AU6770996A - Nitric oxide synthase (nos) inhibitors - Google Patents
Nitric oxide synthase (nos) inhibitorsInfo
- Publication number
- AU6770996A AU6770996A AU67709/96A AU6770996A AU6770996A AU 6770996 A AU6770996 A AU 6770996A AU 67709/96 A AU67709/96 A AU 67709/96A AU 6770996 A AU6770996 A AU 6770996A AU 6770996 A AU6770996 A AU 6770996A
- Authority
- AU
- Australia
- Prior art keywords
- compound
- formula
- alkyl
- aryl
- substituted aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 102000008299 Nitric Oxide Synthase Human genes 0.000 title claims description 20
- 108010021487 Nitric Oxide Synthase Proteins 0.000 title claims description 20
- 239000003112 inhibitor Substances 0.000 title claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 16
- -1 tetrahydroquinolyl Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
- 150000001448 anilines Chemical class 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 230000037396 body weight Effects 0.000 claims description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 16
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 8
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Description
Nitric Oxide Svnthase ( N OS) Inhibitors
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of compounds which are inhibitors of nitric oxide synthase (NOS) . The present invention also includes within its scope methods of treatment where nitric oxide is involved in the biological functions of the human body, e.g. hypotension, inflammation, the damage due to inflammation, acute and/or chronic pain, neuronal disorders such as stroke, memory disorders, and depression, autoimmune diseases, including allograft rejection, diabetes, septic and endotoxic shock and the like. 2. Background of the Art
Nitric oxide is an important component of endothelium-derived relaxing factors (EDRFs). EDRFs have been shown to be involve in the regulation of blood flow and vascular resistance. In addition to the vascular endothelium, macrophages have also been reported to produce nitric oxide in the body which is a component of their cell killing and/or cytostatic function. Nitric oxide is produced in mammalian cells by nitric oxide synthase (NOS) by conversion of L-arginine to citrulline. Moncada, S., Palmer.R. M. J., and Higgs, E. A.
(1991) Pharm. Rev. 43, 109-142. ; Nathan, C. (1992) FASEB J. 6, 3051-3064; Jacob, T. D., Morrell, M. K., Manzi, S., Ochoa, J. B.,
Verdile, V., Udekwu,A. O., Berceli, S. A., Simmons, R. L., and Peitzman, A. B. (1992) in Nitric Oxide: Implications for Drug Research, P. 28, IBC, South Natick, MA.; Langrehr, J. M., Murase, N., Markus, P. M., Cai, X., Neuhaus, P., Schraut, W., Simmons, R. L., and Hoffman, R. A. (1992) J. Clin. Invest. 90, 679-683; Corbett, J. A., Tilton, R. G., Chang, K., Hasan, K. S., Ido, Y., Wang, J. L., Sweetland, M. A., Lancaster, J. R. Jr., Williamson, J. R., and McDaniel, M. L.
(1992) Diabetes 41, 552-556; Griess, P. (1879) Chem. Ber. 12 426.
There are three distinct isoforms of human NOS, neuronal (bNOS), endothelial (eNOS) and inducible (iNOS).
In general eNOS is constitutively expressed and produces reletively low levels of NO. Activity of eNOS is dependent on Ca2+ influx. eNOS is found in vascular smooth muscle cells which is not identical to the form of enzyme found in neurons. Formation of NO by the eNOS in vascular endothelial cells is believed to play a role in regulating blood pressure by relaxing muscles and allowing the vessel to dialate, which lower the blood pressure Pollock, J. S., Forstermann, U., Mitchell, J. A., Warner, T. D., Schmidt, H. H. H. W., Nakane, M. and Murad, F. (1991) Proc. Natl. Acad. Set USA 88, 10480-10484; Lamas, S., Marsden, P. A., Li, G. K., Tempst, P. and Michel, T. (1992) Proc. Natl. Acad. Sci. USA 89, 7773-7777.
Disruption of the neuronal NOS (second isoform of NOS) gene causes no histological abnormalities in the central nervous system Huang, P. L., Dawson, T. M., Bredt, D. S., Snyder, S. H. and Fishman, M. C. (1993) Cell 75, 1273- 1286. iNOS is not dependent on elevated Ca2+ concentration and generally expressed only after induction by certain cytokines or by bacterial lipopolysaccharide (LPS) Wei, X. Q., Charles, I. G., Smith, A., Ure, J., Feng, G. J., Huang, F. P., Xu, D., Muller, W., Moncada, S. and Liew, F. Y. (1995) Nature (London) 375, 408-411.
It is thought that in sepsis or cytokine-induced shock, excess production of nitric oxide by iNOS plays an important role in life- threatening hypotension. Evidence for this has come from observations that serum levels of NO oxidation products are elevated in animals and humans undergoing septic shock and from in vivo studies with NOS inhibitors Goode, H. F., Howdle, P. D., Walker, B. E. and Webster, N. R. (1995) Clin. Set 88, 131-133; Barthlen, W. , Stadler, J. , Lehn, N. L., Miethke, T., Bartles, H. and Siewert, J. R.,
(1994) Shock 2, 398-401; Cunha, F. Q., Assreuy, J.( Mass, D. W., Rees, D., Leal L. M. C, Moncada, S. and Carrier, M. (1994) Immu. 81 , 211- 215.
Furthermore, it has been postulated that excess production of nitric oxide by iNOS is a factor in the unresponsiveness to pressor agents such as alphaj -adrenergic agonists employed in the treatment of septic or cytokine -induced shock patients. We are now describing a new class of compounds useful as inhibitors of iNOS. See for example the paper presented by Mosby et al reported in J. Org. Chem., 24, 374-380 (1959) entitiled "Reactions of 2, 3 -dichloro- 1 ,4-naphthoquinone with 2, Aminopyridine and Related Amines", Offenlegungsschrift DE 3926747 Al entitled " 1 ,2-Naphthochinone enthalende fungizide Mittel", Asahi et al. Chem. Pharm. Bull, 32, 3093-3099 (1984), and Carroll et al. J. Heterocycl. Chem. 7, 297-306 (1970). These compounds are described below.
SUMMARY OF THE INVENTION
The present invention relates to the use of compounds of general formula 1 which are inhibitors of NOS:
FORMULA 1
wherein when R^, is H; R, is selected from the group consisting of: 1) -NH-C0-C10 alkyl -aryl, N-(C0-C 10 alkyl substituted aryl) 2 , -C 0-C 10alkyl substituted aryl, -N(C0-C 10 alkyl substituted aryl)2 (Co-C10 alkyl), in which "aryl" is optionally attached to compound 1 through C or N and is selected from the group consisting of isoindanolyl, isoindolinyl, tetrahydroquinolyl, phenyl, naphthyl,
pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, pyrazinyl.pyrimidyl, quinolyl, isoquinolyl, benzofuiyl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, and benzoxazolyl; and the term "substituted aryl" denotes mono-, di- and / or tri-substituted aryl wherein aryl is as defined above and in which the substituents are independently selected from the group consistng of H, trifluoromethyl, amino, hydroxy, halo, nitro,
-O-C C6 alkyl, -S-C C6 alkyl, -NH- C, -C6 alkyl, -N (C, -C6 alkyl)2 , -C(O) -C, -C6 alkyl, C(O)NHC0-C10alkyl, -NHC(O) C C6 alkyl,
- Cj -Cn CO2R or C, -C6NHR,
-Cj -Cj, CONHR, carboxy, -C(O) O C,-C6 alkyl; trans-CH=CHCO2R; trans CH=CHCONHR wherein R = Cj -Cn alkyl or C, -Cn alkylphenyl;
2) Cyclic -N(CH2 CH2 ) 2 Y, cyclic NCHA(CH2)3.4 , or -NH C2-Cu alkyl-W wherein:
A = i) C, -C10 alkyl, Cι -C10alkylaryl or, ii) COZR3 wherein Z = oxygen, NH and R3= H, or Cι -C10 alkyl, or C0- C10 alkylaryl wherein aryl group is as defined in (1) above,
and Y = i) oxygen, or S, or NH or ii) NC0- C10 alkyl or iii) N Cj -C^ alkylsubstituted aryl, iv) NC=ZMR3 wherein Z = oxygen, or NH; M = C, oxygen, N, and R3 is C0-C10alkyl substituted aryl wherein "substituted aryl" is as defined above; v) N(C1 -C10)CH(COZR3)(NHCOZR3) wherein Z and R3 are as defined above;
and W= i) NH2 ii) NHC0- C10 alkylaryl where aryl is as defined in 1 or iii) ZC(O)MR3 wherein Z, M and R3 is as defined above;
R2 is hydrogen; or R, and R^, taken together forming another aryl group; and X is hydrogen, halo, alkyl, alkoxy, hydroxy, nitro, amino, trifluoromethyl and aryl.
Briefly, the compounds described herein are indicated in the prophylaxis or treatment for a patient suffering from hypotension caused by an excess production of nitric oxide from arginine in vascular cells in the patient induced by therapy with a cytokine, or exposure to a bacterial endotoxin, i.e. septic shock or from immunosuppressant therapy.
The present invention also includes within its scope methods of adininstrating to said patient a therapeutically effective amount, i.e. an effective NOS inhibitory amount of a compound or the corresponding pharmaceutically acceptable salt, ester or solvate selected from the compounds depicted in Formula 1 in an inert pharmaceutical carrier.
Among the preferred compounds for iNOS inhibition are those compounds wherein R! is aniline or substituted aniline, and the following:
or
N N-R4
in which R4 is alkyl as defined above or:
COOMe
in which R5 Rg R7 and Rg are alkyl, aryl or substituted aryl as defined above. The compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof. Pharmaceutically acceptable salts of the compounds of Formula 1, where a basic or acidic group is present in the structure, are also included within the scope of this invention. When an acidic substituent is present, such as -COOH, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, which can be formulated into dosage forms suitable for oral or parenteral adminstration. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, acetate, maleate, pamoate, methanesulfonate, p-toluenesulfonate, and the like, can be formulated into suitable dosage form for oral or parenteral adminstration form. Also, in the case of the -COOH being present, pharmaceutically acceptable esters can be employed, e.g., methyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations. In addition, some of the compounds useful in this invention may form solvates with water or common organic solvents. Such solvates are useful in the methods of treatment of this invention.
The term "therapeutically effective amount" or "effective NOS inhibitory amount" shall mean that amount of compound, as depicted in Formula 1 or its pharmaceutical salt, ester etc. that will elicit the biological or NOS inhibitory response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
According to the present invention, compounds of Formula 1 are prepared according to the followng general reaction Scheme A and/or Scheme B:
Scheme A
Scheme B
The commercially available 1 ,2 -naphthoquinone s 1 or 2 is reacted with the appropriate amine at equal molar ratio in a proper reaction solvent such as DMSO or a lower molecular weight alcohol, such as ethanol (Scheme A, at about 60°C) or in a pH 8-9 aqueous buffer solution (Scheme B, at room temperature) as described above. The reaction products are recovered from the reaction mixtures by the partition between an organic solvent such as ethyl acetate, methylene chloride, and chloroform and water. The organic layer is then dried with sodium sulfate and evaporated in vacuo, yielding the desired products as the residue.
In accordance with the procedure described in Scheme A, the following compounds were prepared:
Example 1 Example 2 Example 3
Example 4 Example 5 Example 6
Example 7 Example 8 Example 9
Example 10 Example 11
OMe
In accordance with the procedure described in Scheme B, the following compounds were prepared:
Example 12 Example 13 Example 14
Example 15
The following compounds were prepared by treatment of compound of 12 using standard aeylation reaction such as with an acid chloride, a carboxylic acid, carbonyl diimidazole, isocyanate, and lH-pyrazole-1-carboxamidine hydrochloric acid.
Example 17 Example 18 Example 19
Example 20 Example 21 Example 22
COOMe
Compound 22 was prepared from the reaction of compound 12 t-butyl a-bromoacetate under standare conditions.
Example 23
Compound 23 was prepared in accordance with the procedure described by Mosby et al. reported in J. Org. Chem ., 24, 374-380 ( 1959) .
Example 24
The Compounds depicted in Formula 1 which are useful as NOS inhibitors were tested in accordance with the procedure described by Stuehr, et al. "Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein." Proc. Natl. Acad. Sci. USA, 88, 7773-7 (1991). Thus, iNOS was isolated from interferon-g and lipopolysaacharide (LPS) stimulated mouse macrophage cells (RAW 264.7 cells). RAW cells were incubated overnight with interferon-G and LPS. A lysate fraction was prepared by lysing the harvested cells in liquid nitrogen and thawing by incubation in a 37° C water bath
and run over an ADP sepharose column for partial purification. The assay was validated and optimized. bNOS was isolated according to the proceedure disclosed in Proc. Nat. Acad. Sci. USA Vol. 88 pp. 365-369, January 1991. To a 96-well microtiter plate the following were added:
35 mL assay buffer (with/3H Arg.)
10 mL bNOS crude extract and
5 mL inhibitor at 10 X FAC
The resulting solution was incubated at 37'C for 20 minutes. The reaction was stopped by the addition of 75 ml of a Stop buffer.
Then 125 ml of 1 : 1 DOWEX AG50 WX-8 was added with gentle mixing. After 15 minutes, 50 mL of the supematent was counted with 200 mL of a scintillation fluid in a Packard microscintillater.
The solutions had the following composition: Assay Buffer:
50 mM Tris pH7.8
200 mM NADPH
10 mM BH4
10 mM FAD
10 mM FMN
4 mM CaCls
20 mg/mL calmodulin
4 mM L-Arg
.35 mC well 3H-L-Arg
Stop Buffer:
100 mM Hepes pH 5.5
1 mM L-Citrulline
10 mM EGTA
Nitric Oxide Synthase activity was assayed by adding 10 mL of crude lysate 10 mL of substrate and 10 mL of a selected Compound as depicted in Formula 1 in DMSO to 70 mL of assay buffer in a 96-well microtiter plate. The wells were mixed gently and incubated for 90 minutes at 37°C. The reaction was stopped by adding 2 units of
L-lactic dehydrogenase (5 mL of stock solution) and 5 mmole of sodium pyruvate (10 mL of stock solution). The solution was incubated for an additional 15 minutes at 37°C. 100 mL of Griess reagent was added and read absorbance at 560 nm. The inhibitory concentraction 50 or IC50 for the Compounds depicted in examples
1-24 as follows:
Examples IC50(mM) or Percentage Inhibition iNOS bNOS
1 27 a
2 16
3 41
4 45
5 12
6 5.4 2.0
7 8 —
8 13 —
9 17 —
10 44 —
11 34%@ 10 mM —
12 9.9 2.1
13 7.8 —
14 7.4 —
15 3.8 1.1
16 11.2 3.2
17 5.4 —
18 6.2 1.2
19 2.2 2.1
20 0.67 0.57
21 15.6 1.9
22 7.3 3.9
23 93% @ mM —
24 2.3 0.27
Footnote: a. ' — ' means the data is not available.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
A compound of Formula 1 may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non¬ irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
For topical use, creams, ointments, jellies, solutions or suspensions, etc. , containing the compounds of Formula 1 are employed.
Generally speaking, the selected compound is adminstered at a dosage level of from about 0.1 mg to about 200mg/kg of the body weight of the subject being treated. This dosage has to be individualized by the clinician based on the specific clinical condition of the subject being treated.
To enhance the therapeutic spectrum of the methods of the present invention.the selected NOS inhibitors may be combined with or replace other therapeutic agents such as alpha, -adrenergic modulators which are currently being used to treat hypotension in septic or cytokine treated patients. These modulators include, for example, epinephrine, norepinephrine dopamine and the like. Again, the dosage needs to be individualized by the clinician.
Claims (28)
1. A method for the inhibition of nitric oxide synthase (NOS) in a subject in need of such inhibition which comprises the administration of an effective amount of nitric oxide synthase (NOS) inhibitors of a compound of Formula 1 :
Formula 1
wherein when 1^ is H; R, is selected from the group consisting of:
1. -NH-C0-C10 alkyl -aryl, N-(C0-C 10 alkyl substituted aryl) 2 , -C 0-C10 alkyl substituted aryl, -N(C0-C 10 alkyl substituted aryl)
(Co-C10 alkyl), in which "aryl" is optionally attached to compound 1 through C or N and is selected from the group consisting of isoindanolyl, isoindolinyl, tetrahydroquinolyl, phenyl, naphthyl, pyridyl, furyl, pyrryl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, triazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, and benzoxazolyl; and "substituted aryl" is selected from the group consisting of mono-, di- and / or tri-substituted aryl wherein aryl is as defined above and in which the substituents are independently selected from the group consistng of H, trifluoromethyl, amino, hydroxy, halo, nitro, -O-C C6 alkyl, -S-C, -C6 alkyl , -NH- C, -C6 alkyl, - N (C, -C6 alkyl)2 , -C(O) -C^Q, alkyl, C(O)NHC0-C10alkyl, -NHC(O) C C6 alkyl, - C, -Cu CO2R or
-C. -C,, CONHR, carboxy,
-C(O) O C C6 alkyl; trans-CH=CHCO2R; trans CH=CHCONHR wherein
R = Cj -Cn alkyl or C Cn alkylphenyl;
2. Cyclic -N(CH2 CH2 ) 2 Y, cyclic NCHA(CH2)3_4 , or -NH C2-Cu alkyl-W, wherein: A = i) C, -C10 alkyl, Cj -C.oalkylaryl or, ii) COZR3 wherein Z = oxygen, NH and R3= H, or C, -C10 alkyl, or C0- CI0 alkylaryl wherein aryl group is as defined in (1) above, and Y = i) oxygen, or S, or NH or ii) NC0- C10 alkyl or iii) N Cι -C10 alkylsubstituted aryl, iv) NC=ZMR3 wherein Z = oxygen, or NH; M = C, oxygen, N, and R3 is C0-C10alkyl substituted aryl wherein "substituted aryl" is as defined above; v) N(C1 -C10)CH(COZR3)(NHCOZR3) wherein Z and R3 are as defined above; and W= i) NH2 ii) NHC0- C10 alkylaryl where aryl is as defined in 1 or iii) ZC(O)MR3 wherein Z, M and R3 is as defined above R-, is hydrogen; or R, and R2 taken together forming another aryl group; and X is hydrogen, halo, alkyl, alkoxy, hydroxy, nitro, amino, trifluoromethyl and aryl, and the corresponding pharmaceutically acceptable salt, ester, and solvate thereof in an inert pharmaceutical carrier.
2. A method according to claim 1 wherein the compound of Formula 1 in which R, is a member selected from the group consisting of aniline, substituted aniline, and the following groups:
in which R4 is alkyl as defined in claim 1 or:
in which R5 Rg R7 and R8 are alkyl, aryl or substituted aryl as defined in claim 1.
3. A method according to claim 1 wherein the compound has the formula:
4. A method according to claim 1 wherein the compound has the formula:
5. A method accordin σg to claim- 1 wherein the compound has the formula:
6. A method according to claim 1 wherein the compound has the formula:
7. A method according to claim 1 wherein the compound has the formula:
8. A method according to claim 1 wherein the compound has the formula:
O
O
9. A method according to claim 1 wherein the compound has the formula:
10. A method according to claim 1 wherein the compound has the formula:
11. A method according to claim 1 wherein the compound has the formula:
12. A method according to claim 1 wherein the compound has the formula:
13. A method according to claim 1 wherein the compound has the formula:
14. A method according to claim 1 wherein the compound has the formula:
15. A method according to claim 1 wherein the compound has the formula:
16. A method according to claim 1 wherein the compound has the formula:
17. A method according to claim 1 wherein the compound has the formula:
18. A method according to claim 1 wherein the compound has the formula:
19. A method according to claim 1 wherein the compound has the formula:
20. A method according to claim 1 wherein the compound has the formula:
21. A method according to claim 1 wherein the compound has the formula:
22. A method according to claim 1 wherein the compound has the formula:
23. A method according to claim 1 wherein the compound has the formula:
COOMe
24. A method according to claim 1 wherein the compound has the formula:
25. A method according to claim 1 wherein the compound has the formula:
26. A method according to claim 1 wherein the compound has the formula:
27. A method according to claim 1 wherein said compound is administered intravenously.
28. A method according to claim 27 wherein said compound is administered in the range of about 0.1 mg-200 mg/kg of the body weight of said subject.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US207895P | 1995-08-09 | 1995-08-09 | |
US002078 | 1995-08-09 | ||
PCT/US1996/013001 WO1997005871A1 (en) | 1995-08-09 | 1996-08-07 | Nitric oxide synthase (nos) inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
AU6770996A true AU6770996A (en) | 1997-03-05 |
Family
ID=21699164
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU67709/96A Abandoned AU6770996A (en) | 1995-08-09 | 1996-08-07 | Nitric oxide synthase (nos) inhibitors |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0843550A1 (en) |
AU (1) | AU6770996A (en) |
CA (1) | CA2229074A1 (en) |
WO (1) | WO1997005871A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2764292B1 (en) * | 1997-06-10 | 2000-12-29 | Innothera Lab Sa | USE OF DICETONIC TETRACYCLE DERIVATIVES, NOVEL COMPOUNDS OBTAINED AND THEIR APPLICATION IN THERAPEUTICS |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4882339A (en) * | 1987-07-10 | 1989-11-21 | Ciba-Geigy Corporation | 4-Amino-substituted 1,2-dihydroxynaphthalene derivatives useful in inhibiting 5-lipoxygenase activity in mammals |
FR2707494B1 (en) * | 1993-07-02 | 1995-08-25 | Roussel Uclaf | New use of beta-naphthoquinone derivatives and their salts. |
-
1996
- 1996-08-07 AU AU67709/96A patent/AU6770996A/en not_active Abandoned
- 1996-08-07 CA CA002229074A patent/CA2229074A1/en not_active Abandoned
- 1996-08-07 EP EP96928121A patent/EP0843550A1/en not_active Withdrawn
- 1996-08-07 WO PCT/US1996/013001 patent/WO1997005871A1/en active Search and Examination
Also Published As
Publication number | Publication date |
---|---|
EP0843550A1 (en) | 1998-05-27 |
WO1997005871A1 (en) | 1997-02-20 |
CA2229074A1 (en) | 1997-02-20 |
EP0843550A4 (en) | 1998-06-03 |
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