US5238950A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Inhibitors of platelet-derived growth factor
Assignee: Merck Sharp & Dohme LLC
•
Filing: 1991-12-17
•
Granted: 1993-08-24
•
Expires: 2011-12-17
Abstract
Abstract A method of inhibiting the binding of PDGF using compounds of the formula I <IMAGE> I useful in the treatment of atherosclerosis, cancer, retinal detachment, pulmonary fibrosis, arthritis, psoriasis and glomerulonephritis, and restenosis following angioplasty or vascular surgery is disclosed. Also disclosed are pharmaceutical compositions and novel PDGF inhibitory compounds of the formula <IMAGE> or a pharmaceutically acceptable addition salt thereof, useful in the treatment of atherosclerosis, cancer, retinal detachment, pulmonary fibrosis, arthritis, psoriasis and glomerulonephritis, and restenosis following angioplasty or vascular surgery.
Inventors
- 👤 John W. Clader
- 👤 Harry R. Davis
- 👤 Deborra Mullins
- 👤 Stuart Rosenblum
- 👤 Jay Weinstein
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 04:24
CPC Classifications
C; C07; C07D; C07D209/00; C07D209/02; C07D209/44; C07D209/48; C07D207/00; C07D207/46; C07D207/48; C07D487/00; C07D487/02; C07D487/04
Claims Analysis
Total Claims: 14
Claim 1
Independent Claim
134 words
A compound of the formula ##STR37## or a pharmaceutically acceptable addition salt thereof, wherein R a is an aryl group substituted by 1-5 substitutents R 4a ; R 1a and R 2a together comprise a fused ring of the formula ##STR38## q is 0 or 1 R 3a is nitro; and wherein the R 4a substituents are independently selected from the group consisting of hydroxy, Y-substituted alkyl, alkylamino, dialkylamino, aryl amino, diarylamino, trialkylammonium, thio, --S(O) m R 7 , --SO 3 , carboxyl, alkoxycarbonyl, benzyloxycarbonyl, alkenyloxycarbonyl, carboxamido, N-phthalimido, cyanoalkoxycarbonyl, carboxyalkoxycarbonyl, benzyloxycarbonyl-alkoxycarbonyl, N,N-dialkylcarboxamido, trifluoromethyl and cyano; Y is selected from the group consisting of halogeno, trialkylammonium, amino, carboxy, pyridinium, triarylphosphonium, benzyloxycarbonyl, hexamethylenetetraminium, --N═CH--alkyl, --N═CH--aryl and --N═CH--N(alkyl) 2 ; R 7 is C 1 -C 8 alkyl or aryl; and m is 0, 1 or 2.
Claim 2
Dependent Claim
134 words
A compound of the formula ##STR37## or a pharmaceutically acceptable addition salt thereof, wherein R a is an aryl group substituted by 1-5 substitutents R 4a ; R 1a and R 2a together comprise a fused ring of the formula ##STR38## q is 0 or 1 R 3a is nitro; and wherein the R 4a substituents are independently selected from the group consisting of hydroxy, Y-substituted alkyl, alkylamino, dialkylamino, aryl amino, diarylamino, trialkylammonium, thio, --S(O) m R 7 , --SO 3 , carboxyl, alkoxycarbonyl, benzyloxycarbonyl, alkenyloxycarbonyl, carboxamido, N-phthalimido, cyanoalkoxycarbonyl, carboxyalkoxycarbonyl, benzyloxycarbonyl-alkoxycarbonyl, N,N-dialkylcarboxamido, trifluoromethyl and cyano; Y is selected from the group consisting of halogeno, trialkylammonium, amino, carboxy, pyridinium, triarylphosphonium, benzyloxycarbonyl, hexamethylenetetraminium, --N═CH--alkyl, --N═CH--aryl and --N═CH--N(alkyl) 2 ; R 7 is C 1 -C 8 alkyl or aryl; and m is 0, 1 or 2.
Claim 3
Dependent Claim
81 words
A compound of claim 1 having the structural formula ______________________________________
##STR39##
wherein:
R.sup.1a, R.sup.2a
R.sup.a
______________________________________
##STR40##
##STR41##
##STR42##
##STR43##
##STR44##
##STR45##
##STR46##
##STR47##
##STR48##
##STR49##
##STR50##
##STR51##
##STR52##
##STR53##
##STR54##
##STR55##
##STR56##
##STR57##
##STR58##
##STR59##
##STR60##
##STR61##
##STR62##
##STR63##
##STR64##
##STR65##
##STR66##
##STR67##
##STR68##
##STR69##
##STR70##
##STR71##
##STR72##
##STR73##
##STR74##
##STR75##
##STR76##
##STR77##
##STR78##
##STR79##
##STR80##
##STR81##
##STR82##
##STR83##
##STR84##
##STR85##
##STR86##
##STR87##
##STR88##
##STR89##
##STR90##
##STR91##
##STR92##
##STR93##
##STR94##
##STR95##
##STR96##
##STR97##
##STR98##
##STR99##
##STR100##
##STR101##
##STR102##
##STR103##
______________________________________
Claim 4
Dependent Claim
19 words
A compound of claim 1 wherein R a is phenyl or naphthyl, substituted by 1-5 groups R 4a .
Claim 5
Dependent Claim
15 words
A compound of claim 3 wherein R 4a is Y-substituted alkyl, alkylamino, dialkylamino or alkoxycarbonyl.
Claim 6
Dependent Claim
12 words
A compound of claim 4 wherein Y is halogeno, benzyloxycarbonyl or triphenylphosphonium.
Claim 7
Dependent Claim
7 words
A compound of claim 1 wherein q=0.
Claim 8
Dependent Claim
19 words
A pharmaceutical composition comprising a PDGF inhibitory amount of a compound of claim 1 in a pharmaceutically acceptable carrier.
Claim 9
Independent Claim
298 words
A method of inhibiting the binding of platelet-derived growth factor by treating a mammal in need of such treatment with a inhibitory effective dose of a compound of the formula ##STR104## or a pharmaceutically acceptable addition salt thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6 and R is hydrogen or an aryl group substituted by 1-5 substitutents R 4 , provided that R is not hydrogen when p=0; R 1 and R 2 taken together comprise a fused ring of the formula ##STR105## q is 0, 1, 2, 3 or 4; X and R 3 are independently selected from the group consisting of hydrogen, halogeno, hydroxy, C 1 -C 8 alkyl, C 1 -C 8 alkenyl, C 1 -C 8 alkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, trialkylammonium, thio, --S(O) 2 R 6 , --S(O) m R 7 , --SO 3 , nitro, --NHS(O) 2 alkyl, carboxyl, alkoxycarbonyl, carboxamido, N-alkylcarboxamido, N,N-dialkylcarboxamido, alkylcarbonylamino, arylcarbonylamino, alkylaminocarbonyloxy, alkoxycarbonyloxyl, alkylcarbonyloxy, trifluoromethyl, cyano, aryl, and substituted aryl, wherein the substitutents are 1-5 groups R 4 ; and wherein the R 4 substituents are independently selected from the group consisting of hydrogen, halogeno, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, hydroxy, C 1 -C 8 alkyl, Y-substituted alkyl, C 1 -C 8 alkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, trialkylammonium, thio, --SO 2 R 6 , --S(O) m R 7 , --SO 3 , nitro, carboxy, alkoxycarbonyl, benzyloxycarbonyl, alkenyloxycarbonyl, carboxamido, N-phthalimido, cyanoalkoxycarbonyl, carboxyalkoxycarbonyl, benzyloxycarbonylalkoxycarbonyl, N-alkylcarboxamido, N,N-dialkylcarboxamido, trifluoromethyl, cyano and aryl; Y is selected from the group consisting of halogeno, trialkylammonium, amino, carboxy, pyridinium, triarylphosphonium, benzyloxycarbonyl, hexamethylenetetraminium, --N═CH--alkyl, --N═CH--aryl and --N═CH--N(alkyl) 2 ; R 6 is amino, arylamino, alkylamino or dialkylamino; R 7 is C 1 -C 8 alkyl or aryl; and m is 0, 1 or 2.
Claim 10
Independent Claim
298 words
A method of inhibiting the binding of platelet-derived growth factor by treating a mammal in need of such treatment with a inhibitory effective dose of a compound of the formula ##STR104## or a pharmaceutically acceptable addition salt thereof, wherein p is 0, 1, 2, 3, 4, 5, or 6 and R is hydrogen or an aryl group substituted by 1-5 substitutents R 4 , provided that R is not hydrogen when p=0; R 1 and R 2 taken together comprise a fused ring of the formula ##STR105## q is 0, 1, 2, 3 or 4; X and R 3 are independently selected from the group consisting of hydrogen, halogeno, hydroxy, C 1 -C 8 alkyl, C 1 -C 8 alkenyl, C 1 -C 8 alkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, trialkylammonium, thio, --S(O) 2 R 6 , --S(O) m R 7 , --SO 3 , nitro, --NHS(O) 2 alkyl, carboxyl, alkoxycarbonyl, carboxamido, N-alkylcarboxamido, N,N-dialkylcarboxamido, alkylcarbonylamino, arylcarbonylamino, alkylaminocarbonyloxy, alkoxycarbonyloxyl, alkylcarbonyloxy, trifluoromethyl, cyano, aryl, and substituted aryl, wherein the substitutents are 1-5 groups R 4 ; and wherein the R 4 substituents are independently selected from the group consisting of hydrogen, halogeno, C 1 -C 8 alkenyl, C 1 -C 8 alkynyl, hydroxy, C 1 -C 8 alkyl, Y-substituted alkyl, C 1 -C 8 alkoxy, aryloxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, trialkylammonium, thio, --SO 2 R 6 , --S(O) m R 7 , --SO 3 , nitro, carboxy, alkoxycarbonyl, benzyloxycarbonyl, alkenyloxycarbonyl, carboxamido, N-phthalimido, cyanoalkoxycarbonyl, carboxyalkoxycarbonyl, benzyloxycarbonylalkoxycarbonyl, N-alkylcarboxamido, N,N-dialkylcarboxamido, trifluoromethyl, cyano and aryl; Y is selected from the group consisting of halogeno, trialkylammonium, amino, carboxy, pyridinium, triarylphosphonium, benzyloxycarbonyl, hexamethylenetetraminium, --N═CH--alkyl, --N═CH--aryl and --N═CH--N(alkyl) 2 ; R 6 is amino, arylamino, alkylamino or dialkylamino; R 7 is C 1 -C 8 alkyl or aryl; and m is 0, 1 or 2.
Claim 11
Dependent Claim
127 words
A method claim 8 wherein the compound has the structural formula __________________________________________________________________________
##STR106##
wherein:
R.sup.1, R.sup.2
R
__________________________________________________________________________
##STR107##
##STR108##
##STR109##
##STR110##
##STR111##
##STR112##
##STR113##
##STR114##
##STR115##
##STR116##
##STR117##
##STR118##
##STR119##
##STR120##
##STR121##
##STR122##
##STR123##
##STR124##
##STR125##
##STR126##
##STR127##
##STR128##
##STR129##
##STR130##
##STR131##
##STR132##
##STR133##
##STR134##
##STR135##
##STR136##
##STR137##
##STR138##
##STR139##
##STR140##
##STR141##
##STR142##
##STR143##
##STR144##
##STR145##
##STR146##
##STR147##
##STR148##
##STR149##
##STR150##
##STR151##
##STR152##
##STR153##
##STR154##
##STR155##
##STR156##
##STR157##
##STR158##
##STR159##
##STR160##
##STR161##
##STR162##
##STR163##
##STR164##
##STR165##
##STR166##
##STR167##
##STR168##
##STR169##
##STR170##
##STR171##
##STR172##
##STR173##
##STR174##
##STR175##
##STR176##
##STR177##
##STR178##
##STR179##
##STR180##
##STR181##
##STR182##
##STR183##
##STR184##
##STR185##
##STR186##
##STR187##
##STR188##
##STR189##
##STR190##
##STR191##
##STR192##
##STR193##
##STR194##
##STR195##
##STR196##
##STR197##
##STR198##
##STR199##
##STR200##
##STR201##
##STR202##
##STR203##
##STR204##
##STR205##
##STR206##
##STR207##
##STR208##
##STR209##
##STR210##
##STR211##
##STR212##
##STR213##
##STR214##
__________________________________________________________________________
Claim 12
Dependent Claim
39 words
A method of treating atherosclerosis, cancer, retinal detachment, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, and restenosis following angioplasty or vascular surgery, in a mammal in need of such treatment, comprising administering an effect amount of a composition of claim 7.
Claim 13
Dependent Claim
24 words
A method of inhibiting PDGF comprising administering an effective amount of a composition of claim 7 to a mammal in need of such treatment.
Claim 14
Dependent Claim
62 words
A method of claim 8 wherein the compound has the structural formula ##STR215## wherein ##STR216## is selected from the group consisting of --CH 2 --C 6 H 5 ,--(CH 2 ) 2 --C 6 H 5 , --(CH 2 ) 3 --C 6 H 5 , --CH 3 , --C 4 H 9 , --C 12 H 15 , 3-chloropropan-1-yl or ##STR217##
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1996-08-23 | 1997-02-22 | 1997-08-24 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2000-08-23 | 2001-02-22 | 2001-08-24 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2004-08-23 | 2005-02-22 | 2005-08-24 | $7700.00 | Window Closed / Lapsed |