Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-06-03
2004-08-31
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S333000, C562S553000
Reexamination Certificate
active
06784158
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a process for preparing a compound of formula I, a GH secretagogue which can be used i.a. in treating medical disorders resulting from a deficiency in growth hormone.
BACKGROUND OF THE INVENTION
Growth hormone is a hormone which stimulates growth of all tissues capable of growing. In addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilisation and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine, L-3,4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, PACAP (pituitary adenylyl cyclase activating peptide), muscarinic receptor agonists and a synthetic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus.
In disorders or conditions where increased levels of growth hormone is desired, the protein nature of growth hormone makes anything but parenteral administration non-viable. Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason parenteral administration is preferred. WO 97/23508 discloses a method for preparing the compound of formula I. This method is very expensive and makes use of reagents which are adverse to the environment.
It is an object of the present invention to provide a novel method for preparing a compound of formula I which method results in high yields and high purity. Moreover the present method is reproducible and more economic, and is suitable for large scale production.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided a novel and improved method for preparing a compound of formula I
or a salt thereof, comprising
a) treating a compound of formula II
or a salt thereof, wherein P is a protecting group, with an agent capable of forming an amide or ester or mixed carbonic anhydride or anhydride or acid halide, in a solvent selected from an organic solvent or mixture of organic solvents or a mixture of organic solvent(s) and water, thereby producing and isolating a compound of formula III
or a salt thereof, wherein R together with the carbonyl moiety is an amide or ester or mixed carbonic anhydride or anhydride or acid halide,
b) treating the isolated compound of formula III, or a salt thereof, with a compound of formula (IV)
or a salt thereof, in a solvent selected from an organic solvent or mixture of organic solvents or a mixture of organic solvent(s) and water, thereby producing a compound of formula (V)
or a salt thereof, which is then deprotected in a conventional manner, to obtain the compound of formula (I) or a salt thereof.
DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to a method for preparing a compound of formula I
or a salt thereof, comprising
a) treating a compound of formula II
or a salt thereof, wherein P is a protecting group, with an agent capable of forming an amide or ester or mixed carbonic anhydride or anhydride or acid halide, in a solvent selected from an organic solvent or mixture of organic solvents or a mixture of organic solvent(s) and water, thereby producing and isolating a compound of formula III
or a salt thereof, wherein R together with the carbonyl moiety is an amide or ester or mixed carbonic anhydride or anhydride or acid halide,
b) treating the isolated compound of formula III, or a salt thereof, with a compound of formula (IV)
or a salt thereof, in a solvent selected from an organic solvent or mixture of organic solvents or a mixture of organic solvent(s) and water, thereby producing a compound of formula (V)
or a salt thereof, which is then deprotected in a conventional manner, to obtain the compound of formula (I) or a salt thereof.
In one embodiment of the present method P is a group of formula —C(═O)—C
1-12
alkyl, —C(═O)—O—C
1-12
alkyl, —C(═O)—C
1-12
alkenyl or —C(═O)—O—C
1-12
alkenyl, optionally substituted with one or more halogen, C
1-6
alkyl, hetaryl, aryl or fused-ring aromatic system. P is preferably selected from —C(═O)H, Troc, Boc, and Fmoc. In one embodiment P is Troc. In a second embodiment P is Boc. In a third embodiment P is Fmoc. In a most preferred embodiment P is Troc.
In another embodiment of the present method the agent capable of forming an amide or ester or mixed carbonic anhydride or anhydride or acid halide is selected from benzotriazole, isobutyl chlorocarbonate, DHOBt, HOBt, HOSu, and HOAt. In a most preferred embodiment the agent capable of forming an amide or ester or mixed carbonic anhydride or anhydride or acid halide is DHOBt.
Furthermore the solvent in step b of the present method is preferably a mixture of an organic solvent and water, preferably an ester and water, such as C
1-6
alkyl-C(═O)—O—C
1-6
alkyl, e.g. ethylacetate and water.
The de-protection is usually carried out by acidic, basic, oxidative or reductive cleavage, e.g. when the protection group is Troc then reductive cleavage is carried out with Zn and acetic acid.
In a preferred embodiment of the present method P is Troc and the agent capable of forming an amide or ester or mixed carbonic anhydride or anhydride or acid halide is DHOBt.
In another aspect the present invention relates to a compound of formula III
or a salt thereof, wherein R together with the carbonyl moiety is an amide or ester or mixed carbonic anhydride or anhydride or acid halide, and P is a protecting group. In one embodiment P is a group of formula —C(═O)—C
1-12
alkyl, —C(═O)—O—C
1-12
alkyl, —C(═O)—C
1-12
alkenyl or —C(═O)—O—C
1-12
alkenyl, optionally substituted with one or more halogen, C
1-6
alkyl, hetaryl, aryl or fused-ring aromatic system. P is preferably selected from —C(═O)H, Troc, Boc, and Fmoc. In one embodiment P is Troc. In a second embodiment P is Boc. In a third embodiment P is Fmoc. In a most preferred embodiment P is Troc. In a further embodiment the agent capable of forming an amide or ester or mixed carbonic anhydride or anhydride or acid halide is selected from benzotriazole, isobutyl chlorocarbonate, DHOBt, HOBt, HOSu, and HOAt, preferably DHOBt. In a most preferred embodiment P is Troc and said amide or ester or mixed carbonic anhydride or anhydride or acid halide is obtained by reacting DHOBt with the carboxylic acid moiety in the compound of formula II.
In a further aspect the present invention relates to a compound of formula V
or a salt thereof, wherein P is Troc or Fmoc.
In one embodiment the compound is
In a second embodiment the compound is
The compounds of the present invention, i.e. formula I, II, III, IV and V may optionally be on a salt form, such as a pharmaceutically acceptable salt form e.g. the pharmaceutically acceptable acid addition salts of compounds of formula I, II, III, IV and V, which include those prepared by reacting the compound of formula I, II, III, IV and V with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, malic, maleic, mandelic phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, trifluoracetic, sulfamic or fumaric acid and/or water.
The process according to the present invention is illust
Bork Richard W.
Green Reza
Low Christopher S. F.
Lukton David
Novo Nordisk A S
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