CA2012634A1 - Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseases - Google Patents
Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseasesInfo
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- CA2012634A1 CA2012634A1 CA 2012634 CA2012634A CA2012634A1 CA 2012634 A1 CA2012634 A1 CA 2012634A1 CA 2012634 CA2012634 CA 2012634 CA 2012634 A CA2012634 A CA 2012634A CA 2012634 A1 CA2012634 A1 CA 2012634A1
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Abstract
TYRPHOSTINS FOR TREATMENT OF ALLERGIC, INFLAMMATORY AND CARDIOVASCULAR DISEASES
ABSTRACT OF THE INVENTION
This invention pertains to the novel use of composi-tions useful in the treatment of inflammation induced diseases comprising: (a) a compound of the formula:
ABSTRACT OF THE INVENTION
This invention pertains to the novel use of composi-tions useful in the treatment of inflammation induced diseases comprising: (a) a compound of the formula:
Description
TYRPHOSTINS FOR TREATMENT OF ALLERGIC, 012634 INFLAMNATORY AND CARDIOVASCULAR DISEASES
FIELD OF THE INVENTION
This invention pertains to the novel use of composi-tions containingbenzylidenemalononitrileand hydroxycinnamamide derivatives in the treatment of asthma, allergic diseases, hay fever, skin rashes, inflammatory bowel diseases, arthritis, adult respiratory distress syndrome (ARDS), migraine, cardiac shock, septic shock, thrombosis, hypotension, hypertension and ischemia. -BACKGROUND OF THE INVENTION
15Tyrphostins are a group of low molecular weight compounds, having the nucleus of benzvlidenemalononitrile and/or hydroxycinnamamide. These compounds are reported to be inhibi-tors of protein tyrosine kinases and their use in the treatment of cancer has been recommended. I have found that these agents also inhibit the action of the mediators of asthma, inflammation and cardiovascular diseases.
Compounds having the nucleus of benzylidene malono-nitrile such as N-~2-(2, 5-dihydroxyphenyl~ ethenyl) formamide, identified with the trade-mark Erbstatin, have been known for several years. Such compounds have the following formula:
I~D / ~CHo H
OH
20~2634 These compounds were initially described as inhibitors of protein tyrosine kinase and their use in cancer chemotherapy was recommended due to their effects on blocking the epidermal growth factor receptor (EGF) kinase (Umezawa, H. et al., J.
5Antibiotics, vol. 39, 170-173, 1986 and Yaish, P. et al., Science, vol. 242, 933-935, 1988).
u.s. Patent No. 4,686,308, granted August 11, 1987, protects a novel compound 2,2-formamidoethenyl-1,4-hydroxy-10quinone. Preparation comprises cultivation of a Streptomyces strain or by its mutant treated by ultraviolet irradiation, or by recombinant DNA techniques of gene coding. This compound purportedly has antitumour and antimicrobial activities, with inhibitory activity against tyrosine specific protein kinase.
Sseveral articles disclose tyrosine kinase inhibitors.
One is entitled "Blocking of EGF-Dependent Cell Proliferation by EGF Receptor Kinase Inhibitors", Pnina Yaish, Aviv Gazit, Chaim Gilon, Alexander Levitzki, Science, vol.242, Nov. 11, 1988, pp.
20933-935. This article describes the synthesis of a systematic series of low mole¢ular weight protein tyrosine kinase inhibi-tors. They had progressively increasing affinity over a 2500-fold range toward the substrate site of epidermal growth factor (EGF) receptor kinase domain. These compounds inhibited EGF
25receptor kinase activity up to three orders of magnitude more than they inhibited insulin receptor kinase, and they also effectively inhibited the EGF-dependent autophosphorylation of the receptor. The most potent compounds effectively inhibited the EGF-dependent proliferation of A431/clone 15 cells with 30little or no effect on the EGF-independent proliferation of these cells. The potential use of tyrosine protein kinase inhibitors as antiproliferative agents is demonstrated.
Another is entitled "Tyrphostins Inhibit Epidermal 35Growth Factor (EGF)-Receptor Tyrosine Kinase Activity in Living Cells and EGF-stimulated Cell Proliferation", R. M. Lyall, A.
Zilberstein, A. Gazit, C. Gilon, A. Levitzki and J. Schlessinger, ;~012634 e Journal of Biological Chemistry, Vol. 264, No. 24, Aug. 25, 1989, pp. 14503-14509. Synthetic compounds ca]led tyrphostins were examined for their effects on cells which are mitogenically responsive to epidermal growth factor (EGF). The writers studied in detail the effects of two tyrphostins on EGF binding, tyrosine phosphorylation in intact cells, EGF-receptor internalization, and mitogenesis. These compounds inhibited EGF-stimulated [3H]
thymidine incorporation in a specific manner and the degree of selectivity varied. Both compounds inhibited EGF-stimulated receptor autophosphyorylation and tyrosine phosphorylation of endogenous substrates in intact cells at doses that correlated with the ICso for [3H] thymidine incorporation. These results are consistent with the notion that tyrosine phosphorylation is a crucial signal in transduction of the mitogenic message delivered by EGF. The compoun~ RGs0864 demonstrated specificity at inhibiting EGF-stimulated cell growth compared with stimulation with either platelet-derived growth factor or serum. These novel synthetic inhibitors, specific for EGF-receptor kinase, allegedly offer a new method to inhibit EGF-stimulated cell proliferation which may be useful in treating specific pathological conditions involving cellular proliferation, including different types of cancers.
A third article is entitled "Specific Inhibitors of Tyrosine-Specific Protein Kinases: Properties of 4-Hydroxycin-namamide Derivatives in Vitro", T. Shiraishi, M. K. Owada, M.
Tatsuka, T. Yamashita, K. Watanabe and T. Kakunaga, Cancer Research 49, 2374-2378, May 1, 1989. Inhibition by seven synthetic 4-hydroxycinnamamide derivatives, ST 271, ST 280, ST
458, ST 494, ST 633, ST 638 and ST 642, of tyrosine-specific protein kinases (tyrosine kinase) of oncogene or proto-oncogene products (pl30gag-v-fps, p70gag-actin-v-fgr, pp60v-src, pp60c-src) and epidermal growth factor (EGF) receptor kinase were investigated. ST 638 (~-cyano-3-ethoxy-4-hydroxy-5-phenylthio-methylcinnamamide) strongly inhibited more of the tyrosine kinases than any of the other compounds. The susceptibilities of these tyrosine kinases to ST 638 increased in the following 20~Z634 rder: EGF receptor > p70gag-actin-v-fgr > pp60c-src > pl30gag-v-fps, pp60v-src, with 50% inhibitory concentration values of 1.1, 4.2, 18, 70, and 87 ~M, respectively. The phosphorylation of the tyrosine residues in particulate fractions from RR1022 5cells expressing pp60v-src was inhibited by ST 638 in a dose-dependent way, while it had a negligible effect on the phosphory-lations of threonine and serine residues. Kinetic analysis showed that ST 638 competitively inhibited the phosphorylation of an exogenous substrate by the EGF receptor kinase with a K; of 102.1 ~M. ST 638 noncompetitively inhibited autophosphorylation by EGF receptor kinase. These results indicate that ST 638 is a potent and specific inhibitor of tyrosine kinases in vitro, and that its inhibitory activity is caused by competing with the substrate protein for the tyrosine kinase binding site.
~ --A fourth article relates specifically to Erbstatin:
"Effective Synthesis of Erbstatin and its Analogs~', E. L. Dulaney and C.A. Jacobsen, The Journal of Antibiotics, Vol. XL, No. 8, Aug. 1987, pp. 1207-1212. Erbstatin, purported to be a new 20potent inhibitor for tyrosine protein kinase (TPK), was isolated from the broth of Stre~tomyces sp. (MH435-hF3) and the structure was determined by X-ray crystallographic analysis. Erbstatin -(3a) and its analogs were expected to be useful for the studies of the functions of oncogenes (tumour inducing genes), and may 25have therapeutic activity for the treatment of cancer. ~
', ':
SUMMARY OF THE INVENTION
The invention is directed to a composition useful in 30the treatment of inflammation induced diseases comprising~
(a) a compound of the formula Rz-R
` 201Z634 wherein Rl is H, OH, OCH3, ETO;
R2 is EtO, CHC(CH3)2, iso-Proline, CH3SCH2, H, OH, NO2, OCH3, OCH, R6Cl;
R3 is H, OH, OCH3, phenyl SCH2, CH. (CH3)2, iso-Proline, CH3SCH2;
R4 is H, OH;
R5 is H, CN, COOH, NHCHO;
R6 is H, CN, COOH, NHCHO, O, S;
R7 is H, OH; and wherein R5 and R6 can form the following cyclic structures:
~ ' '' C/
J
when R1 and R3 are CH3SCH2, R2 is OH, and R4 and R7 are H;
O
1~
<C~_~,3 '' ' C~
O ~:
when R1 is ETO, R2 is OH, R3 is PHSCH2, R4 and R7 are H;
~
~, . i ' '-'~
;' len R1 is ETO, R2 is OH, R3 is PhenylSCH2 and R4 and R7 are ~ a;~
/ \ ~: .
O
when R1 and R3 are iso-Proline, R2 is OH, and R4 and R7 are H, and pharmaceutically acceptable acid addition salts thereof; and -:
"'"-'-.'~'.
(b) a pharmaceutically acceptable carrier.
' ~' ' The invention includes a composition for treating inflammatory diseases comprising:
(a) a benzylidene malononitrile of the formula: ~:
"'~
, . -.
/ ~3 ~ ~
wherein: : ::
( 1 ) R1 =OH, Rz=H, R3=H, R4=OH, Pc5=NHCHO, R6=H
( 2 ) R1=H, R2=OH, R3=H, R4=H, R5=C02H, R6 H
( 3 ) R1 H ~ R2=OH, R3=H, R4=H, R5=C02H, R6=COzH
( 4 ) Rl H , R2=OH , R3=H , R4=H , R5=CN , R6=CN ::
(5) Rl=OH, R2=OH, R3=H, R4=H ~ Rs=C2H, R6 N
( 6 ) Rl OH, Rz H, R3=H, R4=OH, R5=H, R6=NHCHO
( 7 ) Rl=H, R2=H, R3=OH, R4=H, R5=CN, R6=CN
( 8 ) Rl OH, R2=H, R3=H, R4=OH, R5=CN, R6=CO2H
( 9 ) Rl H, Rz=OH, R3=OH, R4=H, R5=CO2H, R6=CN
( 10 ) Rl=H, R2=OH, R3=OH, R4=H, R5=CN, R6=CN
( 11 ) Rl=OCH3, R2=OH, R3=OH, R4=H, R5=CN, R6=CN ~ ~:
-- 6 -- ~
:
:
- ~2) Rl=OH, R2=OH, R3=OH, R4=H, Rs=CN, R6=CN Z012634 (13) R1=OH, ~R2=OH, R3=OH, R4=OH, Rs=CN, R6=CN
( l4 ) R1=OH, R2=OH, R3=OH, R4=H, Rs=NHCHO, R6=H
(l5) R1=H, R2=OH, R3=H, R4=H, Rs=CN, R6=CN
( l 6 ) R1=H, R2=OH, R3=H, R4=H ~ Rs=CN ~ R6=H
(17) R1=OH, R2=02N, R3=H, R4=H, Rs=CN, R6=CN
( l8 ) R1=H, R2=OH, R3=H, R4=H, Rs=CN, R6=CN, R7=OH
(l9) R1=CH30, R2=OH, R3=H, R4=H, R5=CN, R6=CN
( 2 0 ) R1=OH, R2=H, R3=OH, R4=H, Rs=CN, R6=CN
( ) R1 OH, Rz OH, R3=OH, R4=H, R5=CN, R6=CN, R7=OH
(22) R1=H, R2=CH30, R3=H, R4=H, Rs=C02H, R6=CN
(23) R1=H, R2=FlCl, R3=H, R4=H, Rs=C02H, R6=CN
(24) R1=CH30, R2=OH, R3=CH30, R4=H, R5=CO2H, R6 CN
( 2 5 ) R1 H, R2=OH, R3=H, R4=H, R5=C02H, R6=CNlS (26) R1=H, R2=oCH, R3=H, R4=H, R5=C02H, R6 CN
(27) R1=OH, R2=H, R3=H, R4=H, Rs=CN, R6=CO2H
and pharmaceutically acceptable acid addition salts thereof; and (b) a pharmaceutically acceptable carrier.
The invention also includes a composition for treating inflammatory diseases comprising: -(a) a cinnamamide of the formula:
R J~
R~ Rb wherein:
( l ) R1=ETO, R2=OH, R3=PhenylSCH2, R4=H, Rs=CN, R6=O . - -( 2 ) Rl=CH . CMe2, R2=OH, R3=CH . Me2, R4 H, Rs CN, 6 (3) Rl=ETO, R2=OH, R3=PhenylSCH2, R4=H, Rs=CN, R6=S
( 4 ) R1=OH, R2=OH, R3=H, R4=H, R5=CN, R6=S : ~ -(5) R1=iso-Proline, R2=OH, R3=iso-Proline, R4=H, R5=CN, R6=O
'' ~' ;'.
~,) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=o 201Z634 (7) R1=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=o; or -- -(8) R~=OH, R2=OH, R3=OH, R4=I, R5=CN, R6=S; or wherein R5 and R6 -can combine to one of the following structures; and having R1=OCH3, iso-proline or OH, R2=OCH3 or OH, R3=iso-proline or OCH
~ ~ =Q IH ~ ~ ~
o O
oc~3 C~
~ 3 3 =C~H~ C~C~z and acid addition salts thereof; and -(b) a pharmaceutically acceptable carrier. ~
. ~ . . :-In the composition as illustated above, R1 can be OH
2 5 and R2 and R3 can be H, R4 can be OH, Rs can be NHCHO and R6 and R7 can be H. In the composition, the carrier is distilled water.
In the composition as described, compound (a) can be present in compound (b) at a concentration ranging from 0.5 mg/l to l00 mg/l. The composition can include an effective amount of an iron chelation agent, andjor oxygen radicals scavenger.
. . . ~ , I The composition is administered orally, as an aerosol, ;-subcutaneously or intravenously. The composition can be in the form of a tablet. The composition can be used in the treatment of asthma, allergic diseases, hay fever, skin rashes, inflamma-tory bowel diseases, arthritis, adult respiratory distress ZOlZ634 ~yndrome (ARDS), migraine, cardiac shock, septic shock, thrombo-sis, hypotension, hypertension and ischemia.
DETAILED DESCRIPTION OF SPECIFIC
Platelet activating factor (PAF) and Leukotriene D4 (LTD4) are important components of bronchial hyperresponsiveness and inflammation. Elucidation of their mode of cellular action is a crucial step towards the understanding of pathophysiological states caused by PAF and LTD4 and subsequently the management of diseases associated with those molecules.
Initially, the role ofprotein-tyrosinephosphorylation in the signal transduction of PAF was investigated in rabbit platelets. Two tyrosine kinase inhibitors, N-(2-(2,5-dihydroxy-phenyl)ethenyl)formamide-methanolate (coded; TR-lA) and ~-cyano-3,4-dihydroxythiocinnamamide (TR-18) were found to inhibit PAF
responses at the ICso = 15 and 50 ~g/ml, respectively. Inhibi-tion of protein-tyrosine phosphorylation blocked PAF-induced phosphoinositide breakdown, membranous protein kinase C activity, platelet aggregation and serotonin release. These data imply that protein-tyrosine phosporylation plays a critical role in PAF-signal transduction systems. This suggests that the PAF
receptor may be a tyrosine kinase or a tyrosine phosphorylatable protein coupled to a phospholipase C, or alternatively coupled to a phospholipase C amenable to phosphorylation by tyrosine kinases.
30This work provides firm evidence that specific inhibitors of protein-tyrosine kinase should prove to be valuable -tool$ in the management of bronchial hyperresponsiveness and inflammation.
::,--:-: ~ :, 35The drug TR-lA was initially believed to be useful for the study of the functions of oncogenes (tumour inducing genes) ~ ~ ;
due to its action on the inhibition of protein tyrosine kinase. ;~
:, ''`
:,'..~ "-- - .,~':
2012634 ~ ~
~ e to the fact that the receptors for a number of mediators of inflammatory and allergic reactions might have protein tyrosine kinase activity, I have discovered that the drug TR-lA can inhibit the activation of these mediators' receptors and affect the normal interaction of these receptors with their effector system.
Existing drugs used in the treatment of asthma, inflammatory diseases, or allergic diseases, are designed either to inhibit certain enzymes responsible for the syntheses of these mediators, or to block their mode of signal transduction. TR-lA, by inhibiting protein tyrosine kinase, a common enzyme for the transduction of signals for many mediators, should be more effective in preventing the above diseases, since it will work against many mediators at the same time.
I have found the drug TR-lA inhibits platelet activat-ing factor (PAF) (an inflammatory mediator) responses. These included aggregation of platelets and release of serotonin. TR-lA also inhibited constriction o guinea pig's trachea inresponse to leukotiene D4 (LTD4) (a major mediator of allergic and asthmatic reactions). From this, it is evident that TR-lA
has important use in the treatment of asthma, allergy cardiovas-cular and inflammatory diseases.
From the foregoing demonstrations, it follows that the compound TR-lA is useful for the treatment of virtually all kinds of inflammatory diseases (eg. arthritis, inflammatory bowel disease, etc.), all kinds of allergic diseases (eg. asthma, rhenitis, skin allergy, hay fever, systemic anaphylaxis), and all kinds of heart and vascular diseases (eg. septic shock, ARDS, cardiogenic shock, arrythmias, hypotension, hypertension, thrombosis and blood clot).
I have discovered that the compounds of the invention block the action of PAF and LTD4. Although the receptors for these molecules are not characterized, nevertheless, it is ~012634 lieved that these agents inhibit tyrosine phosphorylation of the receptor. Alternatively, the compounds of the invention are interfering with biochemical parameters involved in the trans-duction of signals for PAF or LTD4. Such biochemical parameters could be the component of guanyl nucleotide regulatory proteins (G-proteins), phospholipases, protein kinases or phosphatases.
The compounds of the invention, with their novel uses, can be broadly divided into two main specific groups:
Group A Compounds (Benzvlidene Malononitrile Com~ounds) A composition for treating asthma, allergic diseases, ~:
hay fever, skin rashes, arthritis, inflammatory diseases (bowel, colon, etc.), adult respiratory distress syndrome (ARDS), septic shock, cardiac shock, thrombosis, hypertension, hypotension, tissue ischemia and migraine, comprising a benzylidene malono- .
nitrile of the formula: :
:~
R~ R_ ~3 R~
wherein~
(l) R~=OH~ R2=H, R3=H, R4=OH, Rs=NHCHO, R6=H (TR-lA) ;
(2) R1=H, R2=OH, R3=H~ R4=H~ R5=C2H~ R6 H
( 3 ) R~ H, R2=OH, R3=H, R4=H, Rs=C02H, R6=CO2H :: -( 4 ) ., R~=H , R2=OH ~ R3=H ~ R4=H ~ Rs=CN ~ R6=CN
( 5 ) R1=OH, R2=OH, R3=H ~ R4=~ ~ Rs=C2H ~ R6 N
(6) R1=OH, R2=H, R3=H~ R4=H~ Rs=H~ R6=NHCH ~ ~ -(7) R~=H, R2=H~ R3=OH~ R4=H~ Rs=CN, R6=CN ;
( 8 ) R~=OH, R2=H, R3=H, R4=OH, Rs=CN, R6=CO2H
( 9 ) R~ H, R2=OH, R3=OH, R4=H, Rs=C02H, R6=CN
0) R1=H, R2=OH, R3=OH, R4=H, ~=CN, R6=CN
(ll) R1=0CH3, R2=OH, R3=OH, R4=H, ~=CN, R6=CN 2ol2 (12) R1=OH, R2=OH, R3=OH, R4=H, ~=CN, R6=CN 634 ~ :
(l3) R1=OH, R2=OH, R3=OH, R4=OH, ~=CN, R6=CN
(l4) R1=OH, R2=OH, R3=OH, R4=H, Rs=NHcHo, R6=H
(l5) R1=H, R2=OH, R3=H, R4=H, ~=CN, R6=CN
(l6) R1=H, Rz=OH, R3=H, R4=H, Rs=CN, R6=H
(l7) R1=OH, R2=02N, R3=H, R4=H, ~=CN, R6=CN
(l8) R1=H, R2=OH, R3=H, R4=H, Rs=CN, R6=CN, R7=OH
(l9) R~=CH30, R2=OH, R3=H, R4=H, Rs=CN, R6=CN
(20) R1=OH, R2=H, R3=OH, R4=H, ~=CN, R6=CN
(2l) R1=OH~ R2=OH, R3=OH, R4=H, Rs=CN, R6=CN, R7=OH
(22) R1=H, R2=CH30, R3=H, R4=H, Rs=C02H~ R6 CN
(23) R1=H, R2=FICl, R3=H, R4=H, Rs=C02H~ R6=CN
(24) R1=CH30, R2=OH, R3=CH30, R4=H, ~=C02H, R6 CN
(25) R1 H, R2=OH, R3=H, R4=H, Rs=C02H, R6=CN
( 6) R1 H, R2=OCH, R3=H, R4=H, Rs=C02H~ R6=CN
( ) R1 OH, R2 H, R3=H, R4=H, R5=CN, R6=C02H
Results of Ex~eriments Conducted with Group A Compounds Initial Experiments .:, .
A number of initial experiments were performed with N-25 (2-(2-,5-dihydroxyphenyl)ethenyl) formamide methanolate (TR-lA), to inhibit biological activity of PAF on rabbit platelets.
Rabbit platelets were prepared according to the well-known method of Pinckard et al. J. Immuno~. 123, 1847-1853, 1979.
Platelets at 2 x lO8~ml were challenged with PAF (0.2 nN) at 37 in Tyrode's buffer, pH 7.2. Platelets (0.5 ml) were tested in a Bio-Data aggregometer for aggregation in response to PAF. TR-lA or PAF was added in 50 ul of 0.25% BSA in Tyrode's buffer.
Activities were measured as percent increase in light trans-mission.
ZOlZ634 As can be seen from Table 1, TR-lA, at 10 ~g/ml inhibited PAF-induced platelets aggregation by approximately 30%.
At 25 ~g/ml, it is seen that TR-lA blocked the action of PAF by 100%.
Table 1 Effect of Various Concentrations of TR-lA on PAF Induced Rabbit Platelets Aaareaation ., PAF (200 PM) Induced Aggregation TR-lA conc. (uq/ml) (% of Control mean of five experiments ~
100 ~ ~ "
155 100 ;~
-~
o Second Set of Ex~eriments ' ~''~' In another set of studies, at similar concentrations, -~-~
it was found that TR-lA inhibited PAF induced serotonin release ;~
from rabbit platelets. Platelets were labelled with t3H] ; ;~
serotonin for 1 hour. After this period of time, the unincorpor-ated [3H] serotonin was washed off and the platelets were used ~; ;
for challenge with PAF in the presence and absence of TR-lA. ~;~
TR-lA, from 10 ~g/ml, was found to inhibit PAF (200 PM) induced serotonin release. The IC50 was determined to be about 10 ~g/ml.
At 25 ~g/ml, it was noted that TR-lA entirely blocked PAF induced serotonin release.
. ~. i. . ;, TR-lA, at concentrations below 10 ~g/ml, did not appreciably prevent PAF induced serotonin release from rabbit platelets. At 20 ~g/ml, TR-lA inhibited PAF action by about 50%. At 25 ~g/ml, TR-lA almost completely blocked the action of PAF. These determinations are tabulated in Table 2.
."'~
~ '~
Table 2 Inhibitory Effect of Various Concentrations of TR-lA
on PAF Induced Serotonin Release from Rabbit Platelets TR-lA Conc. (~q/ml)Serotonin Release (% of Control) mean of five experiments 0.5 97 o o Example;
In order to evaluate the specific site of action of TR-lA on platelets, a series of experiments were performed to investigate the cellular second messenger system following PAF
activation. Platelets were labelled with [3H] inositol which became incorporated into phosphatidylinositol. The metabolism of phosphatidylinositol in response to PAF was then investigated.
the results are tabulated in Table 3.
As Table 3 shows, PAF (200 PM), without the presence of TR-lA, caused rapid hydrolysis of phosphatidylinositide.
However, when the platelets were first pretreated with various concentrations of TR-lA for 5 minutes prior to the addition of PAF, the formation of metabolites of phosphoinositide (inositol monophosphate, inositol bisphosphate and inositol trisphosphate) were inhibited. The IC50 for TR-lA was found to be between 20 and 25 ~g/ml. At 50 ~g/ml, it was noted that TR-lA entirely blocked the action of PAF. Similarly, TR-lA blocked the ~' Z01263~
~ctivation of protein kinase C induced by PAF. Protein kinase tPKC) is also a major component of a cell signalling system.
In this assay system, platelets were preincubated for 5 minutes with TR-lA (0-50 ~g/ml) and subsequently treated with PAF (200 PM) for 1 minute. The sample material was chromato-graphed on a mono Q column. 0.5 ml of NP 40-solubilized particulate protein from the platelet extracts was chromato-graphed, and the column fractions assayed for phosphorylating activity. It was found that TR-lA from 10 ~g/ml inhibited (>40%) the activation of PKC by PAF. At 25 ~g/ml, TR-lA blocked about ~
80% of the action of PAF. These results suggest that TR-lA ; -blocks PAF induced activation of rabbit platelets. Thus it ~ ~ -follows that TR-lA can be used in the treatment of diseases where PAF plays an important role (such as asthma, cardiovascular and inflammatory diseases).
Table 3 Inhibitory Effects of TR-lA on PAf Induced Polyphosphoinositide Metabolism in Rabbit Platelets Phosphoinosidide Metabolites Formation (% of control) - -~
TR-lA (~g/ml) IPl IP2 IP3 O 100 100 100 ':
0.5 100 100 100 1 100 100 100 ~;
100 -~ -ZOlZ634 roup B Compounds (Hydroxy Cinnamamide Compounds) Composition containing hydroxy cinnamamide compounds according to the following formula are useful for treating asthma, allergic diseases, hay fever, skin rashes, arthritis, inflammatory diseases (bowel, colon, etc.), ARDS, septic shock, cardiac shock, thrombosis, hypertension, hypotension, tissue ischemia and migraine. The hydroxycinnamamides have the following formula:
~L~ ~ N~z wherein:
(1) R1 ETO, R2=OH, R3=PhenylSCH2, R4=H, R5=CN, R6=O
(2) R1=CH.CMe2, R2=OH, R3=CH.CMe2, R4=H, R5=CN, R6=O
(3) R1 ETO, R2=OH, R3=PhenylscH2, R4=H, R5=CN, R6=S
FIELD OF THE INVENTION
This invention pertains to the novel use of composi-tions containingbenzylidenemalononitrileand hydroxycinnamamide derivatives in the treatment of asthma, allergic diseases, hay fever, skin rashes, inflammatory bowel diseases, arthritis, adult respiratory distress syndrome (ARDS), migraine, cardiac shock, septic shock, thrombosis, hypotension, hypertension and ischemia. -BACKGROUND OF THE INVENTION
15Tyrphostins are a group of low molecular weight compounds, having the nucleus of benzvlidenemalononitrile and/or hydroxycinnamamide. These compounds are reported to be inhibi-tors of protein tyrosine kinases and their use in the treatment of cancer has been recommended. I have found that these agents also inhibit the action of the mediators of asthma, inflammation and cardiovascular diseases.
Compounds having the nucleus of benzylidene malono-nitrile such as N-~2-(2, 5-dihydroxyphenyl~ ethenyl) formamide, identified with the trade-mark Erbstatin, have been known for several years. Such compounds have the following formula:
I~D / ~CHo H
OH
20~2634 These compounds were initially described as inhibitors of protein tyrosine kinase and their use in cancer chemotherapy was recommended due to their effects on blocking the epidermal growth factor receptor (EGF) kinase (Umezawa, H. et al., J.
5Antibiotics, vol. 39, 170-173, 1986 and Yaish, P. et al., Science, vol. 242, 933-935, 1988).
u.s. Patent No. 4,686,308, granted August 11, 1987, protects a novel compound 2,2-formamidoethenyl-1,4-hydroxy-10quinone. Preparation comprises cultivation of a Streptomyces strain or by its mutant treated by ultraviolet irradiation, or by recombinant DNA techniques of gene coding. This compound purportedly has antitumour and antimicrobial activities, with inhibitory activity against tyrosine specific protein kinase.
Sseveral articles disclose tyrosine kinase inhibitors.
One is entitled "Blocking of EGF-Dependent Cell Proliferation by EGF Receptor Kinase Inhibitors", Pnina Yaish, Aviv Gazit, Chaim Gilon, Alexander Levitzki, Science, vol.242, Nov. 11, 1988, pp.
20933-935. This article describes the synthesis of a systematic series of low mole¢ular weight protein tyrosine kinase inhibi-tors. They had progressively increasing affinity over a 2500-fold range toward the substrate site of epidermal growth factor (EGF) receptor kinase domain. These compounds inhibited EGF
25receptor kinase activity up to three orders of magnitude more than they inhibited insulin receptor kinase, and they also effectively inhibited the EGF-dependent autophosphorylation of the receptor. The most potent compounds effectively inhibited the EGF-dependent proliferation of A431/clone 15 cells with 30little or no effect on the EGF-independent proliferation of these cells. The potential use of tyrosine protein kinase inhibitors as antiproliferative agents is demonstrated.
Another is entitled "Tyrphostins Inhibit Epidermal 35Growth Factor (EGF)-Receptor Tyrosine Kinase Activity in Living Cells and EGF-stimulated Cell Proliferation", R. M. Lyall, A.
Zilberstein, A. Gazit, C. Gilon, A. Levitzki and J. Schlessinger, ;~012634 e Journal of Biological Chemistry, Vol. 264, No. 24, Aug. 25, 1989, pp. 14503-14509. Synthetic compounds ca]led tyrphostins were examined for their effects on cells which are mitogenically responsive to epidermal growth factor (EGF). The writers studied in detail the effects of two tyrphostins on EGF binding, tyrosine phosphorylation in intact cells, EGF-receptor internalization, and mitogenesis. These compounds inhibited EGF-stimulated [3H]
thymidine incorporation in a specific manner and the degree of selectivity varied. Both compounds inhibited EGF-stimulated receptor autophosphyorylation and tyrosine phosphorylation of endogenous substrates in intact cells at doses that correlated with the ICso for [3H] thymidine incorporation. These results are consistent with the notion that tyrosine phosphorylation is a crucial signal in transduction of the mitogenic message delivered by EGF. The compoun~ RGs0864 demonstrated specificity at inhibiting EGF-stimulated cell growth compared with stimulation with either platelet-derived growth factor or serum. These novel synthetic inhibitors, specific for EGF-receptor kinase, allegedly offer a new method to inhibit EGF-stimulated cell proliferation which may be useful in treating specific pathological conditions involving cellular proliferation, including different types of cancers.
A third article is entitled "Specific Inhibitors of Tyrosine-Specific Protein Kinases: Properties of 4-Hydroxycin-namamide Derivatives in Vitro", T. Shiraishi, M. K. Owada, M.
Tatsuka, T. Yamashita, K. Watanabe and T. Kakunaga, Cancer Research 49, 2374-2378, May 1, 1989. Inhibition by seven synthetic 4-hydroxycinnamamide derivatives, ST 271, ST 280, ST
458, ST 494, ST 633, ST 638 and ST 642, of tyrosine-specific protein kinases (tyrosine kinase) of oncogene or proto-oncogene products (pl30gag-v-fps, p70gag-actin-v-fgr, pp60v-src, pp60c-src) and epidermal growth factor (EGF) receptor kinase were investigated. ST 638 (~-cyano-3-ethoxy-4-hydroxy-5-phenylthio-methylcinnamamide) strongly inhibited more of the tyrosine kinases than any of the other compounds. The susceptibilities of these tyrosine kinases to ST 638 increased in the following 20~Z634 rder: EGF receptor > p70gag-actin-v-fgr > pp60c-src > pl30gag-v-fps, pp60v-src, with 50% inhibitory concentration values of 1.1, 4.2, 18, 70, and 87 ~M, respectively. The phosphorylation of the tyrosine residues in particulate fractions from RR1022 5cells expressing pp60v-src was inhibited by ST 638 in a dose-dependent way, while it had a negligible effect on the phosphory-lations of threonine and serine residues. Kinetic analysis showed that ST 638 competitively inhibited the phosphorylation of an exogenous substrate by the EGF receptor kinase with a K; of 102.1 ~M. ST 638 noncompetitively inhibited autophosphorylation by EGF receptor kinase. These results indicate that ST 638 is a potent and specific inhibitor of tyrosine kinases in vitro, and that its inhibitory activity is caused by competing with the substrate protein for the tyrosine kinase binding site.
~ --A fourth article relates specifically to Erbstatin:
"Effective Synthesis of Erbstatin and its Analogs~', E. L. Dulaney and C.A. Jacobsen, The Journal of Antibiotics, Vol. XL, No. 8, Aug. 1987, pp. 1207-1212. Erbstatin, purported to be a new 20potent inhibitor for tyrosine protein kinase (TPK), was isolated from the broth of Stre~tomyces sp. (MH435-hF3) and the structure was determined by X-ray crystallographic analysis. Erbstatin -(3a) and its analogs were expected to be useful for the studies of the functions of oncogenes (tumour inducing genes), and may 25have therapeutic activity for the treatment of cancer. ~
', ':
SUMMARY OF THE INVENTION
The invention is directed to a composition useful in 30the treatment of inflammation induced diseases comprising~
(a) a compound of the formula Rz-R
` 201Z634 wherein Rl is H, OH, OCH3, ETO;
R2 is EtO, CHC(CH3)2, iso-Proline, CH3SCH2, H, OH, NO2, OCH3, OCH, R6Cl;
R3 is H, OH, OCH3, phenyl SCH2, CH. (CH3)2, iso-Proline, CH3SCH2;
R4 is H, OH;
R5 is H, CN, COOH, NHCHO;
R6 is H, CN, COOH, NHCHO, O, S;
R7 is H, OH; and wherein R5 and R6 can form the following cyclic structures:
~ ' '' C/
J
when R1 and R3 are CH3SCH2, R2 is OH, and R4 and R7 are H;
O
1~
<C~_~,3 '' ' C~
O ~:
when R1 is ETO, R2 is OH, R3 is PHSCH2, R4 and R7 are H;
~
~, . i ' '-'~
;' len R1 is ETO, R2 is OH, R3 is PhenylSCH2 and R4 and R7 are ~ a;~
/ \ ~: .
O
when R1 and R3 are iso-Proline, R2 is OH, and R4 and R7 are H, and pharmaceutically acceptable acid addition salts thereof; and -:
"'"-'-.'~'.
(b) a pharmaceutically acceptable carrier.
' ~' ' The invention includes a composition for treating inflammatory diseases comprising:
(a) a benzylidene malononitrile of the formula: ~:
"'~
, . -.
/ ~3 ~ ~
wherein: : ::
( 1 ) R1 =OH, Rz=H, R3=H, R4=OH, Pc5=NHCHO, R6=H
( 2 ) R1=H, R2=OH, R3=H, R4=H, R5=C02H, R6 H
( 3 ) R1 H ~ R2=OH, R3=H, R4=H, R5=C02H, R6=COzH
( 4 ) Rl H , R2=OH , R3=H , R4=H , R5=CN , R6=CN ::
(5) Rl=OH, R2=OH, R3=H, R4=H ~ Rs=C2H, R6 N
( 6 ) Rl OH, Rz H, R3=H, R4=OH, R5=H, R6=NHCHO
( 7 ) Rl=H, R2=H, R3=OH, R4=H, R5=CN, R6=CN
( 8 ) Rl OH, R2=H, R3=H, R4=OH, R5=CN, R6=CO2H
( 9 ) Rl H, Rz=OH, R3=OH, R4=H, R5=CO2H, R6=CN
( 10 ) Rl=H, R2=OH, R3=OH, R4=H, R5=CN, R6=CN
( 11 ) Rl=OCH3, R2=OH, R3=OH, R4=H, R5=CN, R6=CN ~ ~:
-- 6 -- ~
:
:
- ~2) Rl=OH, R2=OH, R3=OH, R4=H, Rs=CN, R6=CN Z012634 (13) R1=OH, ~R2=OH, R3=OH, R4=OH, Rs=CN, R6=CN
( l4 ) R1=OH, R2=OH, R3=OH, R4=H, Rs=NHCHO, R6=H
(l5) R1=H, R2=OH, R3=H, R4=H, Rs=CN, R6=CN
( l 6 ) R1=H, R2=OH, R3=H, R4=H ~ Rs=CN ~ R6=H
(17) R1=OH, R2=02N, R3=H, R4=H, Rs=CN, R6=CN
( l8 ) R1=H, R2=OH, R3=H, R4=H, Rs=CN, R6=CN, R7=OH
(l9) R1=CH30, R2=OH, R3=H, R4=H, R5=CN, R6=CN
( 2 0 ) R1=OH, R2=H, R3=OH, R4=H, Rs=CN, R6=CN
( ) R1 OH, Rz OH, R3=OH, R4=H, R5=CN, R6=CN, R7=OH
(22) R1=H, R2=CH30, R3=H, R4=H, Rs=C02H, R6=CN
(23) R1=H, R2=FlCl, R3=H, R4=H, Rs=C02H, R6=CN
(24) R1=CH30, R2=OH, R3=CH30, R4=H, R5=CO2H, R6 CN
( 2 5 ) R1 H, R2=OH, R3=H, R4=H, R5=C02H, R6=CNlS (26) R1=H, R2=oCH, R3=H, R4=H, R5=C02H, R6 CN
(27) R1=OH, R2=H, R3=H, R4=H, Rs=CN, R6=CO2H
and pharmaceutically acceptable acid addition salts thereof; and (b) a pharmaceutically acceptable carrier.
The invention also includes a composition for treating inflammatory diseases comprising: -(a) a cinnamamide of the formula:
R J~
R~ Rb wherein:
( l ) R1=ETO, R2=OH, R3=PhenylSCH2, R4=H, Rs=CN, R6=O . - -( 2 ) Rl=CH . CMe2, R2=OH, R3=CH . Me2, R4 H, Rs CN, 6 (3) Rl=ETO, R2=OH, R3=PhenylSCH2, R4=H, Rs=CN, R6=S
( 4 ) R1=OH, R2=OH, R3=H, R4=H, R5=CN, R6=S : ~ -(5) R1=iso-Proline, R2=OH, R3=iso-Proline, R4=H, R5=CN, R6=O
'' ~' ;'.
~,) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=o 201Z634 (7) R1=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=o; or -- -(8) R~=OH, R2=OH, R3=OH, R4=I, R5=CN, R6=S; or wherein R5 and R6 -can combine to one of the following structures; and having R1=OCH3, iso-proline or OH, R2=OCH3 or OH, R3=iso-proline or OCH
~ ~ =Q IH ~ ~ ~
o O
oc~3 C~
~ 3 3 =C~H~ C~C~z and acid addition salts thereof; and -(b) a pharmaceutically acceptable carrier. ~
. ~ . . :-In the composition as illustated above, R1 can be OH
2 5 and R2 and R3 can be H, R4 can be OH, Rs can be NHCHO and R6 and R7 can be H. In the composition, the carrier is distilled water.
In the composition as described, compound (a) can be present in compound (b) at a concentration ranging from 0.5 mg/l to l00 mg/l. The composition can include an effective amount of an iron chelation agent, andjor oxygen radicals scavenger.
. . . ~ , I The composition is administered orally, as an aerosol, ;-subcutaneously or intravenously. The composition can be in the form of a tablet. The composition can be used in the treatment of asthma, allergic diseases, hay fever, skin rashes, inflamma-tory bowel diseases, arthritis, adult respiratory distress ZOlZ634 ~yndrome (ARDS), migraine, cardiac shock, septic shock, thrombo-sis, hypotension, hypertension and ischemia.
DETAILED DESCRIPTION OF SPECIFIC
Platelet activating factor (PAF) and Leukotriene D4 (LTD4) are important components of bronchial hyperresponsiveness and inflammation. Elucidation of their mode of cellular action is a crucial step towards the understanding of pathophysiological states caused by PAF and LTD4 and subsequently the management of diseases associated with those molecules.
Initially, the role ofprotein-tyrosinephosphorylation in the signal transduction of PAF was investigated in rabbit platelets. Two tyrosine kinase inhibitors, N-(2-(2,5-dihydroxy-phenyl)ethenyl)formamide-methanolate (coded; TR-lA) and ~-cyano-3,4-dihydroxythiocinnamamide (TR-18) were found to inhibit PAF
responses at the ICso = 15 and 50 ~g/ml, respectively. Inhibi-tion of protein-tyrosine phosphorylation blocked PAF-induced phosphoinositide breakdown, membranous protein kinase C activity, platelet aggregation and serotonin release. These data imply that protein-tyrosine phosporylation plays a critical role in PAF-signal transduction systems. This suggests that the PAF
receptor may be a tyrosine kinase or a tyrosine phosphorylatable protein coupled to a phospholipase C, or alternatively coupled to a phospholipase C amenable to phosphorylation by tyrosine kinases.
30This work provides firm evidence that specific inhibitors of protein-tyrosine kinase should prove to be valuable -tool$ in the management of bronchial hyperresponsiveness and inflammation.
::,--:-: ~ :, 35The drug TR-lA was initially believed to be useful for the study of the functions of oncogenes (tumour inducing genes) ~ ~ ;
due to its action on the inhibition of protein tyrosine kinase. ;~
:, ''`
:,'..~ "-- - .,~':
2012634 ~ ~
~ e to the fact that the receptors for a number of mediators of inflammatory and allergic reactions might have protein tyrosine kinase activity, I have discovered that the drug TR-lA can inhibit the activation of these mediators' receptors and affect the normal interaction of these receptors with their effector system.
Existing drugs used in the treatment of asthma, inflammatory diseases, or allergic diseases, are designed either to inhibit certain enzymes responsible for the syntheses of these mediators, or to block their mode of signal transduction. TR-lA, by inhibiting protein tyrosine kinase, a common enzyme for the transduction of signals for many mediators, should be more effective in preventing the above diseases, since it will work against many mediators at the same time.
I have found the drug TR-lA inhibits platelet activat-ing factor (PAF) (an inflammatory mediator) responses. These included aggregation of platelets and release of serotonin. TR-lA also inhibited constriction o guinea pig's trachea inresponse to leukotiene D4 (LTD4) (a major mediator of allergic and asthmatic reactions). From this, it is evident that TR-lA
has important use in the treatment of asthma, allergy cardiovas-cular and inflammatory diseases.
From the foregoing demonstrations, it follows that the compound TR-lA is useful for the treatment of virtually all kinds of inflammatory diseases (eg. arthritis, inflammatory bowel disease, etc.), all kinds of allergic diseases (eg. asthma, rhenitis, skin allergy, hay fever, systemic anaphylaxis), and all kinds of heart and vascular diseases (eg. septic shock, ARDS, cardiogenic shock, arrythmias, hypotension, hypertension, thrombosis and blood clot).
I have discovered that the compounds of the invention block the action of PAF and LTD4. Although the receptors for these molecules are not characterized, nevertheless, it is ~012634 lieved that these agents inhibit tyrosine phosphorylation of the receptor. Alternatively, the compounds of the invention are interfering with biochemical parameters involved in the trans-duction of signals for PAF or LTD4. Such biochemical parameters could be the component of guanyl nucleotide regulatory proteins (G-proteins), phospholipases, protein kinases or phosphatases.
The compounds of the invention, with their novel uses, can be broadly divided into two main specific groups:
Group A Compounds (Benzvlidene Malononitrile Com~ounds) A composition for treating asthma, allergic diseases, ~:
hay fever, skin rashes, arthritis, inflammatory diseases (bowel, colon, etc.), adult respiratory distress syndrome (ARDS), septic shock, cardiac shock, thrombosis, hypertension, hypotension, tissue ischemia and migraine, comprising a benzylidene malono- .
nitrile of the formula: :
:~
R~ R_ ~3 R~
wherein~
(l) R~=OH~ R2=H, R3=H, R4=OH, Rs=NHCHO, R6=H (TR-lA) ;
(2) R1=H, R2=OH, R3=H~ R4=H~ R5=C2H~ R6 H
( 3 ) R~ H, R2=OH, R3=H, R4=H, Rs=C02H, R6=CO2H :: -( 4 ) ., R~=H , R2=OH ~ R3=H ~ R4=H ~ Rs=CN ~ R6=CN
( 5 ) R1=OH, R2=OH, R3=H ~ R4=~ ~ Rs=C2H ~ R6 N
(6) R1=OH, R2=H, R3=H~ R4=H~ Rs=H~ R6=NHCH ~ ~ -(7) R~=H, R2=H~ R3=OH~ R4=H~ Rs=CN, R6=CN ;
( 8 ) R~=OH, R2=H, R3=H, R4=OH, Rs=CN, R6=CO2H
( 9 ) R~ H, R2=OH, R3=OH, R4=H, Rs=C02H, R6=CN
0) R1=H, R2=OH, R3=OH, R4=H, ~=CN, R6=CN
(ll) R1=0CH3, R2=OH, R3=OH, R4=H, ~=CN, R6=CN 2ol2 (12) R1=OH, R2=OH, R3=OH, R4=H, ~=CN, R6=CN 634 ~ :
(l3) R1=OH, R2=OH, R3=OH, R4=OH, ~=CN, R6=CN
(l4) R1=OH, R2=OH, R3=OH, R4=H, Rs=NHcHo, R6=H
(l5) R1=H, R2=OH, R3=H, R4=H, ~=CN, R6=CN
(l6) R1=H, Rz=OH, R3=H, R4=H, Rs=CN, R6=H
(l7) R1=OH, R2=02N, R3=H, R4=H, ~=CN, R6=CN
(l8) R1=H, R2=OH, R3=H, R4=H, Rs=CN, R6=CN, R7=OH
(l9) R~=CH30, R2=OH, R3=H, R4=H, Rs=CN, R6=CN
(20) R1=OH, R2=H, R3=OH, R4=H, ~=CN, R6=CN
(2l) R1=OH~ R2=OH, R3=OH, R4=H, Rs=CN, R6=CN, R7=OH
(22) R1=H, R2=CH30, R3=H, R4=H, Rs=C02H~ R6 CN
(23) R1=H, R2=FICl, R3=H, R4=H, Rs=C02H~ R6=CN
(24) R1=CH30, R2=OH, R3=CH30, R4=H, ~=C02H, R6 CN
(25) R1 H, R2=OH, R3=H, R4=H, Rs=C02H, R6=CN
( 6) R1 H, R2=OCH, R3=H, R4=H, Rs=C02H~ R6=CN
( ) R1 OH, R2 H, R3=H, R4=H, R5=CN, R6=C02H
Results of Ex~eriments Conducted with Group A Compounds Initial Experiments .:, .
A number of initial experiments were performed with N-25 (2-(2-,5-dihydroxyphenyl)ethenyl) formamide methanolate (TR-lA), to inhibit biological activity of PAF on rabbit platelets.
Rabbit platelets were prepared according to the well-known method of Pinckard et al. J. Immuno~. 123, 1847-1853, 1979.
Platelets at 2 x lO8~ml were challenged with PAF (0.2 nN) at 37 in Tyrode's buffer, pH 7.2. Platelets (0.5 ml) were tested in a Bio-Data aggregometer for aggregation in response to PAF. TR-lA or PAF was added in 50 ul of 0.25% BSA in Tyrode's buffer.
Activities were measured as percent increase in light trans-mission.
ZOlZ634 As can be seen from Table 1, TR-lA, at 10 ~g/ml inhibited PAF-induced platelets aggregation by approximately 30%.
At 25 ~g/ml, it is seen that TR-lA blocked the action of PAF by 100%.
Table 1 Effect of Various Concentrations of TR-lA on PAF Induced Rabbit Platelets Aaareaation ., PAF (200 PM) Induced Aggregation TR-lA conc. (uq/ml) (% of Control mean of five experiments ~
100 ~ ~ "
155 100 ;~
-~
o Second Set of Ex~eriments ' ~''~' In another set of studies, at similar concentrations, -~-~
it was found that TR-lA inhibited PAF induced serotonin release ;~
from rabbit platelets. Platelets were labelled with t3H] ; ;~
serotonin for 1 hour. After this period of time, the unincorpor-ated [3H] serotonin was washed off and the platelets were used ~; ;
for challenge with PAF in the presence and absence of TR-lA. ~;~
TR-lA, from 10 ~g/ml, was found to inhibit PAF (200 PM) induced serotonin release. The IC50 was determined to be about 10 ~g/ml.
At 25 ~g/ml, it was noted that TR-lA entirely blocked PAF induced serotonin release.
. ~. i. . ;, TR-lA, at concentrations below 10 ~g/ml, did not appreciably prevent PAF induced serotonin release from rabbit platelets. At 20 ~g/ml, TR-lA inhibited PAF action by about 50%. At 25 ~g/ml, TR-lA almost completely blocked the action of PAF. These determinations are tabulated in Table 2.
."'~
~ '~
Table 2 Inhibitory Effect of Various Concentrations of TR-lA
on PAF Induced Serotonin Release from Rabbit Platelets TR-lA Conc. (~q/ml)Serotonin Release (% of Control) mean of five experiments 0.5 97 o o Example;
In order to evaluate the specific site of action of TR-lA on platelets, a series of experiments were performed to investigate the cellular second messenger system following PAF
activation. Platelets were labelled with [3H] inositol which became incorporated into phosphatidylinositol. The metabolism of phosphatidylinositol in response to PAF was then investigated.
the results are tabulated in Table 3.
As Table 3 shows, PAF (200 PM), without the presence of TR-lA, caused rapid hydrolysis of phosphatidylinositide.
However, when the platelets were first pretreated with various concentrations of TR-lA for 5 minutes prior to the addition of PAF, the formation of metabolites of phosphoinositide (inositol monophosphate, inositol bisphosphate and inositol trisphosphate) were inhibited. The IC50 for TR-lA was found to be between 20 and 25 ~g/ml. At 50 ~g/ml, it was noted that TR-lA entirely blocked the action of PAF. Similarly, TR-lA blocked the ~' Z01263~
~ctivation of protein kinase C induced by PAF. Protein kinase tPKC) is also a major component of a cell signalling system.
In this assay system, platelets were preincubated for 5 minutes with TR-lA (0-50 ~g/ml) and subsequently treated with PAF (200 PM) for 1 minute. The sample material was chromato-graphed on a mono Q column. 0.5 ml of NP 40-solubilized particulate protein from the platelet extracts was chromato-graphed, and the column fractions assayed for phosphorylating activity. It was found that TR-lA from 10 ~g/ml inhibited (>40%) the activation of PKC by PAF. At 25 ~g/ml, TR-lA blocked about ~
80% of the action of PAF. These results suggest that TR-lA ; -blocks PAF induced activation of rabbit platelets. Thus it ~ ~ -follows that TR-lA can be used in the treatment of diseases where PAF plays an important role (such as asthma, cardiovascular and inflammatory diseases).
Table 3 Inhibitory Effects of TR-lA on PAf Induced Polyphosphoinositide Metabolism in Rabbit Platelets Phosphoinosidide Metabolites Formation (% of control) - -~
TR-lA (~g/ml) IPl IP2 IP3 O 100 100 100 ':
0.5 100 100 100 1 100 100 100 ~;
100 -~ -ZOlZ634 roup B Compounds (Hydroxy Cinnamamide Compounds) Composition containing hydroxy cinnamamide compounds according to the following formula are useful for treating asthma, allergic diseases, hay fever, skin rashes, arthritis, inflammatory diseases (bowel, colon, etc.), ARDS, septic shock, cardiac shock, thrombosis, hypertension, hypotension, tissue ischemia and migraine. The hydroxycinnamamides have the following formula:
~L~ ~ N~z wherein:
(1) R1 ETO, R2=OH, R3=PhenylSCH2, R4=H, R5=CN, R6=O
(2) R1=CH.CMe2, R2=OH, R3=CH.CMe2, R4=H, R5=CN, R6=O
(3) R1 ETO, R2=OH, R3=PhenylscH2, R4=H, R5=CN, R6=S
(4) Rl=OH, R2=OH, R3=H, R4=H, R5-CN, R6=S
(5) R1=iso-Proline, R2=OH, R3=iso-Proline, R4=H, R5=CN, R6=O
(6) Rl=H, R2=OH, R3=H, R4=H, R5=CN, R6=O
(7) Rl=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=O
(8) Rl=OH, R2=OH, R3=OH, R4=I,F,Cl, Rs=CN, R6=S :
'~ ' The hydroxycinnamamide can also have the following structures~
~ ~N~
O ~;~-Pv C~3 5 c~
C
E I--O ~ ~ Ph L= 1~0 7N~ H~//~
Ph Sa~ V ~hSC~17 Experiments Conducted with Group B Compounds Results of the studies conducted with four compounds lo of the groups B, ~-cyano-4-hydroxy-3, s-diisopropylcinnamamide and ~-cyano-3, 4-dihydroxythiocinnamamide are shown in Table 4 with LTD4 induced smooth muscle contraction. Leukotriene D4 is the major component of bronchial asthma, contracts bronchial and tracheal smooth muscle cells at the concentrations of 210l0M.
The effects of four different protein tyrosine kinase inhibitors were evaluated against contraction induced by LTD4 in isolated guinea pig tracheal preparation. Trachea from guinea pigs were suspended in a jacketed organ bath containing oxygenated kreb's-Henseleit colution. The tissues were allowed to equilibrate for 60-~0 minutes under 1. 5 g tension and then optimal tension obtained using electrical field stimulation at 0.25 g tension increments. Isometric force generation was measured with Grass FT 0.3 force transducer, and recorded on a polygraph. Responses of each tissue to Acetylcholine (103M) was first evaluated. The tissues were then washed and stimulated with various concentra~
tions of LTD4 (ranging from 101M to 3 x 107M).
As can be seen from Table 4, pretreatment of tissue with tyrosine kinase inhibitors (10 ~g/ml) for 60 minutes, caused significant inhibition of LTD4 (3 x 10-7) induced smooth muscle contraction. The most potent of all the four tested inhibitors was found to be ~-cyano-4-hydroxy-3, 5-diisopropylcinnamamide.
This was greater than ~-cyano-3, 4-dihydroxythiocinnamamide which was greater than 2,5-bis-(3,4-dimethoxybenzylidene) cyclo-pentanone which was more effective than N-(2-(2,5-dihydroxy~
phenyl)ethenyl) formamide methanolate.
:''''''';~';
, 2012634 ~' H o Ul ~0 ~ ~ ~ r~
E~ ~ a) _l O ., C~
~ O ~ ~ ~ ~
O ~ ~ . .
_I X ~o ~r o C I C
~ 1 . I ~ ~ U ~ , U ~ ~, 0~ 0 ~ ~ :
o ~
U~ t) N
~1 0 R f~
~ In ~ ~
,~ ` X X 0-,~ ~ ~ ~ X
~ ~ ~ ~ O
Y O ~ ~ ~ :
o ~ ,~ ,1 :~ .
~ ~ ~ ~ . .
In ~ ` ` I
~r ~q o , , _ ~ o o ~n ~ ., .,~
Q
~1 ~ ~ I
H i I `~
:. :
- 18- ; -.
201263~
- These results clearly indicate that tyrosine kinase inhibitors with the common structure of hydroxycinnamamide are effective in preventing leukotriene D4 and presumably other arachidonic acid metabolites which induce smooth muscle contrac-tion. Therefore, these substances can be used in the treatmentof asthma and other inflammatory and allergic diseases, in which arachidonic acid metabolites play a major role.
Conclusion -~
Leukotrienes are polyunsaturated conjugated trienes derived from arachidonic acid. They consist of leukotriene A4 (LTA4), LTB4~ LTC4, LTD4, and LTE4. Other arachidonic acid metabolites are called prostaglandins and thromboxane A2. Their role in inflammatory diseases such as arthritis and in airway asthma has been recognized for several years. For example, LTC4, LTD4, LTE4, PGD2, and TXAz are potent smooth muscle constrictors.
They also contract vascular smooth muscles. LTB4, PAF and PGE2 are major components of inflammatory diseases such as arthritis.
Recruiting leukocyte to the site of inflammation causes these cells to degranulate and release their dysosomal enzyme. The combination of intracellular enzymes and leukocytes accumula- ;
tion causes acute inflammation. Other arachidonic acid metabo-lites are shown to be involved in the diseases associated with ;
cardiovascular system. For example, TXA2 which is a potent constrictor of vasculature, can induce hypertension. To the contrary, PGI2, a potent vasodilator, induces hypotension.
Cardiac shock and ischemia are also associated with PGI2. In regard to septic shock and ARDS, PAF may play a major role.
Several available reports indicate that PAF, to a large extent, and TXA2, to a lesser extent, play a critical role in the initiation of cardiac shocks associated with endotoxin (septic shock). In regard to migraine, several prostaglandins such as PGE2, El, etc., have been shown to have an important role in the -~
development of migraine. It follows, therefore, that the tyrosine kinase inhibitors of the invention could be valuable drugs for inhibition of the cellular activation by a number of ;;., ~ .,: .
. , .i, ., '"~rostaglandins, l~ukotrienes, and PAF and thus can be valuable tools for the treatment of the above diseases.
Mode of Application The compounds of Groups A or B may be present in the composition of the invention at a concentration in the range of 0.5-100 mg/l or kg of body weight of a pharmaceutically accept-able carrier.
Suitable doses are 1-1,000 mg/kg, especially 1-10 mg, preferably taken 2 to 3 times daily, orally, subcutaneously, intravenously or by aerosol. The pharmaceutically acceptable carrier may be distilled water, a mixture of saline, glucose, lactose or ethylcellulose N100 and water or starch talc. The composition of the invention may be administered orally, by aerosol, subcutaneously or intravenously. Tablets for oral ingestion may be made via compression of approximately 100 mg of a compound of Group A or B, 100 mg of an iron chelator, 200 mg of lactose and 100 mg Avicel.
Capsules may be prepared by makinq micelles of liposomal drugs with lecithin. Micelle injections can be made either in water and propylene glycol with an upwardly adjusted pH in phosphate buffer. The product is typically sterilized through a filter. The micelle can be made in 20 percent propylene glycol and a preservative such as ascorbic acid. The aerosol composition can be made by making liposomes of the compounds of Group A or B in a pharmaceutically acceptable buffer/lecithin, with preservative, and solubilizing agent such as 0.1% ethanol.
.
As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifica-tions are possible in the practice of this invention without -departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the _~bstance defined by the following claims. Z012634 ,`,,`,'' ",`, .' `,..'"'-':
, `. ~`.
`.,,; ~
,; . -. .
'~ ' The hydroxycinnamamide can also have the following structures~
~ ~N~
O ~;~-Pv C~3 5 c~
C
E I--O ~ ~ Ph L= 1~0 7N~ H~//~
Ph Sa~ V ~hSC~17 Experiments Conducted with Group B Compounds Results of the studies conducted with four compounds lo of the groups B, ~-cyano-4-hydroxy-3, s-diisopropylcinnamamide and ~-cyano-3, 4-dihydroxythiocinnamamide are shown in Table 4 with LTD4 induced smooth muscle contraction. Leukotriene D4 is the major component of bronchial asthma, contracts bronchial and tracheal smooth muscle cells at the concentrations of 210l0M.
The effects of four different protein tyrosine kinase inhibitors were evaluated against contraction induced by LTD4 in isolated guinea pig tracheal preparation. Trachea from guinea pigs were suspended in a jacketed organ bath containing oxygenated kreb's-Henseleit colution. The tissues were allowed to equilibrate for 60-~0 minutes under 1. 5 g tension and then optimal tension obtained using electrical field stimulation at 0.25 g tension increments. Isometric force generation was measured with Grass FT 0.3 force transducer, and recorded on a polygraph. Responses of each tissue to Acetylcholine (103M) was first evaluated. The tissues were then washed and stimulated with various concentra~
tions of LTD4 (ranging from 101M to 3 x 107M).
As can be seen from Table 4, pretreatment of tissue with tyrosine kinase inhibitors (10 ~g/ml) for 60 minutes, caused significant inhibition of LTD4 (3 x 10-7) induced smooth muscle contraction. The most potent of all the four tested inhibitors was found to be ~-cyano-4-hydroxy-3, 5-diisopropylcinnamamide.
This was greater than ~-cyano-3, 4-dihydroxythiocinnamamide which was greater than 2,5-bis-(3,4-dimethoxybenzylidene) cyclo-pentanone which was more effective than N-(2-(2,5-dihydroxy~
phenyl)ethenyl) formamide methanolate.
:''''''';~';
, 2012634 ~' H o Ul ~0 ~ ~ ~ r~
E~ ~ a) _l O ., C~
~ O ~ ~ ~ ~
O ~ ~ . .
_I X ~o ~r o C I C
~ 1 . I ~ ~ U ~ , U ~ ~, 0~ 0 ~ ~ :
o ~
U~ t) N
~1 0 R f~
~ In ~ ~
,~ ` X X 0-,~ ~ ~ ~ X
~ ~ ~ ~ O
Y O ~ ~ ~ :
o ~ ,~ ,1 :~ .
~ ~ ~ ~ . .
In ~ ` ` I
~r ~q o , , _ ~ o o ~n ~ ., .,~
Q
~1 ~ ~ I
H i I `~
:. :
- 18- ; -.
201263~
- These results clearly indicate that tyrosine kinase inhibitors with the common structure of hydroxycinnamamide are effective in preventing leukotriene D4 and presumably other arachidonic acid metabolites which induce smooth muscle contrac-tion. Therefore, these substances can be used in the treatmentof asthma and other inflammatory and allergic diseases, in which arachidonic acid metabolites play a major role.
Conclusion -~
Leukotrienes are polyunsaturated conjugated trienes derived from arachidonic acid. They consist of leukotriene A4 (LTA4), LTB4~ LTC4, LTD4, and LTE4. Other arachidonic acid metabolites are called prostaglandins and thromboxane A2. Their role in inflammatory diseases such as arthritis and in airway asthma has been recognized for several years. For example, LTC4, LTD4, LTE4, PGD2, and TXAz are potent smooth muscle constrictors.
They also contract vascular smooth muscles. LTB4, PAF and PGE2 are major components of inflammatory diseases such as arthritis.
Recruiting leukocyte to the site of inflammation causes these cells to degranulate and release their dysosomal enzyme. The combination of intracellular enzymes and leukocytes accumula- ;
tion causes acute inflammation. Other arachidonic acid metabo-lites are shown to be involved in the diseases associated with ;
cardiovascular system. For example, TXA2 which is a potent constrictor of vasculature, can induce hypertension. To the contrary, PGI2, a potent vasodilator, induces hypotension.
Cardiac shock and ischemia are also associated with PGI2. In regard to septic shock and ARDS, PAF may play a major role.
Several available reports indicate that PAF, to a large extent, and TXA2, to a lesser extent, play a critical role in the initiation of cardiac shocks associated with endotoxin (septic shock). In regard to migraine, several prostaglandins such as PGE2, El, etc., have been shown to have an important role in the -~
development of migraine. It follows, therefore, that the tyrosine kinase inhibitors of the invention could be valuable drugs for inhibition of the cellular activation by a number of ;;., ~ .,: .
. , .i, ., '"~rostaglandins, l~ukotrienes, and PAF and thus can be valuable tools for the treatment of the above diseases.
Mode of Application The compounds of Groups A or B may be present in the composition of the invention at a concentration in the range of 0.5-100 mg/l or kg of body weight of a pharmaceutically accept-able carrier.
Suitable doses are 1-1,000 mg/kg, especially 1-10 mg, preferably taken 2 to 3 times daily, orally, subcutaneously, intravenously or by aerosol. The pharmaceutically acceptable carrier may be distilled water, a mixture of saline, glucose, lactose or ethylcellulose N100 and water or starch talc. The composition of the invention may be administered orally, by aerosol, subcutaneously or intravenously. Tablets for oral ingestion may be made via compression of approximately 100 mg of a compound of Group A or B, 100 mg of an iron chelator, 200 mg of lactose and 100 mg Avicel.
Capsules may be prepared by makinq micelles of liposomal drugs with lecithin. Micelle injections can be made either in water and propylene glycol with an upwardly adjusted pH in phosphate buffer. The product is typically sterilized through a filter. The micelle can be made in 20 percent propylene glycol and a preservative such as ascorbic acid. The aerosol composition can be made by making liposomes of the compounds of Group A or B in a pharmaceutically acceptable buffer/lecithin, with preservative, and solubilizing agent such as 0.1% ethanol.
.
As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifica-tions are possible in the practice of this invention without -departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the _~bstance defined by the following claims. Z012634 ,`,,`,'' ",`, .' `,..'"'-':
, `. ~`.
`.,,; ~
,; . -. .
Claims (10)
1. A composition useful in the treatment of inflammation induced diseases comprising:
(a) a compound of the formula wherein R1 is H, OH, OCH3, ETO:
R2 is EtO, CHC(CH3)2, iso-Proline or a halogen, CH3SCH2, H, OH, NO2, OCH3, OCH, halogen, R6Cl;
R3 is H, OH, OCH3, phenyl SCH2, CH.(CH3)2, iso-Proline, CH3SCH2 or halogen;
R4 is H, OH;
R5 is H, CN, COOH, NHCHO;
R6 is H, CN, COOH, NHCHO, O, S;
R7 is H, OH; and wherein R5 and R6 can form the following cyclic structures:
when R1 and R3 are CH3SCH2, R2 is OH, and R4 and R7 are H;
when R1 is ETO, R2 is OH, R3 is PhSCH2, R4 and R7 are H;
when R1 is ETO, R2 is OH, R3 is PhenylSCH2 and R4 and R7 are H; and when R1 and R3 are iso-Proline, R2 is OH, and R4 and R7 are H, and pharmaceutically acceptable acid addition salts thereof; and (b) a pharmaceutically acceptable carrier.
(a) a compound of the formula wherein R1 is H, OH, OCH3, ETO:
R2 is EtO, CHC(CH3)2, iso-Proline or a halogen, CH3SCH2, H, OH, NO2, OCH3, OCH, halogen, R6Cl;
R3 is H, OH, OCH3, phenyl SCH2, CH.(CH3)2, iso-Proline, CH3SCH2 or halogen;
R4 is H, OH;
R5 is H, CN, COOH, NHCHO;
R6 is H, CN, COOH, NHCHO, O, S;
R7 is H, OH; and wherein R5 and R6 can form the following cyclic structures:
when R1 and R3 are CH3SCH2, R2 is OH, and R4 and R7 are H;
when R1 is ETO, R2 is OH, R3 is PhSCH2, R4 and R7 are H;
when R1 is ETO, R2 is OH, R3 is PhenylSCH2 and R4 and R7 are H; and when R1 and R3 are iso-Proline, R2 is OH, and R4 and R7 are H, and pharmaceutically acceptable acid addition salts thereof; and (b) a pharmaceutically acceptable carrier.
2. A composition for treating inflammatory diseases comprising:
(a) a benzylidene malononitrile of the formula:
wherein:
(1) R1=OH, R2=H , R3=H, R4=OH, R5=NHCHO, R6=H
(2) R1=H, R2=OH , R3=H, R4=H, R5=CO2H, R6=H
(3) R1=H, R2=OH, R3=H, R4=H, R5=CO2H, R6=CO2H
(4) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=CN
(5) R1=OH, R2=OH, R3=H, R4=H, R5=CO2H, R6=N
(6) R1=OH, R2=H, R3=H, R4=OH, R5=H, R6=NHCHO
(7) R1=H, R2=H, R3=OH, R4=H, R5=CN, R6=CN
(8) R1=OH, R2=H, R3=H, R4=OH, R5=CN, R6=CO2H
(9) R1=H, R2=OH, R3=OH, R4=H, R5=CO2H, R6=CN
(10) R1=H, R2=OH, R3=OH, R4=H, R5=CN, R6=CN
(11) R1=OCH3, R2=OH, R3=OH, R4=H, R5=CN, R6=CN
(12) R1=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=CN
(13) R1=OH, R2=OH, R3=OH, R4=OH, R5=CN, R6=CN
(14) R1=OH, R2=OH, R3=OH, R4=H, R5=NHCHO, R6=H
(15) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=CN
(16) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=H
(17) R1=OH, R2=O2N, R3=H, R4=H, R5=CN, R6=CN
(18) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=CN, R7=OH
(19) R1=CH3O, R2=OH, R3=H, R4=H, R5=CN, R6=CN
(20) R1=OH, R2=H, R3=OH, R4=H, R5=CN, R6=CN
(2l) R1=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=CN, R7=OH
(22) R1=H, R2=CH3O, R3=H, R4=H, R5=CO2H, R6=CN
(23) R1=H, R2=F1Cl, R3=H, R4=H, R5=CO2H, R6=CN
(24) R1=CH3O, R2=OH, R3=CH3O, R4=H, R5=CO2H, R6=CN
(25) R1=H, R2=OH, R3=H, R4=H, R5=CO2H, R6=CN
(26) R1=H, R2=OCH, R3=H. R4=H, R5=CO2H, R6=CN
(27) R1=OH, R2=H, R3=H, R4=H, R5=CN, R6=CO2H
and pharmaceutically acceptable acid addition salts thereof; and (b) a pharmaceutically acceptable carrier.
(a) a benzylidene malononitrile of the formula:
wherein:
(1) R1=OH, R2=H , R3=H, R4=OH, R5=NHCHO, R6=H
(2) R1=H, R2=OH , R3=H, R4=H, R5=CO2H, R6=H
(3) R1=H, R2=OH, R3=H, R4=H, R5=CO2H, R6=CO2H
(4) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=CN
(5) R1=OH, R2=OH, R3=H, R4=H, R5=CO2H, R6=N
(6) R1=OH, R2=H, R3=H, R4=OH, R5=H, R6=NHCHO
(7) R1=H, R2=H, R3=OH, R4=H, R5=CN, R6=CN
(8) R1=OH, R2=H, R3=H, R4=OH, R5=CN, R6=CO2H
(9) R1=H, R2=OH, R3=OH, R4=H, R5=CO2H, R6=CN
(10) R1=H, R2=OH, R3=OH, R4=H, R5=CN, R6=CN
(11) R1=OCH3, R2=OH, R3=OH, R4=H, R5=CN, R6=CN
(12) R1=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=CN
(13) R1=OH, R2=OH, R3=OH, R4=OH, R5=CN, R6=CN
(14) R1=OH, R2=OH, R3=OH, R4=H, R5=NHCHO, R6=H
(15) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=CN
(16) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=H
(17) R1=OH, R2=O2N, R3=H, R4=H, R5=CN, R6=CN
(18) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=CN, R7=OH
(19) R1=CH3O, R2=OH, R3=H, R4=H, R5=CN, R6=CN
(20) R1=OH, R2=H, R3=OH, R4=H, R5=CN, R6=CN
(2l) R1=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=CN, R7=OH
(22) R1=H, R2=CH3O, R3=H, R4=H, R5=CO2H, R6=CN
(23) R1=H, R2=F1Cl, R3=H, R4=H, R5=CO2H, R6=CN
(24) R1=CH3O, R2=OH, R3=CH3O, R4=H, R5=CO2H, R6=CN
(25) R1=H, R2=OH, R3=H, R4=H, R5=CO2H, R6=CN
(26) R1=H, R2=OCH, R3=H. R4=H, R5=CO2H, R6=CN
(27) R1=OH, R2=H, R3=H, R4=H, R5=CN, R6=CO2H
and pharmaceutically acceptable acid addition salts thereof; and (b) a pharmaceutically acceptable carrier.
3. A composition for treating inflammatory diseases comprising:
(a) a cinnamamide of the formula wherein:
(1) R1=ETO, R2=OH, R3=PhenYlSCH2, R4=H, R5=CN, R6=O
(2) R1=CH.CMe2, R2=OH, R3=CH.CMe2, R4=H, R5=CN, R6=O
(3) R1=ETO, R2=OH, R3=PhenylSCH2, R4=H, R5=CN, R6=S
(4) R1=OH, R2=OH, R3=H, R4=H, R5=CN, R6=S
(5) R1=iso-Proline, R2=OH, R3=iso-Proline, R4=H, R5=CN, R6=O
(6) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=O
(7) R1=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=O; or (8) R,=OH, R2=OH, R3=OH, R4=I,F,Cl, R5=CN, R6=S; or wherein R5 and R6 can combine to one of the following structures:
and acid addition salts thereof; and (b) a pharmaceutically acceptable carrier.
(a) a cinnamamide of the formula wherein:
(1) R1=ETO, R2=OH, R3=PhenYlSCH2, R4=H, R5=CN, R6=O
(2) R1=CH.CMe2, R2=OH, R3=CH.CMe2, R4=H, R5=CN, R6=O
(3) R1=ETO, R2=OH, R3=PhenylSCH2, R4=H, R5=CN, R6=S
(4) R1=OH, R2=OH, R3=H, R4=H, R5=CN, R6=S
(5) R1=iso-Proline, R2=OH, R3=iso-Proline, R4=H, R5=CN, R6=O
(6) R1=H, R2=OH, R3=H, R4=H, R5=CN, R6=O
(7) R1=OH, R2=OH, R3=OH, R4=H, R5=CN, R6=O; or (8) R,=OH, R2=OH, R3=OH, R4=I,F,Cl, R5=CN, R6=S; or wherein R5 and R6 can combine to one of the following structures:
and acid addition salts thereof; and (b) a pharmaceutically acceptable carrier.
4. A composition as claimed in claim 1 wherein R1 is OH, R2 and R3 are H, R4 is OH, R5 is NHCHO and R6 and R7 are H.
5. A composition as claimed in claim 4 wherein the carrier is distilled water.
6. A composition as claimed in claim 1 wherein compound (a) is present in compound (b) at a concentration ranging from 0.5 mg/l to 100 mg/l.
7. A composition as claimed in claim 6 including an effective amount of an iron chelation agent.
8. A composition as claimed in claim 1, 2 or 3 wherein the composition is administered orally, as an aerosol, subcutaneously or intravenously.
9. A composition as claimed in claim 1, 2 or 3 wherein the composition is in the form of a tablet.
10. A composition as claimed in claim 1, 2 or 3 wherein the composition is used in the treatment of asthma, allergic diseases, hay fever, skin rashes, inflammatory bowel diseases, arthritis, adult respiratory distress syndrome (ARDS), migraine, cardiac shock, septic shcok, thrombosis, hypotension, hyperten-sion and ischemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2012634 CA2012634A1 (en) | 1990-03-20 | 1990-03-20 | Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2012634 CA2012634A1 (en) | 1990-03-20 | 1990-03-20 | Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2012634A1 true CA2012634A1 (en) | 1991-09-20 |
Family
ID=4144558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2012634 Abandoned CA2012634A1 (en) | 1990-03-20 | 1990-03-20 | Tyrphostins for treatment of allergic, inflammatory and cardiovascular diseases |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2012634A1 (en) |
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| WO1995002420A2 (en) * | 1993-07-15 | 1995-01-26 | Cancer Research Campaign Technology Ltd. | Prodrugs of protein tyrosine kinase inhibitors |
| US5792783A (en) * | 1995-06-07 | 1998-08-11 | Sugen, Inc. | 3-heteroaryl-2-indolinone compounds for the treatment of disease |
| US6451838B1 (en) | 2000-05-24 | 2002-09-17 | Pharmacia & Upjohn Company | 1-(pyrrolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
| US6531502B1 (en) | 1998-01-21 | 2003-03-11 | Sugen, Inc. | 3-Methylidenyl-2-indolinone modulators of protein kinase |
| US6569868B2 (en) | 1998-04-16 | 2003-05-27 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
| US6573293B2 (en) | 2000-02-15 | 2003-06-03 | Sugen, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| US6599902B2 (en) | 2001-05-30 | 2003-07-29 | Sugen, Inc. | 5-aralkysufonyl-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives as kinase inhibitors |
| US6642232B2 (en) | 2001-10-10 | 2003-11-04 | Sugen, Inc. | 3-[4-Substituted heterocyclyl)-pyrrol-2-ylmethylidene]-2- indolinone derivatives as kinase inhibitors |
| US6653308B2 (en) | 2001-02-15 | 2003-11-25 | Sugen, Inc. | 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as protein kinase inhibitors |
| US6706709B2 (en) | 2000-06-02 | 2004-03-16 | Sugen, Inc. | Indolinone derivatives as protein kinase/phosphatase inhibitors |
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| WO2005000281A2 (en) * | 2003-06-24 | 2005-01-06 | Actelion Pharmaceuticals Ltd. | Pyrazolidinedione derivatives and their use as platelet aggregation inhibitors |
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| WO2013098416A3 (en) * | 2011-12-30 | 2013-08-15 | Ecole Nationale Superieure De Chimie De Clermont Ferrand | Pain relief compounds |
| CN109602735A (en) * | 2018-12-07 | 2019-04-12 | 广州市妇女儿童医疗中心 | The application of the drug and alpha-cyano -4- hydroxycinnamic acid of prevention and/or treatment intestines problem |
| KR20210057305A (en) * | 2019-11-12 | 2021-05-21 | 아주대학교산학협력단 | Novel compound for preventing or treating neuroinflammatory disease and pharmaceutical composition including the same |
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1990
- 1990-03-20 CA CA 2012634 patent/CA2012634A1/en not_active Abandoned
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| WO1995002420A3 (en) * | 1993-07-15 | 1995-03-16 | Caroline Joy Springer | Prodrugs of protein tyrosine kinase inhibitors |
| US5792783A (en) * | 1995-06-07 | 1998-08-11 | Sugen, Inc. | 3-heteroaryl-2-indolinone compounds for the treatment of disease |
| US5834504A (en) * | 1995-06-07 | 1998-11-10 | Sugen, Inc. | 3-(2'-halobenzylidenyl)-2-indolinone compounds for the treatment of disease |
| US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| US5883113A (en) * | 1995-06-07 | 1999-03-16 | Sugen, Inc. | 3-(4'-Bromobenzylindenyl)-2-indolinone and analogues thereof for the treatment of disease |
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| US6225335B1 (en) | 1995-06-07 | 2001-05-01 | Sugen, Inc. | 3-(4′-bromobenzylindenyl)-2-indolinone and analogues thereof for the treatment of disease |
| US6469032B2 (en) | 1995-06-07 | 2002-10-22 | Sugen, Inc. | 3-(4′-bromobenzylindenyl)-2-indolinone and analogues thereof for the treatment of disease |
| US6906093B2 (en) | 1995-06-07 | 2005-06-14 | Sugen, Inc. | Indolinone combinatorial libraries and related products and methods for the treatment of disease |
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| US6531502B1 (en) | 1998-01-21 | 2003-03-11 | Sugen, Inc. | 3-Methylidenyl-2-indolinone modulators of protein kinase |
| US6569868B2 (en) | 1998-04-16 | 2003-05-27 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
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