AP860A - Dipeptide compounds which are growth hormone secretegoques. - Google Patents

Dipeptide compounds which are growth hormone secretegoques. Download PDF

Info

Publication number
AP860A
AP860A APAP/P/1999/001555A AP9901555A AP860A AP 860 A AP860 A AP 860A AP 9901555 A AP9901555 A AP 9901555A AP 860 A AP860 A AP 860A
Authority
AP
ARIPO
Prior art keywords
growth hormone
alkyl
compounds
group
optionally substituted
Prior art date
Application number
APAP/P/1999/001555A
Other versions
AP9901555A0 (en
Inventor
Philip A Carpino
Jardine Paul A Dasilva
Bruce A Lefker
John A Ragan
Original Assignee
Pfizer
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21737850&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AP860(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Pfizer filed Critical Pfizer
Publication of AP9901555A0 publication Critical patent/AP9901555A0/en
Application granted granted Critical
Publication of AP860A publication Critical patent/AP860A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Peptides Or Proteins (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Cooling Or The Like Of Electrical Apparatus (AREA)
  • Steroid Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

This invention is directed to compounds of the formula and the pharmaceutically-acceptable salts thereof, where the substituents are as defined in the Specification, which are growth hormone secretogogues and wnich increase the level of endogenous growth hormone. The compounds of this invention are useful for the treatment and 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 recover/ of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. The compounds of the present invention are also useful in treating osteoporosis when used in combination with; a bisphosphonate compound such as alendronate; estrogen, premarin, and optionally progesterone; an estrogen agonist or antagonist; or calcitonin, and pharmaceutical compositions useful therefor Further, the present invention is directed to pharmaceutical compositions useful fcr increasing the endogenous production or release of growth hormone in a human or other animal which comprises an effective amount of a compound of the present invention and a growth hormone secretagogue selected from GHRP-6, Hexarelin. GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT92Q The invention is also directed to intermediates useful in the preparation of compouncs of formula I.

Description

HETEROCYCLIC CQMEQ.UNPS
This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis.
Background of the.lnyen.tion
Growth hormone (GH), which is secreted from the pituitary gland, 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 process of the body: 1. Increased rate of protein synthesis in substantially all cells of the body; 2. Decreased rate of carbohydrate utilization in cells of the body; 3. Increased mobilization of free fatty acids and use of fatty acids for energy.
Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either 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 an 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 (e.g., Jacob-Creutzfeld disease). Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic growth hormone-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.
Physiologic and pharmacologic stimulators of GH secretion include 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 the secretion of the known secretagogue growth hormone releasing factor (GHRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Patent 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low. WO 94/13696 refers to certain spiropiperidines and homologues which promote release of growth hormone. Preferred compounds are of the general structure shown below.
WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure
where L is
The compounds of WO 94/11012 and WO 94/13696 are reported to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.
Summary of the Invention
This invention provides compounds of the formula:
the racemic-diastereomeric mixtures and optical isomers of said compounds and the ’ pharmaceutically-acceptable salts and prodrugs thereof, wherein e is 0 or 1; n and w are each independently 0, 1 or 2, provided that w and n cannot both be 0 at the same time; Y is oxygen or sulfur; R1 is hydrogen, -ON, -(CH2)qN(X6)C(0)X6, -(CH2)qN(X6)C(O)(CH2)t-A1, -(CH2)qN(X6)SO2(CH2)t-A1, -(CH2)qN(X6)SO2X6, -(CH2)qN(X5)C(0)N(X6)(CH2)t-A1, -(CH2)qN(X6)C(O)N(X6)(X6),-(CH2)qC(O)N(X6)(X6), -(CH2)qC(0)N(X6)(CH2)t-A1, -(CH2)qC(O)OX6, -(CH2)qC(0)0(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),/ -(CH2)qS(O)m(CH2)rA1, -(C-i-G-io)alkyl, -(CH2)t-A , -(CH2)q-(C3-C7)cycloalkyl, -(CH2)q-Y1-(Ci-C5)a!kyl, -(CH2)q-Y1-(CH2)t-A1 or -(CH2)q-Y1-(CH2)r(C3-C7)cycioaikyl; where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (CrC4)alkyl, hydroxyl, (CrC4)alkoxy, carboxyl, -CONH2, -SiO^CvCJalkyl, -C02(C1-C4)alkyl ester, 1 H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y1 is O, S(O)m, -C(O)NX6-, -CH=CH-, -0=0-, -N(X6)C(O)-, -C(O)NX6-, -0(0)0-, -OC(O)N(X6)- or -OC(O)-;
q is Ο, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said (CH2)q group and (CH2)t group may each be optionally substituted with hydroxyl, (CrCJalkoxy, carboxyl, -CONH2, -S(O)m(Ci-C6)alkyl, -CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (Cr CJalkyl; R2 is hydrogen, (CrCejalkyl, -(C0-C3)alkyl-(C3-C8)cycloalkyl, -<C1-C4)alkyl-A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, -C(O)OX6, -C(O)N(X6)(X6), -N(XS)(X6), -S(O)m(C1-C6)alkyl, -C(O)A1, -C(O)(X6), CF3, CN or 1, 2 or 3 halogen; R3 is A1, (CrCwJalkyl, -(C^Cejalkyl-A1, -(C1-C6)alkyl-(C3-C7)cycloalkyl, -(CrCsjalkyl-X’-iCrCsjalkyl, -(CrCsjalkyl-X^Co-Csjalkyl-A1 or -(CrCsJalkyl-X^CrCsjalkyl-iCjj-CTjcycloalkyl; I» where the alkyl groups in the definition of R3 are optionally substituted with, -S(O)m(CrC6)alkyl, -C(O)OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX3; X1 is O, S(O)m, -N(X2)C(O)-, -C(O)N(X2)-, -OC(O)-, -C(O)O-, -cx2=cx2-, -N(X2)C(O)O-, -OC(O)N(X2)- or -C=C-; R4 is hydrogen, (Ci-C6)alkyl or (C3-C7)cyeloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to δ-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or (C-|-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring; R6 is a bond or is
where a and b are independently 0, 1, 2 or 3;
X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted (C1-C6)alkyl; the optionally substituted (O',-Ce)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -3(0)^(0,-C6)alkyl, -C(0)0X2, (C3-C7)cycloalkyl, -N(XZ)(X2) and -C(O)N(X2)(X2); or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then X5 or X5a but not both may be on the carbon atom and R7 or R8 but not both may be on the nitrogen atom and further provided that when two alkylene bridges are formed then X5 and X5a cannot be on the carbon atom and R7 and R8 cannot be on the nitrogen atom; or X5 is taken together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; or Xs is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, 0 or N-X2, provided that when a and b are both 0 then Z1 is not N-X2 or O; R7 and R8 are independently hydrogen or optionally substituted (Ci-C6)alkyl; where the optionally substituted (C,-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, -0(0)0-(0,-C6)alkyl, -S(O)m(C,-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 -0-0(0)(0,-C10)alkyl or 1 to 3 (C,-C6)alkoxy; or R7 and R8 can be taken together to form -(CH2)r-L-(CH2)r-; where L is C(X2)(X2), S(0)m or N(X2); A1 for each occurrence is independently (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 for each occurrence is independently optionally substituted, in one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, -OX6, -C(O)N(X6)(X6), -C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, -SiO^CvCgJalkyl, 1 H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N(X6)(X6), -N(X6)C(O)(X6), -SO^X6)^6), -N(X6)SO2-phenyl, -N(X6)SO2X6, -CONX11X12, -SO2NX11X12, -NX6SO2X12, -NX6CONX11X12, -NX6SO2NX11X12, -NX6C(O)X12, imidazolyl, thiazolyl or tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy; where X11 is hydrogen or optionally substituted (CrC6)alkyl; the optionally substituted (C-|-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (Cr C6)alkoxycarbonyl, -S(O)m(Ci-C6)alkyl 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (CrCio)alkanoyloxy or 1 to 3 (Cr^alkoxy; X12 is hydrogen, (C-|-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3; or X11 and X12 are taken together to form -(CH2)r-L1-(CH2)r-; L1 is C(X2)(X2), 0, S(0)m or N(X2); r for each occurrence is independently 1, 2 or 3; X2 for each occurrence is independently hydrogen, optionally substituted (Ci-C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (CrC6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with -S(O)m(C1-C6)alkyl, -C(O)OX3, 1 to 5 halogens or 1 to 3 OX3; X3 for each occurrence is independently hydrogen or (CpCsJalkyl; X6 is independently hydrogen, optionally substituted (C-|-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenatedcycloalkyl, where optionally substituted (C^CeJalkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted by 1 or 2 (C1-C4)alkyl, hydroxyl, (C-i-C4)alkoxy, carboxyl, CONH2, -SiOjn/CrCgjalkyl, carboxylate (Cr C4)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X6 groups on one atom and both Xs jare independently (C-|-C6)alkyl, the two (Ci-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX7; X7 is hydrogen or (Ci-C6)alkyl optionally substituted with hydroxyl; and m for each occurrence is independently 0, 1 or 2; with the proviso that: X6 and X12 cannot be hydrogen when it is attached to C(O) or SO2 in the form C(O)X6, C(O)X12, SO2X6 or SO2X12; and when R6 is a bond then L is N(X2) and each r in the definition -<CH2)r-L-(CH2)r- is independently 2 or 3. A preferred group of compounds, designated the “A Group’, contains those compounds having the formula I as shown hereinabove wherein X4 is hydrogen; R4 is hydrogen or methyl; R7 is hydrogen or (Ci-C3)alkyl; R8 is hydrogen or (CrC3)alkyl optionally substituted with one or two hydroxyl groups; R is
where Z is a bond and a is 0 or 1; X5 and X5a are each independently hydrogen, trifluoromethyl, phenyl, optionally substituted (CvCgjalkyl;
where the optionally substituted (Ci-C6)alkyl is optionally substituted with OX2, imidazolyl, phenyl, indolyf, p-hydroxyphenyl, (C5-C7)cycloalkyl, -S(O)m(CrC6)alkyl, -N(X2)(X2) or -C(O)N(X2)(X2); or X5 and R7 are taken together to form a (C^Csjalkylene bridge, and the other substituents not defined for the “A Group” compounds are as defined for formula (I) hereinabove. A group of compounds, which is preferred among the “A Group” of compounds, designated the “B Group”, contains those compounds of the “A Group", having the formula I as shown hereinabove, wherein b is 0; X5 and X5a are each independently hydrogen, (CrC^alkyl or hydroxy(C1-C3)alkyl; R3 is selected from the group consisting of 1-indolyl-CH2-, 2-indolyl-CH2-, 3-indolyl-CH2-, 1-naphthyl-CH2-, 2-naphthyl-CH2-, 1-benzimidazolyl-CH2-, 2-benzimidazolyl-CH2-, phenyl-(C-|-C4)alkyl-, 2-pyridyl-(C1-C4)alkyl-, 3-pyridyl-(C-i-C4)alkyl-, 4-pyridyl-(CvC4)alkyl-, phenyl-CH2-S-CH2-, thienyl-(Ci-C4)alkyi-, phenyl-(C0-C3)alkyl-O-CH2-, phenyl-CH2-O-phenyl-CH2-, and 3-benzothienyl-CH2-; where the aryl portion(s) of the groups defined for R3 are optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Ci, CH3, OCH3i OCF3, OCF2H and CF3. A group of compounds, which is preferred among the “B Group” of compounds, designated the “C Group”, contain those compounds of the “B Group”, having the formula I as shown hereinabove, wherein R4 is hydrogen; a is 0; n is 1 or 2; w is 0 or 1; X5 and X5a are each independently, hydrogen, methyl or hydroxymethyl, provided that when X5 is hydrogen then X5a is not hydrogen; R7 and R8 are each hydrogen; and R3 is phenyl-CH2-O-CH2-, phenyl-CH2-S-CH2-, 1-naphthyl-CH2-, 2-naphthyl-CH2-, phenyl-(CH2)3- or 3-indolyl-CH2-; where the aryl portion of the groups defined for R3 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, OCH3, OCF2H, OCF3 and CF3. A group of compounds, which is preferred among the “C Group' of compounds, designated the “D Group’, contains those compounds of the “C Group", having the formula I as shown hereinabove, wherein R1 is -(CH2)t-A1, -(CH2)q-(C3-C7)cycloalkyl or (C1-C10)alkyl; where A1 in the definition of R1 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of fluoro, chloro, methyl, OCH3, OCF2H, OCF3 and CF3; the cycloalkyl and alkyl groups in the definition of R1 are optionally substituted with (Ci-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, -S(O)m(C1-C6)alkyl, -CO2(C1-C4)alkyl ester, 1 H-tetrazol-5-yl or 1 to 3 fluoro; Y is O; R2 is hydrogen, -(C0-C3)alkyl-(C3-C8)cycloalkyl, ohenyl or (G^CsJalkyl where the (C-|-Ca)alkyl group is optionally substituted with hydroxyl, -CF3 or 1 to 3 halogen. A group of compounds, which is preferred among the “D Group" of «* compounds, designated the Έ Group”, contains those compounds of the “D Group” wherein w is 0 and n is 1.
Another group of compounds, which is preferred among the “D Group” of compounds, designated the “F Group”, are those compounds of the “D Group”, having the formula I as shown hereinabove, wherein e is 0; n and w are each 1; R1 is-(CH2)t-A1; where A1 in the definition of R1 is phenyl, thienyl, thiazolyl, pyridyl or pyrimidyl which is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 and OCF2H; t is 0, 1 or 2; and R3 is phenyl-CH2-O-CH2-, phenyl-(CH2)3- or 3-indolyl-CH2-, where the aryl portion is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, Me, OMe, CF3, OCF3 or OCF2H. A group of compounds, which is preferred among the “F Group" of compounds, designated the “G Group”, contains those compounds of the “F Group", having the formula I as shown hereinabove, wherein X5 and X5a are each methyl; R1 is -CH2-phenyl, -CH2-4-fluoro-phenyl, -CH2-pyridyl or -CH2-thiazolyl and R2 is hydrogen, methyl, ethyl, t-butyl or -CH2CF3.

Claims (1)

  1. Original document published without claims.
APAP/P/1999/001555A 1995-12-28 1999-05-27 Dipeptide compounds which are growth hormone secretegoques. AP860A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US946995P 1995-12-28 1995-12-28

Publications (2)

Publication Number Publication Date
AP9901555A0 AP9901555A0 (en) 1999-06-30
AP860A true AP860A (en) 1999-08-06

Family

ID=21737850

Family Applications (2)

Application Number Title Priority Date Filing Date
APAP/P/1996/000881A AP756A (en) 1995-12-28 1996-11-14 Dipeptide compounds which are growth hormone secretagoques.
APAP/P/1999/001555A AP860A (en) 1995-12-28 1999-05-27 Dipeptide compounds which are growth hormone secretegoques.

Family Applications Before (1)

Application Number Title Priority Date Filing Date
APAP/P/1996/000881A AP756A (en) 1995-12-28 1996-11-14 Dipeptide compounds which are growth hormone secretagoques.

Country Status (43)

Country Link
US (7) US6124264A (en)
EP (1) EP0869968B1 (en)
JP (2) JP3511382B2 (en)
KR (1) KR100320167B1 (en)
CN (1) CN1113895C (en)
AP (2) AP756A (en)
AR (2) AR004367A1 (en)
AT (1) ATE361314T1 (en)
AU (1) AU716934B2 (en)
BG (1) BG64055B1 (en)
BR (1) BR9612465B1 (en)
CA (1) CA2241725C (en)
CO (1) CO4480108A1 (en)
CZ (1) CZ293423B6 (en)
DE (1) DE69637063T2 (en)
DK (1) DK0869968T3 (en)
EG (1) EG24195A (en)
ES (1) ES2285715T3 (en)
GT (1) GT199600100A (en)
HN (1) HN1996000085A (en)
HR (1) HRP960618B1 (en)
HU (1) HUP9901246A3 (en)
IL (4) IL138911A (en)
IS (1) IS4758A (en)
MA (1) MA26415A1 (en)
MX (1) MX9805157A (en)
MY (1) MY135727A (en)
NO (1) NO325135B1 (en)
NZ (1) NZ322172A (en)
OA (1) OA10702A (en)
PE (1) PE30398A1 (en)
PL (1) PL186916B1 (en)
PT (1) PT869968E (en)
RS (1) RS49926B (en)
SA (1) SA97170581B1 (en)
SI (1) SI0869968T1 (en)
SK (1) SK285678B6 (en)
TN (1) TNSN96172A1 (en)
TR (1) TR199801233T2 (en)
TW (1) TW432073B (en)
UA (1) UA66754C2 (en)
WO (1) WO1997024369A1 (en)
ZA (1) ZA9610858B (en)

Families Citing this family (146)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW432073B (en) * 1995-12-28 2001-05-01 Pfizer Pyrazolopyridine compounds
HN1996000101A (en) 1996-02-28 1997-06-26 Inc Pfizer COMBINED THERAPY FOR OSTEOPOROSIS
ATE422359T1 (en) 1997-04-15 2009-02-15 Csir COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS HAVING APPETITE SUPPRESSING ACTIVITY
GB2324726A (en) * 1997-05-01 1998-11-04 Merck & Co Inc Combination Therapy for the Treatment of Osteoporosis
UA64751C2 (en) 1997-06-25 2004-03-15 Пфайзер Продактс Інк. Treatment of insulin tolerance using substances increasing growth hormone secretion
JP3514774B2 (en) 1997-06-25 2004-03-31 ファイザー・インク Dipeptide derivatives as growth hormone secretagogues
UA53716C2 (en) 1997-06-25 2003-02-17 Пфайзер Продактс Інк. A substituted dipeptide tartaric salt as an agent stimulating the growth hormone secretion
US6329342B1 (en) 1997-08-19 2001-12-11 Eli Lilly And Company Treatment of congestive heart failure with growth hormone secretagogues
ZA987383B (en) * 1997-08-19 2000-02-17 Lilly Co Eli Treatment of congestive heart failure with growth hormone secretagogues.
US6893877B2 (en) * 1998-01-12 2005-05-17 Massachusetts Institute Of Technology Methods for screening substances in a microwell array
ATE470671T1 (en) 1998-01-16 2010-06-15 Helsinn Therapeutics Us Inc COMPOUNDS HAVING GROWTH HORMONE RELEASING PROPERTIES
US6657063B1 (en) * 1998-04-30 2003-12-02 Pfizer Inc. Combinations of β3 agonists and growth hormone secretagogues
HRP20000825A2 (en) * 1998-06-03 2001-12-31 Pfizer Prod Inc 2-aminopyridines containing fused ring substituents as nitric oxide synthase inhibitors
AR018869A1 (en) * 1998-06-16 2001-12-12 Pfizer Prod Inc PHARMACEUTICAL COMPOSITION, ITS USE FOR THE PREPARATION OF MEDICINES AND CASE THAT CONTAINS IT
PA8471201A1 (en) * 1998-06-16 2000-09-29 Pfizer Prod Inc THERAPEUTIC COMBINATIONS INCLUDING A SELECTIVE STROGEN RECEPTOR AND PARATHYROID HORMONE MODULATOR
HUP0102395A2 (en) * 1998-06-16 2001-11-28 Pfizer Products Inc. Medicines containing a combination of selective estrogen receptor modulators and growth hormone secretagogues (GHS) for the treatment of muscular and skeletal weakness
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US6358951B1 (en) 1998-08-21 2002-03-19 Pfizer Inc. Growth hormone secretagogues
AU6133299A (en) * 1998-09-02 2000-03-21 Merck & Co., Inc. Enhancement of return to independent living status with a growth hormone secretagogue
ES2187195T3 (en) 1998-09-11 2003-05-16 Gerhard Dr Schmidmaier BIOLOGICALLY ACTIVE IMPLANTS.
US6337332B1 (en) 1998-09-17 2002-01-08 Pfizer Inc. Neuropeptide Y receptor antagonists
US6380184B1 (en) 1998-10-28 2002-04-30 Bristol-Myers Squibb Co. Benzoazepines and analogs thereof useful as growth hormone secretagogues
US6194578B1 (en) * 1998-11-20 2001-02-27 Pfizer Inc. Dipeptide derivatives
US6297380B1 (en) * 1998-11-23 2001-10-02 Pfizer Inc. Process and intermediates for growth hormone secretagogues
EP1486498A1 (en) * 1998-11-23 2004-12-15 Pfizer Products Inc. Process and intermediates for growth hormone secretagogues
WO2000048623A1 (en) 1999-02-18 2000-08-24 Kaken Pharmaceutical Co., Ltd. Novel amide derivatives as growth hormone secretagogues
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
US6541634B2 (en) * 1999-02-26 2003-04-01 Pfizer Inc. Process for preparing growth hormone secretagogues
US6518292B1 (en) 1999-03-12 2003-02-11 Bristol-Myers Squibb Co. Heterocyclic aromatic compounds usefuls as growth hormone secretagogues
US6525203B1 (en) 1999-03-12 2003-02-25 Bristol-Myers Squibb Company Heterocyclic aromatic compounds useful as growth hormone secretagogues
EP1204321B1 (en) * 1999-07-26 2005-11-09 Baylor College Of Medicine Super-active porcine growth hormone releasing hormone analog
GB2396815B (en) 1999-10-27 2004-09-08 Phytopharm Plc A composition comprising a pregnenone derivative and an NSAID
EP1113007A1 (en) * 1999-12-24 2001-07-04 Pfizer Inc. Tetrahydroisoquinoline compounds as estrogen agonists/antagonists
US6849597B2 (en) 1999-12-28 2005-02-01 Kaken Pharmaceutical Co., Ltd. Neuroprotective drug
US20020151040A1 (en) 2000-02-18 2002-10-17 Matthew O' Keefe Apparatus and methods for parallel processing of microvolume liquid reactions
WO2001061054A2 (en) * 2000-02-18 2001-08-23 Board Of Trustees Of The Leland Stanford Junior University Apparatus and methods for parallel processing of micro-volume liquid reactions
EP1132388A3 (en) * 2000-03-09 2004-03-03 Pfizer Products Inc. Hexahydropyrazolo[4,3-c]pyridine metabolites
EP1149583A3 (en) * 2000-04-13 2001-11-14 Pfizer Products Inc. Combinations of corticotropin releasing factor antagonists and growth hormone secretagogues
JP2004507456A (en) 2000-05-11 2004-03-11 ブリストル−マイヤーズ　スクイブ　カンパニー Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
DOP2001000154A (en) * 2000-05-25 2002-05-15 Pfizer Prod Inc COMBINATION OF SECRETAGOGOS OF HORMONE OF THE GROWTH AND ANTIDEPRESSANTS
AU2001264977B2 (en) 2000-05-30 2005-04-14 Merck & Co., Inc. Melanocortin receptor agonists
ATE446758T1 (en) 2000-05-31 2009-11-15 Pfizer Prod Inc USE OF GROWTH HORMONE SECRETAGOGENES TO PROMOTE DIGESTIVE MOTILITY
IL143690A0 (en) * 2000-06-19 2002-04-21 Pfizer Prod Inc The use of growth hormone secretagogues to treat systemic lupus erythematosus and inflammatory bowel disease
EP1181933A3 (en) * 2000-06-29 2002-04-10 Pfizer Products Inc. Use of growth hormone secretagogues for stimulating or increasing appetite
IL143942A0 (en) * 2000-06-29 2002-04-21 Pfizer Prod Inc Use of growth hormone secretagogues for treatment of physical performance decline
GB2363985B (en) 2000-06-30 2004-09-29 Phytopharm Plc Extracts,compounds & pharmaceutical compositions having anti-diabetic activity and their use
IL144468A0 (en) * 2000-07-27 2002-05-23 Pfizer Prod Inc Use of growth hormone secretagogues for improvement of functional health status
MXPA03001771A (en) * 2000-08-30 2003-06-04 Pfizer Prod Inc SUSTAINED RELEASE FORMULATIONS FOR GROWTH HORMONE SECRETAGOGS.
IL145106A0 (en) * 2000-08-30 2002-06-30 Pfizer Prod Inc Intermittent administration of a geowth hormone secretagogue
IL145540A0 (en) * 2000-09-28 2002-06-30 Pfizer Prod Inc Use of growth hormone secretagogues in conjunction with physical exercise
US20100261159A1 (en) 2000-10-10 2010-10-14 Robert Hess Apparatus for assay, synthesis and storage, and methods of manufacture, use, and manipulation thereof
AU2001296809A1 (en) * 2000-10-10 2002-04-22 Biotrove, Inc. Apparatus for assay, synthesis and storage, and methods of manufacture, use, and manipulation thereof
CA2372450A1 (en) * 2001-05-10 2001-09-19 Pharmaceutical Partners Of Canada Inc. Liquid injectable formulation of disodium pamidronate
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
WO2003041641A2 (en) 2001-11-09 2003-05-22 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs as modulators of chemokine receptor activity
US20030199514A1 (en) * 2002-03-27 2003-10-23 Fryburg David A. Methods for improving efficacy of treatment with growth hormone secretagogues
WO2003087069A2 (en) * 2002-04-09 2003-10-23 Eli Lilly And Company Dipeptidic growth hormone secretagogues
US7105526B2 (en) 2002-06-28 2006-09-12 Banyu Pharmaceuticals Co., Ltd. Benzimidazole derivatives
US8277753B2 (en) 2002-08-23 2012-10-02 Life Technologies Corporation Microfluidic transfer pin
US20060128615A1 (en) * 2002-09-18 2006-06-15 Pierrette Gaudreau Ghrh analogues
US20060094108A1 (en) * 2002-12-20 2006-05-04 Karl Yoder Thermal cycler for microfluidic array assays
WO2004074818A2 (en) * 2002-12-20 2004-09-02 Biotrove, Inc. Assay apparatus and method using microfluidic arrays
US7772188B2 (en) 2003-01-28 2010-08-10 Ironwood Pharmaceuticals, Inc. Methods and compositions for the treatment of gastrointestinal disorders
WO2004108120A1 (en) * 2003-06-11 2004-12-16 Pfizer Products Inc. Use of growth hormone secretagogues for treatment of fibromyalgia
US7476653B2 (en) 2003-06-18 2009-01-13 Tranzyme Pharma, Inc. Macrocyclic modulators of the ghrelin receptor
WO2005027913A1 (en) * 2003-09-19 2005-03-31 Pfizer Products Inc. Pharmaceutical compositions and methods comprising combinations of 2-alkylidene-19-nor-vitamin d derivatives and a growth hormone secretagogue
JP4765627B2 (en) 2003-09-22 2011-09-07 Ｍｓｄ株式会社 Novel piperidine derivatives
US7129561B2 (en) * 2003-11-19 2006-10-31 International Business Machines Corporation Tri-metal and dual-metal stacked inductors
CA2559171A1 (en) 2004-03-12 2005-09-29 Biotrove, Inc. Nanoliter array loading
WO2005097788A2 (en) * 2004-04-02 2005-10-20 Elixir Pharmaceuticals, Inc. Sulfonamides and uses thereof
US20080125403A1 (en) 2004-04-02 2008-05-29 Merck & Co., Inc. Method of Treating Men with Metabolic and Anthropometric Disorders
WO2005097174A2 (en) * 2004-04-07 2005-10-20 Gastrotech Pharma A/S Uses of a combination of ghrelin and somatotropin for the treatment of cachexia
AU2005266448A1 (en) 2004-07-28 2006-02-02 Glaxo Group Limited Piperazine derivatives useful for the treatment of gastrointestinal disorders
US20060105453A1 (en) 2004-09-09 2006-05-18 Brenan Colin J Coating process for microfluidic sample arrays
US12070731B2 (en) 2004-08-04 2024-08-27 Life Technologies Corporation Methods and systems for aligning dispensing arrays with microfluidic sample arrays
AU2005272598B2 (en) * 2004-08-12 2011-11-17 Helsinn Therapeutics (U.S.), Inc. Method of stimulating the motility of the gastrointestinal system using growth hormone secretagogues
JP2008510706A (en) 2004-08-18 2008-04-10 エリクシアー ファーマシューティカルズ， インコーポレイテッド Growth hormone secretagogue
US8138206B2 (en) 2005-05-30 2012-03-20 Msd. K.K. Piperidine derivative
CA2618112A1 (en) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Pyridone compound
WO2007024004A1 (en) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Phenylpyridone derivative
AU2006288153A1 (en) 2005-09-07 2007-03-15 Msd K.K. Bicyclic aromatic substituted pyridone derivative
KR20080048502A (en) 2005-09-29 2008-06-02 머크 앤드 캄파니 인코포레이티드 Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
RU2008119687A (en) 2005-10-21 2009-11-27 Новартис АГ (CH) COMBINATIONS OF ORGANIC COMPOUNDS
CA2627139A1 (en) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Novel benzoxathiin derivative
ES2381205T3 (en) 2005-11-10 2012-05-24 Msd K.K. Aza-substituted spiro derivative
JPWO2007058359A1 (en) * 2005-11-21 2009-05-07 国立大学法人 宮崎大学 Skin repair promoting therapeutic agent containing ghrelin and derivatives thereof or substance acting on GHS-R1a as active ingredient
US8273702B2 (en) * 2006-02-17 2012-09-25 Wake Forest University Health Sciences Wound healing compositions containing keratin biomaterials
CU23558A1 (en) 2006-02-28 2010-07-20 Ct Ingenieria Genetica Biotech COMPOUNDS ANALOG TO THE PEPTIDIC SECRETAGOGS OF THE GROWTH HORMONE
CU23592A1 (en) * 2006-02-28 2010-11-11 Ct Ingenieria Genetica Biotech METHOD TO PREVENT AND ELIMINATE FIBROSIS AND OTHER FORMS OF PATHOLOGICAL DEPOSIT IN THE FABRICS APPLYING THE GHRP-6 SECRETAGOGO PEPTIDE
WO2007106385A2 (en) 2006-03-10 2007-09-20 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Use of a ghrelin agonist to improve the catabolic effects of glucocorticoid treatment
AU2007294124A1 (en) * 2006-09-08 2008-03-13 Bayer Schering Pharma Aktiengesellschaft Compounds and methods for 18F labeled agents
US8173629B2 (en) 2006-09-22 2012-05-08 Merck Sharp & Dohme Corp. Method of treatment using fatty acid synthesis inhibitors
WO2008047544A1 (en) 2006-09-28 2008-04-24 Banyu Pharmaceutical Co., Ltd. Diaryl ketimine derivative
US20090035215A1 (en) * 2006-10-02 2009-02-05 Ananth Srinivasan Radiofluorination
US20080114055A1 (en) * 2006-11-10 2008-05-15 Zoltan Laboratories Llc Thioxanthone Compounds to Reverse Weight Loss
CA2677399C (en) 2007-02-09 2016-09-13 Tranzyme Pharma, Inc. Macrocyclic ghrelin receptor modulators and methods of using the same
KR20090119966A (en) * 2007-03-01 2009-11-23 바이엘 쉐링 파마 악티엔게젤샤프트 18f fluoro-benzoyl labelled biological active compounds as diagnostic imaging agents as well as benzotriazol-1-yloxy-benzoyl, 2,5-dioxo-pyrrolidin-1-yloxy)benzoyl and trimethylammonio-benzoyl precursers
ATE518544T1 (en) 2007-03-12 2011-08-15 Zadec Aps ROOT BUSH EXTRACT AGAINST DIABETES
EP2002835A1 (en) 2007-06-04 2008-12-17 GenKyo Tex Pyrazolo pyridine derivatives as NADPH oxidase inhibitors
JP5319518B2 (en) 2007-04-02 2013-10-16 Ｍｓｄ株式会社 Indoledione derivative
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
MX2009013293A (en) 2007-06-04 2010-02-15 Synergy Pharmaceuticals Inc Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders.
EP2168602A4 (en) * 2007-06-12 2014-10-29 Inst Pharm & Toxicology Amms Site-specific pegylated linear salmon calcitonin derivatives
JPWO2009110510A1 (en) 2008-03-06 2011-07-14 Ｍｓｄ株式会社 Alkylaminopyridine derivatives
US20110015198A1 (en) 2008-03-28 2011-01-20 Banyu Pharmaceutical Co., Inc. Diarylmethylamide derivative having melanin-concentrating hormone receptor antagonism
EP2810951B1 (en) 2008-06-04 2017-03-15 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
JPWO2009154132A1 (en) 2008-06-19 2011-12-01 Ｍｓｄ株式会社 Spirodiamine-diarylketoxime derivatives
CA2730603C (en) 2008-07-16 2019-09-24 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
JPWO2010013595A1 (en) 2008-07-30 2012-01-12 Ｍｓｄ株式会社 5-membered or 5-membered or 6-membered condensed cycloalkylamine derivative
EP2166009A1 (en) 2008-09-23 2010-03-24 Genkyo Tex Sa Pyrazolo pyridine derivatives as nadph oxidase inhibitors
EP2165707A1 (en) 2008-09-23 2010-03-24 Genkyo Tex Sa Pyrazolo pyridine derivatives as NADPH oxidase inhibitors
EP2166010A1 (en) 2008-09-23 2010-03-24 Genkyo Tex Sa Pyrazolo pyridine derivatives as NADPH oxidase inhibitors
EP2348857B1 (en) 2008-10-22 2016-02-24 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
EP2350010B1 (en) 2008-10-30 2014-03-26 Merck Sharp & Dohme Corp. Isonicotinamide orexin receptor antagonists
JP5557845B2 (en) 2008-10-31 2014-07-23 メルク・シャープ・アンド・ドーム・コーポレーション Novel cyclic benzimidazole derivatives useful as antidiabetic agents
EP2305679A1 (en) 2009-09-28 2011-04-06 GenKyoTex SA Pyrazoline dione derivatives as nadph oxidase inhibitors
EP2361911A1 (en) * 2010-02-18 2011-08-31 GenKyoTex SA Pyrazolo piperidine derivatives as NADPH oxidase inhibitors
EP2361912A1 (en) 2010-02-18 2011-08-31 GenKyoTex SA Pyrazolo piperidine derivatives as NADPH oxidase inhibitors
AU2011218830B2 (en) 2010-02-25 2014-07-24 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
RU2012141061A (en) * 2010-02-26 2014-04-10 Раквалиа Фарма Инк. GREELIN RECEPTOR AGONIST FOR TREATMENT OF CACHEXIA
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
MX348131B (en) 2011-02-25 2017-05-26 Merck Sharp & Dohme Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents.
US8361964B2 (en) * 2011-04-21 2013-01-29 Theratechnologies Inc. Growth hormone releasing factor (GRF) analogs and uses thereof
AR088352A1 (en) 2011-10-19 2014-05-28 Merck Sharp & Dohme ANTAGONISTS OF THE RECEIVER OF 2-PIRIDILOXI-4-NITRILE OREXINE
EP2854810A4 (en) * 2012-05-25 2016-04-06 Raqualia Pharma Inc Ghrelin receptor agonists for the treatment of achlorhydria
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
CN111419845A (en) 2012-09-27 2020-07-17 阿莱塔纳治疗学股份有限公司 Compositions and methods employing compounds for controlling anorexia
KR102499918B1 (en) 2012-10-24 2023-02-14 다이이찌 산쿄 가부시키가이샤 Therapeutic agent for amyotrophic lateral sclerosis
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
JP2016514670A (en) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド Guanylate cyclase receptor agonists in combination with other drugs
JP2016514671A (en) 2013-03-15 2016-05-23 シナジー ファーマシューティカルズ インコーポレイテッド Guanylate cyclase agonists and uses thereof
BR112015029586B1 (en) * 2013-05-28 2022-05-03 Raqualia Pharma Inc polymorphic forms
EA201592263A1 (en) 2013-06-05 2016-05-31 Синерджи Фармасьютикалз, Инк. ULTRASCULAR AGONISTS OF GUANYLACYCLASE C, METHOD OF THEIR RECEIVING AND USING
KR102051433B1 (en) * 2013-08-27 2020-01-08 (주)네오팜 A composition and external application for acceleration of muscle differentiation and improving of muscle mass
US9119832B2 (en) 2014-02-05 2015-09-01 The Regents Of The University Of California Methods of treating mild brain injury
RU2695649C2 (en) * 2014-08-05 2019-07-25 Раквалиа Фарма Инк. Serine derivatives as ghrelin receptor agonists
EP3186242B1 (en) 2014-08-29 2021-10-06 Tes Pharma S.r.l. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
EP3212648A1 (en) * 2014-10-31 2017-09-06 RaQualia Pharma Inc. Tetrahydropyrazolopyridine derivatives as ghrelin receptor agonists
WO2017075535A1 (en) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Methods of treating neurodegenerative conditions
AU2017342083A1 (en) 2016-10-14 2019-04-11 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
EP3479843A1 (en) 2017-11-01 2019-05-08 GenKyoTex Suisse SA Use of nox inhibitors for treatment of cancer
AR117122A1 (en) 2018-11-20 2021-07-14 Tes Pharma S R L A-AMINO-b-CARBOXIMUCONIC ACID INHIBITORS SEMIALDEHYDE DECARBOXYLASE
CN109320515A (en) * 2018-11-22 2019-02-12 常州大学 A kind of asymmetric synthesis method of Capromorelin chiral intermediate
TW202045476A (en) 2019-02-13 2020-12-16 美商默沙東藥廠 5-alkyl pyrrolidine orexin receptor agonists
CN120265641A (en) * 2023-04-21 2025-07-04 长春金赛药业有限责任公司 GHSR 1a agonist, pharmaceutical composition, preparation method and application thereof
CN119285632A (en) * 2024-10-09 2025-01-10 威海中腾医药科技有限公司 A method for preparing a caprelin intermediate based on yeast alcohol dehydrogenase-catalyzed oxidation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995013069A1 (en) * 1993-11-09 1995-05-18 Merck & Co., Inc. Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone
EP0662481A1 (en) * 1992-12-11 1995-07-12 Merck & Co. Inc. Spiro piperidines and homologs promote release of growth hormone

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE400557B (en) * 1971-05-11 1978-04-03 Sandoz Ag PROCEDURE FOR THE PREPARATION OF NEW CONDENSED PYRIDAZINES
DE2221808C2 (en) * 1972-05-04 1985-06-20 Sandoz-Patent-GmbH, 7850 Lörrach Hydrazinopyridazine derivatives, their acid addition salts, processes for their preparation and medicines
JP3670690B2 (en) * 1993-10-04 2005-07-13 トーアエイヨー株式会社 3-pyridazinone derivative, process for producing the same, and cardiovascular agent containing the same
EP0813414A4 (en) * 1993-10-19 1999-07-21 Merck & Co Inc COMBINATION OF GROWTH HORMONE BIPHOSPHONATES AND SECRETAGOGUES
US5935924A (en) * 1994-04-15 1999-08-10 Genentech, Inc. Treatment of congestive heart failure
US5610134A (en) * 1994-04-15 1997-03-11 Genentech, Inc. Treatment of congestive heart failure
US5767118A (en) * 1994-10-26 1998-06-16 Merck & Co., Inc. 4-Heterocyclic peperidines promote release of growth hormone
US5798337A (en) * 1994-11-16 1998-08-25 Genentech, Inc. Low molecular weight peptidomimetic growth hormone secretagogues
CZ238197A3 (en) * 1995-01-27 1997-12-17 Novo Nordisk As Growth hormone formation stimulating compounds
AU4534696A (en) * 1995-02-09 1996-08-27 Novo Nordisk A/S Compounds with growth hormone releasing properties
WO1996024580A1 (en) * 1995-02-09 1996-08-15 Novo Nordisk A/S Compounds with growth hormone releasing properties
AU6772996A (en) * 1995-08-21 1997-03-12 Eli Lilly And Company 2-acylaminopropanamides as growth hormone secretagogues
WO1997007117A1 (en) * 1995-08-21 1997-02-27 Eli Lilly And Company 2-acylaminopropanamines as growth hormone secretagogues
TW432073B (en) 1995-12-28 2001-05-01 Pfizer Pyrazolopyridine compounds
US6020358A (en) * 1998-10-30 2000-02-01 Celgene Corporation Substituted phenethylsulfones and method of reducing TNFα levels

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0662481A1 (en) * 1992-12-11 1995-07-12 Merck & Co. Inc. Spiro piperidines and homologs promote release of growth hormone
WO1995013069A1 (en) * 1993-11-09 1995-05-18 Merck & Co., Inc. Piperidines, pyrrolidines and hexahydro-1h-azepines promote release of growth hormone

Also Published As

Publication number Publication date
BG102533A (en) 1999-09-30
US20020049196A1 (en) 2002-04-25
US6278000B1 (en) 2001-08-21
TR199801233T2 (en) 1998-10-21
MX9805157A (en) 1998-10-31
CA2241725C (en) 2002-06-18
US6124264A (en) 2000-09-26
US6107306A (en) 2000-08-22
IL138910A0 (en) 2001-11-25
CO4480108A1 (en) 1997-07-09
DE69637063T2 (en) 2008-02-07
PL327634A1 (en) 1998-12-21
AR004367A1 (en) 1998-11-04
MA26415A1 (en) 2004-12-20
IL138909A0 (en) 2001-11-25
ES2285715T3 (en) 2007-11-16
CZ293423B6 (en) 2004-04-14
HUP9901246A3 (en) 1999-11-29
SA97170581B1 (en) 2006-03-15
SI0869968T1 (en) 2007-08-31
US6313140B1 (en) 2001-11-06
YU70296A (en) 1999-11-22
AU716934B2 (en) 2000-03-09
BR9612465A (en) 1999-07-13
CZ199598A3 (en) 1999-05-12
US6306875B1 (en) 2001-10-23
NZ322172A (en) 2000-08-25
CN1206422A (en) 1999-01-27
DK0869968T3 (en) 2007-09-10
ATE361314T1 (en) 2007-05-15
PE30398A1 (en) 1998-07-21
RS49926B (en) 2008-09-29
IL138911A (en) 2007-07-24
US6110932A (en) 2000-08-29
JPH11501945A (en) 1999-02-16
KR19990076846A (en) 1999-10-25
HN1996000085A (en) 1997-06-18
OA10702A (en) 2001-05-07
BG64055B1 (en) 2003-11-28
BR9612465B1 (en) 2010-08-10
TW432073B (en) 2001-05-01
MY135727A (en) 2008-06-30
JP2001213800A (en) 2001-08-07
NO325135B1 (en) 2008-02-04
NO982991D0 (en) 1998-06-26
AP9600881A0 (en) 1997-01-31
SK285678B6 (en) 2007-06-07
HRP960618B1 (en) 2007-12-31
WO1997024369A1 (en) 1997-07-10
IL124449A (en) 2004-06-01
CN1113895C (en) 2003-07-09
US6482825B2 (en) 2002-11-19
EP0869968B1 (en) 2007-05-02
IL138911A0 (en) 2001-11-25
JP3511382B2 (en) 2004-03-29
GT199600100A (en) 1998-06-12
AP756A (en) 1999-08-06
SK87498A3 (en) 1999-08-06
EP0869968A1 (en) 1998-10-14
DE69637063D1 (en) 2007-06-14
HRP960618A2 (en) 1998-04-30
ZA9610858B (en) 1998-06-23
NO982991L (en) 1998-08-26
PT869968E (en) 2007-07-11
IL124449A0 (en) 1998-12-06
HUP9901246A2 (en) 1999-08-30
KR100320167B1 (en) 2003-11-14
TNSN96172A1 (en) 2005-03-15
CA2241725A1 (en) 1997-07-10
AP9901555A0 (en) 1999-06-30
UA66754C2 (en) 2004-06-15
PL186916B1 (en) 2004-03-31
AU7585096A (en) 1997-07-28
IS4758A (en) 1998-05-26
AR052506A2 (en) 2007-03-21
EG24195A (en) 2008-10-14

Similar Documents

Publication Publication Date Title
AP756A (en) Dipeptide compounds which are growth hormone secretagoques.
JP5000848B2 (en) Ghrelin-containing pharmaceutical composition
JP2557779B2 (en) Two-component drug for osteoporosis
US8076281B2 (en) Use of a ghrelin agonist to improve the catabolic effects of glucocorticoid treatment
US20230120030A1 (en) Long-Acting Adrenomedullin Derivatives
ES2383796T3 (en) Pharmaceutical compositions comprising non-acylated ghrelin for use in the treatment of insulin resistance
KR20240033207A (en) Nk-3 receptor antagonists for therapeutic or cosmetic treatment of excess body fat
ES2282436T3 (en) ORAL ADMINISTRATION OF PARTIROID HORMONE AND CALCITONINE.
US20020002137A1 (en) Combination of growth hormone secretagogues and antidepressants
KR101228229B1 (en) Gh secretagogues and uses thereof
KR20090019896A (en) Somatostatin-like combination with dopamine or growth hormone receptor antagonist
US20070270341A1 (en) Parathyroid hormone analogues and methods of use
AU6133299A (en) Enhancement of return to independent living status with a growth hormone secretagogue
US20020160961A1 (en) Compositions for the treatment of the catabolic state of prolonged critical illness
Reginster Calcitonins: newer routes of delivery
CA2335112A1 (en) Therapeutic combinations for musculoskeletal frailty
EP1716887B1 (en) Treatment of inclusion body myositis
AU781842B2 (en) Use of growth hormone (hGH) for the treatment of sexual functional disturbances
US8053409B2 (en) Agent for prophylaxis of reflex sympathetic dystrophy after cerebral apoplexy
NAGAI et al. Changes in blood pressure after the first dose of calcitonin (elcatonin)
Ehlers Recombinant human GHRH (1–44) NH2: clinical utility and therapeutic development program
WO2024209050A1 (en) Gip activity modulators and orthostatic intolerance
Nishizaki et al. First Clinical Demonstration of Sustained IGF-1 Elevation via Oral SSTR5 Antagonism: A Phase 1 Trial of SCO-240
JP2006143603A (en) Pharmaceutical compound agent for treating osteopathy
Kinter et al. Toxicity of desmopressin and related peptides