NOVEL MONOTHIOL MUCOLYTIC AGENTSProvided are mucolytic agents represented by formula (la)-(ld) where the structural variables Rl, R2, R5 and R6 are as defined herein. Also provided are a variety of methods of treatment which take advantage of the mucolytic properties of the compounds represented by formula (la)-(ld). One object of the present invention relates to a method to increase the liquefaction of mucus in a patient with excessive mucus or mucus with increased viscoelastic, cohesive, or adhesive properties. The method includes the step of contacting the mucus of a patient with abnormal or excessive mucus with a composition comprising a mucolytic compound containing a dithiol group to decrease mucus viscoelasticity through the reduction of mucin disulfide bonds.A compound represented by formula (Ia)-(Id):Ic IdwhereinR1 and R2 are each, independently, hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxyl-lower alkyl, phenyl, (phenyl)-lower alkyl, (halophenyl)-lower alkyl, ((lower- alkyl)phenyl)-lower-alkyl, ((lower-alkoxy)phenyl)-lower-alkyl, (naphthyl)-lower-alkyl, or (pyridyl)-lower-alkyl ;each R5 is, independently, hydrogen, halogen, trifluoromethyl, lower alkyl, unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower alkyl-thio, lower alkyl- sulfonyl, or phenyl-lower alkyl-sulfonyl, OH, -(CH2)m-OR8, -0-(CH2)m-OR8, -(CH2)n- NR7R10, -(CH2)n-NR7R7 ,-(CH2)n-NR10R10 ,-0-(CH2)m-NR7R10, -0-(CH2)m-NR7R7, -O-(CH2)m-NR10R10 ,-(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -0-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, - (CH2CH20)m-R8, -0-(CH2CH20)m-R8, -(CH2CH20)m-CH2CH2NR7R10, -0-(CH2CH20)m- CH2CH2NR7R10, -(CH2)n-C(=0)NR7R10, -0-(CH2)m-C(=0)NR7R10, -(CH2)n-(Z)g-R7, -O- (CH2)m-(Z)g-R7, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m-NR10- CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-C02R7, -0-(CH2)m-C02R7, -OSO3H, -O- glucuronide, -O-glucose, -Link-(CH2)m-CAP, -Link-(CH2)n(CHOR8)(CHOR8)n-CAP, -Link-(CH2CH20)m- CH2-CAP, -Link-(CH2CH20)m-CH2CH2-CAP, -Link-(CH2)m-(Z)g-CAP, -Link-(CH2)n(Z)g- (CH2)m-CAP, -Link-(CH2)n-NR13-CH2(CHOR8)(CHOR8)n-CAP, -Link-(CH2)n- (CHOR8)mCH2-NR13-(Z)g-CAP, -Link-(CH2)nNRl3-(CH2)m(CHOR8)nCH2NR13-(Z)g-CAP, - Link-(CH2)m-(Z)g-(CH2)m-CAP, -Link-NH-C(=0)-NH-(CH2)m-CAP, -Link-(CH2)m- C(=0)NR13-(CH2)m-CAP, -Link-(CH2) n-(Z)g-(CH2)m-(Z)g-CAP, or -Link-Zg-(CH2)m-Het- (CH2)m-CAP,with the proviso that at least one R5 group contains at least one basic nitrogen; each R6 is, independently, hydrogen, -C(=0)-R7, or an amino acyl of the natural configuration;each R7 is, independently, hydrogen, lower alkyl, phenyl, substituted phenyl, lower alkyl phenyl, -CH2(CHOR8)m-CH2OR8; 2-furyl or 3- furyl;each R8 is, independently, hydrogen, lower alkyl, lower alkyl phenyl, -C(=0)-Rn, glucuronide, 2-tetrah dropyranyl, oreach R9 is, independently, -C02R7, -CON(R7)2, -S02CH3, -C(=0)R7, -C02R13, - CON(R13)2, -S02CH2R13, or -C(=0)R13;each R10 is, independently, -H, -S02CH3, -C02R7, -C(=0)-NR7R9,-C(=0)R7, or -CH2-(CHOH)n-CH2OH; each Z is, independently, -(CHOH)-, -C(=0)-, -(CHNR7R10)-, -(C=NR10)-, -NR10-, - (CH2)n-,-(CHNR13R13)-, -(C=NR13)- , or -NR13, -C02H;each R11 is, independently, hydrogen, lower alkyl, phenyl lower alkyl or substituted phenyl lower alkyl;each R12 is, independently, -S02CH3, -C02R7, -C(=0)NR7R9, -C(=0)R7, - CH2(CHOH)n-CH2OH, -C02R13, -C(=0)NR13R13, or -C(=0)R13;each 13 *R is, indepedently, hydrogen, lower alkyl, phenyl, substituted phenyl or - CH2(CHOR8)m-CH2OR8, -S02CH3, -C02R7, -C(=0)NR7R9,-C(=0)R7, -CH2-(CHOH)n-CH2OH, -(CH2)m-NR7R10,-(CH2)m- NR7R7, -(CH2)m-NRnRn, -(CH^-CNR1^11^,-(CH. CCHOR^^CH^mN^'R' ^ -CCH^^CCHOR^-CCH^NR'R10, -(CH2)m-NR10R10, -(CH2)m-(CHOR8)m-(CH2)m-(NR11R11R11)+, -(CH2)m-(CHOR8)m-(CH2)mNR7R7;each g is, independently, an integer from 1 to 6;each m is, independently, an integer from 1 to 7;each n is, independently, an integer from 0 to 7;each -Het- is, independently, -N(R7)- ,-N(R10)-, -S-, -SO-, -S02-; -0-, -S02NH-, -NHS02-, -NR7CO-, -CONR7-, -N(R13)-, -S02NR13-, -NR13CO-, or -CONR13-;each Link is, independently, -0-, -(CH2)n-, -0(CH2)m-, -NR13-C(=0)-NR13- , -NR13- C(=0)-(CH2)m-, -C(=0)NR13-(CH2)m-, -(CH2)n-(Z)g-(CH2)n- , -S-, -SO-, -S02-, -S02NR7-, - S02NR10-, or -Het-;each CAP is, independently NR13 NR13R¾3oNR13 Ri3¾: with the proviso that when any -CHOR - or -CH2OR groups are located 1,2- or 1,3- with respect to each other, the R8 groups may, optionally, be taken together to form a cyclic mono- or di-substituted 1,3-dioxane or 1,3-dioxolane;and racemates, enantiomers, diastereomers, tautomers, polymorphs,pseudopolymorphs and pharmaceutically acceptable salts, thereof.
신규 모노티올 점액용해제화학식 Ia-Id에 의해 나타내어지는 점액용해제가 제공된다. 또한, 화학식 Ia-Id에 의해 나타내어지는 화합물의 점액용해 특성을 이용하는 다양한 치료 방법이 제공된다. 본 발명의 하나의 목적은 과도한 점액 또는 점탄성, 응집성 또는 부착성 특성이 증가된 점액을 갖는 환자에서 점액의 액화를 증가시키는 방법에 관한 것이다. 방법은 비정상적 또는 과도한 점액을 갖는 환자의 점액을 디티올 기 함유 점액용해 화합물을 포함하는 조성물과 접촉시켜 뮤신 디술피드 결합의 환원을 통해 점액 점탄성을 감소시키는 단계를 포함한다. 여기서 구조 가변기 R1, R2, R5 및 R6은 본원에 정의된 바와 같다.화학식 Ia-Id에 의해 나타내어지는 화합물 및 그의 라세미체, 거울상이성질체, 부분입체이성질체, 호변이성질체, 다형체, 유사다형체 및 제약상 허용되는 염.여기서R1 및 R2는 각각 독립적으로 수소, 저급 알킬, 할로겐, 트리플루오로메틸, 히드록실-저급 알킬, 페닐, (페닐)-저급 알킬, (할로페닐)-저급 알킬, ((저급-알킬)페닐)-저급-알킬, ((저급-알콕시)페닐)-저급-알킬, (나프틸)-저급-알킬, 또는 (피리딜)-저급-알킬이고;각각의 R5는 독립적으로 수소, 할로겐, 트리플루오로메틸, 저급 알킬, 비치환 또는 치환된 페닐, 저급 알킬-티오, 페닐-저급 알킬-티오, 저급 알킬-술포닐, 또는 페닐-저급 알킬-술포닐, OH, -(CH2)m-OR8, -O-(CH2)m-OR8, -(CH2)n-NR7R10, -(CH2)n-NR7R7, -(CH2)n-NR10R10, -O-(CH2)m-NR7R10, -O-(CH2)m-NR7R7, -O-(CH2)m-NR10R10, -(CH2)n(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m(CHOR8)(CHOR8)n-CH2OR8, -(CH2CH2O)m-R8, -O-(CH2CH2O)m-R8, -(CH2CH2O)m-CH2CH2NR7R10, -O-(CH2CH2O)m-CH2CH2NR7R10, -(CH2)n-C(=O)NR7R10, -O-(CH2)m-C(=O)NR7R10, -(CH2)n-(Z)g-R7, -O-(CH2)m-(Z)g-R7, -(CH2)n-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -O-(CH2)m-NR10-CH2(CHOR8)(CHOR8)n-CH2OR8, -(CH2)n-CO2R7, -O-(CH2)m-CO2R7, -OSO3H, -O-글루쿠로니드, -O-글루코스,-링크-(CH2)m-CAP, -링크-(CH2)n(CHOR8)(CHOR8)n-CAP, -링크-(CH2CH2O)m-CH2-CAP, -링크-(CH2CH2O)m-CH2CH2-CAP, -링크-(CH2)m-(Z)g-CAP, -링크-(CH2)n(Z)g-(CH2)m-CAP, -링크-(CH2)n-NR13-CH2(CHOR8)(CHOR8)n-CAP, -링크-(CH2)n-(CHOR8)mCH2-NR13-(Z)g-CAP, -링크-(CH2)nNR13-(CH2)m(CHOR8)nCH2NR13-(Z)g-CAP, -링크-(CH2)m-(Z)g-(CH2)m-CAP, -링크-NH-C(=O)-NH-(CH2)m-CAP, -링크-(CH2)m-C(=O)NR13-(CH2)m-CAP, -링크-(CH2)n-(Z)g-(CH2)m-(Z)g-CAP, 또는 -링크-Zg-(CH2)m-Het-(CH2)m-CAP이며,단 적어도 1개의 R5 기는 적어도 1개의 염기성 질소를 함유하고;각각의 R6은 독립적으로 수소, -C(=O)-R7, 또는 자연 배위의 아미노 아실이고;각각의 R7은 독립적으로 수소, 저급 알킬, 페닐, 치환된 페닐, 저급 알킬 페닐, -CH2(CHOR8)m-CH2OR8; 2-푸릴 또는 3-푸릴이고;각각의 R8은 독립적으로 수소, 저급 알킬, 저급 알킬 페닐, -C(=O)-R11, 글루쿠로니드, 2-테트라히드로피라닐, 또는이고;각각의 R9는 독립적으로 -CO2R7, -CON(R7)2, -SO2CH3, -C(=O)R7, -CO2R13, -CON(R13)2, -SO2CH2R13, 또는 -C(=O)R13이고;각각의 R10은 독립적으로 -H, -SO2CH3, -CO2R7, -C(=O)-NR7R9, -C(=O)R7, 또는 -CH2-(CHOH)n-CH2OH이고;각각의 Z는 독립적으로 -(CHOH)-, -C(=O)-, -(CHNR7R10)-, -(C=NR10)-, -NR10-, -(CH2)n-, -(CHNR13R13)-, -(C=NR13)-, 또는 -NR13, -CO2H이고;각각의 R11은 독립적으로 수소, 저급 알킬, 페닐 저급 알킬 또는 치환된 페닐 저급 알킬이고;각각의 R12는 독립적으로 -SO2CH3, -CO2R7, -C(=O)NR7R9, -C(=O)R7, -CH2(CHOH)n-CH2OH, -CO2R13, -C(=O)NR13R13, 또는 -C(=O)R13이고;각각의 R13은 독립적으로 수소, 저급 알킬, 페닐, 치환된 페닐 또는 -CH2(CHOR8)m-CH2OR8, -SO2CH3, -CO2R7, -C(=O)NR7R9, -C(=O)R7, -CH2-(CHOH)n-CH2OH, -(CH2)m-NR7R10, -(CH2)m-NR7R7, -(CH2)m-NR11R11, -(CH2)m-(NR11R11R11)+, -(CH2)m-(CHOR8)m-(CH2)mNR11R11, -(CH2)m-(CHOR8)m-(CH2)mNR7R10, -(CH2)m-NR10R10, -(CH2)m-(CHOR8)m-(CH2)m-(NR11R11R11)+, -(CH2)m-(CHOR8)m-(CH2)mNR7R7이고;각각의 g는 독립적으로 1 내지 6의 정수이고;각각의 m은 독립적으로 1 내지 7의 정수이고;각각의 n은 독립적으로 0 내지 7의 정수이고;각각의 -Het-는 독립적으로 -N(R7)-, -N(R10)-, -S-, -SO-, -SO2-; -O-, -SO2NH-, -NHSO2-, -NR7CO-, -CONR7-, -N(R13)-, -SO2NR13-, -NR13CO-, 또는 -CONR13-이고;각각의 링크는 독립적으로 -O-, -(CH2)n-, -O(CH2)m-, -NR13-C(=O)-NR13-, -NR13-C(=O)-(CH2)m-, -C(=O)NR13-(CH2)m-, -(CH2)n-(Z)g-(CH2)n-, -S-, -SO-, -SO2-, -SO2NR7-, -SO2NR10-, 또는 -Het-이고;각각의 CAP은 독립적으로이며,단 임의의 -CHOR8- 또는 -CH2OR8 기가 서로에 대해 1,2- 또는 1,3-에 위치하는 경우에, R8 기는 임의로 함께 시클릭 일- 또는 이치환된 1,3-디옥산 또는 1,3-디옥솔란을 형성할 수 있다.