CN1095710A - Enzyme Inhibitors - Google Patents

Enzyme Inhibitors Download PDF

Info

Publication number
CN1095710A
CN1095710A CN93121643A CN93121643A CN1095710A CN 1095710 A CN1095710 A CN 1095710A CN 93121643 A CN93121643 A CN 93121643A CN 93121643 A CN93121643 A CN 93121643A CN 1095710 A CN1095710 A CN 1095710A
Authority
CN
China
Prior art keywords
isothiourea
ethyl
group
methyl
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN93121643A
Other languages
Chinese (zh)
Inventor
E·P·加维
G·J·塔努力
J·A·奥普林格
E·S·富法恩
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wellcome Foundation Ltd
Original Assignee
Wellcome Foundation Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB929224948A external-priority patent/GB9224948D0/en
Priority claimed from GB939315159A external-priority patent/GB9315159D0/en
Priority claimed from GB939319663A external-priority patent/GB9319663D0/en
Application filed by Wellcome Foundation Ltd filed Critical Wellcome Foundation Ltd
Publication of CN1095710A publication Critical patent/CN1095710A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/30—Isothioureas
    • C07C335/32—Isothioureas having sulfur atoms of isothiourea groups bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Disclose isothiourea derivatives and in medical science, especially the application aspect the disease treatment that helps suppressing nitric oxide synthetase also discloses the pharmaceutical preparation and the manufacture method thereof that contain this analog derivative.

Description

Enzyme inhibitors
The present invention relates to isothiourea derivatives, its preparation method, contain the pharmaceutical preparation of these derivatives, and their application aspect disease treatment, particularly they are as the application of nitric oxide synthase inhibitor activity.
From the eighties in 20th century, people are known, and the vasorelaxation due to the vagusstoff is relevant with the existence of endothelium, and this active in the volatility humoral factor owing to so-called endothelium derivation relaxing factor (EDRF).Nitrogen protoxide (NO) is as the activity of vasodilator, knownly exceeded over one hundred year, and NO still is the active ingredient of amyl nitrite, Sanya glycerin trinitrate and other nitro vasodilator.Recently identifying EDRF is NO, and this is just in time with finding that NO is that the NO synthetic enzyme uses amino acid L-arginine synthetic biological chemistry by way of perfectly in harmony by enzyme.
NO is the interior living yield stimulant of solubility guanine nucleosides acid esters (salt) cyclase, and the many biological actions of participation except the endothelium-dependent relaxation diastole, comprise that the interchange between cytophagous cytotoxicity and the central nervous system cell (sees Moncada etc., Biochemical Pharmacology, 38,1709-1715(1989), and Moncada etc., Pharmacological Review, 43,109-142(1991)).Now, it is believed that, in numerous disease, might produce excessive NO, especially relate to systemic ypotension (systemic hypotension) as sepsis (poison) the property shock and the disease of usually treating with some cell.
By the synthetic NO of L-arginine, can be the L-arginine that is similar to L-N-monomethyl arginine (L-NMMA) and suppress, thereby existing people proposes that (WO 91/04024 and GB-A-2240041) treats the systemic ypotension of septic shock and other type with L-NMMA.Except that L-NMMA, some is used for the application of same purpose NO synthetase inhibitors in treatment, also proposes in WO 91/04024 and EP-A-0446699.
Make clear recently, the NO synthetic enzyme has following three classes at least:
(ⅰ) be arranged in a kind of basic Ca of endothelium ++/ calmodulin dependent enzyme, it disengages NO when replying acceptor or physical stimulation.
(ⅱ) be positioned at a kind of basic Ca of brain ++/ calmodulin dependent enzyme, it disengages NO when replying acceptor or physical stimulation.
(ⅲ) a kind of Ca of institute's inductive after vascular smooth muscle, scavenger cell endotheliocyte and many other cells are by intracellular toxin and cytokine activation ++The dependent/non-dependent enzyme.This inducibility NO synthetic enzyme in case expressed, promptly can synthesize NO for a long time.
By the various basic NO that enzyme disengaged, play a part to obey some physiologic response of transduction mechanism.But, then play the cytotoxic molecule effect (Wright etc., the Card.Res.26 that restrain tumour cell and invading micro-organism by the NO that inducible enzyme produces, 48-57(1992) and Moncada etc., Pharmacological Review, 43,109-142(1991)).As if also show, produce the undesirable action of too much NO, especially pathologic vessels diastole and tissue injury might be mainly caused by the effect of the synthetic NO of synthetic enzyme institute that can induce NO.
So far, people propose the NO synthetase inhibitors, the especially L-NMMA that use for treatment, do not have a selectivity, and they had both suppressed basic NO synthetic enzyme, suppressed inductible NO-synthase again.Use a kind of like this NO synthetase inhibitors of non-selectivity, need extreme care, in order to avoid because of excessively suppressing the potential serious consequence that basic NO synthetic enzyme produces, comprising ypotension, thrombosis, CNS toxicity and tissue injury.Particularly, when L-NMMA should be used for curing septic shock, be recommended in the whole therapeutic process necessary continuous monitoring patient's blood pressure in treatment.Therefore, non-selectivity NO synthetase inhibitors, under the prerequisite of suitably noting, has the practicality in the treatment, and suppressing to induce the NO synthetic enzyme to have much bigger optionally NO synthetase inhibitors than the basic NO synthetic enzyme of inhibition, then in treatment, have bigger benefit, and greatly facilitate use.
The preparation of isothiourea and biological property are reported (Schroeder, Chem.Revs., 1955,55,181 in the literature; Doherty etc., J.Am.Chem.Soc., 1957,79,5667; And Brand and Brand, Org.Synth., 1942,22,59; Smirk etc., Brit.Med.J.1941,510-11; J.Physiol., 1942,100,474-483; Lancet, 1942,301-303; J.Physiol., 1943,101,379-388; Fastier, Brit.J.Pharmacol., 1948,3.198).We have now found that isothiourea is the inhibitor of NO synthetic enzyme, and can be used for the therapy system ypotension, and are particularly useful for treating septic shock.In addition, compare with basic NO synthetic enzyme, the chemical compound lot in these compounds is all to inducing the NO synthetic enzyme to have selectivity.
Therefore, the invention provides and a kind of needs are suppressed the treatment of diseases method of nitric oxide synthetase, this method comprise throw give the Mammals significant quantity, to adoptable salt on the inhibited isothiourea derivatives of NO synthetic enzyme or its pharmacology.On the other hand, the present invention proposes of the application of the inhibited isothiourea of NO synthetic enzyme for the medicine of making a kind of treatment disease that helps suppressing the NO synthetic enzyme.
More particularly, the present invention proposes the method for a kind of therapy system ypotension and/or septic shock, this method comprise throw to give the Mammals significant quantity, to adoptable salt on the inhibited isothiourea derivatives of NO synthetic enzyme or its pharmacology.On the other hand, the present invention proposes the application of isothiourea derivatives with NO synthase inhibitory activity for the medicine of manufacturing system ypotension and/or septic shock.
Help suppressing comprising with TNF, IL-1 and IL-2 and so on cytokine and treat by other situations that the L-arginine produces NO, perhaps use the cytokine inductor as 5, the treatment that 6-dimethyl ton ketone acetate carries out, and in transplantation treatment, make short-term immunosuppression assistant agent.In addition, suppressing NO synthetic compound also can be used to reduce and suffers from excessive NO and promote disease to manage physiological inflammatory disease such as adult respiratory distress syndrome (ARDS) and the intravital NO concentration of myocarditic patient.
Show on evidence that also the NO synthetic enzyme may participate in the cartilage sex change of generation in autoimmunity and/or inflammatory diseases such as sacroiliitis, rheumatoid arthritis, chronic enteron aisle disease and the systemic lupus erythematous (SLE).It is also believed that the NO synthetic enzyme may participate in insulin-dependent diabetes.Therefore, one side more of the present invention, isothiourea derivatives or its salt are provided, be used for carrying out cytokine or cytokine inductive treatment, in transplantation treatment, make short-term immunosuppression assistant agent with manufacturing, for treating the inflammatory diseases patient who suffers from excessive NO and promote the illness physiopathology, the medicine that is used for autoimmunity and/or inflammatory indication and insulin-dependent diabetes.
There is an aspect to be again, treatment and the relevant undesirable action of cytokine treatment are provided, transplantation treatment is immunosuppressant a middle or short term, treatment suffers from the inflammatory diseases patient that excessive NO promotes the illness physiopathology, the method of treatment autoimmunity and/or inflammatory symptoms disease and treatment pancreas islet dependent diabetes mellitus, this method comprise throw the Mammals significant quantity of giving needs, to adoptable salt on the inhibited isothiourea derivatives of NO synthetic enzyme or its pharmacology.
" treatment " used herein patient, meaning promptly comprises prevention; " Mammals " meaning promptly comprises the human or animal.
Preferred isothiourea comprises formula I
Figure 931216435_IMG10
Shown isothiourea or its salt are in the formula
R is (1) C 1-14Alkyl; Or
(2) 5-save and 6 heterocycles that save; Or
(3) one the 9 two heterocycle of joint systems
Above-mentioned each R group can be one or two group that is selected from following groups separately respectively and replaces:
(a) halogen;
(b)-XR 1, wherein
X is an oxygen; C(O) m, m is 1 or 2 in the formula; S(O) n, n is 0,1 or 2 in the formula; Perhaps NR 2, R in the formula 2Be hydrogen, C 1-6Alkyl or C 3-6Cycloalkyl, perhaps R 2Link R 1On, form a C 2-6Alkylidene group;
R 1Be hydrogen; Or C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl, C 7-9Aralkyl, C 6-10Aryl or one 5 joint or 6 joint heterocyclic groups, above-mentioned each group can be randomly replaced by one or two groups that are selected from following groups separately respectively: C 1-3Alkyl, hydroxyl, C 1-3Alkoxy grp, amino, C 1-3Alkylamino, halogen, nitro or C(O) m ' R 2bGroup, m ' is 1 or 2 in the formula, R 2bBe hydrogen or C 1-4Alkyl; Perhaps R 1Be a NR 3R 4Group, R in the formula 3And R 4Can be identical or different, and respectively be hydrogen or C 1-4Alkyl, perhaps R 3And R 4Link to each other, form a C 2-6Alkylidene group;
Figure 931216435_IMG11
Group is in the formula
Y is an oxygen; S(O) n, as above defined of n in the formula; Or NR 5, R in the formula 5Be hydrogen or C 1-4Alkyl;
W is 0 or 1;
Q is C 2-4Alkyl;
Perhaps imino-nitrogen is connected on R group or the Q group, forms one 5 and saves or 6 joint heterocycles; Perhaps
(d) group A, wherein A is heterocycle system, it can be randomly be group as defined above
Figure 931216435_IMG12
Replace; Perhaps
(e) C 1-6Alkyl, C 2-6Alkenyl or alkynyl group or C 3-6Cycloalkyl; Perhaps among the R, one of carbon atom is linked shown in the formula I on the imino nitrogen atom in the compound, forms one 5 joint or 6 joint heterocycles; Condition is that R is not a methyl.
Suitable R is
(1) C 1-8Alkyl;
(2) C 2-8Alkenyl or alkynyl group;
(3) one-(CH 2) p
Figure 931216435_IMG13
CH 3Group, wherein p is 0 to 4, q is 0 to 3; Perhaps
Save for (4) one 5 or 6 joint heterocycles,
Above-mentioned each group can be replaced by one or two identical or different following groups:
(a) halogen,
(b) OR 2b, R wherein 2bAs defined above;
(c) mR C(O) 2b, wherein m and R 2bAs defined above;
(d) nR S(O) 6, wherein n as defined above, R 6Be C 1-4Alkyl, this alkyl randomly are selected from amino or C(O as defined above respectively separately by one or two) mR 2bGroup replaces;
(e) NR 7R 8, R wherein 7And R 8And from being selected from hydrogen, C respectively 1-4Alkyl, C 2-4Alkenyl, C 1-4Alkoxyalkyl, perhaps R 7And R 8Link to each other, form one 5 and save or 6 joint heterocycles;
(f) phenyl ring or one 5 joint or 6 joint heterocycles, it can be randomly by OR as defined above 2bGroup replaces, perhaps by one
Figure 931216435_IMG14
Group replaces, and wherein Q as defined above; Perhaps imino-nitrogen links to each other with group Q, forms a thiazole or thiazoline ring; Perhaps
(g) C 1-4Alkyl, condition are that R is a heterocycle; Perhaps a carbon atom among the R is linked shown in the formula I on the imino-nitrogen in the compound, forms a thiazole or thiazoline ring.
Optimum R is
(1) C 1-4Alkyl;
(2) C 2-4Alkenyl,
(3) one
Figure 931216435_IMG15
CH 3Group, wherein p is 1 or 2, q is 0 or 1; Perhaps
Save for (4) one 5 or 6 joint heterocycles, wherein contain one or two nitrogen-atoms;
Above-mentioned each group can be randomly replaced by one or two identical or different following groups:
(a) halogen is preferably bromine;
(b) OR 2b 'Group, wherein R 2b 'Be hydrogen or methyl;
(c) mR C(O) 2b 'Group, wherein m and R 2b 'As defined above;
(d) SR 9Group, wherein R 9Be methyl or ethyl;
(e) NR 7bR 8bGroup, wherein R 7bAnd R 8bBe selected from hydrogen or C separately respectively 1-4Alkyl is preferably hydrogen, methyl or ethyl;
(f) one can randomly be an OR as defined above 2b 'Or one
Figure 931216435_IMG16
The phenyl ring that group replaces;
(g) contain one or two heteroatomic 5 joints or the 6 joint heterocycles that are selected from nitrogen or oxygen separately respectively; Perhaps
(h) C 1-4Alkyl is preferably methyl;
Perhaps a carbon atom among the R is linked on the imino-nitrogen of compound shown in the formula I, forms a thiazole or thiazoline ring.
Formula I comprise formula (I A), (I B), and (I C) shown in isothiourea derivatives.
Figure 931216435_IMG17
, R ' is a C in the formula 1-8Alkylidene group, perhaps a C 2-8Alkenylene or alkynylene, they contain or do not contain a phenyl ring, one 5 joint or 6 joint heterocycles, perhaps X group as defined above, wherein dotted line represent one pair of keys or a singly-bound.
The formula I also comprises formula II
Figure 931216435_IMG18
Shown compound or its salt, R in the formula aBe a C 1-8Alkyl, perhaps 5 joints or 6 joint heterocycles perhaps save bicyclic heterocycle system for one 9, and they are separately randomly by halogen or one or two-X aR 1aGroup replaces, wherein R 1aBe hydrogen, C 1-6Alkyl, C 3-6Cycloalkyl, C 7-9Aralkyl, C 6-10Aryl perhaps saves for one 5 or 6 joint heterocyclic groups, and this heterocyclic group is randomly by C 1-3Alkyl, C 1-3Alkoxyl group, amino, halogen or nitro replace, perhaps R 1aBe a NR 3aR 4aGroup, wherein R 3aAnd R 4aSame or different, and respectively be hydrogen or C 1-3Alkyl, perhaps R 3aAnd R 4aLink to each other, form a C 2-6Alkylidene group, and X aBe oxygen; C(O) m a, m wherein aBe 1 or 2; S(O) n a, n wherein aBe 0,1 or 2; Perhaps NR 2a, R wherein 2aBe hydrogen, C 1-6Alkyl or C 3-6Cycloalkyl, perhaps R 2aLink R 1aOn, form a C 2-6Alkylidene group perhaps is one
Group replaces, and wherein t is 0 to 4, W aBe 0 or 1, Y aBe oxygen, sulphur and NR 7a, R wherein 7aBe hydrogen or C 1-4Alkyl; Perhaps R aSulphur atom is linked shown in the formula I on the nitrogen-atoms in the compound, formed one 5 joint or 6 joint heterocycles, condition is R aIt or not methyl.
Preferred one group of compound is that wherein R is not those compounds of methyl, ethyl, propyl group or sec.-propyl.
Compound comprises shown in the preferred formula I:
The S-(2-aminoethyl) isothiourea
The S-(2-(dimethylamino) isothiourea propyl group)
S-(2-methyl-2-propenyl) isothiourea
S, S '-ethylene (isothiourea)
S, S '-pentamethylene two (isothiourea)
The S-(2-(dimethylamino) isothiourea ethyl)
2-amino-2-thiazoline
S, S '-hexamethylene two (isothiourea)
S, S '-1, the inferior heptyl two (isothiourea) of 7-
The S-benzylisothiourea
S-(2-morpholino ethyl) isothiourea
S-(6-methyl-2-(methylthio group)-and the 4-pyrimidyl) isothiourea
S, S '-(1,4 phenylene two (methylene radical), two isothioureas
S-tertiary butyl isothiourea
The S-(4-Ethylbenzyl) isothiourea
The S-((methylthio group) isothiourea methyl)
The S-(3-bromopropyl) isothiourea
The S-(2-bromotrifluoromethane) isothiourea
S-(3-methyl-2-butene base) isothiourea
S-allyl group isothiourea
The S-(3-aminopropyl) isothiourea
S, S '-(1,3-phenylene two (methylene radical)) two isothioureas
S, S '-(2-methylene radical-trimethylene) two isothioureas
S, S '-(2-butyne-1,4-subunit) two isothioureas
S, S '-(1,3-phenylene two (ethylene) two isothioureas
S, S '-(1,4-phenylene two (ethylene) two isothioureas
2-amino-5-methylthiazol
S-((2-amino-4-thiazolyl) methyl-L-halfcystine
3-((2-amino-4-thiazolyl) methyl-L-L-Ala
2-amino-4-methylthiazol
2-amino-4, the 5-dimethylthiazole
S-(2-(1H-pyrroles-1-yl) isothiourea ethyl)
The S-(3-hydroxypropyl) isothiourea
The S-(2-phenyl) isothiourea ethyl)
The S-(2-(3-p-methoxy-phenyl) isothiourea ethyl)
4-(2-amino-4-thiazolyl) methyl)-the L-high lactamine
N, N-1,3-phenylene two (methylene radical) two (S-methyl-isothiourea)
N, N-(1,3-phenylene two (methylene radical)) two (S-ethyl isothioureas)
S-(2-(5-((amidine sulfenyl) methyl)-and the 2-thienyl) ethyl) isothiourea
S-(3-(4-((amidine sulfenyl) isothiourea propyl group phenyl methyl)))
S-(3-(5-(2-amidine sulfenyl) ethyl)-and the 2-thienyl) propyl group) isothiourea
The S-(2-(4-fluorophenyl) isothiourea ethyl)
The S-(2-(4-bromophenyl) isothiourea ethyl)
The S-(2-(3-p-methoxy-phenyl) isothiourea ethyl)
The S-(2-(3-aminomethyl phenyl) isothiourea ethyl)
The S-(2-(4-ethoxyl phenenyl) isothiourea ethyl)
The S-(2-(4-p-methoxy-phenyl) isothiourea ethyl)
The S-(2-(2-bromophenyl) isothiourea ethyl)
The S-(2-(2-fluorophenyl) isothiourea ethyl)
The S-(2-(3-nitrophenyl) isothiourea ethyl)
S-(3-(1H-pyrroles-1-yl) isothiourea propyl group)
The S-(2-(2-chloro-phenyl-) isothiourea ethyl)
S-(2-(2, the 5-3,5-dimethylphenyl) ethyl) isothiourea
S-(2-(4-oxyethyl group-3-p-methoxy-phenyl) isothiourea ethyl), and their salt.
Particularly preferred compound, comprise S, S '-(1,3-phenylene two (1, the 2-ethylidene) two isothioureas, S, S '-(1,4-phenylene two (ethylene) two isothioureas, S-(2-(5-amidine sulfenyl) methyl)-and the 2-thienyl) ethyl) isothiourea, S-(3-(5-(2-amidine sulfenyl) ethyl)-the 2-thienyl) propyl group) isothiourea and S-(2 '-(3-p-methoxy-phenyl) ethyl) isothiourea.
Other preferably is used for treating the compound of septic shock, is S-ethyl isothiourea, S-propyl group isothiourea and S-isopropyl thiocarbamide, especially is S-ethyl isothiourea and S-isopropyl thiocarbamide, particularly S-ethyl isothiourea.
Term " alkyl " group, meaning i.e. a carbon atoms and hydrogen atom, but can contain two keys and/or three key, and can be ring-type or aromatic group in fact.
Term " heterocycle " meaning promptly contains 1 to 3 and is selected from oxygen, sulphur and nitrogen, is preferably the heteroatomic ring compound of nitrogen or sulphur.
Term " halogen " means fluorine, chlorine, bromine or iodine, is preferably bromine.
Compound shown in the formula I comprise many asymmetric centers of deciding on the definite implication of various groups in molecule, and formula I is intended to comprise various possible isomer.
Another aspect of the present invention, provide and removed benzylisothiourea, S, S(1,4-phenylene two (methylene radical)) two isothioureas and S-(2-(dimethylamino) ethyl) outside the isothiourea, have isothiourea or the acceptable salt of its pharmacology shown in the formula I that suppresses the effect of NO synthetic enzyme, is used for medicine.
On the other hand, the invention provides new compound shown in formula (I A), (the I B) and (I C) as defined above.These compounds comprise:
S, S '-(1,4-phenylene two (ethylene) two isothioureas
S-(2-(1H-pyrroles-1-yl) isothiourea ethyl)
S-((2-amino-4-thiazolyl) methyl)-the L-halfcystine
γ-(2 '-amino-4-thiazolyl) methyl)-the L-high lactamine
S, S '-(1,2-phenylene two (ethylene) two isothioureas
β-(2 '-amino-4 '-thiazolyl)-the L-L-Ala
S-(2 ' amino-5 '-(R, S)-the thiazolinyl methyl)-the L-halfcystine
4-((2-amino-4-thiazolyl) methyl)-the L-high lactamine
N, N-(1,3-phenylene two (methylene radical)) two (S-methyl-isothioureas)
N, N-(1,3-phenylene two (methylene radical)) two (S-ethyl isothioureas)
S-(3-(4-((amidine sulfenyl) isothiourea propyl group phenyl methyl)))
S-(2-(5-((amidine sulfenyl) methyl)-and the 2-thienyl) ethyl) isothiourea
S-(3-(5-((2-amidine sulfenyl) ethyl)-and the 2-thienyl) propyl group) isothiourea
S-((2-amino-4-thiazolyl) methyl)-the D-halfcystine
S-((2-amino-4-thiazolyl) methyl)-(D, L)-homocysteine
S-(2-(2-amino-4-thiazolyl) ethyl)-the L-halfcystine
The S-(2-(4-fluorophenyl) isothiourea ethyl)
The S-(2-(4-bromophenyl) isothiourea ethyl)
The S-(2-(3-p-methoxy-phenyl) isothiourea ethyl)
The S-(2-(3-aminomethyl phenyl) isothiourea ethyl)
The S-(2-(4-ethoxyl phenenyl) isothiourea ethyl)
The S-(2-(4-p-methoxy-phenyl) isothiourea ethyl)
The S-(2-(2-bromophenyl) isothiourea ethyl)
The S-(2-(2-fluorophenyl) isothiourea ethyl)
The S-(2-(3-nitrophenyl) isothiourea ethyl)
S-(3-(1H-pyrroles-1-yl) isothiourea propyl group)
S-(2-(4-oxyethyl group-3-p-methoxy-phenyl) isothiourea ethyl)
S-(2-(2,4, the 6-trimethylphenyl) ethyl) isothiourea
S-(2-(2, the 6-Dimethoxyphenyl) ethyl) isothiourea
And their salt.
The present invention includes salt form, especially the isothiourea of acid salt form.Suitable salt comprises that those are not only with organic acid but also the salt that generates with mineral acid.Such acid salt is generally all accepted by pharmacology, though the salt of not accepting on the pharmacology can be used when preparing and purifying related compound.Therefore, preferred salt comprises the salt that is generated by hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, trifluoroacetic acid, succsinic acid, oxalic acid, fumaric acid, toxilic acid, oxaloacetic acid, methylsulfonic acid, ethyl sulfonic acid, right-toluene sulfonic acide, Phenylsulfonic acid and isethionic acid.The salt of isothiourea can make the suitable compound of free alkali form and suitable acid be used for producing.
Though isothiourea of the present invention can former chemical substance be offerd medicine, be good with the pharmaceutical dosage forms administration.According on the other hand, the invention provides a kind of pharmaceutical preparation, the pharmacology acceptable salts or the solvate that wherein contain a kind of isothiourea of the present invention or a kind of isothiourea, and one or more pharmacology available carriers and one or more optional other treatment components.For example a kind of microbiotic, and/or a kind of body fluid supplementing liquid.Said carrier must with the meaning of other preparation components compatibility on " available ", and must not be harmful to its acceptor.
Preparation comprises that those are suitable for per os, parenteral (comprising subcutaneous, intracutaneous, intramuscular, intravenously and intraarticular), rectum and part (comprising skin, mouth, hypogloeeis and intraocular) form of administration, though optimum therapeutic regimen perhaps depends on the person's that for example is subjected to the medicine illness and obstacle.Preparation can provide with unit dosage form easily, and well-known any method prepares in the available field of pharmacology.All methods all comprise the step that formula I compound or its pharmacology available salt or solvate (" effective ingredient ") and the carrier that constitutes one or more ancillary components are made up mutually.Generally, preparation be by with effective constituent with liquid carrier or finely divided solid-state carrier or two kinds of even thorough mixing of carrier of solid, liquid, be required formulation with formed product where necessary then.
Be suitable for peroral administration preparation of the present invention, can provide by the form of discrete unit, for example capsule, cachet or tablet wherein respectively contain the activeconstituents of predetermined amount; For example pulvis or granula; Solution or suspension agent in for example liquid, aqueous or on-aqueous liquid; Or for example O/w emulsion agent or water in oil emulsion liquor.Effective constituent also can provide by the form of bolus, sugared agent or paste.
Tablet can randomly be made by compacting or molding with one or more ancillary components.The tablet of compacting can will randomly be mixed with tackiness agent in suitable machine, lubricant, and inert diluent, the free-flowing of lubricated, surfactivity or dispersion agent such as powder or particulate effective constituent are pressurizeed and are made.The tablet of molding can be made through the wetting powder compound of inertia liquid diluent by molding in suitable machine.Tablet can randomly be coated or indentation, and can be made into can be slowly or controlledly release and imitate the wherein formulation of effective constituent,
The preparation of confession parenteral admin comprises the sterile solution for injection of moisture and non-water, wherein can contain antioxidant, buffer reagent, bacteriostatic agent and can make preparation and be subjected to the medicine the isoosmotic solute of person's blood; And water quality or the agent of non-water disinfecting suspension, wherein can comprise suspension agent and thickening material.These formulations can be contained in the ampoule of the container of single dose or multidose such as soldering and sealing and the phial for using, and can preserve under freeze-drying (vacuum lyophilization) condition, need to add sterilize liquid carrier, for example salt solution, water for injection with preceding.As selection, these formulations can be for the usefulness of continuous infusion.
Interim injection liquid and suspension, the sterilizing powder of available the above-mentioned type, granula and tablet prepare.
For the formulation that rectum is used, the suppository form that can contain common carrier such as theobroma oil or polyoxyethylene glycol provides.
For local in the oral cavity, for example the formulation of cheek, sublingual administration comprises lozenge, wherein be added with the base-material of seasonings, as be added with in the Sudan Gum-arabic of sucrose or the tragacanth gum and contain effective constituent, and pastille, wherein in the base-material that adds Sudan Gum-arabic such as gelatin glycerol adding or sucrose, contain effective constituent.
Preferred single dose formulation is those formulations that contain the effective constituent of following appointment effective dose or its suitable divided dose.
Should be understood that, except top each composition of mentioning especially, also can comprise commonly used, relevant with the discussion type of dosage form other medicament in this area in each formulation of the present invention, for example be suitable for peroral administration formulation and can contain seasonings.
For above mentioned various diseases, dosage per os or administrated by injection that The compounds of this invention can 0.1-250mg/kg/d.Dosage range to the adult is generally 5mg-17.5g/d, is preferably 5mg-2g/d, most preferably is 10mg-1g/d.Tablet or other form of medication that provides with discrete units can contain the The compounds of this invention of appropriate amount easily, and it is for example to contain 5mg-500mg, and the dose of about 10mg-200mg or multidose are effective usually.
Compound shown in the formula I is preferably with per os or injection (intravenously or subcutaneous) mode administration.Giving accurate consumption with compound to patient, is attending doctor's responsibility.Yet all dosage is multifactorly decided on all, comprising patient's year order and sex, definite illness and severity thereof to be treated.Equally, also visual illness of dosage regimen and severity thereof and different.
The present invention also provides the preparation method of new compound as defined above of known preparation isothiourea derivatives method in this area.
Therefore, the derivative of compound shown in the formula I or its band blocking group can be by making thiocarbamide and compound R L(L ') R is as defined above in the r(formula; L and L ' are leavings group; for example halogen atom such as bromine, r is 0 or 1) reaction, remove blocking group when needing subsequently and prepare.
More particularly,
(ⅰ) formula (I A) as defined above
Shown in compound, can make thiocarbamide and a kind of wherein L, L ' and R as defined above compound L RL ' reaction prepare.Suitable is that this is reflected in polar solvent such as the ethanol, carries out to the solvent refluxing temperature at 20 ℃.
Compound shown in the formula LRL ' is commercially available and get, and perhaps available corresponding diol HO-R '-OH by in polar solvent such as methylene dichloride, reacts in the presence of halogenating agent such as carbon tetrabromide and triphenylphosphine and produces worthily.
Compound shown in formula HO-R '-OH is commercially available and get, and perhaps available method as known in the art prepares.
(ⅱ) compound shown in the formula (I B) as defined above
Can be with formula (I B1)
Figure 931216435_IMG22
Shown in compound remove blocking group and prepare, in the formula (I B1), the definition of R ' and dotted line as mentioned above, P and P ' are same or different, the two is blocking group, for example benzyl, carbobenzoxy-(Cbz) or tertbutyloxycarbonyl.This reaction can be in trifluoroacetic acid, for example under 0 ℃, the scavenging agent molecule is being arranged in the temperature of-20 ℃ to 100 ℃ non-extremes, and for example thioanisole and 1 carry out under existing.
When dotted line was represented singly-bound and substituting group in the 4-position, compound shown in the formula (I B1) can be used formula (I B2)
Shown compound prepares.In the formula (I B2), R ', P and P ' are as defined above.Trinitride is reduced into amine, and is cyclized into thiazoline, can carry out in the presence of triphenylphosphine in tetrahydrofuran (THF).
Compound shown in the formula (I B2), available formula (I B3)
Shown compound can be by using the trinitride negatively charged ion in the polar solvent such as dimethyl formamide, and in-20 ℃-200 ℃, for example the displacement tosylate prepares under the temperature of solvent refluxing, and in the formula (I B3), R, P and P ' are as defined above.
The preparation of the compound shown in the formula (I B3), available formula (I B4)
Figure 931216435_IMG25
Shown in the compound of (wherein R ', P ' and P as defined above), by adding the thiocyanate ion negatively charged ion producing a kind of open loop alkoxide, the p-methyl benzene sulfonic chloride that the form that this alkoxide can tolylsulfonyl derivative (I B3) is added captures.Compound shown in the formula (I B4) can prepare with the method known to the professional of this area.
When dotted line is singly-bound and substituting group on 5 time, the compound shown in the formula (I B1) can be used formula (I B5)
Figure 931216435_IMG26
Shown compound prepares, its method is to replace tosylate (Tetrahedron Asymmetry 1992 with the thiocyanate ion negatively charged ion, 749-752), this replacement(metathesis)reaction can be in polar solvent such as ethanol, in-20 ℃ to 200 ℃, for example carry out under the non-extreme temperature of solvent refluxing temperature, use subsequently similar in appearance to carrying out cyclisation with the method for formula (I B2) compound formula (I B) compound.The compound of formula (I B5) can be used corresponding epoxide, with the trinitride negatively charged ion with its open loop, again in polar solvent such as dimethyl formamide, in-20 ℃ to 200 ℃, for example under 100 ℃ the non-extreme temperature, capture alkoxide with p-methyl benzene sulfonic chloride and prepare (Tetrahedron Lett, 1990,31(2), 221).
When the substituting group on two keys of dotted line representative and the thiazole ring is on 5, formula (I B1) but compound through type (I B6) shown in chloroacetal
Figure 931216435_IMG27
Prepare with the thiocarbamide cyclisation, in formula (I B6), R ', P and P ' as defined above, R 10Be C 1-4Alkyl.This reaction can be carried out (Chem.Abs.54:14230d) under-20 ℃ to 200 ℃ non-extreme temperature in polar solvent such as acetone or alcohol.
Compound shown in the formula (I B6), available sulfuryl chloride and formula (I B7)
Figure 931216435_IMG28
Shown aldehyde prepares, and in the formula (I B7), R ', P and P ' be (Proc.Indian.Acad.Sci.1941,14A, 630-5 as defined above; Chem Abs.36: 410z).Compound is commercially available shown in the formula (I B7) obtains, and the known method of perhaps available this area professional prepares.
When the substituting group on two keys of dotted line representative and the thiazole ring is on 4, compound shown in the formula (I B1), available methods known in the art prepare, for example α-N-benzyloxycarbonyl-β-(2 '-amino-4 '-thiazolyl) alanine benzyl ester (Synthetic Communications 1990,20(30), 3097-3102).
(ⅲ) compound shown in the formula (I C)
Figure 931216435_IMG29
Can prepare as follows:
(a) when dotted line be singly-bound and substituting group on 4 time, use similar in appearance to method to prepare with compound shown in those compound formulas (I B) shown in the formula (I B4).
(b) when dotted line is represented at thiazoline ring 5 of singly-bound and substituting group, use similar in appearance to method to prepare with compound shown in the compound formula (I B) shown in the formula (I B5).
(c) when on the two keys of dotted line representative and substituting group 4 at thiazoline ring, compound shown in the through type (I C1)
Figure 931216435_IMG30
React with thiocarbamide and to prepare.Suitable is that this cyclization can in-20 ℃ to 200 ℃, for example carry out under 20 ℃ the non-extreme temperature in polar solvent such as acetone.
Compound shown in the formula (I C1) can methods known in the art, use general formula HO 2C-R '-CO 2Wherein R ' is as defined above for H() shown in compound prepare (J.Chem.Soc.1940,1304-7; Chem.Abs.35: 113 3).
(d) when dotted line be on two keys and substituting group 5 time at thiazoline ring, use similar in appearance to method to prepare with compound shown in the compound formula (I B) shown in the formula (I B6).
Compound shown in the formula I has contrasted the NO synthetic enzyme of separating in Placenta Hominis, brain and the cytokine inductive cancer cells as the activity of the NO synthetase inhibitors that exsomatizes, and verifies.
To only the present invention be described below with way of example:
Embodiment 1
Preparation S, S '-(1,4-phenylene two (ethylene)) two isothiourea dihydro bromine acidification things
With 1,4-phenylene oxalic acid (10.0g, 51.5mmol) at tetrahydrofuran (THF) (200ml), in solution in 0 ℃ with stir and to be added drop-wise to lithium aluminum hydride down (3.91g 103mmol) mixes in tetrahydrofuran (THF) (30ml) and in the suspension of formation.This mixture heating up was refluxed 3 hours, be chilled to 0 ℃ then.Slowly add entry (4.0ml), 15% sodium hydroxide (4.0ml) and water (12ml), make remaining lithium aluminum hydride quenching.Suspension is stirred 5 minutes, filtration and concentrated together with sal epsom.With the rough oily matter of silica gel chromatography (ethyl acetate/hexane gradient 50-100%) purification, obtain intermediate glycol (7.38g, 86%) transparent, colorless oil.This oily matter is dissolved in methylene dichloride (200ml), gained solution 0 ℃ down with carbon tetrabromide (32.4g, 97.7mmol) and triphenylphosphine (25.6g 97.7mmol) handles.Under 20 ℃, this mixture was stirred 4 hours, add pentane (500ml) then.Place after 15 hours, solution decantation from the brown solid thing is come out, concentrated and purify, obtain oily 1,4-phenylene two (ethylene) dibromide (8.2g, 64%) with silica gel chromatography (ethyl acetate/hexane gradient 0-20%).With this dibromide (4.0g, 13.7mmol) and thiocarbamide (2.09g 27.4mmol) is dissolved in the formed solution reflux of dehydrated alcohol (100ml) 2 hours, cools off and is concentrated into dried.Make initial oily matter recrystallize in ethanol, obtain white, crystalline solids 1,4-phenylene two (ethylene) two isothioureas two hydrobromates (2.89g, 47%), molten point=234-236 ℃.
1H NMR（200 MHz，D 2O）δ7.26（s，4H），3.38（t，J＝7.0Hz，4H），3.01（t，J＝7.0Hz，4H）。
C 12H 20Br 2N 4S 2The analytical calculation value: C, 32.44; H, 4.54; Br, 35.97; N, 12.61; 14.43.Measured value: C, 32.45; H, 4.59; Br, 35.89; N, 12.51; S, 14.35.
Embodiment 2
Preparation S-(2-amino-4-thiazolyl) methyl)-the L-halfcystine
By 2-amino-4-5-chloromethyl thiazole (Spraque, J.M. wait J.Am.Chem.Soc.1946,68,2155-2159) (1.0g, 5.4mmol) and L-cysteine hydrochloride (804mg, 5.1mmol) be dissolved in the solution that dimethyl formamide (10mL) become, add salt of wormwood (2.5g).Under 22 ℃, this suspension was stirred 18 hours.The gained mixture is concentrated into dried, heavy water-soluble, and is added on the ion exchange column (Dowex 50 * 8, strongly-acid).Ammonium hydroxide (0.1N-0.5N) wash-out of product with concentration gradient.The product cut that will compile gives partial concentration and cold do, the brown static electrification solids S-(2 '-amino-4 '-the thiazolyl methyl)-L-halfcystine (1.04g, 87%).
1H NMR（300 MHz，D 2O）δ6.5（s，1H），3.8（m，1H），3.6（s，2H），3.05-2.85（m，2H）。
Mass spectrum (CI) 234(M+1,71%).
Embodiment 3
Preparation γ-(2 '-amino-4 '-thiazolyl)-L-high lactamine (3-((2-amino-4-thiazolyl) methyl-L-L-Ala)
γ-(2 '-amino-4 '-thiazolyl)-the L-high lactamine, press the method for embodiment 6, with α-N-tert-butoxycarbonyl-γ-(2 '-amino-4 '-thiazolyl)-L-high lactamine benzyl ester prepares (Patt etc., Synth.Commun.1990,20(20), 3097-3102), yield is 9.6%.
1H NMR（D 2O）δ6.5（s，1H），3.9（t，J＝6.4Hz），2.75（m，2H），2.2（m，2H）。
C 7H 11N 3O 2SC 2HF 3O 20.3H 2The analytical calculation value of O: C, 29.31; H, 2.89; N, 8.54; S, 6.52.
Measured value: C, 29.37; H, 3.02; N, 8.53; S, 6.63.
Embodiment 4
Preparation S, S '-(1,3-phenylene two (ethylene)) two isothioureas, two hydrobromates
Press the method for embodiment 1, with 1,3-phenylene oxalic acid (Aldrich) preparation S, S '-(1,3-phenylene two (ethylene)) two isothioureas, two hydrobromates.In ethanol, behind the recrystallize, obtain white, crystalline solids (fusing point 194-190 ℃).
1H NMR（200 MHz，D 2O）δ7.4-7.2（m，4H），3.39（t，J＝6.9Hz，4H），3.02（t，J＝6.9Hz，4H）。
C 12H 20Br 2N 4S 2The analytical calculation value: C, 32.44; H, 4.54; Br, 35.97; N, 12.61; S, 14.43.
Measured value: C, 32.52; H, 4.49; Br, 36.04; N, 12.61; S, 14.35.
Embodiment 5
Preparation S, S '-(1,2-phenylene two (ethylene)) two isothioureas, two hydrobromates
Press the method for embodiment 1, with 1,2-phenylene oxalic acid (Aldrich) prepares S, S '-(1,2-phenylene two (ethylene)) two isothioureas, two hydrobromates, and productive rate is 30%, product is yellow foam.
1H NMR（300 MHz，D 2O）δ7.29（s，4H），3.38（t，J＝7.0Hz，4H），3.09（t，J＝7.0Hz）。Recrystallize in ethanol gets sample for analysis, fusing point=205-207 ℃.
C 12H 20Br 2N 4S 2The analytical calculation value: C, 32.44; H, 4.54; Br, 35.97; N, 12.61; S, 14.43.
Measured value: C, 32.47; H, 4.58; Br, 35.92; N, 12.58; S, 14.43.
Embodiment 6
Preparation β-(2 '-amino-4 '-thiazolyl) L-Ala (3-(2-amino-4-thiazolyl)-L-L-Ala)
Under nitrogen atmosphere and-88 ℃, stirring by α-N-tert-butoxycarbonyl-β-(2 '-amino-4 '-thiazolyl) alanine benzyl ester (1.47g) (Patt etc., Synth.Commun.1990,20(20), 2097-3102) be dissolved in the solution that methylene dichloride (15ml) is become, toward wherein adding triethyl silicane (3ml), add trifluoroacetic acid (3ml) again.Gained solution is arrived room temperature at 1 hour internal heating, concentrated then.Residue acetate (30ml), 20% Pd/C(2.0g) and 1 (20ml) processing.In 2 hours, with said mixture in addition sonication make it rise to 33 ℃ from room temperature, and filtration over celite washes with water.Filtrate is concentrated, dissolve in again in the 30ml acetate, and handle with fresh 20% Pd/C of 2.0g and 2ml 1.After 2 hours, using diatomite filtration suspension through sonication.Repeat to add live catalyst three times, then with repeating partly preparation property anti-phase chromatography (C-18 carries out wash-out with the water of 10% methyl alcohol/contain, 0.1% trifluoroacetic acid) purification crude product.The lyophilized products cut gets 337mg(18%) thickness glassy solids thing β-(2 '-amino-4 '-thiazolyl)-the L-L-Ala.
1H NMR（D 2O）δ 6.6（s，1H），4.0（t，J＝7.6Hz，1H），3.15（m，2H）。Mass spectrum (CI) 188(M+1).
C 12H 12N 3F 9O 8The analytical calculation value of S: C, 27.23; H, 2.29; N, 7.94; S, 6.06.
Measured value: C, 27.22; H, 2.42; N, 7.8; S, 5.67.
Embodiment 7
S, S '-(2,6-pyridylidene two (methylene radical)) two isothioureas
At 0 ℃, to by 2,6-pyridine dimethanol (5.0g, 35.9mmol) be dissolved in add in the solution that methylene dichloride (200ml) become carbon tetrabromide (23.83g, 71.9mmol) and triphenylphosphine (18.85g, 71.9mmol).Stirred solution, and at 6 hours internal heating to 20 ℃.Add pentane (300ml).Make solution under 20 ℃, leave standstill 16 hours, filter then, to remove solid impurity.Concentrated filtrate is to oily matter, and purifies with silica gel chromatography (hexane, 10% ethyl acetate/hexane then), canescence powdered solids 2,6-pyridine dibromide (4.47g, 47%).By 2, (3.94g 14.87mmol) is dissolved in the solution that ethanol (100ml) become 6-pyridine dibromide, adds thiocarbamide (2.26g, 29.74mmol), under refluxad, become suspension to stir 2 hours institute, the gained solution concentration is extremely done, get white powdered S, S '-(2,6-pyridylidene two (methylene radical) two isothioureas (5.3g, 83.9%).
1H NMR（200 MHz，DMSO）δ7.95（t，J＝7.6Hz，1H），7.51（d，J＝7.8Hz，2H），4.65（s，4H）。
C 9H 15N 5S 2Br 20.6H 2O analytical calculation value: C, 25.26; H, 3.81; N, 16.36; S, 14.98; Br, 37.34.
Measured value: C, 25.3; H, 3.78; N, 16.25; S, 14.94; Br, 37.38.
Embodiment 8
Preparation S-(2 '-amino-5 '-(R, S)-the thiazolinyl methyl)-the L-halfcystine
By 2-amino-5-iodomethyl thiazoline (4.44g, 12mmol) (Creeke ﹠amp; Mellor, Tet.Lett.1989,30(33), 4435-4438) and the L-cysteine hydrochloride (1.76g 10.0mmol) is dissolved in the solution that dimethyl formamide (75ml) become, add salt of wormwood (5.0g, 36mmol).Under 22 ℃, suspension was stirred 72 hours, and refluxed 30 minutes.Add acetonitrile and filtering mixt.Solids with warm methyl alcohol repetitive scrubbing gained.Use the alcohol dilution methanol solution, produce white precipitate, and remove it with filtration method.Filtrate (oily matter) after concentrating is dissolved in the methanol/ethanol, and handle with alcohol hydrochloric acid, till again not observing precipitation, filtering mixt then.The oily matter of concentrated filtrate gained is handled with ion exchange chromatography (Dowex 50 * 8, strongly-acid), with 0.1N ammonium hydroxide wash-out, thereby with its purification.Compile positive cut of triketohydrindene hydrate and freeze-drying, get 0.453g and mix the shallow brown solids that dimethyl formamide is arranged.This solids is with preparation property HPLC(high pressure lipuid chromatography (HPLC)) (the C18 anti-phase, methyl alcohol: water: trifluoroacetic acid/5: 95: 0.1) purify, 0.36g trifluoroacetic acid salt form S-(2 '-amino-5 '-(R, S)-thiazolinyl methyl)-L-halfcystine.TLC(ammonium hydroxide: Rf=0.5 methyl alcohol/1: 50).
1H NMR（200 MHz，D 2O）δ 4.37-4.24（m，1H），4.11-3.87（m，3H），3.27-3.13（m，2H），3.05-2.97（m，2H）。Mass spectrum (FAB) 236.0(M+1,48%).
C 7H 13N 3O 2S 23(C 2HF 3O 2) the analytical calculation value: C, 27.04; H, 2.79; N, 7.28; S, 11.11.
Measured value: C, 27.32; H, 2.91; N, 7.41; S, 11.17.
Embodiment 9
Preparation 4-((2-amino-4-thiazolyl) methyl)-the L-high lactamine
With (Synth such as Patt, Commun.1990,20(20), method 3097-3102), with the N-t-Boc-L-2-aminoadipic acid 1-tert-butyl ester (Ramsamy etc., Synthesis, 1982,42-43) preparation 4-((2-amino-4-thiazolyl) methyl)-N α-t-Boc-L-high lactamine tert-butyl ester, overall yield is 45%(1.3g).
The method that t-Boc and tert-butyl ester blocking group are removed is as follows:
At 1.68g 4-((2-amino-4-thiazolyl) methyl)-N α-t-Boc-L-high lactamine tert-butyl ester is dissolved in the solution that the 35ml diox become, and adds 1.1ml triethyl silicane and 8ml 4N Yan Suan dioxane solution.Filtering mixt stirs solids 16 hours down at 22 ℃ earlier, and the Yong diox washes again.To the nucleus magnetic resonance of crude samples, show that reaction not exclusively.Rough solids heavily is dissolved in the 20ml diox, handled 4 hours with 4N hydrochloric acid (5ml).Isolate solids with filtration method, it is soluble in water, and freeze-drying, get 1.23g white moisture absorptivity solids 4-((2-amino-4-thiazolyl) methyl)-L-high lactamine (dihydrochloride, hydration 1.4%(mol) water, and fused 0.3%(mol) diox).Analytical HPLC; Phenomenex C18, water/methyl alcohol/trifluoroacetic acid (95/5/0.1), k '=0.34.
1H NMR（300 MHz，DMSO-d 6）δ9.25（brs，2H），8.5（br s 2H），6.55（s，1H），3.93（m，1H），2.6（m，2H），1.8（m，4H）。
C 8H 13N 3O 2S2HCl1.4H 2The analytical calculation value of O0.3 diox: C, 32.51; H, 5.99; N, 12.36; S, 9.43; Cl, 20.86.
Measured value: C, 32.28; H, 5.72; N, 12.71; S, 9.60; Cl, 20.86.
Embodiment 10
Preparation N, N '-(1,3-phenylene two (methylene radical)) two (S-methyl-isothioureas)
Stirring down at 0 ℃ by 3.30g(25mmol) MXDP (Aldrich Chemical product) is dissolved in the solution that the 100ml methylene dichloride is become, to wherein adding 7.0ml(52mmol) benzoyl isothiocyanate.Under 20 ℃, mixture was stirred 18 hours, and removal of solvent under reduced pressure.Rough solids (faint yellow) is suspended in 100ml 10% sodium hydroxide solution, and refluxed 5 minutes.While hot with concentrated hydrochloric acid with the mixture acidifying, ammonium hydroxide is added in cooling back, makes it to be alkalescence.The white solid thing that collecting precipitation comes out, and in 60 ℃ of following drying under reduced pressure to constant weight, the solid-state two thiocarbamide intermediate products of 4.82g canescence.
C 10H 14N 4S 2The analytical calculation value: C, 47.22; H, 5.55; N, 22.03; S, 25.10.Measured value: C, 47.49; H, 5.50; N, 21.81; S, 25.01.
To 2.54g(10mmol) two thiocarbamide intermediate products are dissolved in the solution that the 25ml dimethyl formamide become, and add 5.0ml(80mmol) methyl iodide.Under 20 ℃,, and in hot ethanol, make the residue recrystallization with this solution stirring 65 hours, removal of solvent under reduced pressure.Under 60 ℃, the faint yellow crystallization of drying under reduced pressure gets 4.28g(81%) N, N '-(1,3-phenylene two (methylene radical)) two (S-methyl-isothioureas).Fusing point=164-167 ℃.TLC(produces a color spot with 1% ammonium hydroxide methanol solution on silica gel, Rf=0.48).
1H NMR（300 MHz，DMSO/D 2O）δ7.5-7.4（m，1H），7.35-7.2（m，3H），4.59（s，4H），2.65（s，6H）。
C 12H 18N 4S 21.9HI the analytical calculation value: C, 27.43; H, 3.82; N, 10.66; S, 12.20; 1,45.89.
Measured value: C, 27.30; H, 3.91; N, 10.57; S, 12.19; 1,45.92.
Embodiment 11
Preparation N, N '-(1,3-phenylene two (methylene radical)) two (S-ethyl isothiourea)
By 1.0g(3.93mmol) two thiocarbamides that make in embodiment 10 are dissolved in the solution of 20ml ethanol gained, add 6.29g(78.62mmol) iodic ether.This mixture heating up to reflux temperature, last 8 hours, and concentrating under reduced pressure is become foam.Crude product is purified with methanol dichloromethane solution (10% to 20%) with silica gel chromatography, gets 1.66g(74%) N, N '-(1,3-phenylene two (methylene radical)) two (S-ethyl thioureas).TLC(Rf=0.3-0.48,20% methanol dichloromethane solution).Mass spectrum (FAB) 311.2(M+1).
1H NMR（200 MHz，DMSO-d 6）δ 7.5-7.4（m，1H），7.31-7.22（m，3H），4.58（s，4H），3.20（q，J＝7.4Hz，4H），1.28（t，J＝7.4Hz，6H）。
C 14H 24N 4S 2The analytical calculation value of 2HI: C, 29.69; H, 4.27; N, 9.89; S, 11.32; 1,44.82.
Measured value: C, 29.44; H, 4.25; N, 9.64; S, 11.50; 1,44.65.
Embodiment 12
Preparation S-(3(4-((amidine sulfenyl) isothiourea propyl group phenyl methyl)))
With the method among the embodiment 1, use the 3-(4-carboxyl phenyl) propyl group (Lancaster Synthesis) preparation (3-(4-((amidine sulfenyl) methyl) phenyl) propyl group) isothiourea white solid thing (2.95g, fusing point=190-195 ℃).Mass spectrum (FAB) 283(M+1).
1H NMR（200 MHz，D 2O）δ7.38（d，J＝8.1Hz，2H），7.26（d，J＝8.1，Hz，2H），4.36（s，2H），3.06（t，J＝7.2Hz，2H），2.74（t，J＝7.4Hz，2H），2.1-1.9（m，2H）。
C 12H 18N 4S 2The analytical calculation value of 2HBr: C, 32.44; H, 4.54; N, 12.61; S, 14.43; Br, 35.97.
Measured value: C, 32.53; H, 4.58; N, 12.56; S, 14.34; Br, 35.85.
Embodiment 13
Preparation S-(2-(5-((amidine sulfenyl) methyl)-and the 2-thienyl) ethyl) isothiourea
Under 0 ℃, to by 21.48g(0.19mol), α, α-dichloromethyl methyl ether (Fluka company product) are dissolved in the solution that the 300ml methylene dichloride become, and add 44.76g(0.172mol) tin tetrachloride (Aldrich company product).After 15 minutes, in several minutes clock times, dripping by 24.01g(0.14mol) 2-thiophene acetic acid ethyl ester (Aldrich) is dissolved in the solution that the 50ml methylene dichloride is become.With in the mixture impouring frozen water, and stirred 30 minutes after 1 hour.Dichloromethane layer washes with water, dewaters with sodium sulfate, and is concentrated.Crude product carries out the silica gel chromatography purification with the hexane solution of 10% ethyl acetate, gets 22.85g(82%) 5-formyl radical-2-thiophene acetic acid ethyl ester intermediate product.
Stir down 0.77g(20.29mmol at 0 ℃) suspension that in the 200ml tetrahydrofuran (THF), become of lithium aluminum hydride, to wherein adding by 2.0g(10.09mmol) above-mentioned prepared intermediate product is dissolved in the solution that the 50ml tetrahydrofuran (THF) is become.Under 20 ℃, this suspension was stirred 16 hours, be chilled to 0 ℃, and add 0.8ml water, 0.8ml 1N sodium hydroxide solution and 2.4ml water carefully, so that remaining hydride stopped reaction.Suspension is stirred together with sal epsom, filter, concentrate, and carry out silica gel chromatography with hexane solution to 100% ethyl acetate of 50% ethyl acetate and purify.Separate and obtain 1.07g(67%) the glycol intermediate product, again it is directly changed into dibromide as described below.
With above-mentioned glycol intermediate product (1.07g 6.76mmol) is dissolved in the 50ml methylene dichloride, uses 3.90g(14.87mmol down at 0 ℃) triphenylphosphine and 4.93g(14.87mmol) the carbon tetrabromide processing.With solution stirring 1 hour, toward wherein adding the 200ml pentane, decantation went out supernatant liquor then, made it to separate with the oily residue, concentrated the supernatant liquor that is drained, and carried out silica gel chromatography with hexane and purify, 1.10g(57%) the dibromide intermediate product.Dibromide product (1.10g 3.87mmol) is dissolved in the 50ml ethanol, and uses 0.59g(7.75mmol) thiocarbamide is handled.Under refluxad, with solution stirring 2 hours.Solution is after concentrating, with preparation property HPLC(Waters C18 Bondapak PrepPak cartridge), purify with methanol/trifluoroacetic acid E-test (5/95/0.1 to 90/10/0.1).To compile the after product cut and concentrate, dilute with water, and freeze-drying, the S-(2-(5-((amidine sulfenyl of 306g two (trifluoroacetic acid) salt form and hydration 0.1mol water) methyl)-the 2-thienyl) ethyl) isothiourea (molten point=186-190 ℃)
1H NMR（200 MHz，D 2O）δ 6.98（d，J＝3.5Hz，1H），4.57（s，2H），3.38（t，J＝6.5Hz，2H），3.2（t，J＝6.5Hz，2H）。
C 9H 14N 4S 32.0C 2HF 3O 20.1H 2The analytical calculation value of O: C, 30.96; H, 3.24; N, 11.11; S, 19.08.
Measured value: C, 31.02; H, 3.19; N, 11.00; S, 18.97.
Embodiment 14
Preparation S-(3-(5-(2-(amidine sulfenyl) ethyl)-and the 2-thienyl) propyl group) isothiourea
It is described to press embodiment 13, preparation 5-formyl radical-2-thiophene acetic acid ethyl ester.By 2.0g(10.09mmol) said ester is dissolved in the solution that the 100ml tetrahydrofuran (THF) become, and adds 3.87g(11.10mmol) the positive phosphorus of ethoxycarbonyl methylene tri phenyl
（Carbethoxymethylenetriphenylphosphorane）。This solution refluxed spend the night and concentrate it.Crude product is used 10.54g(30.27mmol for second kind with 2.0g) reflux in the 100ml tetrahydrofuran (THF) reactant of 3 hours gained of the positive phosphorus of ethoxycarbonyl methylene tri phenyl mixes.Mixed crude product is purified with silica gel chromatography (10% ethyl acetate/hexane), gets 2.39g(44%) alkene diester (enediester) intermediate product.To by 1.0g(3.73mmol) said alkene diester is dissolved in the solution that 50ml ethanol become, and adds 1.0g 10% palladium on carbon.Under 20 ℃ and 50psi nitrogen atmosphere, with mixture shake 14 hours.Use the diatomite filtration catalizer, and concentrated solution, the thick diester intermediate product of 1.0g got.Final three kinds of reactions that this intermediate product is carried out are comprising lithium aluminium hydride reduction (82%), one-tenth's glycol is carried out bromination (78%) and makes the dibromide alkylation with thiocarbamide (88%), similar in appearance to those reactions described in the embodiment 13.The crude product of alkylated reaction is with preparation property HPLC(Waters, C18 BondaPak PrePak cartridge) method, with methanol E-test 10% to 90% methyl alcohol in 40min, purify (solution cushions with 0.1% trifluoroacetic acid).The lyophilized products cut gets 1.53g S-((3-(5-(2-(amidine sulfenyl) ethyl)-the 2-thienyl) propyl group) isothiourea, its form is mixing salt (1.0HBr, 1.1TFA) an also fused 0.5mol methyl alcohol.Fusing point=146-151 ℃.
Mass spectrum (FAB) 303.（M+1）。 1H NMR（200 MHz，D 2O）δ6.77（d，J＝3.3，Hz，1H），6.73（d，J＝3.3Hz，1H），3.37（t，J＝6.6Hz，2H），3.21-3.03（m，2H），2.91（t，J＝7.2Hz，2H），2.1-1.95（m，2H）。C 11H 18N 4S 31.0HBr1.1C 2HF 3O 20.5H 2The analytical calculation value of O: C, 31.35; H, 4.24; Br, 15.22; N, 10.68; S, 18.05.
Measured value: C, 31.59; H, 4.01; Br, 14.94; N, 10.45; S, 18.05.
Embodiment 15-17 repeats the method for embodiment 2.Crude product preparation property HPLC(Waters, C18 BondaPak Prepak cartridge) purify.With methanol/trifluoroacetic acid (5/95/0.1 to 90/10/1.0) E-test wash-out, freeze-drying again, get required amino acid, its form is the trifluoroacetic acid additive salt.
Embodiment 15
S-((2-amino-4-thiazolyl) methyl)-the D-halfcystine
With D-halfcystine and 2-amino-4-chloro methylthiazol (Spraque, J.M. etc., J.Am.Chem Soc.1946,68,2155-2159) prepare.Analytical HPLC-phenomenex C18, water/methyl alcohol/hyptafluorobutyric acid (80/20/1.7), a peak, k '=1.9.The UV(pH7.0 buffer reagent) λ max 254nm(log ε 3.73). 1H NMR（200MHz，DMSO-d 6）δ8.1（br，2H），8.1-7.5（br，2H），6.5（s，1H），4.25（m，1H），3.65（d，J＝6Hz，2H），3.0（m，2H）。
C 7H 11N 3O 2S2.3C 2HF 3O 20.1H 2The analytical calculation value of O: C, 27.92; H, 2.72; N, 8.43; S, 12.85.
Measured value: C, 28.00; H, 2.89; N, 8.74; S, 12.62.
Embodiment 16
S-((2-amino-4-thiazolyl) methyl)-(D, L)-homocysteine
With (D, L)-homocysteine and 2-amino-4-chloro methylthiazol prepare (Spraque, J.M. etc., J.Am.Chem Soc.1946,68,2155-2159).Analytical HPLC-phenomenex C18, water/methyl alcohol/trifluoroacetic acid (95/5/0.1), a peak, k '=2.3.The UV(pH7.0 buffer reagent) λ max 254nm(log ε 3.73).
1H NMR（200 MHz，DMSO-d 6）δ 8.5-8.0（br，2H），7.2-7.0（br，2H），6.35（s，1H），4.0（t，J＝4Hz，1H），3.55（s，2H），2.6（m，2H），2.0（m，2H）。
C 8H 13N 3O 2S1.1C 2HF 3O 21.0H 2The analytical calculation value of O: C, 31.35; H, 4.15; N, 10.75; S, 16.41.
Measured value: C, 31.30; H, 4.07; N, 10.73; S, 16.31.
Embodiment 17
S-(2-(2-amino-4-thiazolyl) ethyl)-the L-halfcystine is with L-halfcystine and 2-amino-4-(2-bromoethyl) thiazole is (with 1,5-two bromo-2-butanone are made raw material, method with people such as Spraque makes, J.Am.Chem.Soc.1946,68,2155-2159) prepare as raw material.Analytical HPLC-phenomenex C18, water/methyl alcohol/trifluoroacetic acid (95/5/0.1), a peak, k '=2.6.The UV(pH7.0 buffer reagent) λ max 256nm(log ε 3.71). 1H NMR（200 MHz，DMSO-d 6）δ9.2-8.8（br，2H），8.6-8.2（br，2H），6.6（s，1H），4.2（m，1H），3.0（m，2H），2.8（m，2H）。
C 8H 13N 3O 2S 22.0C 2HF 3O 22.4H 2The analytical calculation value of O: C, 27.79; H, 3.85; N, 8.10; S, 12.37.
Measured value: C, 27.65; H, 3.69; N, 8.02; S, 12.38.
Embodiment 18
Preparation S-(2-(4-bromo phenyl) isothiourea hydrobromate ethyl)
Under 0 ℃, to by 4-bromobenzene ethanol (720mg, 0.5ml, 3.58mmol) and triphenylphosphine (1.13g 4.30mmol) is dissolved in the solution that methylene dichloride (7.0ml) become, add carbon tetrabromide (1.42g, 4.30mmol).Reaction mixture is stirred 30min, be heated to room temperature simultaneously.With solution impouring hexane (100ml), and filtration over celite.Vacuum is steamed and is desolventized, and adds hexane, and makes the solution filtration over celite.After solvent removed in vacuo, coarse fodder is carried out bulb distillation (120 ℃/70 μ m Hg), get transparent oily matter.
Should be dissolved in 95% ethanol (7.0ml) by transparent oily matter, and the adding thiocarbamide (300mg, 3.94mmol).The reacting by heating mixture is to reflux temperature, and backflow 16h, is chilled to room temperature, and solvent removed in vacuo, gets the white solid thing.Be suspended in this solids in the hot acetone and filter it, the 832mg(68% yield) title compound.
1H NMR（300 MHz，d 6-DMSO）δ9.02（s，4H），7.52（d，J＝8.3Hz，2H），7.26（d，J＝8.3Hz，2H），3.43（t，J＝7.6Hz，2H），291（t，J＝7.4Hz，2H）。C 9H 12N 2SBr 2M.S.(CI), the m/z(relative intensity) 259(M+-Br, 100), 183(68), 77(92).
C 9H 12N 2SBr 2The ultimate analysis calculated value: C, 31.79; H, 3.56; N, 8.24; S, 9.43; Br, 46.99.
Measured value: C, 31.84; H, 3.59; N, 8.19; S, 9.34; Br, 46.92.
Embodiment 19
Preparation S-(2-(4-fluoro phenyl) isothiourea hydrobromate ethyl)
Press the method for embodiment 18, prepare with 4-fluorobenzene ethanol.Make title compound recrystallization and with its purification in dehydrated alcohol.
1H NMR（300 MHz，d 6-DMSO）δ 9.10（br，s，2H），8.96（br.s，2H），7.32（m，2H），7.14（m，2H），3.43（t，J＝6.8Hz，2H），2.91（t，J＝6.8Hz，2H）。
C 9H 12N 2The M.S.(CI of SFBr), the m/z(relative intensity) 199(M+-Br, 42), 77(100).
(C 9H 12N 2SF) (CH 4N 2S) 0.63(HBr) 1.06The ultimate analysis calculated value: C, 34.84; H, 4.43; N, 13.75; S, 15.74; Br, 25.51.
Measured value: C, 35.31; H, 4.41; N, 13.62; S, 15.51; Br, 25.92.
Embodiment 20
Preparation S-(2-(4-(oxyethyl group-3-p-methoxy-phenyl) isothiourea hydrobromate ethyl)
Press the method for embodiment 18, prepare with 4-oxyethyl group-3-anisole ethanol.Make title compound recrystallization and with its purification in dehydrated alcohol.
1H NMR（300 MHz，d 6-DMSO）;δ 8.95（br，s，4H），6.87（s，1H），6.84（d，J＝8.1Hz，1H），6.73（d，J＝8.2Hz，1H），3.94（q，J＝7.0Hz，2H），3.73（s，3H），3.39（t，J＝7.3Hz，2H），2.83（t，J＝7.4Hz，2H），1.28（t，J＝7.0Hz，3H）。
C 12H 19N 2O 2The M.S.(CI of SBr), the m/z(relative intensity) 255(M+-Br, 56), 179(100).
C 12H 19N 2O 2The ultimate analysis calculated value of SBr: C, 42.99; H, 5.71; N, 8.36; S, 9.56; Br, 23.83.
Measured value: C, 43.09; H, 5.73; N, 8.42; S, 9.61; Br, 23.89.
Embodiment 21
Preparation S-(2-(4-(ethoxyl phenenyl) isothiuronium salts hydrochlorate ethyl)
Press the method for embodiment 18, prepare with 4-phenetole ethanol.Crude product is water-soluble, and add the moisture sodium picrate of 2 molar equivalents.Isolate the light-yellow precipitate thing with filtration method, and (10: 1 water: meoh eluate) enterprising circumstances in which people get things ready for a trip spectrum is separated, and gets hydrochloride for 200-400 order, muriate state at AG1-X2 anionite-exchange resin.
1H NMR（300 MHz，d 6-DMSO）δ9.19（br.s，4H），7.19（d，J＝8.1Hz，2H），6.82（d，J＝8.1Hz，2H），3.94（q，J＝7.0Hz，2H），3.39（t，J＝7.3Hz，2H），2.83（t，J＝7.4Hz，2H），1.28（t，J＝7.0Hz，3H）。
C 11H 17N 2The M.S.(CI of OSCl), the m/z(relative intensity) 225(M+-Cl, 37), 149(100).
(C 11H 16N 2OS) (HCl) 1.08(CH 4N 2S) 0.08(H 2O) 0.16The ultimate analysis calculated value: C, 48.81; H, 6.55; N, 11.10; S, 12.70; Cl, 14.04.
Measured value: C, 48.91; H, 6.41; N, 11.12; S, 12.55; Cl, 14.20.
Embodiment 22
Preparation S-(2-(2, the 6-Dimethoxyphenyl) ethyl) the isothiuronium salts hydrochlorate
Press the method for embodiment 21, with 2,6-dimethoxy phenylethyl alcohol prepares.
1H NMR（300 MHz，d 6-DMSO）δ 9.14（br，s，4H），7.18（t，J＝8.2Hz，1H），6.07（d，J＝8.2Hz，2H），3.73（s，6H），3.39（t，J＝7.3Hz，2H），2.83（t，J＝7.4Hz，2H）。
C 11H 17N 2O 2The ultimate analysis calculated value of SCl: C, 47.74; H, 6.19; N, 10.12; S, 11.48; Cl, 12.81.
Measured value: C, 47.77; H, 6.19; N, 10.07; S, 11.48; Cl, 12.87.
Embodiment 23
Preparation S-(2-(4-p-methoxy-phenyl) isothiuronium salts hydrochlorate ethyl)
Press the method for embodiment 21, prepare with 4-anisole ethanol.
1H NMR（300 MHz，d 6-DMSO）δ 9.19（br，s，4H），7.19（d，J＝8.0Hz，2H），6.82（d，J＝8.1Hz，2H），3.73（s，3H），3.39（t，J＝7.3Hz，2H），2.83（t，J＝7.2Hz，2H）。
C 11H 17N 2The M.S.(CI of OSCl), the m/z(relative intensity) 211(M+-Cl, 22), 135(100).
(C 10H 15N 2OSCl) ultimate analysis calculated value: C, 48.68; H, 6.13; N, 11.36; S, 12.89; Cl, 14.45.
Measured value: C, 48.70; H, 6.10; N, 11.36; S, 12.89; Cl, 14.45.
Embodiment 24
Preparation 2-(2-(3-p-methoxy-phenyl) isothiuronium salts hydrochlorate ethyl)
Press the method for embodiment 21, prepare with 3-anisole ethanol.
1H NMR（300 MHz，d 6-DMSO）δ 9.00（br，s，4H），7.21（t，J＝7.9Hz，1H），6.80（m，3H），3.72（s，3H），3.43（t，J＝7.0Hz，2H），2.88（t，J＝7.4Hz，2H）。
C 10H 17N 2The M.S.(CI of OSCl), the m/z(relative intensity) 211(M+-Cl, 100), 135(10), 77(70).
(C 10H 15N 2OS) (HCl) 1.05(CH 4N 2S) 0.20(H 2O) 0.05The ultimate analysis calculated value: C, 45.39; H, 6.13; N, 12.62; S, 14.45; Cl, 13.61.
Measured value: C, 45.28; H, 6.18; N, 12.54; S, 14.43; Cl, 13.65.
Embodiment 25
Preparation S-(2-(2,4, the 6-trimethylphenyl) ethyl) the isothiourea hydrobromate
Press the method for embodiment 18, with 2,4,6-trimethoxy-benzene ethyl alcohol prepares.Make title compound recrystallization and with its purification in dehydrated alcohol.
1H NMR（300 MHz，d 6-DMSO）δ 9.00（s，4H），6.80（s，2H），3.24（t，J＝6.8Hz，2H），2.84（t，J＝6.7Hz，2H），2.49（s，3H），2.28（s，6H）。
C 12H 19N 2The M.S.(CI of SBr), the m/z(relative intensity) 223(M+-Br, 50), 147(100).
C 12H 19N 2The ultimate analysis calculated value of SBr: C, 47.53; H, 6.32; N, 9.24; S, 10.57; Br, 26.53.
Measured value: C, 47.26; H, 6.30; N, 9.34; S, 10.49; Br, 26.48.
Embodiment 26
Preparation S-(2-(3-aminomethyl phenyl) isothiourea hydrobromate ethyl)
Press the method for embodiment 18, prepare with 3-methylbenzene ethanol.Make title compound recrystallization and with its purification in dehydrated alcohol.
1H NMR（300MHz，d 6-DMSO）δ9.08（br，s，2H），9.03（br，s，2H），7.20（t，J＝7.5Hz，1H），7.08（m，3H）3.43（t，J＝7.8Hz，2H），2.88（t，J＝7.6Hz，2H），2.28（s，3H）。
C 10H 15N 2The M.S.(CI of SBr), the m/z(relative intensity) 195(M+-Br, 100), 119(56), 77(42).
(C 10H 15N 2SBr) (CH 4N 2S) 0.14The ultimate analysis calculated value: C, 42.60; H, 5.49; N, 11.17; S, 12.79; Br, 27.95.
Measured value: C, 42.66; H, 5.50; N, 11.20; S, 12.57; Br, 27.79.
Embodiment 27
Preparation S-(2-(2-fluorophenyl) isothiuronium salts hydrochlorate ethyl)
Press the method for embodiment 21, prepare with 2-fluorobenzene ethanol.
1H NMR（300MHz，d 6-DMSO）δ9.21（br，s，4H），7.39（m，1H），7.28（m，1H），7.17（m，2H），3.43（t，J＝7.7Hz，2H），2.92（t，J＝7.8Hz，2H）。
C 9H 12N 2The M.S.(CI of SFCl), the m/z(relative intensity) 199(M+-Cl, 100), 123(39).
C 9H 12N 2The ultimate analysis calculated value of SFCl: C, 46.05; H, 5.15; N, 11.93; S, 13.66; Cl, 15.10.
Measured value: C, 45.93; H, 5.11; N, 11.83; S, 13.59; Cl, 15.14.
Embodiment 28
Preparation S-(2-(3-nitrophenyl) isothiourea hydrobromate ethyl)
Under 0 ℃, to by 3-oil of mirbane ethanol (500mg, 2.99mmol) and in the solution that become of pyridine (35.6mg, 36 μ l 0.45mmol) are dissolved in THF(10ml), add phosphorus tribromide (298mg, 0.10ml, 1.10mmol).At once form white depositions.Reaction mixture is heated to room temperature, and stirs 1h.Add entry and ether, and be separated two.Organic phase is washed with saturated sodium bicarbonate aqueous solution, and dewaters with anhydrous magnesium sulfate.Filtering mixt, and solvent removed in vacuo get brown oil.
Rough bromide is dissolved in 95% ethanol (10ml), and to wherein add thiocarbamide (251mg, 3.30mmol).With reaction mixture reflux 16h, be chilled to room temperature, solvent removed in vacuo.Rough yellow solid is suspended in the acetone, and with this mixture heating up backflow 10min.Filtering heat solution gets the white solid thing.
1H NMR（300MHz，d 6-DMSO）δ9.12（br，s，2H），8.96（br，s，2H），8.22（s，1H），8.14（d，J＝7.9Hz，1H），7.78（d，J＝7.6Hz，1H），7.64（t，J＝8.0Hz，1H），3.50（t，J＝7.0Hz，2H），3.10（t，J＝7.2Hz，2H）。
C 9H 12N 3O 2The M.S.(CI of SBr), the m/z(relative intensity) 226(M+-Br, 26), 136(36), 76(81).
C 9H 12N 2O 2The ultimate analysis calculated value of SBr: C, 35.31; H, 3.95; N, 13.72; S, 10.47; Br, 26.10.
Measured value: C, 35.22; H, 3.88; N, 13.62; S, 10.36; Br, 26.18.
Embodiment 29
Preparation S-(2-(1H-pyrroles-1-yl) isothiourea ethyl)
At room temperature, to by new distilled N-(2-bromoethyl) pyrroles (1.00g 5.74mmol) is dissolved in the solution that 95% ethanol (12ml) become, add thiocarbamide (415mg, 5.74mmol).Under refluxing, stirred solution 22h is chilled to room temperature, and this mixture of vacuum concentration, gets thick light beige stain shape thing.Make this oily matter at room temperature more than the crystallization 16h, filter crystal and with chloroform (10ml) flushing, the described compound of 1.078g title, its form is light beige needle crystal (yield 75%).
1H NMR（300 MHz，d 6-DMSO）δ 9.06（br，s，4H），6.80（t，J＝2.10Hz，2H），5.99（t，J＝2.10Hz，2H），4.12（t，J＝6.50Hz，2H），3.52（t，J＝6.50Hz，2H）。
C 7H 12N 3The ultimate analysis calculated value of SBr: C, 33.61; H, 4.84; N, 16.80; S, 12.82; Br, 31.94.
Measured value: C, 33.68; H, 4.84; N, 16.74; S, 12.74; Br, 31.99.
Fusing point 94.6-95.0 ℃.
Embodiment 30
Measured restraining effect with following method to the NO synthetic enzyme:
By people's placenta purification NOS
From fresh human placenta, remove amnion and chorion, then with 0.9% NaCl flushing placenta.In a Waring blendor, add 0.1mM PMSF with 3 volume HEDS damping fluids (20mM HEPES pH7.8,0.1mM EDTA, 5mM DTT, 0.2M sucrose) and make tissue homogenateization.Make homogenate filter dried acid anhydride infantees, again with the centrifugal 20min of 1000g.With 27,500g is at centrifugal 30min with supernatant liquor.In supernatant liquor, add solid ammonium sulfate, make saturation ratio reach 32%.With 25,000g makes granule the protein that is precipitated out, and its heavy HEDS damping fluid that is dissolved in minimum volume is added in the mixed solution that 0.1mM PMSF, 10 μ g/ml leupetins and soybean trypsin press down agent system and 1 μ g/ml Gastric inhibitory polypeptide again.Heavy pill after molten is with 15, the centrifugal 10min of 000g.2.5 ' ADP the agarose resin (Sigma) that in supernatant liquor, adds 1/20 volume, and slurry slowly mixed spend the night.Second day early in the morning, and slurry is packed in the post.Be dissolved in HEDS with HEDS, 0.5M NaCl(successively), the HEDS washing resin, be dissolved in HEDS with 10mM NADPH(again) wash-out NOS.This enzyme can concentrate with ultrafiltration and quick freezing, and stores at least 3 months and non-inactivation down at-70 ℃.
The mensuration of people's placenta NOS
The method (PNAS, 88,365-369,1991) of pressing people such as Schmidt is observed the formation of citrulline, and to measure NOS, the change of this method is as follows: 20mM Hepes, PH7.4,10 μ g/ml calmodulin, 2.5mM CaCl 2, 2.5mM DTT, 125 μ m HADPH, 10 μ m Tetrahydrobiopterins, 0.5mg/ml BSA, and 1 μ ML-[ 14C] arginine (New England Nuclear product).Using before single time point determining speed comes kinetics studied, determining the linearity of NOS catalysis speed earlier.
NOS purifies from the human colon rectal adenocarcinoma DLD-1 cell of cell induction
Under 37 ℃, make DLD-1(ATCC numbering: CCL221) replenishing with L-glutaminate, penicillin, Streptomycin sulphate and 10% heat-inactivated fetal bovine serum, 5% CO 2Be dissolved in the substratum that RPMI 1640 become and grow.Make cell grow to fusion, add following cytokine mixture then: 100 units/ml interferon-, 200 units/ml interleukin-6 (interleukin-6), 10ng/ml tumour necrosis factor, and 0.5ng/ml leukin-1 β (interleukin-1 β).After 18-24h induces, scrape the receipts cell, and with the salt water washing of phosphate buffered.The cell that becomes to be stranded grain is stored under-70 ℃.Under 4 ℃, the NOS that had induced is purified.To place TDGB(20mM tris pH7.5, the cry of certain animals of talking endlessly of 10% glycerine, 1mM DTT, 2 μ M tetrahydrochysene biologies) cell freezing/thaw three times, prepare thick leach liquor with this.Leach liquor directly is added to 2 ', on 5 ' ADP agarose (Pharmacia) post.Come washing resin with TDGB, the TDGB solution of 0.5M NaCl, TDGB in turn.Be dissolved in TDGB with 2mM NADPH() come wash-out NOS.Then, add BSA, with the ultimate density of 1mg/ml.NOS can give quick-frozen, and can store at least February and non-inactivation under-70 ℃.
Can induce the mensuration of human body NOS
Measure the formation of citrulline by the above, but use 10 μ M FAD, and from measure mixture, remove calmodulin and CaCl 2
NOS purifies from human brain
Human brain NOS is with people (Fed.Eur.Biochem.Soc.288 187-191,1991) and Bredt and Snyder(PNAS 87 682-685 such as people such as Schmidt (PNAS88,365-369,1991), Mayer, 1990) the whole bag of tricks that proposes prepares.In brief, with fresh whole brain (3 have separated myeloid tissue, 1050g) at cold buffer liquid A(50mM HEPES, pH7.5(room temperature pH value) and 0.5mM EDTA, 10mM DTT, cumulative volume 3.6L) in, come homogenate with multi-polyester.Mixture is with 13, the centrifugal 1h of 000g, and take out supernatant liquor (about 2050ml).In supernatant liquor, add solid-state ammonium sulfate (365g, about 30% is saturated), and slowly stir total 30min.
Throw out is with 13,000g granulation 30min, and these are suspended in about 400ml again contain 4 μ M Tetrahydrobiopterins, 1 μ M FAD(Sigma) and 1 μ M FMN(Sigma) buffer A in.With suspension with 41, the centrifugal 60min of 000g.Take out supernatant liquor, give freezingly in the impouring liquid nitrogen, and preserve down at-70 ℃ and to spend the night.Mixture is thawed, and make it with 4ml/min flow through 2 ', 5 ' ADP-agarose column (0.4g expands in buffer A).Contain buffer A, the 100ml buffer A of 500mM NaCl with 100ML buffer A, 200ml, and the buffer A that 30ml contains 5mM NADPH is washed this post.In enzyme solution, add Tetrahydrobiopterin to 10 μ M, FAD and FMN to 1 μ M, and add tween (Tween) to 0.1%.With Centriprep-30 this solution concentration to volume is about 500 μ l.Equal described method in 1991 by Schmidt and measure enzymic activity, but when measuring, used 10 μ M Tetrahydrobiopterins.
The result who suppresses shows as table 1.
Numerical value is for suppressing constant (Ki), this constant is by measuring percent inhibition under inhibitor concentration more than three kinds or three kinds, and estimates with respect to behind the arginic competition inhibiting rate and obtain.
Figure 931216435_IMG31
Figure 931216435_IMG32

Claims (20)

1, the isothiourea derivatives with NO synthase inhibitory activity is for the application of making the disease therapeuticing medicine that helps suppressing the NO synthetic enzyme.
2, the described application of claim 1, wherein isothiourea derivatives is logical formula I
Figure 931216435_IMG1
Shown compound or its salt is in the formula
R is (1) C 1-14Alkyl; Or
(2) 5-save and 6 heterocycles that save; Or
(3) one the 9 two heterocycle of joint systems
Above-mentioned each R group can be one or two group that is selected from following groups separately respectively and replaces:
(a) halogen;
(b)-XR 1, wherein
X is an oxygen, C(O) m, and m is 1 or 2 in the formula; S(O) n, n is 0,1 or 2 in the formula; Perhaps NR 2, R in the formula 2Be hydrogen, C 1-6Alkyl or C 3-6Cycloalkyl, perhaps R 2Link R 1On, form a C 2-6Alkylidene group;
R 1Be hydrogen; Or C 1-6Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl, C 7-9Aralkyl, C 6-10Aryl or one 5 joint or 6 joint heterocyclic groups, above-mentioned each group can be randomly replaced by one or two groups that are selected from following groups separately respectively: C 1-3Alkyl, hydroxyl, C 1-3Alkoxy grp, amino, C 1-3Alkylamino, halogen, nitro or C(O) m ' R 2bGroup, m ' is 1 or 2 in the formula, R 2bBe hydrogen or C 1-4Alkyl; Perhaps R 1Be a NR 3R 4Group, R in the formula 3And R 4Can be identical or different, and respectively be hydrogen or C 1-4Alkyl, perhaps R 3And R 4Link to each other, form a C 2-6Alkylidene group;
(c) one
Figure 931216435_IMG2
Group is in the formula
Y is an oxygen; S(O) n, as above defined of n in the formula; Or NH 5, R in the formula 5Be hydrogen or C 1-4Alkyl;
W is 0 or 1;
Q is C 2-4Alkyl;
Perhaps imino-nitrogen is connected on R group or the Q group, forms one 5 and saves or 6 joint heterocycles; Perhaps
(d) group A, wherein A is a heterocycle system, it can be preferably group as defined above Replace; Perhaps
(e) C 1-6Alkyl, C 2-6Alkenyl or alkynyl group or C 3-6Cycloalkyl;
Perhaps one of each carbon atom is linked shown in the formula I on the imino nitrogen atom in the compound among the R, forms one 5 joint or 6 joint heterocycles; Condition is that R is not a methyl.
3, the described application of claim 2, wherein R is
(1) C 1-4Alkyl;
(2) C 2-4Alkenyl,
(3) one
Figure 931216435_IMG4
Group, wherein p is 1 to 2, q is 0 to 1; Perhaps
Save for (4) one 5 or six joint heterocycles, wherein contain one or two nitrogen-atoms;
Above-mentioned each group can be randomly replaced by one or two identical or different following groups:
(a) halogen is preferably bromine;
(b) OR 2b ', R wherein 2b 'Be hydrogen or methyl;
(c) mR C(O) 2b ', wherein m and R 2b 'As defined above;
(d) SR 9Group, wherein R 9Be methyl or ethyl;
(e) NR 7bR AbGroup, wherein R 7bAnd R 8bBe selected from hydrogen or C separately respectively 1-4Alkyl is preferably hydrogen, methyl or ethyl;
(f) one can be randomly be OR as defined above 2b ', or The phenyl ring that group replaced;
(g) contain one or two heteroatomic 5 joints or the 6 joint heterocycles that are selected from nitrogen or oxygen separately respectively, perhaps
(h) C 1-4Alkyl is preferably methyl;
Perhaps a carbon atom among the R is linked on the imino-nitrogen of compound shown in the formula I, forms a thiazole or thiazoline ring.
4, claim 2 or 3 described application, condition are that R is not ethyl, propyl group or sec.-propyl.
5, claim 1 or 2 described application, wherein isothiourea derivatives is the compound shown in formula (I A), (the I B) or (I C).
Figure 931216435_IMG6
R ' is a C in the formula 1-8Alkylidene group, C 2-8Alkenylene or alkynylene,
They contain or do not contain a phenyl ring, one 5 joint or 6 joint heterocycles, perhaps X group as defined above, and wherein dotted line represent one pair of keys or a singly-bound.
6, the described application of claim 1, wherein isothiourea derivatives is a formula II
Figure 931216435_IMG7
Shown compound or its salt, R in the formula aBe a C 1-8Alkynyl, perhaps 5 joints or 6 joint heterocycles perhaps save bicyclic heterocycle system for one 9, and they are separately randomly by halogen or one or two-X aR 1aReplace R wherein 1aBe hydrogen, C 1-6Alkyl, C 3-6Cycloalkyl, C 7-9Aralkyl, C 5-10Aryl perhaps saves for one 5 or 6 joint heterocyclic groups, and this heterocyclic group is randomly by C 1-3Alkyl, C 1-3Alkoxyl group, amino, halogen or nitro replace, perhaps R 1aBe a NR 3aR 4aGroup, wherein R 3aAnd R 4aSame or different, and respectively be hydrogen or C 1-3Alkyl, perhaps R 3aAnd R 4aLink to each other, form a C 2-6Alkylidene group, and X aBe oxygen; C(O) m a, m wherein aBe 1 or 2; S(O) n a, n wherein aBe 0,1 or 2; Perhaps NR 2a, R wherein 2aBe hydrogen, C 1-6Alkyl or C 3-6Cycloalkyl, perhaps R 2aLink R 1aOn, form a C 2-6Alkylidene group perhaps is one
Figure 931216435_IMG8
Group replaces, and wherein t is 0 to 4, W aBe 0 or 1, Y aBe oxygen, sulphur and NR 7a, R wherein 7aBe hydrogen or C 1-4Alkyl;
Perhaps R aSulphur atom is linked shown in the formula I on the nitrogen-atoms in the compound, formed one 5 joint or 6 joint heterocycles, condition is R aIt or not methyl.
7, the described application of claim 1 to 6, wherein said isothiourea derivatives is selected from
The S-(2-aminoethyl) isothiourea
The S-(2-(dimethylamino) isothiourea propyl group)
S-(2-methyl-2-propenyl) isothiourea
S, S '-ethylene (isothiourea)
S, S '-pentamethylene two (isothiourea)
The S-(2-(dimethylamino) isothiourea ethyl)
2-amino-2-thiazoline
S, S '-hexamethylene two (isothiourea)
S, S '-1, the inferior heptyl two (isothiourea) of 7-
The S-benzylisothiourea
S-(2-morpholino ethyl) isothiourea
S-(6-methyl-2-(methylthio group)-and the 4-pyrimidyl) isothiourea
S, S '-(1,4 phenylene two (methylene radical), two isothioureas
S-tertiary butyl isothiourea
The S-(4-Ethylbenzyl) isothiourea
The S-((methylthio group) isothiourea methyl)
The S-(3-bromopropyl) isothiourea
The S-(2-bromotrifluoromethane) isothiourea
S-(3-methyl-2-butene base) isothiourea
S-allyl group isothiourea
The S-(3-aminopropyl) isothiourea
S, S '-(1,3-phenylene two (methylene radical)) two isothioureas
S, S '-(2-methylene radical-trimethylene) two isothioureas
S, S '-(2-butyne-1,4-subunit) two isothioureas
S, S '-(1,3 phenylene two (ethylene), two isothioureas
S, S '-(1,4-phenylene two (ethylene) two isothioureas
2-amino-5-methylthiazol
S-((2-amino-4-thiazolyl) methyl-L-halfcystine
3-((2-amino-4-thiazolyl) methyl-L-L-Ala
2-amino-4-methylthiazol
2-amino-4, the 5-dimethylthiazole
S-(2-(1H-pyrroles-1-yl) isothiourea ethyl)
The S-(3-hydroxypropyl) isothiourea
The S-(2-phenyl) isothiourea ethyl)
The S-(2-(3-p-methoxy-phenyl) isothiourea ethyl)
4-(2-amino-4-thiazolyl) methyl)-the L-high lactamine
N, N-(1,3-phenylene two (methylene radical)) two (S-methyl-isothioureas)
N, N-(1,3-phenylene two (methylene radical)) two (S-ethyl isothioureas)
S-(2-(5-((amidine sulfenyl) methyl)-and the 2-thienyl) ethyl) isothiourea
S-(3-(4-((amidine sulfenyl) isothiourea propyl group phenyl methyl)))
S-(3-(5-(2-amidine sulfenyl) ethyl)-and the 2-thienyl) propyl group) isothiourea
The S-(2-(4-fluorophenyl) isothiourea ethyl)
The S-(2-(4-bromophenyl) isothiourea ethyl)
The S-(2-(3-p-methoxy-phenyl) isothiourea ethyl)
The S-(2-(3-aminomethyl phenyl) isothiourea ethyl)
The S-(2-(4-ethoxyl phenenyl) isothiourea ethyl)
The S-(2-(4-p-methoxy-phenyl) isothiourea ethyl)
The S-(2-(2-bromophenyl) isothiourea ethyl)
The S-(2-(2-fluorophenyl) isothiourea ethyl)
The S-(2-(3-nitrophenyl) isothiourea ethyl)
S-(3-(1H-pyrroles-1-yl) isothiourea propyl group)
The S-(2-(2-chloro-phenyl-) isothiourea ethyl)
S-(2-(2, the 5-3,5-dimethylphenyl) ethyl) isothiourea
S-(2-(4-oxyethyl group-3-p-methoxy-phenyl) isothiourea ethyl)
Or their salt.
8, any one described application in the claim 1 to 3 or 6, wherein said isothiourea derivatives is selected from
S-ethyl isothiourea,
S-propyl group isothiourea,
S-isopropyl thiocarbamide.
9, the described isothiourea of claim 1 is done the hypotensive application of therapy system.
10, claim 1 or 2 described isothioureas are done the application of treatment septic shock.
11, the application of the described isothiourea of claim 9, wherein systemic ypotension is because of due to cytokine or the cytokine antilepsis.
12, the described isothiourea of claim 1 is done the application of short-term immunosuppressant therapy.
13, the described isothiourea of claim 1 is done the application of autoimmune disorders treatment.
14, the described isothiourea of claim 1 is done the application of the treatment of inflammatory diseases.
15, except S-ethyl isothiourea, S-propyl group isothiourea, S-isopropyl thiocarbamide, benzylisothiourea, S, S-(1,4-phenylene two (methylene radical) two isothioureas and S-(2-(dimethylamino) ethyl) outside the isothiourea, isothiourea derivatives shown in the formula I of hyoscine.
16, the new isothiourea derivatives of institute's definition (I A), (I B) or (I C) in the claim of prostatitis.
17, the described isothiourea derivatives of claim 16, this derivative is selected from
S, S '-(1,4-phenylene two (ethylene) two isothioureas
S-(2-(1H-pyrroles-1-yl) two isothioureas ethyl)
S-((2-amino-4-thiazolyl) methyl)-the L-halfcystine
γ-(2 '-amino-4-thiazolyl)-the L-high lactamine
S, S '-(1,2-phenylene two (ethylene) two isothioureas
β-(2 '-amino-4 '-thiazolyl)-the L-L-Ala
S-(2 ' amino-5 '-(R, S)-the thiazolinyl methyl)-the L-halfcystine
4-((2-amino-4-thiazolyl) methyl)-the L-high lactamine
N, N-(1,3-phenylene two (methylene radical)) two (S-methyl-isothioureas)
N, N-(1,3-phenylene two (methylene radical)) two (S-ethyl isothioureas)
S-(3-(4-((amidine sulfenyl) isothiourea propyl group phenyl methyl)))
S-(2-(5-((amidine sulfenyl) methyl)-and the 2-thienyl) ethyl) isothiourea
S-(3-(5-((2-amidine sulfenyl) ethyl)-and the 2-thienyl) propyl group) isothiourea
S-((2-amino-4-thiazolyl) methyl)-the D-halfcystine
S-((2-amino-4-thiazolyl) methyl)-(D, L)-homocysteine
S-(2-(2-amino-4-thiazolyl) ethyl)-the L-halfcystine
The S-(2-(4-fluorophenyl) isothiourea ethyl)
The S-(2-(4-bromophenyl) isothiourea ethyl)
The S-(2-(3-p-methoxy-phenyl) isothiourea ethyl)
The S-(2-(3-aminomethyl phenyl) isothiourea ethyl)
The S-(2-(4-ethoxyl phenenyl) isothiourea ethyl)
The S-(2-(4-p-methoxy-phenyl) isothiourea ethyl)
The S-(2-(2-bromophenyl) isothiourea ethyl)
The S-(2-(2-fluorophenyl) isothiourea ethyl)
The S-(2-(3-nitrophenyl) isothiourea ethyl)
S-(3-(1H-pyrroles-1-yl) isothiourea propyl group)
S-(2-(4-oxyethyl group-3-p-methoxy-phenyl) isothiourea ethyl)
S-(2-(2,4, the 6-trimethylphenyl) ethyl) isothiourea
S-(2-(2, the 6-Dimethoxyphenyl) ethyl) isothiourea
And salt.
18, the preparation method of the described isothiourea derivatives of claim 16, this method comprises
A) thiocarbamide and compound R L(L ') reaction of r, in the formula R as defined above, L and L ' are leavings group, r is 0 or 1, when needing, removes blocking group after reaction; Perhaps
B) remove the blocking group of compound shown in the formula (IB1),
Figure 931216435_IMG9
R ' and dotted line is described as defined above in the formula, and P and P ' are same or different, are blocking group.
19, a kind of pharmaceutical preparation, said preparation comprises except that S-ethyl isothiourea, S-propyl group isothiourea, S-isopropyl thiocarbamide, S-benzylisothiourea, S, S-(1,4-phenylene dimethylene two isothioureas and S-(2-(dimethylamino) ethyl) outside the isothiourea, a kind of isothiourea derivatives as defined above, or the acceptable salt of its any pharmacology or its solvate, and the compatible carrier of one or more pharmacology, and can contain or not contain one or more other therapeutic ingredients.
20, a kind ofly help the methods for the treatment of diseases that the NO synthetic enzyme suppresses, this method comprise throw give treatment effectively amount, have a isothiourea derivatives to the NO synthase inhibitory activity.
CN93121643A 1992-11-27 1993-11-26 Enzyme Inhibitors Pending CN1095710A (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB929224948A GB9224948D0 (en) 1992-11-27 1992-11-27 Nitric oxide synthase inhibitors
GB939315159A GB9315159D0 (en) 1993-07-22 1993-07-22 Nitric oxide synthase inhibitors
GB9224948.1 1993-09-23
GB9319663.2 1993-09-23
GB9315159.5 1993-09-23
GB939319663A GB9319663D0 (en) 1993-09-23 1993-09-23 Enzyme inhibitors

Publications (1)

Publication Number Publication Date
CN1095710A true CN1095710A (en) 1994-11-30

Family

ID=27266488

Family Applications (1)

Application Number Title Priority Date Filing Date
CN93121643A Pending CN1095710A (en) 1992-11-27 1993-11-26 Enzyme Inhibitors

Country Status (7)

Country Link
EP (1) EP0670720A1 (en)
JP (1) JPH08503940A (en)
CN (1) CN1095710A (en)
AU (1) AU5533094A (en)
IL (1) IL107771A0 (en)
SI (1) SI9300616A (en)
WO (1) WO1994012165A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1105706C (en) * 1995-04-20 2003-04-16 G·D·瑟尔公司 Cyclic amidino agents useful as nitric oxide synthase inhibitors
CN101372471B (en) * 2008-10-08 2010-12-22 中国科学院化学研究所 Novel use of alkyl isourea compound and analogues thereof

Families Citing this family (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR9407515A (en) * 1993-08-12 1997-01-07 Astra Ab Compound pharmaceutical formulation use of the compound processes for the treatment of neurodegenerative or migraine disorders or for the prevention and reversal of tolerance to opiates and diazepines or for the treatment of drug addiction and for the preparation of the compound
EP0724570B1 (en) * 1993-10-21 1999-03-03 G.D. Searle & Co. Amidino derivatives useful as nitric oxide synthase inhibitors
EP0759027B1 (en) * 1994-05-07 1999-08-04 Astra Aktiebolag Bicyclic amidine derivatives as inhibitors of nitric oxide synthetase
GB9418912D0 (en) * 1994-09-20 1994-11-09 Fisons Corp Pharmaceutically active compounds
AU4149696A (en) * 1994-11-15 1996-06-06 Merck & Co., Inc. Substituted heterocycles as inhibitors of nitric oxide synthase
WO1996018617A1 (en) * 1994-12-12 1996-06-20 Merck & Co., Inc. Substituted 2-acylamino-pyridines as inhibitors of nitric oxide synthase
DE19530870A1 (en) * 1994-12-14 1996-06-20 Japan Tobacco Inc New 2-amino-1,3-thiazine and -thiazepine derivs.
JPH08333258A (en) 1994-12-14 1996-12-17 Japan Tobacco Inc Thiazine or thiazepine derivative and nitrogen monoxide synthetase inhibitor containing the compound
DE4444930A1 (en) * 1994-12-16 1996-06-27 Cassella Ag 2-amino-1,3-thiazepines and their use as inhibitors of nitric oxide synthase
WO1996021445A1 (en) * 1995-01-13 1996-07-18 The General Hospital Corporation Methods of inhibiting neurodegenerative diseases
TW397812B (en) * 1995-02-11 2000-07-11 Astra Ab Bicyclic isothiourea derivatives useful in therapy
FR2730733B1 (en) * 1995-02-17 1997-07-04 Hoechst Lab NOVEL SULFUR NITROETHYLENIC DERIVATIVES AND THEIR APPLICATIONS AS NO-SYNTHASE INHIBITORS
US5929063A (en) * 1995-03-24 1999-07-27 Children's Hospital Medical Center Mercapto and seleno derivatives as inhibitors of nitric oxide synthase
US5674907A (en) * 1995-03-24 1997-10-07 Children's Hospital Medical Center Mercapto derivatives as inhibitors of nitric oxide synthase
GB9506188D0 (en) * 1995-03-27 1995-05-17 Fujisawa Pharmaceutical Co Amidine derivatives
US5908842A (en) * 1995-12-08 1999-06-01 Merck & Co., Inc. Substituted 2-acylamino-pyridines as inhibitors of nitric oxide synthase
US5945408A (en) * 1996-03-06 1999-08-31 G.D. Searle & Co. Hydroxyanidino derivatives useful as nitric oxide synthase inhibitors
US6160000A (en) * 1996-12-23 2000-12-12 Merck & Co., Inc. Antidiabetic agents based on aryl and heteroarylacetic acids
US6090839A (en) * 1996-12-23 2000-07-18 Merck & Co., Inc. Antidiabetic agents
US5981556A (en) * 1997-07-22 1999-11-09 G.D. Searle & Co. 1,3-diazolino and 1,3-diazolidino heterocycles as useful nitric oxide synthase inhibitors
US6673807B1 (en) * 1998-04-06 2004-01-06 Fujisawa Pharmaceutical Co., Ltd. Immunosuppressive imidazole derivatives and their combination preparations with tacrolimus or cyclosporins
EP1086108A1 (en) 1998-06-10 2001-03-28 G.D. Searle & Co. Heterobicyclic and tricyclic nitric oxide synthase inhibitors
US6552052B2 (en) 1998-06-10 2003-04-22 Monsanto/G.D. Searle Pyrrolo[2,1-c][1,2,4] thiadiazoles and Pyrollo[2,1-c][1,12,4]oxadiazoles useful as nitric oxide synthase inhibitors
GB9903404D0 (en) 1999-02-16 1999-04-07 Angiogene Pharm Ltd Methods of treatment and compositions useful for the treatment of diseases involving angiogenesis
AP1522A (en) * 2000-01-19 2005-12-22 Cadila Healthcare Ltd Compounds having hypolipedemic and hypocholesteremic activities, process for their preparation and pharmaceutical compositions containing them.
ES2256223T3 (en) 2000-03-24 2006-07-16 Pharmacia Corporation AMIDINOCOMPUESTOS USEFUL AS INHIBITORS OF NITRICO SINTASA OXIDE.
US7087633B2 (en) 2000-03-31 2006-08-08 Universitair Medisch Centrum Method for treating perinatal asphyxia in a human or animal neonate
DK1280526T3 (en) 2000-03-31 2005-09-05 Univ Medisch Centrum Utrecht Use of 2-iminobiotin in the manufacture of a drug for the prevention and / or treatment of complications in neonates that occur during birth
US6956131B2 (en) 2000-04-13 2005-10-18 Pharmacia Corporation 2-amino-3, 4 heptenoic compounds useful as nitric oxide synthase inhibitors
AR034120A1 (en) 2000-04-13 2004-02-04 Pharmacia Corp HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-4,5, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND THE USE OF SUCH COMPOUND AND SUCH COMPOSITION IN THE MANUFACTURE OF A MEDICINAL PRODUCT TO INHIBIT OR MODULATE NITRIC ACID SYNTHESIS
US6545170B2 (en) 2000-04-13 2003-04-08 Pharmacia Corporation 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
US6787668B2 (en) 2000-04-13 2004-09-07 Pharmacia Corporation 2-amino-4,5 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
AR032318A1 (en) 2000-04-13 2003-11-05 Pharmacia Corp HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-5,6; PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE MANUFACTURE OF A USEFUL MEDICINAL PRODUCT AS AN INHIBITOR OF NITRICAL SYNTHEASE OXIDE
AR030416A1 (en) 2000-04-13 2003-08-20 Pharmacia Corp HALOGENATED DERIVATIVE COMPOUND OF HEPTENOIC ACID 2-AMINO-3,4, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE IN THE MANUFACTURE OF A USEFUL MEDICINAL PRODUCT AS AN INHIBITOR OF SYNTHETIC NITRIC OXIDE
US6451821B1 (en) 2000-06-09 2002-09-17 Aventis Pharma S.A. Use of 2-aminothiazoline derivatives as inhibitors of inducible no-synthase
FR2832152A1 (en) * 2001-11-09 2003-05-16 Aventis Pharma Sa New 2-amino-thiazoline derivatives having inducible NO-synthase inhibiting activity, useful for treating Parkinson's, cerebral disorders, migraines, depression, diabetes
FR2810036B1 (en) * 2000-06-09 2004-04-23 Aventis Pharma Sa 4,5-DIHYDRO-1,3-THIAZOL-2-YLAMINE DERIVATIVES, THEIR PREPARATION AND THE PHAMARCEUTICAL COMPOSITIONS CONTAINING THEM
US6420566B2 (en) 2000-06-09 2002-07-16 Aventis Pharma S.A. Pharmaceutical compositions containing a 4, 5-dihydro-1, 3-thiazol-2-ylamine derivative, novel derivatives and preparation thereof
FR2810037B1 (en) * 2000-06-09 2004-04-23 Aventis Pharma Sa USE OF 2-AMINOTHIAZOLINE DERIVATIVES AS INDUCTIBLE NO-SYNTHASE INHIBITORS
US6344473B1 (en) 2000-08-07 2002-02-05 G.D. Searle & Co. Imidazoles useful as nitric oxide synthase inhibitors
US7012098B2 (en) 2001-03-23 2006-03-14 Pharmacia Corporation Inhibitors of inducible nitric oxide synthase for chemoprevention and treatment of cancers
ES2250731T3 (en) * 2001-11-09 2006-04-16 Aventis Pharma S.A. DERIVATIVES OF 2-AMINO-4-HETEROARILETIL TIAZOLINA AND ITS USE AS INHIBITORS OF INDUCTIBLE NON-SYNTHASE.
PT1450750E (en) * 2001-11-09 2010-01-18 Aventis Pharma Sa Use of 2-amino-4-pyridylmethyl-thiazoline derivatives as inhibitors of inducible no-synthase
FR2832150B1 (en) * 2001-11-09 2004-07-16 Aventis Pharma Sa USE OF 2-AMINO-4-PYRIDYLMETHYL-THIAZOLINE DERIVATIVES AS INDUCTIBLE NO-SYNTHASE INHIBITORS
CA2669810A1 (en) * 2001-11-09 2003-05-15 Aventis Pharma S.A. 2-amino-thiazoline derivatives and their use as inhibitors of inducible no-synthase
FR2832151B1 (en) * 2001-11-09 2004-12-17 Aventis Pharma Sa USE OF 2-AMINO-4-HETEROARYLETHYL-THIAZOLINE DERIVATIVES AS INDUCTIBLE NO-SYNTHASE INHIBITORS
EP2597087B1 (en) 2005-10-25 2016-03-30 Shionogi&Co., Ltd. Dihydrooxazine and tetrahydropyrimidine derivatives as BACE 1 inhibitors
US20090186854A1 (en) * 2006-03-23 2009-07-23 Meditor Pharmaceuticals Ltd. S-alkylisothiouronium derivatives for the treatment of inflammatory diseases
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
CA2683887A1 (en) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group having inhibitory activity against production of amyloid beta protein
AU2009258496B8 (en) 2008-06-13 2014-06-26 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta-secretase-inhibiting activity
WO2010047372A1 (en) 2008-10-22 2010-04-29 塩野義製薬株式会社 2-aminopyridin-4-one and 2-aminopyridine derivative both having bace1-inhibiting activity
JPWO2010113848A1 (en) 2009-03-31 2012-10-11 塩野義製薬株式会社 Isothiourea derivative or isourea derivative having BACE1 inhibitory action
BR112012013854A2 (en) 2009-12-11 2019-09-24 Shionogi & Co oxazine derivatives.
EP2634186A4 (en) 2010-10-29 2014-03-26 Shionogi & Co Naphthyridine derivative
JP5766198B2 (en) 2010-10-29 2015-08-19 塩野義製薬株式会社 Condensed aminodihydropyrimidine derivatives
WO2012147763A1 (en) 2011-04-26 2012-11-01 塩野義製薬株式会社 Oxazine derivative and bace 1 inhibitor containing same
JP2016501827A (en) 2012-10-24 2016-01-21 塩野義製薬株式会社 Dihydrooxazine or oxazepine derivative having BACE1 inhibitory action

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1178242A (en) * 1966-02-05 1970-01-21 Wellcome Found Novel Biologically Active Bis-Isothioureas
US3790600A (en) * 1972-04-06 1974-02-05 Uniroyal Inc 2-(3-benzo(b)thenyl)-2-thiopseudourea and its pharmaceutically acceptable salts
US3954982A (en) * 1972-04-20 1976-05-04 Smith Kline & French Laboratories Limited Pharmaceutical compositions and method of inhibiting H-1 and H-2 histamine receptors
ZA771408B (en) * 1976-03-29 1978-04-26 Smith Kline French Lab Pharmaceutical compositions
US4208430A (en) * 1979-03-15 1980-06-17 Smithkline Corporation Pharmaceutical compositions and method of inhibiting phenylethanolamine N-methyltransferase
US4262125A (en) * 1979-07-23 1981-04-14 American Home Products Corporation (1H-Imidazol-5-ylmethyl)isothioureas
EP0245669B1 (en) * 1986-05-14 1993-12-01 Medopharm Arzneimittelwerk Dr. Zillich GmbH & Co. Pharmaceutical preparation for preventing damage to living cells by free radicals, or for increasing the efficacy of organic sulphur compounds, and process for increasing the life span of isolated organs
GB8916947D0 (en) * 1989-07-25 1989-09-13 Smith Kline French Lab Medicaments
EP0493468B1 (en) * 1989-09-19 1996-04-17 Syntello Inc Anti-tumor preparation comprising interleukin-2 and histamine, analogs thereof or h2-receptor agonists
CA2085399A1 (en) * 1991-12-16 1993-06-17 Joseph Robert Williamson Method for inhibiting nitric oxide formation
KR100892685B1 (en) * 2007-11-09 2009-04-15 주식회사 하이닉스반도체 Externally asynchronous internally clocked system

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1105706C (en) * 1995-04-20 2003-04-16 G·D·瑟尔公司 Cyclic amidino agents useful as nitric oxide synthase inhibitors
CN101372471B (en) * 2008-10-08 2010-12-22 中国科学院化学研究所 Novel use of alkyl isourea compound and analogues thereof

Also Published As

Publication number Publication date
SI9300616A (en) 1994-06-30
WO1994012165A2 (en) 1994-06-09
EP0670720A1 (en) 1995-09-13
WO1994012165A3 (en) 1994-12-08
JPH08503940A (en) 1996-04-30
IL107771A0 (en) 1994-02-27
AU5533094A (en) 1994-06-22

Similar Documents

Publication Publication Date Title
CN1095710A (en) Enzyme Inhibitors
CN1284783C (en) Substituted nitrogen contg. heterocycles as inhibitors of P38 progein kinase
CN1186324C (en) Condensed heteroaryl derivatives
CN1150195C (en) Bicyclic nitrogen heterocycles
CN1213307A (en) Novel substituted imidazolium compounds
CN1168138A (en) Aryl and heteroaryl purine compounds
CN1646529A (en) Imidazo fused compounds
CN1055182A (en) N-(pyrrolo-" 2,3-d " pyrimidin-3-yl acyl group)-glutamic acid derivatives
CN1538967A (en) Heterocyclic compound and antitumour agent containing the same as active ingredient
CN1094048A (en) Pyrazolopyrimidines
CN1639168A (en) Bicyclic pyridine and pyrimidine P38 kinase inhibitors
CN1028521C (en) Therapeutic agents
CN1807413A (en) Carbazole sulfonamide derivative and its preparation method
CN1076353C (en) New compounds derived from boronic acid, process for their preparation and pharmaceutical compositions containing them
CN1124734A (en) Thiazine- or thiazepine-derivatives
CN1918160A (en) Novel tricyclic spiroderivatives as modulators of chemokine receptor activity
CN1058401A (en) Anti-tumor compositions and methods of treatment
CN1646535A (en) Pyrrolopyrimidine derivative
CN1182127C (en) Substituted 2-benzo [c] furanone compound, its preparing process and medicinal composition containing it
CN1085901A (en) Preparation contains the method for the antineoplastic pharmaceutical compositions of Imidazopyridazine derivative
CN1138583A (en) 9-substituted 2-(2-n-alkoxyphenyl)-purin-6-ones
CN87108111A (en) Novel imidazole derivative and preparation method thereof
CN1552714A (en) 2-substituted benzyl-5,7-dihydrocarbyl-3,7-dihydro pyrroline [2,3-d] pyromidine-4-one derivative ,its preparation and medicinal use
CN1033585C (en) 1, 2, 4-triazolo (1, 5-alpha) pyrimidine derivatives, process for preparing them and their use
CN1049161A (en) Heterogeneous ring compound with serotonine 2-receptor antagonistic activity

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C01 Deemed withdrawal of patent application (patent law 1993)
WD01 Invention patent application deemed withdrawn after publication