IP Library › Patent Application 17776968

Patent Application

App. No. 17/776,968

METHODS AND COMPOSITIONS FOR SMOKING CESSATION

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Patent No.: US None
App. No.: 17/776,968

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Abstract

This disclosure describes the use of a phosphodiesterase-5 (PDE5) inhibitor to reduce an individual's desire to smoke and/or frequency of smoking. In some embodiments, the PDE5 inhibitor is sildenafil (e.g., Viagra).

Claims (283)

1 . A method of reducing an individual's desire to smoke and/or frequency of smoking, comprising:

administering to the individual a phosphodiesterase-5 (PDE5) inhibitor or pharmaceutically acceptable salt thereof in an amount effective to reduce the individual's desire to smoke, reduce the frequency of smoking, or both.

2 . The method of claim 1 wherein the PDE5 inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Z is O or S;

W is N or CR 5 ;

X 1 and X 2 are each independently selected from N, NR 6 , and CR 7 ;

X 3 is N or CR 8 ;

X 4 is C or N;

R 1 is H, C 1-6 alkyl, or -L-O—(C 1-6 alkyl);

R 2 is H, C 1-6 alkyl, or C 4-10 cycloalkyl;

R 3 is H, NO 2 , C 1-6 alkyl, C 4-10 cycloalkyl, C 1-6 alkyl(hetCyc 1 ), C(═O)R 9 , SO 2 (hetCyc 1 ), or SO 2 NR 10 R 11 , wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 4 is H, C 1-6 alkyl, C 4-10 cycloalkyl, or C(═O)(C 1-6 alkyl);

R 5 is H, C 1-6 alkyl, or C 4-10 cycloalkyl;

R 6 is H, C 1-6 alkyl, C 4-10 cycloalkyl, -L-O—(C 1-6 alkyl), -L-O—(C 4-10 cycloalkyl), -L-aryl, -L-hetAr 1 , or -L-hetCyc 1 ;

R 7 is H, C 1-6 alkyl, or C 4-10 cycloalkyl;

R 8 is H, C 1-6 alkyl, or C 4-10 cycloalkyl;

R 9 is C 1-6 alkyl, C 4-10 cycloalkyl, C 1-6 alkyl(hetCyc 1 ), hetCyc 1 , or C 1-6 alkyl(hetCyc 1 )(C 2-6 alkenyl)(aryl), wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 10 is H or C 1-6 alkyl;

R 11 is H, C 1-6 alkyl, C 1-6 alkyl(NR′R″), C 1-6 alkyl(hetCyc 1 ), and (C 1-6 alkyl)C(═O)NR′(C 1-6 alkyl)C(═O)NR′R″, wherein R′ and R″ are each independently selected from H and C 1-6 alkyl;

hetAr 1 is a 5-12 membered heteroaryl ring having 1-3 ring atoms independently selected from N, O, and S which is optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, amino, cyano, C 1-6 alkoxy, and hydroxy;

hetCyc 1 is a 6-10 membered heterocycloalkyl ring system having 1-3 ring atoms independently selected from N, O, and S which is optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, oxo, amino, cyano, C 1-6 alkoxy, hydroxy, C 1-6 hydroxyalkyl, and C 1-6 alkyl(aryl);

L is absent or C 1-6 alkyl; and

the dashed lines can be single or double bonds.

3 . The method of claim 2 , wherein the compound of Formula I is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

Z is O or S;

W is N or CR 5 ;

R 1 is H, C 1-6 alkyl, or -L-O—(C 1-6 alkyl);

R 3 is H, NO 2 , C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), C(═O)R 9 , SO 2 (hetCyc 1 ), or SO 2 NR 10 R 11 , wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 4 is H, C 1-6 alkyl, or C(═O)(C 1-6 alkyl);

R 5 is H or C 1-6 alkyl;

R 6 is H, C 1-6 alkyl, -L-O—(C 1-6 alkyl), -L-aryl, -L-hetAr 1 , or -L-hetCyc 1 ;

R 8 is H or C 1-6 alkyl;

R 9 is C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), hetCyc 1 , or C 1-6 alkyl(hetCyc 1 )(C 2-6 alkenyl)(aryl), wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 10 is H or C 1-6 alkyl;

L is absent or C 1-6 alkyl.

4 . The method of claim 3 , wherein Z is O.

5 . The method of claim 3 , wherein Z is S.

6 . The method of any one of claims 3 - 5 , wherein W is CH.

7 . The method of any one of claims 3 - 6 , wherein R 1 is H.

8 . The method of any one of claims 3 - 6 , wherein R 1 is C 1-3 alkyl.

9 . The method of claim 8 , wherein R 1 is ethyl.

10 . The method of claim 8 , wherein R 1 is propyl.

11 . The method of any one of claims 3 - 10 , wherein R 4 is H.

12 . The method of any one of claims 3 - 11 , wherein R 6 is C 1-3 alkyl.

13 . The method of claim 12 , wherein R 6 is methyl.

14 . The method of any one of claims 3 - 13 , wherein R 8 is C 1-3 alkyl.

15 . The method of claim 14 , wherein R 8 is propyl.

16 . The method of claim 2 , wherein the compound of Formula I is a compound of Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

Z is O or S;

W is N or CR 5 ;

R 1 is H, C 1-6 alkyl, or -L-O—(C 1-6 alkyl);

R 3 is H, NO 2 , C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), C(═O)R 9 , SO 2 (hetCyc 1 ), or SO 2 NR 10 R 11 , wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 4 is H, C 1-6 alkyl, or C(═O)(C 1-6 alkyl);

R 5 is H or C 1-6 alkyl;

R 6 is H, C 1-6 alkyl, -L-O—(C 1-6 alkyl), -L-aryl, -L-hetAr 1 , or -L-hetCyc 1 ;

R 8 is H or C 1-6 alkyl;

R 9 is C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), hetCyc 1 , or C 1-6 alkyl(hetCyc 1 )(C 2-6 alkenyl)(aryl), wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 10 is H or C 1-6 alkyl;

L is absent or C 1-6 alkyl.

17 . The method of claim 16 , wherein Z is O.

18 . The method of claim 16 or 17 , wherein W is CH.

19 . The method of claim 16 or 17 , wherein W is N.

20 . The method of any one of claims 16 - 19 , wherein R 1 is C 1-6 alkyl.

21 . The method of claim 20 , wherein R 1 is ethyl, propyl, or butyl.

22 . The method of any one of claims 16 - 19 , wherein R 1 is —(C 1-6 alkyl)-O—(C 1-6 alkyl).

23 . The method of any one of claims 16 - 22 , wherein R 4 is H.

24 . The method of any one of claims 16 - 22 , wherein R 4 is C(═O)(C 1-6 alkyl).

25 . The method of claim 24 , wherein C 1-6 alkyl is methyl.

26 . The method of any one of claims 16 - 25 , wherein R 6 is C 1-3 alkyl.

27 . The method of any one of claims 16 - 25 , wherein R 6 is —(C 1-6 alkyl)-O—(C 1-6 alkyl).

28 . The method of any one of claims 16 - 25 , wherein R 6 is phenyl.

29 . The method of any one of claims 16 - 25 , wherein R 6 is —(C 1-6 alkyl)-hetAr 1 .

30 . The method of claim 29 , wherein hetAr 1 is pyridine.

31 . The method of any one of claims 16 - 25 , wherein R 6 is hetCyc 1 optionally substituted with C 1-6 alkyl.

32 . The method of claim 31 , wherein R 6 is piperidine or azetidine substituted with C 1-3 alkyl.

33 . The method of any one of claims 16 - 32 , wherein R 8 is C 1-3 alkyl.

34 . The method of claim 33 , wherein R 8 is ethyl.

35 . The method of claim 2 , wherein the compound of Formula I is a compound of Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein:

Z is O or S;

W is N or CR 5 ;

R 1 is H, C 1-6 alkyl, or -L-O—(C 1-6 alkyl);

R 3 is H, NO 2 , C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), C(═O)R 9 , SO 2 (hetCyc 1 ), or SO 2 NR 10 R 11 , wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 4 is H, C 1-6 alkyl, or C(═O)(C 1-6 alkyl);

R 5 is H or C 1-6 alkyl;

R 6 is H, C 1-6 alkyl, -L-O—(C 1-6 alkyl), -L-aryl, -L-hetAr 1 , or -L-hetCyc 1 ;

R 8 is H or C 1-6 alkyl;

R 9 is C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), hetCyc 1 , or C 1-6 alkyl(hetCyc 1 )(C 2-6 alkenyl)(aryl), wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 10 is H or C 1-6 alkyl;

L is absent or C 1-6 alkyl.

36 . The method of claim 35 , wherein Z is O.

37 . The method of claim 35 or 36 , wherein W is CH.

38 . The method of any one of claims 35 - 37 , wherein R 1 is C 1-3 alkyl.

39 . The method of claim 38 , wherein R 1 is ethyl.

40 . The method of any one of claims 35 - 39 , wherein R 4 is H.

41 . The method of any one of claims 35 - 40 , wherein R 6 is C 1-3 alkyl.

42 . The method of claim 41 , wherein R 6 is methyl.

43 . The method of any one of claims 35 - 42 , wherein R 8 is C 1-3 alkyl.

44 . The method of claim 43 , wherein R 8 is propyl.

45 . The method of claim 2 , wherein the compound of Formula I is a compound of Formula Id:

or a pharmaceutically acceptable salt thereof, wherein:

Z is O or S;

W is N or CR 5 ;

R 1 is H, C 1-6 alkyl, or -L-O—(C 1-6 alkyl);

R 3 is H, NO 2 , C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), C(═O)R 9 , SO 2 (hetCyc 1 ), or SO 2 NR 10 R 11 , wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 4 is H, C 1-6 alkyl, or C(═O)(C 1-6 alkyl);

R 5 is H or C 1-6 alkyl;

R 6 is H, C 1-6 alkyl, -L-O—(C 1-6 alkyl), -L-aryl, -L-hetAr 1 , or -L-hetCyc 1 ;

R 8 is H or C 1-6 alkyl;

R 9 is C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), hetCyc 1 , or C 1-6 alkyl(hetCyc 1 )(C 2-6 alkenyl)(aryl), wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 10 is H or C 1-6 alkyl;

L is absent or C 1-6 alkyl.

46 . The method of claim 45 , wherein Z is O.

47 . The method of claim 45 or 46 , wherein W is CH.

48 . The method of any one of claims 45 - 47 , wherein R 1 is C 1-3 alkyl.

49 . The method of claim 48 , wherein R 1 is propyl.

50 . The method of any one of claims 45 - 49 , wherein R 4 is H.

51 . The method of any one of claims 45 - 50 , wherein R 6 is C 1-3 alkyl.

52 . The method of claim 51 , wherein R 6 is ethyl.

53 . The method of any one of claims 45 - 52 , wherein R 8 is C1-3 alkyl.

54 . The method of claim 53 , wherein R 8 is propyl.

55 . The method of claim 2 , wherein the compound of Formula I is a compound of Formula Ie:

or a pharmaceutically acceptable salt thereof, wherein:

Z is O or S;

W is N or CR 5 ;

R 1 is H, C 1-6 alkyl, or -L-O—(C 1-6 alkyl);

R 3 is H, NO 2 , C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), C(═O)R 9 , SO 2 (hetCyc 1 ), or SO 2 NR 10 R 11 , wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 4 is H, C 1-6 alkyl, or C(═O)(C 1-6 alkyl);

R 5 is H or C 1-6 alkyl;

R 6 is H, C 1-6 alkyl, -L-O—(C 1-6 alkyl), -L-aryl, -L-hetAr 1 , or -L-hetCyc 1 ;

R 9 is C 1-6 alkyl, C 1-6 alkyl(hetCyc 1 ), hetCyc 1 , or C 1-6 alkyl(hetCyc 1 )(C 2-6 alkenyl)(aryl), wherein any C 1-6 alkyl is optionally substituted with hydroxy or halogen;

R 10 is H or C 1-6 alkyl;

L is absent or C 1-6 alkyl.

56 . The method of claim 55 , wherein Z is O.

57 . The method of claim 55 or 56 , wherein W is CH.

58 . The method of any one of claims 55 - 57 , wherein R 1 is C 1-3 alkyl.

59 . The method of claim 58 , wherein R 1 is propyl.

60 . The method of any one of claims 55 - 59 , wherein R 4 is H.

61 . The method of any one of claims 55 - 60 , wherein R 6 is H.

62 . The method of any one of claims 2 - 61 , wherein R 3 is selected from

63 . The method of claim 1 , wherein the PDE5 inhibitor is a compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein:

Z 1 is O or S;

Z 2 is O or S;

R 1 is H, C 1-6 alkyl, C 4-10 cycloalkyl, or C 1-6 hydroxyalkyl;

R 2 is H, C 1-6 alkyl, C 4-10 cycloalkyl, or C 1-6 hydroxyalkyl;

R 3 is H, C 1-6 alkyl, C 4-10 cycloalkyl, C 1-6 alkyl(hetCyc 1 ), C 1-6 alkyl(hetAr 1 ), or C 1-6 alkyl(aryl), wherein any C 1-6 alkyl is optionally substituted with one or more hydroxy and halogen, and aryl is optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, amino, cyano, C 1-6 alkoxy, and hydroxy;

R 4 is H, C 1-6 alkyl, C 4-10 cycloalkyl, or NR′R″, wherein R′ and R″ are each independently selected from H, C 1-6 alkyl, C 4-10 cycloalkyl, hetCyc 1 , hetAr 1 , aryl, C 1-6 alkyl(hetCyc 1 ), C 1-6 alkyl(hetAr 1 ), and C 1-6 alkyl(aryl), and wherein any C 1-6 alkyl or C 4-10 cycloalkyl is optionally substituted with one or more hydroxy and halogen, and aryl is optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, amino, cyano, C 1-6 alkoxy, and hydroxy;

64 . The method of claim 63 , wherein Z 1 and Z 2 are each O.

65 . The method of claim 63 or 64 , wherein R 1 is C 1-3 hydroxyalkyl.

66 . The method of any one of claims 63 - 65 , wherein R 2 is C 1-3 alkyl.

67 . The method of claim 66 , wherein R 2 is ethyl.

68 . The method of any one of claims 63 - 67 , wherein R 3 is C 1-3 alkyl(aryl) optionally substituted with one or two substituents independently selected from halogen and C 1-6 alkoxy.

69 . The method of any one of claims 63 - 68 , wherein R 4 is NR′R″.

70 . The method of claim 69 , wherein R′ is H.

71 . The method of claim 69 or 70 , wherein R″ is C 4-10 cycloalkyl optionally substituted with hydroxy.

72 . The method of claim 71 , wherein C 4-10 cycloalkyl is cyclopentyl.

73 . The method of claim 1 , wherein the PDE5 inhibitor is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, hydroxy, C 1-6 alkyl, C 4-10 cycloalkyl, or C 1-6 hydroxyalkyl;

R 2 is H, C 1-6 alkyl, C 4-10 cycloalkyl, or hetCyc 1 ;

R 3 is H, C 1-6 alkyl, C 4-10 cycloalkyl, or C 2-10 alkenyl;

R 4 is H, C 1-6 alkyl, C 4-10 cycloalkyl, or hetCyc 1 ;

R 5 is H, C 1-6 alkyl, C 4-10 cycloalkyl, or C 1-6 alkoxy;

n is 0 to 5.

74 . The method of claim 73 , wherein R 1 is hydroxy.

75 . The method of claim 73 or 74 , wherein R 2 is hetCyc 1 optionally substituted with one to four substituents independently selected from hydroxy and C 1-3 hydroxyalkyl.

76 . The method of claim 75 , wherein R 2 is tetrahydropyran substituted with one to four substituents independently selected from hydroxy and C 1-3 hydroxyalkyl.

77 . The method of any one of claims 73 - 76 , wherein R 3 is C 2-10 alkenyl.

78 . The method of claim 77 , wherein R 3 is C 5 alkenyl.

79 . The method of any one of claims 73 - 78 , wherein R 4 is hetCyc 1 optionally substituted with one to four substituents independently selected from hydroxy and C 1-3 alkyl.

80 . The method of claim 79 , wherein R 4 is tetrahydropyran substituted with one to four substituents independently selected from hydroxy and C 1-3 alkyl.

81 . The method of any one of claims 73 - 80 , wherein R 5 is C 1-6 alkoxy.

82 . The method of claim 81 , wherein R 5 is methoxy.

83 . The method of any one of claims 73 - 82 , wherein n is 1.

84 . The method of claim 1 , wherein the PDE5 inhibitor is a compound of Formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 4-10 cycloalkyl, or hetCyc 1 ;

R 2 and R 3 are each independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 4-10 cycloalkyl, and hetCyc 1 ; and

85 . The method of claim 84 , wherein R 1 is hetCyc 1 .

86 . The method of claim 85 , wherein hetCyc 1 is piperidine.

87 . The method of any one of claims 84 - 86 , wherein R 2 is C 1-3 hydroxyalkyl.

88 . The method of any one of claims 84 - 87 , wherein R 3 is C 1-3 hydroxyalkyl.

89 . The method of any one of claims 84 - 88 , wherein R 2 and R 3 are each C 1-3 hydroxyalkyl.

90 . The method of claim 1 , wherein the PDE5 inhibitor is a compound of Formula V:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 2 , and R 3 are each independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 4-10 cycloalkyl, and hetCyc 1 ; and

91 . The method of claim 90 , wherein R 1 is H.

92 . The method of claim 90 or 91 , wherein R 2 is hetCyc 1 .

93 . The method of claim 92 , wherein hetCyc 1 is 1,3-benzodioxole.

94 . The method of any one of claims 90 - 93 , wherein R 3 is C 1-3 alkyl.

95 . The method of claim 95 , wherein R 3 is methyl.

96 . The method of claim 1 , wherein the PDE5 inhibitor is a compound of Formula VI:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 4-10 cycloalkyl, or hetCyc 1 ;

R 2 , R 2′ , R 3 and R 3′ are each independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 4-10 cycloalkyl, aryl, hetCyc 1 , hetAr 1 , C 1-6 alkyl(aryl), C 1-6 alkyl(hetCyc 1 ), and C 1-6 alkyl(hetAr 1 ), wherein aryl is optionally substituted with halogen, C 1-6 alkyl, C 1-6 alkoxy, amino, cyano, hydroxy, and C 1-6 hydroxyalkyl;

97 . The method of claim 96 , wherein R 1 is hetCyc 1 optionally substituted with C 1-3 hydroxyalkyl.

98 . The method of claim 97 , wherein hetCyc 1 is pyrrolidine.

99 . The method of any one of claim 96 - 98 , wherein R 2 and R 2′ are each H.

100 . The method of any one of claims 96 - 99 , wherein R 3 is C 1-3 alkyl(aryl) substituted with one or two substituents selected from halogen and C 1-3 alkoxy.

101 . The method of any one of claims 96 - 100 , wherein R 3′ is C 1-3 alkyl(hetAr 1 ).

102 . The method of claim 101 , wherein hetAr 1 is pyrimidine.

103 . The method of claim 1 , wherein the PDE5 inhibitor is a compound of Formula VII:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, amino, nitro, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 4-10 cycloalkyl, or hetCyc 1 ;

R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 4-10 cycloalkyl, and hetCyc 1 ;

R 5 is H, amino, nitro, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 4-10 cycloalkyl;

L is —C 1-6 alkyl- or —C 1-6 alkoxy-; and

n is 0 to 5.

104 . The method of claim 103 , wherein R 1 is nitro.

105 . The method of claim 103 or 104 , wherein R 2 is H.

106 . The method of any one of claims 103 - 105 , wherein R 3 is C 1-3 hydroxyalkyl.

107 . The method of any one of claims 103 - 106 , wherein R 4 is H.

108 . The method of any one of claims 103 - 107 , wherein R 5 is C 1-6 alkoxy.

109 . The method of claim 108 , wherein R 5 is methoxy.

110 . The method of any one of claims 103 - 109 , wherein n is 1.

111 . The method of any one of claims 103 - 110 , wherein L is —C 1-3 alkyl-.

112 . The method of any one of claims 1 - 111 , wherein the PDE5 inhibitor is selected from

and pharmaceutically acceptable salts thereof.

113 . The method of claim 1 , wherein the PDE5 inhibitor is selected from

and pharmaceutically acceptable salts thereof.

114 . The method of claim 1 , wherein the PDE5 inhibitor is sildenafil:

or a pharmaceutically acceptable salt thereof.

115 . The method of any one of claims 1 - 114 , wherein the PDE5 inhibitor or pharmaceutically acceptable salt thereof is administered to the individual at a dose of about 1 mg/day to about 150 mg/day.

116 . The method of any one of claims 1 - 115 , wherein the effective amount of the PDE5 inhibitor or pharmaceutically acceptable salt thereof is from about 1 mg/day to about 150 mg/day.

117 . The method of any one of claims 1 - 116 , wherein the PDE5 inhibitor or pharmaceutically acceptable salt thereof is formulated for oral administration.

118 . The method of any one of claims 1 - 117 , wherein the PDE5 inhibitor or pharmaceutically acceptable salt thereof is formulated for extended/delayed release.

119 . The method of any one of claims 1 - 118 , further comprising co-administering to the individual nicotine replacement (e.g., in the form of gum or a transdermal patch), bupropion (e.g., Wellbutrin®), tadalafil (e.g., Cialis®), vardenafil (e.g., Levitra®), or varenicline (e.g., Chantix®), or derivatives, enantiomers, metabolites, or pharmaceutically acceptable salts thereof.

120 . The method of any one of claims 1 - 119 , further comprising applying motivational interviewing, incentive based programming, or other psychological technique(s) to the individual.

121 . The method of any one of claims 1 - 120 , wherein the individual, following administration for a period of time, exhibits an improvement in the lung diffusing capacity for carbon monoxide (DLCO).

122 . The method of any one of claims 1 - 121 , wherein the individual, following administration for a period of time, exhibits tissue re-perfusion.

123 . The method of any one of claims 1 - 122 , wherein the individual, following administration for a period of time, exhibits a reduction in parenchymal inflammation (or lung density).

124 . An article of manufacture, comprising:

at least one dose of a PDE5 inhibitor of any one of claims 2 - 114 or a pharmaceutically acceptable salt thereof in an amount effective to reduce an individual's desire to smoke and/or frequency of smoking; and

at least one dose of a nicotine replacement (e.g., in the form of gum or a transdermal patch), bupropion (e.g., Wellbutrin®) tadalafil (e.g., Cialis®), vardenafil (e.g., Levitra®), or varenicline (e.g., Chantix®), or derivatives, enantiomers, metabolites, or pharmaceutically acceptable salts thereof in an amount effective to reduce an individual's desire to smoke and/or frequency of smoking.

125 . The method of claim 124 , further comprising applying motivational interviewing, incentive based programming, or other psychological technique(s) to the individual.

126 . A method of reducing an individual's desire to smoke and/or frequency of smoking, comprising:

administering to the individual an amount of sildenafil (Viagra®), a derivative of sildenafil, an enantiomer of sildenafil, an active metabolite of sildenafil, or a pharmaceutically acceptable salt of sildenafil effective to reduce the individual's desire to smoke and/or frequency of smoking.

127 . The method of claim 126 , wherein the sildenafil or derivative, enantiomer or pharmaceutically acceptable salt thereof is administered to the individual at a dose of about 1 mg/day to about 150 mg/day.

128 . The method of claim 126 , wherein the effective amount of the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof is from about 1 mg/day to about 150 mg/day.

129 . The method of any one of claims 126 - 128 , wherein the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof is formulated for oral administration.

130 . The method of any one of claims 126 - 129 , wherein the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof is formulated for extended/delayed release.

131 . The method of any one of claims 126 - 130 , further comprising co-administering to the individual a nicotine replacement (e.g., in the form of gum or a transdermal patch), bupropion (e.g., Wellbutrin®), tadalafil (e.g., Cialis®), vardenafil (e.g., Levitra®), or varenicline (e.g., Chantix®), or derivatives, enantiomers, metabolites, or pharmaceutically acceptable salts thereof.

132 . The method of any one of claims 126 - 131 , further comprising applying motivational interviewing, incentive based programming, or other psychological technique(s) to the individual.

133 . The method of any one of claims 126 - 132 , wherein the individual, following administration for a period of time, exhibits an improvement in the lung diffusing capacity for carbon monoxide (DLCO).

134 . The method of any one of claims 126 - 133 , wherein the individual, following administration for a period of time, exhibits tissue re-perfusion.

135 . The method of any one of claims 126 - 134 , wherein the individual, following administration for a period of time, exhibits a reduction in parenchymal inflammation (or lung density).

136 . An article of manufacture, comprising:

at least one dose of sildenafil (Viagra®), a derivative of sildenafil, an enantiomer of sildenafil, an active metabolite of sildenafil, or a pharmaceutically acceptable salt of sildenafil effective to reduce an individual's desire to smoke and/or frequency of smoking; and

at least one dose of a nicotine replacement (e.g., in the form of gum or a transdermal patch), bupropion (e.g., Wellbutrin®) tadalafil (e.g., Cialis®), vardenafil (e.g., Levitra®), or varenicline (e.g., Chantix®), or derivatives, enantiomers, metabolites, or pharmaceutically acceptable salts thereof effective to reduce an individual's desire to smoke and/or frequency of smoking.

137 . The article of manufacture of claim 136 , wherein the at least one dose of the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof comprises about 1 mg to about 150 mg.

138 . The article of manufacture of claim 136 or claim 137 , wherein the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof is formulated for oral administration.

139 . The article of manufacture of any one of claims 136 - 138 , wherein the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof is formulated for extended/delayed release.

140 . An article of manufacture, comprising at least one dose of sildenafil (Viagra®), a derivative of sildenafil, an enantiomer of sildenafil, an active metabolite of sildenafil, or a pharmaceutically acceptable salt of sildenafil, wherein the at least one dose comprises about 1 mg to about 40 mg of the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof.

141 . The article of manufacture of claim 140 , further comprising at least one dose of a nicotine replacement (e.g., in the form of gum or a transdermal patch), bupropion (e.g., Wellbutrin®) tadalafil (e.g., Cialis®), vardenafil (e.g., Levitra®), or varenicline (e.g., Chantix®), or derivatives, enantiomers, metabolites, or pharmaceutically acceptable salts thereof.

142 . The article of manufacture of claim 140 or 141 , wherein the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof is formulated for oral administration.

143 . The article of manufacture of any one of claims 140 - 142 , wherein the sildenafil or derivative, enantiomer, metabolite, or pharmaceutically acceptable salt thereof is formulated for extended/delayed release.