U.S. patent application number 15/420200 was filed with the patent office on 2017-05-18 for arylalkylamine compounds as calcium sensing receptor modulators.
The applicant listed for this patent is LUPIN ATLANIS HOLDINGS SA. Invention is credited to Vinod Dinkar Chaudhari, Rajender Kumar Kamboj, Sanjeev Anant Kulkarni, Venkata P. Palle, Ramesh Dattatraya Phadtare, Dronamraju Prameela, Ankush Gangaram Sarde, Manojkumar Ramprasad Shukla, Mahadeo Bhaskar Tryambake.
Application Number | 20170137371 15/420200 |
Document ID | / |
Family ID | 54203597 |
Filed Date | 2017-05-18 |
United States Patent
Application |
20170137371 |
Kind Code |
A1 |
Shukla; Manojkumar Ramprasad ;
et al. |
May 18, 2017 |
ARYLALKYLAMINE COMPOUNDS AS CALCIUM SENSING RECEPTOR MODULATORS
Abstract
The present invention provides arylalkylamine compounds as
calcium sensing receptor modulators (CaSR). In particular, the
compounds described herein are useful for treating, managing,
and/or lessening the severity of diseases, disorders, syndromes
and/or conditions associated with the modulation of calcium sensing
receptors (CaSR). The invention also provides herein the
pharmaceutical compositions thereof, and methods for treating,
managing, and/or lessening the severity of diseases, disorders,
syndromes and/or conditions associated with the modulation of CaSR.
The invention also relates to process for the preparation of the
compounds of the invention. (Formula I) ##STR00001##
Inventors: |
Shukla; Manojkumar Ramprasad;
(Pune, IN) ; Chaudhari; Vinod Dinkar; (Pune,
IN) ; Sarde; Ankush Gangaram; (Pune, IN) ;
Phadtare; Ramesh Dattatraya; (Pune, IN) ; Tryambake;
Mahadeo Bhaskar; (Pune, IN) ; Prameela;
Dronamraju; (Pune, IN) ; Kulkarni; Sanjeev Anant;
(Pune, IN) ; Kamboj; Rajender Kumar; (Pune,
IN) ; Palle; Venkata P.; (Pune, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LUPIN ATLANIS HOLDINGS SA |
Zug |
|
CH |
|
|
Family ID: |
54203597 |
Appl. No.: |
15/420200 |
Filed: |
January 31, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14952252 |
Nov 25, 2015 |
9598371 |
|
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15420200 |
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14422373 |
Feb 19, 2015 |
9227919 |
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PCT/IB2013/056840 |
Aug 23, 2013 |
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14952252 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 227/02 20130101;
A61P 9/00 20180101; A61P 1/00 20180101; A61P 19/00 20180101; A61P
43/00 20180101; A61P 5/14 20180101; C07C 229/46 20130101; A61P 5/18
20180101; A61P 13/12 20180101; C07C 2602/10 20170501; A61P 3/14
20180101; C07C 303/26 20130101; C07C 229/38 20130101; A61P 1/04
20180101; A61P 1/12 20180101; C07D 215/12 20130101 |
International
Class: |
C07C 229/38 20060101
C07C229/38; C07C 229/46 20060101 C07C229/46; C07D 215/12 20060101
C07D215/12; C07C 227/02 20060101 C07C227/02 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 27, 2012 |
IN |
988/KOL/2012 |
Sep 10, 2012 |
IN |
1031/KOL/2012 |
Claims
1. A compound having the Formula (I): ##STR00111## wherein, W is CH
or N; R.sub.1, which may be same or different at each occurrence,
is independently selected from halogen, nitro, cyano, substituted
or unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted cycloalkyl, --C(O)OR.sub.5,
--(CR.sub.aR.sub.b).sub.r--C(O)OR.sub.S, --O--C(O)OR.sub.5,
--O(CR.sub.aR.sub.b),--C(O)OR.sub.5, --NR.sub.6R.sub.7,
--C(O)R.sub.8, --C(O)NR.sub.6R.sub.7,
--NR.sub.6C(O)R.sub.8,--S(O).sub.0-2R.sub.5,
--S(O).sub.2NR.sub.6R.sub.7, and --NR.sub.6S(O).sub.2R.sub.8;
R.sub.2 is substituted or unsubstituted aryl; R.sub.3 is
substituted or unsubstituted alkyl; R.sub.4, which may be same or
different at each occurrence, is independently selected from
halogen, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl, --OR.sub.S, --NR.sub.6R.sub.7,
--C(O)R.sub.8, --C(O)NR.sub.6R.sub.7, --NR.sub.6C(O)R.sub.8,
--S(O).sub.0-2R.sub.5, --S(O).sub.2NR.sub.6R.sub.7, and
--NR.sub.5S(O).sub.2R.sub.8; X is selected from a bond,
--(CR.sub.aR.sub.b),-, --O--, --NR.sub.7--, --O(CR.sub.aR.sub.b),-,
--C(O)NR.sub.7-, --C(O)NR.sub.7(CR.sub.aR.sub.b).sub.r--,
--(CR.sub.aR.sub.b).sub.rcycloalkylene-, cycloalkylene,
cycloalkylene-(CR.sub.aR.sub.b).sub.r--, and --O-cycloalkylene;
R.sub.a and R.sub.b, which may be same or different at each
occurrence, are independently selected from hydrogen, halogen,
hydroxy, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl and substituted or unsubstituted
cycloalkyl; or R.sub.a and R.sub.b, together with the carbon atom
to which they are attached, may form a substituted or unsubstituted
3 to 7 membered saturated carbocyclic ring; Z is --OR.sub.5 or
--NR.sub.6R.sub.7; R.sub.5, which may be same or different at each
occurrence, is independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted aryl; R.sub.6 and R.sub.7, which may
be same or different at each occurrence, are independently selected
from hydrogen, substituted or unsubstituted alkyl,
--(CR.sub.aR.sub.b),--C(O)OR.sub.5, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkylalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
arylalkyl, substituted or unsubstituted heteroaryl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted
heterocyclyl, and substituted or unsubstituted heterocyclylalkyl;
or R.sub.6 and R.sub.7, together with the nitrogen atom to which
they are attached, may form a substituted or unsubstituted,
saturated or unsaturated 3 to 10 membered cyclic ring, wherein the
unsaturated cyclic ring may have one or two double bonds; at each
occurrence, R.sub.8 is substituted or unsubstituted alkyl or
substituted or unsubstituted aryl; `n` is an integer ranging from 0
to 3, both inclusive; `p` is an integer ranging from 0 to 3, both
inclusive; `q` is an integer ranging from 0 to 3, both inclusive;
and `r` is an integer ranging from 1 to 3, both inclusive; or a
pharmaceutically acceptable salt thereof.
2. The compound of claim 1 having the Formula (II): ##STR00112##
wherein, R.sub.1, R.sub.4, X, Z, `p` and `q` are as defined in
Formula (I); R, which may be same or different at each occurrence,
is independently selected from halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted alkoxy; and `t` is an integer ranging
from 0 to 3, both inclusive; or its pharmaceutically acceptable
salt thereof.
3. The compound of claim 1 having the Formula (III): ##STR00113##
wherein, R.sub.1, R.sub.4, X, Z, `p` and `q` are as defined in
Formula (I); R, which may be same or different at each occurrence,
is independently selected from halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted alkoxy; and T is an integer ranging
from 0 to 3, both inclusive; or its pharmaceutically acceptable
salt thereof.
4. The compound of claim 1 having the Formula (IV): ##STR00114##
wherein, R.sub.1, R.sub.4, X, Z, `p` and `q` are as defined in
Formula (I); R, which may be same or different at each occurrence,
is independently selected from halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted alkoxy; and T is an integer ranging
from 0 to 3, both inclusive; or its pharmaceutically acceptable
salt thereof.
5. The compound of claim 1 having the Formula (V): ##STR00115##
wherein, R.sub.1, R.sub.4, X, Z, `p` and `q` are as defined in
Formula (I); R, which may be same or different at each occurrence,
is independently selected from halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted alkoxy; and `t` is an integer ranging
from 0 to 3, both inclusive; or its pharmaceutically acceptable
salt thereof.
6. The compound of claim 1 wherein R.sub.2 is substituted or
unsubstituted phenyl or substituted or unsubstituted naphthyl;
wherein the substituents are selected from halogen, hydroxy,
substituted or unsubstituted alkyl, substituted or unsubstituted
haloalkyl, and substituted or unsubstituted alkoxy.
7. The compound of claim 1, wherein X is bond,
--(CR.sub.aR.sub.b).sub.r--, --O--, --O(CR.sub.aR.sub.b).sub.r--,
--C(O)NR.sub.7--, --C(O)NR.sub.7(CR.sub.aR.sub.b).sub.r--,
--(CR.sub.aR.sub.b).sub.rcycloalkylene-, cycloalkylene,
cycloalkylene-(CR.sub.aR.sub.b).sub.r--, and --O-cycloalkylene;
wherein R.sub.a and R.sub.b are independently a hydrogen or
substituted or unsubstituted alkyl; R.sub.7 is a hydrogen or
substituted or unsubstituted alkyl; and `r` is 1 or 2.
8. The compound of claim 1, wherein Z is --OR.sub.5 where R.sub.5
is hydrogen or substituted or unsubstituted alkyl.
9. The compound of claim 1 having the Formula (VI) ##STR00116##
wherein, W is CH or N; R.sub.1 is hydrogen or halogen; R.sub.2 is
substituted or unsubstituted aryl wherein the aryl is substituted
or unsubstituted phenyl or substituted or unsubstituted naphthyl
and the substituents are halogen or substituted or unsubstituted
alkoxy; R.sub.4 is halogen, or substituted or unsubstituted alkyl;
X is selected from a bond, --CR.sub.aR.sub.b--,
--O--CR.sub.aR.sub.b--, and --C(O)NR.sub.7--CR.sub.aR.sub.b--;
R.sub.a and R.sub.b are hydrogen, substituted or unsubstituted
alkyl; Z is --OR.sub.5 or --NR.sub.6R.sub.7; R.sub.5 is hydrogen or
substituted or unsubstituted alkyl; R.sub.6 and R.sub.7 are
independently a hydrogen or substituted or unsubstituted alkyl `n`
is an integer ranging from 0 to 3, both inclusive; and `q` is an
integer ranging from 0 to 2, both inclusive; or a pharmaceutically
acceptable salt thereof.
10. The compound of claim 1, which is selected from:
3-(3-((((R)-1-(Naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetrahydronaph-
thalen-1-yl)benzoic acid hydrochloride,
2-Fluoro-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetra-
hydro naphthalen-1-yl)benzoic acid hydrochloride,
2-Methyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetra-
hydro naphthalen-1-yl)benzoic acid hydrochloride,
3-Methyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetra-
hydro naphthalen-1-yl) benzoic acid hydrochloride,
2,6-Dimethyl-3-(34((R)-1-(naphthalen-1-yl) ethyl)amino)
methyl)-1,2,3,4-tetrahydro naphthalen-1-yl)benzoic acid
hydrochloride,
2-Methyl-443S)-3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-te-
trahydro naphthalen-1-yl)benzoic acid hydrochloride,
4-Methyl-343S)-3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-te-
trahydronaphthalen-1-yl)benzoic acid hydrochloride,
5-((3S)-3-((((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4--
tetrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride,
3-((3S)-3-((((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4--
tetrahydro naphthalen-1-yl)-2,6-dimethylbenzoic acid hydrochloride,
5-((3S)-3-((((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride,
2-Methyl-5-(3(((R)-1-(naphthalen-1-yl)ethyl)amino)-1,2,3,4-tetrahydronaph-
thalen-1-yl)benzoic acid hydrochloride,
2-Methyl-4-(3(((R)-1-(naphthalen-1-yl)ethyl)amino)-1,2,3,4-tetrahydronaph-
thalen-1-yl)benzoic acid hydrochloride,
5-((3S)-3-(2-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4--
tetrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride,
2-Methyl-543S)-3-(24(R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-tet-
rahydro naphthalen-1-yl)benzoic acid hydrochloride,
5-((3S)-3-(3-(((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride,
2-Methyl-543R)-3-(34(R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-te-
trahydro naphthalen-1-yl)benzoic acid hydrochloride,
5-((3S)-3-(3-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)propyl)-1,2,3,-
4-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride,
2-Methyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-3,4-dihydroqu-
inolin-1 (2H)-yl)benzoic acid hydrochloride,
4-Methyl-3-(3-((((R)-1-(naphthalen-1-yl) ethyl) amino)
methyl)-3,4-dihydro quinolin-1(2H)-yl) benzoic acid hydrochloride,
2,6-Dimethyl-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)
amino)methyl)-3,4-dihydro quinolin-1(2H)-yl)benzoic acid
hydrochloride, 5-(3-((((R)-1-(4-Fluoro naphthalen-1-yl) ethyl)
amino) methyl)-3,4-dihydro quinolin-1(2H)-yl)-2-methylbenzoic acid
hydrochloride, 5-(3-((((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)
methyl)-3,4-dihydroquinolin -1 (2H)-yl)-2-methylbenzoic acid
hydrochloride, 2-Methyl-4-(3-((((R)-1-(naphthalen-1-yl)ethyl)
amino)methyl)-3,4-dihydro quinolin-1(2H)-yl)benzoic acid
hydrochloride, 5-(6-Fluoro-3-((((R)-1-(naphthalen-1-yl)ethyl)
amino)methyl)-3,4-dihydro quinolin-1(2H)-yl)-2-methyl benzoic acid
hydrochloride, 2-Methyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)
amino) ethyl)-3,4-dihydro quinolin-1(2H)-yl)benzoic acid
hydrochloride,
2-(2-methyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-3,4-dihyd-
roquinolin-1(2H)-yl)phenoxy)acetic acid hydrochloride,
2-Methyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-3,4-dihydro
quinolin-1(2H)-yl)benzoic acid hydrochloride,
3-(3-(3-(((R)-1-(4-Fluoro naphthalen-1-yl)ethyl)
amino)propyl)-3,4-dihydro quinolin-1(2H)-yl)-2-methyl benzoic acid
hydrochloride, 2-(2-Methyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)
amino) propyl)-3,4-dihydro quinolin-1(2H)-yl)phenoxy) acetic acid
hydrochloride,
2-Methyl-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetra-
hydro naphthalen-1-yl)benzoic acid hydrochloride,
2,4-Dimethyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)benzoic acid hydrochloride,
2-Fluoro-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetra-
hydro naphthalen-1-yl)benzoic acid hydrochloride,
4-Fluoro-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetra-
hydro naphthalen-1-yl)benzoic acid hydrochloride,
2,3-Dimethyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)benzoic acid hydrochloride,
2-(3-(3-((((R)-1-(Naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetrahydron-
aphthalen-1-yl)benzamido)acetic acid hydrochloride,
2-Fluoro-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-tetr-
ahydro naphthalen-1-yl)benzoic acid hydrochloride,
3-Methyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-tetr-
ahydro naphthalen-1-yl)benzoic acid hydrochloride,
2,6-Dimethyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)
ethyl)-1,2,3,4-tetrahydro naphthalen-1-yl)benzoic acid
hydrochloride,
2-Methyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-tetr-
ahydro naphthalen-1-yl)benzoic acid hydrochloride,
4-Methyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-tetr-
ahydro naphthalen-1-yl)benzoic acid hydrochloride,
2,4-Dimethyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4--
tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
2-Methyl-4-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-tetr-
ahydro naphthalen-1-yl)benzoic acid hydrochloride,
5-(3-(2-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)ethyl)-1,2,3,4-tetr-
ahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride,
2,3-Dimethyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4--
tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
3-Methyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-tet-
rahydro naphthalen-1-yl)benzoic acid hydrochloride,
2,6-Dimethyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
2-Methyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-tet-
rahydro naphthalen-1-yl)benzoic acid hydrochloride,
4-Methyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-tet-
rahydro naphthalen-1-yl)benzoic acid hydrochloride,
2,4-Dimethyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
2-Methyl-4-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-tet-
rahydro naphthalen-1-yl)benzoic acid hydrochloride,
5-(3-(3-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)propyl)-1,2,3,4-tet-
rahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride and
2,3-Dimethyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride or a
pharmaceutically acceptable salt thereof, their stereoisomers
thereof.
11. A pharmaceutical composition comprising one or more compounds
of Formula (I) according to claim 1, and one or more
pharmaceutically acceptable excipients.
12. Use of a compound for the manufacture of a medicament for
treating, managing and/or lessening the diseases or disorders,
syndromes or conditions associated with the modulation of calcium
sensing receptor (CaSR) in a subject in need thereof wherein the
method comprises administering to the subject a therapeutically
effective amount of a compound of claim 1 or a pharmaceutically
acceptable salt thereof.
13. The use of claim 12, wherein the diseases, disorders, syndromes
or conditions associated with the modulation of calcium sensing
receptor (CaSR) are selected from hyperparathyroidism, chronic
renal failure (with or without dialysis), chronic kidney disease
(with or without dialysis) and their complications.
14. The use of claim 13, wherein hyperparathyroidism is primary
hyperparathyroidism, secondary hyperparathyroidism or tertiary
hyperparathyroidism.
15. The use of claim 12, wherein the diseases, disorders, syndromes
or conditions associated with the modulation of CaSR receptors are
selected from the group consisting of parathyroid adenoma,
parathyroid hyperplasia, parathyroid carcinoma, vascular &
valvular calcification, abnormal calcium homeostasis,
hypercalcemia, abnormal phosphorous homeostasis, hypophosphatemia,
bone related diseases or complications arising due to
hyperparathyroidism, chronic kidney disease or parathyroid
carcinoma, bone loss post renal transplantation, osteitis fibrosa
cystica, adynamic bone disease, renal bone diseases, cardiovascular
complications arising due to hyperparathyroidism or chronic kidney
disease, certain malignancies in which (Ca.sup.2+), ions are
abnormally high, cardiac, renal or intestinal dysfunctions,
podocyte-related diseases, abnormal intestinal motility, diarrhea,
augmenting gastrin or gastric acid secretion to directly or
indirectly benefit in atrophic gastritis or to improve absorption
of pharmacological compounds, drugs or supplements from
gastro-intestinal tract by augmenting gastric acidity.
16. A process for the preparation of compound of Formula (Ia):
##STR00117## wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, `p`
and `q` are as defined in herein above; the process comprising the
steps: a) converting a keto group in Formula (6a, 6b, 6c) where `n`
is 1, 2, or 3, into enol-triflate using
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methane
sulfonamide in presence of potassium bis(trimethylsilyl)amide
(KHMDS) to give compound of Formula (20); ##STR00118## b) coupling
of enol-triflate of compound of Formula (20) with suitable aryl
boronic acids or aryl boronic ester in presence of a base and
tetrakis(triphenylphosphine) palladium(O) to give compound of
Formula (21); ##STR00119## c) reducing a compound of Formula (21)
using palladium on carbon (10%) to give compound of Formula (22);
##STR00120## d) deprotecting a Boc functional group using HCl in
suitable solvent to get compound of Formula (23) ##STR00121## e)
hydrolyzing an ester group of compound of Formula (23) (when Z is
-o-alkyl or O-benzyl) using base to afford corresponding acid
compound of Formula(Ia) ##STR00122##
Description
RELATED APPLICATIONS
[0001] The present application claims the benefit of priority to
Indian Provisional Patent Application Nos. 988/KOL/2012, filed on
Aug. 27, 2012 and 1031/KOL/2012 filed on Sep. 10, 2012.
FIELD OF THE INVENTION
[0002] The present invention relates to arylalkylamine compounds,
pharmaceutically acceptable salts thereof and pharmaceutical
compositions for the treatment, management, and/or lessening the
severity of diseases, disorders, syndromes or conditions associated
with the modulation of calcium sensing receptors (CaSR). The
invention also relates to method of treating, managing and/or
lessening the severity of diseases disorders, syndromes or
conditions associated with the modulation of calcium sensing
receptors (CaSR). The invention also relates to processes for the
preparation of the compounds of the invention.
BACKGROUND OF THE INVENTION
[0003] Ca.sup.2+ is known to be an intracellular second messenger,
with the molecular identification of an extracellular calcium
sensing receptor (CaSR), it has further opened the possibility that
Ca.sup.2+ might also function as a messenger outside the cells.
Information about the local changes in extracellular concentration
of Ca.sup.2+ is conveyed to the interior of many types of cells
through this unique receptor.
[0004] Calcium-sensing receptor (CaSR) is a G-protein-coupled
receptor (GPCR) that signals through the activation of
phospholipase C, increasing levels of inositol 1,4,5-triphosphate
and cytosolic calcium. The CaSR belongs to the subfamily C of the
GPCR superfamily Structurally, CaSR has an exceptionally large
amino-terminal extracellular (ECD) domain (about 600 amino acids),
a feature that is shared by all of the members of the family C
GPCRs.
[0005] In mammals, the expression of CaSR is quite ubiquitous and
its presence in the parathyroid gland plays an important role in
the secretion of parathyroid hormone (PTH). The reduction in serum
calcium leads to the secretion of PTH. Consequently, PTH secretion
leads to conservation of serum Ca.sup.2+ by increasing kidney
retention and intestinal absorption of Ca.sup.2+. This happens
indirectly through the PTH-induced synthesis of the active vitamin
D metabolite, 25-dihydroxyvitamin D. In addition, the pulsatile
action of PTH has anabolic effects on bone development and its
sustained levels can lead to catabolic effects, in which the bones
breakdown releasing Ca.sup.2+ as in the case of osteoporosis. All
these systems converge in maintenance of baseline serum Ca.sup.2+
and it involves a tight regulation between serum PTH and
extracellular calcium which is mediated by the remarkable receptor
CaSR.
[0006] In conditions such as primary and secondary
hyperparathyroidism, there is excessive secretion of parathyroid
hormone due to hyperplasia of the glands. The most common cause of
primary hyperparathyroidism (PHPT) is parathyroid adenoma resulting
from clonal mutations (.about.97%) and associated hypercalcemia. In
the case of secondary hyperparathyroidism (SHPT), it is most
commonly seen in patients with chronic renal failure. The kidneys
fail to convert enough vitamin D to its active form and also does
not adequately excrete phosphorous. Excess phosphorous further
depletes serum calcium by forming calcium phosphate (kidney stones)
leading to hypocalcemia.
[0007] Small molecules that are positive allosteric modulators
called calcimimetics modulate and improve the receptors sensitivity
to the already existing milieu of extracellular ionic calcium. This
would eventually translate in lowering plasma PTH levels thereby
improving conditions of hyperparathyroidism, calcium homeostasis
and bone metabolism. WO 2012/127388, WO 2012/120476, WO
2012/127385, WO 2012/069421, WO 2012/069419, WO 2012/069402, US
2011/0028452, WO 2010/150837, WO 2010/136037, WO 2010/042642, WO
2010/038895, WO 2009/065406, WO 2008/059854, WO 2006/123725, WO
2004/106280, WO 2004/069793, WO 2002/012181 and US 2003/0199497
applications disclose the compounds related to calcium sensing
receptors (CaSR) for the treatment of various diseases mediated by
CaSR. And also J. Med. Chem. (2006), 49, 5119-5128 discloses the
compounds related to calcium sensing receptors (CaSR).
SUMMARY OF THE INVENTION
[0008] In accordance with one aspect, the invention provides
compounds having the structure of Formula (I),
##STR00002##
[0009] wherein,
[0010] W is CH or N;
[0011] R.sub.1, which may be same or different at each occurrence,
is independently selected from halogen, nitro, cyano, substituted
or unsubstituted alkyl, substituted or unsubstituted haloalkyl,
substituted or unsubstituted cycloalkyl, --C(O)OR.sub.5,
--(CR.sub.aR.sub.b).sub.r--C(O)OR.sub.5, --O--C(O)OR.sub.5,
--O(CR.sub.aR.sub.b).sub.r-C(O)OR.sub.5, --NR.sub.6R.sub.7,
--C(O)R.sub.8, --C(O)NR.sub.6R.sub.7, --NR.sub.6C(O)R.sub.8,
--S(O).sub.0--2R.sub.5, --S(O).sub.2NR.sub.6R.sub.7, and
--NR.sub.6S(O).sub.2R.sub.8;
[0012] R.sub.2 is substituted or unsubstituted aryl;
[0013] R.sub.3 is substituted or unsubstituted alkyl;
[0014] R.sub.4, which may be same or different at each occurrence,
is independently selected from halogen, cyano, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl,
--OR.sub.5, --NR.sub.6R.sub.7, --C(O)R.sub.8,
--C(O)NR.sub.6R.sub.7, --NR.sub.6C(O)R.sub.8,
--S(O).sub.0-2R.sub.5, --S(O).sub.2NR.sub.6R.sub.7, and
--NR.sub.5S(O).sub.2R.sub.8;
[0015] X is selected from a bond, --(CR.sub.aR.sub.b).sub.r--,
--O--, --NR.sub.7--, --O(CR.sub.aR.sub.b).sub.r--,
--C(O)NR.sub.7--, --C(O)NR.sub.7(CR.sub.aR.sub.b).sub.r--,
--(CR.sub.aR.sub.b).sub.rcycloalkylene-, cycloalkylene,
cycloalkylene-(CR.sub.aR.sub.b).sub.r--, and --O-cycloalkylene;
[0016] R.sub.a and R.sub.b, which may be same or different at each
occurrence, are independently selected from hydrogen, halogen,
hydroxy, cyano, substituted or unsubstituted alkyl, substituted or
unsubstituted haloalkyl and substituted or unsubstituted
cycloalkyl; or R.sub.a and R.sub.b, together with the carbon atom
to which they are attached, may form a substituted or unsubstituted
3 to 7 membered saturated carbocyclic ring;
[0017] Z is --OR.sub.5 or --NR.sub.6R.sub.7;
[0018] R.sub.5, which may be same or different at each occurrence,
is independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted aryl;
[0019] R.sub.6 and R.sub.7, which may be same or different at each
occurrence, are independently selected from hydrogen, substituted
or unsubstituted alkyl, --(CR.sub.aR.sub.b),--C(O)OR.sub.5,
substituted or unsubstituted cycloalkyl, substituted or
unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted heterocyclyl, and
substituted or unsubstituted heterocyclylalkyl; or R.sub.6 and
R.sub.7, together with the nitrogen atom to which they are
attached, may form a substituted or unsubstituted, saturated or
unsaturated 3 to 10 membered cyclic ring, wherein the unsaturated
cyclic ring may have one or two double bonds;
[0020] at each occurrence, R.sub.8 is substituted or unsubstituted
alkyl or substituted or unsubstituted aryl;
[0021] `n` is an integer ranging from 0 to 3, both inclusive;
[0022] `p` is an integer ranging from 0 to 3, both inclusive;
[0023] `q` is an integer ranging from 0 to 3, both inclusive;
and
[0024] `r` is an integer ranging from 1 to 3, both inclusive;
[0025] or a pharmaceutically acceptable salt thereof.
[0026] According to one embodiment, there are provided compounds of
the Formula (II):
##STR00003##
[0027] or its pharmaceutically acceptable salt thereof;
[0028] wherein,
[0029] R, which may be same or different at each occurrence, is
independently selected from halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted alkoxy;
[0030] `t` is an integer ranging from 0 to 3, both inclusive;
[0031] R.sub.1, R.sub.4, X, Z, `p` and `q` are as defined in
Formula (I).
[0032] According to one embodiment, there are provided compounds of
the Formula (III):
##STR00004##
[0033] or its pharmaceutically acceptable salt thereof;
[0034] wherein,
[0035] R, which may be same or different at each occurrence, is
independently selected from hydroxy, substituted or unsubstituted
alkyl, substituted or unsubstituted haloalkyl, and substituted or
unsubstituted alkoxy;
[0036] `t` is an integer ranging from 0 to 3, both inclusive;
[0037] R.sub.1, R.sub.4, X, Z, `p` and `q` are as defined in
Formula (I).
[0038] According to one embodiment, there are provided compounds of
the Formula (IV):
##STR00005##
[0039] or its pharmaceutically acceptable salt thereof;
[0040] wherein,
[0041] R, which may be same or different at each occurrence, is
independently selected from halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted alkoxy;
[0042] `t` is an integer ranging from 0 to 3, both inclusive;
[0043] R.sub.1, R.sub.4, X, Z, `p` and `q` are as defined in
Formula (I).
[0044] According to another embodiment, there are provided
compounds of the Formula (V):
##STR00006##
[0045] or its pharmaceutically acceptable salt thereof;
[0046] wherein,
[0047] R, which may be same or different at each occurrence, is
independently selected from halogen, hydroxy, substituted or
unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted alkoxy;
[0048] `t` is an integer ranging from 0 to 3, both inclusive;
[0049] R.sub.1, R.sub.4, X, Z, `p` and `q` are as defined in
Formula (I).
[0050] It should be understood that the Formula (I), Formula (II),
Formula (III), Formula (IV), and/or Formula (V) structurally
encompasses all tautomers, stereoisomers, enantiomers and
diastereomers, including isotopes wherever applicable and
pharmaceutically acceptable salts that may be contemplated from the
chemical structure of the genera described herein.
[0051] The details of one or more embodiments of the invention set
forth in the below are illustrative in nature only and not intended
to limit to the scope of the invention. Other features, objects and
advantages of the inventions will be apparent from the description
and claims
[0052] According to one embodiment, there are provided compounds of
Formula (I) in which `n` is 0.
[0053] According to another embodiment, there are provided
compounds of Formula (I) in which `n` is 1.
[0054] According to another embodiment, there are provided
compounds of Formula (I) in which `n` is 2.
[0055] According to another embodiment, there are provided
compounds of Formula (I) in which `n` is 3.
[0056] According to another embodiment, there are provided
compounds of Formula (I), in which `q` is 0, 1 or 2.
[0057] According to another embodiment, there are provided
compounds of Formula (I), (II), (III), (IV) and/or (V) in which
R.sub.1 is selected from halogen, cyano, substituted or
unsubstituted alkyl, and substituted or unsubstituted haloalkyl;
and `p` is 0, 1 or 2.
[0058] According to another embodiment, there are provided
compounds of Formula (I) in which R.sub.2 is substituted or
unsubstituted aryl. In this embodiment R.sub.2 is substituted or
unsubstituted phenyl or substituted or unsubstituted naphthyl
wherein the substituent(s) may be one or more, same or different
and are independently selected from halogen, hydroxy, substituted
or unsubstituted alkyl, substituted or unsubstituted haloalkyl, and
substituted or unsubstituted alkoxy.
[0059] According to another embodiment, there are provided
compounds of Formula (I), (II), (III), (IV) and/or (V) in which X
is bond, --(CR.sub.aR.sub.b).sub.r--, --O --,
--O(CR.sub.aR.sub.b).sub.r, --C(O)NR.sub.7--,
--C(O)NR.sub.7(CR.sub.aR.sub.b).sub.r--,
--(CR.sub.aR.sub.b).sub.rcycloalkylene-, cycloalkylene,
cycloalkylene-(CR.sub.aR.sub.b).sub.r--, and --O-cycloalkylene;
wherein R.sub.a and R.sub.b are independently a hydrogen or
substituted or unsubstituted alkyl; R.sub.7 is a hydrogen or
substituted or unsubstituted alkyl; and `r` is 1 or 2.
[0060] According to another embodiment, there are provided
compounds of Formula (I), (II), (III), (IV) and/or (V) in which Z
is --OR.sub.5 where R.sub.5 is hydrogen or substituted or
unsubstituted alkyl.
[0061] According to another embodiment, there are provided
compounds of Formula (I), (II), (III), (IV) and/or (V) in which Z
is --NR.sub.6R.sub.7 where R.sub.6 and R.sub.7 are independently a
hydrogen or substituted or unsubstituted alkyl.
[0062] According to another embodiment, there are provided
compounds of Formula (I), (II), (III), (IV) and/or (V) in which
R.sub.4 is halogen, cyano, substituted or unsubstituted alkyl,
substituted or unsubstituted haloalkyl or --OR.sub.5 where R.sub.5
is hydrogen or substituted or unsubstituted alkyl and `q` is 0, 1
or 2.
[0063] According to another embodiment, there are provided
compounds of the Formula (V):
##STR00007##
[0064] wherein,
[0065] W is CH or N;
[0066] R.sub.1 is hydrogen or halogen;
[0067] R.sub.2 is substituted or unsubstituted aryl wherein the
aryl is substituted or unsubstituted phenyl or substituted or
unsubstituted naphthyl and the substituents are halogen or
substituted or unsubstituted alkoxy;
[0068] R.sub.4 is halogen, or substituted or unsubstituted
alkyl;
[0069] X is selected from a bond, --CR.sub.aR.sub.b--,
--O--CR.sub.aR.sub.b--, and --C(O)NR.sub.7--CR.sub.aR.sub.b--;
[0070] R.sub.a and R.sub.b are hydrogen, substituted or
unsubstituted alkyl;
[0071] Z is --OR.sub.5 or --NR.sub.6R.sub.7;
[0072] R.sub.5 is hydrogen or substituted or unsubstituted
alkyl;
[0073] R.sub.6 and R.sub.7 are independently a hydrogen or
substituted or unsubstituted alkyl `n` is an integer ranging from 0
to 3, both inclusive; and
[0074] `q` is an integer ranging from 0 to 2, both inclusive;
[0075] or a pharmaceutically acceptable salt thereof.
[0076] Below are the representative compounds, which are
illustrative in nature only and are not intended to limit to the
scope of the invention.
[0077]
3-(3-((((R)1-(Naphthalen1-yl)ethyl)amino)methyl)-1,2,3,4-tetrahydro-
naphthalen1-yl)benzoic acid hydrochloride,
[0078] 2-Fluoro-5
-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetrahydro
naphthalen-1-yl)benzoic acid hydrochloride,
[0079]
2-Methyl-5-(3-((((R)1-(naphthalen1-yl)ethyl)amino)methyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0080]
3-Methyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl) benzoic acid hydrochloride,
[0081] 2,6-Dimethyl-3-(3((R)-1-(naphthalen-1-yl) ethyl)amino)
methyl)-1,2,3,4-tetrahydro naphthalen-1-yl)benzoic acid
hydrochloride,
[0082]
2-Methyl-4-((3S)-3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0083]
4-Methyl-3-((3S)-3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0084]
5-((3S)-3-((((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid
hydrochloride,
[0085]
3-((3S)-3-((((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)-2,6-dimethylbenzoic acid
hydrochloride,
[0086]
5-((3S)-3-((((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)methyl)-1,2-
,3,4-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid
hydrochloride,
[0087]
2-Methyl-5-(3(((R)-1-(naphthalen-1-yl)ethyl)amino)-1,2,3,4-tetrahyd-
ronaphthalen-1-yl)benzoic acid hydrochloride,
[0088]
2-Methyl-4-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)-1,2,3,4-tetrahy-
dronaphthalen-1-yl)benzoic acid hydrochloride,
[0089]
5-((3S)-3-(2-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)ethyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid
hydrochloride,
[0090]
2-Methyl-5-((3S)-3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1-
,2,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0091]
5-((3S)-3-(3-(((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)propyl)-1-
,2,3,4-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid
hydrochloride,
[0092]
2-Methyl-5-((3R)-3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)--
1,2,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0093]
5-((3S)-3-(3-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)propyl)--
1,2,3,4-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid
hydrochloride,
[0094]
2-Methyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-3,4-dih-
ydroquinolin-1 (2H)-yl)benzoic acid hydrochloride,
[0095] 4-Methyl-3-(3-((((R)-1-(naphthalen-1-yl) ethyl) amino)
methyl)-3,4-dihydroquinolin-1(2H)-yl) benzoic acid
hydrochloride,
[0096] 2,6-Dimethyl-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)
amino)methyl)-3,4-dihydroquinolin-1(2H)-yl)benzoic acid
hydrochloride,
[0097] 5-(3-((((R)-1-(4-Fluoro naphthalen-1-yl) ethyl) amino)
methyl)-3,4-dihydroquinolin-1(2H)-yl)-2-methylbenzoic acid
hydrochloride,
[0098] 5-(3-((((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)
methyl)-3,4-dihydroquinolin -1 (2H)-yl)-2-methylbenzoic acid
hydrochloride,
[0099] 2-Methyl-4-(3-((((R)-1-(naphthalen-1-yl)ethyl)
amino)methyl)-3,4-dihydroquinolin-1(2H)-yl)benzoic acid
hydrochloride,
[0100] 5-(6-Fluoro-3-((((R)-1-(naphthalen-1-yl)ethyl)
amino)methyl)-3,4-dihydroquinolin-1(2H)-yl)-2-methyl benzoic acid
hydrochloride,
[0101] 2-Methyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl) amino)
ethyl)-3,4-dihydroquinolin-1(2H)-yl)benzoic acid hydrochloride,
[0102]
2-(2-methyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-3,4-
-dihydroquinolin-1(2H)-yl)phenoxy)acetic acid hydrochloride,
[0103]
2-Methyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-3,4-d-
ihydroquinolin-1(2H)-yl)benzoic acid hydrochloride,
[0104] 3-(3-(3-(((R)-1-(4-Fluoro naphthalen-1-yl)ethyl)
amino)propyl)-3,4-dihydroquinolin-1(2H)-yl)-2-methyl benzoic acid
hydrochloride,
[0105] 2-(2-Methyl-5-(3-(3 -(((R)-1-(naphthalen-1-yl)ethyl) amino)
propyl)-3,4-dihydroquinolin-1(2H)-yl)phenoxy) acetic acid
hydrochloride,
[0106]
2-Methyl-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0107]
2,4-Dimethyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2-
,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0108]
2-Fluoro-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0109]
4-Fluoro-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0110]
2,3-Dimethyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2-
,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0111]
2-(3-(3-((((R)-1-(Naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetra-
hydronaphthalen-1-yl)benzamido)acetic acid hydrochloride,
[0112]
2-Fluoro-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,-
4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0113]
3-Methyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,-
4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0114] 2,6-Dimethyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)
ethyl)-1,2,3,4-tetrahydro naphthalen-1-yl)benzoic acid
hydrochloride,
[0115]
2-Methyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,-
4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0116]
4-Methyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,-
4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0117]
2,4-Dimethyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0118]
2-Methyl-4-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,-
4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0119]
5-(3-(2-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)ethyl)-1,2,3,-
4-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid
hydrochloride,
[0120]
2,3-Dimethyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0121]
3-Methyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3-
,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0122]
2,6-Dimethyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1-
,2,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0123]
2-Methyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3-
,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0124]
4-Methyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3-
,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride,
[0125]
2,4-Dimethyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1-
,2,3,4-tetrahydro naphthalen1-yl)benzoic acid hydrochloride,
[0126]
2-Methyl-4-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3-
,4-tetrahydro naphthalen1-yl)benzoic acid hydrochloride,
[0127]
5-(3-(3-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)propyl)-1,2,3-
,4-tetrahydro naphthalen1-yl)-2-methylbenzoic acid hydrochloride
and
[0128]
2,3-Dimethyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1-
,2,3,4-tetrahydro naphthalen1-yl)benzoic acid hydrochloride
[0129] or a pharmaceutically acceptable salt thereof, or their
stereoisomers thereof.
[0130] In another aspect of the invention, there is provided a
compound of Formula (I) useful in treating, managing and/or
lessening the severity of diseases, disorders, syndromes or
conditions associated with calcium sensing receptor (CaSR)
modulators.
[0131] In another aspect, the invention provides a pharmaceutical
composition comprising at least one compound of Formula (I) and at
least one pharmaceutically acceptable excipient.
[0132] In another aspect, the invention provides a pharmaceutical
composition of compound of Formula (I) useful in treating, managing
and/or lessening the severity of the diseases disorders, syndromes
or conditions associated with calcium sensing receptor (CaSR)
modulators in a subject, in need thereof by administering to the
subject, one or more compounds described herein in a
therapeutically effective amount to cause modulation of such
receptor.
[0133] In another aspect, the invention provides a pharmaceutical
composition comprising a compound of Formula (I) or a
pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable excipient.
[0134] In another aspect, there are provided processes for the
preparation compounds of Formula (Ia):
##STR00008##
[0135] wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4, X, `p` and `q`
are as defined in herein above;
[0136] the process comprising the steps:
[0137] a) converting a keto group in Formula (6a, 6b, 6c) where `n`
is 1, 2, or 3, into enol-triflate using
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)
sulfonyl)methanesulfonamide in presence of potassium
bis(trimethylsilyl)amide (KHMDS) to give compound of Formula
(20);
##STR00009##
[0138] b) coupling of enol-triflate of compound of Formula (20)
with suitable aryl boronic acids or aryl boronic ester in presence
of a base and tetrakis(triphenylphosphine)palladium(0) to give
compound of Formula (21);
##STR00010##
[0139] c) reducing a compound of Formula (21) using palladium on
carbon (10%) to give compound of Formula (22);
##STR00011##
[0140] d) deprotecting a Boc functional group using HCl in suitable
solvent to get compound of Formula (23)
##STR00012##
[0141] e) hydrolyzing an ester group of compound of Formula (23)
(when Z is -o-alkyl or O-benzyl) using base to afford corresponding
acid compound of Formula (Ia)
##STR00013##
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0142] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below.
[0143] For purposes of interpreting the specification and claims,
the following definitions will apply and whenever appropriate,
terms used in the singular will also include the plural and vice
versa.
[0144] The terms "halogen" or "halo" means fluorine, chlorine,
bromine, or iodine.
[0145] The term "alkyl" refers to an alkane derived hydrocarbon
radical that includes solely carbon and hydrogen atoms in the
backbone, contains no unsaturation, has from one to six carbon
atoms, and is attached to the remainder of the molecule by a single
bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl),
n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl) and the like. Unless
set forth or recited to the contrary, all alkyl groups described or
claimed herein may be straight chain or branched, substituted or
unsubstituted.
[0146] The term "alkenyl" refers to a hydrocarbon radical
containing from 2 to 10 carbon atoms and including at least one
carbon-carbon double bond. Non-limiting examples of alkenyl groups
include ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. Unless set
forth or recited to the contrary, all alkenyl groups described or
claimed herein may be straight chain or branched, substituted or
unsubstituted.
[0147] The term "alkynyl" refers to a hydrocarbon radical
containing 2 to 10 carbon atoms and including at least one
carbon-carbon triple bond. Non-limiting examples of alkynyl groups
include ethynyl, propynyl, butynyl and the like. Unless set forth
or recited to the contrary, all alkynyl groups described or claimed
herein may be straight chain or branched, substituted or
unsubstituted.
[0148] The term "alkoxy" refers to an alkyl group attached via an
oxygen linkage. Non-limiting examples of such groups are methoxy,
ethoxy and propoxy and the like. Unless set forth or recited to the
contrary, all alkoxy groups described or claimed herein may be
straight chain or branched, substituted or unsubstituted.
[0149] The term "haloalkyl" refers to an alkyl group as defined
above that is substituted by one or more halogen atoms as defined
above. Preferably, the haloalkyl may be monohaloalkyl, dihaloalkyl
or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have
one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and
polyhaloalkyl groups can be substituted with two or more of the
same halogen atoms or a combination of different halogen atoms.
Preferably, a polyhaloalkyl is substituted with up to 12 halogen
atoms. Non-limiting examples of a haloalkyl include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl, dichloropropyl and the like. A
perhaloalkyl refers to an alkyl having all hydrogen atoms replaced
with halogen atoms. Unless set forth or recited to the contrary,
all haloalkyl groups described or claimed herein may be straight
chain or branched, substituted or unsubstituted.
[0150] The term "cycloalkyl" refers to a non-aromatic mono or
multicyclic ring system having 3 to 12 carbon atoms, such as
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Examples of multicyclic cycloalkyl groups include, but are not
limited to, perhydronapththyl, adamantyl and norbornyl groups,
bridged cyclic groups or spirobicyclic groups, e.g.,
spiro(4,4)non-2-yl and the like. Unless set forth or recited to the
contrary, all cycloalkyl groups described or claimed herein may be
substituted or unsubstituted.
[0151] The term "cycloalkylene" refers to a saturated divalent
cyclic hydrocarbon radical that includes solely carbon and hydrogen
atoms in the backbone. In particular, "C.sub.3-C.sub.7
cycloalkylene" means a saturated divalent cyclic hydrocarbon
radical with 3 to 7 carbon atoms e.g. cyclopropylene,
cyclobutylene, cyclopentylene, cyclohexylene and the like. Unless
set forth or recited to the contrary, all cycloalkylene groups
described or claimed herein may be substituted or
unsubstituted.
[0152] The term "cycloalkenyl" refers to a non-aromatic mono or
multicyclic ring system having 3 to 12 carbon atoms and including
at least one carbon-carbon double bond, such as cyclopentenyl,
cyclohexenyl, cycloheptenyl and the like. Unless set forth or
recited to the contrary, all cycloalkenyl groups described or
claimed herein may be substituted or unsubstituted.
[0153] The term "cycloalkylalkyl" refers to a cycloalkyl group as
defined above, directly bonded to an alkyl group as defined above,
e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, cyclohexylethyl, etc. Unless set forth or recited
to the contrary, all cycloalkylalkyl groups described or claimed
herein may be substituted or unsubstituted.
[0154] The term "aryl" refers to an aromatic radical having 6- to
14-carbon atoms, including monocyclic, bicyclic and tricyclic
aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl,
indanyl, and biphenyl and the like. Unless set forth or recited to
the contrary, all aryl groups described or claimed herein may be
substituted or unsubstituted. The term "arylalkyl" refers to an
aryl group as defined above directly bonded to an alkyl group as
defined above, e.g., --CH.sub.2C.sub.6H.sub.5 and
--C.sub.2H.sub.4C.sub.6H.sub.5. Unless set forth or recited to the
contrary, all arylalkyl groups described or claimed herein may be
substituted or unsubstituted.
[0155] A "carbocyclic ring" or "carbocycle" as used herein refers
to a 3- to 10-membered saturated or unsaturated, monocyclic, fused
bicyclic, spirocyclic or bridged polycyclic ring containing carbon
atoms, which may optionally be substituted, for example,
carbocyclic rings include but are not limited to cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone,
aryl, naphthyl, adamantyl etc. Unless set forth or recited to the
contrary, all carbocyclic groups or rings described or claimed
herein may be aromatic or non-aromatic.
[0156] A "3 to 7" membered saturated carbocyclic ring" as used
herein refers to a monocyclic non aromatic ring systems.
[0157] A "3 to 10" membered cyclic ring" as used herein refers to a
monocyclic, bicyclic, polycyclic heteroaryl or heterocyclic ring
systems.
[0158] The term "heterocyclic ring" or "heterocyclyl ring" or
"heterocyclyl", unless otherwise specified, refers to substituted
or unsubstituted non-aromatic 3- to 15-membered ring which consists
of carbon atoms and with one or more heteroatom(s) independently
selected from N, O, or S. The heterocyclic ring may be a mono-, bi-
or tricyclic ring system, which may include fused, bridged or spiro
ring systems and the nitrogen, carbon, oxygen or sulfur atoms in
the heterocyclic ring may be optionally oxidized to various
oxidation states. In addition, the nitrogen atom may be optionally
quaternized, the heterocyclic ring or heterocyclyl may optionally
contain one or more olefinic bond(s), and one or two carbon
atoms(s) in the heterocyclic ring or heterocyclyl may be
interrupted with --CF.sub.2--, --C(O)--, --S(O)--, S(O).sub.2,
--C(.dbd.N-alkyl)-, or --C(.dbd.N-cycloalkyl), etc. In addition
heterocyclic ring may also be fused with aromatic ring.
Non-limiting examples of heterocyclic rings include azetidinyl,
benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl,
isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl,
morpholinyl, oxazolinyl, oxazolidinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,
octahydroindolyl, octahydroisoindolyl, perhydroazepinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl,
phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl,
tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone
indoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran
and the like. The heterocyclic ring may be attached by any atom of
the heterocyclic ring that results in the creation of a stable
structure. Unless set forth or recited to the contrary, all
heterocyclyl groups described or claimed herein may be substituted
or unsubstituted; substituents may be on same or different ring
atom.
[0159] The term "heteroaryl" unless otherwise specified, refers to
a substituted or unsubstituted 5- to 14-membered aromatic
heterocyclic ring with one or more heteroatom(s) independently
selected from N, O, or S. The heteroaryl may be a mono-, bi- or
tricyclic ring system. The heteroaryl ring may be attached by any
atom of the heteroaryl ring that results in the creation of a
stable structure. Non-limiting examples of a heteroaryl ring
include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl,
isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl,
thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl,
benzimidazolyl, benzothienyl, carbazolyl, quinolinyl,
isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl,
pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl,
thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and
the like. Unless set forth or recited to the contrary, all
heteroaryl groups described or claimed herein may be substituted or
unsubstituted.
[0160] The term "heterocyclylalkyl" refers to a heterocyclic ring
radical directly bonded to an alkyl group. The heterocyclylalkyl
radical may be attached to the main structure at any carbon atom in
the alkyl group that results in the creation of a stable structure.
Unless set forth or recited to the contrary, all heterocyclylalkyl
groups described or claimed herein may be substituted or
unsubstituted.
[0161] The term "heteroarylalkyl" refers to a heteroaryl ring
radical directly bonded to an alkyl group. The heteroarylalkyl
radical may be attached to the main structure at any carbon atom in
the alkyl group that results in the creation of a stable structure.
Unless set forth or recited to the contrary, all heteroarylalkyl
groups described or claimed herein may be substituted or
unsubstituted.
[0162] Unless otherwise specified, the term "substituted" as used
herein refers to a group or moiety having one or more substituents
attached to the structural skeleton of the group or moiety. Such
substituents include, but are not limited to hydroxy, halogen,
carboxyl, cyano, nitro, oxo (.dbd.O), thio (.dbd.S), alkyl,
haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, heteroaryl, heterocyclic ring,
heterocyclylalkyl, heteroarylalkyl, --C(O)OR.sup.x, --C(O)R.sup.x,
-C(S)R.sup.x, --C(O)NR.sup.xR.sup.y, --NR.sup.xC(O)NR.sup.yR.sup.z,
--N(R.sup.x)S(O)R.sup.y, --N(R.sup.x)S(O).sub.2R.sup.y,
--NR.sup.xR.sup.y, --NR.sup.xC(O)R.sup.y, --NR.sup.xC(S)R.sup.y,
--NR.sup.xC(S)NR.sup.yR.sup.z, --S(O).sub.2NR.sup.xR.sup.y,
--OR.sup.x, --OC(O)R.sup.x, --OC(O)NR.sup.xR.sup.y,
--(CR.sup.xR.sup.y).sub.0-2C(O)OR.sup.x,
--(CR.sup.xR.sup.y).sub.0-2C(O)NR.sup.yR.sup.z,
--(CR.sup.xR.sup.Y).sub.0-2C(O)R.sup.y, --SR.sup.x, and
--S(O).sub.2R.sup.x; wherein each occurrence of R.sup.x, R.sup.y
and R.sup.z are independently selected from hydrogen, halogen,
alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,
cycloalkenyl, heteroaryl, heterocyclic ring, heterocyclylalkyl and
heteroarylalkyl. The aforementioned "substituted" groups cannot be
further substituted. For example, when the substituent on
"substituted alkyl" is "aryl" or "alkenyl", the aryl or alkenyl
cannot be substituted aryl or substituted alkenyl,
respectively.
[0163] The compounds of the present invention may have one or more
chiral centers. The absolute stereochemistry at each chiral center
may be `R` or `S`. The compounds of the invention include all
diastereomers and enantiomers and mixtures thereof. Unless
specifically mentioned otherwise, reference to one stereoisomer
applies to any of the possible stereoisomers. Whenever the
stereoisomeric composition is unspecified, it is to be understood
that all possible stereoisomers are included.
[0164] The term "stereoisomer" refers to a compound made up of the
same atoms bonded by the same bonds but having different
three-dimensional structures which are not interchangeable. The
three-dimensional structures are called configurations. As used
herein, the term "enantiomer" refers to two stereoisomers whose
molecules are nonsuperimposable mirror images of one another. The
term "chiral center" refers to a carbon atom to which four
different groups are attached. As used herein, the term
"diastereomers" refers to stereoisomers which are not enantiomers.
The terms "racemate" or "racemic mixture" refer to a mixture of
equal parts of enantiomers.
[0165] A "tautomer" refers to a compound that undergoes rapid
proton shifts from one atom of the compound to another atom of the
compound. Some of the compounds described herein may exist as
tautomers with different points of attachment of hydrogen. The
individual tautomers as well as mixture thereof are encompassed
with compounds of Formula (I).
[0166] The term "treating" or "treatment" of a state, disorder or
condition includes: (a) preventing or delaying the appearance of
clinical symptoms of the state, disorder or condition developing in
a subject that may be afflicted with or predisposed to the state,
disorder or condition but does not yet experience or display
clinical or subclinical symptoms of the state, disorder or
condition; (b) inhibiting the state, disorder or condition, i.e.,
arresting or reducing the development of the disease or at least
one clinical or subclinical symptom thereof; c) lessening the
severity of a disease disorder or condition or at least one of its
clinical or subclinical symptoms or (d) relieving the disease,
i.e., causing regression of the state, disorder or condition or at
least one of its clinical or subclinical symptoms.
[0167] The term "modulate" or "modulating" or "modulation" or
"modulator" refers to an increase in the amount, quality, or effect
of a particular activity or function of the receptor. By way of
illustration and not limitation, it includes agonists, partial
agonists, and allosteric modulators of calcium sensing receptor
(CaSR) of the present invention. Such modulation may be contingent
on the occurrence of a specific event, such as activation of a
signal transduction pathway.
[0168] The term "allosteric modulators of calcium-sensing
receptor", refers to the ability of a compound that binds to
calcium sensing receptors and induces a conformational change that
reduces the threshold for calcium sensing receptor activation by
the endogenous ligand Ca.sup.2+ depending on the concentration of
the compound exposed to the calcium-sensing receptor.
[0169] The term "subject" includes mammals (especially humans) and
other animals, such as domestic animals (e.g., household pets
including cats and dogs) and non-domestic animals (such as
wildlife).
[0170] A "therapeutically effective amount" means the amount of a
compound that, when administered to a subject for treating a
disease, disorder, syndrome or condition, is sufficient to cause
the effect in the subject which is the purpose of the
administration. The "therapeutically effective amount" will vary
depending on the compound, the disease and its severity and the
age, weight, physical condition and responsiveness of the subject
to be treated.
Pharmaceutically Acceptable Salts:
[0171] The compounds of the invention may form salts with acid or
base. The compounds of invention may be sufficiently basic or
acidic to form stable nontoxic acid or base salts, administration
of the compound as a pharmaceutically acceptable salt may be
appropriate. Non-limiting examples of pharmaceutically acceptable
salts are inorganic, organic acid addition salts formed by addition
of acids including hydrochloride salts. Non-limiting examples of
pharmaceutically acceptable salts are inorganic, organic base
addition salts formed by addition of bases. The compounds of the
invention may also form salts with amino acids. Pharmaceutically
acceptable salts may be obtained using standard procedures well
known in the art, for example by reacting a sufficiently basic
compound such as an amine with a suitable acid affording a
physiologically acceptable anion.
[0172] With respect to the overall compounds described by the
Formula (I), the invention extends to these stereoisomeric forms
and to mixtures thereof. To the extent prior art teaches synthesis
or separation of particular stereoisomers, the different
stereoisomeric forms of the invention may be separated from one
another by a method known in the art, or a given isomer may be
obtained by stereospecific or asymmetric synthesis or chiral HPLC
(high performance liquid chromatography. Tautomeric forms and
mixtures of compounds described herein are also contemplated.
[0173] Screening of compounds of invention for calcium sensing
receptor (CaSR) modulation activity can be achieved by using
various in vitro and in vivo protocols mentioned herein below or
methods known in the art.
Pharmaceutical Compositions
[0174] The invention relates to pharmaceutical compositions
containing the compounds of the Formula (I) disclosed herein. In
particular, pharmaceutical compositions containing a
therapeutically effective amount of at least one compound of
Formula (I) described herein and at least one pharmaceutically
acceptable excipient (such as a carrier or diluent). Preferably,
the contemplated pharmaceutical compositions include the
compound(s) described herein in an amount sufficient to modulate
calcium sensing receptor (CaSR) mediated diseases described herein
when administered to a subject.
[0175] The subjects contemplated include, for example, a living
cell and a mammal, including human mammal. The compound of the
invention may be associated with a pharmaceutically acceptable
excipient (such as a carrier or a diluent) or be diluted by a
carrier, or enclosed within a carrier which can be in the form of a
capsule, sachet, paper or other container. The pharmaceutically
acceptable excipient includes pharmaceutical agent that does not
itself induce the production of antibodies harmful to the
individual receiving the composition, and which may be administered
without undue toxicity.
[0176] Examples of suitable carriers or exciptients include, but
are not limited to, water, salt solutions, alcohols, polyethylene
glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil,
gelatin, lactose, terra alba, sucrose, dextrin, magnesium
carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc,
gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers
of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty
acid monoglycerides and diglycerides, pentaerythritol fatty acid
esters, polyoxyethylene, hydroxymethylcellulose and
polyvinylpyrrolidone.
[0177] The pharmaceutical composition may also include one or more
pharmaceutically acceptable auxiliary agents, wetting agents,
emulsifying agents, suspending agents, preserving agents, salts for
influencing osmotic pressure, buffers, sweetening agents, flavoring
agents, colorants, or any combination of the foregoing. The
pharmaceutical composition of the invention may be formulated so as
to provide quick, sustained, or delayed release of the active
ingredient after administration to the subject by employing
procedures known in the art.
[0178] The pharmaceutical compositions described herein may be
prepared by conventional techniques known in the art. For example,
the active compound can be mixed with a carrier, or diluted by a
carrier, or enclosed within a carrier, which may be in the form of
an ampoule, capsule, sachet, paper, or other container. When the
carrier serves as a diluent, it may be a solid, semi-solid, or
liquid material that acts as a vehicle, excipient, or medium for
the active compound. The active compound can be adsorbed on a
granular solid container, for example, in a sachet.
[0179] The pharmaceutical compositions may be in conventional
forms, for example, capsules, tablets, caplets, orally
disintegrating tablets, aerosols, solutions, suspensions or
products for topical application.
[0180] The route of administration may be any route which
effectively transports the active compound of the invention to the
appropriate or desired site of action. Suitable routes of
administration include, but are not limited to, oral, nasal,
pulmonary, buccal, subdermal, intradermal, transdermal, parenteral,
rectal, depot, subcutaneous, intravenous, intraurethral,
intramuscular, intranasal, ophthalmic (such as with an ophthalmic
solution) or topical (such as with a topical ointment).
[0181] Solid oral Formulations include, but are not limited to,
tablets, caplets, capsules (soft or hard gelatin), orally
disintegrating tablets, dragees (containing the active ingredient
in powder or pellet form), troches and lozenges. Tablets, dragees,
or capsules having talc and/or a carbohydrate carrier or binder or
the like are particularly suitable for oral application. Liquid
Formulations include, but are not limited to, syrups, emulsions,
suspensions, solutions, soft gelatin and sterile injectable
liquids, such as aqueous or non-aqueous liquid suspensions or
solutions. For parenteral application, particularly suitable are
injectable solutions or suspensions, preferably aqueous solutions
with the active compound dissolved in polyhydroxylated castor
oil.
[0182] The pharmaceutical preparation is preferably in unit dosage
form. In such form the preparation is subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, the package containing
discrete quantities of preparation, such as pocketed tablets,
capsules, and powders in vials or ampoules. Also, the unit dosage
form can be a capsule, tablet, caplet, cachet, or lozenge itself,
or it can be the appropriate number of any of these in packaged
form.
[0183] For administration to subject patients, the total daily dose
of the compounds of the invention depends, of course, on the mode
of administration. For example, oral administration may require a
higher total daily dose, than an intravenous (direct into blood).
The quantity of active component in a unit dose preparation may be
varied or adjusted from 0.1 mg to 10000 mg according to the potency
of the active component or mode of administration.
[0184] Suitable doses of the compounds for use in treating the
diseases and disorders described herein can be determined by those
skilled in the relevant art. Therapeutic doses are generally
identified through a dose ranging study in subject based on
preliminary evidence derived from the animal studies. Doses must be
sufficient to result in a desired therapeutic benefit without
causing unwanted side effects for the patient. For example, the
daily dosage of the CaSR modulator can range from about 0.1 to
about 30.0 mg/kg. Mode of administration, dosage forms, suitable
pharmaceutical excipients, diluents or carriers can also be well
used and adjusted by those skilled in the art. All changes and
modifications are envisioned within the scope of the invention.
Methods of Treatment
[0185] In another aspect, the invention provides compounds and
pharmaceutical compositions thereof that are useful in treating,
managing and/or lessening the severity of diseases, disorders,
syndromes or conditions modulated by calcium sensing receptor
(CaSR). The invention further provides method of treating diseases,
disorders, syndromes or conditions modulated by CaSR in a subject
in need thereof by administering to the subject a therapeutically
effective amount of a compound or a pharmaceutical composition of
the invention.
[0186] In another aspect of the invention, the methods provided are
also useful for diagnosis of conditions that can be treated by
modulating CaSR for determining if a patient will be responsible to
therapeutic agents.
[0187] In another aspect, the invention provides a method for the
treatment of diseases, disorders or conditions through modulating
CaSR. In this method, a subject in need of such treatment is
administered a therapeutically effective amount of a compound of
Formula (I) described herein.
[0188] The compound and pharmaceutical composition of the present
invention is useful to a subject in need of the treatment having a
disease, disorder, syndrome or condition characterized by one or
more of the following: (a) abnormal calcium ion homeostasis, (b) an
abnormal level of a messenger whose production or secretion is
affected by the calcium sensing receptor (CaSR) activity or (c) an
abnormal level of activity of a messenger whose function is
affected by the calcium sensing receptor activity. In one aspect,
the patient has a disease, disorder, syndrome or condition
characterized by an abnormal level of one or more calcium sensing
receptor-regulated components and the compound is active on a CaSR
of a cell including parathyroid cell, bone cells (pre-osteoclast,
osteoclast, pre-osteoblast, osteoblast), juxtaglomerular kidney
cell, kidney messengial cell, glomerular kidney cell, proximal
tubule kidney cell, distal tubule kidney cell, cell of the thick
ascending limb of Henle's loop and/or collecting duct, Para
follicular cell in the thyroid (C-cell), intestinal cell, platelet,
vascular smooth muscle cell, gastrointestinal tract cell, pituitary
cell or hypothalamic cell. The messenger of the calcium sensing
receptor is Calcium.
[0189] The compound of Formula (I), being modulators of CaSR, is
potentially useful in treating, managing and/or lessening the
severity, morbidity/mortality or complications of diseases,
disorders, syndromes or conditions include but are not limited to
primary hyperparathyroidism, secondary hyperparathyroidism,
tertiary hyperparathyroidism, chronic renal failure (with or
without dialysis), chronic kidney disease (with or without
dialysis) parathyroid adenoma, parathyroid hyperplasia, parathyroid
carcinoma, vascular & valvular calcification, abnormal calcium
homeostasis such as hypercalcemia, abnormal phosphorous homeostasis
such as hypophosphatemia, bone related diseases or complications
arising due to hyperparathyroidism, chronic kidney disease or
parathyroid carcinoma, bone loss post renal transplantation,
osteitis fibrosa cystica, adynamic bone disease, renal bone
diseases, cardiovascular complications arising due to
hyperparathyroidism or chronic kidney disease, certain malignancies
in which (Ca.sup.2+).sub.e, ions are abnormally high, cardiac,
renal or intestinal dysfunctions, podocyte-related diseases,
abnormal intestinal motility, diarrhea, augmenting gastrin or
gastric acid secretion to directly or indirectly benefit in
atrophic gastritis or to improve absorption of pharmacological
compounds, drugs or supplements from gastro-intestinal tract by
augmenting gastric acidity.
[0190] Primary hyperparathyroidism, is a disorder of one or more of
the parathyroid glands, resulting from a hyper function of the
parathyroid glands themselves (acquired sporadically or familial)
resulting in PTH over secretion which could be due to single or
double adenoma, hyperplasia, multigland disease or rarely,
carcinoma of the parathyroid glands. As a result, the blood calcium
rises to a level that is higher than normal (called hypercalcemia).
This elevated calcium level can cause many short-term and long-term
complications.
[0191] Secondary hyperparathyroidism occurs when a decrease in
circulating levels of Ca.sup.2+ level stimulates PTH secretion. One
cause of secondary hyperparathyroidism is chronic renal
insufficiency (also referred to as chronic kidney disease or CKD),
such as that in renal polycystic disease or chronic pyelonephritis,
or chronic renal failure, such as that in hemodialysis patients
(also referred to as end stage renal disease or ESRD). Excess PTH
may be produced in response to hypocalcemia resulting from low
calcium intake, GI disorders, renal insufficiency, vitamin D
deficiency, magnesium deficiency and renal hypercalciuria. Tertiary
hyperparathyroidism may occur after a long period of secondary
hyperparathyroidism and hypercalcemia.
[0192] In one aspect, the compound and composition of the present
invention can be used in treating, managing and/or lessening the
vascular or valvular calcification in a subject. In one aspect,
administration of the compound of the invention retards or reverses
the formation, growth or deposition of extracellular matrix
hydroxyapatite crystal deposits. In another aspect of the
invention, administration of the compound of the invention prevents
the formation, growth or deposition of extracellular matrix
hydroxyapatite crystal deposits. In one aspect, the compounds of
the invention may also be used to prevent or treat atherosclerotic
calcification and medial calcification and other conditions
characterized by vascular calcification. In one aspect, vascular
calcification may be associated with chronic renal insufficiency or
end-stage renal disease or excess calcium or PTH itself. In another
aspect, vascular calcification may be associated with pre- or
post-dialysis or uremia. In a further aspect, vascular
calcification may be associated with diabetes mellitus I or II. In
yet another aspect, vascular calcification may be associated with a
cardiovascular disorder.
[0193] Abnormal calcium homeostasis such as hyperparathyroidism
related diseases can be characterized as described in standard
medical textbooks, but not limited to Harrison's Principles of
Internal Medicine. The compound and composition of the present
invention can be used, in particular, to participate in a reduction
of the serum levels in the parathyroid hormone known as PTH: these
products could thus be useful for the treatment of diseases such as
hyperparathyroidism.
[0194] Abnormal phosphorous homeostasis such as hypophosphatemia
can be characterized as described in standard medical textbooks,
but not limited to Harrison's Principles of Internal Medicine. The
compound and composition of the present invention can be used, in
particular, to participate in a reduction of the serum levels in
the parathyroid hormone known as PTH: these products could thus be
useful for the treatment of diseases such as hypophosphatemia.
[0195] In one aspect, the podocyte diseases or disorders treated by
methods of the present invention stem from the perturbations in one
or more functions of podocytes. These functions of podocytes
include: (i) a size barrier to protein; (ii) charge barrier to
protein; (iii) maintenance of the capillary loop shape; (iv)
counteracting the intraglomerular pressure; (v) synthesis and
maintenance of the glomerular basement membrane (GMB); (vi)
production and secretion of vascular endothelial growth factor
(VEGF) required for the glomerular endothelial cell (GEN)
integrity. Such disorders or diseases include but are not limited
to loss of podocytes (podocytopenia), podocyte mutation, an
increase in foot process width, or a decrease in slit diaphragm
length. In one aspect, the podocyte-related disease or disorder can
be effacement or a diminution of podocyte density. In one aspect,
the diminution of podocyte density could be due to a decrease in a
podocyte number, for example, due to apoptosis, detachment, lack of
proliferation, DNA damage or hypertrophy.
[0196] In one aspect, the podocyte-related disease or disorder can
be due to a podocyte injury. In one aspect, the podocyte injury can
be due to mechanical stress such as high blood pressure,
hypertension, or ischemia, lack of oxygen supply, a toxic
substance, an endocrinologic disorder, an infection, a contrast
agent, a mechanical trauma, a cytotoxic agent (cis-platinum,
adriamycin, puromycin), calcineurin inhibitors, an inflammation
(e.g., due to an infection, a trauma, anoxia, obstruction, or
ischemia), radiation, an infection (e.g., bacterial, fungal, or
viral), a dysfunction of the immune system (e.g., an autoimmune
disease, a systemic disease, or IgA nephropathy), a genetic
disorder, a medication (e.g., anti-bacterial agent, anti-viral
agent, anti-fungal agent, immunosuppressive agent,
anti-inflammatory agent, analgestic or anticancer agent), an organ
failure, an organ transplantation, or uropathy. In one aspect,
ischemia can be sickle-cell anemia, thrombosis, transplantation,
obstruction, shock or blood loss. In one aspect, the genetic
disorders may include congenital nephritic syndrome of the Finnish
type, the fetal membranous nephropathy or mutations in
podocyte-specific proteins.
[0197] In one aspect, the compounds of the invention can be used
for treating abnormal intestinal motilities disorders such as
diarrhea. The methods of the invention comprise administering to
the subject a therapeutically effective amount of the compounds of
Formula I. In a further aspect, diarrhea can be exudative diarrhea,
i.e., resulting from direct damage to the small or large intestinal
mucosa. This type of diarrhea can be caused by infectious or
inflammatory disorders of the gut. In one aspect, exudative
diarrhea can be associated with gastrointestinal or abdominal
surgery, chemotherapy, radiation treatment, inflammation or toxic
traumatic injury. In another aspect, diarrhea can be secretary,
means that there is an increase in the active secretion, or there
is an inhibition of absorption. There is little to no structural
damage. The most common cause of this type of diarrhea is cholera.
In another aspect, diarrhea can be due to acceleration of
intestinal transit (rapid transit diarrhea). Such condition may
occur because the rapid flow-through impairs the ability of the gut
to absorb water.
[0198] The compound and composition of the present invention can be
used, in particular, to participate in an augmenting gastrin or
gastric acid secretion to directly or indirectly benefit certain
medical conditions such as but not limited to atrophic gastritis or
to improve absorption of pharmacological compounds, drugs or
supplements from gastro-intestinal tract by augmenting gastric
acidity.
[0199] All of the patent, patent application and non-patent
publications referred to in this specification are incorporated
herein by reference in their entireties.
General Methods of Preparation
[0200] The compounds described herein may be prepared by techniques
known in the art. In addition, the compounds described herein may
be prepared by following the reaction sequence as depicted in
Scheme-1 to Scheme-5. Further, in the following schemes, where
specific bases, acids, reagents, solvents, coupling agents, etc.,
are mentioned, it is understood that other bases, acids, reagents,
solvents, coupling agents etc., known in the art may also be used
and are therefore included within the scope of the present
invention. Variations in reaction conditions, for example,
temperature and/or duration of the reaction, which may be used as
known in the art, are also within the scope of the present
invention. All the isomers of the compounds described in these
schemes, unless otherwise specified, are also encompassed within
the scope of this invention.
##STR00014##
[0201] The compound of Formula (6a), Formula (6b) and Formula (6c),
where R.sub.1, R.sub.2, R.sub.3 and `p` are as defined herein
above, can be prepared by following the procedure as depicted in
Scheme-1 a, Scheme-1b and Scheme-1c respectively.
[0202] The acid compound of Formula (1) and amine compound of
Formula (2) undergoes amide coupling reaction using suitable amide
coupling reagents to give compound of Formula (3) (Tetrahedron:
Asymmetry 14, 2003, 3689; Journal of Medicinal Chemistry 25, 1982,
535). This compound of Formula (3) undergoes reduction using
suitable reducing agents to give compound of Formula (4) which
further undergoes N-Boc protection to give compound of Formula (5).
The hydroxy group in Formula (5) is oxidized to give compound of
Formula (6a).
##STR00015##
[0203] Similarly, the compound of Formula (6b) can be prepared from
compound of Formula (1) thus, first the acid group in Formula (1)
is converted to corresponding ester of Formula (7) then the keto
group in the ring is protected using ethylene glycol to give
compound of Formula (8). This ester compound of Formula (8) is
converted to aldehyde of Formula (9) which further condensed with
appropriate Wittig salt of Chloromethyl methyl ether,
(CH.sub.3OCH.sub.2Cl) and base like potassium t-butoxide to give
compound of Formula (10). This further undergoes acid hydrolysis to
give compound of Formula (11). This compound of Formula (11)
undergoes reductive amination with compound of Formula (2) using
suitable reductive amination reagents to give compound of Formula
(12) which further protected as N-Boc to give compound of Formula
(6b).
##STR00016##
[0204] Also, the compound of Formula (6c), can be prepared from the
aldehyde compound of Formula (9) which further condensed with
appropriate Wittig reagent (ethyl
2-(triphenylphosphoranylidene)acetate) to give compound of Formula
(13). The alkenyl ester compound of Formula (13) is first undergoes
hydrogenation followed by ester hydrolysis and deprotection to give
compound of Formula (14). This acid compound of Formula (14) is
coupled with amine of Formula (2) in presence of suitable amide
coupling reagents to give compound of Formula (15) after that it is
transformed to give compound of Formula (16) by reduction followed
by N-protection with (Boc).sub.2O to give compound of Formula (17),
which was further oxidized to give compound of Formula (6c).
##STR00017## ##STR00018##
[0205] The compound of Formula (23), (Ia), (Ib), (Ic) and (Id),
where X, Z, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.a,
R.sub.b, `p` and `q` are defined herein above can be prepared as
depicted in Scheme-2.
[0206] The keto group in Formula (6a, 6b, 6c) where `n` is 1, 2 or
3 respectively, are converted into enol triflate in presence of
suitable reaction conditions to give compound of Formula (20). This
enol triflate compound of Formula (20) undergoes coupling reaction
with suitable aryl boronic acids or aryl boronic ester to give
compound of Formula (21). Further, compound of Formula (21) is
converted to compound Formula (23) by reduction of double bond
followed by N-Boc deprotection reactions. If the compound of
Formula (23) is an ester where Z is O-alkyl, O-benzyl etc., it
further undergoes ester hydrolysis to give corresponding acid
compound of Formula (Ia). The acid compound of Formula (Ia) is
converted to corresponding amide in presence of suitable amide
coupling reagents to give an amide-ester of Formula (Ib) (where Ak
is alkyl) which further undergoes hydrolysis to give acid compound
of Formula (Ic). Further hydrochloride salt(s) of compound of
Formula (Ia) and Formula (Ic) can be prepared by using hydrochloric
acid in suitable solvent.
##STR00019## ##STR00020##
[0207] The compound of Formula (Id) and (Ie) where X, Z, R.sub.1,
R.sub.2, R.sub.3, R.sub.4, `p` and `q` are defined herein above is
prepared by following the procedure as depicted in Scheme-3.
Compound of Formula (24) is reacted with compound of Formula (2) by
reductive amination, to obtain compound of Formula (25) which is
BOC protected to afford the compound of Formula (26). The compound
of Formula (26) is oxidized with suitable oxidizing agent like
KMnO.sub.4, to get compound of Formula (27) which is treated with
reagent of formula (27a) to get the O-triflate derivative of
Formula (28). The compound of Formula (28) is reacted with
arylboronic acid or aryl boranic ester to give compound of Formula
(29). The compound of Formula (29) is hydrogenated with suitable
reducing aent to get compound of Formula (30). The compound of
Formula (30) is BOC deprotected to get compound of Formula (Id) (if
Z is O-alkyl or O-benzyl) it further undergoes hydrolysis to give
corresponding acid of Formula (Ie). Further hydrochloride salt(s)
of compound of Formula (Ie) can be prepared by using hydrochloric
acid in suitable solvent.
##STR00021##
[0208] The compound of Formula (35a) is prepared by following the
procedure as depicted in Scheme-4a, thus starting from commercially
available 3-quinolinecarboxylic acid (31) is reacted with
SOCl.sub.2 in presence of alcohol to give corresponding ester
Formula (32) which undergoes reduction with NaBH.sub.3CN to give
compound of Formula (33) (rahedron: Asymmetry 2010, vol. 21,18,2307
-2313). The compound of Formula (33) is reacted with amine of
Formula (2) in presence of trimethyl aluminium to obtain compound
of Formula (34). This compound of Formula (34) undergoes reduction
using suitable reducing agents to give compound of Formula
(35a).
##STR00022##
[0209] The compound of Formula (35b) is prepared from Formula (33)
thus, amine compound of Formula (33) is protected with BOC
anhydride in solvent like acetonitrile, DMF, DCM etc. to give
corresponding BOC protected Formula (36). Compound of Formula (36)
is reduced to give aldehyde of Formula (37). The compound of
Formula (37) undergoes Wittig reaction followed by hydrolysis with
dilute hydrochloric acid to afford compound of Formula (38). The
compound of Formula (38) undergoes reductive amination with amine
of Formula (2) to give compound of Formula (39). Compound of
Formula (39) is BOC-deprotected with methanolic hydrochloric acid
to afford compound of Formula (35b).
##STR00023##
[0210] Similarly, the compound of Formula (35c) is prepared from
Formula (37) which undergoes Wittig reaction with Formula (37a) to
give corresponding alkenes of Formula (40). Compound of Formula
(40) is reduced to give ester compound of Formula (41) which
further carried-out ester hydrolysis to give acid compound of
Formula (42) using suitable base such as NaOH, LiOH, etc. The
compound of Formula (42) reacting with amine of Formula (2) using
suitable reagents such as CDI to give compound of Formula (43). The
compound of Formula (43) undergoes reduction using suitable
reducing agents to give compound of Formula (35c).
##STR00024##
[0211] The compound of Formula (If), (Ig), (Ih) and (Ii), where X,
Z, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.a, R.sub.b,
`p` `q`, and `r` are defined herein above, can be prepared by
following the procedure as depicted in Scheme-5. This compounds of
Formula (35a, 35b, 35c) undergoes carbon-nitrogen (C--N) coupling
reaction with Formula (b) where L' is leaving group by following
the methods known in the art for example Buchwald coupling reaction
using suitable reagents known in the art, is carried out by using
suitable base for example TEA, DIPEA or K.sub.2CO.sub.3 etc., and
in suitable solvent for example toluene, DME etc., to give compound
of Formula (If). If the compound of Formula (If) is an ester where
Z is O-alkyl, O-benzyl etc., it further undergoes hydrolysis by
using suitable base such as NaOH, LiOH, KOH etc., followed by
hydrochloride salt preparation using hydrochloric acid to give
corresponding acid of Formula (Ig) which further converted to amide
of Formula (Ih) by reacting with suitable amines with suitable
amide coupling agents. Further, if these compounds of Formula (Ih)
is an esters then it can further hydrolyzed to give corresponding
acid compound Formula (Ii) using suitable base such as NaOH, LiOH,
KOH etc., followed by hydrochloride salt preparation using
hydrochloric acid.
Experimental
[0212] The invention is further illustrated by the following
examples which are provided merely to be exemplary of the invention
and do not limit the scope of the invention. The examples set forth
below demonstrate the synthetic procedures for the preparation of
the representative compounds. Certain modifications and equivalents
will be apparent to those skilled in the art and are intended to be
included within the scope of the invention. Unless otherwise
stated, work-up implies the following operations: distribution of
the reaction mixture between the organic and aqueous phase,
separation of layers, drying the organic layer over sodium sulfate,
filtration and evaporation of the organic solvent. Purification,
unless otherwise mentioned, implies purification by silica gel
chromatographic techniques, generally using ethyl acetate/petroleum
ether mixture of a suitable polarity as the mobile phase.
INTERMEDIATES
Intermediate-1
32-(((tert-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyflamino)methyl)-3,4--
dihydro naphthalen-l-yl trifluoromethanesulfonate
##STR00025##
[0213] Step-1:
N-((R)-1-(Naphthalen-1-yl)ethyl)-4-oxo-1,2,3,4-tetrahydro
naphthalene-2-carboxamide
[0214] To a mixture of
4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (4.6 g, 24.19
mmol) (Tetrahedron: Asymmetry 14, 2003, 3689; Journal of Medicinal
Chemistry 25, 1982, 535), in DMF (20 mL), CDI (3.92 g, 24.19 mmol)
was added. The reaction mixture was stirred at room temperature
(RT) for 2 h. Then (R)-1-(naphthalen1-yl)ethanamine (5.40 g, 31.5
mmol) was added and the reaction mixture was stirred at RT
overnight. After completion of reaction, ice was added to the
reaction mixture, solid precipitated out was filtered on Buchner
funnel, washed with DM water (50 mL) and dried to get crude
compound. Compound was further purified by flash chromatography
(biotage) using eluent 15% ethyl acetate: hexane to yield the title
compound (8 g, 96%); m/z 344.
Step-2:
3-((((R)1-(Naphthalen1-yl)ethyl)amino)methyl)-1,2,3,4-tetrahydro
naphthalen-1 -ol
[0215] Step-1 intermediate (300 mg, 0.874 mmol) was added to a
suspension of LAH (166 mg, 4.37 mmol) in dioxane (10 mL) at
0.degree. C. The reaction mixture was stirred for 30 minutes at
25.degree. C. then heated to 100.degree. C. and further maintained
for 12 h. The mixture was allowed to RT, further cooled to
0.degree. C. and slowly quenched with ethyl acetate (2 mL) followed
by water (2 mL). Reaction mixture was extracted with ethyl acetate
(30 mL), washed with brine solution (20 mL) and dried over
Na.sub.2SO.sub.4 and concentrated to get crude compound which was
used as it is in next reaction; m/z 332.1.
[0216] Step-3: tert-Butyl ((4-hydro xy-1,2,3,4
-tetrahydronaphthalen-2-yl)methyl)((R)-1-(n
aphthalen-1-yl)ethyl)carbamate
[0217] To a mixture of Step-2 intermediate (290 mg, 0.875 mmol) and
triethylamine (TEA) (0.305 mL, 2.187 mmol) in acetonitrile (10 mL),
Boc.sub.2O (0.244 mL, 1.050 mmol) was added at 25.degree. C. The
reaction mixture was heated to 55.degree. C. and further maintained
for 12 h. To this reaction mixture, water was added (15 mL) and
extracted with ethyl acetate (2.times.15 mL). The organic phase was
washed with brine solution (10 mL), dried over Na.sub.2SO.sub.4 and
filtered. The clear organic phase was evaporated in vacuo to get
crude compound. This crude compound was used as it is in next
reaction. m/z 431.79.
[0218] Step-4: tert-Butyl
((R)-1-(naphthalen-1-yl)ethyl)((4-oxo-1,2,3,4-tetrahydro
naphthalen-2-yl)methyl)carbamate
[0219] To a stirred solution of Step-3 intermediate (270 mg, 0.626
mmol) dichloromethane (DCM) (20 mL), pyridinium chlorochromate (142
mg, 0.657 mmol) was added and stirred for 1 h at 25.degree. C. The
reaction mixture was filtered through celite bed and concentrated
to get crude compound. This crude compound was purified by column
chromatography (Biotage) using eluent (1:9, ethyl acetate:
n-hexane) to get the title compound (210 mg). m/z 430.48.
[0220] Step-5:
3-(((tert-Butoxycarbonyl)((R)-1-(naphthalen-1-ethyl)amino)methyl)-3,4-dih-
ydronaphthalen-1-yl trifluoromethanesulfonate
[0221] Solid Potassium bis(trimethylsilyl)amide (KHMDS) (121 mg,
0.605 mmol) is added to a solution of step-4 intermediate (200 mg,
0.466 mmol) in tetrahydrofuran (THF) (10 ml) at -78.degree. C.
Reaction mixture was stirred for 30 minutes and solid
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)
sulfonyl)methanesulfonamide (233 mg, 0.652 mmol) was added at
-78.degree. C. under nitrogen atmosphere and further stirred for 2
h at -78.degree. C. Then the reaction mixture was quenched with
water (5 mL), extracted with diethylether (2.times.25 mL), dried
over Na.sub.2SO.sub.4 and concentrated to get crude compound. This
crude compound was further purified by flash chromatography
(Biotage) using eluent hexane/Ethyl acetate 90:10 to get the title
compound (210 mg, 80%); m/z-Boc 461.9
Intermediate -2
(R)-3-(((tert-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-3-
,4-dihydronaphthalen-l-yl trifluoromethanesulfonate
##STR00026##
[0223] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-5 of Intermediate-1 by
using (R)-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid and
(R)-1-(naphthalen-1-yl)ethanamine.
Intermediate -3
(R)-3-(((tert-Butoxycarbonyl)((R)-1-(4-fluoro-3-ethoxyphenyl)ethyDamino)me-
thyl)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate
##STR00027##
[0225] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-5 of Intermediate-1 by
using (R)-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid and
(R)-1-(4-fluoro-3-methoxyphenyl)ethanamine; m/z-Boc 460.7.
Intermediate -4
(R)-3-(((tert-Butoxycarbonyl)((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)m-
ethyl)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate
##STR00028##
[0227] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-5 of Intermediate-lby
using (R)-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid and
(R)-1-(4-Fluoronaphthalen-1-yl)ethanamine; m/z-Boc 480.93.
Intermediate -5
3-((tert-Butoxycarbonyl)((R)-1-(naphthalen1-yl)ethyl)amino)-3,4-dihydro
naphthalen1-yl-trifluoromethanesulfonate
##STR00029##
[0228] Step-1:
N-((R)-1-(Naphthalen1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine
[0229] To a stirred solution of (R)-1-(naphthalen-1-yl)ethanamine
(4.77 ml, 29.5 mmol) in methanol (50 mL) was added
3,4-dihydronaphthalen-2(1H)-one (4.80 g, 32.8 mmol) at 0.degree. C.
Acetic acid (2.349 mL, 41.0 mmol) was added and the reaction was
stirred for 5 min. After that the reaction was warmed to RT and
further stirred for 20 minutes. Again reaction was cooled to
0.degree. C. and sodium cyanoborohydride (3.09 g, 49.2 mmol) was
added stirred overnight at RT. After completion of reaction,
NaHCO.sub.3 solution (20 mL) and water (50 mL) were added and the
mixture was extracted with ethyl acetate (50 mL.times.2). The
extract was washed with saturated brine, dried over anhydrous
Na.sub.2SO.sub.4 and evaporated under reduced pressure to get the
crude compound. This was used directly in the next reaction (11.1
g, 36.8 mmol); m/z 302.65.
[0230] Step-2:
tert-Butyl((R)-1-(naphthalen-1-yl)ethyl)(1,2,3,4-tetrahydronaphthalen-2-y-
l) carbamate
[0231] To a stirred solution of Step-1 intermediate (11.1 g, 36.8
mmol) in DCM (40 mL) was added triphosgene (8.12 g, 27.4 mmol) at
0.degree. C. The reaction was allowed to RT and stirred for 2 h.
Reaction mixture was then diluted with DCM (100 mL) and washed with
water (100 mL), dried over sodium sulphate and concentrated to get
crude compound. To this crude, triethylamine (20.35 ml, 146 mmol),
DIPEA (0.496 ml, 2.85 mmol) t-butanol (34.8 ml, 365 mmol) were
added, heated to reflux and further maintained for 6 hours. The
mixture was allowed to RT, t-Butanol was evaporated, reaction
mixture was diluted with water (25 mL) and the resulting mixture
was extracted with ethyl acetate (25 mL). The organic extract was
washed with saturated brine solution (10 mL). The organic phase was
dried (Na.sub.2SO.sub.4), filtered and the solvent evaporated in
vacuo to get 15 g of crude compound. This crude compound was
further purified by flash chromatography (biotage) using eluent 20%
ethyl acetate in hexane to get the title compound (4.2 g, 28.7%
yield); m/z 402.0.
[0232] Step-3: tert-Butyl ((R)
-1-(naphthalen-1-yl)ethyl)(4-oxo-1,2,3,4-tetrahydro
naphthalen-2-yl)carbamate
[0233] To a mixture of Step-2 intermediate (4.2 g, 10.46 mmol) in
acetone (40 mL) and water (20. mL), MgSO.sub.4 (3.02 g, 25.1 mmol)
was added at RT. The reaction mixture was cooled to 0.degree. C. To
this cooled solution, KMnO.sub.4 (3.31 g, 20.92 mmol) was added in
portions wise while maintaining at 0.degree. C. The reaction was
then warmed to RT and stirred overnight. The crude was filtered
through Buckner funnel with a filter paper. The solid residue was
washed repeatedly with dichloromethane (3 times) and the collective
organic layer was combined and evaporated. The residue was then
dissolved in ethyl acetate, and was treated with saturated sodium
sulphite solution. The organic layer was separated and washed with
saturated brine solution, dried over Na.sub.2SO.sub.4 and
concentrated to get 5.4 g of crude compound. This crude compound
was purified by flash chromatography (Biotage) using eluent 7%
ethyl acetate: hexane to get the title compound (1 g, 23.01%
yield); m/z 315.7.
[0234] Step-4: 3-((tert-Butoxycarbonyl) ((R)
-1-(naphthalen-1-yl)ethyl)amino)-3,4-dihydro naphthalen-1-yl
trifluoromethanesulfonate
[0235] Solid KHMDS (0.624 g, 3.13 mmol) was added to a solution of
Step-3 intermediate (1.0 g, 2.407 mmol) in tetrahydrofuran (20 mL)
at -78.degree. C. Reaction mixture was stirred for 30 min and solid
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)
sulfonyl)methanesulfonamide (1.204 g, 3.37 mmol) was added at
-78.degree. C. under nitrogen atmosphere and stirred for 2 h at the
same temperature. After that the reaction mixture was quenched with
H.sub.2O, extracted with diethyl ether, dried over Na.sub.2SO.sub.4
and concentrated to get crude compound. This crude compound was
purified by flash chromatography (Biotage) using eluent
hexane/ethyl acetate 95:5 to get the title compound (500 mg, 37.9%
yield).
Intermediate -6
(S)-3-(2-((tert-Butoxycarbonyl)((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino-
)ethyl)-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate
##STR00030##
[0236] Step-1: (R)-Methyl
4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate
[0237] To the stirred solution of
(R)-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (5.0 g,
26.3 mmol), K.sub.2CO.sub.3 (10.90 g, 79 mmol) and methyl iodide
(6.58 ml, 105 mmol) was added in DMF (50 mL) and stirred for
overnight at 25.degree. C. Water was added (130 mL) and extracted
with ethyl acetate (2.times.30 mL). The organic phase was washed
with aq. Sodium bicarbonate solution (2.times.20 mL), dried over
Na.sub.2SO.sub.4 and filtered. The clear organic phase was
evaporated in vacuo to get title compound (4.5 g) m/z 204.09.
[0238] Step-2: (R)-Methyl 3', 4'-dihydro-2'H-spiro
[[1,3]dioxolane-2,1'-naphthalene]-3'-carboxylate
[0239] To a stirred solution of (R)-methyl
4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (4.5 g, 22.03
mmol) in benzene (40 mL) , ethane-1,2-diol (3.69 mL, 66.1 mmol) and
a catalytic amount of p-toluenesulfonic acid was added. The
reaction mixture was heated to reflux temperature and further
maintained for 20 hours. Then, reaction mixture was allowed to RT,
concentrated under vacuum to yield 12 g of crude compound. This
crude material was purified by flash chromatography (Biotage) using
7% ethyl acetate in hexane to give title compound (4.7 g) m/z
248.6.
Step-3: (R)-3',4'-Dihydro-2'H-spiro
[[1,3]dioxolane-2,1'-naphthalene]-3'-carbaldehyde
[0240] To a stirred solution of (R)-methyl
3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-naphthalene]-3'-carboxylate
(4.7 g, 18.93 mmol) in toluene (50 mL) and CH.sub.2Cl.sub.2 (12.50
mL) to these solution of DIBAL-H (Diisobutylaluminum hydride)
(22.72 mL, 22.72 mmol) was added drop-wise at -78.degree. C. under
argon, and the mixture was stirred for 2 h at this temperature.
[0241] Reaction mixture was quenched with aqueous NH.sub.4C1
solution at -78.degree. C. and allowed to RT, filtered through
celite, diluted with water (25 mL) and extracted with DCM
(2.times.25 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated to get the title compound (4.1 g) as an oily mass.
Step-4: (R)-3'-(2-Methoxyvinyl)-3',4'-dihydro-2'H-spiro
[[1,3]dioxolane-2,1'-naphthalene]
[0242] To a stirred solution of
(methoxymethylene)triphenylphosphorane (6.74 g, 21.99 mmol) in
tetrahydrofuran (30 mL) was added drop-wise a solution of potassium
tert-butoxide (3.08 g, 27.5 mmol) in THF at -30.degree. C. under
argon, and the mixture was stirred for 30 min. Then a solution of
(R)-3',4'-dihydro-2'H-spiro
[[1,3]dioxolane-2,1'-naphthalene]-3'-carbaldehyde (4.0 g, 18.33
mmol) in THF was added drop-wise and reaction was stirred for 1 h
at -30.degree. C. Reaction was monitored by TLC. Reaction mixture
quenched with water at -30.degree. C. and allowed to RT, diluted
with water (25 mL) and extracted with ethyl acetate (2.times.50
mL), dried over Na.sub.2SO.sub.4, filtered and concentrated to give
crude product (8 g). The crude compound was purified with silica
gel flash column chromatography (Biotage) to give
(R)-3'-(2-methoxyvinyl)-3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-napht-
halene] (3.5 g, 14.21 mmol, 78% yield) as colourless liquid; m/z
246.6.
Step-5:
(S)-2-(4-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetaldehyde
[0243] To a stirred solution of
(R)-3'-(2-methoxyvinyl)-3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-napht-
halene] (step-4) (3.5 g, 14.21 mmol) in tetrahydrofuran (20 mL) was
added HCl (2.159 mL, 71.1 mmol) at 25.degree. C. and reaction was
stirred for 16 h. Reaction was monitored by TLC. After completion
solvent was evaporated at reduced pressure. Crude obtained was
purified by column chromatography (Biotage) using eluent 30% ethyl
acetate/hexane to give
(S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetaldehyde (1.8 g,
9.56 mmol, 67.3% yield) as colourless sticky compound; GCMS
188.10.
Step-6:
(S)-3-(2-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)ethyl)-3,4-d-
ihydronaphthalen-1(2H)-one
[0244] To a stirred solution of
(R)-1-(4-fluoronaphthalen-1-yl)ethanamine (1.206 g, 6.38 mmol) in
methanol (5 mL) was added
(S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetaldehyde (1.2 g,
6.38 mmol) at 0.degree. C. Acetic acid (0.365 mL, 6.38 mmol) was
added and reaction was stirred for 5 min. Reaction was warmed to RT
and stirred for 20 min. Again reaction was cooled to 0.degree. C.
Sodium cyanoborohydride (0.401 g, 6.38 mmol) was added to the
reaction mixture and stirred for overnight (16 h).To the reaction
solution were added NaHCO.sub.3 solution (5 mL) and water (10 mL)
and the mixture was extracted with ethyl acetate (20 mL.times.2).
The extract was washed with saturated brine solution, dried over
anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to
get crude title compound (2.0 g, 5.53 mmol, 87% yield).
Step-7: tert-Butyl ((R) -1-(4
-fluoronaphthalen1-yl)ethyl)(2-((S)-4-oxo-1,2,3,4-tetrahydronaphthalen-2--
yl)ethyl)carb amate
[0245] To a mixture of step-6 intermediate (2 g, 5.53 mmol) and
triethylamine (0.727 mL, 5.53 mmol) in acetonitrile (20 mL),
Boc-anhydride (2.54 mL, 11.07 mmol) was added at 25.degree. C. to
the reaction mixture. The reaction was stirred for overnight 15
hrs. To the reaction mixture was added water (20 mL) and the
resulting mixture was extracted with ethyl acetate (50 mL). The
organic extract was washed with saturated brine solution (30 mL).
The organic phase was dried with Na.sub.2SO.sub.4, filtered and the
solvent evaporated in vacuo to get crude compound. Compound was
purified on flash chromatography (biotage) using eluent 10% ethyl
acetate in hexane to give title compound (1.9 g, 74.4% yield) as
sticky compound; m/z-B oc 362.1.
Step-8: (S)-3-(2-((tert-Butoxycarbonyl)
((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)
ethyl)-3,4-dihydronaphthalen-1-yl trifluoro methane sulfonate
[0246] KHMDS (5.88 ml, 5.35 mmol) was added to a solution of
step-7, intermediate (1.9 g, 4.12 mmol) in tetrahydrofuran (30 mL)
at -78.degree. C. Reaction mixture was stirred for 60 min and
solution of 1,1,1 -trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)
methanesulfonamide (2.059 g, 5.76 mmol) in THF was added at
-78.degree. C. under nitrogen and stirred for 3 h at -78.degree. C.
Reaction was monitored by TLC. It was quenched with H.sub.2O,
extracted with diethyl ether and dried with Na.sub.2SO.sub.4 and
concentrated. Compound was purified by flash chromatography
(Biotage) using eluent hexane/ethyl acetate 90:10 to give title
compound (1.2 g, 49.1% yield); m/z 615.7 (M+Na).
Intermediate -7
(S)-3-(2-((tert-Butoxycarbonyl)
((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-3,4-dihydro
naphthalen-1-yl trifluoromethanesulfonate
##STR00031##
[0248] The title compound was prepared by following the similar
procedures as described in Step-1 to Step-8 of Intermediate-6 by
using (S)-2-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetaldehyde
and (R)-1-(naphthalen-1-yl)ethanamine.
Intermediate -8
(R)-3-(3-((tert-Butoxycarbonyl)
((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)propyl)-3,4-dihydronaphthalen-
-1-yl trifluoromethanesulfonate
##STR00032##
[0249] Step-1: (R)-Methyl
4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate
[0250] To the stirred solution of
(R)-4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (5.0 g,
26.3 mmol), K.sub.2CO.sub.3 (10.90 g, 79 mmol) and methyl iodide
(6.58 mL, 105 mmol) was added in DMF (50 mL) and stirred for
overnight at 25.degree. C. Water was added (130 mL) and extracted
with ethyl acetate (2.times.30 mL). The organic phase was washed
with aq. Sodium bicarbonate solution (2.times.20 mL), dried over
Na.sub.2SO.sub.4 and filtered. The clear organic phase was
evaporated in vacuo to get pure title compound (4.5 g) m/z
204.09.
Step-2: (R)-Methyl
3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-naphthalene]-3'-carboxylate
[0251] To the stirred solution of (R)-methyl
4-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (4.5 g, 22.03
mmol) in benzene (40 mL) , ethane-1,2-diol (3.69 mL, 66.1 mmol) and
a catalytic amount of p-toluenesulfonic acid was added. The
reaction mixture was heated to reflux temperature and further
maintained for 20 hours. After 20 hours, the reaction mixture was
allowed to RT, concentrated under vacuum to yield 12 g of crude
compound. Crude material was purified by flash chromatography
(Biotage) using 7% ethyl acetate: hexane get title compound (4.7 g)
m/z 248.6.
Step-3: (R)-3',4'-Dihydro-2'H-spiro
[[1,3]dioxolane-2,1'-naphthalene]-3'-carbaldehyde
[0252] To a stirred solution of (R)-methyl
3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-naphthalene]-3'-carboxylate
(4.7 g, 18.93 mmol) in toluene (50 mL) and DCM (12.50 mL) to these
solution of DIBAL-H (22.72 mL, 22.72 mmol) was added drop-wise at
-78.degree. C. under argon, and the mixture was stirred for 2 h at
this temperature. Reaction mixture was quenched with aqueous
NH.sub.4Cl solution at -78.degree. C. and allowed to RT, filtered
through celite, diluted with water (25 mL) and extracted with DCM
(2.times.25 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated to get the title compound (4.1 g) as an oil.
Step-4: (R)-Ethyl
3-(3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-naphthalen]-3'-yl)acrylate
[0253] To the stirred solution of (R)-3',4'-dihydro-2'H-spiro
[[1,3]dioxolane-2,1'-naphthalene]-3'-carbaldehyde (4.1 g, 18.79
mmol) in DCM (10 mL), ethyl 2-(triphenyl phosphoranylidene)acetate
(7.85 g, 22.54 mmol) was added and reaction mixture was stirred at
RT for 16 h. After completion of reaction, reaction mixture was
concentrated under vacuum to get 5.5 g of crude compound. This
crude compound was further purified by flash chromatography
(Biotage) using eluent hexane/ethyl acetate 80:20 to get the title
compound (2.5 g, 46.2% yield); m/z 288.34
Step-5: (R)-Ethyl
3-(3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-naphthalen]-3'-yl)propanoa-
te
[0254] To a stirred solution of Pd/C (0.535 g, 0.251 mmol) in ethyl
acetate (25 mL), (R)-ethyl
3-(3',4'-dihydro-2'H-spiro[[1,3]dioxolane-2,1'-naphthalen]-3'-yl)acrylate
(2.5 g, 8.67 mmol) was added under nitrogen. Reaction mixture was
stirred for 2 h under hydrogen balloon. After completion of
reaction, reaction mixture was filtered through celite,
concentrated to get the crude compound. This crude compound was
used directly in next reaction (2.3 g, 91%); m/z 290.7
Step-6: (R)-3-(4-Oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoic
acid
[0255] To a stirred solution of (R)-ethyl
3-(3',4'-dihydro-2'H-spiro
[[1,3]dioxolane-2,1'-naphthalen]-3'-yl)propanoate (2.3 g, 7.92
mmol) in THF (10 mL) and water (1 mL) in round bottom flask. LiOH
(1.328 g, 55.4 mmol) was added and reaction mixture was stirred at
25.degree. C. for 2 h. Reaction mixture was concentrated and
acidified with dilute HC1, stirred for 1 h at RT. Extracted with
ethyl acetate (2.times.30 mL), dried over sodium sulphate,
concentrated to get crude title compound (1.6 g, 93%); m/z
262.7
Step-7:
N-((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)-3-((S)-4-oxo-1,2,3,4-tetr-
ahydro naphthalen-2-yl)propanamide
[0256] To the stirred solution of
(R)-3-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoic acid (0.8
g, 3.67 mmol) (Crude) in dry DMF (15 mL), CDI (0.713 g, 4.40 mmol)
was added. The reaction mixture was stirred at RT for 0.5 h. Then
(R)-1-(4-fluoronaphthalen-1-yl)ethanamine (0.832 g, 4.40 mmol) was
added and the reaction mixture was stirred at RT for 2 h. After
completion of reaction ice was added to reaction mixture, solid
precipitated out was filtered through Buchner funnel to get title
compound (830 mg, 58.1%); m/z 390.54. Crude was taken without
purification for next reaction.
Step-8:
(3R)-3-(3-(((R)1-(4-Fluoronaphthalen-1-yl)ethyl)amino)propyl)-1,2,-
3,4-tetrahydro naphthalen-1-ol
[0257] N-((R)1-(4-Fluoronaphthalen1-yl)ethyl)-3-((R)-4-oxo-1,2
,3,4-tetrahydronaphthalen-2-yl)propanamide (830 mg, 2.131 mmol) was
added to a suspension of LAH (162 mg, 4.26 mmol) in dioxane (15 mL)
at 0.degree. C. The reaction mixture was stirred for 30 minutes at
25.degree. C. and heated at 100.degree. C. and further maintained
for 12 h. The mixture was allowed to RT, cooled to 0.degree. C. and
slowly quenched with ethyl acetate (5 mL) followed by water (5 mL).
Reaction mixture was extracted with ethyl acetate (30 mL), washed
with brine solution (20 mL) and dried over Na.sub.2SO.sub.4 and
concentrated to get crude compound which was used as it is in next
reaction; m/z 378.6.
Step-9: tert-Butyl
((R)-1-(4-fluoronaphthalen-1-yl)ethyl)(3-((2R)-4-hydroxy-1,2,3,4-tetrahyd-
ronaphthalen-2-yl)propyl)carbamate
[0258] To a mixture of
(3R)-3-(3-(((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-te-
trahydronaphthalen-1-ol (800 mg, 2.119 mmol) and TEA (0.738 mL,
5.30 mmol) in acetonitrile (10 mL), Boc.sub.2O (0.590 mL, 2.54
mmol) was added at 25.degree. C. The reaction mixture was heated to
55.degree. C. and further maintained for 12 h. To this reaction
mixture, water was added (15 mL) and extracted with ethyl acetate
(2.times.15 mL). The organic phase was washed with brine solution
(10 mL), dried over Na.sub.2SO.sub.4 and filtered. The clear
organic phase was evaporated in vacuo to get crude compound. This
crude compound was used as it is in next reaction. (886 mg, 88%
yield).
Step-10: tert-Butyl
((R)-1-(4-fluoronaphthalen1-yl)ethyl)(3-((R)-4-oxo-1,2,3,4-tetrahydronaph-
thalen-2-yl)propyl)carbamate
[0259] To a stirred solution of tert-Butyl
((R)-1-(4-fluoronaphthalen-1-yl)ethyl)(3-((2R)-4-hydroxy-1,2,3,4-tetrahyd-
ronaphthalen-2-yl)propyl)carbamate (886 mg, 1.855 mmol) DCM (8 mL),
PCC (304 mg, 2.226 mmol) was added at 0.degree. C. and stirred for
1 h at 25.degree. C. The reaction mixture was filtered through
celite bed and the filtrate concentrated to get the crude compound.
This crude compound was purified by column chromatography (Biotage)
using eluent (1:9, ethyl acetate: n-hexane) to get the title
compound (500 mg). m/z 476.42.
Step-11:
(R)-3-(3-((tert-Butoxycarbonyl)((R)-1-(4-fluoronaphthalen-1-yl)et-
hyl) amino) propyl)-3,4-dihydronaphthalen-1-yl
trifluoromethanesulfonate
[0260] The Step-11 compound was prepared by following the similar
procedure as described in step-8 of Intermediate-6; m/z 607.2.
Intermediate -9
(S)-3-(3-((tert-Butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-
-3,4-dihydronaphthalen-1-yl trifluoromethanesulfonate
##STR00033##
[0262] The title compound was prepared by following the similar
procedure as described in step-7 of Intermediate-7 followed by
step-8 and step-10 of Intermediate-8 in sequential manner by using
(S)-3-(4-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoic acid and
(R)-1-(naphthalen-1-yl)ethanamine; m/z 590.58.
Intermediate-10
(R)-3-(3-((tert-Butoxycarbonyl)((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)
amino)propyl)-3,4-dihydronaphthalen1-yl
trifluoromethanesulfonate
##STR00034##
[0264] The title compound was prepared by following the similar
procedure as described in step-7 of Intermediate-7 followed by
step-8 and step-10 of Intermediate-8 in sequential manner by using
(R)-3-(4-oxo-1,2,3,4-tetrahydro naphthalen-2-yl)propanoic acid and
(R)-1-(4-fluoro-3-methoxyphenyl)ethanamine.
Intermediate -11
Methyl quinoline-3-carboxylate
##STR00035##
[0266] The solution of quinoline-3-carboxylic acid (3 g, 17.32
mmol) in methanol (30 mL) was cooled on ice bath at 0.degree.
C.Then thionyl chloride (1.264 mL, 17.32 mmol) was added and the
reaction mixture was heated to 80.degree. C. and maintained
overnight. Reaction was monitored by TLC. After completion of
reaction methanol was evaporated under reduced pressure and the
resultant residue was basified with saturated sodium bicarbonate to
make pH (7 to 8) to get white solid which was filtered and dried to
get methyl quinoline-3-carboxylate (3.2 g, yield-99%) as a white
solid; m/z-187.3.
Intermediate -12
Methyl 1,2,3,4-tetrahydroquinoline-3-caroxylate
##STR00036##
[0268] To a solution of Intermediate-11 (3 g, 16.03 mmol) in MeOH
(100 mL), sodium cyanoborohydride (5.04 g, 80 mmol) and then a
small amount of bromocresol green (pH indicator) was added. 4M HCl
solution in dioxane (5 mL.times.3) in 30 min interval was added
drop-wise into reaction mixture to make pH acidic (4 to 5), till
reaction mixture maintained a yellow color then reaction mixture
was stirred at RT for 16 h. Reaction was monitored by TLC/LCMS.
After completion of reaction, the reaction mixture was quenched
with sodium bicarbonate and extracted with ethyl acetate
(20.times.3 mL). The combined organic layer was dried and
concentrated under reduced pressure. The crude compound was
purified by flash chromatography by using (20% ethyl acetate in
hexane) to get methyl 1,2,3,4-tetrahydroquinoline-3-carboxylate
(1.5 g, yield 49%) as yellow color oily mass; m/z-191.7
Intermediate-13a, 13b
N--((R)-1-(Naphthalen-1-yl)ethyl)-1,2,3,4-tetrahydroquinoline-3-carboxamid-
e
##STR00037##
[0270] A solution of (R)-1-(naphthalen1-yl)ethanamine (25.07 g, 146
mmol) and trimethyl aluminium (54.9 mL, 110 mmol) in toluene (250
mL) was heated at 55.degree. C. for 45 min. To this reaction
mixture Intermediate-12 (14 g, 73.2 mmol) was added at 55.degree.
C. and the reaction mixture was further heated to 110.degree. C.
and maintained for 20 h. The progress of reaction was monitored by
TLC. The reaction mixture was cooled to 0.degree. C. and quenched
with dilute HCl. After basified with saturated Na.sub.2CO.sub.3,
product extracted with ethyl acetate (100 mL.times.2). The organic
layer was washed with water (2.times.50 mL) followed by brine
solution (50 mL). The organic layers were combined, dried over
sodium sulfate and concentrated. Crude product was purified.
Further isomers were separated by flash chromatography (25% ethyl
acetate/hexane) to get Intermediate-13a (8 g) and Intermediate-13b
(4 g); m/z-353 as Na.sup.+l.
Intermediate-14a, 14b
(1R)-1-(Naphthalen-1-yl)-N-((1,2,3,4-tetrahydroquinolin-3-yl)methyl)
ethanamine
##STR00038##
[0272] To a solution of Intermediate-13a (2.3 g, 6.96 mmol) in THF
(20 mL) was cooled to 0.degree. C. then added borane-methyl sulfide
complex (1.74 mL, 17.40 mmol) at the same temperature. The reaction
mixture was heated to 70.degree. C. and maintained for 7 h. The
progress of reaction was monitored by TLC, after completion of
reaction the reaction mixture was cooled to 0.degree. C. and added
1:1 dilute HCl solution very slowly (10 mL). The reaction mixture
was heated to 90.degree. C. and maintained for 1 h. Tetrahydrofuran
was distilled off under vacuum, residue was cooled to 0.degree. C.
and basified with 2M NaOH solution [pH=10] and extracted in ethyl
acetate (50 mL.times.2). The combined organic layer was washed with
water (2.times.25 mL) followed by brine solution (25 mL). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
evaporated the solvent under reduced pressure to get the title
compound (2 g, 90% yield) at as yellow-brown oily mass; m/z-317.1
Similarly Intermediate-14b was also prepared by using
Intermediate-13b from above method.
Intermediate -15
Methyl 6-fluoroquinoline-3-carboxylate
##STR00039##
[0274] To a solution of 5-fluoro-2-nitrobenzaldehyde (5 g, 29.6
mmol), methyl3,3-dimethoxy propanoate (10.95 g, 73.9 mmol) in
ethanol (100 mL). Tin Chloride (22.43 g, 118 mmol) was slowly added
in above solution .The reaction mixture was heated to 90.degree. C.
for 4 h. Reaction progress was monitored by TLC. After completion
of reaction ethanol was evaporated under reduced pressure and the
resultant residue was basified with saturated sodium bicarbonate.
The resulting emulsion was filtered through celite, rinsed well
with ethyl acetate. The remaining aqueous layer was extracted with
ethyl acetate and the combined organic layers were washed with
brine, dried over sodium sulfate and concentrated. The residue was
purified by flash chromatography (30% ethyl acetate/hexanes) to get
desired compound. (3.1 g, 51.1% yield); m/z-206.76.
Intermediate -16
(1R)-N-((6-Fluoro-1,2,3,4-tetrahydroquinolin-3-yl)methyl)-1-(naphthalen-1--
yl) ethanamine
##STR00040##
[0276] The title compound was prepared in three steps:
[0277] Step: 1--Intermediate-15 was carried-out reduction with
sodium cyanoborohydride by following the similar procedure as
described in Intermediate-12;
[0278] Step: 2--Condensation of Step-1 intermediate with
(R)-1-(naphthalen-1-yl)ethanamine by following the similar
procedure as described in Intermediate-13a,13b
[0279] Step: 3--Reduction of Step-2 Intermediate using borane
dimethyl sulphide complex by following the similar procedure as
described in Intermediate-14a,14b; m/z: 334.8.
Intermediate-17
(1R)-1-(4-Fluoronaphthalen-1-yl)-N41,2,3,4-tetrahydroquinolin-3-yl)methyl)
ethanamine
##STR00041##
[0281] The title compound was prepared in two steps:
[0282] Step: 1--Intermediate-12 was reacted with corresponding
(R)-1-(4-fluoronaphthalen-1-yl) ethanamine hydrochloride by
following the similar procedure as described in
Intermediate-13a,13b.
[0283] Step: 2-Step-1 Intermediate was undergone reduction reaction
using borane dimethyl sulphide complex by following the similar
procedure as described in Intermediate-14a,14b; m/z-334.9.
Intermediate -18
(1R)-1-(4-Fluoro-3-methoxyphenyl)-N-1,2,3,4-tetrahydroquinolin-3-yl)methyl-
) ethanamine
##STR00042##
[0285] The title compound was prepared in two steps:
[0286] Step: 1-Intermediate-12 was reacted with corresponding
(R)-1-(4-fluoro-3-methoxy phenyl) ethanamine by following the
similar procedure as described in Intermediate-13a,13b.
[0287] Step: 2: Step-1 Intermediate was carried-out reduction
reaction using borane dimethyl sulphide complex by following the
similar procedure as described in Intermediate-14a,14b;
m/z-315.65.
Intermediate -19
1-tert-Butyl 3-methyl
3,4-dihydroquinoline-1,3(2II)-dicarboxylate
##STR00043##
[0289] To a solution of Intermediate-12 (1 g, 5.23 mmol) in
acetonitrile (10 mL), BOC-anhydride (1.457 mL, 6.28 mmol) was added
at RT. The reaction mixture was heated up to 50.degree. C. for
overnight. Reaction progress was monitored by TLC. Organic solvent
was removed under vacuum. Product was extracted in ethyl acetate
(10 mL.times.2). Washed the organic layer with saturated citric
acid (10 mL) followed by water (10 mL) and saturated brine solution
(10 mL). Organic layer was dried over sodium sulphate, concentrated
under vacuum to get crude product. Further the crude product was
purified by flash chromatography (10% ethyl acetate in n-hexane and
1% NH.sub.4OH) to get title compound (1.35 g, 89% yield); m/z 313.9
as Na+1.
Intermediate -20
tert-Butyl 3-formyl-3,4-dihydroquinoline-1(2H)-carboxylate:
##STR00044##
[0291] To a solution of Intermediate-19 (0.2 g, 0.686 mmol) in a
mixture of dry toluene (8 mL) and DCM (2 mL) DIBAL-H (1.37 mL, 1.37
mmol, 1M) was added in drop wise manner at -78.degree. C. Further
the reaction was stirred for 2 h at the same temperature. The
progress of reaction was monitored by TLC. Reaction mixture was
quenched with MeOH (5 mL) at -65.degree. C. and allowed to RT,
filtered through celite, diluted with water (20 mL). It was
extracted with ethyl acetate (20 mL.times.2) washed with water (15
mL) and brine solution (15 mL), dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure to get the crude product. This
crude product was further purified by flash chromatography (10%
ethyl acetate in hexane) to give the title compound (0.12 g,
66.9%); m/z-283.5 as Na+1
Intermediate -21
tert-Butyl
3-(2-oxoethyl)-3,4-dihydroquinoline-1(2H)-carboxylate
##STR00045##
[0293] To a solution of (methoxymethylene)triphenyl phosphorane
(703 mg, 2.296 mmol) in THF (5 mL). The solution was cooled to
-30.degree. C. for 15 min and potassium tert.butoxide (322 mg, 2.87
mmol) dissolved in THF (5 mL) was added. Stirred this solution for
30 min wine red color solution observed. Intermediate-20 (500 mg,
1.913 mmol) in THF (5 mL) was added to the reaction mixture. This
solution was stirred for 2 h at the same temperature. The progress
of reaction was monitored by TLC. After completion of reaction,
water (5 mL) was added and product was extracted with ethyl acetate
(10 mL.times.3) followed by water (10 mL) and brine (10 mL).
Organic solvent was evaporated under reduced pressure. Further it
was purified by flash column chromatography (5% ethyl acetate in
hexane) to get (E)-tert-butyl
3-(2-methoxyvinyl)-3,4-dihydroquinoline-1(2H)-carboxylate (225 mg,
40.6% yield); m/z-312.1 as Na+1.
[0294] To a solution of (E)-tert-butyl
3-(2-methoxyvinyl)-3,4-dihydroquinoline-1(2H)-carboxylate (225 mg,
0.778 mmol) in THF (5 mL) dilute HCl (0.2 ml, 6.58 mmol) was added.
The reaction mixture was stirred overnight at RT. The progress of
reaction was monitored by TLC. After completion of reaction
methanol was evaporated under reduced pressure. Further it was
purified by flash column chromatography (15% ethyl acetate in
hexane) to get the title compound (160 mg, 30.4% yield); m/z-297.6
as Na+1.
Intermediate-22
tert-Butyl
3-(2-(((R)-1-(naphthalen1-yl)ethyl)amino)ethyl)-3,4-dihydroquin-
oline-1(2H)-carboxylate
##STR00046##
[0296] To a stirred solution of Intermediate-21 (1.15 g, 4.18 mmol)
in methanol (10 mL) (R)-1-(naphthalen-1-yl)ethanamine (0.858 g,
5.01 mmol) was added at 0.degree. C. Acetic acid (0.2 ml, 3.49
mmol) was added and reaction was stirred for 5 min. Reaction was
warmed to RT and stirred for 20 min. Again reaction was cooled to
0.degree. C. Sodium cyanoborohydride (0.525 g, 8.35 mmol) was added
to the reaction mixture and stirred for overnight. Reaction
progress was monitored by TLC. To the reaction NaHCO.sub.3 solution
(20 mL) were added and water (50 mL) and the mixture was extracted
with ethyl acetate (50 mL.times.2). The extract was washed with
saturated brine, dried over anhydrous Na.sub.2SO.sub.4 and
evaporated under reduced pressure to get crude product. Further
compound was purified by using column purification (10% ethyl
acetate-hexane) to get title compound (1.2 g, 66.7% yield);
m/z-431.54.
Intermediate -23
(1R)-1-(Naphthalen1-yl)-N-(2-(1,2,3,4 -tetrahydro
quinolin-3-yl)ethyl)ethanamine
##STR00047##
[0298] Intermediate-22 (1.2 g, 2.79 mmol) was dissolved in DCM (5
mL) and MeOH/HCl (10 mL, 3N). The reaction mixture was stirred at
RT overnight. The progress of reaction was monitored by TLC. The
reaction was evaporated under reduced pressure then added saturated
Na.sub.2CO.sub.3 solution (5 mL). The mixture was extracted with
ethyl acetate (10 mL.times.2) and washed with water (5 mL.times.2)
followed by brine solution (5 mL), dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. This was further purified by
flash chromatography (15% ethyl acetate-hexane) to give title
compound (1 g, 98% yield); m/z-331.65.
Intermediate-24
(E)-tert-Butyl3-(3-ethoxy-3-oxoprop1-en-1-yl)-3,4-dihydroquinoline-1(2H)-c-
arboxylate
##STR00048##
[0300] The solution of Intermediate-20 (8 g, 30.6 mmol) and ethyl
2-(triphenyl phosphoranylidene) acetate (11.73 g, 33.7 mmol) in
toluene (100 mL) was heated to 110.degree. C. and maintained for 3
h. The progress of reaction was monitored by TLC. Reaction mixture
was allowed to RT then diluted with water (50 mL) and extracted
with ethyl acetate (50 mL.times.3). The combined organic layer was
washed with water (50 mL) followed by brine solution (50 mL), dried
over Na.sub.2SO.sub.4 and concentrated to give crude product. The
crude product was further purified by flash chromatography (10%
ethyl acetate in hexane) to give title compound (8.5 g, yield:
84%); m/z-276.58 (M-55).
Intermediate -25
tert-Butyl
3-(3-ethoxy-3-oxopropyl)-3,4-dihydroquinoline-1(2H)-carboxylate
##STR00049##
[0302] To a suspension of 10% palladium on carbon (2 g, 50% wet) in
ethanol (20 mL), Intermediate-24 (9 g, 27.2 mmol) in ethanol (80
mL) was carefully added and the mixture was stirred overnight under
a pressure of hydrogen balloon. The progress of reaction was
monitored by TLC. Reaction mixture was filtered through celite and
the filtrate concentrated to get the crude product (9 g, 99%);
m/z-234.89 (M-98).
Intermediate -26
3-(1-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic
acid
##STR00050##
[0304] To a solution of Intermediate-25 (9.2 g, 27.6 mmol) in THF
(25 mL), MeOH (25 mL) and water (3 mL) lithium hydroxide hydrate
(5.79 g, 138 mmol) was added. The reaction mixture was stirred for
2 h at RT. The progress of reaction was monitored by TLC. The
reaction mixture was concentrated under vacuum then cooled to
0.degree. Cand acidified with citric acid solution. The mixture was
extracted with ethyl acetate (50 mL.times.2), washed with water (25
mL.times.2) followed by brine solution (25 mL), dried over
Na.sub.2SO.sub.4 and concentrated under vacuum to get white
solid.(8.22 g, 99.83%); m/z-306.59.
Intermediate -27
tert-Butyl3-(34(R)-1-(naphthalen-1-yl)ethyl)amino)-3-oxopropyl)-3,4-dihydr-
o quinoline-1(2H)-carboxylate
##STR00051##
[0306] To a solution of Intermediate-26 (2.5 g, 8.19 mmol) in DMF
(10 mL) CDI (1.991 g, 12.28 mmol) was added slowly and stirred for
30 min. Then (R)-1-(naphthalen-1-yl)ethanamine (1.682 g, 9.82 mmol)
was added. The reaction mixture was wormed to 35.degree. C. and
further maintained for 24 h. Reaction progress was monitored by
TLC. Poured RM into water (50 mL) and product was extracted with
ethyl acetate (25 mL.times.2). The organic layer was washed with
20% citric acid (25 mL) followed by water (25 mL.times.2),
saturated Na.sub.2CO.sub.3 solution. Finally the organic layer was
washed with water and saturated brine solution (25 mL). Dried the
organic layer on Na.sub.2SO.sub.4 then evaporated under reduced
pressure to get crude title compound (3.7 g, 99% yield);
m/z-459.48.
Intermediate -28
N-((R)1-(Naphthalen1-yl)ethyl)-3-(1,2,3,4-tetrahydroquinolin-3-yl)propan1--
amine
##STR00052##
[0308] The title compound was prepared by following the similar
procedure as described in Intermediate-14a,14b by taking
Intermediate-27; m/z-345.66.
Intermediate -29
N-((R)1-(4-Fluoronaphthalen1-yl)ethyl)-3-(1,2,3,4-tetrahydroquino
lin-3-yl)propan1-amine
##STR00053##
[0310] The title compound was prepared in two steps:
[0311] Step: 1--Intermediate-26 was reacted with
(R)-1-(4-fluoronaphthalen-1-yl)ethanamine hydrochloride by
following the similar procedure as described in
Intermediate-27.
[0312] Step: 2-Step-1 Intermediate has undergone reduction using
borane dimethyl sulphide complex by following the similar procedure
as described in Intermediate-14a14b; m/z-363.66.
EXAMPLES
Example-1
Methyl
3-(3-((((R)-1-(Naphthalen-1yl)ethyl)amino)methyl)-1,2,3,4-tetrahydr-
o naphthalen-1-yl)benzoate
##STR00054##
[0313] Step-1: Methyl
3-(3-(((tert-butoxycarbonyl)((R)1-(naphthalen-1-yl)ethyl)amino)methyl)-3,-
4-dihydronaphthalen-1-yl)benzoate
[0314] To a solution of Intermidiate-1 (1 g, 1.781 mmol), methyl
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.467 g,
1.781 mmol) and sodium carbonate (0.321 g, 5.34 mmol) in ethanol (5
mL), toluene (5 mL) and water (2 mL) bubbled the nitrogen for 30
minutes. Tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.089
mmol) was added to the reaction mixture and again nitrogen was
bubbled for 10 minutes. The reaction mixture was then heated to
65.degree. C. and further maintained for 1 h. Reaction was
monitored by TLC. The resulting solid was removed by filtration
through celite bed. The filtrate was extracted with ethyl acetate
(2.times.25 mL) and washed with water (15 mL) and brine solution
(15 mL). The organic layer was dried over sodium sulfate and
concentrated under reduced pressure to get crude compound. This
crude compound was further purified by flash chromatography
(Biotage) (ethyl acetate: hexane=1:20) to give title compound (660
mg, 67.7%) m/z 548.57.
Step-2: Methyl
3-(3-(((tert-butoxycarbonyl)((R)-1-(naphthalen-1-yl)ethyl)amino)
methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)benzoate
[0315] To a stirred solution of above step-1 intermediate (660 mg,
1.205 mmol) in MeOH (10 mL), palladium on carbon (10%) (66 mg) was
carefully added and the mixture was stirred under pressure of
balloon of hydrogen for 8 h. Reaction mixture was filtered through
celite bed and concentrated to get the crude compound. This was
used directly in next reaction (570 mg, 86%). m/z 550.57.
Step-3: Methyl
3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-tetra
hydronaphthalen-1-yl)benzoate
[0316] To a stirred solution of step-2 intermediate (570 mg, 1.092
mmol) in methanol (8 ml), HCl in methanol (2.24 mL, 7.26 mmol) was
added and the reaction mixture was stirred at 25.degree. C.
overnight in closed vessel. The reaction mixture was basified with
saturated sodium bicarbonate solution and extracted with ethyl
acetate (2.times.25 mL). Organic layer was washed with brine
solution (20 mL), dried over sodium sulfate and concentrated under
reduced pressure to get crude compound. This crude compound was
purified by reverse phase HPLC. Further the four diastereomers were
separated by chiral preparative HPLC [CELLULOSE 1, 250
mm.times.4.6,5.mu.; A: hexane/IPA (90:10, %v/v, 0.1% DEA)
B:IPA(100%) A:B 80/20%v/v Flow=1.0 ml/min] Isomer `a`:
t.sub.R=6.28, Isomer `b`: t.sub.R=8.66, Isomer `c`: t.sub.R=9.40,
Isomer `d`: t.sub.R=12.56; m/z, 449.60. (t.sub.R is retention
time).
Example-2a, 2b, 2c, 2d
3-(3-((((R)1-(Naphthalen1-yl)ethyl)amino)methyl)-1,2,3,4-tetrahydronaphtha-
len1-yl)benzoic acid hydrochloride
##STR00055##
[0318] To a stirred solution of Isomer `a` of Example-1 (25 mg,
0.056 mmol) in ethanol (2.0 ml), tetrahydrofuran (2.0 mL) and water
(2.0 mL) in round bottom flask. LiOH (9.32 mg, 0.389 mmol) was
added and reaction mixture was heated to 80.degree. C. and further
maintained for 2 h. Reaction mixture was concentrated and acidified
with 6N HCl solution, solid was precipitated out. This solid was
filtered, washed with DM water (20 mL) and n-pentane (20 mL) dried
to get the title product (22 mg, 91%). m/z 435.98.
[0319] This solid compound was dissolved in dry DCM (1 mL), then
slowly added with 2 M ethereal HCl solution (2 mL) and further
maintained for few minutes. The reaction mixture was distilled off
completely and further washed with diethyl ether and dried to get
HCl salt of title compound.
[0320] .sup.1H NMR (400 MHz, DMSO): .delta. 12.92 (bs, 1H), 9.43
(bs, 1H), 9.05 (bs, 1H), 8.14 (d, J=8 Hz, 1H), 8.01-7.93 (m, 3H),
7.77 (d, J=8 Hz, 1H), 7.63-7.58 (m, 3H), 7.53 (m, 1H), 7.43-7.39
(m, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.18-7.17 (m, 2H), 7.09-7.08 (m,
1H), 6.83 (d, J=7.6 Hz, 1H), 5.28(q, J=6.4 Hz, 1H), 4.40-4.37 (m,
1H), 3.21-3.16 (m, 1H), 3.00 (m, 1H), 2.72-2.67 (m, 1H), 2.33-2.18
(m, 2H), 1.92-1.89 (m, 2H), 1.65 (d, J=6.4 Hz, 3H); m/z 435.98
[0321] Similarly, Example-2b, Example-2c and Example-2d were
prepared from Example-1 Isomer `b`, Example-1 Isomer `c` and
Example-1 isomer `d` respectively.
[0322] Example-2b: .sup.1H NMR (400 MHz, DMSO): .delta. 12.95 (bs,
1H), 9.65 (bs, 1H), 9.20 (bs, 1H), 8.26 (d, J=8.4 Hz, 1H),
8.03-7.95 (m, 3H), 7.83-7.80 (m, 1H), 7.72 (m, 1H), 7.67-7.58 (m,
4H), 7.47-7.41(m, 2H), 7.12-7.09 (m, 2H), 7.03-7.00 (m, 1H),
5.36(q, J=6.4 Hz, 1H), 4.14-4.18 (m, 1H), 3.73-3.40 (m, 1H),
3.06-3.04 (m, 1H), 2.88 (m, 1H), 2.68-2.65 (m, 1H), 2.38-2.33 (m,
2H), 2.28-2.23 (m, 1H), 1.72 (d, J=6.4 Hz, 3H); m/z 435.98.
[0323] Example-2c: .sup.1H NMR(400 MHz, DMSO): .delta. 12.91 (bs,
1H), 9.47 (bs, 1H), 9.04 (bs, 1H), 8.13 (d, J=8 Hz, 1H), 8.00-7.94
(m, 3H), 7.77 (d, J=7.6 Hz, 1H), 7.62-7.57 (m, 3H), 7.52 (m, 1H),
7.43-7.39 (m, 1H), 7.27 (d, J=8 Hz, 1H), 7.17-7.16 (m, 2H),
7.08-7.07 (m, 1H), 6.82 (d, J=7.6 Hz, 1H), 5.25(q, J=6.8 Hz, 1H),
4.36-4.33 (m, 1H), 3.14-2.82 (m, 2H), 2.73 (m, 1H), 2.67-2.54 (m,
1H), 2.22 (m, 1H), 1.97-1.93 (m, 2H), 1.65 (d, J=6.8 Hz, 3H); m/z
435.91.
[0324] Example-2d: .sup.1H NMR (400 MHz, DMSO): .delta. 12.96 (bs,
1H), 9.73 (bs, 1H), 9.14 (bs, 1H), 8.25 (d, J=8.4 Hz, 1H),
8.02-7.97 (m, 3H), 7.82-7.80 (m, 1H), 7.71 (m, 1H), 7.64-7.59 (m,
3H), 7.45-7.44 (m, 2H), 7.11-7.10 (m, 2H), 7.02-7.00 (m, 1H), 6.58
(d, J=8.4 Hz, 1H), 5.37 (q, J=6.8 Hz, 1H), 4.20-4.15 (m, 1H), 3.09
(m, 2H), 2.91-2.78 (m, 1H), 2.78-2.41 (m, 1H), 2.69-2.62 (m, 1H),
2.33-2.30 (m, 2H), 1.76 (d, J=6.8 Hz, 3H); m/z 435.98.
[0325] The Example-3 to Example-7 and their isomers given in
Table-1 were prepared by following the similar procedure as
described in Step-1 to Step-3 of Example-1 by taking Intermediate-1
and appropriately substituted phenyl boronic acid/ester. Further
the diastereomers were separated by similar chiral preparative HPLC
method as described in Example-1 a, 1b, 1c,1d.
TABLE-US-00001 TABLE 1 Mass E. No Structure Chemical Name (m/z) 3a,
3b, 3c ##STR00056## Methyl 2-fluoro-5-(3-((((R)-1-
(naphthalene-1-yl)ethyl)amino)methyl)-
1,2,3,4-tetrahydronaphthalen-1-yl) benzoate 466.92 4a, 4b, 4c, 4d
##STR00057## Methyl 2-methyl-5-(3-((((R)-1-
(naphthalen-1-yl)ethyl)amino)methyl)-
1,2,3,4-tetrahydronaphthalen-1- yl)benzoate 464.1 5a, 5b, 5c
##STR00058## Methyl 3-methyl-5-(3-((((R)-1-
(naphthalen-1-yl)ethyl)amino)methyl)-
1,2,3,4-tetrahydronaphthalen-1- yl)benzoate 464.1 6a, 6b, 6c
##STR00059## Methyl 2,6-dimethyl-3-(3-((((R)-1-
(naphthalen-1-yl)ethyl)amino)methyl)-
1,2,3,4-tetrahydronaphthalen-1- yl)benzoate 478.1
[0326] The Example-7 to Example-10 and their isomers given in
Table-2 were prepared by following the similar ester hydrolysis
procedure as described in Example-2a,2b,2c,2d by taking
corresponding ester Example given in Table-1. Further,
hydrochloride salt of these compounds were prepared by following
the similar hydrochloride salt procedure as described in
Example-2a,2b,2c,2d.
TABLE-US-00002 TABLE 2 E. No Structure Chemical Name 7a, 7b 7c
##STR00060## 2-Fluoro-5-(3-((((R)-1- (naphthalen-1-
yl)ethyl)amino)methyl)- 1,2,3,4- tetrahydronaphthalen-1- yl)benzoic
acid hydrochloride 7a: .sup.1H NMR (400 MHz, DMSO): .delta. 13.23
(bs, 1H), 9.40 (bs, 1H), 9.01 (bs, 1H), 8.21 (d, J = 8 Hz, 1H),
8.01-7.92 (m, 3H), 7.63-7.58 (m, 3H), 7.41-7.39 (m, 1H), 7.24-7.22
(m, 2H), 7.17-7.16 (m, 2H), 7.09-7.08 (m, 1H), 8.31 (d, J = 8.4 Hz,
1H), 5.26 (q, J = 6.8 Hz, 1H), 4.34 (m, 1H), 3.16-3.07 (m, 2H),
2.82 (m, 1H), 2.61-2.54 (m, 1H), 2.18 (m, 1H), 1.97-1.87 (m, 2H),
1.66 (d, J = 6.8 Hz, 3H); m/z 454. 7b: .sup.1H NMR (400 MHz, DMSO):
.delta. 13.26 (bs, 1H), 9.48 (bs, 1H), 9.18 (bs, 1H), 8.25 (d, J =
8.4 Hz, 1H), 8.02-7.97 (m, 3H), 7.65-7.59 (m, 4H), 7.43-7.40 (m,
1H), 7.28-7.24 (m, 1H), 7.11-7.09 (m, 2H), 7.46-7.7.01 (m, 1H),
8.59 (d, J = 7.6 Hz, 1H), 5.36 (q, J = 6.4 Hz, 1H), 4.19-4.14 (m,
1H), 3.06 (m, 1H), 2.91-2.87 (m, 1H), 2.76 (m, 1H), 2.68-2.65 (m,
2H), 2.37-2.32 (m, 2H), 1.72 (d, J = 6.4 Hz, 3H); m/z 454. 7c:
.sup.1H NMR (400 MHz, DMSO): .delta. 13.26 (bs, 1H), 9.48 (bs, 1H),
9.18 (bs, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.03-8.00 (m, 2H), 7.91
(d, J = 6.8 Hz, 1H), 7.64-7.60 (m, 4H), 7.24 (m, 1H), 7.30-7.25 (m,
1H), 7.11 (m, 2H), 7.03 (m, 1H), 6.60 (d, J = 8 Hz, 1H), 5.37 (q, J
= 6.4 Hz, 1H), 4.17-4.15 (m, 1H), 3.09-3.05 (m, 1H), 2.96-2.92 (m,
2H), 2.68-2.61 (m, 2H), 2.33 (m, 1H), 2.22-2.20 (m, 1H), 1.70 (d, J
= 6.4 Hz, 3H), m/z 454.1 8a, 8b, 8c, 8d ##STR00061##
2-Methyl-5-(3-((((R)-1- (naphthalen-1- yl)ethyl)amino)methyl)-
1,2,3,4-tetrahydro naphthalen-1-yl)benzoic acid hydrochloride 8a:
.sup.1H NMR (400 MHz, DMSO): .delta. 12.76 (bs, 1H), 9.53 (bs, 1H),
9.06 (bs, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.01-7.96 (m, 3H),
7.63-7.56 (m, 3H), 7.42 (d, J = 1.6 Hz, 1H), 7.20-7.14 (m, 3H),
7.09-7.03 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 5.29-5.24 (m, 1H),
4.28-4.25 (m, 1H), 3.13-3.04 (m, 2H), 2.81 (m, 1H), 2.59-2.55 (m,
1H), 2.46 (s, 3H), 2.22 (m, 1H), 1.94-1.87 (m, 2H), 1.66 (d, J =
6.8 Hz, 3H); m/z 449.85. 8b: .sup.1H NMR (400 MHz, DMSO): .delta.
12.81 (bs, 1H), 9.55 (bs, 1H), 9.02 (bs, 1H), 8.27 (d, J = 8.4 Hz,
1H), 8.03-7.98 (m, 2H), 7.93 (d, J = 6.8 Hz, 1H), 7.66-7.58 (m,
4H), 7.24 (s, 2H), 7.10-7.09 (m, 2H), 7.03-6.99 (m, 1H), 6.60 (d, J
= 8 Hz, 1H), 5.39-5.37 (m, 1H), 4.12-4.08 (m, 1H), 3.40- 3.35 (m,
1H), 3.10 (m, 1H), 2.90-2.87 (m, 1H), 2.77-2.74 (m, 1H), 2.68-2.60
(m, 1H), 2.50 (s, 3H), 2.33-2.24 (m, 2H), 1.71 (d, J = 6.4 Hz, 3H);
m/z 449.79. 8c: .sup.1H NMR (400 MHz, DMSO): .delta. 12.81 (bs,
1H), 9.57 (bs, 1H), 9.14 (bs, 1H), 8.28 (d, J = 8.4 Hz, 1H),
8.03-7.98 (m, 3H), 7.67-7.58 (m, 4H), 7.24 (S, 2H), 7.10(d, J = 8.0
Hz, 2H), 7.03-7.00 (m, 1H), 6.61(d, J = 7.6 Hz, 1H), 5.37 (m, 1H),
4.10-4.06 (m, 1H), 3.06-2.88 (m, 3H), 2.67-2.60 (m, 1H), 2.46 (S,
3H), 2.45-2.35 (m, 3H) 1.67 (d, J = 6.8 Hz, 3H); m/z 450.1 8d:
.sup.1H NMR (400 MHz, DMSO): .delta. 8.15 (d, J = 9.2 Hz, 1H),
8.01-7.96 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.63-7.56 (m, 3H),
7.41-7.40 (m, 1H), 7.20-7.14 (m, 3H), 7.10-7.03 (m, 2H), 6.83 (d, J
= 8.0 Hz, 1H), 5.30-5.28 (m, 1H), 4.32-4.29 (m, 1H), 3.17-3.12 (m,
1H), 3.02-2.97 (m, 1H), 2.73- 2.67 (m, 1H), 2.50-2.46 (m, 4H),
2.32-2.19 (m, 1H), 1.88-1.85 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H); m/z
450.1 9a, 9b, 9c ##STR00062## 3-Methyl-5-(3-((((R)-1- (m, 1H),
2.62-2.55 (m, (naphthalen-1-yl)ethyl) amino)methyl)-1,2,3,4-
tetrahydro naphthalen-1- yl) benzoic acid hydrochloride 9a: .sup.1H
NMR (400 MHz, DMSO): .delta. 12.83 (bs, 1H), 9.24 (bs, 1H), 8.91
(bs, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.01-7.96 (m, 2H), 7.88 (d, J =
7.2 Hz, 1H), 7.73-7.56 (m, 4H), 7.27 (s, 1H), 7.17-7.06 (m, 4H),
6.82 (d, J = 7.6 Hz, 1H), 5.28-5.25 (m, 1H), 4.31-4.29 (m, 1H),
3.13-3.08 (m, 2H), 2.83 (m, 1H), 2.62-2.55 (m, 1H), 2.30 (s, 3H),
2.25- 2.21 (m, 1H), 1.95-1.87 (m, 2H), 1.65 (d, J = 6.8 Hz, 3H);
m/z 450.1 9b: .sup.1H NMR (400 MHz, DMSO): .delta. 12.86 (bs, 1H),
9.43 (bs, 1H), 9.10 (bs, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.03-7.96
(m, 2H), 7.95 (d, J = 7.2 Hz, 1H), 7.67-7.58 (m, 4H), 7.52 (s, 1H),
7.27 (s, 1H), 7.11 (d, J = 4.0 Hz, 2H), 7.04-7.00 (m, 1H), 6.61 (d,
J = 7.6 Hz, 1H), 5.38-5.36 (m, 1), 4.13- 4.09 (m, 1H), 3.05-2.92
(m, 3H), 2.68-2.33 (m, 2H), 2.33-2.21 (m, 5H), 1.70 (d, J = 6.4 Hz,
3H); m/z 450.1 9c: .sup.1H NMR (400 MHz, DMSO): .delta. 12.87 (bs,
1H), 9.61 (bs, 1H), 9.08 (bs, 1H), 8.27 (d, J = 8.8 Hz, 1H),
8.03-7.93 (m, 3H), 7.65-7.58 (m, 4H), 7.52 (s, 1H), 7.25 (s, 1H),
7.10-7.00 (m, 3H), 6.61 (d, J = 8 Hz, 1H), 5.39-5.37 (m, 1), 4.14-
4.10 (m, 1H), 3.40-3.09 (m, 2H), 2.90-2.62 (m, 3H), 2.33-2.26 (m,
5H), 1.71 (d, J = 6.8 Hz, 3H); m/z 450.67. 10a, 10b, 10c
##STR00063## 2,6-Dimethyl-3-(3-((((R)- 1-(naphthalen-1-yl)
ethyl)amino) methyl)- 1,2,3,4-tetrahydro naphthalen-1-yl)benzoic
acid hydrochloride 10a: .sup.1H NMR (400 MHz, DMSO): .delta. 13.19
(bs, 1H), 9.58 (bs, 1H), 9.17 (bs, 1H), 8.26 (d, J = 8.8 Hz, 1H),
8.03-7.92 (m, 3H), 7.66-7.55 (m, 3H), 7.15-6.98 (m, 4H), 6.90-6.78
(m, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.36 (q, J = 6.8 Hz, 1H), 4.32-
4.30 (m, 1H), 3.29-2.78 (m, 3H), 2.72-2.58 (m, 1H), 2.36-2.33 (m,
3H), 2.18 (s, 5H), 1.86 (m, 1H), 1.72 (d, J = 6.8 Hz, 3H), m/z
468.48 10b: .sup.1H NMR (400 MHz, DMSO): .delta. 13.20 (bs, 1H),
9.66 (bs, 1H), 9.09 (bs, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.31-7.96
(m, 3H), 7.66-7.56 (m, 3H), 7.15-7.08 (m, 2H), 7.03-7.00 (m, 2H),
6.82-6.81 (m, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.38 (q, J = 6.4 Hz,
1H), 4.32-4.31 (m, 1H), 3.12-3.08 (m, 1H), 2.88-2.78 (m, 2H),
2.67-2.60 (m, 1H), 2.33 (s, 3H), 2.17 (s, 5H), 1.80(m, 1H), 1.68
(d, J = 6.4 Hz, 3H), m/z 463.8 10c: .sup.1H NMR (400 MHz, DMSO):
.delta. 13.19 (bs, 1H), 9.41(bs, 1H), 9.02 (bs, 1H), 8.18 (d, J =
8.4 Hz, 1H), 8.01-7.94 (m, 3H), 7.63-7.56 (m, 3H), 7.15-7.12 (m,
2H), 7.07-7.03 (m, 1H), 6.87 (d, J = 8 Hz, 1H), 6.76 (d, J = 7.6
Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 5.27(m, 1H), 4.45-4.42 (m, 1H),
3.14-3.06 (m, 3H), 2.83 (m, 1H), 2.34 (s, 3H), 2.22-2.21 (m, 1H),
2.17 (s, 3H), 1.66-1.65 (m, 2H), 1.65 (d, J = 6.4 Hz, 3H), m/z
463.8
Example-11a, 11b
Methyl
2-methyl-4-((3S)-3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)benzoate
##STR00064##
[0328] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-2 and methyl
2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.
[0329] The two diastereomers were separated by chiral preparative
HPLC [CHIRAL PAK ID, 250 mm.times.4.6,5.mu.; A=n-hexane IPA
(90/10%v/v, 0.1%DEA), B=IPA; A:B=90/10%v/v; Flow=1.0 ml/min] Isomer
`a`: t.sub.R=5.07, Isomer `b`: t.sub.R=5.92; m/z, 464.1. (t.sub.R
is retention time).
Example-12a, 12b
Methyl
4-methyl-3-((3S)-3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,-
2,3,4-tetrahydro naphthalen-1-yl)benzoate.
##STR00065##
[0331] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-2 and methyl
4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate.
[0332] The two diastereomers were separated by chiral preparative
HPLC [CHIRAL PAK ID, 250 mm.times.4.6,5 .mu.; A=n-hexane IPA
(90/10%v/v, 0.1%DEA), B=IPA; A:B=90/10%v/v; Flow=1.0 ml/min] Isomer
`a`: t.sub.R=5.76, Isomer `b`: t.sub.R=6.70; m/z, 464.48. (t.sub.R
is retention time).
Example-13a, 13b
2-Methyl-4-((3S)-3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)benzoic acid hydrochloride
##STR00066##
[0334] The title compounds of Example-13a,13b were prepared by
following the similar ester hydrolysis procedure as described in
Example-2a by taking corresponding ester Example-11a and
Example-11b. Further, hydrochloride salt of these compounds was
prepared by following the similar hydrochloride salt procedure as
described in Example-2a.
[0335] 13a: .sup.1H NMR (400 MHz, DMSO): .delta. 12.70 (bs, 1H),
9.21 (bs, 1H), 8.90 (bs, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.01-7.97 (m,
2H), 7.87 (d, J=6.8 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.64-7.57 (m,
3H), 7.19-7.16 (m, 2H), 7.11-7.06 (m, 1H), 6.94 (s, 1H), 6.84-6.79
(m, 2H), 5.29-5.27 (m, 1H), 4.28-4.26 (m, 1H), 3.12-3.07 (m, 2H),
2.83 (m, 1H), 2.58-2.45 (m, 4H), 2.21 (m, 1H), 1.95-1.90 (m, 2H),
1.65 (d, J=6.4 Hz, 3H); m/z 450.1
[0336] 13b: .sup.1H NMR (400 MHz, DMSO): .delta. 12.73 (bs, 1H),
9.47 (bs, 1H), 8.98 (bs, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.02-7.99 (m,
2H), 7.90 (m, 1H), 7.79 (d, J=8 Hz, 1H), 7.62 (m, 3H), 7.10-7.02
(m, 4H), 6.61 (d, J=6.8 Hz, 1H), 5.39 (m, 1H), 4.98 (m, 1H), 3.11
(m, 1H), 2.91-2.61 (m, 4H), 2.50 (s, 3H), 2.33-2.27 (m, 2H), 1.70
(m, 3H); m/z 450.1.
Example-14a, 14b
4-Methyl-3-(3S)-3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-te-
trahydro naphthalen-1-yl)benzoic acid hydrochloride.
##STR00067##
[0338] The title compounds of Example-14a,14b were prepared by
following the similar ester hydrolysis procedure as described in
Example-2a by taking corresponding ester Example-12a and
Example-12b. Further, hydrochloride salt of these compounds was
prepared by following the similar hydrochloride salt procedure as
described in Example-2a.
[0339] 14a: .sup.1H NMR (400 MHz, DMSO): .delta. 12.77 (bs, 1H),
9.73 (bs, 1H), 9.17 (bs, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.03-7.97 (m,
3H), 7.70-7.57 (m, 4H), 7.47 (m, 1H), 7.33-7.31 (m, 1H), 7.11 (m,
2H), 7.02-6.99 (m, 1H), 6.54 (d, J=7.6 Hz, 1H), 5.40-5.35 (m, 1H),
4.39-4.35 (m, 1H), 3.16-3.09 (m, 1H), 2.91-2.88 (m, 1H), 2.80-2.63
(m, 3H), 2.50 (s, 3H), 2.45-2.29 (m, 2H), 1.73 (d, J=6.8 Hz, 3H);
m/z 450.
[0340] 14b: .sup.1H NMR (400 MHz, DMSO): .delta. 12.68 (bs, 1H),
9.23 (bs, 1H), 8.98 (bs, 1H), 8.17 (d, J=7.2 Hz, 1H), 8.01-7.97 (m,
2H), 7.90-7.88 (m, 1H), 7.67-7.60 (m, 4H), 7.33 (m, 1H), 7.18 (s,
2H), 7.06 (m, 2H), 6.80 (d, J=6 Hz, 1H), 5.27 (m, 1H), 4.49 (m,
1H), 3.16-3.12 (m, 2H), 2.82 (m, 1H), 2.67-2.55 (m, 1H), 2.50 (s,
1H), 2.18 (m, 1H), 1.87 (m, 2H), 1.64 (m, 3H); m/z 450.
Example-15a, 15b
Methyl
5-((3S)-3-((((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,-
2,3,4-tetra hydronaphthalen-1-yl)-2-methylbenzoate
##STR00068##
[0342] The title compound was prepared by following the similar
procedure as described Step-1 to Step-3 of Example-1 in sequential
manner by taking Intermediate-3 and
(3-(methoxycarbonyl)-4-methylphenyl)boronic acid.
[0343] The two diastereomers were separated by chiral preparative
HPLC [CHIRAL PAK ID, 250 mm.times.4.6,5.mu.; A=n-hexane IPA
(90/10%v/v, 0.1%DEA), B=IPA; A:B=90/10%v/v; Flow=1.0 ml/min] Isomer
`a`: t.sub.R=6.05, Isomer `b`: t.sub.R=6.62; m/z, 461.9. (t.sub.R
is retention time).
Example-16a, 16b
5-((3S)-3-((((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride
##STR00069##
[0345] The title compounds Example-16a,16b were prepared by
following the similar ester hydrolysis procedure as described in
Example-2a by taking corresponding ester Example-15a and
Example-15b. Further, hydrochloride salt of these compounds was
prepared by following the similar hydrochloride salt procedure as
described in Example-2a.
[0346] 16a: .sup.1H NMR (400 MHz, DMSO): .delta. 12.77 (bs, 1H),
9.29 (bs, 1H), 9.03 (bs, 1H), 7.51 (dd, J=2, 8.4 Hz, 1H), 7.43 (d,
J=1.6 Hz, 1H), 7.25-7.13 (m, 4H), 7.10-7.02 (m, 3H), 6.81 (d, J=7.6
Hz, 1H), 4.29-4.24 (m, 2H), 3.84 (s, 3H), 3.10-3.05 (m, 1H),
2.86-2.84 (m, 1H), 2.67-2.46 (m, 5H), 2.18-2.15 (m, 1H), 1.95-1.87
(m, 2H), 1.57 (d, J=6.4 Hz, 3H); m/z 448.04.
[0347] 16b:.sup.1H NMR (400 MHz, DMSO): .delta. 12.81 (bs, 1H),
9.56 (bs, 1H), 9.21 (bs, 1H), 7.58-7.56 (m, 2H), 7.42-7.21 (m, 3H),
7.15-7.07 (m, 3H), 7.03-6.99 (m, 1H), 6.60 (d, J=7.6 Hz, 1H),
4.40-4.39 (m, 1H), 4.12-4.07 (m, 1H), 3.84 (s, 3H), 2.89-2.86 (m,
2H), 2.69-2.45 (m, 6H), 2.33-2.25 (m, 2H), 1.62 (d, J=6.8 Hz, 3H);
m/z 448.04.
Example-17
3-((3S)-3-((((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)-2,6-dimethylbenzoic acid
hydrochloride
##STR00070##
[0349] Step-1: Benzyl
3-((R)-3-(((tert-butoxycarbonyl)((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)
amino)methyl)-3,4-dihydronaphthalen-1-yl)-2,6-dimethylbenzoate
[0350] To a solution of Intermediate-3 (2.1 g, 3.75 mmol), benzyl
2,6-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
(1.512 g, 4.13 mmol) and sodium carbonate (1.193 g, 11.26 mmol) in
EtOH (10 mL), Toluene (10 mL) and water (5 mL) bubbled nitrogen for
30 min. tetrakis(triphenylphosphine)palladium(0) (0.217 g, 0.188
mmol) was added and again nitrogen was bubbled for 10 min. Reaction
was then heated at 65.degree. C. for 1 hr. The resulting solid was
removed by filtration through Celite. The filtrate was extracted
with ethyl acetate (2.times.25 mL) and washed with water (15 mL)
and brine (15 mL). The organic layer was dried over sodium sulfate,
and filtered, after concentration under reduced pressure to give
crude compound. The crude compound was purified with silica gel
flash column chromatography (Biotage) using eluent 5% EtOAc: hexane
to yield benzyl
3-((R)-3-(((tert-butoxycarbonyl)((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)am-
ino)methyl)-3,4-dihydro naphthalen-1-yl)-2,6-dimethylbenzoate (1.3
g, 53.3%) as an oil; m/z -Boc 550.3.
[0351] Step-2:
3-((3S)-3-(((tert-butoxycarbonyl)((R)-1-(4-fluoro-3-methoxyphenyl)ethyl)a-
mino)
methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-dimethylbenzoic
acid. To a stirred solution of Pd/C (0.130 g, 0.122 mmol) in MeOH
(20 mL), step-1 (1.3 g, 2.001 mmol) was added under nitrogen
atmosphere. Reaction mixture was stirred overnight under hydrogen
balloon pressure. Compound was filtered through celite,
concentrated to yield 1.2 g of crude compound. The crude compound
was purified by Prep HPLC to get pure title compound. Further
diastereomers separated by chiral prep HPLC [CELLULOSE-1, 250
mm.times.4.6,5.mu.; A=n-hexane , 0.2%TFA B=ETOH 100%; A=70/30%V/V;
flow rate 1.0 ml/min] to yield title compound (Isomer `a`:
t.sub.R=3.42, 220 mg, 91.46%); m/z 562.07. (t.sub.R is retention
time).
[0352] Step-3: 3-((3S)-3-((((R)1-(4-Fluoro-3
-methoxyphenyl)ethyl)amino)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,6-
-dimethylbenzoic acid hydrochloride.
[0353] To the stirred solution of step-2 intermediate (220 mg,
0.392 mmol), in DCM (5 mL) was added HCl in methanol (2M) (1.958
mL, 3.92 mmol) at 0.degree. C. and stirred the reaction mixture at
RT for 16 h. Solvent was removed under reduced pressure and solid
obtained was washed with diethyl ether and n-pentane to yield the
title compound as a white solid. (120 mg, 61.5%). .sup.1H NMR (400
MHz, DMSO): .delta. 13.11 (bs, 1H), 9.70 (bs, 1H), 9.27 (bs, 1H),
7.54 (d, J=6.8 Hz, 1H), 7.30-7.25 (m, 1H), 7.12-6.82 (m, 5H),
6.88-6.82 (m, 1H), 6.58-6.55 (m, 1H), 4.39-4.31 (m, 2H), 3.84 (s,
3H), 2.89-2.86 (m, 2H), 2.66-2.49 (m, 5H), 2.33-2.21 (m, 6H), 1.62
(d, J=6.4 Hz, 3H); m/z 462.48.
Example-18a, 18b
Methyl
5-((3S)-3-((((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)methyl)-1,2-
,3,4-tetrahydro naphthalen-1-yl)-2-methylbenzoate
##STR00071##
[0355] The title compound was prepared by following the similar
procedure as described Step-1 to Step-3 of Example-1 in sequential
manner by taking Intermediate-4 and
(3-(methoxycarbonyl)-4-methylphenyl)boronic acid.
[0356] The two diastereomers were separated by chiral preparative
HPLC [CHIRAL PAK IA 250 mm.times.4.6,5.mu.; A=n-hexane:IPA
(90:10%v/v, 0.1%DEA), B=IPA; A:B=95/5%V/V; Flow=1.0 ml/min] Isomer
`a`: t.sub.R=4.71, Isomer `b`: t.sub.R=5.56; m/z, 481.67. (t.sub.R
is retention time).
Example-19a, 19b
5-((3S)-3-((((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-te-
trahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride
##STR00072##
[0358] The title compounds of Example-19a, 19b were prepared by
following the similar ester hydrolysis procedure as described in
Example-2a by taking Example-18a and Example-18b. Further,
hydrochloride salts of these compounds were prepared by following
the similar hydrochloride salt procedure as described in
Example-2a.
[0359] 19a: .sup.1H NMR (400 MHz, DMSO): .delta. 12.80 (s, 1H),
9.40 (bs, 1H), 9.10 (bs, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.14-8.12 (m,
1H), 7.96-7.94 (m, 1H), 7.73-7.69 (m, 2H), 7.50-7.45 (m, 1H),
7.41-7.40 (m, 1H), 7.20-7.07 (m, 3H), 7.05-7.03 (m, 2H), 6.82 (d,
J=7.6 Hz, 1H), 5.25-5.24 (m, 1H), 4.29-4.28 (m, 1H), 3.12-3.04 (m,
2H), 2.81-2.76 (m, 1H), 2.67-2.54 (m, 1H), 2.51-2.45 (m, 3H),
2.19-2.18 (m, 1H), 1.95-1.89 (m, 2H), 1.65 (d, J=6.4 Hz, 3H); m/z:
467.90
[0360] 19b: .sup.1H NMR (400 MHz, DMSO): .delta. 12.80 (s, 1H),
9.79 (bs, 1H), 9.16 (bs, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.16-8.13 (m,
1H), 8.03-8.00 (m, 1H), 7.77-7.69 (m, 2H), 7.60-7.59 (m, 1H),
7.51-7.47 (m, 1H), 7.26-7.22 (m, 2H), 7.09-7.08 (m, 2H), 7.02-6.98
(m, 1H), 6.59 (d, J=7.6 Hz, 1H), 5.35-5.34 (m, 1H), 4.11-4.07 (m,
1H), 3.40-3.34 (m, 2H), 3.10-3.06 (m, 1H), 2.90-2.87 (m, 1H),
2.76-2.45 (m, 3H), 2.35-2.26 (m, 3H), 1.71 (d, J=6.4 Hz, 3H); m/z:
467.90
Example-20
Methyl 2-methyl-5-(3
-(((R)-1-(naphthalen-1-yl)ethyl)amino)-1,2,3,4-tetrahydro
naphthalen-1-yl)benzoate
##STR00073##
[0362] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-5 and
(3-(methoxycarbonyl)-4-methylphenyl)boronic acid; m/z: 449.48.
Example-21
Methyl 2-methyl-4-(3 -(((R)
-1-(naphthalen-1-yl)ethyl)amino)-1,2,3,4-tetrahydro
naphthalen-1-yl)benzoate
##STR00074##
[0364] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-5 and methyl
2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate;
m/z: 449.48
Example-22
2-Methyl-5-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)-1,2,3,4-tetrahydronaph-
thalen-1-yl)benzoic acid hydrochloride
##STR00075##
[0366] The title compound was prepared by following the similar
ester hydrolysis procedure as described in Example-2a by taking
corresponding ester Example-20. Further, hydrochloride salt was
prepared by following the similar hydrochloride salt procedure as
described in Example-2a. .sup.1H NMR(400 MHz, DMSO): .delta. 12.88
(s, 1H), 10.20 (bs, 1H), 9.67 (bs, 1H), 8.41 (d, J=8.4 Hz, 1H),
8.13 (d, J=7.2 Hz, 1H), 8.01-7.98 (m, 2H), 7.66-7.57 (m, 4H),
7.29-7.22 (m, 2H), 7.09-7.06 (m, 2H), 7.02-6.98 (m, 1H), 6.52 (d,
J=7.6 Hz, 1H), 5.58-5.56 (m, 1H), 4.22-4.18 (m, 1H), 3.48-3.40 (m,
1H), 3.38-3.17 (m, 3H), 2.69-2.66 (m, 2H), 2.08-1.97 (m, 2H), 1.76
(d, J=6.4 Hz, 3H); m/z 436.42.
Example-23
2-Methyl-4-(34(R)-1-(naphthalen-1-yl)ethyl)amino)-1,2,3,4-tetrahydronaphth-
alen-1-y1)benzoic acid hydrochloride.
##STR00076##
[0368] The title compound was prepared by following the similar
ester hydrolysis procedure as described in Example-2a by taking
corresponding ester Example 21. Further, hydrochloride salt was
prepared by following the similar hydrochloride salt procedure as
described in Example-2a. .sup.1H NMR(400 MHz, DMSO): .delta. 12.76
(s, 1H), 10.24 (bs, 1H), 9.72 (bs, 1H), 8.41 (d, J=8.4 Hz, 1H),
8.14 (d, J=7.2 Hz, 1H), 8.01-7.97 (m, 2H),7.81 (d, J=8.0 Hz, 1H),
7.66-7.57 (m, 3H), 7.10-6.98 (m, 5H), 6.53 (d, J=7.6 Hz, 1H),
5.58-5.56 (m, 1H), 4.20-4.16 (m, 1H), 3.47-3.35 (m, 2H), 3.31-3.19
(m, 3H), 2.66-2.49 (m, 2H), 2.08-1.99 (m, 1H), 1.76 (d, J=6.4 Hz,
3H m/z 436.1
Example-24
Methyl 5
-((3S)-3-(2-(((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)ethyl)-1-
,2,3,4-tetrahydro naphthalen-1-yl)-2-methylbenzoate
##STR00077##
[0370] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-6 and
(3-(methoxycarbonyl)-4-methylphenyl)boronic acid; m/z 496.49.
Example-25
5-((3S)-3-(2-(((R)-1-(4-Fluoronaphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride
##STR00078##
[0372] The title compound was prepared by following the similar
ester hydrolysis procedure as described in Example-2a by taking
corresponding ester Example-24 given in Table-11. Further,
hydrochloride salt of these compounds was prepared by following the
similar hydrochloride salt procedure as described in
Example-2a.
[0373] .sup.1H NMR (400 MHz, DMSO): .delta. 12.80 (bs, 1H), 9.61
(bs, 1H), 9.12 (bs, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.13 (d, J=7.6 Hz,
1H), 7.95 (m, 1H), 7.77-7.69 (m, 2H), 7.58 (S, 1H), 7.53-7.48 (m,
1H), 7.23 (d, J=8.0 Hz, 2H), 7.10(m,2H), 6.98-6.96 (m, 1H), 6.56
(d, J=8.0 Hz, 1H), 5.29 (m, 1H), 4.07-4.03 (m, 1H), 3.15 (m, 1H),
2.93-2.81 (m, 2H), 2.60-2.50 (m, 2H), 2.46 (S, 3H),
1.75-1.66(m,4H), 1.66 (d, J=6.4 Hz, 3H); m/z 481.6.
Example-26a, 26b
Methyl
2-methyl-543S)-3-(24(R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3-
,4-tetrahydro naphthalen-1-yl)benzo ate
##STR00079##
[0375] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-7 and
(3-(methoxycarbonyl)-4-methylphenyl)boronic acid.
[0376] The two diastereomers were separated by chiral preparative
HPLC [CHIRAL PAK IA 250 mm.times.4.6,5 .mu.; A=n-hexane:IPA
(90:10%v/v, 0.1%DEA), B=IPA; A:B=95/5% V/V; Flow=1.0 ml/min] Isomer
`a`: t.sub.R=8.8, Isomer `b`: t.sub.R=11.35; m/z, 477.8. (t.sub.R
is retention time).
Example-27a, 27b
2-Methyl-543S)-3-(24(R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-tetr-
ahydro naphthalen-1-yl)benzoic acid hydrochloride
##STR00080##
[0378] The title compounds of Example-27a, 27b and its isomers were
prepared by following the similar ester hydrolysis procedure as
described in Example-2a by taking ester compound of Example-26a and
Example-26b. Further, hydrochloride salt of these compounds was
prepared by following the similar hydrochloride salt procedure as
described in Example-2a.
[0379] 27a: .sup.1H NMR (400 MHz, DMSO): .delta. 12.81 (bs, 1H),
9.87 (bs, 1H), 9.25 (bs, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.03-7.97 (m,
3H), 7.65-7.56 (m, 4H), 7.24-7.19 (m, 2H), 7.10-7.05 (m, 2H), 6.97
(m, 1H), 6.57 (d, J=8.0 Hz, 1H), 5.32 (m, 1H), 4.07-4.03 (m, 1H),
3.15 (m, 1H), 2.97-2.79(m, 2H), 2.62-2.60 (m, 2H), 2.46 (S, 3H),
1.73-1.71(m, 4H), 1.68 (d, J=6.4 Hz, 3H); m/z 463.6.
[0380] 27b: .sup.1H NMR (400 MHz, DMSO): .delta. 12.79 (bs, 1H),
9.73 (bs, 1H), 9.09 (bs, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.02-7.93 (m,
3H), 7.65-7.57 (m, 4H), 7.25-7.21 (m, 2H), 7.08-7.07 (m, 2H),
7.01-6.96 (m, 1H), 6.58(d, J=7.6 Hz, 1H), 5.33 (m, 1H), 4.10-4.09
(m, 1H), 3.15 (m, 1H), 2.97-2.79 (m, 2H), 2.62-2.60 (m, 2H), 2.49
(S, 3H), 1.73-1.71 (m, 4H), 1.67 (d, J=6.4 Hz, 3H); m/z 463.6
Example-28
Methyl
5-((3S)-3-(3-(((R)-1-(4-fluoronaphthalen-1-yl)ethyl)amino)propyl)-1-
,2,3,4-tetrahydro naphthalen-1-yl)-2-methylbenzoate
##STR00081##
[0382] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-8 and
(3-(methoxycarbonyl)-4-methylphenyl)boronic acid; m/z 510.1
Example-29
5-((3S)-3-(3-(((R)-1-(4-fluoronaphthalen1-yl)ethyl)amino)propyl)-1,2,3,4-t-
etrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride.
##STR00082##
[0384] The title compound was prepared by following the similar
ester hydrolysis procedure as described in Example-2a by taking
corresponding ester compound of Example-28. Further, hydrochloride
salt was prepared by following the similar hydrochloride salt
procedure as described in Example-2a.
[0385] .sup.1H NMR (400 MHz, DMSO): .delta. 12.80 (bs, 1H), 9.46
(bs, 1H), 9.04 (bs, 1H), 8.28 (d, J=8 Hz, 1H), 8.12 (d, J=7.6 Hz,
1H), 7.79-7.68 (m, 3H), 7.55 (m, 1H), 7.49-7.44 (m, 1H), 7.25-7.20
(m, 2H), 7.09-7.07 (m, 2H), 6.99-6.95 (m, 1H), 6.55 (d, J=7.6 Hz,
1H), 5.28 (q, J=6.8 Hz, 1H), 4.06-4.02 (m, 1H), 3.14-2.97 (m, 1H),
2.84-2.77 (m, 2H), 2.47 (s, 3H), 1.98-1.96 (m, 1H), 1.71-1.68 (m,
3H), 1.64 (d, J=6.8 Hz, 3H), 1.43-1.30 (m, 3H), 1.21 (m, 1H), m/z
496.49
Example-30
Methyl
2-methyl-543R)-3-(34(R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,-
3,4-tetrahy dronaphthalen-1-yl)benzoate
##STR00083##
[0387] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-9 and
(3-(methoxycarbonyl)-4-methylphenyl)boronic acid; m/z 492.0.
Example-31
2-Methyl-543R)-3-(34(R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-tet-
rahydro naphthalen-1-yl)benzoic acid hydrochloride
##STR00084##
[0389] The title compound was prepared by following the similar
ester hydrolysis procedure as described in Example-2a by taking
corresponding Example-30. Further, hydrochloride salt was prepared
by following the similar hydrochloride salt procedure as described
in Example-2a
[0390] .sup.1H NMR (400 MHz, DMSO): .delta. 12.80 (bs, 1H), 9.74
(bs, 1H), 9.16 (bs, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.02-7.95(m, 3H),
7.64-7.7.56 (m, 4H), 7.25-7.20 (m, 2H), 7.07 (d, J=8Hz, 2H),
7.00-6.96 (m, 1H), 6.57 (d, J=7.6 Hz, 1H), 5.31 (q, J=6.8 Hz, 1H),
4.08-4.07 (m, 1H), 2.98 (m, 1H), 2.81-2.78 (m, 2H), 2.45 (s, 3H),
1.98-1.96 (m, 1H), 1.77-1.75 (m, 3H), 1.67 (d, J=6.8 Hz, 3H),
1.41-1.23 (m, 3H), 1.10-1.07 (m, 1H); m/z 477.7.
Example-32
Methyl
5-((3S)-3-(3-(((R)-1-(4-fluoro-3-methoxyphenyeethyl)amino)propyl)-1-
,2,3,4-tetrahydronaphthalen-1-yl)-2-methylbenzoate
##STR00085##
[0392] The title compound was prepared by following the similar
procedure as described in Step-1 to Step-3 of Example-1 in
sequential manner by taking Intermediate-10 and
(3-(methoxycarbonyl)-4-methylphenyl)boronic acid; m/z 490.
Example-33
5-((3S)-3-(3-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)propyl)-1,2,3,4-
-tetrahydro naphthalen-1-yl)-2-methylbenzoic acid hydrochloride
##STR00086##
[0394] The title compound was prepared by following the similar
ester hydrolysis procedure as described in Example-2a by taking
corresponding Example-32. Further, hydrochloride salt was prepared
by following the similar hydrochloride salt procedure as described
in Example-2a. .sup.1H NMR (400 MHz, DMSO): .delta. 12.79 (bs, 1H),
9.51 (bs, 1H), 9.24 (bs, 1H), 7.59 (m, 1H), 7.57-7.54 (m, 1H),
7.28-7.23 (m, 3H), 7.11-7.06 (m, 3H), 7.00-6.96 (m, 1H), 6.58-6.55
(m, 1H), 4.35 (m, 1H), 4.10-4.06 (m, 1H), 3.85 (s, 3H), 2.85-2.18
(m, 2H), 2.67-2.56 (m, 2H), 2.02-2.00 (m, 1H), 1.75-1.72 (m, 3H),
1.57 (d, J=6.8 Hz, 3H), 1.47-1.40 (m, 1H), 1.36-1.31 (m, 2H),
1.27-1.23 (m, 2H), 1.10-1.02 (m, 1H); m/z 476.48
[0395] Similarly, the below examples 34 to 56 given in Table-3 can
also be prepared by following the similar procedure as described in
herein above.
TABLE-US-00003 TABLE 3 Ex. No. Name 34
2-Methyl-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 35
2,4-Dimethyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
- tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 36
2-Fluoro-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 37
4-Fluoro-3-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 38
2,3-Dimethyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
- tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 39
2-(3-(3-((((R)-1-(Naphthalen-1-yl)ethyl)amino)methyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzamido)acetic acid hydrochloride 40
2-Fluoro-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 41
3-Methyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 42
2,6-Dimethyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)
ethyl)-1,2,3,4- tetrahydro naphthalen-1-yl)benzoic acid
hydrochloride 43
2-Methyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 44
4-Methyl-3-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 45
2,4-Dimethyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,-
4- tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 46
2-Methyl-4-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 47
5-(3-(2-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)ethyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)-2-methylbenzoic acid hydrochloride 48
2,3-Dimethyl-5-(3-(2-(((R)-1-(naphthalen-1-yl)ethyl)amino)ethyl)-1,2,3,-
4- tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 49
3-Methyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 50
2,6-Dimethyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3-
,4- tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 51
2-Methyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 52
4-Methyl-3-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 53
2,4-Dimethyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3-
,4- tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 54
2-Methyl-4-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)benzoic acid hydrochloride 55
5-(3-(3-(((R)-1-(4-Fluoro-3-methoxyphenyl)ethyl)amino)propyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)-2-methylbenzoic acid hydrochloride 56
2,3-Dimethyl-5-(3-(3-(((R)-1-(naphthalen-1-yl)ethyl)amino)propyl)-1,2,3-
,4- tetrahydronaphthalen-1-yl)benzoic acid hydrochloride
Example-57a, 57b
Methyl
2-methyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-3,4-dih-
ydroquinolin-1(2H)-yl)benzoate
##STR00087##
[0397] To a suspension of Intermediate-14a (400 mg, 1.264 mmol) in
dry toluene (10 mL) under nitrogen atmosphere in sealed tube,
methyl 5-bromo-2-methylbenzoate (347 mg, 1.517 mmol) and cesium
carbonate (618 mg, 1.896 mmol) was added. The reaction mixture was
stirred for 10 minutes under nitrogen atmosphere at RT. To this
reaction mixture tris (dibenzylideneacetone) dipalladium (0) (57.9
mg, 0.063 mmol) and bis (tri-t-butylphosphine) palladium (0) (64.6
mg, 0.126 mmol) were added and stirred for another 20 minutes under
nitrogen atmosphere. The reaction mixture was heated to reflux and
maintained overnight. After completion of reaction, solvent was
removed and the resultant crude compound was purified by flash
chromatography by using 20% ethyl acetate in hexane to get
isomer-1a (RT-8.61) 180 mg, isomer-lb (RT-9.72) 80 mg.
m/z-465.1;
[0398] Example-57a: .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
8.17(d, J=8 Hz, 1H), 7.88-7.86 (m, 1H), 7.77-7.74 (m,2H), 7.66-7.63
(m, 1H), 7.50-7.43 (m, 3H), 7.27-7.21 (m, 2H), 7.02 (d, J=7.2Hz,
1H), 6.93-6.90 (m, 2H), 6.71-6.64 (m, 1H), 4.60 (m, 1H), 3.89 (s,
3H), 3.83-3.79 (m, 1H), 3.36-3.31 (m, 1H), 2.95-2.91 (m, 1H),
2.73-2.68 (m, 1H), 2.59-2.53 (m, 5H), 1.52 (d, J=6.8 Hz, 3H).
[0399] Similarly, Example-57b was prepared by following the similar
procedure as described in Example-57a by taking
Intermediate-14b.
[0400] .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 8.16 (d, J=9.2
Hz, 1H), 7.88-7.86 (m, 1H), 7.76-7.73 (m, 2H), 7.63 (d, J=7.2 Hz,
1H), 7.50-7.44 (m, 5H), 7.25-7.20 (m, 1H), 7.05 (d, J=7.6 Hz, 1H),
6.93-6.91 (m, 1H), 6.73-6.64 (m, 1H), 4.61-4.56 (m, 1H), 3.87 (s,
3H), 3.71-3.66 (m, 1H), 3.50-3.34 (m,1H), 3.69-3.62 (m, 1H),
2.69-2.53 (m, 6H), 1.62 (d, J=6.8 Hz, 3H).
[0401] The below Examples-58 to 68 given Table-4 were prepared by
following the similar procedures as described in Example-57a,57b by
taking any of corresponding intermediates 14a,14b, 16, 17, 18, 23,
28 and 29 with appropriately substituted halo phenyl ester.
[0402] The below Examples-58,59 and 62 given Table-4 were prepared
by following the similar procedures as described in Example-57a,57b
by taking any of corresponding intermediates 14a,14b.
[0403] Further, two diastereomers of Example-60 was separated by
using following chiral preparative HPLC method. Column: CELLULOSE
1, 250.times.4.6 5u; Mobile Phase : A: Hexane/IPA (95:5%v/v,
0.1%DEA) B=MEOH_ETOH 1:1 A:B=95/5%V/V Further, two diastereomers of
Example-61, 64 to 66 were separated by using following chiral
preparative HPLC method. Column: CHIRAL PAK IA, 250
mm.times.4.65.mu.; Mobile Phase: A=n-hexane: IPA (90:10% v/v, 0.1%
DEA), B=IPA, A=100%.
[0404] Further two diastereomers of Example-67 was separated by
using chiral preparative HPLC method. Column: CHIRAL IB
250.times.4.6 5u; Mobile Phase: A=(n-Hexane/IPA, 90/10, 0.1% DEA),
B=IPA A: B =85/15%V/V.
[0405] Further two diastereomer of Example-63 and 68 were separated
by using chiral preparative HPLC method. Column: CHIRAL CEL OJ-H
250.times.4.6 MM; Column: Mobile Phase: methanol_0.1% DEA_90_10%
ACN.
TABLE-US-00004 TABLE 4 Ex. Mass No. Structure (m/z) 58a, 58b
##STR00088## 465.42 59a, 59b ##STR00089## 479 60a, 60b ##STR00090##
483.11 61a, 61b ##STR00091## 463.1 62a, 62b ##STR00092## 465.42
63a, 63b ##STR00093## 483 64a, 64b ##STR00094## 478.8 65a, 65b
##STR00095## 509.56 66a, 66b ##STR00096## 493 67a, 67b ##STR00097##
496.7 68a, 68b ##STR00098## 523.57
Example-69a,69b
2-Methyl-5-(3-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)-3,4-dihydroqui-
nolin-1(211)-yl) benzoic acid hydrochloride
##STR00099##
[0407] To a mixture of Example-57a (180 mg, 0.387 mmol) in
tetrahydrofuran (5 mL), water (1 mL) MeOH (2 mL), LiOH (46.4 mg,
1.937 mmol) was added. The reaction mixture was heated to
80.degree. C. and maintained for 5 h. The progress of reaction was
monitored by TLC. After completion of reaction mixture was
distilled off under vacuum. The reaction mixture was cooled to
0.degree. C. and acidified with dilute HCl solution [pH=3 to 4].
The product was extracted with Ethyl acetate, and the organic layer
washed with water followed by brine solution, dried over anhydrous
sodium sulfate and concentrated under vacuum to get solid compound.
To this free base compound etheral HCl (2 mL) was added and stirred
for 10 minutes. The solvent was removed to get solid material; then
washed with n-pentane (2 mL) and dried under vacuum to get the
desired compound of Example-69a (90 mg, 51.6% yield).
[0408] m/z-450.7; .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.9
(bs, 1H), 9.78 (bs, 1H), 9.30 (bs, 1H), 8.16 (d, J=9.2 Hz, 1H),
8.0-7.96 (m, 3H), 7.62-7.56 (m, 4H), 7.29-7.24 (m, 2H), 7.00 (d,
J=6.8Hz, 1H), 6.91-6.87 (m, 1H), 6.68-6.64 (m, 1H), 6.53 (d, J=8.4
Hz, 1H), 5.36-5.31 (m, 1H), 4.61-4.56 (m, 1H), 3.71-3.66 (m, 1H),
3.50-3.34 (m, 1H), 3.62-2.96 (m, 1H), 2.69-2.53 (m, 6H), 1.62 (d,
J=6.8 Hz,3H).
[0409] Similarly, Example-69b was prepared by taking Example-57b by
following the similar procedure as described above.
[0410] m/z-450.7; .sup.1H NMR(400 MHz, DMSO-d.sub.6): .sup.1HNMR
(400 MHz, DMSO-d.sub.6): .delta. 13.0 (bs, 1H), 10.05 (bs, 1H),
9.29 (bs, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.03-7.95 (m, 3H), 7.63-7.56
(m, 4H), 7.31-7.24 (m, 2H), 6.98 (d, J=6.8 Hz 1H), 6.89-6.85 (m,
1H), 6.66-6.62 (m, 1H), 6.49 (d, J=8.4Hz, 1H), 5.34-5.31 (m, 1H),
3.86-3.83 (m, 1H), 3.40-3.29 (m, 4H), 3.16-3.01 (m, 1H), 2.96-2.93
(m, 1H), 2.83-2.80 (m, 1H), 2.67-2.61 (m, 2H), 1.69 (d, J=6.8Hz,
3H).
[0411] The below Examples-70 to 80 given Table-5 were prepared by
following the similar procedure as described in Example-69a.
Similarly hydrochloride salts were prepared by following the
similar procedure as mentioned in Example-69a.
TABLE-US-00005 TABLE 5 Ex. No. Structure Ester Mass (m/z) and
.sup.1H NMR 70a,70b ##STR00100## 4-Methyl-3-(3-((((R)-1-
(naphthalen-1-yl) ethyl) amino) methyl)-3,4-dihydro
quinolin-1(2H)-yl) benzoic acid hydrochloride 58a,58b 70a:
m/z-451.1; .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.97 (bs,
1H), 9.76 (bs, 1H), 9.19 (bs, 1H), 8.16 (d, J = 9.2 Hz, 1H),
8.0-7.97 (m, 3H), 7.80-7.70 (m, 1H), 7.64-6.47 (m, 3H), 7.43-7.41
(m, 1H), 7.00 (d, J = 6.8 Hz1H), 6.84-6.82 (m, 1H), 6.66-6.57 (m,
1H), 5.86-5.81 (m, 1H), 5.38-5.35 (m, 1H), 5.36-5.31 (m, 1H),
4.61-4.56 (m, 1H), 3.71-3.66 (m, 1H), 3.50-3.34 (m,1H), 3.62-2.96
(m, 1H), 2.17 (s, 3H), 1.96 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). 70b;
.sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.97 (bs, 1H), 9.61
(bs, 1H), 9.20 (bs, 1H), 8.24 (d, J = 8 Hz, 1H), 8.0-7.99 (m, 3H),
7.97-7.60 (m, 5H), 7.48-7.42 (m, 1H), 6.98 (d, J = 6.8 Hz, 1H),
6.87-6.81 (m, 1H), 6.60-6.56 (m, 1H), 5.87-5.83 (m, 1H), 5.37-5.36
(m, 1H), 3.62-3.60 (m, 1H), 3.69-3.64 (m, 1H), 3.50-3.34 (m, 1H),
3.61-2.94 (m, 1H), 2.17 (s, 3H), 1.96 (s, 3H), 1.62 (d, J = 6.8 Hz,
3H). 71a,71b ##STR00101## 2,6-Dimethyl-3-(3-((((R)-1-
(naphthalen-1-yl)ethyl) amino)methyl)-3,4-dihydro
quinolin-1(2H)-yl)benzoic acid hydrochloride 59a,59b 71a: m/z
465.36; .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 613.14 (bs,
1H), 9.97 (bs, 1H), 9.37 (bs, 1H), 8.22 (d, J = 9.2 Hz, 1H),
8.0-7.87 (m, 3H) , 7.63-7.55 (m, 3H), 7.17 (d, J = 8.4 Hz 1H),
7.08-7.00 (m, 1H), 6.95 (d, J = 7.2 Hz ,1H), 6.83-6.81 (m, 1H),
6.56-6.54 (m,1H), 5.81-5.79 (m, 1H), 5.36-5.34 (m, 1H), 4.61-4.56
(m, 1H),3.71-3.66 (m,1H), 3.50-3.34 (m, 1H), 3.62-2.96 (m,1H),
2.69-2.53 (m, 6H), 2.28 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). 71b: m/z
465.3; .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 13.14 (bs, 1H),
9.97 (bs, 1H), 9.37 (bs, 1H), 8.22 (d, J = 9.2 Hz, 1H), 8.0-7.87
(m, 3H), 7.63-7.55 (m, 3H),7.17(d, J = 8.4 Hz, 1H), 7.08-7.00 (m,
1H), 6.95 (d, J = 7.2 Hz, 1H), 6.83-6.81 (m, 1H), 6.56-6.54 (m,
1H), 5.81-5.79 (m, 1H), 5.36-5.34 (m,1H), 4.61-4.56 (m, 1H),
3.71-3.66 (m,1H), 3.50-3.34 (m, 1H), 3.62-2.96 (m, 1H), 2.69-2.53
(m, 6H), 2.28 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). 72a,72b
##STR00102## 5-(3-((((R)-1-(4-Fluoro naphthalen-1-yl) ethyl) amino)
methyl)-3,4-dihydro quinolin- 1(2H)-yl)-2-methylbenzoic acid
hydrochloride 60a,60b 72a: m/z 469.1; .sup.1HNMR (400 MHz,
DMSO-d.sub.6): .delta. 12.97 (bs,1H), 9.80 (bs, 1H), 9.29 (bs, 1H),
8.16 (d, J = 9.2 Hz, 1H), 8.14-8.12 (m, 1H), 8.03-7.0 (m, 1H),
7.72- 7.69 (m, 2H), 7.60 (d, J = 2 Hz,1H), 7.49- 7.45 (m, 1H),
7.29-7.25 (m, 2H), 6.99 (d, J = 7.6 Hz 1H), 6.89-6.87 (m, 1H),
6.68- 6.64 (m, 1H),6.52 (d, J = 8 Hz, 1H), 5.32- 5.31 (m, 1H),
4.61-4.56 (m, 1H), 3.71- 3.66 (m, 1H), 3.50-3.34 (m, 1H), 3.62-
2.96 (m, 1H), 2.69-2.53 (m,6H), 1.68 (d, J = 6.8 Hz, 3H) 72b:
.sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.96 (bs, 1H), 9.82
(bs, 1H), 9.18 (bs, 1H), 8.29 (d, J = 9.2 Hz,1H), 8.15-8.12 (m,
1H), 7.97-7.94 (m, 1H), 7.74-7.70 (m, 2H), 7.60 (d, J = 2 Hz, 1H),
7.48-7.45 (m, 1H), 7.31-7.25 (m, 2H), 7.00 (d, J = 7.6 Hz 1H),
6.88-6.87 (m, 1H), 6.67-6.66 (m, 1H), 6.51 (d, J = 8 Hz, 1H),
5.34-5.30 (m,1H), 3.82-3.80 (m, 1H), 3.30-3.28 (m, 2H), 3.05-2.79
(m, 5H), 2.67-2.58 (m, 2H), 1.68 (d, J = 6.8 Hz, 3H). 73a,73b
##STR00103## 5-(3-((((R)-1-(4-Fluoro-3- methoxyphenyl)ethyl)amino)
methyl)-3,4-dihydroquinolin-1 (2H)-yl)-2-methylbenzoic acid
hydrochloride 61a,61b 73a: m/z 448.61; .sup.1HNMR (400 MHz,
DMSO-d.sub.6): .delta. 13.1 (bs, 1H), 9.69 (bs, 1H), 9.42 (bs,
1H),7.61-7.58 (m, 2H),7.30-7.20 (m, 3H), 7.11-7.08 (m, 1H), 6.99
(d, J = 7.2 Hz, 1H), 6.91-6.87 (m, 1H), 6.68-6.64 (m, 1H), 6.53 (d,
J = 8 Hz, 1H), 4.37-4.33 (m, 2H), 3.84-3.79 (m, 4H), 3.31-3.26 (m,
1H), 2.96-2.87 (m, 2H), 2.61-2.44 (m, 5H), 1.62 (d, J = 6.8 Hz,
3H). 73b: .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.96 (bs,
1H), 9.65 (bs, 1H), 9.23 (bs, 1H), 7.60 (d, J = 7.2 Hz 1H),
7.54-7.51 (m, 1H), 7.29-7.21 (m, 3H), 7.08-7.00 (m, 2H), 6.86-6.87
(m, 1H), 6.68-6.64 (m, 1H), 6.52 (d, J = 8 Hz, 1H), 4.37-4.36 (m,
2H), 3.84-3.84 (m, 4H), 3.28-3.25 (m, 1H), 2.96-2.85 (m, 2H),
2.67-2.55 (m, 5H), 1.62 (d, J = 6.8 Hz, 3H). 74a,74b ##STR00104##
2-Methyl-4-(3-((((R)-1- (naphthalen-1-yl)ethyl)
amino)methyl)-3,4-dihydro quinolin-1(2H)-yl)benzoic acid
hydrochloride 62a,62b 74a: m/z 451; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 10.13 (bs, 1H), 9.36 (bs, 1H), 8.18 (d, J =
7.6 Hz, 1H), 8.01-7.98 (m, 2H), 7.97-7.95 (m, 2H), 7.63-7.56 (m,
3H), 7.08-6.93 (m, 4H), 6.91-6.77 (m, 2H), 5.33-5.31 (m, 1H),
3.94-3.91 (m, 1H), 3.71-3.66 (m, 1H), 3.50-3.34 (m, 1H), 3.62-2.96
(m, 1H), 2.95-2.77 (m, 1H), 2.69-2.53 (m, 5H), 1.66 (d, J = 6.8 Hz,
3H). 74b: .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 10.13 (bs,
1H), 9.42 (bs, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.2 Hz,
1H), 8.01-7.95 (m, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.61-7.55 (m,
3H), 7.07-6.92 (m, 4H), 6.91 (d, J = 7.6 Hz, 1H), 6.81-6.78 (m,
1H), 5.34-5.29 (m, 1H), 4.19-4.01 (m, 1H), 3.71-3.66 (m, 1H),
3.50-3.34 (m, 1H), 3.62-2.96 (m, 1H), 2.95-2.77 (m, 1H), 2.69-2.53
(m, 5H), 1.62 (d, J = 6.8 Hz, 3H). 75a,75b ##STR00105##
5-(6-Fluoro-3-((((R)-1- 7.20 (m, 2H), 6.89-6.86
(naphthalen-1-yl)ethyl) amino)methyl)-3,4-dihydro
quinolin-1(2H)-yl)-2-methyl benzoic acid hydrochloride 63a,63b 75a:
m/z 469.48; .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 13.0 (bs,
1H), 9.98 (s, 1H), 9.36 (s, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.02-
7.96 (m, 3H), 7.62-7.57 (m, 4H), 7.27- 7.20 (m, 2H), 6.89-6.86 (m,
1H), 6.78- 6.73 (m, 1H), 6.55-6.52 (m, 1H), 5.34- 5.30 (m, 1H),
3.84-3.81 (m, 1H), 3.29- 3.24 (m, 1H), 3.08-3.06 (m, 1H), 2.96-
2.80 (m, 2H), 2.66-2.68 (m, 5H), 1.62 (d, J = 6.8 Hz, 3H). 75b:
.sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.93 (bs, 1H), 9.86
(s, 1H), 9.19 (bs, 1H), 8.19 (d, J = 8.0 Hz,1H), 8.02-7.96 (m, 3H),
7.62-7.56 (m, 4H), 7.30-7.22 (m, 2H), 6.89-6.86 (m, 1H), 6.75-6.73
(m, 1H), 6.53-6.49 (m, 1H), 5.35-5.31 (m, 1H), 3.84-3.79 (m, 1H),
3.31-3.26 (m, 1H), 3.08-3.06 (m, 1H), 2.96-2.80 (m, 2H), 2.66-2.68
(m, 5H), 1.68 (d, J = 6.8 Hz, 3H). 76a,76b ##STR00106##
2-Methyl-5-(3-(2-(((R)-1- (naphthalen-1-yl)ethyl) amino)
ethyl)-3,4-dihydro quinolin- 1(2H)-yl)benzoic acid hydrochloride
64a,64b 76a: m/z = 465.42; .sup.1HNMR (400 MHz, DMSO-d.sub.6):
.delta. 12.99 (bs, 1H), 9.45 (bs, 1H), 8.99 (bs, 1H), 8.25 (d, J =
8.8 Hz, 1H), 8.01 (t, J = 7.6 Hz, 2H), 7.85 (d, J = 7.6 Hz, 1H),
7.66-7.58 (m, 4H), 7.31-7.26 (m, 2H), 7.00 (d, J = 7.2 Hz, 1H),
6.89 (d, J = 8 Hz, 1H), 6.66 (t, J = 7.2 Hz, 1H), 6.54 (t, J = 7.6
Hz, 1H), 5.33 (m, 1H), 3.59-3.55 (m, 1H), 3.22-3.19 (m, 2H),
2.93-2.83 (m, 2H), 2.52 (s, 3H), 2.07-1.95 (m, 2H), 1.75-1.73 (m,
2H), 1.67 (d, J = 6.4 Hz, 3H); 76b: .sup.1HNMR (400 MHz,
DMSO-d.sub.6): .delta. 12.90 (bs, 1H), 9.52 (bs, 1H), 9.04 (bs,
1H), 8.23 (d, J = 8 Hz, 1H), 8.02 (t, J = 7.6 Hz, 2H), 7.99 (d, J =
7.6 Hz, 1H), 7.64-7.59 (m, 4H), 7.30-7.24 (m, 2H), 7.01 (d, J = 7.2
Hz, 1H), 6.91 (d, J = 8 Hz, 1H), 6.66 (t, J = 7.2 Hz, 1H), 6.54 (t,
J = 7.6 Hz, 1H), 5.31 (m, 1H), 3.61 (m, 1H), 3.22-3.19 (m, 2H),
2.93-2.83 (m, 2H), 2.50 (s, 3H), 2.07-1.95 (m, 2H), 1.72-1.71 (m,
2H), 1.67 (d, J = 6.4 Hz, 3H). 77a,77b ##STR00107##
2-(2-methyl-5-(3-(2-(((R)-1- (naphthalen-1-yl)ethyl)
amino)ethyl)-3,4- dihydroquinolin-1(2H)-yl) phenoxy)acetic acid
hydrochloride 65a,65b 77a: m/z = 495.49, .sup.1HNMR (400 MHz,
DMSO-d.sub.6): .delta. 12.99 (bs, 1H), 9.78 (bs, 1H), 9.13 (bs,
1H), 8.24 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 8.8 Hz, 2H), 7.94 (d, J
= 7.2 Hz, 1H), 7.66-7.58 (m, 3H), 7.14 (d, J = 7.6 Hz, 1H), 6.96
(d, J = 7.6 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.67 (d, J = 8 Hz,
2H), 6.60 (t, J = 7.2 Hz, 1H), 6.52 (d, J = 8 Hz, 1H), 5.31-5.28
(m, 1H), 4.66 (s, 2H), 3.78 (m, 1H), 3.56-3.53 (m,1H), 3.37-3.36
(m, 2H), 2.89-2.80 (m, 2H), 2.18 (s, 3H), 2.0 6 (m, 1H), 1.76-1.74
(m, 2H), 1.69 (d, J = 6.4 Hz, 3H); 77b: .sup.1HNMR (400 MHz,
DMSO-d.sub.6): .delta. 12.98 (bs, 1H), 9.55 (bs, 1H), 9.04 (bs,
1H), 8.24 (d, J = 8 Hz, 1H), 8.00 (t, J = 7.6 Hz, 2H), 7.89 (d, J =
7.2 Hz, 1H), 7.65-7.58 (m, 3H), 7.14 (d, J = 7.6 Hz, 1H), 6.98 (d,
J = 6.8 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.68 (d, J = 8 Hz, 2H),
6.61 (t, J = 7.2 Hz, 1H), 6.52 (d, J = 8 Hz, 1H), 5.31-5.30 (m,
1H), 4.65 (s, 2H), 3.41-3.36 (m, 2H), 3.20-3.15 (m, 2H), 2.90-2.85
(m, 3H), 2.18 (s, 3H) ,1.76-1.74 (m, 2H), 1.69 (d, J = 6.4 Hz, 3H).
78a,78b ##STR00108## 2-Methyl-5-(3-(3-(((R)-1-
(naphthalen-1-yl)ethyl) amino) propyl)-3,4-dihydro quinolin-
1(2H)-yl)benzoic acid hydrochloride 66a,66b 78a: m/z = 479.42,
.sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.90 (bs, 1H), 9.49
(bs, 1H), 9.04 (bs, 1H), 8.26 (d, J = 8 Hz, 1H), 8.03 (dd, J = 7.6
Hz, 1.6 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H), 7.64-7.58 (m, 3H), 7.29
(d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 6.8 Hz,
1H), 6.67 (t, J = 6.8 Hz, 2H), 6.65 (t, J = 7.2 Hz, 1H), 6.56(d, J
= 8 Hz, 2H), 5.33-5.30 (m, 1H), 3.60 (m, 1H), 3.17 (m, 1H), 3.03
(m, 1H), 2.81-2.80 (m, 1H), 2.68-2.67 (m, 2H),2.50 (s, 3H), 1.98
(m, 1H), 1.75 -1.73 (m, 2H), 1.69 (d, J = 6.4 Hz, 3H), 1.34 (m,
2H); 78b: .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.99 (bs,
1H), 9.84 (bs, 1H), 9.21 (bs, 1H), 8.24 (d, J = 8 Hz, 1H),
8.02-7.97 (m, 3H), 7.63-7.57 (m, 4H), 7.31(d, J = 9.6 Hz, 2H), 7.01
(t, J = 7.2 Hz, 1H), 6.90 (d, J = 6.8 Hz, 1H), 6.67 (t, J = 6.8 Hz,
1H), 6.56 (d, J = 8.4 Hz, 1H), 5.28-5.27 (m, 1H), 3.58- 3.56 (m,
1H), 3.39-3.37(m, 1H), 3.20-3.15 (m, 1H), 3.03 (m, 1H), 2.85-2.81
(m, 2H), 2.50 (s, 3H), 1.98 (m, 1H), 1.75-1.72 (m, 2H), 1.67 (d, J
= 6.4 Hz, 3H), 1.34-1.29 (m, 2H). 79a,79b ##STR00109##
3-(3-(3-(((R)-1-(4-Fluoro naphthalen-1-yl)ethyl)
amino)propyl)-3,4-dihydro quinolin-1(2H)-yl)-2-methyl benzoic acid
hydrochloride 67a,67b 79a: m/z = 496.7; .sup.1HNMR (400 MHz,
DMSO-d.sub.6): .delta. 12.99 (bs, 1H), 9.59 (bs, 1H), 9.09 (bs,
1H), 8.34 (d, J = 6.4 Hz, 1H), 8.15 (dd, J = 7.6 Hz, 1.6 Hz, 1H),
7.95-7.91 (m, 1H), 7.76-7.69 (m, 3H), 7.51 (t, J = 8.8 Hz, 1H),
7.38 (d, J = 8.8 Hz, 2H) , 6.80 (t, J = 7.6 Hz, 1H), 6.96 (d, J =
7.6 Hz, 1H), 6.55 (t, J = 7.6 Hz,1H), 5.79 (t, J = 8.4 Hz, 1H) ,
5.28 (m,1H), 3.53-3.48 (m, 1H), 3.25 -3.20 (m, 2H), 3.08-2.86 (m,
1H), 2.82-2.67 (m, 2H), 2.28-2.24 (m, 3H), 2.12-2.01 (m, 1H), 1.91
(m, 2H), 1.67 (d, J = 6.4 Hz, 3H), 1.36-1.34 (m, 2H); 79b:
.sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.98 (bs, 1H), 9.29
(bs, 1H), 9.28 (bs, 1H), 8.34 (d, J = 6.4 Hz, 1H), 8.15 (dd, J =
7.6 Hz, 1.6 Hz, 1H), 7.86-7.83 (m, 1H), 7.79-7.71 (m, 3H), 7.52 (t,
J = 8.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 6.96 (t, J = 7.6 Hz,
1H), 6.80 (d, J = 7.6 Hz, 1H), 6.58 (t, J = 7.6 Hz, 1H), 5.79 (t, J
= 8.4 Hz, 1H), 5.30 (m, 2H), 2.82-2.67 (m, 2H), 2.68-2.67 (m, 1H),
2.33-2.32 (m, 1H), 2.28-2.25 (m, 3H), 2.0(m, 1H) , 1.7 (m, 2H),
1.66 (d, J = 6.4 Hz, 3H), 1.36-1.34 (m, 2H), 1.23- 1.22 (m, 1H).
80a,80b ##STR00110## 2-(2-Methyl-5-(3-(3(((R)-1-
(naphthalen-1-yl)ethyl) amino) propyl)-3,4-dihydro quinolin-
1(2H)-yl)phenoxy) acetic acid hydrochloride 68a,68b 80a: m/z =
509.56, .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 12.99 (bs, 1H),
9.65 (bs, 1H), 9.12 (bs,1H), 8.24 (d, J = 8.4 Hz, 1H), 8.02-7.96
(m, 2H), 7.93 (d, J = 6.8 Hz, 1H), 7.65-7.58 (m, 3H), 7.14 (d, J =
7.6 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H),
6.69 (d, J = 8 Hz, 2H), 6.62 (t, J = 7.2 Hz,1H), 6.54 (d, J = 8
Hz,1H), 5.31- 5.26 (m, 1H), 4.66 (s, 2H), 3.41-3.36 (m, 2H),
3.19-3.17 (m, 1H), 2.86-2.81 (m, 1H), 2.85-2.75 (m, 2H), 2.17 (s,
3H), 1.98 (m, 1H), 1.75 -1.73 (m, 2H), 1.69 (d, J = 6.4 Hz, 3H)
1.35-1.28 (m, 2H); 80b: .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta.
12.98 (bs, 1H), 9.72 (bs, 1H), 9.12 (bs,1H), 8.26 (d, J = 8.4 Hz,
1H), 8.03-7.98 (m, 2H), 7.93 (d, J = 6.8 Hz, 1H) , 7.66- 7.58 (m,
3H), 7.14 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.86 (t, J
= 7.2 Hz, 1H), 6.69 (d, J = 8 Hz, 2H), 6.61 (t, J = 7.2 Hz, 1H),
6.53 (d, J = 8 Hz, 1H), 5.31-5.28 (m, 1H), 4.65 (s, 2H), 3.19-3.17
(m, 1H), 2.86-2.81 (m, 1H), 2.84-2.80 (m, 2H), 2.16 (s, 3H), 1.98
(m, 1H), 1.91 (m, 2H), 1.76-1.73 (m, 2H), 1.67 (d, J = 6.4 Hz, 3H)
1.35-1.31 (m, 2H).
In-vitro Pharmacological Activity
[0412] Certain illustrative compounds within the scope of the
invention are screened for CaSR activity according to the procedure
given below. The screening of the compounds may also be carried by
other methods and procedures known to skilled in the art.
[0413] In-vitro assay method of Calcimimetics through modulation of
Calcium Sensing Receptor (CaSR):
[0414] The ability of the compounds to modulate Calcium sensing
receptor is determined by measuring an increase in intracellular
calcium [Ca.sup.2+].sub.i. Stably transfected HEK293 cells
expressing hCaSR_pTriEx-3 hygro vector are developed. Cells are
grown overnight on a 96-well plate to 80% confluency in Ham's F12
containing 20% FBS at 37.degree. C., 5% CO.sub.2 Subsequently,
cells are washed extensively with 20 mM HEPES buffer containing 126
mM NaCl.sub.2, 1 mM MgCl.sub.2 and 4 mM KCl to remove serum
components that might interfere with the assay. Cells are loaded
with calcium sensing Fluo4NW dye in HEPES base buffer containing
0.1% BSA and lmg/ml glucose for 30 minutes to measure changes in
intracellular calcium. The activities of the compounds are measured
in FLIPR using 0.3 mM CaCl.sub.2 in 20 mM HEPES base buffer. The
effectiveness of the compound to modulate receptor activity is
determined by calculating the EC.sub.50 responses for that compound
in an 8-point assay and plotted using GraphPad Prism 5.
[0415] The compounds prepared were tested using the above assay
procedure and the results obtained are given below. The EC.sub.50
(nM) values of few representative compounds are set forth in
Table-6.
[0416] The in-vitro activity data has been given in Table-6 for
representative compounds.
TABLE-US-00006 TABLE 6 Example number EC.sub.50 Range 2a, 7a, 7b,
8a, 8b, 10a, 10b, 10c, 13b, less than 20 nM 14b, 16a, 17, 19a, 27a,
27b, 29, 31, 69a, 71a, 73a, 75a, 77b, 78b, 79a, 79b 2c, 7c, 8d, 9b,
13a, 16b, 19b, 22, 23, 25, between 20.01 to 50.00 nM 72b, 76b, 80b
2b, 8c, 9c, 14a, 70b, 73b, between 50.01 to 200 nM
[0417] Thus, the above in-vitro assay method shows that the
compounds of the invention were found to exhibit agonistic activity
for CaSR, thereby showing utility for treating diseases, disorders
associated with the modulation of CaSR.
In-vivo Activity in CKD Wistar Rats
[0418] Animals were fed with 0.75% adenine diet for a period of 28
days for development of chronic kidney disease (CKD). After
measurement of plasma PTH on day 28, animals were randomized based
on plasma PTH (intact PTH) levels before using them for the study.
Overnight fasted animals were bled retro-orbitally to collect basal
blood sample (0.5 ml). Rats were dosed orally with vehicle and with
test compounds where they Formulated in PEG 300:PG:Captisol
(20:15:65). Six to eight animals were used in each group then
compounds of the invention were administered at 1 mg/kg dose. Post
2 h oral dosing animals were fed with feed and water ad libitum.
Post treatment blood samples were collected by retro-orbital
bleeding under light ether anesthesia at different time points for
plasma PTH estimation. Plasma PTH was measured using sandwich ELISA
kits (Immunotopics, USA). Percentage suppression of plasma PTH was
calculated with respect to individual basal untreated values by
using the following Formula
Percent suppression = Pre - treated individual value - Post -
treated individual Pre - treated individual value .times. 100
##EQU00001##
[0419] Thus, the above in-vivo method shows that the compounds of
the invention were found to exhibit suppress plasma PTH levels,
thereby showing utility for treating diseases, disorders associated
with the modulation of CaSR.
* * * * *