KR20040057377A - Treatment of disorder related to low cyclic gmp levels - Google Patents

Abstract

PURPOSE: A method of treating a disorder associated with low cGMP levels by administering to a subject in need thereof an effective amount of a PDE inhibitor as a pyrazolyl conjugate compound is provided. The composition can be formulated into a capsule, gel or table. CONSTITUTION: Method for the treatment of a disorder associated with low cGMP levels includes administering an effective amount of a pyrazolyl conjugate compound having a pyrazolyl core, a first aryl group bonded to the 3-C position of the pyrazolyl core, and a second aryl group fused at the 4-C position and 5-C position of the pyrazolyl core to a subject in need thereof. The pyrazolyl compound is represented by the formula 1 and formulated into a pharmaceutical composition with a pharmaceutically acceptable carrier prior to use in treating the disorder associated with low cGMP levels.

Description

TREATMENT OF DISORDER RELATED TO LOW CYCLIC GMP LEVELS}

This invention is an application claiming priority of US Provisional Application No. 60 / 344,207, filed Dec. 26, 2001, under USC 119 (e).

Cyclic 3 ', 5'-guanosine monophosphate (cGMP) is converted in GTP by guanylate cyclase and degraded to GMP by phosphodiesterases (PDE) such as PDE5. For example, it plays an important role in various physiological actions, such as relaxing vascular smooth muscle in organs such as the heart, lungs and penis. GMP deficiency causes various abnormalities such as coronary heart disease, high blood pressure and erectile dysfunction.

Since cGMP is hydrolyzed by PDE, abnormalities associated with cGMP deficiency caused by high PDE activity can be treated by increasing cGMP levels by administering PDE inhibitors.

It is intended to provide new methods of treatment and therapeutic pharmaceutical compositions for abnormalities associated with lower cGMP levels.

Summary of the Invention

The present invention relates to a method of treating low-level related abnormalities of cGMP by administering a PDE inhibitor, a pyrazolyl conjugated compound.

A series of pyrazolyl conjugated compounds that can be used to practice the methods of the invention are represented by the following formula (I):

(Ⅰ)

These compounds each comprise a pyrazolyl nucleus and two aryl groups. The first aryl group (Ar ₁ ) is a ring carbon atom halo, alkyl, alkoxy, carboxyl, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, amino Phenyl, thienyl, furyl or pyrrolyl groups optionally substituted with alkyl, thioalkyl, (alkylthio) alkyl, or alkylenedioxy. The second aryl group is a ring carbon atom halo, alkyl, alkoxy, carboxyl, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, Phenyl, thienyl, furyl or pyrrolyl groups substituted with (alkylthio) alkyl, or alkylenedioxy. X attached to 1-N (optionally via an alkylene, alkenylene or alkynylene linker; not shown) is hydrogen, halo, carboxyl, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl , Alkoxyalkyl, amino, aminoalkyl, thioalkyl, or aryl. Aryl may optionally be halo, alkyl, alkoxy, carboxyl, (alkoxy) carbonyl, thioalkyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, (alkylthio) Phenyl, thienyl, furyl, or pyrrolyl substituted with alkyl or alkylenedioxy.

In one example of this compound, the first aryl group is phenyl or furyl optionally substituted with alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, aminoalkyl, thioalkyl, or (alkylthio) alkyl; The first aryl group is linked to 3-C of the pyrazolyl nucleus at the site of 2'-C (eg at the site of 5'-C) and is alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, aminoalkyl Furyl optionally substituted with thioalkyl, or (alkylthio) alkyl; Second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio) Alkyl or phenyl or thienyl substituted with alkylenedioxy; In addition, the second aryl group is substituted with methylenedioxos at both the 5-C and 6-C positions, or at the 6-C position, halo, alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl Or phenyl substituted with (alkylthio) alkyl.

Compounds of formula (I) include a series of other pyrazolyl conjugated compounds for practicing the methods of the invention. The first aryl group (Ar ₁ ) is halo, alkyl, alkoxy, carboxy, thioalkyl, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, (alkoxy) alkyl, amino, amino alkyl, (alkylthio) Phenyl, thienyl, furyl, or pyrrolyl substituted with alkyl or alkylenedioxy. The second aryl group (Ar ₂ ) is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, amino at the carbon ring atom Phenyl, thienyl, furyl, or pyrrolyl optionally substituted with alkyl, thioalkyl, (alkylthio) alkyl, or alkylenedioxy. X is the same as defined above. As described above, X attaches directly to the 1-N site or through an alkylene, alkenylene, or alkynylene linking group.

Examples of this compound include those in which the first aryl group is phenyl or furyl, substituted by alkyl, (alkoxy) alkyl, aminoalkyl, or (alkylthio) alkyl; The first aryl group is linked at the 3-C position of the pyrazolyl nucleus and is, for example, furyl substituted at the 5'-C position with alkyl, (alkoxy) alkyl, aminoalkyl, or (alkylthio) alkyl ; And the second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, amino alkyl, thioalkyl, (alkylthio Alkyl, or phenyl or teenyl optionally substituted with alkylenedioxy.

In the term "alkyl", the prefix of "alk" (such as in alkoxy) and the suffix of "-alkyl" (such as in hydroxyalkyl) are either straight or branched herein. Means terrain C _1-18 . The terms "alkylene", "alkenylene" and "alkynylene" refer to divalent alkyl, alkene, and alkyne groups, respectively. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Examples of compounds defined above include 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -6-fluoroindazole, 1-benzyl-3- (5'-hydroxymethyl-2 ' -Furyl) -6-methylindazole, 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -6-methoxyindazole, 1-benzyl-3- (5'-hydroxymethyl -2'-furyl) -5,6-methylenedioxoindazole, and 1-benzyl-3- (5'-methoxymethyl-2'-furyl) indazole. The structure of 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -5,6-methylenedioxoindazole is numbered on the aryl ring as shown below:

.

Briefly, such pyrazolyl conjugated compounds include pharmaceutically acceptable salts and prodrugs thereof where possible. Such salts may be formed between negatively charged ionic groups (eg carbonates) and positively charged counterions (eg sodium) in the pyrazolyl conjugated compound. Positively charged ionic groups (eg ammonium) in pyrazolyl conjugated compounds may also form salts with negatively charged counterions (eg chlorides). Examples of such salts are the chlorates of 1-benzyl-3- (5'-aminomethyl-2'-furyl) -5,6-methylenedioxindazole and 1-benzyl-3- (5'-carboxy-2 ' Sodium salt of -furyl) -5,6-methylenedioxoindazole. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives that can provide the pyrazolyl conjugated compound when administered to a subject.

The pyrazolyl conjugated compounds used to practice the methods of the invention are formulated into pharmaceutical compositions prior to use in the treatment of abnormalities associated with low levels of cGMP. Accordingly, the scope of the present invention includes pharmaceutical compositions comprising a pyrazolyl conjugated compound and a pharmaceutically usable carrier for use in treating abnormalities associated with low levels of cGMP.

The present invention also relates to the use of one of the pyrazolyl conjugated compounds in the manufacture of a medicament for the treatment of abnormalities associated with low levels of cGMP.

Various embodiments of the present invention are described in detail in the following description. Other features, objects, and advantages of the invention will be apparent from the following description, and from the claims.

Detailed description of the invention

The present invention relates to the use of pyrazolyl conjugated compounds for the treatment of abnormalities associated with a decrease in cGMP levels caused by elevated PDE activity.

The pyrazolyl conjugated compound can be synthesized as follows. Arylcarbonyl chlorides, such as benzyl chloride, may be combined with other aryl group-containing compounds, such as trifluoromethylbenzene, containing at least one hydrogen atom on another aryl group, such as aryl aryl ketones (eg tri Fluoromethylphenylphenylketone). Two of the aryl groups (for example, phenyl and phenyl) correspond to Ar ₁ and Ar ₂ in formula (I) or (II), respectively. The arylarylketone is then reacted with hydrazine (eg benzylhydrazine) to form a hydrazone, which is then converted by the catalyst to a pyrazolyl conjugated compound. Thus, in the pyrazolyl conjugated compound, one aryl group is directly linked to 3-C and the other aryl group is conjugated at 4-C and 5-C sites of the pyrazolyl nucleus. Further modifications may also yield derivatives of pyrazolyl conjugated compounds.

The synthesis of 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -6-methoxyindazole is briefly shown in the following scheme (detailed in Example 1 below):

The same synthetic procedure as above for synthesizing other compounds that can be used to practice the process of the invention is for example 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -6-fluoro Indazole, 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -6-methylindazole, 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -5 It can also be employed for, 6-methylenedioxoindazole and 1-benzyl-3- (5'-methoxymethyl-2'-furyl) indazole. The synthesis process of these compounds is described in detail in Examples 2, 3, 4 and 5 below.

Derivatives of such compounds include, but are not limited to, single or multiple substituted benzoyl chlorides (except 4-methoxybenzoyl chloride shown in the above diagram), single or multiple substituted 2-furoates (except methyl-2-furoate shown in the above diagram). , And single or multiple substituted benzylhydrazones (substituted benzylhydrazones shown in the above scheme).

3-phenyl-indazole compounds can be prepared according to the synthesis methods described above, except that optionally single or multiple substituted benzophenones are used instead of 2-furyl phenyl ketone. As an initiation step, benzophenone was oxidized with CrO ₃ to form benzoylbenzoic acid. The benzoylbenzoic acid then reacts with ethanol to form ethylbenzoylbenzoate which is converted to 3-phenyl-indazole through a series of reactions (similar to the scheme described above). If desired, 3-phenyl-indazole can be converted to its derivatives by further modification.

The pyrazolyl conjugated compound having a thienopyrazole group may also be prepared according to the synthesis method described in the above scheme except that 2-thienyl aryl ketone is used instead of 2-furylphenylketone. Thus, if there is a single or multiple substituent of the obtained thienopyrazolyl compound, it may be modified to obtain additional thienopyrazolyl compound.

An effective amount of pyrazolyl conjugated compound or salt thereof is formulated into a pharmaceutical composition and then administered to a subject in need of treatment for abnormalities associated with low levels of cGMP (e.g., cardiovascular diseases such as coronary heart disease and hypertension or erectile dysfunction). . The term "effective amount" refers to the amount of compound necessary to obtain a therapeutic effect in a subject to be treated. The interrelationship of dosage (based on mg per square meter of body surface area) in animals and humans is described by Freireich et al., Cancer Chemother. Rep., 1966, 50: 219. Body surface area may be approximately determined from the height and weight of the patient. See, eg, Scientific Tables, Geigy Pharmaceuticals, Ardley, N.T., 1970, 357. The effective amount will vary to the extent determined by one skilled in the art depending upon the route of administration, whether excipients are used, and co-administration with other therapeutic agents, including the use of other agents that increase the level of cGMP. Examples of pharmaceutically acceptable carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate and D & C Yellow # 10.

Pharmaceutical compositions may also be administered via parenteral routes such as, for example, topical, subcutaneous, intraperitoneal, intramuscular, and intravenous. Examples of formulations for parenteral administration include isotonic saline, 5% glucose, or an aqueous solution of the active compound in any known pharmaceutically acceptable carrier. Solubilizers such as cyclicdextrins or other solubilizers well known to those skilled in the art can also be included in the pharmaceutical compositions of the present invention.

Pyrazolyl conjugated compounds that can be used to practice the methods of the invention can also be formulated in dosage forms for other routes of administration (eg oral, intramucosal, transdermal) utilizing known methods. Pharmaceutical compositions may also be formulated in dosage forms for oral administration, eg, in capsules, gel seals or tablets. Capsules may comprise any known pharmaceutically acceptable substance such as gelatin or cellulose derivatives. Tablets may also be formulated according to conventional methods by pressing a mixture of the active compound, a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite. The compound may also be administered in the form of transdermal tablets or capsules, including, for example, lactose or mannitol, conventional fillers and tableting agents as binders.

A suitable in vitro assay may also preliminarily assess the effect of pyrazolyl conjugated compounds on inhibiting PDEs that hydrolyze cGMP. For example, platelets are washed, suspended in buffer and cleaved by ultrasound to obtain a solution containing PDE. Add the compound to be tested and cGMP (substrate of PDE) to the solution. The poison of the Ophiophagus hannah snake is then added to remove the phosphate at 5'-GMP (converted from cGMP by PDE) to form uncharged guanosine. Remove the remaining cGMP with an ion exchange resin. The solution without cGMP is centrifuged and the droplets of the supernatant taken to quantify uncharged guanosine in a liquid scintillation counter. The activity of PDE is determined based on the uncharged guanosine content. In vivo screening can be carried out by the following methods known in the art.

Those skilled in the art believe that, without further processing, the present invention may be fully utilized based on the description herein. All publications described herein are incorporated by reference in their entirety. The following specific examples describe methods for synthesizing and physiologically testing the various pyrazolyl conjugated compounds used to practice the methods of the present invention. Accordingly, these examples are merely intended to illustrate the invention but are not intended to limit the disclosure of the invention in any way.

(Example)

Example 1

Synthesis of 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -6-methoxyindazole (Compound 1 )

0.42 g of anhydrous ferric chloride and 35.8 g of 4-methoxybenzoyl chloride were dissolved in 40 mL of CCl ₄ . To this solution was added 25.22 g of methyl-2-furoate numerically over 10 minutes. The solution was heated under reflux for 36 hours, cooled and mixed with 120 mL of water. The resulting mixture was stirred for 1 hour and left to stand until it was separated into two layers and a precipitate. The aqueous layer (upper layer) and the precipitated layer were extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and filtered. The solvent of the filtrate was removed under reduced pressure and the residue was recrystallized from isopropanol to give 18.5 g of 4-methoxyphenyl 5'-methoxycarbonyl-2'-furyl ketone in 44% yield.

6.25 g of this prepared ketone was dissolved in 60 ml of methanol. To this solution was added 9.0 g of benzylhydrazine and 0.5 ml of acetic acid. The resulting solution was heated under reflux until the reaction was complete. After cooling, the solvent was removed to obtain a residue. This residue was dissolved in chloroform and subsequently washed with dilute HCl solution and water, then dried over anhydrous magnesium sulfate and filtered. The solvent of the filtrate was removed to obtain 7.8 g of 5'-methoxycarbonyl-2'-furyl 4-methoxyphenyl ketone benzylhydrazone.

All of the 5'-methoxycarbonyl-2'-furyl 4-methoxyphenyl ketone benzylhydrazone was dissolved in 100 ml of dichloromethane. The solution thus obtained was added dropwise to 40 ml of a dichloromethane solution containing 28.2 g of Pb (OAc) ₄ . The solution in the 30 ± 2 ℃ 30 minutes of reaction and was mixed with (containing _{BF 3 47%) BF 3 ·} Et 2 O 122㎖. The mixture was heated at reflux for 30 minutes and placed in 1000 ml of ice water to terminate the reaction. The resulting mixture was separated into two phases, an organic phase and an aqueous phase. The organic layer (lower layer) was separated, washed with water and 10% sodium carbonate solution, neutralized by water washing, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford an oily crude product. Ethanol was then added to the crude product and the mixture was left overnight until a solid precipitate formed. This precipitate was collected and recrystallized from ethanol to give 4.35 mg of 1-benzyl-3- (5'-methoxycarbonyl-2'-furyl) 6-methoxyindazole (4-methoxy phenyl-5'- From methoxy carbonyl-2'-furyl ketone).

A calcium borohydride solution was first prepared by stirring together 88.8 mg of calcium chloride and 60 mg of sodium borohydride for 4 hours in 20 ml of anhydrous THF. 30 ml of THF containing 93.0 mg of 1-benzyl-3- (5'-methoxycarbonyl-2'-furyl) -6-methoxyindazole was added numerically to calcium borohydride at 30 ± 2 ° C. . The resulting solution was heated under reflux for 6 hours, cooled, quenched with ice, left under reduced pressure to remove THF, and filtered to give a solid product. The solid product was purified by column chromatography (silica gel-benzene) to give 77.2 mg of compound 1 in 88.0% yield.

Example 2

Synthesis of 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -6-fluoroindazole (Compound 2 )

Compound 2 was synthesized according to the procedure described in Example 1 except that 4-fluorobenzoyl chloride was used instead of 4-methoxybenzoyl chloride. Overall yield was 22%.

Example 3

1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -6-methylindazole (Compound 3 )

Compound 3 was synthesized according to the procedure described in Example 1 except that 4-fluorobenzoyl chloride was used instead of 4-methoxybenzoyl chloride. Overall yield was 13%.

Example 4

1-benzyl-3- (5'-hydroxymethyl-2'-furyl) -5,6-methylenedioxoindazole (Compound 4 )

Compound 4 was synthesized according to the procedure described in Example 1 except that 3,4-methylenedioxobenzoyl chloride was used instead of 4-methoxybenzoyl chloride. Overall yield was 29%.

Example 5

1-benzyl-3- (5'-hydroxymethyl-2'-furyl) indazole (Compound 5 )

1.0 M BCl ₃ / CH ₂ Cl ₂ solution 1.5 in 5 ml of dichloromethane solution containing 0.2 g of 1-benzyl-3- (5'-hydroxymethyl-2'-furyl) indazole at 10 ± 2 ° C. Ml was added. The obtained solution was reacted at this temperature for 4 hours. 5 ml of methanol was added to this solution. The solution was stirred for an additional 1 h and then quenched with ice water to give a mixture for extraction with dichloromethane. The extract was neutralized with water washing and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the remaining residue was purified by column chromatography (silica gel-benzene) to give 0.15 g of liquid 1-benzyl-3- (5'-methoxymethyl-2'-furyl) indazole in 70% yield. Got it.

Example 6

Inhibition of PDE 5

Washed human platelets were prepared by Teng et al. Biochem. Biphys. Acta. Prepared as described in 1989, 990, 315-320 and suspended in 50 mM Tris-HCl buffer (containing 5 mM MgCl ₂ ) at pH 7.4 and cleaved by ultrasound at 4 ° C. The eluate obtained was centrifuged at 35,000 × g for 20 minutes at 4 ° C. to obtain a supernatant containing PDE5. A drop of the supernatant was taken to prepare a PDE 5 solution in Tris-HCl buffer. Each of these contained 10 μM of the pyrazolyl conjugated compound (ie, Compound 1 , Compound 2 , Compound 3 , Compound 4 , or Compound 5 ) to be tested. Each of the PDE5 solutions was first incubated at 37 ° C. for 5 minutes and 10 μM cGMP was added thereto. The cGMP-containing solution was incubated at 37 ° C. for 30 minutes (conversion of cGMP to 5′-GMP by PDE5 during this period), heated at 100 ° C. for 1 minute and then cooled to room temperature. Toxin solution (0.1 mL, 1 mg / mL) of Ophiophagus hannah snake was added to this solution. The resulting solution was incubated at 25 ° C. for 30 minutes before 5'-GMP was converted to uncharged guanosine. An ion exchange resin slurry (1.0 mL; Dowex-1, purchased from Sigma Chemical, St. Louis, Missouri, USA) was added to this solution to remove remaining cGMP after mixing. The resulting cGMP free solution was centrifuged and 0.5 mL of the supernatant was taken to quantify uncharged guanosine with a liquid beneficiation counter.

The results show that all of compounds 1-5 are potent inhibitors of PDE 5. For example, it was found that surprisingly low IC ₅₀ values (3.5 μM) in Compound 1 inhibited PDE 5.

Other Example

While a number of embodiments of the invention have been disclosed, it will be appreciated that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are also within the scope of the following claims.

It has become possible to provide new methods of treatment and therapeutic pharmaceutical compositions for abnormalities associated with lower cGMP levels.

Claims (36)

CGMP levels of an effective amount of a compound comprising a pyrazolyl nucleus, a first aryl group bonded to the 3-C site of the pyrazolyl nucleus, and a second aryl group conjugated to the 4-C and 5-C sites of the pyrazolyl nucleus A method of treating abnormalities associated with low levels of cGMP comprising administering to a low subject, Wherein the pyrazolyl nucleus is at the 1-N site, via an alkylene, alkenylene, or alkynylene linking group, halo, carboxy, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, amino, amino Alkyl, thioalkyl, or aryl—wherein aryl is optionally halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, thioalkyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl , Phenyl, thienyl, furyl, or pyrrolyl substituted with amino, aminoalkyl, (alkylthio) alkyl, or alkylenedioxy; The first aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, amino alkyl, thioalkyl, (alkylthio) Phenyl, thienyl, furyl, or pyrrolyl optionally substituted with alkyl, or alkylenedioxy; The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio) Phenyl, thienyl, furyl, or pyrrolyl substituted with alkyl, or alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 1, Wherein the first aryl group is phenyl or furyl optionally substituted with alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, aminoalkyl, thioalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 2, The first aryl group is linked to the 3-C site of the pyrazolyl nucleus at the site of 2'-C and is alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, aminoalkyl, thioalkyl, or (alkylthio) alkyl Furyl optionally substituted with Treatment of dysplasia associated with low levels of cGMP. The method of claim 3, Said furyl substituted at the 5'-C position with alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, aminoalkyl, thioalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 1, The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio Alkyl, or phenyl or thienyl substituted with alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 5, Wherein the first aryl group is phenyl or furyl substituted with alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, aminoalkyl, thioalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 5, The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio Alkyl, or phenyl substituted with alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 7, wherein The phenyl is substituted with methylenedioxos at both the 5-C and 6-C sites, or at halo, alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, or at 6-C Substituted with (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 7, wherein Wherein the first aryl group is phenyl or furyl optionally substituted with alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, amino alkyl, thioalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 8, Wherein the first aryl group is phenyl or furyl optionally substituted with alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, amino alkyl, thioalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 10, The first aryl group is linked to the 3-C site of the pyrazolyl nucleus at the site of 2′-C and is alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, amino alkyl, thioalkyl, or (alkylthio) Furyl optionally substituted with alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 11, The furyl is substituted at the 5'-C position by alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, aminoalkyl, thioalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 12, The furyl is substituted with hydroxymethyl at the position of 5'-C Treatment of dysplasia associated with low levels of cGMP. The method of claim 13, The phenyl is substituted with methylenedioxo at both the 5-C and 6-C sites Treatment of dysplasia associated with low levels of cGMP. The method of claim 13, The phenyl is substituted at the position of 6-C with halo, alkyl, alkoxy, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 15, The phenyl is substituted with fluorine Treatment of dysplasia associated with low levels of cGMP. The method of claim 15, The phenyl is substituted with methyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 15, The phenyl is substituted with methoxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 1, A method of treating abnormalities associated with low levels of cGMP in which the compound is represented by the following structure: CGMP levels of an effective amount of a compound comprising a pyrazolyl nucleus, a first aryl group bonded to the 3-C site of the pyrazolyl nucleus, and a second aryl group conjugated to the 4-C and 5-C sites of the pyrazolyl nucleus A method of treating abnormalities associated with low levels of cGMP comprising administering to a low subject, The pyrazolyl nucleus is halo, carboxy, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, amino, amino at the 1-N site via an alkylene, alkenylene, or alkynylene linking group. Alkyl, thioalkyl, or aryl—wherein aryl is optionally halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, thioalkyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl , Phenyl, thienyl, furyl, or pyrrolyl substituted with amino, aminoalkyl, (alkylthio) alkyl, or alkylenedioxy; The first aryl group is halo, alkyl, alkoxy, carboxy, thioalkyl, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, (alkoxy) alkyl, amino, amino alkyl, (alkylthio) alkyl, or alkyl Phenyl, thienyl, furyl, or pyrrolyl substituted with lendioxy; The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio) Phenyl, thienyl, furyl, or pyrrolyl, optionally substituted with alkyl, or alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 20, Wherein the first aryl group is phenyl or furyl substituted with alkyl, (alkoxy) alkyl, aminoalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 21, The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, amino alkyl, thioalkyl, (alkylthio Alkyl, or phenyl or thienyl, optionally substituted with alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 21, Wherein the first aryl group is substituted with alkyl, (alkoxy) alkyl, aminoalkyl, or (alkylthio) alkyl at the 3-C position of the pyrazolyl nucleus Treatment of dysplasia associated with low levels of cGMP. The method of claim 23, wherein Said furyl is substituted at the 5'-C position with alkyl, (alkoxy) alkyl, aminoalkyl, or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 24, The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, amino alkyl, thioalkyl, (alkylthio Alkyl or phenyl or teenyl optionally substituted with alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 24, The furyl is substituted by (alkoxy) alkyl or (alkylthio) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 26, The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio Alkyl or phenyl or teenyl optionally substituted with alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 26, Wherein said furyl is substituted by (alkoxy) alkyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 28, The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio Alkyl or phenyl or teenyl optionally substituted with alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 29, The second aryl group is phenyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 30, The furyl is substituted with methoxymethyl Treatment of dysplasia associated with low levels of cGMP. The method of claim 31, wherein A method of treating abnormalities associated with low levels of cGMP in which the compound is represented by the following structure: . The method of claim 20, The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio Alkyl or phenyl or teenyl optionally substituted with alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. The method of claim 33, wherein The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio Alkyl, or phenyl optionally substituted with alkylenedioxy Treatment of dysplasia associated with low levels of cGMP. Low levels of cGMP comprising a compound comprising a pyrazolyl nucleus, a first aryl group bonded to the 3-C site of the pyrazolyl nucleus, and a second aryl group conjugated to the 4-C and 5-C sites of the pyrazolyl nucleus As a pharmaceutical composition for treating abnormalities, Wherein the pyrazolyl nucleus is in the 1-N site, optionally via an alkylene linking group, halo, carboxy, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, amino, aminoalkyl, thioalkyl, Or aryl—wherein aryl is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, thioalkyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, ( Optionally substituted with alkylthio) alkyl, or phenyl, thienyl, furyl, or pyrrolyl, optionally substituted with alkylenedioxy; The first aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, amino alkyl, thioalkyl, (alkylthio) Phenyl, thienyl, furyl, or pyrrolyl optionally substituted with alkyl, or alkylenedioxy; The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio) Phenyl, thienyl, furyl, or pyrrolyl substituted with alkyl, or alkylenedioxy Pharmaceutical compositions for treating abnormalities associated with low levels of cGMP. Low levels of cGMP comprising a compound comprising a pyrazolyl nucleus, a first aryl group bonded to the 3-C site of the pyrazolyl nucleus, and a second aryl group conjugated to the 4-C and 5-C sites of the pyrazolyl nucleus As a pharmaceutical composition for treating abnormalities, Wherein the pyrazolyl nucleus is in the 1-N site, optionally via an alkylene linking group, halo, carboxy, alkoxycarbonyl, thiocarbonyl, aminocarbonyl, hydroxyalkyl, alkoxyalkyl, amino, aminoalkyl, thioalkyl, Or aryl—wherein aryl is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, thioalkyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, ( Optionally substituted with alkylthio) alkyl, or phenyl, thienyl, furyl, or pyrrolyl, optionally substituted with alkylenedioxy; The first aryl group is halo, alkyl, alkoxy, carboxy, thioalkyl, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, (alkoxy) alkyl, amino, amino alkyl, (alkylthio) alkyl, or alkyl Phenyl, thienyl, furyl, or pyrrolyl substituted with lendioxy; The second aryl group is halo, alkyl, alkoxy, carboxy, (alkoxy) carbonyl, (alkylthio) carbonyl, aminocarbonyl, hydroxyalkyl, (alkoxy) alkyl, amino, aminoalkyl, thioalkyl, (alkylthio) Phenyl, thienyl, furyl, or pyrrolyl, optionally substituted with alkyl, or alkylenedioxy Pharmaceutical compositions for treating abnormalities associated with low levels of cGMP.