EP0374210A1 - Flevoxate and derivatives for erectile dysfunctions - Google Patents

Flevoxate and derivatives for erectile dysfunctions

Info

Publication number
EP0374210A1
EP0374210A1 EP89904810A EP89904810A EP0374210A1 EP 0374210 A1 EP0374210 A1 EP 0374210A1 EP 89904810 A EP89904810 A EP 89904810A EP 89904810 A EP89904810 A EP 89904810A EP 0374210 A1 EP0374210 A1 EP 0374210A1
Authority
EP
European Patent Office
Prior art keywords
methylflavon
treatment
erectile
erectile dysfunctions
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP89904810A
Other languages
German (de)
French (fr)
Inventor
Ralf Ruffmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Recordati SA
Original Assignee
Recordati SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Recordati SA filed Critical Recordati SA
Publication of EP0374210A1 publication Critical patent/EP0374210A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • This invention relates to the use of 3-methyl-f la- von-8-carboxyl ⁇ c acid and derivatives thereof for the preparation of a drug for the treatment and for the diagnosis of erectile impotence.
  • the invention relates to pharma ⁇ ceutical compositions for the treatment of erectile impotence containing as the active principle 3-methylfla- von-8-carboxyl ⁇ c acid or a derivative thereof of formula I
  • A is a linear or branched C -C alkyl residue
  • Z is a dimethylamino, diethylammo, di-n-propylamino, di- lsopropylammo, piperidmo or morpholmo residue, or pharmaceutically acceptable salts thereof.
  • Flavoxate is a very well tolerated drug; the large therapeutic index found in preclinical studies (C. Pietra et al., II Farmaco Ed. Prat., 4_1, 267, (1986)) and the absence of serious side effects during clinical application, attest its excellent tolerability. Particularly, cardiocirculatory complica ⁇ tions have never been reported. 3-methylflavon-8-carbo- xylic acid(MFCA) is the main metabolite of flavoxate. In terms of pharmacokinetics and - dynamics MFCA is most similar to flavoxate.
  • Erectile dysfunction is a well known and common disease, of vascular, hormonal, neurogenic or psychogenic origin which causes impaired penile erection.
  • the insufficient erectile ability of the penis has serious implications for psychological, physical and social well-being of the afflicted individuals. Self confidence in particular, and quality of life in general, are strongly reduced.
  • Prosthetic devices that are implanted in the penis to mimic erection or are located outside in the scrotal sac or in an adjacent area to stimulate for instance to trasmitting electrical energy to the nervi erigentes.
  • Pharmacological substances which are also injected directly into the corpora cavernosa, where they increase the inflow of blood and consequently generate tumescence of the penis, are also used.
  • Human tissue was obtained from patients undergoing penile prothesis implantation.
  • Biopsies of human corpus cavernosum tissue were obtained in the operating room and immediately placed in chilled (4°C) physiological salt solution of the following millimolar composition: NaCl 118.3; KC1 4.7; Mg ⁇ O 0.6; KH PO 1.2; CaCl 2.5; NaHCO 25.0; Calcium EDTA 0.026 and glucosio 11.1.
  • the solution is gassed with 95% 0 , 5% CO ; pH maintained at 7.4 and temperature at 37°C.
  • Isometric tension was measured throught the experiment with a tension transducer (Grass FT03, Quincy, MA) .
  • the strips of corpus cavernosum were fixed with silk ties on one end to the electrode support and the other end to a wire connected to the force transducer.
  • the strips were allowed to equilibrate for a period of approximately three hours.
  • the optimal isometric tension for contraction was determined during this period by stepwise stretching of the tissue followed by
  • Drugs were provided in powder form. Stock solutions were made in distilled water. For papaverine and flavoxate
  • Flavoxate up to 10 M, induced relaxation of HCC contracted with norepinephrine, PG F2 alpha or potassium. Maximal relaxations to this concentration were: 73.1 +/- 7.7%, 66 +/- 13.2%, and 55.5 +/- 23% of maximal relaxation, respectively (see figures 1-3).
  • the threshold for the response to flavoxate was approximately 3 x 10 M. The relaxation response was slow in onset and several minutes were required before the maximal relaxation
  • 3-methylflavon-8-carboxylic acid and its basic esters of formula I, particularly flavoxate may be conveniently used in human therapy for the treatment of erectile impairments.
  • pharmaceutical compositions suited for the oral, topical or parenteral (intracavernous) administration are provided.
  • the oral administration is particularly convenient for its compliance and it is moreover useful as support therapy in patients who otherwise undergo papaverine or alpha-blockers injection. This regimen allows a reduction of the papaverine and alpha-blocker dosage and improves therefore the safe use of these agents.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les dérivés d'acide 3-méthylflavon-8-carboxylique décrits sont utiles dans le traitement des dysfonctionnements érectiles du pénis et dans des procédés de diagnostic de l'impuissance érectile.The 3-methylflavon-8-carboxylic acid derivatives described are useful in the treatment of erectile dysfunctions of the penis and in methods of diagnosing erectile impotence.

Description

FLEVOXATE AND DERIVATIVES FOR ERECTILE DYSFUNCTIONS
This invention relates to the use of 3-methyl-f la- von-8-carboxylιc acid and derivatives thereof for the preparation of a drug for the treatment and for the diagnosis of erectile impotence.
In particular, the invention relates to pharma¬ ceutical compositions for the treatment of erectile impotence containing as the active principle 3-methylfla- von-8-carboxylιc acid or a derivative thereof of formula I
wherein:
A is a linear or branched C -C alkyl residue and
1 6
Z is a dimethylamino, diethylammo, di-n-propylamino, di- lsopropylammo, piperidmo or morpholmo residue, or pharmaceutically acceptable salts thereof.
Compounds of formula I are known (US Patent No. 2.921.070) and particularly one of them, methylflavone-8- carboxylic acid 2-pιperιdιnoethyl ester (flavoxate) is used in therapy peculiarly for its antispasmodic activity on the smooth muscle of the bladder, ureter and uterus (Ruffmann R., Drug Exp. Clm. Res., 13, 57, (1987)) and it has also been shown that Flavoxate accumulates preferen¬ tially in the genito-urinary tract (Inoue S. et al., Jyakunin Kenkyu, _6, 260, (1975)). Flavoxate is a very well tolerated drug; the large therapeutic index found in preclinical studies (C. Pietra et al., II Farmaco Ed. Prat., 4_1, 267, (1986)) and the absence of serious side effects during clinical application, attest its excellent tolerability. Particularly, cardiocirculatory complica¬ tions have never been reported. 3-methylflavon-8-carbo- xylic acid(MFCA) is the main metabolite of flavoxate. In terms of pharmacokinetics and - dynamics MFCA is most similar to flavoxate.
Erectile dysfunction is a well known and common disease, of vascular, hormonal, neurogenic or psychogenic origin which causes impaired penile erection.
The insufficient erectile ability of the penis has serious implications for psychological, physical and social well-being of the afflicted individuals. Self confidence in particular, and quality of life in general, are strongly reduced.
Since vascular surgery holds reasonable chances of success only in a limited number of cases, additional attempts to treat this disability have led to various therapeutic approaches. Prosthetic devices that are implanted in the penis to mimic erection or are located outside in the scrotal sac or in an adjacent area to stimulate for instance to trasmitting electrical energy to the nervi erigentes. Pharmacological substances which are also injected directly into the corpora cavernosa, where they increase the inflow of blood and consequently generate tumescence of the penis, are also used.
However, all these methods have evident disadvanta¬ ges, causing strong psychological apprehensions and also physical discomfort. Among the pharmacological substances, 6,7-dimetho- xy-1-veratryl isoquinoline (papaverine) and/or alpha blocking agents (as for example phentolamine) are the most frequently used to induce human penile erection and need to be injected direcly into the corpora cavernosa. This procedure has been shown to be most efficient for arterio- genic erectile dysfunctions. Usually the treatment begins with a first injection, performed by a physician as a diagnostic step to differentiate between arteriogenic, psychogenic and the other forms of erectile dysfuntions. In many cases of psychogenic dysfunction this single injection is sufficient to obtain a curative result. If further injections are required, these can be performed either by the physician (office-injection) or by the patient himself (auto-injection). The major drawback of papaverine and/or alpha blockers in erectile dysfunction is the risk of prolonged and painful erection (priapism) which occurs with a certain frequency.
Further serious complications are of cardiocircula- tory nature such as arterial hypotension and hypotensive shock which represent typical toxicity of these agents. In some cases fatalities have been reported. Both, papaverine and alpha blockers have a narrow therapeutic index (ratio between the lethal dose and the effective dose) and absolute or relative overdosing can occur especially during self injections. Objects and summary of the invention
The shortcomings of available therapeutic modalities as described above are quite evident. Useful pharmaceutical agents for the induction and maintainance of penile erection with low toxicity and easy administration, preferably oral, are strongly and essen¬ tially needed and hence are the target of intense research. It has now been found that 3-methylflavon-8-carbo- xylic acid and compounds of formula I have a relaxing activity on human corpus cavernosum tissue which is comparable to the activity exerted by papaverine during the same experiments. This finding is new and surprising in as much as previously it has been consistently unable to identify any relaxing activity on vascular smooth muscle for flavoxate or MFCA. Any therapeutic activity for erectile dysfunctions has never been reported either.
In fact, numerous investigations in vitro and in vivo, also versus papaverine, had failed to confirm a hypothesized and postulated vasodilating activity of flavoxate. Consequently initial high hopes to develope and market flavoxate as a coronary dilating agent had to be abandoned. On the other side, the absence of a vasodilating activity, resulted in a complete and most beneficial lack of cardiovascular type side effects.
The results obtained in a pharmacological experimentation using flavoxate and MFCA in comparison with papaverine are hereinbelow reported. Methods
Human tissue was obtained from patients undergoing penile prothesis implantation.
Biopsies of human corpus cavernosum tissue were obtained in the operating room and immediately placed in chilled (4°C) physiological salt solution of the following millimolar composition: NaCl 118.3; KC1 4.7; MgΞO 0.6; KH PO 1.2; CaCl 2.5; NaHCO 25.0; Calcium EDTA 0.026 and glucosio 11.1. The solution is gassed with 95% 0 , 5% CO ; pH maintained at 7.4 and temperature at 37°C. Isometric tension measurement
Isometric tension was measured throught the experiment with a tension transducer (Grass FT03, Quincy, MA) . The strips of corpus cavernosum were fixed with silk ties on one end to the electrode support and the other end to a wire connected to the force transducer.
The strips were allowed to equilibrate for a period of approximately three hours. The optimal isometric tension for contraction was determined during this period by stepwise stretching of the tissue followed by
— f, contraction with 40 mM KC1 or 10 M phenylephrine.
Whenever the potassium or phenylephrme-induced contraction was within 10% of the previous contraction, that tension was considered optimal for isometric contraction. In all tissues, a standardized three hour equilibration period and isometric tension determination study was utilized. In this fashion, the effect of a molecule on a tissue was able to be compared to the effect of the same molecule on different corpus cavernosum tissues .
To study contraction, the tissue was maintained at the baseline tension. To study relaxion, the tissue was contracted with different agents. Agents
Drugs were provided in powder form. Stock solutions were made in distilled water. For papaverine and flavoxate
-4 the maximal concentration reached 10 M. At higher concentrations, these molecules would become out of solution. Drugs were introduced to the chamber by cumula¬ tive additions in one half log increments. Calculations
Data is given as means +/- SE. Relaxation are expressed as the percentage relaxation for the maximal
-3 relaxation produced by 10 M sodium mtroprusside.
Results
1) Responses of human corpus cavernosum to papaverine, flavoxate and MFCA at baseline tension.
None of the molecules tested demonstrates any contractile effects of human corpus cavernosum tissue. Two experiments were performed for each molecule.
2a) Responses of human corpus cavernosum (HCC) to papaverine HC1 at contracted tension.
-4 Papaverine, at concentration of 10 M, induced relaxation in HCC contracted with norepinephrine, PG F2 alpha or potassium. Maximal relaxations to the concentration were: 89.9 + 3.1%, 90% and 91.6 + 1.6% of maximal relaxation, respectively (see figures 1-3). The threshold for the response to this drug was approximately 10~5 M. Tipically the relaxation response to papaverine was slow in onset, requiring more than 10 minutes to reach maximal effect (see figure 1). It was difficult to wash out the effect of papaverine. Repeated washes were required before the tissue recovered the ability to contract normally. 2b) Responses of HCC to flavoxate HC1 at contracted tension.
-4 Flavoxate, up to 10 M, induced relaxation of HCC contracted with norepinephrine, PG F2 alpha or potassium. Maximal relaxations to this concentration were: 73.1 +/- 7.7%, 66 +/- 13.2%, and 55.5 +/- 23% of maximal relaxation, respectively (see figures 1-3). The threshold for the response to flavoxate was approximately 3 x 10 M. The relaxation response was slow in onset and several minutes were required before the maximal relaxation
-4 response to 10 M flavoxate was achieved.
2c) Responses of HCC to MFCA Na Salt at contracted tension. MFCA was easily put into solution and was tested to
-4 a concentration of 3 x 10 M. It induced relaxation of
HCC contracted with norepinephrine, PG F2 alpha or potassium. Maximal relaxations to 3 x 10-4 M was: 54.2 +/-
5.4%, 92.8 +/- 3.5%, and 62% of maximal relaxation, respectively (seee figures 1-3). The threshold of HCC for
-4 relaxation by MFCA was 10 M for norepinephrine and
-5 potassium contracted strips and 10 M for PG F2 alpha contracted tissue.
From what above reported, it is evident how 3-methylflavon-8-carboxylic acid and its basic esters of formula I, particularly flavoxate, may be conveniently used in human therapy for the treatment of erectile impairments. For this purpose, pharmaceutical compositions suited for the oral, topical or parenteral (intracavernous) administration are provided. The oral administration is particularly convenient for its compliance and it is moreover useful as support therapy in patients who otherwise undergo papaverine or alpha-blockers injection. This regimen allows a reduction of the papaverine and alpha-blocker dosage and improves therefore the safe use of these agents. The doses for an effective treatment of erectile impairments will depend on usual factors such as kind and seriousness of the pathology and patient's weight; nevertheless, a daily oral dose of 1.200 mg proved to be generally effective and well-tolerated. Lower dosage are obviously required in case of intracavernous injection. Transdermal administra¬ tion forms may also be particularly convenient. The preparation of pharmaceutical forms is within the skill of any expert in the field and it is described for instance in Remington's Pharmaceutical Sciences Handbook, Hack Pub. Co., N.Y. USA.

Claims

C L A I M S
1. Use of 3-methylflavon-8-carboxylιc acid or a deri¬ vative thereof of formula I
wherein:
A is a linear or branched C -C alkyl residue and
1 6
Z is a dimethylammo, diethylamino, di-n-propylammo, diisopropylammo, piperidino or morpholmo residue, or pharmaceutically acceptable salts thereof, for the preparation of a medicament for the treatment and diagnosis of erectile dysfunctions.
2. The use of 3-methylflavon-8-carboxylic acid or of a pharmaceutically acceptable salt thereof for the prepara¬ tion of a medicament for the treatment and diagnosis of erectile dysfunctions.
3. The use of 2-pιperidino-ethyl 3-methylflavon-8-car- boxylate or of a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and diagnosis of erectile dysfunctions.
4. Pharmaceutical compositions for the treatment of erectile dysfunctions comprising an effective amount of 3-methylflavon-8-carboxylic acid or of a salt or derivatives of formula I wherein :
A is a linear or branched C -C alkyl residue and
1 6 Z is a dimethyla ino, diethylamino, di-n-propylamino, diisopropylamino, piperidino or morpholino residue, or pharmaceutically acceptable salts thereof , in admixture with a suitable carrier.
5. Pharmaceutical compositions according to claim 4, suited for the oral, topical or parenteral administration.
EP89904810A 1988-04-22 1989-04-19 Flevoxate and derivatives for erectile dysfunctions Withdrawn EP0374210A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT2029988 1988-04-22
IT20299/88A IT1217190B (en) 1988-04-22 1988-04-22 USEFUL COMPOUNDS FOR THE TREATMENT AND DIAGNOSIS OF HURRY DYSFUNCTIONS

Publications (1)

Publication Number Publication Date
EP0374210A1 true EP0374210A1 (en) 1990-06-27

Family

ID=11165532

Family Applications (1)

Application Number Title Priority Date Filing Date
EP89904810A Withdrawn EP0374210A1 (en) 1988-04-22 1989-04-19 Flevoxate and derivatives for erectile dysfunctions

Country Status (8)

Country Link
EP (1) EP0374210A1 (en)
JP (1) JPH02504146A (en)
KR (1) KR900700098A (en)
AU (1) AU3438289A (en)
HU (1) HU202754B (en)
IT (1) IT1217190B (en)
WO (1) WO1989010123A1 (en)
ZA (1) ZA892911B (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9301192D0 (en) 1993-06-09 1993-06-09 Trott Francis W Flower shaped mechanised table
US6143746A (en) * 1994-01-21 2000-11-07 Icos Corporation Tetracyclic cyclic GMP-specific phosphodiesterase inhibitors, process of preparation and use
GB9514465D0 (en) * 1995-07-14 1995-09-13 Glaxo Lab Sa Chemical compounds
US5503843A (en) * 1994-04-22 1996-04-02 Flora Inc. Transdermal delivery of alpha adrenoceptor blocking agents
GB9423911D0 (en) 1994-11-26 1995-01-11 Pfizer Ltd Therapeutic agents
GB9423910D0 (en) 1994-11-26 1995-01-11 Pfizer Ltd Therapeutic agents
GB9514473D0 (en) * 1995-07-14 1995-09-13 Glaxo Lab Sa Chemical compounds
GB9514464D0 (en) 1995-07-14 1995-09-13 Glaxo Lab Sa Medicaments
SK154498A3 (en) * 1996-05-10 2000-01-18 Icos Corp Carboline derivatives, process for the preparation thereof, pharmaceutical compositions containing same and use of mentioned derivatives as drugs
US6821978B2 (en) 2000-09-19 2004-11-23 Schering Corporation Xanthine phosphodiesterase V inhibitors
WO2003042216A1 (en) 2001-11-09 2003-05-22 Schering Corporation Polycyclic guanine derivative phosphodiesterase v inhibitors
WO2011023287A1 (en) * 2009-08-27 2011-03-03 Merck Patent Gmbh Use of faa and its derivatives in cosmetics and dermatology

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0266968A3 (en) * 1986-11-03 1988-08-24 Gérard G. Cohen Gelled ointment of vasodilating agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8910123A1 *

Also Published As

Publication number Publication date
KR900700098A (en) 1990-08-11
HUT53804A (en) 1990-12-28
HU892651D0 (en) 1990-11-28
AU3438289A (en) 1989-11-24
WO1989010123A1 (en) 1989-11-02
ZA892911B (en) 1989-12-27
IT1217190B (en) 1990-03-14
JPH02504146A (en) 1990-11-29
HU202754B (en) 1991-04-29
IT8820299A0 (en) 1988-04-22

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