Promestriene Chemical Properties

Melting point:

64-660C

Boiling point:

436.8±45.0 °C(Predicted)

Density 

1.06±0.1 g/cm3(Predicted)

storage temp. 

Sealed in dry,2-8°C

solubility 

Chloroform (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly)

form 

Solid

color 

White to Off-White

InChI

InChI=1/C22H32O2/c1-4-13-24-16-6-8-17-15(14-16)5-7-19-18(17)11-12-22(2)20(19)9-10-21(22)23-3/h6,8,14,18-21H,4-5,7,9-13H2,1-3H3/t18-,19-,20+,21+,22+/s3

InChIKey

IUWKNLFTJBHTSD-PRXAPIQKNA-N

SMILES

[C@@]12([H])CCC3C=C(OCCC)C=CC=3[C@@]1([H])CC[C@]1(C)[C@H](CC[C@@]21[H])OC |&1:0,14,18,20,23,r|

CAS DataBase Reference

39219-28-8(CAS DataBase Reference)

Safety Information

Safety Statements 

24/25

HS Code 

29093090

Promestriene Usage And Synthesis

Outline

Promestriene is a topical estrogen supplements studied and developed by Monaco Dudley beauty pharmaceutical companies (wholly purchased by Merck Company of the United State in 1999) and has gotten the US patent approval in 1977 with the formulation reagents mainly including the Colpotrophine which entered into market in 1975 in France and Delipoderm which entered into the French market in 1978, promestriene, colpotrophine (promestriene soft capsules and cream) and chlorquinaldol. Promestriene (chloroquinaldol/ Promestriene vaginal tablets) have been collected by Martindale Drug Manual and have entered into market in more than 40 foreign countries for over 40 years. Currently, in many countries, Promestriene is still the first-line drugs for the treatment of vaginal infections and atrophic vaginitis. Clinical practice has shown that it is safe and effective with the patient being well tolerated.
Promestriene is a kind of special estradiol diether with its special molecular structure making it cause the biological effects in situ without the necessity of exerting the effect after being metabolized. It has a biological half-life of being smaller than 24 h. Therefore, upon vaginal administration, drug will directly take effect on the vaginal mucosa without being absorbed by the mucosa. There is no accumulation of estrogen in the body, particularly in the estrogen-sensitive organs far away from the vagina. Clinical observation further noted that the topical administration of promestriene has no effect on the plasma sex hormone binding globulin (SHBG), estrone (E1), estradiol (E2), estriol (E3), LH and FSH, and can effectively prevent and treat the atrophic vaginitis with strict local estrogen effect. Compared with other drugs, advantages of promestriene lie in that it is hardly absorbed through the vagina, and thus being able to avoid the systemic risk of long-term vaginal topical supplement of estrogen with fewer adverse reactions which are of lesser extent and no systemic effects. It only has mild side effect and high safety, and the vast majority of patients are willing to accept, and therefore is an excellent choice for the treatment of atrophic vaginitis, especially for those with estrogen-dependent diseases.

Pharmacological effects

This product is a chemically synthesized steroidal estrogen and mainly takes effect through local effect on vaginal mucosa, by thickening of the mucous membranes, maintaining the balance of vaginal pH, improving the vaginal environment, enhancing the resistance of the vaginal tissue and reducing vaginal infections. It has excellent effect on alleviating the symptoms of atrophy vaginitis vulva and vaginal topical symptoms. It can also produce local estrogenic effect on the bottom mucous of the female reproductive tract. This product should be subject to topical administration and will not exert systemic estrogenic effect on organs far from the vagina after administration inside the vagina.

Synthetic route

Take estradiol as raw material, adopt the Williamson synthesis method for preparation of estradiol-propyl ether, and then apply sodium hydride as alkaline catalyst and methyl iodide reagent for preparation of promestriene.

Figure 1 the synthetic route of Promestriene

Indications

1. Cold cream or cream: used for the treatment of the atrophic lesions in vulva, vestibule and vaginal ring portion.
2. Vaginal Capsules: for the treatment of vaginal atrophy due to estrogen deficiency; the persistent delayed healing, delayed crust in the mucous membrane part of cervical, vulvar and vaginal due to childbirth, local surgery or partial physical therapy (such as laser, freezing or burning, etc.).

Estriol

In the years around menopause (naturally occurring or surgically induced), estriol can be used to treat estrogen deficiency-related symptoms and diseases. Estriol is particularly effective in the treatment of urogenital symptoms. Application of estriol in the treatment of urogenital atrophy can normalize the vaginal epithelial cells, thus helping to restore normal physiological pH and flora of the genitourinary system, increasing the resistance of the urogenital tract epithelial cells to infection and inflammation. Being different from other different estrogen, because estriol can only be retained in the intima nucleus for a very short time, estriol is short-acting. Single administration of recommended daily dose will not cause endometrial proliferation. Therefore, it is also not necessarily for periodically taking progestin. Moreover, for postmenopausal women, withdrawal bleeding will not occur. The intravaginal application of estriol can produce optimal effectiveness locally. Estriol can also enter into the systemic circulation system because it has been observed of the eruption phenomenon of the unconjugated estriol peaks in the plasma. The peak of plasma will appear after 1-2 hours. Almost all the estriol (90%) can bind with the plasma albumin. Being different from other kinds of estrogen, estriol will not bind to sex hormone binding globulin. The metabolism of the estriol is primarily the association and dissociation in the enterohepatic circulation process. Estriol, as the metabolic end products, is mainly excreted through urine in the bound-form and only has only a small part (± 2%) that is discharged through feces in the non-binding form. Clinically, due to estrogen deficiency caused urinary and reproductive tract atrophy symptoms, namely treating the symptoms of vaginal areas, such as drying, sexual pain and itching; prevention of recurrent infection of the vagina and the lower part of urethra; urination symptoms (such as frequent urination and painful urination) and mild urinary incontinence. It can also be applied to the menopausal women before and after vagina surgery. It can further used for the auxiliary diagnosis of doubtful atrophic cervical sheet.

Dosage

1. Cold cream or cream: 1 to 2 times per day; apply sufficient amount of cream to paint around the surface of the sites in need of treatment. In case of sustained cause of disease (for example menopause, ovariectomy, use of estrogen-progestin for contraception), or the persistence of impact factors (such as radiation therapy), it is necessary to carry out continuous treatment.
2. Vaginal Capsules: usually take 1 capsule per day with the course of 20 days. Put the moistened soft capsule deep into the vagina. In case of sustained cause of disease (for example menopause, ovariectomy, use of estrogen-progestin for contraception), or the persistence of impact factors (such as radiation therapy), it is necessary to carry out continuous treatment.
The above information is edited by the chemicalbook of Xiongfeng Dai.

Side effects

It can cause irritation, itching, and allergic reactions.

Medicine interactions

Ginseng can caused excessive estrogen effect, and therefore the combination should be cautious.

Precautions

Patients of vaginal stenosis, prolapse and endometriosis as well as uterine fibroids should take with caution.

Contraindications

1. Patients allergic to this drug should be disabled.
2. Patients of unspecified diagnostic gynecological bleeding and patients with estrogen hormone-dependent tumors should be disabled.

Overdose

This product should be subject to topical administration with a very small amount of the active ingredient entering into the circulatory system. Within the scope of medical advice, it is less prone to overdose. As indeed the overdose of this drug causes adverse reactions, it should be discontinued immediately and the patients should be subject to appropriate treatment timely.

Combination therapy

1. The combination between recombinant human interferon α-2b vaginal effervescent capsule and chloroquinaldol-promestriene tablets in the treatment of vaginal atrophic vaginitis has a total effective rate of 96% with the advantages of high efficiency and low recurrence rate with relative good clinical effect.
2. The combination between live lactobacillus preparation and chloroquinaldol-promestriene tablets in the treatment of vaginal atrophic vaginitis has a total effective rate of 95%. It is an effective and safe way, worthy of clinical use.
3. The combination of chloroquine/promestriene and metronidazole has a total effective rate of 92.5% in the treatment of bacterial vaginosis (BV) with low recurrence rate and no adverse reactions, being worthy of clinical application.

Chemical Properties

White Solid

Uses

Estradiol derivative

Uses

A synthetic diethyl-ether of Estradiol with no distal hormonal effects, in patients undergoing surgical correction for stress urinary incontinence (SUI).

Definition

ChEBI: Promestriene is a steroid. It derives from a hydride of an estrane.

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