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WO1998032437A1 - Utilisation de 3, 4-diphenyle chromanes pour preparer une composition pharmaceutique servant a inhiber une ou plusieurs maladies psychiatriques - Google Patents

Utilisation de 3, 4-diphenyle chromanes pour preparer une composition pharmaceutique servant a inhiber une ou plusieurs maladies psychiatriques Download PDF

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Publication number
WO1998032437A1
WO1998032437A1 PCT/DK1998/000033 DK9800033W WO9832437A1 WO 1998032437 A1 WO1998032437 A1 WO 1998032437A1 DK 9800033 W DK9800033 W DK 9800033W WO 9832437 A1 WO9832437 A1 WO 9832437A1
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WO
WIPO (PCT)
Prior art keywords
use according
anyone
compound
phenyl
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DK1998/000033
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English (en)
Inventor
Birte Kloppenborg Skrumsager
Erik Bardrum Nielsen
Birgitte Hjort Guldhammer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
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Novo Nordisk AS
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Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Priority to AU55504/98A priority Critical patent/AU5550498A/en
Publication of WO1998032437A1 publication Critical patent/WO1998032437A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim

Definitions

  • the present invention relates to the use of compounds of the general formula I for inhibiting one or more psychiatric disorders.
  • the present invention also embraces pharmaceutical compositions comprising these compounds and methods of using the compounds and their pharmaceutical compositions.
  • Psychiatric disorders are those disorders known to be included in the definition by those skilled in the art, which includes e.g. anxiety, depression, tension, irri- tability, memory loss, mood swings, motivational defects, cognitive disorders, attention deficits, schizophrenia, psychoses, winter depressions.
  • Corticotropin-releasing factor (CRF) levels have been associated with depression, anxiety and sleeplessness (Nemeroff, Neuropsychopharmacology ( 1 992) 6, 69- 75, Nerozzi et al., J. Endocrinol. Invest. ( 1 988) 1 1 , 697-701 and Glowa et al., Prog. Neuropsychopharmacol Biol. Psychiatry ( 1 991 ) 1 5, 379-391 ). It is known that estrogens can regulate negatively CRF expression in the brain (Grino et al., Endocrine ( 1 995) 3, 395-398). Thus, this may provide a mechanism by which low levels of estrogens may lead to enhanced CRF tonus which again in turn may mediate depression, anxiety and sleeplessness.
  • CRF Corticotropin-releasing factor
  • estradiol increases the density of 5- HT 2A receptors in cerbral cortex and nucleus accumbens. This may provide an additional mechanism by which estrogen therapy is effective in reducing significantly the symptoms in women with major depressive disorder (Fink et al., Cellular and Molecular Neurobiology ( 1 996) 1 6, 325-344) as low levels of 5-HT activity in the brain is associated with depression (eg 5-HT uptake inhibitors which increase 5-HT tonus are effective antidepressants).
  • estrogen may affect cognitive functions in women.
  • the hippocampus a brain structure that is critically important in learning and memory, contains estrogen receptors (Pfaff D.W.: Estrogen and brain function, New York, Springer-Verlag 1 980).
  • Estrogen and brain function a brain structure that is critically important in learning and memory
  • estrogen increases choline acetyltransferase, the enzyme needed to synthezise acetylcholine, a neurotransmitter thought to be critical for memory and learning (Bartus et al.: The cholinergic hypothesis of memory dysfunction in Science 21 7 ( 1 982), 408-41 7).
  • Centchroman is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Patent Specification No. 4,447,622; Singh et al.. Acta Endocrinal (Copenh) 1 26 ( 1 992), 444 - 450; Grubb, Curr Opin Obstet Gynecol 3. ( 1 991 ), 491 - 495;
  • Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 ( 1 989), 781 - 783. Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical expressed by a significant decrease of the serum concentrations (S.D. Bain et al., J Min Bon Res £ (1 994), S 394).
  • U.S. patent 5,453,442 describes methods of lowering serum cholesterol and inhibiting smoother muscle cell proliferation in humans and inhibiting uterine fibroid disease and endometriosis in women by administering compounds of formula I as shown therein.
  • US patent 5,280,040 describes methods and pharmaceutical compositions for reducing bone loss using 3,4-diaryl chromans and their pharmaceutically acceptable salts. There is no disclosure in the patents of using the compounds to treat or prevent one or more psychiatric disorders.
  • One object of the present invention is to provide compounds which can effec- tively be used in the treatment or prophylaxis of one or more psychiatric disorders and which is safe and causes less side effects.
  • R 1 , R 4 and R 5 are individually hydrogen, hydroxy, halogen, trifluoro- methyl, C,_ 6 alkyl, C,. 6 alkoxy or (tertiary amino)(C.,. 6 alkoxy); and R 2 and R 3 are individually hydrogen or C, ⁇ alkyl, or as a pharmaceutically acceptable salt for the manufacture of a pharmaceutical composition for inhibiting one or more psychiatric disorders.
  • the compounds of above general formula I can be used in methods for in- hibiting mood swings.
  • the compounds have a specific mood stabilizing effect not only counteracting the fluctations in mood during the pre menstrual period or the menopause, but also for example due to stressfull situations.
  • the compounds can be used in therapy against any illness associated with mood swings.
  • the compounds can be used in treatment of the symptoms of mood swings not only seen during hormonal changes in a patient, but also in general, for example where CFR levels are increased (e.g. endogenous depression or stress conditions) .
  • the compounds of general formula I can also be used for delaying or preventing loss of cognitive function or enhancing the cognitive function.
  • the compounds can be used in therapy against any illness associated with loss of memory or cognitive performance and in therapy to enhance the cognitive performance.
  • the compounds can be used in treatment of both hormonally related changes and changes of cognitive performance related to normal ageing.
  • the compounds of the general formula I can furthermore be used in the prevention or treatment of anxiety, depression or sleeplessness.
  • the present invention is based on the discovery that the compounds of formula I are useful for prevention or treatment of a psychiatric disorder such as mood swings, anxiety, depression or sleeplessness.
  • the present invention furthermore is based on the discovery that the compounds of formula I as stated in claim 1 is useful for delaying or preventing loss of cognitive function or enhancing the cognitive function in a patient.
  • compounds of formula I are used for prevention or treatment of one or more psychiatric disorders in a patient.
  • inhibitor is defined to include its generally accepted meaning which in- eludes prophylactically treating a human subject to incurring the characteristics described, and holding in check and/or treating existing characteristics.
  • the present method includes both medical therapeutic and/or prophylatic treatment, as appropriate.
  • patient includes men, women and children.
  • Psychiatric disorders are those mental disorders which appears in the absence of any known or observable organic/structural brain damage known to be included in the definition by those skilled in the art which includes e.g. anxiety, depression, tension, irritability, memory loss, mood swings, motivational defects, cognitive disorders, attention deficits, schizophrenia, psychoses, winter depressions.
  • R , R ⁇ and R° are individually hydrogen, hydroxy, halogen, trifluoromethyl, C ⁇ alkyl, C.,. 6 alkoxy or (tertiary amino)(C 1 . 6 alkoxy); and R ⁇ and
  • R 3 are individually hydrogen or a C ⁇ alkyl.
  • C.,. 6 alkyl includes straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-amyl, sec- amyl, n-hexyl, 2-ethylbutyl, 2,3-dimethylbutyl and the like.
  • C ⁇ alk- oxy includes straight and branched chain alkoxy radicals containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert- butoxy, n-amyloxy, sec-amyloxy, n-hexyloxy, 2-ethylbutoxy, 2,3-dimethylbutoxy and the like.
  • Hydrogen includes chloro, fluoro, bromo and iodo.
  • (tertiary amino) (C ⁇ alkoxy) is a C, ⁇ alkoxy group which is substituted by a ter- tiary amino radical.
  • the tertiary amino radical may be a N,N-dialkylamine such as a N,N-dimethylamino, N,N-diethylamino, N,N-dipropylamino and N,N- dibutylamino or a polymethyleneimine, e.g., piperidine, pyrrolidine, N-methyl- piperazine or morpholine.
  • Preferred compounds include those in which R ⁇ is C,. 6 alkoxy; R ⁇ and R 3 are C,. 6 alkyl, especially methyl; R ⁇ is hydrogen; and R ⁇ is (tertiary amino) ⁇ C 1-6 alkoxy) of the polymethyleneimine type.
  • R " " is in the 7-position and is C 1 -6 alkoxy, particularly methoxy; each of R ⁇ and R 3 is methyl, R ⁇ is hydrogen, and R ⁇ is in the 4-posi- tion and is a (tertiary amino)(C 1 . 6 alkoxy) radical such as 2-(pyrrolidin-1 -yl)ethoxy with formula II
  • the compounds of formula I in the transconfiguration. These compounds may be used as racemic mixtures, or the isolated d- or I- enantiomers may be used. The trans-l-enantiomers are more preferred.
  • centchroman having the formula IV
  • 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Patent Specification No. 3,340,276 to Carney et al., U.S. Patent Specification No. 3,822,287 to Bolger, and Ray et al., J Med Chem 1 9 (1 976), 276 - 279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organo- metallic base-catalyzed rearrangement is disclosed in U.S. Patent Specification No. 3,822,287.
  • the optically active d- and l-enantiomers may be prepared as disclosed by Salman et al. in U.S. Patent Specification No.
  • 3,4-diarylchromans of formula I may be prepared in the form of pharmaceutically acceptable salts, especially acid-addition salts, including salts of organic acids and mineral acids.
  • salts include salts of organic acids such as formic acid, fumaric acid, maleic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, succinic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid and the like.
  • Suitable inorganic acid-addition salts include salts of hydrochloric, hydrobromic, sulphuric and phosphoric acids and the like.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • a preferable salt is the hydrogen fumarate salt.
  • 3,4-diarylchromans of formula I and their salts are useful within human and veterinary medicine, for example, in the treatment of patients suffering from a psychiatric disorder.
  • 3,4-diarylchromans of formula I and their pharmaceutically acceptable salts are formulated with a pharmaceutically acceptable carrier to provide a medicament for parenteral, oral, na- sal, rectal, subdermal or intradermal or transdermal administration according to conventional methods.
  • Formulations may further include one or more diluents, fillers, emulsifiers, preservatives, buffers, excipients, etc.
  • the active compound of formula I is prepared in a form suitable for oral administration, such as a tablet or capsule.
  • a pharmaceutically acceptable salt of the compound of formula I is combined with a carrier and moulded into a tablet.
  • Suitable carriers in this regard include starch, sugars, dicalcium phosphate, calcium stearate, magnesium stearate and the like.
  • Such compositions may further include one or more auxiliary substances, such as wetting agents, emulsifiers, preservatives, stabilizers, colouring additives, etc.
  • compositions containing a compound of formula I may be administered one or more times per day or week.
  • An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against one or more psychiatric disorders. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art.
  • a typical daily dose will contain a nontoxic dosage range of from about 0.001 to about 75 mg/kg patient per day of a compound of the present invention.
  • compositions containing a compound of formula I may be administered in unit dosage form one or more times per day or week. In the alternative, they may be provided as controlled release formulations suitable for dermal implantation. Implants are formulated to provide release of active compound over the desired period of time, which can be up to several years. Con- trolled-release formulations are disclosed by, for example, Sanders et al., J Pharm Sci 73 ( 1 964), 1 294 - 1 297, 1 984; U.S. Patent Specification No. 4,489,056; and U.S. Patent Specification No. 4,21 0,644, which are incorporated herein by reference.
  • Examples of preferred compounds of formula I are centchroman as a racemic mixture and as isolated l-centchroman and d-centchroman enantiomers. Furthermore, 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-(pyrrolidin-1 -yl)ethoxy)phenyl-7- hydroxychroman is a preferred compound. The more preferred compound is isolated l-centchroman (l-3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1 - yl)ethoxy)phenyl]-7-methoxychroman).
  • Examples of pharmaceutically acceptable acid addition salts are salts with non- toxic acids, either inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid, or organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • inorganic acids such as hydrochloric acid, sulphuric acid and phosphoric acid
  • organic acids such as formic acid, fumaric acid, acetic acid, propionic acid, succinic acid, gluconic acid, lactic acid, citric acid, ascorbic acid, benzoic acid, embonic acid, methanesulphonic acid and malonic acid.
  • Test 1 Three to fifty women are selected for the clinical study. The women are in general good health, and suffer from one or more of the above-mentioned psychiatric disorders. Because of the idiosyncratic and subjective nature of these disorders, the study has a placebo control group, i.e., ' the women are divided into two groups, one of which receive the active agent of this invention and the other re- ceive a placebo. Women in the test group receive between 0.001 -75 mg/kg patient of the drug per day by the oral route. They continue this therapy for 3-1 2 months. Accurate records are kept as to the number and severity of the above mentioned disorders in both groups and at the end of the study these results are compared.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouvelles utilisations de composés représentés par la formule (I) dans laquelle R?1, R4 et R5¿ représentent individuellement hydrogène, hydroxy, halogène, trifluorométhyle, alkyle C¿1?-C6, alkoxy C1-C6 ou (amino tertiaire)(alkoxy C1-C6); R?2 et R3¿ représentent individuellement hydrogène ou alkyle C¿1?-C6, ou un de leurs sels acceptables sur le plan pharmaceutique, afin de préparer une composition pharmaceutique servant à inhiber une ou plusieurs maladies psychiatriques.
PCT/DK1998/000033 1997-01-29 1998-01-28 Utilisation de 3, 4-diphenyle chromanes pour preparer une composition pharmaceutique servant a inhiber une ou plusieurs maladies psychiatriques Ceased WO1998032437A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55504/98A AU5550498A (en) 1997-01-29 1998-01-28 Use of 3,4-diphenyl chromans for the manufacture of a pharmaceutical compositionfor inhibiting one or more psychiatric disorders

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK0110/97 1997-01-29
DK11097 1997-01-29

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WO1998032437A1 true WO1998032437A1 (fr) 1998-07-30

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022091A1 (fr) * 1995-01-20 1996-07-25 Novo Nordisk A/S Utilisation des 3,4-diphenylchromanes pour la preparation d'une composition pharmaceutique destinee au traitement preventif ou curatif de degenerescences cerebrales

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996022091A1 (fr) * 1995-01-20 1996-07-25 Novo Nordisk A/S Utilisation des 3,4-diphenylchromanes pour la preparation d'une composition pharmaceutique destinee au traitement preventif ou curatif de degenerescences cerebrales

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
INDIAN JOURNAL OF EXPERIMENTAL BIOLOGY, Volume 15, December 1977, I.M. CHAK et al., "Acute Toxicity & Pharmacology of Centchroman", pages 1159-1161. *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601855B2 (en) 2004-09-21 2009-10-13 Novogen Research Pty Ltd Substituted chroman derivatives, medicaments and use in therapy
US8080675B2 (en) 2004-09-21 2011-12-20 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8084628B2 (en) 2004-09-21 2011-12-27 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8461361B2 (en) 2004-09-21 2013-06-11 Marshall Edwards, Inc. Chroman derivatives, medicaments and use in therapy
US8697891B2 (en) 2004-09-21 2014-04-15 Marshall Edwards, Inc. Substituted chroman derivatives, medicaments and use in therapy
US8957109B2 (en) 2004-09-21 2015-02-17 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US9138478B2 (en) 2004-09-21 2015-09-22 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9198895B2 (en) 2004-09-21 2015-12-01 Mei Pharma, Inc. Chroman derivatives, medicaments and use in therapy
US9381186B2 (en) 2004-09-21 2016-07-05 Mei Pharma, Inc. Substituted chroman derivatives, medicaments and use in therapy
US9708283B2 (en) 2010-11-01 2017-07-18 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US9663484B2 (en) 2010-11-01 2017-05-30 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US9981936B2 (en) 2010-11-01 2018-05-29 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10105346B2 (en) 2010-11-01 2018-10-23 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10369132B2 (en) 2010-11-01 2019-08-06 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US10973799B2 (en) 2010-11-01 2021-04-13 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US11583514B2 (en) 2010-11-01 2023-02-21 Mei Pharma, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US11723893B2 (en) 2010-11-01 2023-08-15 Mei Pharma, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US12318364B2 (en) 2010-11-01 2025-06-03 Aardvark Therapeutics, Inc. Isoflavonoid compositions and methods for the treatment of cancer
US12329739B2 (en) 2010-11-01 2025-06-17 Aardvark Therapeutic, Inc. Isoflavonoid compounds and methods for the treatment of cancer
US10980774B2 (en) 2015-02-02 2021-04-20 Mei Pharma, Inc. Combination therapies
US12414934B2 (en) 2015-02-02 2025-09-16 Aardvark Therapeutics, Inc. Combination therapies

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ZA98682B (en) 1998-07-29
AU5550498A (en) 1998-08-18

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