Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-09-28
2002-08-13
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06432943
ABSTRACT:
FIELD OF THE INVENTION
This invention provides a method for using 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, for the treatment of sexual dysfunction.
BACKGROUND OF THE INVENTION
During recent years, sexual dysfunction in humans has become recognized as an increasingly important clinical entity. Such recognition is due in no small part to the pioneering work of William H. Masters and Virginia E. Johnson. In their books,
Human Sexual Response,
Little Brown and Company, Boston, 1966, and
Human Sexual Inadequacy,
Little Brown and Company, Boston, 1970, human sexual response is divided into four phases—excitement phase, plateau phase, orgasmic phase and resolution phase. Any disturbance or variation in this pattern is characterized by them (and others) as a sexual dysfunction.
A more recent, and preferable, categorization of human sexual response is that set forth in
Disorders of Sexual Desire,
Helen Singer Kaplan, M.D., Ph.D., Brunner Mazel Book, Inc., New York, N.Y., 1979. Dr. Kaplan utilizes a triphasic concept of human sexuality—desire, excitement and orgasm. In males, the term “libido” has been used previously to describe the pre-excitement phase of sexual response. The excitement phase in both males and females is characterized by reflex vasodilatation of the genital blood vessels, resulting in an erection in males and by heightened coloring of the labia and lubrication in females. Disorders of the male excitement and desire phases are generally classified under the term impotence, inability to attain or maintain an erection, although some authors restrict the term to an erection disability alone. Dysfunction of the female excitement phase, inhibition of lubrication and swelling, is a relatively uncommon clinical syndrome.
Disorders of the orgasm phase in males includes premature or retarded ejaculation, and anorgasm in both males and females.
Sexual dysfunction, a disorder of one or more of the three phases of sexual response, has generally been treated by counseling. Drug treatment of such disorders has been rare. Masters and Johnson do record the treatment of elderly males with androgens, limited success only being attained.
Sexual dysfunction, besides being in part psychogenic in origin, also includes dysfunctions brought about as a direct result of disease (diabetes) or as an indirect result; i.e., drugs used for treating hypertension in males frequently cause impotence. Kaplan, in Table 1, an appendix, lists the effect of drugs on the sexual response. Drugs are classed as sedative-hypnotics, including alcohol and barbiturates, antianxiety drugs, such as valium and librium, narcotics, such as morphine, the various antipsychotic agents, including phenothiazines and haldol, antidepressants, including the tricyclic antidepressants and the MAO inhibitors, stimulants such as cocaine, hallucinogens including LSD, miscellaneous CNS agents, including L-DOPA and parachlorophenylalanine, hormones, antihypertensives, antiadrenergic drugs, anticholinergic drugs, aphrodisiacs, etc. An examination of Table 1 indicates that a great majority of the drugs and drug types have no effect on the desire or excitement phase of the sexual response. A number of the drugs or drug types, however, are shown to cause impotence and thus may be a cause of sexual dysfunction. Cocaine and the aphrodisiacs alone seem to affect impotence in a positive manner. Many of the drugs in the table are said to cause impotence. It might also be noted that in the centrally acting antihypertensives, impotence is a major problem. L-DOPA, while having no affect on the excitement or orgasmic phases, is reported to increase desire in the elderly male patients afflicted with Parkinsonism. p-Chlorophenylalanine, an inhibitor of serotonin synthesis, is an aphrodisiac in rats but apparently has no effect on humans as well as will be set forth below.
It should also be noted that many of the drugs treat symptoms associated with sexual dysfunction and not the organic cause of the disease itself. For example, Kaplan reports a high degree of anxiety associated with sexual dysfunction in both males and females. An antianxiety drug would, therefore, be expected to have some positive effect in the treatment of such patients merely by alleviating the anxiety.
Extensive research has been conducted for a number of years directed toward the development of compounds for treating sexual dysfunction in mammals. For example, bromocriptine, yohimbine, buproen, naltrixine, methysergide, susperene and gonadotropin releasing hormone have all been evaluated for treating sexual dysfunction. However, to date such compounds have proven unsatisfactory for a variety of reasons including insufficient efficacy or presence of undesirable side effects.
It is known that the compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine can provide antipsychotic activity and is less likely to induce extrapyramidal symptoms. However, Applicant has discovered that surprisingly 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine can be useful for treating sexual dysfunction. The compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine is known and described in U.S. Pat. No. 5,229,382, herein incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
The presently claimed invention provides a method for treating sexual dysfunction comprising administering an effective amount of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.
DETAILED DESCRIPTION OF THE INVENTION
The 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine compound is of the formula
or an acid addition salt thereof. The free base of formula (I) is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.
The substantially pure crystalline anhydrous Form I 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (Form I) has a typical X-ray powder diffraction pattern substantially as follows, using a Sieman's D5000 diffractometer equipped with a copper radiation source, wherein d represents the interplaner spacing:
d
I/I
1
10.2689
100.00
8.577
7.96
7.4721
1.41
7.125
6.50
6.1459
3.12
6.071
5.12
5.4849
0.52
5.2181
6.86
5.1251
2.47
4.9874
7.41
4.7665
4.03
4.7158
6.80
4.4787
14.72
4.3307
1.48
4.2294
23.19
4.141
11.28
3.9873
9.01
3.7206
14.04
3.5645
2.27
3.5366
4.85
3.3828
3.47
3.2516
1.25
3.134
0.81
3.0848
0.45
3.0638
1.34
3.0111
3.51
2.8739
0.79
2.8102
1.47
2.7217
0.20
2.6432
1.26
2.6007
0.77
Form II 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (Form II) has a typical X-ray powder diffraction pattern substantially as follows, using a Sieman's D5000 diffractometer equipped with a copper radiation source, wherein d represents the interplaner spacing:
d
I/I
1
9.9463
100.00
8.5579
15.18
8.2445
1.96
6.8862
14.73
6.3787
4.25
6.2439
5.21
5.595
1.10
5.3055
0.95
4.9815
6.14
4.8333
68.37
4.7255
21.88
4.6286
3.82
4.533
17.83
4.4624
5.02
4.2915
9.19
4.2346
18.88
4.0855
17.29
3.8254
6.49
3.7489
10.64
3.6983
14.65
3.5817
3.04
3.5064
9.23
3.3392
4.67
3.2806
1.96
3.2138
2.52
3.1118
4.81
3.0507
1.96
2.948
2.40
2.8172
2.89
2.7589
2.27
2.6597
1.86
2.6336
1.10
2.5956
1.73
The x-ray powder diffraction patterns set forth herein were obtained with a copper K of wavelength=1.541A. The interplanar spacings in the column marked “d” are in Angstroms. The typical relative intensities are in the column marked “I/I
1
”. The detector was a Kevex silicon lithium solid state detector.
As used herein “substantially pure” shall refer to anhydrous Form I associated with <5% Form II; and most preferably it shall refer to <2% Form II. It is further preferred that “substantially pure” shall refer to <0.5% non-Form I polymorph.
As used herei
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