Guixue YU. (8 Greene Drive, Lawrenceville, NJ, 08548, US)
Rotella, David P. (1360 Fountain Road, Newton, PA, 18940, US)
Macor, John E. (644 Moose Hill Rd, Guilford, CT, 06437, US)
Yingzhi BI. (5 Mershon Lane, Plainsboro, NJ, 08536, US)
Guixue YU. (8 Greene Drive, Lawrenceville, NJ, 08548, US)
Rotella, David P. (1360 Fountain Road, Newton, PA, 18940, US)
Macor, John E. (644 Moose Hill Rd, Guilford, CT, 06437, US)
| 1. | A compound of the formula (I) : or a pharmaceuticallyacceptable salt thereof, wherein: R2, R6, R7 and R8 are independently hydrogen, halogen, alkyl, substituted alkyl, alkoxy, nitro, cyano, aryl, heteroaryl, or heterocyclo ; R3 is (CH2),, Y, wherein z is 0,1,2, or 3; R4 and R5 (i) are independently hydrogen, alkyl, substituted alkyl, cycloalykl, substituted cycloalkyl, aryl, or heteroaryl, with the proviso that R4 and R5 are not both hydrogen; (ii) taken together form a heterocyclo ring; or (iii) one of R4 and R5together with Y forms a heterocyclo ring; Y is (i) independently selected from OR9, CO2R9, CH(CO2R9)2, O(C=O)NR10R11, NR10R11, NR10(C=O)NR11R12, CH[(C=O)NR10R11]2, (C=O) NR10R11, NR10(C=O)R12, S(O)mR9, SO2NR10R11, imidazole, substituted imidazole, triazole, substituted triazole, or cyano, or (ii) together with R4or R5 forms a heterocylo ring; and m is 0,1, or 2 ; Rg is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, or pentafluorophenyl ; and R10, R11, and R12 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, and heteroaryl ; or (ii) taken together, wherein RIO forms a threeto sevenmembered heterocyclo ring with R11 or R12, or R11 forms a threeto sevenmembered heterocyclo ring with R, 2. |
| 2. | A compound of Claim 1 or a pharmaceuticallyacceptable salt thereof, wherein: R2 is hydrogen, halogen, lower alkyl, or heteroaryl ; R4 is hydrogen, lower alkyl, or forms a heterocyclo ring with Y; R5 is substituted alkyl having at least one substitutent that is aryl, cycloalkyl, or heteroaryl ; R6 is hydrogen, halogen, trifluoromethyl, or cyano; R7 is hydrogen or trifluoromethyl ; Ra is hydrogen, lower alkyl, or substituted alkyl having at least one substituent that is (CH2)nNR13,R14, wherein R13 and R14 (i) are independently selected from hydrogen, alkyl, and substituted alkyl, or (ii) taken together form a heterocylco ring; n is 0, 1,2, or 3; Y is (i) OR9, CO2R9, CH(CO2R9)2, OR9NR10R11, NR10R11, (C=O)NR10R11, or NR10(C=O)R12, or (ii) together with R4forms a heterocylo ring; Rg is hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, or pentafluorophenyl ; Rio and R11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, and heteroaryl ; or (ii) taken together wherein R10 and R11 forms a threeto sevenmembered heterocyclo ring; and R12 is aryl, cycloalkyl, or heteroaryl. |
| 3. | A compound of Claim 1 or a pharmaceuticallyacceptable salt thereof, wherein: R2 is hydrogen or chloro ; R4 is hydrogen; R5 is 3chloro4methoxyphenylmethyl ; R6 is cyano; R7is hydrogen; and R8 is hydrogen, alkyl or substituted alkyl. |
| 4. | A compound of Claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R4 is hydrogen or lower alkyl, and R5 is an alkyl substituted with cycloalkyl or aryl. |
| 5. | A compound of Claim 1 or a pharmaceuticallyacceptable salt thereof, in which R5 is a substituted alkyl having a monoor disubstituted aryl group in which at least one of the aryl substituents is selected from halogen and methoxy. |
| 6. | A compound of Claim 5 or a pharmaceuticallyacceptable salt thereof, wherein R5 is 3chloro4methoxyphenylmethyl. |
| 7. | A compound of Claim 1 or a pharmaceuticallyacceptable salt thereof, wherein Y is (i) OR9, CO2R9, CH(CO2R9)2, OR9NR10R11, NR10R11, (C=O) NR10R11, or NR10(C=O)R12, or (ii) together with R4forms a heterocylo ring. |
| 8. | A compound of Claim 1 or a pharmaceuticallyacceptable salt thereof, wherein Y is CO2Rg, and Rg is hydrogen, lower alkyl, alkoxy, or substituted alkyl having at least one substituent that is a heterocyclo group, wherein when said heterocyclo group has the heteroatom N, said heteroatom N is substituted with a group X, selected from alkyl, substituted alkyl, and cycloalkyl. |
| 9. | A compound of Claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R3 is (CH2)zNR10R11, (C=O)NR10R11 or (CH2)zNR9R10R11 ; Rg is alkoxy having from 1 to 4 carbon atoms, said alkoxy having a substituent selected from hydroxy and alkoxy ; and R10 and R11 are (i) independently hydrogen, alkyl, substituted alkyl, cycloalkyl, alkoxy, or heterocyclo, or (ii) together form a heterocylco ring. |
| 10. | The compound of claim 1, wherein z is zero, R3 is ORg, and Rg is hydrogen or lower alkyl. |
| 11. | The compound of claim 1, wherein R6 is cyano. |
| 12. | The compound of claim 1 selected from (i)4[[(3Chloro4methoxyphenyl)methyl]amino]6cyano8ethylN(2 pyridinylmethyl)3quinolinecarboxamide ; 4[[(3Chloro4 methoxyphenyl) methyl] amino]3 (hydroxymethyl)6quinolinecarbonitrile ; 4 [[(3Chloro4methoxyphenyl)methyl]amino[3[[(3R)3hydroxy1 pyrrolidinyl] methyl]6quinolinecarbonitrile ; N [ [4 [ [ (3Chloro4 methoxyphenyl) methyl] amino]6cyano3quinolinyl] methyl] benzamide; N [ [4 [ [ (3Chloro4methoxyphenyl) methyl] amino]6cyano3 quinolinyl] methyl] cyclohexanecarboxamide ; N[[4[[(3Chloro4 methoxyphenyl) methyl] amino]6cyano3quinolinyl] methyl]2 pyridinecarboxamide; 4[[(3Chloro4methoxyphenyl)methyl]amino]8ethyl 3 (propoxymethyl)6quinolinecarbonitrile ; 4[[(3Chloro4 methoxyphenyl) methyl] amino]8ethyl3 (methoxymethyl)6 quinolinecarbonitrile ; 4 [ ( (3Chloro4methoxyphenyl) methyl] amino]8ethyl3 [[(tetrahydro2furanyl)methoxy]methyl]6quinolinecarbonitrile ; 41 [ (3Chloro4methoxyphenyi) methyl] amino]8ethyl3 [ (l methylethoxy) methyl]6quinolinecarbonitrile ; 4[[(3Chloro4 methoxyphenyl) methyl] amino]8ethyl3 (ethoxymethyl)6 quinolinecarbonitrile ; 4[[(3Chloro4methoxyphenyl)methyl]amino]3[(2 ethoxyethoxy) methyl]8ethyl6quinolinecarbonitrile ; 4[[(3Chloro4methoxyphenyl)methyl]amino]8ethyl3[(2 hydroxyethoxy) methyl]6quinolinecarbonitrile ; 4[[(3Chloro4 methoxyphenyl) methyl] amino]8ethyl3 [ (oxiranylmethoxy) methyl]6 quinolinecarbonitrile ; 4[[(3Chloro4methoxyphenyl)methyl]amino]8ethyl3 [[[(2S)1methyl2pyrrolidinyl] methoxy] methyl]6quinolinecarbonitrile ; 4[[(3Chloro4methoxyphenyl)methyl]amino]8ethyl3[[[(2S)1cyclopentyl 2pyrrolidinyl] methoxy] methyl]6quinolinecarbonitrile ; 4[[(3Chloro4 methoxyphenyl) methyl] amino]8ethyl3[[2hydroxy3(1 pyrrolidinyl) propoxy] methyl]6quinolinecarbonitrile ; 4[[(3Chloro4methoxyphenyl)methyl]amino]3[[3(dimethylamino)2 hydroxypropoxy] methyl]8ethyl6quinolinecarbonitrile ; [[4[[(3Chloro4methoxyphenyl)methyl]amino]6cyano8ethyl3 quinolinyl] methyl] propanedioic acid dimethyl ester; 4[[(3Chloro4methoxyphenyl)methyl]amino]6cyanoNethyl3 quinolinepropanamide ; 1[3[4[[(3Chloro4methoxyphenyl)methyl] amino]6 cyano3quinolinyl]loxopropyl]4 (Imethylethyl)piperazine; 1[3[4[[(3Chloro4methoxyphenyl)methyl]amino]6cyano3quinolinyl]1 oxopropyl] piperidine, trifluoroacetate ; or 4[[(3Chloro4 methoxyphenyl) methyl] amino]6cyanoNcyclopentyl3 quinolinepropanamide ; and (ii) a pharmaceuticallyacceptable salt thereof. |
| 13. | A pharmaceutical composition adapted for treating a cGMPassociated condition comprising (a) one or more compounds of the formula (I), or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutical acceptable carrier or diluent, wherein: R2, R6, R, and R8 are independently hydrogen, halogen, alkyl, substituted alkyl, alkoxy, nitro, cyano, aryl, or heteroaryl ; R3 is hydrogen or(CH2) zY, wherein z is 0,1,2, or 3; R4 and R5 (i) are independently hydrogen, alkyl, substituted alkyl, cycloalykl, substituted cycloalkyl, aryl, or heteroaryl, with the proviso that R4 and R5 are not both hydrogen; or (ii) taken together form a heterocyclo ring; or (iii) one of R4 and R5together with Y forms a heterocyclo ring; Y is selected (i) independently from OR9, CO2R9, CH(CO2R9)2, O (C=O) NR10R11, NR10R11, NR10(C=O)NR11R12, CH[(C=O)NR10R11]]2, (C=O) NR10R11, NR10(C=O)R12, S(O)mR9, SO2NR10R11, imidazole, substituted imidazole, triazole, substituted triazole, and cyano, or (ii) together with R4 or R5, forming a heterocylo ring therewith; m is 0, 1, or 2 ; Rg is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, or pentafluorophenyl ; and RIO, RII, and R, 2 (i) are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, and heteroaryl ; or (ii) taken together wherein RIO forms a threeto sevenmembered heterocyclo ring with R11 or R12, or R11 forms a threeto sevenmembered heterocyclo ring with R12. |
| 14. | The pharmaceutical composition of claim 13, wherein: R2 is hydrogen or chloro ; R4 is hydrogen; Rs is 3chloro4methoxyphenylmethyl ; R6 is cyano; R7 is hydrogen; and R8 is hydrogen, alkyl or substituted alkyl. |
| 15. | A method of treating a cGMPassociated condition comprising administering to a mammal in need thereof a therapeuticaleffective amount of one or more compounds of Claim 1. |
| 16. | A method of treating a cGMPassociated condition comprising administering to a mammal in need thereof a therapeuticaleffective amount of a composition according to Claim 13. |
| 17. | A method of treating a cardiovascular disorder comprising administering to a mammal in need thereof a therapeuticaleffective amount of a composition according to Claim 13. |
| 18. | A method of treating sexual dysfunction in a male or female mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a composition according to Claim 13. |
| 19. | A method of treating diabetes comprising diabetes mellitus comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a composition according to Claim 13. |
| 20. | A method of treating gastrointestinal disorders comprising gastric paresis comprising administering to a mammal in need thereof a therapeuticaleffective amount of a composition according to Claim 13. |
Field of the Invention The present invention relates to quinoline compounds, to methods of using such compounds in treating cGMP-associated conditions such as erectile dysfunction, and to pharmaceutical compositions containing such compounds.
Background of the Invention Erectile dysfunction is the inability to obtain and maintain a penile erection sufficient for sexual intercourse or other sexual expression. A number of factors can place an individual at risk for this disorder, for example, trauma, pelvic surgery, hypercholesterolemia, ischemic heart disease, peripheral vascular disease, chronic renal failure, diabetes, the use of certain medicaments including some types of antihypertensive agents, digoxin, or the excessive use of narcotics, alcohol, tobacco, etc. Methods for treating erectile dysfunction include the use of vacuum devices and penile implants, as well as the administration of medicaments such as yohimbine, papaverine and apomorphine. Improved methods for treating this disorder are sought, however, as the aforementioned methods do not provide sufficient efficacy and/or are accompanied by drawbacks or side effects such as erosion, pain, priapism, or gastrointestinal discomfort.
A penile erection is dependent upon the presence of adequate levels of cyclic guanosine 3', 5'-monophosphate (cGMP), especially in corpora cavernosa tissue. Thuss administering an inhibitor of a cGMP phosphodiesterase (cGMP PDE), particularly a selective inhibitor of cGMP
PDE Type 5 (PDE 5), provides a means for achieving and maintaining an erection and therefore, for treating erectile dysfunction. See Trigo-Rocha et al., l'Nitric Oxide and cGMP : Mediators of Pelvic Nerve-Stimulated Erection in Dogs,"Am. J. Physio., Vol. 264 (Feb. 1993); Bowman et al.,"Cyclic GMP Mediates Neurogenic Relaxation in the Bovine Retractor Penis Muscle,"Br. J.
Pharmac., 81, 665-674 (1984); and Rajfer et al.,"Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic, Noncholinergic Neurotransmission,"New England J. Med., 326,2,90-94 (Jan. 1992). Sildenafil, for example, has been described as a PDE 5 inhibitor useful for treating erectile dysfunction. See Drugs of the Future, 22,138-143 (1997).
Recent examples of other compounds claimed as PDE 5 inhibitors include fused pyridazine compounds (WO 96/05176 and US Patent application Serial No. 09/393, 833), anthranilic acid derivatives (US 5,716,993), fused pyridopyridazine compounds (US Patent application Serial No. 09/526, 162), and quinazolinone compounds (US Patent No. 6,087,368).
The present invention provides compounds that are potent and selective inhibitors of cGMP PDE 5. These compounds may be employed in treating erectile dysfunction. In view of their activity, these compounds can also be used in treating other disorders responding to the inhibition of cGMP PDE, such as various cardiovascular disorders.
Summary of the Invention The present invention provides quinoline compounds of the following formula (I) or salts thereof, for use as inhibitors of cGMP PDE, especially Type 5:
wherein: R2, R6, R7 and R8 are independently hydrogen, halogen, alkyl, substituted alkyl, alkoxy, nitro, cyano, aryl, heteroaryl, or heterocyclo ; R3 is-(CH2) zY, wherein z is 0,1,2, or 3; R4 and R5 (i) are independently hydrogen, alkyl, substituted alkyl, cycloalykl, substituted cycloalkyl, aryl, or heteroaryl, with the proviso that R4 and R5 are not both hydrogen; or (ii) taken together form a heterocyclo ring; Y is selected (i) independently from-OR9,-C02Rg,-CH (C02R9) 2, -O(C=O)NR10R11, -NR10R11, -NR10(C=O)NR11R12, -CH[(C=O)NR10R11]2, - (C=O) NR10R11, -NR10(C=O)R12, -S(O)mR9, -SO2NR10R11, imidazole, substituted imidazole, triazole, substituted triazole, or cyano, or (ii) together with one of R4 and R5 to form a heterocylo ring therewith; m is 0,1, or 2; Rg is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, or pentafluorophenyl ; and R10, R11, and R12 (i) are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, and heteroaryl ; or (ii) taken together wherein Reforms a three-to seven-membered heterocyclo ring with R11 or R12, or R11 forms a three-to seven-membered heterocyclo ring with R12.
The invention further provides pharmaceutical compositions adapted for use in treating cGMP-associated conditions comprising a pharmaceutically acceptable diluent or carrier and at least one compound of the formula (I) or salt thereof, wherein R2 and R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as defined above and R3is selected from hydrogen and-(CH2) zY, with the proviso that at least one of R2, R3, R6, R7, and Rugis not hydrogen. The invention further provides methods for treating cGMP-associated conditions comprising administering to a mammal in need of such treatment a therapeutically-effective amount of one or more compounds of the formula (I) or salt thereof, wherein R2 and R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as defined above and R3 is selected from hydrogen and-(CH2) zY, with the proviso that at least one of R2, R3, R6, R7, and R8 is not hydrogen.
Detailed Description of the Invention The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.
The term"alkyl"refers to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. Lower alkyl groups, that is, alkyl groups of 1 to 4 carbon atoms, are most preferred.
The term"substituted alkyl"refers to an alkyl group as defined above having one, two or three substituents selected from the group consisting of halo, amino, cyano, hydroxy, alkoxy, alkylthio,-NH (alkyl),-NH (cycloalkyl),- N (alkyl) 2,-C (=O) H,-CO2H,-CO2-alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, or heterocycle. The term"substituted alkyl"also includes an alkyl group as defined above substituted with N (substituted alkyl) or N (substituted alkyl) 2, or in other words, the groups (CH2) nNHR'and (CH2) nNR'R", wherein each of R'and R"comprises a substituted alkyl or R'and R"together form a heterocyclo ring.
The term"alkoxy"refers to an alkyl group as defined above bonded through an oxygen (-O-). The term"alkylthio"refers to an alkyl group as defined above bonded through a sulfur (-S-).
The term"cycloalkyl"refers to fully saturated and partially unsaturated hydrocarbon rings of 3 to 9, preferably 3 to 7, carbon atoms as well as such rings having a fused aryl ring such as indan.
The term"substituted cycloalkyl"refers to such rings having one, two or three substituents, preferably one, selected from the group consisting of alkyl, substituted alkyl, alkoxy, alkylthio, halo, hydroxy, cyano, amino,- NH (alkyl),-NH (cycloalkyl),-N (alkyl) 2,-CO2H,-CO2-lower alkyl, aryl, heterocyclo, heteroaryl, keto, =N-OH, =N-O-lower alkyl, and a five or six membered ketal, i. e. 1,3-dioxolane or 1,3-dioxane.
The term"halo"refers to chloro, bromo, fluoro and iodo.
The term"aryl"refers to phenyl, 1-naphthyl and 2-naphthyl, with phenyl being preferred. The term"aryl"includes such rings having from zero, one, two or three substituents, selected from the group consisting of alkyl, substituted alkyl, alkoxy, alkylthio, halo, hydroxy, nitro, cyano, amino,- NH (alkyl),-NH (cycloalkyl),-N (alkyl) 2,-CO2H,- (C=O) alkyl,-CO2-alkyl, cycloalkyl, substituted cycloalkyl,- (C=O) NH2,- (C=O) NH (alkyl),- (C=O) NH (cycloalkyl),- (C=O) N (alkyl) 2,-NH-CH2-CO2H,-NH-CH2-CO2-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, heterocyclo, and heteroaryl.
The term"heterocyclo"refers to substituted and unsubstituted non- aromatic 3 to 7 membered monocyclic groups, 7 to 11 membered bicyclic groups, and 10 to 15 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heterocyclo group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. The heterocyclo group may be attached at any available nitrogen or carbon atom. The heterocyclo ring may contain one, two or three substituents selected from the group consisting of hala, amino, cyano, alkyl, substituted alkyl,-NH (alkyl),-NH (cycloalkyl),-N (alkyl) 2, alkoxy, alkylthio, hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,-CO2H, -CO2-alkyl, cycloalkyl, substituted cycloalkyl,- (C=O) NH2,- (C=O) NH (alkyl),- (C=O) NH (cycloalkyl),- (C=O) N (alkyl) 2,-NH-CH-CO2H,-NH-CH2-CO2-alkyl, heterocyclo, heteroaryl, keto, =N-OH, =N-O-lower alkyl, and a five or six membered ketal, i. e., 1,3-dioxolane or 1,3-dioxane.
Exemplary monocyclic groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl,
tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, <BR> <BR> <BR> 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like.
Exemplary bicyclic heterocyclo groups include quinuclidinyl.
The term"heteroaryl"refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. The heteroaryl ring system may contain one, two or three substituents selected from the group consisting of halo, amino, cyano, alkyl, substituted alkyl,-NH (alkyl),- NH (cycloalkyl),-N (alkyl) 2, alkoxy, alkylthio, hydroxy, nitro, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio,-CO2H,-CO2-alkyl, cycloalkyl, substituted cycloalkyl,- (C=O) NH2,- (C=O) NH (alkyl),- (C=O) NH (cycloalkyl),- (C=O) N (alkyl) 2,-NH-CH2-CO2H,-NH-CH2-CO2-alkyl, heterocylco, and heteroaryl.
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term"substituted imidazole"refers to an imidazole, an aryl-fused imidazole such as benzimidazole, or a heteroaryl-fused imidazole such as a pyridoimidazole which contain one or two substituents selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, alkylthio, halo, hydroxy, nitro, cyano, amino,-NH (alkyl),-NH (cycloalkyl),-N (alkyl) 2,-CO2H,- CO2-alkyl, cycloalkyl, substituted cycloalkyl,- (C=O) NH2,- (C=O) NH (alkyl),- (C=O) NH (cycloalkyl),- (C=O) N (alkyl) 2,-NH-CH2-CO2H,-NH-CH2-CO2-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, heterocyclo, and heteroaryl.
The term"substituted triazole"refers to a triazole having at least one substituent selected from the group consisting of alkyl, substituted alkyl, alkoxy, alkylthio, halo, hydroxy, nitro, cyano, amino,-NH (alkyl),- NH (cycloalkyl),-N (alkyl) 2,-CO2H,-C02-alkyl, cycloalkyl, substituted cycloalkyl, - (C=O) NH2,- (C=O) NH (alkyl),- (C=O) NH (cycloalkyl),- (C=O) N (alkyl) 2,-NH- CH2-CO2H,-NH-CH2-CO2-alkyl, phenyl, benzyl, phenylethyl, phenyloxy, phenylthio, heterocyclo, and heteroaryl.
Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.
The compounds of formula I form salts which are also within the scope of this invention. Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
The term"salt (s)", as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, when a
compound of formula 1 contains both a basic moiety, such as, but not limited to an amine or a pyridine or imidazole ring, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term"salt (s)" as used herein. Pharmaceutical acceptable (i. e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e. g., in isolation or purification steps which may be employed during preparation. Salts of the compounds of the formula I may be formed, for example, by reacting a compound of the formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
The compounds of formula I which contain a basic moiety, such as, but not limited to an amine or a pyridine or imidazole ring, may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.
The compounds of formula I which contain an acidic moiety, such as, but not limited to a carboxylic acid, may form salts with a variety of organic
and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines [formed with N, N-bis (dehydro-abietyl) ethylenediamine], N- methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e. g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e. g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e. g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e. g., benzyl and phenethyl bromides), and others.
Prodrugs and solvates of the compounds of this invention are also contemplated herein. The term"prodrug", as employed herein, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula 1, and/or a salt and/or solvate thereof. Solvates of the compounds of formula I are preferably hydrates.
Compounds of the formula 1, and salts thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
All stereoisomers of the present compounds, such as those, for example, which may exist due to asymmetric carbons on the R2 to R12 substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons) and diastereomeric forms, are contemplated and within the scope of this invention. Individual stereoisomers of the compounds of this invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
Methods of Preparation The compounds of the present invention may be prepared by methods such as those illustrated in the following Schemes I to X. Starting materials are commercially available or can be readily prepared by one of ordinary skill in the art using known methods. For all of the schemes and compounds, the groups R2, R3, R4, R5, R6, R7, and R8 are as described above for a compound of formula 1, unless otherwise indicated.
Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. For example, in these schemes exemplary hydroxide sources may include sodium hydroxide or lithium hydroxide; an exemplary reducing reagent and inert solvent (for reducing a carboxylic acid or ester group to an alcohol) includes lithium tri-t- butoxyaluminohydride and tetrahydrofuran (THF); exemplary dehydrating/ chlorinating agents include POCI3, PC15, SOCl2 or oxalyl chloride ; exemplary leaving groups (LG) include triflate, mesylate, tosylate, or halide ; and exemplary reagents (for converting a hydroxyl group to a leaving group) include trifluoromethanesulfonyl chloride, toluenesulfonyl chloride, methanesulfonyl chloride, phosphorus oxychloride, thionyl chloride, and phosphorus pentachloride. Exemplary solvents, as appropriate, may be selected from 1,2-dichlorobenzene, methylene chloride, dimethylformamide (DMF), alcohols, ethers, including diphenyl ether, tetrahydrofuran and dioxane, N, N-dimethylformamide, and acetonitrile, water, mixtures of ethers and water, and the like.
High Speed Analoging (HSA) may be employed in the preparation of compounds.
SCHEME)
Id (R3 = -CH2OH) Ib (R3 = -CO2H) Ia (R3 = -H) Compounds of formula la wherein R3 is hydrogen can be prepared via the decarboxylation of a compound of formula lb in an appropriate degassed inert solvent (e. g., 1,2-dichlorobenzene and diphenyl ether) at elevated temperature.
Compounds of formula lb wherein R3 is-COsH can be prepared by the hydrolysis of compounds of formula Ic using a hydroxide source and appropriate solvent (e. g., water, alcohols, and mixtures of ethers and water).
Compounds of formula Id wherein R3 is-CH2OH can be prepared by reducing a compound of formula Ib or Ic with an appropriate reducing reagent in an inert (reaction) solvent.
Compounds of formula Ic wherein R3 is-CO2Rg can be prepared by reacting compounds of formula 11 with an amine of the formula NHR4R5. The reaction may be performed in a solvent as appropriate, such as an alcohol, in
the presence of an appropriate base, such as triethylamine, and typically under elevated temperatures.
Compounds of formula 11 can be prepared by reacting compounds of formula III with an appropriate dehydrating/chlorinating agent, typically under elevated temperatures.
Compounds of formula III can be prepared from compounds of formula IV via an intramolecular cyclization typically under elevated temperatures in an inert solvent, as appropriate, or in neat form.
Compounds of formula IV can be prepared by combining compounds of formula V and VI either neat or in an inert solvent as appropriate, typically under elevated temperatures.
Compounds of formula V and formula VI are either commercially available or available via methods known to one skilled in the art.
SCHEME)) le (R2 =-halogen If (R2 =-halogen Ig (R2 =-halogen R3=-CH20H) R3 =-C02H) R3 =-C02Rg) Compounds of formula le wherein R2 is halogen and R3 is-CH2OH can be prepared by reducing a compound of formula If or Ig with an appropriate reducing reagent in an inert (reaction) solvent.
Compounds of formula If wherein R2 is halogen and R3 is-CO2H can be prepared by the hydrolysis of compounds of formula Ig using a hydroxide source in appropriate solvent.
Compounds of formula Ig wherein R2 is halogen and R3 is-CO2Rg (R9 is other than hydrogen) can be prepared by reacting compounds of formula Vil with an amine of the formula NHR4R5 (as in Scheme I for formula Ic).
Compounds of formula Vil can be prepared by reacting compounds of formula Vlil with an appropriate dehydrating/chlorinating agent typically under elevated temperatures.
Compounds of formula VIII can be prepared from compounds of formula IX by a condensation with a malonate derivative using base in an appropriate solvent. Sodium alkoxide are exemplary bases and alcohols exemplary solvents.
Compounds of formula IX are either commercially available or available via methods known to one skilled in the art.
SCHEME t !)
Compounds of formula Ih wherein R3 is- (CH2) 2OH can be prepared by reducing a compound of formula li with an appropriate reducing reagent in an inert solvent.
Compounds of formula li wherein R3 is-CH2CO2H can be prepared by the hydrolysis of compounds of formula Ij using a hydroxide source in appropriate solvent.
Compounds of formula Ij wherein R3 is-CH2CN can be prepared via the displacement of the leaving group (LG) from a compound of formula X using an appropriate nucleophile in an inert solvent (e. g., methylene chloride).
Nucleophiles may include cyanides from HCN, KCN, or NaCN, or tetrabutylammonium cyanide.
Compounds of formula X can be prepared via reaction of compounds of formula Id or le with an appropriate reagent which converts the hydroxyl group to a leaving group (LG) in an inert solvent (e. g., methylene chloride).
Compounds of formula Id or le wherein R3 is-CH2OH, can be prepared by the methods described above in Schemes I and li.
Compounds of formula Ik wherein R3 is- (CH2) 30H can be prepared by reducing a compound of formula 11 with an appropriate reducing reagent in an inert solvent. Compounds of formula 11 can be prepared by decarboxylation of compounds of formula XI at elevated temperature in an inert solvent (e. g., DMF).
Compounds of formula XI can be prepared by the hydrolysis of compounds of formula Im using a hydroxide source and an appropriate solvent.
Compounds of formula Im wherein R3 is-CH2CH can be prepared via the displacement of the leaving group (LG) from a compound of formula X using an appropriate nucleophile (e. g., alkyl malonate) in an inert solvent (e. g., methylene chloride).
SCHEME IV
Compounds of formula In wherein R3 is-(CH2) zY can be prepared via the displacement of the leaving group (LG) from a compound of formula XI using an appropriate nucleophile in an inert solvent. Exemplary nucleophiles include alcohols of the formula HORg, amines of the formula HNR10R11, mercaptans of the formula HSR9, cyanides as in Scheme 111, imidazole, substituted imidazoles, triazole, and substituted triazoles.
Compounds of formula XII can be prepared via reaction of compounds of formulas Id, le, Ih, Ik with an appropriate reagent which converts the hydroxyl group to a leaving group (LG) in an appropriate inert solvent.
Compounds of formulas Id (z=1), le (z=1), Ih (z=2), Ik (z=3) can be prepared using the methods described above in Schemes, I, II or III.
SCHEME V
Compounds of formula lo wherein R3 is- (CH2) z (C=O) NR, oR" can be prepared via the aminolysis of an active ester (AE) of formula XIII using an amine of the formula NHR10R, 1 in an inert solvent (e. g., ethers, described above, and methylene chloride).
Compounds of formula Ip wherein R3 is- (CH2) ZC02R9 can be prepared via the esterification of a compound of formula XIII using an alcohol of the formula HORg, with the alcohol used as solvent or in an inert solvent such as ethers, described above, or methylene chloride.
Compounds of formula XIII can be prepared via the activation of the carboxylic acid in compounds of formula Iq using an appropriate carboxylic acid activating agent in an appropriate solvent. Exemplary activating agents include carbonyldiimidazofe or dicyclohexyl carbodiimide and pentafluorophenol.
Compounds of formula Iq wherein R3 is -(CH2)zCO2H can be prepared with the methods described in Schemes III and IV.
SCHEME VI Compounds of formula Ir wherein R3 is -(CH2)zSO2NR10R11 can be prepared via the aminolysis of a sulfonyl chloride of formula XIV using an
amine of the formula NHR., oRn in an inert solvent (e. g., ethers or methylene chloride).
Compounds of formula XIV can be prepared by reacting compounds of formula Is with an appropriate dehydrating/chlorinating agent typically under elevated temperatures.
Compounds of formula Is wherein R3 is-(CH2) zSO2OH can be prepared by oxidation of compounds of formula It.
Compounds of formula It wherein R3 is-(CH2) zSH can be prepared by the methods described above in Scheme IV.
SCHEMEVII Compounds of formula lu wherein R3 is -(CH2)zNR10(C=O)OR11 can be prepared by reacting compounds of formula Iv with a chloroformate in an inert solvent.
Compounds of formula Iw wherein R3 is -(CH2)zNR10(C=O)NR11R12 can be prepared by reacting compounds of formula Ix with an alkylating agent under basic conditions in an inert solvent.
Compounds of formula Ix wherein R3 is -(CH2z)NR10(C=O)NHR11 can be prepared by reacting compounds of formula Iv with an isocynate in an inert solvent.
Compounds of formula Iv can be prepared with the methods described above in Scheme IV.
SCHEME VIII Compounds of formula ly wherein R3 and R5 form a heterocyclo carboxamide ring can be prepared from compounds of formula Iz by hydrolysis and decarboxylation.
Compounds of formula Iz wherein R3 and R5 form a 2-carboxylate heterocyclo carboxamide ring can be prepared from compounds of formula laa by a base effected cyclization.
Compounds of formula laa wherein R3 is -CH2CH(CO2R9)2 and R5 is hydrogen can be prepared with the methods described in Scheme Ill.
SCHEME IX
lab Compounds of formula lab wherein R3 is -(CH2)z OR9(OR10)NR11R12 can be prepared from compounds of formula lac by a base-effected alkylation.
Compounds of formula lac wherein R3 is-(CH2) z ORg (OH) NR11R1 can be prepared from compounds of formula lab by an aminolysis of the epoxide.
Compounds of formula lad wherein R3 is -(CH2)z OR9NR10R11 can be prepared by the method described in Scheme IV.
SCHEME X
Compounds of formula la wherein R3 is hydrogen can also be prepared from compounds of formula XV by a base-effected alkylation.
Compounds of formula XV can be prepared from compounds of formula XVI by a Curtius rearrangement.
Compounds of formula XVI can be prepared by reacting compounds of formula XVII with an appropriate methyl ketone.
Compounds of formula XVII are either commercially available or available via methods known to one skilled in the art.
Preferred Compounds Preferred compounds of this invention are those of formula (I) and/or pharmaceutical acceptable salts thereof having the following definitions: wherein, R2, R6, and R7 are independently hydrogen, halogen, alkyl, substituted alkyl, nitro, cyano, aryl, or heteroaryl ; Rg is hydrogen, alkyl, or substituted alkyl, including-(CH2) nNR13, R/14, wherein R13 and R14 (i) are independently selected from hydrogen, alkyl, or substituted alkyl, or (ii) taken together form a heterocylco ring; R3 is-(CH2) zY ; R4 is hydrogen, lower alkyl, or forms a heterocyclo ring with Y or R3 ; R5 is substituted alkyl ; R6 is hydrogen, halogen, trifluoromethyl, nitro, cyano, or aryl ; Y is (i) independently selected from-OR9,-CO2R9,-CH (C02R9) 2, -O(C=O) NR10R11, -NR10R11, -NR10(C=O)NR11R12, -CH[(C=O)NR10R11]2, - (C=O) NR10R11, -NR10(C=O)R12, -S(O)mR9, -SO2NR10R11, imidazole,
substituted imidazole, triazole, substituted triazole, or cyano, or (ii) taken together with R4 or R5, forming a heterocylo ring therewith; m is 0,1, or 2; n is 0,1,2, or 3; z is 0, 1,2, or 3 ; Rg is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, or pentafluorophenyl ; and Rio, Roll, and R, 2 (i) are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, or heteroaryl ; or (ii) taken together wherein R10 with R11 or R12forms a three-to seven-membered heterocyclo ring, or R10 with R12 forms a three-to seven-membered heterocyclo ring.
More preferred are the compounds of formula (I), above, and/or pharmaceutically acceptable salts thereof, wherein R2 is hydrogen, halogen, lower alkyl, or pyridine; R3 is-(CH2) zY ; R4 is hydrogen, methyl, or forms a heterocyclo ring with Y or R3 ; R5 is substituted alkyl, wherein said substituted alkyl comprises an aryl, cycloalkyl, or heteroaryl substituent; R6 is hydrogen, halogen, trifluoromethyl, or cyano; R7 is hydrogen or trifluoromethyl ; Rg is hydrogen, alkyl, substituted alkyl, or-(CH2) nNR13, R14, wherein R13and R14 (i) are independently selected from hydrogen, alkyl, or substituted alkyl, or (ii) together form a heterocylco ring; Y is (i) -OR9, -CO2R9, -CH(CO2R9)2, -OR9NR10R11, -NR10R11, -(C=O)NR10R11, -NR10(C=O)R12, or (ii) together with R4forms a heterocylo ring; n is 0, 1,2, or 3 ; z is 0,1,2, or 3 ;
Rg is hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, or pentafluorophenyl ; Rio and R11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, or heteroaryl ; or (ii) taken together wherein RIO and R11 forms a three-to seven-membered heterocyclo ring; and R12 is aryl, cycloalkyl, or heteroaryl.
Advantageously, R5 comprises cycloalkyl or an alkyl substituted with aryl. When R5 is an alkyl substituted with an aryl, advantageously the aryl has one to two substituents wherein at least one of the substituents is selected from halogen (e. g., chloro, bromo, fluoro), alkoxy (e. g., methoxy), or a lower alkyl. Advantageously, when Rg comprises a heterocyclo ring with a nitrogen heteroatom, said nitrogen heteroatom has a substituent X, selected from lower alkyl, substituted alkyl, and cycloalkyl When R4 and R3 (or Y) form a heterocyclo ring, said ring advantageously is unsubstituted or has at least one substituent X2 comprising CO2(alkyl).
Most preferred are the compounds of formula (I) and/or pharmaceutically acceptable salts thereof, wherein : R2 is hydrogen or chloro ; R3 is-(CH2) zY, wherein z is 0,1,2, or 3; R4 ishydrogen; R5 is 3-chloro-4-methoxyphenylmethyl ; R6 is cyano; R7 is hydrogen; Ra is hydrogen, alkyl, or substituted alkyl ; Y is -OR9, -NR10R11, -CO2R9, or -(C=O)NR10R11 ; Rg is hydrogen, alkyl, or substituted alkyl ; and
R10 and R11 (i) are each independently hydrogen, alkyl, substituted alkyl, aryl, heterocyclo, or heteroaryl ; or (ii) together form a five-to seven- membered heterocyclo ring.
Preferred Pharmaceutical Compositions for Treating cGMP-Associated Conditions Preferred pharmaceutical compositions of this invention are those compositions adapted for use in treating cGMP-associated conditions comprising a pharmaceutical acceptable diluent or carrier and at least one compound of the formula (I) and/or pharmaceutically acceptable salts thereof: wherein, R2, R6, and R7 are independently hydrogen, halogen, alkyl, substituted alkyl, nitro, cyano, aryl, or heteroaryl ; R8 is hydrogen, alkyl, substituted alkyl, or-(CH2) nNR13, R14, wherein R13and R14 (i) are independently selected from hydrogen, alkyl, or substituted alkyl, or (ii) taken together form a heterocylco ring ; R3 is hydrogen or-(CH2) zY ; R4 is hydrogen, lower alkyl, or forms a heterocyclo ring with Y or R3 ; R5 is substituted alkyl ; R6 is hydrogen, halogen, trifluoromethyl, nitro, cyano or aryl ; Y is selected (i) independently from-ORg,-CO2R9,-CH (C02R9) 2,-O (C=O) NR10R11, -NR10R11, -NR10(C=O)NR11R12, -CH[(C=O)NR10R11]2, - (C=O)NR10R11, -NR10(C=O)R12, -S(O)mR9, -SO2NR10R11, imidazole, substituted imidazole, triazole, substituted triazole, or cyano, or (ii) together with R4 or R5, forming a heterocylo ring therewith ;
mis 0,1, or 2 ; n is 0, 1,2, or 3 ; z is 0,1,2, or 3; Rg is hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, cycloalkyl, substituted cycloalkyl, heterocyclo, aryl, heteroaryl, or pentafluorophenyl ; and R10, R11, and R, 2 (i) are independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, or heteroaryl ; or (ii) taken together wherein R10 with R11 or R12forms a three-to seven-membered heterocyclo ring, or R10with R12 forms a three-to seven-membered heterocyclo ring.
In the pharmaceutical compositions wherein R3 of formula (I) is hydrogen, it is preferred that R6 is cyano. In an alternative embodiment where R3 is hydrogen, R2 advantageously is selected from heteroaryl including pyridine. Advantageously, when Rugis hydrogen, R2 does not include hydrogen, chlorine, or methyl.
More preferred pharmaceutical compositions are those including a pharmaceutically acceptable diluent or carrier and at least one compound of the formula (I) and/or pharmaceutically acceptable salts thereof, wherein R2 is hydrogen, halogen, lower alkyl, or pyridine ; R3 is hydrogen or-(CH2) zY ; R4 is hydrogen, methyl, or forms a heterocyclo ring with Y or R3 ; Rosis alkyl substituted with aryl, cycloalkyl, or heterocyclo ; R6 is hydrogen, halogen, trifluoromethyl, or cyano; R7 is hydrogen or trifluoromethyl ; R8 is hydrogen, alkyl, substituted alkyl, or-(CH2) nNR13, R14, wherein R13and R14 (i) are independently selected from hydrogen, alkyl, or substituted alkyl, (ii) together form a heterocylco ring ; Y is (i) -OR9, -CO2R9, -CH(CO2R9)2, -OR9NR10R11, -NR10R11, -(C=O)NR10R11, -NR10(C=O)R12, or (ii) together with R4 forms a heterocylo ring;
n is 0, 1,2, or 3 ; z is 0,1,2, or 3; Rg is hydrogen, alkyl, substituted alkyl, alkoxy, heterocyclo, or pentafluorophenyl ; R10 and R11 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, cycloalkyl, substituted cycloalkyl, aryl, heterocyclo, or heteroaryl ; or (ii) taken together wherein RIO and R11 forms a three-to seven-membered heterocyclo ring; and R, 2is aryl, cycloalkyl, or heteroaryl.
Advantageously, R5 comprises an alkyl substituted with cycloalkyl or an aryl group. When R5 is alkyl substituted with aryl, advantageously the aryl has one to two substituents wherein at least one of the substituents is selected from halogen (e. g., chloro, bromo, fluoro), alkoxy (e. g., methoxy), or a lower alkyl. Advantageously, when Rg comprises a heterocyclo ring with a nitrogen heteroatom, said nitrogen heteroatom has a substituent X, selected from lower alkyl, substituted alkyl, and cycloalkyl. When R4 and R3 (or Y) form a heterocyclo ring, said ring advantageously is unsubstituted or has at least one substituent X2 comprising CO2 (alkyl).
Most preferred pharmaceutical compositions are those including a pharmaceutical acceptable diluent or carrier and at least one compound of the formula (I) and/or pharmaceutical acceptable salts thereof, wherein R2 is hydrogen or chloro ; R3 is -(CH2)zY, wherein z is 0,1,2, or 3; R4 ishydrogen; R5 is 3-chloro-4-methoxyphenylmethyl ; R6 is cyano; R7 is hydrogen; Ra is hydrogen, alkyl or substituted alkyl ; Y is -OR9, -NR10R11, -CO2R9, -(C=O)NR10R11;
Rg is hydrogen, alkyl, or substituted alkyl ; and R10 and Rl, (i) are each independently hydrogen, alkyl, substituted alkyl, aryl, heterocyclo, or heteroaryl ; or (ii) together form a five-to seven- membered heterocyclo ring.
Utility The compounds and compositions of this invention inhibit cGMP PDE, and in particular are potent and selective inhibitors of cGMP PDE 5. Thus, these compounds and compositions are useful in treating cGMP-associated conditions. A"cGMP-associated condition", as used herein, denotes a disorder which can be treated by inhibiting cGMP PDE or elevating the level of cGMP in a subject, wherein treatment comprises prevention, partial alleviation, or cure of the disorder. inhibition of cGMP PDE or elevation of the cGMP level may occur locally, for example, within certain tissues of the subject, or more extensively throughout the subject being treated for such a disorder. Treatment may be facilitated wherein elevation of the cGMP level potentiates additional beneficial therapeutic effects, such as where elevation of the cGMP level potentiates the effects of endothelium-derived relaxing factor.
The inventive compounds and compositions are useful for treating a variety of cardiovascular diseases including, but not limited to, hypertension, angina (stable, unstable, and variant), (congestive) heart failure, restenosis, atherosclerosis, and dyslipidemia, as well as reduced blood vessel patency, thrombus, both venous and arterial, myocardial infarction, peripheral vascular disease, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, benign prostate hyperplasia (BPH), and forms of cancer responsive to the inhibition of cGMP PDE. In addition, these compounds are useful in treating sexual dysfunction in both men (erectile dysfunction, for example, due to diabetes mellitus, spinal cord injury, radical prostatectomy, psychogenic etiology or any other cause) and women by improving blood flow
to the genitalia, especially, the corpus cavernosum. The compounds and compositions of this invention also are useful in treating diabetes mellitus and related conditions, and diseases of the gastrointestinal tract, such as those characterized by disorders of gut motility, including gastric paresis.
The present invention thus provides methods for treating cGMP- associated conditions, comprising administering to a subject in need thereof an effective amount of at least one compound of the formula) or a salt thereof, and/or pharmaceutical compositions as described above. Other therapeutic agents such as those described below may be employed in combination with the compounds of formula 1. In the methods of the present invention, such other therapeutic agent (s) may be administered prior to, simultaneously with, or following the administration of the inventive compound (s) and compositions.
The present invention also provides pharmaceutical compositions capable of treating a cGMP-associated condition, as described above. The compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The compounds and compositions of formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually ; bucally ; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e. g., as sterile injectable aqueous or non-aqueous solutions or suspensions) ; nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories ; or liposomally ; in dosage unit formulations containing non-toxic, pharmaceutical acceptable vehicles or diluents. These compounds may, for
example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of formula I may also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms that may be used. Exemplary compositions include those formulating the inventive compound (s) with fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICELO) or polyethylene glycols (PEG). Such formulations may also include an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymer (e. g., GANTREZO), and agents to control release such as polyacrylic copolymer (e. g., CARBOPOL 934@). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono-or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as PLASTIBASEO (mineral oil gelled with polyethylene).
The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for an adult human of from about 0.05 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like, subject to cGMP-associated conditions.
The inventive compounds and compositions may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in treating cGMP-associated conditions such as other cGMP PDE inhibitors, particularly other cGMP PDE 5 inhibitors, modulators of the
large-conductance calcium-activated potassium (BK) channels, prostanoids, a-adrenergic agonists, endothelin antagonists, angiotensin 11 (especially, subtype AT,) antagonists, angiotensin converting enzyme (ACE) inhibitors, renin inhibitors, and serotonin (5-HT2C) agonists.
Exemplary of such other therapeutic agents are the following : phentolamine, yohimbine, papaverine, apomorphine, sildenafil, pyrazolopyrimidinones as described in U. S. Patent Nos. 5,272,147; 5,250,534; 5,426,107; and 5,346,901, quinazolinones as described in U. S.
Patent No. 5,482,941; AT, antagonists such as from losartan, irbesartan, valsartan, and candesartan; ETA antagonists such as bosentan, ABT-627, and those described in U. S. Patent No. 5,612,359 and U. S. Patent Application Serial No. 60/035,832, filed January 30,1997; PDE 5 inhibitors selected from imidazoquinazolines (see WO 98/08848), carbazoles (see WO 97/03675, WO 97/03985 and WO 95/19978), imidazopurinones (see WO 97/19947), benzimidazoles (see WO 97/24334), pyrazoloquinolines (see U. S.
Patent No. 5,488,055), quinazolinones as described in U. S. Patent No.
6,087,368, pyridines as described in U. S. Patent Application Serial No.
60/100,655 filed September 16,1998, anthranilic acid derivatives (see WO 95/18097), fused heterocycles (see WO 98/07430) and thienopyrimidines (see DE 19632423); and 5-HT2C agonists selected from indoles (see J. Med.
Chem., 40,2762-2769 [1997], EP 655440 and EP 657426), and modulators of the large-conductance calcium-activated potassium (BK) channels as described in U. S. Patent Nos. 5,565,483 and 5,602,169, and in WO 98/04135 and W098/23273.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians'Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
The following assay can be employed in ascertaining the degree of activity of a compound as a cGMP PDE inhibitor. Compounds described in
the following Examples have been tested in this assay, and have shown activity.
PDE Scintillation Proximity Assay Protocol Sonicated human platelet homogenates are prepared by the method of Seiler, et al. (Seiler, S., Gillespie, E., Arnold, A. J., Brassard, C. L., Meanwell, N. A. and Fleming, J. S.,"Imidazoquinoline Derivatives: Potent Inhibitors of Platelet Camp Phosphodiesterase which Elevate Camp Levels and Activate Protein Kinase in Platelets,"Thrombosis Research, 62: 31-42 (1991)). PDE 5 is abundant in human platelets, and accounts for approximately 90% of the cGMP hydrolytic activity in the homogenates. When necessary, PDE 5 can be resolved from other PDE activities in the homogenates by anion exchange chromatography on a fast protein liquid chromatography system (FPLC) using a Mono-Q anion exchange column (Pharmacia) eluted with a linear gradient of 10 mM-450 mM NaCI.
The phosphodiesterase activity is assayed using a commercially available phosphodiesterase [3H] cGMP scintillation proximity (SPA) assay kit (Amersham). The manufacturer's protocol is followed explicitly except that the reactions are carried out at RT and 3 mM nonradioactive cGMP is included in the suspension of SPA beads to prevent the synthesis of any additional radioactive products.
All documents cited in the present specification are incorporated herein by reference in their entirety.
The following Examples illustrate embodiments of the inventive compounds and starting materials, and are not intended to limit the scope of the claims. For ease of reference, the following abbreviations are used in the Examples, below : Abbreviations DMSO = dimethylsulfoxide HPLC = high pressure liquid chromatography LRMS = low resolution mass spectrometry mp = melting point
tic = thin layer chromatography RT = room temperature h = hour (s) Ac = acetyl Et = ethyl Me = methyl HOAc = acetate EtOAc = ethyl acetate EDAC#HCl = ethyl-3- (dimethylamino) propyl carbodiimide, hydrochloride salt HOBT = hydroxybenztriazole NMP = N-methyl pyrrolidinone TEA triethylamine Preparation of Starting Materials Preparation 1 2-Amino-5-bromo-benyzlalcohol To 13 mmol of methyl 2-amino-5-bromobenzoate in 20 mL of THF at RT was added 65 mmol of 1 M lithium tri-tert-butoxyaluminohydride over 10- 15 minutes. The solution was heated at reflux for 17 hours. The solution was cooled, poured directly onto silica gel, and eluted with methylene chloridelethyl acetate; 3: 1 followed by 1: 1. The product was eluted with 100% methanol to give 2.59g of the title compound as an off-white solid.
MH+ : 202; LC : 1. 09'.
Preparation 2 Diethyl 2- (4-cyanophenylamino) methylenemalonate
To 5.00 g (42.3 mmol) 4-aminobenzonitrile (Aldrich, 98%) was added 10.1 g (9.41 mL, 46.6 mmol, 1.1 eq) diethylethoxymethylenemalonate (Aldrich, 99%), and the mixture was dissolved in 50 mL toluene (HPLC grade). The solution was refluxed for four hours with a condensor open to the air. The solution was then poured into 200 mL hexane, and the resulting white precipitate was filtered and washed well with more hexane to yield 10.62 g (37.0 mmol, 85% yield) of the title compound as a slightly off-white solid (per LC/MS and'H NMR). LC [MH+] 289,97% purity.
Preparations 3-6 Diethyl 2- (arylamino) methylenemalonate Preparations 3-6 of formula (P1) having values for R6, R8 listed in Table 1 were prepared by the same method as in preparation 2, using the corresponding 4 amino-benzene.
TABLE 1 Preparation R6 R8 3 Et CN 4 Cl CN 5 HOCH2 Br 6 C02CH3 Br
Preparation 7 Diethyl 2-(2-acetoxymethyl-4-bromophenylamino) methylenemalonate To a solution of 5.83 mmole of product from preparation 5 in 5ml of pyridine was added 8.74 mmole of acetic anhydride over 15 minutes and the mixture stirred at RT for 1.5 hours. Another 8.74 mmole of acetic anhydride were added, and the mixture stirred at RT for 15.5 hours. Another 2.94 mmole of acetic anhydride were added and the mixture stirred at RT for 4 hours. The mixture was poured into water, and an organic layer extracted with ethyl acetate. The organic layer was washed with water and saturated NaCI, dried over MgSO4, and filtered. The filtrate was concentrated to give 2.10g of the title compound as an off-white solid. MH+ : 416; LC: 4.25'.
Preparation 8 6-Cyano-4-hydroxyquinoline-3-carboxylic acid ethyl ester
To 100 mL vigorously refluxing diphenyl ether (Aldrich) was added in open air, in portions over the course of one hour, 10.5 g (36.5 mmol) diethyl 2- (4-cyanophenylamino) methylenemalonate. The solution was refluxed for one additional hour. After allowing the solution to cool to below 100°C, it was poured into 200 mL hexane. The resulting precipitate was filtered and washed well with hexane to yield 8.39 g (34.6 mmol, 94%) of the title compound as a light brown solid : MH+ : 243, mp >265°C.
Preparations 9-12 6,8-Disubstituted 4-hydroxyquinoline-3-carboxylic acid ethyl esters (P2) Preparations 9-12 of formula (P2) wherein R6 and R8 have the values listed in Table 2, were prepared by the same method as in preparation 8, using an appropriately substituted diethyl 2- (phenylamino) methylenemalonate.
TABLE 2 Preparation R6 R8 9 CN Et 10 CN Cl 11 Br AcOCH2- 12 Br-CO2CH3 Preparation 13 4-Chloro-6-cyanoquinoline-3-carboxylic acid ethyl ester
To 9.50 g (39.2 mmol) ethyl 6-cyano-4-hydroxyquinoline-3- carboxylic acid was added 50 mL POCI3 (Aldrich, 99%), and the resulting mixture was refluxed for 48 hrs. The POCf3 was evaporated under reduced pressure, and the residue codistilled once with CHCl3, and twice with toluene.
The resulting brown solid was dissolved in CH2Cl2 and treated with triethylamine until aqueous washings of aliquots had pH >10. The solution was then filtered through a 2"silica pad to yield 10.5 g (40.2 mmol, 103% yield) of the title compound as an off-white crystalline solid ; MH+ : 261,97% purity.
Preparations 14-22 4-Chloroquinoline-3-carboxylic acid ethyl esters The compounds of formula (P3) were prepared, wherein R2, Rs, R7, and R8 have the values listed in Table 3, using the same method as in preparation 13, with an appropriately-substituted ethyl 4-hydroxyquinoline-3- carboxylic acid.
TABLE 3 Preparation R2 R6 R7 R8 14 H CN H Et 15 H CN H Cl 16 H H CF3 H 17 H CF3 H H 18 H Br H AcOCH2 19 H Br H C02CH3 20 Cl Br H H 21 Cl CN H H 22 Cl CN H Et
Preparations 23 a) and b) a) Methyl 2-amino-5-cyanobenzoate b) Methyl 2-amino-3-ethyl-5-cyanobenzoate , wherein R8 is H or Et A mixture of methyl 2-amino-5-bromobenzoate (4.6 g, 20 mmol), and CuCN (1.97 g, 22 mmol) in NMP (20 mL) was heated to 190°C and stirred for 3 h. The reaction mixture was poured into a solution of ethylene diamine (4 mL) in H2O (16 mL) and extracted with toluene (4x20 mL). The combined extracts were dried (Na2SO4). Removal of the solvent gave the title compound a) (i. e., R8 is hydrogen). Use of methyl 2-amino-5-bromo-3-ethyl bromobenzoate gave the title compound b) (i.e., R8 is ethyl).
Preparations 24 a) and b) a) 6-Bromo-2,4-dihydroxylquinoline-3-carboxylic acid ethyl ester b) 6-Cyano-2, 4-dihydroxylquinollne-3-carboxyllc acid ethyl ester
wherein R6 is Br or CN.
Diethyl malonate was added to a freshly prepared solution of sodium ethoxide in ethyl alcohol. The resulting mixture was stirred for 30 min. To it was then added dropwise a solution of 2-amino-5-bromobenzoic acid methyl ester in ethyl alcohol. The resultant mixture was refluxed overnight. The ethyl alcohol was removed under reduced pressure, and the residue was dissolved in water and extracted with EtOAc. The aqueous layer was acidified with glacial AcOH to pH5. The precipitate was collected by filtration to yield 2.6 g, (94% yield) the title compound a) (wherein R6 is Br).
Use of 1.76 g (10 mmol) 2-amino-5-cyanobenzoic acid methyl ester yielded 1.7 g (66% yield) of the title compound b) (wherein R6 is CN).
Preparation 25 6-Cyano-2,4-dihydroxyl-8-ethylquinoline-3-carboxylic acid ethyl ester
To a solution of methyl 2-amino-5-cyano-3-ethylbenzoate (1.36 g, 6.2 mmol) and TEA (2.6 mL, 18.6 mmol) in THF (50 mL) was added methyl malonyl chloride (1 mL, 9.3 mmol). The mixture was stirred at RT for
overnight. Additional TEA (2.6 mL) and methyl malonyl chloride (1 mL) were added, and the reaction was continued for another 24 h. The mixture was diluted with EtOAc and washed with H20 and brine. The solvent was removed, and the residue was chromatographed (silica gel, EtOAc/hexane, 3: 7) to give the amide intermediate. NaH (400 mg, 60% oil dispersion) was washed with dry hexane and dried under nitrogen. To it was added a solution of methyl 2-amino-5-cyano-3-ethylbenzoate (1 g, 3 mmol) in toluene (40 mL), which was followed by dropwise addition of EtOH (4 mL). The resultant mixture was refluxed for overnight. The solvent was removed and the residue was dissolved in H20 (insoluable particulates were removed by filtration).
Upon acidification with HOAc, the title compound (590 mg) was precipitated out and collected by filtration.
Preparation 26 6-Bromo-2-(2-pyridinyl) quinoline-4-carboxylic acid To a suspension of 5-bromo isatin (5 g, 20.5 mmol) and 2- acetylpyridine (2.5 g, 20.5 mmol) in aqueous KOH (1.2 g, 33%) was added EtOH until a solution formed. The mixture was refluxed over night. The reaction mixture was neutralized with HOAc (50%) and filtered. The solid was resuspended in EtOH and filtered to give the title compound (5.5 g). LC : 1.66 and MH+ : 329.
Preparation 27 Azido-6-bromo-2- (2-pyridinyl) quinoline-4-carboxylate
A mixture of 6-bromo-2- (2-pyridine) quinoline-3-carboxylic acid (2.5 g) in SOC12 (30 mL) was refluxed for 2 h, and the excess SOC12 was removed. The residue was resuspended in acetone (100 mL). To the suspension was added a solution of NaN3 (0.5 g) in water (50 mL) and stirred for 2h. The solid product was collected by filtration and washed throughly with water, then dried at 40°C overnight to give the title compound (2.3 g).
LC:2.13'.
Preparation 28 6-Bromo-4-tbutoxycarbonylamino-2- (2-pyridinyl) quinoline A mixture of preparation 27 (2 g) in toluene (50 mL) was refluxed for 3h. Then tBuOH (1 mL) was added and continue to reflux for 2 h. The reaction mixture was cooled to RT and filtered. The filtrate was concentrated to give the title compound (2 g).
Example 1 4-[[(2-Chloro-4-methoxyphenyl)methyl]amino]-6-cyanoquinoline -3-carboxylic acid ethyl ester
To 10.0 g (38.4 mmol) 4-chloro-6-cyanoquinoline-3-carboxylic acid ethyl ester was added 10.4 g (50 mmol, 1.5 eq) 3-chloro-4-methoxybenzyl amine hydrochloride and 35 mL (228 mmol, 6 eq) diisopropylethylamine (Aldrich, 99.5+%). The mixture was dispersed in 200 mL n-propanol and brought to reflux for two hours. The solution was then poured into 500 mL water. The resulting precipitate was filtered, then washed with 500 mL water, then twice washed with 50 mL absolute ethanol to yield 14.87 g (37.6 mmol, 97% yield) of the title compound as a white fiberous solid after codistilling with absolute ethanol : mp: 161-162°C ; LC/MS (M/Z) 396 [M+H] observed, 97% purity.
Examples 2-55 4-Aminoquinoline-3-carboxylic acid ethyl esters
Using the same or similar method of Example 1, compounds having the formula (lae) were prepared, wherein R2, R5, R6, R7, and R8 have the values listed in Table 4, starting with corresponding 3-carboxylate-4- chloroquinolines and amine hydrochlorides.
TABLE 4 HPLC MH-* Ex.-R5 R2 Rs R7 R$ retention time (min.) No. t ! me (mm.) 2 H H CF3 H 3.63 439 H3CO 3 Fm Cl Br H H 4.75 437 4 ci Cl Br H H 4.56 485 H3C0- 5 Cl H CF3 H H 3.64 439 H3C0 6 H CN H H 3.73 352 '-"CHs 7 CN H H 3.82 352 / 8 H F H H 3.41 389 H, go 9 H Br H CO2nPr 3.29 535 H3CO 10 o H Br H CO2Me 3.52 507 H3CO 11 H Br H H 2.82 449 H3CO 12 Cl H CN H Et 2.78 424 H3CoA3a 13 Cl H CN H Cl 3.89b 430 H3COa 14 H Br H ACOCH2 1.73a 521 H3CO 15 H Br H Me 3.68 463 H3COtx _ 16 H CN H Et 1.56a 394 W\ 17 H CN H Et 1.68a 428 18 ci H CN H Et 1.65a 428 19 H3C/\ H CN H Et 1.46a 390 20/</H CN H Et 1.73a 380 \/CH3 21 </H CN H Et 1.73a 380 22 ci H CN H C02nPr 3.43 482 H3CO _ 23 Ci H CN H C02Me 3.11 454 H3CO 24 H CN H CO2Et 3.27 468 H3COw _ 25 r'\ H CN H Et 1.23a 350 O 26 °Q3\ H CN H Et 1 33'404 r 27 FsC H CN H Et 1 49a 428 28 F H CN H Et 1. 38a 396 F 29 F3C H CN H Et 1.49a 428 30 H3C H CN H Et 1. 65a 402 Hic 31 HIC H CN H Et 1.70a 416 H3C hic 32 ci H CN H Et 1.60a 428 Cl 33 H>sò H CN H Et 1. 42a 420 HsCO 34 H3CO H CN H Et 1. 39a 420 H\ H3C0 35 F3COe H CN H Et 1.53a 444 36 C H CN H Et 1.53a 442 _. CI 37 H3CO H H 1. 28a H3C0 H3CO 38 F H CN H Et 1 S5'446 / 39 N 3 \ H CN H Et 1.34a 444 N'S 40 O, CH3 H CN H Et 3.54 374 41 H CN H Et 3.55 374 42 CH3 H CN H Et 3.94 452 Br-a--- 43 CHs H CN H Et 3.95 452 44 H3Ce, H CN H Et 3.78 388 H3C-U' : 45 H3Cm H C N H Et 3.77 388 46 \ H CN H Et 3.26 360 47 H CN H Et 3. 65 438 48 H3C H CN H Et 3.53 374 49 HF2CO Et 1.38a 426 50 H3CSw H CN H Et 1. 46a 406 HsCS-V")- 51 H CN H Et 1.46a 386 52 ci H CN CN Et 1. 80a 442 53 H3CO H CN H Et 1.41 a 434 H3CO H3CO 54 H3C H CN H Et 1.36a 448 H3CO- ( :)- 55 HOU1, H CN H Et 1. su'424 cri
Example 56 6-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl] amino]-8- hydroxymethylquinoline-3-carboxylic acid ethyl ester
A mixture of 1.84 mmole 6-bromo-4-[[(3-chloro-4- methoxyphenyl) methyl] amino]-8-(acetoxymethyl) quinoline-3-carboxylic acid ethyl ester (i. e., Example 14) and 1.84 mmole of potassium carbonate in 20 mL of ethanol was stirred at RT for 20 hours. The mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The resultant organic layer was dried over MgSO4 and filtered, and the filtrate concentrated to give 0.85g of the title compound as a tan solid. MS: 481; LC: 3.43'.
Example 57 6-Bromo-4-[[(3-Chloro-4-ethoxyphenyl)methyl]amino]-8- (chloromethyl) quinoline-3-carboxylic acid ethyl ester
A solution of 1.73 mmole 6-bromo-4-[[(3-chloro-4- methoxyphenyl) methyl) amino)-8-hydroxymethylquinoline-3-carboxylic acid ethyl ester (i. e., Example 56) in 8 mi of thionyl chloride was stirred at RT for 1.5 hours. The solution was concentrated to give 0.86 g of the title compound as an orange foam. MS: 499; LC: 4.15' Example 58 6-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-(N,N- dimethylaminomethyl) quinoline-3-carboxylic acid ethyl ester
A solution of 0.20 mmole of example 57 and 2 mmole of 2M dimethyamine in 1 mi of THF was stirred at RT for 22 hours. An additional 0.25 ml of 2M dimethylamine in THF was added and the solution stirred for 4 hours. The solution was diluted with ethyl acetate and washed with water.
The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel eluted with methylene chloride followed by methylene chloride/ethyl acetate; 95: 5 and finally with ethyl acetate to give 71 mg of the title compound as a beige solid.
MS: 507; LC: 3.71' Example 59 4- (3-Chloro-4-methoxyphenyl) methyl] amino]-6-cyano-3- quinolinecarboxylic acid
To 8.0 g (20 mmol) 4- (3-Chloro-4-methoxyphenylmethylamino)-6- cyanoquinoline-3-carboxylic acid ethyl ester was added 100 mL THF, 100 mL MeOH and 100 mL 1 M NaOH, and the resulting mixture was stirred well. The solids gradually dissolved as the reaction progressed. After 1 h, the THF and most of the MeOH was evaporated under reduced pressure to leave an aqueous slurry of a white solid. The slurry was acidified to pH 1.5 with HCI, stirred well for 1 h, and then filtered and washed well with water to give 7.5 g (20 mmol, #100% yield) of a white chalky solid. Codistilling twice to dryness with absolute ethanol afforded the title compound: LC/MS: M/Z 368 (M+H) observed, 90+% purity; mp: decomposed 255-260°C. LC 2.93'.
Examples 60-64 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarbo xylic acids
Using the same or similar method as described in Example 59, compounds having the formula (laf) were prepared, wherein R2, R8, R7, and R8 have the values listed in Table 5, starting with corresponding 3- carboxylatequinolines.
TABLE 5 HPLC Ex. R2 R6 R7 R8 retention time (min.) MH+ No. 60 H H CF3 H 3.67 411 61 Cl Br H H 4. 29 455 62 H F H H 3. 31 361 63 H CN H Et 2. 56 396 64 H CN H Cl 3.23 402
Example 65 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-quinolinecarbo nitrile To 2.16 g (5.87 mmol) 4-[[(3-chloro-4-methoxyphenyl)- methyl] amino]-6-cyano-3-quinolinecarboxylic acid was added 50 mL diphenyl ether (Aldrich), and nitrogen was vigorously bubbled through this mixture for 20 minutes. The resulting mixture was then heated to 240 °C under nitrogen for 30 minutes. During the course of the reaction, the dispersed starting material slowly dissolved, and gas evolution was observed. The resulting solution was poured into 200 mL hexane, and a precipitated solid was filtered to yield 1.43 g (4.42 mmol, 75% yield) of the title compound as a off-white solid : LC/MS: M/Z 324 (M+H) observed, 96% purity; mp: decomposed 227- 230 °C. LC: 2.84'.
Example 66 4- [ [ (3-Chloro-4-methoxyphenyl) methyl] amino]-8-ethyl-6-quinolinecarbonitrile
The reaction procedure used was similar to that described for Example 65 with the following changes: 101 mg (0.255 mmol) of 4-[[(3-chloro- 4-methoxyphenyl) methyl] amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid was used to afford 51 mg (57% yield) of the title compound. LC: 1.20' M/Z 352 mp: 206-207 °C.
Example 67 4-[[(3-Chloro-4-methoxyphenyl)methyl]N-methylamino]-6-quinol inecarbonitrile To 250 mg 4-[[(3-chloro-4-methoxyphenyl)methyl] amino]-6- quinolinecarbonitrile (i. e., Example 65) was added 50 mg of NaH, and the mixture was flushed with nitrogen. 5 mL of DMF was added, and it was stirred for half hour. To the mixture was then added 70 of CH31, and it was
stirred at RT. After 1 hour the reaction was quenched with aqueous NH4CI and diluted with water, and the precipitate collected by filtration to give (153 mg) of the title compound. LC: 2.48; M/Z 338 m. p. 153-155°C.
Example 68 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyanoquinoline -3-carboxylic acid pentafluorophenyl ester To 275 mg (0.748 mmol) of 4-[[(3-chloro-4-methoxyphenyl)- methyl] amino]-6-cyano-3-quinolinecarboxylic acid was added 276 mg (1. 50 mmol, 2.0 eq) pentafluorophenol, and the mixture was dispersed in 5 mL anhydrous DMF under nitrogen. To this dispersion was added a solution of 231 mg (1.12 mmol, 1.5 eq) of dicyclohexylcarbodiimide (Aldrich) in 2 mL anhydrous ethyl acetate at RT. The resulting mixture was stirred for 18 hours. The reaction was then diluted with 10 mL EtAc, and the white precipitate was filtered and discarded. The filtrate was concentrated in vacuo, and the residue was triturated with 5% MeOH/95% CH2CI2 to give 164 mg (0.307 mmol, 41 % yield) of the title compound as a white solid : LC/MS: M/Z 534 (M+H) observed, 100% purity; mp: decomposed 215-217 °C. LC: 4.15.
Example 69 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-8-ethylq uinoline-3- carboxylic acid pentafluorophenyl ester
The reaction procedure used was similar to that described for . Example 68 with the following changes: 3.95 g (10.0 mmol) 4-[[(3-chloro-4- methoxyphenyl) methyl] amino]-6-cyano-8-ethyl-3-quinolinecarboxylic acid was used to afford 2.81 g (5.00 mmol, 50% yield) of the title compound as a white solid : mp : 169-170 °C ; LC: 2.14a; MH+ 562.
Examples 70-122 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-quinolinecarbo xamides
Compounds having the formula (lag), wherein R2, R6, R7, R8, R10, and R11 have the values listed in Table 6, were prepared by the following method, starting with corresponding 3-carboxylatequinolines and an appropriate amine: To 1 eq of 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]- 3- quinolinecarboxylic acid pentafluorophenyl ester in THF (approx. 25 mg per 1 mL THF) was added 2 eq of an appropriate primary or secondary amine. The resulting reaction solution was allowed to stir for 18 hours at RT. The THF was then evaporated in vacuo, and the residue was triturated with a 1 : 1 solution of ether/hexane. The precipitated solid was filtered and washed with 1: 1 ether/hexane to yield the desired 4-[[(3-chloro-4-methoxyphenyl) methyl] amino]-3-quinolinecarboxamide. Yields were generally > 25%.
TABLE 6 HPLC MH+ Ex. R2 R6 R7 R8-NRIORI, retention No. time (min.) 70 H H CF3 H-NH2 3.35 410 71 H H CF3 H HN 3. 09 501 HN 72 H H CF3 H HN 3. 06 515 ZON 73 H H CF3 H H. 1. 78a 523 HN-./-\ U 74 H H CF3 H OH oH 1. 81" 482 75 H H CF3 H 1. 92a 508 HN- (\"OH U 76 H H CF3 H ! 1. 92a 438 HN CH3 77 H H CF3 H N30H 1. 73a 494 78 H CN H H I 2. 49 458 Han 79 H CN H H 2. 56 480 NN- N V 80 H CN H H HN NS) _ 507 HN 81 H CN H H 2. 18 450 LYNCHS 82 H CN H H-NH2 2.73 367 83 H CN H H/-CH3 2.99 423 -N -CHg 84 H CN H H HN--\ 1. 57a 438 1-N (cl3) 2 -N (CH3) 2 85 H CN H H HN 2. 57 410 -NH2 86 H CN H H 1. 47a 503 Han OH HO 87 H CN H H H 1. 91 a 478 NON N 0 H 88 H CN H H 1. 55 464 ON, CH3 89 H CN H H NUN 1.80 504 U 90 H CN H H 1. 63 494 NOCH3 91 H CN H H 1. 64 504 92 H CN H H _NAND 1.70 518 93 H CN H Et-NH2 2.34 395 94 H CN H Et 2. 20 486 Han N 95 H CN H Et _N/--\ 2.05 532 \/\ 96 H CN H Et-N NH3 1. 92 506 \_p CH3 - CHs 97 H CN H H-N NCH3 2. 38 478 \_2 CH3 98 Cl Br H H-N 3. 36 551 ON, CH3 99 Cl Br H H-N N CHs 3.38 565 \_2 CH3 CHs 100 Cl Br H H-N/--\ 3. 48 591 zu 101 Cl Br H H HN N 3.49 545 Han N / 102 Cl Br H H-N 2. 74 537 ONC3 103 Cl Br H H ! 1. 57a 539 HNsw\, (CH3) 2 104 Cl Br H H NCH3 1. 52a 594 NNNJ 105 Cl Br H H ri 1. 55a 581 HNow NJ 106 Cl Br H H °tß 3.61 579 ! Y"\ 107 Cl CN H H I 3. 09 492 HNt Han N 108 Cl CN H Et 1. 73a 520 Ho N 109 H CN H Et 1. 35a 449 N 110 H CN H Et 1 1, 21a 532 0"D Li
Examples 111-179 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3- quinolinecarboxamides Compounds having the formula (lah), wherein Rio and Rll have the values listed in Table 7, were prepared by the following method: To a solution of 1.0 eq of the appropriate primary amine or 2.0 eq of the appropriate secondary amine in anhydrous THF (3 mL) was added 15 mg 4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3-quinol inecarboxylic acid pentafluorophenyl ester (0.028 mmol). Where the amine was a hydrohalide salt, 3 eq of triethylamine were also added. The solutions were stirred overnight at 50 °C, then filtered and purified by SCX cartridges (2 g capacity, p-toluene sulfonic acid) on a Bohdan SPD robot (10 mL MeOH wash, 10 mL 2M NH3/MeOH elution). The desired 4-[[(3-chloro-4- methoxyphenyl) methyl] amino]-6-cyano-3-quinolinecarboxamide was recovered either by filtration (manual), by concentration of the SCX eluent (by Savant Speedvac), or (if further purification was required) by preparative HPLC (Shimadzu). Average purity: 93% (LC/MS). Average yield : > 25%.
TABLE 8 HPLC MH+ Ex. retention No. time (min.)' 111 Chug 1. 63 395 -N CH3 112 jCH3 1.83 423 -N--CH3 113 HN 1. 96 435 114 2. 17 451 HN-1CH3 115 HN~OuzCH3 1.84 439 116 1. 70 455 HO OH 117 1. 81 439 118 1 2. 01 467 119/ 1.97 451 _N-OH 120 pH 1.69 411 121 1 1. 66 425 OU 122 HNoH 0. 64 439 123 1 1. 77 453 OU 124 OH 2.16 453 HN ~ CH3 125 OH 1. 78 453 N CH3 126 COH 1. 57 455 OH 127 1. 70 465 128 I 1. 178 453 HN4OCH3 129 1 1. 83 467 OCH3 130 cl3 1. 66 452 HO 131 0 1.77 492 ' 132 CCH3 1.59 466 HN~Ns, CH3 133 (CH3) 2 1.49 466 CHs 134 CCH3 1.49 480 -NNCH3 CH3 135 gCH3 1.74 494 HN 136 HN N 1. 60 464 137 1. 66 478 HN 138 FA 1.48 492 CH3 "CHg 139 I 1. 53 424 HN NH2 140 OH 1.53 440 HNJ NH2 141 j CH3 1.58 452 HN, j,, NH2 CH3 142 I 1.54 452 HN, N (CH3) 2 143 CH3 1. 58 480 HN \NsCH3 144 j CHs 1. 52 494 N \NX, CH3 145 1 H3C 1.63 506 HN/\, N 146 hex 1. 59 478 un "CHs 147 I 1. 46 478 HsC LYNCHS 148 han 1. 96 522 un NOTCH3 I I O 149 I 1. 73 540 HN,, 43 N 1 150 1. 75 514 HN/N CH3 151 HN/\ o^\/N (CH3) 2 1. 54 466 152 HN N (CH3) 2 1.63 494 153 ro 1. 63 437 . NJ 154 Cs 1.78 453 NJ 155 I 1. 66 452 HN 156 ri 1. 55 494 HNow NJ 157 F~R 1. 59 437 OH 158 0 1. 59 478 -NNHs H 159.-N (CH3) 2 1.43 464 NS 160 1. 83 435 N 161 OH 1. 59 451 NJ 162 OH 1.69 479 N 163 1. 91 507 N/$0CH3 0 164 0 1.63 478 'NEZ -N J 165 1. 63 478 Nzl0NH2 o 166 0 1.90 493 -nez 167 H 1.43 436 -N 168 SN\-/N (CH3) 2 1. 43 521 169 CN~oH 1. 41 480 -NJ 170-N T--\N 1. 64 518 V 171 N 1. 48 513 U 1. 76 514 172 ND 173 1. 45 450 -NNH 174 1. 44 464 \CH3 175 2. 00 457 HN 176 1. 61 458 HAN N 177/\ 1. 87 458 HN N=' 178 HN< OH 1. 86 487 Han 179/o 2. 25 501 zero HN\=
Example 180 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3-(hydroxymethyl )-6- quinolinecarbonitrile
To 530 mg (1.0 mmol) of 4-[[(3-chloro-4- methoxyphenyl) methyl] amino]-6-cyano-3-quinolinecarboxylic acid pentafluorophenyl ester was added 15 mL of anhydrous DMF, and the resulting mixture was cooled to 0 °C. A solution of 75 mg of NaBH4 in 5 mL of anhydrous DMF was added to the reaction mixture, resulting in a clear red
solution with gas evolution. After stirring for 1 hour at 0 °C, the reaction was quenched with 2% TFA/MeOH, and the solvent was removed under reduced pressure. The oily residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2CI2) to afford 87 mg (25% yield) of the title compound. LC: 2.60' ; MH+: 354.
Example 181 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-8-ethyl-3-(hydro xymethyl)-6- quinolinecarbonitrile To a suspension of 100 mg (0.236 mmol) of 4-[[(3-chloro-4- methoxyphenyl) methyl] amino]-6-cyano-8-ethylquinoZine-3-carboxylic acid ethyl ester in 2.8 mL anhydrous THF under nitrogen, was added 1.2 mL (5.0 eq) of 1 M lithium tri-t-butoxyaluminohydride/THF. The resulting mixture was refluxed overnight with stirring. The reaction was quenched with 1 mL of MeOH and partitioned between 75 mL 1 M NaOH and 100 mL CH2CI2. The organic phase was washed with 1 M NaOH (2x30 mL) and dried over MgS04.
Removal of the solvent under reduced pressure gave 75 mg (84% yield) of the title compound as a light yellow solid. The analytical sample was obtained by trituration in ether: mp: 188-189 °C. LC: 3.15' ; MH': 382.
Examples 182-190 4-Amino-3- (hydroxymethyi) quinolines
Using the same method of Example 181, compounds having the formula (lai) were prepared, wherein R5, R6, and R8 have the values listed in Table 8, using an appropriate amine (having the group Rg)) In Example 190, the reaction was started with 3-ethyl-8-methyldicarboxylatequinoline.
TABLE 8 HPLC MH+ Ex. retention Found No. time (min.) 182 Br H 2.41 407 H3CO 183 Cl CN ci 2.92 388 H3CO 184 CN Et 1.50a 338 CH3 _ 185/\/CN Et 1.51a 338 < CH3 186 ci CN Et 1.45a 386 Cl 187 CIUCI CN Et 1.43a 386 9\ _ 188 ci CN Et 1. 38a _ 189 H3CO CN Et 1. 25a 348 190 Ho \ CN-(CH2) OH 2. 59 384 HsCO-V.;-
Examples 191-194 3-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6- quinolinecarbonitriles
Compounds having the formula (laj) were prepared, wherein R10 and Rll have the values listed in Table 9, by the following method.
To 70 mg 4-[[(3-chloro-4-methoxyphenyl)methyl] amino]-3- (hydroxymethyl)-6-quinolinecarbonitrile was added 5 mL anhydrous CH2CI2 and 70 µL (0.44 mmol, 2.0 eq) diisopropylethylamine, and the resulting solution was cooled to 0°C under nitrogen. Methanesulfonyl chloride (17 µL, 0.22 mmol, 1.1 eq) was then added, and the resulting reaction solution was stirred at 0°C for 30 minutes. The solution was then quenched with 0.24 mmol (1.1 eq) of the appropriate amine (having groups R16, R11), and the resulting solution was stirred for 30 minutes. The solvent was evaporated under reduced pressure and the residue was chromatographed in 5% MeOH/CH2CI2 to yield the title compound.
TABLE 9 HPLC MH+ E NR R retention CX.-MKoK <-,- 10 12 time (min.) No. 191-N<_NCH3 2. 39 436 192-N H2 1.12 353 193 HtX 1. 83 444 HN 194-No 1. 84 421
Example 195 6-Bromo-4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-3- [ (4-methyl-1-piperazinyl) methyl] quinoline To 4-[[(3-chloro-4-methoxyphenyl)methyl]amino] -3-(hydroxymethyl)-6- bromoquinoline was addedSOC12, and the resulting reaction solution was stirred at RT under nitrogen for 30 minutes. The SOC12 was then evaporated under reduced pressure, and the residue was left overnight under high vacuum. The yellow residue was redissolved in anhydrous DMF, and this solution was then added to a solution of N-methylpiperazine in anhydrous
THF. The resulting reaction solution was stirred for 6 hours at RT, by which time HPLC showed the reaction to be complete. After evaporating the solvent, the crude product was chromatographed in 3% MeOH/CH2CI2 to yield the title compound. LC: 2. 12'; MH+ : 489 Examples 196-224 3-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6- quinolinecarbonitriles Compounds having the formula (lak) were prepared, wherein values for R2, R8, Rio and R11 are as in Table 10, using the same or similar method as in Example 195, starting with the corresponding 4-[[(3-chloro-4- methoxyphenyl) methyl] amino]-3- (hydroxymethyl)-6-quinolinecarbonitrile.
TABLE 10 Ex.-NR1oR11 R2 R8 HPLC MH+ No. retention Found time (min.) 196 N+CH3 H H 2.55 437 CH3 197 I H H 3. 43 465 H C )-)-CH3 HgC HgC 198 OH Cl H 1. 43a 471 -nez 199 CH3 H H 2.40 381 cl3 CHs 200 H H 2.43 449 H3C"' 201 H H 1.96 437 M OU 202 _NCCH3 H H 2.21 435 .. _ u 203 H H 2.24 451 Vi _... CH3 204 9 aH H 1. 81 437 Oh 205 NaOH H H 1.60 423 OH 206 OH H H 1. 97 451 zu 207 HgC H H 2.33 435 -nid u 208 I H H 2.61 435 H3C"'T-) 209 NaoH H H 1.86 423 OU 210 H H 2.74 449 rcH, 211 COH H H 2. 25 451 OH 212 OH H H 1.17 a 437 -NE 213 iy\, H H 2.80 477 HO 214 1 F H H 2. 50 461 HN== 215 OCH, H H 2. 45 473 NON 216 OH H Et 1.34a 465 N,) V 217 HN/d3 H H 2.40 443 NON 218 ß H Et 1.27a 465 OH 219/\ H Cl 1.20a 457 OH 220}/H Cl 1.23a 485 221 H Cl 1.35a 457 -N 0 222 Ni3rOH H Et 1.20a 451 OH 223 0 H Et 1. 45a 479 EUH 224 j o H Et 1.45a 479 dz Examples 225-263 3-Aminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-6- quinolinecarbonitriles
Compounds of formula (lal) were prepared, wherein R10 and R11 have the values listed in Table 10, with the following method (Automated parallel synthesis).
A mixture of 1 eq. of 4-[[(3-chloro-4-methoxyphenyl)methyl] amino]-3- chloromethyl-6-cyanoquinoline and 3 eq. of an appropriate amine in THF was reacted for overnight at RT. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2CI2 and washed with H2O, then dried. Removal of the solvent gives the product.
TABLE 11 Ex.-NRIORII HPLC MHs No. retention time (min.) 225 HN<O 2. 54 407 226 HN 2. 65 421 227 HN 2. 82 435 228-NN 2.99 420 H3C 229 N~OH 2 42 411 HIC 230 NX 2. 83 438 kCHs 231 1 2.4 393 232 NS 2 46 407 233 2. 92 423 -N\ 0 234-N/\S 3. 18 438 \1 235 2. 76 435 "U 236 | dCH3 2.48 395 HAN 237 ! chu 2. 42 411 OH -OH 238 CES DHs 2.99 437 HN'v'CH3 239 !/-CH3 2.73 423 Han-\ -CHs 240 CHs 2.8 423 HN)--CH3 241 1-, 3.28 435 HN CF3 242 CH3 2. 84 423 CHEZ 243 2. 44 381 HN CH3 244 2. 5 410 HN -OCHs 245 2. 4 397 HN ou 246 H CHs 3. 07 437 H3 247 CH3 2.91 423 H IN'-'CH3 248 HN~CH3 2. 395 249-N'CH3 2.44 395 CH3 250-NI^CH3 2.55 409 CH3 251 CH3 2. 64 409 CH3 252 2. 56 406 HNN 253 cHs 3 423 H3C'J\CH3 254 HN~OX, CH3 2. 65 425 255 CH3 2.54 409 CH3 CHs 256 CH3 3.09 437 H3CoN4sCH3 257 HNttOH 2.44 411 258 CH3 2.43 410 259 Chug 2. 61 409 HN------ 260 CH3 2.61 409 261 2. 64 437 HN ole 262-NOCH3 2. 71 425 CH3 263 hot 2. 63 437 HO OU
Examples 264-266 3-(N-acylaminomethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]am ino]-6- quinolinecarbonitriles
Compounds of formula (lam) were prepared, wherein R12 has the values in Table 12, below. To a mixture of acyl chloride and triethylamine in CH2CI2 was added a solution of 3-aminomethyl-4-[[(3-chloro-4- methoxyphenyl) methyl] amino]-6-quinolinecarbonitrile (i. e., Example 192) in dioxane. The reaction mixture was stirred at RT for 1 h. Then the mixture was diluted with EtOAc and washed with water brine and dried (MaS04). The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography (silica gel, CH2Cl2/MeOH, 10: 1) to give the compounds of Table 12.
TABLE 12 Ex. R12 HPLC MH retention time (min.) 264 2. 76 457 265 ~} 3. 00 463 v 266 ge 2. 50 458
Examples 267-283 3-Alkoxymethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]qu inolines Compounds of formula (lan) were prepared, wherein R2, R6 R8, and Rg have the values listed in Table 13, with the following method.
To 4-[[(3-chloro-4-methoxyphenyl)methyl]amino] -3-(hydroxymethyl)-6- bromoquinoline was added SOCI2, and the resulting reaction solution was stirred at RT under nitrogen for 30 minutes. The SOC12 was then evaporated under reduced pressure, and the residue was left overnight under high vacuum. The yellow residue was redissolved in anhydrous DMF, and this solution was then added to a solution of appropriate alcohol in anhydrous THF (or the yellow residue was treated directly with an appropriate liquid alcohol). The resulting reaction solution was stirred for 6 hours at elevated temperature, by which time HPLC showed the reaction to be complete. After evaporating the solvent, the crude product was chromatographed to yield the title compound.
TABLE 13 Ex.-Rg R2 R6 R8 HPLC MH+ No. retention time (min.) 267 CHs H CN Et 1.69a 424 268-CH3 H CN Et 3.10 396 269 H CN Et 3. 35 466 270 J\CH3 H CN Et 3.42 424 ACH3 271/\CH3 H CN Et 3.29 410 272 H CN Et 1.60a 454 273 ~OH H CN Et 1.39a 426 274 H CN Et 3.91 565 oRO ou /0 3 CH3 CHs 275/li.. H CN Et 3.91 565 N N zu CH3 Chus 276 HO CHIA H CN Et 3.80 551 NCNA CH3 N'\ CH3 O 277 CHg H Br H 2.78 435 278/Ill. Cl CN H 2.13a 571 NU N H3C---CH3 3 279/li.. ; 1 Cl CN Et 2.37a 599 /N- N 280 CH3 H Br CIC 3.55 469 H2 281 CHs H Br CIC 3.78 497 CHs Hz 282 o H CN Et 3.18 438 o 283 3 H CN CIC 3.17 H2
Examples 284-288 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino-8-ethyl-3-[[[(2S) -2- pyrrolidinyl] methoxy] methyl]-6-quinolinecarbonitriles
Compounds of formula (lao) were prepared, wherein R2and X, have the values listed in Table 14, with the methods set forth below.
Example 284 : Example 275 was treated with TFA/CH2C12 (1: 1) for 2 hours.
The reaction mixture was concentrated. The residue was treated with NaHC03 (aq. 10%) and extracted with CH2CI2. The combined extracts were dried (NaSO4) and the solvent was removed. The residue was then purified by preparative HPLC to give Example 284.
Example 285: The same method as Example 285 was used, starting with Example 279.
Example 286: To a solution of Example 284 (30 mg) in THF was added triethylamine (28) iL) which was followed by CH31 (4.5 1L). The resultant mixture was stirred at RT for overnight. The solvent was removed and the residue was chromatographed (silica gel, CH30H/CHCI3, 1: 9) to give Example 286 (5.1 mg).
Examples 287 & 288: To a solution of 0.127 mmole of Example 284 and 1.27 mmole of the ketone in 0.5 mL of methanol cooled in an ice bath was added 0.635 mmole of sodium cyanoborohydride. The ice bath was removed and the suspension stirred for 4 hours to 2 days. The solution was acidified with concentrated HCI and allowed to stir for a few minutes. The solution was neutralized with concentrated NH40H and extracted with methylene chloride.
The organic layer was dried over MgSO4 and filtered, and the filtrate concentrated. The residue was chromatographed on silica gel eluted with methylene chloride/methanol ; 95: 5 and 9: 1 to give Examples 287 and 288.
TABLE 14 Ex. No. R2 X1 HPLC MH+ retention time (min) 284 H H 1. 27a 465 285 Cl H 1. 83 a 499 286 H-CH3 1. 27a 479 287 H 2. 72 533 288 H-CH (CH3) 2 2. 57 507 288-CH (CH3) 2 2. 57 507 Examples 289-296 8-Aminomethyl-3-alkoxymethyl-4-[[(3-chloro-4- methoxyphenyl) methyllamino] quinolines
Compounds having the formula (lap) were prepared, wherein R6, Rg, R13 and R14 have the values listed in Table 15. A solution of 0.072 mmole of 8-chloromethyl quinoline and 0.072 mmole of amine in 0.5 mL of THF was stirred at RT for 16 hours. Another 0.144 mmole of amine were added to the incompleted reactions and the solution stirred for 24 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over MgS04, and filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel eluted with methylene chloride/methanol ; 98: 2,95: 5 followed by methylene chloride/methanol/NH40H ; 90: 9: 1, to give the products.
TABLE 15 Ex. #-Rg Rs-NR3R, 4 HPLC MH+ retention time (min.) 289-CH (CH3) 2 Br C, H3 1.54a 506 -CH, 290-CH (CH3) 2 Br-NHCH3 1. 47a 492 291-CH3 CN ICH3 2.81 425 NCH3 292-CH3 CN, 2. 15 480 293-CH3 CN I 1.60 468 294-CH3 CN H3CsN {3NCH 2.30 508 -N-/NCHs 295-CH3 CN HN 1.62 494 296-CH3 CN HN 1.62 508 HN
Examples 297-299 3-Alkoxymethyl-4-[[(3-chloro-4-methoxyphenyl)methyl]amino]-8 -ethyl-6- quinolinecarbonitriles Compounds having the formula (laq) were prepared, wherein Rg is substituted alkyl comprising CH2CH (OH) CH2NR10R11, and R10 and R11 have the values listed in Table 16. A solution of 0.11 mmole of Example 282 and 0.22 mmole of the appropriate amine in 1 mL of propanol was heated at 60- 70°C for 45 minutes to 30 hours. The solution was concentrated and the
residue chromatographed (silica gel, methylene chloride/methanol ; 95: 5,9: 1 and 4: 1) to give the products.
TABLE 16 Ex.-NR10R11 HPLC MHs No. retention time (min.) 297 1 2.51 509 298 H3C 2.67 539 SCH3 -N >-CH3 H3C 299 Chs 2.48 483 N CH
Example 300 3-[[3-[Bis(1-methylethyl)amino]-2-methoxypropoxy]methyl]-4-[ [(2-chloro-4- methoxyphenyl) methyl] amino]-8-ethyl-6-quinolinecarbonitrile
To 0.069 mmole of Example 298 in 0.5m ! of DMF cooled in an ice bath was added 0.072 mmole of 60% NaH in mineral oil. The ice bath was removed, the suspension stirred for 90 minutes, and 0.076 mmole of iodomethane were added. The solution was stirred at RT for 16 hours. An
additional 0.038 mmole of 60% NaH in mineral oil and 0.038 mmole of iodomethane were added and the solution stirred for 4 hours. The solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCI solution, dried over MgSO4 and filtered, and the filtrate concentrated. The residue was chromatographed on silica gel eluted with methylene chloride/methanol ; 95: 5 to give 19 mg of the title compound as a colorless oil. MH+ : 553; LC: 3.21'.
Examples 301 and 302 [[4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3- quinolinyl] methyl] propanedioic acid dialkyl ester Compounds having the formula (lar) were prepared, wherein R8 and Rg have the values listed in Table 17. To a dry clean reaction flask was charged 1.3 g (33 mmole) of sodium hydride (60% in mineral oil) and 160 ml of dry THF. To this mixture was added dropwise 6.5 g (30 mmole) of di-t- butylmalonate over a period of 20 minutes at RT. After completion of the addition, the reaction mixture was stirred at RT for an additional 15 minutes then cooled to-78°C. A solution of the 3-chloromethyl quinoline (-10 mmole) in 160 ml of DMF was added via an addition funnel over a period of 1 hour. After completion of the addition, the reaction mixture was stirred at- 78°C for one more hour then was quenched with water at 0°C. THF was removed under reduced pressure. The resulting solution was diluted with
ethyl ether washed with water three times, brine, dried over sodium sulfate, and concentrated, and then purified by column chromatograph (silica gel CH2CI2/MeOH, 100: 5) to give the product (2.75g).
TABLE 17 Ex. No. R8 Rg HPLC MH+ retention time (min.) 301 H t-butyl 3. 19 552 302 Et Me 3. 22 496
Example 303 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-3- quinolinepropanoic acid
Example 301 (200mg) was dissolved in 10 mi of ethanol. 1 ml of 10% LiOH/H2O aqueous solution was added. The reaction solution was stirred at 45OC for 2 hours. Ethanol was removed under reduced pressure. The resulting aqueous solution was adjusted to pH=4 with 10% HCI. The solid was collected by filtration, rinsed with water, dried to afford 160mg slightly yellow solid. This product (300mg) was mixed in 0.3 ml of DMF and stirred at 130°C for 10 minutes. The reaction mixture was cooled to room temperature.
Water was added. The solid was collected by filtration, rinsed with water, and dried to afford 244mg of the title compound. LC: 2.20', MN+ : 396 Examples 304-306 1- [ (3-Chloro-4-methoxyphenyl) methyl]-1,2,3,4-tetrahydro-2-oxobenzo [h]-1,6- naphthyridine-9-carbonitriles
Compounds having the formula (las) wherein R8 and X2 have the values listed in Table 18, were prepared as follows.
Examples 304-305: To a suspension of NaH (123 mg) in THF (10 mL) was added dimethylmalonate (370 mg) dropwise. The mixture was stirred at RT for 15 min. then cooled to-78°C. A solution of 4- (3-chloro-4- methoxyphenylmethylamino)-3-chloromethyl-6-cyanoquinoline (0.85 mmol) in DMF was then added dropwise. The reaction was quenched at low temperature and diluted with Et2O then washed with water. The ether layer was concentrated and the residue was purified by flash column (silica gel, CH2CI2/MeOH, 100: 4) to give example 303 (160 mg).
Example 306: A mixture of the compound of Example 305 (20 mg), 1- isopropylpypirizine (13 mg), EDACHCI (20 mg), HOBT. H2O (15 mg) and DMAP (trace) in pyridine (1.5 mL) was stirred at RT for over night. The crude product was purified by preparative HPLC to give Example 306.
TABLE 18 Ex. No. R8 -X2 HPLC MH+ retention time (min.) 304 H -(C=O)OCH3 2.91 4.36 305 Et- (C=O) OCH3 4. 04 464 306 H H 2. 79 378
Examples 307-314 4-[[(3-Chloro-4-methoxyphenyl)methyl]amino]-6-cyano-N-alkyl- 3- quinolinepropanamides
Compounds of formula (lat) wherein R10 and R11 have the values listed in Table 19, were prepared as follows.
The compound of Example 303 (20mg, 0.05mmole) was mixed with BOP reagent (44 mg, 0.1mmole) in 3ml of pyridine and stirred at RT for 3 hours. The resulting reaction mixture was purified by preparative HPLC to afford a cream-colored solid.
TABLE 19 Ex.-NR10R11 HPLC MH+ No. retention time (min.) 307 I--2. 16 486 Han 308 I NH3 2. 08 395 I N NCH3 2. 22 478 310 2. 34 423 HN-\ CHs 311/--\ CHs 2.14 506 -N\ N--/\ 312-No 2. 66 463 313 HN 2.91 477 314 HNX 2.71 463
Example 315<BR> <BR> <BR> 6-Bromo-N- [ (3-chloro-4-methoxyphenyl) methyl]-2- (2-pyridinyl)-4-<BR> <BR> quinolinamine
To a suspension of 6-bromo-2- (2-pyridine) quinoline-3-aminotbutyl ester (preparation 28) (300 mg) in DMF (10 mL) was added a solution of HMDSNa in THF (1 M, 0.9 mL) at RT to generate a brown solution. Then 3- chloro-4-methoxybenzyl chloride (160 mg) was added. The reaction mixture was stirred at RT for 2 h. An additional solution of HMDSNa in THF (0.9 mL) and 3-chloro-4-methoxybenzyl chloride (2 eq) was added and continue to stir.
When the starting material was consumed, the reaction mixture was treated with TFA. Removal of the solvent and the residue was redissolved in EtOAc and washed with 1 N NaOH and water. Removal of the solvent and tritrated with Et20 to give the title compound (163 mg) as a light yellow solid. LC: 1. 73' MH+ : 454.