
added and the reaction kept stirring overnight. The solution was
concentrated using a rotavapor and the crude material was purified
via column chromatography (silica gel, eluent: cloroform/methanol
95:5 (volume/volume) to give 0.58 g of the desired product (47% of
theoretical yield) having a melting point of 90-95.degree. C.
[0132] IR (KBr, cm.sup.-1): 3650, 3494, 3338, 2903, 1656, 1569,
1431, 1363, 1213. .sup.1H-NMR (CDCl.sub.3, .delta.): 1.4 (s, 18H),
3.5 (m, 4H), 3.6 (s, 2H), 4.8 (m, 1H), 5.2 (bs, 1H), 5.6 (bs, 2H),
7.0 (s, 2H).
Example 16
Synthesis of
(2S,3R)-N-[1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-2-methyl-azetidin-3-yl-
]-2,2,2-trifluoro-acetamide
a) 3,5-Di-tert-butyl-4-hydroxy-benzoyl chloride
[0133] 3,5-Di-tert-butyl-4-hydroxy-benzoyl chloride was prepared
according to step (a) of example 1.
b)
N-[1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-(2S,3R)-2-methyl-azetidin-3--
yl]-2,2,2-trifluoro-acetamide
[0134] ##STR13##
[0135] (2S,3R)-2,2,2-trifluoro-N-(2-methyl-azetidin-3-yl)-acetamide
(1.04 g, 4.74 mmoles) hydrochloride was dissolved in
dichloromethane (30 ml) and triethylamine (2.7 ml) was added, the
mixture stirred for 10 minutes at room temperature, cooled to
0.degree. C. and a solution of 3,5-di-tert-butyl-4-hydroxy-benzoyl
chloride (1.16 g, 4.3 mmoles) in dichloromethane (20 ml) was added.
The reaction mixture was stirred at room temperature overnight,
then poured on ice, the phases were separated, the aqeous phase
extracted with dichloromethane and the combined organic phases were
dried over magnesium sulfate, filtered and evaporated to dryness to
give 1.42 g (80% of theoretical yield) of
N-[1-(3,5-di-tert-butyl-4-hydroxy-benzoyl)-(2S,3R)-2-methyl-azetidin-3-yl-
]-2,2,2-trifluoro-acetamide.
[0136] IR (KBr, cm.sup.-1): 2967, 1722, 1618, 1560, 1420, 1225,
1187, 1160. .sup.1H NMR (CDCl.sub.3, .delta.): 1.4 (s, 18H), 1.5
(s, 3H), 4.3 (m, 2H), 4.7 (m, 2H), 5.5 (s, 1H), 7.3 (s, 2H), 9.0
(d, 1H)
Example 17
Synthesis of
1-(3,5-di-tert-butyl-4-hydroxy-benzyl)-azetidin-3-ol
[0137] ##STR14##
[0138] A suspension of lithium aluminium hydride (1.35 g, 36.7
mmoles) in anhydrous tetrahydrofuran (60 ml) was cooled to
0.degree. C., and a solution of
(3,5-di-tert-butyl-4-hydroxy-phenyly)-(3-hydroxy-azetidin-1-yl)-methanone
(1.78 g, 6.12 mmoles) in anhydrous tetrahydrofuran (40 ml) was
added. The cooling bath was removed, the mixture was stirred at
room temperature overnight and then heated to reflux for 5 hours.
The mixture was then cooled to 0.degree. C. and the excess of the
reducing agent was eliminated by the addition of a saturated
solution of ammonium chloride. The mixture is filtered and the
filtrate was evaporated to dryness by use of a rotavapor. The
residue was dissolved in diethyl ether, the resulting solution
washed with water, dried over sodium sulfate and evaporated to
dryness with a rotavapor. The resulting crude solid was
crystallized from chloroform/petrol ether to give 1.33 g (75% of
theoretical yield).of the desired product having a melting point of
139-142.degree. C. ##STR15##
[0139] IR (KBr, cm.sup.-1): 3513, 3331, 3076, 2956, 1434, 1360,
1162, 788. .sup.1H NMR (CDCl.sub.3, .delta.): 1.4 (s, 18H), 2.7
(bs, 1H), 2.9 (dd, 2H), 3.5 (s, 2H), 3.6 (dd, 2H), 4.4 (m, 1H), 5.1
(s, 1H), 7.0 (s, 2H).
Example 19
Synthesis of 3-hydroxy-azetidine-1-carboxylic acid
3,5-di-tert-butyl-phenyl ester
(a) 3,5-Di-tert-butyl-phenyl chloroformiate
[0140] ##STR16##
[0141] A solution of 3,5-di-tert-butyl-phenol (3.6 g, 17.4 mmoles)
in 30 ml of tetrahydrofuran was cooled to 0.degree. C. and a
solution of trichloro methyl chloroformiate (2.9 ml, 22.56 mmoles)
in 20 ml of tetrahydrofurane was added. The cooling bath was
removed and the mixture was stirred at room temperature overnight.
The solution so obtained was used in the following step.
(b) 3-Hydroxy-azetidine-1-carboxylic acid 3,5-di-tert-butyl-phenyl
ester
[0142] 3-azetidinol hydrochloride (2.47 g, 22.62 mmoles) was
suspended in tetrahydrofurane (30 ml), triethylamine (19 ml) was
added and the mixture was heated to reflux for 30 minutes. The
mixture was then cooled to room temperature and the solution of the
chloroformiate according to step (a) was slowly added via a canule.
The reaction mixture was heated to reflux overnight, cooled and
filtered. The filtrate is evaporated to dryness in a rotavapor and
the residue is purified via column chromatography (silica gel,
eluent: ethyl acetate petrol ether 3:7 volume/volume). 0.83 g of
3-hydroxy-azetidine-1-carboxylic acid 3,5-di-tert-butyl-phenyl
ester were obtained in form of a white solid having a melting point
of 166-70.degree. C.
[0143] IR (KBr, cm.sup.-1): 3481, 2962, 1700, 1612, 1400. .sup.1H
NMR (CDCl.sub.3, .delta.): 1.3 (s, 18H), 2,7 (m, 1H), 4.0 (m, 2H),
4.3 (m, 2H), 4.6 (m, 1H), 6.9 (s, 2H), 7.3 (s, 1H).
[0144] The compounds of examples 2 and 11 were prepared according
to the method described in example 1. The compounds of examples 4,
7, 9, 10, 12, 13, 17 and 18 were prepared according to the method
described in example 3. The compound of example 14 was prepared
analoguesly to the method described in J. M. Janusz et al., J. Med.
Chem., 1998, 41(7), 1112-1123. The respective description is
incorporated by reference and forms part of the disclosure.
[0145] The compounds of examples 1-4, 7, and 9-19 and their
spectroscopic data is given in the following tables 1 and 2:
TABLE-US-00001 TABLE 1 ##STR17## Exam- Z ple R.sup.4 R.sup.5
R.sup.6 ##STR18## 1 H OH H ##STR19## 2 H OH H ##STR20## 3 H OH
CH.sub.3 ##STR21## 4 CH.sub.3 OH H ##STR22## 7 H Br H ##STR23## 9 H
OH H ##STR24## 10 H OH H ##STR25## 11 H. O(CH.sub.2).sub.4ONO.sub.2
H ##STR26## 12 Ph OH H ##STR27## 13 H Ph OH ##STR28## 14 H OH H
##STR29## 15 H N(OH)CONH.sub.2 H ##STR30## 16 CH.sub.3 NHCOCF.sub.3
H ##STR31## 17 H OH H ##STR32## 18 H OH H ##STR33## 19 H OH H
[0146] TABLE-US-00002 TABLE 2 Melting point IR .sup.1H NMR Example
.degree. C. (KBr, cm.sup.-1) (CDCl.sub.3, .delta.) 1 185-9 3506,
3262, 2956, 1611, 1.43 (s, 18 H), 2.8 (bs, 1 H), 4.0-4.2 (m, 1572,
1449, 1421, 1406, 2 H), 4.45 (m, 2 H), 4.7 (m, 1 H), 5.5 (s, 1113 1
H), 7.5 (s, 2 H) 2 146-9 3444, 3344, 3287, 2957, 1.3 (s, 18 H), 3.5
(d, 1 H), 4.0-4.2 (m, 1613, 1587, 1456, 1125 2 H), 4.4 (dd, 2 H),
4.6 (m, 1 H), 7.4 (s, 2 H), 7.5 (s, 1 H). 3 148-53 3497, 3274,
2963, 1612, 1.4 (s, 18 H), 1.5 (s, 3 H), 3.9 (s, 1 H), 1598, 1415,
1235, 1120 4.1 (m, 3 H), 4.3 (m, 1 H), 5.5 (s, 1 H), 7.5 (s, 2 H).
4 162-6 3469, 3250, 2960, 1608, 1.4 (s, 21 H), 3.3 (bs, 1 H), 3.9
(m, 1 H), 1571, 14011239, 1090 4.1 (m, 1 H), 4.4 (m, 2 H), 5.5 (s,
1 H), 7.5 (s, 2 H). 7 160-3 3506, 2953, 1632, 1600, 1.4 (s, 18 H),
4.4-4.8 (m, 5 H), 7.5 (s, 1383, 1131, 1110 2 H) 9 115-120 3296,
2963, 1602, 1555, 1.4 (s, 18 H), 3.7 (s, 3 H), 3.9-4.2 (m, 1474,
1449, 1410, 1396 3 H), 4.4 (m, 2 H), 4.7 (m, 1 H), 7.5 (s, 2 H) 10
156-60 3330, 1615, 1605, 1565, 1.3 (s, 12 H), 3.4 (m, 2 H), 4.1-4.3
(m, 1463, 1433, 1412, 1202 3 H), 4.4-4.6 (m + s, 3 H), 4.7 (m, 1
H), 7.4 (s, 2 H) 11 oil 2962, 1637, 1594, 1459, 1.3 (s, 18 H), 1.7
(m, 2 H), 1.8 (m, 2 H), 3.4 (m, 2 H), 4.0-4.15 (m, 2 H), 4.3-4.4
(m, 3 H), 4.5 (t, J=6.3 Hz, 2 H), 7.4 (s, 2 H), 7.5 (s, 1 H) 12
178-81 3400, 3310, 2956, 1607, 1.3 (s, 18 H), 3.7 (d, 1 H), 4.1
(dd, 1 H), 1570, 1395, 4.3 (m, 1 H), 4.6 (m, 1 H), 5.3 (bs, 1 H),
5.45 (bs, 1 H), 7.3-7.4 (m, 7 H) 13 163-5 3530-3300, 2956, 1606,
1.43 (s, 18 H), 3.3 (bs, 1 H), 4.4-4.6 (m, 1452, 1116 4 H), 5.5 (s,
1 H), 7.4 (m, 3 H), 7.5 (m, 4 H) 14 144-8 3265, 2955, 1603, 1582,
1.31 (s, 6 H), 1.34 (s, 9 H), 3.2 (bs, 1 H), 1450, 1410, 1129, 995,
4.0-4.3 (m + s, 4 H), 4.45 (m, 2 H), 4.7 956 (m, 1 H), 7.3 (s, 1
H), 7.35 (s, 1 H). 15 90-5 3650, 3494, 3338, 2903, 1.4 (s, 18 H),
3.5 (m, 4 H), 3.6 (s, 2 H), 1656, 1569, 1431, 1363, 4.8 (m, 1 H),
5.2 (bs, 1 H), 5.6 (bs, 2 H), 1213 7.0 (s, 2 H) 16 amorph 2967,
1722, 1618, 1560, 1.4 (s, 18 H), 1.5 (s, 3 H), 4.3 (m, 2 H), 1420,
1225, 1187, 1160 4.7 (m, 2 H), 5.5 (s, 1 H), 7.3 (s, 2 H), 9.0 (d,
1 H) 17 139-42 3513, 3331, 3076, 2956, 1.4 (s, 18 H), 2.7 (bs, 1
H), 2.9 (dd, 2 H), 1434, 1360, 1162, 788 3.5 (s, 2 H), 3.6 (dd, 2
H), 4.4 (m, 1 H), 5.1 (s, 1 H), 7.0 (s, 2 H) 18 154-6 2295, 2955,
1637, 1435, 1.43 (s, 18 H), 3.0 (d, 1 H), 3.36 (s, 2 H), 1100 3.8
(dd, 1 H), 4.0 (dd, 1 H), 4.2 (t, 1 H), 4.3 (t, 1 H), 4.6 (m, 1 H),
7.0 (s, 2 H) 19 166-70 3481, 2962, 1700, 1612, 1.3 (s, 18 H), 2.7
(m, 1 H), 4.0 (m, 2 H), 1400 4.3 (m, 2 H), 4.6 (m, 1 H), 6.9 (s, 2
H), 7.3 (s, 1 H)
Pharmacological Data: I. Cox-1/Cox-2 Enzyme Assay:
[0147] The Cox-1/Cox-2 assay for the inventive azetidine compounds
was carried out as described. The values for enzyme inhibition of
some inventive compounds are given in the following table I.
TABLE-US-00003 TABLE I Compound % inhibition IC.sub.50 according to
5 .times. 10.sup.-5 M .mu.M Example COX-1 COX-2 COX-1 COX-2 1 -- --
37.7 1.51 2 9 78 -- 1.8 3 -- -- 349 3.51 4 -- -- 246 3.75 7 35 --
-- 0.2 14 -- -- 48.3 0.6 18 4 1 -- --
II. Determination of Cox-1- and Cox-2-Activity in Human Whole
Blood
[0148] The Cox-1- and Cox-2-activity in human whole blood is
determined as described above. The values of some inventive
compounds are given in the following table II. TABLE-US-00004 TABLE
II Compound hWB inhibition hWB inhibition according to COX-1 COX-2
Example IC.sub.50 (.mu.M) IC.sub.50 (.mu.M) 1 0.1 0.2 2 0.5 0.8 3
0.1 0.1 4 0.5 0.5 14 0.05 0.1
III. Analgesia Test in Rats
[0149] The test of the inventive compounds for analgesic activity
was carried out as described above. The values for some of the
inventive compounds is given in the following table III.
TABLE-US-00005 TABLE III Compound according to Example ED.sub.50
(mg/kg) 1 0.4 2 1.65 3 0.14 4 0.7 14 3
IV. Test for Activity Against Edema in Rats
[0150] The test for activity agaunst edema was carried out as
described above. The values of some of the inventive compounds are
given in the following table IV: TABLE-US-00006 TABLE IV Compound
according to Example ED.sub.50 (mg/kg) 1 3 2 28 3 58 4 31 17 62
V: Test for Antiarthritic Activity in Rats
[0151] The test for antiarthritic activity was carried out as
described above. The values of some of the inventive compounds are
given in the following table V. TABLE-US-00007 TABLE V Compound
according to Example ED.sub.50 (mg/kg) 1 0.5 3 0.34
VI: PGE2 Production In Rat Inflammatory Exudate And Gastric
Mucosa
[0152] The PGE2 production in rat inflammatory exudate and gastric
mucosa was carried out as described above. The values for some of
the inventive compounds are given in the following table VI.
TABLE-US-00008 TABLE VI PGE.sub.2 Inflam. PGE.sub.2 gastric mucose
exudade Example ED.sub.50 (mg/kg) ED.sub.50 (mg/kg) 1 0.16 0.28 2
3.7 5.9 3 7.3 0.5 4 1.0 5.8 14 2.7 1.8
* * * * *