Patent Grant
6849621
WO 95/14007 published May 26, 1995 discloses H3 receptor antagonists of the imidazole type.
WO 99/24405 published May 20, 1999 discloses H3 receptor ligands of the imidazole type.
U.S. Pat No. 5,869,479 issued Feb. 9, 1999 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H1 receptor antagonist and at least one histamine H3 receptor antagonist.
In view of the art's interest in compounds which affect H3 receptors, novel compounds that are antagonists of H3 receptors would be a welcome contribution to the art. This invention provides just such a contribution.
The present invention provides novel compounds of structure I.
or a pharmaceutically acceptable salt or solvate thereof, wherein:
(A) R1 is selected from:
(B) X is selected from alkyl (e.g., —(CH2)q— or branched alkyl) or —S(O)2—;
(C) Y represents
(D) M1 and M2 are independently selected from C or N;
(E) Z is selected from: C1-C6 alkyl, —SO2—, —C(O)— or —C(O)NR4—;
(F) R2 is selected from:
(G) R3 is is selected from:
(H) R4 is selected from:
(I) each R4B is independently selected from: H, heteroaryl (e.g., pyridyl), alkyl, alkenyl (e.g., allyl), a group of the formula
arylalkyl (e.g., benzyl), or arylalkyl wherein the aryl moiety is substitued with 1-3 substituents independently selected from: halogen (e.g. —CH2-p-Clphenyl); preferably one R4B is H;
(J) R5 is selected from: hydrogen, C1-C6 alkyl, —C(O)R20 (e.g., —C(O)alkyl, such as —C(O)CH3), —C(O)2R20, —C(O)N(R20)2 (wherein each R20 is the same or different);
(K) each R10A is independently selected from H or C1 to C6 alkyl (e.g., methyl), or each R10A, taken together with the nitrogen atom to which they are bound, forms a 4 to 7 membered heterocycloalkyl ring;
(L) R12 is
(M) R13 is
(N) R20 is selected from hydrogen, alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from: halogen, —CF3, —OCF3, hydroxyl, or methoxy; or when two R20 groups are present, said two R20 groups taken together with the nitrogen to which they are bound form a five or six membered heterocyclic ring;
(O) R22 is selected from: heterocycloalkyl (e.g., morpholinyl or pyrrolidinyl), alkyl or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, —CF3, —OCF3, hydroxyl, or methoxy;
(P) R24 is selected from: hydrogen, alkyl, —SO2R22, or aryl, wherein said aryl group is optionally substituted with 1 to 3 groups independently selected from halogen, —CF3, —OCF3, hydroxyl, or methoxy;
(Q) a is 0 to 2;
(R) b is 0 to 2;
(S) k is 1 to 5;
(T) m is 2 to 5;
(U) n is 1, 2 or 3 with the proviso that when M1 is N, then n is not 1;
(V) p is 1, 2 or 3 with the proviso that when M2 is N, then p is not 1;
(W) q is 1 to 5; and
(X) r is 1, 2, or 3 with the proviso that when r is 2 or 3, then M2 is C and p is 1.
This invention also provides a pharmaceutical composition comprising an effective amount of compound of Formula I, and a pharmaceutically acceptable carrier.
This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, hypotension, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), disturbances of the central nervous system, attention deficit hyperactivity disorder ADHD), hypo and hyperactivity of the central nervous system (for example, agitation and depression), and/or other CNS disorders (such as Alzheimer's, schizophrenia, and migraine) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: allergy-induced airway (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a method of treating: congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I.
This invention further provides a pharmaceutical composition comprising an effective amount of a compound of Formula I, and an effective amount of a H1 receptor antagonist in combination with a pharmaceutically acceptable carrier.
This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, and congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
This invention further provides a method of treating: allergy comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
This invention further provides a method of treating: allergy-induced airway (e.g., upper airway) responses comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
This invention further provides a method of treating: congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a compound of Formula I in combination with an effective amount of an H1 receptor antagonist.
As used herein, the following terms have the following meanings, unless indicated otherwise:
Also, as used herein, “upper airway” usually means the upper respiratory system—i.e., the nose, throat, and associated structures.
Also, as used herein, “effective amount” generally means a therapeutically effective amount.
Lines drawn into the rings indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms.
Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers and geometric) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included.
The compounds of this invention are ligands for the histamine H3 receptor. The compounds of this invention can also be described as antagonists of the H3 receptor, or as H3 antagonists.
The compounds of the invention are basic and form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their corresponding free base forms for purposes of this invention.
The compounds of Formula I can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention.
The compounds of this invention can be combined with an H1 receptor antagonist (i.e., the compounds of this invention can be combined with an H1 receptor antagonist in a pharmaceutical composition, or the compounds of this invention can be administered with H1 receptor antagonist).
Numerous chemical substances are known to have histamine H1 receptor antagonist activity and can therefore be used in the methods of this invention. Many H1 receptor antagonist useful in the methods of this invention can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines. Representative H1 receptor antagonists include, without limitation: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine (also known as SCH-34117), diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine and triprolidine. Other compounds can readily be evaluated to determine activity at H1 receptors by known methods, including specific blockade of the contractile response to histamine of isolated guinea pig ileum. See for example, WO 98/06394 published Feb. 19, 1998.
Those skilled in the art will appreciate that the H1 receptor antagonist is used at its known therapeutically effective dose, or the H1 receptor antagonist is used at its normally prescribed dosage.
Preferably, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.
More preferably, said H1 receptor antagonist is selected from: astemizole, azatadine, azelastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, carebastine, descarboethoxyloratadine, diphenhydramine, doxylamine, ebastine, fexofenadine, loratadine, levocabastine, mizolastine, norastemizole, or terfenadine.
Most preferably, said H1 receptor antagonist is selected from: azatadine, brompheniramine, cetirizine, chlorpheniramine, carebastine, descarboethoxy-loratadine (also known as SCH-34117), diphenhydramine, ebastine, fexofenadine, loratadine, or norastemizole.
Even more preferably, said H1 antagonist is selected from: loratadine, descarboethoxyloratadine, fexofenadine or cetirizine. Still even more preferably, said H1 antagonist is loratadine or descarboethoxyloratadine.
In one preferred embodiment, said H1 receptor antagonist is loratadine.
In another preferred embodiment, said H1 receptor antagonist is descarboethoxyloratadine.
In still another preferred embodiment, said H1 receptor antagonist is fexofenadine.
In yet another preferred embodiment, said H1 receptor antagonist is cetirizine.
Preferably, in the above methods, allergy-induced airway responses are treated.
Also, preferably, in the above methods, allergy is treated.
Also, preferably, in the above methods, nasal congestion is treated.
In the methods of this invention wherein a combination of an H3 antagonist of this invention (compound of Formula I) is administered with a H1 antagonist, the antagonists can be administered simultaneously, consecutively (one after the other within a relatively short period of time), or sequentially (first one and then the other over a period of time). In general, when the antagonists are administered consecutively or sequentially, the H3 antagonist of this invention (compound of Formula I) is administered first.
Compounds of Formula I include compounds of the formula:
wherein R1, X, n, M1, R12, a, Y, M2, R13, b, p, Z and R2 are as defined for Formula I.
Compounds of Formula I also include compounds of the formula:
wherein R1, X, n, M1, R12, a, Y, R13, b, r, Z and R2 are as defined for Formula I.
R1 is preferably selected from:
Preferably, when R1 is a substituted phenyl group, the phenyl group has 1 to 3 substituents and the substituents are independently selected from:
Preferably, when R1 is a substituted isoxazolyl group the isoxazolyl group has 1 or 2 substituents independently selected from:
Examples of R1 groups include but are not limited to:
Preferably X is selected from —CH2— (i.e., q is preferably 1) or —SO2—. More preferably X is —CH2—.
Preferably n is 2.
Preferably M1 is N.
Preferably Y is —C(O)—.
Preferably M2 is C.
Preferably p is 2.
Preferably r is 1.
Preferably Z is a C1 to C6 alkyl group. More preferably Z is
Most preferably Z is —CH2—.
Preferably R2 is a six membered heteroaryl ring or a substituted six membered heteroaryl ring, and more preferably the heteroaryl ring contains one nitrogen atom. Preferably the substituted heteroaryl ring is substituted with one —NR4R5, and more preferably the substituent is —NH2. Most preferably R2 is selected from
Preferably a is 0 and therefore there is no R12 group present.
Preferably b is 0 or 1, more preferably 0. When b is 1 R13 is preferably —OH. More preferably, when b is 1, R13 is —OH bound to the M2 substituent and M2 is C.
Representative compounds of this invention include, but are not limited to: Compounds 18 (Example 1), 25 (Example 2), 26 (Example 3), 31 (Example 4), 33 (Example 5), 37 (Example 6), 41 (Example 7), 45 (Example 8), 49 (Example 9), 51 (Example 10), 52 (Example 11), 57 (Example 12), 58 to 67, 73 to 84, 89 to 157, 159 to 168, 212 to 269, 271 to 272, 276 to 282, 284, 285, 287 to 300, 306, 309 to 319, 321 to 336, 338 to 340, 342 to 349, 351 to 361, 363 to 371, 374 to 377, 380 to 383, 387 to 390, 392 to 406, and 408 to 410.
Preferred compounds are Compounds 93, 276, 306, 317, 331, 332, 333, 336, 366, 343, 366, 367, 374, and 376
More preferred compounds are Compounds 306, 332, 333, 336, 366, 374, and 376.
Structures for the above compounds are given below.
The following processes may be employed to produce compounds of the invention.
Step 1
In Step 1, compound 1, in which Q is a protecting group such as a carbamate, amide, or a substituted benzylic group, is allowed to react with compound 2, in which L is a leaving group such as a halogen atom, in a suitable solvent such as THF, DMSO or DMF in the presence of a base such as a tertiary amine or an inorganic base such as Na2CO3 at a temperature sufficient to achieve a reasonable reaction rate. R12, M1, n, a, R1, and X are as defined above. Alternatively, in the case when X is —(CH2)q—, L can equal an aldehyde group, CHO and X is —(CH2)q-1—. In that case, compounds 1 and 2 are combined in a solvent such as trifluoroethanol in the presence of sieves. A reducing agent, such as NaBH(OAc)3 or NaCNBH3 is added and the reaction stirred at a temperature suitable to complete the reaction.
Step 2
In Step 2, the protecting group Q is removed. When said protecting group is a carbamate such as t-BOC, dilute acid is used. In the case of a benzyl group, catalytic hydrogenation is used.
Step 3
When Y is C═O, amine 4 can be coupled to acid 5 (D is CO2H, M2 is carbon) using a number of methods well known in the art such as DCC or PyBOP. Alternatively, the acid 5 can be activated by conversion to the acid chloride or mixed anhydride and then reacted with the amine 4 to give 6. Suitable protecting groups for 5 include t-Boc or the like. Alternatively, when Y is —CH2— and M2 is carbon, D can be —CH2—L (where L is a halogen) and the reaction can be performed as in Step 1.
Step 4
Compound 6 in which the protecting group is a t-Boc can be deprotected under acidic conditions such as HCl in dioxane or TFA in CH2Cl2 to give the amine 7.
Step 5
The amine 7 can be alkylated by reaction with the electrophile 8. In one case, L represents a carbonyl group and Z is a branched or straight chain alkyl group. Compounds 7 and 8 are combined in a solvent such as CH2Cl2 in the presence of sieves. After a suitable amount of time, a reducing agent such as NaBH(OAc)3 is added to give the product I. Alternatively, when L is a halogen atom such as Cl or Br, and Z is a branched or straight chain alkyl group or —SO2— 7 and 8 are combined in a solvent such as DMF in the presence of a tertiary amine base to give the product I.
An alternative approach to the synthesis of compounds of Formula I is given below.
Step 1
In the same manner as Step 5, compounds 8 and 9 can be converted to 10. In the case when M2 is carbon, D is CO2alkyl and when M2 is nitrogen, D is a protecting group such as the BOC group.
Step 2
Compound 10 (D is CO2alkyl) is saponified in a mixed solvent such as EtOH or MeOH and water, or THF, water, and MeOH using an alkali metal base such as LiOH or NaOH at a temperature of from 50 to 100° C. to give 11.
Compound 11 can be combined with compound 4 as described in Step 3.
Step 3 (D is a Protecting Group)
Compound 10, in which D is a protecting group such as t-Boc and M2 is nitrogen, can be deprotected under acidic conditions such as HCl in dioxane or TFA in CH2Cl2 to give the amine 12.
Step 4
Compound 12 can be coupled with compound 4 using a reagent such as carbonyl diimidazole or the like in a solvent such as THF, ether or the like at a temperature from 0 to 60° C. to give compound I (Y is C═O, M1 and M2 are nitrogen).
Step 5
Compound I (Y is C═O) can be converted to compound I (Y is C═S) by treatment of I with a reagent such as Lawesson's reagent in a solvent such as toluene at a temperature from 20 to 100° C.
Step 1
A solution of an excess of 13 in a solvent such as THF, CH2Cl2 or the like is treated with a reagent such as BOC2O or an acid chloride or anhydride at a temperature of from −20° C. to +30° C. to produce 14A in which PG is a BOC group, or an amide. Alternatively, a solution of an excess of 13 in a solvent such as THF, CH2Cl2 or the like is treated with a substituted or unsubstituted benzyl bromide in the presence of a base such as triethylamine to give 14A in which PG is a substituted benzyl group.
Step 2
In Step 2, compound 14A, in which PG is a protecting group such as a carbamate, amide, or a substituted benzylic group, is allowed to react with compound 2, in which L is a leaving group such as a halogen atom, in a suitable solvent such as THF, DMSO or DMF in the presence of a base such as a tertiary amine or an inorganic base such as Na2CO3 at a temperature sufficient to achieve a reasonable reaction rate to give compound 15A. R12, R13, M1, n, p, a, b, r, R1, and X are as defined for formula I. Alternatively, in the case when X is —(CH2)q—, L can equal an aldehyde group, CHO, and X is —(CH2)q-1—. In that case, compounds 14A and 2 are combined in a solvent such as trifluoroethanol in the presence of sieves and stirred for a suitable time. A reducing agent, such as NaBH(OAc)3 or NaCNBH3 is added and the mixture stirred at a temperature suitable to complete the reaction.
Step 3
Compound 15A in which the protecting group is t-Boc can be deprotected under acidic conditions such as HCl in dioxane or TFA in CH2Cl2 to give the amine 16A. Alternatively, when PG is a benzyl group, it can be removed by catalytic hydrogenation using a catalyst such as Pd/C.
Step 4
The amine 16A can be alkylated by reaction with the electrophile 8. In one case, L represents a carbonyl group and Z is a branched or straight chain alkyl group. Compounds 16A and 8 are combined in a solvent such as CH2Cl2 in the presence of sieves. After a suitable amount of time, a reducing agent such as NaBH(OAc)3 is added to give the product 17A. Alternatively, when L is a halogen atom such as Cl or Br, and Z is a branched or straight chain alkyl group or —SO2— 16A and 8 are combined in a solvent such as DMF in the presence of a tertiary amine base to give the product 17A.
Compounds useful in this invention are exemplified by the following examples which should not be construed as limiting the scope of the disclosure. Alternative mechanistic pathways and analogous structures within the scope of the invention may be apparent to those skilled in the art.
Step 1
Compound 14 (5 g, 43.8 mmol) and 2-bromobenzaldehyde (4.1 g, 22.2 mmol) were combined in CH2Cl2 (130 mL) and stirred for 2 h. Na(OAc)3BH (6.4 g, 30.2 mmol) was added and the mixture stirred overnight at room temperature. The reaction was then washed with saturated NaHCO3 and brine and dried. Filtration and concentration gave a residue which was purified by flash column chromatography (5% to 10% MeOH/NH3 in CH2Cl2) to give 15 (3.44 g, 55%) Mass spectrum=453 (M+H).
Step 2
A solution of 15 (2 g, 7.06 mmol), N-Boc isonipecotic acid (1.47 g, 6.42 mmol) and PyBOP (3.34 g, 6.42 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and diisopropyl ethyl amine (2.49 g, 19.3 mmol) was added. After 1 minute, the cooling bath was removed and the reaction stirred at room temperature for 48 hours. The reaction was washed with saturated NaHCO3, dried (Na2SO4), and concentrated and the residue was purified by flash column chromatography (30% to 50% ethyl acetate in hexane) to give 16 (3 g, 60%).
Step 3
A solution of 16 (3 g, 6.07 mmol) in CH2Cl2 (100 mL) at 0° C. was treated with 4 N HCl (8 mL) and the reaction stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in water and the pH adjusted to 8 by addition of aqueous NaOH. The water was removed in vacuo and the residue dissolved in MeOH, filtered and concentrated to give 17 as a white solid (3 g, >100%) which was used as is. Mass spectrum: 394 (M+H).
Step 4
In a manner similar to that described in Example 1, Step 1, 17 (0.95 g, 2.4 mmol) and pyridine-4-carboxaldehyde (0.22 g, 2.02 mmol) was converted to 18 (0.57 g, 58%). Mass spectrum: 485 (M+H).
Step 1
In a manner similar to that described in Example 1, Step 1, 19 (5 g, 26 mmol) and 2-bromobenzaldehyde (4.1 g, 21.7 mmol) was converted to 20 (6.2 g, 80%).
Step 2
In a manner similar to that described in Example 1, Step 3, 20 (6.2 g, 17.5 mmol) was converted to 21 (5.5 g, 100%).
Step 3
In a manner similar to that described in Example 1, Step 1, 22 (0.45 g, 3.6 mmol) and ethyl isonipecotate (0.7, 4.4 mmol) were converted to 23 (0.45 g, 64%).
Step 4
A solution of 23 (0.45 g, 1.69 mmol) in MeOH (10 mL) was treated with 1 N KOH (5 mL) and the mixture was heated to 60° C. overnight. The reaction was cooled and concentrated. The residue was dissolved in water and extracted with ethyl acetate. The pH of the aqueous phase was adjusted to 6-7 by addition of 1N HCl. The water was removed in vacuo and the residue taken up in MeOH, filtered and concentrated to give 24 which was used in the next step as is.
Step 5
In a manner similar to that described in Example 1, Step 2, 21 (0.35 g, 1.39 mmol) and 24 (0.3 g, 1.26 mmol) was converted to 25 (0.50 g, 66%). Mass spectrum: 475 (M+H).
To a solution of 25 (0.11 g, 0.23 mmol) in 2-propanol (6 mL) in a pressure vessel was added triethylamine (7 mL) and methylamine hydrochloride (3 g, 44.4 mmol) and the reaction heated to 95° C. for 6 days. The reaction was cooled and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with half saturated NaHCO3. The organic layer was dried and concentrated, and the residue purified on a flash column (20% MeOH in ethyl acetate) to give 26 (40 mg, 36%). Mass spectrum: 486 (M+H).
Step 1
In a manner similar to that described in Example 1, Step 1, 27 (2 g, 18.3 mmol) and ethyl isonipecotate (3.5, 22 mmol) were converted to 28 (4.5 g, 99%).
Step 2
A solution of n-BuLi (3 mL of a 1.6 M solution in hexane, 4.8 mmol) in THF (25 mL) was treated at −25° C. with (i-Pr)2NH (0.49 g, 4.8 mmol). The reaction was stirred for 1 h at 0° C. and then cooled to −70° C. Compound 28 (1.0 g, 4 mmol) in THF (3 mL) was added dropwise and the reaction stirred at −70° C. for 2 h and −50° C. for 2 h. The reaction was recooled to −70° C. and (1S)-(+)-(10-camphorsulfonyl)oxaziridine (1.04 g, 4.52 mmol) in THF (10 mL) was added. The reaction was stirred at −70° C. for 2 h and slowly warmed to room temperature overnight. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried and concentrated, and the residue purified by column chromatography (4% MeOH in ethyl acetate) to give 29 (0.75 g, 71%).
Step 3
In a manner similar to that described in Example 2, Step 4, 29 (0.35 g, 1.32 mmol) was converted to 30 (0.32 g, 99%).
Step 4
In a manner similar to that described in Example 1, Step 2, 30 (0.2 g, 0.85 mmol) was converted to 31 (0.10 g, 25%). Mass spectrum: 473 (M+H).
To a solution of 32 (0.52 g, 1.43 mmol; synthesized in the same manner as compound 17) and 3-chloromethyloxadiazole (0.25 g, 2.11 mmol) in toluene (10 mL) was added triethylamine (0.6 mL) and the reaction was heated to 75° C. overnight. The reaction was cooled, diluted with ethyl acetate and washed with saturated NaHCO3. The organic layer was dried and concentrated and the residue purified by flash column chromatography (10% MeOH in ethyl acetate) to give 33 (0.2 g, 31%) Mass spectrum: 448 (M+H).
Step 1
In a manner similar to that described in Example 1, Step 2, compound 34 (1.2 g, 4.93 mmol) was coupled with compound 21 (1.4 g, 5.43 mmol) to give compound 35 (1.7 g, 74%).
Step 2
In a manner similar to that described in Example 1, Step 3, compound 35 (1.7 g, 3.54 mmol) was converted to 36 (1.3 g, 97%).
Step 3
In a manner similar to that described in Example 1, Step 1, compound 36 (0.41 g, 1.08 mmol) was converted to 37 (0.2 g, 45%). Mass Spectrum: 471 (M+H).
Step 1
To a stirred mixture of 38 (2.0 g, 12.5 mmol) and Na2CO3 (1.45 g, 13.7 mmol) in acetone (15 mL) was added chloroacetonitrile (1.05 g, 13.7 mmol) and the reaction mixture stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was dried (Na2SO4) and concentrated to give 37 (2.3 g, 94% ) which was used as is.
Step 2
To a solution of 39 (2.2 g, 11.2 mmol) in toluene (20 mL) was added n-Bu3Sn (5.7 g, 16.8 mmol) and the reaction heated to reflux for 48 h. Additional n-Bu3Sn (0.5 mL) was added and the reaction was stirred at reflux for 6 h and at room temperature for 18 h. The reaction was cooled to room temperature, 5 N NaOH (35 mL) and hexane (35 mL) were added and the reaction was stirred for 2 h. The aqueous phase was separated and neutralized with concentrated HCl. The water was evaporated in vacuo and the residue taken up in MeOH, filtered, and the filtrate concentrated to give 40 (3.6 g) which was used in the next step without further purification.
Step 3
In a manner similar to that described in Example 1, Step 2, compound 40 (0.2 g, 0.95 mmol) was converted to 41 (0.2 g, 47%). Mass spectrum: 448 (M+H).
Step 1
To a solution of 38 (2.57 g, 16 mmol) in THF (30 mL) was added propargyl bromide (1.34 g, 8.98 mmol) and the reaction heated to reflux overnight. After cooling to room temperature, the reaction was diluted with CH2Cl2 and washed with 1 N NaOH. The organic layer was dried and concentrated to give a residue which was purified by flash column chromatography (5% ethyl acetate in hexane) to give 42 (1.31 g, 75%). Mass spectrum: 196 (M+H).
Step 2
To a solution of 42 (0.5 g, 2.56 mmol) in toluene (10 mL) was added trimethylsilyl azide (0.62 g, 5.12 mmol) and the reaction was heated to reflux for 18 h. The reaction was cooled to room temperature, additional trimethylsilyl azide was added (0.7 mL). The reaction was stirred at 50° C. for 8 days and 110° C. for 10 days. The solvent was evaporated in vacuo, MeOH (100 mL) was added, and the MeOH removed in vacuo. The residue so obtained was chromatographed (4% MeOH in ethyl acetate) to give 43 (0.5 g, 82%) Mass spectrum: 239 (M+H).
Step 3
In a manner similar to that described in Example 2, Step 4, Compound 43 (0.5 g, 2.1 mmol) was converted to compound 44 (0.44 g, 100%).
Step 4
In a manner similar to that described in Example 1, Step 2, 44 (0.25 g, 1.2 mmol) and 21 (0.36, 1.4 mmol) were converted to 45 (0.11 g, 20%). Mass spectrum: 447 (M+H).
Step 1
A solution of compound 46 (2 g, 7.5 mmol), 19 (1.6 g, 8.2 mmol) and triethylamine (3.1 mL) in toluene (30 mL) was heated to reflux overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated NaHCO3. The organic layer was dried and concentrated and the residue purified by flash column chromatography (30% ethyl acetate in hexane) to give 47 (1.6 g, 78%).
Step 2
In a manner similar to that described in Example 1, Step 3, 47 (1.6 g, 4.3 mmol) was converted to 48 (1.5 g, 100%).
Step 3
In a manner similar to that described in Example 1, Step 2, 48 (0.38 g, 1.1 mmol) was converted to 49 (0.15 g, 35%). Mass spectrum: 475 (M+H).
To a suspension of 32 (0.5 g, 1.14 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (0.59 g, 4.56 mmol) followed after 10 min by 50 (0.23 g, 1.37 mmol). The mixture was stirred at room temperature for 48 h. The acetonitrile was removed, xylene (10 mL) was added and the reaction refluxed overnight. The reaction was cooled, diluted with ethyl acetate and washed with water. The organic layer was dried and concentrated and chromatographed (10% to 20% MeOH in ethyl acetate) to give 51 (0.13 g, 25%). Mass spectrum: 463 (M+H).
A solution of 25 (0.13 g, 0.27 mmol) in 1:1 5% HCl in DME/water (4 mL) was heated to 60° C. for 6 h. The reaction was cooled to room temperature, saturated NaHCO3 and solid NaCl was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried, concentrated and the residue purified by flash column chromatography (5-10% NH3/MeOH in CH2Cl2) to give 52 (40 mg, 31%). Mass spectrum: 473 (M+).
Step 1
Compound 53 (3.6 g, 29.1 mmol), ethyl isonipecotate (5.8 g, 36.4 mmol) and Ti(OiPr)4 (10.3 g, 36.4 mmol) were combined and stirred at room temperature overnight. CH2Cl2 (100 mL) was added followed by NaBH(OAc)3 (8.6 g, 40.8 mmol) and the reaction stirred overnight. Saturated NaHCO3 was added and the mixture filtered through Celite. The filter cake was washed with additional CH2Cl2, and the combined filtrates were washed with saturated NaHCO3 and dried. Concentration gave a residue which was purified by flash column chromatography (8% MeOH in ethyl acetate) to give 54 (5 g, 83%). Mass spectrum: 277 (M+H).
Step 2
In a manner similar to that described in Example 4, Step 2, 54 (1 g, 3.6 mmol) was converted to 55 (0.4 g, 37%). Mass spectrum: 293 (M+H).
Step 3
In a manner similar to that described in Example 2, Step 4, 55 (0.4 g, 1.4 mmol) was converted to 56 (0.4 g, 100%).
Step 4
In a manner similar to that described in Example 1, Step 2, 56 (0.38 g, 1.6 mmol) was converted to 57 (0.36 g, 47%). Mass spectrum: 505 (M+H).
Using the procedures described in Examples 1-12, the compounds in Table 1 were synthesized:
Step 1
Dissolved amine 68 (25.0 g, 0.134 mol) in CH2Cl2 (500 mL) and added 3 A sieves (25 g), 3-chlorobenzaldehyde (28.3 g, 0.201 mol), and sodium triacetoxyborohydride (42.6 g, 0.201 mol). Stirred at 23° C. for 16 h and filtered. Washed filtrate with saturated NaHCO3 then saturated NaCl. Dried organic extract (MgSO4), filtered, and concentrated. Purified by silica gel chromatography (eluant: 20% EtOAc-hexane) to give 31.0 g (0.100 mol, 74% ) of the product 69 as a yellow oil. MS (ES for M+1): m/e 312.
Step 2
Dissolved compound 69 (27.0 g, 0.087 mol) in CH2Cl2 (500 mL) and added 1.0 N HCl in ether (275 mL, 0.275 mol). Stirred at 23° C. for 96 h. Filtered and washed with ether to give 20.0 g of the dihydrochloride salt of compound 70. Dissolved the dihydrochloride salt in 1 N NaOH (500 mL) and extracted with EtOAc. Dried combined organic extracts (MgSO4), filtered, and concentrated to give 14.9 g (0.071 mol, 82%) of the product 70 as a yellow oil. MS (ES for M+1): m/e 211.
Step 3
Combined compound 70 (13.03 g, 0.062 mol), N-tBOC-isonipecotic acid (21.38 g, 0.093 mol), HOBT (16.28 g, 0.12 mol), and DEC (23.01 g, 0.12 mol) in CH2Cl2 (400 mL). Stirred at 23° C. for 4 h. Added 2 N NaOH and extracted with CH2Cl2. Dried combined organic extracts (MgSO4), filtered, and concentrated. Purified by silica gel chromatography (eluant: CH2Cl2 then 2% MeOH with NH3—CH2Cl2) to give 25.0 g (0.059 mol, 95%) of the product 71 as a yellow oil. MS (ES for M+1): m/e 422.
Step 4
Dissolved compound 71 (20.0 g, 0.048 mol) in CH2Cl2 (250 mL) and cooled to 0° C. Added TFA (50 mL) and stirred at 23° C. for 3 h. Concentrated, added 6.25 N NaOH, and extracted with CH2Cl2. Dried combined organic extracts (MgSO4), filtered, and concentrated. Purified by silica gel chromatography (eluant: CH2Cl2 then 5% MeOH with NH3—CH2Cl2) to give 7.18 g (0.022 mol, 47%) of the product 72 as a yellow oil. MS (ES for M+1): m/e 322.
Step 5
Dissolved compound 72 (255 mg, 0.79 mmol) in CH2Cl2 (10 mL) and cooled to 0° C. Added triethylamine (158 mg, 0.22 mL, 1.56 mmol) and mesyl chloride (115 mg, 0.078 mL, 1.01 mmol). Warmed to 23° C. and stirred for 16 h. Added saturated NaHCO3 and extracted with CH2Cl2. Dried combined organic extracts (MgSO4), filtered, and concentrated. Purified by silica gel chromatography (eluant: CH2Cl2 then 2% MeOH with NH3—CH2Cl2) to give 164 mg (0.41 mmol, 52%) of the product 73 as a white foam. MS (ES for M+1): m/e 400.
Following the above procedure compound 74 was prepared:
(MS(ES) 462 (M+1)).
Dissolved compound 72 (250 mg, 0.78 mmol) and triethylamine (158 mg, 0.22 mL, 1.56 mmol) in CH2Cl2 (10 mL) and cooled to 0° C. Added benzoyl chloride (142 mg, 0.12 mL, 1.01 mmol). Warmed to 23° C. and stirred for 16 h. Added saturated NaHCO3 and extracted with CH2Cl2. Dried combined organic extracts (MgSO4), filtered, and concentrated. Purified by silica gel chromatography (eluant: CH2Cl2 then 3% MeOH with NH3—CH2Cl2) to give 191 mg (0.45 mmol, 58%) of the product 75 as a white foam. MS (ES for M+1): m/e 426.
Following the above procedure compound 76 was prepared:
(MS(ES) 427 (M+1)).
Dissolved compound 72 (250 mg, 0.78 mmol) and triethylamine (158 mg, 0.22 mL, 1.56 mmol) in dry THF (10 mL). Added phenylisocyanate (120 mg, 0.11 mL, 1.0 mmol) and stirred at 23° C. for 16 h. Added water and extracted with EtOAc. Dried combined organic extracts (MgSO4), filtered, and concentrated. Purified by silica gel chromatography (eluant: CH2Cl2 then 3% MeOH with NH3—CH2Cl2) to give 170 mg (0.39 mmol, 50%) of the product 77 as a white foam. MS (ES for M+1): m/e 441.
Following the above procedure compound 78 was prepared:
(MS(ES) 407 (M+1)).
Combined compound 72 (550 mg, 1.71 mmol), benzaldehyde (109 mg, 1.03 mmol), 0.5 g of crushed 3A sieves, and sodium triacetoxyborohydride (347 mg, 1.64 mmol) in 2:1 CH2Cl2:EtOH (15 mL). Stirred at 23° C. for 16 h. Added saturated NaHCO3 and extracted with CH2Cl2. Dried combined organic extracts (MgSO4), filtered, and concentrated. Purified by silica gel chromatography (eluant: CH2Cl2 then 3% MeOH with NH3—CH2Cl2) to give 260 mg (0.63 mmol, 37%) of the product 79 as a white foam. MS (ES for M+1): m/e 412.
Following the above procedure the compounds in Table 2 were prepared.
A solution of the amine 85 (0.063 mmol) and the aldehyde 86 (0.32 mmol, 1.0 M in dichloroethane) is treated with NaBH(OAc)3 (0.32 mmol, 0.5 M in dichloroethane) and placed on shaker for an average period of 18 h. Where needed more NaBH(OAc)3 is added to force the reaction into completion. Amberlyst-15 resin (˜100 mg) is added and the reaction mixture shaken for an additional hour while monitoring by TLC. (10% NH3 saturated methanol in CH2Cl2, Rf˜0.3) to ensure no amine product remained in solution. The resin is filtered and alternately washed six times with MeOH and dichloroethane. The resin is extracted by stirring twice, for 30 min, with 2N NH3/MeOH (2 ml) and rinsing twice with MeOH (2 ml). The combined extracts are concentrated in vacuo to provide the desired product 65.
Using this procedure, the compounds listed in Table 3 were synthesized. In Table 3 X1 represents the moiety:
(i.e., the moiety 88 is compound 87 without the R1CH2-group).
Thus, compounds in Table 3 have the formulas given in Table 4 below.
Library Preparation on Solid Phase
TentaGel amino resin (1 eq.) was placed in a reaction vessel, dichloromethane, FMOC-Lysine (2 eq.) and HOBT (2.2 eq.) were added followed by the addition of DIC (2 eq.). The mixture was shaken at room temperature for 12 hours, then drained and the resin was washed with dichloromethane twice and DMF three times, and treated with 20% piperazine in DMF (v/v) for 30 minutes. The resin was then washed with DMF twice, methanol twice and dichloromethane three times, and dried overnight in vacuo to give amine resin 169.
The amine resin 169 (1 eq.) was placed in a reaction vessel, dichloromethane, 4-bromomethyl-3-nitrobenzoic acid (2 eq.) and HOBT (2.2 eq.) were added followed by the addition of DIC (2 eq.). The mixture was shaken at room temperature for 12 hours, then drained and the resin was washed with dichloromethane twice, methanol twice and dichloromethane three times, and dried overnight in vacuo to give bromoresin 170.
The bromo resin 170 was divided into 24 portions, and each (1 eq.) was treated with an amine (see 172 to 196 below) (5 eq.) in THF. The mixture was shaken at room temperature overnight, drained and the resin was washed with THF twice, DMF twice and dichloromethane three times, and dried overnight in vacuo to give amine resin 171.
The amine resin 171 was divided into 3 portions, and each (1 eq.) was treated with an acid chloride (see 198 to 200 below)(2 eq.) and 2,6-lutidine (4 eq.) in dichloromethane. The mixture was shaken at room temperature for 30 minutes, drained and the resin was washed with dichloromethane twice, methanol twice and dichloromethane three times, and dried overnight in vacuo to give chlororesin 197.
The chlororesin 197 was divided into 7 portions, and each (1 eq.) was treated with an appropriate amine (see 202 to 208 below) (5 eq.) in DMSO. The mixture was shaken at room temperature overnight, drained and the resin was washed with methanol twice, dichloromethane twice, methanol twice and dichloromethane three times, and dried in vacuo to give amine resin 201.
The amine resin 201 was divided into 2 reaction vessels, and each was treated with 2% HOAc in DMF and an appropriate aldehyde (see 210-211 below). The mixture was shaken at room temperature for 30 minutes, and NaBH3CN was added to each reaction vessel. The mixture was shaken for overnight, drained, and the resin was washed with DMF twice, methanol three times and 10% HCl in methanol, and dried in vacuo to give resin 209.
In the above Schemes, R1A represents the substituents on R1, R2A represents R1, R3A represents R12 or R13, and R4A represents R2.
Examples of compounds made by the above library procedure include:
Compound 218 was prepared in solution in large quantity. The following is the procedure for the preparation of 218, which serves as the general protocol for preparation of other analogs.
To a solution of Phenylethyl amine (120 mg, 1 mmole) and triethyl amine (200 mg, 2 mmole) in CH2Cl2 (10 mL) at 0° C. was added 4-(Chloromethyl)benzoyl chloride (230 mg, 1.2 mmole). After 30 min., the reaction mixture was poured into a separational funnel and washed with 1N HCl (10 mL), 1N NaOH (10 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to give compound 273 as colorless oil (260 mg, 95%).
To a refluxed solution of compound 273 (260 mg, 0.95 mmole) in THF (10 mL) was added piperazine (430 mg, 5 mmole). The mixture was under reflux for 1 h and cooled to room temperature. Solvent was removed and the residue was dissolved in EtOAc (20 mL), which was washed with H2O (2×10 mL), 1N NaOH (10 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to give compound 274 as a slightly yellow oil (290 mg, 95%).
To a solution of Boc-isonipecotic acid (230 mg, 1 mmole) in EtOAc (10 mL) at 0° C. was added DCC (206 mg, 1 mmole) followed by the addition of compound 274 (290 mg, 0.9 mmole) in EtOAc (5 mL). The reaction mixture was stirred at room temperature for 8 h, and filtered. The filtrate was concentrated. Flash chromatography of the residue gave compound 275 as a colorless oil (390 mg, 80%)
To a solution of compound 275 (270 mg, 0.5 mmole) in CH2Cl2 (5 mL) was added trifluoroacetic acid (0.5 mL). After 30 min., the mixture was concentrated, and the residue was dissolved in EtOAc (10 mL), which was washed with 1N NaOH (10 mL) and brine (10 mL). The organic layer was separated, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was dissolved in DMF (5 mL). Acetic acid (0.2 mL), 4-pyridinecarboxaldehyde (64 mg, 0.6 mmole) and NaBH3CN (64 mg, 1 mmole) were added to the solution. The reaction mixture was kept at room temperature for 8 h. EtOAc (15 mL) and H2O (10 mL) were added to the mixture, and the mixtures were poured into a separational funnel. The organic layer was washed with H2O (10 mL), 1N NaOH (10 mL) and brine (10 mL), separated and dried over Na2SO4. After filtration, the filtrate was concentrated. Flash chromatography of the residue to give compound 218 as a white foam (132 mg, 50%).
Following the procedure of Examples 1 to 17 the compounds in Table 5 were prepared.
General Procedure for H3-Receptor Binding Assay
The source of the H3 receptors in this experiment was guinea pig brain. The animals weighed 400-600 g. The brain tissue was homogenized with a solution of 50 mM Tris, pH 7.5. The final concentration of tissue in the homogenization buffer was 10% w/v. The homogenates were centrifuged at 1,000×g for 10 min. in order to remove clumps of tissue and debris. The resulting supernatants were then centrifuged at 50,000×g for 20 min. in order to sediment the membranes, which were next washed three times in homogenization buffer (50,000×g for 20 min. each). The membranes were frozen and stored at −70° C. until needed.
All compounds to be tested were dissolved in DMSO and then diluted into the binding buffer (50 mM Tris, pH 7.5) such that the final concentration was 2 μg/ml with 0.1% DMSO. Membranes were then added (400 μg of protein) to the reaction tubes. The reaction was started by the addition of 3 nM [3H]R-α-methyl histamine (8.8 Ci/mmol) or 3 nM [3H]Nα-methyl histamine (80 Ci/mmol) and continued under incubation at 30° C. for 30 min. Bound ligand was separated from unbound ligand by filtration, and the amount of radioactive ligand bound to the membranes was quantitated by liquid scintillation spectrometry. All incubations were performed in duplicate and the standard error was always less than 10%. Compounds that inhibited more than 70% of the specific binding of radioactive ligand to the receptor were serially diluted to determine a Ki (nM).
Compounds 89 to 157, 159 to 168, 276 to 279, 282, 284, 285,287 to 300, 306, 309 to 319, 321 to 336, 338 to 340, 342 to 349, 351 to 361, 363 to 371, 374 to 377, 380 to 383, 387 to 390, 392 to 406, and 408 to 410 had a Ki within the range of about 0.2 to about 600 nM.
Preferred Compounds 93, 276, 306, 317, 328, 331, 332, 333, 336, 343, 366, 367, 374 and 376 had a Ki within the range of about 0.2 to about 35 nM.
More preferred Compounds 306, 332, 333, 336, 366, 374 and 374 had a Ki within the range of about 2 to about 22 nM.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 150 mg, preferably from about 1 mg to about 75 mg, more preferably from about 1 mg to about 50 mg, according to the particular application.
The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 300 mg/day, preferably 1 mg/day to 75 mg/day, in two to four divided doses.
While the present has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.
This Application claims the benefit of U.S. Provisional Application No. 60/275,417 filed Mar. 13, 2001.
| Number | Name | Date | Kind |
|---|---|---|---|
| 5463074 | Shih et al. | Oct 1995 | A |
| 5578616 | Aslanian et al. | Nov 1996 | A |
| 5633250 | Shih | May 1997 | A |
| 5807872 | Shih et al. | Sep 1998 | A |
| 5869479 | Kreutner et al. | Feb 1999 | A |
| 5883096 | Lowe et al. | Mar 1999 | A |
| 5889006 | Lowe et al. | Mar 1999 | A |
| 5990147 | Aslanian | Nov 1999 | A |
| 6034251 | Aslanian et al. | Mar 2000 | A |
| 6100279 | Vaccaro et al. | Aug 2000 | A |
| 6448242 | Ishiwata et al. | Sep 2002 | B1 |
| Number | Date | Country |
|---|---|---|
| 0 407 217 | Jul 1990 | EP |
| WO 9514007 | May 1995 | WO |
| WO 9805292 | Feb 1998 | WO |
| WO 9806394 | Feb 1998 | WO |
| WO 9924405 | May 1999 | WO |
| WO 9942446 | Aug 1999 | WO |
| WO 0000488 | Jan 2000 | WO |
| WO 2000039092 | Jul 2000 | WO |
| WO 02072093 | Sep 2002 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20030109564 A1 | Jun 2003 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60275417 | Mar 2001 | US |
