Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use

• US 20020019405A1
• Filed: 08/30/2001
• Published: 02/14/2002
• Est. Priority Date: 11/01/1996
• Status: Active Grant

• Current Assignee: David S. Garvey, Inigo Saenz De Tejada, Richard A. Earl, Subhash P. Khanapure
• Original Assignee: David S. Garvey, Inigo Saenz De Tejada, Richard A. Earl, Subhash P. Khanapure
• Inventors: Tejada, Inigo Saenz de, Earl, Richard A., Garvey, David S., Khanapure, Subhash P.
• Granted Patent: US 6,462,044 B2
• Time in Patent Office: Days
• US Class Current: 514/253.03
• CPC Class Codes: A61K 31/075 Ethers or acetals
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention describes novel nitrosated and/or nitrosylated phosphodiesterase inhibitors, and novel compositions containing at least one nitrosated and/or nitrosylated phosphodiesterase inhibitor, and, optionally, one or more compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or one or more vasoactive agents. The present invention also provides novel compositions containing at least one phosphodiesterase inhibitor, and one or more compounds that donate, transfer or release nitric oxide, elevate endogenous levels of endothelium-derived relaxing factor, stimulate endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or one or more vasoactive agents. The present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing diseases induced by the increased metabolism of cyclic guanosine 3′,5′-monophosphate (cGMP), such as hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis (BPH), bladder outlet obstruction, incontinence, conditions of reduced blood vessel patency, e.g., postpercutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, allergic rhinitis, glucoma, and diseases characterized by disorders of gut motility, e.g., irritable bowel syndrome (IBS).

Claims

1. A compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XII), formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII) or formula (XIX):

wherein the compound of formula (I) is;

wherein

R₁ is an alkoxy, a cycloalkoxy, a halogen, or

R₂ is a hydrogen, an alkoxy, or a haloalkoxy; and

R₃ is;

wherein,

D is;

(i) —

NO,

(ii) —

NO₂,

(iii) —

CH(R_d)—

O—

C(O)-Y-Z(C(R_e)(R_f))_p-T-Q,

(iv) —

C(O)-Y-Z-(G-(C(R_e)(R_f))_b-T-Q)_p;

(v) —

P-Z-(G-(C(R_e)(R_f))_b-T-Q)_p;

(vi) —

P₁-B₁-W-B_t-L_r-E_s-[C(R_e)(R_f)]_w-E_c-[C(R_e)(R_f)]_x-L_d-[C(R_e)(R_f)]_y-L_i-E_j-L_g-[C(R_e)(R_f)]_z-T-Q or

(vii) —

P₁-F′

_n-L_r-E_s-[C(R_e)(R_f)]_w-E_c-[C(R_e)(R_f)]_x-L_d-[C(R_e)(R_f)]_y-L_i-E_i-L_g-[C(R_e)(R_f)]_z -T-Q

wherein,

R_d is a hydrogen, a lower alkyl, a cycloalkyl, an aryl or an arylalkyl;

Y is oxygen, S(O)_o, lower alkyl or NR₁;

o is an integer from 0 to 2;

R_i is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, —

CH₂—

C(T-Q)(R_e)(R_f), or —

(N₂O₂—

)⁻



M⁺, wherein M⁺ in an organic or inorganic cation;

R_e and R_f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, -T-Q , or [C(R_e)(R_f)]_k-T-Q, or R_e and R_f taken together are a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group;

k is an integer from 1 to 3;

p is an integer from 1 to 10;

T is independently a covalent bond, oxygen, S(O)_o or NR₁;

Z is a covalent bond, an alkyl, an aryl, an arylalkyl, an alkylaryl, a heteroalkyl, or (C(R_e)(R_f))_p;

Q is —

NO or —

NO₂;

G is a covalent bond, -T-C(O)—

, —

C(O)-T- or T;

b is an integer from 0 to 5;

P is a carbonyl, a phosphoryl or a silyl;

l and t are each independently an integer from 1 to 3;

r, S, c, d, g, i and j are each independently an integer from 0 to 3;

w, x, y and z are each independently an integer from 0 to 10;

P₁ is a covalent bond or P;

B at each occurrence is independently an alkyl group, an aryl group, or [C(R_e)(R_f)]_p;

E at each occurrence is independently -T-, an alkyl group, an aryl group, or —

(CH₂CH₂O)_q,

q is an integer of from 1 to 5;

L at each occurrence is independently —

C(O)—

, —

C(S)—

,-T-, a heterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, an arylheterocyclic ring, or —

(CH₂CH₂O)_q;

W is oxygen, S(O)_o, or NR_I;

F′

at each occurrence is independently selected from B or carbonyl;

n is an integer from 2 to 5;

with the proviso that when R₁ is —

CH₂—

C(T-Q)(R_e)(R_f) or —

(N₂O₂)⁻

M⁺, or R_e or R_f are T-Q or [C(R_e)(R_f)]_k-T-Q, then the “

-T-Q”

subgroup designated in D can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, or an aryl.

R₄ is;

(i) hydrogen;

(ii) —

CH(R_d)—

O—

C(O)-Y-Z-(C(R_ef)(R_f))_p-T-Q,

(iii) —

C(O)-T-(C(R_e)(R_f))_p-T-Q;

(iv) —

C(O)-Z-(G-(C(R_e)(R_f))_p-T-Q)_p or

(v) —

W_o-L_r-E_s-[C(R_e)(R_f)]_w-E_c-[C(R_e)(R_f)]_x-L_d-[C(R_e)(R_f)]_y-L_l-E_j-L_g-[C(R_e)(R_f)]_z-T-Q

wherein r, s, c, d, g, i, j, o, p, w, x, y, z, R_d, R_eR_f, E, L, G, T, Q, W, Y, and Z areas defined herein;

R₅ is a lone pair of electrons or —

CH(R_d)—

O—

C(O)-Y-Z-(C(R_e)(R_f))_p-T-Q;

R₁₁ and R₁₂ are independently selected from hydrogen or R₄;

wherein R₄, R_d, R_eR_f, p, T, Q, Y, and Z are as defined herein;

X is a halogen, and D₁ is D or hydrogen, wherein D is as defined herein; and

with the proviso that if the structure does not contain D, then at least one of the variables R₄, R₅, R₁₁ or R₁₂ must contain the element “

-T-Q”

;

wherein the compound of formula (II) is;

wherein,

R₄ is as defined herein;

with the proviso that R₄ cannot be hydrogen;

R₈ is a hydrogen, a lower alkyl group or a haloalkyl group;

R₉ is a hydrogen or a halogen; and

R₁₀ is;

(i) hydrogen,

wherein R₈ is as defined herein;

wherein the compound of formula (III) is;

wherein,

E₁ is nitrogen or —

CH—

;

G₁ is nitrogen or —

C(R₈)—

;

R₂₁ is

R₂₂ is R₁₂ or a lower alkyl;

R₃₃ is a lower alkyl or [C(R_e)(R_f)]_p-T-Q; and

p, R_e, R_f, R₁₁, R₁₂, T and Q are as defined herein;

with the proviso that at least one of the variables R₁₁, R₁₂, R₂₂ or R₃₃ must contain the element “

T-Q”

;

wherein the compound of formula (IV)⁻

is;

wherein,

G₂ is —

CH₂—

or sulfur;

R₄ and R₈ are each as defined herein; and

R₁₃ is;

wherein,

R₆ and R₇are independently selected from R₄, wherein R₄is as defined herein;

with the proviso that at least one of the variables R₄, R₆ or R₇ must contain the element “

T-Q”

;

wherein the compound of formula (V) is;

wherein,

R₄ is as defined herein; and

R₁₄ is;

wherein R₆ is as defined herein, with the proviso that at least one of the variables R₄, or R₆ must contain the element “

T-Q”

;

wherein the compound of formula (VI) is;

wherein,

R₁₅ is a hydrogen, a lower alkyl, R₄, or —

(CH₂)₄—

C(CH₃)₂—

O-D₁;

wherein R₄ is as defined herein;

R₁₆ is a lower alkyl; and

R₁₇ is a hydrogen, a lower alkyl, CH₃—

C(O)—

CH₂—

;

CH₃—

O—

CH₂—

, or D with the proviso that either R₁₅ or R₁₇ must contain D, wherein D and D₁ are as defined herein;

wherein the compound of formula (VII) is;

wherein,

R₄ and R₈ are as defined herein; and

R₁₈ is;

and wherein is as defined herein;

with the proviso that R₄ cannot be hydrogen;

wherein the compound of formula (VIII) is;

wherein,

R₁₉ is;

and wherein R₄, R₁₁, and R₁₂ are as defined herein;

with the proviso that at least one of the variables R₄, R₁₁ or R₁₂ must contain the element “

T-Q”

;

wherein the compound of formula (IX) is;

wherein,

R₂₀ is;

or (iii) -D;

wherein R₄ is as defined herein;

with the proviso that when R₂₀ is not D, then R₄ cannot be hydrogen;

wherein the compound of formula (X) is;

wherein,

a is an integer from 2 to 3 and D and D₁ are as defined herein;

wherein the compound of formula (XI) is;

wherein

D₂ is hydrogen, a lower alkyl or D;

wherein D is as defined herein;

with the proviso that at least one D₂ must be D;

wherein the compound of formula (XII) is;

wherein,

R₈ is as defined herein;

J is;

R₂₄ is hydrogen or K-G-D;

wherein,

K is;

G₃ is (CH), (CH₂), oxygen, sulfur or nitrogen;

V is carbon or nitrogen;

A₁, A₂ and A₃ comprise the other subunits of a 5- or 6-membered monocyclic aromatic ring and each is independently (i) C—

R₂₃ wherein R₂₃ at each occurrence is independently D, a hydrogen, a halogen, an alkoxy, a nitrile, an alkyl, an arylalkyl, an alkylaryl, a carboxamido, a carboxyl, a haloalkyl, an alkoxyalkyl, an alkoxyaryl or a nitro;

(ii) sulfur;

(iii) oxygen; and

(iv) B_a=B_b wherein B_a and B_b are each independently nitrogen or C—

R₂₃ wherein at each occurrence R₂₃ is as defined herein; and

wherein R₂₆, R₂₇, R₂₈, R₂₉, and R₃₀ are independently a hydrogen, a halogen, a hydroxy, a haloalkyl, an alkoxy, an alkoxyalkyl, an alkoxyaryl, an alkoxyhaloalkyl, a nitrile, a nitro, an alkyl, an alkylaryl, an arylalkyl, a hydroxy alkyl, a carboxamido, or a carboxyl; and

wherein d, g, p, E, L, G, T, Y and D are as defined herein;

with the proviso that at least one of the variables A₁, A₂, A₃, J or R₂₄ must contain the element “

-T-Q”

or “

D”

;

wherein the compound of formula (XIII) is;

wherein,

R₃₁ is an alkyl, a halogen, a haloalkyl, or a haloalkoxy;

R₃₂ is D₁ or —

C(O)—

R₈; and

D, D₁ and R₈ are as defined herein;

wherein the compound of formula (XIV) is;

wherein

A is CH₂, a carbonyl or a methanethial;

G₄ is oxygen or sulfur;

R₃₄ is hydrogen, lower alkyl, alkenyl, alkynyl or L_r-E_s-[C(R_e)(R_f)]_w-E_c-[C(R_e)(R_f)]_x-L_d-[C(R_e)(R_f)]_y-L_i-E_j-L_g-[C(R_e)(R_f)]_z-T-Q;

R₃₅ and R₃₆ are independently a hydrogen, a lower alkyl, an arylalkyl, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, T-Q or [C(R_e)(R_f)]_k-T-Q,

R₃, and R₃₆ taken together are a carbonyl group, a methanethial group, a heterocyclic group or a cycloalkyl group;

R₃₄ and R₃₅ taken together are [C(R_g)(R_h)]_u or —

C(R_g)(R_h)-C(R_g)=C(R_g)-[C(R_g)(R_h)]_v wherein u is an integer of 3 or 4, v is an integer of 1 or 2 and R_g and R_h at each occurrence is independently a hydrogen, an alkyl, T-Q or [C(R_e)(R_f)]_k-T-Q;

R₃₈ is a hydrogen, a halogen or a lower alkyl; and

R₃₇ is;

wherein,

c, d, g, i, j, k, r, s, w, x, y, z, D₁, E, L, G₃, T, Q, R_e, R_f, R₂₆, R₂₇, R₂₈, R₂₉, R₃₀ and R₃₈ are as defined herein;

with the proviso that D₁ must be D if R₃₄, R₃₅ R₃₆ or R₃₇ do not contain the element “

T-Q”

;

wherein the compound of formula (XV) is;

wherein

R₂₅ at each occurrence is a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an amino an alkoxy, an aryl, an arylalkyl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a carboxamido, an alkylcarboxamido, an arylcarboxamido, a haloalkoxy, a sulfonamido, a urea, a nitro, or L_r-E_s[C(R_e)(R_f)]_w-E_c-[C(R_e)(R_f)]_x-L_d-[C(R_e)(R_f)]_y-L_l-E_j-L_z-[C(R_e)(R_f)]_z-T-Q; and

wherein c, d, g, i, j, k, r, s, w, x, y, z, G₄, D₁, E, L, T, Q, R_e, R_f, R₃₇ and R₃₈ are as defined herein; and

with the proviso that D₁ must be D if R_e or R₂₅ do not contain the element “

T-Q”

;

wherein the compound of formula (XVI) is;

wherein

R₄₀ is a hydrogen, a lower alkyl, a haloalkyl, a halogen, an alkoxy, an alkenyl, an alkynyl, a carbamoyl, a sulfonamido or L_r-E_s-[C(R_e)(R_f)]_w-E_c-[C(R_e)(R_f)]_x-L_d-[C(R_e)(R_f)]_y-L_i-E_j-L_g-[C(R_e)(R_f)]_z-T-Q; and

wherein c, d, g, i, j, k, r, s, w, x, y, z, D₁, E, L, T, Q, R_e and R_f are as defined herein;

R₄₁ is a lower alkyl, a hydroxyalkyl, an alkylcarboxylic acid, an alkylcarboxylic ester an alkylcarboxamido or L_r-E_s-[C(R_e)(R_f)]_w-E_c-[C(R_e)(R_f)]_x-L_d-[C(R_e)(R_f)]_y-L_l-E_j-L_g-[C(R_e)(R_f)]_z-T-Q; and

wherein c, d, g, i, j, k, r, s, w, x, y, z, E, L, T, Q, R_e and R_f are as defined herein;

R₄₂ is;

wherein

R₄₃ at each occurrence is independently an amino, a cyano, a halogen, a nitro group, a carboxyl, a carbamoyl, a sulfonic acid, a sulfonic ester, a sulfonamido, a heterocyclic ring, a carboxamido, a carboxylic cster, an ester, an amidyl, a phosphoryl or L_r-E₂-[C(R_e)(R_f)]_w-E_c-[C(R_e)(R_f)]_x-L_d-[C(R_e)(R_f)]_y-L_i-E_j-L₆-[C(R_c)(R_f)]₇-T-Q; and

c, d, g, i, j, k, r, s, w, x, y, z, F, L, T, Q, R_c, and R_f are as defined herein;

with the proviso that at least one of R₄₀, R₄₁, or R₄₃ must contain the element “

T-Q”

;

wherein the compound of formula (XVII) is;

wherein R₈, R₂₃, R₂₄, p and J are as defined herein and with the proviso that at least one R₂₄ or J must contain the element “

-T-Q”

or “

-D”

;

wherein the compound of formula (XVIII) is;

wherein

R₄₄ is;

wherein d, g, p, D, E, L, G₃, G₄, T, R₈, R₂₆, R₂₇, R₂₈, R₂₉, and R₃₀ are as defined herein;

wherein the compound of formula (XIX) is;

wherein,

R₄₆ and R₄₇ are independently selected from lower alkyl, hydroxyalkyl or D, or R₄₆ and R₄₇ taken together are a heterocyclic ring, wherein G₄, T, R₈, and k are defined herein;

with the proviso that at least one of the variables R₄₆ or R₄₇ must be D or when the variables taken together are a heterocyclic ring, the ring must contain NR_i, wherein R₁ must contain the element “

T-Q”

.

2. The compound of claim 1, wherein the compound is a nitrosated, nitrosylated or nitrosated and nitrosylated member selected from the group consisting of filaminast, piclamilast, rolipram, Org 20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, zaprinast, sildenafil, pyrazolopyrimidinones, motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, a 3-pyridinecarbonitrile derivative, denbufyllene, albifylline, torbafylline, doxofylline, theophylline, pentoxofylline, nanterinone, cilostazol, cilostamide, MS 857, piroximone, milrinone, amrinone, tolafentrine, dipyridamole, papaverine, E4021, triflusal, ICOS-351, a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, a carboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazine derivative, a quinazoline derivative, an anthranilic acid derivative or an imidazoquinazoline derivative.

3. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

4. A method for treating a sexual dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 3.

5. The method of claim 4, wherein the patient is female.

6. The method of claim 4, wherein the patient is male.

7. The method of claim 4, wherein the composition is administered orally, by intracavernosal injection, by transurethral application, or by transdermal application.

8. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 3.

9. The method of claim 8, wherein the disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.

10. The composition of claim 3, further comprising at least one vasoactive agent.

11. The composition of claim 10, wherein the vasoactive agent is a potassium channel activator, a calcium blocker, an α

-blocker, a β

-blocker, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, an opioid antagonist, a prostaglandin, an endothelin antagonist or a mixture thereof.

12. A method for treating a sexual dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 10.

13. The method of claim 12, wherein the patient is female.

14. The method of claim 12, wherein the patient is male.

15. The method of claim 12, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.

16. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 10.

17. A method of claim 16, wherein the disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.

18. A composition comprising at least one compound of claim 1 and at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase.

19. The composition of claim 18, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is an S-nitrosothiol.

20. The composition of claim 19, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.

21. The composition of claim 19, wherein the S-nitrosothiol is:

(i) HS(C(R_e)(R_f))_mSNO;

(ii) ONS(C(R_e)(R_f))_mR_e;

or

(iii) H₂N—

CH(CO₂H)—

(CH₂)_m—

C(O)NH—

CH(CH₂SNO)—

C(O)NH—

CH₂—

CO₂H;

wherein m is an integer of from 2 to 20;

R_e and R_f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, am alkoxy, a haloalkoxy, an amino, an alkyiamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, or -T-Q;

or R_e and R_f taken together are a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group;

Q is —

NO or —

NO₂; and

T is independently a covalent bond, an oxygen, S(O)_o or NR_i, wherein o is an integer from 0 to 2, and R_i is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, carboxamido, —

CH₂—

C(T-Q)(R_e)(R_f), or —

(N₂O₂—

)M⁺, wherein M⁺ in an organic or inorganic cation;

with the proviso that when R_i is —

CH₂—

C(T-Q)(R_e)(R_f) or —

(N₂O₂—

)M⁺;

then “

-T-Q”

can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.

22. The composition of claim 18, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine or glutamine.

23. The composition of claim 18, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is:

(i) a compound that comprises at least one ON—

O—

, ON—

N—

or ON—

C—

group;

(ii) a compound that comprises at least one O₂N—

O—

, O₂N—

N—

, O₂N—

S—

or —

O₂N—

C—

group;

(iii) a N-oxo-N-nitrosoamine having the formula;

R¹R²—

N(O-M⁺)—

NO, wherein R¹ and R² are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M⁺ is an organic or inorganic cation;

or

(iv) a thionitrate having the formula;

R¹—

(S)—

NO₂, wherein R¹ is a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group.

24. The composition of claim 23, wherein the compound comprising at least one ON—

O—

, ON—

N—

or ON—

C—

group is an ON—

O-polypeptide, an ON—

N-polypepetide, an ON—

C-polypeptide, an ON—

O-amino acid, an ON—

N-amino acid, an ON—

C-amino acid, an ON—

O-sugar, an ON—

N-sugar, an ON—

C-sugar, an ON—

O-oligonucleotide, an ON—

N-oligonucleotide, an ON—

C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

C-hydrocarbon, an ON—

O-heterocyclic compound, an ON—

N-heterocyclic compound or a ON—

C-heterocyclic compound.

25. The composition of claim 23, wherein compound comprising at least one O₂N—

O—

, O₂N—

N—

, O₂N—

S—

or O₂N—

C—

group is an O₂N—

O-polypeptide, an O₂N—

N-polypeptide, an O₂N—

S-polypeptide, an O₂N—

C-polypeptide, an O₂N—

O-amino acid, O₂N—

N-amino acid, O₂N—

S-amino acid, an O₂N—

C-amino acid, an O₂N—

O-sugar, an O₂N—

N-sugar, O₂N—

S-sugar, an O₂N—

C-sugar, an O₂N—

O-oligonucleotide, an O₂N—

N-oligonucleotide, an O₂N—

S-oligonucleotide, an O₂N—

C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

S-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

C-hydrocarbon, an O₂N—

O-heterocyclic compound, an O₂N—

N-heterocyclic compound, an O₂N—

S-heterocyclic compound or an O₂N—

C-heterocyclic compound.

26. A method for treating a sexual dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 18.

27. The method of claim 26, wherein the patient is female.

28. The method of claim 26, wherein the patient is male.

29. The method of claim 26, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.

30. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 26.

31. A method of claim 30, wherein the disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.

32. The composition of claim 18, further comprising at least one vasoactive agent.

33. The composition of claim 32, wherein the vasoactive agent is a potassium channel activator, a calcium blocker, an α

-blocker, a β

-blocker, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, an opioid antagonist, a prostaglandin, an endothelin antagonist or a mixture thereof.

34. A method for treating a sexual dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 32.

35. The method of claim 34, wherein the patient is female.

36. The method of claim 34, wherein the patient is male.

37. The method of claim 34, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.

38. A method of treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 32.

39. A method of claim 38, wherein the disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.

40. A composition comprising at least one phosphodiesterase inhibitor and at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase.

41. The composition of claim 40, wherein the phosphodiesterase inhibitor is filaminast, piclamilast, rolipram, Org 20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, zaprinast, sildenafil, a pyrazolopyrimidinone, motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, a 3-pyridinecarbonitrile derivative, denbufyllene, albifylline, torbafylline, doxofylline, theophylline, pentoxofylline, nanterinone, cilostazol, cilostamide, MS 857, piroximone, milrinone, amrinone, tolafentrine, dipyridamole, papaverine, E4021, triflusal, ICOS-351, a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, a carboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazine derivative, a quinazoline derivative, an anthranilic acid derivative or an imidazoquinazoline derivative.

42. The composition of claim 40, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is an S-nitrosothiol.

43. The composition of claim 42, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.

44. The composition of claim 42, wherein the S-nitrosothiol is:

(i) HS(C(R_e)(R_f))_mSNO;

(ii) ONS(C(R_e)(R_f))_mR_e;

or

(iii) H₂N—

CH(CO₂H)—

(CH₂)_m—

C(O)NH—

CH(CH₂SNO)—

C(O)NH—

CH₂—

CO₂H;

wherein m is an integer of from 2 to 20;

R_e and R_f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, am alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, or -T-Q;

or R_e and R_f taken together are a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group;

Q is —

NO or —

NO₂; and

T is independently a covalent bond, an oxygen, S(O)_o or NR_i, wherein o is an integer from 0 to 2, and R₁ is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, carboxamido, —

CH₂—

C(T-Q)(R_e)(R_f), or —

(N₂O₂—

)M⁺, wherein M⁺ in an organic or inorganic cation;

with the proviso that when R₁ is —

CH₂—

C(T-Q)(R_e)(R_f) or —

(N₂O₂—

)M⁺;

then “

-T-Q”

can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.

45. The composition of claim 40, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine or glutamine.

46. The composition of claim 40, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is:

(i) a compound that comprises at least one ON—

O—

, ON—

N—

or ON—

C-group;

(ii) a compound that comprises at least one O₂N—

O—

, O₂N—

N—

, O₂N—

S—

or —

O₂N—

C—

group;

(iii) a N-oxo-N-nitrosoamine having the formula;

R¹R²—

N(O-M⁺)-NO, wherein R¹ and R² are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M⁺ is an organic or inorganic cation;

or

(v) a thionitrate having the formula;

R¹—

(S)—

NO₂, wherein R¹ is a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group.

47. The composition of claim 46, wherein the compound comprising at least one ON—

O—

, ON—

N—

or ON—

C—

group is an ON—

O-polypeptide, an ON—

N-polypepetide, an ON—

C-polypeptide, an ON—

O-amino acid, an ON—

N-amino acid, an ON—

C-amino acid, an ON—

O-sugar, an ON—

N-sugar, an ON—

C-sugar, an ON—

O-oligonucleotide, an ON—

N-oligonucleotide, an ON—

C-oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

O-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—

C-hydrocarbon, an ON—

O-heterocyclic compound, an ON—

N-heterocyclic compound or a ON—

C-heterocyclic compound.

48. The composition of claim 46, wherein compound comprising at least one O₂N—

O—

, O₂N—

N—

, O₂N—

S—

or O₂N—

C—

group is an O₂N—

O-polypeptide, an O₂N—

N-polypeptide, an O₂N—

S-polypeptide, an O₂N—

C-polypeptide, an O₂N—

O-amino acid, O₂N—

N-amino acid, O₂N—

S-amino acid, an O₂N—

C-amino acid, an O₂N—

O-sugar, an O₂N—

N-sugar, O₂N—

S-sugar, an O₂N—

C-sugar, an O₂N—

O-oligonucleotide, an O₂N—

N-oligonucleotide, an O₂N—

S-oligonucleotide, an O₂N—

C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

S-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

C-hydrocarbon, an O₂N—

O-heterocyclic compound, an O₂N—

N-heterocyclic compound, an O₂N—

S-heterocyclic compound or an O₂N—

C-heterocyclic compound.

49. A method for treating a sexual dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 40.

50. The method of claim 49, wherein the patient is female.

51. The method of claim 49, wherein the patient is male.

52. The method of claim 49, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.

53. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 40.

54. A method of claim 53, wherein the disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.

55. The composition of claim 40, further comprising at least one vasoactive agent.

56. The composition of claim 55, wherein the vasoactive agent is a potassium channel activator, a calcium blocker, a β

-blocker, an α

-blocker, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, an opioid antagonist, a prostaglandin, an endothelin antagonist or a mixture thereof.

57. A method for treating a sexual dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 55.

58. The method of claim 57, wherein the patient is female.

59. The method of claim 57, wherein the patient is male.

60. The method of claim 57, wherein the composition is administered orally, by intracavernosal injection, by transurethral application or by transdermal application.

61. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 55.

62. A method of claim 61, wherein the disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.

63. A composition comprising at least one phosphodiesterase inhibitor and at least one vasoactive agent.

64. The composition of claim 63, wherein the vasoactive agent is a potassium channel activator, a calcium blocker, a β

-blocker, an α

-blocker, adenosine, an ergot alkaloid, a vasoactive intestinal peptide, a dopamine agonist, an opioid antagonist, a prostaglandin, an endothelin antagonist or a mixture thereof.

65. The composition of claim 63, wherein the phosphodiesterase inhibitor is filaminast, piclamilast, rolipram, Org 20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, zaprinast, sildenafil, a pyrazolopyrimidinone, motapizone, pimobendan, zardaverine, siguazodan, CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, a 3-pyridinecarbonitrile derivative, denbufyllene, albifylline, torbafylline, doxofylline, theophylline, pentoxofylline, nanterinone, cilostazol, cilostamide, MS 857, piroximone, milrinone, amrinone, tolafentrine, dipyridamole, papaverine, E4021, triflusal, ICOS-351, a tetrahydropiperazino[1,2-b]beta-carboline-1,4-dione derivative, a carboline derivative, a 2-pyrazolin-5-one derivative, a fused pyridazine derivative, a quinazoline derivative, an anthranilic acid derivative or an imidazoquinazoline derivative.

66. A method for treating a sexual dysfunction in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 63.

67. The method of claim 66, wherein the patient is female.

68. The method of claim 66, wherein the patient is male.

69. The method of claim 66, wherein the composition is administered by intracavernosal injection, by transurethral application or by transdermal application.

70. A method for treating or preventing a disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 63.

71. A method of claim 70, wherein the disease induced by the increased metabolism of cyclic guanosine 3′

,5′

-monophosphate is hypertension, pulmonary hypertension, congestive heart failure, renal failure, myocardial infraction, stable, unstable and variant (Prinzmetal) angina, atherosclerosis, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, asthma, bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, dementia, immunodeficiency, premature labor, dysmenorrhoea, benign prostatic hyperplasis, bladder outlet obstruction, incontinence, a condition of reduced blood vessel patency, postpercutaneous transluminal coronary angioplasty, peripheral vascular disease, allergic rhinitis, or glucoma, or a disease characterized by a gut motility disorder.