WO2002080896A1 - Uses of benzylideneamino guanidines as ligands to the melanocortiin receptors - Google Patents

Uses of benzylideneamino guanidines as ligands to the melanocortiin receptors Download PDF

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Publication number
WO2002080896A1
WO2002080896A1 PCT/GB2002/001589 GB0201589W WO02080896A1 WO 2002080896 A1 WO2002080896 A1 WO 2002080896A1 GB 0201589 W GB0201589 W GB 0201589W WO 02080896 A1 WO02080896 A1 WO 02080896A1
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Prior art keywords
receptors
compound
msh
hydrogen
disorders
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PCT/GB2002/001589
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English (en)
French (fr)
Inventor
Torbjörn Lundstedt
Per Andersson
Arne Boman
Elisabeth Seifert
Anna Skottner
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TOWLER PHILIP DEAN
Melacure Therapeutics AB
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TOWLER PHILIP DEAN
Melacure Therapeutics AB
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Priority to US10/472,768 priority Critical patent/US20040106683A1/en
Priority to JP2002578935A priority patent/JP2004531510A/ja
Priority to CA002443099A priority patent/CA2443099A1/en
Priority to IL15824802A priority patent/IL158248A0/xx
Priority to EP02707025A priority patent/EP1372625A1/en
Priority to MXPA03008973A priority patent/MXPA03008973A/es
Priority to BR0208657-3A priority patent/BR0208657A/pt
Priority to KR10-2003-7012904A priority patent/KR20030092045A/ko
Publication of WO2002080896A1 publication Critical patent/WO2002080896A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of benzylideneamino guanidines as melanocortin receptor agonists or antagonists.
  • the present invention particularly relates to benzylideneamino guanidines which show selectivity to the MCI and MC4 melanocortin receptors as agonists and/or antagonists.
  • MC melanocortin
  • MC melanocortin
  • the agonistic and/or antagonistic properties of these peptides are also known. See for example "Melanocortin Receptor ligands and methods of using same” by Dooley, Girten and Houghten (WO 99/21571).
  • Two patent applications (WO 99/55679 and WO 99/64002) have been published which include small molecules showing activity on the melanocortin receptors.
  • the compounds in the present application are structurally different from the previously published melanocortin agonists, and hence the observed effects are unexpected.
  • hydroxyguanidines e.g. WO98/23267
  • Other compounds known in the art are benzylideneamino guanidines which have shown anti- depressive effects (US 4060640).
  • Other examples of pharmacologically active guanidines known in the art are described in patent US3982020 and GB1223491.
  • Other application areas are also known in the art and are described in patents DEI 165013 and US3941825.
  • Guanabenz is a compound which is well known in the art as an antihypertensive drug (US Pharmacopeia, 1999, The United States Pharmacopeial Convention, Lie, ISBN 1-889788- 03-1). Whilst Guanabenz might appear to be structurally similar to the compounds in the present invention, it shows no affinity to the melanocortin receptors. Therefore it is very su ⁇ rising that the benzylideneamino guanidine compounds in the present invention show affinity to the melanocortin receptors as agonist and/or antagonists.
  • One aspect of the present invention is therefore to provide low molecular weight compounds showing activity on melanocortin receptors and which may be taken up after per oral administration and which may penetrate well through the blood brain barrier.
  • the present invention provides for the use of compounds of the general formula (I):
  • R 2 is selected from hydrogen, chloro, bromo or nitro group
  • R 3 is selected from a hydrogen or bromo group
  • R 4 is selected from a hydrogen or methoxy group
  • R 5 is selected from a hydrogen or hydroxy group
  • R 4 and R 5 may together be a methylenedioxy group.
  • At least one of R 3 , R 4 and R 5 is not a hydrogen.
  • R 2 is selected from a c loro, hydrogen, or bromo group.
  • the present invention includes the use of the following compounds, inter alia, for modulating melanocortin related systems:
  • the present invention relates to the use of benzylideneamino guanidines with activity on the melanocortin receptors.
  • the compounds of the present invention have been biologically tested in the melanocortin system and have su ⁇ risingly been shown to be capable of binding to melanocortin receptors as well as showing activity in functional assays.
  • the compounds of the present invention may either be agonists or antagonists of a specific MC-receptor or of a number of MC-receptors, e.g. MCI, MC3, MC4 or/and MC5 receptors.
  • the MC-receptors belong to the class of G-protein coupled receptors which are all built from a single polypeptide forming 7 transmembrane domains. Five such receptors types, termed MCI, MC2, MC3, MC4 and MC5, have been described.
  • the MC receptor's signalling is mainly mediated via cAMP but also other signal transduction pathways are known. They are distinctly distributed in the body.
  • MC-receptors axe linked to a variety of physiological actions that are thought to be mediated by distinct subtypes of the MC-receptors. In many cases, however, it is not entirely clear which of the subtypes is responsible for the effect.
  • Some of the compounds provided in the present invention can be used for modulating melanocortin related systems and therefore used for the treatment of diseases such as drug abuse, feeding disorders, immunomodulatory action, pain, skin and sexual function/dysfunctions associated with the melanocortin receptors or related systems, e.g. the melanocyte stimulating hormones.
  • diseases such as drug abuse, feeding disorders, immunomodulatory action, pain, skin and sexual function/dysfunctions associated with the melanocortin receptors or related systems, e.g. the melanocyte stimulating hormones.
  • MSH-peptides may affect many different processes such as motivation, learning, memory, behaviour, inflammation, body temperature, pain perception, blood pressure, heart rate, vascular tone, brain blood flow, nerve growth, placental development, aldosterone synthesis and release, thyroxin release, spermatogenesis, ovarian weight, prolactin and FSH secretion, uterine bleeding in women, sebum and pheromone secretion, blood glucose levels, intrauterine foetal growth, as well as other events surrounding parturition (Eberle, AN: The melanotropins: Chemistry, physiology and mechanisms of action. Basel: Karger, Switzerland. 1988, ISBN 3-8055- 4678-5; Gruber, and Callahan, Am.
  • the compounds of the invention are useful for inhibiting or stimulating the in vivo formation of second messenger elements such as cAMP. Such inhibition/stimulation may be used in cells or crushed cell systems in vitro, e.g. for analytical or diagnostic memeposes.
  • the compounds of the invention may be used in radioactive form where they comprise one or more radioactive labels or gamma or positron emitting isotopes, to be used in radioligand binding for the quantification as well as tissue localisation of MC-receptors, for analysis of dissociation/association constants, and for imaging of in vivo binding by the use of scintigraphy, positron emission tomography (PET) or single photon emission computed tomography (SPECT), or for the diagnosis of disease and treatment of any malignancy where the malignant cells contain MC receptors.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the compounds of the invention can be labelled with any other type of label that allows detection of the respective compound, e.g. fluorescence, biotin, or labels activated by gamma-irradiation, light photons or biochemical processes, or by light or UN- light (the latter in order to obtain a compound useful for covalent labelling of MC receptors by a photoaffinity technique).
  • any other type of label that allows detection of the respective compound, e.g. fluorescence, biotin, or labels activated by gamma-irradiation, light photons or biochemical processes, or by light or UN- light (the latter in order to obtain a compound useful for covalent labelling of MC receptors by a photoaffinity technique).
  • Some of the compounds of formula (I) or the pharmacologically acceptable salts thereof may also be tagged with a toxic agent (i.e. doxorubicin, ricin, diphtheria toxin or other) and used for targeted delivery to malignant cells bearing MC receptors, or tagged with a compound capable of activating the endogenous immune system for triggering the immune system (for example a compound, monoclonal antibody or other, capable of binding to a T-cell antigen, e.g. CD3 or other) for treatment of malignancies and other MC receptor expressing diseases.
  • a toxic agent i.e. doxorubicin, ricin, diphtheria toxin or other
  • a compound capable of activating the endogenous immune system for triggering the immune system for example a compound, monoclonal antibody or other, capable of binding to a T-cell antigen, e.g. CD3 or other
  • the thus formed hybrid compound will direct cytotoxic cells to the malignant melanom
  • Compounds of the invention may be used for the treatment and diagnosis of diseases, disorders and/or pathological conditions in an animal, in particular in man.
  • the present invention also relates to a pro-drug which, upon administration to an animal or a human, is converted to a compound of the invention.
  • Pro-drugs of the compounds of formula (I) and their pharmacologically acceptable salts may be used for the same pu ⁇ oses as described in this specification for the compounds of the invention, as well as is disclosed in the examples given below.
  • the compounds of the present invention may be bound covalently or non-covalently to one or several of other molecule(s) of any desired structure(s); the thus formed modified compound or complex may be used for the same pu ⁇ oses as described in this specification for the compounds of the invention as well as is disclosed in the examples given below.
  • a radioactively-labelled molecule is covalently bound to a compound of formula (I) or a pharmacologically acceptable salt thereof so as to make a compound of formula (I) or a pharmacologically acceptable salt thereof radioactively labelled.
  • the invention also relates to uses of pharmaceutical preparations comprising one or more of the compounds of the invention for various medical and veterinary practices related to melanocyte stimulating hormone receptors.
  • the compounds of formula (I) are known in the art and may be prepared by methods such as described in WO 01/25192. For example, by reaction of the appropriate aromatic aldehyde and amino guanidine salt.
  • the compounds having the general formula (I) may be prepared by the following general method. Method 1.
  • This example illustrates the potency of compounds of formula (I) and their therapeutically active acid addition salts.
  • the binding assay was carried out essentially as described by Lunec et al., Melanoma Res. 1992; 2; 5-12 using I 125 -NDP- MSH as ligand. Test 2. Affinity for the MC3-receptors, the MC4-receptors and the MC5-receptors
  • the binding assays were carried out essentially as described by Szardenings et al, J. Biol. Chem. 1997; 272; 27943-27948 and Schioth et al, FEBS Lett. 1997; 410; 223-228 using I 125 -NDP- ⁇ MSH as ligand.
  • the affinity of the compounds for the different melanocortin receptors were determined by using either insect cells (Sf9) or COS cells, which were transfected with recombinant human MC3, MC4 or MC5 receptors.
  • Sf9 insect cells
  • COS cells which were transfected with recombinant human MC3, MC4 or MC5 receptors.
  • B16 mouse melanoma cells were used, which endogenously express the (mouse) MCI receptor.
  • the compounds were tested at different concentrations for their ability to displace a 125 I- labelled NDP-MSH from the respective receptor. Incubation was performed in 96-well plates, using 50,000 cells/well (Sf9 or COS cells) up to 200,000 cells/well (mouse melanoma cells). The test compound or standard (NDP-MSH) was added in an appropriate concentration (generally between 10 "4 M and 10 "12 M) together with labelled tracer (approx. 50,000 cpm/well) and incubated for 2 hours (at room temperature for Sf9 cells and at +37°C for COS cells and mouse melanoma cells).
  • the cells were washed twice to get rid of the excess tracer and compound, and the cells were lysed with 0.1 M NaOH. The lysate was counted in a gamma-counter, binding was calculated and the affinity determined.
  • Ki ( ⁇ M) Compound MCI MC3 MC4 MC5
  • Guanobenz nb nb nb nb nb nb non-binding, i.e. no affinity.
  • Sprague-Dawley male rats were used, which were cannulated intracerebroventricularly.
  • Stainless steel guide cannulae were placed in the lateral ventricle and fixed in the skull. Animals were acclimatized for a week before the experiments took place. After the experiments were done, the rats were killed and placement of the cannulae were checked.
  • Nocturnal protocol Rats were cannulated as described above. They were used without prior starvation, and compounds were administered at 5 pm in a total volume of 5 ⁇ l. Doses of compounds used were in between 0.25 to 50 nmoles. Food intake was measured at 3, 15 and 24 hours after dosing, and body weight was recorded at 24 hours. For comparison, the well- known MC4 receptor agonist, Melanotan II (MTU) was used, at a dose of 1 nmole.
  • MTU Melanotan II
  • mice Female BALB/c mice (weight 20-22 g) were sensitized by treatment of the shaved abdomen with 30 ⁇ l of 0.5% 2,4-dinitrofluorobenzene (DNFB). After 4 days they were challenged with 10 ⁇ l of 0.3 % DNFB to the paw. The unchallenged mice paws served as a control. Twenty-four hours after the last challenge, the differences in paws weight were determined as an indicator of the inflammation (paw edema). alpha-MSH and prednisolone controls
  • mice were treated as the control but were additionally injected i.p. with ⁇ -MSH (0.5 mg/kg) or prednisolone (20 mg/kg) two hours before sensitization (day 0) and the same dose was administered repeatedly after sensitization during four consecutive days.
  • ⁇ -MSH 0.5 mg/kg
  • prednisolone 20 mg/kg
  • mice were treated as the control but were additionally injected i.p. with various doses (0.05, 0.15 or 0.25, 0.375, 0.5, 0.75 and in later studies also 1.5, 3 and occasionally 6 mg/kg) of each compound two hours before sensitization (day 0) and the same dose was administered repeatedly after sensitization during four consecutive days.
  • the paw edema inhibition as described above. Groups containing at least 10 mice each were used for all experiments.
  • Example of a preparation comprising a capsule
  • the amount of lactose used may be reduced.
  • Example of a suitable tablet formulation Example of a suitable tablet formulation.
  • a solution for parenteral administration by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable acid addition salt of the active substance preferably in a concentration of 0.1 % to about 5 % by weight.
  • These solutions may also contain stabilising agents and/or buffering agents.

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PCT/GB2002/001589 2001-04-05 2002-04-05 Uses of benzylideneamino guanidines as ligands to the melanocortiin receptors Ceased WO2002080896A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US10/472,768 US20040106683A1 (en) 2001-04-05 2002-04-05 Uses of benzylideneamino guanidines as ligands to the melnocortin receptors
JP2002578935A JP2004531510A (ja) 2001-04-05 2002-04-05 ベンジリデンアミノグアニジンの、メラノコルチンレセプターリガンドとしての使用方法
CA002443099A CA2443099A1 (en) 2001-04-05 2002-04-05 Uses of benzylideneamino guanidines as ligands to the melanocortiin receptors
IL15824802A IL158248A0 (en) 2001-04-05 2002-04-05 Uses of benzylideneamino guanidines as ligands to the melanocortiin receptors
EP02707025A EP1372625A1 (en) 2001-04-05 2002-04-05 Uses of benzylideneamino guanidines as ligands to the melanocortiin receptors
MXPA03008973A MXPA03008973A (es) 2001-04-05 2002-04-05 Uso de bencilidenaminoguanidinas como ligandos para receptores de melanocortina.
BR0208657-3A BR0208657A (pt) 2001-04-05 2002-04-05 Usos de benzilideno amino guanidinas como ligantes para os receptores de melanocortina
KR10-2003-7012904A KR20030092045A (ko) 2001-04-05 2002-04-05 벤질리덴아미노 구아니딘의 멜라노코르틴 수용체에 대한리간드로서의 사용방법

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GBGB0108631.3A GB0108631D0 (en) 2001-04-05 2001-04-05 Novel benzylideneamino guanidines and their uses as ligands to the melanocortin receptors
GB0108631.3 2001-04-05

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PCT/GB2002/001589 Ceased WO2002080896A1 (en) 2001-04-05 2002-04-05 Uses of benzylideneamino guanidines as ligands to the melanocortiin receptors

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US (2) US20040106682A1 (enExample)
EP (2) EP1372625A1 (enExample)
JP (2) JP2004531510A (enExample)
KR (2) KR20030088056A (enExample)
BR (2) BR0208657A (enExample)
CA (2) CA2443099A1 (enExample)
GB (1) GB0108631D0 (enExample)
IL (2) IL158247A0 (enExample)
MX (2) MXPA03008972A (enExample)
WO (2) WO2002081430A2 (enExample)
ZA (1) ZA200307453B (enExample)

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US8148429B2 (en) 2000-08-07 2012-04-03 Anamar Ab Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
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US8329914B2 (en) 2008-10-31 2012-12-11 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
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CN105764916B (zh) 2013-06-05 2021-05-18 博士医疗爱尔兰有限公司 鸟苷酸环化酶c的超纯激动剂、制备和使用所述激动剂的方法
WO2015051496A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
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US20180230105A1 (en) 2017-01-13 2018-08-16 Regents Of The University Of Minnesota Therapeutic compounds

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3592935A (en) * 1969-12-11 1971-07-13 Sandoz Ag Substituted benzylidene hydrazines as anti-inflammatory agents
US3896232A (en) * 1973-01-11 1975-07-22 Sandoz Ag Substituted benzylidene hydrazines as anti-migraine syndrome agents
US3982020A (en) * 1970-03-17 1976-09-21 Sandoz, Inc. Substituted benzylidene hydrazines for treating hyperglycemia, obesity and inflammation
US4006250A (en) * 1975-08-25 1977-02-01 American Home Products Corporation Systemic treatment of psoriasis
WO1993003714A2 (en) * 1991-08-27 1993-03-04 The Upjohn Company Method for treatment of metabolic disorders
US5599984A (en) * 1994-01-21 1997-02-04 The Picower Institute For Medical Research Guanylhydrazones and their use to treat inflammatory conditions
WO1998023267A1 (en) * 1996-11-26 1998-06-04 Wapharm Ab Use of hydroxyguanidines
WO2001013921A1 (en) * 1999-08-23 2001-03-01 Ockert David M Triple drug therapy for the treatment of narcotic and alcohol withdrawal symptoms
WO2001025192A1 (en) * 1999-10-06 2001-04-12 Melacure Therapeutics Ab Guanidine derivatives and their use in the production of a medicament for blocking xanthine oxidase/dehydrogenase
WO2002011715A2 (en) * 2000-08-07 2002-02-14 Melacure Therapeutics Ab The use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2584784A (en) * 1949-05-21 1952-02-05 Du Pont Salts of 1-salicylalaminoguanidine
DE1165013B (de) * 1960-08-09 1964-03-12 Vismara Francesco Spa Verfahren zur Herstellung von Guanylhydrazonen
GB1223491A (en) * 1967-10-13 1971-02-24 American Home Prod Guanidines
US4060640A (en) * 1970-04-29 1977-11-29 Shell Oil Company Therapeutic agents
US3816531A (en) * 1970-07-01 1974-06-11 American Home Prod (2,6-disubstituted benzylidene)amino guanidines and related compounds
US3941825A (en) * 1973-07-27 1976-03-02 American Cyanamid Company Substituted aminobenzylideneamino guanidine compounds
GB0019359D0 (en) * 2000-08-07 2000-09-27 Melacure Therapeutics Ab Novel guanidines
GB0108631D0 (en) * 2001-04-05 2001-05-30 Melacure Therapeutics Ab Novel benzylideneamino guanidines and their uses as ligands to the melanocortin receptors

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3592935A (en) * 1969-12-11 1971-07-13 Sandoz Ag Substituted benzylidene hydrazines as anti-inflammatory agents
US3982020A (en) * 1970-03-17 1976-09-21 Sandoz, Inc. Substituted benzylidene hydrazines for treating hyperglycemia, obesity and inflammation
US3896232A (en) * 1973-01-11 1975-07-22 Sandoz Ag Substituted benzylidene hydrazines as anti-migraine syndrome agents
US4006250A (en) * 1975-08-25 1977-02-01 American Home Products Corporation Systemic treatment of psoriasis
WO1993003714A2 (en) * 1991-08-27 1993-03-04 The Upjohn Company Method for treatment of metabolic disorders
US5599984A (en) * 1994-01-21 1997-02-04 The Picower Institute For Medical Research Guanylhydrazones and their use to treat inflammatory conditions
WO1998023267A1 (en) * 1996-11-26 1998-06-04 Wapharm Ab Use of hydroxyguanidines
WO2001013921A1 (en) * 1999-08-23 2001-03-01 Ockert David M Triple drug therapy for the treatment of narcotic and alcohol withdrawal symptoms
WO2001025192A1 (en) * 1999-10-06 2001-04-12 Melacure Therapeutics Ab Guanidine derivatives and their use in the production of a medicament for blocking xanthine oxidase/dehydrogenase
WO2002011715A2 (en) * 2000-08-07 2002-02-14 Melacure Therapeutics Ab The use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BENELLI A ET AL: "Male sexual behaviour: further studies on the role of alpha 2-adrenoceptors.", PHARMACOLOGICAL RESEARCH: THE OFFICIAL JOURNAL OF THE ITALIAN PHARMACOLOGICAL SOCIETY. ENGLAND 1993 JUL-AUG, vol. 28, no. 1, July 1993 (1993-07-01), pages 35 - 45, XP001095156, ISSN: 1043-6618 *
CHANG J ET AL: "THE ANTIINFLAMMATORY ACTION OF GUANABENZ IS MEDIATED THROUGH 5-LIPOXYGENASE AND CYCLOOXYGENASE INHIBITION", EUROPEAN JOURNAL OF PHARMACOLOGY, AMSTERDAM, NL, vol. 142, no. 2, 1987, pages 197 - 205, XP000974753, ISSN: 0014-2999 *
DIMMOCK J R ET AL: "EVALUATION OF THE THIOSEMICARBAZONES OF SOME ARYL ALKYL KETONES AND RELATED COMPOUNDS FOR ANTICONVULSANT ACTIVITIES", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 26, no. 5, 1991, pages 529 - 534, XP002014742, ISSN: 0223-5234 *
KAZIC, T. ET AL: "Central presynaptic alpha2 agonists guanabenz and clonidine act as alpha1 adrenoceptor antagonists in the isolated vas deferens of the guinea pig", IUGOSL. PHYSIOL. PHARMACOL. ACTA (1994), 30(1), 25-34, XP001098531 *
NAKATSUKA MIKIYA ET AL: "Metabolism-based inactivation of penile nitric oxide synthase activity by Guanabenz.", DRUG METABOLISM AND DISPOSITION, vol. 26, no. 5, May 1998 (1998-05-01), pages 497 - 501, XP001095628, ISSN: 0090-9556 *
OSAWA Y ET AL: "Inactivation of penile nitric oxide synthase by Guanabenz, an antihypertensive agent: Potential implications in drug induced impotence.", FASEB JOURNAL, vol. 9, no. 6, 1995, Annual Meeting of the American Society for Biochemistry and Molecular Biology;San Francisco, California, USA; May 21-25, 1995, pages A1495, XP001095624, ISSN: 0892-6638 *

Cited By (11)

* Cited by examiner, † Cited by third party
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US8148429B2 (en) 2000-08-07 2012-04-03 Anamar Ab Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
US8309609B2 (en) 2000-08-07 2012-11-13 Anamar Ab Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
US8410174B2 (en) 2000-08-07 2013-04-02 Anamar Ab Method for treating arthritis
US9227927B2 (en) 2000-08-07 2016-01-05 Anamar Ab Method of treating inflammation
EP2933265A2 (en) 2005-06-03 2015-10-21 Amicus Therapeutics, Inc. Pharmacological chaperones for treating obesity
WO2010056717A1 (en) 2008-11-17 2010-05-20 Merck Sharp & Dohme Corp. Substituted bicyclic amines for the treatment of diabetes
WO2011011508A1 (en) 2009-07-23 2011-01-27 Schering Corporation Benzo-fused oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
WO2011011506A1 (en) 2009-07-23 2011-01-27 Schering Corporation Spirocyclic oxazepine compounds as stearoyl-coenzyme a delta-9 desaturase inhibitors
WO2011137024A1 (en) 2010-04-26 2011-11-03 Merck Sharp & Dohme Corp. Novel spiropiperidine prolylcarboxypeptidase inhibitors
WO2011143057A1 (en) 2010-05-11 2011-11-17 Merck Sharp & Dohme Corp. Novel prolylcarboxypeptidase inhibitors
WO2011156246A1 (en) 2010-06-11 2011-12-15 Merck Sharp & Dohme Corp. Novel prolylcarboxypeptidase inhibitors

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