Patent Application
20050009754
The present invention provides a method of using growth hormone secretagogues, prodrugs thereof and pharmaceutically acceptable salts of said secretagogues and said prodrugs, for the treatment of fibromyalgia in patients in need thereof. The present invention provides such a method wherein the growth hormone secretagogues are compounds of Formula I below.
Fibromyalgia, also referred to as fibromyositis, fibrositis and myofascial pain syndrome, is a chronic rheumatic syndrome generally characterized by decreased pain thresholds (tender points), fatigue, sleep disturbance, numbness, anxiety and cognitive impairment. There are currently no specific diagnostic tests for fibromyalgia, however, in some cases, fibromyalgia has been associated with reduced pulsatile secretion of growth hormone and with low levels of insulin growth factor-I (IGF-I)/somatomedin C. Treatment of patients suffering from fibromyalgia and low IGF-I levels with growth hormone has been shown to improve clinical endpoints.
Numerous medications are currently in use to treat fibromyalgia. Medications commonly employed to treat fibromyalgia include nonsteroidal anti-inflammatories (NSAIDS), analgesics, sedatives and antidepressants including selective serotonin reuptake inhibitors (SSRIs). Opioids are occasionally used to treat fibromyalgia patients however opioids are generally not recommended in the treatment of fibromyalgia because of the high risk of abuse. Moreover, these therapeutic regimens suffer from numerous problems such as side effects that range from mild side effects such as drowsiness, dizziness and nausea to severe side effects such as addiction and liver damage. Accordingly, a more effective, physiological way to treat fibromyalgia is highly desirable.
Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) increased rate of protein synthesis in all cells of the body; (2) decreased rate of carbohydrate utilization in cells of the body; and (3) increased mobilization of free fatty acids and use of fatty acids for energy. As is known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. See “Human Growth Hormone,” Strobel and Thomas, Pharmacological Reviews, 46, pg. 1-34 (1994). Also, these varied uses of growth hormone are summarized in International Patent Application Publication Number WO 97/24369 and U.S. Pat. No. 6,107,306.
Various ways are known to release growth hormone (see Recent Progress in Hormone Research, vol. 52, pp. 215-245 (1997); and Front Horm Res. Basel, Karger, vol. 24, pp. 152-175 (1999)). For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase secretion of growth hormone releasing factor (GRF) or ghrelin (see Nature, vol. 402, pp. 656-660 (9 Dec. 1999)), or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF, IGF-I or a peptidyl compound which stimulated growth hormone production and/or release. In any case, the peptidyl nature of the compound necessitated that it be administered by injection. Initially, the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product that must be given by injection. In addition, administration of exogenous growth hormone may result in undesirable side-effects, including edema, and does not correlate with the pulsatile release seen in the endogenous release of growth hormone.
Certain compounds have been developed which stimulate the release of endogenous growth hormone. Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone and its analogs, the growth hormone releasing peptides, GHRP-6 and GHRP-1 (described in U.S. Pat. No. 4,411,890; International Patent Application Publication No. WO 89/07110; U.S. Pat. No. 5,534,494 and International Patent Application Publication No. WO 89/07111), and GHRP-2 (described in International Patent Application Publication No. WO 93/04081 and U.S. Pat. No. 5,663,146), as well as hexarelin (J. Endocrinol. Invest., 15 (Suppl. 4): 45 (1992)). In addition, the following growth hormone secretagogues are known in the art: MK-0677, L-162752 and L-163022 (Merck); NN703 and ipamorelin (Novo Nordisk); hexarelin (Pharmacia); GPA-748 (KP102, GHRP-2) (American Home Products); and LY444711 (Eli Lilly). The following agents that stimulate GH release via GHRH/GRF receptor (including GHRH/GRF derivatives, analogs and mimetics) are known in the art: Geref (Ares/Serono); GHRH (1-44) (BioNebraska); Somatorelin (GRF 1-44) (Fujisawa/ICN); and ThGRF (Theratechnologies).
Endocrine Reviews 18(5): 621-645 (1997) provides an overview of peptidomimetic regulation of growth hormone secretion by growth hormone secretagogues. Horm. Res. 1999; 51(suppl 3):16-20 (1999), examines the clinical and experimental effects of growth hormone secretagogues on various organ systems.
International Patent Application Publication Nos. WO 97/24369, U.S. Pat. No. 6,107,306, WO 98/58947 and U.S. Pat. No. 6,251,902 disclose that certain growth hormone secretagogues are useful for the treatment or prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity, accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing or accelerating the recovery of burn patients or patients having undergone major surgery, improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. Published European patent application 0995748 discloses that certain dipeptide growth hormone secretagogues are useful for the treatment or prevention of musculoskeletal frailty, including osteoporosis.
The administration of a growth hormone secretagogue is also known to enhance the quality of sleep, which is disclosed in International Patent Application Publication No. WO 97/24369 and U.S. Pat. No. 6,107,306. Commonly assigned U.S. nonprovisional patent application Ser. No. 09/290,985, filed 13 Apr. 1999, discloses pharmaceutical compositions comprising certain β3 adrenergic agonists and growth hormone secretagogues or growth hormone, and their use for treating diabetes, obesity, hyperglycemia, frailty associated with obesity or frailty associated with aging, and for enhancing the quality of sleep in a mammal. International Patent Application Publication No. WO 98/58949, discloses the treatment of insulin resistance with certain growth hormone secretagogues.
Drug Discovery Today, Vol. 4, No. 11, November 1999; and TEM Vol. 10, No. 1, 1999, disclose potential therapeutic applications of growth hormone secretagogues, including their use in treating growth hormone disorders such as growth hormone deficiency (GHD), age-related conditions, obesity and catabolic conditions, and their use in sleep enhancement.
The present invention provides a method for treating fibromyalgia in a patient comprising the administration of a therapeutically effective amount of a growth hormone secretagogue to the patient in need thereof. The present invention provides such a method for treating fibromyalgia in a patient in need thereof that comprises administering to the patient a therapeutically effective amount of a growth hormone secretagogue, which is a compound of the Formula I:
or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, or a tautomer thereof,
wherein
HET is a heterocyclic moiety selected from the group consisting of
d is 0, 1 or 2;
e is 1 or 2;
f is 0 or 1;
n and w are 0, 1 or 2, provided that n and w cannot both be 0 at the same time;
Y2 is oxygen or sulfur;
A is a divalent radical, where the left hand side of the radical as shown below is connected to C″ and the right hand side of the radical as shown below is connected to C′, selected from the group consisting of —NR2—C(O)—NR2—, —NR2—S(O)2—NR2—, —O—C(O)—NR2—, —NR2—C(O)—O—, —C(O)—NR2—C(O)—,
—C(O)—NR2—C(R9R10)—, —C(R9R10)—NR2—C(O)—, —C(R9R10)—C(R9R10)—C(R9R10)—, —S(O)2—C(R9R10)—C(R9R10)—, —C(R9R10)—O—C(O)—, —C(R9R10)—O—C(R9R10)—, —NR2—C(O)—C(R9R10)—, —O—C(O)—C(R9R10)—, —C(R9R10)—C(O)—NR2—, —C(R9R10)—C(O)—O—, —C(O)—NR2—C(R9R10)—C(R9R10)—, —C(O)—O—C(R9R10)—, —C(R9R10)—C(R9R10)—C(R9R10)—C(R9R10)—, —S(O)2—NR2—C(R9R10)—C(R9R10)—, —C(R9R10)—C(R9R10)—NR2—C(O)—, —C(R9R10)—C(R9R10)—O—C(O)—, —NR2—C(O)—C(R9R10)—C(R9R10)—, —NR2—S(O)2—C(R9R10)—C(R9R10)—, —O—C(O)—C(R9R10)—C(R9R10)—, —C(R9R10)—C(R9R10)—C(O)—NR2—, —C(R9R10)—C(R9R10)—C(O)—, —C(R9R10)—NR2—C(O)—O—, —C(R9R10)—O—C(O)—NR2, —C(R9R10)—NR2—C(O)—NR2—, —NR2—C(O)—O—C(R9R10)—, —NR2—C(O)—NR2—C(R9R10)—, —NR2—S(O)2—NR2—C(R9R10)—, —O—C(O)—NR2—C(R9R10)—, —C(O)—N═C(R11)—NR2—, —C(O)—NR2—C(R11)═N—, —C(R9R10)—NR12—C(R9R10)—, —NR12—C(R9R10)—, —NR12—C(R9R10)—C(R9R10)—, —C(O)—O—C(R9R10)—C(R9R10)—, —NR2—C(R11)═N—C(O)—, —C(R9R10)—C(R9R10)—N(R12)—, —C(R9R10)—NR12—, —N═C(R11)—NR2—C(O)—,
—C(R9R10)—C(R9R10)—NR2—S(O)2—, —C(R9R10)—C(R9R10)—S(O)2—NR2—, —C(R9R10)—C(R9R10)—C(O)—O—, —C(R9R10)—S(O)2—C(R9R10)—, —C(R9R10)—C(R9R10)—S(O)2—,
—O—C(R9R10)—C(R9R10)—, —C(R9R10)—C(R9R10)—O—, —C(R9R10)—C(O)—C(R9R10)—, —C(O)—C(R9R10)—C(R9R10)— and —C(R9R10)—NR2—S(O)2—NR2—;
Q is a covalent bond or CH2;
W is CH or N;
X is CR9R10, C═CH2 or C═O;
Y is CR9R10, O or NR2;
Z is C═O, C═S or S(O)2;
G1 is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl, carboxyl, —CONH2, —(C1-C4)alkyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, —(C1-C4)alkoxy optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, —(C1-C4)alkylthio, phenoxy, —COO(C1-C4)alkyl, N,N-di-(C1-C4)alkylamino, —(C2-C6)alkenyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, —(C2-C6)alkynyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, —(C3-C6)cycloalkyl optionally independently substituted with one or more (C1-C4)alkyl groups, one or more halogens or one or more hydroxy groups, —(C1-C4)alkylamino carbonyl or di-(C1-C4)alkyl amino carbonyl;
G2 and G3 are each independently selected from the group consisting of hydrogen, halo, hydroxy, —(C1-C4)alkyl optionally independently substituted with one to three halo groups and —(C1-C4)alkoxy optionally independently substituted with one to three halo groups;
R1 is hydrogen, —CN, (CH2)qN(X6)C(O)6, (CH2)qN(X6)C(O)(CH2)t-A1, (CH2)qN(X6)S(O)2(CH2)t-A1, —(CH2)qN(X6)S(O)2X6, —(CH2)qN(X6)C(O)N(X6)(CH2)t-A1, —(CH2)qN(X6)C(O)N(X6)(X6), —(CH2)qC(O)N(X6)(X6), —(CH2)qC(O)N(X6)(CH2)t-A1, —(CH2)qC(O)OX6, —(CH2)qC(O)O(CH2)t-A1, —(CH2)qOX6, —(CH2)qOC(O)X6, —(CH2)qOC(O)(CH2)t-A1, —(CH2)qOC(O)N(X6)(CH2)t-A1, —(CH2)qOC(O)N(X6)(X6), —(CH2)qC(O)X6, —(CH2)qC(O)(CH2)t-A1, —(CH2)qN(X6)C(O)OX6, —(CH2)qN(X6)S(O)2N(X6)(X6), —(CH2)qS(O)mX6, —(CH2)qS(O)m(CH2)t-A1, —(C1-C10)alkyl, —(CH2)t-A1, —(CH2)q—(C3-C7)cycloalkyl, —(CH2)q—Y1—(C1-C6)alkyl, —(CH2)q—Y1—(CH2)t-A1 or —(CH2)q—Y1—(CH2)t—(C3-C7)Cycloalkyl;
The present invention provides such a method wherein the compound has the structural formula below, which is designated herein as Formula I-A
a racemic-diastereomeric mixture or optical isomer of said compound or a pharmaceutically-acceptable salt or a prodrug thereof, or a tautomer thereof, wherein
f is 0;
n is 0 and w is 2, or n is 1 and w is 1, or n is 2 and w is 0;
Y is oxygen or sulfur;
R1 is hydrogen, —CN, (CH2)qN(X6)C(O)X6, (CH2)qN(X6)C(O)(CH2)t-A1, —(CH2)qN(X6)SO2(CH2)t-A1, —(CH2)qN(X6)SO2X6, —(CH2)qN(X6)C(O)N(X6)(CH2)t-A1, —(CH2)qN(X6)C(O)N(X6)(X6), —(CH2)qC(O)N(X6)(X6), —(CH2)qC(O)N(X6)(CH2)t-A1, —(CH2)qC(O)OX6, —(CH2)qC(O)O(CH2)t-A1, —(CH2)qOX6, —(CH2)qOC(O)X6, —(CH2)qOC(O)(CH2)t-A1, —(CH2)qOC(O)N(X6)(CH2)t-A1, —(CH2)qOC(O)N(X6)(X6), —(CH2)qC(O)X6, —(CH2)qC(O)(CH2)t-A1, —(CH2)qN(X6)C(O)OX6, —(CH2)qN(X6)SO2N(X6)(X6), —(CH2)qS(O)mX6, —(CH2)qS(O)m(CH2)t-A1, —(C1-C10)alkyl, —(CH2)t-A1, —(CH2)q—(C3-C7)cycloalkyl, —(CH2)q—Y1—(C1-C6)alkyl, —(CH2)q—Y1—(CH2)t-A1 or —(CH2)q—Y1—(CH2)t—(C3-C7)cycloalkyl;
The present invention provides the above method wherein the compound is 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug thereof or a pharmaceutically acceptable salt of the compound or the prodrug. The present invention also provides such a method wherein the compound is 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide, L-tartrate.
The present invention provides the above method wherein the compound is 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of the compound or the prodrug. The present invention also provides such a method wherein the compound is the (L)-(+)-tartaric acid salt of 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide.
The present invention provides the above method wherein the compound is 2-amino-N-(1-(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of the compound or the prodrug. The present invention also provides such a method wherein the compound is the (L)-(+)-tartaric acid salt of 2-amino-N-(1-(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.
Also, the present invention provides the above method, which further comprises administering a recombinant growth hormone or a growth hormone secretagogue selected from the group consisting of GHRP-6, GHRP-1, GHRP-2, hexarelin, growth hormone releasing factor, an analog of growth hormone releasing factor, IGF-I and IGF-II.
Also, the present invention provides the above method, which further comprises administering an antidepressant, a prodrug thereof or a pharmaceutically acceptable salt of said antidepressant or said prodrug. The present invention provides such methods wherein said antidepressant is a norepinephrine reuptake inhibitor (NERI), selective serotonin reuptake inhibitor (SSRI), monoamine oxidase inhibitor (MAO), combined norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (NERI/SSRI) such as a tricyclic antidepressant, or an atypical antidepressant, a prodrug of said antidepressant or a pharmaceutically acceptable salt of said antidepressant or said prodrug.
The present invention provides such a method wherein said antidepressant is a selective serotonin reuptake inhibitor (SSRI), a prodrug thereof or a pharmaceutically acceptable salt of said SSRI or said prodrug. Furthermore, the present invention provides such a method wherein said SSRI is citalopram, femoxetine, fluoxetine, fluvoxamine, indalpine, indeloxazine, milnacipran, paroxetine, sertraline, sibutramine or zimeldine, a prodrug of said SSRI or a pharmaceutically acceptable salt of said SSRI or said prodrug. The present invention also provides such a method wherein said SSRI is sertraline, a prodrug thereof or a pharmaceutically acceptable salt of sertraline or said prodrug.
The present invention provides such a method wherein said antidepressant is a combined norepinephrine reuptake inhibitor/selective serotonin reuptake inhibitor (NERI/SSRI) such as a tricyclic antidepressant. The present invention also provides such a method wherein said NERI/SSRI is amitriptyline, clomipramine, dosulepin (dothiepin) or doxepin, a prodrug of said NERI/SSRI or a pharmaceutically acceptable salt of said NERI/SSRI or said prodrug.
The present invention also provides the above method, which further comprises administering a therapeutically effective amount of a compound selected from gabapentin, ademetionine (S-adenosylmethionine), oxitriptan (5-hydroxytryptophan), γ-hydroxybutyrate, pramipexole, ketamine, dextromorphan, memantine, amantadine, methadone, dextropropoxyphene, ketobemidone, and tropisetron.
In addition, the present invention provides the above method, which further comprises administering a therapeutically effective amount of a compound selected from apomorphine, bromocriptine, pergolide, ropinirole, an octahydropyrazolo[3,4-g]quinoline or a trans-(±)-substituted-5,5a,6,7,8,9,9a, 10-octahydropyrimido[4,5-g]quinoline.
In addition, the present invention provides the above method, which further comprises administering a therapeutically effective amount of a compound selected from (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one, (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine or 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino)propyl]-3-ethylurea, or a pharmaceutically acceptable salt thereof.
The present invention is directed to the use of a growth hormone secretagogue compound, which has the ability to stimulate or amplify the release of endogenous growth hormone, for the treatment of fibromyalgia. Furthermore, the present invention provides a method for treating fibromyalgia in a patient comprising the administration of certain growth hormone secretagogues of Formula I as described hereinabove.
According to the present invention, growth hormone secretagogues, including growth hormone secretagogues of Formula I, are useful for treating fibromyalgia. Fibromyalgia is a common clinical syndrome characterized by widespread musculoskeletal pain, with a high prevalence both in the general population and among patients attending rheumatology clinics. In addition to musculokeletal pain, most fibromyalgia patients also experience other symptoms including fatigue, poor sleep, visceral pain, such as irritable bowel or bladder, exercise intolerance and neurologic symptoms such as dizziness, numbness and tingling. Although there is no specific diagnostic test for fibromyalgia, it can be diagnosed by using established criteria known in the art such as the American College of Rheumatology 1990 criteria for fibromyalgia, Wolfe, F. et al. Arthritis Rheum. 1990, 33, 160-172.
The efficacy of a growth hormone secretagogue for the treatment of fibromyalgia can be determined by assessing the effects of the administration of a growth hormone secretagogue on the patient in need thereof. Methods for determining these results are known in the art and include the use of the Fibromyalgia Impact Questionnaire, the McGill Pain Questionnaire, the number of tender points and total myalgic score.
The Fibromyalgia Impact Questionnaire is a self-report system composed of 19 items as disclosed by Burckhardt, C S et al. in J. Rheumatol. 1991, 18, 728-734. This questionnaire evaluates a patient based on criteria such as their physical functioning, the number of days they felt well or missed work due to fibromyalgia symptoms, and a visual analog scale which rated the difficulty in performing their job responsibilities, pain, fatigue, morning tiredness, stiffness, anxiety and depression. The Fibromyalgia Impact Questionnaire consists of ten questions designed to identify patients with fibromyalgia, Burckhardt, C S et al. in J. Rheumatol. 1991, 18, 728-734:
The responses to the first item in the questionnaire are scaled in a Likert format from 0=Always, 1=Most times, 2=Occasionally to 3=Never. The ten sub-items are added together and divided by the number of valid responses to yield one physical functioning score. Items 2 and 3 ask the patient to circle the appropriate number of days (from 1 to 7 for item 2 and 1 to 5 for item 3). Items 3-10 are all measured by 100 mm anchored horizontal visual analog scales. The instructions for the first and third through tenth items in the questionnaire ask patients to mark the category in the scale or the point on the line that best describes their abilities or feelings for the past week. Each item is standardized on a scale ranging from 0 to 10 with 10 indicating greater impairment. The patient suffering from fibromyalgia can answer the Fibromyalgia Impact Questionnaire for a period of time prior to and following initiation of therapy with a growth hormone secretagogue. The results of the Fibromyalgia Impact Questionnaire can then be analyzed and the efficacy of the growth hormone secretagogue therapeutic regimen is determined by comparing the Fibromyalgia Impact Questionnaire results from the period prior to initiation of the growth hormone secretagogue therapy with the results from the period after initiation of the growth hormone secretagogue therapy.
The McGill Pain Questionnaire consists of a sum of ranked values for adjectives used by a patient suffering from fibromyalgia to describe their subjective pain experience and is described by Melzack, R. in Pain, 1975, 1, 277-299. The number of positive tender points and total myalgic score of a patient can be determined by physical examination of the patient. The total myalgic score of a patient suffering from fibromyalgia can be determined by applying a Fischer dolorimeter (Fischer, A. A. Pain, 1987, 30, 115-126) with a rubber disc of 1 cm2 at a 90° vertical angle to 18 tender point sites, and pressure is increased at a rate of 1 kilogram per second. Patients are instructed to indicate verbally when discomfort is first felt, the pressure is then stopped and the measurement is recorded. The individual scores are then summed to provide a total myalgic score. The efficacy of the growth hormone secretagogue therapeutic regimen is determined by comparing the results from the period prior to initiation of the growth hormone secretagogue therapy with the results from the period after initiation of the growth hormone secretagogue therapy.
By the term “growth hormone secretagogue” is meant any exogenously administered compound or agent that directly or indirectly stimulates or increases the endogenous release of growth hormone, growth hormone-releasing hormone or somatostatin in an animal, in particular, a human. This term shall at all times be understood to include all active forms of such secretagogues, including, for example, the free form thereof, e.g., the free acid or base form, and also, all prodrugs, polymorphs, hydrates, solvates, stereoisomers, e.g., diastereomers and enantiomers, and the like, and all pharmaceutically acceptable salts as described above, unless specifically stated otherwise. It will also be appreciated that suitable active metabolites of secretagogues within the scope of the present invention, in any suitable form, are also included herein.
The growth hormone secretagogue may be peptidyl or non-peptidyl in nature, however, the use of an orally active growth hormone secretagogue is preferred. In addition, it is preferred that the growth hormone secretagogue induce or amplify a pulsatile release of endogenous growth hormone.
The expression “prodrug” refers to compounds that are drug precursors which, following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). For example, a prodrug of the compound of Formula I may be used in the present invention. Exemplary prodrugs are disclosed in the art, particularly in the references cited herein and incorporated herein by reference.
The growth hormone secretagogue of the present invention may be used alone or in combination with one or more other growth hormone secretagogues or with one or more other agents that are known to be beneficial for treating fibromyalgia. The growth hormone secretagogue and the other agent may be coadministered, either in concomitant therapy or in a fixed combination.
Representative growth hormone secretagogues are disclosed in the following International Patent Applications (listed by Publication Nos.), issued U.S. patents and published European patent applications, which are incorporated herein by reference: WO 98/46569, WO 98/51687, WO 98/58947, U.S. Pat. No. 6,251,902, WO 98/58949, WO 98/58950, U.S. Pat. No. 6,127,341, WO 99/08697, U.S. Pat. No. 6,329,342, WO 99/09991, WO 95/13069, U.S. Pat. No. 5,492,916, U.S. Pat. No. 5,494,919, WO 95/14666, U.S. Pat. No. 5,663,171, WO 94/19367, U.S. Pat. No. 5,536,716, WO 94/13696, U.S. Pat. No. 5,578,593, WO 94/11012, U.S. Pat. No. 5,726,319, WO 95/11029, WO 95/17422, U.S. Pat. No. 5,854,211, WO 95/17423, U.S. Pat. No. 5,767,085, WO 95/34311, U.S. Pat. No. 5,777,112, WO 96/02530, U.S. Pat. No. 5,783,582, WO 96/22996, WO 96/22997, U.S. Pat. No. 6,013,658, WO 96/24580, WO 96/24587, U.S. Pat. No. 5,559,128, WO 96/32943, WO 96/33189, WO 96/15148, U.S. Pat. No. 5,798,337, WO 96/38471, U.S. Pat. No. 5,936,089, WO 96/35713, WO 97/00894, WO 97/07117, WO 97/06803, U.S. Pat. No. 5,773,441, WO 97/11697, WO 97/15573, U.S. Pat. No. 5,723,616, WO 97/22367, U.S. Pat. No. 5,830,433, WO 97/23508, U.S. Pat. No. 5,977,178, WO 97/22620, WO 97/22004, U.S. Pat. No. 6,242,199, WO 97/21730, U.S. Pat. No. 6,531,314, WO 97/24369, U.S. Pat. No. 6,107,306, U.S. Pat. No. 5,663,171, WO 97/34604, U.S. Pat. No. 5,880,125, WO 97/36873, U.S. Pat. No. 5,804,578, WO 97/40071, U.S. Pat. No. 5,990,084, WO 97/40023, U.S. Pat. No. 5,919,777, WO 97/41878, WO97/41879, WO 97/46252, WO 97/44042, U.S. Pat. No. 6,071,926, WO 97/38709, WO 98/03473, U.S. Pat. No. 5,922,770, WO 97/43278, U.S. Pat. No. 6,127,343, U.S. Pat. No. 5,721,251, U.S. Pat. No. 5,721,250, WO 98/10653, WO 00/01726, U.S. Pat. No. 5,830,433 and EP 0995748.
A representative first group of growth hormone secretagogues is set forth in International Patent Application Publication No. WO 97/24369 and U.S. Pat. No. 6,107,306, as compounds having the structural formula below, which is designated herein as Formula II:
wherein the various substituents are as defined therein and said compounds are prepared as disclosed therein.
2-Amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, having the following structure:
and 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, having the following structure:
and the pharmaceutically acceptable salts thereof, are within the scope of the disclosure of International Patent Application Publication Number WO 97/24369 and U.S. Pat. No. 6,107,306. The L-(+)-tartaric acid salt of 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide is disclosed within U.S. Pat. No. 6,248,717.
A representative second group of growth hormone secretagogues is set forth in International Patent Application Publication No. WO 98/58947 and U.S. Pat. No. 6,251,902, as compounds having the structural formula below, which is designated herein as Formula III:
wherein the various substituents are as defined therein and said compounds are prepared as disclosed therein.
A compound within this second group which may be employed in the method of the present invention is identified as having the following name and structure: 2-amino-N-(1 (R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide,
This compound and the pharmaceutically acceptable salts thereof are within the scope of the disclosure of International Patent Application Publication No. WO 98/58947 and U.S. Pat. No. 6,251,902, and may be prepared as described in Examples Five and Six therein.
A representative third group of growth hormone secretagogues is set forth in Published European patent application 0995748, which discloses certain dipeptide growth hormone secretagogues of the structural formula above, which is designated herein as Formula III, and their use for the treatment or prevention of musculoskeletal fraility including osteoporosis.
A representative fourth group of growth hormone secretagogues is set forth in U.S. Pat. No. 5,206,235 as having the following structure:
wherein the various substituents are as defined therein and said compounds are prepared as disclosed therein.
Certain compounds within this fourth group are identified as having the following structures:
A representative fifth group of growth hormone secretagogues is set forth in U.S. Pat. No. 5,283,241 as having the following structural formula:
wherein the various substituents are as defined therein and said compounds are prepared as disclosed therein.
A representative sixth group of growth hormone secretagogues is disclosed in International Patent Application, Publication No. WO 97/41879, as compounds having the following structural formulas:
wherein the various substituents are as defined therein and said compounds are prepared as disclosed therein.
A certain compound within this sixth group is identified as having the following structure:
and pharmaceutically acceptable salts thereof, in particular, the methanesulfonate salt.
A representative seventh group of growth hormone secretagogues is disclosed in U.S. Pat. No. 5,492,916, as being compounds of the following structural formula:
wherein the various substituents are as defined therein and said compounds are prepared as disclosed therein.
All of the compounds identified above may be prepared by procedures disclosed in the cited publications. Full descriptions of the preparation of the growth hormone secretagogues which may be employed in the present invention may be found in the art, particularly in the references cited herein, which are incorporated by reference herein.
The compounds of Formula I used in the methods of the present invention all have at least one asymmetric center as noted, e.g., by the asterisk in the structural Formula I-B below. Additional asymmetric centers may be present in the compounds of Formula I depending upon the nature of the various substituents on the molecule. Each such asymmetric center will produce two optical isomers and it is intended that all such optical isomers, as separated, pure or partially purified optical isomers, racemic mixtures or diastereomeric mixtures thereof, be included within the scope of the methods of the present invention. In the case of the asymmetric center represented by the asterisk, it has been found that the absolute stereochemistry of the more active and thus more preferred isomer is shown in Formula I-B below:
with the R4 substituent as hydrogen, the spatial configuration of the asymmetric center corresponds to that in a D-amino acid. In most cases this is also designated an R-configuration although this will vary according to the values of R3 and R4 used in making R- or S-stereochemical assignments.
Certain compounds within the scope of the present invention may have the potential to exist in different tautomeric forms. All tautomers of a compound used in the method of the present invention are within the scope of the present invention. Also, for example, all keto-enol or imine-enamine forms of the compounds are included within the scope of the present invention. Those skilled in the art will recognize that the compound names contained herein may be based on a particular tautomer of a compound. While the name for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the name of the particular tautomer and all tautomers are considered as compounds useful in the method of the present invention.
A compound within the scope of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. A solvate wherein the solvent is water forms a hydrate or hydrated ions. The present invention contemplates and encompasses the use of both the solvated and unsolvated forms of the compounds within its scope.
Also included within the scope of the present invention are the use of isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds used in the methods of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds within the scope of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds within the scope of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in compound and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds within the scope of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the references cited herein as well as others known in the art, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Full descriptions of the preparation of the growth hormone secretagogues employed in the present invention may be found, for example, in the following International Patent Applications (listed by Publication Nos.), issued U.S. patents and published European patent applications, which are incorporated herein by reference: WO 98/46569, WO 98/51687, WO 98/58947, U.S. Pat. No. 6,251,902, WO 98/58949, WO 98/58950, U.S. Pat. No. 6,127,341, WO 99/08697, U.S. Pat. No. 6,329,342, WO 99/09991, WO 95/13069, U.S. Pat. No. 5,492,916, U.S. Pat. No. 5,494,919, WO 95/14666, U.S. Pat. No. 5,663,171, WO 94/19367, U.S. Pat. No. 5,536,716, WO 94/13696, U.S. Pat. No. 5,578,593, WO 94/11012, U.S. Pat. No. 5,726,319, WO 95/11029, WO 95/17422, U.S. Pat. No. 5,854,211, WO 95/17423, U.S. Pat. No. 5,767,085, WO 95/34311, U.S. Pat. No. 5,777,112, WO 96/02530, U.S. Pat. No. 5,783,582, WO 96/22996, WO 96/22997, U.S. Pat. No. 6,013,658, WO 96/24580, WO 96/24587, U.S. Pat. No. 5,559,128, WO 96/32943, WO 96/33189, WO 96/15148, U.S. Pat. No. 5,798,337, WO 96/38471, U.S. Pat. No. 5,936,089, WO 96/35713, WO 97/00894, WO 97/07117, WO 97/06803, U.S. Pat. No. 5,773,441, WO 97/11697, WO 97/15573, U.S. Pat. No. 5,723,616, WO 97/22367, U.S. Pat. No. 5,830,433, WO 97/23508, U.S. Pat. No. 5,977,178, WO 97/22620, WO 97/22004, U.S. Pat. No. 6,242,199, WO 97/21730, U.S. Pat. No. 6,531,314, WO 97/24369, U.S. Pat. No. 6,107,306, U.S. Pat. No. 5,663,171, WO 97/34604, U.S. Pat. No. 5,880,125, WO 97/36873, U.S. Pat. No. 5,804,578, WO 97/40071, U.S. Pat. No. 5,990,084, WO 97/40023, U.S. Pat. No. 5,919,777, WO 97/41878, WO97/41879, WO 97/46252, WO 97/44042, U.S. Pat. No. 6,071,926, WO 97/38709, WO 98/03473, U.S. Pat. No. 5,922,770, WO 97/43278, U.S. Pat. No. 6,127,343, U.S. Pat. No. 5,721,251, U.S. Pat. No. 5,721,250, WO 98/10653, WO 00/01726, U.S. Pat. No. 5,877,182, U.S. Pat. No. 5,830,433 and EP 0995748.
A growth hormone secretagogue is a compound that, when administered to a patient, increases the production and/or secretion of growth hormone when compared with baseline plasma concentrations of growth hormone in a normal healthy individual. Thus, to identify a growth hormone secretagogue, one need simply measure the baseline plasma concentrations of growth hormone over a time period, typically one day, and compare the plasma concentrations of growth hormone after administration of a growth hormone secretagogue with the baseline concentration over the time period. Various examples of growth hormone secretagogues are disclosed herein.
The identification of a compound as a “growth hormone secretagogue” which is able to directly or indirectly stimulate or increase the endogenous release of growth hormone in an animal may be readily determined without undue experimentation by methodology well known in the art, such as the assay described by Smith et al., Science, 260, 1640-1643 (1993) (see text of FIG. 2 therein). In a typical experiment, pituitary glands are aseptically removed from 150-200 g Wistar male rats and cultures of pituitary cells are prepared according to Cheng et al., Endocrinol., 124, 2791-2798 (1989). The cells are treated with the subject compound and assayed for growth hormone secreting activity, as described by Cheng et al. (ibid.). In particular, the intrinsic growth hormone secretagogue activity of a compound which may be used in the present invention may be determined by this assay.
The term “patient” means animals, such as humans, companion animals such as dogs, cats and horses, and livestock such as cattle, swine and sheep. Particularly the term “patient” includes mammals, including both males and females, and more particularly the term “patient” includes humans.
The term “pharmaceutically acceptable” means that a substance or mixture of substances must be compatible with the other ingredients of a formulation, and not deleterious to the patient.
The terms “treating”, “treat” or “treatment” include preventive (e.g., prophylactic) and palliative treatment.
The term “therapeutically effective amount” means an amount of a growth hormone secretagogue that ameliorates, attenuates, or eliminates a particular disease or condition associated with growth hormone secretion and/or production, or prevents or delays the onset of a disease or condition associated with growth hormone secretion and/or production.
The phrases “a compound within the scope of the present invention or a compound of Formula I” and the like, shall at all times be understood to include all active forms of such compounds, including, for example, the free form thereof, e.g., the free acid or base form, and also, all prodrugs, polymorphs, hydrates, solvates, stereoisomers, e.g., diastereomers and enantiomers, and the like, and all pharmaceutically acceptable salts as described above, unless specifically stated otherwise. It will also be appreciated that suitable active metabolites of compounds within the scope of the present invention, in any suitable form, are also included herein.
This particular application of growth hormone secretagogues provides benefits relative to the administration of exogenous growth hormone. In particular, the growth hormone secretagogue enhances the normal pulsatile release of endogenous growth hormone and thus is more likely to reproduce the natural pattern of endogenous growth hormone release (see J. Clin. Endocrinol. Metab. 81: 4249-4257, 1996). Growth hormone secretagogues which are orally active also have the benefit of being able to be administered orally, rather than just intravenously, intraperitoneally or subcutaneously.
In view of their use according to the present invention, the growth hormone secretagogues of the present invention may be formulated into various pharmaceutical forms for administration purposes. A growth hormone secretagogue may be administered, alone or in combination, by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual, or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules and for companion animals the solid dosage forms include an admixture with food and chewable forms. In such solid dosage forms, the compounds and combinations of this invention can be admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. In the case of chewable forms, the dosage form may comprise flavoring agents and perfuming agents.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the compound of the present invention, excipients such as cocoa butter or a suppository wax. Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
The dosage of the compound within the scope of the present invention in the method of the present invention may be varied; however, it is necessary that the amount of the compound be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals, to obtain effective release of growth hormone. A particular dosage range in humans is 0.01 to 5.0 mg/kg of body weight daily that can be administered as a single dose or divided into multiple doses.
A dosage range in animals other than humans is 0.01 to 10.0 mg/kg of body weight daily that can be administered as a single dose or divided into multiple doses. A particular dosage range in animals other than humans is 0.1 to 5 mg/kg of body weight daily that can be administered as a single dose or divided into multiple doses.
Where the pharmaceutically acceptable salt of the compound(s) within the scope of the present invention is used, the skilled person will be able to calculate effective dosage amounts by calculating the molecular weight of the salt form and performing simple stoichiometric ratios.
The present invention includes within its scope the use of a growth hormone secretagogue according to the present invention, alone or in combination with a growth promoting agent or another growth hormone secretagogue, such as those referenced herein, including the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Pat. No. 4,411,890 and International Patent Applications, Publication Nos. WO 89/07110, WO 89/07111), GHRP-2 (described in WO 93/04081) and B-HT920, as well as hexarelin and growth hormone releasing hormone (GHRH, also designated GRF) and its analogs, growth hormone, natural or recombinant, and its analogs and somatomedins including IGF-I and IGF-II, or in combination with other therapeutic agents, such as α-adrenergic agonists such as clonidine or serotonin 5-HT1D agonists such as sumatriptan, or agents which inhibit somatostatin or its release such as physostigmine and pyridostigmine. Preferably, the growth hormone secretagogue may be used in combination with growth hormone releasing factor, an analog of growth hormone releasing factor, IGF-I or IGF-II.
Methods to obtain the growth hormone releasing peptides GHRP-6 and GHRP-1 are described in U.S. Pat. No. 4,411,890 and PCT Patent Publications WO 89/07110, WO 89/07111, methods to obtain the growth hormone releasing peptide GHRP-2 are described in PCT Patent Publication WO 93/04081, and methods to obtain hexarelin are described in J. Endocrin. Invest., 15 (Suppl. 4), 45 (1992), all of which are incorporated herein by reference.
Also, the present invention includes within its scope the use of a growth hormone secretagogue according to the present invention, alone or in combination with an antidepressant, a prodrug thereof or a pharmaceutically acceptable salt of said antidepressant or said prodrug. Any antidepressant may be used in the methods of the present invention. The term antidepressant means an agent used to treat affective or mood disorders and related conditions. Affective mood disorders are characterized by changes in mood as the primary clinical manifestation. Either extreme of mood may be associated with psychosis, manifested as disordered or delusional thinking and perceptions which are often incongruent with the predominant mood. Affective disorders include major depression and mania, including bipolar manic-depressive illness. Preferred classes of antidepressants include norepinephrine reuptake inhibitors (NERIs), including secondary and tertiary amine tricyclics; selective serotonin reuptake inhibitors (SSRIs); combined NERI/SSRIs; monoamine oxidase (MAO) inhibitors; and atypical antidepressants.
Any norepinephrine reuptake inhibitor (NERI) may be used in the methods of the present invention. The term norepinephrine reuptake inhibitor means agents which potentiate the actions of biogenic amines by blocking their major means of physiological inactivation, which involves transport or reuptake into nerve terminals, and specifically, agents which block the reuptake of norepinephrine into said nerve terminals.
Particular tertiary amine tricyclic norepinephrine reuptake inhibitors which may be used in accordance with the present invention include, but are not limited to, amitriptyline, which may be prepared as described in U.S. Pat. No. 3,205,264; chlomipramine, which may be prepared as described in U.S. Pat. No. 3,467,650; doxepin, which may be prepared as described in U.S. Pat. No. 3,420,851; imipramine, which may be prepared as described in U.S. Pat. No. 2,554,736; and trimipramine, which may be prepared as described in Jacob and Messer, Compt. Rend. 252, 2117 (1961).
Particular secondary amine tricyclic norepinephrine reuptake inhibitors which may be used in accordance with the present invention include, but are not limited to, amoxapine, which may be prepared as described in U.S. Pat. No. 3,663,696; desipramine, which may be prepared as described in U.S. Pat. No. 3,454,554; maprotiline, which may be prepared as described in U.S. Pat. No. 3,999,201; nortriptyline, which may be prepared as described in U.S. Pat. No. 3,442,949; and protriptyline, which may be prepared as described in U.S. Pat. No. 3,244,748.
Any selective serotonin reuptake inhibitor (SSRI) may be used in the methods of the present invention. The term selective serotonin reuptake inhibitor refers to a compound which inhibits the reuptake of serotonin by afferent neurons. Such inhibition is readily determined by those skilled in the art according to standard assays such as those disclosed in U.S. Pat. No. 4,536,518 and other U.S. patents recited in the next paragraph.
Particular selective serotonin reuptake inhibitors (SSRIs) which may be used in accordance with the present invention include, but are not limited to: citalopram, which may be prepared as described in U.S. Pat. No. 4,136,193; femoxetine, which may be prepared as described in U.S. Pat. No. 3,912,743; fluoxetine, which may be prepared as described in U.S. Pat. No. 4,314,081; fluvoxamine, which may be prepared as described in U.S. Pat. No. 4,085,225; indalpine, which may be prepared as described in U.S. Pat. No. 4,064,255; indeloxazine, which may be prepared as described in U.S. Pat. No. 4,109,088; milnacipran, which may be prepared as described in U.S. Pat. No. 4,478,836; paroxetine, which may be prepared as described in U.S. Pat. No. 3,912,743 or U.S. Pat. No. 4,007,196; sertraline and the hydrochloride salt of sertraline, which may be prepared as described in U.S. Pat. No. 4,536,518; sibutramine, which may be prepared as described in U.S. Pat. No. 4,929,629; and zimeldine, which may be prepared as described in U.S. Pat. No. 3,928,369. Fluoxetine is also known as Prozac®. Sertraline hydrochloride is also known as Zoloft®. Sibutramine is also known as Meridia®.
Any combined NERI/SSRI may be used in the methods of the present invention. The term combined NERI/SSRI refers to a compound which blocks the reuptake of both serotonin and norepinephrine by afferent neurons. A combined NERI/SSRI which may be used in accordance with the present invention is venlafaxine, which may be prepared as described in U.S. Pat. No. 4,535,186.
Any monoamine oxidase (MAO) inhibitor may be used in the methods of the present invention. The term monoamine oxidase inhibitor refers to a compound which inhibits monoamine oxidase, for example, by blocking the metabolic deamination of a variety of monoamines by mitochondrial monoamine oxidase. Monoamine oxidase inhibitors, which may be used in accordance with the present invention, include, but are not limited to, phenelzine, which may be prepared as described in U.S. Pat. No. 3,000,903; tranylcypromine, which may be prepared as described in U.S. Pat. No. 2,997,422; and selegiline, which may be prepared as described in U.S. Pat. No. 4,564,706.
Any atypical antidepressant may be used in the methods of the present invention. The term atypical antidepressant refers to any antidepressant not within any of the aforesaid classes of antidepressants. Atypical antidepressants which may be used in accordance with the present invention include, but are not limited to, bupropion, which may be prepared as described in U.S. Pat. No. 3,885,046; nefazodone, which may be prepared as described in U.S. Pat. No. 4,338,317; and trazodone, which may be prepared as described in U.S. Pat. No. 3,381,009.
In addition, the present invention includes within its scope the use of a pharmaceutical composition according to the present invention comprising at least one growth hormone secretagogue of the present invention in association with a pharmaceutical carrier, vehicle or diluent. The present invention also includes within its scope the use of a compound of Formula I for the preparation of a medicament for the uses disclosed herein.
Combinations of these therapeutic agents, some of which have been mentioned herein, with a growth hormone secretagogue of the present invention may bring additional complementary properties to enhance the desirable properties of these various therapeutic agents.
In these combinations, the growth hormone secretagogue and the other therapeutic agent(s) may be independently present in the dose ranges from 0.01 to 1 times the dose levels which are effective when these compounds and secretagogues are used singly.
Typically, the individual daily dosages for these combinations may range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. These dose ranges may be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
These combinations may be formulated into pharmaceutical compositions as known in the art and as discussed herein. Since the present invention has an aspect that relates to treatment with a combination of active ingredients that may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a growth hormone secretagogue of the present invention, a prodrug thereof or a pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug; and a second therapeutic agent as described herein. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container. Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the dosage form so specified should be ingested. Another example of such a memory aid is a calendar printed on the card e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several tablets or capsules to be taken on a given day. Also, a daily dose of a second therapeutic agent as described herein can consist of one tablet or capsule while a daily dose of the growth hormone secretagogue, prodrug thereof or pharmaceutically acceptable salt of said growth hormone secretagogue or said prodrug can consist of several tablets or capsules or vice versa. The memory aid should reflect this.
In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered microchip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The utility of the compounds described herein in the methods of the present invention are demonstrated by their activity in one or more of the assays described below:
Compounds having the ability to stimulate GH secretion from cultured rat pituitary cells are identified using the following protocol. This test is also useful for comparison to standards to determine dosage levels.
Cells are isolated from pituitaries of 6-week old male Wistar rats. Following decapitation, the anterior pituitary lobes are removed into cold, sterile Hank's balanced salt solution without calcium or magnesium (HBSS). Tissues are finely minced, then subjected to two cycles of mechanically assisted enzymatic dispersion using 10 U/mL bacterial protease (EC 3.4.24.4, Sigma P-6141, St. Louis, Mo.) in HBSS. The tissue-enzyme mixture is stirred in a spinner flask at 30 rpm in a 5% CO2 atmosphere at 37° C. for 30 min., with manual trituration after 15 min. and 30 min. using a 10-mL pipet. This mixture is centrifuged at 200×g for 5 min. Horse serum (35% final concentration) is added to the supernatant to neutralize excess protease. The pellet is resuspended in fresh protease (10 U/mL), stirred for about 30 min. more under the previous conditions, and manually triturated, ultimately through a 23-gauge needle. Again, horse serum (35% final concentration) is added, then the cells from both digests are combined, pelleted (200×g for about 15 min.), resuspended in culture medium (Dulbecco's Modified Eagle Medium (D-MEM) supplemented with 4.5 g/L glucose, 10% horse serum, 2.5% fetal bovine serum, 1% non-essential amino acids, 100 U/mL nystatin and 50 mg/mL gentamycin sulfate, Gibco, Grand Island, N.Y.) and counted. Cells are plated at 6.0-6.5×104 cells per cm2 in 48-well Costar™ (Cambridge, Mass.) dishes and cultured for 3-4 days in culture medium.
Just prior to carrying out a GH secretion assay, culture wells are rinsed twice with release medium, then equilibrated for 30 minutes in release medium (D-MEM buffered with 25 mM Hepes, pH 7.4 and containing 0.5% bovine serum albumin at 37° C.). Test compounds are dissolved in DMSO, then diluted into prewarmed release medium. Assays are typically run in quadruplicate. The assay is initiated by adding 0.5 mL of release medium (with vehicle or test compound) to each culture well. Incubation is carried out at 37° C. for 15 minutes, then terminated by removal of the release medium, which is centrifuged at 2000×g for 15 minutes to remove cellular material. Rat growth hormone concentrations in the supernatants are determined by a standard radioimmunoassay protocol described below.
Twenty-one day old female Sprague-Dawley rats (Charles River Laboratory, Wilmington, Mass.) are allowed to acclimate to local vivarium conditions (24° C., 12 hr light, 12 hr dark cycle) for approximately 1 week before testing of a compound of this invention. All rats are allowed access to water and a pelleted commercial diet (Agway Country Food, Syracuse N.Y.) ad libitum.
On the day of the experiment, test compounds are dissolved in vehicle containing 1% ethanol, 1 mM acetic acid and 0.1% bovine serum albumin in saline. Each test is conducted in three rats. Rats are weighed and anesthetized via intraperitoneal injection of sodium pentobarbital (Nembutol®, 50 mg/kg body weight). Fourteen minutes after anesthetic administration, a blood sample is taken by nicking the tip of the tail and allowing the blood to drip into a microcentrifuge tube (baseline blood sample, approximately 100 μl). Fifteen minutes after anesthetic administration, a test compound is delivered by intravenous injection into the tail vein, with a total injection volume of 1 mL/kg body weight. Additional blood samples are taken from the tail at 5, 10 and 15 minutes after administration of a compound of this invention. Blood samples are kept on ice until serum separation by centrifugation (1430×g for 10 minutes at 10° C.). Serum is stored at −80° C. until serum growth hormone determination by radioimmunoassay as described below.
Rat growth hormone concentrations are determined by double antibody radioimmunoassay using a rat growth hormone reference preparation (NIDDK-rGH-RP-2) and rat growth hormone antiserum raised in monkey (NIDDK-anti-rGH-S-5) obtained from Dr. A. Parlow (Harbor-UCLA Medical Center, Torrance, Calif.). Additional rat growth hormone (1.5 U/mg, #G2414, Scripps Labs, San Diego, Calif.) is iodinated to a specific activity of approximately 30 μCi/μg by the chloramine T method for use as tracer. Immune complexes are obtained by adding goat antiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) plus polyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%; recovery is accomplished by centrifugation according to methods well known to those skilled in the art. This assay has a working range of 0.08-2.5 μg rat growth hormone per tube.
On the day of dosing, the test compound is weighed out for the appropriate dose and dissolved in water. Doses are delivered at a volume of 0.5-3 mL/kg by oral gavage to 2-4 dogs for each dosing regimen. Blood samples (5 mL) are collected from the jugular vein by direct venipuncture pre-dose and at 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8 and 24 hours post dose using 5 mL vacutainers containing lithium heparin. The prepared plasma is stored at −20° C. until analysis.
Canine growth hormone concentrations are determined by a standard radioimmunoassay protocol using canine growth hormone (antigen for iodination and reference preparation AFP-1983B) and canine growth hormone antiserum raised in monkey (AFP-21452578) obtained from Dr. A. Parlow (Harbor-UCLA Medical Center, Torrence, Calif.). Tracer is produced by chloramine T-iodination of canine growth hormone to a specific activity of 20-40 μCi/μg. Immune complexes are obtained by adding goat antiserum to monkey IgG (ICN/Cappel, Aurora, Ohio) plus polyethylene glycol, MW 10,000-20,000 to a final concentration of 4.3%; recovery is accomplished by centrifugation according to methods well known to those skilled in the art. This assay has a working range of 0.08-2.5 μg canine GH/tube.
The disclosures of each of the publications, patents and published patent applications cited hereinabove are incorporated herein by reference.
This application claims priority from U.S. Provisional Patent Application No. 60/478,108 filed Jun. 11, 2003.
| Number | Date | Country | |
|---|---|---|---|
| 60478108 | Jun 2003 | US |
