AU705321B2 - Halomethyl amides as IL-1beta protease inhibitors - Google Patents
Halomethyl amides as IL-1beta protease inhibitors Download PDFInfo
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- AU705321B2 AU705321B2 AU24634/95A AU2463495A AU705321B2 AU 705321 B2 AU705321 B2 AU 705321B2 AU 24634/95 A AU24634/95 A AU 24634/95A AU 2463495 A AU2463495 A AU 2463495A AU 705321 B2 AU705321 B2 AU 705321B2
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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Description
II_ I WO 95/29672 PCT/US95/05347 HALOMETHYL AMIDES AS IL-1 PROTEASE INHIBITORS BACKGROUND OF THE INVENTION Field of the Invention This invention relates to a series of novel non-peptides which exhibit selective in vitro and in vivo inhibition of interleukin-lp converting enzyme, to compositions containing the novel non-peptides and to methods for therapeutic utility. More particularly, the interleukin 13 converting enzyme inhibitors described in this invention comprise novel a-halomethyl amides and a-halomethyl sulfonamides which possess particular utility in the treatment of inflammatory and immune-based diseases of lung, central nervous system, and connective tissues.
Reported Developments Interleukin-lp (IL-1 p) protease (also known as interleukin-lp converting enzyme or ICE) is the enzyme responsible for processing of the biologically inactive 31 kD precursor IL-1 to the biologically active 17 kD form (Kostura, Tocci, M.J.; Limjuco, Chin, Cameron, Hillman, Chartrain, Schmidt, ero.
Nat. Acad. Sci.. (1989), 86, 5227-5231 and Black, Kronheim, Sleath, P.R., ,EEBS,.Le, (1989), 24Z, 386-391). In addition to acting as one of the body's early responses to injury and infection, IL-1p has also been proposed to act as a mediator of a wide variety of diseases, including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, acute and chronic myelogenous leukemia and osteoporosis (Dinarello, Wolff, New Engl. J. Med.. (1993), 328. 106). A naturally occurring IL-lp receptor antagonist has been used to demonstrate the intermediacy of IL-p in a number of human diseases and animal models (Hannum, Wilcox, C.J.; Arend, Joslin, Dripps, Heimdal, Armes, Sommer, A.; Eisenberg, Thompson, Nature, (1990), 343, 336-340; Eisenberg, S.P.; i Evans, Arend, Verderber, Brewer, Hannum, Thompson, Nature (1990), 43., 341-346; Ohlsson, Bjork, Bergenfeldt, Hageman, Thompson, Nature, (1990), 34, 550-552; Wakabayashi, FASEB, (1991), y WO 95/29672 PCTrUS95/05347 338-343; Pacifici, et al. Proc N. Natl. Acad. Sci. (1989), 2398-2402 and Yamamoto, et al. Cancer Rsh (1989), 49, 4242-4246). The specific role of IL-1p in inflammation and immunomodulation is supported by the recent observation that the cowpox virus employs an inhibitor of ICE to suppress the inflammatory response of its host (Ray, C.A. et al, Cell, (1992), 9, 597-604).
In summary, the utility of ICE inhibitors in modifying certain IL-1 mediated disease states has been suggested and demonstrated in vivo by several workers in the field. The following review of the current state of the art in ICE research further supports such utility of ICE inhibitors: 1) WO 9309135, published 11 May 1993, teaches that peptide-based aspartic acid arylacyloxy-and aryoxymethyl ketones are potent inhibitors of ICE in vitro. These compounds also specifically inhibited ICE in the whole cell (in vivo) by their ability to inhibit the formation of mature IL-1 in whole cells. These ICE inhibitors also demonstrated utility in reducing fever and inflammation/swelling in rats.
2) Patients with Lyme disease sometimes develop Lyme arthritis. B. burgdorferi, the causative agent of Lyme disease, is a potent inducer of IL-1 synthesis by mononuclear cells. Miller et al. (Miller, Lynch, E.A. Isa, Logan, J.W.; Dinarello, and Steere, "Balance of synovial fluid IL-1 1 and IL-1 Receptor Antagonist and Recovery from Lyme arthritis", Lancet (1993) 341; 146-148) showed that in patients who recovered quickly from Lyme Arthritis, the balance in synovial fluid of IL-1-beta and IL-1ra was in favor of IL-ra. When the balance was shifted in favor of IL- 13, it took significantly longer for the disease to resolve. The conclusi t was that the excess IL-1 ra blocked the effects of the IL-1 B in the patients studied.
3) IL-1 is present in affected tissues in ulcerative colitis in humans. In animal models of the disease, IL-1 B levels correlate with disease severity. In the 'mdel, administration of 1L-1ra reduced tissue necrosis and the number of inflammatory cells in the colon.
See, Cominelli, Nast, Clark, Schindler, Llerena, Eysselein, V.E.; Thompson, and Dinarello, "lnterleukin-1 Gene Expression, Synthesis, and -2- -2- WO 95/29672 PCT/US95/05347 Effect of Specific IL-1 Receptor Blockade in Rabbit Immune Complex Colitis" JLQij Investigations (1990) Vol. 8, pp, 972-980.
4) IL-1 ra supresses joint swelling in the PG-APS model of arthritis in rats.
See Schwab, Anderle, Brown, Dalldorf, F.G. and Thompson, R.C., "Pro- and Anti-Inflammatory Roles of Interelukin-1 in Recurrence of Bacterial Cell Wall- Induced Arthritis in Rats". Infect. Immun, (1991) 5S; 4436-4442.
IL-1 ra shows efficacy in an small open-label human Rheumatoid Arthritis trial.
See, Lebsack, Paul, Bloedow, Burch, Sack, Chase, W., and Catalano, M.A. "Subcutaneous IL-1 Receptor Antagonist in Patients with Rheumatoid Arthritis", Arth. Rheum. (1991) 34; 545.
6) IL-1 appears to be an autocrine growth factor for the proliferation of chronic myelogenous leukemia cells. Both IL-1ra and slL-1R inhibit colony growth in cells removed from leukemia patients.
See, Estrov, Kurzrock, Wetzler, Kantarjian, Blake, Harris, D.; Gutterman, and Talpaz, "Supression of Chronic Myelogenous Leukemia Colony Growth by Interleukin-1 (IL-1) Receptor Antagonist and Soluble IL-1 Receptors: a Novel Application for Inhibitors of IL-1 Activity". Blood (1991) 78; 1476-1484.
7) As in 6) above, but for acute myelogenous leukemia rather than chronic myelogenous leukemia.
See, Estrov, Kurzrock, Estey, Wetzler, Ferrajoli, Harris, Blake, M.; Guttermann, and Talpaz, M. "Inhibition of Acute Myelogenous Leukemia Blast Proliferation by Interleukin-1 (IL-1) Receptor Antagonist and Soluble IL-1 Receptors".
(1992) Blood 1938-1945.
An effective therapy has yet to be fully developed commercially for the treatment of IL-113 mediated inflammatory diseases. Consequently, there is a need for therapeutic agents effective in the treatment and prevention of these diseases.
A
1+ CC-- 311 II~ II WO 95/29672 PCT/US95/05347 SUMMARY OF THE INVENTION According to the present invention, there is provided a compound of the formula or a pharmaceutically acceptable salt thereof:
R
2
R
3
-N-Y-R
1
(A)
(A)
wherein: Y CO or SO2; R1 independently selected from alkyl, haloalkyl and alkoxyalkyl; R2 H, alkyl, (CH2)-alkenyl, aralkyl, heteroaralkyl, carboxyalkyl, cyanoaikyl, aryl, heteroaryl; and R3 H, alkyl, (CH2)-alkenyl, aralkyl, heteroaralkyl, aryl, heteraryl; "Alkyl" is defined as a saturated aliphatic hydrocarbon which may be either straight or branched chain. Preferred groups have no more than 12 carbon atoms and may be methyl, ethyl, and structural isomers of propyl, butyl, up to dodecyl. A "Haloalkyl" is defined as an alkyl radical substituted by one or more halogen Cl, Br, For example chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, fluorochloromethyl.
"Alkoxyalkyl" is defined as an alkyl radical substituted by an alkoxy group. For example methoxymethyl.
"Aryl" is defined as a phenyl on naphthyl ring which may be unsubstituted or substituted wherein one or more of the hydrogen atoms has been replaced by the same or different substituents including halo, alkyl, aryl, nitro, cyano, amino, alkylacylamino, hydroxyl, alkoxy, haloalkyl.
AL
WO 95/29672 PCTIUS95/05347 "Halo" means iodo, bromo, chloro, fluoro.
"Carboxyalkyl" means an alkyl radical substituted by a carboxyl group. For example, carboxymethyl.
"Aralkyl" means an alkyl radical substituted with an aryl ring. For example benzyl, 4chlorobenzyl.
"Heteroaryl" means pyridyl, thienyl or furanyl and structural isomers thereof.
"Heteroaralkyl" means an alkyl radical substituted by an heteroaryl ring. For example 2-thienyl ethyl.
"Alkenyl" is defined as an alkyl group containing one or more sites of unsaturation. For example, ethenyl, ethynl, 1-butenyl, 2-butynyl, 1,3-hexadienyl.
"Cyanoalkyl" means an alkyl radical substituted by a cyano group. For example, cyano ethyl.
The present invention also concerns the pharmaceutical composition and method of treatment of IL-113 protease mediated disease states or disorders in a mammal in need of such treatment comprising the administration of IL-1P protease inhibitors of formula as the active agent. These disease states and disorders include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain tumors and leukemias.
The present invention has particular utility in the modulation of processing of IL- 11 for the treatment of rheumatoid arthritis. Levels of IL-11 are known to be elevated in the synovial fluid of patients with the disease. Additionally, IL-1P stimulates the synthesis of enzymes believed to be involved in inflammation, such as collagenase and -1 WO 95/29672 PCT/US95/05347 PLA2, and produces joint destruction which is very similar to rheumatoid arthritis following intra-articular injection in animals.
In the practice of this invention an effective amount of a compound of the invention or a pharmaceutical composition thereof is administered to the subject in need of, or desiring, such treatment. These compounds or compositions may be administered by any of a variety of routes depending upon the specific end use, including orally, parenterally (including subcutaneous, intraarticular, intramuscular and intravenous administration), rectally, buccally (including sublingually), transdermally or intranasally. The most suitable route in any given case will depend upon the use, the particular active ingredient, and the subject involved. The compound or composition may also be administered by means of controlled-release, depot implant or injectable formulations as described more fully herein.
In general, for the uses as described in the instant invention, it is expedient to administer the active ingredient in amounts between about 0.1 and 100 mg/kg body weight, most preferably from about 0.1 to 30 mg/kg body weight for human therapy, the active ingredient will be administered preferably in the range of from about 0.1 to about 20-50 mg/kg/day. This administration may be accomplished by a single administration, by distribution over several applications or by slow release in order to achieve the most effective results. When administered as a single dose, administration will most preferably be in the range of from about 0.1 to mg/kg to about 10 mg/kg.
The exact dose and regimen for administration of these compounds and compositions will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment, and the degree of affliction or need. In general, parenteral administration requires lower dosage than other methods of administration which are more dependent upon absorption.
A further aspect of the present invention relates to pharmaceutical compositions comprising as an active ingredient a compound of the present invention in admixture with a pharmaceutically acceptable, non-toxic carrier. As mentioned above, such compositions may be prepared for use for parenteral (subcutaneous, intraarticular, intramuscular or intravenous) administration, particularly in the form of liquid solutions i -6- WO 95/29672 PCTIUS95/05347 or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops or aerosols.
When administered orally (or rectally) the compounds will usually be formulated into a unit dosage form such as a tablet capsule, suppository or cachet. Such formulations typically include a solid, semi-solid or liquid carrier or diluent. Exemplary diluents and vehicles are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobroma, aginates, tragacanth, gelatin, syrup, methylcellulose, polyoxyethylene sorbitar monolaurate, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, and magnesium stearate.
The compositions may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985. Formulations for parenteral administration may contain as common excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Examples of vehicles for parenteral administration include water, aqueous vehicles such as saline, Ringer's solution, dextrose solution, and Hank's solution and nonaqueous vehicles such as fixed oils (such as corn, cottonseed, peanut, and sesame), ethyl oleate, and isopropyl myristate. Sterile saline is a preferred vehicle and the compounds are sufficiently water soluble to be made up as a solution for all foreseeable needs. The vehicle may contain minor amounts of additives such as substances that enhance solubility, isotonicity, and chemical stability, antioxidants, buffers, and preservatives. For oral administration, the formula can be enhanced by the addition of bile salts and also by the addition of acylcarnitines (Am. J. Physiol. 251:332 (1986)). Formulations for nasal administration may be solid and contain as excipients, for example, lactose or dextran, or may be aqueous or oily solutions for administration in the form of nasal drops or metered spray. For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
When formulated for nasal administration the absorption across the nasal mucous membrane is enhanced by surfactant acids, such as for example, glycocholic acid, cholic acid, taurocholic acid, ethocholic acid, desoxycholic acid,
I
-I- I WO 95/29672 PCT/US95/05347 chenodesoxycholic acid, dehydrocholic acid, glycodeoxy-cholic acid, and the like (See, B.H. Vickery, "LHRH and its Analogs-Contraception and Therapeutic Applications", Pt.
2, B.H. Vickery and J.S. Nester, Eds., MTP Press, Lancaster, UK, 1987).
DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention were prepared by using the general synthetic methods described in the Schemes below.
In Scheme I, the desired amine (Formula 1) was either purchased commercially or prepared by reductive amination of an aldehyde (Formula 2) and an amine (Formula and then acylated or sulfonylated with an appropriate acid or sulfonyl chloride. This afforded compounds of the type in Formula 4.
Alternatively (Scheme II), direct alkylation of an acylateci amine (Formula 5) was performed to give differentially N,N-disubstituted amides of the type in Formula 6. The alkylation reaction proceeds nicely using potassium t-butoxide as a base and tetrahydrofuran as a solvent.
Methods for the preparation of acid chlorides, sulfonyl chlorides, reductive amination and alkylation of amines are well known in the art. See "Advanced Organic Chemistry", J. March, eds. McGraw-Hill Book Co., Second Edition, 1977.
J t -8- I -,A WO 95/29672 PTU9/54 PCTfUS95/05347 Scheme I
R
3
-NH
2 (formula 2)
R
2
-CHO
(formula 3) NaBH(OAC) 3
R
3 -NH (formula 1) CI-Y-Rj base C1--R 1
CH
2 C1 2
R
3
-N-Y-RI
(formula 4) Scheme II
H
R
3
-N-Y-RI
(formula 5) KOt13u
THE
W-CH
2
R
2 rKR2
R
3
-N-Y-RI
(formula 6) -ai i\ ri 4~ WO 95/29672 PCTUS95/05347 Example 1 Preparation of N-Allvl-N-(2.4-dichlorobenzvyl chloroacetamide
H
2
N-N/
H
CI
I +jc
CIN
Part A: To 1 g of 2,4-dichlorobenzaldehyde in 6 mL of 1,2-dichloroethane was added 428 pL of allyl amine, 280 pL of acetic acid, and 1.8 g of NaBH(OAc) 3 in the giVen order. After 30 minutes, the reaction mixture was diluted with chloroform and saturated aqueous NaHCO 3 The layers were separated and the organic layer was dried (MgS0 4 and concentrated in vacuo affording a colorless oil. Flash chromatography EtOAc-hexane) afforded 476 mg of as a colorless oil.
Part B: 476 mg of 1 was dissolved in 5 mL of methylene chloride and 306 pL of Et 3
N
was added. The reaction mixture was cooled to 00C and 175 pL of chloroacetyl chloride was added and the mixture was stirred for 2 h. The reaction was then diluted with chloroform and washed twice with water. The combined organic layers were dried (MgSO 4 and concentrated in vacuo provided a white solid. Flash chromatography EtOAc-hexane) afforded 500 mg of 2as a white solid: Low Resolution Mass Spec. m/z (relative intensity): 292 100), 256 174 159 146
I
'r I-*L l WO 95/29672 PCT/US95/05347 Example 2 Preparation of N-Benzvl-N-(2.4-dichlorobenzyl) chloroacetamide CI C IC- 3- Ph Br i,.
Part A: 100 g of 2,4-dichlorobenzylamine was dissolved into 600 mL of CH 2 C12 and the reaction mixture was cooled to 0°C. Next, 89 mL of Et 3 N was added followed by the dropwise addition of 50 mL of chloroacetyl chloride. The reaction mixture was stirred for 24 h. The reaction was then washed twice with H 2 0, dried (MgSO4) and concentrated in vacuo affording a solid which was triturated with 10% hexane-EtOAc affording 131 g of 3 as a pure white solid.
Part B: 500 mg of 3 was dissolved in 2 mL of THF and 2 mL (10 equiv) of benzyl bromide was added. Next, 276 mg of potassium t-butoxide in 7 mL of THF was added dropwise to the reaction mixture which was then stirred for 30 minutes and finally was concentrated in vacuo. The residue was dissolved in chloroform and washed twice with
H
2 0, dried (MgSO4) and concentrated in vacuo affording a yellow oil. Flash chromotography (15% EtOAc-hexane) afforded 500 mg of 4 as a white solid.
Low Resolution Mass Spec. m/z (relative intensity): 356 11), 196 91 (100) Using the methods described in Examples 1 and 2, the following were also prepared: -11- WO 95/29672PT/S9057 PCT/US95/05347 Example 3 N-(2.4-Dichlorobenzyl)-N-methyl ch loroacetamide Low Resolution Mass Spec. mn/z (relative intensity): 266 16), 232 214 188 (100), 173 (16).
Example 4 N-Benzyl-N-(3-chlorobenzyl) chioroacetamide Low Resolution Mass Spec. mn/z (relative intensity): S(MI+H; 36), 216 182 106 91 (100).
Example chioroacetamide Low Resolution Mass Spec. mn/z (relative intensity): 342 58), 306 182 106 91 (100).
Example 6 N-(4-Chlorobenzyl) chlorgacetamide Low Resolution Mass Spec. mn/z (relative intensity): 308 22), 274 230 125 91 (100).
Example 7 N-Benzyl-N-(3.4-dichlorobenzy1) chloroacetamide
OW;
Low Resolution Mass Spec. mn/z (relative intensity): 342 20), 106 91 (100).
ii -2.2- WO 95/29672 PTU9/54 PCTIUS95/05347 Example 8 N-Benzyl-N-(2-chlorobenzfl) chioroacetamide Low Resolution Mass Spec. mn/z (relative intensity): 308 50), 272 182 125 106 91 (100).
Example 9 N-Benzyl-N-(2.3-dichlorobenzyl) chloroacetamide Low Resolution Mass Spec. mn/z (relative intensity): 342 36), 306 182 106 91 (100).
Example N-Cyanoethyl-N-(2.4-dichlorobenzyl) methoxyacetamide 1 H NMR (ODC1 3 8 7.44-7.06 (in, 3H, Ar), 4.70 2H, (00H 2 4.23 and 4.11 (two singlets, 2H (rotamners), ArCH 2 3.63 and 3.55 (two triplets, 2H (rotamners) J 6.53 Hz each, N-0H 2
-CH
2 2.68 and 2.63 (two triplets, 2H, J 6.53Hz each (rotamners) 0H 2
-CN)
Example 11 N-Cyanomethyl-N-(2,4-dighlorobenzyl) chloronnethylsu Ifonamide, 1 H NMR (ODC1 3 8 7.55-7.28 (in, 3H, Ar), 4.72 2H, SO 2
CH
2 -CI) 4.58 2H, ArCH 2 N) 3.70 2H, J 7.02Hz, N-CH 2
CH
2 2.61 2H, J 7.21 Hz, 0H 2
-CN).
Example 12 N-Cyan oethvl-N-(2,4-di chi orobenzyl) propionamide Low Resolution Mass Spec. mn/z (relative intensity): 285 72), 249 (100), 188 159 109 -13- WO095/29672 PCTUS95/05347 Example 13 N-Cyanoethyl-N-(2.4-dichlorobenzyl) fluoroacetamide Low Resolution Mass Spec. m/z (relative intensity): 289 100), 253 159 Example 14 N-(2,4-D ich I oro ben zy hen yl) propyll chioroacetamide Low Resolution Mass Spec. mn/z (relative intensity): 370 62), 336 302 185 159 125 93 (100).
Example [(N-Chloroacetyl)-N-(2.4-dichlorobenzyl)I glycine Low Resolution Mass Spec. mn/z (relative intensity): 311 (M+H;1 00), 274 232 159 115 Example 16 N-(2.4-Dichlorobenzyl)-N-[(2-thienyl)ethylI chioroacetamide Low Resolution Mass Spec. m/z (relative intensity): 364 100), 326 266 159 110 (56).
Example 17 N-(2,4-Dichlorobenzyl-N-r(2-thienyl'methyll chloroacetamide 1 H NMR (ODC1 3 8 7.49-6.98 (in, 6H, Ar), 4.78 and 4.66 (two singlets, 2H (rotamners) Ar-CH 2 4.75 2H, COCH 2 4.28 and 4.12 (two singlets, 2H, N-0H 2 -thiophene) -14- WO 95/29672 PTU9/54 PCT[US95/05347 Example 18 N-(3-Chlorobenzyfl chioroacetamide Low Resolution Mass Spec. m/z (relative intensity): 218 80), 182 153 141 125 (100), 106 (42).
Example 19 N-(2.3-Dich lorobenzyl) chioroacetamid~e Low Resolution Mass Spec. m/z (relative intensity): 254 H; 59), 216 (100), 159 106 (42).
Example chioroacetamide Low Resolution Mass Spec. m/z (relative intensity): 254 95), 216 (100), 159 141 106 (89).
Example 21 N-(2,4-Dichlorobenzl) chioroacetamide Low Resolution Mass Spec. m/z (relative intensity): 252 38), 217 185 159 132 110 93 (100), 75 (32).
Example 22 N-[(2.4-Dichlorophenyl)ethyll chioroacetamide Low Resolution Mass Spec. m/z (relative intensity): 266 23), 232 185 139 170 93 (100), 75 (24).
I
A
r -li: WO 95/29672 PCT/US95/05347 Compounds of the present invention were tested for IL-1P protease inhibition activity according to the following protocols: In Vitro Partially purified IL-183 protease is stored at -80oC, thawed on ice, and preincubated for 10 minutes at 37°C with 2.5 mM dithiothreitol in a buffer solution containing 10 mM Tris-HCI (pH 8.0) and 25% glycerol. Inhibitors are prepared as stock solutions in dimethyl sulfoxide (DMSO). The protease is preincubated with inhibitor in a volume of 20 pL in a 1.5 mL polypropylene microcentrifuge tube for minutes at 370C. The volume of compound added to the assay is adjusted to yield a DMSO concentration in the preincubation of <15% The enzyme assay is then initiated by the addition of substrate (TRITC-AYVHDAPVRS-NH2) (SEQ I.D. No. 1) to yield a final concentration of 67 pM in a final volume of 30 pL. The reaction are carried out for 60 minutes at 370C in the dark and are terminated by the addition of 10 mL of trifluoroacetic acid (TFA). Following the addition of 115 pL of 0.1% TFA, the samples are analyzed by high pressure liquid chromatography using a reverse phase (C18) column and elution with an acetonitrile/water/TFA gradient. Substrate and product are monitored by their absorbance at 550 nm and elute at 4.2 and 5.2 minutes, respectively.
The compound in example 1- possesses IL-13 protease inhibition (IC50 pM).
In Vivo In vivo inhibition (IC50) was determined as follows: Human monocytes were isolated from heparinized leukopheresis units obtained 30 through Biological Specialty Corporation (Lansdale, PA). Monocytes were purified by Ficoll-Hupaque (Pharmacia Fine Chemicals, Piscataway, NJ) gradient centrifugation and more than 95% pure monocyte populations obtained by centrifugal elutriation. The assay was performed on duplicate samples of freshly isolated human monocytes, cultured in suspension at 370C and rotated gently in conical bottom polypropylene 't* -16- WO 95/29672 PCT/US95/05347 tubes (Sardstedt Inc., Princeton, NJ). Human monocytes at a concentration of 5 x 106 cells/mL were resuspended in 1 mL of RPMI 1640 (a common tissue buffer from M.A.
Bioproducts, Walkersville, MD) containing 1% fetal calf serum (FCS) (HyClone, Logan, UT) and 50 pg/mL gentamycin (Gibco, Grand Island, NY). The cells were treated either with a compound of the invention test compound) or with a non-inhibitor (control compound, typically 0.03% DMSO) for 15 minutes and then activated with 0.01% fixed Staphylococcus aureus (The Enzyme Center, Malden, MA) for 1 hour. The cells were then centrifuged and resuspended in 1 mL of cysteine, methionine-free RPMI media containing 1% dialyzed FCS (Hyclone). The cells were pretreated with a test compound or control compound for 15 minutes after which 0.01% fixed S. aureus plus 100 pCi Tran 35-S label (ICN, Irvine, CA) was added and the cells incubated at 37 0
C
for 1 hour. After incubation, cells were centrifuged, washed once in phosphate buffer saline and resuspended in 1 mL RPMI containing 1% fetal calf serum. The cells were again pretreated with a test or control compound for 15 minutes and then 0.01% S.
aureus for 2 hours. At the end of the incubation, cells were centrifuged and supernates saved for immunoprecipitation. Cells were washed once in phosphate buffer saline and then lysed in RIPA, a continuous cell media buffer containing 2 mM phenylmethylsulfonyl fluoride, 10 mM iodoacetate, 1 pg/mL pepstatin A, 1 pg/mL leupeptin and 0.5 TIU aprotinin.
For the immunoprecipitations, an equal volume of 1% dry milk in RIPA buffer plus 50 pL of resuspended protein A sepharose CL-4B (Pharmacia, Piscataway, New York) was added to supernates and 1 mL of 4% dry milk containing protein A sepharose CL-4B to cell lysates and samples rotated for 30 minutes at 4°C. Beads were then centrifuged down, samples transferred to fresh tubes and incubated overnight with 40 pg rabbit anti-human IL-10 polyclonal antibody (Genzyme, Cambridge, MA). The IL-p proteins were then precipitated with 70 pL protein A sepharose, resuspended in 60 pL SDS sample buffer and run on 15% SGD-PAGE gels.
Autoradiography was performed on dried gels and the amount of radioactivity (counts per minute, cpm) quantitated using a Betascope 603 analyzer.
s -17- Data Analysis In the monocyte pulse chase assay, each test parameter was run in duplicate.
Data was collected from the Beta Scope using a personal computer, then transferred to the VAX system for calculation of mean cpm and standard deviation of the mean.
When test compounds were evaluated, the percent inhibition of release of mature IL-1p was calculated as follows: 100 x [1 (cells treated with stimuli test compound unstimulated cells)/(ceils treated with stimuli control compoundunstimulated cells)] These inhibition values were then used to calculate IK1::, ie for each compound. Since the human monocyte pulse chase assay uses primary cells from different donors, each test compound was run in 2-3 separate experiments, using monocytes from 2-3 different donors.
The compound in Example 1 had in vivo IC50 of <10 pM.
.4 o Throughout the description and claims of the specification the word "comprise" and variations of the word, such as S "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.
Is 11 0 i* 0 -18d I 1i I. -wry WO 95/29672 GENERAL INFORMATION: APPLICANT:
D
R:
PCTIUS95/05347 SEQUENCE LISTING olle, Roland E.
inker, James M.
(ii) TITLE OF INVENTION: Halomethyl Amides As IL-1p Protease Inhibitors (iii) NUMBER OF SEQUENCES: 1 (iv) CORRESPONDENCE ADDRESS: ADDRESSEE: Sterling Winthrop Inc.
STREET: 9 Great Valley Parkway STREET: P.O. Box 3026 CITY: Malvern STATE: PA COUNTRY: USA ZIP: 19355 COMPUTER READABLE FORM: MEDIUM TYPE: Diskette, 3.5 inch, 2.0 MB storage COMPUTER: Apple Macintosh OPERATING SYSTEM: Macintosh 7.1 SOFTWARE: Microsoft Word 5.1a (vi) CURRENT APPLICATION DATA; APPLICATION NUMBER: To be Assigned FILING DATE: 4/29/94 CLASSIFICATION: 1811 (viii) ATTORNEY/AGENT INFORMATION: NAME: Doreen M. Wells REGISTRATION NUMBER: 34,278 (ix) TELECOMMUNICATION INFORMATION: TELEPHONE: (610) 889-8684 TELEFAX: (610) 889-6364 INFORMATION FOR SEQ ID NO: 1 SEQUENCE CHARACTERISTICS: LENGTH: 10 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Modified-site LOCATION: -1 OTHER INFORMATION: /label= TRITC /note= "TRITC is tetramehylrhodamine isothiocyanate".
(ix) FEATURE: NAME/KEY: Modified-site LOCATION: 11 OTHER INFORMATION: /label= Xaa /note= "Xaa is NH2".
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1 Ala Tyr Val His Asp Ala Pro Val Arg Ser 1 5 r ja i; ~~i -19-
Claims (18)
1. Acompotind of the formula or a~ pharmac-eutically acceptable salt thareof: A) R 3 -N-Y-R, wherein: Y is CO or SO,; R, is alkyl, wherein the alkyl iLs 'ptionally substituted with halo or alkoxy; R 2 i-s H, alkyl, (CH 2 )-alkenyl, araDlyL, heteroaralkyl, carboxyalkyl, cyanoalkyl, aryL or heteroaryl; and R3 is H, alkyl, (CH- 2 )-alkenyl, araikyt, het-eroaralky., aryl. or heteroaryl; O09 00*09 with the proviso that, when Y is CO, is hetaroaralkyl ir A 0:0 0heteroaryl, wherein heteroaryl is not pyridyL. 0990 The comoound according to claim I 41 wherein: Y is Cc; is alky:., substituted with halo; R2 is (CH 2 -alkenyl or aralkyl; and .0099. 009 is heteroaralkyl.
3. The compound according to C352aim 1 wherein: Y is SO,; R, is alkyl, substituted with halo; R2 is (CH 2 )-alkenyl or aralkyli &nit R3 is aralkyl. sRTAt -21.-
4. The compound according to claim I1 selected from a group consisting of: N-Cyartooet~hyI.-N- 4-cdich-orchenzyl)chloromethyl-suloflmidcic, f- (2,4- dichlorobenzyl) -NT- (2-thienyl) ethyl] chloroac-'-:ZLMide, N- 4-dicnlorobenzyl) (2-thienyl) methyl]I chloroacetarti.de. A pharmaceutical composition or:r-sing a compound of the formula according t~o aay o:ne of claims 1-4 and a pharmaceutically acceptablc carrier.-
6. A method for inhibiting interleeukin-l3 protease activity in a amimal in need of such t:ieatment comprising the step of administering to saiut maxnmal an effective interleukin-. inhibitory amount t- za composition comprising a compound of the t~o Tm.iul or a pharmaceutically acceptable salt thereof: 004* S OO~ S Se #5 0 0 0* 0 5 S. *5 OOSe *595 *0 0 5* R 3 -N-Y-R 1 wherein: IL I j I I g; C C. C SO. C Y is CO or S02.; P 3 is alkyl, wherein the alkyl is opt Lonally substituted with halo or alkoxy; D 2 is H, alkyl, (CH,-ley, r.ki heteroaralkyl, carboxyalkyl, cyanoalkyl, axyl or he ;eroaryl; and R3 is H, alkyl, (CH 2 )-alkenyl, ar.LJ.ky.l, heteroaralkyl, aryl or heteroaryl.
7. The method according to clasmi 5 wherein, in said compound: Y CO; is alkyl., wheroin the alkyl optionally substituted with halo or alkoxy; j I, M V -22- is H, alkcyl, (CH 2 .)-alkenyl, arali:/J, heteroaralkyl, carboxyalkyl, cyanoalcyl, aryi or heteroaryl; and RL3 is aralkyl or aryl.
8. The method according to claim 7 wrerein, in said comoound: Rl.is alkyl, substituted with halo; Rz is (CH 2 )-alkenyl or ar~alkyl; and A3 is aralkyl. 9, A method for inhibiting JintC-rLiukil-lP3 protease activity in a mammaal in need of sucri treatment. comprising the step of administering to saird matrimal an effective interleukin-lp inhibitory amount )E a composition comprising a compound according any one of claims 1-4.
10. A method for treating or prevaaring a disease or di"sorder selected frona infectious disease, respiratory disease, inflammixatory condition--s, inmune- based disease, auto-jimmune disease, bone diP eaze, tumors, or leukemia in a mam~mal in need of ach treatment comprising the step of administerinig t~o said mammal a pharmaceutical Composition comprising an effective amount of a compound of the formula (2K) or a pharmaceutically acceptable salt thereof: a.. 0 *000 00 ~a a, 0 0 O 00 a 0a a 0 *040 a 0f a a a ,t t t V I 4~ c 00 Oa a a *a a. 0 0 0 0~00a a Pr R 3 -N-Y-R wharein: Y is CO or S0 2 R, is alkyl, wherein th'-e alkyl is :)ptionally substituted with halo or alkoxy; -23- R 2 is H, alkyl, (CH 2 )-alkenyl, araliz., heteroaralkyl, carboxyalkyl, cyanoalkyl, ary. cr heteroaryl; and R-1 is H, alkyli (CH )-alkenyl, aral.:l, heteroaralkyl, aryl. or heteroaryl.
11. A method for treating or prev.,n1:irng a disease or disorder selected from meningitis, salpingitis, septic shock, arthritis, cholanq.~tis, colitis, encephalitis, endocerolitis, hepati;.1, pancreatitis, reperfus ion inj ury, hyperser-si c ivity, multiple sclerosis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sep is, acute myelogenous leukemia, chronic myelagernous leukemia, osteopcrosis, or ulcerative coliLis in a mammal in need of such treatment comprising the step of administering to said mammal a pharmaceuticedl composition comprising an effLect-*ve amount rf a ow..9 compound of the formula or a pharmaceuticaL.Xy 00. acceptable salt thereof: R 3 -N-y-R 1 wherein: *Y .sCO or SO 2 PI i s alkyl, wherein the alkyl is optionally subctituted with halo or alkoxy; *1R, i s H, alkyl., (CH 2 )-alkenyl, araLKyl, heteroaralkyl, carboxyalkyl, cyanoalkyl, arC or heteroaryl; andL Ij .R 3 is alkyl, (CH. 2 )-alkenyl, acatkyl,r heteroaraikyl, aryl. or heteroaryl.
12. The method according to claina LI, K~RA&wherein the disease or disorder is rheunacold Cr -2 4- arthritis, osteoarthritis, inflammatory bowe. disease, pancreatitis, or -lcerative colitis.
13. The method according to an~y oaB of claims 6 and 10-12, wherein the compound i~s i'Allyl-N- 4-dichlorobenzyl) chioroacetatide, N-Benz jL--N- (2,4- dichlorobenzyl) chloroacetamide, N-Benzy.-N- (3- ch.Lorobenzyl) ch-oroacetanide, N-Senzyl-N- dichlorobeny2-) chicroacetamide, N-Benzyl-N- dichlorobanzvl) chloroacetamide, N-Benzyl-K- (2- chlorobenzyl) chloroacetamide, or N-Benzyl-N-(2,3- dichlorobenzyl chloroacetamide.
14. The method according to any one of claims 5 and 10-12, wherein the compound is [q- Cyranoethyl1-N-(2,4-dichlorobenzy-) methoxyac~r-and~de, N~- a Cyanomethy1-N- 4-dichlorobonz2.) chioromet by2 .*.sulfonamide, N-C yanoethvl 4-dichlorober.zy-) propionamide, or N-Cyanloethyl-N-(2, 4-dichilo2 cbeni~zyi) fluoroacetamide. The mehdacrigto any o-neo clis6ad10-12, weinthe compound is -24 Chlorobenzyl) chioroacetaknide, i- (3- chlorobenzyJ4 chloroacetamide, N- (2,3- dichlorobenzyl) chioroacetanide, N- dichlor,,' -nzyl}chloroacetamide, cor N- (2,4- dichlor:obenzvl) chicroacetamide. *16. The method according to any on of c3.aims 6 and 10-12, wherein the compound Js 11--(2,4- Dichlorobenzy1) -N--C(3-phenyl) propyl) chloro,,ceraide, 4 [(N-Chloroacetyl) 4--dichlorobenzyl) Igl tclna, N- 4-dichlorobenzy.) -N-[(2-thienyl) ethyl] chioroacetamide, 4-dichlorobenzyl) I( thienyl)meth7l: chloroacetamide, or 4- dichJlorcophenyl) -etchyl) chioroacetaraide.
17. A use of a compound of the fo~irmia (A) or a pharmaceutically acceptable salt theri -o: I i R 3 -N-Y-R, wherein: Y is Co or SO 2 R 1 's alkyl, wherein the alkyl is c pt.onally substitated with halo or alkoxy; R? is H, alkyl, (C1 2 )-aJlkenyl, aralkyl, hetroaalklcarboxyalkyl, cvftnoalkyl, acyt or heteroaryl; and 0.S R3 i s H, alkyl, (CH 2 -a-*kenyl aral k, 0he,!eroaralkyl, aryl. or het-eroaryl; in the manufacture of a medicament for inhititing *interleukin-lp protease activity in a namiual J~ aeed of such treatment. *18. The use according to claim 1i whorein, in said compound- 7,Y is CO; is alkyl, wherein the alkyl 15 Dprionally substituted with halo or alkoxy; R 2 i s H, alkyl, (CH 2 )-alkenyl, arai.:yl,F hetaroaralkyl, carboxyalkyl, cyanoalkyl, ar-I o:. heteroaryl; and P.z is aralky. or aryl.
19. The use according to claim wherein, in said compound: j -26- R,1 is alkyl, substit,.ited with halo; R2 L'S alkenyl or aralkyl; arnd R3 is aral.kyl. A Use Of a compound according t~o any one of claims 1-4 in the manufacture of a medicame~nt for inhibiting interleukin-l0 protease activity ni a mammal in need of such treatment.
21. A use of a compound of the fociftula (A) or a pharmaceut-ically acceptable salt thereo~t R 2 R 3 -N.YR wherein: 0V C C t f. Y is CO or S02; R, 1s alkyl, wherein ths alkyl is cqptiu~nally substituted with halo or alkoxcy; R 2 is 1E, alkyl, (CH 2 )-akenyl, aralkyl., heteroaralkyl, carboxyalkyl, cyanoalkyl, aryl :)i heter'oaryl; and R 3 is H, alkyl, (CH 2 )-alkenyj., ritl heteroaralkyll aryl or heteroaryl; in the manufacture of a muedicament for treat Ing or preventing a disease or disorder selected fi om -nfectious disease, respiratory disease, ij lanmiuatorv conditions/ irrmune-based disease, auto-iui~ur~c cbsease, bone disease, tumors, or leukemia in a miuncul.
22. A use of a compound of the E'.rmula (A) or a pharmaceutically acceptable salt thereolf: -27- V I '1 a BO p a a, a 0e R, is alkyl, wherein the alk-yl is opcLonally substituted with halo or alkoxy; R 2 is H, alkyl, (CH 2 )-alkenyl, arali~v3, her-eroaralky-, carboxyalkyl, cyanoalkyJ-, Fryli cr heteroaryJ-; and R3 is al~kyl, -alkenyl, arali:yl, heteroaralkyl, aryl or her-eroaryl; in the manufacture of a mredicament for treat ng or preventing a disease or disorder selected frifm meningizis, salpingitis, septic shock, arthr,.tis, cholangitiz, colitis, encephalitis, endoceroi..t,.Ls, hepatitis, anrtiireperfuzion injury, hypersensitivity, multiple sclerosis, rheuamai:oid arthritis, osteoarthritis, inflarmatory bowei. disease, sepsis, acute myelogenous leukemia, chronic; ayelogenous leukemia, osteoporosis, or ulcerative colitji, a.n a na=ai.
23. The use according to claim 22, wherein the disease or disorder is rheumatoid arthri:L:i, osteoarthritis, inflammatory bowel disease, pancreatitis, or ulcerative colitis.
24. The use according to any one )f claims 17 and 21-23, wherein the compound is N-AllyL-N- (2,4- dichlorobenzyl) chloroacetamide, N-Berizyl.-N-(2,'I- dichlorobenzyl) chioroacetamide, N-Benzy]L-N- (3- chlorobenzyl) chioroacetamide, N-Beflzyl-l- dichlorobenzyl) chloroacetamide, N-Benzyl-N- '4- dichlorobenzyl) chloroacetamide, N-Benzyl-N- (2- chlorobenzy-) chioroacetamide, or X-Bnzyl-i- (2,3- dichlorcbenzy! chloroacetamide. a 4 B~ as a 4@ a I a a. Qa a Ilk, TIM -28- The use according to any one c-f claims 17 and 21-23, wherein the compound is N-Cyan~ etthyl-N- 4-dic-ilorobenzyl) inthoxyacetanide, N-Cyancnethyl-N- 4-dichnlorobenzyl) claloromethyl-sulfonamidp Cyancethyl-N- 4-dichlorobenzyl) prop-Jonaiace, or N- Cyanoethyl-N- 4-dichlorobenzyl) flv.oroacet orricle, 26, The use according to any one c f cl~aims 17 and 21-23, wherein the compound is Dl-(2,4. Dichlcrobenzy)-N-mrethyl chjloroacetauide, Chlorobenzyl) chioroacetamide, N- (3- chlorcobenzyl) chioroacetamide, N- 3- dicl-alorobenzyl) chioroacetamide, W- dichiorobeizyl) chioroacetamide, or N- 4- dichlorobenzyL) chioroacetanide.
27. The use according t-o any onie wclaims 9 Ov W 17 and 21-23, wherein the compound is N- 4 94A Dichlorcboenzyl) 3-pheny.) propyl) chloroa,.:etamide, **:((N-Chlcroacety1) (2 /4-ichlorobenzyl)gy.*rne, N- 4-dichlorobenzyl) (2-thienyl) ethyl] chloroacetamide, N- 4-dichlorobenzyl) thienyl)methyllchloroacetamide, or dic-hlorphenyl) -ethyl] chlo -oacetamide. 0 too
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US23642594A | 1994-04-29 | 1994-04-29 | |
US08/236425 | 1994-04-29 | ||
PCT/US1995/005347 WO1995029672A1 (en) | 1994-04-29 | 1995-04-28 | HALOMETHYL AMIDES AS IL-1β PROTEASE INHIBITORS |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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AU20365/99 Division | 1995-04-28 |
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AU2463495A AU2463495A (en) | 1995-11-29 |
AU705321B2 true AU705321B2 (en) | 1999-05-20 |
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AU24634/95A Ceased AU705321B2 (en) | 1994-04-29 | 1995-04-28 | Halomethyl amides as IL-1beta protease inhibitors |
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EP (1) | EP0758891A4 (en) |
JP (1) | JPH09512556A (en) |
CN (1) | CN1147201A (en) |
AU (1) | AU705321B2 (en) |
CA (1) | CA2189036A1 (en) |
FI (1) | FI964342A (en) |
MX (1) | MX9605196A (en) |
NO (1) | NO964472L (en) |
WO (1) | WO1995029672A1 (en) |
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US6204261B1 (en) | 1995-12-20 | 2001-03-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β Converting enzyme inhibitors |
US5874424A (en) * | 1995-12-20 | 1999-02-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
US6008217A (en) * | 1995-12-20 | 1999-12-28 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
US6420522B1 (en) | 1995-06-05 | 2002-07-16 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
CA2215211A1 (en) * | 1995-03-31 | 1996-10-03 | Takeda Chemical Industries, Ltd. | Cysteine protease inhibitor |
US5843904A (en) * | 1995-12-20 | 1998-12-01 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1βconverting enzyme |
WO1999046248A1 (en) | 1998-03-09 | 1999-09-16 | Vertex Pharmaceuticals Incorporated | 1,2-diazepane derivatives as interleukin-1beta converting enzyme inhibitors |
AP2000001919A0 (en) | 1998-03-19 | 2000-09-30 | Vertex Pharma | Inhibitors of caspases. |
GB9922830D0 (en) | 1999-09-27 | 1999-11-24 | Novartis Ag | Processes |
AU779855B2 (en) * | 2000-01-06 | 2005-02-17 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions as protease inhibitors |
PE20011350A1 (en) | 2000-05-19 | 2002-01-15 | Vertex Pharma | PROPHARMAC OF AN INHIBITOR OF INTERLEUKIN-1ß CONVERTER ENZYME (ICE) |
ES2277142T3 (en) | 2002-08-30 | 2007-07-01 | Japan Tobacco Inc. | DIBENCILAMINE COMPOSITE AND ITS MEDICINAL USE. |
CN100441186C (en) * | 2003-12-03 | 2008-12-10 | 和记黄埔医药企业有限公司 | Medical use of artificial lywrine |
CA2567080A1 (en) | 2004-05-27 | 2005-12-15 | Vertex Pharmaceuticals Incorporated | Ice inhibitors for the treatment of autoinflammatory diseases |
US9956260B1 (en) | 2011-07-22 | 2018-05-01 | The J. David Gladstone Institutes | Treatment of HIV-1 infection and AIDS |
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DE1806291A1 (en) * | 1968-10-31 | 1970-05-14 | Badische Anilin Und & Soda Fab | fungicide |
GB2077713A (en) * | 1980-06-12 | 1981-12-23 | Ciba Geigy Ag | Use of iodoacetamide for the control of harmful organisms |
AU3481184A (en) * | 1983-10-29 | 1985-05-02 | Bayer Aktiengesellschaft | N-substituted-halo acetamides |
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US4195096A (en) * | 1977-01-12 | 1980-03-25 | Gaf Corporation | Carboxylic amides as fungicides to eumycotina in phanerogamia plant life |
DE2946910A1 (en) * | 1979-11-21 | 1981-07-02 | Hoechst Ag, 6230 Frankfurt | FUNGICIDAL SULFONYL, BZW. SULFINYL ACETANILIDE |
US4377587A (en) * | 1980-07-25 | 1983-03-22 | Ciba-Geigy Corporation | Arylamine derivatives and use thereof as microbicides |
JPS5798202A (en) * | 1980-12-09 | 1982-06-18 | Kumiai Chem Ind Co Ltd | Herbicide |
GB2094786B (en) * | 1981-03-04 | 1985-09-11 | Ici Plc | Herbicidal and fungicidal amide derivatives |
US4800211A (en) * | 1986-08-18 | 1989-01-24 | Merck & Co., Inc. | 5-methylthio-3-hydroxybenzo [b]thiophene-2-carboxamide derivatives as cyclooxygenase and lipoxygenase inhibitors |
US4874864A (en) * | 1988-05-24 | 1989-10-17 | Pfizer Inc. | Benzamide protease inhibitors |
US5258407A (en) * | 1991-12-31 | 1993-11-02 | Sterling Winthrop Inc. | 3,4-disubstituted phenols-immunomodulating agents |
-
1995
- 1995-04-28 CN CN95192847A patent/CN1147201A/en active Pending
- 1995-04-28 WO PCT/US1995/005347 patent/WO1995029672A1/en not_active Application Discontinuation
- 1995-04-28 EP EP95918877A patent/EP0758891A4/en not_active Withdrawn
- 1995-04-28 MX MX9605196A patent/MX9605196A/en unknown
- 1995-04-28 CA CA002189036A patent/CA2189036A1/en not_active Abandoned
- 1995-04-28 JP JP7528446A patent/JPH09512556A/en active Pending
- 1995-04-28 AU AU24634/95A patent/AU705321B2/en not_active Ceased
-
1996
- 1996-10-21 NO NO964472A patent/NO964472L/en not_active Application Discontinuation
- 1996-10-28 FI FI964342A patent/FI964342A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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DE1806291A1 (en) * | 1968-10-31 | 1970-05-14 | Badische Anilin Und & Soda Fab | fungicide |
GB2077713A (en) * | 1980-06-12 | 1981-12-23 | Ciba Geigy Ag | Use of iodoacetamide for the control of harmful organisms |
AU3481184A (en) * | 1983-10-29 | 1985-05-02 | Bayer Aktiengesellschaft | N-substituted-halo acetamides |
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NO964472D0 (en) | 1996-10-21 |
FI964342A0 (en) | 1996-10-28 |
NO964472L (en) | 1996-10-21 |
WO1995029672A1 (en) | 1995-11-09 |
CA2189036A1 (en) | 1995-11-09 |
EP0758891A1 (en) | 1997-02-26 |
CN1147201A (en) | 1997-04-09 |
JPH09512556A (en) | 1997-12-16 |
EP0758891A4 (en) | 1997-12-03 |
FI964342A (en) | 1996-10-28 |
AU2463495A (en) | 1995-11-29 |
MX9605196A (en) | 1997-12-31 |
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