JP2002525299A - New cataract formation inhibitor - Google Patents

Abstract

  (57) [Summary] A method for reducing the risk of cataract development in a mammal is provided, the method comprising administering to the mammal an effective amount of a tetracycline derivative. A preferred tetracycline derivative administered according to the method of the present invention is 6α-deoxy 5-hydroxy-4-dedimethylaminotetracycline.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] This invention was supported by United States government. The United States Government has certain rights in the invention. BACKGROUND OF THE INVENTION Cataracts are an abnormally progressive state of the lens of the eye, characterized by reduced transparency. Gray-white opacity is seen in the lens behind the pupil. The majority of cataracts are caused by degenerative changes, most often after the age of 50, but in susceptible patients such as diabetes, cataracts can occur at an earlier age. Two types of cataracts have been described. (1) Metabolic and juvenile cataracts seen in children and adolescents with uncontrolled diabetes, and (2) Senile cataracts that are more common than metabolic cataracts. Diabetic cataracts are similar to senile cataracts found in non-diabetic patients, but tend to occur at an earlier age (eg, the aging process is accelerated). The tendency to develop cataracts is inherited and is accelerated by diseases such as diabetes. If the cataract is untreated, vision will eventually be lost. It may blur the field of vision first, then diffuse the bright light, and finally cause distortion and double vision.

Conventionally, cataracts have been treated as a progressive condition of the lens of the eye. In particular, senile cataracts were usually treated by excision of lenses and special prescription of contact lenses and glasses. Mild cataracts in children and adolescents are minced by incision and drainage or ultrasound, followed by washing and aspiration of the fragments for several minutes. As noted above, the predisposition to cataracts is hereditary and is accelerated by diseases such as diabetes. Diabetes is the leading cause of blindness in adults, with 8% of legal blindness in the United States due to loss of vision (Klein and Klein, 1995). Diabetes 65
% Are blind within 5 years of the discovery of proliferative retinopathy (Lavine, 1990). An additional complication of diabetes in the eye is related to lens swelling. This swelling is the result of the accumulation of fructose and sorbitol, which increase the osmolality within the lens. This process continues, and the lens proteins degenerate to form cataracts (Lavine, 1990).

[0003] Vascular studies in the eyes of an animal model of Type II diabetes (ZDF / Gmi-fa rats) show increased capillary cell nuclear density and increased basal thickness when compared to non-diabetic animals. Such microscopic changes in the retina have been demonstrated (Danis et al., 1993). D
have demonstrated that these animals develop microvascular retinopathy, which is determined morphologically by the expansion of many endothelial cells (endothelial proliferation) and is associated with capillaries.
A prominent early marker trait for diabetic retinopathy is the development of pericyte degeneration and pericyte morphology. Another ocular complication seen in this diabetic rat model is the development of cataracts. Compounds approved for use in humans and available via oral, injectable or topical routes, such as tetracycline, have not been proposed for treating diseases or conditions such as cataracts. This compound, tetracycline, is represented by the following general structure.

[0004]

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[0005] The ring numbering system is as follows.

[0006]

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[0007] Like the 5-OH (terramycin) and 7-Cl (aureomycin) derivatives, tetracyclines are naturally occurring and well-known antibiotics. Natural tetracycline can be modified without losing its antibiotic properties, but it must retain structural elements. Modifications that can and cannot produce the basic tetracycline structure are described by Mitscher in The Chemistry of Tetracyclines, Chapter 6, Marce.
l Reviewed in Dekker, Publishers, New York (1978). According to Mitscher, substituents at positions 5-9 of the tetracycline ring system can be modified without slight loss of antibiotic properties. However, changes in the basic ring system or substitution of substituents at positions 1-4 and 10-12 generally lead to synthetic tetracyclines having substantially less or no effective antimicrobial activity. Examples of the chemically modified tetracycline (hereinafter referred to as CMT) include 4-dedimethylaminotetracycline, which is generally considered to be a non-antibacterial tetracycline.

In addition to their antibiotic properties, tetracyclines have been described as having many other uses. For example, tetracycline is also known to inhibit the activity of collagen-destroying enzymes such as mammalian collagenase, gelatinase, macrophage elastase and bacterial collagenase (Golub
J. Periodont. Res. 20: 12-23 (1985); Golub et al. Crit. Revs. Oral Biol.
Med. 2: 297-322 (1991), U.S. Patent Nos. 4,666,897, 4,704,383, 4,935,411.
No. 4,935,412). In addition, tetracycline is known to inhibit mammalian skeletal muscle destruction and protein degradation (US Pat. No. 5,045,538). In addition, tetracycline has been shown to increase bone protein synthesis in US Pat. No. 34,656 and to reduce bone resorption in organ culture in US Pat. No. 4,704,383. Similarly, US Pat. No. 5,532,227 to Golub et al. Discloses that tetracycline can restore excessive glycosylation of proteins. In particular, tetracycline blocks excess collagen crosslinking resulting from excessive glycosylation of collagen in diabetes.

[0009] These properties make tetracycline useful in the treatment of many diseases. For example, many tetracyclines, including non-antibacterial tetracyclines, have been suggested to be effective in treating arthritis. For example, Greenwald et al., “Tetracyclines S
uppress Metalloproteinase Activity in Adjuvant Arthritis and, in Combina
tion with Flurbiprofen, Ameliorate Bone Damage, ”Journal of Rheumatology
19: 927-938 (1992), “Treatment of Destructive Arthritic Di” by Greenwald et al.
sorders with MMP Inhibitors: Potential Role of Tetracyclines in, Inhibit
ion of Matrix Metalloproteinases: Therapeutic Potential, ”Annals of the
New York Academy of Sciences 732: 181-198 (1994), Kloppenburg et al., “Minocy
cline in Active Rheumatoid Arthritis, ”Arthritis Rheum 37: 629-636 (1994)
Ryan et al., “Potential of Tetracycline to Modify Cartilage Breakdown in O
steoarthritis, ”Current Opinion in Rheumatology 8: 238-247 (1996), O'Dell
“Treatment of Early Rheumatoid Arthritis with Minocycline or Placeb
o, "Arthritis Rheum 40: 842-848 (1997).

[0010] Tetracycline has also been proposed for use in treating skin diseases. For example,
White et al., Lancet, Apr. 29, p. 966 (1989) show that tetracycline minocycline is effective in treating dystrophic epidermal lysing bullosa, a life-threatening skin disease believed to be associated with excess collagenase. Report that there is. Elewski et al. Journal of the Am
Also studied by the erican Academy of Dermatology 8: 807-812 (1983).
Elewski et al. Disclosed that tetracycline antibiotics may have anti-inflammatory activity against skin diseases. Similarly, Plewig et al., Journal of Investigative Dermatology 65: 532 (1975) disclosed experiments designed to test the hypothesis that antimicrobial agents are effective in treating inflammatory skin diseases. The experiments of Plewig et al. Have demonstrated that tetracycline has anti-inflammatory properties in the treatment of pustules induced by potassium iodide patches.

[0011] The use of tetracyclines in combination with non-steroidal anti-inflammatory agents has been studied in the treatment of inflammatory skin disorders caused by acne vulgaris. Wong et al. Journal of
The American Academy of Dermatology 1: 1076-1081 (1984) studied the combination of tetracycline and ibuprofen, and tetracycline is an effective drug against acne vulgaris, and ibuprofen reduces the resulting inflammation by inhibiting cyclooxygenase. It has been found to be useful in reducing it. Funt et al. Journal
of the American Academy of Dermatology 13: 524-525 (1985) disclosed similar results by combining ibuprofen with an antimicrobial dose of minocycline. Doxycycline, an antibacterial tetracycline derivative, has been used to control nitrate products. D'Agostino et al. Journal of Infectious Diseases: 1
77: 489-92 (1998) reported that doxycycline injected with bacterial lipopolysaccharide (hereinafter abbreviated as LPS) and administered to mice exerted a protective effect by suppressing nitrate products by an IL-10-independent mechanism. The experiments performed have been disclosed. Experiments performed in vitro also showed that doxycycline inhibited nitric oxide synthesis by LPS-activated macrophages without enhancing endogenous IL-10 release. Based on the foregoing, tetracycline has been found to be effective in different treatments. However, there is no suggestion that tetracycline can be used to reduce the risk of developing cataracts in mammals. Therefore, one of the objects of the present invention is to provide, in particular, an economical, relatively non-concurrent method for reducing the risk of cataract development.

SUMMARY OF THE INVENTION It has been discovered that these and other objects are achieved by the present invention which provides a method of reducing the risk of developing cataract in a mammal. The methods of the present invention provide for reducing the risk of cataract development in a mammal by administering to the mammal an effective amount of a tetracycline derivative. A preferred method of the present invention provides that the tetracycline derivative is a non-antibacterial tetracycline. Another preferred method of the invention provides for reducing the risk of cataract development by administering to a mammal an effective amount of a chemically modified tetracycline derivative, eg, dedimethylaminotetracycline. A preferred dedimethylaminotetracycline derivative is 6α-deoxy 5-hydroxy 4-dedimethylaminotetracycline (CMT-8).

Other dedimethylaminotetracyclines administered by the method of the present invention include 4-dedimethylaminotetracycline, 4-dedimethylamino-5-oxytetracycline, 4-dedimethylamino-7-chlorotetracycline, -Hydroxy-
4-dedimethylaminotetracycline, 5a, 6-anhydro-4-hydroxy-4-dedimethylaminotetracycline, 6α-deoxy-5-hydroxy-4-dedimethylaminotetracycline, 6-demethyl-6-deoxy-4-digi Methylaminotetracycline, 4-dedimethylamino-12a-deoxytetracycline, 12α-deoxy-4-
Deoxy-4-dedimethylaminotetracycline, 12a, 4α-anhydro-4-dedimethylaminotetracycline, 7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 5-hydroxy-6-α- Deoxy-4-dedimethylaminotetracycline, 4-dedimethylamino-12α-deoxyanhydrotetracycline and 4-dedimethylamino-11-hydroxy-12a-deoxytetracycline.

Another dedimethylaminotetracycline administered in the method of the present invention is 4-demethylaminotetracycline.
It has a D-ring substituent at the C7 and / or C9 position of the dedimethylaminotetracycline molecule. These compounds include 7-azido-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 7-dimethylamino-9-azido-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 9 -Amino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 9-azido-6-demethyl-6-deoxy-4-
Dedimethylaminotetracycline, 9-nitro-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 9-amino-7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 7- Acetamide-6-demethyl-6-
Deoxy-4-dedimethylaminotetracycline, 9-acetamido-6-demethyl-6
-Deoxy-4-dedimethylaminotetracycline, 7-amino-9-nitro-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 9- (N, N, -dimethyl) glycylamino-6-demethyl-6 -Deoxy-4-dedimethylaminotetracycline, 7,9
-Diamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 9-ethoxythiocarbonylthio-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 7-dimethylamino-9-acetamido-6 -Demethyl-6-deoxy-4-dedimethylaminotetracycline, 9-azido-7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 9-azido-7-dimethylamino-6-
Demethyl-6-deoxy-4-dedimethylaminotetracycline, 7-azido-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 7-dimethylamino-9
-Azido-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 9-amino-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 9-azido-5-hydroxy-6-deoxy-4 -Dedimethylaminotetracycline, 9-nitro-
5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 9-amino-7-
Dimethylamino-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 7-acetamido-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 9-acetamido-5-hydroxy-6-deoxy-4 -Dedimethylaminotetracycline, 7-amino-9-nitro-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 9- (N, N-dimethyl) glycylamino-5-hydroxy-6-deoxy
-4-dedimethylaminotetracycline, 7,9-diamino-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 7-dimethylamino-9-amino-5-hydroxy-6-deoxy-4-dedimethyl Aminotetracycline, 9-ethoxythiocarbonylthio-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 7
-Dimethylamino-9-acetamido-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 9-azido-7-dimethylamino-5-hydroxy-6-deoxy-4-
Dedimethylaminotetracycline, 9-amino-8-chloro-5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 9- (N, N-dimethyl) glycylamino-
5-hydroxy-6-deoxy-4-dedimethylaminotetracycline, 9-nitro-7-
Dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 9-acetamido-7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 9- (N, N-dimethyl ) Glycylamino-7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline and 9-ethoxythiocarbonylthio-7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline No.

In addition, the D ring may be halogenated at the C8 position to provide an 8-haro-dedimethylaminotetracycline derivative. Halogen, as used herein, is chlorine, fluorine, bromine and iodine. 8-haro-dedimethylaminotetracycline derivatives include 9-amino-8-chloro-7-dimethylamino-6-demethyl-6-deoxy
-4-dedimethylaminotetracycline, 9-amino-8-chloro-7-dimethylamino-
5-hydroxy-6-deoxy-4-dedimethylaminotetracycline and 9-amino-8
-Chloro-6-demethyl-6-deoxy-4-dedimethylaminotetracycline. Another preferred method of the present invention comprises 6a-benzylthiomethylenetetracycline,
Tetracycline derivative, tetra-cycline mono-N-alkylated amide, 6-fluoro-6-demethyltetracycline, 11a-chlorotetracycline, tetracycline pyrazole and 12a-deoxytetracycline and a tetracycline derivative selected from the group consisting of derivatives thereof are administered. To reduce the risk of cataract development in mammals.

[0016] Another preferred method of the present invention provides that the tetracycline derivative is an antibacterial tetracycline. Antibacterial tetracycline derivatives used in the method of the present invention include tetracycline, minocycline and doxycycline. Another method of the invention provides for reducing the risk of developing cataract in a mammal by systemically administering a tetracycline derivative. Preferably, the tetracycline derivative is administered systemically via a controlled release delivery system. Additional methods of the invention provide for reducing the risk of developing cataract in a mammal by oral or topical administration of a tetracycline derivative. These and other advantages of the present invention will be appreciated from the detailed description and drawings set forth herein. The detailed description and drawings enhance the understanding of the invention, but are not intended to limit the scope of the invention. Preferred embodiments of the present invention are chosen for purposes of illustration and description, but are not intended to limit the scope of the present invention. Preferred embodiments of certain aspects of the invention are illustrated in the accompanying drawings.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of reducing the risk of developing cataract in a mammal. The method provides for administering an effective amount of a tetracycline derivative to a mammal. The method of the present invention can be used on any living mammal. For example, mammals include humans, as well as pet animals such as dogs and cats, laboratory animals such as rats and mice, and livestock animals such as horses and cows. The tetracycline derivative used here has the following general ring structure.

[0018]

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The number system of the polycyclic nucleus is as follows.

[0020]

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Tetracycline derivatives, as well as 5-OH (oxytetracycline, eg, teramycin) and 7-Cl (chlorotetracycline, eg, aureomycin) derivatives, are naturally occurring and are all well known antibiotics. For example, semi-synthetic tetracyclines include doxycycline, minocycline and metacycline. Classes of compounds are defined by their structural relationship to the antibiotic tetracycline, but also by chemical modification to substantially or completely eliminate the activity of those antibiotics. Substantial elimination of antibiotic activity occurs when the activity of the antibiotic is substantially less than that of tetracycline. Preferably, the activity of the antibiotic is at least about 2-fold less than that of tetracycline, more preferably at least about 5-fold less than that of tetracycline, and even more preferably at least about 10-fold less than that of tetracycline. Modifications that can and cannot produce the basic tetracycline structure are described in Mitscher,
The Chemistry of the Tetracycline Antibiotics, Marcel Dekker,
New York (1978), Ch.6. According to Mitscher, modifications at positions 5-9 of the tetracycline ring system can be made without any loss of antibiotic properties. However, changes in the basic structure of the ring system or substitution of substituents at positions 1-4 and 10-12 generally result in synthetic tetracyclines with a substantial reduction in antimicrobial activity or essentially no antimicrobial activity. I do. For example, chemically modified tetracycline (CMT's) derivatives include 4-dedimethylaminotetracycline (CMT-1), tetracyclinonitrile (CMT-2),
6-demethyl-6-deoxy-4-dedimethylaminotetracycline (CMT-3), 7-chloro-4-dedimethylaminotetracycline (CMT-4), tetracyclinopyrazole (CMT-5), 4-hydroxy- 4-dedimethylaminotetracycline (CMT-6)
, 12α-deoxy-4-dedimethylaminotetracycline (CMT-7), 5-hydroxy-6-α-deoxy-4-dedimethylaminotetracycline (CMT-8), 4-dedimethylamino-12-α-deoxy Anhydrotetracycline (CMT-9) and 7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline (CMT-10
). All are used as non-antibacterial tetracyclines to reduce the risk of developing cataracts in mammals. A particularly preferred tetracycline derivative suitable for use in the present invention is CMT-8.

[0022] Tetracycline derivatives having antibacterial activity have also been investigated according to the invention. However, it is preferred that such compounds be used in an amount that has substantially no antimicrobial activity but has the effect of reducing the risk of developing cataract in a mammal. Preferred compounds of this type include tetracycline, minocycline and doxycycline. Chemically modified and antibacterial tetracycline derivatives can be prepared by methods known in the art. For example, The Chemistry of t from Mitscher, LA
See he Tetracycline Antibiotics, Marcel Dekker, New York (1978), Ch. 6, and U.S. Patent Nos. 4,704,383 and 5,532,227.

According to the method of the present invention, an effective amount of a tetracycline derivative is administered.
As used herein, "effective amount" is an amount effective to achieve a particular result that reduces the risk of cataract formation. Preferably, the tetracycline derivative is provided in an amount that has little or no antimicrobial activity. Tetracycline derivatives are not effective antibacterial agents unless they clearly prevent bacterial growth. Thus, the methods of the present invention can advantageously use tetracycline derivatives that have been chemically modified to reduce or eliminate their antimicrobial properties. They can be used at higher levels than antibacterial tetracyclines, and have certain disadvantages, such as indiscriminate killing of beneficial bacteria and the emergence of resistant bacteria, which often involves the use of antibacterial amounts of such compounds. For avoidance, the use of CMT's is preferred in the present invention.

It is clear that the tetracycline derivatives that are effective in the method of the present invention show their beneficial effects in a dose-dependent manner, but when absorbed, CMT-8 shows the best effect. Thus, within broad limits, it has been observed that administration of higher amounts of the tetracycline derivative further reduces the risk of cataract formation than administration of lower amounts. Further efficacy has been observed at doses below the level at which toxicity is seen. The maximum dose for a patient is the highest dose that will not cause undesired or intolerable side effects. For example, a tetracycline compound can be used at about 0.1 mg / kg / day to
It is administered in an amount of about 30 mg / kg / day, preferably about 1 mg / kg / day to about 18 mg / kg / day. For the purposes of the present invention, side effects can include clinically significant antimicrobial activity, as well as toxic effects. For example, an overdose of about 50 mg / kg / day will cause side effects in most mammals, including humans. At a minimum, the practitioner will be guided by the skills and knowledge in the field, and the present invention will not be limited, but will include dosages that are effective to achieve the described effects.

The method of the invention involves administering a tetracycline derivative in an amount effective to reduce the risk of cataract formation in the mammal. Administration of the tetracycline derivative can be performed by various methods. For example, tetracycline derivatives are administered systemically by parenteral and enteral routes, and include controlled release delivery systems. For example, the tetracycline derivative is easily administered intravenously (eg, intravenous injection), which is the preferred route of delivery. Intravenous administration is accomplished by mixing the tetracycline derivative with a suitable pharmaceutical carrier (vehicle) or excipient as understood by practitioners in the art.

[0026] Oral or enteral use is also contemplated, and formulations such as tablets, capsules, pills, troches, elixirs, suspensions, syrups, cachets, chewing gums and the like are used to provide the tetracycline derivative. Alternatively, delivery of the tetracycline derivative can involve topical application. Accordingly, it is preferred that the carrier be suitable for topical use. Formulations that are considered suitable for such topical use include gels, salves, lotions, creams, ointments and the like. The tetracycline derivative can be applied directly to the skin,
It is mixed with a support base or substrate or the like to give a surgical or baked bandage or bandage pre-packaged. Therefore, it is preferred to apply the tetracycline derivative locally to the medium in an amount of about 25% (W / W) or less. More preferably, from about 0.1% to
Applying the tetracycline derivative in an amount of about 10% appears to effectively reduce the risk of cataract formation of the present invention. These amounts do not appear to result in significant toxicity for therapeutic purposes.

The combination or coordination of local and systemic administration of tetracycline derivatives has also been investigated according to the invention. For example, a non-absorbable tetracycline compound such as CMT-2
Or, CMT-6 is administered locally, but is substantially absorbable and can be effectively systemically delivered to a patient, such as a tetracycline compound, such as CMT-1, CMT-3, CMT-7 or CMT-6.
MT-8 is administered systemically. The present invention has found, based on unexpected medical examination by volunteers, that tetracycline derivatives reduce the risk of cataract formation in mammals. Volunteers are unaware of any physiological or biochemical basis for predicting that tetracycline reduces the risk of cataract formation in mammals. It is therefore surprising to find that tetracycline derivatives reduce the risk of cataract formation in mammals. Diabetes develops a posterior subcapsular cataract characterized by opaque central nuclei and cortex. In studies of ZDF / Gmi-fa rats, for example, non-diabetic controls do not produce clinically recognized cataracts, but 6
Five percent had these visual impairments at five months with a statistically significant increase in incidence (p <0.001). Curiously, treatment with CMT-8 reduced the incidence of these cataracts in 5 months, but the antibacterial compound, doxycycline, was not effective. In this study, administration of CMT-8 to Type II diabetic rats reduced the incidence of cataracts to 37% in 5 months. Indeed, the effect of this treatment may be underestimated because it is an unexpected finding, and therefore cannot be elaborated earlier. The mechanism by which Type II (and Type I) diabetes causes these cataracts to occur is not yet understood.

[0028] Systemic administration of a tetracycline derivative, such as CMT-8, will reduce the incidence of blind cataracts if left untreated. Proactively for people who easily form cataracts,
Using this therapy will reduce the need for surgical procedures. In the case of surgical treatment, the use of CMT-8 may reduce the occurrence of cataracts. FIG. 1 shows the development of cataract in untreated Type II ZDF / GMI diabetic rats and Type II ZDF / GMI diabetic rats treated with different tetracycline analogs. In particular, approximately 60% of untreated Type II ZDF / GMI diabetic rats developed cataracts and were treated with CMT-8
About 42% of Type II ZDF / GMI diabetic rats developed cataracts. Type II ZDF / GMI diabetic rats treated with other tetracycline analogs did not show cataract development with a lower probability than Type II ZDF / GMI diabetic rats treated with CMT-8. In particular, about 60% of Type II ZDF / GMI diabetic rats treated with doxycycline developed cataract, and about 70% of Type II ZDF / GMI diabetic rats treated with CMT-3 developed cataract. The lack of potency for doxycycline and CMT-3 appears to be due to the serum levels achieved. Doxycycline, CMT-3 and CMT-8 were each administered at an oral dose of 15 mg / kg in a rat pK study demonstrating that equal oral doses resulted in significantly different peak serum concentrations. The peak serum concentration of doxycycline was determined to be 0.9 ug / ml, and the peak serum concentration of CMT-3 was determined to be 4.6 ug / ml. However, the peak serum concentration of CMT-8 was determined to be 15 ug / ml (Liu et al.
ipophilicity and Pharmacokinetics of Different Chemically-Modified Tetra
cyclines (CMTs) In Vivo, Current Medicinal Chemistry , submitted for publ
ication in September 1999). Clearly, higher oral doses of CMT-3 and doxycycline would be required to achieve similar serum concentrations as CMT-8.

FIGS. 2 and 3 provide a comparison between healthy untreated rats and untreated Type II ZDF / GMI diabetic rats and Type II ZDF / GMI diabetic rats treated with doxycycline and CMT-8. No cataracts occurred in diabetic rats treated with CMT-8 as in non-diabetic control rats. Treating diabetic rats with doxycycline to suppress cataract development was not effective, but the lack of efficacy appears to be due to the low serum concentrations as described above. Having described what is believed to be the preferred embodiment of the invention, those skilled in the art will realize that other and further embodiments may be performed without departing from the spirit of the invention. And all such further modifications and variations that fall within the true scope of the claims set forth herein.

[Brief description of the drawings]

FIG. 1. Untreated Type II ZDF / GMI diabetic rats and doxycycline, CMT
-3 (6-demethyl-6-deoxy-4-dedimethylaminotetracycline) and CMT
1 is a bar graph showing the development of cataract in diabetic rats treated with -8 (5-hydroxy-6-α-deoxy-4-dedimethylaminotetracycline).

FIG. 2 is a photograph of cataract development in untreated Type II ZDF / GMI diabetic rats compared to healthy control rats.

FIG. 3 is a photograph showing the occurrence of cataract in Type II ZDF / GMI diabetic rats treated with doxycycline and CMT-8.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Invention Gollaw Loan M United States of America New York 11787 Smithtown Whitney Gate 29 (72) Inventor Ramamoosie Nungabam S. United States of America 11787 Smithtown Lynam Court 10 F-term (reference) 4C086 AA01 AA02 DA29 MA52 MA55 NA10 NA14 ZA33 ZC61

Claims (34)

[Claims] 1. A method of reducing the risk of developing cataract in a mammal, comprising administering to the mammal an effective amount of a tetracycline derivative. 2. The method according to claim 1, wherein said tetracycline derivative is a non-antibacterial tetracycline. 3. The method according to claim 1, wherein said tetracycline derivative is dedimethylaminotetracycline. 4. The method according to claim 1, wherein the dedimethylaminotetracycline is 4-dedimethylaminotetracycline, 4-dedimethylamino-5-oxytetracycline, 4-dedimethylamino-7-chlorotetracycline, 4-hydroxy-4-dedimethylaminotetracycline. 5a, 6-anhydro-4-hydroxy-4-dedimethylaminotetracycline, 6α-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 4-dedimethylamino-12a-deoxytetracycline, 12α-deoxy-4-deoxy-4-dedimethylaminotetracycline, 12a, 4α-anhydro-4-digi Methylaminotetracycline, 7-dimethylamino-6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 5-hydroxy-6-α-deoxy-4-dedimethylaminotetracycline, 4-dedimethylamino-12α-deoxy 4. The method according to claim 3, wherein the method is selected from the group consisting of anhydrotetracycline and 4-dedimethylamino-11-hydroxy-12a-deoxytetracycline. 5. The method according to claim 1, wherein the tetracycline derivative is 6α-deoxy 5-hydroxy-4.
2. The method according to claim 1, which is -dedimethylaminotetracycline. 6. The tetracycline derivative is 6a-benzylthiomethylenetetracycline, tetracyclinotrile, mono-N-alkylated amide of tetracycline, 6-fluoro-6-demethyltetracycline, 11a-chlorotetracycline, tetracycline pyrazole and 12a The method according to claim 1, wherein the method is selected from the group consisting of -deoxytetracycline and derivatives thereof. 7. The method according to claim 1, wherein said tetracycline derivative is an antibacterial tetracycline. 8. The method according to claim 7, wherein said tetracycline derivative is tetracycline. 9. The method according to claim 7, wherein said tetracycline derivative is minocycline. 10. The method according to claim 7, wherein said tetracycline derivative is doxycycline. 11. The method of claim 1, wherein said tetracycline derivative is administered systemically. 12. The method of claim 11, wherein said tetracycline derivative is administered systemically by a controlled release delivery system. 13. The method of claim 1, wherein said tetracycline derivative is administered orally. 14. The method of claim 1, wherein said tetracycline derivative is administered topically. 15. The method according to claim 1, wherein said tetracycline derivative is a tetracycline compound of the following structural formula and pharmacologically acceptable and non-acceptable salts thereof. Embedded image Or Or Or (Wherein R7 is hydrogen, amino, nitro, mono (lower alkyl) amino, halogen,
R6-a is selected from the group consisting of hydrogen and methyl; R6 and R5 are selected from the group consisting of hydrogen and hydroxyl; di (lower alkyl) amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano and hydroxyl R8 is selected from the group consisting of hydrogen and halogen; R9 is hydrogen, amino, azide, nitro, acylamino, hydroxyl, ethoxythiocarbonylthio, mono (lower alkyl) amino, halogen, diazonium, di ( R is selected from the group consisting of lower alkyl) amino and RCH (NH ₂ ) CO, wherein R is hydrogen or lower alkyl. With the proviso that when both R7 and R9 are hydrogen, R8 must be halogen, and R6-a, R6, R5 and R9 are all hydrogen and R7 is hydrogen, amino, nitro, halogen, dimethylamino or When diethylamino, R8 must be halogen, and R6-a is methyl, R6 and R9 are both hydrogen, R5 is a hydroxyl group, and R7 is hydrogen, amino, nitro, halogen or diethylamino. In some cases, R8 is halogen, and when R6-a is methyl, R6 is a hydroxyl group, and R5, R7 and R9 are all hydrogen, then R8 must be halogen, and R6-a, R6 And R5 are all hydrogen, R9 is methylamino, and R7 is dimethylamino, R8 must be halogen, and R6-a is methyl, R6 is hydrogen, and R5 is hydroxyl. Yes, R9 is methylamino If R7 is dimethylamino, R8 must be halogen, and if R6-a is methyl, R6, R5 and R9 are all hydrogen and R7 is cyano, then R8 must be halogen No. ) 16. The method according to claim 1, wherein said tetracycline derivative is a tetracycline compound of the following structural formula and pharmacologically acceptable and non-acceptable salts thereof. Embedded image Or Or Or Wherein R7 is selected from the group consisting of hydrogen, amino, nitro, mono (lower alkyl) amino, halogen and di (lower alkyl) amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano and hydroxyl; -a is selected from the group consisting of hydrogen and methyl, R6 and R5 are selected from the group consisting of hydrogen and hydroxyl, R4 is selected from the group consisting of NOH, N-NH-A and NH-A, and A is lower R8 is selected from the group consisting of hydrogen and halogen, R9 is hydrogen, amino, azide, nitro, acylamino, hydroxyl, ethoxythiocarbonylthio, mono (lower alkyl) amino, halogen, di (lower alkyl) selected from the group consisting of amino and RCH (NH ₂₎ CO, R is hydrogen or lower alkyl. However, R4 is NOH, an N-NH- alkyl or NH- alkyl, R7, R6-a, R6 , R5 And R
When 9 are all hydrogen, R8 must be halogen, and R4 is NOH, R6-a is methyl, R6 is hydrogen or hydroxyl, R7 is halogen, and both R5 and R9 Is hydrogen, R8 must be halogen, and R4 is N-NH-alkyl, R6-a is methyl, R6 is hydroxyl, R7, R5, R
When 9 are all hydrogen, R8 must be halogen, and R4 is NH-alkyl, R6-a, R6, R5, and R9 are all hydrogen and R7 is hydrogen, amino, mono (lower). (Alkyl) amino, halogen, di (lower alkyl) amino or hydroxyl, R8 must be halogen, and R4 is NH-alkyl, R6-a is methyl, and both R6 and R9 are hydrogen And R
When 5 is a hydroxyl group and R7 is mono (lower alkyl) amino or di (lower alkyl) amino, R8 must be halogen, and R4 is NH-alkyl, R6-a is methyl, R6 is hydroxyl or If it is hydrogen and R7, R5 and R9 are all hydrogen, then R8 must be halogen. ) 17. The method according to claim 1, wherein said tetracycline derivative is a 4-dedimethylaminotetracycline compound having the general formulas (I) to (IV), and pharmacologically acceptable and unacceptable salts thereof. the method of. General formula (I) (Wherein R7, R8 and R9 are combinations of the following groups: General formula (II) Or Or Or (Wherein R7, R8 and R9 are combinations of the following groups: General formula (III) Wherein R8 is hydrogen or halogen, and R9 is selected from the group consisting of nitro, (N, N-dimethyl) glycylamino and ethoxythiocarbonylthio. Or (Wherein R7, R8 and R9 are combinations of the following groups: 18. A method for treating cataract formation in a mammal comprising administering to the mammal an effective amount of a tetracycline derivative. 19. The method according to claim 18, wherein said tetracycline derivative is a non-antibacterial tetracycline. 20. The method according to claim 18, wherein said tetracycline derivative is dedimethylaminotetracycline. 21. The method of claim 21, wherein the dedimethylaminotetracycline is 4-dedimethylaminotetracycline, 4-dedimethylamino-5-oxytetracycline, 4-dedimethylamino-7-chlorotetracycline, 4-hydroxy-4-dedimethylaminotetracycline. , 5a, 6-anhydro-4-hydroxy-4-dedimethylaminotetracycline, 6α-deoxy-5-hydroxy-4-dedimethylaminotetracycline, 6-demethyl-6-deoxy-4-dedimethylaminotetracycline, 4- Dedimethylamino-12a-deoxytetracycline, 12α-deoxy-4-deoxy-4-dedimethylaminotetracycline, 12a, 4α-anhydro-4-dedimethylaminotetracycline, 7-dimethylamino-6-demethyl-6-deoxy- 4-dedimethylaminotetracycline, 5-hydroxy-6-α-deoxy-4-dedimethylamino Torasaikurin, 4dedimethylamino -12α- deoxy anhydrotetracycline and scope paragraph 20 A process according to claims 4 selected from dedimethylamino-11-hydroxy -12a- group consisting deoxytetracycline. 22. The method according to claim 18, wherein said tetracycline derivative is 6α-deoxy 5-hydroxy 4-dedimethylaminotetracycline. 23. The tetracycline derivative is 6a-benzylthiomethylenetetracycline, tetracyclinotrile, mono-N-alkylated amide of tetracycline, 6-fluoro-6-demethyltetracycline, 11a-chlorotetracycline, tetracycline pyrazole and 12a 19. The method according to claim 18, wherein the method is selected from the group consisting of -deoxytetracycline and derivatives thereof. 24. The method according to claim 18, wherein said tetracycline derivative is an antibacterial tetracycline. 25. The method according to claim 24, wherein said tetracycline derivative is tetracycline. 26. The method according to claim 24, wherein said tetracycline derivative is minocycline. 27. The method according to claim 24, wherein said tetracycline derivative is doxycycline. 28. The method of claim 18, wherein said tetracycline derivative is administered systemically. 29. The method of claim 28, wherein said tetracycline derivative is administered systemically by a controlled release delivery system. 30. The method according to claim 18, wherein said tetracycline derivative is administered orally. 31. The method of claim 18, wherein said tetracycline derivative is administered topically. 32. The method of claim 18, wherein said tetracycline derivative is a tetracycline compound of the following structural formula and pharmaceutically acceptable and non-acceptable salts thereof. Embedded image Or Or Or (Wherein R7 is hydrogen, amino, nitro, mono (lower alkyl) amino, halogen,
R6-a is selected from the group consisting of hydrogen and methyl; R6 and R5 are selected from the group consisting of hydrogen and hydroxyl; di (lower alkyl) amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano and hydroxyl R8 is selected from the group consisting of hydrogen and halogen; R9 is hydrogen, amino, azide, nitro, acylamino, hydroxyl, ethoxythiocarbonylthio, mono (lower alkyl) amino, halogen, diazonium, di ( R is selected from the group consisting of lower alkyl) amino and RCH (NH ₂ ) CO, wherein R is hydrogen or lower alkyl. With the proviso that when both R7 and R9 are hydrogen, R8 must be halogen, and R6-a, R6, R5 and R9 are all hydrogen and R7 is hydrogen, amino, nitro, halogen, dimethylamino or When diethylamino, R8 must be halogen, and R6-a is methyl, R6 and R9 are both hydrogen, R5 is a hydroxyl group, and R7 is hydrogen, amino, nitro, halogen or diethylamino. In some cases, R8 is halogen, and when R6-a is methyl, R6 is a hydroxyl group, and R5, R7 and R9 are all hydrogen, then R8 must be halogen, and R6-a, R6 And R5 are all hydrogen, R9 is methylamino, and R7 is dimethylamino, R8 must be halogen, and R6-a is methyl, R6 is hydrogen, and R5 is hydroxyl. Yes, R9 is methylamino If R7 is dimethylamino, R8 must be halogen, and if R6-a is methyl, R6, R5 and R9 are all hydrogen and R7 is cyano, then R8 must be halogen No. ) 33. The method of claim 18, wherein said tetracycline derivative is a tetracycline compound of the following structural formula and pharmaceutically acceptable and non-acceptable salts thereof. Embedded image Or Or Or Wherein R7 is selected from the group consisting of hydrogen, amino, nitro, mono (lower alkyl) amino, halogen and di (lower alkyl) amino, ethoxythiocarbonylthio, azido, acylamino, diazonium, cyano and hydroxyl; -a is selected from the group consisting of hydrogen and methyl, R6 and R5 are selected from the group consisting of hydrogen and hydroxyl, R4 is selected from the group consisting of NOH, N-NH-A and NH-A, and A is lower R8 is selected from the group consisting of hydrogen and halogen, R9 is hydrogen, amino, azide, nitro, acylamino, hydroxyl, ethoxythiocarbonylthio, mono (lower alkyl) amino, halogen, di (lower alkyl) selected from the group consisting of amino and RCH (NH ₂₎ CO, R is hydrogen or lower alkyl. However, R4 is NOH, an N-NH- alkyl or NH- alkyl, R7, R6-a, R6 , R5 And R
When 9 are all hydrogen, R8 must be halogen, and R4 is NOH, R6-a is methyl, R6 is hydrogen or hydroxyl, R7 is halogen, and both R5 and R9 Is hydrogen, R8 must be halogen, and R4 is N-NH-alkyl, R6-a is methyl, R6 is hydroxyl, R7, R5, R
When 9 are all hydrogen, R8 must be halogen, and R4 is NH-alkyl, R6-a, R6, R5, and R9 are all hydrogen and R7 is hydrogen, amino, mono (lower). (Alkyl) amino, halogen, di (lower alkyl) amino or hydroxyl, R8 must be halogen, and R4 is NH-alkyl, R6-a is methyl, and both R6 and R9 are hydrogen And R
When 5 is a hydroxyl group and R7 is mono (lower alkyl) amino or di (lower alkyl) amino, R8 must be halogen, and R4 is NH-alkyl, R6-a is methyl, R6 is hydroxyl or If it is hydrogen and R7, R5 and R9 are all hydrogen, then R8 must be halogen. ) 34. The method according to claim 18, wherein said tetracycline derivative is a 4-dedimethylaminotetracycline compound having the general formulas (I) to (IV) and pharmacologically acceptable and unacceptable salts thereof. Method. General formula (I) (Wherein R7, R8 and R9 are combinations of the following groups: General formula (II) Or Or Or (Wherein R7, R8 and R9 are combinations of the following groups: General formula (III) Wherein R8 is hydrogen or halogen, and R9 is selected from the group consisting of nitro, (N, N-dimethyl) glycylamino and ethoxythiocarbonylthio. Or (Wherein R7, R8 and R9 are combinations of the following groups: