Patent Application
20050038065
This invention relates to a new route for the preparation and purification of substituted 1,5-naphthyridine-3-carboxyamides and the pharmaceutically acceptable non-toxic salts thereof. These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive and seizure disorders, and overdose with benzodiazepine drugs and for enhancement of alertness.
The substituted 1,5-naphthyridine-3-carboxyamides that are prepared in accord with the process of the present invention are disclosed in U.S. Pat. No. 6,143,760 and PCT International Publication No. WO99/10347 A1, each of which is incorporated herein by reference in its entirety.
The present invention provides a process of preparing a compound of the following formula
wherein X is hydrogen, halogen, —OR1, C1-C6 alkyl optionally substituted with up to three groups selected independently from halogen and hydroxy, or —NR2R3; phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzofuranyl, benzothienyl, each of which is optionally substituted with up to three groups selected from halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C6 alkylthio, hydroxy, amino, mono or di(C1-C6)alkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy; or a carbocyclic group (“the X carbocyclic group”) containing from 3-7 members, up to two of which members are optionally hetero atoms selected from oxygen and nitrogen, where the X carbocyclic group is optionally substituted with one or more groups selected from halogen, alkoxy, mono- or dialkylamino, sulfonamide, azacycloalkyl, cycloalkylthio, alkylthio, phenylthio, or a heterocyclic group;
R8 is lower alkyl having 1-6 carbon atoms, cycloalkyl having 3-7 carbon atoms, or optionally substituted phenyl;
The compounds which may be prepared by the process of the present invention can be described by general formulas I-III set forth above. In a further embodiment of the process of the present invention, in any of the aforesaid general formulas I-IV, X or Y may be —NR2R3 which is a heterocyclic group such as, for example, piperidine in the case where R2 and R3 together form a C5-alkylene group. Further, R2 and R3 together may represent an alkylene or alkenylene group optionally containing up to two heteroatoms selected from nitrogen and oxygen. The resulting groups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl.
Similarly, the —NR5R6 group in formula I above can also represent a heterocyclic group such as, for example, piperidine in the case where R5 and R6 together form a C5-alkylene group. Further, R5 and R6 together may represent an alkylene or alkenylene group optionally containing up to two heteroatoms selected from nitrogen and oxygen. The resulting groups include imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, and piperidinyl.
Preferred compounds of formulas II and III are those where X represents (C1-C6) alkoxy, more preferably (C1-C3)alkoxy. Particularly preferred compounds of formulas II and III include methoxy or ethoxy as the X group.
For the process of the present invention other preferred compounds of formulas I-III include those where the Y is lower alkyl, e.g., methyl or ethyl, substituted with phenyl, pyridyl, or pyrimidinyl. A more preferred Y group is benzyl optionally substituted with halogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, or mono- or di(C1-C6) alkyl.
Where R2 and R3 in Formulas I-III represent optionally substituted aryl or aryl(C1-C6)alkyl, the aryl group is preferably phenyl, pyridyl, or pyrimidinyl and the alkyl groups are preferably methyl and ethyl. More preferred are benzyl and phenyl. Particularly preferred is benzyl.
Where X is optionally substituted C1-C6 alkyl, the alkyl group is preferably optionally substituted methyl, ethyl, or propyl. More preferred are perhalomethyl and trihaloethyl. Preferred halogens are fluorine. Particularly preferred is 2,2,2-trifluoroethyl.
X in formulas II and III may be an optionally substituted phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl, 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, isoquinolinyl, benzofuranyl, or benzothienyl group, or preferably a 1,2,3,4-tetrahydroisoquinolinyl group.
In addition to the compounds of formula III the process of the present invention encompasses the preparation of compounds of the formula
from compounds of the formula
and
H2N—Y IA
wherein substituent group X and substituent group Y when present either together or separately in any of the aforesaid general formulas IIA or IIIA are defined as follows:
R16 is hydrogen, lower alkyl having 1-6 carbon atoms, or cycloalkyl having 3-7 carbon atoms;
Specific compounds made by the process of the invention include those having pyrimidinyl(C1-C6)alkyl Y groups, wherein Y is more specifically 2- and 4-pyrimidinylmethyl, or having pyridyl(C1-C6)alkyl Y groups, wherein Y is more specifically 2- and 4-pyridylmethyl.
Specific benzyl Y groups are those where R18 is amino or a substituted methyl or ethyl group. More specific R18 substituents are piperazin-1-yl or piperidin-1-yl substituted at the 4-position with a halogenated benzyl group.
Other specific benzyl Y groups are 4-[1-[4-(4-Fluorobenzyl)piperazinyl]methyl]benzyl and 4-[1-[4-(4-Fluorobenzyl)piperidinyl]methyl]benzyl.
Specific “X” groups in formulas IIIA and IIA are various quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl groups, e.g., groups of the formulas:
The following formulae represent specific compounds prepared by the process of the present invention:
wherein Y is defined above.
wherein Z represents halogen and Y is as defined above.
Specific compounds prepared by the process of the present invention are encompassed by the following formula:
wherein A is C1-C6 alkylene;
Other specific compounds of Formula XXIX made in accord with the invention are those wherein A is methylene, Ra is phenyl optionally substituted with methyl or ethyl, and Rb is lower alkyl. Still other specific compounds of Formula XXIX are those wherein A is methylene, Ra is phenyl and Rb is C1-C3 alkyl
wherein A is C1-C6 alkylene;
Specific compounds of Formula XXX made in accord with the invention are those where A is methylene, Ra and Ra are independently phenyl optionally substituted with methyl or ethyl, and Rc is lower alkyl. Other specific compounds of Formula XXX are those where A is methylene, Ra is phenyl substituted in the para position with lower alkyl, Ra is phenyl, and Rc is C1-C3 alkyl.
wherein A is C1-C6 alkylene;
Specific compounds of Formula XXXI made in accord with the invention are those where A is C2-C4 alkylene. Other specific compounds of Formula XXXI are those where A is C2-C4 alkylene, Rd is C1-C3 alkyl, and Rd is C2-C4 alkyl.
wherein A is C1-C6 alkylene;
Specific compounds of Formula XXXII made in accord with the invention are those where A is C1-C3 alkylene. Other specific compounds of Formula XXXII are those where A is C2-C4 alkylene, Rd is C1-C3 alkyl, and Re is C2-C4 alkyl. Yet other specific compounds of Formula XXXII are those where A is C2-C4 alkylene, Rd is C1-C3 alkyl, Re is C2-C4 alkyl, and E is nitrogen and M is methylene, E is oxygen and M is methylene or ethylene, or E and M are both nitrogen. Further specific compounds of Formula XXXII are those where Rf is furanyl, tetrahydrofuranyl, or imidazolyl.
wherein
Ra is phenyl optionally mono-, di-, or trisubstituted with halogen, lower alkyl, lower alkoxy, or mono- or di-C1-C6 alkylamino, or mono- or di-C1-C6 alkylamino lower alkyl.
Other specific compounds of Formula XXXIII are those where A is C1-C3 alkylene, Ra is phenyl optionally substituted with methyl or ethyl, and Rd is C1-C3 alkyl. Still other specific compounds of Formula XXXIII are where A is methylene, Ra is phenyl optionally substituted with methyl or ethyl, and Rd is C3-C6 alkyl. Other specific compounds of Formula XXXIII are those where Ra is phenyl substituted with mono- or di-(C1-C6) alkylamino lower alkyl
wherein
Other specific compounds of Formula XXXIIla are those where Ra″ is imidazolyl and Rd is C1-C3 alkyl. Still other preferred compounds of Formula XXXIIla are where A is methylene, Ra″ is imidazolyl, and Rd is C3-C6 alkyl.
wherein
Specific compounds of Formula XXXIV are those where A is C1-C3 alkylene. Other specific compounds of Formula XXXIV are those where A is C1-C3 alkylene, Rd is C1-C3 alkyl, and Re is C1-C3 alkyl.
wherein
Specific compounds of Formula XXXV are those where A is C1-C3 alkylene, Ra is phenyl optionally substituted with lower alkyl or halogen, and D is nitrogen. Other specific compounds of Formula XXXV are where A is methylene, Ra is phenyl optionally substituted with lower alkyl or halogen, D is nitrogen, and D′ is oxygen.
wherein
Specific compounds of Formula XXXVI are those where A is C1-C3 alkylene, and Ra is phenyl optionally substituted with lower alkyl or halogen. Other specific compounds of Formula XXXVI are where A is methylene, Ra is phenyl optionally substituted with lower alkyl, lower alkoxy or halogen.
wherein
Specific compounds of Formula XXXVII are those where A is C1-C3 alkylene. Other specific compounds of Formula XXXVII are those where A is C1-C3 alkylene, and Rd is C1-C3 alkyl.
wherein A is C1-C6 alkylene; and
Specific compounds of Formula XXXVIIa are those where A is C1-C3 alkylene. Other specific compounds of Formula XXXVIIa are those where A is C1-C3 alkylene, and Rh is C1-C3 alkyl.
wherein A is C1-C6 alkylene;
Specific compounds of Formula XXXX are those where Rl is lower alkoxy and Rm is tetrahydropyranyl.
wherein
Specific compounds of Formula XXXXIV are those where V is nitrogen and X is C1-C6 alkoxy or C1-C6 alkyl optionally substituted with up to three halogen atoms. Other specific compounds of XXXXIV are those where V and V′ are nitrogen; X is C1-C3 alkoxy or C1-C3 alkyl optionally substituted with up to three halogen atoms; A″ is methylene or ethylene; and R20 is halogenated phenyl. A specific R20 group is 4-fluorophenyl. Yet other specific compounds of XXXXIV are those where X is 2,2,2-trifluoroethyl; V and V′ are nitrogen; R20 is halogenated phenyl; and A and A″ are methylene or ethylene.
In certain situations, compounds of Formulas II and III may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds which are encompassed by Formula III, and may be prepared by the process of the present invention include, but are not limited to, the compounds in Table I and their pharmaceutically acceptable acid and base addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH2)n-COOH where n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The process of the present invention also encompasses the acylated prodrugs of the compounds of Formula III. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula III.
By lower alkyl in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
By cycloalkyl in the present invention is meant cycloalkyl groups having 3-7 atoms such as, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
By aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensed rings in which at least one is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
By lower alkoxy in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
By cycloalkoxy in the present invention is meant cycloalkylalkoxy groups having 3-7 carbon atoms where cycloalkyl is defined above.
By halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
By heteroaryl (aromatic heterocycle) in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.
Specific examples of heteroaryl groups are the following:
wherein Q is nitrogen or —CR9;
Where X is a carbocyclic group, such moiety or group includes both aromatic heterocycles (heteroaryl), unsaturated heterocylic ring systems, and saturated heterocyclic ring systems. Examples of such groups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl. Specific X carbocyclic groups are linked to the parent naphthyridine moiety by a nitrogen atom in the X carbocyclic group. Thus, for example, when pyrrolidinyl is the X carbocyclic group, it is specifically a 1-pyrrolidinyl group of the formula:
Where Y is a carbocyclic group, such moiety or group includes both aromatic heterocycles (heteroaryl groups), unsaturated heterocylic ring systems, and saturated heterocyclic ring systems. Examples of such groups are imidazolyl, pyrrolidinyl, morpholinyl, piperazinyl, or piperidinyl. Specific Y carbocyclic groups are linked to the parent naphthyridine carboxamide group by a nitrogen atom in the Y carbocyclic group. Thus, for example, when piperidinyl is the Y carbocyclic group, it is specifically a 1-piperidinyl group of the formula:
By “optionally substituted phenyl” as used herein is meant phenyl groups that are unsubstituted or substituted with up to 3 groups selected independently from halogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, and mono- or di-lower alkylamino.
Representative compounds that may be prepared by the process of the present invention are shown below in Table 1.
The process of the present invention and the preparation of the compounds of the present invention are illustrated in Scheme 1. The preparation of the compound of Formula III from the compound of Formula II is described in Scheme 1 and the discussion that follows, wherein, unless otherwise indicated, X and Y are as defined above.
Overall the synthetic sequence of the scheme involves a single step which is direct reaction of the ester having structure II with primary amine I to form the carboxyamide having structure III.
In Scheme 1 the ester having structure II is treated with a primary amine, preferably an excess of primary amine, and heated to form carboxyamide III directly. Scheme 1 may be carried out without a solvent other than the amine but the use of a solvent, especially a polar solvent, is preferred. Preferred solvents include amide solvents such as dimethylacetamide (DMAc), dimethylformamide (DMF) or N-methylpyrollidone (NMP), or a sulfoxide solvent, such as dimethylsulfoxide (DMSO). Scheme 1 is carried out by heating the ester of formula II from about 90° C. to approximately the reflux temperature of the solvent, preferably to about 150° C., more preferably to about 105° C. to about 1100 C for about 1 hour to about 24 hours, with about 14 hours preferred. The process of Scheme 1 is preferably carried out under an inert atmosphere such as nitrogen or argon although this is not essential. The solution is cooled to about 5° C. to about 35° C., with about 22° C. preferred. The solution is then poured into water and the precipitated solid washed filtered and dried and optionally recrystallized. In a preferred variation, the reaction mixture is filtered and the residue is washed with solvent with the washings added to the filtrate. While maintaining the filtrate below about 35° C. equal quantities of acetone and water are added and the mixture is acidified to about pH 3 with an acid, preferably HCl to form a slurry which is then filtered dried and optionally recrystallized. Other variants on this general procedure will be evident to those skilled in the art.
The present invention is illustrated by the following examples, but it is not limited to the details thereof.
N-benzyl-6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide
A mixture of 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (0.964 g, 4.1 mM) and benzylamine (1.97 g, about 5 equivalents) in 10 mL of DMAc was heated at 150° C. overnight. The clear solution was cooled to room temperature and poured into 50 mL water. The precipitated solid was filtered and dried. HPLC showed about 9% of the title product was present with the remainder unreacted starting material.
N-benzyl-6-ethoxy-4-oxo-1,4-dihydro-1.5-naphthyridine-3-carboxamide—DMSO Solvent
A slurry of 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (10 g, 0.038 M) and 50 ml dimethylsulfoxide (DMSO) were heated to 105°-110° C. Benzylamine (12.5 g, 0.12 M −15.0 g, 0.14 M) was added to the heated slurry. The addition flask was rinsed with 5 ml DMSO which was also added to the slurry. The heated reaction mixture was stirred for 2-6 hours and then cooled to room temperature. The reaction mixture was filtered and the residue rinsed with 5 ml DMSO. Acetone (25 mL) and water 25 mL were added to the filtrate while maintaining it at a temperature below 35° C. The acidity of the mixture was adjusted to pH 3 with 6-8 mL of concentrated HCl. The slurry was diluted with 23 mL water and cooled to about 50 C. The product was collected by filtration and washed with 100 mL water and then dried under vacuum at about 70° C. to give an average of 12 g (97.4% yield) of the title compound.
The product was recrystallized by dissolving the solid in 120 mL acetic acid at temperatures greater than 90° C. and filtering the resultant solution. The filtrate was cooled to about 60° C. and then diluted with 32-50 mL of water having a temperature of approximately 55° C. The filtrate was slowly cooled to about 3° C. The product was collected and washed with 60 mL water and dried under vacuum at about 70° C. to recover an average of 8.35 g (69.6% recovery) for an average overall yield of 67.5%. The product was milled through a 0.05 round hole screen.
N-benzyl-6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxamide—DMF Solvent
A slurry of 6-ethoxy-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid ethyl ester (10 g, 0.038 M) and 50 ml dimethylformamide (DMF) were heated to 1050-1100 C. Benzylamine (17 g, 0.16 M) was added to the heated slurry. The addition flask was rinsed with 5 ml DMSO which was also added to the slurry. The heated reaction mixture was stirred at least 14 hours and then cooled to about 40° C. The reaction mixture was filtered and the residue rinsed with 5 ml DMF. Water (120 mL) was added to the filtrate while maintaining it at a temperature below 45° C. The acidity of the mixture was adjusted to pH 4 with about 15 mL of concentrated HCl. The mixture was cooled to about 5° C. The product was collected by filtration and washed with 40 mL water and then dried under vacuum at about 70° C. to give 8.9 g (72.2% yield) of the title compound.
The product was recrystallized by dissolving the solid in 89 mL acetic acid at temperatures greater than 90° C. and filtering the resultant solution. The filtrate was cooled to about 55° C. and then diluted with 22 mL of water having a temperature of approximately 50° C. The filtrate was slowly cooled to about 3° C. The product was collected by filtration and washed with 53 mL water and dried under vacuum at about 70° C. to recover 6.3 g (70.8% recovery) for an average overall yield of 51%. The product was milled through a 0.05 round hole screen.
| Number | Date | Country | |
|---|---|---|---|
| 60473731 | May 2003 | US |
