US2002173645A1PendingUtilityA1
Non-solvated crystalline 6-hydroxy-2- (4-hydroxyphenyl) -3- [4- (2-piperidinoethoxy) benzoyl] benzo [b] thiophene hydrochloride
Priority: Sep 19, 1994Filed: Feb 26, 2002Published: Nov 21, 2002
Est. expirySep 19, 2014(expired)· nominal 20-yr term from priority
Inventors:Wayne Douglas Luke
A61P 5/24A61P 43/00C07D 333/56A61P 15/18C07D 409/10
51
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Claims
Abstract
The present invention is directed to chemical processes for preparing 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl]benzo[b]-thiophenes. The present invention is also directed to crystalline solvates and a non-solvated crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride, as well as processes for their preparation.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A process for preparing a crystalline solvate of a compound of the formula
wherein:
R 1 is hydrogen or hydroxyl;
R 2 and R 3 are independently C 1 -C 4 alkyl, or R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr;
comprising the steps of:
(a) acylating a benzothiophene of the formula
wherein:
R 4 is hydrogen or C 1 -C 4 alkoxy, and
R 5 is C 1 -C 4 alkyl,
with an acylating agent of the formula
wherein:
R 6 is chloro, bromo, or hydroxyl, and
HX, R 2 , and R 3 are as defined above,
in the presence of BX′ 3 , wherein X′ is chloro or bromo;
(b) dealkylating one or more phenolic groups of the acylation product of step (a) by reacting with additional BX 3 ′, wherein X′ is as defined above; and
(c) isolating the crystalline solvate.
2 . The process of claim 1 wherein R 6 is chloro and HX is HCl.
3 . The process of claim 2 wherein R 1 is hydroxyl and R 4 is C 1 -C 4 alkoxy.
4 . The process of claim 3 wherein R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, and hexamethyleneimino.
5 . The process of claim 4 wherein X′ is chloro.
6 . The process of claim 5 wherein R 4 is methoxy and R 5 is methyl.
7 . The process of claim 6 wherein R 2 and R 3 together with the adjacent nitrogen atom form a piperidino group.
8 . The process of claim 7 wherein the acylation is conducted in the presence of 2-5 molar equivalents of BCl 3 .
9 . The process of claim 7 wherein the dealkylation is conducted in presence of 3-10 molar equivalents of BCl 3 .
10 . The process of claim 7 wherein the reaction solvent is one or more solvents selected from the group consisting of chloroform, methylene chloride, 1,2-dichloroethane, 1,2,3-trichloropropane, 1,1,2,2-tetrachloroethane, 1,2-dichlorobenzene, chlorobenzene, and fluorobenzene.
11 . The process of claim 7 wherein the reaction solvent is 1,2-dichloroethane.
12 . A process for preparing a compound of the formula
or the hydrochloride or hydrobromide salt thereof, wherein:
R 4 is hydrogen or C 1 -C 4 alkoxy;
R 5 is C 1 -C 4 alkyl; and
R 2 and R 3 are independently C 1 -C 4 alkyl, or R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino;
comprising acylating a benzothiophene of the formula
wherein:
R 4 and R 5 are as defined above,
with an acylating agent of the formula
wherein:
R 6 is chloro, bromo, or hydroxyl;
R 2 and R 3 are independently C 1 -C 4 alkyl, or R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr;
in the presence of BX′ 3 , wherein X′ is chloro or bromo.
13 . The process of claim 12 wherein R 6 is chloro and HX is HCl.
14 . The process of claim 13 wherein R 4 is C 1 -C 4 alkoxy.
15 . The process of claim 14 wherein R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, and hexamethyleneimino.
16 . The process of claim 15 wherein X′ is chloro.
17 . The process of claim 16 wherein R 4 is methoxy, and R 5 is methyl.
18 . The process of claim 17 wherein R 2 and R 3 together with the adjacent nitrogen atom form a piperidino group.
19 . The process of claim 18 wherein the acylation is conducted in the presence of 2-5 molar equivalents of BCl 3 .
20 . The process of claim 18 wherein the reaction solvent is one or more solvents selected from the group consisting of chloroform, methylene chloride, chlorobenzene, 1,2-dichloroethane, 1,2,3-trichloropropane, 1,1,2,2-tetrachloroethane, 1,2-dichlorobenzene, bromobenzene, and fluorobenzene.
21 . The process of claim 18 wherein the reaction solvent is methylene chloride.
22 . A process for preparing a crystalline solvate of a compound of the formula
wherein
R 1 is hydrogen or hydroxyl;
R 2 and R 3 are independently C 1 -C 4 alkyl, or R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr;
comprising (a) dealkylation of one or more of the phenolic groups of a compound of the formula
wherein:
R 4 is hydrogen or C 1 -C 4 alkoxy;
R 5 is C 1 -C 4 alkyl; and
HX, R 2 , and R 3 are as defined above;
by reacting with BX′ 3 , wherein X′ is chloro or bromo; and
(b) isolating the crystalline solvate.
23 . The process of claim 22 wherein X′ is chloro and HX is HCl.
24 . The process of claim 23 wherein R 1 is hydroxyl and R 4 is C 1 -C 4 alkoxy.
25 . The process of claim 24 wherein R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, and hexamethyleneimino.
26 . The process of claim 25 wherein R 4 is methoxy and R 5 is methyl.
27 . The process of claim 26 wherein R 2 and R 3 together with the adjacent nitrogen atom form a piperidino group.
28 . The process of claim 27 wherein the reaction solvent is one or more solvents selected from the group consisting of methylene chloride, chlorobenzene, 1,2-dichloroethane, chloroform, 1,1,2,2-tetrachloroethane, 1,2,3-trichloropropane, 1,2-dichlorobenzene, and fluorobenzene.
29 . The process of claim 27 wherein the reaction solvent is 1,2-dichloroethane.
30 . A crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
d-line spacing
I/I o
(Angstroms)
(×100)
10.4311
22.64
8.9173
10.73
8.4765
5.31
8.0095
50.39
7.3068
4.23
6.6094
79.23
5.6196
22.34
5.4223
89.86
5.1959
11.81
5.0746
74.90
4.8017
100.00
4.7262
57.97
4.6569
53.35
4.5378
96.75
4.4376
10.83
4.3397
56.89
4.2782
48.23
4.2129
40.94
4.1037
12.80
3.9880
14.76
3.8863
8.17
3.7999
42.13
3.7662
57.09
3.6738
38.58
3.5701
18.50
3.5393
19.00
3.4622
39.57
3.3867
5.02
3.3321
4.33
3.2686
6.79
3.1535
14.86
3.0450
13.58
2.9028
12.30
2.8302
19.59
2.7544
12.30
2.6366
6.89
31 . The crystalline solvate of claim 30 which is a 1,2-dichloroethane solvate.
32 . The crystalline solvate of claim 30 which is a 1,2,3-trichloropropane solvate.
33 . A crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
d-line spacing
I/I o
(Angstroms)
(×100)
16.1265
3.80
10.3744
8.63
8.3746
5.29
7.9883
36.71
7.2701
5.06
6.5567
70.77
6.2531
6.79
5.5616
24.05
5.3879
100.00
5.0471
89.64
4.7391
85.96
4.6777
39.36
4.6332
62.60
4.5191
77.56
4.2867
36.82
4.2365
41.66
4.1816
49.60
4.0900
11.28
3.9496
11.85
3.7869
36.25
3.7577
56.16
3.6509
40.62
3.5751
15.65
3.5181
21.52
3.4964
18.53
3.4361
33.60
3.3610
6.21
3.3115
4.95
3.2564
7.36
3.2002
3.80
3.1199
15.77
3.0347
14.84
2.8744
9.67
2.8174
10.82
2.7363
11.51
34 . The crystalline solvate of claim 33 which is a 1,2-dichloroethane solvate.
35 . A process for preparing the crystalline solvate of claim 30 , comprising the steps of: (a) dealkylating the hydrochloride salt of a compound of the formula
wherein R 7 is C 1 -C 4 alkyl,
by reacting with BCl 3 in an organic solvent selected from the group consisting of 1,2-dichloroethane and 1,2,3-trichloropropane; (b) quenching the reaction of step (a) with methanol; and (c) isolating the crystalline solvate.
36 . The process of claim 35 wherein the organic solvent is 1,2-dichloroethane.
37 . The process of claim 36 wherein R 7 is methyl.
38 . The process of claim 35 wherein the organic solvent is 1,2,3-trichloropropane.
39 . A process for preparing the crystalline solvate of claim 33 , comprising the steps of:
(a) dealkylating the hydrochloride salt of a compound of the formula wherein R 7 is C 1 -C 4 alkyl, by reacting with BCl 3 in 1,2-dichloroethane; (b) quenching the reaction of step (a) with ethanol; and (c) isolating the crystalline solvate.
40 . The process of claim 39 wherein R 7 is methyl.
41 . A process for preparing a crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
d-line spacing
I/I o
(Angstroms)
(x100)
14.3518
7.24
10.3335
6.17
8.8305
4.29
7.9475
38.16
6.5904
64.25
6.2848
6.52
5.6048
28.06
5.4107
100.00
5.1544
11.26
5.0493
53.26
5.0224
46.11
4.8330
76.94
4.7694
34.23
4.6461
50.22
4.5754
38.61
4.4953
72.65
4.3531
49.15
4.2940
41.64
4.2425
35.75
4.1856
21.63
4.1338
9.47
4.0793
12.69
3.9960
18.50
3.9037
9.03
3.7854
40.39
3.7521
54.16
3.6787
28.60
3.6509
17.96
3.5444
31.72
3.4679
41.55
3.3899
7.69
3.3101
5.72
3.2561
7.42
3.1784
15.19
3.0445
11.17
3.0146
8.94
2.9160
11.89
2.8217
18.23
2.7500
12.06
2.6436
9.65
2.6156
6.97
comprising the steps of:
(a) dealkylating the hydrochloride salt of a compound of the formula
wherein R 7 is C 1 -C 4 alkyl,
by reacting with BCl 3 in chlorobenzene;
(b) quenching the reaction of step (a) with methanol; and
(c) isolating the crystalline solvate.
42 . The process of claim 41 wherein R 7 is methyl.
43 . A process for preparing a crystalline solvate of a compound of the formula
wherein:
R 1 is hydrogen or hydroxyl;
R 2 and R 3 are independently C 1 -C 4 alkyl, or R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr;
comprising the steps of:
(a) chlorinating with phosgene a compound of the formula
wherein:
HX, R 2 , and R 3 are as defined above, and
R 6 is hydroxyl
to produce a formula III compound wherein R 6 is chloro;
(b) acylating a benzothiophene of the formula
wherein:
R 4 is hydrogen or C 1 -C 4 alkoxy, and
R 5 is C 1 -C 4 alkyl,
with a compound of formula III, wherein R 6 is chloro, in the presence of BX′ 3 , wherein X′ is chloro or bromo;
(c) dealkylating one or more phenolic groups of the acylation product of step (b) by reacting with additional BX′ 3 , wherein X′ is as defined above; and
(d) isolating the crystalline solvate.
44 . The process of claim 43 wherein R 1 is hydroxyl and R 4 is C 1 -C 4 alkoxy.
45 . The process of claim 44 wherein X′ is chloro and HX is HCl.
46 . The process of claim 45 wherein R 4 is methoxy and R 5 is methyl.
47 . The process of claim 46 wherein R 2 and R 3 together with the adjacent nitrogen atom form a piperidino group.
48 . A process for preparing a crystalline solvate of a compound of the formula
wherein:
R 1 is hydrogen or hydroxyl;
R 2 and R 3 are independently C 1 -C 4 alkyl, or R 2 and R 3 together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, and morpholino; and
HX is HCl or HBr;
comprising the steps of:
(a) chlorinating a compound of the formula
wherein:
HX, R 2 , and R 3 are as defined above, and
R 6 is hydroxyl,
with a chlorination reagent to produce a formula III compound wherein R 6 is chloro;
(b) removing the excess chlorination agent;
(c) acylating a benzothiophene of the formula
wherein:
R 4 is hydrogen or C 1 -C 4 alkoxy, and
R 5 is C 1 -C 4 alkyl,
with a compound of formula III, wherein R 6 is chloro, in the presence of BX′3, wherein X′ is chloro or bromo;
(d) dealkylating one or more phenolic groups of the acylation product of step (c) by reacting with additional BX′3, wherein X′ is as defined above; and
(e) isolating the crystalline solvate.
49 . The process of claim 48 wherein R 1 is hydroxyl and R 4 is C 1 -C 4 alkoxy.
50 . The process of claim 49 wherein X′ is chloro and HX is HCl.
51 . The process of claim 50 wherein R 4 is methoxy and R 5 is methyl.
52 . The process of claim 51 wherein R 2 and R 3 together with the adjacent nitrogen atom form a piperidino group.
53 . A process for preparing the crystalline solvate of claim 30 , comprising the steps of:
(a) acylating a benzothiophene of the formula wherein:
R 4 is C 1 -C 4 alkoxy and R 5 is C 1 -C 4 alkyl, with an acylating agent of the formula
wherein:
R 6 is chloro, and R 2 and R 3 together with the adjacent nitrogen atom form a piperidino group, and HX is HCl, in the presence of BCl 3 in an organic solvent selected from the group consisting of 1,2-dichloroethane and 1,2,3-trichloropropane;
(b) dealkylating the hydrochloride salt of the compound of the formula wherein R 7 is C 1 -C 4 alkyl; by reacting with additional BCl 3 ; (c) quenching the reaction of step (b) with methanol; and (d) isolating the crystalline solvate.
54 . The process of claim 53 wherein the organic solvent is 1,2-dichloroethane.
55 . The process of claim 53 wherein R 4 is methoxy, and R 5 and R 7 are methyl.
56 . A process for preparing the crystalline solvate of claim 33 , comprising the steps of:
(a) acylating a benzothiophene of the formula wherein:
R 4 is C 1 -C 4 alkoxy and R 5 is C 1 -C 4 alkyl, with an acylating agent of the formula
wherein:
R 6 is chloro, and R 2 and R 3 together with the adjacent nitrogen atom form a piperidino group, and HX is HCl, in the presence of BCl 3 in 1,2-dichloroethane;
(b) dealkylating the hydrochloride salt of the compound of the formula wherein R 7 is C 1 -C 4 alkyl; by reacting with additional BCl 3 ; (c) quenching the reaction of step (b) with ethanol; and (d) isolating the crystalline solvate.
57 . The process of claim 56 wherein R 4 is methoxy, and R 5 and R 7 are methyl.
58 . A process for preparing a crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
d-line spacing
I/I o
(Angstroms)
(x100)
14.3518
7.24
10.3335
6.17
8.8305
4.29
7.9475
38.16
6.5904
64.25
6.2848
6.52
5.6048
28.06
5.4107
100.00
5.1544
11.26
5.0493
53.26
5.0224
46.11
4.8330
76.94
4.7694
34.23
4.6461
50.22
4.5754
38.61
4.4953
72.65
4.3531
49.15
4.2940
41.64
4.2425
35.75
4.1856
21.63
4.1338
9.47
4.0793
12.69
3.9960
18.50
3.9037
9.03
3.7854
40.39
3.7521
54.16
3.6787
28.60
3.6509
17.96
3.5444
31.72
3.4679
41.55
3.3899
7.69
3.3101
5.72
3.2561
7.42
3.1784
15.19
3.0445
11.17
3.0146
8.94
2.9160
11.89
2.8217
18.23
2.7500
12.06
2.6436
9.65
2.6156
6.97
comprising the steps of:
(a) acylating a benzothiophene of the formula
wherein:
R 4 is C 1 -C 4 alkoxy and R 5 is C 1 -C 4 alkyl, with an acylating agent of the formula
wherein:
R 6 is chloro, and R 2 and R 3 together with the adjacent nitrogen atom form a piperidino group, and HX is HCl, in the presence of BCl 3 in chlorobenzene;
(b) dealkylating the hydrochloride salt of the compound of the formula
wherein R 7 is C 1 -C 4 alkyl;
by reacting with additional BCl 3 ;
(c) quenching the reaction of step (b) with methanol; and
(d) isolating the crystalline solvate.
59 . The process of claim 58 wherein R 4 is methoxy, and R 5 and R 7 are methyl.
60 . A process for preparing non-soLvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride comprising (a) reacting a solvated form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride in methanol or in a mixture of methanol and water with about one equivalent of base,
(b) extracting the solution from step (a) with an aliphatic hydrocarbon solvent, (c) adding about one equivalent of hydrochloric acid to the methanolic solution from step (b), and (d) isolating the crystalline compound.
61 . The process of claim 60 wherein the aliphatic hydrocarbon solvent is hexane or heptane.
62 . The process of claim 60 wherein the base is sodium hydroxide.
63 . The process of claim 60 wherein the hydrochloric acid is a 2 N aqueous solution.
64 . A process for preparing non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-benzo[b]thiophene hydrochloride comprising
(a) reacting a solvated form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride in methanol or in a mixture of methanol and water with about one equivalent of base, and (b) adding about one equivalent of hydrochloric acid to the methanolic solution from step (a), and (c) isolating the crystalline compound.
65 . The process of claim 64 wherein the base is sodium hydroxide.
66 . The process of claim 64 wherein the hydrochloric acid is a 2 N aqueous solution.
67 . Non-solvated crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride, having substantially the following X-ray diffraction pattern obtained with copper radiation:
d-line spacing
I/I o
(Angstroms)
(x100)
13.3864
71.31
9.3598
33.16
8.4625
2.08
7.3888
7.57
6.9907
5.80
6.6346
51.04
6.1717
29.57
5.9975
5.67
5.9135
9.87
5.6467
38.47
5.4773
10.54
5.2994
4.74
4.8680
4.03
4.7910
5.98
4.6614
57.50
4.5052
5.75
4.3701
9.03
4.2516
69.99
4.2059
57.64
4.1740
65.07
4.0819
12.44
3.9673
22.53
3.9318
100.00
3.8775
9.07
3.7096
33.38
3.6561
21.65
3.5576
3.36
3.5037
7.97
3.4522
18.02
3.4138
4.65
3.2738
10.23
3.1857
8.90
3.1333
6.24
3.0831
9.43
3.0025
12.13
2.9437
4.96
2.8642
7.70
2.7904
11.95
2.7246
3.05
2.6652
3.32
2.5882
7.30
68 . The crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride of claim 67 wherein the amount of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydro-chloride present is at least 95% by weight.
69 . The crystalline 6-hydroxy-2-(4—hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride of claim 68 substantially free from chlorobenzene.
70 . The crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride of claim 69 substantially free from aluminum salts or organoaluminum impurities.
71 . The crystalline 6-hydroxy-2-(4—hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride of claim 70 substantially odor free.
72 . A pharmaceutical formulation comprising the crystalline compound of any one of claims 67 to 71 and one or more pharmaceutically-acceptable carriers, diluents, or excipients.
73 . Crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride when prepared by the process of claim 60 .
74 . Crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride when prepared by the process of claim 64 .
75 . A process for preparing a crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride having the following X-ray diffraction pattern obtained with copper radiation:
d-line spacing
I/I o
(Angstroms)
(x100)
10.3696
14.40
8.9032
10.19
8.3125
7.61
7.9818
41.03
7.2036
7.34
6.5411
74.18
6.2367
6.39
5.5539
20.11
5.3689
100.00
5.0272
95.92
4.7085
89.13
4.6406
73.37
4.6199
77.58
4.5347
69.70
4.4818
49.86
4.2589
47.69
4.2067
44.43
4.1659
44.16
4.0957
11.96
3.9347
11.28
3.7818
40.90
3.7614
53.53
3.6375
36.68
3.5773
20.11
3.5037
25.14
3.4409
32.34
3.4270
39.54
3.3088
12.64
3.2611
9.65
3.1046
12.77
3.0263
17.53
2.8536
8.29
2.8131
12.09
2.7309
8.97
comprising the steps of:
(a) dealkylating the hydrochloride salt of a compound of the formula
wherein R 7 is C 1 -C 4 alkyl,
by reacting with BCl 3 in chloroform or methylene chloride;
(b) quenching the reaction of step (a) with methanol, ethanol, or i-propanol; and
(c) isolating the crystalline solvate.
76 . The process of claim 75 wherein R 7 is methyl.Join the waitlist — get patent alerts
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