CN1723059A - Insulin receptor activators for the treatment of human body metabolic disorder resulting from treatment of HIV infection with HIV protease inhibitors - Google Patents

Insulin receptor activators for the treatment of human body metabolic disorder resulting from treatment of HIV infection with HIV protease inhibitors Download PDF

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CN1723059A
CN1723059A CNA018171419A CN01817141A CN1723059A CN 1723059 A CN1723059 A CN 1723059A CN A018171419 A CNA018171419 A CN A018171419A CN 01817141 A CN01817141 A CN 01817141A CN 1723059 A CN1723059 A CN 1723059A
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alkyl
rudimentary
virtue
chemical compound
heteroaryl
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普拉萨德·V·V·S·V·曼查姆
罗伯特·T·卢姆
史蒂文·R·舍伟
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Telik Inc
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Priority to FR0113040A priority patent/FR2814953A1/en
Priority to JP2002533952A priority patent/JP2004510831A/en
Priority to AU2002211922A priority patent/AU2002211922A1/en
Priority to PCT/US2001/042733 priority patent/WO2002030514A2/en
Priority to EP01980019A priority patent/EP1355698A2/en
Priority to CNA018171419A priority patent/CN1723059A/en
Priority to CA002421622A priority patent/CA2421622A1/en
Publication of CN1723059A publication Critical patent/CN1723059A/en
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    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

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Abstract

The present invention comprises the use of insulin receptor activating compounds, optionally in conjunction with insulin, for the treatment of HIV protease inhibitor-induced metabolic disorders. Any insulin receptor activating compounds is suitable for the practice of the invention. In addition, preferred compounds are disclosed. Methods of treating a person suffering from HIV protease inhibitor-induced metabolic disorders such as lipodystrophy, hypertriglyceridemia, insulin resistance, hyperglycemia, diabetes and ketoacidosis are also provided.

Description

The insulin receptor activators that is used for the treatment of the human body metabolic disorder that causes by using treatment of HIV infection with HIV protease inhibitors
Technical field
The present invention relates to be used for the treatment of method, chemical compound and the compositions of the disease of bringing out because of use HIV (HIV (human immunodeficiency virus) (Human Immunodeficiency Virus)) protease inhibitor.The invention particularly relates to the method, chemical compound and the compositions that are used for the treatment of the Developmental and Metabolic Disorder of bringing out by the hiv protease inhibitor.
Background technology
It is very effective that existing HIV treatment of infection method has been proved the viral destruction to health of control infection latter stage (acquired immune deficiency syndrome (AIDS) AIDS).At the pharmacotherapy that is used for suppressing virus assembling and acquired immune deficiency syndrome (AIDS) symptom, the hiv protease inhibitor is a kind of very important composition.Unfortunately, these medicines that are used to keep HIV infection population health have significant side effects.Thereby being the hiv protease inhibitor, a serious side effects of recent findings brings out the hyperglycemia that the generation insulin resistance causes, then can develop into diabetes and life-threatening ketoacidosis (Carr, A., Samaras, K., Chrisholm, D.J., and Cooper, D.A. (1998) Lancet " lancet " 351 1881-1883; Carr, A., Samaras, K., Burton, S., Freund, I., Chisholm, D.J., Cooper D.A. (1998) AIDS " acquired immune deficiency syndrome (AIDS) " 12, F51-F58).
Except insulin resistance, also observe other relevant Developmental and Metabolic Disorder on one's body the patient who accepts the hiv protease inhibitor for treating, as lipodystrophy and hypertriglyceridemia (Roth, V.R., Kravcik, S., Angel, J.B. (1998) Clin Infect Dis " clinical infectious disease " 27,65-67; Safrin, S., and Grunfeld, C., (1999) AIDS 13,2493-2505; Carr, A., Samaras, K., Thorisdottir, A., Kaufmann, G.R., Chrisholm, D.J., and Cooper, D.A. (1999) Lancet 353,2093-2099; Behrens, G., Dejam, A., Schmidt, H., Balks, H-J., Brabant, G., Korner, T., Stoll, M., and Schmidt, R.E. (1999) AIDS 13, F63-F70).The complicated metabolic side effect of these very important medicines has all features of insulin resistance state, this state be called as X syndrome (Reaven, G.M. (1993) Annu.Rev.Med. " medical science review annual " 44,121-131).
For a part of patient, these metabolism side effect have limited the application of the described medicine that earns a bare living greatly.People do not recognize this side effect earlier in the development process of these medicines, in case and these inhibitor enter routine clinical and use, described problematic side effect vast scale in the crowd who receives treatment occurs.This problem has certain universality, because all available hiv protease inhibitor medicaments have all confirmed this serious adverse at present.
The molecular basis of this phenomenon is verified 3T3L1 adipose cell (Murata, H., the Hruz of being positioned at recently, P.W., and Mueckler, M. (2000) The Journal of BiologicalChemistry " journal of biological chemistry " 275:27,20251-20254).This report produces evidence to show, the hiv protease inhibitor medicaments that at least three kinds of market can be purchased also suppresses the transhipment of glucose carrier from the part to the cell membrane, has suppressed the absorption of these cells to glucose then.This by the hiv protease inhibitor cause that glucose is entered the rising of the inhibition of cell traffic process and the patient's of the more observed treatment of accepting the hiv protease inhibitor medicaments clinically glucose and lipid level is consistent.
Known that insulin receptor activators can stimulate the migration of glucose carrier to cell membrane, can stimulate the absorption of the outer glucose of pair cell then.The chemical compound of known several types can be used as insulin receptor activators.Insulin receptor activators comprises the chemical compound of chemical constitution shown in the following structural formula I to VII.Examples of compounds with chemical constitution among the structural formula I-II is described in WO 00/71506 and 01/12591 to some extent.Have chemical compound synthetic of chemical constitution among structural formula II I and the IV will be below " embodiment " part be described.Examples of compounds with chemical constitution among structural formula V and the VI is the 6th, 051, reports among No. 597 United States Patent (USP)s and the WO 99/51225, examples of compounds with chemical constitution among the structural formula VII is being numbered 5,851,988 and 5, report to some extent in 830,918 the United States Patent (USP).In addition, Geier etc. have reported azo dye compounds (United States Patent (USP) of numbering 6,020,374).
The invention summary
The present invention relates to use the treatment of Insulin receptor INSR activated compounds by the disease of using HIV (human immunodeficiency virus) (Human Immunodeficiency Virus) (HIV) protease inhibitor to bring out.Especially, the present invention has disclosed and has used human insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy (lipodystrophy) and the hypertriglyceridemia that the treatment of Insulin receptor INSR activated compounds is brought out by the hiv protease inhibitor.Described Insulin receptor INSR activated compounds can also be used in combination with insulin, be used for the treatment of and use hiv protease inhibitor diseases associated, for example hiv protease inhibitor human insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and the hypertriglyceridemia of bringing out.
The applicant finds that the chemical compound that can increase Insulin receptor INSR sensitivity has overcome the side effect of the top listed Metabolic disorder of hiv protease inhibitor.The applicant finds that also the chemical compound of insulin receptor activators can remove the glucose uptake that caused by the hiv protease inhibitor and suppress.Therefore, the applicant discloses at this, can strengthen the chemical compound of the glucose transport of the cell of handling through the hiv protease inhibitor, can eliminate patient's side effect of being seen limit treatment on one's body of accepting protease inhibitors for treating at those.Insulin receptor activators chemical compound described herein can effectively be treated insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and the hypertriglyceridemia that the hiv protease inhibitor brings out.
The present invention includes the application of any insulin receptor activators aspect the treatment disease relevant except that insulin, for example insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia with the use of hiv protease inhibitor.Application aspect human insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy or the hypertriglyceridemia that any Insulin receptor INSR activated compounds that the present invention further comprises non-insulin brings out at treatment hiv protease inhibitor.Especially, the chemical compound of structural formulas I-VI I of the present invention can be used for treating the relevant disease of hiv protease inhibitor, and treats human insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and the hypertriglyceridemia that the hiv protease inhibitor brings out.Method of the present invention comprises that also insulin and the merging of receptor activation chemical compound are administered for the relevant disease of treatment hiv protease inhibitor, and is used for the treatment of human insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and the hypertriglyceridemia that the hiv protease inhibitor brings out.The chemical compound of structural formula I-IV is useful equally when being used for treating diabetes, and associated description sees also homologous series pending application application U. S. application number the 09/579th, 279,60/208, No. 591 and PCT/US00/14644.
On the one hand, the present invention relates to pharmaceutical composition, comprise (i) a kind of pharmaceutically acceptable carrier and (ii) as the compound in structural formula I of effective ingredient:
Figure A0181714100161
Structural formula I
Wherein: R 1And R 2Be the group on the A ring, be independently of one another-SO 2NR 7 2,-C (O) NR 7 2,-NR 7SO 2R 7,-NR 7C (O) R 7,-SO 2OR 7,-C (O) OR 7,-OSO 2R 7Or-OC (O) R 7,
R 3And R 4Be hydrogen or low alkyl group independently of one another, or R 3And R 4Be together-(CH 2) 2-,-(CH 2) 3-or-(CH 2) 4-,
R 5And R 6Be independently of one another hydrogen, low alkyl group, replacement low alkyl group, cyano group, halogen, nitro ,-SR 8,-C (O) R 8,-SO 2OR 8,-OSO 2R 8,-SO 2NR 8 2,-NR 8SO 2R 8,-OC (O) R 8,-C (O) OR 8,-C (O) NR 8 2,-NR 8C (O) R 8,-OR 8, or-NR 8 2,
Each R 7And R 8Be hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, virtue (rudimentary) alkyl independently of one another, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, heteroaryl or substituted heteroaryl
Each Y is a non-interfering substituent,
Each x is 0,1 or 2 independently of one another, and
The carbon that carbamide linker (urea linker) will be numbered c couples together with the carbon that is numbered d,
Or its pharmaceutically acceptable salt, selectively with its single stereoisomers form or the form of its mixing stereoisomer,
Be used for the treatment of the human insulin resistance, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and the ketoacidosis that bring out by the hiv protease inhibitor.
In the present invention's first example in this respect, compound in structural formula I or its pharmaceutically acceptable salt in the pharmaceutical composition are provided, wherein there is not Y to be connected on the naphthalene nucleus, and if R by the azo linker 1And R 2All be-SO 2OH, (i) do not have Y to be-SO so 2OH; (ii) R 5And R 6Be not-SO 2OR 8Or-OSO 2R 8(iii) R 5And R 6Be not selected from the group of forming by hydroxyl and hydrogen, unless have one (Y) at least xBe (Y ') X ', wherein x ' be 1 or 2 and Y ' be a halogen.
On the other hand, the present invention relates to pharmaceutical composition, comprise (i) a kind of pharmaceutically acceptable carrier and, be used for the treatment of the human insulin resistance, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and the ketoacidosis that bring out by the hiv protease inhibitor (ii) as the chemical compound of the structural formula II of effective ingredient:
Figure A0181714100181
Structural formula II
Wherein:
R 1And R 2Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl ,-C (O) R 4,-C (O) OR 4,-C (O) NR 4R 5,-S (O) 2R 4,-S (O) 2OR 4, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl or low-grade alkenyl or R 1And R 2Be C together with the nitrogen that is connected 3-C 9Heteroaryl, C 3-C 5Heterocyclic radical or-NO 2,
R 3Be a substituent group on the B ring, for-SO 2OR 6,-C (O) OR 6,-SO 2NR 6 2,-C (O) NR 6 2, or tetrazolium;
Each between naphthalene nucleus and the phenyl ring-A ring on WY-linker and the naphthalene nucleus links to each other, and can be-C (O) NR independently 7-,-NR 7C (O)-,-C (O) O-,-OC (O)-,-CH=CH-,-NR 7CH 2-,-CH 2NR 7-,-NR 7C (O) NR 7-,-NR 7C (O) O-,-OC (O) NR 7-,-NR 7SO 2O-,-OSO 2NR 7-,-OC (O) O-,-SO 2NR 7-,-NR 7SO 2-,-OSO 2-or-SO 2O-,
Each R 4And R 5Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, substituted heteroaryl, heteroaryl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical or low-grade alkenyl
Each R 6And R 7Be independently of one another: hydrogen or low alkyl group,
Each R 8Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, substituted heteroaryl, heteroaryl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, low-grade alkenyl, nitro, halogen, cyano group ,-OR 9,-SR 9,-C (O) R 9,-OC (O) R 9,-C (O) OR 9,-NR 9 2,-C (O) NR 9 2,-NR 9C (O) R 9,-OSO 2R 9,-SO 2OR 9,-SO 2NR 9 2, or-NR 9SO 2R 9,
Each R 9Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, virtue (rudimentary) alkyl of mixing, the assorted virtue of replacement (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, virtue (rudimentary) alkyl or replacement virtue (rudimentary) alkyl
Each Z is non-interfering substituent,
Each x and v be independently of one another, 0,1,2 or 3, and
R 10Be aryl, substituted aryl, heteroaryl or substituted heteroaryl,
Or its pharmaceutically acceptable salt, selectively with the form of the mixture of its single stereoisomers form or stereoisomer.
On the other hand, the present invention relates to pharmaceutical composition, comprise (i) a kind of pharmaceutically acceptable carrier and, be used for the treatment of the human insulin resistance, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and the ketoacidosis that bring out by the hiv protease inhibitor (ii) as the chemical compound of the structural formula II I of effective ingredient:
Structural formula II I
Wherein:
R 1And R 2Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl or low-grade alkenyl, perhaps R 1And R 2Be C together with the nitrogen that is connected 3-C 9Heteroaryl or C 3-C 5Heterocyclic radical.
Z is OH, halogen, OR 1Or NR 1R 2(R wherein 1And R 2Define in front),
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers or the form of stereoisomer mixture.
On the other hand, the present invention relates to pharmaceutical composition, comprise (i) a kind of pharmaceutically acceptable carrier and, be used to be used for the treatment of the human insulin resistance, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and the ketoacidosis that bring out by the hiv protease inhibitor (ii) as the chemical compound of the structural formula IV of effective ingredient:
Figure A0181714100211
Structural formula IV
Wherein
R 1, R 3And R 4Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, halogen, hydroxyl, substituted alkoxy, carboxyl ,-NR 11R 12, or-C (O) NR 11R 12,
R 2For hydrogen, low alkyl group, replacement low alkyl group, halogen, hydroxyl, alkoxyl, substituted alkoxy, carboxyl ,-NR 11R 12,-NR 11C (O) R 12, or-C (O) NR 11,
R 5Be hydrogen, low alkyl group, replacement low alkyl group or aryl,
R 6And R 7Be hydrogen or carboxyl independently of one another,
R 8And R 9Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, halogen, hydroxyl, alkoxyl, carboxyl ,-NR 11R 12,-C (O) NR 11R 12,
R 10For low alkyl group, replace low alkyl group, halogen, carboxyl ,-C (O) NR 11R 12,
R 11And R 12Be independently of one another, hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, heteroaryl or replace assorted virtue-C (O)-aryl or aryl
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers or the form of stereoisomer mixture.
On the other hand, the present invention relates to pharmaceutical composition, comprise (i) a kind of pharmaceutically acceptable carrier and, be used to be used for the treatment of the human insulin resistance, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and the ketoacidosis that bring out by the hiv protease inhibitor (ii) as the chemical compound of the structural formula V of effective ingredient:
Figure A0181714100221
Structural formula V
Wherein
The aryl or the heteroaryl condensed ring of a 5-6 unit of Y ring expression, it optionally is selected from R by 1-4 1Group replace,
X represents O, S (O) mOr N, wherein m is 0,1 or 2;
A represents a material that is selected from the group that is made of following material:
(a) list of a 6-10 unit or bicyclic aryl
(b) the isolated bicyclic heteroaryl of a 5-6 unit
(c) a 9-10 unit bicyclic heteroaryl is coupled by one 6 yuan rings, or
(d) 8 yuan of bicyclic heteroaryls, heteroaryl has 1-4 hetero atom, and hetero atom is selected from O, S (O) mAnd N, described aryl and heteroaryl can be by 1-3 R 1Based selective replaces
R 1Be independently selected from:
Halogen ,-OH ,-C 1-12Alkyl (R 2) 3,-C 2-10Alkenyl (R 2) 3,-C 2-10Alkynyl (R 2) 3,-C 6-10Alkyl (R 2) 3,-heteroaryl (R 2) 3,-heterocyclic radical (R 2) 3,-NH 2,-NHC 1-6, alkyl (R 2) 3,-N (C 1-6Alkyl (R 2) 3) 2,-N 3,-OC 1-6Alkyl (R 2) 3,-S (O) mH, S (O) mC 1-6Alkyl (R 2) 3,-CHO ,-C (O) C 1-6Alkyl (R 2) 3,-CO 2H ,-C (O) OC 1-6Alkyl (R 2) 3,-C (O) SC 1-6Alkyl (R 2) 3,-C (O) NH 2,-C (O) NHC 1-6, alkyl (R 2) 3,-NHC (O) C 1-6Alkyl (R 2) 3,-S (O) mNH 2,-NHS (O) mC 1-6Alkyl (R 2) 3, S (O) mNHC 1-6Alkyl (R 2) 3With-S (O) mN (C 1-6Alkyl (R 2) 3) 2
Wherein m is 0,1 or 2;
R 2Be independently selected from:
H, OH, halogen ,-C 1-4Alkyl ,-C 2-4Alkenyl ,-C 2-4Alkynyl ,-CF 3,-OCF 3,-NO 2,-N 3,-CHO ,-OC 1-6Alkyl ,-S (O) mC 1-6Alkyl ,-NH 2,-NHC 1-6Alkyl ,-N (C 1-6Alkyl) 2,-C (O) C 1-6Alkyl ,-CO 2H ,-CO 2C 1-6Alkyl ,-C (O) NH 2,-C (O) NHC 1-6Alkyl ,-C (O) N (C 1-6Alkyl) 2,-OC (O) C 1-6Alkyl ,-NHC (O) C 1-6Alkyl ,-S (O) mNH 2,-S (O) mNHC 1-6Alkyl ,-S (O) m(C 1-6Alkyl) 2, aryl, heteroaryl and heterocyclic radical,
Wherein m is 0,1 or 2,
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers form or stereoisomer mixture.
On the other hand, the present invention relates to pharmaceutical composition, comprise (i) a kind of pharmaceutically acceptable carrier and, be used for the treatment of the human insulin resistance, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and the ketoacidosis that bring out by the hiv protease inhibitor (ii) as the chemical compound of the structural formula VI of effective ingredient:
Figure A0181714100241
Structural formula VI
Wherein
R 1Be hydrogen or methyl
R 2Be-CH 2CH 3Or-CH=CH 2
R 3Be-CH=CH-C (CH 3)=CH 2CH 2-CH=C (CH 3) 2Or-CH 2-CH 2-CH=C (CH 3) 2,
Or its pharmaceutically acceptable salt, selectively be the form of the mixture of the form of its single stereoisomers or stereoisomer.
On the other hand, the present invention relates to pharmaceutical composition, comprise (i) a kind of pharmaceutically acceptable carrier and, be used for the treatment of the human insulin resistance, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and the ketoacidosis that bring out by the hiv protease inhibitor (ii) as the chemical compound of the structural formula VII of effective ingredient:
Structural formula VII
Wherein
Q and Q ' are hydrogen or following structure:
Figure A0181714100252
R 1And R 2Be-SO independently of one another 2NR 7 2,-C (O) NR 7 2,-NR 7SO 2R 7,-SO 2OR 7,-C (O) OR 7,-PO 3R 7 2, or tetrazolium
R 3And R 4Be-SO independently of one another 2NR 7 2,-C (O) NR 7 2,-NR 7C (O) R 7,-SO 2OR 7,-C (O) OR 7,-PO 3R 7 2, or tetrazolium
R 5And R 6Be independently of one another, hydrogen, low alkyl group, replacement low alkyl group, cyano group, halogen, nitro ,-SR 8,-C (O) R 8,-SO 2OR 8,-OSO 2R 8,-SO 2NR 8 2,-NR 8SO 2R 8,-OC (O) R 8,-C (O) OR 8,-C (O) NR 8 2,-NR 8C (O) R 8,-OR 8, or-NR 8 2,
Each R 7And R 8Be independently of one another, hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, heteroaryl or substituted heteroaryl
Each Y is a non-interfering substituent, and
Each x is independently of one another, 0,1 or 2,
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers or the form of its stereoisomer mixture.
Detailed Description Of The Invention
(a) definition:
" alkyl " as in " alkyl " or " alkoxyl ", is meant a C 1-C 20The univalence hydrocarbyl part can be chain, branch-like or ring-type." low alkyl group " as described in " low alkyl group ", " junior alkyl halides ", " virtue (rudimentary) alkyl " or " heteroaryl (rudimentary) alkyl ", represents a C 1-C 10Alkyl.Term " low alkyl group " comprises following structure, as methyl, ethyl, isopropyl, propyl group, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, cyclopenta, ring third methyl, cyclohexyl or cyclohexyl methyl.C 1-C 6Low alkyl group is preferred.
Substituted alkyl or replacement low alkyl group are respectively an alkyl or low alkyl group, described alkyl or low alkyl group are single, double or three replace by following structure usually, described structure can be aryl, substituted aryl, heteroaryl, nitro, cyano group, halogen ,-OR ,-SR ,-C (O) R ,-OC (O) R ,-NRR ' ,-S (O) 2OR ,-OS (O) 2R ,-S (O) 2NRR ' ,-NRS (O) 2R ' ,-C (O) OR ,-C (O) NRR ' or-NRC (O) R ', wherein R and R ' are independently of one another, hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, heteroaryl, assorted virtue (rudimentary) alkyl, replacement virtue (rudimentary) alkyl or virtue (rudimentary) alkyl.By one to three substituted alkyl or replacement low alkyl group that is selected from the substituent group replacement of the group of being made up of cyano group, halogen, lower alkoxy, sulfur, nitro, amino or hydroxyl is particularly preferably.
Term " junior alkyl halides " refers to the alkyl that is replaced by one to three halogen, and further example comprises-CF 3,-CH 2CF 3With-CH 2CCl 3Such group.
" aryl ", as described in " aryl ", " aryloxy group " and " virtue (rudimentary) alkyl ", refer to a group of deriving and obtaining by the aromatic hydrocarbon that contains 6 to 20 ring carbon atoms, have a monocycle (as, phenyl) or two or more condensed ring, be preferably 2 to 3 (as, naphthyl) or two or more aromatic rings, preferred 2 to 3 aromatic rings, they are by a singly-bound be connected (as, xenyl).Aryl is preferably C 6-C 16Aryl, C 6-C 14Aryl is then better.
" substituted aryl " is can be by down array structure list or polysubstituted aryl, described structure can be alkyl, substituted alkyl, halogen, cyano group, nitro ,-OR ,-SR ,-C (O) R ,-OC (O) R ,-NRR ' ,-S (O) 2OR ,-OS (O) 2R ,-S (O) 2NRR ' ,-NRS (O) 2R ' ,-C (O) OR ,-C (O) NRR ' or-NRC (O) R ', wherein R and R ' are independently of one another, hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, heteroaryl, assorted virtue (rudimentary) alkyl, virtue (rudimentary) alkyl or replacement virtue (rudimentary) alkyl.Substituted aryl can by above-mentioned group with any group and mode replace one to seven time.Yet preferred substituted aryl is single, double or three replacements.Optimum substituent group is low alkyl group, junior alkyl halides, halogen, cyano group, sulfur, nitro, amino, lower alkoxy or hydroxyl on the substituted aryl.Group-S (O) 2OR ,-S (O) 2NRR ' ,-C (O) OR and-C (O) NRR ', also be the particularly preferred substituent group of substituted aryl in the The compounds of this invention, wherein R and R ' they are hydrogen or low alkyl group independently of one another.
" heteroaryl ", as described in heteroaryl and heteroaryl (rudimentary) alkyl, refer to the group of deriving and obtaining by aromatic hydrocarbon, described aromatic hydrocarbon contains 5 to 14 annular atomses, wherein 1 to 5 is the hetero atom that is selected from N, O or S independently of one another, and heteroaryl also comprises monocycle, annelated heterocycles and fused iso and aromatic heterocycle (as thienyl, furyl, pyrrole radicals, pyrimidine radicals, isoxazolyl, oxazolyl, indyl, isobenzofuran, purine radicals, isoquinolyl, pteridyl, imidazole radicals, pyridine radicals, pyrazolyl, pyrazinyl, quinolyl etc.).
One " substituted heteroaryl " can have one to three substituent group, described substituent group can be alkyl, substituted alkyl, halogen, cyano group, nitro ,-OR ,-SR ,-C (O) R ,-OC (O) R ,-NRR ' ,-S (O) 2OR ,-OS (O) 2R ,-S (O) 2NRR ' ,-NRS (O) 2R ' ,-C (O) OR ,-C (O) NRR ' or-NRC (O) R ', wherein R and R ' are independently of one another, hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, heteroaryl, assorted virtue (rudimentary) alkyl, virtue (rudimentary) alkyl or replacement virtue (rudimentary) alkyl.In addition, any two adjacent substituent groups optionally form a rudimentary epoxy alkyl jointly on heteroaryl.Optimum substituent group comprises hydroxyl, halogen, lower alkoxy, cyano group, sulfur, nitro, low alkyl group, junior alkyl halides or amino on the substituted heteroaryl.
" heterocyclic radical " refers to the group of being derived and being obtained by an alicyclic hydrocarbon that contains 5 to 14 annular atomses, and 1 to 5 annular atoms wherein is a hetero atom, is selected from N, O or S independently of one another.Monocycle (for example, tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, etc.) be preferred.
One " substituted heterocyclic radical " can have one to three substituent group, preferred substituted be alkyl, substituted alkyl, halogen, cyano group, nitro ,-OR ,-SR ,-C (O) R ,-OC (O) R ,-NRR ' ,-S (O) 2OR ,-OS (O) 2R ,-S (O) 2NRR ' ,-NRS (O) 2R ' ,-C (O) OR ,-C (O) NRR ' or-NRC (O) R ', wherein R and R ' are independently of one another, hydrogen, low alkyl group, substituted alkyl, aryl, substituted aryl, heteroaryl, assorted virtue (rudimentary) alkyl, virtue (rudimentary) alkyl or replacement virtue (rudimentary) alkyl.Preferred substituted comprises low alkyl group, junior alkyl halides, halogen, cyano group, sulfur, amino, lower alkoxy or hydroxyl on the substituted heterocyclic radical.
" virtue (rudimentary) alkyl " is meant the low alkyl group that is replaced by foregoing aryl, and one " replacing virtue (rudimentary) alkyl " refers to virtue (rudimentary) alkyl that has one to three substituent group (or two parts have substituent group simultaneously) at aryl or moieties.
The low alkyl group that " assorted virtue (rudimentary) alkyl " replaced by heteroaryl as previously mentioned.One " replace assorted virtue (rudimentary) alkyl " is meant assorted virtue (rudimentary) alkyl that heteroaryl or the moieties at this group has one to three substituent group (or two parts have substituent group simultaneously).
One " lower alkoxy " is meant one-OR group, and wherein R is a low alkyl group.
" low-grade alkenyl " refers to any ramose or unbranched unsaturated C 2-C 10Group contains the carbon atom of described quantity, if there is not restricted number can reach 10 carbon atoms; And this group has one or more pairs of keys.The example of low-grade alkenyl is the various isomeric forms of vinyl, acrylic, cyclobutenyl, pentenyl and hexenyl, and unsaturated bond wherein can be arranged in the group optional position.
" halogen " is meant bromine, iodine, fluorine or chlorine.
" non-interfering substituent " is meant a substituent group, when described substituent group is present in certain given chemical compound, can obviously not reduce or suppress certain biological activity distinctive, expection of this chemical compound, what for example described chemical compound had, can reverse (overcoming) and take in inhibition by the glucose that the hiv protease inhibitor brings out, with the activation Insulin receptor INSR, or irritation cell is to the absorption effect of glucose.The existence of non-interfering substituent should not surpass 30% to the bioactive adverse effect of described chemical compound.Conveniently, non-interfering substituent to the bioactive reduction of chemical compound less than 10%.Optimum ground, non-interfering substituent to the biological activity of described chemical compound can not be reduced to any can detected degree.Yet the influence that non-interfering substituent exists in this chemical compound needs not be neutral.For example, non-interfering substituent can selectivity improves certain biological activity of described chemical compound.Suitable non-interfering substituent comprises, but not only is confined to, hydrogen, alkyl, substituted alkyl, cyano group, halogen, nitro ,-SR ,-OR and-NRR ', R wherein and R ' be independently of one another, hydrogen, low alkyl group or replace low alkyl group.
" pharmaceutically acceptable salt " can be any one salt of deriving inorganic or organic acid or organic or inorganic alkali.Term " pharmaceutically acceptable anion " is meant the anion that acid and described chemical compound reaction obtain.Term " pharmaceutically acceptable cation " is meant by adding the cation that base forms.Described salt and/or anion or cation should be harmless in biology and others.
" stereoisomer " is meant to have identical covalent bond order and the different chemical compound of its atoms in space relative position.
" inner salt " or " amphion " can be by forming a proton translocation on the carboxyl to the lonely electron pair of amino nitrogen atom.
" treatment effective dose " is meant, when being when treating certain disease to animals administer, is enough to the dosage that this treatment of diseases is exerted an influence.
Mammiferous certain disease " is treated " or " treatment " comprising:
(1) make those to disease-susceptible humans but not ill or the performance disease symptoms mammal avoid ill,
(2) suppress disease, promptly stop or the deterioration of the disease that slows down,
(3) eliminate a disease, even disease disappears, or
(4) alleviate disease symptoms, promptly reduce the influence of disease.
" disease " comprises human any non-health status, is meant the insulin resistance that the hiv protease inhibitor brings out, hyperglycemia, diabetes, ketoacidosis, lipodystrophy (lipodystrophy) and hypertriglyceridemia especially.
(b) chemical compound of the present invention
On the one hand, the present invention relates to pharmaceutical composition, comprise (i) a kind of pharmaceutically acceptable carrier, and, be used for the treatment of the human insulin resistance, hyperglycemia, diabetes, lipodystrophy, hypertriglyceridemia and the ketoacidosis that bring out by the hiv protease inhibitor (ii) as the Insulin receptor INSR activated compounds of effective ingredient.Described pharmaceutical composition can comprise any Insulin receptor INSR activated compounds, comprises the chemical compound of the chemical constitution with structural formulas I-VI I that this paper discloses.
The chemical compound that is used for practical application of the present invention can be prepared by the known method of the professional and technical personnel of chemical field.In addition, the examples for compounds and synthesizing in WO 00/71506 and WO 01/12591 with chemical constitution of structural formula I-II is illustrated.The synthetic of chemical compound with chemical constitution of structural formula II I and IV will carry out recapitulative explanation below.Chemical compound (and synthetic) with chemical constitution of structural formula V and VI is the 6th, 051, be described among No. 597 United States Patent (USP)s and the WO 99/51225, chemical compound (and synthetic) with chemical constitution of structural formula VII is being numbered 5,851,988 and 5,830, describe to some extent in 918 the United States Patent (USP).
Some chemical compound among the present invention can comprise one or more chiral centres.In this case, all stereoisomers also are contained within the scope of the present invention.The compounds of this invention comprises the mixture of single isolating stereoisomer and stereoisomer.
Chemical compound of the present invention further comprises the pharmaceutically acceptable salt of the chemical compound that this paper is disclosed.These pharmaceutically acceptable salts are applicable to the application of all methods of the present invention and pharmaceutical composition.
The salt that pharmaceutically acceptable salt forms when comprising the acid proton that exists in the described chemical compound and inorganic or organic base reaction.Usually parent compound is handled with the excessive corresponding cationic alkaline reagent that contains, for example hydroxide, carbonate or alkoxide.The cation that exists in the pharmaceutically acceptable salt can be Na +, K +, Ca 2+, and NH 4 +Na wherein +The salt optimum.Therefore, Shi Yi inorganic base comprises aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.Described salt also can utilize organic base to be prepared, for example ethanolamine, diethanolamine, triethanolamine, N-methyl glucoside amine, ethanolamine and tromethane.
If chemical compound of the present invention contains a basic group, then can prepare the salt that forms with acid reaction.The salt that described chemical compound and acid reaction form adopts the standard method preparation that utilizes parent compound and a kind of excessive acid reaction in a kind of suitable solvent, described acid can be hydrochloric acid, hydrobromic acid, sulphuric acid (generating sulfate and disulfate), nitric acid, mineral acids such as phosphoric acid, and organic acid, acetic acid for example, propanoic acid, glycolic, acetone acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, Fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, salicylic acid, p-methyl benzenesulfonic acid, caproic acid, enanthic acid, the Pentamethylene. propanoic acid, lactic acid, o-(4-hydroxyl-benzoyl) benzoic acid, 1, the 2-ethane disulfonic acid, the 2-ethylenehydrinsulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, the 2-LOMAR PWA EINECS 246-676-2, camphorsulfonic acid, 4-methyl-bicyclo-[2.2.2.]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, gluconic acid, 4,4 '-two (3-hydroxyl-2-naphthalene first) acid of inferior first, the 3-benzenpropanoic acid, trimethylacetic acid, the t-butylacetic acid, Laurel sulphuric acid, glucuronic acid, glutamic acid, 3-hydroxyl-2-naphthoic acid, stearic acid, muconic acid etc.
Some chemical compound of the present invention can form inner salt or amphion.
The pharmaceutical composition of all chemical compounds of the present invention will be described.These pharmaceutical compositions comprise that (i) is as the insulin receptor activators of effective ingredient and (ii) a kind of pharmaceutically acceptable carrier.Further, these drug compositions comprise (i) chemical compound of the present invention and (ii) a kind of pharmaceutically acceptable carrier as effective ingredient.
The pharmaceutical composition or derivatives thereof of The compounds of this invention can be made into solution or is frozen into dry powder and is used for parenteral.Dry powder can heavily be processed by adding a kind of suitable diluent or the method for other pharmaceutically acceptable carrier before use.Liquid formulations normally a kind of buffered, etc. the aqueous solution opened.Suitable diluents has a saline solution, 5% D/W or buffering sodium acetate or liquor ammonii acetatises such as standard.Described prescription is particularly suitable for parenteral, but also can be used for oral.Can add excipient, for example polyvinylpyrrolidone, gel, oxidized cellulose, Radix Acaciae senegalis, polyoxyethylene, mannitol, sodium chloride or sodium citrate.Alternatively, these chemical compounds can be made into capsule, tablet or make Emulsion or syrup, are used for oral.Can add pharmaceutically acceptable solid or liquid-carrier and strengthen or stablize described compositions, or its preparation process of facilitation.Liquid-carrier comprises syrup, Oleum Arachidis hypogaeae semen, olive oil, glycerol, saline, ethanol and water.Solid carrier comprises starch, lactose, calcium sulfate, dihydrate, Gypsum Fibrosum powder, magnesium stearate or stearic acid, Talcum, colloid, Radix Acaciae senegalis, agar or gel.Carrier can also comprise a kind of lasting release (slow release) material, and for example glycerol Monostearate or glycerol distearate can use separately or share with wax.The amount of solid carrier is unfixed, and every dosage unit 20mg to 1g is comparatively suitable.These pharmaceutical preparatioies are according to carry out powder process, mixing, granulating and the tabletting of needs when comprising the preparation tablet according to traditional pharmaceutics technology; Or powder process, mixing and the filling of using during preparation hard gel capsule form.When using liquid-carrier, dosage form adopts syrup, ingredients, Emulsion or a kind of aqueous or nonaqueous suspending agent usually.Such liquid preparation can be directly oral or be packed in the soft capsule.
(c) using method of The compounds of this invention
Insulin receptor INSR activated compounds of the present invention is through finding to can be used for activating the automatic phosphorylation of Insulin receptor INSR.In addition, described chemical compound has demonstrated and can strengthen glucose transport in the cultivation fibroblast of handling through multiple hiv protease inhibitor.Although the applicant does not want to be bound by theory, but people generally believe that the hiv protease inhibitor can reduce combining of glucose carrier and cell membrane, the film of chemical compound of the present invention by strengthening the glucose carrier relevant with other activity, can effectively strengthen the glucose transport in the cell that influenced by the hiv protease inhibitor.
The ability that the irritation cell that The compounds of this invention had is taken in glucose shows that they can be used for treating and handling the patient who suffers from human insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy or the hypertriglyceridemia of being brought out by the hiv protease inhibitor.Utilize the active advantage of The compounds of this invention, they can be used to stimulate the kinase activity of Insulin receptor INSR, to strengthen insulin to the activation of Insulin receptor INSR, the glucose absorption that increases the stimulation of insulin pair cell glucose absorption and stimulate those patients that suffer from the disease (diabetes, ketoacidosis, insulin resistance, hyperglycemia, lipodystrophy or hypertriglyceridemia) of being brought out by the hiv protease inhibitor.Therefore, the Insulin receptor INSR activated compounds, more specifically, chemical compound of the present invention can be used for preparing the medicine of treatment by above-mentioned any disease of using the hiv protease inhibitor to bring out.
This method can further comprise, adopt the treatment medicine of one or more additional form to treat the patient that those suffer from the complication of being brought out by the hiv protease therapy, for example give patient's administration of insulin, described complication is human body insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy or hypertriglyceridemia.When with the compounds of the present invention time spent, the application dosage of the medicine of insulin or other additional form for the treatment effective dose.When with certain compounds time spent of the present invention, the dose therapeutically effective of the medicine of insulin or other additional form can be lower than the dose therapeutically effective that they are used for the treatment of patient separately.Be appreciated that the insulin that any therapy adopted among the present invention can be a natural extract, also can be Recombulin.In addition, insulin analog can replace insulin in any Therapeutic Method of the present invention.Thereby, the medicine (being used for the treatment of any disease of being brought out by the hiv protease inhibitor) that utilizes Insulin receptor INSR activated compounds (further refering in particular to chemical compound of the present invention) to prepare can further comprise the medicine of additional form, for example, insulin or insulin analog.
Of the present inventionly be used for the treatment of the method for diabetes, ketoacidosis, lipodystrophy, hyperglycemia, insulin resistance or the hypertriglyceridemia of bringing out, also can comprise to patient and use the medicine of uniting a kind of non-insulin, antidiabetic medicine or other type ii diabetes of use with The compounds of this invention by the hiv protease inhibitor by conjoint therapy.For example, can be co-administered in mammiferous glucagon medicine with The compounds of this invention, optionally be a kind of thiazolidinedione (thiazolidinedione) (such as troglitazone (troglitazone)) or a kind of sulfonylurea drugs.The medicine accumulated dose that is used for the treatment of mammals type ii diabetes in drug combination (The compounds of this invention adds insulin and/or other antidiabetic medicine) must reach the treatment effective dose, although therapeutic effect may be not ideal enough when being used for the treatment of the mammals type ii diabetes separately for the various drug doses in the drug combination.Thereby, utilize the Insulin receptor INSR activated compounds (further to refer in particular to, chemical compound of the present invention) medicine for preparing (being used for the treatment of any disease of bringing out) by the hiv protease inhibitor, the medicine that can further comprise a kind of additional form by any disease of using the hiv protease inhibitor to bring out, for example, a kind of non-insulin, the diabetes medicine.
The method of diabetes, ketoacidosis, lipodystrophy, hyperglycemia, insulin resistance or hypertriglyceridemia of being brought out by the hiv protease inhibitor by conjoint therapy treatment of the present invention also can comprise a kind of chemical compound of the co-administered the present invention of patient and another kind of chemical compound of the present invention.Thereby the medicine (being used for the treatment of any disease of being brought out by the HIV proteinase inhibitor) that utilizes Insulin receptor INSR activated compounds (further refering in particular to chemical compound of the present invention) to prepare can further comprise another chemical compound of the present invention.
Chemical compound of the present invention can be used for preparing a kind of medicine, is used for the treatment of by the disease of using the hiv protease inhibitor to cause.
Thereby chemical compound of the present invention is used to strengthen through the hiv protease inhibitor for treating and needs the patient's of this type of treatment glucose to take in.Therapeutic Method comprises the chemical compound of the present invention of using a kind of effective dose, and described chemical compound preferably is dispersed in the pharmaceutical carrier.Preferred route of administration is the outer and oral administration route of intestinal.
Chemical compound of the present invention can adopt the administration of any suitable patient and disease feature.Route of administration includes, but are not limited to, administrated by injection (comprising intravenous injection, lumbar injection, intramuscular injection and subcutaneous injection), see through mucosa or transdermal administration, by local application's (nasal spray, suppository etc.) or can be taken orally.Pharmaceutical dosage form optionally for liposome, Emulsion, be used for seeing through the pharmaceutical dosage form of mucosa or transdermal administration.The suitable dosage form of every kind of medication can be referring to document, for example, and Remington ' s PharmaceuticalSciences, latest edition (latest edition), Mack Publishing Company, Easton (Easton), PA (Pennsylvania).
The common range of choice of the dosage unit of active component is 0.01 to 1000mg/kg, is preferably 0.01 to 100mg/kg, and 0.1 to 50mg/kg is better, but is easy to be determined according to route of administration, patient's age and disease by the professional and technical personnel.Chemical compound of the present invention optimum (single) dosage unit is 1 to 10mg/kg.Can administration every day one to ten time with described dosage unit, treat acute or chronic disease.
(d) embodiment
The following example is used for illustrating the present invention, is not that the present invention is construed as limiting, but is used for explaining how to prepare and use chemical compound of the present invention.
Chemical compound of the present invention is prepared by vitochemical conventional method.In some cases, we introduce the protectiveness group and at last with its removal.The blocking group that is fit to of amino, hydroxyl, carboxyl is at " the protectiveness group in the organic synthesis " (Greene, et al, Protective Groups in Organic Synthesis; Second Edition; John Wileyand Sons, New York, 1991) describe to some extent in the book.The carboxylic acid activation can obtain by using multiple different reagent, referring to " comprehensive organic transformation " (Larock, ComprehensiveOrganic Transformations, VCH Publishers, New York, 1989).
The chemical compound of structural formula II I adopts the organic chemistry conventional method to be prepared.
Usually, the chemical compound of tool following structural
Wherein:
R 1And R 2Be independently of one another, hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl or low-grade alkenyl, perhaps R 1And R 2Be C together with the nitrogen that is connected 3-C 9Heteroaryl or C 3-C 5Heterocyclic radical.
Z is OH, Cl, Br, F, OR 1Or NR 1R 2(R wherein 1And R 2Define in front),
Or its pharmaceutically acceptable salt, or its single stereoisomers or the mixture of its stereoisomer;
Can prepare by following method:
(a) 1,3, the HNR of 5-benzene three carbonyl trihalids and at least 1 to 3 mole 1R 2(R wherein 1And R 2Describe in front) react, wherein halogenide is selected from the group that is made of Cl, Br and F;
(b) has the activatory carboxyl diamides of following structural
With primary amine R 3NH 2Or secondary amine R 3R 4NH reacts, and wherein M is any group that can react with described amine; For example, M can be halogen, formates (ester), imidazoles or some other activating agent or coupling agent; Or
(c) the chemical compound esterification with following structural formula forms the chemical compound of the chemical constitution with structural formula A; Or
Figure A0181714100381
(d) R of one or more replacements 1And R 2Substituent chemical process, wherein said substituent group can be converted into another substituent group; Or
(e) will have three NR 1R 2The chemical compound of the chemical constitution with structural formula A of group changes into and has one or two NR 1R 2The chemical compound of chemical constitution with structural formula I; Or
(f) chemical compound that will have the chemical constitution of structural formula A is converted into a kind of pharmaceutically acceptable salt; Or
(g) salt of chemical compound that will have the chemical constitution of structural formula A is converted into a kind of free cpds (free compound); Or
(h) salt of chemical compound that will have the chemical constitution of structural formula A is converted into a kind of pharmaceutically acceptable salt; Or
(i) racemic mixture of the chemical compound of the chemical constitution with structural formula A of separation arbitrary proportion obtains its stereoisomer.
Asymmetric compound with chemical constitution of structural formula II I can be prepared by following reaction scheme:
The benzyl ester of The compounds of this invention obtains the carboxylic acid of this chemical compound through hydrolysis (under the basic hydrolysis condition or pass through catalytic hydrogenation); This carboxylic acid compound is converted into the acyl chlorides of this chemical compound subsequently, and the latter and amine reaction obtain the asymmetrical form of The compounds of this invention.
As mentioned above, can be converted into acyl chlorides with the oxalyl chloride reaction, generate corresponding monoacyl chloride with the benzene tricarbonic acid's of different protecting groups protection monomethyl, single benzyl ester.Described chemical compound and amine reaction generate monoamine compound.Under alkaline environment methyl ester is carried out the selectivity saponification, carry out acidify then, can produce another kind of carboxylic acid, the latter can utilize oxalyl chloride to be converted into acyl chlorides.Can obtain asymmetric chemical compound with the secondary amine reaction.Final carboxylate can change into carboxylic acid by stronger saponification or by catalytic hydrogenation.After separating carboxylic acid, can be translated into acyl chlorides, follow and reactive tertiary amine, formation has three kinds of different amino benzene compounds that replace.Specially the field those of ordinary skill can be very clear, and in above-mentioned building-up process, diamidogen can be used to substitute monoamine.
In some cases, can introduce protectiveness group and removal afterwards.The blocking group that is fit to of amino, hydroxyl, carboxyl is at " the protectiveness group in the organic synthesis " (Greene, etal, Protective Groups in Organic Synthesis; Second Edition; John Wileyand Sons, New York, 1991) describe to some extent in the book.The carboxylic acid activation can obtain by using multiple different reagent, referring to " comprehensive organic transformation " (Larock, ComprehensiveOrganic Transformations, VCH Publishers, New York, 1989).
The chemical compound of structural formula VI is prepared by traditional organic chemistry method.
Usually, preparation process comprises:
(a) has the iodo diamide compound (R wherein of following structural 1-R 7Define)
With the styrene with following structural or substituted phenylethylene (R wherein 8-R 10Define)
Figure A0181714100402
React; Or
(b) one or more substituent R 1-R 10Chemical process, wherein said substituent group can be converted into other substituent R 1-R 10Or
(c) with substituent R 1-R 10Introduce one, two or all three phenyl ring; Or
(d) deprotection of protectiveness group; Or
(e) formation of salt or change; Or
(f) ester hydrolysis; Or
(g) release of the free acid of the chemical compound of structural formula IV or alkali, R wherein 1-R 12Being taken at the front defines; Or
(h) separation of stereoisomer or synthetic.
The reaction of iodo diamide compound and styrene or substituted phenylethylene described in the front (a) can be carried out in DMF, toluene, dichloromethane equal solvent under 40 ℃ to 120 ℃ condition.
By a substituent group being changed into another substituent one or more substituent R 1-R 10Chemical process can be by hydrolysis, form salt, acidify, alkylation, esterification, oxidation or reduction reaction and finish.
In hydrolysis, ester or amide compound can be by decomposing with the reaction of water.Hydrolysis is with acid or base catalysis, and compares with the hydrolysis of ester, and the hydrolysis of amide needs more violent reaction condition (for example, under the condition that the sulphuric acid of higher concentration exists, 1 to 100 ℃ of reaction 1 to 5 hour) usually.Hydrolysis also can adopt hydrochloric acid, at 100 to 150 ℃, may need 18 hours.
In the forming process of salt, by adding alkaline reagent, such as sodium hydroxide solution or triethanolamine, free acid transforms salify, and all or part hydrion in the acid is replaced by the one or more cationes in the alkaline reagent.A kind of chemical compound is changed into its salt corresponding and that acid reaction obtains to be obtained by handling with stoichiometric corresponding acid (for example hydrochloric acid), in general, free alkali is dissolved in polar organic solvent (for example methanol or ethanol) and acid also is to be dissolved in methanol or the ethanol to add.Temperature remains on 0 to 50 ℃.Corresponding salt precipitates automatically, perhaps extracts with weak polar solvent.In acidization, chemical compound changes into acid.
In alkylating, introduce an alkyl in the described chemical compound or replace with alkyl.Alkylating carries out under 0 to 160 ℃ in the solvent (for example acetonitrile, DMF or THF) that is fit to, and generally refluxes 1 to 18 hour at about 25 ℃.
Esterification forms a kind of esters product at least.In brief, described chemical compound and 1.0 to 5.0 molar equivalents, the alkanol of preferred 2.0 molar equivalents, mercaptan or ammonia, monoalkyl or two alkylamine or heterocyclic amino group alkanol react, optionally exist uncle's organic base (for example 4-dimethylamine pyrimidine or, be preferably triethylamine, molar equivalent is 1.0 to 1.5, is preferably 1.25), be reflected in the organic solvent (for example dioxane, oxolane or preferred dichloromethane) and carry out.Be reflected under-10 to 50 ℃ and carry out, be preferably room temperature, in 1 to 24 hour response time, be preferably 4 hours.
Be the synthetic embodiment of particular compound that the present invention uses below.
Embodiment 1
Chemical compound 1
The preparation of chemical compound 1
4-hydroxyl-7-{[(5-hydroxyl-7-sulfo group (2-naphthyl)) amino] carbonyl amino } the naphthalene-2-sulfonic acid disodium salt.In the 45ml1N NaOH and 50ml water that contain 10.77g (0.045 mole) 7-amino-4-hydroxy naphthalene-2-sulfonic acid, add 3.70g (0.045 mole) sodium acetate.The pH of solution is higher than 9.Be reflected in the ice-water bath that is lower than 5 ℃ and cool off.Then, divide three times and add the 15ml THF that contains 2.23g (0.045 mole) triphosgene.The pH of reactant liquor reduces to 4-5, and is adjusted to 7-8 by dropwise adding 1N NaOH solution.(6: 2: 1 ethyl acetate: isopropyl alcohol: water) detection reaction is incomplete for TLC.Gradation adds the 10ml THF that another part is contained 2.20 gram (0.045 mole) triphosgenes, adds 1N NaOH solution simultaneously pH is remained on more than 7.When reaction detects when complete through TLC, pH is transferred to 1 and remove volatile matter through rotary evaporation with hydrochloric acid.Collect solid product by vacuum filtration.Obtain the 10.85g expecting compound.
7-{[(7-chlorine sulphonyl)-and 5-hydroxyl (2-naphthyl) amino] carbonyl amino }-4-hydroxyl naphthalene-2 sulfonic acid chloride.To containing 500mg (0.912 mole) 4-hydroxyl-7-{[(5-hydroxyl-7-sulfo group (2-naphthyl)) amino] carbonyl amino } in the 8ml phosphoryl chloride phosphorus oxychloride suspension of naphthalene-2-sulfonic acid disodium salt, add 1: 1 (v: sulfolane v): acetonitrile and 0.5ml acetic acid dimethylamide of 25ml.Reactant mixture stirring at room 16 hours.Reactant liquor becomes clear solution, joins in the 500ml ice.The ice mixture places ice bath and slowly rises to room temperature.The gained solid collects by vacuum filtration and water cleans.Solid under vacuum dry 24 hours.Obtain the 412mg expecting compound.
5-{[(7-{[N-(7-{[(4-chloro-3-benzenesulfonic acid) amino] sulphonyl }-5-hydroxyl (2-naphthyl)) carbamyl] amino }-4-hydroxyl (2-naphthyl) } sulphonyl] amino }-the 2-chlorobenzenesulfonic acid.To 0.15g (0.277mmol) 7-{[(7-chlorine sulphonyl)-5-hydroxyl (2-naphthyl) amino] carbonyl amino-4-hydroxyl naphthalene-2 sulfonic acid chloride in, add the fresh distillatory THF of 1.5ml, add 0.105g (0.610mmol) 5-amino-2-chlorobenzenesulfonic acid subsequently.In this solution, add 67 μ l (0.831mmol) pyridines.Reactant liquor at room temperature stirred 16 hours.Then, reactant distributes in 1N HCl and ethyl acetate.Reextraction is carried out with ethyl acetate in the water-bearing layer, merges organic layer MgSO 4Carry out drying, filter, the volatile matter rotary evaporation is to doing.Obtain 0.14g expection product.
Chemical compound 2
Embodiment 2
Reverse the retardance of glucose transport in the hiv protease inhibitor pair cell
Stimulate Insulin receptor INSR cause glucose from blood to intracellular transport, thereby blood sugar regulation level.3T3 L1 fibroblast (ATCC) is growth in Eagle ' the s culture medium (DMEM) that the Dulbecco ' s that is added with 10% hyclone (FBS) modifies.Cell is with 3 * 10 4The concentration of cell/ml joins (0.1ml/ hole) in 96 orifice plates.Merge two days later, cell was handled 3 days with 0.5mM isobutyl methyl purine (IBMX), 1 μ M dexamethasone and 1.7 μ M insulins.Then cell is changed among the DMEM that contains 10%FBS, and replenish 1.7 μ M insulins and cultivate more than two days.Cell continues to cultivate 4 days in containing the DMEM of 10%FBS.At last, cell hunger in the DMEM that contains 0.1% bSA (BSA) is spent the night.
Second day, cell was containing 150mM NaCl, 1.7mM KCl, 0.9mM CaCl 2, 1.47mM K 2HPO 4(pH7.4) and in the buffer of 0.01%BSA, with indinavir (Indinavir), ritonavir (Ritonavir) or amprenavir (Amprenavir) (adopting the concentration that shows in the following table) pretreatment 6 minutes, then with chemical compound (56 μ M chemical compounds 1 described in the present invention who has or do not have the 100nM insulin; 20 μ M chemical compounds 2) handled 30 minutes.After hatching, cell is used 14The 2-deoxy-D-glucose of C-labelling (0.5 μ Ci/ml) carries out labelling, and continues to hatch 30 minutes at 37 ℃.Cell then washs three times with ice-cold PBS/20mM glucose, and dissolves 30 minutes under room temperature in 100 μ l dissolving (lysis) buffer (50mM Hepes pH7.6,1%Triton X-100).The radioactivity of solute adopts scintillation counting technique to carry out quantitatively.
In case 14The C-2-DDG is changed in the cell, just can not be released.
Therefore, glucose transport is directly proportional with the radioactivity of lysate.
The result:
Chemical compound 1 and chemical compound 2 shows the glucose transport activity that can increase 3T3 L1 adipose cell (commerce can purchase hiv protease inhibitor class medicine indinavir, ritonavir or amprenavir can suppress described activity).Generally believe that these medicines can bring out the insulin resistance Metabolic disorder relevant with other in those accept the patient body of hiv protease inhibitor for treating, for example lipodystrophy and hypertriglyceridemia.
The result is summarized as follows:
Indinavir
Chemical compound 5 μ M indinavirs 10 μ M indinavirs 20 μ M indinavirs
1 1.34 50nM insulin doubly 1.16 50nM insulin doubly 1.12 50nM insulin doubly
2 1.38 50nM insulin doubly 1.25 50nM insulin doubly 1.02 50nM insulin doubly
Amprenavir
Chemical compound 5 μ M amprenavirs 10 μ M amprenavirs 20 μ M amprenavirs
1 1.83 50nM insulin doubly 1.53 50nM insulin doubly 1.21 50nM insulin doubly
2 1.25 50nM insulin doubly 1.07 50nM insulin doubly -
Ritonavir
Chemical compound 5 μ M ritonavirs 10 μ M ritonavirs 20 μ M ritonavirs
1 1.32 50nM insulin doubly - -
Embodiment 3
Chemical compound 3
The preparation of chemical compound 3
Except 7-{[(7-chlorine sulphonyl)-5-hydroxyl (2-naphthyl) amino] carbonyl amino }-4-hydroxyl naphthalene-2 sulfonic acid chloride is synthetic last several steps (being described in down) afterwards, and similar method is synthesized among chemical compound 3 employings and the embodiment 1.
5-{[(7-{[N-(7-{[(3-carboxyl-4-chlorphenyl) amino] sulphonyl }-5-hydroxyl (2-naphthyl)) carbamyl] amino }-4-hydroxyl (2-naphthyl) sulphonyl) amino]-the 2-chlorobenzoic acid.To 0.15g (0.277mmol) 7-{[(7-chlorine sulphonyl)-5-hydroxyl (2-naphthyl) amino] carbonyl amino-4-hydroxyl naphthalene-2 sulfonic acid chloride in, add the fresh distillatory THF of 1.5ml, add 0.105g (0.610mmol) 5-amino-2-chlorobenzoic acid subsequently.In this solution, add 67 μ l (0.831mmol) pyridines.Reactant liquor at room temperature stirred 16 hours.Then, reactant distributes in 1N HCl (aqueous) and ethyl acetate.Reextraction is carried out with ethyl acetate in the water-bearing layer, merges organic layer MgSO 4Carry out drying, filter, the volatile matter rotary evaporation is to doing.Obtain 0.14g expection product.
Embodiment 4
Reverse the insulin resistance of the normal rat that protease inhibitor brings out with chemical compound 1
7 to 10 ages in week male CD rat (Charles River laboratory, Hollister CA) are used to study the influence of protease inhibitor and chemical compound 1.Animal was raised with the cycle of 12h/12h sunshine/dark, and hunger is spent the night.
Indinavir sulfate is added to the water standby, and chemical compound 1 joins among the PBS standby.Every kind of treatment condition adopts 7 animals (average weight 300 grams).Animal is used excipient or indinavir sulfate or indinavir sulfate, and to add chemical compound 1 oral.After 30 minutes, animal oral glucose (2g/kg) carried out blood sugar test by tail blood at 0,10,20,30,60,90 and 120 minute.Blood sugar test adopts blood-glucose meter and blood sugar test paper (Bayer).The result is presented among Fig. 1 and 2.
After Fig. 1 showed oral glucose, indinavir was to the influence of blood sugar level.Blood sugar level is represented with the percent value of " 0 time " blood glucose.
Fig. 2 shows that indinavir and indinavir add the influence of chemical compound to plasma insulin level.(ALPCO Diagnostics, Windham NH) have carried out the plasma insulin level analysis to 0 and 30 minute blood glucose specimen (blood sample) with the ELISA method.

Claims (24)

1. an Insulin receptor INSR activated compounds or its pharmaceutically acceptable salt are used for the treatment of by the application in the medicine of the disease of using the hiv protease inhibitor to bring out, wherein said chemical compound and non-insulin in preparation.
2. according to the described application of claim 1, wherein said disease of being brought out by use hiv protease inhibitor is selected from the group that is made of insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia.
3. according to claim 1 or 2 described application, wherein said Insulin receptor INSR activated compounds is a kind of chemical compound with following structural
Structural formula I
Wherein:
R 1And R 2Be the substituent group on the A ring, be independently of one another-SO 2NR 7 2,-C (O) NR 7 2,-NR 7SO 2R 7,-NR 7C (O) R 7,-SO 2OR 7,-C (O) OR 7,-OS 2OR 7Or-OC (O) R 7,
R 3And R 4Be hydrogen or low alkyl group independently of one another, or R 3And R 4Be together-(CH 2) 2-,-(CH 2) 3-or-(CH 2) 4-,
R 5And R 6Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, cyano group, halogen, nitro ,-SR 8,-C (O) R 8,-SO 2OR 8,-OSO 2R 8,-SO 2NR 8 2,-NR 8SO 2R 8,-OC (O) R 8,-C (O) OR 8,-C (O) NR 8 2,-NR 8C (O) R 8,-OR 8, or-NR 8 2,
Each R 7And R 8Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, heteroaryl or substituted heteroaryl
Each Y is a non-interfering substituent,
Each x is 0,1 or 2 independently of one another, and
The carbon atom that the carbamide linker will be numbered c couples together with the carbon atom that is numbered d,
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers form or stereoisomer mixture.
4. according to the described application of claim 3, wherein in described chemical compound, there is not Y to be connected on the naphthalene nucleus by the azo linker.
5. according to each described application, wherein R in claim 3 or 4 1And R 2All be-SO 2OH,
(i) Y is not-SO 2OH;
(ii) R 5And R 6Be not-SO 2OR 8Or-OSO 2R 8With
(iii) wherein (Y) xNot (Y ') X ', x ' 1 wherein or 2 and Y ' be a halogen, R 5And R 6Be not selected from the group of forming by hydroxyl and hydrogen simultaneously.
6. according to claim 1 or 2 described application, wherein said Insulin receptor INSR activated compounds is the chemical compound with following structural formula
Structural formula II
Wherein:
R 1And R 2Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl ,-C (O) R 4,-C (O) OR 4,-C (O) NR 4R 5,-S (O) 2R 4,-S (O) 2OR 4, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl or low-grade alkenyl or R 1And R 2With the nitrogen that connects is C 3-C 9Heteroaryl, C 3-C 5Heterocyclic radical or-NO 2,
R 3Be a substituent group on the B ring, for-SO 2OR 6,-C (O) OR 6,-SO 2NR 6 2,-C (O) NR 6 2, or tetrazolium;
Each between naphthalene nucleus and the phenyl ring-A ring on WY-linker and the naphthalene nucleus links to each other, and can be-C (O) NR independently 7-,-NR 7C (O)-,-C (O) O-,-OC (O)-,-CH=CH-,-NR 7CH 2-,-CH 2NR 7-,-NR 7C (O) NR 7-,-NR 7C (O) O-,-OC (O) NR 7-,-NR 7SO 2O-,-OSO 2NR 7-,-OC (O) O-,-SO 2NR 7-,-NR 7SO 2-,-OSO 2-or-SO 2O-,
Each R 4And R 5Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, substituted heteroaryl, heteroaryl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical or low-grade alkenyl
Each R 6And R 7Be independently of one another, hydrogen or low alkyl group,
Each R 8Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, substituted heteroaryl, heteroaryl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, low-grade alkenyl, nitro, halogen, cyano group ,-OR 9,-SR 9,-C (O) R 9,-OC (O) R 9,-C (O) OR 9,-NR 9 2,-C (O) NR 9 2,-NR 9C (O) R 9,-OSO 2R 9,-SO 2OR 9,-SO 2NR 9 2, or-NR 9SO 2R 9,
Each R 9Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, virtue (rudimentary) alkyl of mixing, the assorted virtue of replacement (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, virtue (rudimentary) alkyl or replacement virtue (rudimentary) alkyl
Each Z is non-interfering substituent,
Each x and v are 0,1,2 or 3 independently of one another, and
R 10Be aryl, substituted aryl, heteroaryl or substituted heteroaryl,
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers form or stereoisomer mixture.
7. according to each described application in claim 1 or 2, wherein said Insulin receptor INSR activated compounds is the chemical compound with following structural formula
Structural formula II I
Wherein
R 1And R 2Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl or low-grade alkenyl, perhaps R 1And R 2With the nitrogen that connects is C 3-C 9Heteroaryl or C 3-C 5Heterocyclic radical,
Z is OH, halogen, OR 1Or NR 1R 2,
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers form or stereoisomer mixture.
8. according to each described application in claim 1 or 2, wherein said Insulin receptor INSR activated compounds is the chemical compound with following structural formula
Structural formula IV
Wherein
R 1, R 3And R 4Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, halogen, hydroxyl, substituted alkoxy, carboxyl ,-NR 11R 12, or-C (O) NR 11R 12,
R 2For hydrogen, low alkyl group, substituted alkyl, halogen, hydroxyl, substituted alkoxy, carboxyl ,-NR 11R 12,-NR 11C (O) R 12, or-C (O) NR 11,
R 5Be hydrogen, low alkyl group, replacement low alkyl group or aryl,
R 6And R 7Be hydrogen or carboxyl independently of one another,
R 8And R 9Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, halogen, hydroxyl, alkoxyl, carboxyl ,-NR 11R 12,-C (O) NR 11R 12,
R 10For low alkyl group, replace low alkyl group, halogen, carboxyl ,-C (O) NR 11R 12,
R 11And R 12Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, heteroaryl or replace assorted virtue-C (O)-aryl or aryl
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers or the form of stereoisomer mixture.
9. according to each described application in claim 1 or 2, wherein said Insulin receptor INSR activated compounds is the chemical compound with following structural formula
Structural formula V
Wherein
The condensed ring of 5-6 unit's aryl of Y ring expression or heteroaryl, it optionally is selected from R by 1-4 1Group replace,
X represents O, S (O) mOr N, wherein m is 0,1 or 2;
A represents a material that is selected from the group that is made of following material:
(a) list of a 6-10 unit or bicyclic aryl
(b) isolated bicyclic heteroaryl of 5-6 unit
(c) a 9-10 unit bicyclic heteroaryl is coupled by one 6 yuan rings, or
(d) 8 yuan of bicyclic heteroaryls, described heteroaryl have 1-4 and are selected from O, S (O) mWith the hetero atom of N, described aryl and heteroaryl can be by 1-3 R 1Based selective ground replaces
R 1Be independently selected from:
Halogen ,-OH ,-C 1-12Alkyl (R 2) 3,-C 2-10Alkenyl (R 2) 3,-C 2-10Alkynyl (R 2) 3,-C 6-10Alkyl (R 2) 3,-heteroaryl (R 2) 3,-heterocyclic radical (R 2) 3,-NH 2,-NHC 1-6, alkyl (R 2) 3,-N (C 1-6Alkyl (R 2) 3) 2,-N 3,-OC 1-6Alkyl (R 2) 3,-S (O) mH, S (O) mC 1-6Alkyl (R 2) 3,-CHO ,-C (O) C 1-6Alkyl (R 2) 3,-CO 2H ,-C (O) OC 1-6Alkyl (R 2) 3,-C (O) SC 1-6Alkyl (R 2) 3,-C (O) NH 2,-C (O) NHC 1-6Alkyl (R 2) 3,-NHC (O) C 1-6Alkyl (R 2) 3,-S (O) mNH 2,-NHS (O) mC 1-6Alkyl (R 2) 3, S (O) mNHC 1-6Alkyl (R 2) 3With-S (O) mN (C 1-6Alkyl (R 2) 3) 2
Wherein m is 0,1 or 2;
R 2Be independently selected from:
H, OH, halogen ,-C 1-4Alkyl ,-C 2-4Alkenyl ,-C 2-4Alkynyl ,-CF 3,-OCF 3,-NO 2,-N 3,-CHO ,-OC 1-6Alkyl ,-S (O) mC 1-6Alkyl ,-NH 2,-NHC 1-6Alkyl ,-N (C 1-6Alkyl) 2,-C (O) C 1-6Alkyl ,-CO 2H ,-CO 2C 1-6Alkyl ,-C (O) NH 2,-C (O) NHC 1-6Alkyl ,-C (O) N (C 1-6Alkyl) 2,-OC (O) C 1-6Alkyl ,-NHC (O) C 1-6Alkyl ,-S (O) mNH 2,-S (O) mNHC 1-6Alkyl ,-S (O) m(C 1-6Alkyl) 2, aryl, heteroaryl and heterocyclic radical,
Wherein m is 0,1 or 2,
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers form or stereoisomer mixture.
10. according to each described application in claim 1 or 2, wherein said Insulin receptor INSR activated compounds is the chemical compound with following structural formula
Figure A018171410008C1
Structural formula VI
Wherein
R 1Be hydrogen or methyl
R 2Be-CH 2CH 3Or-CH=CH 2
R 3Be-CH=CH-C (CH 3)=CH 2CH 2-CH=C (CH 3) 2Or-CH 2-CH 2-CH=C (CH 3) 2,
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers form or stereoisomer mixture.
11. according to each described application in claim 1 or 2, wherein said Insulin receptor INSR activated compounds is the chemical compound with following structural formula
Figure A018171410009C1
Structural formula VII
Wherein
Q and Q ' are hydrogen or following structure:
R 1And R 2Be independently of one another :-SO 2NR 7 2,-C (O) NR 7 2,-NR 7SO 2R 7,-SO 2OR 7,-C (O) OR 7,-PO 3R 7 2, or tetrazolium
R 3And R 4Be independently of one another :-SO 2NR 7 2,-C (O) NR 7 2,-NR 7C (O) R 7,-SO 2OR 7,-C (O) OR 7,-PO 3R 7 2, or tetrazolium
R 5And R 6Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, cyano group, halogen, nitro ,-SR 8,-C (O) R 8,-SO 2OR 8,-OSO 2R 8,-SO 2NR 8 2,-NR 8SO 2R 8,-OC (O) R 8,-C (O) OR 8,-C (O) NR 8 2,-NR 8C (O) R 8,-OR 8, or-NR 8 2,
Each R 7And R 8Be independently of one another: hydrogen, low alkyl group, replacement low alkyl group, aryl, substituted aryl, virtue (rudimentary) alkyl, replace virtue (rudimentary) alkyl, assorted virtue (rudimentary) alkyl, replace assorted virtue (rudimentary) alkyl, heterocyclic radical, substituted heterocyclic radical, heteroaryl or substituted heteroaryl
Each Y is a non-interfering substituent, and
Each x is independently of one another, 0,1 or 2,
Or its pharmaceutically acceptable salt, selectively be the form of its single stereoisomers form or stereoisomer mixture.
12. according to each described application in the claim 1 to 11, wherein said medicine further comprises the treatment medicine to the additional form of insulin resistance, hyperglycemia, diabetes, ketoacidosis, lipodystrophy and hypertriglyceridemia.
13. according to the described application of claim 12, the dose therapeutically effective when the treatment medicine that the dose therapeutically effective of the treatment medicine of wherein said additional form with chemical compound drug combination of the present invention the time can be lower than described additional form is used for the treatment of patient separately.
14. according to the described application of claim 12, the treatment medicine of wherein said additional form is an insulin.
15. according to the described application of claim 12, the treatment medicine of wherein said additional form is the analog of insulin.
16. according to each described application in claim 14 or 15, the dose therapeutically effective when wherein said insulin or the insulin analog dose therapeutically effective with chemical compound drug combination of the present invention the time can be lower than insulin or insulin analog and is used for the treatment of patient separately.
17. according to each described application in the claim 1 to 11, wherein said medicine further comprises second chemical compound that uses among the claim 3-11.
18. according to each described application in the claim 1 to 4, wherein said chemical compound is
Figure A018171410011C1
Chemical compound 1.
19. according to each described application in the claim 1 to 4, wherein said chemical compound is
Figure A018171410011C2
Chemical compound 2.
20. according to each described application in the claim 1 to 4, wherein said chemical compound is
Chemical compound 3.
21. pharmaceutical composition, comprise a kind of Insulin receptor INSR activated compounds or its pharmaceutically acceptable salt, and a kind of pharmaceutically acceptable carrier, being used for the treatment of by the disease of using the hiv protease inhibitor to bring out, wherein said chemical compound is not an insulin.
22. a pharmaceutical composition comprises each described a kind of chemical compound or its pharmaceutically acceptable salt in claim 3 to 11 or 18 to 20, and a kind of pharmaceutically acceptable carrier, is used for the treatment of by the disease of using the hiv protease inhibitor to bring out.
23. a treatment comprises Insulin receptor INSR activated compounds or its pharmaceutically acceptable salt of using dose therapeutically effective by the method for the disease of using the hiv protease inhibitor to bring out, wherein said chemical compound is not an insulin.
24. method according to claim 23, wherein said Insulin receptor INSR activated compounds are each described chemical compound or its pharmaceutically acceptable salts in claim 3 to 11 or 18 to 20.
CNA018171419A 2000-10-11 2001-10-10 Insulin receptor activators for the treatment of human body metabolic disorder resulting from treatment of HIV infection with HIV protease inhibitors Pending CN1723059A (en)

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IT2001TO000950A ITTO20010950A1 (en) 2000-10-11 2001-10-09 INSULIN RECEPTOR ACTIVATORS FOR THE TREATMENT OF METABOLIC DISORDERS IN HUMAN BEINGS RESULTING FROM THE TREATMENT OF INFECTIONS FROM
FR0113040A FR2814953A1 (en) 2000-10-11 2001-10-10 Use of compounds, known to activate insulin receptors, to treat disorders due to the administration of human immunodeficiency virus protease inhibitors, e.g. insulin resistance, diabetes, keto-acidosis or lipodystrophia
JP2002533952A JP2004510831A (en) 2000-10-11 2001-10-10 Insulin receptor activators for the treatment of metabolic disorders in humans resulting from treatment of HIV infection with HIV protease inhibitors
AU2002211922A AU2002211922A1 (en) 2000-10-11 2001-10-10 Insulin receptor activators for the treatment of metabolic disorders in humans resulting from treatment of HIV infection with HIV protease inhibitors
PCT/US2001/042733 WO2002030514A2 (en) 2000-10-11 2001-10-10 Insulin receptor activators for the treatment of metabolic disorders in humans resulting from treatment of hiv infection with hiv protease inhibitors
EP01980019A EP1355698A2 (en) 2000-10-11 2001-10-10 Insulin receptor activators for the treatment of metabolic disorders in humans resulting from treatment of hiv infection with hiv protease inhibitors
CNA018171419A CN1723059A (en) 2000-10-11 2001-10-10 Insulin receptor activators for the treatment of human body metabolic disorder resulting from treatment of HIV infection with HIV protease inhibitors
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