AP756A - Dipeptide compounds which are growth hormone secretagoques. - Google Patents
Dipeptide compounds which are growth hormone secretagoques. Download PDFInfo
- Publication number
- AP756A AP756A APAP/P/1996/000881A AP9600881A AP756A AP 756 A AP756 A AP 756A AP 9600881 A AP9600881 A AP 9600881A AP 756 A AP756 A AP 756A
- Authority
- AP
- ARIPO
- Prior art keywords
- compounds
- group
- alkyl
- growth hormone
- phenyl
- Prior art date
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
Abstract
This invention is directed to compounds of the formula and the pharmaceulically-acceptable salts thereof, where the subslituents are as defined in the Specification, which are growth hormone secretogogues and which increase the level of endogenous growth hormone. The compounds of this Invention are useful for (the treatment and prevention of osleoporosis. congestive heart failure, frailly associated with aging, obesity; accelerating bone fracture repair, attenuating .protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeoslasis or renal homeostasis. The compounds of (he present invention are also useful in treating osleoporosis when used in combination with: a bisphosphonale compound such as alendronale; estrogen. premarin, and optionally progesterone; an estrogen agonist or antagonist; or cslcilonin, and pharmaceutical compositions useful therefor. Further, (he presenl invention is directed (o pharmaceutical compositions useful for increasing (he 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 growlh hormone secretagogue selected from GHRP-6. Hexarelin. GHRP-1. growth hormone releasing factor (GRF), IGF-1, IGF-2 or B-HT920. The invention is also directed lo intermediates useful in the preparation of compounds of formula I.
Description
HETEROCYCLIC COMPOUNDS
This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis.
Background of the Invention
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 Jonger 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 c 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.
\N0 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
I the same time; Y is oxygen or sulfur; R1 is hydrogen, -CN, -(CH2)qN(X6)C(O)X6, -(CH2)qN(X6)C(0)(CH2)t-A1, -(CH2)qN(X6)S02(CH2)t-A1,-(CH2)qN(X6)SO2X6,-(CH2)qN(X6)C(0)N(X6)(CH2),-A1, -(CH2)qN(X6)C(O)N(X6)(X6),-(CH2)qC(O)N(X6)(X6), -(CH2)qC(O)N(X6)(CH2)rA1, -(CH2)qC(0)0X6, -(CH2)qC(O)O(CH2)t-A1, -(CH2)qOX6, -(CH2)qOC(O)X6, -(CH2)qOC(O)(CH2)t-A1, -(CH2)qOC(O)N(X6)(CH2)t-A1, -(CH2)qOC(O)N(X6)(X6), -(CH2)qC(O)X6, -(CH2)qC(O)(CH2)t-A1, -(CH2)qN(X6)C(O)OX®, -(CH2)qN(X6)SO2N(X6)(X6), -(CH^O)^6 -(CH2)qS(O)m(CH2)t-A1, -(CrC10)alkyl, -(CH2)rA1, -(CH2)q-(C3-C7)cycloalkyl, -(CH2)q-Y1-(CrC6)alkyl, -(CH2)q-Y1-(CH2)t-A1 or -(CH2)q-Y1-(CH2)t-(C3-C7)cycloalkyl; where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (CrC4)alkyl, hydroxyl, (Ci-C4)alkoxy, carboxyl, -CONH2, -S(O)m(Ci-C6)alkyl, -CO2(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-, -CO, -N(Xe)C(O)-, -C(O)NX6-, -0(0)0-, -OC(0)N(X6)- or -0C(0)-;
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, (C1-C4)alkoxy, carboxyl, -CONH2, -S(O)m(Ci-C6)alkyl, -CO2(Ci-C4)alkyl ester, 1 H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (Cr C4)aikyl; R2 is hydrogen, (Ci-C8)alkyl, -(C0-C3)alkyl-(C3-C8)cycloalkyl, -{CT-CJalkyl-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(X5)(Xe), -ΝίΧθχΧ6), -S(O)m(CrC6)alkyl, -C(O)A1, -C(O)(X6), CF3, CN or 1, 2 or 3 halogen; R3 is A1, (CrCwJalkyl, -(CrC6)alkyl-A1, -(CrC6)alkyl-(C3-C7)cycloalkyl, -(C1-C5)alkyl-X1-(C1-C5)alkyl, -(CrC5)alkyl-X1-(Co-C5)alkyl-A1 or -(Ci-CsJalkyl-X^C-i-CsJalkyl-CCTj-CyJcycloalkyl; 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-O6)alkyl or (C3-C7)cycloalkyl, 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 8-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 (C-|-C6)alkyl; the optionally substituted (C-|-C6)a,ky· in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, -S(O)m(CrC6)alkyl, -C(O)OX2, (C3-C7)cycloalkyl, -N(X2)(X2) and -C(G)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 Xs 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 X5 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, O 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 (CrCgJalkyl; where the optionally substituted (CrC6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, -CiOJO-iCvCeJalkyl, -S(O)m(Ci-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 -O-C(O)(Cr C10)alkyl or 1 to 3 (Ci-C6)alkoxy; or R7 and R8 can be taken together to form -(CH2)r-L-(CH2)r-; where L is C(X2)(X2), S(O)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, (C-|-C6)alkyl, nitro, cyano, benzyl, -S(O)m(Ci-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, -N(X6)(X6), -N(X6)C(O)(X6), -SO2N(Xs)(X6), -N(X6)SO2-phenyl, -N(X6)SO2X6, -C0NX11X12, -SO2NX11X12, -NX6SO2X12, -NX6CONX11X12, -NX6SO2NX11X12, -NX6C(O)X12, imidazolyl, thiazolyl or tetrazoiyl, 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 (C1-C6)alkyl; the optionally substituted (CrC6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (Cr C6)alkoxycarbonyl, -SfO^fCrCJalkyl 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (C1-C10)alkanoyloxy or 1 to 3 (CrC6)alkoxy; X12 is hydrogen, (CrC6)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, 0CH3, OCF3 and CF3; or X11 and X12 are taken together to form -(CH2)r-L1-(CH2)r-; L1 is C(X2)(X2), O, 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 (Cr C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (CvC^alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with -SCO^C^-C^alkyl, -C(O)OX3, 1 to 5 halogens or 1 to 3 OX3; X3 for each occurrence is independently hydrogen or (CrCgJalkyl; 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-,-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted by 1 or 2 (C^C^alkyl, hydroxyl, (CrC4) alkoxy, carboxyl, CONH2, -S(O)m(Ci-C6)alkyl> carboxylate (Cp C4)alkyl ester, or 1 H-tetrazol-5-yl; or when there are two X6 groups on one atom and both X6 are independently (Cr C6)alkyl, the two (C-,-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 (CrC^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 (CrC3)alkyl; R8 is hydrogen or (Ci-C3)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 (CrC6)alkyl;
where the optionally substituted (CrC^alkyl is optionally substituted with OX2, imidazolyl, phenyl, indolyl, 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 (Ci-C5)alkylene 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 X53 are each independently hydrogen, (C-,-C3)alkyl or hydroxy(C-|-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-, phenyHC-i-C^alkyl-, 2-pyridyl-(C1-C4)alkyl-, 3-pyridyl-(CrC4)alkyl-, 4-pyridyl-(Ci-C4)alkyl-, phenyl-CH2-S-CH2-, thienyl-(CrC4)alkyl-, phenyl-(C0-C3)aIkyl-O-CH2-, phenyl-CH2-O-phenyl-CH2-, and 3-benzothienyl-CH2-; where the aryl portion(s) of the groups defined for R3 are optionally l substituted with one to three 'substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH3, OCH3i OCF3i 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 (C-,-Ci0)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 (C1-C4)alkyl, hydroxyl, (Ci-C4)alkoxy, carboxyl, CONH2, -S(0)m(CrC6)alkyl, -CO^Ct-C4)alkyl ester, 1 H-tetrazol-5-yl or 1 to 3 fluoro; Y is O; R2 is hydrogen, -(Co-C3)alkyl-(C3-C8)cycloalkyl, phenyl or (Ci-C8)alkyl where the (Ci-C8)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 pyrimidyi 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. A group of compounds, which is preferred among the “G Group” of compounds, designated the “G1 Group”, contains those compounds of the “G Group”, and have the formula
the racemic-diastereomeric mixtures and optical isomers of said compounds wherein R1 is -CH2-phenyl, R2 is methyl and R3 is -(CH2)3-phenyl; R1 is -CH2-phenyl, R2 is methyl and R3 is 3-indolyl-CH2-; R1 is -CH2-phenyl, R2 is ethyl and R3 is 3-indolyl-CH2-; R1 is -CH2-4-fluoro-phenyl, R2 is methyl and R3 is 3-indolyl-CH2-; R1 is -CH2-phenyl, R2 is methyl and R3 is -CH2-O-CH2-phenyl; R1 is -CH2-phenyl, R2 is ethyl and R3 is -CH2-O-CH2-phenyl; R1 is -CH2-phenyl, R2 is -CH2-CF3 and R3 is -CH2-O-CH2-phenyl; R1 is -CH2-4-fiuoro-phenyl, R2 is methyl and R3 is -CH2-O-CH2-phenyl; R1 is -CH2-phenyl, R2 is t-butyl and R3 is -CH2-O-CH2-phenyl; or R1 is -CH2-phenyl, R2 is methyl and R3 is -CH2-O-CH2-3,4-di-fluoro-phenyl.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(3,4-difluoro-benzyl-oxymethyl)-2-oxo-ethyl]-2-methyl-propionamide is preferred among the “G1 Group” of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture. A group of compounds, which is preferred among the “G Group" of compounds, designated the “H Group”, contains those compounds of the “G Group”, having the formula I as shown hereinabove, wherein R1 is -CH2-phenyl and R3 is phenyl-(CH2)3-.
The diastereomeric mixture of 2-amino-N-[1-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carbonyI)-4-phenyl-(R)-butyl]-isobutyramide is preferred among the “H Group’ of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
A group of compounds, which is preferred among the “G Group” of compounds, designated the “I Group”, contains those compounds of the “G Group” wherein R1 is -CH2-phenyl or -CH2-4-fluoro-phenyl and R3 is 3-indolyl-CH2-.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyi-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide is preferred among the “I Group” of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide is also preferred among the “I Group" of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-[2-[3a-(R,S)-(4-fluoro-benzyl)-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl]-1-(R)-(1H-indol-3-ylmethyl)-2-oxo-ethyl]-isobutyramide is also preferred among the “I Group” of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture. A group of compounds which is preferred among the “G Group” of compounds, designated the “J Group”, contains those compounds of the “G Group” wherein R1 is -CH2-phenyl or -CH2-4-fIuoro-phenyl and R3 is phenyl-CH2-O-CH2-.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide is preferred among the “J Group” of compounds, the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture, the 3a-(R) isomer is preferred over the 3a-(S) isomer, and the L-tartaric acid salt of the 3a-(R) isomer is a preferred salt.
The diastereomeric mixture of 2-amino-N-[2-(3a-(R,S)-benzyl-2-ethyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide is also preferred among the “J Group” of compounds and the separated 3a-(R) and 3a-(S) isomers are preferred of the diastereomeric mixture.
The diastereomeric mixture of 2-amino-N-{2-[3a-(R,S)-benzyl-3-oxo-2-(2,2,2-triflijoro-ethyl)-213,3a14,6,7-hexahydro-pyrazolo[413-c]pyridin-5-yl]-'l-(R)- - benzyloxymethyl-2-oxo-ethyl}-isobutyramide is also preferred among the “J Group”
Claims (1)
- Original document published without claims.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US946995P | 1995-12-28 | 1995-12-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
AP9600881A0 AP9600881A0 (en) | 1997-01-31 |
AP756A true AP756A (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 After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
APAP/P/1999/001555A AP860A (en) | 1995-12-28 | 1999-05-27 | Dipeptide compounds which are growth hormone secretegoques. |
Country Status (43)
Families Citing this family (141)
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 |
KR100891756B1 (en) | 1997-04-15 | 2009-04-07 | 씨에스아이알 | Pharmaceutical compositions having appetite suppressant 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 |
AU7445498A (en) * | 1997-06-25 | 1999-01-04 | Pfizer Inc. | 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 |
ZA987383B (en) * | 1997-08-19 | 2000-02-17 | Lilly Co Eli | Treatment of congestive heart failure with growth hormone secretagogues. |
US6329342B1 (en) | 1997-08-19 | 2001-12-11 | Eli Lilly And Company | 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 |
JP4382279B2 (en) | 1998-01-16 | 2009-12-09 | サファイア セラピューティクス,インコーポレイティド | Compounds with growth hormone releasing properties |
US6657063B1 (en) * | 1998-04-30 | 2003-12-02 | Pfizer Inc. | Combinations of β3 agonists and growth hormone secretagogues |
ES2235475T3 (en) * | 1998-06-03 | 2005-07-01 | Pfizer Products Inc. | 2-AMINOPIRIDINES CONTAINING SUBSTITUTES OF CONDENSED RINGS AS INHIBITORS OF NITRICO SINTASA OXIDE. |
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 |
JP2002518328A (en) * | 1998-06-16 | 2002-06-25 | ファイザー・プロダクツ・インク | Therapeutic combination of (selective) estrogen receptor modulator (SERM) and growth hormone secretagogue (GHS) for treatment of musculoskeletal weakness |
PA8471201A1 (en) * | 1998-06-16 | 2000-09-29 | Pfizer Prod Inc | THERAPEUTIC COMBINATIONS INCLUDING A SELECTIVE STROGEN RECEPTOR AND PARATHYROID HORMONE MODULATOR |
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 |
CA2341649A1 (en) * | 1998-09-02 | 2000-03-09 | Merck & Co., Inc. | Enhancement of return to independent living status with a growth hormone secretagogue |
DK1112095T3 (en) | 1998-09-11 | 2003-03-17 | Michael Dr Raschke | 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 |
SI1004583T1 (en) * | 1998-11-23 | 2004-12-31 | Pfizer Products Inc. | Process and hydantoin intermediates for the synthesis of growth hormone secretagogues |
US6297380B1 (en) | 1998-11-23 | 2001-10-02 | Pfizer Inc. | Process and intermediates for growth hormone secretagogues |
AU759022B2 (en) | 1999-02-18 | 2003-04-03 | 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 |
US6525203B1 (en) | 1999-03-12 | 2003-02-25 | Bristol-Myers Squibb Company | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
US6518292B1 (en) | 1999-03-12 | 2003-02-11 | Bristol-Myers Squibb Co. | Heterocyclic aromatic compounds usefuls 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 |
WO2001047558A1 (en) | 1999-12-28 | 2001-07-05 | Kaken Pharmaceutical Co., Ltd. | Nerve protective drugs |
US20020151040A1 (en) * | 2000-02-18 | 2002-10-17 | Matthew O' Keefe | Apparatus and methods for parallel processing of microvolume liquid reactions |
CA2400644C (en) * | 2000-02-18 | 2009-07-14 | 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 |
AU5959201A (en) | 2000-05-11 | 2001-11-20 | Bristol Myers Squibb Co | 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 |
IL143942A0 (en) * | 2000-06-29 | 2002-04-21 | Pfizer Prod Inc | Use of growth hormone secretagogues for treatment of physical performance decline |
EP1181933A3 (en) * | 2000-06-29 | 2002-04-10 | Pfizer Products Inc. | Use of growth hormone secretagogues for stimulating or increasing appetite |
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 |
IL145106A0 (en) * | 2000-08-30 | 2002-06-30 | Pfizer Prod Inc | Intermittent administration of a geowth hormone secretagogue |
JP2004507502A (en) * | 2000-08-30 | 2004-03-11 | ファイザー・プロダクツ・インク | Sustained release formulation for growth 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 |
EP1330306A2 (en) * | 2000-10-10 | 2003-07-30 | BioTrove, Inc. | Apparatus for assay, synthesis and storage, and methods of manufacture, use, and manipulation thereof |
CA2347330C (en) * | 2001-05-10 | 2002-03-12 | 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 |
US6649606B1 (en) | 2001-11-09 | 2003-11-18 | Bristol-Myers Squibb Co. | 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 |
ES2271557T3 (en) * | 2002-04-09 | 2007-04-16 | Eli Lilly And Company | DIPEPTIDIC SECRETAGOGS OF THE HORMONE OF GROWTH. |
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 |
MXPA05002991A (en) * | 2002-09-18 | 2005-10-05 | Univ Montreal Ct Hospitalier Chum | Ghrh analogues. |
US20060094108A1 (en) * | 2002-12-20 | 2006-05-04 | Karl Yoder | Thermal cycler for microfluidic array assays |
EP1608952B1 (en) * | 2002-12-20 | 2016-08-10 | Life Technologies Corporation | 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 |
WO2005028438A1 (en) | 2003-09-22 | 2005-03-31 | Banyu Pharmaceutical Co., Ltd. | Novel piperidine derivative |
US7129561B2 (en) * | 2003-11-19 | 2006-10-31 | International Business Machines Corporation | Tri-metal and dual-metal stacked inductors |
AU2005222618A1 (en) | 2004-03-12 | 2005-09-29 | Biotrove, Inc. | Nanoliter array loading |
EP2305352A1 (en) | 2004-04-02 | 2011-04-06 | Merck Sharp & Dohme Corp. | 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders |
JP2007531739A (en) * | 2004-04-02 | 2007-11-08 | 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 | Sulfonamides and their use |
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 |
BRPI0513713A (en) | 2004-07-28 | 2008-05-13 | Glaxo Group Ltd | 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 |
ES2388501T3 (en) * | 2004-08-12 | 2012-10-16 | Helsinn Healthcare S.A. | Use of growth hormone secretagogues to stimulate the motility of the gastrointestinal system |
AU2005277389A1 (en) | 2004-08-18 | 2006-03-02 | Elixir Pharmaceuticals, Inc. | Growth-hormone secretagogues |
ES2574014T3 (en) | 2005-05-30 | 2016-06-14 | Msd K.K. | Novel Piperidine Derivative |
EP1916239A4 (en) | 2005-08-10 | 2009-10-21 | Banyu Pharma Co Ltd | Pyridone compound |
EP1921065B1 (en) | 2005-08-24 | 2010-10-20 | Banyu Pharmaceutical Co., Ltd. | Phenylpyridone derivative |
WO2007029847A1 (en) | 2005-09-07 | 2007-03-15 | Banyu Pharmaceutical Co., Ltd. | Bicyclic aromatic substituted pyridone derivative |
EP1940842B1 (en) | 2005-09-29 | 2012-05-30 | Merck Sharp & Dohme Corp. | Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators |
BRPI0617621A2 (en) | 2005-10-21 | 2011-08-02 | Novartis Ag | combination of organic compounds |
AU2006307046A1 (en) | 2005-10-27 | 2007-05-03 | Msd K.K. | Novel benzoxathiin derivative |
MY146564A (en) | 2005-11-10 | 2012-08-30 | Msd Kk | Aza-substituted spiro derivatives |
CA2630006A1 (en) * | 2005-11-21 | 2007-05-24 | Asubio Pharma Co., Ltd. | Skin repair accelerating 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 |
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 |
CU23558A1 (en) | 2006-02-28 | 2010-07-20 | Ct Ingenieria Genetica Biotech | COMPOUNDS ANALOG TO THE PEPTIDIC SECRETAGOGS OF THE GROWTH HORMONE |
EP2012809B1 (en) | 2006-03-10 | 2013-05-22 | Ipsen Pharma | Use of a ghrelin agonist to improve the catabolic effects of glucocorticoid treatment |
CA2858907A1 (en) * | 2006-09-08 | 2008-03-13 | Bayer Schering Pharma Aktiengesellschaft | Compounds and methods for 18f labeled agents |
EP2698157B1 (en) | 2006-09-22 | 2015-05-20 | Merck Sharp & Dohme Corp. | Method of treatment using fatty acid synthesis inhibitors |
WO2008038692A1 (en) | 2006-09-28 | 2008-04-03 | Banyu Pharmaceutical Co., Ltd. | Diaryl ketimine derivative |
WO2008040441A2 (en) * | 2006-10-02 | 2008-04-10 | Bayer Schering Pharma Aktiengesellschaft | Silicon derivatives for pet imaging |
US20080114055A1 (en) * | 2006-11-10 | 2008-05-15 | Zoltan Laboratories Llc | Thioxanthone Compounds to Reverse Weight Loss |
JP2010518090A (en) | 2007-02-09 | 2010-05-27 | トランザイム・ファーマ,インコーポレイテッド | Macrocyclic ghrelin receptor modulators and methods of use thereof |
US20090317326A1 (en) * | 2007-03-01 | 2009-12-24 | Ananth Srinivasan | Radiofluorination methods |
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 |
AU2008233662B2 (en) | 2007-04-02 | 2012-08-23 | Msd K.K. | Indoledione derivative |
US7879802B2 (en) | 2007-06-04 | 2011-02-01 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
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 |
WO2008151512A1 (en) * | 2007-06-12 | 2008-12-18 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Site-specific pegylated linear salmon calcitonin derivatives |
CA2714617A1 (en) | 2008-03-06 | 2009-09-11 | Banyu Pharmaceutical Co., Ltd. | Alkylaminopyridine derivative |
US20110015198A1 (en) | 2008-03-28 | 2011-01-20 | Banyu Pharmaceutical Co., Inc. | Diarylmethylamide derivative having melanin-concentrating hormone receptor antagonism |
EP3239170B1 (en) | 2008-06-04 | 2019-03-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
EP2301936A1 (en) | 2008-06-19 | 2011-03-30 | Banyu Pharmaceutical Co., Ltd. | Spirodiamine-diarylketoxime derivative |
EP3241839B1 (en) | 2008-07-16 | 2019-09-04 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
EP2319841A1 (en) | 2008-07-30 | 2011-05-11 | Msd K.K. | (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative |
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 |
EP2166009A1 (en) | 2008-09-23 | 2010-03-24 | Genkyo Tex Sa | Pyrazolo pyridine derivatives as nadph oxidase inhibitors |
CA2741125A1 (en) | 2008-10-22 | 2010-04-29 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
CA2741644C (en) | 2008-10-30 | 2013-05-07 | Merck Sharp & Dohme Corp. | Isonicotinamide orexin receptor antagonists |
WO2010051206A1 (en) | 2008-10-31 | 2010-05-06 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic 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 |
US8895596B2 (en) | 2010-02-25 | 2014-11-25 | Merck Sharp & Dohme Corp | Cyclic benzimidazole derivatives useful as anti-diabetic agents |
EP2540721B1 (en) * | 2010-02-26 | 2016-12-14 | RaQualia Pharma Inc. | Ghrelin 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 |
EP2677869B1 (en) | 2011-02-25 | 2017-11-08 | Merck Sharp & Dohme Corp. | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents |
WO2012142706A1 (en) * | 2011-04-21 | 2012-10-26 | 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 |
TW201400506A (en) * | 2012-05-25 | 2014-01-01 | Raqualia Pharma Inc | Ghrelin receptor agonists for the treatment of achlorhydria |
AU2013296470B2 (en) | 2012-08-02 | 2016-03-17 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
KR20210009438A (en) | 2012-09-27 | 2021-01-26 | 아라타나 세라퓨틱스, 인크. | Compositions and methods of use of an inappetance-controlling compound |
CN104853778A (en) | 2012-10-24 | 2015-08-19 | 第一三共株式会社 | Therapeutic agent for amyotrophic lateral sclerosis |
AU2014219020A1 (en) | 2013-02-22 | 2015-07-23 | Merck Sharp & Dohme Corp. | Antidiabetic bicyclic compounds |
US9708367B2 (en) | 2013-03-15 | 2017-07-18 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase and their uses |
CA2905435A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
RU2670978C9 (en) * | 2013-05-28 | 2018-11-22 | Раквалиа Фарма Инк. | Polymorphic forms |
JP6606491B2 (en) | 2013-06-05 | 2019-11-13 | 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 | Ultra high purity agonist of guanylate cyclase C, method for producing and using the same |
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 |
CN106459147B (en) * | 2014-08-05 | 2021-08-06 | 拉夸里亚创药株式会社 | Serine derivatives as ghrelin receptor agonists |
JP6769963B2 (en) | 2014-08-29 | 2020-10-14 | ティエエッセ ファルマ ソチエタ レスポンサビリタ リミタータ | Inhibitor of α-amino-β-carboxymuconic acid semialdehyde decarboxylase |
JP2017532350A (en) * | 2014-10-31 | 2017-11-02 | ラクオリア創薬株式会社 | 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 |
CN109320515A (en) * | 2018-11-22 | 2019-02-12 | 常州大学 | A kind of method of asymmetric synthesis of Capromorelin chiral intermediate |
WO2020167706A1 (en) | 2019-02-13 | 2020-08-20 | Merck Sharp & Dohme Corp. | 5-alkyl pyrrolidine orexin receptor agonists |
Citations (2)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NO136251C (en) * | 1971-05-11 | 1977-08-10 | Sandoz Ag | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIDAZINE DERIVATIVES. |
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 |
KR960705575A (en) * | 1993-10-19 | 1996-11-08 | 도나 엘. 폴락 | Combination of bisphosphonates and growth hormone secretagogues (bisphosphonates and growth hormone secretagogues) |
US5610134A (en) * | 1994-04-15 | 1997-03-11 | Genentech, Inc. | Treatment of congestive heart failure |
US5935924A (en) * | 1994-04-15 | 1999-08-10 | 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 |
ATE272069T1 (en) * | 1995-01-27 | 2004-08-15 | Novo Nordisk As | COMPOUNDS WITH GROWTH HORMONE RELEASING PROPERTIES |
WO1996024587A1 (en) * | 1995-02-09 | 1996-08-15 | 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 |
WO1997007117A1 (en) * | 1995-08-21 | 1997-02-27 | Eli Lilly And Company | 2-acylaminopropanamines as growth hormone secretagogues |
CA2203428A1 (en) * | 1995-08-21 | 1997-02-27 | Philip Arthur Hipskind | 2-acylaminopropanamides 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 |
-
1996
- 1996-11-13 TW TW085113857A patent/TW432073B/en not_active IP Right Cessation
- 1996-11-14 AP APAP/P/1996/000881A patent/AP756A/en active
- 1996-12-04 KR KR10-1998-0704973A patent/KR100320167B1/en not_active IP Right Cessation
- 1996-12-04 AT AT96938434T patent/ATE361314T1/en not_active IP Right Cessation
- 1996-12-04 IL IL13890996A patent/IL138909A0/en unknown
- 1996-12-04 UA UA98063368A patent/UA66754C2/en unknown
- 1996-12-04 NZ NZ322172A patent/NZ322172A/en unknown
- 1996-12-04 BR BRPI9612465-2A patent/BR9612465B1/en not_active IP Right Cessation
- 1996-12-04 SK SK874-98A patent/SK285678B6/en not_active IP Right Cessation
- 1996-12-04 SI SI9630755T patent/SI0869968T1/en unknown
- 1996-12-04 PT PT96938434T patent/PT869968E/en unknown
- 1996-12-04 CZ CZ19981995A patent/CZ293423B6/en not_active IP Right Cessation
- 1996-12-04 TR TR1998/01233T patent/TR199801233T2/en unknown
- 1996-12-04 IL IL138911A patent/IL138911A/en not_active IP Right Cessation
- 1996-12-04 IL IL12444996A patent/IL124449A/en not_active IP Right Cessation
- 1996-12-04 CN CN96199388A patent/CN1113895C/en not_active Expired - Lifetime
- 1996-12-04 EP EP96938434A patent/EP0869968B1/en not_active Expired - Lifetime
- 1996-12-04 PL PL96327634A patent/PL186916B1/en not_active IP Right Cessation
- 1996-12-04 WO PCT/IB1996/001353 patent/WO1997024369A1/en active IP Right Grant
- 1996-12-04 IL IL13891096A patent/IL138910A0/en unknown
- 1996-12-04 AU AU75850/96A patent/AU716934B2/en not_active Ceased
- 1996-12-04 JP JP52412497A patent/JP3511382B2/en not_active Expired - Lifetime
- 1996-12-04 DE DE69637063T patent/DE69637063T2/en not_active Expired - Lifetime
- 1996-12-04 HU HU9901246A patent/HUP9901246A3/en unknown
- 1996-12-04 ES ES96938434T patent/ES2285715T3/en not_active Expired - Lifetime
- 1996-12-04 DK DK96938434T patent/DK0869968T3/en active
- 1996-12-04 CA CA002241725A patent/CA2241725C/en not_active Expired - Lifetime
- 1996-12-06 HN HN1996000085A patent/HN1996000085A/en unknown
- 1996-12-09 AR ARP960105571A patent/AR004367A1/en active IP Right Grant
- 1996-12-19 GT GT199600100A patent/GT199600100A/en unknown
- 1996-12-20 CO CO96066996A patent/CO4480108A1/en unknown
- 1996-12-23 ZA ZA9610858A patent/ZA9610858B/en unknown
- 1996-12-24 EG EG117796A patent/EG24195A/en active
- 1996-12-24 TN TNTNSN96172A patent/TNSN96172A1/en unknown
- 1996-12-24 MA MA24438A patent/MA26415A1/en unknown
- 1996-12-26 RS YUP-702/96A patent/RS49926B/en unknown
- 1996-12-26 MY MYPI96005499A patent/MY135727A/en unknown
- 1996-12-27 HR HR960618A patent/HRP960618B1/en not_active IP Right Cessation
- 1996-12-27 PE PE1996000961A patent/PE30398A1/en not_active Application Discontinuation
-
1997
- 1997-01-27 SA SA97170581A patent/SA97170581B1/en unknown
-
1998
- 1998-05-26 IS IS4758A patent/IS4758A/en unknown
- 1998-06-11 BG BG102533A patent/BG64055B1/en unknown
- 1998-06-19 OA OA9800090A patent/OA10702A/en unknown
- 1998-06-24 MX MX9805157A patent/MX9805157A/en active IP Right Grant
- 1998-06-26 NO NO19982991A patent/NO325135B1/en not_active IP Right Cessation
-
1999
- 1999-03-01 US US09/259,776 patent/US6124264A/en not_active Expired - Lifetime
- 1999-03-01 US US09/259,691 patent/US6107306A/en not_active Expired - Lifetime
- 1999-03-01 US US09/258,956 patent/US6110932A/en not_active Expired - Lifetime
- 1999-05-27 AP APAP/P/1999/001555A patent/AP860A/en active
- 1999-12-22 US US09/470,668 patent/US6278000B1/en not_active Expired - Lifetime
-
2000
- 2000-06-13 US US09/593,582 patent/US6306875B1/en not_active Expired - Lifetime
- 2000-06-13 US US09/593,581 patent/US6313140B1/en not_active Expired - Lifetime
- 2000-12-11 US US09/734,274 patent/US6482825B2/en not_active Expired - Lifetime
- 2000-12-20 JP JP2000386997A patent/JP2001213800A/en active Pending
-
2006
- 2006-03-03 AR ARP060100824A patent/AR052506A2/en active IP Right Grant
Patent Citations (2)
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
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AP756A (en) | Dipeptide compounds which are growth hormone secretagoques. | |
JP5000848B2 (en) | Ghrelin-containing pharmaceutical composition | |
ES2333097T3 (en) | USE OF SECRETAGOGS OF GROWTH HORMONE TO STIMULATE GASTROINTESTINAL MOTILITY. | |
US6313133B1 (en) | Sleep quality improvement using a growth hormone secretagogue | |
US20230120030A1 (en) | Long-Acting Adrenomedullin Derivatives | |
JPH10509152A (en) | Low molecular weight peptide-like growth hormone release promoter | |
EP3271015B1 (en) | Nk-3 receptor antagonists for therapeutic or cosmetic treatment of excess body fat | |
WO2006023608A2 (en) | Growth-hormone secretagogues | |
AU711884B2 (en) | Enhancement of sleep with a growth hormone secretagogue | |
KR101228229B1 (en) | Gh secretagogues and uses thereof | |
JP2003335752A (en) | Growth hormone secretagogue | |
US20070270341A1 (en) | Parathyroid hormone analogues and methods of use | |
AU2004281084B2 (en) | Use of growth hormone releasing factor analogs in treating patients suffering from wasting | |
AU2003229724B2 (en) | Novel use of guanylate cyclase activators for the treatment of respiratory insufficiency | |
EP1184035A2 (en) | Use of growth hormone secretagogues for treatment of physical performance decline | |
WO2001089570A2 (en) | Combination of growth hormone secretagogues and antidepressants | |
EP1716887B1 (en) | Treatment of inclusion body myositis | |
CA2335112A1 (en) | Therapeutic combinations for musculoskeletal frailty | |
US20020160961A1 (en) | Compositions for the treatment of the catabolic state of prolonged critical illness | |
RU2172742C2 (en) | Stimulating agents of growth hormone secretion | |
EA044055B1 (en) | USING A NEUROKININ-3 (NK-3) RECEPTOR ANTAGONIST TO INCREASE CIRCULATORY LEPTINA LEVELS IN PATIENTS | |
Kinter et al. | Toxicity of desmopressin and related peptides | |
WO1993018769A2 (en) | A new use of quinazoline derivative | |
RU98112108A (en) | STIMULATORS OF THE SECRETION OF GROWTH GROWTH |