CA2176377A1 - Inhibition of smooth muscle migration and proliferation with hydroxy carbazole compounds - Google Patents
Inhibition of smooth muscle migration and proliferation with hydroxy carbazole compoundsInfo
- Publication number
- CA2176377A1 CA2176377A1 CA002176377A CA2176377A CA2176377A1 CA 2176377 A1 CA2176377 A1 CA 2176377A1 CA 002176377 A CA002176377 A CA 002176377A CA 2176377 A CA2176377 A CA 2176377A CA 2176377 A1 CA2176377 A1 CA 2176377A1
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- Prior art keywords
- formula
- compound
- use according
- smooth muscle
- proliferation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The present invention provides a new medical use of the hydroxycarbazole compounds of Formula (I), preferably the hydroxylated metabolites of 1 (carbazol-4-yloxy-3-¢¢2-(o-methoxyphenoxy)ethyl!amino!-2-propanol) (carvedilol), for inhibiting the migration and proliferation of smooth muscle cells. In particular, the present invention provides a new use for the hydroxycarbazole compounds of Formula (I) for prevention of restenosis following percutaneous transluminal coronary angioplasty (PTCA), suppression of the progression of vascular hypertrophy associated with hypertension, and prevention of development of atherosclerosis. In formula (I) R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH.
Description
WO 95/1438.1 2 1 7 6 3 7 7 PCT/US9~/13561 INHIBITION OF SMOOTH MUSCLE MIGRATION AND PROLIFERATION
WITH HYDROXY CARBAZOLE COUMPOUNDS
Field of Invention The present invention rela~es to a new medical use of the ~ LU~.y1dUVd~VIe 5 C~-mrOI~nrIC of Formula (I), preferably the l-y~Lv~y' ' ~ of 1-(carbazol4-yloxy-3-[[2-(o-~ ,Lllu,~y,ul.~,lv~y)ethyl]amino]-2-propanol) (carvedilol), for inhibiting the migration and proliferation of smooth muscle cells. In particular, the present invention provides a new use of ll~LuAyl,~u1d~VlC compounds of Fommula I for prevention of restenosis following r~ Lld..~lUlll;lldl coronary ,, , ' 10 (PTCA), au~Jlcaiivl. of the ylv~;lc,aaiun of Yascular IIJ~.I Llvplly associated with u~lL~lla;vl~, and prevention of .ICVCIU~ .L of dtll.,luacl~,lusis.
R~ O~N~
R ~H H ~ R~
RC H RS ` (I) wherein:
5 Rl-Rg are i.~ y -H or-OH, with the proviso that a at least one of Rl-Rg is OH.
B,i~ 1~- . v~ d of the Invention Abnormal vascular smooth muscle migratiûn and proliferation is associated with ,dldiuv~(,ulcl disorders such as d~ lua~l~luais, lly~ iOl~ and most endovasculat procedures. Abnormal vascular smooth muscle migration and proliferation is a common ~ of t~ UIdl~CVU5 LldllSlulll;.,dl coronary angioplasty (PTCA). The incidence of chronic restenosis resulting from vascular smooth muscle ~lulircla~ivll following r'TCA has been reported to be as high as 40-45~ within 3-6 months. Capron, L., Huedes, D., Chajara, A. and Bruneval, P. (1991) J. Cardiovasc. Pharmacol., 18, 207-211; Bourassa, M. (1992) J. Am. Co~l. Cardiol19, 1410-1411. Several n~,.vl.u.llv.dl factors, including ~.n~ ncin 11 and -ululB~ ine, as well aâ growth factors, including platelet-derived growth factor (PDGF) and basic fibroblast growth factor ~GF), have been implicatcd in the d~ ,lu,u,.lclll of vascular restenosis in vivo. Bourassa, M. et al. supra; Powell, J.S., Clozel, ~.P., Muller, R.K.M., Kuhn, H., Hefti, F., Hosang, M. and B.lul~l~duLII~,-, H.R.
(1989) Science, 24~, 186-198; Clozel, J.P., Hess, P., Michael, C., Schietinger, K. and 2 17 ~ 3 ~ ! PCTIIIS9.~113561 Baumgartner,H.R,(1991)Hypenension,18(Suppl.11),1155-1159;Fingerle,J., Sanders, K.H. and Fotev, Z. (1991 ) Basic Res~ Cardiol., 86, 75-81; Fomey-Prescott, M., Webb, R.L. and Reidy, M.A. (1991) Am. J. Pathol., 139, 1291-1296; Kauffman, R.F., Bean, J.S., 7imnn~rm~n~ K.M., Brown, R.F. and Steinberg, M.l. (1991) Life Sci., 49, 223-228; Azuma, H.Y. and Hamasaki, H. (1992) Br. J. Phar~nacol., 106, 665-671; Fems, G.A.A., Raines, E.W., Sprugel, K.H., Motani, A.S., Reidy, M.A. and Ross, R. (1991~ SCienCe, 253, 1129-1132; and Lindner, V. and Reidy, M.A. (1991) Proc. Nad. Acad. Sci. (USAJ, 88, 3739-3743.
The high incidence of vascular reocclusion associated with PTCA has led to the .I~ ,lvy~ of in vivo animal models of restenosis and the search for agents to prevent restenosis. Angiotensin 11 receptor An-~oniC~C angiotensin converting cnzyme (ACE) inhibitors, a-ad~ ., c~ ., antagonists and growth factor antibodieshave generally produced only a modest (10-50~) reduction of vascular restenosis in such animal models. Powell, J.S., et al., supra; Fingerle, J. et al., supra; Fomcy-Prescott, M. et al., supra; and Kauffman, R.F., et al., supra. Clinical studies with AOE inhibitors (which showed only a moderate protective effect in animal models of restenosis) have failed to ~ a significant efficacy in the prevention of A'~gi~ ly-defined restenosis in humans. Popma, J.J., Califf. R.M. and Topol, EJ. (1991) Circulation, 84, 426-1436. This limited or i..ci~-,;ri. - .l protection 20 against vascular restenosis affected by agents with specific .... ~ of actionmost likely reflects the complex nature of the yatlloyllJ~;vlo~y underlying vascular restenosis. A l"~.:li,. li-,ily of ~ l ,.. l- l ;~ and mitogenic factors are believed to be involved in this response to vascular wall injury, and it is likely that interfering with the actions of only one of these factors ~Yill prove to be beneficit~l.
Therefore, therapeutic anti-mitotic agents which reduce or inhibit the abnormal migration and proliferation of smooth muscle cells associated with cardiovæular disorders such as ~ ,.U~cl~"usis and vascular l~ uyll~ associated with l~y~ iol~ or resulting from ~ y~ n c following pTcA and causing chronic restenosis are highly desirable.
3û
Surnmarv vrthe InYention In the first aspect, the present invention provides a new medical use for the l~ydlu~y~ ,le Anmrollnrlc of Fommula (I), preferably the I~UAYb~a~1 metabolites of 1-(carbazol-~yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino~-2-propanol) (hereinafter referred to as carvedilol), as anti-mitotic agents for inhibition of smooth muscle cell growth.
WO95/14384 21 763 77 PcrluS94/1356t ~ ~R1 wherein:
Rl-Rg are i"~ ly -H or-OH, with the proviso îhat at IQSt one of R l-Rg is -OH.
In a second aspeet, the present invention also provides a method of treatment for inhibition of restenosis following PTCA, for ~upp.. ~ th2 plV~ IC~:~;Ol~ of vascular IIYP~I II VIJIIY assoeiated with llyp~ ;vl-, and prevention of the dc~clup..l~,.,tof ~ .u~ lu~ inmammalcomprisingint2rnally~ ,: L,;..g, toa 10 mammal, preferably a human, in need thereof an effeeive amount of a compound seleeted from the consisting essentially of compounds of Formula (I) or pl~ c~.Li~,~lly acceptable salts thereof.
r - - Description of the Invention U.S. Pat. No. 4,503,067 (hereinafter " the '067 patent") discloses earbazolyl-(4)-v~yplull,u n~ compounds of Formula II:
R3 /Rs N/~X--Ar~
OR, R2 Rs 1"~ ~ ~ R4 (II) .
wherein R I is hydrogen, lower alkanoyl of up to 6 earbon atoms or aroyl selected from benzoyl and naphthoyl R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benyl, ~ lcLl,yl and ~ ,.lyl~lvpyl, WO9S/14384 2~7 ~3~ PcrnJS94/13561 R3 is hydrogen or lower alkyl of up to 6 carbon aloms;
R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-0-;
X is a valency bond, -CH2, oxygen or sulfur;
Ar is selected from phenyl, naphthyl, indanyl and tu~ yvlu~ Ll~yl, Rs and R6 are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, ~ower alkyl of up to 6 carbon atoms, a - CONH2 group, lower alkoxy of up to 6 carbon atoms, benzyloxy. Iower alkylthio of up to 6 carbon atoms, lower alkyaul~l.;.lyl of up to 6 carbon atoms and lower alkylaul~.h~ l of up to 6 carbon atoms; or Rs and R6 together represent ~ ,Ll~yL,.l~l;v~-y;
and ~ ",.~ y acceptable salts thereo This patent further discloses a compound of Formula ll better known as 15 carvedilol (1-(carbazol4-yloxy-3-[[2-(o-.. ~11u,.y~ ,.. v,.y)~,~l-yllamino]-2-propanol), having the structure shown in Formula nl:
O--~N~ ~~
alI) ~0 The cu~ uullva of the '067 patent, of which carvedilol is exemplary, are novel multiple action drugs useful in the treatment of mild to moderate lly~ cl~siull and having utility in angina and congestive heart failure (CHF). Carvedilol is known to be both a CUllllJ~,Li~ -a~clloc~ u~ antagonist and a vasodilator, and is 25 also a calcium channel antagonist at higher ~ u"~ . The ~ ' ' y actions of carvedilol result primarily from c~ blockade, whereas the p-a~c,lo~ ul blocking activity of the drug prevents reflex tachycardia when used in the treatment of II,YP~ IIS;( II. These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug in animals, particularly in humans, as 30 well as for utility in the treatment of angina and CHF. See Wlllette, R.l~., Sauermelch~ C.F. & Ruffolo, R.R., Jr. (1990) Eur. ~. Pharmacol., 176, 237-240;
wo95114384 Pcrr~ss4/l3 Nichols, A.J., Gellai, M. & Ruffolo, R.R., Ir. (199l) Fundam. Cfin. Pharmacol., v, 25-38; Ruffolo, R.R., Jr., Gellai, M., Hieble, J.P., Willette, R.N. & Nichols, A.J.
(1990) Eur. J. Clin. Pharmacol., 38, S82-S88; Ruffolo, R.R., Jr., Boyle, D.A., - Venuti, R.P. & Lukas, M.A. (1991) Drugs of Today, 27, 465-492; and Yue, T.-L., 5 Cheng, H., Lysko, P.G., McKenna, P.J., Feuerstein, R., Gu, J., Lysko, K.A., Davis, L.L. & Feuerstein, G. (1992) J. Pharmacol. Exp. Ther., 263, 92-98.
The ~ L~ v action of carvedilol is mediated primarily by decreasing total peripheral vascular resistance without causing the cn ~ reflex changes in heart rate commonly associated with othem~ y~ L..~; iC agents. Willette, R.N., et l0 al. supra; Nichols, A.J., et al. supra; Ruffolo, R.R., Jr., Gellai, M., Hieble, J.P., Willette, R.N. & Nichols, A.J. (1990) Eur. J. Clin. Pharmacof., 38, S82-S88.
Carvedilol also markedly reduces infarct size in rat, canine and porcine models of acute myocardial infarction, Ruffolo, R.R., Jr., et al., Drugs of Today, supra, possibly as a ...~ c of its antioxidant action in attenuating oxygen free radical-initiated lipid p.,.u~-id.l~io--. Yue, T.L., et al. supra.
Carbazolyl-(4)-~v~J~ . ' in panicular carvedilol, have also been disclosed as inhibiting of smooth muscle migration and l~lulirc~Lu~l in copending patent application Serial No. 08/026892~
Recently, it has been discovered that the i'l,~dlU~ lLUIc r ' of Formula (1), preferably wherein R I, R2, R3, Rs, R6 or R8 are ' r ~ ~y OH, are also able to block mitogen-stimulated ~"UI;~ Lic,l~ of cultured rat aortic vascular smooth muscle cells in Yirro~ These ~,UII r ~ are potent inhibitors both of migration, measured by PDGF, and proliferation, measured by 3H-thymidine.
Because said ~ . ' inhibit the proliferative actions of multiple mitogenic 25 stimuli, the use of said <~ u~ , preferably those ,1,.1~ wherein Rl, R2, R3 Rs, R6 or R8 are ~ 'y OH, to inhibit the migration and ~ulirv.~l~iu~ of smooth muscle cells, and therefore to prevent the ~ lly ~ sequelae of such proliferation, has a clear advantage over specific growth factor: - v It has been funher discovered that the rnmrol~n~ic of Formula (1), preferably those ~- . I.o~ wherein Rl, R2, R3, Rs, R6 or R8 are ;~ y OH, IIUII~ . superior protective effects against vascular smooth muscle migration and ~lulir~ iull in blood vessels. More panicularly, the cnmrolln~ic of Formula (I) produce potent inhibition of vascular smooth muscle cell ~lulircl~liull, migration, and neointimal ~,luli[~ tiul~ in aneries subjected to acute injury induced by balloon angioplasty.
To that end, the present invention provides a use for a compound selected from the group consisting essentially of the cnmrolln~ic of Formula (1), preferably those cnmro~ln~ic wherein Rl, R2, R3, Rs, R6 or R8 are ;~ ly OH, or a WO95/14384 2~ 637~ PCTIUS94113~61 ~
y acceptable salt thereof, said use bcing for inhibition of ~lulirc~ i and migration of smooth muscle cells in mammals, preferably human beings, particularly for inhibiting restenosis by angioplasty-induced neointimal plvl;
in blood vessels of patients surviving PTCA; for inhibition of dGV. r of 5 alll.,.u~ .u~;~, or for ~u~p.-,";"6 the l,-u6. C~;UII of vascular ~ ,I LlU~Ilr associated with hypenension.
The present invention also provides a method of treatment for inhibition of plul;r.,,illiu,, and migration of smooth muscle cells in mammals, preferably human beings, ~ h,uLulr a method of treamment for preventing restenosis by ill,6;u~,1. ,ly-lû inducGd neointimal plul;rc-~;u~l in blood vessels of patients surviving PTCA; for inhibition of ~c~clop..l.,... of ,slll.,.uSCI~,.uD;S, or for suppressing the ~,lu6lc,,;u-~ of vascular IIY~J~,. L-upllr associated with lly~ t~ ;ull, said method comprising intemally to a patient in need thereof an effective dose of a 1-l - ", - ~ ";- 1 o~ili..,.comprisingacompoundofFormula(l),preferablythosecompounds wherein R l, R2, R3, R5, R6 or R8 are ', ' 'y OH, or a ~ lly acceptable salt thereo As funher illustrated in the Examples below, cnmrm-n~lc of Formula (I) , inhibit vascular smooth muscle cell migration in vitro, and inhibit human vascular smooth muscle ~ mediated by a wide variey of diffcerent mitogens.
('hrrnn-~r~ir migration of medial smooth muscle cells into the intima is an imponant first step in the 1~ of neointima formation following balloon angioplasty PDGF is believed to be a key substance for promoting smooth muscle cell migration and l,-ul;f~ ;ul~. Ferns, G A.A., et al., supra; Ross, R. (1986) N.
Engl. J . Med. 314 488-500. According to the present invention, compounds of Formula (I) inhibit smooth muscle cell migraion induced by PDGF with IC50 valuesranging from 0.2 to 1.7 ~LM. Without being limited by any ~
or theory of operation, the ability of these compounds to inhibit myointimal formation in vivo may in pan be related to direct inhibition of the physical migration of vascular smooth muscle from the tunica media into the tunica intima, and also in pan through antioxidant activity of these compounds which may inhibit the recruitment of ..I.I~,.u~ .6~ and monocytes to the injury site.
While the precise molecular events leading to the anti-~J.ul;rc~ ., and anti-migratory actions oF compounds of Formula (I) await funhe m~ ri~--inn, the new 35 medical use of these l~y~Lu~yh.j~ metabolites of carvedilol and method of treatment using these llydlu:~r~ i metabolites of carvedilol according to the present invention afford ~u~vu~,ed protection in an animal model of neointimal formation and stenosis following angioplasty.
~17~377 7 Compounds of Formula (I) may be Cu~ LIy prepared as described by way of example in Example l.
Pl~cu ~ ,u~i~cd ~ of the cu---~,c u~d~ of Formula (I) may be n~ d tO patients according to the present invention in any medically 5 acceptable manner, preferably parenterally. For parenteral ~ , the ", ~ ", will be in the form of a sterile injectable liquid stored in a suitable container such as an ampule, or in the forttt of an aqueous or ,;- ~ t , -liquid sllcr~ncinn The nature and cc~ of the l,l ." - ;~ nl carrier, diluentor cxcipient will, of course, depend on the intended route of a~ ,u ;~ for 10 example whether by i~Llc~ uu~ or ;~ injection rl~ c of the cnmro~ lc of Formula (l) for use according to the present invention may be formulated as solutions or Iyophilizedpowders for parenteral ~.l.,.;.- ~l, ..I;na Powders may be ~c 1 by addition of asuitable diluent or other ullcu ll~ lly acceptable carrier prior to use. The liquid fi.. l~t;n.. is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammnnil~rn acetate solution. Such r...,....1 ,;nA iS especially suitable for parenteral ' ' ' nn, but may also be used for oral r ' ' ' ' or conuined in a metered dose inhaler or nebulizer for inc..m ~-inn It may bc desirable 20 to add excipients such as ethanol, polyvinyl-~ y~ulidu"c, gelatin, hydroxy cellulose, acacia, POI~ IIYI~IG glycol, mannitol, sodium chloride or sodium citrate.
Alternatively, these c~ ...~ .~..., .. l~ may be, , ' ~, tableted or prepared in a emulsion or syrup for oral ~, l. . ,-, ;~l . ,.l ;. ~ rl ~ . " ;. ~Iy acceptable solid or liquid cartiers may be added to enhance or stabilize the c~ or to facilitate 25 preparation of the c~ Liquid carriers include syrup, peanut oil, olive oil, glycerin, sa~ine, ethanol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate. terra alba, ... ~. ~; ,. stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl ~u~O~ ,cu or glyceryl distearate, alone or with a wax. The amount of 30 solid carrier varies but, preferably, will be between ahout 20 mg to ahout I g per dosage unit. The ~ ,-c,u..,.:Lic..~s are made following the "o--~.
techniques of pharmacy involving milling, mixing, grrn~ in~. and cu...l,.c:,:.i..g, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a 35 syrup, elixir, emulsion or an aqueous or non-aqueous sllcr~ncinn Such a liquid r""...lnli....maybe:nl.,.;~ ddirectlyp.o.orfilledintoasoftgelatincapsule.
Dosing in humans for the treatment of disease according to the present invention should not exceed about 100 mg/day of the compounds of Formula I. For WO 95/14384 2 1 7 6 3 ~ ~ PCI/US94/13561 prevention of reocclusion following PTCA, the preferred range of dosing is ad~ .;aL.a.iu.~ oFfrom aboul 12.5 mg/day to about ]00 mg/day of a compound of Formula I in a single dose or multiple doses up to three times daily before, during, and for up to six months pOst-.-llE,iupl~aly, most preferably thc dosage is about 25 5 mg/day 3 times daily. It will be a~ c ' ' that the actual preferred dosages of the o~ ic being used in the ~ of this invention will vary according to theparticular....,.,~ i..,.formulated,themodeofA.I",.,~ ".l;.,,,theparticularsite of ddll.il.iaL- aLivll, the host being treated, and the particular disease being treated.
No lln~ rt~hll~ ~. .. ;, ol~i~ ~1 effects are expected when the cûmpounds of 10 Formula I are used according tû the present invention.
In the following Examples, all t~ p~,.aLb.c:~ are in degrees Centigrdde (C).
Unless otherwise indicated, all of the starting materials were obudined from commercial sources. Without further ~ ~r~tirm, it is believed that one skilled in the art can, using the preceding ~irc~rirrin~, utilize the invention to itâ fullest extent.
15 These Examples are given to illustrdte the invention, not to limit its scope. Reference is made to the claims for what is reserved to the inventors hereunder.
EXAMpl .F~
Example I
The compound of Formula (I) wherein R3 is -OH and R I-R2 and R4-Rg are all H was synthesized as follows and is exemplary of the synthetic route to the compounds of Formula (1).
3-Benyl g ~ u~y~ul l,u~ole Benzoyl peroxide (881 mg, 2.73 mmol) was added in one portion to a suspension of ~ h.~JIu~r~,~lba~ul~ (500 mg, 2.73 mmol) in 20 ml CHCl3 at 25C
The mixture was stl-rred for 2 h, then washed with water. The organic layer was dried 30 over sodium sulfate and ..,. ,., ., l .. ~. ~1 Flash ~,1..- ~, . ' ~ of the residue (silica, methylene chloride) provided 15 mg of 3-benzylOxy-4-l.~.Lu~y.,a ba~l~. MS
(DCVNH3): 304.2 (M+H)+.
Subsequent steps to yield the product are well-known: reaction with e~ u.ul..~i.., then 2-..,~Ll.u,~y~ Ll.ylamine, and finally - "....,;ri -~;..., of the 35 benzoyl ester.
E~xa ,mRle 2 ~ioration of Y~ i ~imooth M~
The procedure for assessing vascular smooth muscle cell migrdtion was described previously in Hidaka, Y., Eda, T., Yonemoto, M. & Kamei, T. (1992) ~ W095/14384 217637~ 9 PCT/US94/13561 ~
Atheroscler. 95, 87-94. Briefly, rat aortic vascular smooth muscle cells (passage 3) were suspended (Ix106 cells/ml) in serum free DMEM ,"~ i with 0.2%
(w/v) bovine serum albumin (Sigma). Migration assays were performed in modified Boyden chambers using Transwell (Costar, Cambridge, MA) cell culture chambers S with a poly~ 8 ~Lm pore size membrane. PDGF was dissolved in DMEM and placed in the lower CUIII~ in the presence, or absence, of c--mro~n~lc Of Formula (I) wherein Rl, R2, R3, Rs, R6 or R8 are ~, ' 'y OH. Vascular smooth muscle cells (5xl 05) were then loaded in the upper ~.U~ and incubated for 24 h at 37C in a humidified aL...v,~ containing 5% C02. Non-10 migrated cells on the upper surface were scraped away gently and washed three timeswith PBS. Filters were fixed in methanol and stained with Giemsa. The number of vascular smooth muscle cells per 100 x high power field (HPF) that had migrated to the lower surface of the filters was determined ~ ua~,u~i~,ally. Four HPFs were counted per filter. E~ ".L~ were performed either in duplicate or triplicate.
PDGF produced - dependent increases in the migration of rat vascular smooth muscle cells with maximal effect obtained at a ~ ;. .- - of I
nM. When cnmro~ of Formula (I) wherein are ;~ ly Rl, R2, R3, R5, R6 or R8 is OH were placed in the lower chamber with PDGF, the migration response was inhibited sl6,lirl~,a-lLly in a dependent manner. ICso values for 20 ~'I"J" I~ of Formula (I) wherein Rl, R2, R3, Rs, R6 or R8 are i --i- ~ ly OH
we as follows.
Position of OH group ICso [llM]
R 1 0.99 R2 0.41 R3 0.20 Rs 0.18 R6 1.72 R8 0.36 The above description fully discloses how to make and use the present invention. However, the present invention is not limited to the particular ~."l~l;."~ .
described hereinabove, but includes all ~.o.lir~iu-ls thereof wilhin the scopc of the claims.
WITH HYDROXY CARBAZOLE COUMPOUNDS
Field of Invention The present invention rela~es to a new medical use of the ~ LU~.y1dUVd~VIe 5 C~-mrOI~nrIC of Formula (I), preferably the l-y~Lv~y' ' ~ of 1-(carbazol4-yloxy-3-[[2-(o-~ ,Lllu,~y,ul.~,lv~y)ethyl]amino]-2-propanol) (carvedilol), for inhibiting the migration and proliferation of smooth muscle cells. In particular, the present invention provides a new use of ll~LuAyl,~u1d~VlC compounds of Fommula I for prevention of restenosis following r~ Lld..~lUlll;lldl coronary ,, , ' 10 (PTCA), au~Jlcaiivl. of the ylv~;lc,aaiun of Yascular IIJ~.I Llvplly associated with u~lL~lla;vl~, and prevention of .ICVCIU~ .L of dtll.,luacl~,lusis.
R~ O~N~
R ~H H ~ R~
RC H RS ` (I) wherein:
5 Rl-Rg are i.~ y -H or-OH, with the proviso that a at least one of Rl-Rg is OH.
B,i~ 1~- . v~ d of the Invention Abnormal vascular smooth muscle migratiûn and proliferation is associated with ,dldiuv~(,ulcl disorders such as d~ lua~l~luais, lly~ iOl~ and most endovasculat procedures. Abnormal vascular smooth muscle migration and proliferation is a common ~ of t~ UIdl~CVU5 LldllSlulll;.,dl coronary angioplasty (PTCA). The incidence of chronic restenosis resulting from vascular smooth muscle ~lulircla~ivll following r'TCA has been reported to be as high as 40-45~ within 3-6 months. Capron, L., Huedes, D., Chajara, A. and Bruneval, P. (1991) J. Cardiovasc. Pharmacol., 18, 207-211; Bourassa, M. (1992) J. Am. Co~l. Cardiol19, 1410-1411. Several n~,.vl.u.llv.dl factors, including ~.n~ ncin 11 and -ululB~ ine, as well aâ growth factors, including platelet-derived growth factor (PDGF) and basic fibroblast growth factor ~GF), have been implicatcd in the d~ ,lu,u,.lclll of vascular restenosis in vivo. Bourassa, M. et al. supra; Powell, J.S., Clozel, ~.P., Muller, R.K.M., Kuhn, H., Hefti, F., Hosang, M. and B.lul~l~duLII~,-, H.R.
(1989) Science, 24~, 186-198; Clozel, J.P., Hess, P., Michael, C., Schietinger, K. and 2 17 ~ 3 ~ ! PCTIIIS9.~113561 Baumgartner,H.R,(1991)Hypenension,18(Suppl.11),1155-1159;Fingerle,J., Sanders, K.H. and Fotev, Z. (1991 ) Basic Res~ Cardiol., 86, 75-81; Fomey-Prescott, M., Webb, R.L. and Reidy, M.A. (1991) Am. J. Pathol., 139, 1291-1296; Kauffman, R.F., Bean, J.S., 7imnn~rm~n~ K.M., Brown, R.F. and Steinberg, M.l. (1991) Life Sci., 49, 223-228; Azuma, H.Y. and Hamasaki, H. (1992) Br. J. Phar~nacol., 106, 665-671; Fems, G.A.A., Raines, E.W., Sprugel, K.H., Motani, A.S., Reidy, M.A. and Ross, R. (1991~ SCienCe, 253, 1129-1132; and Lindner, V. and Reidy, M.A. (1991) Proc. Nad. Acad. Sci. (USAJ, 88, 3739-3743.
The high incidence of vascular reocclusion associated with PTCA has led to the .I~ ,lvy~ of in vivo animal models of restenosis and the search for agents to prevent restenosis. Angiotensin 11 receptor An-~oniC~C angiotensin converting cnzyme (ACE) inhibitors, a-ad~ ., c~ ., antagonists and growth factor antibodieshave generally produced only a modest (10-50~) reduction of vascular restenosis in such animal models. Powell, J.S., et al., supra; Fingerle, J. et al., supra; Fomcy-Prescott, M. et al., supra; and Kauffman, R.F., et al., supra. Clinical studies with AOE inhibitors (which showed only a moderate protective effect in animal models of restenosis) have failed to ~ a significant efficacy in the prevention of A'~gi~ ly-defined restenosis in humans. Popma, J.J., Califf. R.M. and Topol, EJ. (1991) Circulation, 84, 426-1436. This limited or i..ci~-,;ri. - .l protection 20 against vascular restenosis affected by agents with specific .... ~ of actionmost likely reflects the complex nature of the yatlloyllJ~;vlo~y underlying vascular restenosis. A l"~.:li,. li-,ily of ~ l ,.. l- l ;~ and mitogenic factors are believed to be involved in this response to vascular wall injury, and it is likely that interfering with the actions of only one of these factors ~Yill prove to be beneficit~l.
Therefore, therapeutic anti-mitotic agents which reduce or inhibit the abnormal migration and proliferation of smooth muscle cells associated with cardiovæular disorders such as ~ ,.U~cl~"usis and vascular l~ uyll~ associated with l~y~ iol~ or resulting from ~ y~ n c following pTcA and causing chronic restenosis are highly desirable.
3û
Surnmarv vrthe InYention In the first aspect, the present invention provides a new medical use for the l~ydlu~y~ ,le Anmrollnrlc of Fommula (I), preferably the I~UAYb~a~1 metabolites of 1-(carbazol-~yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino~-2-propanol) (hereinafter referred to as carvedilol), as anti-mitotic agents for inhibition of smooth muscle cell growth.
WO95/14384 21 763 77 PcrluS94/1356t ~ ~R1 wherein:
Rl-Rg are i"~ ly -H or-OH, with the proviso îhat at IQSt one of R l-Rg is -OH.
In a second aspeet, the present invention also provides a method of treatment for inhibition of restenosis following PTCA, for ~upp.. ~ th2 plV~ IC~:~;Ol~ of vascular IIYP~I II VIJIIY assoeiated with llyp~ ;vl-, and prevention of the dc~clup..l~,.,tof ~ .u~ lu~ inmammalcomprisingint2rnally~ ,: L,;..g, toa 10 mammal, preferably a human, in need thereof an effeeive amount of a compound seleeted from the consisting essentially of compounds of Formula (I) or pl~ c~.Li~,~lly acceptable salts thereof.
r - - Description of the Invention U.S. Pat. No. 4,503,067 (hereinafter " the '067 patent") discloses earbazolyl-(4)-v~yplull,u n~ compounds of Formula II:
R3 /Rs N/~X--Ar~
OR, R2 Rs 1"~ ~ ~ R4 (II) .
wherein R I is hydrogen, lower alkanoyl of up to 6 earbon atoms or aroyl selected from benzoyl and naphthoyl R2 is hydrogen, lower alkyl of up to 6 carbon atoms or arylalkyl selected from benyl, ~ lcLl,yl and ~ ,.lyl~lvpyl, WO9S/14384 2~7 ~3~ PcrnJS94/13561 R3 is hydrogen or lower alkyl of up to 6 carbon aloms;
R4 is hydrogen or lower alkyl of up to 6 carbon atoms, or when X is oxygen, R4 together with R5 can represent -CH2-0-;
X is a valency bond, -CH2, oxygen or sulfur;
Ar is selected from phenyl, naphthyl, indanyl and tu~ yvlu~ Ll~yl, Rs and R6 are individually selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, ~ower alkyl of up to 6 carbon atoms, a - CONH2 group, lower alkoxy of up to 6 carbon atoms, benzyloxy. Iower alkylthio of up to 6 carbon atoms, lower alkyaul~l.;.lyl of up to 6 carbon atoms and lower alkylaul~.h~ l of up to 6 carbon atoms; or Rs and R6 together represent ~ ,Ll~yL,.l~l;v~-y;
and ~ ",.~ y acceptable salts thereo This patent further discloses a compound of Formula ll better known as 15 carvedilol (1-(carbazol4-yloxy-3-[[2-(o-.. ~11u,.y~ ,.. v,.y)~,~l-yllamino]-2-propanol), having the structure shown in Formula nl:
O--~N~ ~~
alI) ~0 The cu~ uullva of the '067 patent, of which carvedilol is exemplary, are novel multiple action drugs useful in the treatment of mild to moderate lly~ cl~siull and having utility in angina and congestive heart failure (CHF). Carvedilol is known to be both a CUllllJ~,Li~ -a~clloc~ u~ antagonist and a vasodilator, and is 25 also a calcium channel antagonist at higher ~ u"~ . The ~ ' ' y actions of carvedilol result primarily from c~ blockade, whereas the p-a~c,lo~ ul blocking activity of the drug prevents reflex tachycardia when used in the treatment of II,YP~ IIS;( II. These multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug in animals, particularly in humans, as 30 well as for utility in the treatment of angina and CHF. See Wlllette, R.l~., Sauermelch~ C.F. & Ruffolo, R.R., Jr. (1990) Eur. ~. Pharmacol., 176, 237-240;
wo95114384 Pcrr~ss4/l3 Nichols, A.J., Gellai, M. & Ruffolo, R.R., Ir. (199l) Fundam. Cfin. Pharmacol., v, 25-38; Ruffolo, R.R., Jr., Gellai, M., Hieble, J.P., Willette, R.N. & Nichols, A.J.
(1990) Eur. J. Clin. Pharmacol., 38, S82-S88; Ruffolo, R.R., Jr., Boyle, D.A., - Venuti, R.P. & Lukas, M.A. (1991) Drugs of Today, 27, 465-492; and Yue, T.-L., 5 Cheng, H., Lysko, P.G., McKenna, P.J., Feuerstein, R., Gu, J., Lysko, K.A., Davis, L.L. & Feuerstein, G. (1992) J. Pharmacol. Exp. Ther., 263, 92-98.
The ~ L~ v action of carvedilol is mediated primarily by decreasing total peripheral vascular resistance without causing the cn ~ reflex changes in heart rate commonly associated with othem~ y~ L..~; iC agents. Willette, R.N., et l0 al. supra; Nichols, A.J., et al. supra; Ruffolo, R.R., Jr., Gellai, M., Hieble, J.P., Willette, R.N. & Nichols, A.J. (1990) Eur. J. Clin. Pharmacof., 38, S82-S88.
Carvedilol also markedly reduces infarct size in rat, canine and porcine models of acute myocardial infarction, Ruffolo, R.R., Jr., et al., Drugs of Today, supra, possibly as a ...~ c of its antioxidant action in attenuating oxygen free radical-initiated lipid p.,.u~-id.l~io--. Yue, T.L., et al. supra.
Carbazolyl-(4)-~v~J~ . ' in panicular carvedilol, have also been disclosed as inhibiting of smooth muscle migration and l~lulirc~Lu~l in copending patent application Serial No. 08/026892~
Recently, it has been discovered that the i'l,~dlU~ lLUIc r ' of Formula (1), preferably wherein R I, R2, R3, Rs, R6 or R8 are ' r ~ ~y OH, are also able to block mitogen-stimulated ~"UI;~ Lic,l~ of cultured rat aortic vascular smooth muscle cells in Yirro~ These ~,UII r ~ are potent inhibitors both of migration, measured by PDGF, and proliferation, measured by 3H-thymidine.
Because said ~ . ' inhibit the proliferative actions of multiple mitogenic 25 stimuli, the use of said <~ u~ , preferably those ,1,.1~ wherein Rl, R2, R3 Rs, R6 or R8 are ~ 'y OH, to inhibit the migration and ~ulirv.~l~iu~ of smooth muscle cells, and therefore to prevent the ~ lly ~ sequelae of such proliferation, has a clear advantage over specific growth factor: - v It has been funher discovered that the rnmrol~n~ic of Formula (1), preferably those ~- . I.o~ wherein Rl, R2, R3, Rs, R6 or R8 are ;~ y OH, IIUII~ . superior protective effects against vascular smooth muscle migration and ~lulir~ iull in blood vessels. More panicularly, the cnmrolln~ic of Formula (I) produce potent inhibition of vascular smooth muscle cell ~lulircl~liull, migration, and neointimal ~,luli[~ tiul~ in aneries subjected to acute injury induced by balloon angioplasty.
To that end, the present invention provides a use for a compound selected from the group consisting essentially of the cnmrolln~ic of Formula (1), preferably those cnmro~ln~ic wherein Rl, R2, R3, Rs, R6 or R8 are ;~ ly OH, or a WO95/14384 2~ 637~ PCTIUS94113~61 ~
y acceptable salt thereof, said use bcing for inhibition of ~lulirc~ i and migration of smooth muscle cells in mammals, preferably human beings, particularly for inhibiting restenosis by angioplasty-induced neointimal plvl;
in blood vessels of patients surviving PTCA; for inhibition of dGV. r of 5 alll.,.u~ .u~;~, or for ~u~p.-,";"6 the l,-u6. C~;UII of vascular ~ ,I LlU~Ilr associated with hypenension.
The present invention also provides a method of treatment for inhibition of plul;r.,,illiu,, and migration of smooth muscle cells in mammals, preferably human beings, ~ h,uLulr a method of treamment for preventing restenosis by ill,6;u~,1. ,ly-lû inducGd neointimal plul;rc-~;u~l in blood vessels of patients surviving PTCA; for inhibition of ~c~clop..l.,... of ,slll.,.uSCI~,.uD;S, or for suppressing the ~,lu6lc,,;u-~ of vascular IIY~J~,. L-upllr associated with lly~ t~ ;ull, said method comprising intemally to a patient in need thereof an effective dose of a 1-l - ", - ~ ";- 1 o~ili..,.comprisingacompoundofFormula(l),preferablythosecompounds wherein R l, R2, R3, R5, R6 or R8 are ', ' 'y OH, or a ~ lly acceptable salt thereo As funher illustrated in the Examples below, cnmrm-n~lc of Formula (I) , inhibit vascular smooth muscle cell migration in vitro, and inhibit human vascular smooth muscle ~ mediated by a wide variey of diffcerent mitogens.
('hrrnn-~r~ir migration of medial smooth muscle cells into the intima is an imponant first step in the 1~ of neointima formation following balloon angioplasty PDGF is believed to be a key substance for promoting smooth muscle cell migration and l,-ul;f~ ;ul~. Ferns, G A.A., et al., supra; Ross, R. (1986) N.
Engl. J . Med. 314 488-500. According to the present invention, compounds of Formula (I) inhibit smooth muscle cell migraion induced by PDGF with IC50 valuesranging from 0.2 to 1.7 ~LM. Without being limited by any ~
or theory of operation, the ability of these compounds to inhibit myointimal formation in vivo may in pan be related to direct inhibition of the physical migration of vascular smooth muscle from the tunica media into the tunica intima, and also in pan through antioxidant activity of these compounds which may inhibit the recruitment of ..I.I~,.u~ .6~ and monocytes to the injury site.
While the precise molecular events leading to the anti-~J.ul;rc~ ., and anti-migratory actions oF compounds of Formula (I) await funhe m~ ri~--inn, the new 35 medical use of these l~y~Lu~yh.j~ metabolites of carvedilol and method of treatment using these llydlu:~r~ i metabolites of carvedilol according to the present invention afford ~u~vu~,ed protection in an animal model of neointimal formation and stenosis following angioplasty.
~17~377 7 Compounds of Formula (I) may be Cu~ LIy prepared as described by way of example in Example l.
Pl~cu ~ ,u~i~cd ~ of the cu---~,c u~d~ of Formula (I) may be n~ d tO patients according to the present invention in any medically 5 acceptable manner, preferably parenterally. For parenteral ~ , the ", ~ ", will be in the form of a sterile injectable liquid stored in a suitable container such as an ampule, or in the forttt of an aqueous or ,;- ~ t , -liquid sllcr~ncinn The nature and cc~ of the l,l ." - ;~ nl carrier, diluentor cxcipient will, of course, depend on the intended route of a~ ,u ;~ for 10 example whether by i~Llc~ uu~ or ;~ injection rl~ c of the cnmro~ lc of Formula (l) for use according to the present invention may be formulated as solutions or Iyophilizedpowders for parenteral ~.l.,.;.- ~l, ..I;na Powders may be ~c 1 by addition of asuitable diluent or other ullcu ll~ lly acceptable carrier prior to use. The liquid fi.. l~t;n.. is generally a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammnnil~rn acetate solution. Such r...,....1 ,;nA iS especially suitable for parenteral ' ' ' nn, but may also be used for oral r ' ' ' ' or conuined in a metered dose inhaler or nebulizer for inc..m ~-inn It may bc desirable 20 to add excipients such as ethanol, polyvinyl-~ y~ulidu"c, gelatin, hydroxy cellulose, acacia, POI~ IIYI~IG glycol, mannitol, sodium chloride or sodium citrate.
Alternatively, these c~ ...~ .~..., .. l~ may be, , ' ~, tableted or prepared in a emulsion or syrup for oral ~, l. . ,-, ;~l . ,.l ;. ~ rl ~ . " ;. ~Iy acceptable solid or liquid cartiers may be added to enhance or stabilize the c~ or to facilitate 25 preparation of the c~ Liquid carriers include syrup, peanut oil, olive oil, glycerin, sa~ine, ethanol, and water. Solid carriers include starch, lactose, calcium sulfate dihydrate. terra alba, ... ~. ~; ,. stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl ~u~O~ ,cu or glyceryl distearate, alone or with a wax. The amount of 30 solid carrier varies but, preferably, will be between ahout 20 mg to ahout I g per dosage unit. The ~ ,-c,u..,.:Lic..~s are made following the "o--~.
techniques of pharmacy involving milling, mixing, grrn~ in~. and cu...l,.c:,:.i..g, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a 35 syrup, elixir, emulsion or an aqueous or non-aqueous sllcr~ncinn Such a liquid r""...lnli....maybe:nl.,.;~ ddirectlyp.o.orfilledintoasoftgelatincapsule.
Dosing in humans for the treatment of disease according to the present invention should not exceed about 100 mg/day of the compounds of Formula I. For WO 95/14384 2 1 7 6 3 ~ ~ PCI/US94/13561 prevention of reocclusion following PTCA, the preferred range of dosing is ad~ .;aL.a.iu.~ oFfrom aboul 12.5 mg/day to about ]00 mg/day of a compound of Formula I in a single dose or multiple doses up to three times daily before, during, and for up to six months pOst-.-llE,iupl~aly, most preferably thc dosage is about 25 5 mg/day 3 times daily. It will be a~ c ' ' that the actual preferred dosages of the o~ ic being used in the ~ of this invention will vary according to theparticular....,.,~ i..,.formulated,themodeofA.I",.,~ ".l;.,,,theparticularsite of ddll.il.iaL- aLivll, the host being treated, and the particular disease being treated.
No lln~ rt~hll~ ~. .. ;, ol~i~ ~1 effects are expected when the cûmpounds of 10 Formula I are used according tû the present invention.
In the following Examples, all t~ p~,.aLb.c:~ are in degrees Centigrdde (C).
Unless otherwise indicated, all of the starting materials were obudined from commercial sources. Without further ~ ~r~tirm, it is believed that one skilled in the art can, using the preceding ~irc~rirrin~, utilize the invention to itâ fullest extent.
15 These Examples are given to illustrdte the invention, not to limit its scope. Reference is made to the claims for what is reserved to the inventors hereunder.
EXAMpl .F~
Example I
The compound of Formula (I) wherein R3 is -OH and R I-R2 and R4-Rg are all H was synthesized as follows and is exemplary of the synthetic route to the compounds of Formula (1).
3-Benyl g ~ u~y~ul l,u~ole Benzoyl peroxide (881 mg, 2.73 mmol) was added in one portion to a suspension of ~ h.~JIu~r~,~lba~ul~ (500 mg, 2.73 mmol) in 20 ml CHCl3 at 25C
The mixture was stl-rred for 2 h, then washed with water. The organic layer was dried 30 over sodium sulfate and ..,. ,., ., l .. ~. ~1 Flash ~,1..- ~, . ' ~ of the residue (silica, methylene chloride) provided 15 mg of 3-benzylOxy-4-l.~.Lu~y.,a ba~l~. MS
(DCVNH3): 304.2 (M+H)+.
Subsequent steps to yield the product are well-known: reaction with e~ u.ul..~i.., then 2-..,~Ll.u,~y~ Ll.ylamine, and finally - "....,;ri -~;..., of the 35 benzoyl ester.
E~xa ,mRle 2 ~ioration of Y~ i ~imooth M~
The procedure for assessing vascular smooth muscle cell migrdtion was described previously in Hidaka, Y., Eda, T., Yonemoto, M. & Kamei, T. (1992) ~ W095/14384 217637~ 9 PCT/US94/13561 ~
Atheroscler. 95, 87-94. Briefly, rat aortic vascular smooth muscle cells (passage 3) were suspended (Ix106 cells/ml) in serum free DMEM ,"~ i with 0.2%
(w/v) bovine serum albumin (Sigma). Migration assays were performed in modified Boyden chambers using Transwell (Costar, Cambridge, MA) cell culture chambers S with a poly~ 8 ~Lm pore size membrane. PDGF was dissolved in DMEM and placed in the lower CUIII~ in the presence, or absence, of c--mro~n~lc Of Formula (I) wherein Rl, R2, R3, Rs, R6 or R8 are ~, ' 'y OH. Vascular smooth muscle cells (5xl 05) were then loaded in the upper ~.U~ and incubated for 24 h at 37C in a humidified aL...v,~ containing 5% C02. Non-10 migrated cells on the upper surface were scraped away gently and washed three timeswith PBS. Filters were fixed in methanol and stained with Giemsa. The number of vascular smooth muscle cells per 100 x high power field (HPF) that had migrated to the lower surface of the filters was determined ~ ua~,u~i~,ally. Four HPFs were counted per filter. E~ ".L~ were performed either in duplicate or triplicate.
PDGF produced - dependent increases in the migration of rat vascular smooth muscle cells with maximal effect obtained at a ~ ;. .- - of I
nM. When cnmro~ of Formula (I) wherein are ;~ ly Rl, R2, R3, R5, R6 or R8 is OH were placed in the lower chamber with PDGF, the migration response was inhibited sl6,lirl~,a-lLly in a dependent manner. ICso values for 20 ~'I"J" I~ of Formula (I) wherein Rl, R2, R3, Rs, R6 or R8 are i --i- ~ ly OH
we as follows.
Position of OH group ICso [llM]
R 1 0.99 R2 0.41 R3 0.20 Rs 0.18 R6 1.72 R8 0.36 The above description fully discloses how to make and use the present invention. However, the present invention is not limited to the particular ~."l~l;."~ .
described hereinabove, but includes all ~.o.lir~iu-ls thereof wilhin the scopc of the claims.
Claims (32)
1. Use of a compound of Formula (I):
(I) wherein:
R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of proliferation and migration of smooth muscle cells in mammals.
(I) wherein:
R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of proliferation and migration of smooth muscle cells in mammals.
2. A use according to claim 1 wherein said mammal is human.
3. A use according to claim 1 wherein in said compound of Formula (I), R1 is OH and R2-R9 are H.
4. A use according to claim 1 wherein in said compound of Formula (I), R2 is OH and R1, and R3-R9 are H.
5. A use according to claim 1 wherein in said compound of Formula (I), R3 is OH and R1, R2, and R4-R9 are H.
6. A use according to claim 1 wherein in said compound of Formula (I), R5 is OH and R1-R4 and R6-R9 are H.
7. A use according to claim 1 wherein in said compound of Formula (I), R6 is OH and R1-R5 and R7-R9 are H.
8. A use according to claim 1 wherein in said compound of Formula (I), R8 is OH and R1-R7 and R9 are H.
9. Use of a compound of Formula (I):
(I) wherein:
R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of human patients surviving percutaneous transluminal coronary angioplasty (PTCA) to inhibit restenosis by angioplasty-induced neointimal proliferation in blood vessels following PTCA.
(I) wherein:
R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of human patients surviving percutaneous transluminal coronary angioplasty (PTCA) to inhibit restenosis by angioplasty-induced neointimal proliferation in blood vessels following PTCA.
10. A use according to claim 9 wherein said pharmaceutical composition is suitable for parenteral administration.
11. A use according to claim 9 wherein in said compound of Formula (I), R1 is OH and R2-R9 are H.
12. A use according to claim 9 wherein in said compound of Formula (I), R2 is OH and R1, and R3-R9 are H.
13. A use according to claim 9 wherein in said compound of Formula (I), R3 is OH and R1, R2, and R4-R9 are H.
14. A use according to claim 9 wherein in said compound of Formula (I), R5 is OH and R1-R4 and R6-R9 are H.
15. A use according 10 claim 9 wherein in said compound of Formula (I), R6 is OH and R1-R5 and R7-R9 are H.
16. A use according to claim 9 wherein in said compound of Formula (I), R8 is OH and R1-R7 and R9 are H.
17. Use of a compound of Formula (I):
(I) wherein:
R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibition of development of atherosclerosis in human patients.
(I) wherein:
R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibition of development of atherosclerosis in human patients.
18. A use according to claim 17 wherein said pharmaceutical composition is suitable for parenteral administration.
19. A use according to claim 17 wherein in said compound of Formula (I), R1 is OH and R2-R9 are H.
20. A use according to claim 17 wherein in said compound of Formula (I), R2 is OH and R1, and R3-R9 are H.
21. A use according to claim 17 wherein in said compound of Formula (I), R3 is OH and R1, R2, and R4-R9 are H.
22. A use according to claim 17 wherein in said compound of Formula (I), R5 is OH and R1-R4 and R6-R9 are H.
23. A use according to claim 17 wherein in said compound of Formula (I), R6 is OH and R1-R5 and R7-R9 are H.
24. A use according to claim 17 wherein in said compound of Formula (I), R8 is OH and R1-R7 and R9 are H.
25. Use of a compound of Formula (I):
(I) wherein:
R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for suppressing the progression of vascular hypertrophy associated with hypertension.
(I) wherein:
R1-R9 are independently -H or -OH, with the proviso that at least one of R1-R9 is OH, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for suppressing the progression of vascular hypertrophy associated with hypertension.
26. A use according to claim 25 wherein in said pharmaceutical composition is suitable for parenteral treatment.
27. A use according to claim 25 wherein in said compound of Formula (I), R1 is OH and R2-R9 are H.
28. A use according to claim 25 wherein in said compound of Formula (I), R2 is OH and R1, and R3-R9 are H.
29. A use according to claim 25 wherein in said compound of Formula (I), R3 is OH and R1, R2, and R4-R9 are H.
30. A use according to claim 25 wherein in said compound of Formula (I), R5 is OH and R1-R4 and R6-R9 are H.
31. A use according to claim 25 wherein in said compound of Formula (I), R6 is OH and R1-R5 and R7-R9 are H.
32. A use according to claim 25 wherein in said compound of Formula (I), R8 is OH and R1-R7 and R9 are H.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/157,588 | 1993-11-24 | ||
| US08/157,588 US5393772A (en) | 1993-11-24 | 1993-11-24 | Use of, and method of treatment using, hydroxycarbazole compounds for inhibition of smooth muscle migration and proliferation |
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| Publication Number | Publication Date |
|---|---|
| CA2176377A1 true CA2176377A1 (en) | 1995-06-01 |
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| CA002176377A Abandoned CA2176377A1 (en) | 1993-11-24 | 1994-11-22 | Inhibition of smooth muscle migration and proliferation with hydroxy carbazole compounds |
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|---|---|
| US (1) | US5393772A (en) |
| EP (1) | EP0741567B1 (en) |
| JP (1) | JPH09505809A (en) |
| KR (1) | KR100386229B1 (en) |
| CN (1) | CN1102388C (en) |
| AT (1) | ATE226072T1 (en) |
| AU (1) | AU686706B2 (en) |
| CA (1) | CA2176377A1 (en) |
| DE (1) | DE69431568T2 (en) |
| ES (1) | ES2185691T3 (en) |
| WO (1) | WO1995014384A1 (en) |
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Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US6515009B1 (en) | 1991-09-27 | 2003-02-04 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5811447A (en) * | 1993-01-28 | 1998-09-22 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6395494B1 (en) * | 1993-05-13 | 2002-05-28 | Neorx Corporation | Method to determine TGF-β |
| US5770609A (en) | 1993-01-28 | 1998-06-23 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
| US6306421B1 (en) | 1992-09-25 | 2001-10-23 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6251920B1 (en) | 1993-05-13 | 2001-06-26 | Neorx Corporation | Prevention and treatment of cardiovascular pathologies |
| US5595722A (en) * | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
| US6491938B2 (en) | 1993-05-13 | 2002-12-10 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US6663881B2 (en) | 1993-01-28 | 2003-12-16 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5981568A (en) | 1993-01-28 | 1999-11-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| JPH08510451A (en) * | 1993-05-13 | 1996-11-05 | ネオルックス コーポレイション | Prevention and treatment of pathogenesis associated with hyperproliferative smooth muscle cells |
| US20030083733A1 (en) * | 1997-10-10 | 2003-05-01 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
| US5837313A (en) * | 1995-04-19 | 1998-11-17 | Schneider (Usa) Inc | Drug release stent coating process |
| US6099562A (en) * | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
| US20020091433A1 (en) * | 1995-04-19 | 2002-07-11 | Ni Ding | Drug release coated stent |
| US7611533B2 (en) * | 1995-06-07 | 2009-11-03 | Cook Incorporated | Coated implantable medical device |
| ATE377418T1 (en) * | 1995-06-07 | 2007-11-15 | Poniard Pharmaceuticals Inc | PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASES WITH TAMOXIFEN ANALOGUES |
| ZA967892B (en) * | 1995-09-21 | 1998-03-18 | Lilly Co Eli | Selective β3 adrenergic agonists. |
| JP2001504804A (en) * | 1996-08-23 | 2001-04-10 | ベーリンガー・マンハイム・ファーマシューティカルズ・コーポレイション−スミスクライン・ベックマン・コーポレイション・リミテッド・パートナーシップ・ナンバー１ | Method for inhibiting FAS expression |
| US5808080A (en) * | 1996-09-05 | 1998-09-15 | Eli Lilly And Company | Selective β3 adrenergic agonists |
| ATE215369T1 (en) * | 1996-09-05 | 2002-04-15 | Lilly Co Eli | CARBAZOLE ANALOGUES AS SELECTIVE BETA3-ADRENERGIC AGONISTS |
| AU765934B2 (en) * | 1996-10-09 | 2003-10-02 | Boehringer Mannheim Pharmaceuticals Corporation-Smithkline Beecham Corporation Limited Partnership No. 1 | Method for inhibiting stress-activated protein kinases |
| JP2002512591A (en) * | 1996-10-09 | 2002-04-23 | ベーリンガー・マンハイム・ファーマシューティカルズ・コーポレイション―スミスクライン・ビーチャム・コーポレイション・リミテッド・パートナーシップ・ナンバー１ | Inhibition of stress-activated protein kinases |
| CO5011072A1 (en) | 1997-12-05 | 2001-02-28 | Lilly Co Eli | ETANOLAMINAS PIRAZINIL SUBSTITUTED AS AGFONISTS OF THE RECEPTORS |
| DE19830472B4 (en) * | 1998-07-08 | 2013-06-27 | Robert Bosch Gmbh | External component for a microprocessor system and operating procedures |
| US20050002986A1 (en) * | 2000-05-12 | 2005-01-06 | Robert Falotico | Drug/drug delivery systems for the prevention and treatment of vascular disease |
| US8236048B2 (en) * | 2000-05-12 | 2012-08-07 | Cordis Corporation | Drug/drug delivery systems for the prevention and treatment of vascular disease |
| US20040243097A1 (en) * | 2000-05-12 | 2004-12-02 | Robert Falotico | Antiproliferative drug and delivery device |
| US6776796B2 (en) | 2000-05-12 | 2004-08-17 | Cordis Corportation | Antiinflammatory drug and delivery device |
| DE60124285T3 (en) * | 2000-09-29 | 2011-03-17 | Cordis Corp., Miami Lakes | COATED MEDICAL EQUIPMENT |
| US20020051730A1 (en) * | 2000-09-29 | 2002-05-02 | Stanko Bodnar | Coated medical devices and sterilization thereof |
| US7261735B2 (en) * | 2001-05-07 | 2007-08-28 | Cordis Corporation | Local drug delivery devices and methods for maintaining the drug coatings thereon |
| US20020111590A1 (en) * | 2000-09-29 | 2002-08-15 | Davila Luis A. | Medical devices, drug coatings and methods for maintaining the drug coatings thereon |
| US6613083B2 (en) * | 2001-05-02 | 2003-09-02 | Eckhard Alt | Stent device and method |
| US7195640B2 (en) * | 2001-09-25 | 2007-03-27 | Cordis Corporation | Coated medical devices for the treatment of vulnerable plaque |
| US20030065345A1 (en) * | 2001-09-28 | 2003-04-03 | Kevin Weadock | Anastomosis devices and methods for treating anastomotic sites |
| JP2005507899A (en) * | 2001-09-28 | 2005-03-24 | エフ．ホフマン−ラ ロシュ アーゲー | Pseudopolymorphic form of carvedilol |
| US20030065377A1 (en) * | 2001-09-28 | 2003-04-03 | Davila Luis A. | Coated medical devices |
| US7108701B2 (en) * | 2001-09-28 | 2006-09-19 | Ethicon, Inc. | Drug releasing anastomosis devices and methods for treating anastomotic sites |
| US8101209B2 (en) * | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
| AU2003231283A1 (en) * | 2002-04-30 | 2003-11-17 | Sb Pharmco Puerto Rico Inc. | Carvedilol monocitrate monohydrate |
| AU2003248746B2 (en) * | 2002-06-27 | 2009-01-08 | Smithkline Beecham (Cork) Limited | Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment |
| CA2492084A1 (en) * | 2002-06-27 | 2004-01-08 | Sb Pharmco Puerto Rico Inc. | Carvedilol hydobromide |
| JP5072364B2 (en) * | 2003-11-25 | 2012-11-14 | スミスクライン ビーチャム （コーク） リミテッド | Carvedilol free base, carvedilol salt, anhydrous form or solvate thereof, corresponding pharmaceutical composition, controlled release formulation and treatment or delivery method |
| EP1686967A4 (en) * | 2003-11-25 | 2012-08-08 | Smithkline Beecham Cork Ltd | Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods |
| EP1686986A4 (en) * | 2003-11-25 | 2009-05-27 | Sb Pharmco Inc | Carvedilol salts, corresponding compositions, methods of delivery and/or treatment |
| US10281374B2 (en) * | 2015-11-04 | 2019-05-07 | Diagnostic Biosystems | Method of pretreatment of biological samples for an analyte-staining assay method |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2815926A1 (en) * | 1978-04-13 | 1979-10-18 | Boehringer Mannheim Gmbh | NEW CARBAZOLYL- (4) -OXY-PROPANOLAMINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
| US5308862A (en) * | 1993-03-05 | 1994-05-03 | Boehringer Mannheim Pharmaceuticals Corporation - Smithkline Beecham Corp., Ltd. Partnership No. 1 | Use of, and method of treatment using, carbazolyl-(4)-oxypropanolamine compounds for inhibition of smooth muscle cell proliferation |
-
1993
- 1993-11-24 US US08/157,588 patent/US5393772A/en not_active Expired - Lifetime
-
1994
- 1994-11-22 ZA ZA949246A patent/ZA949246B/en unknown
- 1994-11-22 JP JP7515231A patent/JPH09505809A/en active Pending
- 1994-11-22 CA CA002176377A patent/CA2176377A1/en not_active Abandoned
- 1994-11-22 KR KR1019960702460A patent/KR100386229B1/en not_active IP Right Cessation
- 1994-11-22 CN CN94194188A patent/CN1102388C/en not_active Expired - Fee Related
- 1994-11-22 AT AT95902689T patent/ATE226072T1/en not_active IP Right Cessation
- 1994-11-22 DE DE69431568T patent/DE69431568T2/en not_active Expired - Fee Related
- 1994-11-22 EP EP95902689A patent/EP0741567B1/en not_active Expired - Lifetime
- 1994-11-22 WO PCT/US1994/013561 patent/WO1995014384A1/en active IP Right Grant
- 1994-11-22 AU AU11867/95A patent/AU686706B2/en not_active Ceased
- 1994-11-22 ES ES95902689T patent/ES2185691T3/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1135161A (en) | 1996-11-06 |
| DE69431568D1 (en) | 2002-11-21 |
| ATE226072T1 (en) | 2002-11-15 |
| CN1102388C (en) | 2003-03-05 |
| ES2185691T3 (en) | 2003-05-01 |
| KR100386229B1 (en) | 2003-08-21 |
| AU1186795A (en) | 1995-06-13 |
| WO1995014384A1 (en) | 1995-06-01 |
| AU686706B2 (en) | 1998-02-12 |
| EP0741567B1 (en) | 2002-10-16 |
| EP0741567A4 (en) | 1996-12-04 |
| JPH09505809A (en) | 1997-06-10 |
| US5393772A (en) | 1995-02-28 |
| EP0741567A1 (en) | 1996-11-13 |
| ZA949246B (en) | 1995-07-04 |
| DE69431568T2 (en) | 2003-06-26 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |