U.S. patent application number 14/243599 was filed with the patent office on 2014-07-31 for novel benzyl azetidine derivatives as sphingosine 1-phosphate (s1p) receptor modulators.
This patent application is currently assigned to Allergan, Inc.. The applicant listed for this patent is Allergan, Inc.. Invention is credited to Ken Chow, Evelyn G. Corpuz, Wenkui K. Fang, Wha Bin Im, Liming Wang.
Application Number | 20140213573 14/243599 |
Document ID | / |
Family ID | 45048252 |
Filed Date | 2014-07-31 |
United States Patent
Application |
20140213573 |
Kind Code |
A1 |
Fang; Wenkui K. ; et
al. |
July 31, 2014 |
NOVEL BENZYL AZETIDINE DERIVATIVES AS SPHINGOSINE 1-PHOSPHATE (S1P)
RECEPTOR MODULATORS
Abstract
The present invention relates to novel benzyl azetidine
derivatives, processes for preparing them, pharmaceutical
compositions containing them and their use as pharmaceuticals as
modulators of sphingosine-1-phosphate receptors.
Inventors: |
Fang; Wenkui K.; (Irvine,
CA) ; Wang; Liming; (Irvine, CA) ; Chow;
Ken; (Newport Coast, CA) ; Corpuz; Evelyn G.;
(Irvine, CA) ; Im; Wha Bin; (Irvine, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Assignee: |
Allergan, Inc.
Irvine
CA
|
Family ID: |
45048252 |
Appl. No.: |
14/243599 |
Filed: |
April 2, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13294460 |
Nov 11, 2011 |
8729062 |
|
|
14243599 |
|
|
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|
61419293 |
Dec 3, 2010 |
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Current U.S.
Class: |
514/210.18 ;
546/269.1; 548/131 |
Current CPC
Class: |
A61K 31/4245 20130101;
A61P 19/00 20180101; A61P 19/02 20180101; A61P 11/00 20180101; A61P
1/00 20180101; A61P 19/10 20180101; A61P 27/06 20180101; A61K 31/41
20130101; A61P 25/00 20180101; A61P 37/08 20180101; A61P 7/10
20180101; A61P 17/04 20180101; A61P 25/28 20180101; A61P 9/10
20180101; A61K 31/397 20130101; A61P 13/12 20180101; A61P 1/04
20180101; A61P 27/02 20180101; A61P 29/00 20180101; C07D 413/10
20130101; A61P 35/04 20180101; A61P 1/02 20180101; A61P 17/02
20180101; C07D 413/14 20130101; A61P 17/06 20180101; A61P 21/04
20180101; A61P 27/00 20180101; A61P 17/00 20180101; A61P 39/02
20180101; A61P 9/00 20180101; A61P 9/14 20180101; A61P 37/00
20180101; A61P 43/00 20180101; A61P 31/04 20180101; A61P 37/02
20180101; A61P 11/08 20180101; A61P 37/06 20180101; A61P 11/06
20180101 |
Class at
Publication: |
514/210.18 ;
548/131; 546/269.1 |
International
Class: |
C07D 413/14 20060101
C07D413/14; C07D 413/10 20060101 C07D413/10 |
Claims
1. A compound having Formula I, its enantiomers, diastereoisomers,
hydrates, solvates, crystal forms and individual isomers, tautomers
or a pharmaceutically acceptable salt thereof, ##STR00020##
wherein: A is C.sub.6-10 aryl; B is C.sub.3-8 cycloalkyl; R.sup.1
is H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN,
C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl; R.sup.2 is H, halogen,
--OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; R.sup.3 is H, halogen, --OC.sub.1-8
alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or
hydroxyl; R.sup.4 is H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8
alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl; R.sup.5 is
H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; R.sup.6 is H, halogen, --OC.sub.1-8
alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or
hydroxyl; R.sup.7 is H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8
alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl; R.sup.8 is
halogen, --OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; L is CH.sub.2; R.sup.9 is H,
hydroxyl or C.sub.1-6 alkyl; R.sup.10 is H or C.sub.1-8 alkyl;
R.sup.11 is H or C.sub.1-8 alkyl; and a is 0 or 1.
2. A compound according to claim 1 wherein: ##STR00021##
3. A compound according to claim 1 wherein: ##STR00022## R.sup.1 is
H, halogen or --C.sub.1-6 alkyl; R.sup.2 is H or halogen; R.sup.3
is H, halogen or --C.sub.1-6 alkyl; R.sup.4 is H or C.sub.1-6
alkyl; R.sup.5 is H or C.sub.1-6 alkyl; R.sup.6 is H or C.sub.1-6
alkyl; R.sup.7 is H; and a is 0.
4. A compound according to claim 3 wherein: ##STR00023## R.sup.1 is
H, chloro, fluoro, trifluoromethyl or methyl; R.sup.2 is H, chloro
or fluoro; R.sup.3 is H, fluoro or methyl; R.sup.4 is H or methyl;
R.sup.5 is H or methyl; R.sup.6 is H or methyl; R.sup.7 is H; and a
is 0.
5. A compound according to claim 1, which is:
1-(4-{5-[1-(3-chlorophenyl)-2-cyclohexylethyl]-1,2,4-oxadiazol-3-yl}benzy-
l)azetidine-3-carboxylic acid.
6. A pharmaceutical composition comprising as active ingredient a
therapeutically effective amount of a compound according to claim 1
and a pharmaceutically acceptable adjuvant, diluent or carrier.
7. A pharmaceutical composition according to claim 6 wherein the
compound is:
1-(4-{5-[1-(3-chlorophenyl)-2-cyclohexylethyl]-1,2,4-oxadiazol-3-yl}b-
enzyl)azetidine-3-carboxylic acid;
8. A method of treating a disorder associated with
sphingosine-1-phosphate receptor modulation, which comprises
administering to a mammal in need thereof, a pharmaceutical
composition comprising a therapeutically effective amount of at
least one compound of Formula I ##STR00024## wherein: A is
C.sub.6-10 aryl; B is C.sub.3-8 cycloalkyl; R.sup.1 is H, halogen,
--OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; R.sup.2 is H, halogen, --OC.sub.1-8
alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or
hydroxyl; R.sup.3 is H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8
alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl; R.sup.4 is
H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; R.sup.5 is H, halogen, --OC.sub.1-8
alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or
hydroxyl; R.sup.6 is H, halogen, --OC.sub.1-8 alkyl, C.sub.1-6
alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl; R.sup.7 is
H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; R.sup.8 is halogen, --OC.sub.1-8
alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or
hydroxyl; L is CH.sub.2; R.sup.9 is H, hydroxyl or C.sub.1-6 alkyl;
R.sup.10 is H or C.sub.1-8 alkyl; R.sup.11 is H or C.sub.1-8 alkyl;
and a is 0 or 1.
9. A method of claim 8, wherein the pharmaceutical composition is
administered to the mammal to treat ocular disease, wet and dry
age-related macular degeneration, diabetic retinopathy, retinopathy
of prematurity, retinal edema, geographic atrophy, glaucomatous
optic neuropathy, chorioretinopathy, hypertensive retinopathy,
ocular ischemic syndrome, prevention of inflammation-induced
fibrosis in the back of the eye, various ocular inflammatory
diseases including uveitis, scleritis, keratitis, and retinal
vasculitis; or systemic vascular barrier related diseases such as
but not limited to: various inflammatory diseases, including acute
lung injury, its prevention, sepsis, tumor metastasis,
atherosclerosis, pulmonary edemas, and ventilation-induced lung
injury; or autoimmune diseases and immunosuppression such as but
not limited to: rheumatoid arthritis, osteoarthritis, Crohn's
disease, Graves' disease, inflammatory bowel disease, multiple
sclerosis, Myasthenia gravis, Psoriasis, ulcerative colitis,
antoimmune uveitis, renal ischemia/perfusion injury, contact
hypersensitivity, atopic dermititis, and organ transplantation
including cornea, graft vs. host diseases, pterygium, dry eye, and
posterior blepharitis; or allergies and other inflammatory diseases
such as but not limited to: urticaria, bronchial asthma, and other
airway inflammations including pulmonary emphysema and chronic
obstructive pulmonary diseases pulmonary injuries from virulent
influenza virus infection; or cardiac protection such as but not
limited to: ischemia reperfusion injury and atherosclerosis; or
wound healing such as but not limited to: scar-free healing of
wounds from cosmetic skin surgery, ocular surgery, GI surgery,
general surgery, oral injuries, various mechanical, heat and burn
injuries, prevention and treatment of photoaging and skin ageing,
and prevention of radiation- or chemotherapy-induced injuries; or
bone formation such as but not limited to: treatment of
osteoporosis and various bone fractures including hip and ankles;
or anti-nociceptive activity such as but not limited to: visceral
pain, pain associated with diabetic neuropathy, rheumatoid
arthritis, chronic knee and joint pain, tendonitis, osteoarthritis,
neuropathic pains; or central nervous system neuronal activity in
Alzheimer's disease, age-related neuronal injuries; or in organ
transplant such as renal, corneal, cardiac or adipose tissue
transplant.
10. The method of claim 9 wherein the mammal is a human.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/294,460 filed on Nov. 11, 2011 which claims the benefit
of U.S. Provisional Application Ser. No. 61/419,293 filed Dec. 3,
2010, which are hereby incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel benzyl azetidine
derivatives, processes for preparing them, pharmaceutical
compositions containing them and their use as pharmaceuticals, as
modulators of sphingosine-1-phosphate receptors. The invention
relates specifically to the use of these compounds and their
pharmaceutical compositions to treat disorders associated with
sphingosine-1-phosphate (S1P) receptor modulation.
BACKGROUND OF THE INVENTION
[0003] Sphingosine-1 phosphate is stored in relatively high
concentrations in human platelets, which lack the enzymes
responsible for its catabolism, and it is released into the blood
stream upon activation of physiological stimuli, such as growth
factors, cytokines, and receptor agonists and antigens. It may also
have a critical role in platelet aggregation and thrombosis and
could aggravate cardiovascular diseases. On the other hand the
relatively high concentration of the metabolite in high-density
lipoproteins (HDL) may have beneficial implications for
atherogenesis. For example, there are recent suggestions that
sphingosine-1-phosphate, together with other lysolipids such as
sphingosylphosphorylcholine and lysosulfatide, are responsible for
the beneficial clinical effects of HDL by stimulating the
production of the potent antiatherogenic signaling molecule nitric
oxide by the vascular endothelium. In addition, like
lysophosphatidic acid, it is a marker for certain types of cancer,
and there is evidence that its role in cell division or
proliferation may have an influence on the development of cancers.
These are currently topics that are attracting great interest
amongst medical researchers, and the potential for therapeutic
intervention in sphingosine-1-phosphate metabolism is under active
investigation.
SUMMARY OF THE INVENTION
[0004] A group of novel benzyl azetidine derivatives which are
potent and selective sphingosine-1-phosphate modulators has been
discovered. As such, the compounds described herein are useful in
treating a wide variety of disorders associated with modulation of
sphingosine-1-phosphate receptors. The term "modulator" as used
herein, includes but is not limited to: receptor agonist,
antagonist, inverse agonist, inverse antagonist, partial agonist,
partial antagonist.
[0005] This invention describes compounds of Formula I, which have
sphingosine-1-phosphate receptor biological activity. The compounds
in accordance with the present invention are thus of use in
medicine, for example in the treatment of humans with diseases and
conditions that are alleviated by S1P modulation.
[0006] In one aspect, the invention provides a compound having
Formula I or a pharmaceutically acceptable salt thereof or a
stereoisomer thereof, or the geometrical isomers, enantiomers,
diastereoisomers, tautomers, zwitterions or a pharmaceutically
acceptable salts thereof:
##STR00001## [0007] wherein: [0008] A is C.sub.6-10 aryl,
heterocycle, C.sub.3-8 cycloalkyl or C.sub.3-8 cycloalkenyl; [0009]
B is C.sub.6-10 aryl, heterocycle, C.sub.3-8 cycloalkyl or
C.sub.3-8 cycloalkenyl [0010] R.sup.1 is H, halogen, --OC.sub.1-8
alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or
hydroxyl; [0011] R.sup.2 is H, halogen, --OC.sub.1-8 alkyl,
C.sub.1-8 alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl;
[0012] R.sup.3 is H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8 alkyl,
CN, C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl; [0013] R.sup.4 is
H, halogen, --OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0014] R.sup.5 is H, halogen,
--OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0015] R.sup.6 is H, halogen,
--OC.sub.1-8 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0016] R.sup.7 is H, halogen,
--OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0017] R.sup.8 is halogen,
--OC.sub.1-8 alkyl, C.sub.1-8 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0018] L is O, S, NH or CH.sub.2;
[0019] R.sup.9 is H, hydroxyl or C.sub.1-6 alkyl; [0020] R.sup.10
is H or C.sub.1-8 alkyl; [0021] R.sup.11 is H or C.sub.1-8 alkyl;
and [0022] a is 0 or 1.
[0023] In another aspect, the invention provides a compound having
Formula I wherein L is CH.sub.2.
[0024] In another aspect, the invention provides a compound having
Formula I wherein [0025] A is C.sub.6 aryl or heterocycle; [0026] B
is C.sub.6 aryl or C.sub.3-8 cycloalkyl; [0027] R.sup.1 is H,
halogen, --OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0028] R.sup.2 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0029] R.sup.3 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0030] R.sup.4 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0031] R.sup.5 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0032] R.sup.6 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0033] R.sup.7 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0034] R.sup.8 is halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0035] L is CH.sub.2; [0036] R.sup.9
is H, hydroxyl or C.sub.1-6 alkyl; [0037] R.sup.10 is H or
C.sub.1-6 alkyl; [0038] R.sup.11 is H or C.sub.1-6 alkyl; and
[0039] a is 0 or 1.
[0040] In another embodiment, the invention provides a compound
having Formula I wherein:
##STR00002##
[0041] In another embodiment, the invention provides a compound
having Formula I wherein:
##STR00003##
[0042] In another embodiment, the invention provides a compound
having Formula I wherein:
##STR00004##
[0043] In another embodiment, the invention provides a compound
having Formula I wherein:
##STR00005## [0044] R.sup.1 is H, halogen, --OC.sub.1-6 alkyl,
C.sub.1-6 alkyl, CN, C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl;
[0045] R.sup.2 is H, halogen, --OC.sub.1-6 alkyl, C.sub.1-6 alkyl,
CN, C(O)R.sup.9, NR.sup.10R.sup.11 or hydroxyl; [0046] R.sup.3 is
H, halogen, --OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0047] R.sup.4 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0048] R.sup.5 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0049] R.sup.6 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0050] R.sup.7 is H, halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0051] R.sup.8 is halogen,
--OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)R.sup.9,
NR.sup.10R.sup.11 or hydroxyl; [0052] L is CH.sub.2; [0053] R.sup.9
is H, hydroxyl or C.sub.1-6 alkyl; [0054] R.sup.10 is H or
C.sub.1-6 alkyl; [0055] R.sup.11 is H or C.sub.1-6 alkyl; and
[0056] a is 0 or 1.
[0057] In another aspect, the invention provides a compound having
Formula I wherein
##STR00006## [0058] R.sup.1 is H, halogen or --C.sub.1-6 alkyl;
[0059] R.sup.2 is H or halogen; [0060] R.sup.3 is H, halogen or
--C.sub.1-6 alkyl; [0061] R.sup.4 is H or C.sub.1-6 alkyl, [0062]
R.sup.5 is H or C.sub.1-6 alkyl; [0063] R.sup.6 is H or C.sub.1-6
alkyl; [0064] R.sup.7 is H; [0065] a is 0; and [0066] L is
CH.sub.2.
[0067] In another embodiment, the invention provides a compound
having Formula I wherein:
##STR00007## [0068] R.sup.1 is H, chloro, fluoro, trifluoromethyl
or methyl; [0069] R.sup.2 is H, chloro or fluoro; [0070] R.sup.3 is
H, fluoro or methyl; [0071] R.sup.4 is H or methyl; [0072] R.sup.5
is H or methyl; [0073] R.sup.6 is H or methyl; [0074] R.sup.7 is H;
[0075] a is 0; and [0076] L is CH.sub.2.
[0077] The term "alkyl", as used herein, refers to saturated,
monovalent hydrocarbon moieties having linear or branched moieties
or combinations thereof and containing 1 to 8 carbon atoms. One
methylene (--CH.sub.2--) group, of the alkyl can be replaced by
oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl,
or by a divalent C.sub.3-6 cycloalkyl. Alkyl groups can be
substituted by halogen, hydroxyl, cycloalkyl, amino, non-aromatic
heterocycles, carboxylic acid, phosphonic acid groups, sulphonic
acid groups, phosphoric acid.
[0078] The term "cycloalkyl", as used herein, refers to a
monovalent or divalent group of 3 to 8 carbon atoms, derived from a
saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic
or polycyclic. Cycloalkyl can be substituted by alkyl groups or
halogen atoms.
[0079] The term "cycloalkenyl", as used herein, refers to a
monovalent or divalent group of 3 to 8 carbon atoms, preferably 3
to 6 carbon atoms derived from a saturated cycloalkyl having one
double bond. Cycloalkenyl groups can be monocyclic or polycyclic.
Cycloalkenyl groups can be substituted by alkyl groups or halogen
atoms.
[0080] The term "halogen", as used herein, refers to an atom of
chlorine, bromine, fluorine, iodine.
[0081] The term "alkenyl", as used herein, refers to a monovalent
or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived
from a saturated alkyl, having at least one double bond. C.sub.2-6
alkenyl can be in the E or Z configuration. Alkenyl groups can be
substituted by alkyl groups.
[0082] The term "alkynyl", as used herein, refers to a monovalent
or divalent hydrocarbon moiety having 2 to 6 carbon atoms, derived
from a saturated alkyl, having at least one triple bond. Alkynyl
groups can be substituted by alkyl groups.
[0083] The term "heterocycle" as used herein, refers to a 3 to 10
membered ring, which can be aromatic or non-aromatic, saturated or
non-saturated, containing at least one heteroatom selected form O
or N or S or combinations of at least two thereof, interrupting the
carbocyclic ring structure. The heterocyclic ring can be
interrupted by a C.dbd.O; the S heteroatom can be oxidized.
Heterocycles can be monocyclic or polycyclic. Heterocyclic ring
moieties can be substituted by hydroxyl, alkyl groups or halogen
atoms.
[0084] The term "aryl" as used herein, refers to an organic moiety
derived from an aromatic hydrocarbon consisting of a ring
containing 6 to 10 carbon atoms by removal of one hydrogen. Aryls
can be monocyclic or polycyclic. Aryl can be substituted by halogen
atoms, --OC.sub.1-6 alkyl, C.sub.1-6 alkyl, CN, C(O)(C.sub.1-6
alkyl), N(C.sub.1-6 alkyl) (C.sub.1-6 alkyl) or NH.sub.2 or
NH(C.sub.1-6 alkyl) or hydroxyl groups. Usually aryl is phenyl.
Preferred substitution site on aryl are meta and para
positions.
[0085] The term "hydroxyl" as used herein, represents a group of
formula "--OH".
[0086] The term "carbonyl" as used herein, represents a group of
formula "--C(O)".
[0087] The term "carboxyl" as used herein, represents a group of
formula "--C(O)O--".
[0088] The term "sulfonyl" as used herein, represents a group of
formula "--SO.sub.2".
[0089] The term "sulfate" as used herein, represents a group of
formula "--O--S(O).sub.2--O--".
[0090] The term "carboxylic acid" as used herein, represents a
group of formula "--C(O)OH".
[0091] The term "sulfoxide" as used herein, represents a group of
formula "--S.dbd.O".
[0092] The term "phosphonic acid" as used herein, represents a
group of formula "--P(O)(OH).sub.2".
[0093] The term "phosphoric acid" as used herein, represents a
group of formula "--(O)P(O)(OH).sub.2".
[0094] The term "sulphonic acid" as used herein, represents a group
of formula "--S(O).sub.2OH".
[0095] The formula "H", as used herein, represents a hydrogen
atom.
[0096] The formula "O", as used herein, represents an oxygen
atom.
[0097] The formula "N", as used herein, represents a nitrogen
atom.
[0098] The formula "S", as used herein, represents a sulfur
atom.
[0099] Some compounds of the invention are: [0100]
1-(4-{5-[1-(3-Chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol--
3-yl}benzyl)azetidine-3-carboxylic acid; [0101]
1-(4-{5-[1-(3-fluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol--
3-yl}benzyl)azetidine-3-carboxylic acid; [0102]
1-(4-{5-[1-(5-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxad-
iazol-3-yl}benzyl)azetidine-3-carboxylic acid; [0103]
1-(4-{5-[1-(3-chlorophenyl)-2-cyclohexylethyl]-1,2,4-oxadiazol-3-yl}benzy-
l)azetidine-3-carboxylic acid; [0104]
1-(4-{5-[2-(3,4-Dimethylphenyl)-1-(3,5-dimethylphenyl)ethyl]-1,2,4-oxadia-
zol-3-yl}benzyl)azetidine-3-carboxylic acid; [0105]
1-[4-(5-{2-(3,4-Dimethylphenyl)-1-[3-(trifluoromethyl)phenyl]ethyl}-1,2,4-
-oxadiazol-3-yl)benzyl]azetidine-3-carboxylic acid; [0106]
1-(4-{5-[1-(3,5-Difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadia-
zol-3-yl}benzyl)azetidine-3-carboxylic acid; [0107]
1-(4-{5-[2-(3,4-Dimethylphenyl)-1-(3-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}-
benzyl)azetidine-3-carboxylic acid; [0108]
1-(4-{5-[2-(4-methylphenyl)-1-(3-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benz-
yl)azetidine-3-carboxylic acid; [0109]
1-(4-{5-[2-(4-Methylphenyl)-1-(2-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}benz-
yl)azetidine-3-carboxylic acid; [0110]
1-(4-{5-[2-(3,4-dimethylphenyl)-1-(2-thienyl)ethyl]-1,2,4-oxadiazol-3-yl}-
benzyl)azetidine-3-carboxylic acid.
[0111] Some compounds of Formula I and some of their intermediates
have at least one stereogenic center in their structure. This
stereogenic center may be present in an R or S configuration, said
R and S notation is used in correspondence with the rules described
in Pure Appli. Chem. (1976), 45, 11-13.
[0112] The term "pharmaceutically acceptable salts" refers to salts
or complexes that retain the desired biological activity of the
above identified compounds and exhibit minimal or no undesired
toxicological effects. The "pharmaceutically acceptable salts"
according to the invention include therapeutically active,
non-toxic base or acid salt forms, which the compounds of Formula I
are able to form.
[0113] The acid addition salt form of a compound of Formula I that
occurs in its free form as a base can be obtained by treating the
free base with an appropriate acid such as an inorganic acid, for
example, hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, nitric acid and the like; or an organic acid such
as for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic,
malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid,
succinic acid, malic acid, ascorbic acid, benzoic acid, tannic
acid, pamoic acid, citric, methylsulfonic, ethanesulfonic,
benzenesulfonic, formic and the like (Handbook of Pharmaceutical
Salts, P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag
Helvetica Chemica Acta-Zurich, 2002, 329-345).
[0114] Compounds of Formula I and their salts can be in the form of
a solvate, which is included within the scope of the present
invention. Such solvates include for example hydrates, alcoholates
and the like.
[0115] With respect to the present invention reference to a
compound or compounds, is intended to encompass that compound in
each of its possible isomeric forms and mixtures thereof unless the
particular isomeric form is referred to specifically.
[0116] Compounds according to the present invention may exist in
different polymorphic forms. Although not explicitly indicated in
the above formula, such forms are intended to be included within
the scope of the present invention.
[0117] The compounds of the invention are indicated for use in
treating or preventing conditions in which there is likely to be a
component involving the sphingosine-1-phosphate receptors.
[0118] In another embodiment, there are provided pharmaceutical
compositions including at least one compound of the invention in a
pharmaceutically acceptable carrier.
[0119] In a further embodiment of the invention, there are provided
methods for treating disorders associated with modulation of
sphingosine-1-phosphate receptors. Such methods can be performed,
for example, by administering to a subject in need thereof a
pharmaceutical composition containing a therapeutically effective
amount of at least one compound of the invention.
[0120] These compounds are useful for the treatment of mammals,
including humans, with a range of conditions and diseases that are
alleviated by S1P modulation.
[0121] Therapeutic utilities of S1P modulators are:
[0122] Ocular Diseases: wet and dry age-related macular
degeneration, diabetic retinopathy, retinopathy of prematurity,
retinal edema, geographic atrophy, glaucomatous optic neuropathy,
chorioretinopathy, hypertensive retinopathy, ocular ischemic
syndrome, prevention of inflammation-induced fibrosis in the back
of the eye, various ocular inflammatory diseases including uveitis,
scleritis, keratitis, and retinal vasculitis;
[0123] Systemic vascular barrier related diseases: various
inflammatory diseases, including acute lung injury, its prevention,
sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and
ventilation-induced lung injury;
[0124] Autoimmune diseases and immnuosuppression: rheumatoid
arthritis, Crohn's disease, Graves' disease, inflammatory bowel
disease, multiple sclerosis, Myasthenia gravis, Psoriasis,
ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion
injury, contact hypersensitivity, atopic dermititis, and organ
transplantation;
[0125] Allergies and other inflammatory diseases: urticaria,
bronchial asthma, and other airway inflammations including
pulmonary emphysema and chronic obstructive pulmonary diseases;
[0126] Cardiac functions: bradycardia, congestional heart failure,
cardiac arrhythmia, prevention and treatment of atherosclerosis,
and ischemia/reperfusion injury;
[0127] Wound Healing: scar-free healing of wounds from cosmetic
skin surgery, ocular surgery, GI surgery, general surgery, oral
injuries, various mechanical, heat and burn injuries, prevention
and treatment of photoaging and skin ageing, and prevention of
radiation-induced injuries;
[0128] Bone formation: treatment of osteoporosis and various bone
fractures including hip and ankles;
[0129] Anti-nociceptive activity: visceral pain, pain associated
with diabetic neuropathy, rheumatoid arthritis, chronic knee and
joint pain, tendonitis, osteoarthritis, neuropathic pains;
[0130] Anti-fibrosis: ocular, cardiac, hepatic and pulmonary
fibrosis, proliferative vitreoretinopathy, cicatricial pemphigoid,
surgically induced fibrosis in cornea, conjunctiva and tenon;
[0131] Pains and anti-inflammation: acute pain, flare-up of chronic
pain, musculo-skeletal pains, visceral pain, pain associated with
diabetic neuropathy, rheumatoid arthritis, chronic knee and joint
pain, tendonitis, osteoarthritis, bursitis, neuropathic pains;
[0132] CNS neuronal injuries: Alzheimer's disease, age-related
neuronal injuries;
[0133] Organ transplants: renal, corneal, cardiac and adipose
tissue transplants.
[0134] In still another embodiment of the invention, there are
provided methods for treating disorders associated with modulation
of sphingosine-1-phosphate receptors. Such methods can be
performed, for example, by administering to a subject in need
thereof a therapeutically effective amount of at least one compound
of the invention, or any combination thereof, or pharmaceutically
acceptable salts, hydrates, solvates, crystal forms and individual
isomers, enantiomers, and diastereomers thereof.
[0135] The present invention concerns the use of a compound of
Formula I or a pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of:
[0136] Ocular Diseases: wet and dry age-related macular
degeneration, diabetic retinopathy, retinopathy of prematurity,
retinal edema, geographic atrophy, glaucomatous optic neuropathy,
chorioretinopathy, hypertensive retinopathy, ocular ischemic
syndrome, prevention of inflammation-induced fibrosis in the back
of the eye, various ocular inflammatory diseases including uveitis,
scleritis, keratitis, and retinal vasculitis;
[0137] Systemic vascular barrier related diseases: various
inflammatory diseases, including acute lung injury, its prevention,
sepsis, tumor metastasis, atherosclerosis, pulmonary edemas, and
ventilation-induced lung injury;
[0138] Autoimmune diseases and immnuosuppression: rheumatoid
arthritis, Crohn's disease, Graves' disease, inflammatory bowel
disease, multiple sclerosis, Myasthenia gravis, Psoriasis,
ulcerative colitis, antoimmune uveitis, renal ischemia/perfusion
injury, contact hypersensitivity, atopic dermititis, and organ
transplantation;
[0139] Allergies and other inflammatory diseases: urticaria,
bronchial asthma, and other airway inflammations including
pulmonary emphysema and chronic obstructive pulmonary diseases;
[0140] Cardiac functions: bradycardia, congestional heart failure,
cardiac arrhythmia, prevention and treatment of atherosclerosis,
and ischemia/reperfusion injury;
[0141] Wound Healing: scar-free healing of wounds from cosmetic
skin surgery, ocular surgery, GI surgery, general surgery, oral
injuries, various mechanical, heat and burn injuries, prevention
and treatment of photoaging and skin ageing, and prevention of
radiation-induced injuries;
[0142] Bone formation: treatment of osteoporosis and various bone
fractures including hip and ankles;
[0143] Anti-nociceptive activity: visceral pain, pain associated
with diabetic neuropathy, rheumatoid arthritis, chronic knee and
joint pain, tendonitis, osteoarthritis, neuropathic pains; [0144]
Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,
proliferative vitreoretinopathy, cicatricial pemphigoid, surgically
induced fibrosis in cornea, conjunctiva and tenon; [0145] Pains and
anti-inflammation: acute pain, flare-up of chronic pain,
musculo-skeletal pains, visceral pain, pain associated with
diabetic neuropathy, rheumatoid arthritis, chronic knee and joint
pain, tendonitis, osteoarthritis, bursitis, neuropathic pains; CNS
neuronal injuries: Alzheimer's disease, age-related neuronal
injuries; [0146] Organ transplants: renal, corneal, cardiac and
adipose tissue transplants.
[0147] The actual amount of the compound to be administered in any
given case will be determined by a physician taking into account
the relevant circumstances, such as the severity of the condition,
the age and weight of the patient, the patient's general physical
condition, the cause of the condition, and the route of
administration.
[0148] The patient will be administered the compound orally in any
acceptable form, such as a tablet, liquid, capsule, powder and the
like, or other routes may be desirable or necessary, particularly
if the patient suffers from nausea. Such other routes may include,
without exception, transdermal, parenteral, subcutaneous,
intranasal, via an implant stent, intrathecal, intravitreal,
topical to the eye, back to the eye, intramuscular, intravenous,
and intrarectal modes of delivery. Additionally, the formulations
may be designed to delay release of the active compound over a
given period of time, or to carefully control the amount of drug
released at a given time during the course of therapy.
[0149] In another embodiment of the invention, there are provided
pharmaceutical compositions including at least one compound of the
invention in a pharmaceutically acceptable carrier thereof. The
phrase "pharmaceutically acceptable" means the carrier, diluent or
excipient must be compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
[0150] Pharmaceutical compositions of the present invention can be
used in the form of a solid, a solution, an emulsion, a dispersion,
a patch, a micelle, a liposome, and the like, wherein the resulting
composition contains one or more compounds of the present
invention, as an active ingredient, in admixture with an organic or
inorganic carrier or excipient suitable for enteral or parenteral
applications. Invention compounds may be combined, for example,
with the usual non-toxic, pharmaceutically acceptable carriers for
tablets, pellets, capsules, suppositories, solutions, emulsions,
suspensions, and any other form suitable for use. The carriers
which can be used include glucose, lactose, gum acacia, gelatin,
mannitol, starch paste, magnesium trisilicate, talc, corn starch,
keratin, colloidal silica, potato starch, urea, medium chain length
triglycerides, dextrans, and other carriers suitable for use in
manufacturing preparations, in solid, semisolid, or liquid form. In
addition auxiliary, stabilizing, thickening and coloring agents and
perfumes may be used. Invention compounds are included in the
pharmaceutical composition in an amount sufficient to produce the
desired effect upon the process or disease condition.
[0151] Pharmaceutical compositions containing invention compounds
may be in a form suitable for oral use, for example, as tablets,
troches, lozenges, aqueous or oily suspensions, dispersible powders
or granules, emulsions, hard or soft capsules, or syrups or
elixirs. Compositions intended for oral use may be prepared
according to any method known in the art for the manufacture of
pharmaceutical compositions and such compositions may contain one
or more agents selected from the group consisting of a sweetening
agent such as sucrose, lactose, or saccharin, flavoring agents such
as peppermint, oil of wintergreen or cherry, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets containing invention compounds in
admixture with non-toxic pharmaceutically acceptable excipients may
also be manufactured by known methods. The excipients used may be,
for example, (1) inert diluents such as calcium carbonate, lactose,
calcium phosphate or sodium phosphate; (2) granulating and
disintegrating agents such as corn starch, potato starch or alginic
acid; (3) binding agents such as gum tragacanth, corn starch,
gelatin or acacia, and (4) lubricating agents such as magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they
may be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate may
be employed.
[0152] In some cases, formulations for oral use may be in the form
of hard gelatin capsules wherein the invention compounds are mixed
with an inert solid diluent, for example, calcium carbonate,
calcium phosphate or kaolin. They may also be in the form of soft
gelatin capsules wherein the invention compounds are mixed with
water or an oil medium, for example, peanut oil, liquid paraffin or
olive oil.
[0153] The pharmaceutical compositions may be in the form of a
sterile injectable suspension. This suspension may be formulated
according to known methods using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example,
as a solution in 1,3-butanediol. Sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono- or diglycerides, fatty acids (including oleic acid),
naturally occurring vegetable oils like sesame oil, coconut oil,
peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like
ethyl oleate or the like. Buffers, preservatives, antioxidants, and
the like can be incorporated as required.
[0154] Invention compounds may also be administered in the form of
suppositories for rectal administration of the drug. These
compositions may be prepared by mixing the invention compounds with
a suitable non-irritating excipient, such as cocoa butter,
synthetic glyceride esters of polyethylene glycols, which are solid
at ordinary temperatures, but liquefy and/or dissolve in the rectal
cavity to release the drug.
[0155] Since individual subjects may present a wide variation in
severity of symptoms and each drug has its unique therapeutic
characteristics, the precise mode of administration and dosage
employed for each subject is left to the discretion of the
practitioner.
[0156] The compounds and pharmaceutical compositions described
herein are useful as medicaments in mammals, including humans, for
treatment of diseases and/or alleviations of conditions which are
responsive to treatment by agonists or functional antagonists of
sphingosine-1-phosphate receptors. Thus, in further embodiments of
the invention, there are provided methods for treating a disorder
associated with modulation of sphingosine-1-phosphate receptors.
Such methods can be performed, for example, by administering to a
subject in need thereof a pharmaceutical composition containing a
therapeutically effective amount of at least one invention
compound. As used herein, the term "therapeutically effective
amount" means the amount of the pharmaceutical composition that
will elicit the biological or medical response of a subject in need
thereof that is being sought by the researcher, veterinarian,
medical doctor or other clinician. In some embodiments, the subject
in need thereof is a mammal. In some embodiments, the mammal is
human.
[0157] The present invention concerns also processes for preparing
the compounds of Formula I. The compounds of Formula I according to
the invention can be prepared analogously to conventional methods
as understood by the person skilled in the art of synthetic organic
chemistry. The synthetic schemes set forth below, illustrate how
compounds according to the invention can be made.
[0158] The following abbreviations are used in the general scheme
and in the specific examples: [0159] CDI 1,1'-Carbonyldiimidazole
[0160] THF tetrahydrofuran [0161] RT room temperature [0162] MPLC
medium pressure liquid chromatography [0163] NMO 4-Methylmorpholine
N-oxide [0164] AcCN acetonitrile [0165] DCM dichloromethane [0166]
TPAP Tetrapropylammonium perruthenate [0167] MeOH methanol [0168]
NaCNBH.sub.3 sodium cyanoborohydride [0169] H.sub.2O water [0170]
CD.sub.3OD deuterated methanol [0171] MgCl.sub.2 magnesium chloride
[0172] NaCl sodium chloride [0173] DMSO-d.sub.6 deuterated dimethyl
sulfoxide
##STR00008##
[0174] A solution of substituted carboxylic acid and CDI in THF was
stirred at RT for 30 min., N-Hydroxy-4-(hydroxymethyl)benzamidine
(prepared according to Li, Zhen et al, J. Med. Chem., 2005, 48
(20), pp 6169-6173) was added and the resulting solution and
stirred at RT overnight. The acid was prepared according to
Vaccaro, Wayne; Amore, Cindy; Berger, Joel; Burrier, Robert;
Clader, John; et al. Journal of Medicinal Chemistry, 1996, 39(8),
1704-1719. The reaction mixture was then transferred to a microwave
suitable reaction vessel and heated to 150.degree. C. for 20 min
under microwave condition. After cooling to RT, the solvent was
removed under reduced pressure. The alcohol was isolated by MPLC
using 5 to 10% ethyl acetate in hexane.
[0175] The alcohol was mixed with NMO, molecular sieves in AcCN and
DCM. A catalytic amount of TPAP was added. The resulting reaction
mixture was stirred at RT for 1 hour and evaporated to dryness. The
obtained aldehyde compound was purified by MPLC using 0-10% ethyl
acetate in hexane. The aldehyde intermediate, 3-azetidinecarboxylic
acid (and TEA were mixed with MeOH. Upon stirring at 60.degree. C.
for 90 min, the reaction solution was cooled to RT. NaBH.sub.4 was
added and stirred at RT for 2 hour. In some cases acetic acid and
NaCNBH.sub.3 were used. The reaction was quenched with 0.5 mL of
water and concentrated to minimal amount. The compound of Formula I
was isolated by reverse phase MPLC using H.sub.2O in AcCN.
[0176] Those skilled in the art will be able to routinely modify
and/or adapt the following scheme to synthesize any compounds of
the invention covered by Formula I.
DETAILED DESCRIPTION OF THE INVENTION
[0177] It is to be understood that both the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of the invention
claimed. As used herein, the use of the singular includes the
plural unless specifically stated otherwise.
[0178] It will be readily apparent to those skilled in the art that
some of the compounds of the invention may contain one or more
asymmetric centers, such that the compounds may exist in
enantiomeric as well as in diastereomeric forms. Unless it is
specifically noted otherwise, the scope of the present invention
includes all enantiomers, diastereomers and racemic mixtures. Some
of the compounds of the invention may form salts with
pharmaceutically acceptable acids or bases, and such
pharmaceutically acceptable salts of the compounds described herein
are also within the scope of the invention.
[0179] The present invention includes all pharmaceutically
acceptable isotopically enriched compounds. Any compound of the
invention may contain one or more isotopic atoms enriched or
different than the natural ratio such as deuterium .sup.2H (or D)
in place of protium .sup.1H (or H) or use of .sup.13C enriched
material in place of .sup.12C and the like. Similar substitutions
can be employed for N, O and S. The use of isotopes may assist in
analytical as well as therapeutic aspects of the invention. For
example, use of deuterium may increase the in vivo half-life by
altering the metabolism (rate) of the compounds of the invention.
These compounds can be prepared in accord with the preparations
described by use of isotopically enriched reagents.
[0180] The following examples are for illustrative purposes only
and are not intended, nor should they be construed as limiting the
invention in any manner. Those skilled in the art will appreciate
that variations and modifications of the following examples can be
made without exceeding the spirit or scope of the invention.
[0181] As will be evident to those skilled in the art, individual
isomeric forms can be obtained by separation of mixtures thereof in
conventional manner. For example, in the case of diasteroisomeric
isomers, chromatographic separation may be employed.
[0182] The IUPAC names of the compounds mentioned in the examples
were generated with ACD version 8 and intermediates and reagent
names used in the examples were generated with software such as
Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS
Draw 2.5 SP1.
[0183] In general, characterization of the compounds was performed
according to the following methods proton nuclear magnetic
resonance (.sup.1H NMR) spectra were recorded on a Varian 300 or
600 MHz spectrometer in deuterated solvent. Chemical shifts were
reported as .delta. (delta) values in parts per million (ppm)
relative to tetramethylsilane (TMS) as an internal standard (0.00
ppm) and multiplicities were reported as s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad. Data were reported in
the following format: chemical shift (multiplicity, coupling
constant(s) J in hertz (Hz), integrated intensity).
[0184] All the reagents, solvents, catalysts for which the
synthesis is not described are purchased from chemical vendors such
as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR,
Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge,
Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle,
Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some
known intermediates, were prepared according to published
procedures.
[0185] Usually the compounds of the invention were purified by
column chromatography (Auto-column) on an Teledyne-ISCO CombiFlash
with a silica column, unless noted otherwise.
EXAMPLE 1
Intermediate 1
4-{5-[1-(3-Chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl-
}benzaldehyde
[0186] A solution of
2-(3-chlorophenyl)-3-(3,4-dimethylphenyl)propanoic acid (2.18 mmol)
and CDI (390 mg, 2.40 mmol) in THF was stirred at rt for 30 min.
N-Hydroxy-4-(hydroxymethyl)benzamidine (608 mg, 2.18 mmol) was
added and the resulting solution was stirred at rt overnight. The
reaction solution was then transferred to a microwave suitable
reaction vessel and heated at 150.degree. C. for 20 min under
microwave condition. After cooling to rt, the solvent was removed
under reduced pressure. The titled alcohol was isolated by MPLC
using 5 to 10% ethyl acetate in hexane.
[0187] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm 2.15 (s, 6H)
3.22-3.32 (m, 1H) 3.52 (dd, J=13.48, 8.50 Hz, 1H) 4.71 (t, J=7.91
Hz, 1H) 6.81-6.97 (m, 3H) 7.25-7.34 (m, 3H) 7.42 (m, 1H) 7.63 (d,
J=8.2 Hz, 1H) 7.99-8.06 (d, J=8.2 Hz, 2H) 8.24 (d, J=8.20 Hz, 1H)
10.05(s, 1H).
Example 2
Compound 1
1-(4-{5-[1-(3-Chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-
-yl}benzyl)azetidine-3-carboxylic acid
##STR00009##
[0188] Intermediate 1 (0.55 mmol), 3-azetidinecarboxylic acid (82
mg, 0.81 mmol) and TEA (0.1 ml, 0.7 mmol) were mixed with MeOH (10
ml). Upon stirring at 60.degree. C. for 90 min, the reaction
solution was cooled to RT. NaBH.sub.4 (50 mg, 1.35 mmol) was added
and stirred at RT for 2 hour. The reaction was quenched with 0.5 mL
of water and concentrated to minimal amount. Compound 1 was
isolated by reverse phase MPLC using H.sub.2O in AcCN.
[0189] .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm 2.13 (s, 6H)
3.20-3.35 (m, 2H) 3.45-3.55 (m, 1H) 3.86 (d, J=7.91 Hz, 2H) 3.92
(d, J=9.08 Hz, 2H) 4.11 (s, 2H) 4.66 (t, J=7.91 Hz, 1H) 6.78-6.95
(m, 3H) 7.23-7.33 (m, 3H) 7.40 (m, 1H) 7.53 (d, J=8.20 Hz, 2H) 8.06
(d, J=8.20 Hz, 2H).
Compounds 2 through 11 were prepared in a similar manner to the
method described in Examples 1 and 2. The starting materials and
the results are tabulated below in Table 1 for each case.
TABLE-US-00001 TABLE 1 Compound Starting .sup.1 NMR (Solvent;
.delta. number IUPAC name material ppm) 2
1-(4-{5-[1-(3-fluorophenyl)-2- (3,4-dimethylphenyl)ethyl]-
1,2,4-oxadiazol-3- yl}benzyl)azetidine-3- carboxylic acid
##STR00010## 2-(3- fluorophenyl)-3- (3,4- dimethylphenyl) propanoic
acid .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. ppm 2.15 (s, 6 H)
3.17-3.27 (m, 2 H) 3.37 (t, J = 8.06 Hz, 2 H) 3.48-3.61 (m, 3 H)
3.70 (s, 2 H) 4.68 (t, J = 7.91 Hz, 1 H) 6.81- 6.88 (m, 1 H) 6.89-
7.06 (m, 3H) 7.12- 7.23 (m, 2 H) 7.33 (m, 1 H) 7.45 (d, J = 8.20
Hz, 2 H) 8.00 (d, J = 8.20 Hz, 2H). 3
1-(4-{5-[1-(5-chloropyridin-3- yl)-2-(3,4-
dimethylphenyl)ethyl]-1,2,4- oxadiazol-3- yl}benzyl)azetidine-3-
carboxylic acid ##STR00011## 2-(5- chloropyridin-3- yl)-3-(3,4-
dimethylphenyl) propanoic acid .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. ppm 2.14 (s, 6 H) 3.14-3.42 (m, 4 H) 3.49-3.63 (m, 3 H)
3.69 (s, 2 H) 4.82 (d, J = 7.91 Hz, 1 H) 6.81 (d, J = 7.62 Hz, 1 H)
6.86-6.98 (m, 2 H) 7.44 (d, J = 8.20 Hz, 2 H) 7.95 (t, J = 2.05 Hz,
1 H) 8.00 (d, J = 8.20 Hz, 2 H) 8.43 (d, J = 6.59, 2 H). 4
1-(4-{5-[1-(3-chlorophenyl)-2- cyclohexylethyl]-1,2,4- oxadiazol-3-
yl}benzyl)azetidine-3- carboxylic acid ##STR00012## 2-(3-
chlorophenyl)-3- cyclohexyl- propanoic acid .sup.1H NMR (600 MHz,
CD.sub.3OD) .delta. ppm 0.91-1.07 (m, 2H) 1.10-1.24 m, 4 H)
1.60-1.71 (m, 3 H) 1.74-1.83 (m, 2H) 1.95-2.03 (m, 1 H) 2.10-2.18
(m, 1 H) 3.33 (m, 1 H) 3.84 (t, J = 7.91 Hz, 2 H) 3.93 (t, J = 9.08
Hz, 2 H) 4.11 (s, 2 H) 4.53 (t, J = 7.92 Hz, 1 H) 7.28-7.31 (m, 1
H) 7.32-7.38 (m, 2 H) 7.43-7.47 (m, 1 H) 7.54 (d, J = 8.22 Hz, 2 H)
8.05-8.09 (m, 2 H). 5 1-(4-{5-[2-(3,4- dimethylphenyl)-1-(3,5-
dimethylphenyl)ethyl]-1,2,4- oxadiazol-3- yl}benzyl)azetidine-3-
carboxylic acid ##STR00013## of 4-(5-(2-(3,4- dimethylphenyl)-
1-(3,5- dimethylphenyl) ethyl)-1,2,4- oxadiazol-3- yl)benzaldehyde
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 2.09 (s, 3 H) 2.10
(s, 3 H) 2.22 (s, 6H) 3.09-3.52 (m, 7 H) 3.59 (s, 2 H) 4.67- 4.77
(m, 1 H) 6.85- 6.94 (m, 3 H) 7.04 (br. s, 3 H) 7.41 (d, J = 8.20
Hz, 2 H) 7.83-7.96 (m, 2 H). 6 1-[4-(52-(3,4-dimethylphenyl)- 1-[3-
(trifluoromethyl)phenyl]ethyl}- 1,2,4-oxadiazol-3-
yl)benzyl]azetidine-3- carboxylic acid ##STR00014## 4-(5-(2-(3,4-
dimethylphenyl)- 1-(3- (trifluoromethyl) phenyl)ethyl)-
1,2,4-oxadiazol- 3- yl)benzaldehyde .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 2.13 (s, 6 H) 3.23 (br. s., 3 H) 3.30-
3.47 (m, 3 H) 3.50- 3.71 (m, 3 H) 5.09 (t, J = 7.91 Hz, 1 H)
6.88-7.01 (m, 2 H) 7.03 (br. s., 1 H) 7.46 (d, J = 7.62 Hz, 2 H)
7.56-7.73 (m, 2 H) 7.75-7.87 (m, 2 H) 7.94 (d, J = 7.91 Hz, 2 H). 7
1-(4-{5-[1-(3,5-difluorophenyl)- 2-(3,4-dimethylphenyl)ethyl]-
1,2,4-oxadiazol-3- yl}benzyl)azetidine-3- carboxylic acid
##STR00015## of 4-{5-[1-(3,5- difluorophenyl)- 2-(3,4-
dimethylphenyl) ethyl]-1,2,4- oxadiazol-3- yl}benzaldehyde .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 2.10 (d, J = 2.64 Hz, 6 H)
3.12-3.53 (m, 7 H) 3.59 (s, 2 H) 4.96 (t, J = 8.06 Hz, 1 H)
6.84-6.91 (m, 1 H) 6.92-6.97 (m, 1 H) 7.00 (br. s., 1 H) 7.10-7.17
(m, 1 H) 7.17-7.26 (m, 2 H) 7.42 (d, J = 8.50 Hz, 2 H) 7.84-7.94
(m, 2 H). 8 1-(4-{5-[2-(3,4- dimethylphenyl)-1-(3-
thienyl)ethyl]-1,2,4-oxadiazol- 3-yl}benzyl)azetidine-3- carboxylic
acid ##STR00016## (4-{5-[2-(3,4- dimethylphenyl)- 1-(3-
thienyl)ethyl]- 1,2,4-oxadiazol- 3-yl}phenyl) methanol .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 2.10 (s, 6 H) 3.09- 3.48 (m, 7
H) 3.50- 3.67 (m, 2 H) 4.94 (t, J = 7.91 Hz, 1 H) 6.83-6.90 (m, 1
H) 6.91 -6.96 (m, 1 H) 6.98 (br. s, 1 H) 7.18 (dd, J = 4.98, 1.47
Hz, 1 H) 7.41 (d, J = 8.50 Hz, 2 H) 7.45-7.49 (m, 1 H) 7.49-7.54
(m, 1 H) 7.89 (d, J = 8.20 Hz, 2 H). 9
1-(4-{5-[2-(4-methylphenyl)-1- (3-thienyl)ethyl]-1,2,4-
oxadiazol-3- yl}benzyl)azetidine-3- carboxylic acid ##STR00017##
4-{5-[2-(4- methylphenyl)-1- (3-thienyl)ethyl]- 1,2,4-oxadiazol- 3-
yl}benzaldehyde .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm
2.19 (s, 3 H) 3.09- 3.52 (m, 7 H) 3.59 (s, 2 H) 4.95 (t, J = 8.20
Hz, 1 H) 6.97-7.03 (m, 2 H) 7.05-7.11 (m, 2 H) 7.18 (dd, J = 4.98,
1.46 Hz, 1 H) 7.41 (d, J = 8.50 Hz, 2 H) 7.45-7.48 (m, 1 H)
7.49-7.54 (m, 1 H) 7.85-7.93 (m, 2 H). 10
1-(4-{5-[2-(4-methylphenyl)-1- (2-thienyl)ethyl]-1,2,4-
oxadiazol-3- yl}benzyl)azetidine-3- carboxylic acid ##STR00018##
4-{5-[2-(4- methylphenyl)-1- (2-thienyl)ethyl]- 1,2,4-oxadiazol- 3-
yl}benzaldehyde .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm
2.19 (s, 3 H) 3.08- 3.46 (m, 7 H) 3.59 (s, 2 H) 5.21 (t, J = 7.91
Hz, 1 H) 6.96 (dd, J = 4.98, 3.52 Hz, 1 H) 6.99- 7.04 (m, 2 H)
7.07- 7.14 (m, 2 H) 7.39- 7.46 (m, 4 H) 7.90 (d, J = 8.50 Hz, 2 H).
11 1-(4-{5-[2-(3,4- dimethylphenyl)-1-(2-
thienyl)ethyl]-1,2,4-oxadiazol- 3-yl}benzyl)azetidine-3- carboxylic
acid ##STR00019## 4-{5-[2-(3,4- dimethylphenyl)- 1-(2-
thienyl)ethyl]- 1,2,4-oxadiazol- 3- yl}benzaldehyde .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 2.10 (s, 3 H), 2.10 (s, 3H),
3.18 (s, 2 H), 3.27-3.42 (m, 2 H), 3.48 (dd, J = 13.48, 8.79 Hz, 2
H), 3.59 (s, 2 H), 5.20 (t, J = 8.06 Hz, 1 H), 6.80-6.99 (m, 3 H),
7.02 (s, 1 H), 7.10 (d, J = 3.22 Hz. 1 H), 7.33-7.50 (m, 3 H), 7.89
(d, J = 8.20 Hz, 2 H).
Biological Data
[0190] Compounds were synthesized and tested for S1P1 activity
using the GTP .gamma..sup.35S binding assay. These compounds may be
assessed for their ability to activate or block activation of the
human S1P1 receptor in cells stably expressing the S1P1
receptor.
[0191] GTP .gamma..sup.35S binding was measured in the medium
containing (mM) HEPES 25, pH 7.4, MgCl.sub.2 10, NaCl 100,
dithitothreitol 0.5, digitonin 0.003%, 0.2 nM GTP .gamma..sup.35S,
and 5 .mu.g membrane protein in a volume of 150 .mu.l. Test
compounds were included in the concentration range from 0.08 to
5,000 nM unless indicated otherwise. Membranes were incubated with
100 .mu.M 5'-adenylylimmidodiphosphate for 30 min, and subsequently
with 10 .mu.M GDP for 10 min on ice. Drug solutions and membrane
were mixed, and then reactions were initiated by adding GTP
.gamma..sup.35S and continued for 30 min at 25.degree. C. Reaction
mixtures were filtered over Whatman GF/B filters under vacuum, and
washed three times with 3 mL of ice-cold buffer (HEPES 25, pH7.4,
MgCl.sub.2 10 and NaCl 100). Filters were dried and mixed with
scintillant, and counted for .sup.35S activity using a
.beta.-counter. Agonist-induced GTP .gamma..sup.35S binding was
obtained by subtracting that in the absence of agonist. Binding
data were analyzed using a non-linear regression method. In case of
antagonist assay, the reaction mixture contained 10 nM S1P in the
presence of test antagonist at concentrations ranging from 0.08 to
5000 nM. [0192] Table 2 shows activity potency: S1P1 receptor from
GTP .gamma..sup.35S: nM, (EC.sub.50). [0193] Activity potency: S1P1
receptor from GTP .gamma..sup.35S: nM, (EC.sub.50),
TABLE-US-00002 [0193] TABLE 2 S1P1 EC.sub.50 IUPAC name (nM)
1-(4-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]- 17.08
1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
1-[4-(5-{2-(3,4-dimethylphenyl)-1-[3- 89.3
(trifluoromethyl)phenyl]ethyl}-1,2,4-oxadiazol-3-
yl)benzyl]azetidine-3-carboxylic acid
1-(4-{5-[2-(3,4-dimethylphenyl)-1-(3,5-dimethylphenyl)ethyl]- 535
1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
1-(4-{5-[1-(3-Chloro-phenyl)-2-(3,4-dimethyl-phenyl)-ethyl]- 3.77
[1,2,4]oxadiazol-3-yl}-benzyl)-azetidine-3-carboxylic acid
1-(4-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]- 1.5
1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
1-(4-{5-[1-(3-chlorophenyl)-2-cyclohexylethyl]-1,2,4- 1240
oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
1-(4-{5-[2-(3,4-dimethylphenyl)-1-(3-thienyl)ethyl]-1,2,4- 76.7
oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
1-(4-{5-[1-(5-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-
29.9 1,2,4-oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
1-(4-{5-[2-(4-methylphenyl)-1-(3-thienyl)ethyl]-1,2,4- 146
oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
1-(4-{5-[2-(3,4-dimethylphenyl)-1-(2-thienyl)ethyl]-1,2,4- 134
oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
1-(4-{5-[2-(4-methylphenyl)-1-(2-thienyl)ethyl]-1,2,4- 209
oxadiazol-3-yl}benzyl)azetidine-3-carboxylic acid
* * * * *